Ligand Platforms in Homogenous Catalytic Reactions with Metals: Practice and Applications for Green Organic Transformations

Ligand PLatforms in Homogenous CataLytiC reaCtions witH metaLs

Ligand PLatforms in Homogenous CataLytiC reaCtions witH metaLs

Practice and applications for green organic transformations

ryoHei yamaguCHiEmeritus ProfessorGraduate School of Human and Environmental StudiesKyoto University, Kyoto, Japan

Ken-iCHi fujitaAssociate ProfessorGraduate School of Human and Environmental StudiesKyoto University, Kyoto, Japan

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Yamaguchi, Ryohei. Ligand platforms in homogenous catalytic reactions with metals: practice and applications for green organic transformations / Ryohei Yamaguchi, emeritus professor of chemistry, Graduate School of Human and Environmental Studies, Kyoto University, Ken-ichi Fujita, associate professor of chemistry, Graduate School of Human and Environmental Studies, Kyoto University. pages cm Includes bibliographical references and index. ISBN 978-1-118-20351-4 (cloth)1. Organometallic chemistry. 2. Transition metal catalysts. 3. Catalysts. 4. Ligands. I. Fujita, Ken-ichi. II. Title. QD411.Y34 2015 547′.05044242–dc23 2014020582

Printed in the United States of America

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v

contents

Preface ix

abbreviation xi

Part i n-Heterocyclic carbene ligands in transition Metal catalyzed Hydrogen transfer and deHydrogenative reactions 1

1 oxidation and Hydrogenation reactions catalyzed by transition Metal complexes bearing n-Heterocyclic carbene ligands 3

1.1 Introduction, 31.2 Oxidation of Alcohols Based on Hydrogen Transfer, 31.3 Oxidation of Alcohols Based on Dehydrogenation, 101.4 Hydrogenation and Transfer Hydrogenation of Carbon–Heteroatom

Unsaturated Bonds, 121.5 Other Related Hydrogenative Reactions, 21 References, 25

2 bond-forming reactions catalyzed by transition Metal complexes bearing n-Heterocyclic carbene ligands 27

2.1 Introduction, 272.2 Carbon–Carbon Bond Formation Based on Hydrogen Transfer, 272.3 Carbon–Nitrogen Bond Formation Based on Hydrogen Transfer and

Dehydrogenation, 37

vi CONTeNTs

2.4 Carbon–Oxygen Bond Formation Based on Hydrogen Transfer and Dehydrogenation, 46

References, 52

Part ii η4-cycloPentadienone/ η5-HydroxycycloPentadienyl and related ligands in transition Metal catalyzed Hydrogen transfer and deHydrogenative reactions 55

3 oxidation and Hydrogenation catalyzed by transition Metal complexes bearing η4-cyclopentadienone/ η5-Hydroxycyclopentadienyl and related ligands 57

3.1 Introduction, 573.2 Oxidation of Alcohol Based on Hydrogen

Transfer and Dehydrogenation, 593.3 Oxidation of Amine Based on Hydrogen Transfer, 683.4 Hydrogenation and Transfer Hydrogenation

of Carbonyl Compounds, 713.5 Hydrogenation and Transfer Hydrogenation

of Imines and Related Compounds, 79 References, 84

4 bond-forming reactions catalyzed by transition Metal complexes bearing η4-cyclopentadienone/η5-Hydroxycyclopentadienyl and related ligands 87

4.1 Introduction, 874.2 Carbon–Nitrogen Bond-Forming Reactions Based on

Hydrogen Transfer and Dehydrogenation, 884.3 Carbon–Oxygen Bond-Forming Reactions Based on

Hydrogen Transfer and Dehydrogenation, 974.4 Carbon–Carbon Bond-Forming Reactions Based on

Hydrogen Transfer and Dehydrogenation, 102 References, 105

Part iii Pincer ligands in transition Metal catalyzed Hydrogen transfer and deHydrogenative reactions 107

5 dehydrogenation of alkanes catalyzed by transition Metal complexes bearing Pincer ligands 109

5.1 Introduction, 1095.2 Conversion of Alkanes into Alkenes Based on Hydrogen Transfer, 1095.3 Dehydroaromatization of Alkanes Based on Hydrogen Transfer, 115

CONTeNTs vii

5.4 Alkane Metathesis by Tandem Alkane Dehydrogenation and Alkene Metathesis, 118

5.5 Conversion of Alkanes into Alkenes Based on Dehydrogenation, 121 References, 126

6 oxidation and Hydrogenation reactions catalyzed by transition Metal complexes bearing Pincer ligands 128

6.1 Introduction, 1286.2 Oxidation of Alcohols Based on Hydrogen

Transfer and Dehydrogenation, 1286.3 Dehydrogenation of Amines, 1376.4 Hydrogenation and Transfer Hydrogenation of

Carbon–Heteroatom Unsaturated Bonds, 141 References, 157

7 bond-forming reactions catalyzed by transition Metal complexes bearing Pincer ligands 159

7.1 Introduction, 1597.2 Carbon–Carbon Bond Formation Based on Hydrogen Transfer, 1597.3 Carbon–Nitrogen Bond Formation Based on Hydrogen

Transfer and Dehydrogenation, 1617.4 Carbon–Oxygen Bond Formation Based on Hydrogen

Transfer and Dehydrogenation, 173 References, 182

Part iv bidentate and Miscellaneous ligands in transition Metal catalyzed Hydrogen transfer and deHydrogenative reactions 183

8 oxidation and dehydrogenation of alcohols and amines catalyzed by Well-defined transition Metal complexes bearing bidentate and Miscellaneous ligands 185

8.1 Introduction, 1858.2 Oxidation of Alcohols Based on Hydrogen Transfer with Oxidant, 1858.3 Dehydrogenative Oxidation of Alcohols without Oxidant, 2098.4 Oxidation of Amines Based on Hydrogen Transfer

and Dehydrogenation, 220 References, 224

9 Hydrogenation and transfer Hydrogenation of carbon–Heteroatom unsaturated bonds catalyzed by Well-defined transition Metal complexes bearing bidentate and Miscellaneous ligands 228

9.1 Introduction, 2289.2 Hydrogenation and Transfer Hydrogenation of

Carbonyl and Related Compounds, 229

viii CONTeNTs

9.3 Hydrogenation and Transfer Hydrogenation of Imines and Related Compounds, 263

References, 274

10 bond-forming reactions based on Hydrogen transfer catalyzed by Well-defined transition Metal complexes bearing bidentate and Miscellaneous ligands 278

10.1 Introduction, 27810.2 Carbon–Carbon Bond-Forming Reactions

Based on Hydrogen Transfer, 27910.3 Carbon–Nitrogen Bond-Forming Reactions

Based on Hydrogen Transfer, 29610.4 Carbon–Oxygen Bond-Forming Reactions

Based on Hydrogen Transfer, 321 References, 330

index 335

ix

Preface

The developments of higher atom-economical methodologies and usage of less harmless reactants and reagents are increasingly important in modern organic synthesis from environmental points of view. In this context, catalytic organic trans-formations based on the hydrogen transfer catalyzed by metal-complexes have been attracting considerable attention and are widely investigated. Thus, it is indispens-able to design and create the metal complexes exhibiting high catalytic performance for the hydrogen transfer between organic substances. It has been well recognized that the catalytic performance of metal-complexes depends on not only the inherent nature of the metal but also the ligand that stabilizes the atomic metal and also governs the catalytic activity of the metal center. In addition, the metal-ligand cooper-ative catalysis and functional ligands have been widely recognized for the important role especially in the hydrogen transfer processes [1].

This monograph aims to survey the notable ligand platforms in homogeneous transition metal complexes those catalyze organic transformations based on the hydrogen transfer and consists of 4 parts including 10 chapters. Topics of N-heterocyclic carbene ligands are described in the part I, those of η4-cyclopetadienone/η5-hydroxycyclopentadienyl and related ligands in the part II, those of pincer ligands in the part III, and bidentate and miscellaneous functional ligands in the part IV. Owing to limited space, this monograph is focused on the recent progress (ca. 2000 ~ the beginning of 2012) of homogeneous catalytic organic transformations based on the hydrogen transfer catalyzed by well- defined transition metal complexes, but asymmetric reactions are not included in most cases. R. Y. wrote the parts II and IV (Chapters 3, 4, 8–10) and K. F. wrote the parts I and III (Chapters 1, 2, 5–7).

x PREFACE

We hope this monograph would help to understand the notable roles of the ligands, design the highly active transition metal complex catalysts, and develop the efficient green organic transformations in not only basic researches but also industrial applications.

April, 2014Ryohei Yamaguchi

Ken-ichi Fujita

reference

[1] Recent representative reviews on the metal-ligand cooperative catalysis and functional ligands:(a) Grützmacher H. Angew Chem Int Ed 2008;47:1814. (b) Grotjahn BD. Dalton Trans 2008:6497. (c) van der Vlugt JI, Reek JNH. Angew Chem Int Ed 2009;48:8832. (d) Haak RM, Wezenberg SJ, Kleij AW. Chem Commun 2010;46:2713. (e) Crabtree RH. New J Chem 2011;35:18. (f) Ikariya T. Bull Chem Soc Jpn 2011;84:1. (g) Gunanathan C, Milstein D. Acc Chem Res 2011;44:588. (h) Askevold B, Roesky H, Schneider S. Chem Cat Chem 2012;4:307.

xi

AbbreviAtion

Ac acetylacac acetylacetonateAd adamantylAr arylArF, Arf 3,5-bis(trifluoromethyl)phenylBINAP, binap 2,2′-bis(diphenylphosphino)-1,1′-binaphthylBIPHEP 2,2′-bis(diphenylphosphino)biphenylBMIM 1-butyl-3-methylimidazoliumBn benzylBoc tert-butoxycarbonylbpy 2,2′-bipyridylbpym 2,2′-bipyrimidylBQC dipotassium 2,2′-bisquioline-4,4′-dicarboxylateBu butyltBu tert-butylCataXCium®Pcy N-phenyl-2-(dicyclohexylphosphinyl)pyrrolecod 1,5-cyclooctadienecoe cycloocteneconc. concentrationCp cyclopentadienylCp* 1,2,3,4,5-pentamethylcyclopentadienylCSA camphorsulfonic acidCy cyclohexylCyp cyclopentylDABCO 1,4-diazabicyclo[2.2.2]octaneDBAD di-tert-butyl azodicarboxylateDCE dichloroethane

xii ABBrEvIAtION

DCPE 1,2-bis(dicyclohexylphosphino)ethaneDFt density functional theoryditz 1,2,4-triazol-di-ylideneDKr dynamic kinetic resolutionDMBQ 2,6-dimethoxy-1,4-benzoquinoneDME dimethoxyethaneDMF dimethylformamideDMHQ 2,6-dimethoxy-1,4-hydroquioneDMSO dimethyl sulfoxideDPEphos bis(2-diphenylphosphinophenyl)etherDPPB, dppb 1,3-bis(diphenylphosphino)butaneDPPF, dppf 1,1′-bis(diphenylphosphino)ferroceneDPPM, dppm bis(diphenylphosphino)methaneDPPP, dppp 1,3-bis(diphenylphosphino)propaneEDA, eda ethylenediamineEDtA, edta ethylenediaminetetraacetic acidee enantiomeric excessEt ethylGC gas chromatographytHex tert-hexyl (1,1-dimethylbutyl)IPr N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylideneMe methylMes mesityl (2,4,6-trimethylphenyl)MMA methyl methacrylateMs methansulfonylMS molecular sievesMtBE methyl tert-butyl etherMW microwaveNBE, nbe norborneneNHC N-heterocyclic carbeneNHPI N-hydroxyphthalimideNp neopentyl1-Oct 1-octene2-Oct 2-octenePEG polyethylene glycolPh phenylPr propyliPr iso-propylPy pyridylrt room temperaturetba tert-butylethanetbe tert-butylethylenetEMPO 2,2,6,6-tetramethylpiperidine-1-oxyltf trifluoromethanesulfonyltFA trifluoromethylacetic acidtHF tetrahydrofurantHQ 1,2,3,4-tetrahydroquinolinetMEDA, tmeda tetramethylethylenediamine

ABBrEvIAtION xiii

tMS trimethylsilyltOF turnover frequencytol 4-methylphenyltON turnover numbertPent tert-pentyl (1,1-dimethylpropyl)ts p-toluenesulfonylXantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

N-Heterocyclic carbeNe ligaNds iN traNsitioN Metal catalyzed HydrogeN traNsfer aNd deHydrogeNative reactioNs

Part i

Ligand Platforms in Homogenous Catalytic Reactions with Metals: Practice and Applications for Green Organic Transformations, First Edition. Ryohei Yamaguchi and Ken-ichi Fujita. © 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.

3

OxidatiOn and HydrOgenatiOn reactiOns catalyzed by transitiOn Metal cOMplexes bearing n-HeterOcyclic carbene ligands

1

1.1 intrOductiOn

The aim of this chapter is to survey the oxidative reactions of alcohols based on hydrogen transfer as well as dehydrogenation and hydrogenation reactions catalyzed by transition metal complexes having N-heterocyclic carbene (NHC) ligands. Herein, catalytic reactions useful for environmentally benign organic synthesis will be classified into four types: (i) oxidation of alcohols based on hydrogen transfer, (ii) oxidation of alcohols based on dehydrogenation, (iii) hydrogenation reactions of carbon–heteroatom unsaturated bond, and (iv) other related hydrogenative reactions. This chapter is not exhaustive on the catalytic chemistry of NHC complexes of transition metals. There are a number of good review articles on such subjects [1].

1.2 OxidatiOn Of alcOHOls based On HydrOgen transfer

1.2.1 ruthenium complex with nHc ligand

The ruthenium complex 1 bearing an NHC ligand with mesityl substituent was found to undergo a facile dehydrogenative reaction in the presence of acetone to afford a cyclometalated complex 1′ [2]. The original complex 1 can be restored by the reac-tion of the complex 1′ with 2-propanol, enabling a reversible transformation system between 1 and 1′ (Scheme 1.1). On the basis of this reversible reaction associated

4 OxidaTiON aNd HydrOgeNaTiON reaCTiONS

with hydrogen transfer, a catalytic system for the oxidation of alcohols catalyzed by 1 using acetone as a hydrogen acceptor in NMr scale has been investigated (Scheme 1.2). When the reaction of 1-phenylethanol catalyzed by 1 (2 mol%) was performed in C

6d

6 at 50 °C for 12 h using 5 equiv of acetone as a hydrogen acceptor,

acetophenone was formed in the yield of 88%. Various secondary alcohols were also converted to the corresponding ketones although the yield depended on equilibrium position.

1.2.2 iridium complex with nHc ligand

The dicationic iridium complex 2 bearing an NHC ligand has been synthesized, and its high activity for the oxidation of alcohols using acetone as a hydrogen acceptor based on hydrogen transfer process (Oppenauer-type oxidation [3]) has been revealed [4]. results of the oxidation of secondary alcohols into ketones catalyzed by the NHC iridium complex 2 are summarized in Table 1.1. For example, the reaction of 1-phenylethanol in the presence of 2 (0.1 mol%) and K

2CO

3 (0.1 mol%) in acetone

N N

RuHPh3P

OC HPPh3

N N

RuPh3P

OC HPPh3

1 1ʹ

Acetone

2-Propanol

scHeMe 1.1

N N

RuHPh3P

OC H

PPh3 1 (2 mol%)

Cat.

R1 R2

OH

R1 R2

O

Acetone (5 equiv)C6D6, 50 ºC, 12 h

O O O O

F MeO

O

88% 87% 96% 30% 47%

scHeMe 1.2

OxidaTiON OF aLCOHOLS BaSed ON HydrOgeN TraNSFer 5

gave acetophenone in excellent yield (entry 1). The highest turnover number up to 6640 was achieved for the oxidation of cyclopentanol (entry 6).

results of the oxidation of primary alcohols catalyzed by 2 are summarized in Table 1.2 [4]. While larger quantities of the catalyst (0.5 mol%) were required, the oxidation of primary alcohols into aldehydes proceeded selectively in moderate to excellent yields.

Cat.

2 (0.1 mol%)

N

N

Ir NCMe

NCMe

[OTf]2

K2CO3 (0.1 mol%)Acetone, 40 ºC

R1 R2

OH

R1 R2

O

Entry Alcohol Time (h) Conversion (%) Yield (%)

OH

OH

OH

Cl OH

OH

OH

5

4

4

4

4

424

7

95 95

98 94

90 89

93 91

9185

9083

78 76

1

2

3

4

56a

7

aCatalyst loading was 0.0125 mol%.

table 1.1 Oxidation of secondary alcohols catalyzed by 2.


a possible mechanism for the Oppenauer-type oxidation of alcohols is shown in Scheme 1.3 [4]. Firstly, an iridium alkoxo species is generated from 2 and an alcohol mediated with a base. Then, β-hydrogen elimination occurs to yield a carbonyl prod-uct and a hydrido iridium species. Finally, the insertion of acetone into iridium hydride bond followed by the exchange of the alkoxo moiety proceeds to regenerate the iridium alkoxo species.

The iridium complex 3 bearing a dimethylamino-tethered cyclopentadienyl as well as NHC ligand has been found to be a good catalyst for Oppenauer-type oxidation of various alcohols [5]. Owing to the basic dimethylamino moiety in the ligand, the reaction catalyzed by 3 can be conducted in the absence of an additional base. Compared to the dicationic catalyst 2, the catalytic system composed of 3 and agOTf exhibited a higher activity (Scheme 1.4).

The NHC iridium complex 4 has been utilized as a good catalyst for the racemi-zation of secondary alcohols, which is incorporated with enzyme catalyst for kinetic resolution to construct an efficient system for the dynamic kinetic resolution.

Cat.

2 (0.5 mol%)

N

N

Ir NCMe

NCMe

[OTf]2

K2CO3 (0.5 mol%)Acetone, 40 ºC

R OH

Entry Alcohol Time (h) Conversion (%) Yield (%)

4

2

2

4

6

89 86

98 98

75 73

76 75

57 54

1

2

3

4

5

RCHO

OH

OH

OH

OH

MeO

OMe

Cl

OH6

table 1.2 Oxidation of primary alcohols catalyzed by 2.


as shown in Scheme 1.5, the reaction of racemic 1-phenylethanol with isopropenyl acetate in the presence of 4 (0.1 mol%) and Novozyme 435 at 70 °C for 8 h gave an acetyl ester in 95% yield with 97% enantiomeric excess (ee) [6].

1.2.3 palladium complex with nHc ligand

The palladium complex 5 bearing an NHC ligand and two acetate ligands has been reported to catalyze the aerobic oxidation of alcohols (Table 1.3) [7]. For example, the reaction of 1-phenylethanol in the presence of NHC palladium complex 5 (0.5 mol%) and acetic acid (2 mol%) in toluene under an oxygen atmosphere for 5 h gave acetophenone in the yield of 98% (entry 1). Various types of alcohols could be oxidized by this system.

[(NHC)Ir] OR1

R2

[(NHC)Ir] H

R1 R2

O

[(NHC)Ir] O

R1 R2

OH

iPrOH

Acetone

2

R1 R2 , K2CO3

OH

scHeMe 1.3

Cat.

3 (0.026 mol%)

N

N

Ir Cl

Cl

AgOTf (0.05 mol%)Acetone, 40 ºC, 6 h

NMe2

OH O

90%

scHeMe 1.4


Cat.

4 (0.1 mol%)

N

N

Ir Cl

Cl

C6F5

Novozyme 435Toluene, 70 ºC, 8 h

OH

O

O+

OAc

95% yield, 97% ee

scHeMe 1.5

R1 R2

OH

R1 R2

O

N N

iPr iPr

iPriPr Pd OO

OOO

H H

Cat.

5 (0.5 mol%)

AcOH, MS3Å, O2, toluene, 60 ºC

Entry Substrate AcOH (mol%) Time (h) Yield (%)

OH

OH

F3C

OH

OH

7

OH

MeO

2

2

2

1

2

5

12

12

13

3.5

98

99

84

93

99

1

2

3

4

5

table 1.3 aerobic oxidation of alcohols catalyzed by 5.


The mechanism for the oxidation catalyzed by 5 is illustrated in Scheme 1.6 [7]. after the loss of H

2O from 5, an alcohol coordinates to the metal center. Then, an

intramolecular deprotonation releasing acetic acid occurs to generate a palladium alkoxide species, which undergoes β-hydrogen elimination to yield the carbonyl product and a hydrido palladium species. reductive elimination of acetic acid proceeds to give zerovalent palladium, which is subject to oxidized by oxygen giving peroxo palladium species. Finally, protonation by 2 equiv of acetic acid occurs to regenerate the NHC palladium diacetate accompanying the elimination of H

2O

2.

an efficient system for the oxidative kinetic resolution of secondary alcohols has been developed using an NHC palladium complex and (−)-sparteine as catalyst [8]. as shown in Scheme 1.7, the reaction of racemic 1-phenylethanol in the presence of the dimeric NHC palladium complex 6 (1.5 mol%) and (−)-sparteine (15 mol%) under oxygen atmosphere in dichloroethane at 65 °C for 20 h gave an (S)-isomer of 1-phenylethanol (96% ee) at the conversion of 65%.

R1 R2

OH

R1 R2

O

NHC

Pd OO

OOO

H H

NHC

Pd OAcO

OO

HR1

R2H

HOAc

HOAc

NHC

PdO

AcO

R1

HR2

NHC

PdH

AcO

HOAc

HOAc

NHC

PdO2

NHC

Pd

O O

NHC

Pd

AcO OAc H2O2 2 HOAc

5

scHeMe 1.6

Ph

OH

N

NPd

iPr

iPr

iPr

iPr

Cl

2

Cat.

6 (1.5 mol%)

(–)–sparteine (15 mol%)

O2, MS3Å, DCE, 65 ºC, 20 h

Ph

O

Ph

OH+

Conversion: 65%; 96% ee; krel: 11.6

Cl

scHeMe 1.7


1.3 OxidatiOn Of alcOHOls based On deHydrOgenatiOn


dehydrogenative oxidation of alcohols is important for the production of syntheti-cally useful aldehydes and ketones from readily available alcohols with high atom efficiency without the use of any oxidant [9]. The ruthenium complexes 7–10 bearing an NHC ligand have been applied as catalysts for such a reaction [10]. as shown in Table 1.4, some arene ruthenium complexes bearing NHC ligand exhibited catalytic activity for the dehydrogenative oxidation of benzyl alcohol into benzaldehyde. among ruthenium complexes 7–10, the complex 7 having a triazolylidene-based NHC and p-cymene ligand showed the highest activity (entry 1). The complex 10

NNN

Bu

Bu

RuCl

Cl

p-cymene

+ H2OH

CHOCatalyst (5 mol%)

Toluene, re�ux

Entry Catalyst Time (h) Yield (%)

NNN

Bu

Bu

RuCl

Cl

Hexamethylbenzene

NNN

Bu

Bu

Ru O

O

p-cymene

O

N

NBu

Bu

RuCl

Cl

p-cymene

7

8

9

10

16

20

16

20

>95

55

82

60

1

2

3

4

table 1.4 Catalyst screening in the oxidation of benzyl alcohol.

OxidaTiON OF aLCOHOLS BaSed ON deHydrOgeNaTiON 11

having imidazolylidene-based NHC ligand was slightly less active than 7 (entry 4), probably because of the difference of electronic properties of NHC ligands.

results of the dehydrogenative oxidation of a variety of alcohols catalyzed by the ruthenium complex 7 are summarized in Table 1.5 [10]. Both primary and secondary benzylic alcohols were oxidized into benzaldehydes and acetophenone, respectively. electron-withdrawing substituents such as nitro or chloro group reduced the activity of the catalyst. By this catalytic system, aliphatic alcohols could not be oxidized.

NNN

Bu

Bu

RuCl

Cl

p-cymeneCat.

7 (5 mol%)

R1 R2

OH

R1 R2

O

H2+Toluene, re�ux

Entry Alcohol Time (h) Yield (%)

OH

OH

OH

OH

OH

OH

O2N

Cl

Cl

Br

OH

Me

OH

MeO

24

16

22

22

22

16

16

16

>95

>95

65

68

70

91

>95

90

1

2

3

4

5

6

7

8

table 1.5 dehydrogenative oxidation of various secondary alcohols catalyzed by 7.



Catalytic activity of the iridium complex 11 bearing a pentamethylcyclopentadienyl (Cp*) and imidazolylidene-based NHC ligands in dehydrogenative oxidation of alcohols has been reported (Scheme 1.8) [11]. When the reaction of 1-phenylethanol was carried out in the presence of the NHC iridium complex 11 (5 mol%) and Cs

2CO

3

(20 mol%) at 110 °C for 24 h, acetophenone was obtained in the yield of 70%. Similar reaction using benzyl alcohol as a substrate gave benzaldehyde in 50% yield.

1.4 HydrOgenatiOn and transfer HydrOgenatiOn Of carbOn–HeterOatOM unsaturated bOnds


The water-soluble ruthenium complex 12 bearing an imidazolylidene-based NHC and 1,3,5-triaza-7-phosphaadamantane ligands has been synthesized, and its catalytic application to the hydrogenation of carbonyl substrates in aqueous media has been studied (Scheme 1.9) [12]. Hydrogenation of acetone and propanal catalyzed by the NHC ruthenium complex 12 (0.7 mol%) in water (pH 6.9) at 80 °C under 10 atm of H

2 gave acetone and 1-propanol in high yields, respectively.The ruthenium complex 13 bearing two NHC ligands exhibited high catalytic

performance for the hydrogenation of acetophenone [13]. When the reaction of ace-tophenone catalyzed by 13 (0.4 mol%) was carried out in 2-propanol at 75 °C under H

2 (10 atm), 1-phenylethanol was obtained in excellent yield (Scheme 1.10).

O

+ H2

Cat.

11 (5 mol%)

N

N

BuIr Cl

ClBu

OH

CS2CO3 (20 mol%)110 °C, 24 h

CS2CO3 (20 mol%)110 °C, 24 h

70%

CHO+ H2

Cat.

11 (5 mol%)

N

N

BuIr Cl

ClBu

OH

50%

scHeMe 1.8

HydrOgeNaTiON aNd TraNSFer HydrOgeNaTiON 13

The NHC ruthenium catalyst generated in situ from [ru(cod)(2-methallyl)2] 14,

imidazolium salt 15, and KOtBu effectively catalyzes the hydrogenation of carbon–nitrogen triple bond of nitrile (Table 1.6) [14]. For example, the reaction of benzonitrile in the presence of 14 (0.5 mol%), 15 (0.5 mol%), and KOtBu (10 mol%) in toluene at 40 °C under 35 bar of hydrogen for 6 h gave benzylamine in almost quantitative yield (entry 1). a variety of aromatic nitriles were also converted into primary amines in good to excellent yields (entries 2–6).

N

NRu

Cl

PN

NN

Bu

p-cymene ClCat.

12 (0.7 mol%)O OH

98%

N

NRu

Cl

PN

NN

Bu

p-cymene ClCat.

12 (0.7 mol%)

CHO

86%

OH

scHeMe 1.9

Ru

NN

N N

iPr iPr

iPr

iPr

iPriPr

iPr

iPrClH

OC

O OH

Cat.

13 (0.4 mol%)

H2 (10 atm), 2-Propanol, 75 °C, 20 h96%

scHeMe 1.10


The arene ruthenium complex 16 with amine-tethered NHC has been prepared, and its catalytic activity toward transfer hydrogenation of aromatic ketones has been revealed (Table 1.7) [15]. When the reaction of acetophenone was conducted in the presence of 16 (1 mol%), agOTf (1 mol%), and KOtBu (5 mol%) in 2-propanol at 80 °C for 12 h, 1-phenylethanol was formed almost quantitatively (entry 1). Substituted acetophenone derivatives were also converted into secondary alcohols in excellent yields.

The ruthenium complex 17 bearing an orthometalated NHC ligand has been found to be a highly efficient catalyst for the transfer hydrogenation of ketones [16]. results are summarized in Table 1.8. Various kinds of ketones with or without functional groups were converted into the corresponding secondary alcohols with high turnover numbers using a very small amount of 17 (0.05 mol%). it should be also noted that the reduction of 5-hexene-2-one proceeded selectively at the carbonyl group without hydrogenation or isomerization of the carbon–carbon double bond (entry 7).

Entry Substrate Yield (%)

1

2

3

4

98

99

99

92

C NR

Cat. [Ru(cod)(methallyl)2] 14 (0.5 mol%)

MesN NMes+

BF4−

15 (0.5 mol%)

KOtBu (10 mol%)

H2 (35 bar), tolueneRCH2NH2

CN

CN

CN

CN

CN

CN

Ph

MeO

OMe

MeO

Temperature (ºC) Time (h)

5

6

40 6

80 1

80 1 78

40 16

40 16

40 6 99

table 1.6 Hydrogenation of nitriles to primary amines catalyzed by 14 and 15.


Other NHC ruthenium complex-catalyzed transfer hydrogenation reactions of carbon–heteroatom unsaturated bond have been known [17].

1.4.2 rhodium complex with nHc ligand

The rhodium complex 18 bearing a chelating bis-NHC ligand showed high catalytic performance in the transfer hydrogenation of ketones and imines using 2-propanol as a hydrogen donor [18]. results are summarized in Table 1.9. When the reaction of aceto-phenone was performed in the presence of NHC rhodium complex 18 (0.1 mol%) and KOH (50 mol%) in 2-propanol under reflux for 10 h, 1-phenylethanol was obtained in quantitative yield (entry 1). Both aromatic and aliphatic ketones were also converted to the corresponding secondary alcohols (entries 1–4). The complex 18 also catalyzed the transfer hydrogenation of imines to the corresponding amines (entries 5 and 6).

RuN

N

Cl

Cl

iPr2N

NiPr2

Cat.

16 (1 mol%)

AgOTf (1 mol%), KOtBu (5 mol%)2-Propanol, 80 ºC,12 h

R1 R2

O

R1 R2

OH

Entry Substrate Product Yield (%)

O OH

O OH

O OH

O OHMeO

F

MeO

F

OMe OMe

1

2

3

4

98

97

96

99

table 1.7 Transfer hydrogenation of aromatic ketones catalyzed by 16.


Other NHC rhodium complex-catalyzed transfer hydrogenation reactions of carbon–heteroatom unsaturated bond have been also reported [19].


The cationic iridium complex 19 bearing an imidazolylidene-based NHC ligand exhibits very high catalytic performance in the transfer hydrogenation [20]. as shown in Table 1.10, ketones, alkenes, and nitro compounds were effectively converted to

Entry Substrate Time (min) Product Conversion (%)

O OH

O OH

1

2

3

4

5

6

7

5

10

99

90

98

N

NNPh

Ph

Ru

H2N

NClPh3P

Cat.

17 (0.05 mol%)

NaOH (2.5 mol%)2-Propanol, 82 °C

R1 R2

O

R1 R2

OH

Cl ClO OH

10MeO MeO

O OH

2MeO MeO

MeO MeO

O OH

O OH

O OH

98

5 99

10 96

15 96

table 1.8 Transfer hydrogenation of ketones catalyzed by 17.


alcohols, alkanes, and amines by 0.025 mol% of NHC iridium complex 19 using 2-propanol as a hydrogen donor.

Selective transfer hydrogenation of bifunctional substrate (3-acetylbenzaldehyde) has been accomplished by the employment of the cationic iridium complex 20 with NHC and phosphine ligands (Scheme 1.11) [21].

Cat.

18 (0.1 mol%)

2-Propanol, re�ux, 10 h

Substrate Product


KOH (50 mol%)

1

N

N

N

NRh

iPr

iPr

O

O

I

I

O OH

>98

2 N

O

N

OH

>98

O OH

O OH

NHN

NHN

3

4

5

6

>98

>98

>98

85

table 1.9 Transfer hydrogenation of ketones and imines catalyzed by 18.


Ir

Pyridine

Cat.

19 (0.025 mol%)

N

NCy

Cy

PF6

2-Propanol, 80 ºC

Substrate Product

Entry Substrate Time Product Conversion (%)

KOH (5 mol%)

tBu

O

tBu

OH

O OH

O OH

NO2 NH2

35 min

10 min

22 h

5.5 h

48 h

100

100

90

100

48

1

2

3

4

5

table 1.10 Transfer hydrogenation of ketones, alkenes, and nitro compounds catalyzed by 19.

Ir

PPh3

Cat.

20 (1 mol%)

N

NNn-C5H11

Bu

BF4

K2CO3 (50 mol%)2-Propanol, re�ux, 20 min

O

O

H

O

OH

>95%

scHeMe 1.11


The iridium complex 21 bearing a hemilabile O-donor-functionalized NHC ligand has been prepared, and it was found to be a good catalyst for the transfer hydrogena-tion [22]. Transfer hydrogenation of various kinds of substrates including ketones, aldehydes, alkenes, and imines was catalyzed by the cationic iridium complex 21 using 2-propanol as a hydrogen donor (Table 1.11). a positive effect of the methoxy

Ir

NCMe

Cat.

21 (0.1 mol%)

N

NBF4

MeO

KOH (0.5 mol%)2-Propanol, 80 ºC

Substrate Product

Entry Substrate Time (min) Product Conversion (%)

O OH

O OH

Br Br

CHOOH

CHO6

6 OH

N NH

N NH

1

2

3

4

5

6

7

80

85

25

80

2470

60

345

90

91

96

96

63

93

93

table 1.11 Transfer hydrogenation of various substrates catalyzed by 21.


group in the NHC ligand on the catalytic activity would be due to the facilitation of the β-hydrogen elimination step in the catalytic process.

Transfer hydrogenation of ketones, aldehydes, and imines has been achieved at room temperature by the employment of the iridium complex 22 bearing Cp* and NHC ligands (Table 1.12) [23]. For example, the reaction of 2-butanone in the presence of the NHC iridium complex 22 (2 mol%) and agOTf (6 mol%) in 2-propa-nol at room temperature for 2 h gave 2-butanol quantitatively (entry 1). The reaction catalyzed by 22 proceeded in a short time without using base.

The catalytic system for the transfer hydrogenation of ketones and aldehydes using glycerol as a hydrogen donor has been developed [24]. The introduction of sul-fonate groups into the NHC ligand promoted a higher solubility of the catalyst in glycerol. Thus, the iridium complex 23 bearing bis-SO

3-tethered NHC ligand has

been prepared, and its high activity for the transfer hydrogenation of carbonyl substrates in glycerol has been revealed (Table 1.13).

Other NHC iridium complex-catalyzed transfer hydrogenation reactions of carbon-heteroatom unsaturated bond have been reported [25].


Cat.

N

N

Bu

Bu

Ir Cl

Cl

Substrate ProductAgOTf (6 mol%)

2-Propanol, rt

O OH

Ph

O

Ph

OH

Ph CHO Ph OH

CHOOHCOH

HO

PhN Ph

Ph

HN Ph

1

2

3

4

5

>99

Time

2 h

15 min

30 min

30 min

48 h

Catalyst(mol%)

2

2

2

2

0.1

90

>99

>99

>99

22(2 mol%)

table 1.12 Transfer hydrogenation of ketones, aldehydes, and imines catalyzed by 22.

OTHer reLaTed HydrOgeNaTiVe reaCTiONS 21

1.5 OtHer related HydrOgenative reactiOns

Hydrogenation of aza-heterocyclic compounds under mild conditions (room tempera-ture to 35 °C and 1 atm of H

2) has been achieved by using the cationic NHC iridium

complex 24 as catalyst (Table 1.14) [26]. When the reaction of 2-methylquinoline was conducted in the presence of the NHC iridium complex 24 (1 mol%) and PPh

3 (1 mol%)

in toluene at 35 °C under atmosphere of H2 (1 atm) for 18 h, 1,2,3,4-tetrahydro-2-

methylquinoline was formed in excellent yield (entry 1). Various N-heterocycles could be hydrogenated effectively catalyzed by 24.

Transfer hydrogenation of quinoline using formic acid as a hydrogen donor catalyzed by a similar NHC iridium complex 25 has been also reported (Scheme 1.12) [27].

Catalytic hydrogenation of nonactivated esters under mild conditions is a highly challenging subject. By the employment of the cationic ruthenium complex 26 bearing a tridentate NHC ligand as catalyst, efficient system for the hydrogenation

N

N

N

N

Ir

SO3K

SO3K

I

I

O

O

Cat.

23 (2.5 mol%)

R1 R2

O

R1 R2

OH

KOH (100 mol%)Glycerol, 120 ºC

Entry Substrate Time (h) Product Yield (%)

Ph

O

Ph

OH

Ph Ph

O

Ph Ph

OH

Ph OHPh CHO

24

20

1.5

69

91

99

1

2

3

table 1.13 Transfer hydrogenation using glycerol as a hydrogen donor catalyzed by 23.


Ir

PPh3

N

N

Cat.

24 (1 mol%)

PF6

PPh3 (1 mol%)H2 (1atm), toluene, 35 ºC, 18 h

Substrate Product


N NH

N Ph NH

Ph

N NH

N Ph NH

Ph

1

2

3

4

>95%

>95%

94%

>95%

table 1.14 Hydrogenation of aza-heterocyclic compounds catalyzed by 24.

Ir

PPh3

N

NN

Cat.

25 (1 mol%)

Bu

BF4

tBu

N NH

HCOOH (5 equiv)80 ºC, 24 h

60%

scHeMe 1.12

OTHer reLaTed HydrOgeNaTiVe reaCTiONS 23

of esters has been developed (Table 1.15) [28]. When the reaction of pentyl pen-tanoate catalyzed by 26 (1 mol%) and KOtBu (1 mol%) was carried out under 5.4 atm of H

2 in toluene at 135 °C for 2 h, 1-pentanol was formed in 96% yield

(entry 1). Other aliphatic and aromatic esters could be also hydrogenated by the catalyst 26.

reduction of CO2 into formic acid is highly important subject in catalytic chem-

istry. The catalytic systems for the reduction of CO2 by means of hydrogenation with

H2 and transfer hydrogenation with 2-propanol catalyzed by the NHC iridium

complexes 22, 27, and 28 have been reported [29]. results of the reduction of CO2

with H2 are shown in Table 1.16. The reactions were carried out using 60 atm of CO

2

and H2 mixture (1:1) in aqueous solution of KOH (1 M) at 80 °C. The NHC iridium

complex 27 bearing a bis-NHC ligand showed the highest catalytic activity to afford HCOOK with the turnover numbers of 894 after 18 h.

Furthermore, a new approach to the reduction of CO2 by transfer hydrogenation

was also reported (Scheme 1.13) [29]. in the case of transfer hydrogenation of CO2,

N

N

N

NRu

H

PPh3

COMes

ClCat.

26 (1 mol%)

KOtBu (1 mol%)H2 (5.4 atm), toluene, 135 ºC, 2 h

R1 OR2

O

R1 OH R2 OH+

Entry Substrate Product

O

O

OH

O

OOH OH

O

O

OH

OH

O

O

OH

1

2

3

4

96%

97% 95%

89%

97% 94%

table 1.15 Hydrogenation of esters catalyzed by 26.


the complex 22 exhibited a higher activity compared to 27 and 28. When the reduction of CO

2 (50 atm) catalyzed by 22 (0.018 mM solution) was carried out at 110 °C in a

solution of KOH (0.5 M) in H2O/2-propanol (9:1), HCOOK was formed with the

turnover numbers of 150 after 72 h.

N

N

Bu

Bu

Ir Cl

Cl

Cat.

Solution of KOH (0.5 M) in H2O/2-Propanol (9:1)110 ºC, 72 h

HCOOK

22 (0.018 mM)CO2

(50 atm)

TON = 150

scHeMe 1.13

N

N

Bu

Bu

Ir Cl

Cl

Catalyst (0.17 mM)

Aqueous solution of KOH (1M)80 ºC, 18 h

HCOOK

Entry Catalyst TON

N

N

Ir Cl

N

N

PF6

NIr Cl

Cl

N

1

2

3

291

894

516

CO2 / H2 (1:1)(60 atm)

22

27

28

table 1.16 reduction of CO2 catalyzed by iridium complexes having

NHC ligand.

reFereNCeS 25

references

[1] recent reviews on N-heterocyclic carbene complexes of transition metals: (a) Casin CSJ, editor. N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis. dordrecht/New york: Springer; 2011. (b) díez-gonzález S, editor. N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools. Cambridge: rSC Publishing; 2011. (c) Herrmann Wa. angew Chem int ed 2002;41:1290. (d) Peris e, Crabtree rH. Coord Chem rev 2004;248:2239. (e) Scott NM, Nolan SP. eur J inorg Chem 2005:1815. (f) Normand aT, Cavell KJ. eur J inorg Chem 2008:2781. (g) Hahn Fe, Jahnke MC. angew Chem int ed 2008;47:3122. (h) Corberán r, Mas-Marzá e, Peris e. eur J inorg Chem 2009:1700. (i) Fortman gC, Nolan SP. Chem Soc rev 2001;40:5151.

[2] Burling S, Whittlesey MK, Williams JMJ. adv Synth Catal 2005;347:591.

[3] recent publications on Oppenauer-type oxidation of alcohols: (a) almeida MLS, Beller M, Wang g-Z, Bäckvall J-e. Chem eur J 1996;2:1533. (b) gauthier S, Scopelliti r, Saverin K. Organometallics 2004;23:3769. (c) Suzuki T, Morita K, Tsuchida M, Hiroi K. J Org Chem 2003:68:1601.

[4] (a) Hanasaka F, Fujita K, yamaguchi r. Organometallics 2004;23:1490. (b) Hanasaka F, Fujita K, yamaguchi r. Organometallics 2005;24:3422.

[5] Hanasaka F, Fujita K, yamaguchi r. Organometallics 2006;25:4643.

[6] Marr aC, Pollock CL, Saunders gC. Organometallics 2007;26:3283.

[7] (a) Jensen dr, Schultz MJ, Mueller Ja, Sigman MS. angew Chem int ed 2003;42:3810. (b) Mueller Ja, goller CP, Sigman MS. J am Chem Soc 2004;126:9724. (c) Schultz MJ, Hamilton SS, Jensen dr, Sigman MS. J Org Chem 2005;70:3343.

[8] Jensen dr, Sigman MS. Org Lett 2003;5:63.

[9] recent publications on dehydrogenative oxidation of alcohols: (a) adair gra, Williams JMJ. Tetrahedron Lett 2005;46:8233. (b) Van Buijtenen J, Meuldijk J, Vekemans JaJM, Hulshof La, Kooijman H, Spek aL. Organometallics 2006;25:873. (c) Fujita K, Tanino N, yamaguchi r. Org Lett 2007;9:109. (d) Baratta W, Bossi g, Putignano e, rigo P. Chem eur J 2011;17:3474. (e) Fujita K, yoshida T, imori y, yamaguchi r. Org Lett 2011;13:2278.

[10] Prades a, Peris e, albrecht M. Organometallics 2011;30:1162.

[11] Prades a, Corberán r, Poyatos M, Peris e. Chem eur J 2008;14:11474.

[12] Csabai P, Joó F. Organometallics 2004;23:5640.

[13] Chantler VL, Chatwin SL, Jazzar rFr, Mahon MF, Saker O, Whittlesey MK. dalton Trans 2008:2603.

[14] addis d, enthaler S, Junge K, Wendt B, Beller M. Tetrahedron Lett 2009;50:3654.

[15] yiğit M, yiğit B, Özdemir İ, Çetinkaya e, Çetinkaya B. appl Organomet Chem 2006;20:322.

[16] Baratta W, Schütz J, Herdtweck e, Herrmann Wa, rigo P. J Organomet Chem 2005;690:5570.

[17] (a) danopoulos aa, Winston S, Motherwell WB. Chem Commun 2002:1376. (b) Özdemir i, yaşar S. Transit Metal Chem 2005;30:831. (c) Poyatos M, Maisse-François a, Bellemin-Laponnaz S, Peris e, gade LH. J Organomet Chem 2006;691:2713. (d) Zeng F, yu Z. Organometallics 2008;27:6025. (e) ding N, Hor TSa. Chem asian J 2011;6:1485. (f) Monney a, Venkatachalam g, albrecht M. dalton Trans 2011;40:2716. (g) del Pozo C,


iglesias M, Sánchez F. Organometallics 2011;30:2180. (h) Fernández Fe, Puerta MC, Valerga P. Organometallics 2011;30:5793.

[18] albrecht Ma, Crabtree rH, Mata J, Peris e. Chem Commun 2002:32.

[19] (a) Mas-Marzá e, Poyatos M, Sanaú M, Peris e. Organometallics 2004;23:323. (b) yang L, Krüger a, Neels a, albrecht M. Organometallics 2008;27:3161.

[20] Hillier aC, Lee HM, Stevens ed, Nolan SP. Organometallics 2001;20:4246.

[21] gnanamgari d, Moores a, rajaseelan e, Crabtree rH. Organometallics 2007;26:1226.

[22] Jiménez MV, Fernández-Tornos J, Pérez-Torrente JJ, Modrego FJ, Winterle S, Cunchillos C, Lahoz FJ, Oro La. Organometallics 2011;30:5493.

[23] Corberán r, Peris e. Organometallics 2008;27:1954.

[24] azua a, Mata Ja. Peris e. Organometallics 2011;30:5532.

[25] (a) albrecht M, Miecznikowski Jr, Samuel a, Faller JW, Crabtree rH. Organometallics 2002;21:3596. (b) Miecznikowski Jr, Crabtree rH. Organometallics 2004;23:629. (c) Miecznikowski Jr, Crabtree rH. Polyhedron 2004;23:2857. (d) Corberán r, Sanaú M, Peris e. Organometallics 2007;26:3492. (e) Türkmen H, Pape T, Hahn Fe, Çetinkaya B. Organometallics 2008;27:571. (f) Türkmen H, Pape T, Hahn Fe, Çetinkaya B. eur J inorg Chem 2008:5418. (g) gnanamgari d, Sauer eLO, Schley Nd, Butler C, incarvito Cd, Crabtree rH. Organometallics 2009;28:321. (h) Binobaid a, iglesias M, Beetstra d, dervisi a, Fallis i, Cavell KJ. eur J inorg Chem 2010:5426.

[26] dobereiner ge, Nova a, Schley Nd, Hazari N, Miller S, eisenstein O, Crabtree rH. J am Chem Soc 2011;133:7547.

[27] Voutchkova aM, gnanamgari d, Jakobsche Ce, Butler C, Miller SJ, Parr J, Crabtree rH. J Organomet Chem 2008;693:1815.

[28] Fogler e, Balaraman e, Ben-david y, Leitus g, Shimon LJW, Milstein d. Organometallics 2011;30:3826.

[29] Sanz S, Benítez M, Peris e. Organometallics 2010;29:275.


27

Bond-Forming reactions catalyzed By transition metal complexes Bearing n-Heterocyclic carBene ligands

2

2.1 introduction

The aim of this chapter is to survey the bond-forming reactions (C–C bond formation, C–N bond formation, and C–O bond formation) catalyzed by transition metal complexes having N-heterocyclic carbene (NHC) ligands. Herein, catalytic bond-forming reactions will be classified into three types: (i) carbon–carbon bond formation based on hydrogen transfer, (ii) carbon–nitrogen bond formation based on hydrogen transfer and dehydrogenation, (iii) carbon–oxygen bond formation based on hydrogen transfer and dehydrogenation. These reactions provide a useful and environmentally benign method for the synthesis of various organic compounds [1].

2.2 carBon–carBon Bond Formation Based on Hydrogen transFer

2.2.1 ruthenium complex with monodentate nHc ligand

The ruthenium complex 1 bearing an NHC ligand exhibited high catalytic activity for the carbon–carbon bond-forming reaction between alcohol and phosphonium ylide (Scheme 2.1) [2]. When the reaction of benzyl alcohol with ester ylide was performed in the presence of ruthenium complex 1 (5 mol%) and vinyltrimethylsi-lane (5 mol%) in toluene at 80 °C for 24 h, the dihydrocinnamate product was obtained

28 BONd-FOrmiNg reaCTiONS CaTalyzed By NHC COmplexeS

in high yield. as illustrated in Scheme 2.2, the reaction proceeds through hydrogen transfer processes, so-called borrowing hydrogen. Firstly, alcohol is dehydrogenated to afford benzaldehyde. Then, the Wittig reaction of the aldehyde with phosphonium ylide occurs to give an alkene intermediate. Finally, the borrowed hydrogen returns to the C∙C bond to give the product. The role of vinylsilane is to activate the ruthe-nium complex 1 into cyclometalated catalyst by accepting the hydrides.

Similar ruthenium complex 2 also catalyzed the carbon–carbon bond-forming reac-tion between alcohol and cyano ylide (Table 2.1) [3]. By the reaction of benzylic alcohols with cyano phosphonium ylide in the presence of ruthenium complex 2 (5 mol%) in toluene at 70 °C, various saturated cyano products were obtained in good yields.

The ruthenium complex 3 bearing an NHC ligand besides the xantphos showed catalytic activity for the sequential oxidation–Knoevenagel–reduction reaction of benzyl alcohol with a β-carbonyl cyano compound [4]. alkylated product was obtained quanti-tatively in the reaction catalyzed by ruthenium complex 3 (0.5 mol%) in toluene at 120 °C for 3.5 h (Scheme 2.3), although the related ruthenium complex [ru(pph

3)(xantphos)

(CO)H2] without NHC ligand showed slightly higher catalytic activity than 3.

N N

RuHPh3P

OC H

PPh3

Ph OH

Ph3P CO2Bn, SiMe3

PhCO2Bn

1 (5 mol%)

Cat.

(1.1 equiv) (5 mol%)90%

Toluene, 80 ºC, 24 h

scHeme 2.1

R1 OH

R1 OPh3P

R2

R1R2

R1R2

[M]

[M] + 2[H]

Overall transformation

scHeme 2.2

CarBON–CarBON BONd FOrmaTiON 29

N

N

CH2

Ru

PPh3

H

PPh3

CO

R OH

Ph3P CN

RCN

RCN

+

Cat.

2 (5 mol%)

Toluene, 70 °C, 2 h+

OHCN

1 87 285

OHCN

2 61 754

OHCN

3 88 286

OHCN

4 85 283

OHCN

5 65 164

MeO MeO

F F

O O

Entry Alcohol Product Conversion (%) Alkene (%)Alkane (%)

taBle 2.1 C–C Bond formation between alcohol and cyano ylide catalyzed by 2.

N NCy

RuP

OC HP

Ph OH3 (0.5 mol%)

Cat.

100%

OPPh2 PPh2

P

P=

CN

O

tBu Ph

CN

O

tBuPiperidinium acetate (5 mol%)Toluene, 120 ºC, 3.5 h

+

scHeme 2.3

30 Bond-Forming reactions catalyzed By nHc complexes

the ruthenium complexes 4–8 bearing p-cymene and a variety of nHc ligands have been reported to catalyze carbon–carbon bond-forming reaction between two alcohol molecules (β-alkylation of secondary alcohol with primary alcohol) [5]. as shown in table 2.2, the reaction of 1-phenylethanol with 1-butanol catalyzed by ruthenium complexes 4–8 in the presence of 1 equiv of KoH in toluene at 110 °c

Ph

OHPr OH

Ph Pr

OH

Ph Pr

O+

KOH (1 equiv)Toluene, 110 ºC

+

NN

RuCl

Cl

p-cymene

NN

RuCl

Cl

NN

RuCl

Cl

Ph

NN

RuCl

Cl

p-cymene

NN

Ru

Cl N N

PF6

Catalyst (1 mol%)

Entry Catalyst Time (h) Yield (%) Alcohol : Ketone

p-cymene

p-cymene

p-cymene

1

2

3

4

5

22

22

22

13

10

60

>95

86

>95

95

78 : 22

90 : 10

91 : 9

90 : 10

90 : 10

4

5

6

7

8

Table 2.2 c–c bond formation between two alcohol molecules catalyzed by ruthenium nHc complexes.


gave the mixture of 1-phenyl-1-hexanol and 1-phenylhexan-1-one. The cationic complex 8 showed the best catalytic activity, achieving high yield of desired alcohol product in a shorter reaction time (entry 5).

The reaction proceeds via successive hydrogen transfer reactions (borrowing hydrogen) and aldol condensation (Scheme 2.4): (i) hydrogen transfer oxidation of alcohols to afford a ketone and an aldehyde accompanied by the transitory generation of metal hydride, (ii) cross-aldol condensation mediated by base to afford an α,β-unsaturated ketone, and (iii) transfer hydrogenation of the α,β-unsaturated ketone with the metal hydride [6].

The dimetallic and tetrametallic ruthenium Janus-head complexes 9 and 10 having triazolediylidene-type NHC ligand (ditz) also showed the catalytic activity for the β-alkylation of secondary alcohols with primary alcohols [7]. When the reaction of 1-phenylethanol with benzyl alcohol was carried out in the presence of dimetallic complex 9 and tetrametallic complex 10, the β-alkylated product was formed in 75 and 88%, respectively (Scheme 2.5).

The ruthenium complex 11 bearing an NHC and benzylidene ligands was uti-lized as an active catalyst for the synthesis of quinolines by the hydrogen transfer reaction between 2-aminobenzyl alcohol with ketones (modified Friedländer reaction) [8,9]. as shown in Table 2.3, the reactions of 2-aminobenzylalcohol with acetophenone derivatives or aliphatic ketones in the presence of 11 (1 mol%) and KOH (1 equiv) in dioxane at 80 °C for 1 h gave various quinolines in moderate to excellent yields.

a possible mechanism for the formation of quinolines by the reaction of 2-aminobenzyl alcohol with ketones is illustrated in Scheme 2.6 [8]. Firstly, 2-amino-benzyl alcohol is converted into 2-aminobenzaldehyde by hydrogen transfer oxidation catalyzed by 11. Then, the aldehyde and ketone undergo a cross-aldol reaction under basic condition. The aldol product cyclizes via imination followed

R2 OH

[M]

Overall transformationR1

OH

R1

OH

R2+

R2 O

R1

O

+ R1

O

R2

Base

Cross aldolcondensation

[M] + 4[H]

scHeme 2.4


by the dehydration to give quinoline as a product. alternatively, dehydration of aldol product and transfer hydrogenation by ruthenium hydride species afford an amino ketone, which also lead to the formation of quinoline via imination and dehydrogenation.

2.2.2 iridium complex with multidentate nHc ligand

The cationic iridium complex 12 bearing a Cp* (pentamethylcyclopentadienyl) and bidentate pyrimidine-functionalized NHC ligands has been reported to cata-lyze carbon–carbon bond-forming reaction (β-alkylation of secondary alcohol with primary alcohol) [10]. as shown in Scheme 2.7, the reactions of 1-phenylethanol with benzylic primary alcohols catalyzed by the iridium complex 12 in the presence of 1 equiv of KOH in toluene at 110 °C for 3 h gave β-alkylated secondary alcohols in excellent yields.

The pentamethylcyclopentadienyl-tethered NHC ligands have been synthesized, and the iridium complexes 13 and 14 bearing these ligands have been prepared. Catalytic performance of these complexes in the carbon–carbon bond-forming reac-tion (β-alkylation of alcohols) has been reported (Table 2.4) [11]. Both dihalide iridium complexes 13 and 14 were catalytically active for the reaction of 1-phenyleth-anol with benzyl alcohol to give 1,3-diphenylpropanol under strong basic conditions via hydrogen transfer processes similar to the aforementioned. although simple [Cp*irCl

2]

2 also catalyzes the same reaction [6b], the complexes 13 and 14 exhibit

improved catalytic activity.

NN

NRu Ru

ClCl

p-cymene

Cl Cl

p-cymene

NN

NRu Ru

ClCl

p-cymene

Cl Cl

p-cymene

NN

NRu Ru

p-cymene p-cymene

OH

OH

OH

+Catalyst (1 mol%)

KOH (1 equiv)Toluene, 110 ºC, 20 h

Catalyst:

Catalyst:

Yield 75%

Yield 88%

9

10

scHeme 2.5


OH

NH2 R1

O

R2

N

R2

R1

N NMes Mes

RuPh

Cl

ClPCy3

Cat.

11 (1 mol%)

KOH (1 equiv)Dioxane, 80 ºC, 1 h

+

Entry Ketone Product Yield (%)

R

O

R = PhR = 2-MeC6H4R = 3-MeC6H4R = 4-MeC6H4R = 2-MeOC6H4R = 4-MeOC6H4R = Me

O

O

Ph

O

O

O

N RR = PhR = 2-MeC6H4R = 3-MeC6H4R = 4-MeC6H4R = 2-MeOC6H4R = 4-MeOC6H4R = Me

N C5H11

N C4H9

N Ph

N

N

1234567

8

9

10

11

12

1006691868773

100

76

51

87

100

100

taBle 2.3 Synthesis of quinolines from 2-aminobenzyl alcohol and ketones catalyzed by 11.


OH

NH2

O

NH2

R2R1

OH

R2

R1

O

[Ru]

[RuH2]

Base

R2R1

O

Crossaldol

O

R1

R2

OH

NH2

O

R1

R2NH2

O

R1

R2

NH2

N

OH

R2

R1 N

R2

R1N

R2

R1

–H2O

–H2O

IminationImination

Dehydrogenation

[Ru][RuH2]

scHeme 2.6

Cat.

12 (1 mol%)


IrCl

N

N

N

N

BuPF6

Ph

OHAr OH

Ph

OH

ArKOH (1 equiv)+

Yield 93% [Ar = Ph]96% [Ar = 4-Cl(C6H4)]90% [Ar = 4-Me(C6H4)]

scHeme 2.7


The iridium complex 15 bearing a p,C-chelating abnormal N-heterocyclic ligand has been prepared by the reaction of precursor complex [ir(cod)Cl]

2 with

phosphine-tethered imidazolium ion through the selective addition of C–H bond at 5-position. Table 2.5 summarizes the results of the β-alkylation of secondary alcohols with primary alcohols catalyzed by the abnormal NHC complex 15 [12]. Various 1-phenylethanol derivatives were alkylated by benzylic or aliphatic primary alcohols to give secondary alcohols selectively. it should be noted that the abnormal N-heterocyclic complex 15 showed higher catalytic activity than the normal N-heterocyclic iridium complex prepared from phosphine-tethered imidazolium ion through the addition of C–H bond at 2-position.

2.2.3 palladium complex with multidentate nHc ligand

The palladium complex 16 bearing a tridentate pincer-type NHC ligand has been utilized as a catalyst for β-alkylation of secondary alcohols with primary alcohols [13]. When the reaction of 1-tetralol with benzyl alcohol was carried out in the presence of the palladium catalyst 16 (4 mol%) in p-xylene at 125 °C for 12 h, 2-benzyl-1-tetralol was obtained in good yield along with a small amount of 2-benzyl-1-tetralone (Scheme 2.8). in this catalytic system, no more than 40 mol% of base was required.

KOH (1 equiv)Toluene, 110 ºC

+

IrCl

N

N Cl

Ph

OH

Ph OHPh

OH

Ph

Catalyst (1 mol%)

Entry Catalyst Yield (%)Time

IrI

N

N

Ph

I

1

2

3

4

5

6

3

6

24

3

6

24

70

80

>99

70

90

>99

13

14

taBle 2.4 β-alkylation of 1-phenylethanol with benzyl alcohol catalyzed by 13 and 14.


Ir

H

Cl

Ph2 PF6P

N

NiPr

R1

OH

R2 OHR1 R2 R1 R2

OH O

Cat.

15 (1 mol%)

+KOH (1 equiv)

Toluene, 110 °C

+

Entry R1 R2 Time (h) Alcohol : Ketone Yield of alcohol (%)

Ph

4-MeOC6H4

4-MeC6H4

4-FC6H4

4-C1C6H4

4-BrC6H4

4-CF3C6H4

3-BrC6H4

2-Naphthyl

1-Naphthyl

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

PhCH2

Ph

n-Hexyl

2

1.5

2

2

1

1.5

2

2

1

1

1

2

100 : 0

87 : 13

92 : 8

94 : 6

96 : 4

98 : 2

93 : 7

81 : 19

95 : 5

90 : 10

88 : 12

85 : 15

92

61

73

90

81

90

84

74

84

83

68

61

1

2

3

4

5

6

7

8

9

10

11

12

taBle 2.5 β-alkylation of secondary alcohols with primary alcohols catalyzed by 15.

N

N

Bu

N

N

Bu

Pd

Br

OH

Ph OH

+

OH Ph O Ph

Cat.

CsOH (40 mol%)p-Xylene, 125 ºC, 12 h

+

18 : 1Yield 97%

16(4 mol%)

scHeme 2.8

CarBON–NiTrOgeN BONd FOrmaTiON 37

2.3 carBon–nitrogen Bond Formation Based on Hydrogen transFer and deHydrogenation

in this section, C–N bond-forming reactions based on hydrogen transfer and dehy-drogenation are surveyed. Catalytic C–N bond formation based on hydrogen transfer proceeds via three cascade reactions (Scheme 2.9): (i) hydrogen transfer oxidation of an alcohol to afford a carbonyl compound accompanied by the transitory generation of metal hydride, (ii) condensation of the carbonyl compound with an amine to afford an imine, and (iii) transfer hydrogenation of the imine with the metal hydride.

Catalytic C–N bond formation based on dehydrogenation also proceeds via three cascade reactions (Scheme 2.10): (i) dehydrogenative oxidation of a primary alcohol to afford an aldehyde, (ii) formation of an aminal by addition of an amine to the alde-hyde, and (iii) dehydrogenation of the aminal to afford an amide.


The ruthenium NHC complex generated in situ from ru(CO)(H)2(pph

3)

3 17 and the

carbene ligand 18 has been reported to catalyze the carbon–nitrogen bond formation using nitroarenes and primary alcohols as starting materials [14]. For example, the reaction of nitrobenzene with an excess amount of benzyl alcohol in the presence of

R2 OH

[M]

Overall transformation+

R2 O

+ R1N R2

Condensation

R1

HN R2

[M] + 2[H]

R1NH2

R1NH2

scHeme 2.9

R OH

R O

H

R′NH2

R NH

R′OH

+ 2H2


R NH

R′O

+

Cat.−H2

Cat.−H2

scHeme 2.10


17 (5 mol%) and 18 (7.5 mol%) at 150 °c for 16 h gave N,N-dibenzylaniline in excel-lent yield (scheme 2.11). a variety of tertiary amines can be synthesized by this method. the reaction proceeds through the hydrogen transfer processes (borrowing hydrogen mechanism). Firstly, oxidation of primary alcohol and reduction of nitroarene occur through hydrogen transfer mediated by ruthenium catalyst. then, n-alkylation based on the usual mechanism (scheme 2.9) takes place.

the ruthenium complex 19 bearing an nHc ligand showed catalytic activity for the oxidative homocoupling of primary amines to give imines accompanying a formation of carbon–nitrogen bond [15]. as illustrated in scheme 2.12, the reaction of benzylamine was catalyzed by the ruthenium complex 19 (5 mol%) in toluene at 150 °c, resulting in selective formation of N-benzylidenebenzylamine under oxidant-free conditions. the reaction of aliphatic amines also gave imines, although the yield was slightly lower.

the nHc ruthenium catalyst generated in situ from ru(cod)cl2 20 and the imid-

azolium salt 21 and a phosphine in the presence of strong base effectively catalyzes

NO2OH

N

N N MesMes+

Cat. Ru(CO)(H)2(PPh3)3 17 (5 mol%)

18 (7.5 mol%)

150 °C, 16 h

96%

SCHEME 2.11

N

NBu

Bu

RuCl

Cl

p-cymene

NH2 N

NH2N

Cat.

19 (5 mol%)

Toluene, 150 °C, 12 h


2

2

>95%

N

NBu

Bu

RuCl

Cl

p-cymeneCat.

19 (5 mol%)

70%

SCHEME 2.12


the formation of amides by the reaction of primary alcohols with amines [16]. When the reaction of phenethyl alcohol with benzylamine was performed in the presence of 20 (2 mol%), 21 (2 mol%), KOtBu (8 mol%), and pCyp

3 · HBF

4 (2 mol%) in toluene

at 110 °C for 24 h, N-benzyl-2-phenylacetamide was formed in high yield, accompa-nying the evolution of 2 equiv of H

2 (Scheme 2.13).

Closely similar NHC ruthenium catalyst generated from [ru(p-cymene)Cl2]

2 22

and the imidazolium salt 23 was also reported (Scheme 2.14) [17].Synthesis of various cyclic imides has been accomplished by the reaction of diols

with amines based on the dehydrogenative amidation strategy [18]. as shown in Scheme 2.15, the reaction of hexylamine with 1,4-butanediol in the presence of ruH

2(pph

3)

4 24 (5 mol%), imidazolium salt 23 (5 mol%), NaH (20 mol%), and CH

3CN

(5 mol%) in toluene under reflux for 24 h gave N-hexylsuccinimide in good yield.The ruthenium complex 4 bearing p-cymene and an NHC ligand exhibited high

activity for the dehydrogenative amidation of alcohols with amines [19]. as shown in

OH

NH2

O

NH

+

N N iPriPr+

Cl−

Cat. Ru(cod)Cl2 20 (2 mol%)

21 (2 mol%)

KOtBu (8 mol%)PCyp3 HBF4 (2 mol%)


93%

+ 2H2

scHeme 2.13

Toluene, re�ux, 36 h

Cat. [Ru(p-cymene)Cl2]2 22 (2.5 mol%)

N NiPr iPr+

Br−

23 (5 mol%)

NaH (15 mol%), CH3CN (5 mol%)

OH

NH2

+

O

NH

96%

+ 2H2

scHeme 2.14

+

C6H13NH2

N

O

O

C6H13

OHHO

Cat. RuH2(PPh3)4 24 (5 mol%)

N N iPriPr+

Br−

23 (5 mol%)

NaH (20 mol%), CH3CN (5 mol%)

Toluene, re�ux, 24 h81%

+ 4H2

scHeme 2.15


table 2.6, the reaction catalyzed by nHc ruthenium complex 4 proceeds to give good yields with various combination of starting materials.

in addition to the aforementioned catalysts, nHc ruthenium complexes 25–27, and 19 have been reported to catalyze the dehydrogenative amidation of alcohols with amines (scheme 2.16).

2.3.2 Iridium Complex with Monodentate NHC Ligand

the iridium complex 28 bearing an nHc ligand has been reported to catalyze the carbon–nitrogen bond-forming reactions based on hydrogen transfer (see scheme 2.9). some of the results are shown in table 2.7 [22]. When the reaction of benzyl alcohol with aniline

NN

Ru ClCl

p-cymeneCat.

4 (5 mol%)

KOtBu (15 mol%)Toluene, reflux, 24 h

R1 OH R2R3NH R1 R2

R3N

O

+ 2H2+

Entry Alcohol Amine Product Yield (%)

PhOH Ph NH2 Ph

HN

NH

NH

NH

Ph

O

C5H11C5H11NH2 C5H11

C5H11OH

O

Ph OH HN NPh

O

HO NH2

NHO

OH

MeOPh NH2

O

Ph

MeO

Ph OH Ph NH2 Ph

O

Ph

1

2

3

4

5

6

93

95

83

88

85

81

TabLe 2.6 dehydrogenative amidation of alcohols with amines catalyzed by 4.


N

N

iPr

iPr

RuCl

Cl

p-cymene

N N MesMes

RuPy

PyCl

Cl Ph

PCy3, KOtBuRef. [21]NaH, Ref. [20]

N

N

Bu

Bu

RuCl

Cl

p-cymene

NaH, Ref. [15]

19

2625

N N CyCy

Ru

PCy3

Cl

Cl Ph

KOtBu, Ref. [21]

27

scHeme 2.16

Cat.

28 (5 mol%)

N

N

Bu

Bu

Ir Cl

Cl

R1R2CHOH (R1R2CH)2NR3+ +AgOTf (15 mol%)

110 ºC

Entry Alcohol Amine Time (h)Yield of secondary

amine (%)Yield of tertiary

amine (%)

Benzyl alcohol

Benzyl alcohol

1-Butanol

1-Phenylethanol

1-Phenylethanol

1-Phenylethanol

Aniline

Benzylamine

Benzylamine

Hexylamine

Benzylamine

Cyclohexylamine

7

7

7

24

24

24

>95

0

50

51

>95

52

0

>95

50

19

0

13

1

2

3

4

5

6

R3NH2 R1R2CHNHR3

taBle 2.7 N-alkylation of primary amines with alcohols catalyzed by 28.


was carried out at 110 °C for 7 h in the presence of the NHC iridium complex 28 (5 mol%) and silver triflate (15 mol%), monoalkylated N-benzylaniline was obtained selectively (entry 1). On the other hand, the reaction of benzyl alcohol with benzylamine resulted in the selective formation of dialkylated tribenzylamine (entry 2). The selectivity of the reaction highly depended on the combination of alcohols and amines employed.

N-alkylation of aniline derivatives with primary amines has been also catalyzed by the NHC iridium complex 28 [22]. Various secondary amines were synthesized in moderate to excellent yields using primary amines as an alkylating agent (Table 2.8). The reaction proceeds through catalytic hydrogen transfer processes as follows: (i) dehydrogenation of a primary amine giving an imine, (ii) nucleophilic addition of aniline to the imine giving an aminoaminal, (iii) elimination of ammonia affording a secondary imine, and (iv) transfer hydrogenation of the secondary imine giving an alkylated aniline as a product.

Cat.

28 (5 mol%)

N

N

Bu

Bu

Ir Cl

Cl

+AgOTf (15 mol%)

Toluene-d8, 150 ºC, 24 h, -NH3

Entry Arylamine Alkylamine Yield (%)

Aniline

Aniline

Aniline

Aniline

o-Toluidine

o-Toluidine

o-Toluidine

o-Toluidine

p-Toluidine

p-Fluoroaniline

p-Chloroaniline

p-Methoxyaniline

2,4,6-Methylaniline

Hexylamine

Benzylamine

Cyclohexylamine

Dodecylamine

Hexylamine

Benzylamine

Cyclohexylamine

Dodecylamine

Hexylamine

Hexylamine

Hexylamine

Hexylamine

Hexylamine

>95

94

>95

>95

80

80

>95

70

70

>95

>95

50

90

1

2

3

4

5

6

7

8

9

10

11

12

13

NH2

R1

HN

R1 R2R2NH2

taBle 2.8 N-alkylation of aniline derivatives with primary amines catalyzed by 28.


The similar NHC iridium complex 29 is an effective catalyst for the amination of 1,3-propanediol with aniline [23]. N,N-diphenyl-1,3-propanediamine was synthe-sized in moderate yield by the reaction of aniline with 1,3-propanediol catalyzed by 29 (1 mol%) and K

2CO

3 (10 mol%) in toluene at 115 °C for 24 h (Scheme 2.17).

The boron–NHC iridium polymeric catalyst 31 was prepared by ionic convolution of a poly(catechol borate) and the NHC iridium complex 30 (Scheme 2.18) [24]. The polymeric NHC iridium catalyst 31 exhibited high activity for the N-alkylation of amines with primary alcohols in water under aerobic conditions. For example, the

Cat.

29 (1 mol%)

N

N

Ir Cl

Cl

Ph

HO OH

NH

NH

Ph Ph

PhNH2

NH

Ph++K2CO3 (10 mol%)

Toluene, 115 ºC, 24 h 65% 35%

scHeme 2.17

OB

O

HO

O10

n

Cp*Ir(κ2-CO3)(IPr)

N N

iPr

iPriPr

iPr

IPr =O

B−O

O

O10

2n

• [Cp*Ir2+(IPr)]n

Polymeric iridium catalyst 31

NH2OH H

N

Polymeric iridium catalyst 31(1 mol%Ir)

Polymeric iridium catalyst 31(1 mol%Ir)

H2O, 100 ºC, 24 hUnder air

H2O, 150 ºC, 24 hMicrowave

+

85%

NH3 aq OH+ (PhCH2)3N

84%

30

scHeme 2.18


reaction of aniline with benzyl alcohol in the presence of 31 (1 mol%) in water at 100 °C for 24 h gave N-benzylaniline in high yield. Furthermore, the catalyst 31 was also effec-tive for the N-alkylation of aqueous ammonia to afford tertiary amines by trialkylation.

The NHC complex of monovalent iridium 32 has been prepared by carbene transfer method using an NHC tungsten carbonyl complex and [ir(cod)Cl]

2 followed by the

treatment with pph3. The complex 32 showed catalytic activity for the N-alkylation of

primary amines with primary alcohols (Table 2.9) [25]. The reaction of p-tert-butyl-aniline with benzyl alcohol catalyzed by 32 (1 mol%) and CsOH (50 mol%) gave N-monoalkylated product almost quantitatively (entry 1). Heteroaromatic amines and aliphatic alcohols can be also employed as substrate for this catalytic system.

2.3.3 iridium complex with multidentate nHc ligand

The cationic iridium complex 12 bearing a Cp* and bidentate pyrimidine-tethered NHC ligands has been reported to catalyze N-alkylation of primary amines with

Cat.

32 (1 mol%)+

N

NIr

CO

Cl

PPh3

Bn

Bn

CsOH (50 mol%)100 ºC, 24 h

R1 R2

NH2

R3 OHR1 R2

HN R3

Amine Alcohol Product Yield (%)

p-tBuC6H4NH2

Aniline

Aniline

Aniline

4-Aminopyridine

Benzyl alcohol

p-MeOC6H4CH2OH

p-ClC6H4CH2OH

1-Octanol

Benzyl alcohol

H2C

HN tBu

H2C

HNMeO

H2C

HNCl

H2C

HN N

C8H17HN

99

72

87

67

99

Entry

1

2

3

4

5

taBle 2.9 N-alkylation of primary amines with primary alcohols catalyzed by 32.


primary alcohols [10]. as shown in Scheme 2.19, the reaction of aniline with benzyl alcohol in the presence of 12 (1 mol%) and NaHCO

3 (50 mol%) in toluene at 150 °C

for 45 h gave N-benzylaniline in excellent yield.The iridium complex 14 bearing a pentamethylcyclopentadienyl-functionalized

NHC ligand was also catalytically active for the N-alkylation (Scheme 2.20) [11].

2.3.4 iridium–palladium Heterodimetallic complex with Bridging nHc ligand

Homodimetallic and heterodimetallic complexes of iridium and palladium bridged by 1,2,4-trimethyltriazolyldiylidene (ditz) 33–35 have been prepared. Catalytic performance of these complexes for the reaction of nitrobenzene with benzyl alcohol to afford N-benzylideneaniline was examined [26]. as shown in Table 2.10, heterodimetallic ir–pd complex 33 showed the highest catalytic activity. Various imines were synthesized by the reaction of nitroarenes with pri-mary alcohols catalyzed by 33 (2 mol%) in the presence of Cs

2CO

3 (100 mol%)

at 110 °C (Table 2.11).

NH2OH

+

Cat.

12 (1 mol%)

IrCl

N

N

N

N

BuPF6

NaHCO3 (50 mol%)MS4Å, toluene, 150 ºC, 45 h

HN

98%

scHeme 2.19

NH2OH

+

Cat.

14 (0.75 mol%)

KOtBu (100 mol%)Toluene, 110 ºC, 16 h

HN

85%

IrI

N

N

Ph

I

scHeme 2.20


2.4 carBon–oxygen Bond Formation Based on Hydrogen transFer and deHydrogenation


The ruthenium complex 26 bearing p-cymene and an NHC ligand exhibited catalytic activity for the carbon–oxygen bond-forming reaction by dehydrogenative coupling of primary alcohols leading to esters [27]. For example, the reaction of 1-pentanol in the presence of the NHC ruthenium complex 26 (2.5 mol%), pCy

3 (4.5 mol%), and

KOH (10 mol%) in mesitylene at 163 °C for 18 h gave pentyl pentanoate in 70% yield (Table 2.12, entry 1). Similar reactions of aliphatic primary alcohols or diols also gave esters in moderate to good yields (entries 2–6), although the reaction of aro-matic alcohols resulted in poor yield of esters.

The mechanism of dehydrogenative coupling of primary alcohols leading to esters is illustrated in Scheme 2.21. Firstly, catalytic dehydrogenative oxidation of a pri-mary alcohol occurs to generate an aldehyde. Then, addition of the alcohol to the

Ir

N

N

N

ClCl

Pd

Cl

Cl

pyridine

Ph OH

Entry Yield (%)

PhNO2 PhN Ph

Catalyst (0.5 mol%)Cs2CO3 (0.3 mmol)

0.3 mmol 5 mmol

+110 ºC, 20 h

Catalyst

Pd

N

N

N

Pd

Cl

Cl

pyridine

Cl

pyridine

Cl

Ir

N

N

N

ClCl

IrCl

Cl

1

2

3

33

34

35

76

7

35

taBle 2.10 Catalytic imination of nitrobenzene with benzyl alcohol.

CarBON–OxygeN BONd FOrmaTiON 47

aldehyde occurs to give a hemiacetal. Finally, the hemiacetal is dehydrogenated to give esters as a product.

2.4.2 iridium complex with monodentate nHc ligand

The iridium complex 28 bearing an NHC ligand is reported to be a good catalyst for the dehydrative etherification of benzyl alcohol with various alcohols [22]. When the reaction of benzyl alcohol with an excess amount of methanol was carried out using NHC iridium complex 28 (1 mol%) and agOTf (3 mol%) as catalyst at 110 °C for 12 h, it resulted in the formation of benzyl methyl ether in high yield (Table 2.13, entry 1). a variety of benzyl ethers were synthesized by this reaction. The key intermediate of this etherification is proposed to be ir(V)–H species, which acts as a Brønsted acid to activate an alcohol by electrophilic attack to the oxygen atom leading to the dehydrative coupling to give an ether.

2.4.3 nickel complex with monodentate nHc ligand

The NHC nickel catalyst generated in situ from Ni(cod)2 36 and the free NHC ligand

37 effectively catalyzes the hydroacylation of aldehydes (Tishchenko reaction)

Cat.

33 (2 mol%)

Ir

N

N

N

ClCl

Pd

Cl

Cl

pyridineR1 NO2

R2 OH

+ NR2

R1Cs2CO3 (100 mol%)

110 ºC, 20 h

Entry R1 R2 Product Yield (%)

N

N

NOMe

NMeO

1

2

3

4

C6H5CH2

4-MeC6H4

4-OMeC6H4

4-MeC6H4

H

4-Me

4-Me

4-OMe

92

89

83

84

taBle 2.11 imination of nitroarenes with benzyl alcohols catalyzed by 33.


N

N

iPr

iPr

RuCl

Cl

p-cymene

R OH2

Cat.

26 (2.5 mol%)

PCy3 (4.5 mol%)KOH (10 mol%)

Mesitylene, 163 ºC, 18 h

R O R

O+ 2 H2

Entry Alcohol Product Yield (%)

OH O

O

C9H19 OHC9H19 O C9H19

O

OH O

O

HOOH

HOOH

HOOH

O O

O O

O O

70

81

64

71

78

61

1

2

3

4

5

6

taBle 2.12 dehydrogenative coupling of primary alcohols leading to esters catalyzed By 26.

R OH

R O

H

R O

OH

+ 2H2


Cat.−H2

Cat.−H2

R OH

R

R O

O

R

scHeme 2.21

CarBON–OxygeN BONd FOrmaTiON 49

including a carbon–oxygen bond formation and hydrogen transfer. The results are summarized in Table 2.14 [28]. When the reaction of benzaldehyde catalyzed by Ni(cod)

2 36 (1 mol%) and the free NHC 37 (1 mol%) was performed in toluene at

60 °C for 3 h, benzyl benzoate was obtained quantitatively (entry 1). Not only various aromatic aldehydes but also aliphatic aldehydes were applicable for this catalytic system.

The mechanism for NHC nickel complex catalyzed Tishchenko reaction is shown in Scheme 2.22 [28]. The oxidative cyclization of two aldehyde molecules with a zerovalent NHC nickel complex would be an important key step.

Furthermore, esterification by the cross-coupling of aliphatic aldehyde and aromatic aldehyde (crossed Tishchenko reaction) has been achieved (Table 2.15) [29]. For example, the reaction of cyclohexanecarbaldehyde with benzaldehyde catalyzed by Ni(cod)

2 36 (2 mol%) and the NHC ligand 38 (2 mol%) gave benzyl

cyclohexanecarboxylate in an excellent yield (entry 1). it should be noted that equimolar amount of the starting two aldehydes was employed in this catalytic system.

2.4.4 ruthenium complex with multidentate nHc ligand

The ruthenium complex 39 bearing a pincer-type pyridine-based NHC complex has been reported to be catalytically active for the dehydrogenative coupling of primary alcohols leading to esters [30]. The NHC ruthenium complex 39 effectively cata-lyzed the transformation of 1-butanol into butyl butanoate (Scheme 2.23).

Cat.

28 (1 mol%)

N

N

Bu

Bu

Ir Cl

Cl

AgOTf (3 mol%)

OH+ R–OH

OR

Entry Alcohol Temperature (ºC) Time (h) Yield (%)

Methanol

Ethanol

1-Butanol

Allyl alcohol

Isopropyl alcohol

110

110

130

110

110

12

12

2

12

12

88

>95

>95

85

80

1

2

3

4

5

taBle 2.13 dehydrative etherification of benzyl alcohol with alcohols catalyzed by 28.

ONi

OR

R

H

H

L

O

Ni

OR

R

H

L

H

O

O

R

R

H

HNi

L

R H

O

R

O

O R

H H

scHeme 2.22

R H

O

R

O

O R

H H2

Ni(cod)2 / NN

Cl Cl

iPr

iPr

iPr

iPr

Toluene, 60 ºC

Cat.

O

O

O

O

O

O

MeO OMe

O

O

MeO2C CO2Me

O

OO

tBu O tBu

>99% (Cat. 1 mol%, 3 h) 87% (Cat. 3 mol%, 24 h)

>99% (Cat. 2 mol%, 2 h) >99% (Cat. 2 mol%, 3 h, 80 ºC)

>99% (Cat.1 mol%, 1 h) >99% (Cat. 1 mol%, 1 h)

3637

taBle 2.14 Hydroacylation of aldehydes (Tishchenko reaction) catalyzed by 36 and 37.

Alk H

O

Alk

O

O Ar

H H

Ni(cod)2 / NN

iPr

iPr

iPr

iPr

Toluene

Cat.

Ar H

O+

Entry ProductCat.

(mol%)Temperature

(ºC)Time(h)

Yield(%)

Selectivity(%)

O

O

O

O

O

O

OMe

O

O

O

OtBu

O

O

2

2

2

4

4

10

40

40

40

50

50

23

4

4

4

2

2

12

94

94

87

92

61

75

94

94

87

94

99

93

1

2

3

4

5

6

3638

Table 2.15 Esterification by the cross-coupling of aliphatic aldehyde and aryl aldehyde catalyzed by 36 and 38.

N

NRuN

NMes

CO

H

Cat.

39 (1 mol%)

Toluene, 110 ºC, 3 hOH

O

O2 + 2H2

100%

scheme 2.23


reFerences

[1] a number of insightful reviews on the chemistry of N-heterocyclic carbene complexes of transition metals have been published: (a) Casin CSJ, editor. N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis. dordrecht/New york: Springer; 2011. (b) díez-gonzález S, editor. N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools. Cambridge: rSC publishing; 2011. (c) Herrmann Wa. angew Chem int ed 2002;41:1290. (d) peris e, Crabtree rH. Coord Chem rev 2004;248:2239. (e) Scott Nm, Nolan Sp. eur J inorg Chem 2005:1815. (f) Normand aT, Cavell KJ. eur J inorg Chem 2008:2781. (g) Hahn Fe, Jahnke mC. angew Chem int ed 2008;47:3122. (h) Corberán r, mas-marzá e, peris e. eur J inorg Chem 2009:1700. (i) Fortman gC, Nolan Sp. Chem Soc rev 2001;40:5151.

[2] edwards mg, Jazzar rFr, paine Bm, Shermer dJ, Whittlesey mK, Williams JmJ, edney dd. Chem Commun 2004:90.

[3] Burling S, paine Bm, Nama d, Brown VS, mahon mF, prior TJ, pregosin pS, Whittlesey mK, Williams JmJ. J am Chem Soc 2007;129:1987.

[4] ledger aeW, mahon mF, Whittlesey mK, Williams JmJ. dalton Trans 2009:6941.

[5] prades a, Viciano m, Sanaú m, peris e. Organometallics 2008;27:4254.

[6] Such a catalytic mechanism has been previously proposed in the carbon–carbon bond forming reactions between primary alcohols and secondary alcohols catalyzed by ruthe-nium and iridium complexes: (a) Cho CS, Kim BT, Kim H-S, Kim T-J, Shim SC. Organometallics 2003;22:3608. (b) Fujita K, asai C, yamaguchi T, Hanasaka F, yamaguchi r. Org lett 2005;7:4017.

[7] Viciano m, Sanaú m, peris e. Organometallics 2007;26:6050.

[8] mierde HV, Voort pVd, Vos dd, Verpoort F. eur J Org Chem 2008:1625.

[9] The Friedländer reaction is a base- or acid-catalyzed condensation of an aromatic 2-amino-substituted carbonyl compound with a carbonyl derivative containing a reactive α-methylene group followed by cyclodehydration. marco-Contelles J, perez-mayoral e, Samadi a, Carreiras mC, Soriano e. Chem rev 2009;109:2652.

[10] gnanamgari d, Sauer elO, Schley Nd, Butler C, incarvito Cd, Crabtree rH. Organometallics 2009;28:321.

[11] (a) da Costa ap, Viciano m, Sanaú m, merino S, Tejeda J, peris e, royo B. Organometallics 2008;27:1305. (b) da Costa ap, Sanaú m, peris e, royo B. dalton Trans 2009:6960.

[12] gong x, zhang H, li x. Tetrahedron lett 2011;52:5596.

[13] Kose O, Saito S. Org Biomol Chem 2010;8:896.

[14] Feng C, liu y, peng S, Shuai Q, deng g, li C-J. Org lett 2010;12:4888.

[15] prades a, peris e, albrecht m. Organometallics 2011;30:1162.

[16] Nordstrøm lU, Vogt H, madsen r. J am Chem Soc 2008;130:17672.

[17] ghosh SC, muthaiah S, zhang y, xu x, Hong SH. adv Synth Catal 2009;351:2643.

[18] zhang J, Senthilkumar m, gosh SC, Hong SH. angew Chem int ed 2010;49:6391.

[19] zhang y, Chen C, ghosh SC, li y, Hong SH. Organometallics 2010;29:1374.

[20] ghosh SC, Hong SH. eur J Org Chem 2010:4266.

[21] dam JH, Osztrovszky g, Nordstrøm lU, madsen r. Chem eur J 2010;16:6820.

[22] prades a, Corberán r, poyatos m, peris e. Chem eur J 2008;14:11474.

reFereNCeS 53

[23] liu S, rebros m, Stephens g, marr aC. Chem Commun 2009:2308.

[24] Ohta H, yuyama y, Uozumi y, yamada yma. Org lett 2011;13:3892.

[25] Chang y-H, Fu C-F, liu y-H, peng S-m, Chen J-T, liu S-T. dalton Trans 2009:861.

[26] zanardi a, mata Ja, peris e. Chem eur J 2010;16:10502.

[27] Sølvhøj a, madsen r. Organometallics 2011;30:6044.

[28] (a) Ogoshi S, Hoshimoto y, Ohashi m. Chem Commun 2010:3354. (b) dzik lJ, gooßen lJ. angew Chem int ed 2011;50:11047.

[29] Hoshimoto y, Ohashi m, Ogoshi S. J am Chem Soc 2011;133:4668.

[30] del pozo C, iglesias m, Sánchez F. Organometallics 2011;30:2180.

η4-CyClopentadienone/ η5-HydroxyCyClopentadienyl and related ligands in transition Metal Catalyzed Hydrogen transfer and deHydrogenative reaCtions

part ii


57

OxidatiOn and HydrOgenatiOn Catalyzed by transitiOn Metal COMplexes bearing η4-CyClOpentadienOne/ η5-HydrOxyCyClOpentadienyl and related ligands

3

3.1 intrOduCtiOn

The main subjects discussed in this chapter are oxidation of alcohols and amines and hydrogenation of polar unsaturated bonds such as C5O and C5N bonds based on the hydrogen transfer catalyzed by transition metal complexes bearing η4-cyclopentadienone/ η5-hydroxycyclopentadienyl and related ligands. In 1986, the structure of the catalyst in several oxidation and hydrogenation reactions was revealed to be a dimeric ruthenium complex, [(η5-Ph

4C

4CO)

2H]Ru

2(μ-H)(CO)

4 (1) (so-called Shvo’s catalyst).

Furthermore, it has been found that the complex 1 dissociates to two monomeric complexes, an unsaturated 16-electron complex, (η4-Ph

4C

4CO)Ru(CO)

2 (2), and a

saturated 18-electron complex, (η5-Ph4C

4COH)RuH(CO)

2 (3), which are the active

catalytic species (Scheme 3.1, the 1st equation) [1]. The interconversion between the complexes 2 and 3 readily takes place in the presence of hydrogen donors (reductant) (AH

2) such as H

2 and alcohols or hydrogen acceptors (oxidant) (A) such as O

2 and

ketones (Scheme 3.1, the 2nd equation). Since then, tremendous amounts of catalytic reactions using the complex 1 and analogous complexes have been reported [2]. This chapter describes the recent progress in the last decade (since 2000) of catalytic oxidation and hydrogenation reactions using transition metal complexes bearing

58 OxIdATION ANd HydROgeNATION CATAlyzed by TRANSITION meTAl COmPlexeS

η4-cyclopentadienone/η5-hydroxycyclopentadienyl and related ligands. As mentioned in the preface, asymmetric reactions including dynamic kinetic resolution (dKR) are not discussed [3].

There have been two modified synthetic methods of the complex 1 and its analogues (Scheme 3.2). The first one is the two-step process: the reaction of Ru

3(CO)

12 with

tetracyclones (2,3,4,5-tetraaryl-2,4-cyclopentadienone) in mesitylene gives (η4-Ar

4C

4CO)Ru(CO)

3, which is treated with aq. Na

2CO

3 in acetone to furnish the desired

complexes [4a, 4b]. The second one is more convenient: the mixture of Ru3(CO)

12

and tetracyclones in meOH is simply refluxed to afford the desired complex 1 via [(η5-Ar

4C

4CO)Ru(CO)

2]

2 (a) [4c, 4d].

Ru

O

Ph

PhPh

Ph

Ru

O

Ph

PhPh

Ph

HOCCO CO

CO

H

Ru

O

PhPh

PhPh

OCOC

Ru

HO

Ph Ph

PhPh

HCO

CO

∆+

12 3

2 3

[AH2]Hydrogen donor (reductant)

H2, Me2CHOH, etc.

[A]Hydrogen acceptor (oxidant)

O2, Me2C=O, etc.

sCHeMe 3.1

Ru

O

Ar

ArAr

Ar

Ru

O

Ar

ArAr

Ar

HOCCO CO

CO

H

O

OCOC

Ru3(CO)12 +

CO

O

ArAr

ArAr

CH3OHreflux Na2CO3 aq.

Acetone, rt

Mesitylenere�ux

1

Ru

O

ArAr

ArAr

RuAr Ar

ArAr

COOC

Ar

OAr

Ar

ArRu

COCO

Heptanereflux

MeOH

A

sCHeMe 3.2

OxIdATION OF AlCOHOl bASed ON HydROgeN TRANSFeR 59

3.2 OxidatiOn Of alCOHOl based On HydrOgen transfer and deHydrOgenatiOn

The oxidation of alcohols to carbonyl compounds such as aldehydes and ketones is one of the most fundamental organic transformations. Since classical methods have usually used a stoichiometric amount of harmful heavy metals such as Cr, mn, etc. as the oxidants to leave much of poisonous wastes, these processes are undesirable from the viewpoint of green chemistry. Nowadays, much more attention has been paid to catalytic hydrogen transfer oxidations using greener oxidants such as oxygen or air (aerobic oxidation), hydrogen peroxide, and harmless carbonyl compounds (usually acetone, so-called Oppenauer-type oxidation) [5]. This section describes the recent development of homogeneous catalytic oxidations catalyzed by 1 and the related complexes.

3.2.1 Catalytic Cycle

A general catalytic cycle for the oxidation of alcohols catalyzed by the complex 1 with a hydrogen acceptor (oxidant) is shown in Scheme 3.3: 1) the ruthenium dimer complex 1 dissociates to the unsaturated ruthenium (0) complex 2 and the saturated ruthenium (II) complex 3, 2) hydrogen transfer from an alcohol to 2 gives a carbonyl compound and the complex 3, and 3) hydrogen transfer from 3 to a hydrogen acceptor (oxidant) [a] regenerates the active catalytic species 2. Thus, the hydrogen transfer plays important roles in this catalytic cycle [6].

There have been many reports and discussions on the mechanism of the hydrogen transfer step [2c]. The kinetic isotope effect experiments have been conducted, and these results suggest the hydrogen transfer process proceeds in a concerted manner [4c, 7a, 7b]. Two mechanisms for the concerted hydrogen transfer step have been proposed. The first one is the so-called inner-sphere mechanism (Scheme 3.4a): the coordination of an alcohol to the metal center of the complex 2 would occur at first, and then the β-elimination and hydrogen transfer could proceed simultaneously through η4–η2 ring slippage forming the vacant site for the β-elimination (η2-complex) [7a].

The second one is the so-called outer-sphere mechanism (Scheme 3.4b): the hydrogen transfer from an alcohol to the complex 2 could take place in a single step without the precoordination (TS) [7b]. The theoretical calculation studies have sup-ported that the outer-sphere mechanism is energetically more favorable [7c,7d]. Thus, the hydrogen transfer process proceeds very smoothly by the metal–ligand

∆1 2 3

R1 R2 R1 R2

OH O

+

[A]Hydrogen acceptor

(oxidant)

[AH2]

Hydrogen transfer

Hydrogen transfer

sCHeMe 3.3


cooperative catalysis of the complex 2: the lewis acidic metal center accepts hydride of the C–H bonds and the lewis basic carbonyl group of the ligand does proton of the O–H bond. These catalytic cycles are reversible, and the hydrogenation of car-bonyl compounds proceeds in an anticlockwise direction (Section 3.4.1).

3.2.2 aerobic Oxidation of alcohol Catalyzed by 1 with a Combination of 1,4-benzoquinone and Co Complex

It has been reported that a biomimetic catalyst combination of 1, electron-rich 2,6-dimethoxy-1,4-benzoquinone (dmbQ), and the cobalt–salen complex (i) efficiently

sCHeMe 3.4b

Ru

O

PhPh

PhPh

OCOC

O

H

R2R1

Ru

O

PhPh

PhPh

OCOC

O

HRu

Ph

Ph Ph

OHPh

COOC H

OH

RR1 R2

H

H

O

R2R1 R2R1

[A]

[AH2]

2

3

Ru

O

PhPh

PhPh

OCOC

η3 to η5

η4 to η3

Ru

O

PhPh

PhPh

OCOC

O

H

R2R1

H

η2-complex

OH

R1 R1R2 R2

Ru

Ph

Ph Ph

OHPh

COOC H

O

[AH2] [A]32

Ru

O

Ph

PhPh

Ph

OCOC

O

H

H

R1 R2

Ru

O

PhPh

PhPh

OCOC

TS

sCHeMe 3.4a


catalyzes the aerobic oxidation of secondary alcohols [8a, 8b]. The reactions were carried out using 1, dmbQ, and i under air in toluene at 100 °C. Some examples are shown in Table 3.1. A variety of secondary alcohols including aliphatic and alicyclic ones were oxidized to the corresponding ketones in good to high yields. The isolated C5C double bond was tolerated.

The catalytic cycle for this biomimetic aerobic oxidation is proposed (Scheme 3.5). As mentioned earlier, the initial dissociation of 1 generates 2 and 3, and the former acts as an active catalytic species. The dehydrogenation of alcohols with 2 produces ketones and 3, which is oxidized with dmbQ to regenerate 2 with concomitant

R1 R2

OH

Cat. 1 (0.5 mol%),DMBQ (20 mol%)

Co complex I (2 mol%)

R1 R2

O

Toluene, 100 ºCUnder air, 1 – 2.8 h

OCo

N

O

NN

I

Entry Product Yield (%)

O

O

C4H93

O

O


1

2

34

89

88

8192

PhCOMe

PhCOCO2MeC6H13COEt

5

6

7

92

88

92

table 3.1 Aerobic oxidation of secondary alcohols catalyzed by 1 with dmbQ and Co complex i.

R1 R2

OH

R1 R2

O O

O

MeO OMe

DMBQ

I

∆+1 2 3

OH

OH

MeO OMe

DMHQ

2

3 [CoL]

[CoL]ox

Iʹ

1/2O2

H2O

sCHeMe 3.5


formation of 2,6-dimethoxy-1,4-hydroquione (dmHQ). Finally, the reoxidation of dmHQ to dmbQ by air is mediated by the Co complex i. This catalytic cascade resembles the biological dehydrogenation of alcohols by means of the NAd+/NAdH–ubiquinone–cytochrome c electron transfer system.

more efficient aerobic catalytic oxidation has been developed by combining the two catalyst components, quinone (hydroquinone) and Co(salen) complex, into one hybrid catalyst component [8c]. The reactions were carried out using 1 and a hybrid Co(salen) complex (ii) having hydroquinone moiety under air in meCN at 75 °C. Several examples are shown in Table 3.2. A variety of secondary alcohols including aliphatic and alicyclic ones were oxidized to the corresponding ketones in good to high yields. The lower cocatalyst loading (1 mol%) and lower reaction temperature (75 °C) are advantageous as compared with the aforementioned catalytic system (Table 3.1), though longer reaction time (9–17 h) is required.

3.2.3 Oppenauer-type Oxidation of alcohol

3.2.3.1 The Complex 1 The Oppenauer-type oxidation of secondary alcohols including 3β-hydroxysteroids catalyzed by 1 in the presence of K

2CO

3 using acetone as

the oxidant was reported before 2000 [9a, 9b]. After that, it has been reported that the Oppenauer-type oxidation of sugars catalyzed by 1 using cyclohexanone as the oxidant affords δ-lactones selectively [9c]. The reactions were carried out in cyclohexanone with or without dmF. examples are shown in Table 3.3. Instead of the thermody-namically more stable γ-lactones, the less stable δ-lactones were obtained selec-tively. It should be noted that δ-d-galactonolactone can be isolated for the first time (entry 2).

3.2.3.2 Fe Complexes with η4-Cyclopentadienone/η5-Hydroxycyclopentadienyl Ligands It has been reported that an Fe(CO)

3 complex (4) bearing 2,3,4,5-tetraphe-

nyl-2,4-cyclopentadienone catalyzes the Oppenauer-type oxidation of secondary benzylic alcohols using acetone as the oxidant [10a], although the reactions were

R1 R2

OHCat. 1 (0.5 mol%),

Co complex II (1 mol%)

R1 R2

O

MeCN, 75 ºC, under air, 9–17 h


12345

9296878493

OCo

N

O

NN

OH

HO

HO

OHII

PhCOMe4-MeOC6H4COMe4-CF3C6H4COMe

PhCOCO2MeC6H13COMe

table 3.2 Aerobic oxidation of secondary alcohols catalyzed by 1 with Co complex ii.


rather sluggish and a large amount of 4 and long reaction time were needed. examples are shown in Table 3.4. Addition of H

2O (d

2O) increased the yield (entry 2), and it

was proposed that hydrolysis of one CO ligand would generate a 16-electron unsat-urated active species.

An FeH(CO)2 complex (5) bearing a bicyclic η5-hydroxycyclopentadienyl ligand

catalyzed the Oppenauer-type oxidation of alcohols using acetone as the oxidant [10b]. The complex 5 was already synthesized via a [2 + 2 + 1] cycloaddition of 1,8-bistri-methylsilylocta-1,7-dyne and CO mediated by Fe(CO)

5 [10c,10d]. The reactions

were carried out in acetone at 60 °C. Some examples are shown in Table 3.5. A variety of functional groups including C5C double bond were survived. It should be noted

Method ACat. 1 (1.25 mol%)

Cyclohexanone, DMF21 ºC, 87 h

Entry

O

R3

R4

HO

R1

R2

OH

OH

O

HO

HHO

OHOH

OH

Sugarδ-lactone

Method BCat. 1 (1.25 mol%)

Cyclohexanone45 ºC, 16 h

O

R3

R4

HO

R1

R2

OH

O R6

R5

HO R1O

O

R2

OH

HO O

OHOH

HO O

OHOH

γ-lactone

+

Sugar

O

O

OH

Method Yield (%)

OHO

HOOH

OH

OH

D-Glucose

D-Galactose

OHO

HOOH

OH

O

δ-Lactone γ-Lactone

(99.9 : 0.1)

(Ratio)

O

HO

HHO

OH

OH

O

(93 : 7)

1

2

B

A

86

54

δ-D-Galactonolactone

table 3.3 Oppenauer-type oxidation of sugars catalyzed by 1 to give δ-lactones.

Cat. 4

Acetone-d6

Fe

O

PhPh

PhPh

OCOC

4

CO

Entry Cat. 4 (mol %)R Temperature (ºC)

Time (d) Yield (%)

12a

HMeO

1020

5480

44

3852

a D2O (100 mol%) was added.

R CH(OH)Me R COMe

table 3.4 Oppenauer-type oxidation of alcohols catalyzed by 4.


that the C5C double bond in 3β-hydroxysteroid did not migrate (entry 6) in contrast to the reaction using 1 as the catalyst [9b]. The trimethylsilyl (TmS) substituents on the cyclopentadienyl ring are essential for the high catalytic activity. It is pro-posed that the bulky TmS groups may prevent decomposition of the complex 5 by loss of H

2 through the intermolecular interaction between the hydride and the

hydroxy moieties.While the complex 5 is air and moisture sensitive, an Fe(CO)

3 complex (6) bearing

a bicyclic η4-2,4-cyclopentadienone ligand prepared before [10c] is stable in air. The complex 6 exhibits the high catalytic activity for the Oppenauer-type oxidation when activated with me

3NO · H

2O to remove CO, generating the 16-electron unsaturated

active species similar to 2 [10e]. The reactions were carried out in the presence of me

3NO · H

2O in acetone under reflux. Several examples are shown in Table 3.6.

Although secondary benzylic and allylic alcohols were oxidized to the corresponding ketones in good to high yields, the oxidation of aliphatic alcohol gave a lower yield (entry 5).

It has been reported that an air-stable Fe(CO)2(meCN) complex (7) bearing the

bicyclic η4-2,4-cyclopentadienone ligand catalyzes the Oppenauer-type oxidation of alcohols without any additive such as me

3NO [10f]. The reactions were conducted in

acetone at 90 °C. Several examples are shown in Table 3.7. The oxidation of an allylic alcohol with a terminal alkene gave mainly a saturated ketone due to alkene isomer-ization (entry 6).

A couple of Fe(CO)3 complexes (8) bearing bicyclic 2,4-cyclopentadienone

ligands were synthesized, and their catalytic activities for the Oppenauer-type oxidation were compared with those of the complexes 4 and 6 [10 g]. The reactions were carried out using 4, 6, or 8 in the presence of H

2O or me

3NO · H

2O.

Some examples are shown in Table 3.8. Among the complexes examined, the

Entry Yield (%)

1234

5

FeTMS

OHTMS

CO

5OC HR1 R2

OH Cat. 5 (3 mol%)

R1 R2

O

Acetone, 60 ºC, 12–24 h

PhCOMe4-BrC6H4COMe

4-MeOC6H4COMe4-CF3C6H4COMe

Product

Ph

O

H

OH H

R

R = (CH2)3CHMe2

91908688

87

Entry Yield (%)Product

6 72



complex 4 exhibited the higher catalytic activity in the both reaction conditions. Addition of H

2O increased the conversions (entries 1 and 2). Use of me

3NO · H

2O

for decarbonylative activation of the complexes significantly accelerated the reactions (entries 5–7). Although the Oppenauer-type oxidation using parafor-maldehyde as the hydrogen acceptor was examined, formate esters were mainly produced.

3.2.3.3 Heterobimetallic Rh–Ru Complex with η4-Cyclopentadienone Ligand It has been reported that a heterobimetallic Rh(I)–Ru(II) complex [(η4-Ph

4C

4CO)Rh(μ-

Cl)3RuCl

2(PPh

3)

2(acetone)] (9) exhibits the high catalytic activity for the Oppenauer-

type oxidation of alcohols [11]. The reactions were conducted with low catalyst loading (0.1–0.5 mol%) of 9 in the presence of K

2CO

3 in acetone at room tempera-

ture. Several examples are shown in Table 3.9. A variety of secondary and primary alcohols were oxidized in moderate to high conversions.

Entry Yield (%)

123

FeTMS

OTMS

CO

6

OC COR1 R2

OH Cat. 6 (10 mol%)Me3NO⋅H2O (10 mol%)

R1 R2

O

Acetone, reflux, 18 h

PhCOMe4-MeOC6H4COMe

4-FC6H4COMe

Product

929469


4

5

87

42

Ph

O

C6H13COMe


Entry Yield (%)

a C6H13CH(OH)CH=CH2 was used as the substrate.

1234

FeTMS

OTMS

CO

7OC NCMe

R1 R2

OH Cat. 7 (5 mol%)

R1 R2

O

Acetone, 90 ºC, 18 h

PhCOMe4-MeOC6H4COMe

4-FC6H4COMe(E)-PhCH=CHCOMe

Product

93999299


56a

9169

MeCHPhCH2COMeC6H13COCH2CH3 (94%)C6H13COCH=CH2 (6%)



3.2.4 Oxidation of alcohol with Other Oxidants

3.2.4.1 Ru Complex with Hydroxycyclopentadienyl Ligand An RuCl(CO)2

complex (10) bearing η5-hydroxycyclopentadienyl ligand, prepared by treatment of 1 with CHCl

3 containing etOH, catalyzed oxidation of alcohols using CHCl

3 as the

oxidant [12]. The reactions were carried out in the presence of Na2CO

3 in CHCl

3 at

90 °C. Some examples are shown in Table 3.10. Various secondary and benzylic alcohols were oxidized in high yields.

3.2.4.2 Iodine-Bridged Bimetallic Ru Complexes with Hydroxycyclopentadienyl and Cyclopentadienone Ligands It has been reported that iodine-bridged bimetallic ruthenium complexes (11a and 11b) catalyze the oxidation of alcohols using Ag

2O as

the oxidant [13]. The reactions were carried out in the presence of Ag2O in CH

2Cl

2 at

Entry Cat.

R1 R2

OH Cat. (10 mol%)Additive

R1 R2

O

Acetone

R1 Conversion (%)R2

1234567

PhPhPhPhPhPh

4-MeOC6H4

MeMeMeMeMeMeH

44

8a–8c8d644

6395

TraceTrace

619988

FeR4

OPh

CO8a: R3 = H, R4 = Ph8b: R3 = Me, R4 = Ph8c: R3 = Me, R4 = TMS

O

OC COFe

TMS

OTMS

CO

(tBoc)N

OC CO

8d

R3

Temperature (ºC) TimeAdditive (mol%)

–H2O (1000)

H2O (1000)H2O (1000)

Me3NO⋅2H2O (10)Me3NO⋅2H2O (10)Me3NO⋅2H2O (10)

80808080606060

4 d4 d2 d2 d24 h24 h5 h

table 3.8 Oppenauer-type oxidation of alcohols catalyzed by 4, 6, or 8.

Entry Cat. 9 (mol%)

R1 R2

OHCat. 9 (0.1–0.5 mol%), K2CO3 (100 mol%)

R1 R2

O

Acetone, rt, 6–24 h

Conversion (%)

12345

PhPh

C6H13

0.50.10.10.50.5

Rh

Cl

Cl

Cl

Ru

Ph

Ph

Ph

Ph

O

9

PPh3

PPh3

O

Time (h)R1 R2

MeMeMe

H–(CH2)6–

4-MeOC6H4

624242424

947877

>9990

table 3.9 Oppenauer-type oxidation of alcohols catalyzed by a hetrobimetallic complex 9.

OxidatiOn Of alcOhOl Based On hydrOgen transfer 67

room temperature. a few examples are shown in table 3.11. the complex 11a showed higher catalytic activity than 11b.

3.2.5 Dehydrogenative Oxidation of Alcohol without Oxidant

the dehydrogenative oxidation of secondary alcohols to ketones catalyzed by 1 without oxidant or hydrogen acceptor was briefly reported in 1985 (at that time, the structure of 1 was not confirmed) [14a]. after almost 20 years, more precise investigation was reported [14b]. the dehydrogenative oxidation of 1-phenylethanol catalyzed by 1 was carried out in various solvents. examples are shown in table 3.12. the reaction in refluxing octane (bp. 126 °c) gave acetophenone in 98% yield, whereas that in refluxing benzene (bp. 80 °c) gave the product in 50% yield after 24 h. in addition, the siO

2-supported heteroge-

neous catalyst containing the structure of 1 showed higher catalytic activity than 1.

R1 R2

OH Cat. 10 (2–4 mol%), Na2CO3 (150 mol%)

R1 R2

O

CHCl3, 90 ºC, 6–20 h

Entry Product Yield (%) Entry Product Yield (%)

123

456

989996

PhCOMe4-MeOC6H4COMe

4-ClC6H4COMe

Ru

HOPh Ph

PhPh

Cl COCO

10

C6H13COMeMe2C=CH(CH2)2COMe

PhCHO

999987

TAble 3.10 Oxidation of alcohols catalyzed by 10 with chcl3.

Ru

OH

R

PhPh

R

Ru

O

R

PhPh

R

IOCCO CO

CO

R1 R2

OH Cat. 11 (2 mol%)Ag2O (100 mol%)

R1 R2

O

CH2Cl2, rt


123

>99>9993

PhCOMeC6H13COMe

PhCHO

11a: R = Ph11b: R = Me

Time (h)

433

Cat. 11aYield (%)

868588

Time (h)

101010

Cat. 11b

TAble 3.11 Oxidation of alcohols catalyzed by 11 with ag2O.

Ph Me

OH Cat. 1 (4 mol%)

Ph Me

O

Solvent, reflux

Entry Yield (%)Time (h)Solvent

123

C6H6C8H18PhMe

2499

509889

+ H2

TAble 3.12 dehydrogenative oxidation of 1-phenylethanol catalyzed by 1.


3.3 OxidatiOn Of aMine based On HydrOgen transfer

Oxidation of amines to imines is a very important chemical transformation, especially for synthesis of biologically active organic molecules including pharmaceuticals [15]. This section describes the recent development of oxidation of amines using transition metal complexes bearing η4-cyclopentadienone/η5-hydroxycyclopentadienyl and related ligands.


A general catalytic cycle (Scheme 3.6) is almost the same as that for the oxidation of alcohols catalyzed by 1 with hydrogen acceptors (oxidants) (Scheme 3.3): (1) the ruthenium dimer complex 1 dissociates to the unsaturated ruthenium complex 2 and the saturated ruthenium complex 3, (2) hydrogen transfer from an amine to 2 gives an imine and the complex 3, and (3) hydrogen transfer from 3 to a hydrogen acceptor (oxidant) regenerates the active catalytic species 2.

3.3.2 Oxidation of amines Catalyzed by 1 and related Complexes

3.3.2.1 The Complex 1 It has been reported that the complex 1 catalyzes oxidation of secondary N-arylamines using dmbQ as a hydrogen acceptor [16a]. The reactions were carried out in the presence of dmbQ (150 mol%) in toluene under reflux to give the corresponding imines in good to high yields. examples are shown in Table 3.13. electron-donating substituents accelerated the reactions.

Similarly, a catalyst combination of the complex 1 and dmbQ successfully oxi-dized amines using mnO

2 as the final oxidant [16a]. The reactions were conducted in

the presence of mnO2 (150 mol%) in toluene under reflux to give the corresponding

imines in good to high yields. A few examples are shown in Table 3.14. The reactions proceeded slower than the aforementioned.

A catalytic cycle is proposed (Scheme 3.7) [16a]. At first, the dissociation of the complex 1 generates the complexes 2 and 3 (vide supra). The complex 2 dehydroge-nates an amine to give an imine with concomitant formation of the complex 3, which

∆1 2 3

R1 R2

NHR3

R1 R2

NR3

+

[A][AH2]Hydrogen aceptor

(oxidant)

Hydrogen transfer

Hydrogen transfer

sCHeMe 3.6

OxIdATION OF AmINe bASed ON HydROgeN TRANSFeR 69

is oxidized by dmbQ to regenerate the complex 2. When the catalytic amount of dmbQ and a stoichiometric amount of mnO

2 are used, the resulting 1,4-hydroquinone

dmHQ is oxidized by mnO2 to produce dmbQ. Kinetic deuterium effects and race-

mization studies suggest that the rate-determining step is a β-hydrogen elimination of coordinated amine and that the hydrogen transfer from amine to the oxygen of 2,4-cyclopentadienone ligand is not a concerted reaction [16b].

2

3

R1

NHR2

R1

NR2

MnO2

DMBQ

DMHQ

sCHeMe 3.7

R1

NHR2 Cat. 1 (2 mol%)DMBQ (150 mol%)

R1

NR2

O

O

MeO OMe

DMBQ

Entry R1 Yield (%)R2 Time

1234

Ph4-FC6H4

4-MeC6H4Ph

PhPhPh

4-MeOC6H4

70719595

5622

Toluene, re�ux

table 3.13 Oxidation of secondary N-arylamines catalyzed by 1 using dmbQ as a hydrogen acceptor.

R1

NHR2

R1

NR2

Entry R1 Yield (%)R2

1234

Ph4-FC6H4

4-MeOC6H4Ph

PhPhPh

2-MeC6H4

76709490

Cat. 1 (2 mol%), DMBQ (20 mol%), MnO2 (150 mol%)


table 3.14 Oxidation of secondary N-arylamines catalyzed by 1 and dmbQ using mnO

2 as the final oxidant.


3.3.2.2 Various Related Ru Complexes The catalytic activities of ruthenium complexes 1, 12, and 4 were compared in the dehydrogenative oxidation of amines using dmbQ as the hydrogen acceptor [16c], since the catalytically active species 2 can be also generated from the dimeric complex 12 [4c] or the complex 4. The oxidation of N-4-methoxyphenyl-1-phenylethylamine was conducted in the presence of dmbQ (150 mol%) in toluene at 110 °C. Some examples are shown in Table 3.15. The complexes 1 and 12 exhibited much higher catalytic activity than the complex 4. It should be noted that (p-cymene)Ru(NTsCHPhCHPhNH

2) and RuCl

2(PPh

3)

3, good

hydrogenation catalysts for transfer hydrogenation of imines, show very low activities.

Thus, the dehydrogenative oxidation of various N-arylamines was carried out using 12 as a catalyst under the conditions similar to the aforementioned. examples are shown in Table 3.16. The reactions of 1-phenethylamines gave the corresponding imines in good to high yields.

1 (Y = 97%)4 (Y = 33%)

Ph

NHC6H4OMe-4 Cat. (2 mol%), DMBQ (150 mol%)

Ph

NC6H4OMe-4

Ru

O

PhPh

PhPh

COOC

Ph

OPh

Ph

PhRu

COCO

12 (Y = 95%)

RuCl2(PPh3)3


(Y = 10%)

(Y = 5%)Ru

NH2

TsN Ph

Ph

table 3.15 Oxidation of N-4-methoxyphenyl-1-phenylethylamine catalyzed by various Ru complexes in the presence of dmbQ.

R1R1 R2

NHR3

R1 R2

NR3


1234

4-MeOC6H4Ph

4-MeOC6H4Ph

MeMeMeMe

Cat. 12 (2 mol%), DMBQ (150 mol%)

R3

4-MeOC6H42-MeC6H4

PhPh

>95879068


table 3.16 Oxidation of N-arylamines catalyzed by 12 in the presence of dmbQ as a hydrogen acceptor.

HydROgeNATION ANd TRANSFeR HydROgeNATION OF CARbONyl COmPOUNdS 71

Furthermore, aerobic dehydrogenative oxidation of amines was accomplished using a biomimetic catalyst combination of 12, dmbQ, and the Co(salen) complex (i) [16c]. The reactions were carried out under a moderate stream of air in toluene at 110 °C. Several examples are shown in Table 3.17. A variety of benzylic and non-benzylic N-arylamines were dehydrogenated to the corresponding imines in good to high yields, whereas the formation of the aldimine required longer reaction time (entry 4). The air stream would remove the water formed, preventing hydrolysis of resulting imines.

3.4 HydrOgenatiOn and transfer HydrOgenatiOn Of CarbOnyl COMpOunds

The reduction of carbonyl compounds such as aldehydes and ketones to alcohols is one of the most fundamental organic transformations. Since conventional methods have usually used a stoichiometric amount of metal hydrides such as liAlH

4 and

NabH4 as the reducing agents to leave much of harmful wastes, these processes are

undesirable from the viewpoint of green chemistry. Nowadays, much more attention has been paid to catalytic hydrogenation based on hydrogen transfer using greener reductants such as hydrogen, harmless alcohols (usually 2-propanol), and formic acid [2b, 6, 17]. This section describes the recent development of catalytic hydroge-nation and transfer hydrogenation catalyzed by 1 and the related complexes, though asymmetric reactions are not included.


A general catalytic cycle for the hydrogenation of carbonyl compounds catalyzed by 1 with a hydrogen donor (reductant) (Scheme 3.8) is the reverse of that shown earlier in the oxidation of alcohols (Scheme 3.3): (1) the ruthenium dimer complex 1 disso-ciates to the unsaturated ruthenium complex 2 and the saturated ruthenium complex 3,

R1 R2

NHR3

R1 R2

NR3


12345

4-MeOC6H4Ph

4-MeOC6H4Ph

C5H11

MeMeMeH

Me

6126

2412

Cat. 12 (2–4 mol%), DMBQ (20 mol%)Co complex I (2 mol%)

R3 Time (h)

4-MeOC6H42-MeC6H4

PhPhPh

9095889976

Air stream, toluene, 110 ºC

OCo

N

O

NN

I

table 3.17 Aerobic oxidation of N-arylamines catalyzed by 12 with dmbQ and Co complex i.


(2) hydrogen transfer from 3 to a carbonyl compound gives an alcohol and the com-plex 2, and (3) hydrogenation of 2 with a hydrogen donor (reductant) regenerates the active catalytic species 3. Thus, the hydrogen transfer steps play important roles [6].

As mentioned earlier (Section 3.2.1), there have been many reports on the mech-anism of the hydrogen transfer step, and two mechanisms for the hydrogen transfer step have been proposed (Scheme 3.4) [2c]. In the inner-sphere mechanism (Scheme 3.4a), the hydrogenation of carbonyl compounds starts by coordination of a carbonyl compound to the metal center of the complex 3 (the bottom of the catalytic cycle) and proceeds in an anticlockwise direction [7a]. In the outer-sphere mecha-nism (Scheme 3.4b), the hydrogen transfer takes place from the complex 3 to car-bonyl compounds in a single step without the precoordination [7b]. The theoretical calculation studies have supported that the outer-sphere mechanism is energetically more favorable [7c, 7d].

3.4.2 Hydrogenation of aldehyde and Ketone with Hydrogen

3.4.2.1 The Complex 1 and Related Ru Complexes The hydrogenation of aldehydes and ketones catalyzed by 1 was firstly reported in 1985 (at that time, the structure of 1 was not confirmed), although the reactions were conducted at high reaction temperature (145°C) under high H

2 pressure (34 atm) [18a].

The high temperature is required for the dissociation of 1 to the monomeric complexes 3 and 2, and the active species 3 is rather unstable. It has been reported that an RuH(CO)PPh

3 complex (13a) bearing η5-(2,5-diphenyl-3,4-ditolyl)- hydroxy-

cyclopentadienyl ligand is synthesized as a stable monomeric complex and exhibits high catalytic activity for the hydrogenation of benzaldehyde under milder conditions [18b]. The reactions were carried out under H

2 in toluene. A few examples are shown

in Table 3.18. The H2 pressure did not affect the rate of hydrogenation (entries 2 and

3), indicating that the rate-determining step would be the hydrogen transfer from 13a to benzaldehyde. Propanal was also hydrogenated under the similar conditions earlier. Furthermore, it has been revealed that the complex 13a shows higher catalytic activity and chemoselectivity in catalytic hydrogenation of benzaldehyde over acetophenone than the analogous dimeric ruthenium complex [(η5-2,5-Ph

2-3,4-Tol

2-C

4CO)

2H]-

Ru2(μ-H)(CO)

4 that generates the monomeric active species 13b [18c].

∆1 3 2

R1 R2

O

R1 R2

OH

+

[A] [AH2]

Hydrogen donor(reductant)

Hydrogen transfer

Hydrogen transfer

sCHeMe 3.8


A couple of RuH(CO)2 complex (14) bearing bicyclic η5-(2,5-TmS)-hydroxy-

cyclopentadienyl ligands were synthesized, and their catalytic activities were com-pared with those of the analogous Fe complex 5 (Section 3.2.3.2) and the complexes 13 mentioned earlier [18d]. The hydrogenation of benzaldehyde and acetophenone were carried out using 14 or 5 under H

2 in toluene at 25 °C. Some examples are shown

in Table 3.19. As shown in the table, the complexes 14 exhibited the high catalytic activity under low H

2 pressure (3 atm) at low temperature (25 °C). The complex 5

showed the comparable activity.The relative catalytic activities of the ruthenium complexes including 13a and 13b

for the hydrogenation of benzaldehyde were 14a ~ 14b > 13a ≫ 13b, and this order was not consistent with their relative activities for the stoichiometric reduction (14a > 13b ≫ 13a) [18d]. The reasons for the high catalytic activities of the complexes 14 would be as follows: (1) the hydrogen transfer from 14 to aldehydes and ketones pro-ceeds rapidly, and (2) the formation of the inactive dimeric hydride-bridging complex could be prevented by the bulky TmS substituents. A two-step process for the hydrogen transfer was proposed by kinetics and NmR studies (Scheme 3.9): (1) fast and reversible hydrogen bond formation between the OH group of 14a and the carbonyl oxygen and (2) slow hydrogen transfer of proton and hydride from 14a to the carbonyl group.

Ph H

O Cat. 13a, H2

Ph OHToluene

Ru

OH

PhTol

TolPh

LOC H

13a: L = PPh313b: L = CO

Entry Cat. 13a (mol%) Temperature (°C) k (10–3M–1s–1)

123

0.820.590.54

224545

351135

7.02931

H2 (atm)

table 3.18 Hydrogenation of benzaldehyde catalyzed by 13a with H2.

Ph R

O Cat. (2 mol%), H2 (3 atm)

Toluene, 25ºC

Entry Cat.

123456

HHH

MeMeMe

14a14b

514a14b

5

111

202420

919290808383

RuTMS

OHTMS

CO14b

OC HRu

TMS

OHTMS

CO14a

OC H

O

Ph R

OH

R Time (h) Yield (%)

table 3.19 Hydrogenation of benzaldehyde and aetophenone catalyzed by 14 or Fe complex 5.


3.4.2.2 Fe Complex Prior to the catalytic hydrogenation using the ruthenium complexes 14 discussed earlier, the analogous iron complex 5 (Section 3.2.3.2) was reported to exhibit the high catalytic activity of hydrogenation of benzalde-hyde and various ketones [19a]. The reactions were carried out under very mild conditions (3 atm of H

2 at 25 °C) in toluene. Some examples are shown in Table 3.20.

benzaldehyde was hydrogenated faster than ketones. A variety of functional groups including isolated C 5 C double and C ≡ C triple bonds were tolerated. The elec-tron-deficient ketones were hydrogenated very fast. As mentioned earlier, the formation of the inactive dimeric hydride-bridging complex could be prevented by the bulky TmS substituents, keeping the active monomeric structure of 5 in the

14aRu

TMS

OTMS

COOC H

OPh R

OH

OPh

R

RuTMS

OTMS

COOC

OH

O

HPh

R

RuTMS

OTMS

COOC

O

Ph R

OH

H2 Hydrogen transferSlow

sCHeMe 3.9

R1 R2

O Cat. 5 (2 mol%), H2 (3 atm)

Toluene, 25 °C

Entry

123456a

PhPh

4-NO2C6H4Ph

CH2=CHCH2CH2

HMeMeCF3MeMe

1206

0.173624

908389918757

a The reaction was carried out in EtOEt.

R1 R2

OH

R1 Time (h) Yield (%)R2

C)C6H44-(HOCH2CH2C

FeTMS

OHTMS

CO5

OC H

table 3.20 Hydrogenation of aldehydes and ketones catalyzed by 5.


catalytic cycle. Precise mechanistic studies and theoretical calculations were also reported [19b, 19c].

3.4.3 transfer Hydrogenation of aldehyde and Ketone with 2-propanol

3.4.3.1 Ru Complex It has been reported that the complexes 1 and 12 efficiently catalyze transfer hydrogenation of cyclic 1,3-diketones in contrast with much lower activities of (p-cymene)Ru(NTsCHPhCHPhNH

2) and RuCl

2(PPh

3)

3 [20]. Since the

complex 1 was readily synthesized as compared with the complex 12, the reactions were carried out using 1 with 2-propanol in toluene under mW heating at 110 °C to give the corresponding 1,3-diols as diastereomeric mixtures in good to high yields. examples are shown in Table 3.21. While1,3-cyclohexanediones were rapidly hydro-genated to 1,3-diols, the reactions of seven- and five-membered 1,3-diketones needed to be conducted at lower temperature (80 °C) under H

2 for longer reaction time

(entries 3 and 4); otherwise, a 1:1 equilibrium mixture of a diol and a hydroxyl ketone was formed.

3.4.3.2 Fe Complex The iron complex 7, a good catalyst for the Oppenauer-type oxidation of alcohols (Section 3.2.3.2, Table 3.7), also catalyzed the reverse reaction, that is, the transfer hydrogenation of aldehydes and ketone with 2-propanol [10f]. The reactions were conducted in 2-propanol at 80 °C. Some examples are shown in Table 3.22. A variety of benzylic and aliphatic aldehydes were reduced in high yields. The C5C double bonds of α,β-unsaturated aldehydes were survived (entries 4 and 5). In the transfer hydrogenation of ketones, higher catalyst loading (5 mol%) was necessary. It should be noted that the transfer hydrogenation of α,β-unsaturated ketone such as PhCH5CHCOme gave a mixture of allylic and saturated alcohols in contrast with that of α,β-unsaturated aldehyde described earlier.

Cat. 1 (1 mol%)2–Propanol (2400 mol%)

O O

nR

HO OH

nR

Toluene, 110 °C, under MW

Entry

1

2

a The reaction was conducted using 2 mol% of 1 at 80 °C under H2.

Time (h) Yield (%)Substrate

O O

O O

O O

O O

1

0.5

85

88

Entry Time (h) Yield (%)Substrate

3a

4a

24

48

73

69

table 3.21 Transfer hydrogenation of cyclic 1,3-diketones catalyzed by 1 with 2-propanol.


3.4.3.3 Re Complexes It has been reported that ReH(NO) complexes (15a and 15b) bearing 1-hydroxycyclopentadienyl ligand are synthesized and exhibit high catalytic activities for transfer hydrogenation of ketones with 2-propanol [21]. The reactions were carried out in 2-propanol at 120 °C. Some examples are shown in Table 3.23. The high TOFs were observed, and the catalytic performance of the complexes 15a and 15b depended on the substrates. On the other hand, the transfer hydrogenation of benzaldehyde was found to be very slow (TOF 5 19 h−1 for 15a and 18 h−1 for 15b), probably due to deactivation through the reaction of the formed benzyl alcohol with the catalytic species.

The dFT calculations on the mechanism were also conducted, and the catalytic cycle similar to those described earlier (Scheme 3.8) via the outer-sphere mechanism

R1 R2

O Cat.7 (2 or 5 mol%)

2-Propanol80 °C, 18 h

Entry

1234

5

PhCHO4-BrC6H4CHO

4-MeOC6H4CHOPhCH=CHCHO

85969898

85

R1 R2

Substrate Yield (%)

CHO


OH

678

9

PhCOMe4-ClC6H4COEt

4-MeOC6H4CH2COMe

O

929387

81

FeTMS

OTMS

CO

7OC NCMe

table 3.22 Transfer hydrogenation of aldehydes and ketones catalyzed by 7 with 2-propanol.

R1 R2

OCat. 15 (0.5 mol%)

2-Propanol, 120 °C

Entry

1

2

3

4

Ph

4-FC6H4

tBu

Me

4-FC6H4

Me

10 min30 min

1 h3 h

2.5 h2.5 h1 h

35 min

9795989897929894

Re

OH

15a: R = iPr15b: R = Cy

H

R1 R2

OH

R1 Time Yield (%)R2 R3PNO

O

Cat.

15a15b15a15b15a15b15a15b

TOF (h–1)

1164380196657874196322

table 3.23 Transfer hydrogenation of ketones catalyzed by 15 with 2-propanol.


was proposed (Scheme 3.10). This was supported by the experimental results: the presumed unsaturated 16-electron active species 15′ were trapped as the pyridine complexes 15″ that catalyzed the transfer hydrogenation of acetophenone.

3.4.4 transfer Hydrogenation of Ketone and aldehyde with formic acid

Transfer hydrogenation of ketones and aldehydes catalyzed by 1 using HCO2H as a

hydrogen donor was firstly reported in 1996 [22a]. The reactions were carried out using very low catalyst loading of 1 (0.013–0.12 mol%) with a slight excess of HCO

2H (110 mol%) in the presence of H

2O and HCO

2Na at 100 °C (Scheme 3.11).

Simple cyclic and acyclic ketones were rapidly hydrogenated to the corresponding alcohols in high yields. benzaldehyde was hydrogenated very fast and TON reached up to 8000. The transfer hydrogenation of α,β-unsaturated ketones gave saturated ketones, although simple alkenes were not hydrogenated. It should be noted that the transfer hydrogenation of cyclohexanone with HCO

2H is much faster (a factor

of ca. 17) than that with H2.

Since the transfer hydrogenation of cyclohexanone catalyzed by 1 with dCO2H

gave 1-d-cyclohexanol (95% d), a possible catalytic cycle was proposed (Scheme 3.12). A Ru–OCHO complex (16), a key catalytic intermediate, is formed by coordination of HCO

2H to the unsaturated 16-electron complex 2 followed by proton

transfer to the carbonyl oxygen of cyclopentadienone ligand. Finally, β-elimination of CO

2 regenerates the active species 3.

While the key catalytic intermediate 16 was not isolated, the analogous complex 16′ was detected by 1H NmR at −20°C by the reaction of the dimeric ruthenium complex 12′

R1 R2

O

R1 R2

OH

15

Re

OH

HR3PNO

Re

O

R3PNO15′

Me2CHOHMe2CO

Re

O

R3PNO

C5H5N

15″

N

sCHeMe 3.10

R1 R2

O Cat. 1 (0.013–0.12 mol%), HCO2H (110 mol%)

R1 R2

OH

H2O (10 mol%), HCO2Na (20 mol%),100 ºC, 0.5–6.6 h Y = 92–100%

TON = 810–8000

sCHeMe 3.11


with an excess amount of HCO2H (Scheme 3.13, the 1st equation) [22b]. When dCO

2H

was used, formation of only a Ru–OCdO complex (16′) was observed. Warming the solution to 1°C gave the active species 13b and the dimeric ruthenium complex {[2,5-Ph

2-3,4-Tol

2(η5-C

4CO)]

2H}Ru

2(CO)

4(μ-H) analogous to 1 as a 10:1 mixture. A

possible mechanism for decarboxylation of the complex 16′ was also proposed (Scheme 3.13, the 2nd equation): (1) the reversible dissociation of HCO

2H to form

the unsaturated 16-electron complex [2,5-Ph2-3,4-Tol

2(η4-C

4CO)]Ru(CO)

2 analogous

to 2 and (2) the subsequent concerted hydride transfer to the ruthenium center from the formic carbon accompanied by the proton transfer to the carbonyl oxygen of the ligand from the acid OH, generating the active species 13b.

∆1 3 2

R1 R2

O

R1R1 R2

OH

+

CO2HCO2H

Ru

Ph

Ph Ph

OHPh

O

OCOC

H O

Ru

O

PhPh

PhPh

OCOC HO

OH

16

sCHeMe 3.12

Ru

Tol

Tol Ph

OHPh

HOC

OCRu

O

PhTol

TolPh

OCOC

HO

O

Ru

O

PhTol

TolPh

COOC

Ph

OPh

Tol

TolRu

COCO

12′

H(D)CO2H (10 equiv)–20 °C

Ru

Tol

Tol Ph

OHPh

O

OCOC

(D)HO

16′

5 : 95 in CD2Cl2by 1H NMR

H

Ru

O

PhTol

TolPh

OCOC

OH

O

H–CO2

13b

16′

sCHeMe 3.13

HydROgeNATION ANd TRANSFeR HydROgeNATION OF ImINeS 79

3.5 HydrOgenatiOn and transfer HydrOgenatiOn Of iMines and related COMpOunds

The reduction of imines to amines has been one of the most fundamental organic transformations for synthesis of biologically active compounds such as pharmaceuti-cals, agrochemicals, and other industrial chemicals. As mentioned earlier, much more attention has been paid to catalytic hydrogenation protocols based on hydrogen transfer using greener hydrogen donors (reductants) such as H

2, harmless alcohols

(usually 2-propanol), and formic acid [23]. This section is focused on the recent progress of catalytic hydrogenation and transfer hydrogenation of imines including reductive amination, though asymmetric reactions are not described.


A general catalytic cycle for the hydrogenation of imines catalyzed by 1 with a hydrogen donor (reductant) (Scheme 3.14) is almost the same as that for the hydro-genation of carbonyl compounds (Scheme 3.8).

There have been many reports and discussions on the mechanism of the hydrogen transfer step, and the two mechanisms similar to those for the hydrogenation of car-bonyl compounds (Section 3.4.1) have been proposed [2c, 23a, 24]. In the inner-sphere mechanism (Scheme 3.15a), the coordination of an imine to the metal center of the complex 3 firstly occurs via η5 to η3 ring slippage. The subsequent hydrogen transfer via a η2 complex gives a η4 complex coordinated with an amine, which gener-ates the unsaturated 16-electron complex 2 by liberation of an amine product [24a–24c].

In the outer-sphere mechanism (Scheme 3.15b), the hydrogen transfer takes place from the complex 3 to an imine in a single step without the precoordination to give the η4 complex coordinated with an amine [4c, 24d–24 g]. The theoretical calculation studies have supported that the outer-sphere mechanism is energetically more favorable [24 h].

3.5.2 Hydrogenation of imine

It has been briefly reported that the iron complex 5, the efficient catalyst for hydro-genation of ketones, also catalyzes the hydrogenation of N-benzylideneaniline at 65 °C in a moderate yield (Scheme 3.16) [19a].

∆1 3 2

R1 R2

NR3

R1 R2

NR3

+

[A] [AH2]

Hydrogen donor(reductant)

Hydrogen transfer

Hydrogen transfer

sCHeMe 3.14


Ph H

NPhCat. 5 (2 mol%), H2 (3 atm)

Toluene, 65 °C, 40 hPh NHPh

Y = 50%

sCHeMe 3.16

sCHeMe 3.15b

Ru

Ph

Ph Ph

OPh

COOC H

NR3

H

Hydrogen transfer

3

NR3

R2

R2R1

R1

NHR3

R2R2R1

R1

2

[A]

[AH2]

Ru

O

PhPh

PhPh

OCOC

NR3

H

H

Hydrogen transfer

Ru

O

PhPh

PhPh

OCOC

NR3

H

R2R1

Ru

OH

PhPh

PhPh

OCOC

NR3

R2R1

Ru

Ph

Ph Ph

OHPh

COOC H

NR3

R2R1

Ru

O

PhPh

PhPh

OCOC

NR3

H

R2R1

H

H

�2-complex

NHR3

R2R1

[A]

[AH2]

Hydrogen transfer

3

H

�5 to � 3

�3 to �2

Ru

O

PhPh

PhPh

OCOC

�2 to �4

2

Hydrogen transfer

�3-complex

�4-complex

sCHeMe 3.15a


3.5.3 transfer Hydrogenation of imine with 2-propanol

3.5.3.1 Ru Complex It has been reported that the complex 1 catalyzes transfer hydrogenation of imines with 2-propanol [25a]. The reactions were carried out with a large excess of 2-propanol in the presence of a small amount of H

2O in benzene at

70 °C. Several examples are shown in Table 3.24. Addition of a small amount of H2O

accelerated the reaction rate. The reactions of various imines completed within sev-eral hours to give the corresponding amines in high yields. It should be noted that a ketimine reacts faster than an aldimine (entries 1 and 6).

The dimeric complex 12 (Section 3.3.2.1, Table 3.15) also catalyzed the transfer hydrogenation of imines with 2-propanol [25b]. The reactions were conducted with wet 2-propanol in toluene at 110 °C. examples are shown in Table 3.25. It is worth noting that the initial TOF (1150 h−1) of the transfer hydrogenation of benzylidene-aniline for the complex 12 is much larger than that for the complex 1 (<30 h−1). A variety of ketimines and aldimines were hydrogenated within a few hours to give the corresponding amines in excellent yields.

R1 R2

NR3Cat. 1, 2-Propanol (2400 mol%)

R1 R2

NHR3

H2O, Benzene, 70 °C

Entry

123456

Ph4-MeOC6H4

4-FC6H4Cyclo-C6H11

PhPh

MeMeMeMeMeH

R1 Time (h) Yield (%)R2 Cat. 1 (mol%)

0.30.31

0.50.50.3

1.50.75

8665

979795979498

R3

PhPhPhPh

PhCH2Ph

table 3.24 Transfer hydrogenation of imines catalyzed by 1 with 2-propnaol.

R1 R2

NR3Cat. 12, 2-Propanol (2400 mol%)

R1 R2

NHR3

H2O, Toluene, 110 °C

Entry

12345

Ph4-FC6H4

Me2C=CHCH2CH2EtOCO

3-Py

MeMeMeHH

R1 Time (h) Yield (%)R2 Cat. 12 (mol%)

0.0313

0.063

1.51114

93>99969596

R3

PhPh

4-MeOC6H44-MeOC6H44-MeOC6H4

table 3.25 Transfer hydrogenation of imines catalyzed by 12 with 2-propnaol.

82 OxidatiOn and HydrOgenatiOn Catalyzed by transitiOn metal COmplexes

it was also reported that mW irradiation greatly shortened the reaction time to 10–20 min (scheme 3.17).

3.5.3.2 Fe Complex it has been briefly reported that the iron complex 7, the effi-cient catalyst for transfer hydrogenation of aldehydes and ketones (section 3.4.3.2, table 3.22), also catalyzes the transfer hydrogenation of N-benzylideneaniline with 2-propanol (scheme 3.18) [10f].

3.5.3.3 Re Complex it has been reported that the rhenium complexes 15, the efficient catalysts for the transfer hydrogenation of ketones (section 3.4.3.3, table 3.23), also catalyze the transfer hydrogenation of aldimines with 2-propanol [21]. the reactions were carried out in 2-propanol at 80 °C. a few examples are shown in table 3.26. the reaction rates were slower than those of the transfer hydrogenation of ketones, and the complex 15b showed slightly higher catalytic activity than 15a.

3.5.4 Reductive Amination of Carbonyl Compounds and Amines

Catalytic reductive amination of carbonyl compounds using H2 as a hydrogen donor

has been a valuable protocol for synthesis of variety of amines. the hydrogenation of imine intermediates produced by condensation of carbonyl compounds and amines

R2R1

NR3

R2R1

NHR3Cat. 12 (0.1–3 mol%), 2-Propanol (4700 mol%)

H2O, Toluene, 110 °C, MW, 10–20 min

Y = 94–98%

SCHEME 3.17

Ph H

NPh Cat. 7 (2 mol%)Ph NHPh

Conversion = 67%2-Propanol, 80 ºC, 3 d

SCHEME 3.18

R1 H

NR2Cat. 15 (0.5 mol%)

2-Propanol, 120 °C

Entry

1

2

Ph

4-ClC6H4

Ph

4-ClC6H4

32.533

97997386

Re

OH

15a : R = iPr15b : R = Cy

H

R1 NHR2

R1 R2 Time (h) Yield (%)R3P

NO

Cat.

15a15b15a15b

TAblE 3.26 transfer hydrogenation of imines catalyzed by 15 with 2-propanol.


is the most important step in the catalytic cycle, and many catalytic systems have been studied [26].

It has been reported that the iron complex 5, the efficient catalyst for the Oppenauer-type oxidation of alcohols (Section 3.2.3.2, Table 3.5) and the hydrogenation of car-bonyl compounds (Section 3.4.2.2, Table 3.20), catalyzes reductive amination of aliphatic aldehydes and aliphatic amines [27]. Among the many iron complexes exam-ined, the complex 5 gave the best result. The similar result was obtained by a combination of the Fe(CO)

3 complex 6 and me

3NO generating the complex 5 in situ via decarbon-

ylation followed by hydrogenation of the resulting unsaturated 16-electron species with H

2 (see Section 3.2.3.2, Table 3.6). Since the complex 5 is air sensitive and the complex

6 is not, the in situ generation method is applied in the following reductive amination. The reactions of aliphatic aldehydes and aliphatic amines were carried out under H

2 in

etOH at 85 °C. Some examples are shown in Table 3.27. The reactions of citronellal and various amines gave the corresponding products in moderate to high yields without hydrogenation of the C5C double bond (entries 1–4). The reactions of other aliphatic aldehydes and amines also proceeded smoothly.

The reductive amination of ketones and amines was also achieved under the similar conditions in the presence of NH

4PF

6 in meOH to give the corresponding

amines in good to high yields [27]. examples are shown in Table 3.28. It should be noted that the reaction of 4-hydoxy-4-methylpentan-2-one gave N-isopropyl-2-phenylethylamine, a product of the reductive amination of acetone (entry 3).

A possible mechanism is proposed (Scheme 3.19) [27]. Oxidative decarbonyl-ation of the complex 6 by me

3NO produces the unsaturated 16-electron species (a),

which is converted to the complex 5 through the reaction with H2. Condensation of a

carbonyl compound and an amine produces an imine and/or an enamine, which is

Cat. 6 (5 mol%), Me3NO (5 mol%)

H2 (5 bar), EtOH85 °C, 16 h

Entry

123

4

56

R1

747594

83

7963

Yield (%)

PiperidineC4H9NH2

4-MeOC6H4CH2NH2

PiperidinePhCH2NHMe

Me2CH=CH(CH2)2CHMeCH2




PhCH2CH2C5H11

R1CHO + R2R3NH R1CH2–NR2R3

56Me3NO, H2

NH

Amine

table 3.27 Reductive amination of aldehydes and amines catalyzed by 6 and me

3NO under H

2.


hydrogenated by the complex 5 to furnish the reduced amine along with the starting catalytic species a.

referenCes

[1] Shvo y, Czarkie d, Rahamim y, Chodosh dF. J Am Chem Soc 1986;108:7400.

[2] For reviews: (a) Karvembu R, Prabhakaran R, Natarajan K. Coord Chem Rev 2005;249:911. (b) bullock Rm. Angew Chem Int ed engl 2007;46:7360. (c) Conley bl, Pennington-boggio mK, boz e, Williams TJ. Chem Rev 2010;110:2294. See also (d) Prabhakaran R.

Cat. 6 (5 mol%), Me3NO (5 mol%)NH4PF6 (10 mol%)

H2 (5 bar), MeOH, 85 °C, 16 hR1COR2 + R3R4NH R1R2CH–NR3R4

Entry R1 Yield (%)Amine

123

4

R2

PhCH2CH2C5H11

MeC(OH)CH2

MeMeMe

–(CH2)5–

PhCH2CH2NH2

PhCH2CH2NH2

PhCH2CH2NH2

NH

636195a

64

a The product was Me2CH–NHCH2CH2Ph.

table 3.28 Reductive amination of ketones and amines catalyzed by 6 and me

3NO under H

2.

6Me3NO

FeTMS

OHTMS

CO5

OC HFe

TMS

OTMS

COOC

R1CH2CHO+

R2NH2

R1CH2CH=NR2

R1CH=CHNR2

–H2O

FeTMS

OTMS

COOC H

H

N R2

CH2R1

FeTMS

OTMS

COOC H

H

NR2

R1

or

R1CH2CH2NHR2

H2

CO2Me3N

A

sCHeMe 3.19

ReFeReNCeS 85

SyNleTT 2004:2048. (e) Samec JSm, bäckvall J-e. Hydroxytetraphenylcyclopen- tadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II). In: Fuchs Pl. editor. Encyclopedia of Reagents for Organic Synthesis. Vol. 7. 2nd ed. New york: Wiley; 2009. p 5557–5564.

[3] For recent representative reviews on dKR: (a) martín-matute b, bäkvall J-e. Curr Opin Chem biol 2007;11:226. (b) Ahn y, Ko S-b, Kim m-J, Park J. Coord Chem Rev 2008;252:647. (c) lee JH, Han K, Kim m-J, Park J. eur J Org Chem 2010;2010:999. (d) Kim y, Park J, Kim m-J. ChemCatChem 2011;3:271.

[4] (a) menashe N, Shvo y. Organometallics 1991;10:3885. (b) Persson bA, larsson Ale, Ray ml, bäckvall J-e. J Am Chem Soc 1999;121:1645. (c) Casey CP, Singer SW, Powell dR, Hayashi RK, Kavana m. J Am Chem Soc 2001;123:1090. (d) mays mJ, morris mJ, Raithby PR, Shvo y, Czarkie d. Organometallics 1989;8:1162.

[5] For recent representative reviews: (a) Schultz mJ, Sigman mS. Tetrahedron 2006;62:8227. (b) Piera J, bäckvall J-e. Angew Chem Int ed engl 2008;47:3506. (c) Parmeggiani C, Cardona F. green Chem 2012;14:547.

[6] For representative reviews: (a) bäckvall J-e. J Organomet Chem 2002;652:105. (b) Samec JSm, bäckvall J-e, Andersson Pg, brandt P. Chem Soc Rev 2006;35:237.

[7] (a) Johnson Jb, bäckvall J-e. J Org Chem 2003;68:7681. (b) Casey CP, Jeffrey b, Johnson Jb. Can J Chem 2005;83:1339. (c) Comas-Vives A, Ujaque g, lledós A. Organometallics 2007;26:4135. (d) Comas-Vives A, Ujaque g, lledós A. J mol Struct: THeOCHem 2009;903:123.

[8] (a) Wang g, Andreasson U, bäckvall J-e. J Chem Soc Chem Commun 1994:1037. (b) Csjernyik g, Éll AH, Fadini l, Pugin b, bäckvall J-e. J Org Chem 2002;67:1657. (c) Johnston eV, Karlsson eA, Tran l-H, Åkermark b, bäckvall J-e. eur J Org Chem 2010:1971.

[9] (a) Almeida mlS, beller m, Wang g-z, bäckvall J-e. Chem eur J 1996;2:1533. (b) Almeida mlS, Kočovský P, bäckvall J-e. J Org Chem 1996;61:6587. (c) bierenstiel m, Schlaf m. eur J Org Chem 2004:1474.

[10] (a) Thorson mK, Klinkel Kl, Wang J, Williams TJ. eur J Inorg Chem 2009:295. (b) Coleman mg, brown AN, bolton bA, guan H. Adv Synth Catal 2010;352:967. (c) Knölker H-J, Heber J, mahler CH. SyNleTT 1992:1002. (d) Knölker H-J, baum e, goesmann H, Klauss R. Angew Chem Int ed engl 1999;38:2064. (e) moyer SA, Funk TW. Tetrahedron lett 2010;51:5430. (f) Plank TN, drake Jl, Kim dK, Funk TW. Adv Synth Catal 2012;354:597. (g) Johnson TC, Clarkson gJ, Wills m. Organometallics 2011;30:1859.

[11] gauthier S, Scopelliti R, Severin K. Organometallics 2004;23:3769.

[12] Jung Hm, Choi JH, lee SO, Kim yH, Park JH, Park J. Organometallics 2002;21:5674.

[13] do y, Ko S-b, Hwang I-C, lee K-e, lee SW, Park J. Organometallics 2009;28:4624.

[14] (a) blum y, Shvo y. J Organomet Chem 1985;282:C7. (b) Choi JH, Kim N, Shin yJ, Park JH, Park J. Tetrahedron lett 2004;45:4607.

[15] murahashi S-I, zhang d. Chem Soc Rev 2008;37:1490.

[16] (a) Éll AH, Samec JSm, brasse C, bäckvall J-e. Chem Commun 2002:1144. (b) Éll AH, Johnson Jb, bäckvall J-e. Chem Commun 2003:1652. (c) Samec JSm, Éll AH, bäckvall J-e. Chem eur J 2005;11:2327.

[17] (a) de Vries Jg, elsevier CJ, editors. The Handbook of Homogeneous Hydrogenation. Vols. 1–3. Weinheim: Wiley-VCH; 2007. (b) Clapham Ae, Hadzovic A, morris RH. Coord Chem Rev 2004;248:2201. (c) bullock Rm. Chem eur J 2004;10:2366. (d) Ito m,


Ikariya T. Chem Commun 2007:5134. (e) gaillard S, Renaud J-l. ChemSusChem 2008;1:505. (f) Chakraborty S, guan H. dalton Trans 2010;39:7427. (g) Robertson A, matsumoto T, Ogo S. dalton Trans 2011;40:10304. (h) Junge K, Schröder K, beller m. Chem Commun 2011;47:4849. (i) bauer g, Kirchner KA. Angew Chem Int ed 2011; 50:5798.

[18] (a) blum y, Czarkle d, Rahamlm y, Shvo y. Organometallics 1985;4:1459. (b) Casey CP, Strotman NA, beetner Se, Johnson Jb, Priebe dC, Vos Te, Khodavandi b, guzei IA. Organometallics 2006;25:1230. (c) Casey CP, Strotman NA, beetner Se, Johnson Jb, Priebe dC, guzei IA. Organometallics 2006;25:1236. (d) Casey CP, guan H. Organometallics 2012;31:2631.

[19] (a) Casey CP, guan H. J Am Chem Soc 2007;129:5816. (b) Casey CP, guan H. J Am Chem Soc 2009;131:2499. (c) zhang H, Chen d, zhang y, zhang g, liu J. dalton Trans 2010;39:1972.

[20] leijondahl K, Fransson Abl, bäckvall J-e. J Org Chem 2006;71:8622.

[21] landwehr A, dudle b, Fox T, blacque O, berke H. Chem eur J 2012;18:5701.

[22] (a) menashe N, Salant e, Shvo y. J Organomet Chem 1996;514:97. (b) Casey CP, Singer SW, Powell dR. Can J Chem 2001;79:1002.

[23] For recent reviews: (a) Fabrello A, bachelier A, Urrutigoïty m, Kalck P. Coord Chem Rev 2010;254:273. (b) Wang C, Villa-marcos b, xiao J. Chem Commun 2011;47:9773.

[24] (a) Samec JSm, Éll AH, bäckvall J-e. Chem Commun 2004:2748. (b) Samec JSm, Éll AH, Åberg Jb, Privalov T, lars eriksson l, bäckvall J-e. J Am Chem Soc 2006;128:14293. (c) Privalov T, Samec JSm, bäckvall J-e. Organometallics 2007;26:2840. (d) Casey CP, Johnson Jb. J Am Chem Soc 2005;127:1883. (e) Casey CP, bikzhanova gA, Cui Q, guzei IA. J Am Chem Soc 2005;127:14062. (f) Casey CP, bikzhanova gA, guzei IA. J Am Chem Soc 2006;128:2286. (g) Casey CP, Clark Tb, guzei IA. J Am Chem Soc 2007;129:11821. (h) Comas-Vives A, Ujaque g, lledós A. Organometallics 2008;27:4854.

[25] (a) Samec JSm, bäckvall J-e. Chem eur J 2002;8:2955. (b) Samec JSm, mony l, bäckvall J-e. Can J Chem 2005;83:909.

[26] For representative reviews: (a) gomez S, Peters JP, maschmeyer T. Adv Synth Catal 2002;344:1037. (b) Nugent TC, el-Shazly m. Adv Synth Catal 2010;352:753.

[27] Pagnoux-Ozherelyeva A, Pannetier N, mbaye md, gaillard S, Renaud J-l. Angew Chem Int ed 2012;51:4976.


87

Bond-Forming reactions catalyzed By transition metal complexes Bearing η4-cyclopentadienone/ η5-Hydroxycyclopentadienyl and related ligands

4

4.1 introduction

Bond formation is one of the most important chemical transformations in organic synthesis. The main subjects discussed in this chapter are C–N, C–O, and C–C bond-forming reactions based on hydrogen transfer catalyzed by transition metal complexes bearing η4-cyclopentadienone/η5-hydroxycyclopentadienyl and related ligands. As men-tioned in Chapter 3, a dimeric ruthenium complex, [(η5-Ph

4C

4CO)

2H]Ru

2(μ-H)(CO)

4 (1)

(so-called Shvo’s catalyst), which dissociates to two monomeric complexes, unsatu-rated 16-electron (η4-Ph

4C

4CO)Ru(CO)

2 (2) and saturated 18-electron (η5-Ph

4C

4COH)

RuH(CO)2 (3) (Scheme 4.1, the 1st equation), exhibits high catalytic activities for

hydrogen transfer reactions such as dehydrogenation (oxidation) and hydrogenation (reduction), since the interconversion between the complexes 2 and 3 readily takes place in the presence of a hydrogen donor (reductant) (AH

2) such as H

2 and alcohols or a

hydrogen acceptor (oxidant) (A) such as O2 and ketones (Scheme 4.1, the 2nd equation)

[1]. Since then, a great number of catalytic reactions using the complex 1 and analo-gous complexes have been reported [2]. This chapter describes the recent progress (since ca. 2000) of C–N, C–O, and C–C bond-forming reactions based on hydrogen transfer catalyzed by transition metal complexes bearing η4-cyclopentadienone/

88 BONd-FORmiNg ReACTiONS CATAlyzed By TRANSiTiON meTAl COmPlexeS

η5-hydroxycyclopentadienyl and related ligands [3]. As mentioned in the preface, asymmetric reactions are not discussed.

4.2 carBon–nitrogen Bond-Forming reactions Based on Hydrogen transFer and deHydrogenation

Carbon–nitrogen bond-forming reactions have been extensively studied in organic synthesis since nitrogen-containing organic compounds such as amines, amides, and sulfonamides are key functional groups in biomolecules, biologically active compounds, pharmaceuticals, agrochemicals, and a variety of industrial chemicals. There have been many synthetic methods including alkylation of amines with alkyl halides or sulfonates, reductive amination of carbonyl compounds, etc. Recently, the C–N bond-forming reactions based on hydrogen transfer processes (so-called redox neutral, borrowing hydrogen, or hydrogen autotransfer) have been attracting considerable attention from viewpoints of atom-economical and green organic transformations [3, 4].

4.2.1 n-alkylation of amines with alcohols

A general catalytic cycle for the N-alkylation of an amine with an alcohol via hydrogen transfer processes consists of three cascade reactions: (1) [m]-catalyzed dehydrogenation of an alcohol to give a carbonyl compound along with [mH

2] or

[mH] species, (2) formation of an N-alkylimine (or iminium ion) by condensation of the resulting carbonyl compound and an amine, and (3) hydrogenation of the N-alkylimine by the transiently generated [mH

2] or [mH] species (Scheme 4.2).

Thus, no oxidant or reductant is required because the metal catalyst [m] carries out hydrogen transfer processes two times, that is, transiently accepts and donates hydrogen. Since this protocol can avoid use of harmful alkyl halides as alkylating

Ru

O

Ph

PhPh

Ph

Ru

O

Ph

PhPh

Ph

HOCCO CO

CO

H

Ru

O

PhPh

PhPh

OCOC

Ru

HO

Ph Ph

PhPh

HCO

CO

∆+

1 2 3

2 3

[AH2]Hydrogen donor (reductant)

H2, Me2CHOH, etc.

[A]Hydrogen acceptor (oxidant)

O2, Me2C=O, etc.

scHeme 4.1

CARBON–NiTROgeN BONd-FORmiNg ReACTiONS 89

agents and only water is produced as a coproduct or waste, providing environmentally benign and atom-economical synthetic methods for amines.

4.2.1.1 Selective N-Alkylation of Indoles with Alcohols Catalyzed by the Complex 1it has been reported that the complex 1 catalyzes the selective N-alkylation of indoles with alcohols [5a] in spite of the possible C-alkylation at the C3-position of indole (Section 4.4.1). Among many catalysts examined, the complex 1 gave the best result. The reactions were carried out in the presence of TsOH in toluene at 110–130 °C for 24 h. Some examples are shown in Table 4.1. Various indoles were alkylated with primary alcohols to afford selectively N-alkylated indoles in good to high yields.

Since a small amount of N-hexyl-2,3-indoline was formed (entry 1) and the reac-tion of indoline with hexanal gave N-hexylindole in 72% yield, a possible catalytic cycle was proposed (Scheme 4.3). At first, the unsaturated complex 2 ([Ru]) generated

R1 OH

R1 O R1 NR2

R1 NH

R2

Cat. [M]

Imine forming step

N-Alkylimine

–H2O

H HR2–NH2

R2–NH2 H2O

Cat. [MH2] or [MH]

Dehydrogenation(β-hydrogenelimination)

Hydrogenation(hydro-metalation)

Carbonylcompound

scHeme 4.2

Cat. 1, TsOH (0.025 mol%)

Toluene, 110–130 °C, 24 h+ R4CH2OH

Entry

123456

R1

HMeOMeO

HHH

858073948988

Yield (%)Cat. 1 (mol%)

0.20.50.50.50.50.2

NH

R1R2

R3

N

R1R2

R3

CH2R4

R2 R3 R4

HHHHH

Me

HHHH

MeH

C5H114-MeOC6H4

FC6H4PhCH(OH)

C5H11C5H11

taBle 4.1 N-Alkylation of indoles with alcohols catalyzed by 1.


by thermal dissociation of 1 dehydrogenates an alcohol to give an aldehyde along with the saturated complex 3 ([RuH

2]), which hydrogenates indole to afford indoline and

the complex 2. Condensation of the aldehyde and indoline followed by metal-cata-lyzed isomerization of a double bond furnishes N-alkylated indole.

4.2.1.2 N-Alkylation of Ammonium Salts with Alcohols Catalyzed by 1 Ammonia or its salts is the simplest, fundamental, and abundant nitrogen source for a wide variety of organic nitrogen compounds. The complex 1 catalyzed N-alkylation of ammonia salts with alcohols to give tertiary amines in excellent yields [5b]. The reactions were conducted without solvent at 130–140 °C. Several examples are shown in Table 4.2. When NH

4OAc was used, a base such as NaHCO

3 was not nec-

essarily required (entries 1 and 2) and the reactions were completed in 17 h. On the

NH

RCH2CHO +N

R

N

R

–H2O

Cat. 2 ([Ru]) Cat. 3 ([RuH2])

RCH2CH2OH RCH2CHO

NH

NH

1 2 + 3∆

Metal-catalyzedisomerization

Dehydrogenation

Hydrogenation

scHeme 4.3

Cat. 1, base

130–140 °CR–OH+NH4X R3N

Entry

12345

R

PhCH2

PhCH2

PhCH2

4-ClC6H4CH2

C4H9

9999999993

Yield (%)Cat. 1 (mol%)

0.50.5533

X Base (mol%) Time (h)

OAcOAcCl

OAcOAc

NaHCO3 (3)–

KOH (100)––

1717391717

taBle 4.2 N-Alkylation of ammonium salts with alcohols catalyzed by 1.


other hand, when NH4Cl was used, higher catalyst loading (5 mol%), a stoichio-

metric amount of KOH, and longer reaction time (39 h) were necessary (entry 3).

4.2.2 n-alkylation of amines with amines

A general catalytic cycle for the N-alkylation of amines with amines via hydrogen transfer processes (Scheme 4.4) is similar to that for the N-alkylation of amines with alcohols shown earlier (Scheme 4.2): (1) [m]-catalyzed dehydrogenation of an amine to give an imine along with [mH

2] or [mH] species, (2) formation of an N-alkylimine

(or iminium ion) via nucleophilic addition of another amine followed by elimination of ammonia, and (3) hydrogenation of the N-alkylimine by the transiently generated [mH

2] or [mH] species. Thus, no oxidant or reductant is required and only ammonia

is produced as a coproduct or waste, providing environmentally benign and highly atom-economical synthetic methods for amines.

4.2.2.1 N-Alkylation of Arylamines with Alkylamines Catalyzed by 1 it has been reported that among many other ruthenium catalysts examined, the complex 1 and the analogous complex [(η5-Ph

4C

4CO)Ru(CO)

2]

2 (4) efficiently catalyze N-alkylation

of arylamines with alkylamines and that the complex 1 is more active than the complex 4 [6a]. Thus, the reactions were carried out using 1 in tert-amyl alcohol at 150 °C for 24 h. Some examples are shown in Table 4.3. Various arylamines were alkylated with a variety of primary alkylamines to afford N-alkylated arylamines in high to excellent yields. A variety of functional groups on the aromatic ring were tolerated. Amines substituted with heteroaromatics were successfully used as the alkylating agents.

A possible catalytic cycle is proposed (Scheme 4.5). At first, the unsaturated complex 2 generated by thermal dissociation of 1 (Scheme 4.1) dehydrogenates an

R1 NH2

R1 NH R1 NR2

R1 NH

R2

Cat. [M]

N-Alkylimine formation

Imine N-Alkylimine

–NH3

H HR2–NH2

R2–NH2 NH3

Cat. [MH2] or [MH]


Hydrogenation(hydro-metalation)

scHeme 4.4


alkylamine to give an imine and the saturated complex 3. Nucleophilic addition of an arylamine to the imine followed by elimination of ammonia from the resulting ami-noaminal gives an N-arylimine. Finally, hydrogenation of the N-arylimine by the complex 3 produces an N-alkylated arylamine to regenerate the starting complex 2.

4.2.2.2 N-Alkylation of Aniline with Di- and Trialkylamines Catalyzed by 1 The N-alkylation of aniline with di- and trialkylamines catalyzed by the complex 1 has been also reported [6b]. When the reaction of aniline with hexyl-, dihexyl-, or trihex-ylamine (2 equiv of aniline per hexyl group) was conducted in the presence of the complex 1 (1 mol%) in tert-amyl alcohol at 150 °C, N-hexylaniline was obtained in all cases (Scheme 4.6, the 1st equation). The similar reaction of aniline with a mixture of

Cat. 1 (1 mol%)

tert-Amyl alcohol150 °C, 24 h

Entry

12a

345

Product

PhNHC6H13PhNHC6H13

4-MeOC6H4NHC6H134-BrC6H4NHC6H13

2-PyNHC6H13

9470989496

Yield (%)

a The complex 4 (1 mol%) was used as a catalyst.

ArNH–R + NH3 Ru

O

PhPh

PhPh

COOC

Ph

OPh

Ph

PhRu

COCO

4


6

7

OPhNHCH2

NH

PhNHCh2CH2

89

93

ArNH2 + RNH2

taBle 4.3 N-Alkylation of arylamines with alkylamines catalyzed by 1.

R1 NH2

R1 NH R1 NAr

R1 NHAr

Cat. 2

Cat. 3

–NH3

H HCat. 1, ArNH2

ArNH2

R1 NH2

NHAr

NH3

1 2 + 3∆

Nucelophilicaddition Elimination

Dehydrogenation Hydrogenation

scHeme 4.5


mono-, di-, and trihexylamines gave N-hexylaniline selectively (Scheme 4.6, the 2nd equation). These results indicated that an equilibrium between mono-, di-, and trial-kylamines occurred under the reaction conditions and that the final reaction of aniline with hexylamine producing ammonia was irreversible (Scheme 4.6, the 3rd equation).

The N-alkylation of aniline with various di- or trialkylamines was conducted using the complex 1 as a catalyst. examples are shown in Table 4.4. N-Alkylated anilines were obtained in good to high yields except for tribenzylamine (entry 4). it should be noted that it is practically convenient to use nonvolatile et

3N and iPr

2NH as

alkylating agents instead of volatile etNH2 and iPrNH

2 (entries 1 and 2). The reaction

of aniline-15 N with dibenzylamine gave N-benzylaniline-15 N (>99% 15 N), support-ing the hydrogen transfer mechanism (entry 3).

Cat. 1 (1 mol%)

Cat. 1 (1 mol%)

tert-Amyl alcohol

tert-Amyl alcohol

150 °C, 24 h

150 °C, 24 h

+ PhNH–C6H13

PhNH–C6H13

Y = 89%(yield based on hexyl group)

(yield based on hexyl group)

+Y = 87, 80, or 75%

(C6H13)2NH(C6H13)3N

PhNH2

PhNH2

PhNH2

PhNH2 PhNH2PhNH–C6H13 PhNH–C6H13 PhNH–C6H13

C6H13NH2

Cat. 1Cat. 1Cat. 1NH3

or

or

+

+(C6H13)3N

(C6H13)3N

(C6H13)2NH

(C6H13)2NH

C6H13NH2

C6H13NH2

scHeme 4.6

Cat. 1 (1 mol%)

tert-Amyl alcohol, 150 °C, 24 h+

Entry

123b

456

Alkylamine

Et3NiPr2NH

(PhCH2)2NH(PhCH2)3N

(Cyclo-C6H11)2NH

MeO(CH2)3NH2

959292

219992

Yield (%)a

a Isolated yield based on alkyl groups.b Ph15NH2 was used and Ph15NH–CH2Ph was produced.

PhNH–R + NH3PhNH2

R2NHor

R3N

taBle 4.4 N-Alkylation of aniline with di- and trialkylamines catalyzed by 1.


4.2.2.3 N-Alkylation of tert-Alkylamines with Alkylamines Catalyzed by 1 it has been reported that the N-alkylation of tert-alkylamines with mono-, di-, and trialkylamines is catalyzed by the complex 1 [6c]. Among several other ruthenium catalysts including the complex 4 examined, the complex 1 gave the best result. The reactions were carried out in dme at 170 °C for 24 h. Several examples are shown in Table 4.5. tert-Octylamine (1,1,3,3-tetramethylbutylamine) and 1-adamantylamine were employed as the substrates. Various mono-, di-, and trialkylamines except for tribenzylamine gave the products in good to excellent yields.

4.2.2.4 N-Alkylation of Ammonia with Alkylamines Catalyzed by 1 The N-alkylation of ammonia with dialkylamines catalyzed by the complex 1 has been reported to produce primary amines [6d]. Among several other ruthenium catalysts including the complex 4 examined, the complex 1 gave the best result. The reactions were conducted in tert-amyl alcohol/mTBe (tBuOme) at 150–170 °C for 16 h to give primary alkylamines in moderate to high yields. Some examples are shown in Table 4.6. Addition of water improved the yields in the reactions with non-α-branched dialkylamines (entry 5). it should be noted that the similar reaction with trioctyl-amine for 40 h gave comparable yields of octyl-, dioctyl-, and trioctylamines (71, 25, and 2%, respectively) to those of the reaction with dioctylamine (entry 5), indicating an equilibrium between primary, secondary, and tertiary amines (Scheme 4.6).

A possible catalytic cycle was proposed (Scheme 4.7) and analogous to that for the N-alkylation of amines with amines (Scheme 4.5).

4.2.2.5 Double N-Alkylation of Arylamines with Cyclic Alkylamines Catalyzed by 1 it has been reported that the N-alkylation of arylamines with cyclic alkylamines such as pyrrolidine and piperidine is catalyzed by the complex 1 to afford N-arylpyrrolidines and N-piperidine via double N-alkylation [6e]. The reactions were conducted in tert-amyl alcohol at 150 °C for 24 h. Several examples are shown in Table 4.7. The yields were low to moderate. electron-rich anilines gave higher yields than electron-poor ones.

Cat. 1 (1 mol%)

DME, 170 °C, 24 h+

Entry

123456

Alkylamine

PhCH2CH2NH2

(PhCH2CH2)2NH(PhCH2CH2)3N

C8H17NH2

C8H17NH2

(PhCH2)2NH

759087909990

Yield (%)a

a Yield based on alkyl groups.

tRNH2tRNH–CH2R + NH3

NH2

1-Adamatylamine

NH2

tert-Octylaminetert-Alkylamine

tert-Octylaminetert-Octylaminetert-Octylaminetert-Octylamine

1-Adamatylamine1-Adamatylamine

RCH2NH2or

(RCH2)2NHor

(RCH2)3N

taBle 4.5 N-Alkylation of tert-alkylamines with alkylamines catalyzed by 1.


A possible catalytic cycle is proposed (Scheme 4.8). The reaction starts with the intermolecular N-alkylation of aniline with pyrrolidine, and the subsequent intramo-lecular elimination gives rise to the ring opening to produce an N-phenyl-1,4-diamine intermediate after hydrogenation. Finally, the intramolecular N-alkylation of the resulting N-phenyl-1,4-diamine affords the N-phenylpyrrolidine.

4.2.3 Heterocyclization of amines and 2-aminophenols

it has been reported that the complex 1 catalyzes oxidative heterocyclization of amines with 2-aminophenols to give benzoxazoles [7]. The reactions were carried out in the presence of 2,6-dimethoxy-1,4-benzoquinone (dmBQ) as a hydrogen

Cat. 1 (1 mol%)

tert-Amyl alcohol, tBuOMe, 16 h

Entry

12

3

5b4b

R1

Cyclo-C6H11

Cyclo-C6H11

C8H17

Me2CHCH2

8481a

81

7373c

Yield (%)

a Yield based on cyclohexylamine. 8% of dicyclohexylamine was formed.b 0.5 ml of H2O was added.c 24% of dioctylamine and 2% of trioctylamine were also formed.

R2 Temperature (°C)

150150

170

170170

R1

HN

R2+R1 NH2 R2 NH2

O

Cyclo-C6H11iPr

C8H17

Me2CHCH2

O

NH3 (g)

11

1.5

22

NH3 +

taBle 4.6 N-alkylation of ammonia with dialkylamines catalyzed by 1 to give primary amines.

R NH

R N

R

Cat. 3

Cat. 2

Cat. 1, NH3

R NH

NH2

1 2 + 3∆


R 2

R

NH3

RHN R

R NH2

NH2

HydrogenationDehydrogenation

scHeme 4.7


acceptor in mesitylene at 150 °C for 24 h. Some examples are shown in Table 4.8. Among several hydrogen acceptors examined, dmBQ gave the best result. The reactions of various primary benzylic amines with 2-aminophenols gave benzoxa-zoles in moderate to good yields. The yields were relatively high for the substrates with electron-donating groups compared to those with electron-withdrawing group.

A possible catalytic cycle is proposed (Scheme 4.9). dehydrogenation of a pri-mary amine by the complex 2 gives an imine and the complex 3 that is oxidized with dmBQ to regenerate the complex 2. After transimination between the imine and 2-aminophenol, intramolecular cyclization of the resulting N-(2-hydoxyphenyl)imine followed by dehydrogenation by the complex 2 furnishes benzoxazole along with the complex 3 that is again oxidized with dmBQ to regenerate the complex 2.

Cat. 1 (1 mol%)

tert-Amyl alcohol150 °C, 24 h

+

Entry

1a

23456

Ar

Ph4-MeOC6H4

3-MeC6H4

4-FC6H4

4-MeOC6H4

4-MeOC6H4

326751315868

Yield (%)

a Without solvent.

Ar–NH2 HN Rn

N Rn

Ar

n = 1, 2

n R

111112

HHHH

2-MeH

+ NH3

taBle 4.7 double N-alkylation of anilines with cyclic alkyamines catalyzed by 1.

HN

NHPh

H2N H2N

H2N

NHPh NHPh

HNNHPh

NPhNPh

NPh

PhNH2 Intramolecular

Elimination

NH3

Elimination

Hydrogenation

Nucelophilicaddition

Nucelophilicaddition

Intramolecular

HN NDehydrogenation

Cat. 2 Cat. 3

Cat. 3 Cat. 2 Cat. 2 Cat. 3

Dehydrogenation

Hydrogenation

Cat. 3 Cat.2

scHeme 4.8

CARBON–OxygeN BONd-FORmiNg ReACTiONS 97

4.3 carBon–oxygen Bond-Forming reactions Based on Hydrogen transFer and deHydrogenation

The dehydrogenative C–O bond-forming reactions of alcohols with alcohols via hydrogen transfer process give esters and lactones. A general catalytic cycle con-sists of the three cascade reactions: (1) [m]-catalyzed dehydrogenation (β-hydrogen elimination) of an alcohol to give a carbonyl compound along with [mH

2] or [mH]

Cat. 1 (1 mol%)DMBQ (200 mol%)

Mesitylene150 °C, 24 h

Entry

1234567

R1

Ph4-MeOC6H4

4-ClC6H4

4-MeC6H4

4-MeOC6H4

PhC5H11

43703668505255

Yield (%)R2

HHH

MeClHH

R1 NH2

HO

H2N

R2

R3

+

R2

R3

O

NR1

DMBQ

R3

HHHHH

MeH

O

O

MeO OMe

taBle 4.8 Oxidative N-heterocyclization of amines and 2-aminophenols catalyzed by 1.

R NH2

Cat. 2

R1 NH

HO

H2NHO

NR

O

NH

R

O

N

R

Cat. 3

NH3

Cat. 2

Cat. 3

DMBQDehydrogenation Dehydrogenation

Intramolecularcyclization

HO

H2N

Cat.1,

1 2 + 3∆

DMBQ

Transimination

scHeme 4.9


species that is converted to the starting cat. [m] by reaction with [a] (hydrogen acceptor) or by release of H

2, (2) formation of a hemiacetal by nucleophilic addition

of an alcohol to the resulting carbonyl compound, and (3) [m]-catalyzed dehydro-genation (β-hydrogen elimination) of the hemiacetal to furnish an ester and [mH

2]

or [mH] species from which the starting cat.[m] is regenerated by reaction with [a] (hydrogen acceptor) or by release of H

2 (Scheme 4.10).

The dehydrogenative esterification of benzyl alcohol catalyzed by the complex 1 at high temperature (145 °C) was already reported in 1985 [8]. This section describes the recent progress of the dehydrogenative lactonization of diols and esterification of alcohols catalyzed by the complex 1 and the related complexes.

4.3.1 dehydrogenative lactonization of diols

4.3.1.1 Aerobic Lactonization of Diols Catalyzed by the Complex 1 it has been reported that a biomimetic electron transfer catalyst combination of 1, electron-rich dmBQ, and the Co(salen) complex (i) efficiently catalyzes the aerobic lactonization of various diols [9]. The same catalyst combination is used for the biomimetic aer-obic oxidation of alcohols (Chapter 3, Section 3.2.2). The reactions were carried out under air in chlorobenzene at 80 °C. Some examples are shown in Table 4.9. Among several ruthenium complexes and solvents examined, the complex 1 and chloroben-zene gave the best results. A variety of 1,4- and 1,5-diols were converted to the corresponding γ- and δ-lactones in good to high yields. The lactonization of 1,6-, 1,7- and 1,8-diols also proceeds well under diluted conditions to give the corresponding lactones in high yields.

A possible catalytic cycle for this biomimetic aerobic oxidation is proposed (Scheme 4.11). The initial thermal dissociation of the complex 1 generates complexes

R1 OR2

R1 OR2

Hemiacetal

O

OH

R2OH

R1 OH

R1 O

Cat. [M]

Hemiacetal formation

Carbonylcompound

[A] (hydrogen acceptor) or –2H2

H R2–OH

Cat. [M]



Cat. [MH2]or [MH]

Cat. [MH2]or [MH]

or –H2

or –H2

[A]

[A]

scHeme 4.10

Cat. 1 (0.5 mol%),DMBQ (20 mol%)

Co complex I (2 mol%)

Chlorobenzene, 80 °Cunder air, 24–48 h

OCo

N

O

NN

I


O

O

O


1

2

3

4

5

6

7

8

9

OHOH

O

O

R R

n n

O

O

O

O

OPh

O

O

+

95

73

92

91 (57:43)

O

O

NO

OPh

93

85

86

89

89

O

O

O

O

O

O

Table 4.9 Aerobic lactonization of diols catalyzed by 1 with DMBQ and Co complex (I).

OH

OHR

n

O

O

MeO OMe

I

∆1 2 + 3

OH

OH

MeO OMe2

3 [CoL]

[CoL]ox

I′

1/2O2

H2O

OH

OR

n

nO

OH

R

nO

O

R DMBQ

DMHQ

I

2

3 [CoL]

[CoL]oxI′

1/2O2

H2ODMHQ

CyclizationDMBQ

SCHeMe 4.11


2 and 3, and the former acts as an active catalytic species. The dehydrogenation of 1,n′-diols with the complex 2 produces n′-hydroxyaldehydes and the complex 3, which is oxidized with dmBQ to regenerate the complex 2 with concomitant formation of 2,6-dimethox-1,4-hydroquione (dmHQ). The reoxidation of dmHQ to dmBQ by air is mediated by the Co complex i. Cyclization of n′-hydroxyaldehydes producing lactols followed by the dehydrogenation with the complex 2 furnishes lactones and the complex 3, which is again aerobically oxidized to the complex 2 by the biomimetic electron transfer catalyst system.

4.3.1.2 Oppenauer-Type Lactonization of Diols Catalyzed by Fe Complexes with Acetone it has been reported that dehydrogenative lactonization of 1,4-diols is catalyzed by iron complexes (5a and 5b) bearing η5-hydroxycyclopentadienyl and η4-cyclopentadienone ligands, respectively [10a,10b]. Both complexes exhibit high catalytic activity for the Oppenauer-type oxidation of alcohols (Chapter 3, Section 3.2.3.2). While the complex 5a is air sensitive, the complex 5b is air stable and more easily handled. The reactions were carried out in acetone at 60 or 90 °C. examples are shown in Scheme 4.12.

4.3.1.3 Lactonization of Diols Catalyzed by the Complex 1 with Chloroform The complex 1 catalyzed the lactonization of diols using chloroform as a hydrogen acceptor [11]. The reactions were carried out in the presence of Na

2CO

3 in

FeTMS

OHTMS

CO5a

OC H

OH

OH

Cat. 5a (3 mol%)

Acetone, 60 °C, 8 h



O

O

Y = 87%

HOOH

Cat. 5a (3 mol%)O

O

Y = 84%

FeTMS

OTMS

CO5b

OC NCMeOH

OH O

O

Y = 98%

Cat. 5b (5 mol%)

scHeme 4.12

chloroform at 90 °C. A few examples are shown in Table 4.10. γ-, δ-, and ε-lactones were produced in excellent yields.

4.3.1.4 Lactonization of Diols Catalyzed by 1 without Hydrogen Acceptor it has been reported that the dehydrogenative lactonization of 1,4-butanediol is catalyzed by 1 at as high as 205 °C to give γ-butyrolactone with release of H

2

(Scheme 4.13) [12].

4.3.2 dehydrogenative esterification of alcohols

it has been reported that iodine-bridged bimetallic Ru complexes (6a and 6b), which exhibit high catalytic activity for oxidation of alcohols using Ag

2O (Chapter 3,

Section 3.2.4.2), also catalyze dehydrogenative esterification of alcohols using Ag

2O as a hydrogen acceptor [13]. The reactions were conducted in the presence

of Ag2O in CH

2Cl

2 at room temperature (Scheme 4.14). The complex 6a showed

higher catalytic activity than 6b.

Entry Product Yield (%) Entry Product Yield (%)

1

2

3

4

Cat. 1 (1 mol%)Na2CO3 (150 mol%)

CHCl3, 90 °C, 20 – 36 hOH

OH

n

R O

O

nR

O

O

O

O

O

OO

O

99

99

99

90

n = 1–3

taBle 4.10 dehydrogenative lactonization of diols catalyzed by 1 with CHCl3.

HOOH

Cat. 1 (0.5 mol%)

205 °C, 12 hO

O

(87 : 13)

+ 1,4-Butanediol + H2

scHeme 4.13

CARBON–OxygeN BONd-FORmiNg ReACTiONS 101


4.4 carBon–carBon Bond-Forming reactions Based on Hydrogen transFer and deHydrogenation

Whereas a tremendous amount of reports on C–C bond-forming reactions via hydrogen transfer process have appeared [3, 14], there have been only a few reports using 1 as the catalyst.

4.4.1 c-alkylation of indoles with amines catalyzed by 1

it has been reported that the complex 1 catalyzes the selective C-alkylation of indoles with amines at the C3-position of indoles [15]. Among the several complexes (Ru, Rh, and ir) examined, the complex 1 gave the best result. The reactions were carried out in the presence of K

2CO

3 at 140 °C for 24 h. Some examples are shown in

Table 4.11. excess amounts of a variety of primary and secondary amines including alkyl-, benzyl-, and heteroarylmethylamines were employed as the alkylating agents

Ru

OH

R

PhPh

R

Ru

O

R

PhPh

R

IOCCO CO

CO

Cat. 6 (2 mol%)Ag2O (100 mol%)

CH2Cl2rt, 3 or 10 h

6a: R = Ph6b: R = Me

C8H17OH C7C15CO2C8H17

6a: Y = 90%6b: Y = 86%

scHeme 4.14

Cat. 1 (1 mol%)K2CO3 (5 mol%)

140–160 °C, 24 h+

Entry

123

4

567

R1

HHH

H

MeOBrH

859487

89

958589

Yield (%)

NH

R1

R2

NH

R1

R2

R2 R3 R4

HHH

H

HH

Me

C6H133-ClC6H4CH2

4-MeOC6H4CH2

C6H13C6H13C6H13

R3

HN

R4

(R4 = H or R3)

R3

H3-ClC6H4CH2

H

C6H13C6H13C6H13

SCH2

SCH2

taBle 4.11 C-Alkylation of indoles with amines catalyzed by 1.

CARBON–CARBON BONd-FORmiNg ReACTiONS 103

to give 3-alkylated indoles in good to high yields. The reactions with primary amines required slightly higher temperature than those with secondary ones. it should be noted that the reaction of indole with trihexylamine also gave 3-hexylindole in 70% yield.

A possible catalytic cycle is proposed (Scheme 4.15). The unsaturated 16-electron complex 2, generated by the thermal dissociation of 1, dehydrogenates an amine to give an imine and the saturated complex 3. Base-promoted C-alkylation of indole with the imine at the C3-position followed by elimination of ammonia gives unsatu-rated 3-alkylene-3H-indole intermediate, which is hydrogenated by the saturated complex 3 to furnish 3-alkylated indole along with the starting complex 2.

4.4.2 alkylation of silylalkynes with amines catalyzed by 1

it has been reported that the complex 1 catalyzes the alkylation of terminal silylalkynes with tertiary amines [16]. The reactions were conducted with a large excess of tertiary amines (1–3 ml) at 100–150 °C for 7–46 h to give the corresponding aminoalkylated silylalkynes in moderate to good yields. examples are shown in Table 4.12. Addition of cyclohexanone (1 equiv) as a hydrogen acceptor improved the yields in the reactions with noncyclic amines (entries 2 and 4). However, the reaction with cyclic amines in the presence of cyclohexanone gave the hydrogenated silylalkane products (entry 6), indicating that the alkyne moiety could be hydrogenated by the initially formed cyclohexanol.

A possible catalytic cycle is proposed (Scheme 4.16). The unsaturated 16-electron complex 2 generated by the thermal dissociation of 1 dehydrogenates an amine to

R NH2

R NH

Cat. 2

Cat. 3

–NH3

HCat. 1, indole

NH3

1 2 + 3∆


Dehydrogenation Hydrogenation

NH

CH2R

NH

N

RCH

N

CHR

Base

NH2

scHeme 4.15


Cat. 2

([RuH])

1 2 + 3∆

R1

R1

H SiR3

(R1CH2)2N

R1

SiR3

++

H

(R1CH2)2N(R1CH2)2N

(R1CH2)2N

R1

SiR3

Cat. 1, H SiR3

Nucleophilic addition

–H2

H2 or Hydrogenation ofcyclohexanone

Cat. 3



Iminium ion

scHeme 4.16

Cat. 1 (1 mol%)

100–150 °C20–46 h

+

Entry

12a

34a

5

6a

7

(C4H9)3N(C4H9)3N

Et3N(C6H13)3N

Yield (%)

a Cyclohexanone (1 equiv) was added.

Product

R3Si H

(R1CH2)3NR3Si

N(CH2R1)2

R1

or

R3Si

or

NMe

Amine Temperature (°C) Time (h)

150150100150

120

150

150

20244024

30

19

20

CHMeNEt2CH(C5H11)N(C6H13)2

NMe

NMe

NMe

NMe

NMe

NMe

NMe

55715775

39

32

65

Me3Si

Me3Si

Me3Si

Me3Si

Me3SiMe3Si

Me3SiCH(C3H7)N(C4H9)2CH(C3H7)N(C4H9)2

taBle 4.12 Alkylation of terminal silylalkynes with tertiary amines catalyzed by 1.

ReFeReNCeS 105

give an iminium ion and the postulated ruthenium monohydride complex [RuH]. Nucleophilic addition of a silylalkyne to the iminium ion followed by dehydrogena-tion gives the aminoalkylated silylalkyne product along with the complex 3, which is dehydrogenated by release of H

2 or hydrogenation of cyclohexanone to regenerate

the staring complex 2.

reFerences

[1] Shvo y, Czarkie d, Rahamim y, Chodosh, dF. J Am Chem Soc 1986;108:7400 and refer-ences cited therein.

[2] For reviews: (a) Karvembu R, Prabhakaran R, Natarajan K. Coord Chem Rev 2005;249:911. (b) Bullock Rm. Angew Chem int ed 2007;46:7360. (c) Conley Bl, Pennington-Boggio mK, Boz e, Williams TJ. Chem Rev 2010;110:2294. See also (d) Prabhakaran R. SyNleTT 2004:2048. (e) Samec JSm, Bäckvall J-e. Hydroxytetraphenylcyclopen- tadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(ii). in: Fuchs, Pl, editor. Encyclopedia of Reagents for Organic Synthesis. Vol. 7. 2nd ed. New york: Wiley; 2009. p 5557–5564.

[3] For recent representative reviews: (a) Hamid mHSA, Slatford PA, Williams JmJ. Adv Synth Catal 2007;349:1555. (b) Nixon Td, Whittlesey mK, Williams JmJ. dalton Trans 2009:753. (c) Fujita K, yamaguchi R. Catalytic activities of Cp* iridium complexes in hydrogen transfer reactions. in: Oro lA, Claver C, editors. Iridium Complexes in Organic Synthesis. Weinheim: Wiley-VCH Verlag gmbH; 2009. p 107–143. (d) ishii y, Obora y, Sakaguchi S. iridium-catalyzed coupling reactions. in: Oro lA, Claver C, editors. Iridium Complexes in Organic Synthesis. Weinheim: Wiley-VCH Verlag gmbH; 2009. p 251–275. (e) dobereiner ge, Crabtree RH. Chem Rev 2010;110:681. (f) Obora y, ishii y. SyNleTT 2011;30. (g) Suzuki T. Chem Rev 2011;111:1825. (h) marr AC. Catal Sci Technol 2012;2:279.

[4] (a) Fujita K, yamaguchi R. SyNleTT 2005:560. (b) Krüger K, Tillack A, Beller m. ChemSusChem 2009;2:715. (c) Watson AJA, Williams JmJ. Science 2010;329:635. (d) guillena g, Ramón dJ, yus m. Chem Rev 2010;110:1611. (e) yamaguchi R, Fujita K, zhu m. Heterocycles 2010;81:1093. (f) Norinder J, Börner A. ChemCatChem 2011;3:1407. (g) Bähn S, imm S, Neubert l, zhang m, Neumann H, Beller m. ChemCatChem 2011;3:1853.

[5] (a) Bähn S, imm S, mevius K, Neubert l, Tillack A, Williams JmJ, Beller m. Chem eur J 2010;16:3590. (b) Segarra C, mas-marza e, mata JA, Peris e. Adv Synth Catal 2011;353:2078.

[6] (a) Hollmann d, Bähn S, Tillack A, Beller m. Angew Chem int ed 2007;46:8291. (b) Hollmann d, Bähn S, Tillack A, Beller m. Chem Commun 2008:3199. (c) Bähn S, Hollmann d, Tillack A, Beller m. Adv Synth Catal 2008;350:2099. (d) Bähn S, imm S, Neubert l, zhang m, Neumann H, Beller m. Chem eur J 2011;17:4705. (e) Hollmann d, Bähn S, Tillack A, Parton R, Altink R, Beller m. Tetrahedron lett 2008;49:5742.

[7] Blacker AJ, Farah mm, marsden SP, Saidi O, Williams JmJ. Tetrahedron lett 2009;50:6106.

[8] Blum y, Shvo y. J Organomet Chem 1985;282:C7.

[9] endo y, Bäckvall J-e. Chem eur J 2011;17:12596.


[10] (a) Coleman mg, Brown AN, Bolton BA, guan H. Adv Synth Catal 2010;352:967. (b) Plank TN, drake Jl, Kim dK, Funk TW. Adv Synth Catal 2012;354:597.

[11] Jung Hm, Choi JH, lee SO, Kim yH, Park JH, Park J. Organometallics 2002;21:5674.

[12] zhao J, Hartwig JF. Organometallics 2005;24:2441.

[13] do y, Ko S-B, Hwang i-C, lee K-e, lee SW, Park J. Organometallics 2009;28:4624.

[14] guillena g, Ramón dJ, yus m. Angew Chem int ed 2007;46:2358.

[15] imm S, Bähn S, Tillack A, mevius K, Neubert l, Beller m. Chem eur J 2010;16:2705.

[16] Jovel i, Prateeptongkum S, Jackstell R, Vogl N, Weckbecker C, Beller m. Chem Commun 2010;46:1956.

Pincer Ligands in TransiTion MeTaL caTaLyzed Hydrogen Transfer and deHydrogenaTive reacTions

ParT iii


109

DehyDrogenation of alkanes CatalyzeD by transition Metal CoMplexes bearing pinCer liganDs

5

5.1 introDuCtion

The aim of this chapter is to survey the dehydrogenative reactions of alkanes catalyzed by transition metal complexes having pincer ligands. Herein, catalytic dehydrogenative reactions of alkanes will be classified into four types: (i) conversion of alkanes into alkenes based on hydrogen transfer, (ii) dehydroaromatization of alkanes based on hydrogen transfer, (iii) alkane metathesis by tandem alkane dehy-drogenation and alkene metathesis, and (iv) conversion of alkanes into alkenes based on dehydrogenation. This chapter is not intended to be comprehensive. Earlier reviews on the topics described in this chapter are available [1].

5.2 Conversion of alkanes into alkenes baseD on hyDrogen transfer

5.2.1 iridium Complex with pCp-pincer ligand

The iridium complex 1 bearing a PCP-pincer ligand was found to be a good catalyst for conversion of cycloalkanes to cycloalkenes based on hydrogen transfer (transfer dehydrogenation of cycloalkanes) [2]. When the reaction of cyclooctane and t-butyl-ethylene in the presence of 1 was conducted at 150 °C, cyclooctene was formed at the rate of 82 turnovers per hour (Scheme 5.1). At 200 °C, rate of the reaction

110 DEHyDrogEnATion of AlkAnES CATAlyzED by PinCEr CoMPlEXES

increased up to 12 min−1. Similar rhodium complex, [rhH2{C

6H

3(CH

2Ptbu

2)

2-2,6}],

also catalyzed the same reaction with rate of 1.8 min−1 at 200 °C; however, its activity was significantly lower than the iridium complex 1.

The iridium complexes bearing a PCP-pincer ligand also exhibit transfer dehydrogenation of n-alkanes. results of the reactions of octane at 150 °C cata-lyzed by the iridium complexes 1 and 2 are summarized in Table 5.1 [3]. With a short reaction time (10 or 15 min), 1-octene was the predominant product, indi-cating that the initial activation of alkane would proceed at terminal position. However, with longer reaction time (60 min), subsequent isomerization leads to the formation of thermodynamically stable internal alkenes. Additionally, the complex 2 with iPr

2P moiety was more catalytically active than the complex 1

with tbu2P moiety.

The mechanism for the conversion of alkanes to alkenes based on hydrogen transfer catalyzed by iridium complexes bearing a PCP-pincer ligand would be as follows (Scheme 5.2). firstly, insertion of sacrificial alkene (t-butylethylene) into an iridium–hydride bond followed by reductive elimination of alkane (t-butylethane) occurs to generate an unsaturated 14e− iridium species. Then, oxidative addition of C–H bond in substrate alkane takes place to generate an alkyl hydrido iridium species. finally, β-hydrogen elimination occurs to afford alkene as a product and regenerate the dihydrido iridium species.

influence of the steric bulkiness of the substituents on the phosphorus atoms in the PCP-pincer ligand toward the catalytic activity for transfer dehydrogenation of octane was investigated [4]. As shown in Scheme 5.3, when the tetrahydrido complex 3 (1 mM) with four tbu groups on phosphorus atoms was used as a catalyst, concentration of formed octenes was 68 mM after the reaction at 150 °C for 60 min. The complex 4 with four iPr groups showed higher catalytic activity to give 265 mM of octenes. The optimal catalyst was the complex 5 with three tbu groups and one Me group, giving 446 mM of products after 60 min. These experimental results were in accord with the computational studies.

The iridium complexes 6 and 7 bearing a metallocene-based PCP-pincer ligand have been synthesized, and their high catalytic activity in the transfer dehydrogena-tion of cycloalkane was revealed [5]. As shown in Scheme 5.4, very large turnover

PtBu2

PtBu2

IrH

H

+

Cat.

tButBu+

TOF at 150 °C: 82 h–1

TOF at 200 °C: 12 min–1

37 mmol 1.6 mmol

1 (0.0051 mmol)

sCheMe 5.1

(PCP)IrH2

(PCP)Ir

tBu

HH

(PCP)Ir

Ir(PCP)

R

H

tBu

tBuR

R

sCheMe 5.2

PR2

PR2

IrH

H

Cat.

Octane +

Norbornene [nbe]or

t-Butylethylene [tbe]

Hydrogenacceptor

Catalyst Acceptor Time (min) 1-Oct Other

nbe(0.5 M)

nbe(0.5 M)

nbe(0.2 M)

tbe(0.5 M)

153060

103060

103060

103060

232730

195959

23406

274441

47

15

256

105

44582

665

103

235

14071

34340

64578

000

003

03

63

01

19

Total

293750

22154238

30132208

40155250

150 °C

Concentration of product in mM

1 or 2 (1 mM)1-Octene + 2-Octenes + Others

cis-2-Octtrans-2-Oct

R = tBu (1)(1 mM)

R = iPr (2)(1 mM)

R = iPr (2)(1 mM)

R = iPr (2)(1 mM)

table 5.1 Transfer dehydrogenation of octane catalyzed by 1 and 2.


numbers 3300 and 2571 were achieved with the complex 6 with ferrocene-PCP ligand and the complex 7 with ruthenocene-PCP ligand, respectively, in the reaction of cyclooctane and t-butylethylene (molar ratio = 1:1) at 180 °C for 8 h.

The iridium complex 9 bearing a p-methoxy-substituted PCP-pincer ligand was proven to be a highly effective catalyst for the transfer dehydrogenation of n-alkane (Table 5.2) [6]. The reaction of octane with norbornene (nbe, 790 mM) in the presence of 9 (15 mM) at 150 °C for 60 min resulted in 100% hydrogenation of nbe along with the formation of octenes (787 mM). The catalytic activity of 9 was much higher than similar complexes 1 and 8.

The iridium complex 10 bearing a bisphosphinite-based PCP-pincer ligand also showed catalytic activity for the transfer dehydrogenation of alkanes [7]. When the reaction of cyclooctane (37 mmol) and t-butylethylene (1.6 mmol) was performed in

150 °C

PR2

PRRʹ

IrH4

Cat.

Concentration (mM) of octenes after 60 min

with cat. 3 (R = tBu, Rʹ = tBu): 68

with cat. 4 (R = iPr, Rʹ = iPr): 265

with cat. 5 (R = tBu, Rʹ = Me): 446

Octane +

Initial conc.0.45 M

(1 mM)

tBu tBuOctenes +

3–5

sCheMe 5.3

+

Cat.

tButBu

+

M

Ir

P

P

H

H

tBu2

tBu2

1 : 1 (mol : mol)

180 °C, 8 h

TONM = Fe (6): 3300M = Ru (7): 2571

6 or 7

sCheMe 5.4

ConVErSion of AlkAnES inTo AlkEnES bASED on HyDrogEn TrAnSfEr 113

the presence of 10 (0.006 mmol) at 200 °C, cyclooctene was formed with a turnover rate of 13 min−1 (Scheme 5.5). This catalytic activity was slightly higher than that of bisphosphinite-based PCP-pincer complex 1.

Systematic study on the influence of the substituent at the p-position of the aro-matic ring in bisphosphinite-based PCP-pincer ligand toward the catalytic transfer dehydrogenation of cyclooctane was performed (Table 5.3) [8]. The complexes 15 and 16 having electron-withdrawing groups [C

6f

5 and 3,5-(Cf

3)

2C

6H

3] showed high

catalytic activity giving cyclooctene after 2398 min with turnover number of 2041

150 °COctane + Norbornene

(nbe)

Catalyst (15 mM)Octenes + Norbornane

Time (min)

Cat.

[Octenes] [nbe]

IrH

H

PtBu2PtBu2

PtBu2

IrH

HMeO Ir

H

HMeO

Cat. Cat.

[Octenes] [nbe] [Octenes] [nbe]

0

10

20

30

60

0

163

234

277

393

790

615

550

503

378

0

113

167

211

352

790

638

580

540

390

0

234

435

612

787

790

560

350

181

0

Concentration (mM)1 8 9

PtBu2 PiPr2

PiPr2

table 5.2 Transfer dehydrogenation of octane catalyzed by 1, 8, and 9.

O

O

PiPr2

PiPr2

IrH

H

+

Cat.

tButBu+

TOF: 13 min–137 mmol 1.6 mmol

10 (0.006 mmol)

H

H

200 °C

sCheMe 5.5


and 2070, respectively. on the other hand, with the complex 11 having an electron-donating group (oMe), the yield of cyclooctene was lower in a shorter reaction time (8 min); however, in the course of further reaction (after 2398 min), turnover number became close to those of 15 and 16.

5.2.2 iridium Complex with CCC-pincer ligand

not only the PCP-pincer iridium complexes mentioned earlier but also the CCC-pincer iridium complexes have been studied as catalysts for the transfer dehydrogenation of alkanes. The iridium complex 18 bearing a CCC-pincer n-heterocyclic carbene ligand has been prepared, and its catalytic performance in the transfer dehydrogena-tion of cyclooctane was examined (Scheme 5.6) [9]. However, its activity was quite low compared to those of PCP-pincer iridium complexes.

5.2.3 ruthenium Complex with pCp-pincer ligand

The ruthenium complex 19 bearing a π-accepting PCP-pincer ligand with Cf3 groups

on phosphorus atom has been prepared, and its catalytic activity for the transfer dehydrogenation of cycloalkanes was investigated (Scheme 5.7) [10]. When the reac-tion of cyclooctane with t-butylethylene (molar ratio = 1:1) was carried out in the presence of 19 (1.65 × 10−4 mol%) at 200 °C, the catalytic activity ceased after only

Time (min)

8

918

2398

806

1674

1904

811

1413

1484

Cat. O

O

IrH

ClX

Cat.

PtBu2

PtBu2

tBu

PtBu2

PtBu2

IrH

Cl

++

1 : 1 (mol : mol)

200 °C

922

1512

1583

840

1465

1530

1150

1863

2041

1162

1893

2070

156

212

227

(17)TON

Ar = 3,5-bis(tri�uoromethyl)phenyl

X = OMe(11)TON

X = Me(12)TON

X = H(13)TON

X = F(14)TON

X = C6F5(15)TON

X = Ar(16)TON

Catalyst / NaOtBu(0.033mol%)tBu

table 5.3 Transfer dehydrogenation of cyclooctane catalyzed by 11–17.

DEHyDroAroMATizATion of AlkAnES bASED on HyDrogEn TrAnSfEr 115

30 min with turnover number of 186, showing lower catalytic performance than iridium PCP-pincer complexes.

5.3 DehyDroaroMatization of alkanes baseD on hyDrogen transfer


The iridium complex 1 bearing a PCP-pincer ligand was found to be a good catalyst for the dehydrogenative aromatization of cycloalkanes based on hydrogen transfer. results of the dehydroaromatization of a variety of substrates are summarized in Table 5.4 [11]. for example, when the reaction of cyclohexane (4.0 ml) and t-butylethylene (0.20 ml, 1.55 mmol) in the presence of 1 (0.005 mmol) was conducted at 150 °C for 1 h, indicated amounts of benzene and cyclohexene were formed along with t-butylethane. With this catalytic system, dehydroaromatization of methylcyclohexane, ethylcy-clohexane, decaline, and tetrahydrofuran was also accomplished.

N

NIr

N

MesN

N

C

Me

Cl

H

18

Mes

sCheMe 5.6

+

Cat.

tButBu+

200 °C, 30 min

P(CF3)2

P(CF3)2

Rucod

H

TON = 186

19 (1.65 × 10−4 mol%)

1 : 1 (mol : mol)

sCheMe 5.7


Dehydroaromatization of n-alkanes has been achieved by using the iridium complexes bearing a PCP-pincer ligand as a catalyst [12]. The most effective catalyst was found to be the iridium complex 20 having a hybrid phosphine/phosphonite PCP-pincer ligand (Scheme 5.8). The reaction of hexane (1.53 M) with t-butylethyl-ene (6.13 M) catalyzed by 20 (0.005 M) at 165 °C for 120 h resulted in the formation of benzene in 44% yield (0.670 M).

Dehydroaromatization of octane was also accomplished by using 20 as a catalyst with greater efficiency, giving o-xylene and ethylbenzene in high total yield (Scheme 5.9) [12]. The formation of o-xylene was predominant over ethylbenzene. furthermore, dehydroaromatization of decane catalyzed by 20 gave o-propyltoluene, 1,2-diethylbenzene, and butylbenzene (Scheme 5.9). it should be noted that the syn-thesis of aromatic product having linear alkyl substituent has been achieved using abundant alkanes as starting materials.

PtBu2

PtBu2

IrH

H

Cat.

tBuSubstrate + Products +

Substrate Time (h) Temperature(˚C)

Products (mol/mol of 1)

(Tba)

Cyclohexane

Cyclohexane

Methylcyclohexane

Methylcyclohexane

Methylcyclohexane

Decalin

Tetrahydrofuran

Ethylcyclohexane

1

0.5

1

1

120

72

1

1

150

200

150

200

150

150

200

200

Methylcyclohexanes: 1 (8), 3 (20), 4 (41),Toluene (11), Tba (105)



Dihydrofuranes: 2,3 (86), 3,4 (6),Furan (53), Tba (192)

Ethylcyclohexenes (13), Ethylbenzene (43),Styrene (76), Tba (441)

(4.0 ml) (0.20 ml, 1.55 mmol)

Cyclohexene (44), Benzene (54),Tba (211)

Cyclohexene (86), Benzene (77),Tba(310)

Octahydronaphthalenes (24),Tetrahydronaphthalene (8),Naphthalene (8), Tba (71)

1 (0.005 mmol)tBu

table 5.4 Dehydroaromatization of cycloalkanes based on hydrogen transfer catalyzed by 1.

DEHyDroAroMATizATion of AlkAnES bASED on HyDrogEn TrAnSfEr 117

tBu

tBu tBu

tBu3 3

Catalyst

Catalyst

+tBu

O PiPr2

PiPr2

Ir

Cat.

tBu+

1.53 M 6.13 M

165 °C, 120 h

0.670 M(44%)

20 (0.005 M)

sCheMe 5.8

+tBu

O PiPr2

PiPr2

PiPr2

PiPr2

Ir

Cat.

tBu+

1.46 M 5.84 M

165 °C, 118 h

165 °C, 120 h

75%

n-C8H18

n-C10H22

20 (0.005 M)

20 (0.005 M)

+

11%

+tBu

O

Ir

Cat.

tBu

+1.39 M 5.57 M

45%

+

5%

2% 2%

sCheMe 5.9


5.4 alkane Metathesis by tanDeM alkane DehyDrogenation anD alkene Metathesis


An intriguing system for the alkane metathesis by tandem alkane dehydrogenation and alkene metathesis using combinations of the PCP-pincer complexes of iridium and the Schrock-type molybdenum complexes as catalysts has been developed [13]. The reaction pathway of alkane metathesis is as follows (Scheme 5.10): (i) dehydro-genation of alkane (C

n) at terminal position catalyzed by PCP-pincer iridium com-

plex to generate 1-alkene (Cn), (ii) catalytic alkene metathesis to afford internal

alkene (C2n−2

) and ethylene, and (iii) hydrogenation of these alkenes to give alkane (C

2n−2) and ethane.

The combination of the PCP-pincer iridium complex 1 and the Schrock-type molybdenum complex 22 was effective for the tandem alkane metathesis based on the reaction pathway shown earlier (Scheme 5.11) [13]. When the reaction of hexane (7.6 M) was conducted in the presence of 1 (10 mM), 22 (6.4 mM), and t-butylethyl-ene (20 mM) at 125 °C for 23 h, various n-alkanes (C

2 to C

15) were obtained in a total

concentration of 1250 mM. The reaction using 21 (10 mM) and 22 (16 mM) pro-ceeded more efficiently to give n-alkanes (C

2 to C

15) in a total concentration of

2050 mM after 24 h.in the catalytic system for tandem alkane metathesis, selection of the catalyst

for alkene metathesis was highly important because the molybdenum catalyst was relatively unstable at high reaction temperature, while the iridium catalyst for alkane dehydrogenation was more stable. After a number of molybdenum and tungsten alkylidene catalysts were surveyed, it was revealed that the combination of PCP-pincer iridium complex 23 and alkylidene tungsten com-plex 24 was highly effective for the metathesis of octane to give products of C

2

R2

R2R

R

H2C CH2

+

RR

C2H6

+

Dehydrogenation catalyst [M]Alkene metathesis catalyst [Mʹ ]=CX2

[M]

[M]H

H

[Mʹ ] CX2


sCheMe 5.10

AlkAnE METATHESiS by TAnDEM AlkAnE DEHyDrogEnATion 119

to C15

in the total concentration of 3380 mM by the reaction at 125 °C for 4 days (Scheme 5.12) [14].

The dual catalyst system for alkane metathesis using thermally stable hetero-geneous alkene metathesis catalyst re

2o

7/Al

2o

3 in combination with PCP-pincer

complex of iridium as alkane dehydrogenation catalyst has been also reported [13, 15].

The combination of PCP-pincer iridium complex 25 and Schrock-type molybdenum complex 22 was also effective for the oligomerization of cycloalkanes based on alkane metathesis (Scheme 5.13) [16]. The reaction of cyclooctane (0.75 ml) in the presence of 25 (10 mM), 22 (6.5 mM), and t-butylethylene (20 mM) at 125 °C for 12 h gave cyclooligomers C

16H

32, C

24H

48, C

32H

64, and C

40H

80 in the yields of 14,

10, 5.6, and 2.7%, respectively.Proposed mechanism for the oligomerization of cycloalkanes based on alkane

metathesis is illustrated in Scheme 5.14 [16].

X

X

PtBu2

PtBu2

IrH

H

1 or 21 (10 mM)Hexane

7.6 M

Dehydrogenation catalyst

NMo

CHC(CH3)2Ph

(H3C)(F3C)2CO

(H3C)(F3C)2CO

iPr

iPr

Ole�n metathesis catalyst

C2 to C15products

22 (6.4 or 16 mM)

tBu (20 mM) 125 °C

Product concentration (mM)

C2 C3 C4 C5 C7 C8 C9 C10 C11 C12 C13 C14 C15

131 176 127 306 155 37 49 232 18 4 4 10 2

Total

C2 C3 C4 C5 C7 C8 C9 C10 C11 C12 C13 C14 C15 Total

1250with 1 (X = CH2)and 22 (6.4 mM)

2050with 21 (X = O)and 22 (16 mM) 458 345 547 258 151 139 95 29 13 6 3 2

Reaction time (h)Catalyst

23

24

sCheMe 5.11

O

O

PtBu2

PtBu2

Ir

23 (10 mM)Octane


NW

CHC(CH3)2Ph

Ph3SiO

Ph3SiO

iPr

iPr


C2 to C15 products24 (16 mM)

125 °C, 4 daysTotal concentration

3380 mM

sCheMe 5.12


[M] [M]H

H[Mʹ ]

[Mʹ]

CX2

X2C

[Mʹ]

X2C

Higheroligomers

[M]: Dehydrogenation catalyst[Mʹ ]=CX2: Alkene metathesis catalyst

sCheMe 5.14

C6 to C40cycloalkanes

125 °C, 12 h

PtBuMe

PtBu2

IrH

H

25 (10 mM)


NMo

CHC(CH3)2Ph

(H3C)(F3C)2CO

(H3C)(F3C)2CO

iPr

iPr


22 (6.5 mM)

tBu (20 mM)0.75 ml

Cycloalkanes (% by weight)

C6 C7 C15 C16 C17 C24 C32 C33 C40

0.1 0.3 0 14 0.3 10 5.6 0.2 2.7

Sum of C6 to C40 product

34

sCheMe 5.13

ConVErSion of AlkAnES inTo AlkEnES bASED on DEHyDrogEnATion 121

5.5 Conversion of alkanes into alkenes baseD on DehyDrogenation


The iridium complex 1 bearing a PCP-pincer ligand was found to be an efficient catalyst for acceptorless dehydrogenation of cycloalkanes to cycloalkenes accompa-nying the evolution of hydrogen gas [17]. for example, refluxing cyclodecane (201 °C) in the presence of 1 gave cyclodecene in turnover numbers of 170 and 360 after 4 and 24 h, respectively (Scheme 5.15).

The mechanism for the conversion of alkanes to alkenes based on dehydrogena-tion (acceptorless dehydrogenation) catalyzed by iridium complexes bearing a PCP-pincer ligand would be as follows (Scheme 5.16). firstly, oxidative addition of C–H

PtBu2

PtBu2

IrH

H

Cyclodecane Cyclodecene + H2Re�ux (201 °C)

Cat.

TON after 4 h: 170after 24 h: 360

1

sCheMe 5.15

PR2

PR2

Ir

PR2

PR2 PR2

PR2

IrH

HIr

H

Rʹ

Rʹ H

Alkene

H2

Oxidativeaddition

β-Hydrogenelimination

Reductiveelimination

sCheMe 5.16


bond in substrate alkane to a 14e− iridium species would occur to generate an alkyl hydrido iridium complex. Then, β-hydrogen elimination takes place to afford alkene as a product along with the dihydrido iridium species. finally, reductive elimination of hydrogen (H

2) proceeds to regenerate the catalytically active 14e− iridium species.

The iridium complex 2 bearing a sterically less crowded PCP-pincer ligand with iPr substituents on phosphorus atoms showed higher catalytic activity in acceptorless dehydrogenation of cycloalkanes, giving cycloalkenes with turnover numbers close to 1000 after 20 h (Table 5.5) [18].

influence of the steric bulkiness of the substituents on the phosphorus atoms in the PCP-pincer ligand toward the catalytic activity for acceptorless dehydrogenation of cyclodecane was investigated [4]. reactions of cyclodecane at 230 °C were performed using 3–5 as catalysts (Scheme 5.17). The complex 5 with three tbu groups and one Me group was found to be the best catalyst, giving dehydrogenated products with turnover number of 929 after 4 h. This order of the catalytic activities of 3–5 was same as that in the case for transfer dehydrogenation of alkanes previously mentioned in Scheme 5.3.

Acceptorless dehydrogenation of acyclic linear alkane was also accomplished by using the PCP-pincer complexes of iridium 3–5 as catalysts (Scheme 5.18) [4]. However, turnover numbers of the catalyst were far smaller than those for the reactions of cycloalkanes. in the acceptorless dehydrogenation of undecane, the order of the catalytic activity was 5 > 3 > 4.

The iridium complex 26 bearing a PCP-pincer ligand with adamantyl substituent on the phosphorus atoms was prepared, and its catalytic performance in the acceptor-less dehydrogenation of cyclodecane was compared with 1 and 2 (Scheme 5.19) [19]. introduction of adamantyl group would contribute to improve the stability of the complex at high temperature, since cyclometalation or phosphorus–carbon bond cleavage, which could lead to the decomposition of the catalyst in the case of 1 or 2,

table 5.5 Acceptorless dehydrogenation of cyclodecane catalyzed by 2.

PiPr2

PiPr2

IrH

H

CyclodecaneRe�ux (201 °C)

−H2

Cat.

Cyclodecenes + Diethylcyclohexanes(DEC)

Time (h)

Turnover number (TON)

cis-Cyclodecene

1

4

8

20

378

619

692

700

82

145

163

163

16

38

42

43

10

59

79

81

2

trans-DECcis-DECtrans-Cyclodecene

Cyclodecene+

Diethylcyclohexanes+

H2230 °C

PR2

PRRʹ

IrH4

TON after 4 h

R = tBu, Rʹ = Me (5): 929

R = tBu, Rʹ = tBu (3): 298R = iPr, Rʹ = iPr (4): 400

3–5

Cyclodecane

Cat.

sCheMe 5.17

230 °C

PR2

PRRʹ

IrH4

Cat.

TON after 4 h

R = tBu, Rʹ = tBu (3): 49R = iPr, Rʹ = iPr (4): 21

R = tBu, Rʹ = Me (5): 57

Undecane

1-Undecene+

2-Undecenes+

H2

sCheMe 5.18

PAd2

PAd2

IrH

H

CyclodecaneRe�ux (201 °C)

Cat.

Catalyst (1.0 mM)

Total cyclodecenes (mM)

After 1 h reaction

After 24 h reaction

PtBu2

PtBu2

IrH

H

Cat. PiPr2

PiPr2

IrH

H

Cat.

74

509

102

267

136

364

26Ad = adamantyl

1 2

Cyclodecenes + H2

sCheMe 5.19


would be suppressed. Actually, although the turnover numbers in shorter reaction time (1 h) using 27 were no greater than those of 1 and 2, total turnover number (509) after 24 h was noticeably greater than those of 1 and 2.

The iridium complex 27 bearing an anthraphos-type PCP-pincer ligand has been prepared, and this complex was found to be stable even at 250 °C [20]. Thus, the catalytic activity of 27 in the acceptorless dehydrogenation of cyclodecane was examined (Scheme 5.20). The reaction of cyclodecane at 250 °C gave cyclodecene with turnover numbers of 40 and 136 after 1 and 148 h, respectively. However, these values were smaller than those obtained by the reactions catalyzed by other normal PCP-pincer complexes of iridium such as 1.

The iridium complex 9 bearing a p-methoxy-substituted PCP-pincer ligand with iPr group on phosphorus atoms was proven to be a highly effective catalyst for the acceptorless dehydrogenation of cycloalkanes (Scheme 5.21) [6]. The reaction of

Cyclodecane Cyclodecene + H2250 °C

TON after 1 h:after 148 h:

40136

Ir

H H

Cat.

27

tBu2P PtBu2

sCheMe 5.20

Cyclodecane250 °C

PR2

PR2

IrXH

H

Cat.

TON after 4 h

X = H, R = tBu (1):X = OMe, R = tBu (8):X = OMe, R = iPr (9):

170430714

TON after 24 h

X = H, R = tBu (1):X = OMe, R = tBu (8):

X = OMe, R = iPr (9):

3608202120

Cyclodecene + H2

sCheMe 5.21

ConVErSion of AlkAnES inTo AlkEnES bASED on DEHyDrogEnATion 125

cyclodecane catalyzed by 9 at 250 °C resulted in the formation of cyclodecene accom-panying the evolution of hydrogen with turnover numbers of 714 and 2120 after 4 and 24 h, respectively. The catalytic activity of 9 was much higher than similar complexes 1 and 8.

5.5.2 iridium Complex with CCC-pincer ligand

Catalytic performance of the iridium complex 18 bearing a CCC-pincer ligand in the acceptorless dehydrogenation of cycloalkanes was studied (Scheme 5.22) [9]. When the reaction of cyclooctane in the presence of 18 (1.0 mM) and naotbu (2.0 mM) was carried out under reflux for 20 h, cyclooctene was formed with turnover number of 68. However, catalytic activity of 18 was lower than that of PCP-pincer complexes of iridium.

5.5.3 ruthenium Complex with pCp-pincer ligand

Catalytic activity of the ruthenium complex 19 bearing a PCP-pincer ligand with Cf3

groups on phosphorus atom in the acceptorless dehydrogenation of cyclooctane was investigated (Scheme 5.23) [10]. The reaction of cyclooctane catalyzed by 19 (2.5 mM) under reflux (~140 °C at 590 Torr) gave cyclooctene with turnover number of 10 after 1 h. Although catalytic activity of 19 was comparable to that of PCP-pincer

NIr

N

MesN

N

C

Me

Cl

H

Cat.

18(1.0 mM)

TON = 68

NaOtBu (2.0 mM)Re�ux, 20 h

MesN

sCheMe 5.22

P(CF3)2

Rucod

H

Cat.

TON = 10

Re�ux at ~ 140 °C, 590 Torr of N21 h

P(CF3)2

19(2.5 mM)

sCheMe 5.23


complexes of iridium such as 1 under similar conditions, the catalytic lifetime of 19 was very limited.

The mechanism for the acceptorless dehydrogenation of alkanes to alkenes catalyzed by a PCP-pincer complex of ruthenium would be as follows (Scheme 5.24) [10]. firstly, oxidative addition of an alkane to four-coordinate 14e− hydrido ruthe-nium species would occur to generate an alkyl dihydrido complex. Then, reductive elimination of hydrogen takes place to afford an alkyl ruthenium species. finally, β-hydrogen elimination occurs to give the alkene product along with the catalytically active 14e− hydrido ruthenium species.

referenCes

[1] Several insightful reviews on the topics described in this chapter have been published. (a) Jensen CM. Chem Commun 1999:2443. (b) Albrecht M, van koten g. Angew Chem int Ed 2001;40:3750. (c) Serrano-becerra JM, Morales-Morales D. Curr org Synth 2009;6:169. (d) Albrecht M, Morales-Morales D. Pincer-type iridium complexes for oragnic transforma-tions. in: oro lA, Claver C, editors. Iridium Complexes in Organic Synthesis. Weinheim: Wiley-VCH Verlag gmbH; 2009. p 299–323. (e) Choi J, MacArthur AHr, brookhart M, goldman AS. Chem rev 2011;111:1761.

[2] gupta M, Hagen C, flesher rJ, kaska WC, Jensen CM. Chem Commun 1996:2083.

[3] liu f, Pak Eb, Singh b, Jensen CM, goldman AS. J Am Chem Soc 1999;121:4086.

[4] kundu S, Choliy y, zhuo g, Ahuja r, Emge TJ, Warmuth r, brookhart M, krogh-Jespersen k, goldman AS. organometallics 2009;28:5432.

PR2

PR2

Ru

PR2

PR2

Ru Ru

RʹHAlkene

H2

H

H

H

Rʹ

Rʹ


Oxidative addition


PR2

PR2

sCheMe 5.24

rEfErEnCES 127

[5] kuklin SA, Sheloumov AM, Dolgushin fM, Ezernitskaya Mg, Peregudov AS, Petrovskii PV, koridze AA. organometallics 2006;25:5466.

[6] zhu k, Achord PD, zhang X, krogh-Jespersen k, goldman AS. J Am Chem Soc 2004;126:13044.

[7] Morales-Morales D, redón r, yung C, Jensen CM. inorganica Chim Acta 2004;357:2953.

[8] (a) göttker-Schnetmann i, White P, brookhart M. J Am Chem Soc 2004;126:1804. (b) göttker-Schnetmann i, White P, brookhart M. organometallics 2004;23:1766. (c) göttker-Schnetmann i, brookhart M. J Am Chem Soc 2004;126:9330.

[9] Chianese Ar, Mo A, lampland nl, Swartz rl, bremer PT. organometallics 2010;29:3019.

[10] gruver bC, Adams JJ, Warner SJ, Arulsamy n, roddick DM. organometallics 2011;30:5133.

[11] (a) gupta M, kaska WC, Jensen CM. Chem Commun 1997:461. (b) gupta M, Hagen C, kaska WC, Cramer rE, Jensen CM. J Am Chem Soc 1997;119:840.

[12] Ahuja r, Punji b, findlater M, Supplee C, Schinski W, brookhart M, goldman AS. nat Chem 2011;3:167.

[13] goldman AS, roy AH, Huang z, Ahuja r, Schinski W, brookhart M. Science 2006;312:257.

[14] bailey bC, Schrock rr, kundu S, goldman AS, Huang z, brookhart M. organometallics 2009;28:355.

[15] Huang z, rolfe E, Carson EC, brookhart M, goldman AS, El-khalafy SH, MacArthur AHr. Adv Synth Catal 2010;352:125.

[16] Ahuja r, kundu S, goldman AS, brookhart M, Vicente bC, Scott Sl. Chem Commun 2008:253.

[17] Xu W-W, rosini gP, gupta M, Jensen CM, kaska WC, krogh-Jespersen k, goldman AS. Chem Commun 1997:2273.

[18] liu f, goldman AS. Chem Commun 1999:655.

[19] Punji b, Emge TJ, goldman AS. organometallics 2010;29:2702.

[20] Haenel MW, oevers S, Angermund k, kaska WC, fan H-J, Hall Mb. Angew Chem int Ed 2001;40:3596.


128

OxidatiOn and HydrOgenatiOn reactiOns catalyzed by transitiOn Metal cOMplexes bearing pincer ligands

6

6.1 intrOductiOn

The aim of this chapter is to survey the oxidative reactions of alcohols and amines based on hydrogen transfer as well as dehydrogenation and hydrogenation reactions catalyzed by transition metal complexes having pincer ligands. Herein, catalytic reactions useful for environmentally benign organic synthesis will be classified into three types: (i) oxidation of alcohols based on hydrogen transfer and dehydrogena-tion, (ii) dehydrogenation of amines, and (iii) hydrogenation reactions. This chapter is not intended to be comprehensive. Earlier reviews on the topics described in this chapter are available [1].

6.2 OxidatiOn Of alcOHOls based On HydrOgen transfer and deHydrOgenatiOn

6.2.1 ruthenium complex with pnp- or pnn-pincer ligand

The ruthenium complex 1 bearing a PNP-pincer ligand has been reported to cata-lyze dehydrogenative oxidation of secondary alcohols [2, 3]. As shown in Scheme 6.1, when the reaction of 2-propanol was conducted in the presence of 1 (0.4 mol%) and NaOiPr (0.4 mol%) in dioxane at 100 °C for 70 h, acetone was formed in 91% yield with turnover number of 228. Other secondary alcohols, such

OxidATiON Of AlCOHOlS 129

as 1-phenylethanol or 2-butanol, could be also converted to the corresponding ketones by this catalytic system. However, the oxidation of primary alcohols to aldehydes was not successful.

A proposed mechanism for the dehydrogenative oxidation of secondary alcohols catalyzed by 1 is shown in Scheme 6.2 [2]. The reaction starts with the activation of the catalyst precursor by the reaction with NaOiPr. The catalytic cycle would be com-posed of three elementary steps: (i) oxidative addition of alcohol to Ru(0) species, (ii) β-hydrogen elimination to give a carbonyl product and dihydrido Ru(ii) species, and (iii) reductive elimination of hydrogen to regenerate Ru(0) species.

The dinuclear ruthenium complex 2 bearing PNN-pincer ligand exhibited a high catalytic performance for the dehydrogenative oxidation of various secondary

N Ru

PtBu2

P

Cl

H

N2

Cat.

1 (0.4 mol%)OH O

NaOiPr (0.4 mol%)Dioxane, 100 °C, 70 h

91% (TON = 228)

tBu2+ H2

scHeMe 6.1

(L) RuH

Cl

OiPr(L) Ru

H

OiPr

RuH

H(L)

Ru(L)

RuOCHR1R2

H(L)

H2

R1R2CHOH

OR1

R2

–Me2CO

scHeMe 6.2

130 OxidATiON ANd HydROgENATiON REACTiONS

alcohols (Table 6.1) [4]. for example, the oxidation of 2-propanol catalyzed by 2 gave acetone in high yield with turnover number of 470 after 70 h.

The PNN-pincer ruthenium hydrido borohydride complex 3 has been prepared from 2 and found to exhibit higher activity in the dehydrogenative oxidation of secondary alcohols (Table 6.2) [5]. Turnover number for the oxidation of 2-propanol to acetone reached up to 900 in the reaction for 48 h (Entry 1). Reactions of other secondary alcohols also gave ketones in good yields.

An efficient hydrogen production system from 2-propanol and ethanol was developed using the ruthenium catalyst bearing a PNP-pincer ligand with an ali-phatic NH moiety [6]. The results are shown in Table 6.3. When the reaction of 2-propanol was carried out under reflux in the presence of the ruthenium complex

R1 R2

OH

N Ru

P

N

Cl

Cl

N

Cat.

2 (0.2 mol%)Et2

N NRu

P

N

Cl

Cl Et2

NaOiPr (0.8 mol%), dioxane, 100 °C R1 R2

O

Entry Alcohol Time (h) Yield (%) TON

OH

OH

OH

OH

OH

1

2

3

4

5

70

100

100

100

100

94

85

90

48

64

470

426

450

240

322

+ H2

tBu2tBu2

table 6.1 dehydrogenative oxidation of various secondary alcohols catalyzed by 2.

(32 ppm) bearing a PNP-pincer ligand in situ generated from 4 and 5, turnover frequency (TOf) of the catalyst for the production of hydrogen was 2048 h−1 after 2 h (Entry 1). lowering the concentration of the catalyst to 4 ppm resulted in the improvement of TOf (2 h) up to 8382 h−1 (Entry 2). Employing ethanol instead of 2-propanol led to TOf (2 h) of 1483 h−1 (Entry 3).

6.2.2 iridium complex with pcp-pincer ligand

The iridium complex 6 bearing a dibenzobarrelene-based PCP-pincer ligand, in which central ligating atom is sp3 carbon, has been synthesized. The complex 6 also possess an acidic sidearm, which is capable of interacting with the catalytic site.

R1 R2

OH

N Ru

P

N

H

H

Cat.

3 (0.1 mol%)

Et2

R1 R2

O+ H2

H B H

H

Toluene

Entry Alcohol Temperature (˚C) Time (h) Yield (%)

OH

OH

OH

OH

OH

1

2

3

4

5

105

110

115

115

115

48

48

48

48

24

90

89

83

56

87

tBu2

table 6.2 dehydrogenative oxidation of secondary alcohols catalyzed by 3.


RuH2(PPh3)3(CO) 4

NH

iPr2P PiPr2 5

Cat.

R1 R2

OH

R1 R2

O+ H2

Entry Alcohol Cat. (ppm) TOF for 2 h (h–1) TOF for 6 h (h–1)

OH

OH

OH

1

2

3

32

4.0

3.1

2048

8382

1483

1109

4835

690

Re�ux

table 6.3 Hydrogen production from 2-propanol and ethanol catalyzed by 4 with 5.

Ph2P PPh2

Ir

Cl

OHHO

H

Cat.

p-Xylene, re�ux

6 (0.1 mol%)

R1 R2

OH

R1 R2

O+ H2

Entry Alcohol Product Yield (%)

OH

OH

OH

O

O

O

1

2

3

94

93

92

Time (h)

10

12

10

table 6.4 dehydrogenative oxidation of secondary alcohols catalyzed by 6.

Thus, the complex 6 exhibited very high performance in dehydrogenative oxidation of alcohols (Table 6.4) [7]. When the reaction of 1-phenylethanol was carried out in the presence of 6 (0.1 mol%) in p-xylene under reflux for 10 h, acetophenone was formed in an excellent yield (Entry 1). Reactions of other secondary alcohols also gave corresponding ketones (Entries 2 and 3).

Similar iridium complex 7 also bearing a dibenzobarrelene-based PCP-pincer ligand but without an acidic sidearm has been found to be a good catalyst for hydrogen transfer oxidation (Oppenauer-type oxidation [8]) of secondary alcohols using acetone as a hydrogen acceptor (Scheme 6.3) [9]. for example, the reaction of 1-phenylethanol in acetone in the presence of 7 (0.1 mol%) and tBuONa (5 mol%) at 56 °C for 6 h gave acetophenone in almost quantitative yield.

6.2.3 ruthenium complex with nnn-pincer ligand

The ruthenium complex 8 bearing a NNN-pincer ligand has been reported to be a good catalyst for selective oxidation of alcohols to aldehydes and ketones using aqueous H

2O

2 as a waste-avoiding oxidant (Table 6.5) [10]. for example, the reaction

of cyclopentanol with aqueous H2O

2 at room temperature in the presence of 8

(0.01 mol%) gave cyclopentanone in almost quantitative yield after 24 h (Entry 1). Reactions of benzylic primary alcohols gave benzaldehyde derivatives in good to excellent yields (Entries 3–6).

6.2.4 palladium complex with ncn- or cnc-pincer ligand

The palladium complex 9 bearing a NCN-pincer ligand exhibited catalytic activity for the aerobic oxidation of alcohols in polyethylene glycol (PEg), a sustainable reaction media [11]. As shown in Table 6.6, a variety of secondary alcohols were

P PIr

Cat.

7 (0.1 mol%)

OC

Cl ClOH O

tBuONa (5 mol%)Acetone, 56 °C, under air, 6 h

98%

iPr2

iPr2

scHeMe 6.3



efficiently converted into the corresponding carbonyl products by 0.01 mol% of 9 in PEg 400.

The palladium complex 10 bearing a CNC-pincer ligand also showed high catalytic performance for the aerobic oxidation of alcohols under similar conditions (Table 6.7) [11].

N

N NRu

N

O

OO

O

Cat.

H2O2 aq (2.5 equiv)R1 R2

OH

R1 R2

O

AlcoholEntry Temperature (°C) Time (h) Product Yield (%)

OH

OH

OH

F

OH

Cl

OH

F

OH

O2N

O

O

O

F

O

Cl

O

F

O

O2N

1

2

3

4

5

6

rt

rt

rt

rt

rt

60

24

48

0.4

16

1

4

98

89

90

93

92

81

8(0.01 mol%)

table 6.5 Oxidation of alcohols with H2O

2 into aldehydes or ketones catalyzed by 8.

N N

Pd

MeO2C N

N

Cl

Cat.

O2 (1 atm), NaOAc (10 mol%)PEG 400, 120 °C, 48 h

R Rʹ

OH

R Rʹ

O


OH

tBu

OH

CO2H

OH

OH

ClOH

O

OH

OH

OH

O

tBu

O

CO2H

O

O

ClO

O

O

O

O

1

2

3

4

5

6

7

99

98

99

98

99

96

97

9(0.01 mol%)

table 6.6 Aerobic oxidation of secondary alcohols to ketones catalyzed by 9.



NHO2C

N

N N

N

Pd Br

Bu

Bu

BrCat.

O2 (1 atm), NaOAc (10 mol%)PEG 400, 120 °C, 48 h

R Rʹ

OH

R Rʹ

O


OH

tBu

OH

CO2H

OH

OH

ClOH

O

OH

OH

OH

O

tBu

O

CO2H

O

O

ClO

O

O

O

O

1

2

3

4

5

6

7

97

94

98

99

97

94

98

10(0.01 mol%)

table 6.7 Aerobic oxidation of secondary alcohols to ketones catalyzed by 10.

dEHydROgENATiON Of AMiNES 137

6.3 deHydrOgenatiOn Of aMines

dehydrogenative transformations of amines to imines, enamines, nitriles, and aro-matic cyclic amines are attractive route for the synthesis of these compounds because easily available amines can be used as starting materials for such transformations without requiring toxic and wasteful oxidants.


The iridium complex 11 bearing a PCP-pincer ligand has been reported to be a good catalyst for dehydrogenation of secondary amines to imines based on hydrogen transfer using t-butylethylene as a hydrogen acceptor [12]. The results are summarized in Table 6.8. When the reaction of dibutylamine was carried out using the catalyst 11

PtBu2

Ir

PtBu2

H

H

Cat.

NH

R tBuRʹN

RRʹ

11 (14 mol%)

Toluene, 200 °C, 72 h+ +


NH

NH

HN

NH

NH

NH

N

N

N

N

N

N

1

2

3

4

5

6

72

77

94

64

53

60

tBu

table 6.8 imination of secondary amines catalyzed by 11 using a hydrogen acceptor.


(14 mol%) in toluene at 200 °C for 72 h with adding equimolar amount of t-butyl-ethylene, a corresponding imine was obtained in 72% yield (Entry 1). Various secondary amines were also converted to imines (Entries 2–6).

dehydrogenation of tertiary amines using the same catalyst 11 has been also reported [13]. Under the similar reaction conditions to the case of secondary amines, various tertiary amines were converted to enamines. The results are summarized in Table 6.9. for example, N,N-diisopropylethylamine was almost quantitatively con-verted to the vinylamine by dehydrogenation (Entry 1). Additionally, N-ethylpyrrolidine was dehydrogenated to N-vinylpyrrole in modest yield (Entry 4).

The iridium complex bearing a PCP-pincer ligand with bis(phosphinite) donor moieties (POCOP ligand) has been reported to be catalytically active for the unique

PtBu2

Ir

PtBu2

H

H

Cat.

R1R2N

tButBu

11 (14 mol%)

Toluene, 200 °C, 72 h+ +


R3R1R2N

R3

N

N

N

N

N

N

N

N

N

N

TBE (equiv)

2.0

2.0

1.0

2.0

3.0

Time (h)

5

24

12

24

24

1

2

3

4

5

98

65

65

35

67

table 6.9 dehydrogenation of tertiary amines catalyzed by 11.

dEHydROgENATiON Of AMiNES 139

transformation of primary amines into nitriles by dehydrogenation based on hydrogen transfer. The results are summarized in Table 6.10 [14]. The reaction was carried out at 185 °C in mesitylene-d

12 in the presence of 12 (5 mol%) and 5 equiv of t-butylethylene.

Benzylamines with electron-donating groups underwent more facile dehydrogenation relative to those with electron-withdrawing groups.

The mechanism for the complex 12-catalyzed dehydrogenation of primary amines to nitriles is illustrated in Scheme 6.4 [14].

The complex 12 also exhibited catalytic activity for the dehydrogenation of N-ethyl perhydrocarbazole accompanying the evolution of hydrogen [15]. As shown in Scheme 6.5, the reaction of N-ethyl perhydrocarbazole catalyzed by 12 (1 mol%) at 200 °C for 24 h gave partial dehydrogenation products N-ethyl octahydrocarbazole and N-ethyl tetrahydrocarbazole in 60 and 40% yield, respectively. The reaction with longer time (216 h) gave 82% of N-ethyl tetrahydrocarbazole along with 18% of N-ethylcarbazole.

O

O

PtBu2

Ir

PtBu2

H

H

Cat.

tBu tBu12 (5 mol%)

Mesitylene-d12, 185 °C, 45 h+ +

Entry Substrate Product Yield(%)

1

2

3

4

5

R NH2

(5 equiv)

C NR

NH2

NH2

NH2

NH2

NH2

MeO

F3C F3C

CN

CN

MeO

CN

CN

CN

80

93

85

84

39

table 6.10 dehydrogenation of primary amines into nitriles catalyzed by 12.


O

O

PtBu2

Ir

PtBu2

H

H

+TBE

+iBuNH2–TBA

[Ir]H2N

[Ir]

HN

H

[Ir]

HN

H

H

[Ir]

HN[Ir]

N

H

[Ir] N

H

H

[Ir] N

+iBuNH2

iPrCN

12

tBu +tBu–

tBu+ tBu–

scHeMe 6.4

O

O

PtBu2

Ir

PtBu2

H

H

Cat.

12 (1 mol%)

NEt

NEt

NEt

NEt

200 °C

24 h216 h

60%0%

40%82%

0%18%

scHeMe 6.5

HydROgENATiON ANd TRANSfER HydROgENATiON 141

6.4 HydrOgenatiOn and transfer HydrOgenatiOn Of carbOn–HeterOatOM unsaturated bOnds

6.4.1 iron complex with pnp-pincer ligand

The iron complex 13 bearing a PNP-pincer ligand has been prepared by the reaction of PNP ligand with feBr

2 under CO atmosphere followed by the reduction with NaHBEt

3.

The catalytic performance of 13 for the hydrogenation of ketones has been investigated (Table 6.11) [16]. The reaction proceeded under very mild conditions (at room temper-ature) with turnover numbers up to 1880 using 4.1 atm hydrogen pressure.

Similar iron dihydride complex 14 with PNP-pincer ligand has been reported to be catalytically active for the hydrogenation of bicarbonate and carbon dioxide [17]. As shown in Scheme 6.6, the hydrogenation of sodium bicarbonate under H

2 (8.3 bar)

at 80 °C in the presence of 14 (0.1 mol%) gave sodium formate with turnover number of 320.

Moreover, the complex 14 exhibited high catalytic activity for the hydrogenation of CO

2. When the reaction of carbon dioxide (3.33 bar) with H

2 (6.66 bar) catalyzed

by 14 (0.1 mol%) was performed at 80 °C for 5 h in the presence of NaOH, sodium formate was formed in 39% with turnover number of 788, showing high catalytic performance of 14 under low-pressure conditions (Scheme 6.7) [17].

A possible mechanism for the hydrogenation of CO2 catalyzed by 14 is shown in

Scheme 6.8 [17].

6.4.2 ruthenium complex with pnp or pnn ligand

By using the ruthenium complex 15 bearing a PNN-pincer ligand as a catalyst, hydrogenation of esters to alcohols has been achieved [18]. The results are sum-marized in Table 6.12. for example, the reaction of methyl benzoate catalyzed by 15 (1 mol%) under atmosphere of H

2 (5.3 atm) at 115 °C gave benzyl alcohol and

methanol in almost quantitative yields (Entry 1). A variety of esters were effectively converted into alcohols in high yield.

A possible mechanism for the hydrogenation of esters catalyzed by 15 is illus-trated in Scheme 6.9 [18]. The first step of the reaction involves the addition of H

2,

which leads to the aromatization of the ligand. The labile amine arm (NEt2 moiety)

in the ligand would be important for the catalytic activity.The PNN-pincer ruthenium hydrido borohydride complex 3 also exhibited high

activity for the hydrogenation of esters (Table 6.13) [5].Hydrogenation of organic carbamates has been firstly accomplished by using the

ruthenium complex 16 bearing a bipyridine-based PNN-pincer ligand [19]. When the reaction of N-benzyl carbamate was carried out under H

2 (10 atm) at 110 °C for 48 h

using 16 (1 mol%) as a catalyst, benzylamine and methanol were formed almost quantitatively (Scheme 6.10). Hydrogenation of methyl formate to methanol has been also achieved by the employment of the same catalyst 16 (Scheme 6.11).

The ruthenium complex 16 also exhibited high catalytic performance in the hydro-genation of amides [20]. As shown in Table 6.14, a variety of amides were efficiently


N

PiPr2

PiPr2

Fe COBr

H

Cat.

13 (0.05 mol%)

R Rʹ

O+ H2

(4.1 atm) R Rʹ

OH

KOtBu (0.1 mol%)Ethanol, rt

Entry Substrate Time (h) Product Yield (%)

O

O

Cl O

BrO

O

O

O

O

N

O

CHO

OH

OH

Cl OH

BrOH

OH

OH

OH

O

N

OH

OH

1

2

3

4

5

6

7

8

9

21.5

18

22

22

24

24

20

15

24

94

86

78

72

70

64

67

87

36

table 6.11 Hydrogenation catalyzed by 13.

HCOONa + H2O

39%(TON = 788)

N

PtBu2

PtBu2

Fe COH

H

Cat.

14 (0.1 mol%)

H2O / THF (10 : 1)80 °C, 5 h

+ H2(6.66 bar)

NaOHCO2(3.33 bar)

+

scHeMe 6.7

N

PtBu2

PtBu2

Fe COH

H

N

PtBu2

PtBu2

Fe COO

H

O

H

N

PtBu2

PtBu2

Fe CO

OH2

H

N

PtBu2

PtBu2

Fe CO

H2

H

N

PtBu2

PtBu2

Fe CO

H

H

HOH

N

PtBu2

PtBu2

Fe CO

H2

H + H2Oor

H2O

OH–

H2H2O

H2O

HCOO–

CO2

14

scHeMe 6.8

N

PtBu2

PtBu2

Fe COH

H

Cat.

14 (0.1 mol%)

H2O / THF (10 : 1)80 °C, 16 h

NaHCO3 + H2(8.3 bar)

HCOONa + H2O

32%(TON = 320)

scHeMe 6.6


converted to alcohols and amines by the reactions under 10 atm of H2 using 16

(1 mol%) as a catalyst.A possible mechanism for the hydrogenation of amides catalyzed by 16 is

illustrated in Scheme 6.12 [20]. The aromatization and dearomatization of the pincer ligand and the coordination and decoordination of the pyridyl arm would be important for high catalytic activity like as the case of 15.

N

PtBu2

NEt2

Ru

H

CO

Cat.

15 (1 mol%)

Dioxane, 115 °CR O

O

Rʹ + H2(5.3 atm)

RCH2OH RʹOH+

Entry Substrate Time (h) Products (yield [%])

O

O

On-C6H13n-C5H11

n-C3H7

O

O

O

O

O

O

O

O

O

CO2MeMeO2C

OH CH3OH

OH C2H5OH

OH

n-C6H13OH

C2H5OH

n-C4H9OH C2H5OH

CH2OHHOH2C CH3OH

97% 100%

96% 99%

98%

82%

86%

98% 99%

97% 100%

4

4

7

5

12

4

5

1

2

3

4

5

6

7


On the basis of high catalytic activity of the ruthenium complex 16 for the hydro-genation of methyl formate as mentioned earlier, a cascade catalytic system for the hydrogenation of CO

2 to methanol has been investigated using a high-pressure dual

vessel [21]. As shown in Scheme 6.13, hydrogenation of CO2 catalyzed by RuCl(OAc)

(PMe3)

4 and Sc(OTf)

3 affords methyl formate in the inner vessel. Volatile methyl for-

mate would be easily transferred into the outer vessel in which the catalyst 16 is loaded. Thus, hydrogenation of methyl formate catalyzed by 16 occurs to give methanol as a final product.

The ruthenium complex 17 bearing a PNP-pincer ligand exhibited high catalytic performance in hydrogenation of nitriles under neutral conditions (Table 6.15) [22]. for example, the reaction of 4-chlorobenzonitrile in the presence of 17 (0.4 mol%) and H

2O (2 mol%) under 75 bar of hydrogen in toluene at 135 °C for 24 h gave

4-chlorobenzylamine in an excellent yield (Entry 1). Not only aromatic nitriles but

N

PtBu2

NEt2

Ru

H

CO

N

PtBu2

NEt2

Ru

H

CO

H

N

PtBu2

Et2N

Ru

H

CO

HO

R ORʹ

N

PtBu2

Et2N

Ru

H

CO

O

R ORʹH

N

PtBu2

NEt2

Ru

H

CO

H

N

PtBu2

Et2N

Ru

H

CO

HO

R H

N

PtBu2

Et2N

Ru

H

CO

O

R H

H

R ORʹ

OH–RʹOH

RCHO

RCH2OHRCO2Rʹ

+H2

+H2

15

scHeMe 6.9


N

NPtBu2

Ru

CO

H

+ MeOH

Cat.

16 (1 mol%)NH

O

OMeH2 (10 atm)

THF, 110 °C, 48 h

NH2

97%

scHeMe 6.10

N

PtBu2

NEt2

Ru

H

H

Cat.

3 (0.5 mol%)

THF, 110 °C, 12 h

R O

O

Rʹ

+

H2(10 atm)

RCH2OH

RʹOH

+

Entry Substrate Products (yield [%])

O

O

O

O

O

O

n-C3H7

n-C5H11

O

O

n-C4H9

n-C6H13

OH CH3OH

OH

n-C6H13OH

96% 93%

99%

94%1

2

3

4

H B

H

H

97%n-C4H9OH


N

NPtBu2

Ru

CO

H

Cat.

16 (0.067 mol%)

H2 (10 atm)THF, 110 °C, 48 h

H

O

OMe2 MeOH

96%

scHeMe 6.11


table 6.14 Hydrogenation of a variety of amides catalyzed by 16.

N

NPtBu2

Ru

CO

H

R NH

RʹO

+ H2(10 atm)

RʹNH2 R OH+THF, 110 °C, 48 h

Cat.

16 (1 mol%)

Entry Amide Products (yield [%])

NH

O

O OOH NH2

n-C6H13 NH

O

OO

OHn-C6H13NH2

NH

O

OO

OHNH2

HN

O

OHNH2

HN

O

n-C5H11 n-C6H13OHNH2

O

N

O

OHO

NH

N

O

OO

OHNH

O

N

O

HCH3OH

O

NH

89% 90%

91% 90%

88% 87%

94% 95%

92%92%

97% 98%

97% 97%

97% 98%

1

2

3

4

5

6

7

8

N

NPtBu2

Ru

CO

H

N

NPtBu2

Ru

COH

H

N

NPtBu2

Ru COH

H

O

RNH

Rʹ

N

N PtBu2

RuCO

H

OR

NHRʹ

HH

N

N PtBu2

RuCO

H

OR

H

N

N PtBu2

Ru CO

H

H

O

R H

N

N PtBu2

RuCO

H

O

RH

+H2

R

O

NH

Rʹ

RʹNH2

+H2

R OH

16

scHeMe 6.12

N

NPtBu2

Ru

CO

H

Cat.

16 (0.067 mol%)

+ H2(30bar)

13CO2(10 bar)

Cat.

Ru

PMe3

Cl

Me3P

Me3P

PMe3

OAc, Sc(OTf)3

12CH3OH, dioxane75 °C, 1 h

H13C

O

O12CH3

+ H2O

Inner vessel

Ramp to 135 °C (transfer to outer vessel)

H13C

O

O12CH3 135 °C, 16 h–12CH3OH

Outer vessel

13CH3OH

scHeMe 6.13


also aliphatic nitriles were converted into primary amines by this catalytic system (Entries 2–5). it should be noted that the addition of a small amounts of H

2O increases

the rate of the reaction and the selectivity for the primary amines.A mechanism proposed based on dfT calculation is illustrated in Scheme 6.14

[22]. The catalytic cycle would start with an unsaturated dihydrido ruthenium species. Coordination of a nitrile to the unsaturated species followed by successive hydrogen transfer to carbon–nitrogen triple bond would occur to give primary amines.

6.4.3 iridium complex with pnp-pincer ligand

The iridium complex 18 bearing an aminodiphosphine-type PNP-pincer ligand has been reported to be highly active for the transfer hydrogenation of ketones under mild conditions (Table 6.16) [23]. for example, the hydrogenation of acetophenone


1

2

3

95

80

93

C NRH2 (75 bar)

H2O (2 mol%), toluene, 135 °C, 24 h

RCH2NH2

CN

CN

CN

Cl

MeO

4

5

96

92

N Ru

PH

H

Cat.

17 (0.4 mol%)tBu2

PtBu2

H H

MeO

CN

CN

Cl

MeO

MeO

Product

NH2

NH2

NH2

NH2

NH2

table 6.15 Hydrogenation of nitriles to primary amines catalyzed by 17.

N Ru

L

LH

H

17 (L = tBu2)

H H

–H2

N Ru

L

L

H

H

N Ru

L

L

H

H

N

R

N Ru

L

L

H

N R

H

N Ru

L

L

H

N R

H

H H

N Ru

L

L

H

H

NH

R

N Ru

L

L

H

NH

R

N Ru

L

L

H

NH

H H

R

N Ru

L

L

H

H

NH2

R

NRR NH2

scHeMe 6.14

catalyzed by 0.02 mol% of 18 was accomplished in almost quantitatively to afford 1-phenylethanol at 25 °C for 2 h using 2-propanol as a hydrogen source. Transfer hydrogenation of various ketones as well as an imine (benzylideneaniline) was also achieved.

The transfer hydrogenation of ketones catalyzed by 18 would proceed as illus-trated in Scheme 6.15 [23]. The first step of the catalytic cycle involves the concerted transfer of a hydride and the NH proton to the carbonyl carbon and oxygen of the ketone, respectively, forming an unsaturated amidodihydride intermediate. The trihy-dride catalyst would be regenerated by the reaction of an unsaturated amidodihydride intermediate with 2-propanol.


2-Propanol

N

PiPr2

PiPr2

IrH

H

H

H

Cat.

Substrate Product

Entry Substrate Cat. (mol%) Temperature (ºC) Time (h) Yield (%)

O

O

O

O

N

1

2

3

4

5

0.02

0.01

0.02

0.04

0.1

25

25

25

40

80

2

2.5

1

2

1

98

97

98

82

90

18

table 6.16 Transfer hydrogenation catalyzed by 18.


The iridium complex 19 bearing a PNP-pincer ligand exhibited a high catalytic activity for the hydrogenation of CO

2 to formate in aqueous base [24]. When the

reaction of H2 and CO

2 (1:1, 6 MPa) was carried out in aqueous KOH (1 M) in the

presence of 19 (0.001 μmol) at 120 °C for 48 h, potassium formate was formed in 70% yield with turnover number of 3,500,000 (Scheme 6.16).

6.4.4 ruthenium complex with cnn-pincer ligand

The ruthenium complex 20 with a CNN-pincer ligand (pyridyl-supported pyrazol NHC) has been reported to be catalytically active in the transfer hydrogenation of ketones [25]. As shown in Table 6.17, a variety of ketones were quantitatively

N Ir

P

P

H H

H

H

N Ir

P

P

H H

H

H

ORʹ

R

N Ir

P

P

H

H

N Ir

P

P

H H

H

H

O

R Rʹ

O

O

R Rʹ

OH

OH

scHeMe 6.15

N

iPr2P PiPr2IrH

H

H

H2 + CO2

1 : 16 MPa

Cat.

19 (0.001 μmol)

1 M KOH aqTHF, 120 °C, 48 h

HCOOK

70%TON = 3,500,000

scHeMe 6.16

N N

NH

N N

tBu

BuRu

COI

I

Cat.

20 (4 mol%)

iPrOK (0.2 mol%)2-Propanol, 82 °C

R Rʹ

O

R Rʹ

OH

Entry Ketone Time (h) Yield (%)

O

OCl

O

Cl

O

Cl

OMe

O

O

1

2

3

4

5

6

7

2

12

0.5

0.3

5

1.5

5

98

98

98

98

96

100

96




converted into the corresponding secondary alcohols by the reaction using 4 mol% of 20 and 0.2 mol% of iPrOK in 2-propanol.

The ruthenium complex 21 bearing a CNN-pincer ligand (pyridine-based NHC and amine) has been prepared, and its high activity for the transfer hydrogenation of aldehydes and ketones has been revealed (Table 6.18) [26]. for example, the reaction of heptanal using 21 (1 mol%) and KOH (1 mol%) as catalysts at 82 °C for 1 h in 2-propanol gave 1-heptanol quantitatively (Entry 1). The transfer hydrogenation of ketones has been also accomplished.

Using the cationic ruthenium complex 22 bearing a CNN-pincer ligand (bipyridine with NHC) as a catalyst, an efficient system for the hydrogenation of esters has been developed (Table 6.19) [27]. When the reaction of pentyl pen-tanoate catalyzed by 22 (1 mol%) and KOtBu (1 mol%) was carried out under 5.4 atm of H

2 in toluene at 135 °C for 2 h, 1-pentanol was formed in 96% yield

N

NRuN

N

MesCO

H

Cat.

21 (1 mol%)

KOH (1 mol%)2-Propanol, 82 °C

R Rʹ

O

R Rʹ

OH

Entry Substrate Time (h) Yield (%)

CHO

O

O

O

1

2

3

4

1

1

0.75

4

100

100

98

36

table 6.18 Transfer hydrogenation of carbonyl compounds catalyzed by 21.

(Entry 1). Other aliphatic and aromatic esters could be also hydrogenated by the catalyst 22.

6.4.5 ruthenium complex with OnO-pincer ligand

The ruthenium complex 23 bearing an ONO-pincer ligand has been synthesized, and its catalytic application has been reported. The complex 23 showed catalytic activity in the transfer hydrogenation of ketones to alcohols [28]. As shown in Table 6.20, a variety of both aromatic and aliphatic ketones were efficiently converted into the corresponding secondary alcohols by using 23 (1 mol%) as a catalyst and 2-propanol as a hydrogen donor.

N

NN

Ru

CO

H

R ORʹ

O

+ H2(5.4 atm)

R OH + RʹOH

Cat.

22 (1 mol%)

NMes

PPh3

Cl

KOtBu (1 mol%)Toluene,135 °C, 2 h

Entry Ester Products (Yield [%])

O

O

n-C5H11

n-C3H7

n-C4H9

O

On-C4H9OH 97%

n-C5H11OH 96%

EtOH 95%

O

OOH

89%

O

OOH

97%EtOH 94%

1

2

3

4




Cat.

23 (1 mol%)

NN N

O ORu

ClPh3P

PPh3 tButBu

Cl

Cs2CO3 (20 mol%)2-Propanol, re�ux

R

O

R RʹRʹ

OH


O

O

F

O

Br

O

MeO

OBr

O

O

1

2

3

4

5

6

7

18

24

6

8

6

24

24

95

88

96

95

82

84

88

table 6.20 Transfer hydrogenation of various ketones catalyzed by 23.

REfERENCES 157

references

[1] A number of insightful reviews on the topics described in this chapter have been pub-lished. (a) friedrich A, Schneider S. ChemCatChem 2009;1:72. (b) van der Vlugt Ji, Reek JNH. Angew Chem int Ed 2009;48:8832. (c) Milstein d. Top Catal 2010;53: 915. (d) debereiner gE, Crabtree RH. Chem Rev 2010;110:681. (e) gunanathan C, Milstein d. Acc Chem Res 2011;44:588. (f) Choi J, MacArthur AHR, Brookhart M, goldman AS. Chem Rev 2011;111:1761.

[2] Zhang J, gandelman M, Shimon lJW, Rozenberg H, Milstein d. Organometallics 2004;23:4026.

[3] Recent publications on dehydrogenative oxidation of alcohols: (a) Adair gRA, Williams JMJ. Tetrahedron lett 2005;46:8233. (b) Van Buijtenen J, Meuldijk J, Vekemans JAJM, Hulshof lA, Kooijman H, Spek Al. Organometallics 2006;25:873. (c) fujita K, Tanino N, yamaguchi R. Org lett 2007;9:109. (d) Baratta W, Bossi g, Putignano E, Rigo P. Chem Eur J 2011;17:3474. (e) Prades A, Peris E, Albrecht M. Organometallics 2011;30:1162. (f) fujita K, yoshida T, imori y, yamaguchi R. Org lett 2011;13:2278.

[4] Zhang J, gandelman M, Shimon lJW, Milstein d. dalton Trans 2007:107.

[5] Zhang J, Balaraman E, leitus g, Milstein d. Organometallics 2011;30:5716.

[6] Nielsen M, Kammer A, Cozzula d, Junge H, gladiali S, Beller M. Angew Chem int Ed 2011;50:9593.

[7] Musa S, Shaposhnikov i, Cohen S, gelman d. Angew Chem int Ed 2011;50:3533.

[8] Recent publications on Oppenauer-type oxidation of alcohols: (a) Almeida MlS, Beller M, Wang g-Z, Bäckvall J-E. Chem Eur J 1996;2:1533. (b) gauthier S, Scopelliti R, Saverin K. Organometallics 2004;23:3769. (c) Suzuki T, Morita K, Tsuchida M, Hiroi K. J Org Chem 2003;68:1601. (d) Hanasaka f, fujita K, yamaguchi R. Organometallics 2005;24:3422.

[9] levy R, Azerraf C, gelman d, Rueck-Braun K, Kapoor PN. Catal Commun 2009;11:298.

[10] Shi f, Tse MK, Beller M. Chem Asian J 2007;2:411.

[11] Urgoitia g, SanMartin R, Herrero MT, domínguez E. green Chem 2011;13:2161.

[12] gu x-Q, Chen W, Morales-Morales d, Jensen CM. J Mol Catal 2002;189:119.

[13] Zhang x, fried A, Knapp S, goldman AS. Chem Commun 2003:2060.

[14] Bernskoetter WH, Brookhart M. Organometallics 2008;27:2036.

[15] Wang Z, Tonks i, Belli J, Jensen CM. J Organomet Chem 2009;694:2854.

[16] langer R, leitus g, Bem-david y, Milstein d. Angew Chem int Ed 2011;50:2120.

[17] langer R, diskin-Posner y, leitus g, Shimon lJW, Bem-david y, Milstein d. Angew Chem int Ed 2011;50:9948.

[18] Zhang J, leitus g, Bem-david y, Milstein d. Angew Chem int Ed 2006;45:1113.

[19] Balaraman E, gunanathan C, Zhang J, Shimon lJW, Milstein d. Nat Chem 2011;3:609.

[20] Balaraman E, gnanaprakasam B, Shimon lJW, Milstein d. J Am Chem Soc 2010; 132:16756.

[21] Huff CA, Sanford MS. J Am Chem Soc 2011;133:18122.


[22] gunanathan C, Hölscher M, leitner W. Eur J inorg Chem 2011:3381.

[23] Clarke ZE, Maragh PT, dasgupta TP, gusev dg, lough AJ, Abdur-Rashid K. Organometallics 2006;25:4113.

[24] Tanaka R, yamashita M, Nozaki K. J Am Chem Soc 2009;131:14168.

[25] Zeng f, yu Z. Organometallics 2008;27:6025.

[26] Pozo C, iglesias M, Sánchez f. Organometallics 2001;30:2180.

[27] fogler E, Balaraman E, Ben-david y, leitus g, Shimon lJW, Milstein d. Organometallics 2011;30:3826.

[28] Zhang y, li x, Hong SH. Adv Synth Catal 2010;352:1779.


159

Bond-Forming reactions catalyzed By transition metal complexes Bearing pincer ligands

7

7.1 introduction

The aim of this chapter is to survey the bond-forming reactions catalyzed by transition metal complexes having pincer ligands. Herein, catalytic bond-forming reactions useful for environmentally benign organic synthesis will be classified into three types: (i) carbon–carbon bond formation based on hydrogen transfer, (ii) carbon–nitrogen bond formation based on hydrogen transfer and dehydrogenation, and (iii) carbon–oxygen bond formation based on hydrogen transfer and dehydrogenation. A variety of organic compounds including alcohols, amines, imines, amides, esters, and acetals can be synthesized with high atom efficiency by the methodologies described in this chapter [1].

7.2 carBon–carBon Bond Formation Based on Hydrogen transFer

7.2.1 ruthenium complex with nnn-pincer ligand

The NNN-pincer ruthenium complex 1 prepared from RuCl2(PPh

3)

3 and terpyridine

has been reported to catalyze carbon–carbon bond-forming reaction based on hydrogen transfer [2]. As shown in Table 7.1, cross-coupling of alcohols (β-alkylation of alcohol) was achieved under aerobic conditions using the ruthenium complex 1.

160 BoNd-FoRmiNg ReACTioNs CATAlyzed By PiNCeR ComPleXes

When the reaction of 1-phenylethanol with benzyl alcohol was carried out in the presence of 1 (1 mol%) and KoH (100 mol%) in toluene under air for 1 h, 1,3-diphe-nyl-1-propanol was selectively obtained in 65% (entry 1). Various combinations of starting materials were applicable.

The reaction proceeds via successive hydrogen transfer reactions and aldol con-densation (scheme 7.1): (i) hydrogen transfer oxidation of alcohols to afford a ketone and an aldehyde accompanied by the transitory generation of a metal hydride, (ii) cross-aldol condensation mediated by base to afford an α,β-unsaturated ketone, and (iii) transfer hydrogenation of the α,β-unsaturated ketone with the metal hydride.

7.2.2 iridium complex with nnn-pincer ligand

The NNN-pincer iridium complex 2 prepared by the reaction of irCl3 with terpyridine

exhibits high catalytic activity for the β-alkylation of alcohols under neat conditions requiring no solvent [2]. As shown in Table 7.2, β-alkylated products were obtained in good to excellent yields by the reactions in short time (<3 h), indicating higher catalytic activity of this system using iridium complex 2 relative to prior catalytic systems.

N

N NRuCl

Ph3P Cl

Cat.

1 (1 mol%)

Ar

OH

R OH+Ar

OH

R Ar

O

RKOH (100 mol%)Toluene, re�ux, under air

+

Entry Ar R Time (h) Yield (%) Alcohol : Ketone

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

4-ClC6H4

4-MeC6H4

Ph

4-BuOC6H4

4-ClC6H4

4-MeC6H4

4-tBuC6H4

PhCH2

PriPr

Ph

Ph

1

2

2

2

1

4

4

7

2

2

65

60

56

62

61

72

84

70

61

66

100 : 0

100 : 0

100 : 0

100 : 0

100 : 0

89 : 11

90 : 10

90 : 10

100 : 0

100 : 0

1

2

3

4

5

6

7

8

9

10

taBle 7.1 β-Alkylation of secondary alcohols with primary alcohols catalyzed by 1.

CARBoN–NiTRogeN BoNd FoRmATioN 161

7.3 carBon–nitrogen Bond Formation Based on Hydrogen transFer and deHydrogenation

7.3.1 ruthenium complex with pnn-pincer ligand

The ruthenium complex 3 bearing a dearomatized PNN-pincer ligand catalyzes the reaction of primary alcohols with amines to form amides and H

2. Results are summa-

rized in Table 7.3 [3]. For example, the reaction of benzylamine with 1-hexanol using

OH

[M]

Overall transformationR1

R2

OH

OH+

O

O

+

OBase

Cross aldolcondensation

[M] + 4[H]

R1 R2

R1

R1 R2

R2

scHeme 7.1

N

N NIrCl

Cl Cl

Cat.

2 (1 mol%)

Ar

OH

R OH+Ar

OH

R Ar

O

RKOH (20 mol%)Neat, 120 °C, under N2

+

Entry Ar R Time (h) Yield (%) Alcohol : Ketone

Ph

Ph

Ph

Ph

Ph

Ph

Pr

4-ClC6H4

4-BuOC6H4

4-tBuC6H4

0.5

3

2

2

2

95

65

95

88

77

93 : 7

93 : 7

96 : 4

92 : 8

88 : 12

1

2

3

4

5

taBle 7.2 β-Alkylation of 1-phenylethanol with primary alcohols catalyzed by 2.


ruthenium complex 3 (0.1 mol%) as a catalyst under toluene reflux for 7 h gave N-benzylhexanamide in the yield of 96% accompanying the evolution of H

2 (entry 1).

A variety of amides can be synthesized by this system.The mechanism is illustrated in scheme 7.2 [3]. Firstly, dehydrogenation of an

alcohol occurs to give an aldehyde, which is immediately converted to a hemiaminal

N

PtBu2

NEt2

Ru

H

CO

Cat.

3 (0.1 mol%)

R2 OH R1

NH

R2

O

+Toluene, re�ux

+ 2 H2

Entry Amine Alcohol Time (h) Product Yield (%)

Ph

Ph

Ph

Ph

NH2

NH2

NH2

NH2

NH2

NH2

NH2

NH2

NH2

OHPh N

H

O

OHPh N

H

O

MeOOH Ph N

H

O

OMe

Ph NH

O

OH

NH

O

O

PhNH

O

NH

O

OMe

NH

O

HN

O

OMeMeOOH

OH

MeOOHn-C5H11

n-C5H11

n-C4H9

n-C5H11

n-C5H11n-C5H11

n-C5H11

n-C4H9

n-C4H9

n-C5H11

n-C5H11

n-C4H9

n-C5H11n-C5H11

OHPh

OHO

1

2

3

4

5

6

7

8

9

7

7

9

12

8

8

8

8

8

96

97

99

70

78

58

99

72

99

R1NH2

taBle 7.3 Amidation of primary amines with primary alcohols catalyzed by 3.

by the reaction with an amine. Then, dehydrogenation of the hemiaminal proceeds by the catalyst 3 to give an amide as a product. in the course of these processes, (i) aro-matization and dearomatization of the pincer ligand and (ii) lability of the Net

2

moiety of the pincer ligand must be very important for high catalytic performance.The PNN-pincer ruthenium complex 3 is also effective catalyst for the acylation

of amines using esters as the acylating agents [4]. As shown in Table 7.4, a variety of amides can be synthesized under neutral conditions without any waste generation. it should be noted that both the acyl and alkoxo parts in the esters are incorporated into the amide product.

Catalytic synthesis of cyclic dipeptides from β-amino alcohols has been also accomplished using the PNN-pincer ruthenium complex 3 [5]. When the reaction of an (S)-isomer of amino alcohol was conducted in the presence of the ruthenium complex 3 (1 mol%) under 1,4-dioxane reflux for 19 h, (S,S)-isomer of piperazine-2,5-dione was obtained in good yield without racemization (scheme 7.3).

By using the PNN-pincer ruthenium complex 3 as a catalyst, the direct synthesis of polyamides via dehydrogenative carbon–nitrogen bond formation between diols and diamines has been achieved (scheme 7.4) [6]. Polyamides of molecular weight from 10 to 30 kda were synthesized from various diols and diamines having aliphatic or aromatic spacers.

N

PtBu2

PtBu2

PtBu2

PtBu2

R2CHO

RtNH2

NEt2

Ru

H

COR2

R2

OH

NH

O

N

Et2N

Ru

H

CO

O

R1NH

N

Et2N

Ru

H

CO

O

N

NEt2

Ru

H

CO

H

R2

R2R1

R2

R1NH

OH

H2

3

scHeme 7.2



N

PtBu2

NEt2

Ru

H

CO

Cat.

3 (0.1 mol%)

Toluene, re�ux+ 2 H2

R O

O

R2 R1R2NH+

R

O

NR1R2

Entry Ester Amine Time (h) Product Yield (%)

O

O

n-C3H7

n-C3H7

n-C3H7

n-C3H7

n-C4H9

n-C4H9

n-C4H9

n-C6H13

n-C4H9

n-C3H7

n-C3H7

n-C3H7

n-C3H7

n-C3H7

n-C4H9n-C4H9

n-C4H9n-C4H9

n-C4H9

n-C4H9

n-C3H7n-C3H7

n-C4H9

n-C4H9

n-C3H7

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

HN

NMe

HN

HN

HN

O

HN

NMe

HN

n-C6H13NH2

NH2

O

NH

O

NH

O

N

NMe

O

N

O

O

N

O

N

NMe

O

N

O

O

N1

2

3

4

5

6

7

8

19

21

24

19

26

24

24

18

94

95

94

96

92

94

97

98

taBle 7.4 Acylation of amines using esters as the acylating agent catalyzed by 3.

7.3.2 ruthenium complex with pnp-pincer ligand

The acridine-based PNP-pincer complex of ruthenium 4 has been synthesized, and its catalytic performance in the carbon–nitrogen bond-forming reaction between ammonia and alcohols has been investigated [7]. As shown in Table 7.5, the PNP-pincer ruthenium complex 4 showed high catalytic activity for the monoalkylation of ammonia with alcohols leading to primary amines. For example, the reaction of 4-methylbenzyl alcohol with ammonia (7.5 atm) in toluene catalyzed by 4 (0.1 mol%) gave 4-methylbenzylamine in 83% yield (entry 1). The reaction proceeds with high atom efficiency without forming toxic waste. A variety of primary amines can be synthesized by this catalytic system.

Furthermore, catalytic synthesis of primary amines from ammonia and alcohols catalyzed by 4 has been achieved in aqueous media. synthesis of some aromatic and aliphatic primary amines has been reported (Table 7.6) [7].

A possible mechanism for the synthesis of primary amines catalyzed by 4 is illustrated in scheme 7.5 [7]. The mechanism is based on usual hydrogen transfer processes (bor-rowing hydrogen) involving aldehydes and imines as important intermediates.

N

PtBu2

NEt2

Ru

H

CO

Cat.

3 (1 mol%)

1,4-Dioxane, re�ux,19 h+ 2H2

H2NOH

HN

NHO

O2

78%

scHeme 7.3

N

PtBu2

NEt2

Ru

H

CO

Cat.

3 (1 mol%)HO R OH

H2N Rʹ NH2

O

R

O

NH

Rʹ NH

Polyamide

−Η2 n

n

n+

scHeme 7.4



N

RuP

PCl

HCO

Cat.

R OH NH3(7.5 atm)

R NH2

4 (0.1 mol%)

Toluene, re�ux+

Entry Alcohol Time (h) Product Yield (%)

OH

OH

MeO

OH

F

N

OH

OOH

OH

OH

OOH

OH

OH

O

OH

12

14

24

30

12

20

32

12

18

25

25

NH2

NH2

MeO

NH2

F

N

NH2

ONH2

NH2

NH2

ONH2

NH2

NH2

O

NH2

83

78

91

96

95

61

69

95

68

82

90

1

2

3

4

5

6

7

8

9

10

11

iPr2iPr2

taBle 7.5 N-Alkylation of ammonia with primary alcohols catalyzed by 4.

The ruthenium complex 5 bearing a dearomatized PNP-pincer ligand has been reported to catalyze the direct synthesis of imines from primary amines and alcohols (Table 7.7) [8]. When the reaction of benzylamine with benzyl alcohol was carried out in the presence of the PNP-pincer ruthenium complex 5 (0.2 mol%) under toluene reflux for 56 h, benzylidenebenzylamine was formed in 79% yield (entry 1). Reactions using aliphatic amines or aliphatic alcohols catalyzed by 5 also gave imines in moderate to good yields (entries 2–5). it should be noted that the reaction of primary amines with alcohols catalyzed by the PNN-pincer ruthenium complex 3 gave amides (see Table 7.3); however, the reaction catalyzed by the PNP-pincer ruthenium complex 5 resulted in the selective formation of imines.

The mechanism for the imination catalyzed by the PNP-pincer ruthenium complex 5 is shown in scheme 7.6 [8]. The reaction starts with the oxidation of a primary alcohol into an aldehyde similar to the case of PNN-pincer catalyst 3 (see also scheme 7.2). Then, the reaction of the aldehyde with an amine occurs to give a hemiaminal, which is converted to an imine product by dehydration in the case of catalyst 5. in contrast, the hemiaminal coordinates to ruthenium and is

N

RuP

PCl

HCO

Cat.

R OH NH3(7.5 atm)

R NH2

4 (0.1 mol%)

H2O, 135 °C+

Entry Alcohol Time (h) Product Yield (%)

OH

OH

OH

18

18

36

30

30

95

92

80

80

70

1

2

3

4a

5a

OH

OH

NH2

NH2

NH2

NH2

NH2

iPr2iPr2

aMixture of water and dioxane was used as solvent.

taBle 7.6 N-Alkylation of ammonia with primary alcohols catalyzed by 4 in H2o.



dehydrogenated into an amide in the case of catalyst 3 because of higher lability of the Net

2 arm of the pincer ligand.

The synthesis of pyrazine derivatives by the reaction of β-amino alcohols catalyzed by the PNP-pincer ruthenium complex 5 has been reported [5]. When the reaction of β-alkyl-β-amino alcohol was performed in the presence of 5 (1 mol%) under toluene

N

RuP

PCl

HCO

RCH2OH+

NH3

RCH2O−NH4+

N

Ru

H

COOR

N

Ru

H

COOR

N

Ru

H

COH

N

Ru

H

COHN

R

RCHO

R NH2

OH

R NH

NH3 −Η2Ο

RCH2OH

RCH2NH2

iPr2

iPr2P

iPr2P

iPr2P

iPr2P

PiPr2

PiPr2

PiPr2

PiPr2

iPr2

4

scHeme 7.5

reflux for 24 h, 2,6-dialkylpyrazine was formed in moderate yield (scheme 7.7). in contrast, by a similar reaction using PNN-pincer catalyst 3, cyclic dipeptides have been obtained (see scheme 7.3).

7.3.3 osmium complex with pnp-pincer ligand

The osmium complex 6 bearing a PNP-pincer ligand involving NH moiety at the central part of the ligand has been reported to exhibit high catalytic activity in the carbon–nitrogen bond formation between amines and alcohols leading to alkylated amines (Table 7.8) [9]. Reactions of various primary amines with alcohols catalyzed by the PNP-pincer osmium complex 6 (0.1 mol%) at 200 °C resulted in mono-N-alkylation to give secondary amines. The turnover number of this catalytic system reaches up to 900.

7.3.4 iridium complex with pnp-pincer ligand

The iridium complex 7 bearing a PNP-pincer ligand has been prepared, and its catalytic activity for the N-alkylation of amines with alcohols and diols has been revealed [10]. Results of the N-methylation of various amines catalyzed by the

N

PtBu2

PtBu2

Ru

H

CO

Cat.

5 (0.2 mol%)

Toluene, re�ux

R1 NH2 R2 OH R1 N R2+

H2 H2O+ +

Entry Amine Alcohol Time (h) Product Yield (%)

Ph NH2

Ph NH2

Ph OH

Ph OH

OH

MeO

OH

OH

Ph N Ph

NH2

NH2

NH2

n-C5H11

n-C5H11n-C5H11

n-C5H11

n-C5H11n-C5H11n-C5H11

n-C5H11

n-C5H11

n-C5H11

N Ph

N

Ph N

N

OMe

56

52

48

90

96

79

82

89

65

57

1

2

3

4

5

taBle 7.7 direct synthesis of imines from primary amines and alcohols catalyzed by 5.



N

PtBu2

PtBu2

Ru COH

N

PtBu2

PtBu2

Ru COH

OR2

R1

R2

R2

R1

R2

R1

NH2

R2 OH

N

N

PtBu2

tBu2P

Ru CO

HH

OH

N

PtBu2

PtBu2

Ru COH

H

NH

OH

−Η2Ο

−Η2

R2CHO

5

scHeme 7.6

N

PtBu2

PtBu2

Ru

H

CO

Cat.

5 (1 mol%)

Toluene, re�ux, 24 h+ 3 H22

H2NOH N

N

53%

+ 2 H2O

scHeme 7.7

PNP-pincer iridium complex 7 are shown in Table 7.9. For example, the reaction of piperidine with methanol catalyzed by 7 (1 mol%) at 120 °C for 24 h gave N-methylpiperidine quantitatively (entry 1). Reactions of other primary or secondary amines also gave tertiary amines by monomethylation or dimethylation catalyzed by 7 (entries 2–5). N-Alkylation of diethylamine with various primary alcohols catalyzed by 7 has been also reported.

selective monoamination of diols catalyzed by PNP-pincer iridium complex 7 was accomplished [10]. When the reaction of ethylene glycol with diethylamine (ratio = 1:3) was performed in the presence of 7 (1 mol%) at 120 °C for 20 h, N,N-diethylethanolamine was selectively obtained almost quantitatively (scheme 7.8).

Os

PiPr2

NH

P H

CO

H

RNH2 Rʹ OH Rʹ NH

R

Cat.

6 (0.1 mol%)

200 °C+

Entry Amine Alcohol Time (h) Yield (%)

NH2OH

NH2

OH

NH2 OH

NH2OH

NH2

OH

NH2OH

NH2 OH

1

2

3

4

5

6

7

24

30

30

30

30

30

30

91

84

91

68

74

88

62

iPr2

taBle 7.8 N-Alkylation of primary amines with primary alcohols catalyzed by 6.



A catalytic synthesis of dialkylamines catalyzed by a cationic PNP-pincer iridium complex has been reported. The complex 8 bearing a PNP-pincer ligand with neopentyl-metalated iridacycle structure has been prepared, and its application as a cat-alyst for the reaction of primary amines has been reported (Table 7.10) [11]. For example, the reaction of octylamine in the presence of 8 (0.1 mol%) and NaH (0.4 mol%) at

120 °C, 20 h+

N

PiPr2

PiPr2

IrCl

H

H

H

Cat.

7 (1mol%)

HOOH HNEt2 HO

NEt2

99%

scHeme 7.8

120 °C, 24 h+

Entry Amine Product Yield (%)

1

2

3

4

5

>99

80

>99

95

>99

N

PiPr2

PiPr2

IrCl

H

H

H

Cat.

7 (1 mol%)CH3OH

NH

O NH

NH2

NH2

RNH2

or

R2NH

RN(CH3)2

or

R2N(CH3)

NH2

NMe

O NMe

NMe2

NMe2

NMe2

taBle 7.9 N-methylation of various amines with methanol catalyzed by 7.

180 °C for 20 h gave dioctylamine in high yield (entry 1). Reactions of other aliphatic amines also resulted in the formation of secondary amines (entries 2–4).

The mechanism for the formation of dialkylamine catalyzed by 8 is illustrated in scheme 7.9 [11]. Firstly, deprotonation of a primary amine and β-hydrogen elimina-tion proceed to give a terminal imine a. Then, the reaction of the terminal imine a with the primary amine occurs to give N-alkylaldimine B with liberation of ammonia. Finally, transfer hydrogenation of N-alkylaldimine B followed by the reductive elimination gives a secondary amine c as product. in the course of these catalytic processes, formation and disconnection of iridacycle by oxidative addition and reductive elimination of the neopentyl group are important for high performance.

7.4 carBon–oxygen Bond Formation Based on Hydrogen transFer and deHydrogenation

7.4.1 ruthenium complex with pnn-pincer ligand

Catalytic homocoupling of two molecules of primary alcohols leading to esters via carbon–oxygen bond formation catalyzed by ruthenium complexes 3, 9, and 10 bearing a pincer ligand has been investigated (Table 7.11) [12]. When the reaction

N

Ir PNp2

H

NpP

Np = Neopentyl

BF4Cat.

8 (0.1 mol%)

NaH (0.4 mol%)Neat, 180 °C

RNH2 R2NH


20

60

40

40

86

86

81

40

1

2

3

4

NH2

NH2

NH2

NH2

taBle 7.10 synthesis of dialkylamines from primary amines catalyzed by 8.

CARBoN–oXygeN BoNd FoRmATioN 173


of 1-hexanol in the presence of PNP-pincer ruthenium complex 9 (0.1 mol%) and KoH (0.1 mol%) at 157 °C for 24 h, hexyl hexanoate was formed in 67% yield (entry 1). No reaction took place in the absence of KoH (entry 2). The complex 10 bearing a PNN-pincer ligand with much labile Net

2 moiety exhibited superior

activity relative to that of 9, giving the ester product in 90% yield by the reaction in the presence of KoH (entry 3). Furthermore, the complex 3 bearing a dearoma-tized PNN-pincer ligand showed the highest catalytic activity giving the ester product in 91% yield in relatively short reaction time under neutral conditions (entry 6).

N

Ir

H

NpP

BF4RCH2NH2

NaH

–H2N

Ir

H

NH R

N

Ir PNp2

PNp2

NpP

HN

R

H

N

IrNp2P

H

N

IrNp2P PNp2

N

R R

N

Ir PNp2

H

NpP

NR

R

N

Ir PNp2

PNp2PNp2

NpP

NpP

NHRN

R

R

RCH2NH2

−ΝΗ3

RCH2NH2 (RCH2)2NH

(RCH2)2NHRCH2NH2

Oxidativeadditionof Np


Insertionof imine


of amine


of Np

Oxidativeadditionof amine

8

AB

C

scHeme 7.9


The reaction pathway of dehydrogenative coupling of primary alcohols leading to esters is illustrated in scheme 7.10. Firstly, catalytic dehydrogenative oxidation of a primary alcohol proceeds to generate an aldehyde. Then, addition of the alcohol to the aldehyde occurs to give a hemiacetal. Finally, the hemiacetal is dehydrogenated to give ester as a product.

N

PiPr2

PiPr2

Ru

H

Cl

CO

N

PtBu2

PtBu2

NEt2

Ru

H

Cl

CO

N

NEt2

Ru

H

CO

OH

O

O 2 H2+

Cat.(0.1 mol%)

Entry CatalystKOH

(mol%)Temperature

(°C)Time (h) Yield (%)

1

2

0.1

0

157

157

24

24

67

0

3

4

5

6

7

0.1

0

0.1

157

157

115a

0 157

115a0

24

24

24

2.5

6

90

0

95

91

99

9

10

3

aunder re�ux in toluene.

taBle 7.11 dehydrogenative homocoupling of 1-hexanol to give hexyl hexanoate.

R OH

R O

H

R O

OH

+ 2H2


Cat.−H2

Cat.−H2

R OH

R

R O

O

R

scHeme 7.10


The PNN-pincer ruthenium complex 3 also showed catalytic activity for the transesterification of esters with secondary alcohols under neutral conditions accom-panying liberation of H

2 (Table 7.12) [13]. For example, when the reaction of ethyl

acetate with cyclohexanol was conducted in the presence of 3 (1 mol%) in toluene

N

PtBu2

NEt2

Ru

H

CO

Cat.

3 (1 mol%)

R O R

O OH

R1 R22+

R O R1

O R2

2 + 2 H2Toluene, re�ux

Entry Ester Alcohol Time (h) Product Yield (%)

O

O

n-C5H11 n-C5H11

n-C5H11

n-C5H11

n-C5H11

n-C4H9

n-C4H9

n-C4H9

O

O

n-C5H11

n-C5H11

n-C5H11

n-C5H11

n-C5H11

n-C5H11

n-C5H11

n-C4H9

n-C4H9

n-C4H9

n-C3H7 n-C3H7

n-C3H7

n-C3H7

n-C3H7

n-C3H7

n-C4H9

n-C4H9

n-C4H9

n-C3H7

n-C3H7

n-C3H7

O

OO

OO

OO

OO

OO

O

O

OO

O

OH

OH

OH

OH

OH

OH

OH

OH

O

O

OH

OH

OH

O

OO

OO

OO

OO

OO

OO

OO

O

O

OO

O

O

O

95

83

95

70

90

93

85

90

92

74

76

1

2

3

4

5

6

7

8

9

10

11

28

20

26

26

26

36

36

26

34

28

18

taBle 7.12 Transesterification of esters with secondary alcohols catalyzed by 3.


under reflux for 28 h, cyclohexyl acetate was obtained in an excellent yield (entry 1). A variety of esters could be prepared by this system (entries 2–11). it should be noted that both the acyl and alkoxo parts of the starting ester are incorporated into the product.

The mechanism for the transesterification catalyzed by PNN-pincer ruthenium complex 3 is shown in scheme 7.11 [13]. Firstly, the activation of a starting ester and a secondary alcohol occurs generating d. Then, intramolecular nucleophilic substitution proceeds to afford a cationic intermediate e followed by the deprotonative

N

PtBu2

PtBu2

PtBu2

PtBu2

PtBu2

PtBu2

NEt2

NEt2

NEt2

Ru COH

N Ru COH

O

O

N RuCO

OO

N RuCO

OO

O

N

NEt2

NEt2

RuCO

OO

O

N

NEt2

RuCO

OO

O R4

R4

R1

R2

R3

R1 R2

R4

R2

R1

R4

R3

R3

R1

R3O

O R2

R2

R2

R1

R2R2

R1

R1

O

Insertion

O–H activationaromatization

Intramomecularnucleophillicsubstitution

Deprotonationdearomatization


HO

Cat.

−H2

O

O1/2

3

D

E

F

+R3R4CHOH

scHeme 7.11


dearomatization leading to F. Finally, β-hydrogen elimination occurs to give the product. in these processes, aromatization and dearomatization of the PNN-pincer ligand are highly important to drive the reaction.

The PNN-pincer ruthenium hydrido borohydride complex 11 has been prepared and found to be highly active in the dehydrogenative esterification via carbon–oxygen bond formation [14]. When the reaction of benzyl alcohol catalyzed by 11 (0.1 mol%) was conducted under toluene reflux for 24 h, benzyl benzoate was formed quantitatively (scheme 7.12).

The PNN-pincer ruthenium complex 11 is also an effective catalyst for the dehydrogenative lactonization of diols [14]. Aliphatic and aromatic lactones were synthesized by using 0.33 mol% of complex 11 as a catalyst (Table 7.13).

7.4.2 ruthenium complex with pnp-pincer ligand

The acridine-based PNP-pincer complex of ruthenium 4 showed an interesting catalytic performance in the reaction using primary alcohols as substrates [15]. As shown in Table 7.14, reactions of primary alcohols catalyzed by 4 (0.1 mol%) in the absence of base without solvent gave acetals predominantly (entries 1 and 3). on the contrary, similar reactions in the presence of KoH (0.1 mol%) gave esters selectively (entries 2 and 4).

A possible mechanism for the formation of acetals from primary alcohols cata-lyzed by 4 is illustrated in scheme 7.13 [15]. Firstly, dehydrogenation of a primary alcohol catalyzed by 4 occurs to give an aldehyde. Then, the aldehyde is converted to hemiacetal by the reaction with an alcohol. Finally, dehydration of hemiacetal leading to enol ether followed by addition of the alcohol proceeds to give an acetal as a product.

7.4.3 osmium complex with pnp-pincer ligand

The osmium complex 6 bearing an aliphatic PNP-pincer ligand exhibited catalytic activity for esterification of primary alcohols under neat conditions without solvent at relatively high temperature (Table 7.15) [9]. For example, the reaction of 1-hexanol

N

PtBu2

NEt2

Ru

H

HH B H

H

Cat.

11 (0.1 mol%)


OH O

O

2 + 2H2

99%

scHeme 7.12

at 157 °C for 5 h catalyzed by 6 (0.1 mol%) resulted in the formation of hexyl hexanoate in 91% yield (entry 2).


The iridium complex 12 bearing a dibenzobarrelene-based PCP-pincer ligand has been synthesized, and its catalytic activity for the carbon–oxygen bond formation via dehydrogenative transformation has been reported [16]. The reaction of primary alcohols or diols catalyzed by the PCP-pincer iridium complex 12 gave esters and lactones (Table 7.16). For example, when the reaction of benzyl alcohol was con-ducted in the presence of 12 (0.1 mol%) and Cs

2Co

3 (5 mol%) in p-xylene for 36 h,

benzyl benzoate was obtained almost quantitatively (entry 1).

N

PtBu2

NEt2

Ru

H

HH B H

H

Cat.

11 (0.33 mol%)

Toluene, re�ux, 48 h+ 2 H2

OHHOO

O

Entry Diol Product Yield (%)

OH

OH

HO OH

HOOH

OH

OH

O

O

O

O

O

O

O

O

1

2

3

4

72

81

86

90

taBle 7.13 dehydrogenative lactonization of diols catalyzed by 11.



7.4.5 ruthenium complex with cnn-pincer ligand

The ruthenium complex 13 bearing an N-heterocyclic carbene-connected CNN-pincer ligand has been reported to be catalytically active for the dehydrogenative coupling of primary alcohols leading to esters [17]. The CNN-pincer ruthenium com-plex 13 effectively catalyzed the transformation of 1-butanol into butyl butanoate (scheme 7.14).

OH

O

O

OH

O

R

R

R

R

R R

OH

R

Cat. [Ru]

−H2

O

R

−H2O

OR R

OHR

scHeme 7.13

N

RuP

PiPr2

Cl

HCO

Cat.

4 (0.1 mol%)

OHO

O

Entry Alcohol

KOH (0 or 0.1 mol%)Neat, re�ux

KOH(equiv)

Temperature(˚C)

Time(h)

Acetal(%)

Ester(%)

OH

OH

OH

OH

1

2

3

4

0

1

0

1

157

157

137

137

72

40

72

60

82

1

92

1

10

93

1

78

RR

R

R

O

O+ R R

iPr2

taBle 7.14 Reactions of primary alcohols leading to acetals and esters catalyzed by 4.

R OH2R O

O

R+ 2 H2

Os

PiPr2

PiPr2

NH

H

CO

HCat.

6 (0.1 mol%)

Entry Alcohol Temperature (˚C) Time (h) Yield (%)

OH

OH

OH

1

2

3

130

157

205

8

5

2

93

91

88

taBle 7.15 esterification of primary alcohols under neat conditions catalyzed by 6.

PPh2

Ir

Cl

OHHO

H

Cat.

12 (0.1 mol%)

Entry Alcohol Product Yield (%)Time (h)

R O

O

R+ 2H2

Cs2CO3 (5 mol%)p-Xylene, re�ux

OH

OH

Cl

HOO

OH

HOOH

O

O

O

O

Cl Cl

O O

O

OO

1

2

3

4

36

36

12

12

98

92

96

96

Ph2P

R OH2

taBle 7.16 dehydrogenative ester and lactone formation catalyzed by 12.


reFerences

[1] A number of insightful reviews on the topics described in this chapter have been published. (a) grützmacher H. Angew Chem int ed 2008;47:1814. (b) Friedrich A, schneider s. ChemCatChem 2009;1:72. (c) van der Vlugt Ji, Reek JNH. Angew Chem int ed 2009;48:8832. (d) milstein d. Top Catal 2010;53:915. (e) debereiner ge, Crabtree RH. Chem Rev 2010;110:681. (f) guillena g, Ramón dJ, yus m. Chem Rev 2010;110:1611. (g) gunanathan C, milstein d. Acc Chem Res 2011;44:588.

[2] gnanamgari d, leung CH, schley Nd, Hilton sT, Crabtree RH. org Biomol Chem 2008;6:4442.

[3] gunanathan C, Ben-david y, milstein d. science 2007;317:790.

[4] gnanaprakasam B, milstein d. J Am Chem soc 2011;133:1682.

[5] gnanaprakasam B, Balaraman e, Ben-david y, milstein d. Angew Chem int ed 2011; 50:12240.

[6] zeng H, guan z. J Am Chem soc 2011;133:1159.

[7] gunanathan C, milstein d. Angew Chem int ed 2008;47:8661.

[8] gnanaprakasam B, zhang J, milstein d. Angew Chem int ed 2010;49:1468.

[9] Bertoli m, Choualeb A, lough AJ, moore B, spasyuk d, gusev dg. organometallics 2011;30:3479.

[10] Andrushko N, Andrushko V, Roose P, moonen K, Börner A. ChemCatChem 2010;2:640.

[11] yamashita m, moroe y, yano T, Nozaki K. inorganica Chim Acta 2011;369:15.

[12] (a) zhang J, leitus g, Ben-david y, milstein d. J Am Chem soc 2005;127:10840. (b) zhang J, gandelman m, shimon lJW, milstein d. dalton Trans 2007:107.

[13] gnanaprakasam B, Ben-david y, milstein d. Adv synth Catal 2010;352:3169.

[14] zhang J, Balaraman e, leitus g, milstein d. organometallics 2011;30:5716.

[15] gunanathan C, shimon lJW, milstein d. J Am Chem soc 2009;131:3146.

[16] musa s, shaposhnikov i, Cohen s, gelman d. Angew Chem int ed 2011;50:3533.

[17] del Pozo C, iglesias m, sánchez F. organometallics 2011;30:2180.

N

NRuN

N

MesCO

H

Cat.

13 (1 mol%)

Toluene, 110 °C, 3 hOH

O

O

2 + 2H2

100%

scHeme 7.14

Bidentate and Miscellaneous ligands in transition Metal catalyzed Hydrogen transfer and deHydrogenative reactions

Part iv


185

OxidatiOn and dehydrOgenatiOn Of alcOhOls and amines catalyzed by Well-defined transitiOn metal cOmplexes bearing bidentate and miscellaneOus ligands

8

8.1 intrOductiOn

The main subjects in this chapter are oxidation of alcohols and amines to carbonyl compounds and imines catalyzed by well-defined transition metal complexes bearing bidentate and miscellaneous chelating ligands. This chapter describes the recent development (since ~2000) of environmentally benign methods for the catalytic oxidation based on hydrogen transfer and dehydrogenation reactions. As mentioned in the preface, asymmetric oxidation including dynamic kinetic resolution (DKR) is not discussed.

8.2 OxidatiOn Of alcOhOls based On hydrOgen transfer With Oxidant

Oxidation of alcohols to carbonyl compounds is one of the most fundamental and important organic transformations. Since classical methods have usually used a stoichiometric amount of harmful heavy metals such as Cr, Mn, etc. as the oxidant to leave much of wastes, these processes are undesirable from the viewpoint of green chemistry. Nowadays, much more attention has been paid to catalytic hydrogen transfer oxidations using greener oxidants. This section describes the

186 OxiDATiON AND DehyDROgeNATiON Of AlCOhOlS AND AMiNeS

recent development (since ~2000) of oxidation catalyzed by well-defined transition metal complex using oxygen or air (aerobic oxidation), hydrogen peroxide, and harmless carbonyl compounds (usually acetone, so-called Oppenauer-type oxidation) as the sole and greener oxidants.

8.2.1 Oxidation of alcohols with Oxygen as the sole Oxidant (aerobic Oxidation)

A large number of reports on homogeneous transition metal complex-catalyzed oxidation using air or oxygen as a terminal oxidant have appeared, and there have been many excellent and comprehensive reviews [1]. While there have been a number of metal-catalyzed oxidation reactions using metal salts and additive ligand as the catalyst or a combination of a mediator (TeMPO, DBAD, NhPi, etc.) and oxygen as the oxidant, we focus here on the oxidation of alcohols catalyzed by well-defined homogeneous transition metal complexes bearing bidentate and related ligands as the catalyst using oxygen (air) as the sole oxidant.

8.2.1.1 Pd Complexes with (N,N)-Chelating Ligands Pd(OAc)2 has been the most

popular transition metal catalyst used in the aerobic oxidation. in order to reoxidize generated Pd(0) to Pd(ii) by molecular oxygen, several effective catalytic systems, such as Pd(OAc)

2/DMSO [2], Pd(OAc)

2/pyridine [3], and Pd(OAc)

2/et

3N [4], have been

developed.Meanwhile, the well-defined homogeneous palladium complex of bathophenan-

throline disulfonate, that is, PhenS*Pd(OAc)2 (1a), has been found to effectively

catalyze aerobic oxidation of alcohols in water [5a,5b]. Aerobic oxidations of both primary and secondary alcohols were accomplished in the presence of NaOAc under air (30 bar) at 100 °C in water. Several examples are shown in Table 8.1. The catalyst was recycled five times without substantial loss of reactivity and selectivity. 2,2,6,6-Tetramethylpiperidinyl-1-oxyl (TeMPO) was required for the oxidation of

1a

R1 R2

OH Cat. 1a (0.25–0.5 mol%)NaOAc (5–10 mol%)

R1 R2

O

H2O, air (30 bar), 100 °C, 5–15 hN

N

NaO3SC6H4

NaO3SC6H4

Pd(OAc)2

12345

C3H7CH(OH)MetBuCH(OH)Me

CH2=CHCH(OH)C5H11C5H11OH

Me2C=CHCH2OH


55

121510

90907590a

88a TEMPO (4 equiv to Pd) was added.

table 8.1 Aerobic oxidation of alcohols catalyzed by 1a.

OxiDATiON Of AlCOhOlS BASeD ON hyDROgeN TRANSfeR WiTh OxiDANT 187

a primary alcohol to obtain an aldehyde (entry 4); otherwise, a carboxylic acid was obtained by further oxidation.

As mentioned earlier, reoxidation of Pd(0) to Pd(ii) by molecular oxygen must take place to maintain the catalytic cycle to avoid the irreversible Pd-black formation (Δh = ca. −378 kJ/mol), and therefore, coordinative sulfoxide and amines, such as DMSO, pyridine, et

3N, etc., are necessary to facilitate reoxidation of Pd(0) to

Pd(ii). Some bidentate ligands were tested in oxidation of 2-hexanol, and batho-phenanthroline disulfonate (PhenS*) ligand gave the best performance (Table 8.2) [5b]. These results are contrast with those in the Pd(OAc)

2/pyridine catalytic system,

in which bipyridine ligand gave almost no effect [3a]. A low conversion in the case of 4,5-diazafluorene indicates that the ligand should have the proper bite angle for the lone pairs of amines to overlap with Pd.

Anion effect of the PhenS*Pdx2 complexes on the aerobic oxidation was also

investigated, and among the anions examined (AcO, Cf3CO

2, NO

3, Cl, acac, ClO

4,

Bf4, and Cf

3SO

3), acetate and trifluoroacetate anions gave the highest rates without

Pd-black formation [5b].Since it has been reported that (bathocuproine)Pd(0) complex (bathocuproine =

2,9-dimethyl-4,7-diphenyl-1,9-phenanthroline) was readily oxidized to (bathocupro-ine)Pd(O

2) by O

2 [5c], the most plausible catalytic cycle is proposed (Scheme 8.1) [5b].

At the beginning of the catalytic cycle, the palladium dimer complex is formed and dissociates upon coordination of alcohol (hOR) to give a Pd(ii)-(Oh)-(hOR) complex that eliminates water to form a Pd(ii)-(OR) species. This species affords a carbonyl product through β-hydrogen elimination with concomitant formation of a palladium(0) complex, which is oxidized with O

2 to regenerate the starting dimer.

A series of (4,4′-disubstituted bipyridine)PdCl2 complexes (2) were synthesized,

and their catalytic activities for the aerobic oxidation of 2-hexnaol were investigated (Scheme 8.2) [5d]. A positive ρ-value of 0.18 was obtained in the hammett equation, showing that the reaction rate increased with electron-withdrawing substituents on the ligand. This result supports that the rate-limiting step would be the reduction of (bipy)Pd(ii) to (bipy)Pd(0) or [(bipy)Pdh+] and that reoxidation of (bipy)Pd(0) is facile. in fact, the oxygen pressure had little influence on the reaction rate.

Ligand/conversion (Pd black formation)

N NSO3Na

NaO3SH4C6 C6H4SO3Na

N N

60% (–)PhenS*

C4H9

OHCat. LPd(OAc)2 (0.25 mol%), NaOAc (5 mol%)

O

H2O, air (30 bar), 100 °C, 5 h

NN35% (+/–)<15% (+/–)

4,5-Diaza�uorene

C4H9

table 8.2 ligands used in Pd-catalyzed oxidation of 2-hexanol.


in the plausible mechanism described earlier (Scheme 8.1), the palladium(ii) complexes with phenanthroline ligand would form palladium dihydroxo-bridged dimer in aqueous solution and dissociate into two monomers that are the active species in aerobic oxidation. Therefore, steric hindrance on the 2- and 9-positions of phenanthroline ligand is expected to facilitate the dissociation of the dimer to the monomer, enhancing the catalytic activity (Scheme 8.3) [5e,5f].

Pd

H

H

O

O

N

N

Pd

N

N

2+

HO

OHPd

N

NR

OPd

N

N

Pd(0)

N

N

Pd

N

NO

O +

HOR

O

R

O2

0.5

H+

H

H2O2

H2O

0.5 O2

"Pd"


+

R

Pd(II)

N

N

2

H2O

N

N

=PhenS*

Pd

N

N

H+

H+

H2O

scheme 8.1

C4H9

OH

N N

X X

PdCl2

Cat. 2 (0.5 mol%), NaOAc (10 mol%)

C4H9Conv. <10%

O

H2O/DMSO(1:1)8% O2 in N2 (30 bar), 100 °C

log(kx/kH) = 0.18∗σ

2(bipy)PdII OC4H9

(bipy)PdII H

++

(bipy)Pd0 + H+

O

C4H9

scheme 8.2


A series of palladium complexes having 2- and 9-substituted phenanthroline ligands were synthesized, and their catalytic activities were explored [5e,5f]. firstly, aerobic oxidation of 2-hexanol in water was investigated using a few water-soluble complexes (1a–1c) (Scheme 8.4). Among them, the complex 1b showed much higher activity (TOf = 150 h−1) than that of 1a (TOf = 49 h−1), supporting the working hypothesis described earlier. On the other hand, the complex 1c showed no catalytic activity, probably due to coordination of the sulfonate groups to Pd or metalation of a phenyl ring by Pd.

A series of Pd(OAc)2 complexes having various 2-substituted and 2,9-disubstituted

phenanthroline ligands were also synthesized and their catalytic activities for the aer-obic oxidation of 2-hexanol [5e,5f]. A h

2O/DMSO (1:1) solvent was used to dissolve

all of these palladium complexes. Some examples are shown in Table 8.3. The highest activity (TOf = 170 h−1) was obtained when (neocuproine)Pd(OAc)

2 (neocuproine =

2,9-dimethyl-1,10-phenanthroline) (3a) was used as the catalyst (entry 1).The aerobic oxidation of a wide range of substituted benzyl alcohols was also

carried out using 3a as a catalyst (Scheme 8.5) [5d]. A moderate negative ρ-value of −0.58 in the hammett equation suggests that electron-donating substituents in alcohols favor the β-hydrogen elimination, which would be the rate-limiting step, by stabilizing the developing positive charge on carbon.

Since the above catalytic system (cat. 3a, NaOAc, 30 bar air in h2O/DMSO) gave

the significant performance for the aerobic oxidation, the substrate scope was further investigated [5e,5f]. Some examples of the oxidation of various secondary alcohols are shown in Table 8.4. An unsaturated alcohol was oxidized in high selectivity

N

N

Pd

R

R

OH

Pd

HO N

N

R

R

2+

N

N

Pd

R

R

OH2

+

scheme 8.3

N

N

C4H9

OH Cat 1. (0.25 mol%)NaOAc (5 mol%)

C4H9

O

H2O, air (30 bar),100 °C, 1 h Pd(OAC)2

R1

R1

R2

R2

1a: R1= H, R2 = C6H4SO3Na1b: R1= CH3, R2 = C6H4SO3Na1c: R1 = C6H4CO3Na, R2 = H

1a: TOF = 49/h1b: TOF = 150/h1c: TOF = 0

scheme 8.4


Cat. 3a (0.5 mol%), NaOAc (25 mol%)

H2O/DMSO (4:6), air (30 bar), 70 °C

XOH CHOX

log(Kx/KH) = –0.58*σ

N

N

PdII

O C

H

H

X

B–+

N

N

Pd0CHOX

+—HB


scheme 8.5

Entry

1

2

3

4

5

Conversion (%)

90

58

100

71

30

Selectivity (%)

100

100

100

100

95+

R1 R2 R2R1

OH OCat. 3a (0.5 mol%), NaOAc (25 mol%)

H2O/DMSO (4:6), air (30 bar), 80 °C, 4 h

Alcohol

C4H9CH(OH)CH3

4-MeOC6H4CH(OH)Ph

OH

OH

CH2=CHCH(OH)C5H11

table 8.4 Aerobic oxidation of various secandary alcohols catalyzed by 3a.

TOF0(h–1)

17012511560

CH3CF3Bu

CH3

R1

CH3CF3BuH

R2

N

N

Cat. (0.1 mol %)NaOAc (5 mol %)

H2O/DMSO (1:1)Air (30 bar), 80 °C, 2 h

Pd(OAC)2Cat. =

R1

R21234

Entry

Me C4H9

OH

Me C4H9

O

3a: R1 = R2 = Me

table 8.3 Substituent effects at the 2,9-positions of phenathroline ligands.


without the Wacker-type oxidation of the alkene moiety observed in the oxidations catalyzed by 1a described earlier.

Several examples of the aerobic oxidations of primary alcohols are shown in Table 8.5. for the oxidation of an aliphatic alcohol such as 1-heptanol, a catalytic amount of TeMPO was required to inhibit further oxidation to a carboxylic acid (entry 1) as described earlier. Benzylic alcohols having various functional groups were oxidized with high conversions and selectivity. it has been also reported that Pd nanoparticle stabilized by both the neocuproine ligand and DMSO is involved in the present aerobic oxidation [5 g].

The dimeric complex [(neocuprine)Pd(μ-OAc)]2[OTf]

2 (4a) has been synthesized

and exhibits very fast initial rates of aerobic alcohol oxidation at room temperature under ambient pressure of air [5 h]. The oxidation of 2-heptanol using the complexes 3a, 4a, or 4b as the catalysts was conducted at room temperature under ambient pressure of air. A few examples are shown in Table 8.6. The neutral complex 3a showed very low catalytic activity under mild reaction conditions. On the other hand, the cationic complexes 4a and 4b exhibited high initial TOf, although the total conversions after 24 h were rather low.

in order to clarify the rapid deactivation of the complex 4a, the reaction mixture was analyzed after 24 h, revealing the presence of the cationic palladium carboxylate 4d (Scheme 8.6), which was inactive as a catalyst. The reaction of 4a with hydrogen peroxide gave the cationic dimer complex 4b and the alkoxide complexes 4c and 4d. furthermore, 4c was converted to 4d in the presence of air. Thus, it is highly probable that the ligand oxidation in 4a is mediated by a hydroperoxide intermediate generated during the catalytic cycle, degrading the catalyst 4a.

8.2.1.2 Pd Complexes with (N,O)-Chelating Ligands it has been reported that palladium complexes (5) bearing anionic N,O-chelating ligands exhibit the high catalytic activities for the aerobic oxidation of alcohol [6]. The initial TOf for oxidation of 2-octanol by a variety of lPd(OAc)

2 complexes were investigated and

compared with that for the oxidation by (neocuprine)Pd(OAc)2 (3a). The reactions

were carried out in the presence of Bu4NOAc as a base under 8% O

2 in N

2 gas

Entry

12345

Conversion (%)

3028948660

Selectivity (%)

90a

10010010099

a TEMPO (5 mol%) was added.

Alcohol

C7H15OHPhCH=CHCH2OH

4-Me2NC6H4CH2OH4-MeSC6H4CH2OH4-MeOC6H4CH2OH

R OHR H

OCat. 3a (0.5 mol%), NaOAc (25 mol%)

H2O/DMSO (4:6), air (30 bar), 80 °C, 4 h

table 8.5 Aerobic oxidation of various primary alcohols catalyzed by 3a.


mixture. Some examples are shown in Table 8.7. The excellent catalytic performance was observed for the complexes (5b)Pd(OAc)

2 and (5c)Pd(OAc)

2, both of which

include 8-hydroxyquinoline structures with an acidic group at the 2-position. in the similar oxidation of 2-octanol in a DMSO/h

2O (1:1) solvent, the conversion was

100% after 1 h by using (5c)Pd(OAc)2 (0.5 mol%) as the catalyst, while it was 67%

when the complex 3a was used.

8.2.1.3 Pd Complexes with (C,N)-Chelating Ligands A dimeric cyclometalated palladium complex (6) bearing C,N-chelating ligand has been synthesized and cata-lyzes oxidation of alcohol with air as the sole oxidant [7a]. The complex 6 showed higher activity than Pd(OAc)

2 under the reaction conditions (Table 8.8), while

Pd(OAc)2 was more active than 6 in DMSO.

Several cyclometalated palladium complexes (7a–7e) having C,N-chelated ligands were also synthesized, and their catalytic activities for the aerobic oxidation of 1-phenylethanol were examined [7b]. Several examples are shown in Table 8.9. The small difference of the activities was observed.

N

N

PdNCMe

[OTf]

30% H2O2 aq.

MeCN

O N

N

PdNCMe

O

O

+

O2

4a 4b +

[OTf]

4c 4d

scheme 8.6

Cat. (3 mol%/Pd)

Solvent, air (1 atm), rt

Entry Catalyst Solvent TOF (Pd–1 h–1) TON (Pd–1) after 24h

123

3a4a4b

MeCN/CH2Cl2 (1:1)MeCN

MeCN/DMSO (1:1)

0.24782.0

—~12~9

Pd

HO

OH

N

N

PdN

N

N

N

N

N

=N

N

Pd PdN

N

O O

O O

[OTf]2[OTf]2

4a 4b

C5H11CH(OH)Me C5H11COMe

table 8.6 Aerobic oxidation of 2-heptanol catalyzed by 3a and 4.


LPd(OAc)2 (0.005 mol%), DMSO

Bu4NOAc (0.5 mol%), O2/N2(8:92, 45 bar), 100 °C, 1 h

Ligand/TOF h–1

N N

NeocuproinTOF = 750

5aTOF = 820

NOH

O

5bTOF = 1010

OHN S

5cTOF =1500

OHOHO

ON

OHO

C6H13COMeC6H13CH(OH)Me

table 8.7 initial TOf for the oxidation of 2-octanol

Ph

OH

Ph

O

Pd N

O

AcO

26

Catalyst

6Pd(OAc)2

Yield (%)

10058

Toluene, MS 3Å, 80 °C, 24 h

Entry

12

Cat. (5 mol%/Pd), pyridine (20 mol%), air

table 8.8 Aerobic oxidation of 1-phenylethanol catalyzed by 6 or Pd(OAc)2

Cat. (5 mol%/Pd), pyridine (20 mol%), air

Catalyst

67a7b7c7d7e

Conversion (%) after 2 h

576052244351

Entry

123456

<21<22<19<22<22<19

Time (h) for 100% conversion

Pd NAcO

2

7a : R = H7b : R = 4-CF37c : R = 2-Me7d : R = 4-OMe

R

Pd NAcO

2

7e

MS 3Å, toluene, 80 °CPhCH(OH)Me PhCOMe

table 8.9 Aerobic oxidation of 1-phenylethanol catalyzed by various palladacycles 6 and 7.


On the basis of some theoretical calculations, a possible mechanism was proposed (Scheme 8.7) [7b]. As described earlier, the rate-limiting step would be the β-hydrogen elimination step, and the coordinated acetate facilitates an intramolecular deprot-onation of the coordinated alcohol. it should be noted that the calculations show a distinct hydrogen bond between acetate and coordinated alcohol. More precise theoretical studies on this catalytic system were also reported [7c].

8.2.1.4 Ir Complexes with (N,N)-Chelating Ligand it has been reported that cat-ionic iridium complexes (8) catalyze aerobic oxidations of methanol, ethanol, and benzyl alcohol in the presence of a base (Scheme 8.8) [8]. The TONs of the aerobic oxidation of benzyl alcohol were 5 for the complex 8a and 70 for the complex 8b, respectively.

A possible catalytic cycle is proposed (Scheme 8.9). Substitution of the chloride followed by deprotonation would produce an iridium(iii) alkoxide complex a. The subsequent rapid β-hydrogen elimination could give a iridium(iii) hydride complex b.

Ph

OH

Base, L

–AcOH

N

Pd H

O

Ph

–Lβ-Hydrogen elimination

Ph

O

AcO–

Ph

OHO2

(L = Pyridine)

7aN

Pd O

OOHPh

N

Pd L

O

Ph

N

Pd H

O

O

scheme 8.7

Ir

N

N ClIr

NN

N N Cl

RCH2OHCat. 8a or 8b

RCHOBase (NaOH or Na2CO3), air, ΔR = H, CH3, CH2Ph

8a 8b

[OTf][OTf]

scheme 8.8


Deprotonation of the hydride complex would generate an iridium(i) complex c, which could be oxidized by air and solvated by an alcohol to regenerate the starting catalytic species.

8.2.1.5 Ir, Rh, and Ru Complexes with (C,N)-Chelating Ligands A series of bifunctional cyclometalated Cp*ir, Cp*Rh, and (p-cymene)Ru complexes (9–11) bearing C,N-chelating amido and hydrido(amine) ligands efficiently catalyze the aerobic oxidation of alcohols under mild conditions (30 °C, 0.1 MPa air) [9a]. Some examples of the oxidation of 1-phenylethanol are shown in Table 8.10. The complexes having phenyl group on the α-carbon to the nitrogen atom generally exhibited higher activities than those having methyl group. The amido-ir complex 9a showed slightly higher activities than the hydrido(amine)ir complex 9c. While the catalytic systems generated by treatment of the chloro(amine)M complexes with tBuOK were also effective, that of the Ru complexes 11 and tBuOK showed lower activities.

–H+

–H+

[Cp*Ir(Cl)(N^N)]+ [Cp*Ir(HOCH2R)(N^N)]2+

Cl–[Cp*Ir(OCH2R)(N^N)]+

[Cp*Ir(H)(N^N)]+

Cp*Ir(N^N)C

+O2, +2H+

+HOCH2R–H2O2

N^N = bpy or bpym

RCH2OH A

B

RCHO

scheme 8.9

Cat. (10 mol%)

Catalyst

9a9b9c

Yield (%)

726663

Entry

123a

THF, air (0.1 MPa), 30 °C, 3 h

NHIr

RR

Cp*

9a: R = Ph9b: R = Me

NH2

IrPh

Ph

Cp*

9c: X = H9d: X = Cl

X NH2

RhPh

Ph

Cp*

10

Cl NH2

RuPh

Ph11

a tBuOK (10 mol%) was added.

Catalyst

9d1011

Yield(%)

837242

Entry

4a

5a

6a

PhCOMePhCH(OH)Me

p-cymene

Cl

table 8.10 Aerobic oxidation of 1-phenylethanol catalyzed by 9 – 11.


The aerobic oxidation of secondary alcohols was conducted by using 9a as the catalyst. A few examples are shown in Table 8.11. The C = C double bond was tolerated. The aerobic oxidation of primary alcohols by 9a produces ester products and is described in Chapter 10 (Section 10.4.1.2). Aerobic oxidative kinetic resolu-tion of racemic secondary alcohols with chiral bifunctional amido complexes was also reported [9b].

A plausible catalytic cycle based on hydrogen transfer by the bifunctional cat-alyst is proposed (Scheme 8.10) [9a]. The amido complex readily takes place dehydroge nation of alcohols to give ketones with concomitant generation of the hydrido(amine) complex, which is dehydrogenated by O

2 to regenerate the starting

amido complex.

8.2.1.6 Ru Complexes with (N,O;N,O)-Chelating Ligands A series of (nitrosyl)-Ru(salen) complexes (12) have been synthesized and catalyze selective aerobic oxidation of primary alcohols over secondary ones [10]. firstly, the competitive aerobic oxidation of primary and secondary alcohols catalyzed by the complex 12a was carried out at under air (1 atm) at room temperature under photoirradiation (Scheme 8.11) [10a]. Oxidation of a 1:1 mixture of primary and secondary alcohols gave exclusively aldehydes with no formation of ketones. Benzyl alcohols were oxidized to benzaldehydes in excellent yields.

The aerobic oxidation of several 2-hydroxybenzyl alcohols was catalyzed by 12a under similar conditions to give the corresponding benzaldehydes in high yields [10b]. A few examples are shown in Table 8.12. The oxidation of 6-hydroxymethyl-2-naphthol

R1 R2 R1 R2

OH OCat. 9a (10 mol%)

THF, air (0.1 MPa), 30 °C, 3 h

Alcohol

PhCH(OH)CH3PhCH2CH2CH(OH)CH3

2-Cyclohexen-1-ol

Yield (%)

648747

Entry

123

table 8.11 Aerobic oxidation of secondary alcoholes catalyzed by 9a.

NH

IrPh

Ph

Cp*

NH2

IrPh

Ph

Cp*

H

H2O 1/2 O2

R1 R2

OH

R1 R2

O

scheme 8.10


afforded the corresponding aldehyde as a sole product (entry 3), whereas that of 2-naphthol gave a coupling product.

As mentioned earlier, the complex 12a catalyzes the selective aerobic oxidation of primary alcohols in the presence of secondary alcohols, possibly due to the steric repulsion between the substituents on the salen ligand and the incoming alcohol. A series of (nitrosyl)Ru(salen) complexes 12 having bulkier substituents have been synthesized, and their catalytic performance is investigated [10c]. Some examples are shown in Table 8.13. The complexes 12c and 12d having bulkier tert-pentyl or tert-hexyl group exhibited much higher selectivity (initial rate ratio: iRR > 30) than the complexes 12a and 12b. The similar high selectivity (iRR > 30) was observed in the competitive reaction of 1-decanol and a propargyl alcohol, PhC ≡ CCh(Oh)Me.

The precise mechanistic investigation for this selective aerobic oxidation was carried out [10d]. The kinetics of oxidation of 1-decanol catalyzed by 12a and 12b imply that the hydrogen atom transfer (hAT) is the rate-determining step (RDS) for

NO

Ru

Cl

N

O O

N

t-Bu

tBu

t-Bu

tBu

12a

Cat.12a (10 mol%), hν

Toluene, air, rt, 24 hArCHO

Ar = Ph (Y = quant.)Ar = 4-NO2C6H4 (Y = quant.)Ar = 4-CH3OC6H4 (Y = quant.)

ArCH2OH

Cat.12a (10 mol%), hν

Benzene-d6Air, rt,12 h

C9H19CH2OH+

C9H19CHO(quant.)

C8H17COCH3(0%)

C8H17CH(OH)CH3

scheme 8.11

Cat. 12a (2 mol%), hν

AcOEt, air, rtArCHO

OH

OH

Ph


OH

OH

O2N

OH

HO

1

2

3

16

72

13

83

92

92

ArCH2OH

table 8.12 Aerobic oxidations of hydroxylated benzyl alcohols catalyzed by 12a.


12b but not for 12a. furthermore, the competitive aerobic oxidation of 1-decanol and 1-phenylethanol was carried out using the (nitrosyl)Ru(salen) complexes (e.g., 12e and 12f) as the catalysts [10d]. A few examples are shown in Table 8.14. The iRRs decreased slightly in the oxidation with the complex 12e, which have no pseudoaxial methyl group at the methylene unit (R4 = h) (entry 3). On the other hand, the iRRs went down in the oxidations catalyzed by the complex 12f having no substituent at C3 and C3′ of the phenyl rings (entry 4).

These results suggest that the selective oxidation of primary alcohol is ascribed to steric repulsion between the alkyl part of alcohols and the substituents at C3 and C3′ on the ligand in the hAT step (Scheme 8.12).

On the basis of the mechanism proposed in aerobic oxidative desymmetrization of meso-diols [10e], the similar mechanism consisting of SeT, hAT, and ligand exchange steps has been proposed (Scheme 8.13) [10d]. The high selectivity is mainly attributed to steric repulsion caused by the hAT step as shown earlier.

NO

Ru

X

N

O O

N

R

R

R

R

12d: R = tHex, X = OH12c: R = tPent, X = OH12b: R = tBu, X = OH12a: R = tBu, X = Cl

Entry Cat.Yield of

aldehyde (%)

Cat. (2 mol%), hν

C6D6, air, rt, 24 h

C9H19CH2OH+

PhCH(OH)CH3

C9H19CHO+

PhCOCH3

IRRa Yield ofketone (%)

1234b

12a12b12d12e

1518

>30>30

1007581

100

29119

6.5a Initial reaction ratio. IRR = (% yield of aldehyde)/ (%yield of ketone) x 100 at ca. 20% converion.b The reaction was carried out for 48 h at 10 °C with 4 mol% of the catalyst.

table 8.13 Aerobic oxidations of a 1 : 1 mixture of 1-decanol and 1-phenylethanol catalyzed by 12.

NO

Ru

X

N

O O

N

R3 R3

R4

R2

R1 R1

R2

R4

12e: R1 = R2 = tBu, R3 = -(CH2)4-, R4 = H,

12f: R1 = H, R2 = tBu, R3 =R4 = Me, X = OHX = OH

Cat. (1 mol%), hν

C6D6Air, rt, 24 h

Entry

1234

Catalyst

12a12b12e12f

a Initial reaction ratio (20% coversion).

IRRa

1518145.5

C9H19CH2OH+

PhCH(OH)CH3

C9H19CHO+

PhCOCH3

35 5′3′

table 8.14 iRRs in aerobic oxidation of a 1 : 1 mixture of 1-decanol and 1-phenylethanol catalyzed by 12.


it has been reported that Ru(PPh3)(Oh)(salen) complex 12 g is synthesized and

catalyzes aerobic oxidation of alcohols at room temperature under nonirradiation and irradiated conditions [10f]. examples are shown in Table 8.15. Primary and ben-zylic secondary alcohols were smoothly oxidized to the corresponding carbonyl compounds in high yields under ambient conditions. formation of carboxylic acid through overoxidation was not observed. The catalytic activity of 12 g was higher than that of 12a.

The competitive aerobic oxidation of primary and secondary alcohols catalyzed by 12 g was also conducted, and the high selectivity (iRR > 50) was obtained in the reaction using chloroform as the solvent. furthermore, intramolecular selective oxidation of 1,n-diols gave the corresponding hydroxy aldehydes or lactols selectively. A few examples are shown in Table 8.16.

8.2.1.7 Co Complexes with (N,O;N,O)-Chelating Ligands Cobalt complexes (13) bearing bis-salen ligands have been reported to catalyze oxidation of secondary alcohols with O

2 (1 atm) at room temperature [11]. Some examples are

RuIII

N

O O

N

R1OH

RR

R2 R2

MeMe

R1

R1 = Me or HR2 = tBu or H

3

3ʹ

X

scheme 8.12

hν, –NO

RCH2OH

N NRuIV

OP

R

O OX

O2 •O2– or •O2H

hνSET

P = H or non

N N

RuIII

OP

R

O+ OX

HH

P = H or non

N NRuIII

O

R

O OX

H

H2O2

RCH2OH

RCH=O

ligand exchange

HAT

12

•O2– or •O2H

HH

N N

RuIII

OH

R

O OX

HH

scheme 8.13


shown in Table 8.17, and benzoins were readily oxidized to the corresponding diketones in excellent yields (entries 3, 4).

8.2.1.8 V Complexes with (N,O,O,O)- and (N,O;N,O)-Chelating Ligands A vanadium complex (14a) bearing 2-hydroxypicolinate ligand (hhpic) and a tetranuclear complex 14b catalyzed oxidation of benzylic alcohols with O

2 (1 MPa) [12a]. The

L

Ru

X

N

O O

N

R

R

R

R

12g: R = tBu, X = OH, L = PPh3

Entry Alcohol

Cat. 12g (2 mol%)

CDCl3, air, rt, 24 h

1a

2b

3a

4a

PhCH2OHPhCH2OH

C9H19CH2OHPhCH(OH)CH3

a The reaction was carried out under light shielding conditions.b The reaction was carried out under visible light irradiation.

Time (h)

1.51.5

34

AlcoholAldehyde

orKetone

Yield (%)

97979796

table 8.15 Aerobic oxidation of alcohols catalyzed by 12g under non-irradiation.

Entry

1

2

3

Diol

Ph OH

OH

Ph

OHOH

Ph

OHOH

Product

Ph O

OH

OPh OH

Ph

OHO

Time (h)

5

5

2

Yield (%)

41

96

73

table 8.16 intramolecular aerobic oxidation of 1,n-diols catalyzed by 12g.


1234

R1 R2

OHCat. 13 (5 mol%)

MeCN, O2 (1 atm), MS 3Å, rt R1 R2

O

PhCH(OH)PhPhCH(OH)CH3

PhCH(OH)COPh4-Me2NC6H4CH(OH)COPh

35.52.51.5

96949596

CoN

O N

O

PhMe

PhMe

13

table 8.17 Oxidations of various secondary alcohols with O2 catalyzed by 13.


reaction was conducted using 14a or 14b under O2 at 120 °C. Several examples

are shown in Table 8.18. The oxidation of benzyl alcohols in MeCN gave aldehydes selectively. On the other hand, the oxidation of secondary benzylic alcohols proceeded more smoothly in etOh. in addition, the complex 14b was reused until five runs. The oxidation in the ionic liquid [bmim]Bf

4 was also mentioned.

it has been reported that a vanadium complex (15) bearing bis(8-quinolinate) ligand catalyzes aerobic oxidation of a variety of primary and secondary alcohols [12b]. Among many vanadium complexes examined, the complex 15 exhibited the highest activity. The reactions were carried out in the presence of et

3N under air at

60 °C. Some examples are shown in Table 8.19. 2-Allyloxybenzyl alcohol was oxidized to the aldehyde without formation of ring-closed product (entry 6), indi-cating no involvement of a radical intermediate. The oxidation of propargylic alcohols also proceeded in high yields.

8.2.1.9 Other Complexes Cobalt complexes bearing tetradentate phthalocya-nine ligands have been reported to catalyze oxidation of α-hydroxyketones and secondary alcohols under O

2 (1 atm) [13a, 13b]. A rhodium tetra (p-sulfonatophenyl)

porphyrin complex, [(TSPP)Rh], efficiently catalyzed the oxidation of various pri-mary and secondary alcohols under O

2 (1 atm) in water with high selectivity [13c].

it should be added that the sulfonylimido-bridged dinuclear rhodium complex, [(Cp*Rh)

2(μ-NTs)

2], was applied to the catalytic oxidation of 2-octanol with O

2

(1 atm) as the first well-defined dinuclear catalyst [13d].

Cat. 14, O2 (1.0 MPa)

Solvent, 120 °CAlcohol Aldehyde or ketone

O

VN

O

O

N+

O

HO

O

OO

V N

O

O

NO

O

O

O

H

–

O

VN

O

O

NO

O

O

O

V

V O

O

VOSO4,MeONa

N

OHCO2H

H2SO4

14a

14b

Entry Catalyst (mol%) Yield (%)Solvent

12345

14a (2)14b (0.5)14a (2)14a (2)

14b (0.5)

MeCNMeCNMeCNEtOHEtOH

6162869089

Alcohol

PhCH2OHPhCH2OH

4-MeC6H4CH2OHPhCH(OH)PhPhCH(OH)Ph

Time (h)

3361515

table 8.18 Oxidation of benzylic alcohols with O2 catalyzed by 14.


8.2.2 Oxidation of alcohols with hydrogen peroxide as the sole Oxidant

hydrogen peroxide (h2O

2) has been used as another green oxidant, because only water

is generated as coproduct. however, use of high concentration of h2O

2 should be

avoided from safety reasons. While catalytic oxidation using 30% h2O

2 as the sole oxi-

dant is desirable, it is inevitable to face the following problems; the reaction is con-ducted in an aqueous (heterogeneous with organic compounds) solution, h

2O

2

is relatively labile in the presence of metals, and homogeneous catalysts tend to be decomposed or oxidized by a strong oxidant, h

2O

2. Thus, metal oxides, mainly

tungsten and vanadium peroxides, have been widely used as the catalysts, and the rep-resentative recent reports are listed as follows: Na

2WO

4 + Ch

3(n-C

8h

17)

3 N+SO

4− (PTC)

[14a, 14b], Na12

[WZnZn2(h

2O)

2(ZnW

9O

34)

2] [14c], [W(O

2)

4]2−[Ph

3P(Ch

2)

2PPh

3]2+

[14d], [PO4(WO

5)

4]3−[bmim]+

3 (bmim = 1-butyl-3-methylimidazolium) [14e], [W

10O

23]4−

[bmim]+4 in the ionic liquid [bmim][Bf

4] [14f], V

2O

5 + PhCh

2(C

2h

5)

3 N+Br− (PTC)

[14 g], (VO2)P

2O

7 + VOPO

4 [14 h], and nano-fe

2O

3 [14i, 14j]. This section describes

the recent development of the oxidation of alcohols catalyzed by well-defined homogeneous transition metal complexes using h

2O

2 as the sole oxidant.

8.2.2.1 Cu and Co Complexes with (O,N,N,O)-Chelating Ligands it has been reported that a copper complex (16a) bearing bis(salen-h

4) ligand catalyzed

oxidation of alcohols with a large excess amount of 30% h2O

2 in acetonitrile [15a].

Some examples are shown in Table 8.20. While the oxidation of primary alcohols gave carboxylic acids (entries 1–3), that of secondary alcohols gave ketones (entries 4 and 5).

Similarly, a cobalt complex (16b) bearing bis(salen-h4) ligand catalyzed the

oxidation of alcohols with a large excess amount of 30% h2O

2 in acetonitrile

under O2 [15b]. Some examples are shown in Table 8.21. The oxidation of pri-

mary alcohols gave carboxylic acids (entries 1–3), and that of secondary ones gave ketones (entries 4 and 5). Compared with the above oxidation using the

Cat. 15 (2 mol%), NEt3 (10 mol%)

Air (1 atm), 60–80 °C, 24–72 hClCH2CH2Cl

AlcoholAldehyde

orketone

O

OH

Ph CH(OH)Me

PhCH2OH4-MeOC6H4CH2OH4-NO2C6H4CH2OH

PhCH(OH)PhPhCH=CHCH2OH Ph CH2OH

NV

N

O OOiPrO

Entry Alcohol Yield (%)

12345

15


6

78

9296969398

95

9680

table 8.19 Aerobic oxidation of various primary and secondary alcohols catayzed by 15.


complex 16a, yields of products generally decreased and larger amount of 30% h

2O

2 was required.

8.2.2.2 Mo and W Complexes with (N,O)-Chelating Ligand Anionic oxodiper-oxo molybdate and tungstate complexes (17a and 17b) bearing 8-quinolinolate ligand have been synthesized and exhibit very high catalytic activities for the oxidation of alcohols [16a]. The reactions were carried out with low catalyst loading (0.1 mol%) in MeCN under reflux. The oxidation of primary alcohols gave aldehydes and/or carboxylic acids. examples are shown in Table 8.22. The W complex 17b was slightly more active than the Mo complex 17a. The reaction with bubbling of O

2 slightly

improved the yields of products. While the oxidation benzyl and cinnamyl alcohols afforded the corresponding aldehydes exclusively (entries 1 and 2), those of aliphatic alcohols gave a mixture of aldehyde and carboxylic acid. The increasing chain length in aliphatic alcohols made the selectivity much higher but decreased the total yields of products (entries 3 and 4).

Entry

12345

Yield (%)

9294939999

Alcohol

PhCH2OH4-BrC6H4CH2OH

C9H19CH2OHPhCH(OH)CH3Cyclohexanol

OCu

NH

O

NH

16a

H2O2 (equiv)

10101555

Time (h)

548

0.54

MeCN, O2, 80 °C

OH

R1R1 R2R1CO2H

R2

OCat. 16a (1 mol%)

30% H2O2or

table 8.20 Oxidation of alcohols with h2O

2 catalyzed by 16a.

Entry

12345

Yield (%)

7678598292

Alcohol

PhCH2OH4-MeOC6H4CH2OH

C15H31CH2OHCyclophexanolPhCH(OH)CH3

OCo

NH

O

NH

16bTime (h)

65

1143

MeCN, O2, 80 °CR1 R2

OH

R1 R2

OCat.16b (5 mol%)

30% H2O2 (20 equiv)R1CO2H or


2 catalyzed by 16b.


The oxidation of secondary alcohols proceeded smoothly to give the corresponding ketones in high yields (Scheme 8.14).

Similar oxodiperoxo molybdate and tungstate complexes (18a and 18b) bearing 1-(2′-hydroxyphenyl)ethanone oxime ligand have been also synthesized, and they catalyze the oxidation of alcohols with 30% h

2O

2 [16b]. Several examples are shown

in Table 8.23. While the oxidation of benzyl and cinnamyl alcohols gave the corre-sponding aldehydes exclusively (entries 1 and 2), those of primary aliphatic alcohols gave aldehydes with a small amount of carboxylic acids (entries 3 and 4). The oxidation of secondary alcohols also proceeded smoothly to give the corresponding ketones in high yields (entry 5).

MeCN, re�ux

Entry

Yield (%)a

1234

a Values in parentheses are reaction time and yields in the oxidation under O2 bubbling.b Yield of aldehyde.c Yield of carboxylic acid.

84 (81)b

83 (82)b

48 (51)b + 28 (33)c

76 (79)b + 1 (1)c

Alcohol

PhCH2OHPhCH=CHCH2OH

CH3CH2OHC11H23CH2OH

Cat. 17a or 17b (0.1 mol%)30% H2O2 (4 equiv) (+O2)

Time (h)a

RCH2OH RCHO + RCO2H

15 (12)14 (11)13 (10)22 (22)

N

O

Mo

OO

OO

O[PPh4] [PPh4]

N

O

W

OO

OO

O

Cat. 17a Cat. 17b

89 (84)b

86 (85)b

51 (51)b + 29 (37)c

79 (82)b + 1 (1)c

17a 17b

RCHO + RCO2H RCHO + RCO2H

table 8.22 Oxidation of primary alcohols catalyzed by 17a or 17b with h2O

2

or h2O

2 + O

2.

Cat 17a: Yield = 81 (84), 84 (91), or 81 (83)%Cat 17b: Yield = 85 (86), 87 (94), or 85 (86)%

OH

MeCN, re�ux24 (19), 11 (9), or 20 (16) h

Cat. 17a or 17b (0.1 mol%)30% H2O2 (4 equiv) (+O2)

CH3CH(OH)CH3or

C6H13CH(OH)CH3

O

CH3COCH3or

C6H13COCH3

or or

scheme 8.14


8.2.2.3 Fe Complexes with (N,O,S)-Chelating Ligand it has been reported that a series of iron complexes (19) bearing tridentate Schiff base ligands [N-(2-mercaptophenyl)salicylidenenimines] catalyze the oxidation of alcohols with 30% h

2O

2 [17]. Among the complexes, 19a exhibited the superior catalytic activity. The

oxidation was carried out using 19a and an excess amount of 30% h2O

2 (5 equiv) in

MeCN. Several examples are shown in Table 8.24. The oxidation of benzylic, allylic, and secondary alcohols afforded the corresponding aldehydes and ketones, respec-tively, in good to high yields.

8.2.2.4 Fe Complexes with (N,N,O)-Chelating Ligand (In Situ Preparation) An iron complex prepared in situ from feCl

2 with 6-(N-phenylbenzimidazole)-2-

pyridinecarboxylic acid (20) in the presence of a base has been reported to catalyze the

MeCN, re�ux

EntryYield(%) of Product(s)

12345

63a

89a

60a+20b

80a+2a

93

Alcohol

PhCH2OHPhCH=CHCH2OH

C3H7CH2OHC11H23CH2OH

CH3CH(OH)CH3

Cat.18a or 18b (0.1 mol%)30% H2O2 (4 equiv)

Time (h)

+ R1CO2H

2424153020

N

O

Mo

OO

OO

O

18a

18b

Cat. 18a Cat. 18b

65a

92a

67a+24b

83a+3b

97

HO

N

O

W

OO

OO

O

HO

[PPh4]

[PPh4]

R2R1 R2R1

OH O

a Yield of aldehyde.b Yield of carboxylic acid.


2 catalyzed by 18a or 18b.

Cat.19a (4 mol%), 30% H2O2 (5 equiv)

MeCN, 80 °C, 1.5 h

Entry Yield (%)

123456

R2R1 R2R1

OH O

808080767271

Alcohol

S

N OFe(PPh)2

R19a: R=H19b: R=Cl19c: R=Br19d: R=NO2

PhCH2OH4-MeC6H4CH2OH

3-NO2C6H4CH2OHPhCH(OH)Ph

PhCH=CHCH2OHCyclohexanol


2 catalyzed by 19a.


oxidation of alcohols with 30% h2O

2 at room temperature to afford the corresponding

aldehydes and ketones with high selectivity [18]. Among the several other ligands and the different metal salts including fe, Mn, Cu, Ni, Ru, and Cr, the catalyst combination of the ligand 20 and feCl

2 gave the best result. Some examples are

shown in Table 8.25. The oxidation of various benzylic alcohols selectively produced the corresponding benzaldehydes. it should be noted that the present catalytic system is also applied to the oxidation of various primary and secondary allylic alcohols.

8.2.2.5 Other Complexes As the non-heme metalloenzyme mimics, a few dinuclear μ-oxo diiron complexes with polydentate ligands have been synthesize and used as the catalysts in the oxidation of alcohols with 30% h

2O

2. The structures of these complexes

are as follows: [lfe(μ-O)fel]ClO4 (lh = 2-({[di(2-pyridyl)methyl](2-pyridylmethyl)

amino}methyl)phenol) [19a], [fe(ind)Cl]2(μ-O) (indh = 1,3-bis (2′-pyridylimino)isoin-

doline) [19b], and [fe2(μ-OMe)

2(PAP)Cl

4] (PAP = 1,4-di(2′-pyridyl)aminophthalazine)

[19b] (Scheme 8.15).

FeCl2 (5–8 mol%), 20 (5 mol%), Na2CO3 (5 mol%)

30% H2O2 (2 equiv), CH2Cl2, 0.5 h, rt

NN

NHO

Ph

O

20

Entry Yield (%)

12345

7693766556

R2R1 R2R1

OH O

Alcohol

PhCH2OH4-ClC6H4CH2OH2-MeC6H4CH2OH

PhCH(OH)CH3Cyclohexanol

table 8.25 Oxidation of various alcohols with h2O

2 catalyzed by feCl

2/20/

Na2CO

3 catalyst combination.

N

N N

NOH

LH = 2-{[di(2-Pyridyl)methyl](2-pyridylmethyl)amino]methyl}phenol

NH

N

N

N

N

indH = 1,3-bis(2ʹ-Pyridyl-imino)isoindoline

NN

HN

HN

N

N

PAP = 1,4-di(2ʹ-pyridyl)-aminophthalazine

scheme 8.15


8.2.3 Oppenauer-type Oxidation of alcohols with acetone or its analogues as the sole Oxidant

hydrogen transfer reaction between alcohols and ketones or aldehydes is another mild and environmentally benign method for oxidation of alcohols. This transforma-tion is derived from the Oppenauer oxidation originally mediated by an equimolar amount of aluminum tri(t-butoxide). There had been many reports and reviews on metal-catalyzed Oppenauer-type reactions (including asymmetric versions such as DKR of secondary alcohols) [20]. Among the various ketones or aldehydes used as the oxidant (hydrogen acceptor), acetone is superior because it is relatively harm-less, easy to be handled, and economically advantageous despite its low boiling point. This section describes the recent development of the Oppenauer-type oxidation of alcohols catalyzed by well-defined homogeneous transition metal complexes bearing bidentate and related ligands using acetone or its analogue as the sole oxi-dant. As mentioned in the preface, asymmetric versions are not included.

8.2.3.1 Ir Complex with (N,O)-Chelating Ligand An iridium complex (21) bearing a bidentate amido–alkoxo ligand has been synthesized and exhibits a high catalytic activity for the Oppenauer-type oxidation of primary alcohols, which was rather difficult by the previous methods using lewis acidic catalysts due to formation of undesired side reactions of the resulting aldehydes [21]. The Oppenauer-type oxidation of various primary alcohols was conducted in 2-butanone under the high-dilution condition (0.08 M) to avoid dimerization of the resulting aldehyde. Some examples are shown in Table 8.26. The reaction proceeded with almost no by-product such as a dimeric ester, probably due to the neutral nature of the complex 21. The sulfide group susceptible to oxidation was tolerated. The oxidation of an allylic alcohol, cinnamic alcohol, gave a good yield, while that of an aliphatic alcohol, 1-octanol, resulted in a low conversion.

8.2.3.2 Polymetallic Complexes A chloro-bridged heterobimetallic complex (22) has been synthesized, and it exhibits high catalytic activity for the Oppenauer-type oxidation of secondary alcohols [22a]. The reaction was conducted in the presence of

Cat. 21 (1 mol%)

2-Butanone, re�ux, 16–18 hRCH2OH

Entry Yield (%)

12345

3,4-(MeO)2C6H34-MeSC6H4

PhPhCH=CH

C7H15

9681717233

HN OIr

Cp*

Ph Ph

21

RCHO

R

table 8.26 Oppenauer-type oxidation of primary alcohol catalyzed by 21 in 2-butanone.


an equimolar amount of K2CO

3 in 2-butanone. examples are shown in Table 8.27.

Secondary alcohols were oxidized to give the corresponding ketones in good to excellent yields.

it has been reported that a tetrametallic ruthenium complex (23) has been synthe-sized and catalyzes the Oppenauer-type oxidation of alcohols [22b]. The reaction was conducted in acetone at 80 °C. A few examples are shown in Table 8.28. A variety of primary and secondary alcohols were oxidized to give the corresponding aldehydes and ketones in good to excellent yields. The hammett studies revealed the opposite ρ-values for the oxidation of primary versus secondary alcohols (ρ = −0.45 for 4-xC

6h

4Ch

2Oh, ρ = +0.22 for 4-xC

6h

4Ch(Oh)Me). further kinetic and mech-

anistic investigations suggest the cooperative nature of the complex for the oxidation of secondary alcohols through the cooperative outer-sphere mechanism [20].

8.2.3.3 Other Catalyst Systems The catalyst combinations of [M(cod)Cl]2

(M = ir, Rh) and dipotassium 2,2′-bisquioline-4,4′-dicarboxylate (BQC) have been reported to catalyze the Oppenauer-type oxidation of secondary alcohols in water

RhCl

Cl

Cl Ru

Cl

PPh3

PPh3

Cat. 22 (0.2 mol%), K2CO3 (100 mol%)

R2R1 R2R1

OH O

2-Butanone, re�ux, 1 h


22

1234

PhCH(OH)MeCyclopentanolCyclohetanol

C6H13CH(OH)Me

99959986

Cp*

table 8.27 Oppenauer-type oxidation of secondary alcohols catalyzed by 22 in 2-butanone.

RuRu

OH

O

Ru Ru

OH

H

CO

H

OC HCO

OC

H

Cy3PPCy3

PCy3PCy3

23

Cat. 23 (2.5 mol%/Ru)

R2R1 R2R1

OH O

Acetone, 80 °C


1

2

34

PhCH2OH

PhCH(OH)MePhCH(OH)COPh

22

3.5

2016

84

85

9779

OH

table 8.28 Oppenauer-type oxidation of secondary alcohols catalyzed by 23 in acetone.

DehyDROgeNATiVe OxiDATiON Of AlCOhOlS WiThOUT OxiDANT 209

[23a, 23b]. The various secondary alcohols were oxidized to the corresponding ketones using the water-soluble [ir(cod)Cl]

2/BQC catalyst system in the presence of

an equimolar amount of Na2CO

3 at 90 °C in h

2O/acetone.

it has been reported that a simple iridium complex, Cp*irCl(μ-Cl)2irCp*Cl

([Cp*irCl2]

2), exhibits high catalytic performance for the Oppenauer-type oxidation

of primary and secondary alcohols in the presence of a catalytic amount (10 mol%) of K

2CO

3 in acetone at room or reflux temperature [23c]. The reactions of aliphatic

alcohols were conducted at reflux temperature.

8.3 dehydrOgenative OxidatiOn Of alcOhOls WithOut Oxidant

Catalytic dehydrogenative oxidation of alcohols without any oxidant or hydrogen acceptor accompanied by evolution of hydrogen (h

2) must be highly desirable and

promising from the standpoints of atom-economical and environmental concerns. furthermore, dehydrogenative oxidation of alcohols is synthetically important not only for the production of aldehydes and ketones from easily available alcohols with high atom efficiency but also for the production of h

2, which is one of the most promising

energy carriers in future energy plans. however, this transformation is an endothermic process and usually requires high reaction temperature and removal of generated h

2

from the reaction equilibrium. So far, various catalytic systems for the dehydrogenative oxidation of alcohols have been reported from not only synthetic aspects but also view-points of production of h

2. The reviews on the progress of the various catalytic systems

have recently appeared [1n, 24]. in this section, we focus on recent development of dehydrogenative oxidation of alcohols to carbonyl compounds catalyzed by well- defined transition metal complexes bearing bidentate and related ligands.

8.3.1 dehydrogenative Oxidation of alcohols catalyzed by ru complexes

following the earlier reports on the dehydrogenative oxidation of alcohols catalyzed by Ru(OCOCf

3)

2(CO)(PPh

3)

2 and related complexes [25], several dinuclear

bis(tetrafluorosuccinate)-bridged ruthenium complexes (24) and a dihydro-bridged complex (25) have been synthesized, and their catalytic activities for the dehydroge-native oxidation of 1-phenylethanol have been investigated [26]. Some examples are shown in Table 8.29. Compared with the previous reaction catalyzed by Ru(OCOCf

3)

2(CO)(PPh

3)

2 in the presence of TfA [25d], the reaction catalyzed by

the dinuclear complex 24a markedly reduced formation of by-products such as PhMeChOCOCf

3 and (PhMeCh)

2O (entry 1), but the complex 24a was not very

stable (TON = 50 after 24 h). The bis(tetrafluorosuccinate)-bridged ruthenium complexes (24b–24e) bearing bidentate phosphine ligands exhibited much higher catalytic activities (entries 2–6). Since no additive such as acid or base was required, the dehydrogenation was conducted under relatively neutral conditions. The dihydro-bridged complex 25 formed during the dehydrogenation of 1-phenylethanol also showed the relatively reduced catalytic activity (entry 6), indicating that the complex 25 could be a resting state in the catalytic cycles.


Based on VT-NMR experiments showing formation of a mononuclear complex similar to Ru(OCOCf

3)

2(CO)(PPh

3)

2, a possible catalytic cycle has been proposed

(Scheme 8.16) [26]. firstly, the mononuclear complex a having one tridentate tetra-fluorosuccinate (TfSA) ligand is formed by splitting of the dinuclear complex 24 at elevated temperature. Coordination of an alcohol followed by proton transfer to one of the carboxylate functions of the TfSA ligand produces the complex b. β-hydrogen elimination generating the complex c and the subsequent release of a coordinated ketone occur to give the hydride complex d having bidentate TfSA ligand. intramolecular attack of the free carboxylic acid function on the hydride regenerates the active catalyst a by release of h

2.

8.3.2 dehydrogenative Oxidation of alcohols catalyzed by ir complexes

8.3.2.1 Ir Complexes with (N,O)-Chelating Ligand it has been reported that a Cp*ir complex (26a) bearing 2-hydroxypyridineas ligand exhibited high catalytic performance for dehydrogenation of various secondary alcohols [27a]. The new complex was designed on the concept of “ligand-promoted” dehydrogenation

Cat. 24 or 25 (0.2 mol%)

p-Xylene, 130 °C, 24 h

Entry Catalyst Yield (%)

1234a

56a

a Catalyst was not completely dissolved during the reaction.b After 22 h.

207971768156b

50197178191203132

Ru

O

PPh3

PPh3

PPh3

Ph3P O

O

O

F2C

CO

F2 F2

F2F2

C

CF2 CF2

OO

RuO

OCOO

OCRu

O

PP O

O

OF2C

C

O

C

OO

RuO

O

P

CO

P

O

OC

24a 24b: P—P = dppp24c: P—P = dppb24d: P—P = dppf24e: P—P = rac-binap

RuP

P H

H

O

OC

RuP

P

OC

(CF2)2

O–O

CO

+

25: P—P = rac-binap

TON

24a24b24c24d24e25

HH

HH H

H

HH

PhCH(OH)Me PhCOMe + H2

table 8.29 Dehydrogenative oxidation of 1-phenylethanol catalyzed by 24 and 25.


(Scheme 8.17). The reaction of a metal complex e bearing a protic group (xδ−–hδ+) containing functional ligand with an alcohol would produce a metal hydride intermediate g via β-hydrogen elimination of a metal alkoxide f. An intramolecular reaction of the hydride on the metal with the protic hydrogen on the ligand could promote release of h

2 (ligand-promoted dehydrogenation). finally, the reaction of

the resulting metalacycle h with a substrate alcohol readily regenerates the metal alkoxide f, the starting catalytic species.

On the basis of the concept, hydroxypyridines having an acidic hydroxy group have been employed as a functional ligand. The dehydrogenation of 1-phenyletha-nol using various Cp*ir complexes bearing 2-, 3-, and 4-hydroxypyridines (26a–26c) as catalysts was conducted in toluene under reflux [27a]. A few examples are shown in Table 8.30. Among the complexes, 26a gave the best result (entry 1).

1/2 24Ru

P

OC O

O

O

P

F2C

CF2

O

RuP

OCO

O

O

P

F2C

CF2

O

OHR2

R1H

RuP

OCH

O

O

P

CF2

CF2

OHO

–2H2O

+2H2O

A

B

D

OH

R2

R1

O

R2

R1

H2

RuP

OCH

O

O

P

F2C

CF2

O

R2

R1

HO O

C

H

β-Hydrogen elimination

scheme 8.16

[M] L Xδ–Hδ+ [M]

OR1

R2

L Xδ–Hδ+

R1 R

O

[M]H

LXδ–Hδ+

[M]X

L H2

Ligand-promoteddehydrogenation

E

FG

H

R1 R2

OH


R1 R2

OH

scheme 8.17


3-hydroxy-, 4-hydroxy-, or unsubstituted pyridine ligand decreased the yield sig-nificantly (entries 2–4), indicating that the hydroxy group at the 2-position is indispensable.

The dehydrogenative oxidation of various secondary alcohols catalyzed by 26a was carried out in toluene under reflux. Some examples are shown in Table 8.31. The dehydrogenation of secondary alcohols proceeded very smoothly to give the corresponding ketones in good to high yields. On the other hand, the dehydrogena-tion of primary alcohols was not achieved efficiently.

A Cp*ir complex 26d (or its resonance form 26d′) bearing 2-pyridonate ligand corresponding to the supposed catalytic intermediate d (Scheme 8.17) was pre-pared. The complex 26d exhibited high catalytic activity for dehydrogenation of 1-phenylethanol, supporting the proposed mechanism (Scheme 8.18).

The more precise mechanistic investigation on catalytic species in the dehydroge-nation reaction catalyzed by the complex 26d (26d′) has been also reported (Scheme 8.19) [27b]. The reaction of 26d′ with 1-phenylethanol gave the stable dinu-clear dihydride complex [26e]Cl via the monohydride 2-hydroxypyridine complex

Cat. (0.1 mol%/Ir)


Entry Cat. Yield (%)

1234

7010139

26a26b26c

Cp*Ir(pyridine)Cl2

Cp*

IrN

Cl

Cl

OH

Cp*

IrN

Cl

Cl

26a 26b : 3-OH26c : 4-OH


HO

table 8.30 Dehydrogenative oxidation of 1-phenylethanol catalyzed by 26.

Cat. 26a (0.2–1 mol%)

R2R1 R2R1

OH O

Toluene, re�ux, 20–50 h


12

3a

45

a K2CO3 (1.0 mol%) was added.

+ H2

9482

76

9385

4-MeOC6H4CH(OH)CH34-BrC6H4CH(OH)CH3

C6H13CH(OH)CH3Cyclohexanol

OHO

table 8.31 Dehydrogenative oxidation of various secondary alcohols catalyzed by 26a.


26f, which, under the catalytic conditions, was rapidly converted to [26e]Cl as the predominant species.

The catalytic activities of various Cp*ir complexes bearing 2-pyridonate (2-hp) ligand has been compared [27b]. A few examples are shown in Table 8.32. The com-plex 26d′ was more active than the complex [26e]Cl. The bis-pyridonate complex, [Cp*ir(2-pyridonate)

2], was a poor catalyst. These experimental results suggest that

[26e]Cl would be a resting state that converts to more active species, 26d′ and 26f.furthermore, computational mechanistic studies proposed a new catalytic pathway

called the ligand rotational-promoted hydrogen transfer (Scheme 8.20) [27c]. The

Cat. 26d (0.1 mol%)


Cp*

IrN ClO

Cp*

IrN Cl

O26d

Y = 84%

26dʹ


scheme 8.18

Cp*

IrN Cl

O2

2 PhCH(OH)CH3

–2 PhCOCH3

IrH

Ir

H

Cp* Cp*

NO

+

Cl–

+

26dʹ

[26e]

Cp*

IrNCl

OHH

26f

HClN OH

100 °C[26e]C1

PhCH(OH)CH3 (5 equv)

26dʹ

scheme 8.19

123

Entry Catalysta

571408167

26dʹ[26e]Cl

Cp*Ir(2-hp)2

TON (21 h)

PhCH(OH)CH3 PhCOCH3 + H2Cat. (0.1 mol%)

Toluene, re�ux

a 2-hp = 2-Pyridonate. 2-hpH = 2-Hydroxypyridine.

table 8.32 TON for dehydrogenation of 1-phenylethanol catalyzed by various Cp*ir complexes.


facile ligand rotation between the 18-electron complex 26d and the 16-electron reac-tive species i would be responsible for the bifunctional reactivity of the complex 26d and the dehydrogenation could proceed through the outer-sphere mechanism.

The heterocyclic 6-(carboxymethyl)-4-methyl-2-hydroxypyridine (cmhph2) is a

simplified analogue of the guanylylpyridone (gP) cofactor in the enzyme h2-forming

methylenetetrahydromethanopterin dehydrogenase (hmd). A Cp*ir complex (27) bearing cmhph ligand has been reported to efficiently catalyze the dehydrogenation of 1-phenylethanol to acetophenone [27d]. examples are shown in Table 8.33. The related complexes lacking the α-hydroxy group showed much less catalytic activity

HOR1

R2

H2

26d

Cp*

IrN Cl

O

Cp*

IrN Cl

OO

R2

R1H

H

Cp*

IrNCl

26fOH

H

Cp*

IrNCl

O

H

H

I

OR1

R2

scheme 8.20

Cat. (0.1 mol%)

Neat, 130 °C

Entry Catalyst

1234a

a The reaction was conducted in toluene under re�ux.

Cp*

IrN

ClO27

Cp*Ir(C5H4N–2-CH2CO2)ClCp*Ir(C5H4N–2-CO2)Cl

27

TON (24 h)

169648

339

OH

27O

NH

O

CH2CO2H

Me

Me

GMP-O NH

O

CH2CO2H

N

OH

CH2CO2HGuanylylpyridone (GP)

(GMP = guanine monophosphate) cmhpH2

PhCH(OH)CH3 PhCOCH3 + H2

table 8.33 Dehydrogenative oxidation of 1-phenylethanol catalyzed by 27.


(entries 2 and 3), indicating that the α-hydroxy group significantly influences the reactivity of the sixth coordination site in octahedral complexes.

8.3.2.2 Ir Complexes with (C,N)-Chelating Ligand it has been reported that a cyclometalated Cp*ir complex (28a) bearing a functional C,N-chelating ligand exhibits the high catalytic performance for the dehydrogenative oxidation of both primary and secondary alcohols [28]. The dehydrogenative oxidation of benzyl alcohol was carried out using 28a and other related Cp*ir complexes (28b and 26a) as catalysts. Several examples are shown in Table 8.34. The complex 28a exhibited the high catalytic activity in the presence of a catalytic amount of base. Among the base employed, NaOMe in refluxed toluene and NahCO

3 in refluxed p-xylene

gave high yields (entries 2 and 3). it was apparent that the α-hydroxy group was indispensable, because the complex 28b having no hydroxy group showed poor activity (entry 4).

The dehydrogenative oxidation of various primary alcohols was achieved by using the catalyst 28a under the condition A (NaOMe in refluxed toluene) or the condition B (NahCO

3 in refluxed p-xylene) with high selectivity. Some examples are

shown in Table 8.35. in the cases of electron-poor benzylic alcohols, the reactions under condition B improved the yields (entries 3 and 4). The dehydrogenation of aliphatic primary alcohols resulted in the moderate yields and selectivity (entry 5). it should be noted that the dehydrogenative oxidation of secondary alcohols proceeds very smoothly with much smaller amount of 28a (0.10–0.50 mol%) without base to give the corresponding ketones in high to excellent yields.

An iridium hydride complex 28c, the possible catalytic intermediate (corresponding to g in Scheme 8.17), was prepared and the dehydrogenation of benzyl alcohol catalyzed by 28c proceeded without base to give benzaldehyde in 78% yield, sub-stantiating a catalytic active species (Scheme 8.21).

8.3.2.3 Ir Complexes with (N,N)-Chelating Ligand Water-soluble dicationic Cp*ir complexes (29) bearing bipyridine-based functional ligands have been synthe-sized and used at catalysts for the dehydrogenative oxidation of primary and secondary

Cat. (2 mol%), base (5 mol%)

Solvent, re�ux, 20 h


12345

849088830

28a28a28a28b26a

Base

NaHCO3NaOMeNaHCO3NaOMeNaOMe

PhCH2OH PhCHO + H2

NIr

Cp* ClXSolvent

TolueneToluenep-xyleneTolueneToluene

28a : X = OH28b : X = H

table 8.34 Dehydrogenative oxidation of benzyl alcohol catalyzed by various Cp*ir complexes.


alcohols in environmentally benign aqueous media for the first time [29]. The catalytic activities of the new complexes (29a and 29b) as well as the known complexes (29c and 29d) were compared by the dehydrogenation of benzyl alcohol in h

2O. Several exam-

ples are shown in Table 8.36. The complex 29a bearing the α-monohydroxybipyridine ligand and the complex 29b bearing the α,α′-dihydroxybipyridine ligand exhibited high activity (entries 1 and 2). On the other hand, other complexes 29c having no hydroxy group and 29d having γ,γ′-dihydroxy groups were apparently inferior as the catalysts (entries 3 and 4), indicating that the α-hydroxy group on the bipyridine ligand is crucial for the high catalytic performance. The yield of benzaldehyde was raised up to 92% when a slightly larger amount of 29b (1.5 mol%) was used (entry 5). The evolved h

2 gas was measured and the yield was 89%.

The dehydrogenative oxidation of primary and secondary alcohols was conducted by using 29b as the catalyst in h

2O. Some examples are shown in Table 8.37. Benzylic

alcohols that have electron-donating and electron-withdrawing groups were dehy-drogenated very smoothly to give the corresponding aldehydes and ketones in high yields. The TON of the reaction of 1-(4-methoxyphenyl)ethanol reached up to as high as 2550. The dehydrogenation of aliphatic secondary alcohols also proceeded well when a small amount of tBuOh was added as a cosolvent because of the low solubility of these substrates in h

2O.

Entry

12345

a 5.0 mol% of 28a was used.

7995574234

RCH2OH RCHO + H2Condition A: NaOMe, tolueneCondition B: NaHCO3, p-xylene

Cat. 28a (2 mol%), base (5 mol%)Solvent, re�ux, 20 h

Alcohol

2-MeC6H4CH2OH4-MeOC6H4CH2OH

4-BrC6H4CH2OH4-MeOCOC6H4CH2OH

C7H15CH2OH

Yield (%): Condition A Yield (%): Condition B

95

716046a

table 8.35 Dehydrogenative oxidation of various primary alcohols catalyzed by 28a.

N

IrCp* H

OH

28c

Toluene, re�ux, 20 hPhCH2OH PhCHO

Cat. 28c (2 mol%), no base

Y= 78%

scheme 8.21


Taking advantage of the water solubility of the complex 29b, reuse of 29b was easily achieved by a simple phase separation with extraction of organic compounds, and the dehydrogenative oxidation of 4-methoxyphenyl-1-ethanol was repeated eight times with almost no loss of the catalytic activity of 29b. furthermore, reuse of 29b by the simple phase separation was applied to the dehydrogenative oxidation of dif-ferent alcohols (Scheme 8.22). Thus, 1-(4-chlorophenyl)ethanol, 4-methylbenzyl alcohol, and 1-(4-methoxyphenyl)ethanol were consecutively dehydrogenated to give the corresponding carbonyl compounds in high yields, respectively.

A very similar catalytic cycle to those for the dehydrogenative oxidation catalyzed by 26a and 28a has been proposed (Scheme 8.23). elimination of TfOh produces a unsaturated 16- electron monocationic species a, which is converted to an alkoxo iridium species b trough activation of an alcohol. β-hydrogen elimination followed by release of h

2 via the ligand-promoted dehydrogenation occurs to regenerate the

initial catalytic species a.Thus, the dehydrogenative oxidation of various alcohols has been achieved by

using the complex 29b as the catalyst in environmentally benign h2O solvent at mild

reaction temperature (<100 °C) with high selectivity.

N NIr

Cp* OH2R1 R2

R3 R4

29a: R1= H, R2 = OH, R3 = R4 = H, X = OTf29b: R1 = R2 = OH, R3 = R4 = H, X = OTf29c: R1 = R2 = R3 = R4 = H, X = OTf29d: R1 = R2 = H, R3 = R4 = OH, X = OTf

[X]2

Cat. (0.5 mol%)

H2O, 20 h, re�uxPhCH2OH PhCHO + H2

Entry Catalyst

12345a

a1.5 mol% of 29b was used.

5062252292

29a29b29c29d29b

Yield (%)

table 8.36 Dehydrogenative oxidation of benzyl alcohol in water catalyzed by 29.

Entry

1234

a tBuOH (0.5 mL) was added as a cosolvent.

93919377

Yield (%)Alcohol

4-MeOC6H4CH2OH2-MeC6H4CH2OH4-BrC6H4CH2OH

4-MeOCOC6H4CH2OH

Cat. 29b (1.5–3 mol%)

H2O, re�ux, 20 h+ H2

OH

R2 R2R1R1

O

PhCH(OH)Me4-BrC6H4CH(OH)MeC6H13CH(OH)CH3

Cyclohexanol

Entry Yield (%)Alcohol

567a

8a

92928580

table 8.37 Dehydrogenative oxidation of various alcohols in h2O catalyzed by 29b.


8.3.3 dehydrogenative Oxidation of alcohols catalyzed by Other complexes

8.3.3.1 Ru and Os Complexes with (N,N)(P,P)-Chelating Ligands Various ruthe-nium and osmium complexes (30 and 31) bearing diamine and diphosphine ligands have been synthesized and catalyze the dehydrogenative oxidation of secondary alcohols [30]. At first, the dehydrogenative oxidation of 1-tetralol was examined in the presence of base (tBuOK). Several complexes exhibiting high catalytic activity are shown in Table 8.38. DPPf was superior as a diphosphine ligand.

The complexes 30b and 31 smoothly dehydrogenated various secondary alcohols in the presence of tBuOK to give the corresponding ketones in high conversions. The present catalytic system was also applicable to the dehydrogenative oxidation of ste-roidal alcohols. The reactions proceeded with C = C double-bond isomerization to afford the corresponding steroidal ketones in high conversions. The reactions cata-lyzed by the complex 31 are shown in Scheme 8.24.

4-MeC6H4CH2OH

Aqueous phase1st

2nd

3rd29b (1 mol%), H2O

re�ux, 20 h

4-MeOC6H4CH(OH)Me

4-MeOC6H4COMeY= 95%

4-MeC6H4CHOY = 90%

4-ClC6H4CH(OH)Me

4-ClC6H4COMeY = 92%

scheme 8.22

29b–TfOH

Activation ofalcohol

N NIr

Cp*

HO O

+

N NIr

Cp*

HO OH

+O R2

R1

N NIr

Cp*HO OH

+H

A

B

C

R1 R2

OH


R1 R2

O

Ligand-promoteddehydrogenation

H2

scheme 8.23


8.3.3.2 Catalyst Combination of Metal Complex and Additive Ligand A couple of catalyst combinations of metal complexes and additive ligands have been reported and are listed here. 2-Propnanol was dehydrogenated by a catalyst combination of RuCl

3 · xh

2O/2-di-tert-butylphosphinyl-1H-pyrrole/Na at 90 °C [31a]. The dehydro-

genative oxidation of various aromatic secondary alcohols was carried out by using a catalyst combination of PhCh = Ru(PCy

3)

2Cl

2/liOh or [(p-cymene)RuCl

2]

2/PPh

3

in toluene at 110 °C [31b]. The dehydrogenation of alcohols to produce h2 was also

conducted by catalyst combinations of [(p-cymene)RuCl2]

2/TMeDA and [(p-cymene)-

RuCl2]

2/Me

2NCh

2Ch

2Oh in the presence of iPrONa at 90 °C [31c].

Cat. 30 or 31 (0.4 mol%), tBuOK (2 mol%)

tBuOH, 130 °C (bath temperature)

Entry Cat.

12345

+ H2

33446

9798979098

30a30b30c30d31

dach = 1,2-diaminocyclohexaneen = H2NCH2CH2NH2ampy = 2-aminomethylpyridine

RuN

N P

P

Cl

Cl30a

N–N = trans-dachP–P = dppf

RuN

N P

P

Cl

Cl30b

N–N = enP–P = dppf

RuN

N P

P

Cl

Cl

30cN–N = ampyP–P = dppf

RuCl

N P

P

Cl

N

30dN–N = ampyP–P = dppf

OsN

N P

P

Cl

Cl

31N–N = en

P–P = dppf

OH O

Time (h) Conversion (%)

table 8.38 Dehydrogenative oxidation of 1-tetralol catalyzed by 30 and 31.

Cat. 31 (0.8 mol%),tBuOK (4 mol%)

tBuOH, toluene20 h, 145 °C (bath temperature)

+ H2

R: –CH(CH3)CH2CH2CH2CH(CH3)2R: –CH(CH3)CH=CHCH(C2H5)CH(CH3)2R: =O(ketone)R: –C(CO)CH3

conversion = >98%conversion = >98%conversion = 86%conversion = 95%

R

HO

R

O

scheme 8.24


8.4 OxidatiOn Of amines based On hydrOgen transfer and dehydrOgenatiOn

Oxidative dehydrogenation of amines to imines and nitriles is a very important chemical transformation, especially for synthesis of biologically active organic mol-ecules including pharmaceuticals [32]. in this section, the recent development of dehydrogenative oxidation of amines using well-defined homogeneous transition metal complexes is described [1n, 26c].

8.4.1 dehydrogenative Oxidation of amines with Oxygen as the sole Oxidant

8.4.1.1 Ru Complex with (C,N),(N,N,N)-Chelating Ligands A cyclometalated ruthenium complex (32a) bearing 2-phenylpyridine and terpyridine ligands cata-lyzed aerobic oxidation of benzylic primary amines to give nitriles [33a]. The reactions were carried out in the presence of K

2CO

3 (1 equiv) in CD

3OD under O

2

(1 atm) at reflux temperature. Some examples are shown in Table 8.39. Benzylamines with electron-donating groups were readily oxidized to give the corresponding ben-zonitriles in good to high yields. The reaction of aliphatic amines did not produce any desired nitriles. The oxidation using a ruthenium complex (32b) bearing bipyridine ligand under the same conditions did not proceed (entry 2), suggesting that the redox potential of 32a was sufficiently low for aerobic oxidation of the ruthenium center due to the σ-donor character of the cyclometalated ligand. The oxidation of secondary amines catalyzed by 32a under the similar conditions gave imines in moderate yields.

A plausible catalytic cycle has been proposed (Scheme 8.25). Since the formation of ruthenium hydride intermediate via the usual β-hydrogen elimination would be unlikely because of coordinatively saturated nature of a supposed catalytic intermediate, the dehydrogenation would proceed through removal of two protons and two electrons in the intermediate Ru-amine and Ru-imine complexes.

Cat. 32a (5 mol%), K2CO3 (1 equiv)

O2 (1 atm), CD3OD, re�ux

Entry Yield (%)

12a

345

a The complex 32b was used as a catalyst.

Ar–CH2NH2 Ar–CN

Ar Temperature (°C) Time (h)

4-MeC6H44-MeC6H42-MeC6H4

Ph4-ClC6H4

re�uxre�uxre�uxre�ux

30

111124

870

837361

[PF6]

32a: X=C32b: X=N

N

N NRu

XN

Cl

table 8.39 Oxidative dehydrogenation of benzylamines catalyzed by 32a.

OxiDATiON Of AMiNeS BASeD ON hyDROgeN TRANSfeR AND DehyDROgeNATiON 221

A similar cyclometalated ruthenium complex (33a) bearing benzo[h]quinoline and terpyridine ligands has been synthesized and used as a catalyst for aerobic oxidation of benzylamines [33b]. The reactions were carried out under the similar conditions as earlier. Several examples are shown in Table 8.40. The catalytic activity of 33a was slightly lower than that of 32a. The oxidation using a ruthenium complex (33b) bearing phenanthroline ligand did not proceed under the same conditions (entry 2).

it has been also reported that the complex 32a catalyzes oxidative dehydrogena-tion of 2-substituted imidazolines [33c]. The reactions were carried out in the presence of K

2CO

3 (1 equiv) in MeOh under O

2 (1 atm) at 55 °C. A few examples are

shown in Table 8.41. 2-Arylimidazolines were smoothly oxidized to give the corresponding imidazoles in high yields, whereas the reaction of 2-alkylimidazoline were very slow. it should be noted that the presence of N-h group was indispensable for the oxidative dehydrogenation.

8.4.1.2 Dinuclear Ru Complex with (O,O)-Chelating Ligands it has been reported that a dinuclear [Ru–Ru] complex, Ru

2(OAc)

4Cl, (34) catalyzes aerobic

oxidation of secondary amines to imines [34]. Among several ruthenium complexes examined, the complex 34 exhibited the excellent catalytic activity. The reactions were carried out in toluene at 50 °C under O

2 (1 atm). Some examples are shown in

PhCH2NH232a [Ru] NH2CH2Ph

Base

[Ru] NH=CHPh

[Ru] N CPh

–2H+, –2e–

–2H+, –2e–

PhCH2NH2

PhCN

scheme 8.25


O2 (1 atm), CD3OD, re�ux

Entry Yield (%)

12a

345

aThe complex 33b was used as a catalyst.

Ar–CH2NH2 Ar–CN

Ar Temperature (°C) Time (h)

4-MeC6H44-MeC6H4

4-MeOC6H4Ph

4-ClC6H4

re�uxre�uxre�uxre�ux

30

1.51.51.51.524

890

937472

[PF6]

33a: X = C33b: X = N

NN N

RuClX

N

table 8.40 Aerobic oxidation of benzylamines catalyzed by 33a.


Table 8.42. Cyclic and acyclic amines were dehydrogenated in moderate to good yields. The oxidation of a primary amine, benzylamine, gave benzonitrile.

8.4.1.3 Other Catalyst Combinations it has been reported that CuCl or CuCl2

catalyzes dehydrogenative oxidation of primary or secondary amines to nitriles or imines under O

2 (1 atm) in the presence of MS 3 Å as a dehydrating agent [35a]. A

catalyst combination of PdCl2/PPh

3 also catalyzed the dehydrogenative oxidation of

secondary amines to imines under O2 (1 atm) [35b].

8.4.2 dehydrogenative Oxidation of amines without Oxidant

8.4.2.1 Ir Complexes with (N,O)-Chelating Ligand Dehydrogenation of nitrogen heterocyclic compounds accompanied by release of h

2 has recently attracted much

attention from the viewpoints of organic hydride hydrogen storage systems [36].

Cat. 34 (4 mol%), O2 (1 atm)

Toluene, 50–80 °C

Entry Yield (%)

1

2

3

45

Amine Time (h)

3

72

1

187

HN N R2R2

R1 R1

Ru2(OAc)4Cl34

O

Ru RuO OO

O OOOClNH

NH

N

N

NH

PhCH2NHCH2PhPhCH2NH2

Product

PhCH=NHCH2PhPhCN

NH

77

55

83

7266

table 8.42 Aerobic oxidation of amines catalyze by 34.


O2 (1 atm), MeOH, 55 °C

Entry Yield (%)

1234

R Time (h)

Ph4-MeOC6H44-CF3C6H4

C3H7

888

72

quant.808770

HN

NR

HN

NR

table 8.41 Aerobic oxidation of imidazolines catalyze by 32a.

OxiDATiON Of AMiNeS BASeD ON hyDROgeN TRANSfeR AND DehyDROgeNATiON 223

Several Cp*ir complexes (26) bearing (N,O)-chelating ligands (Section 8.3.2.1) have been reported to catalyze dehydrogenation of 1,2,3,4-tetrahydroquinolines (ThQ) [37a]. The dehydrogenation reactions were carried out in p-xylene under reflux. Several examples are shown in Table 8.43. Among the complexes 26, the complex 26f bearing 5-trifluoromethyl-2-pyridonate ligand exhibited the highest activity (entry 3), and the dehydrogenation of 2-methyl-1,2,3,4-tetrahydroquinoline (2-MeThQ) catalyzed by 26f gave 2-methylquinoline (2-MeQ) in quantitative yield with release of two molecules of h

2 (entry 4).

in addition, the complex 26f efficiently catalyzes hydrogenation of 2-MeQ to give back the starting 2-MeThQ. Thus, reversible dehydrogenation–hydrogenation reactions between 2-MeThQ and 2-MeQ were achieved by using the complex 26f and could be repeated five times without almost no loss of efficiency (Scheme 8.26), demonstrating the first example of homogeneous catalytic system for reversible dehydrogenation–hydrogenation of nitrogen heterocycles using a single complex as the catalyst.

further investigations have revealed that the reversible dehydrogenation–hydro-genation reactions proceed with reversible interconversion of catalytic species bet-ween 26f and [Cp*irhCl]

2, depending on the absence or presence of h

2 (Scheme 8.27).

Cat. 26 (2 mol%)

p-Xylene, re�ux, 20 h

Entry Yield (%)

12345

R

HHH

2-Me3-Me

695773

10086

NO

IrCp* Cl

Y

NH

R

N

R + 2H2

26d: Y = H26e: Y = 5-Me26f: Y = 5-CF3

Cat.

26d26e26f26f26f

NIr

Cp* Cl

Cl

OH

26a

table 8.43 Dehydrogenation of 1,2,3,4-tetrahydroquinolies catalyzed by 26.

NH

N

Cat. 26f (5 mol%), p-xylene, 20 h

2H2

2H2

Dehydrogenation (%)Hydrogenation (%)

100 100 100 99 98100 100 99 98 98

Cycle 1 2 3 4 5

Re�ux

H2 (1 atm), 110 °C

2-MeTHQ 2-MeQ

scheme 8.26


The dehydrogenation of 2-MeThQ is catalyzed by 26f to give 2-MeQ with evolution of h

2 (step 1). The complex 26f is converted to [Cp*irhCl]

2 and the ligand 5-trifluo-

romethyl-2-hydroxypyridine under h2 (step 2). Then, hydrogenation of 2-MeQ is

catalyzed by [Cp*irhCl]2 (step 3) to give the starting substrate 2-MeThQ. finally,

removal of h2 brings about the recombination of [Cp*irhCl]

2 and the ligand to

regenerate the starting complex 26 f. Computational studies on the mechanism of the reversible dehydrogenation–hydrogenation reactions of nitrogen heterocycles have been also reported [37b, 37c].

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2H2

2-MeTHQ 2-MeQ

26f

[Cp*HCl]2 +N OH

F3C

–H2 +H2

NH

N

2H2

Step 1

Step 2

Step 3

Step 4

scheme 8.27

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RefeReNCeS 227

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228

Hydrogenation and transfer Hydrogenation of Carbon–Heteroatom UnsatUrated bonds Catalyzed by Well-defined transition metal Complexes bearing bidentate and misCellaneoUs ligands

9

9.1 introdUCtion

Reduction of polar carbon–heteroatom unsaturated bonds such as C5O and C5N bonds has been a fundamental and important transformation in organic chemistry and synthesis as well as industrial chemistry, and great numbers of methods have been developed [1]. Compared to conventional reductions by means of more than equimolar amount of metal hydride reagents, catalytic hydrogenation and transfer hydrogenation are more desirable and atom-economical chemical transforma-tions from environmental points of view. The main subjects discussed in this chapter are the recent progress during the past decade (since 2000) of reduction of polar carbon–heteroatom unsaturated bonds such as C5O and C5N bonds based on the hydrogen transfer process catalyzed by well-defined homogeneous transition metal complex. As mentioned in the preface, asymmetric reduction is not included.

HYDROGENATION AND TRANSFER HYDROGENATION OF CARBONYL COmpOuNDS 229

9.2 Hydrogenation and transfer Hydrogenation of Carbonyl and related CompoUnds

This section describes the recent progress of catalytic hydrogenation and transfer hydrogenation of a variety of carbonyl compounds (aldehydes, ketones, esters, and amides) based on the hydrogen transfer process catalyzed by well-defined homoge-neous transition metal complex using green hydrogen sources such as molecular hydrogen (H

2), 2-propanol, and formic acid or sodium formate [2]. While asymmetric

versions are not included in this section, tremendous amounts of ruthenium, rhodium, and iridium complexes bearing chiral diamine–diphosphine, diamine, or amino alcohol ligands named bifunctional catalysts have been developed for asymmetric hydrogenation and transfer hydrogenation of carbonyl compounds, and extensive mechanistic investigations have been also accomplished [3, 4].

9.2.1 Hydrogenation and transfer Hydrogenation of Ketones and aldehydes

Since there have been considerable amounts of reports and comprehensive reviews on hydrogenation and transfer hydrogenation including asymmetric versions cata-lyzed by ruthenium, rhodium, and iridium complexes bearing diamine–diphosphine, arene–diamine or Cp*–diamine, or arene–amino alcohol ligands as mentioned earlier [2–4], this part is focused on hydrogenation and transfer hydrogenation catalyzed by other well-defined metal complexes bearing bidentate and miscellaneous ligands.

9.2.1.1 Catalytic Hydrogenation with H2

Ru Complexes with (N,P)(N,P)-Chelating Ligands Ruthenium complexes (1) bearing bis-aminophosphine ligands have been synthesized and used as catalysts for hydro-genation of ketones [5]. The reactions were carried out with low catalyst loading (0.025–0.26 mol%) in the presence of base without or with solvent under H

2 (3 atm) at

room temperature. Examples are shown in Table 9.1. The complexes 1a and 1b exhib-ited high catalytic activities to give the corresponding alcohols in quantitative yields, respectively. The C5C double bond remained intact.

PPh2

H2N

H2N

PPh2

Ru

L

Cl

R1COR2Cat. 1, base (1 : base = 1 : 3–5)

H2 (3 atm), no solvent or C6D6, rt, 12 hR1CH(OH)R2

Entry Ketone Base

12345

PhCOMePhCOMePhCOtBuMeCOMe

CH2=CH(CH2)2COMe

Cat. (mol%)

1a: L = Cl1b: L = H

1a (0.045)1b (0.045)1a (0.26)1b (0.025)1b (0.041)

iPrOKiPrOKtBuOKtBuOKtBuOK

Solvent

NoNoC6D6NoNo

Conv. = 100%

table 9.1 Hydrogenation of ketones catalyzed by 1.

230 HYDROGENATION AND TRANSFER HYDROGENATION

Os Complexes with (N,N)(P,P)-Chelating Ligands While a great number of hydro-genation reactions of carbonyl compounds catalyzed by Ru, Rh, and Ir complexes bearing diamine–diphosphine ligands have been reported as mentioned earlier, anal-ogous osmium complexes have been rarely used as catalysts [6a]. A few osmium complexes (2) bearing diamine and diphosphine ligands have been synthesized, and they exhibit extremely high catalytic activities for hydrogenation of ketones and aldehydes [6b]. Hydrogenation catalyzed by the complexes 2a–2c was con-ducted in the presence of EtONa as a base in ethanol under low H

2 pressure (5 atm).

Some examples are shown in Table 9.2. The hydrogenation of ketones and alde-hydes was completed with a very low catalyst loading (>0.01 mol%) within 1 h. Asymmetric hydrogenation catalyzed by chiral osmium complexes was also mentioned.

Rh Complexes with (N,C5C,C5C)-Chelating Ligands Rhodium complexes (3) bearing tridentate trop

2NH {bis(5-H-dibenzo[a,d]cyclohepten-5-yl)amine} ligand

have been synthesized and used as catalysts for hydrogenation of ketones [7]. A few examples are shown in Table 9.3. mechanistic studies including DFT calculations were performed.

CpMo Complexes with (P)-Tethered Cp Ligands Several molybdenum complexes (4) bearing Cp ligand tethered by phosphine have been synthesized, and their catalytic activities have been investigated in the hydrogenation of ketones, since

R1COR2Cat. 2, H2 (5 atm), EtONa (1 or 0.5 mol%)

R1CH(OH)R2

Entry Cat.Conversion

(%) TOF (h–1)a

1234567

2a2b2c2a2a2a2a

>99>99

98959799

>99

170,000300,000150,000

80,00090,00090,00057,000

a TOF at 50% conversion.

FeP

PPh2

OsNH2

H2N

Cl

Cl

Ph2

FeP

PPh2

OsNH2

OCH2CF3

OCH2CF3

NH2

Ph2

FeP

PPh2

OsNH2

H2N

Cl

Cl

Ph2

2a 2c2b

EtOH, 60 – 70 °C

Substrate

PhCOMePhCOMePhCOMe

C8H17COMe Cyclohexanone

PhCHOC5H11CHO

Time (min)

10301060601010

Cat. (mol%)

0.010.0020.010.0020.0020.010.01

table 9.2 Hydrogenation of ketones and aldehydes catalyzed by 2.

molybdenum is inexpensive and the use of precious metals can be avoided [8]. The cationic molybdenum catalysts with B(Arf)

4− {Arf = 3,5-(CF

3)C

6H

3} and BF

4−

counter anions were generated in situ by reaction of 4a–4c with ph3C+[B(Arf)

4]− and

ph3C+BF

4−, respectively. The corresponding triflate complexes 4d–4f are isolated

and added to neat 3-pentanone. Hydrogenation of 3-pentanone catalyzed by 4 was carried out under solvent-free condition. Several examples are shown in Table 9.4.

R1COR2Cat. 3 (1 mol%), H2 (100 bar)

THF, 25 °C, 16 hR1CH(OH)R2

Entry Cat. Conversion (%)

123

3a3a3b

>97>97>97

HN

trop2NH

3a

N

Rh

PPh2Tol

N

Rh

PPh2TolH

H

3b

Ketone

CyclohexanonePhCOMePhCOMe

H2

NH =

table 9.3 Hydrogenation of ketones catalyzed by 3.

C2H5COC2H5Cat, H2 (4 atm)

C2H5CH(OH)C2H5

Entry Cat.a P/H2 (atm)Temperature

(°C) TON (ca. 10 d)

123456

B(Arf)44a + Ph3CB(Arf)44b + Ph3CB(Arf)4

4b + Ph3CBF44e4e4f

505050507575

444444

6212099

12038845

a Arf = 3,5-(CF3)2C6H3.

4a: R = Ph4b: R = Cy4c: R = tBu

Mo PR2

H

COOC

Mo PR2COOC

(trans + cis)

4d: R = Ph4e: R = Cy4f: R = tBu

Aniona

B(Arf)4B(Arf)4

BF4OTfOTfOTf

Cat. (mol%)

0.350.350.350.350.170.17

TfO

No solvent

table 9.4 Hydrogenation of neat 3-pentanone catalyzed by 4.



The catalytic activity of a combination of 4b + ph3C+B(Arf)

4− was higher than that

of 4a + ph3C+B(Arf)

4−. The complex 4e shows high TON at higher reaction temper-

ature (75 °C) (Entry 6), indicating that 4e is more stable and long lived. It should be noted that the analogous untethered complex TfOmo(CO)

2Cp(pCy)

3 gives much

inferior result.

Ru Complexes with (P,N,N,P)-Chelating Ligands It has been reported that a ruthe-nium complex (5a) bearing tetradentate diamino–diphosphine ligands efficiently catalyzes hydrogenation of ketones and aldehydes [9a]. The catalytic hydrogenation was conducted in 2-propanol with H

2 (45 bar) at 60 °C. Some examples are shown in

Table 9.5. Addition of iprOK increased the reaction rate, and the C = C double bonds of α,β-unsaturated carbonyl compounds remained intact.

Several ruthenium complexes (5b–5f) bearing tetradentate diimino- or diamino-diphosphine ligands have been synthesized, and their catalytic activities are compared in hydrogenation of acetophenone [9b]. Several examples are shown in Table 9.6. The reaction proceeded more rapidly in more polar solvent 2-propanol than in benzene (Entries 1 and 2). The complexes 5c and 5f are more active than the complexes 5d and 5e, respectively, indicating that a cyclohexyl backbone between the amines is superior to a tetramethylethylene one. The relative rate was largest in the reaction using 5c/tBuOK (Entry 3). The similar activity of 5b in 2-propanol to that of 5d/tBuOK suggests that the complex 5d reacts with the base to form the amide complex 5b (Entries 2 and 4).

Based on the experimental results that the reaction of 5d with tBuOK produces the hydrido–amido complex 5b, which reacts with H

2 to give a dihydrido–amine

complex 5 g, a possible catalytic cycle is proposed (Scheme 9.1). The concerted transfer of hydride and proton to a ketone from the complex 5 g could occur through the outer-sphere transition state (TS).

PPh2

NH NH

PPh2

Ru

Cl

Cl

R1COR2Cat. 5a, H2 (45 bar)

iPrOK, iPrOH, 60 °CR1CH(OH)R2

Entry SubstrateConversion

(%)

123

4

5

PhCOMePhCOMe

Cyclo-C6H11COMe

9810099

100

96

C/B/Sa

1/0/105

1/90/106

1/4500/104

1/90/105

1/450/105

a C/B/S = molar ratio of cat./base/substrate.

5a

CHO

O

Time (h)

633

1

24

table 9.5 Hydrogenation of ketones and aldehydes catalyzed by 5a.

It should be noted that asymmetric transfer hydrogenation of aromatic ketones with 2-propanol by using the similar ruthenium complexes bearing chiral tetraden-tate (p,N,N,p) ligands as catalysts has been already reported [9c, 9d].

Fe Complexes with (P,N,N,P)-Chelating Ligands A couple of cationic iron complexes (6) bearing diimino-diphosphine or diamino-diphosphine ligands have been synthe-sized, and their catalytic activities for hydrogenation of acetophenone have been

PPh2

N N

PPh2

Ru

PhCOMeSolvent, 20 °C

PhCH(OH)Me

Entry Cat.

123456

5b5b

5c/tBuOK5d/tBuOK5e/tBuOK5f/tBuOK

Solvent

C6H6iPrOHiPrOHiPrOHiPrOHiPrOH

5b

Rate (Ms–1)

5c

H

PPh2

N N

PPh2

Ru

5e

Cl

H

PPh2

N N

PPh2 Ph2

Ru

5f

Cl

H

9 × 10–7

3.7 × 10–6

5.0 × 10–3

4.6 × 10–6

1.3 × 10–5

6.0 × 10–4

Rel. Rate

14

55554

14667

H

PPh2

N N

PPh2

Ru

Cl

H

H H

5d

PPh2

N N

PPh2

Ru

Cl

HH H

Cat. 5 (2.0 × 10–4), H2 (6 atm)

table 9.6 Comparison of initial rates of the hydrogenation of acetophenone catalyzed by 5.

5b P

N N

PPh2Ph2

Ru

5g

H

HHH

5dtBuOK

H2

PhCOMePhCH(OH)Me

RuP

P N

N

H

H

O

H

H

R1

R2

TS

THF

sCHeme 9.1



studied [10], because iron is attractive from the standpoints of its great abundance, lower cost, and less toxicity [2g–2i, 2 k, 2l, 3j]. The hydrogenation proceeded smoothly in the presence of tBuOK under 25 atm of H

2 at 50 °C. A few examples are shown in

Table 9.7. Among the complexes, 6c exhibited the highest activity, indicating that the diimine ligand could be reduced to the diamine ligand to generate the same active trans-dihydride species. The outer-sphere mechanism for the transfer of hydride and proton to the ketone is proposed, as shown in the analogous ruthenium systems. The DFT calculations also supported the mechanism.

Other Catalyst Systems It has been reported that cationic dinuclear complex {[Cp*Ru(CO)

2]

2(μ-H)}[OTf] catalyzes hydrogenation of ketones [11a]. It is worth not-

ing that a few Cu complexes and catalyst combinations, [η2-meC(CH2pph

2)

3Cu(μ-H)]

2,

[(pph3)CuH]

6/me

2php, and [Cu(NO

3)(pph

3)]/ph

2p(CH

2)

4pph

2, catalyze hydrogenation

of ketones and aldehydes chemoselectively without hydrogenation of C = C double bonds [11b–11d].

9.2.1.2 Transfer Hydrogenation with HCO2H (HCO2Na) and/or 2-PropanolRu, Rh, and Ir Complexes with (N,N)-Chelating Ligands(Arene)Ru, Cp*Rh, and Cp*Ir Complexes with 2,2′-Bipyridine Ligands It has been reported that a water-soluble cationic (η6-C

6me

6)Ru complex (7a) bearing

2,2′-bipyridine ligand catalyzes the pH-dependent transfer hydrogenation of ketones with HCO

2Na in water [12a]. Transfer hydrogenation of water-soluble and water-insoluble

PPh2

N N

PPh2

Fe

N

N

CMe

C

Me

[BF4]2

PPh2

N N

PPh2

Fe

N

N

C

Me

[BF4]2C

Me

PPh2

N N

PPh2

Fe

N

N

CMe

C

Me

[BF4]2

6a6b

6c

PhCOCH3

Cat. 6 (0.44 mol%), H2 (25 atm)

tBuOK (0.67 mol%), iPrOH, 50 °C, 18 hPhCH(OH)CH3

HHEntry Cat. Conversion (%)

123

6a6b6c

70–958099

table 9.7 Hydrogenation of acetophenone catalyzed by 6.

ketones proceeded in high yields. A few examples are shown in Table 9.8. The rate of reaction was pH dependent and showed the maximum value around pH = 4.0 at 70 °C.

The reaction of the cationic complex 7a with HCO2Na gave a formate complex 7b

as a catalytic intermediate at pH = 4.0 and also produced a hydride complex 7c as the actual catalytic species at 70 °C in the range of pH = ca. 4–10 (Scheme 9.2).

Based on the aforementioned experimental results, a possible mechanism has been proposed in Scheme 9.3, in which the pH-dependent transfer hydrogenation is controlled not only by the stability of the catalyst but also by the activation of ketones with higher concentration of proton (pH = 4).

Similarly, the pH-dependent transfer hydrogenation of ketones catalyzed by [Cp*Rh(bpy)Cl]Cl (8a), [Cp*I(bpy)Cl]Cl (8b), and [(η6-C

6me

6)Ru(bpy)Cl]Cl (8c)

has been reported [12b]. The reactions were carried out with HCO2H/HCO

2Na as a

hydrogen source in H2O. Several examples are shown in Table 9.9. The highest yields

were obtained at pH = 3.5. The catalytic activities decreased in the order of Rh > Ir ≫ Ru. Various ketones are also reduced by the complex 8a in high yields.

A water-soluble cationic Cp*Ir complex (9a) bearing 2,2′-bipyridine ligand has been synthesized and used as a catalyst for the pH-dependent transfer hydrogenation

7a[SO4] + HCO2Na N N

Ru

C6Me6 OCH [HCO2]

H2O, 3M HCO2H40 °C, 0.5 h

pH = 4.0

7b[HCO2]

O

7a[SO4] + HCO2Na

(1) H2O, 1M NaOH,pH = 8.0, 70 °C, 0.5 h

(2) NaPF6, 70 °CN N

Ru

C6Me6 H [PF6]

7c[PF6]Y = 65%

Y = 50%

sCHeme 9.2

R1COR2Cat. 7a[SO4] (0.5 mol%), pH = 4.0

HCO2Na, H2O, 70 °CR1CH(OH)R2


1

2

3

4

CyclohexanoneMeCOCO2H

4-MeCOC6H4SO3Na

PhCOMe

4

4

3

4

99

99

98

98

N N

Ru

C6Me6 OH2

7a

2+

table 9.8 Transfer hydrogenation of ketones catalyzed by 7a[SO4] in H

2O.



of ketones with HCO2H in water [12c]. The reactions were conducted at pH = 2.0,

since the reaction rate showed the sharp maximum at pH = ca. 2.0. Some examples are shown in Table 9.10. A variety of ketones were reduced in excellent yields. It should be noted that the complex 9a is more active than the similar ruthenium complex 7a.

Reaction of the air-stable complex 9a with HCO2H or HCO

2Na readily produced

the hydride complex 9b under the controlled conditions (pH = 2.0–6.0, 25 °C) (Scheme 9.4, the 1st equation) [12c]. Stoichiometric reactions of 9b with cyclohexanone

7a

N N

Ru

η4-C6Me6 O

H

O +

7c

7b

CO2HCO2

–

H2O

R1COR2 R1CH(OH)R2

H+

H2O

β−Hydrogenelimination

(>pH = 3.6)

N N

Ru

C6Me6 H C O

R1

R2H+

+

Hydrogen transfer activated by H+

sCHeme 9.3

N N

Rh

Cp* Cl

R1COR2Cat. 8 (0.5 mol%)

HCO2H/HCO2Na/H2O, pH = 3.5, 40 °CR1CH(OH)R2

Catalyst

8a8b8c8a8a

[Cl]

8a

N N

Ir

Cp* Cl [Cl]

8b

N N

Ru

C6Me6 Cl [Cl]

8c

Entry Substrate Yield (%)a

12345

MeCOMeMeCOMeMeCOMe

CyclohexanoneMeCOCO2C2H5

>999813

>99>99

Time (h)

12121241.5


and acetophenone in the absence of HCO2H gave the corresponding alcohols, respec-

tively, in moderate yields (the 2nd equation), while transfer hydrogenation of the same ketones catalyzed by 9b afforded the alcohols in quantitative yields (the 3rd equation). These results suggest that the actual catalytic species is the hydride complex 9b.

A catalytic cycle of the present pH-dependent transfer hydrogenation has been proposed (Scheme 9.5) [12c]. The hydride complex 9b is selectively formed at pH = 2–6, and the activation of ketones by higher proton concentration at pH = 2–3 is required in the step of hydride transfer from 9b to ketones.

It has been reported that water-soluble cationic Cp*Ir complexes (10) bearing 4,4-disubstituted 2,2′-bipyridine ligands catalyze pH-dependent transfer hydrogena-tion of α,β-unsaturated carbonyl compounds [12d]. Among the complexes including the parent complex 9a, the complex 10a exhibited the highest catalytic activity.

R1COR2 Cat. 9a [SO4] (0.5 mol%), pH = 2.0

HCO2H, H2O, 70 °C, 1 hR1CH(OH)R2


12345

CyclohexanonePhCOMePhCOCF3

MeCOCO2H4-MeCOC6H4SO3Na

9997999899

N N

Ir

Cp* OH2 [SO4]

9a[SO4]

table 9.10 Transfer hydrogenation of ketones catalyzed by 9a[SO4] with

HCO2H.

N N

Ir

Cp* OH2

9b9a

N N

Ir

Cp* H +

HCO2H or HCO2Na, H2O,

pH = 2.0–6.0, 25 °C, 5 min

R1COR2 + 9b R1CH(OH)R2pH = 2.0

H2O, 70 °C, 20 minCyclohexanonePhCOMe

Cyclohexanol (Y = 43%)C6H5CH(OH)CH3 (Y = 40%)

R1COR2 + HCO2H R1CH(OH)R2

Cat. 9b 9a

H2O, pH = 2.0, 70 °C, 2 hCyclohexanonePhCOMe

(excess) Y = 99%(9b/ketones/HCO2H = 1/200/1000)

2+

sCHeme 9.4



Transfer hydrogenation of variety of carbonyl compounds catalyzed by 10a[SO4] was

conducted at pH = 2.6 and 7.3. Some examples are shown in Table 9.11. The transfer hydrogenation of α,β-unsaturated carbonyl compounds at pH = 2.6 gave selectively saturated alcohols, while those at pH = 7.3 afforded the 1,4-reduction products. It was also revealed that the order of the reactivity at pH = 2.6 was aldehyde > C = C bond of α,β-unsaturated carbonyl compounds > ketone, while that at pH = 7.3 was C = C bond of α,β-unsaturated carbonyl compounds > aromatic aldehydes ≫ ketone.

The investigations of absorption spectra of 10a at various pH indicated the structure change as follows: a protonated form 10a at pH = ca. 2.6, a deprotonated form 10e at pH = ca. 7.3, and a hydroxo complex 10f at pH > 10 (Scheme 9.6). The complexes at pH = 2–10 readily react with formic acid or formate to generate the corresponding hydride complexes 10 g or 10 h as active species.

[M–OH2]2+ [M–H]+pKa = 6.6

[M–OH]+ + H+

9a 9bHCO2H

pKa = 3.6

HCO2– + H+

pH = 2–6 CO2 + H+

pH = 2–3

OR1R1

R2R2

H+OH

N N

IrIII

Cp*

M =

2+

sCHeme 9.5

N NIr

Cp* OH2

9a: R = H10a: R = OH10b: R = Me10c: R = OMe10d: R = CO2H

R R

2+

Cat. 10a[SO4] (0.025–0.05 mol%)

HCO2H/HCO2Na, H2O, 40 °CProduct


123456

2-Cyclohexene–1-oneCH2=CHCOMe

2-Cyclohexene–1-oneCH2=CHCOMe

PhCHOCyclohexanone

24242

0.568

9472

> 99> 99> 99> 99

Major productpH

2.62.67.37.32.62.6

CyclohexanolEtCH(OH)MeCyclohexanone

EtCOMePhCH2OH

Cyclohexanol

R1COR2

table 9.11 Transfer hydrogenation of various carbonyl compounds catalyzed by 10a[SO

4].

A couple of (arene)Ru complexes (11) bearing 6,6′-disubstituted 2,2′-bipyridine ligand have been synthesized, and their catalytic activities have been studied [12e]. Transfer hydrogenation of acetophenone was conducted in different solvent systems. A few examples are shown in Table 9.12. The complex 11a having the 6,6′-dihydroxy groups was highly effective in aqueous media.

N NIr

Cp* OH2

HO OH

2+

N NIr

Cp* OH2

O O

2+

N NIr

Cp* OH

O O10a 10fpH = c a . 2.6 pH = c a . 7.3 pH > 10

HCO2H

CO2 + H+H2O

H–

N NIr

Cp* H

HO OH

+

HCO2–

H2O

H–

N NIr

Cp* H

O O

–

10h

–2H+

+2H+

–2H+ –H+

+H+

+2H+

10g

H2O

H–

HCO2–

CO2

CO2

10e

–

sCHeme 9.6

N N

Ru

L Cl

R R11a: L = p-cymene, R = OH 11b: L = p-cymene, R = OMe 11c: L = C6Me6, R = OH 11d: L = p-cymene, R = H

[Cl]

Entry Solvent

123

KOHHCO2NaHCO2Na

Conversion (%)/ Time (h)

100/2429/1895/18

Base

iPrOHH2O

MeOH/H2O (1:9)

11a 11b 11c 11d

100/2013/2022/20

100/2115/2150/21

98/245/24

22/24

PhCOMeCat. 11 (1 mol%), HCO2Na or KOH

Solvent, 85–90 °C, PhCH(OH)Me

table 9.12 Transfer hydrogenation of acetophenone catalyzed by 11.



Transfer hydrogenation of various aromatic ketones catalyzed by 11a and HCO2Na

was conducted under optimum conditions [meOH/H2O (1:9)] to give the

corresponding alcohols. A few examples are shown in Table 9.13.

(Arene)Ru Complexes with 1,10-phenanthroline Ligands Several cationic (arene)Ru complexes (12) bearing 1,10-phenanthroline ligands have been synthe-sized and used as catalysts for the transfer hydrogenation of acetophenone with HCO

2Na in water [13a]. Some examples are shown in Table 9.14. Among the

complexes, (C6me

6)Ru complexes 12c and 12d exhibited higher and similar catalytic

activities. The reaction was dependent on pH, and the best pH was found to be around 4, which corresponds to the pK

a of HCO

2H (3.77). The complex 12c was less active

than the analogues (C6me

6)Ru complex 7a having bipyridine ligand. The similar

catalytic cycle to that using 7a (Scheme 9.3) was proposed. The electrochemical studies of the complexes demonstrated that the catalytic activity was correlated with their reduction potentials, indicating the decisive role of η6-arene ring directly ligated to the catalytic center ruthenium [13b].

(Arene)Ru, Cp*Rh, and Cp*Ir Complexes with Other (N,N)-Chelating Ligands Cationic mononuclear and dinuclear Cp*Rh, Cp*Ir, and (η6-arene)Ru complexes (13) bearing 2,2′-bipyrimidine ligands have been synthesized, and they

Entry Ketone

123

C6H5COMe4-MeC6H4COMe4-BrC6H4COMe

R1COR2Cat. 11a (1 mol%), HCO2Na

MeOH/H2O (1 : 9), 90 °C, 6 hR1CH(OH)R2

Conversion (%)

976697

table 9.13 Transfer hydrogenation of aromatic ketones catalyzed by 11a.

N NRu

L OH2

PhCOMeCat. 12[SO4] (0.5 mol%), HCO2Na

H2O, pH = 3.8, 50 °C, 60 hPhCH(OH)Me


1

2

3

4

12a[SO4]

12b[SO4]

12c[SO4]

12d[SO4]

12

20

78

82 R

2+

12a: L = C6H6, R = H12b: L = p-cymene, R = H12c: L = C6Me6, R = H12d: L = C6Me6, R = NO2

TOF (h–1)a

0.40

0.67

2.60

2.73a Intial TOF at 20% conversion.

table 9.14 Transfer hydrogenation of acetophenone catalyzed by 12[SO4].

catalyze the pH-dependent transfer hydrogenation of acetophenone with HCO2H/

HCO2Na in water [14a]. Some examples are shown in Table 9.15. The reactions at

pH = 4 gave the best results. The dinuclear Rh complex 13d exhibited the highest activity (Entry 5), though it was less active than the bipyridine Ru complex 7a and the phenanthroline Ru complex 12a.

A series of cationic (arene)Ru complexes (14) bearing 2,2′-dipyridylamine ligand have been synthesized and used as catalysts for the transfer hydrogenation with HCO

2H/HCO

2Na in water [14b]. Some examples are shown in Table 9.16. Among

the complexes, 14b exhibited the highest catalytic activity. Thus, as to the arene ligand, p-cymene was better than C

6me

6 in contrast with the complexes 12 having

1,10-phenanthroline ligands. Recycle use of the catalyst by simple phase separation was possible.

A number of cationic (arene)Ru complexes (15) bearing bis(pyrazol-1-yl)methane ligands have been synthesized and used as catalysts for the transfer hydrogenation of ketones with or without base (KOH) with 2-propanol [14c, 14d]. Several examples are shown in Table 9.17. Among the complexes, the p-cymene complexes 15a and 15b exhibited high catalytic activities without base. mechanistic investigations were also carried out, and formation of a hydride species was observed when the complex 15b was heated at reflux in 2-propanol.

Cationic 16-electron Cp*Ru and (arene)Ru complexes (16) bearing highly elec-tron-donating bis(imidazolin-2-imine) ligands have been synthesized and used as cat-alysts for the transfer hydrogenation of acetophenone with 2-propanol in the presence

N

N

N

N

M

L Cl

13a: M = Rh, L = Cp*13b: M = Ir, L = Cp*13c : M = Ru, L = p-cymene

+

PhCOMeCat. 13 (1.0 mol%), HCO2H/HCO2Na

H2O, pH = 4, 50 °CPhCH(OH)Me

Entry Cat. Conversion (%)

123456

13a[PF6]13b[PF6]13c[PF6]13d[PF6]213e[PF6]213f[PF6]2

997621989982

N

N

N

N

M

L Cl

13d: M = Rh, L = Cp*13e: M = Ir, L = Cp*13f: M = Ru, L = p-cymene

2+

MCl L

Time (h)

1514148

1014




of KOH [14e]. Some examples are shown in Table 9.18. Among the complexes, 16a exhibited higher catalytic activity.

Several (arene)Ru, Cp*Rh, and Cp*Ir complexes (17) bearing rigid and better σ-donating and π-accepting acenaphthylene-1,2-diimine ligand have been synthe-sized and used as catalysts for the transfer hydrogenation of terephthalaldehyde with HCO

2H in water [14f]. A few examples are shown in Table 9.19. Only one formyl

group was selectively reduced. Among the complexes, the rhodium complex 17b exhibited the highest activity.

A number of ruthenium complexes (18) bearing diamine and hemilabile phos-phine (me

2pCH

2CH

2Ome) ligands have been synthesized and used as catalysts for

the transfer hydrogenation of acetophenone with 2-propanol [14 g]. Some examples are shown in Scheme 9.7. Among them, the complexes 18a and 18c showed higher catalytic activities than others after 0.5 h.

It has been reported that several (diene)Ir complexes (19) bearing 2,2′-bipyridine and 1,10-phenanthroline ligands catalyze the transfer hydrogenation of acetophe-none and polyketones with 2-propanol [14 h]. The transfer hydrogenation of poly-ketones was conducted in the presence of KOH to afford the corresponding polyalcohols. Some examples are shown in Scheme 9.8. Among the complexes 19,

R1COR2Cat. 14 (5 mol%), HCO2H/HCO2Na

H2O, 65 °C, 24 hR1CH(OH)R2

Entry Ketone Conversion (%)

12345

PhCOMePhCOMePhCOMe

2-MeOC6H4COMe4-BrC6H4COMe

89100

659975

N

NH

NRu

L Cl [Cl]

14a: L = C6H614b: L = p-cymene14c: L = C6Me6

Cat.

14a14b14c14b14b


R1COR2Cat. 15a or 15b

iPrOH, re�ux, 24 hR1CH(OH)R2

Entry Ketone Yield (%)

123456

15a (0.1)15b (0.1)15a (0.6)15b (0.6)15b (0.4)15b (0.1)

98>99

6098

>9996

N N

Ru

p-cymene Cl

15a: Ar = 2-HOC6H415b: Ar = 2-NO2C6H4

NN

Ar

[BPh4]

Cat. (mol%)

PhCOMePhCOMe

PhCOCH2PhPhCOCH2Ph

CyclohexanonePhCHO

table 9.17 Transfer hydrogenation of ketones and aldehydes catalyzed by 15.

PhCOCH3

Cat. 16 (1 mol%), KOH (10 mol%)

iPrOH, 82 °CPhCH(OH)CH3

Entry Cat. Time (h) Conversion. (%)

123456

[16a][Cl][16a][BArf

4]a

[16b][BArf4]a

[16c][Cl]2[16d][Cl]2[16e][Cl]2

1.51.56262

969890969799

a Arf = 3,5-(CF3)2C6H3

N NRuN

N N

N

Cp*R

R

R

R

+ +– –

N NRuN

N N

N

areneR

R

R

R

– –

16b: R = iPr

16c : Arene = C6H6, R = Me16d : Arene = C6H6, R = iPr16e : Arene = p-cymene, R = Me

+

2+

+ +

16a: R =Me


Cat. 17 (1 mol%), H2O (THF in trace)

HCO2H + AcONa, 40 °C

Entry Cat. Time (h) TOF (h–1)

123

[17a][BF4][17b][BF4][17c][BF4]

30.75

3

3313350

N NPh PhM

L Cl +

17a: M = Ru, L= p-cymene17b: M = Rh. L = Cp*17c: M = Ir, L = Cp*

HCO CHO HCO CH2OH

conversion > 99%

table 9.19 Transfer hydrogenation of terephthalaldehyde catalyzed by 17.

PhCOMeCat. 18 (0.2 mol%), KOH (2 mol%)

iPrOH, 82 °C, 0.5 hPhCH(OH)Me

Ru

Cl

Cl

N

N

PMe2(CH2CH2OMe)

PMe2(CH2CH2OMe)

N = H2NCH2CH2NH2

N = H2NCH2CHMeNH2

N = H2NCH2CH2CH2NH2

N = H2NCH2C(Me)2CH2NH2

N

18a: Y = 93% (94% after 1 h)18b: Y = 82% (94% after 1h) 18c: Y = 90% (94% after 1h)18d: Y = 73% (98% after 1 h)

18a:

N18b:

N18c:

N18d:

sCHeme 9.7


the (cod)Ir complexes 19a and 19b exhibited higher catalytic activities. The complex 19a was more active than 19b.

(Arene)Ru Complexes with (N,P)-Chelating Ligands Several (arene)Ru complexes bearing phosphinooxazoline ligands (20) have been synthesized and used as catalysts for the transfer hydrogenation of acetophenone with 2-propanol [15a]. The reactions were conducted in the presence of iprONa. A few examples are shown in Table 9.20. Among the complexes 20, 20c showed the highest TOF.

Several cationic (arene)Ru complexes (21) bearing bidentate iminophosphorane–phosphine ligand have been synthesized and used as catalysts for the transfer hydro-genation of cyclohexanone with 2-propanol [15b]. The reactions were conducted in the presence of NaOH. A few examples are shown in Table 9.21. The catalytic activity was highly dependent on the arene ligand [C

6me

6 (21e) ≫ C

6H

6 (21a) > 1,2,3,4-me

4C

6H

2

Cat. 19 (1 mol%), KOH (2 mol%)

iPrOH/dioxane (5 : 3)83 °C , 7 h

O

Ar O

Ar

n

OH

Ar OH

Ar

n

19a: Ar = p-Tol, Conversion= 90%19b: Ar = p-Tol, Conversion= 45%19a: Ar = Ph, Conversion= 70%19b: Ar = Ph, Conversion= 65%

N N

Ir

cod Cl

19a

N N

Ir

cod Cl

19b

sCHeme 9.8

PhCOMeCat. 20 (0.5 mol%), iPrONa (2.5 mol%)

iPrOH, re�ux, 1 hPhCH(OH)Me


123

20a20b20c

344961

Ru

p-cymene

PPh2

N Cl

O

Ru

C6H6

PPh2

N Cl

O

[Cl] [OTf]Ru

p-cymene

PPh2

N Cl

O

20a 20b 20c

TOF (h–1)

6898

122


(21c) > p-cymene (21b)], indicating that both of electronic and steric effects affect the catalytic activity.

A cationic (p-cymene)Ru complex (22) bearing 1-(2-methylpyridine)phosphole ligand has been synthesized and used as a catalyst for the transfer hydrogenation of various ketones with 2-propanol [15c]. The reactions were conducted in the presence of KOH. Some examples are shown in Table 9.22. The complex 22 exhibited extremely high activity and the reactions proceeded with only a very low catalyst loading (5 × 10−6 mol%). TON reached up to 20 × 106 in the reduction of cyclohexanone.

Several CpRu and (p-cymene)Ru complexes (23) bearing aminophosphine ligands have been synthesized and used as catalysts for the transfer hydrogenation of ketones with 2-propanol [15d]. The reactions of various ketones were carried out using 23b and 23c in the presence of iprONa. Some examples are shown in Table 9.23.

Cationic (p-cymene)Ru complexes (24) bearing 2-(diphenylphosphino)aniline ligands have been synthesized and used as catalysts for the transfer hydrogenation of acetophenone with 2-propanol [15e]. The reactions were conducted in the presence of KOH. A few examples are shown in Table 9.24. The complexes 24a[Cl] and

Cat. 21 (0.4 mol%), NaOH (9.6 mol%)

iPrOH, 82 °C, 2.5 h

Entry Cat. TOF (h–1)aYield (%)

1234

21a21b21c21d

822053

249

7122

53>99b

a TOF at 50% conversion.b Yield after 1 h.

Ph2P

Ru

Arene Cl

PPh2

N N

F F

F F

[SbF6]

21a: Arene = C6H621b: Arene = p-cymene21c: Arene = 1,2,3,4-Me4C6H221d: Arene = C6Me6

O OH

table 9.21 Transfer hydrogenation of cyclohexanone catalyzed by 21.

R1COR2Cat. 22 (5 × 10–6 mol%), KOH (50 mol%)

R1CH(OH)R2

[BF4]

22

iPrOH, 90 °C, 15 h

P N

Ru

p-cymene ClPh

Ph

Entry Ketone Yield (%)

1234

CyclohexanonePhCOMe

2-PyCOMe4-BrC6H4COMe

100908767

TON/60 h

20.0 × 106

18 × 106

17.4 × 106

13.4 × 106

table 9.22 Transfer hydrogenation of various ketones catalyzed by 22.



24a[pF6] exhibited high catalytic activities, whereas the activity of 24b[Cl] was very

low due to devoid of N-H functionality, indicating the bifunctional outer-sphere mechanism for hydrogen transfer.

A twitterionic (p-cymene)Ru complex (25a) bearing 2-amino-1-phosphinoindenide ligand has been synthesized and used as a catalyst for the transfer hydrogenation of various ketones with 2-propanol [15f]. The reactions were conducted with very low catalyst loading (0.05 mol%) in the presence of tBuOK. Examples are shown in Table 9.25. The complex 25a exhibited remarkably high catalytic activity, and a

R1COR2

(0.1 M)

Cat. 23 (0.5 mol%), iPrONa (1 mol%)R1CH(OH)R2

Entry Ketone Yield (%) with 23a

12345

3-MeOC6H4COMe4-BrC6H4COMe

3-NH2C6H4COMe

PhCOPhCyclohexanone

787562

>99>99

iPrOH, 82 °C, 48 h

Yield (%) with 23b

>99>99>99

80

Ph2P NMe2

Ru

Cp Br

Ph2P NMe2

Ru

p-cymene Cl [OTf]

23a

23b


PhCOMeCat. 24 (0.1 mol%), KOH (0.4 mol%)

iPrOH, re�uxPhCH(OH)Me

Ph2P NR2

Ru

p-cymene Cl +

24a: R = H24b: R = Me

Entry Cat.Conversion

(%) TOF (h–1)

123

24a[Cl]24a[PF6]24b[Cl]

373310

44403960100

Time (min)

55

60

table 9.24 Tansfer hydrogenation of acetophenone catalyzed by 24.

R1COR2Cat. 25a (0.05 mol%), tBuOK (1 mol%)

R1CH(OH)R2

iPrOH, re�ux

Entry KetoneConversion

(%)

1234

PhCOMePhCOPh

CyclopentanoneC5H11COMe

99989799

a TOF was measured at 20 s.

TOF (h–1)a

180,000220,000

91,000150,000

NMe2

Ru+

iPr2

P p-cymene

X

–Time (min)

555

15

25a: X = Cl25b: X = H

table 9.25 Transfer hydrogenation of ketones catalyzed by 25a.

variety of aromatic and aliphatic ketones were reduced within 15 min in excellent yields. TOF reached up to 220,000. It should be noted that the hydride complex 25b, which was readily prepared by treatment of 25a with tBuOK, was completely inac-tive, indicating other active catalytic species.

Several five-coordinated ruthenium complexes (26) bearing imino- and amino-phosphine ligands have been synthesized and used as catalysts for the transfer hydro-genation of ketones with 2-propanol [15 g, 15 h]. The reactions were conducted in the presence of NaOH under the condition A or B. Some examples are shown in Table 9.26.

Cp*Ir Complexes with (C,N)-Chelating Ligands Several cyclometalated Cp*Ir complexes (27) bearing (2-aminomethyl)phenyl ligands were synthesized and used as catalysts for the transfer hydrogenation of acetophenone with 2-propanol [16]. The reactions were conducted without base at room temperature for 1 h. Examples are shown in Scheme 9.9. The complexes 27 exhibited much higher catalytic activ-ities than Cp*Ir(Ts–diamine) complexes such as Cp*Ir[TsNCHphCHphNH].

R1COR2Cat. 26 (0.2 mol%), NaOH (0.5 or 4.8 mol%)

R1CH(OH)R2

Entry Cat. Time (h) Yield (%)

1234567

26a26a26b26c26d26a26a

0.52122

0.750.08

91979897969599

Ru

Cl

Cl

N

PPh2

PPh3

R

Ru

Cl

Cl

N

PPh2

PPh3

R

26a: R = tBu26b: R = Ph

26c: R = tBu26d: R = Ph

PhCOMePhCOMePhCOMePhCOMePhCOMeEtCOMe

Cyclohexanone

Ketone

Condition A: NaOH (0.5 mol%), 90 °C, iPrOHCondition B: NaOH (4.8 mol%), 82 °C, iPrOH

Condition

ABBBBAA


Cat. 27 (1 mo%)

iPrOH, rt, 1 h

NHIr

RR

Cp*

27a: R = Ph27b: R = Me

NH2

IrR

R

Cp*

27c: R = Ph27d: R = Me

H

PhCOMe PhCH(OH)Me

27a: Y = 95%27b: Y = 96%27c: Y = 88%27d: Y = 98%

sCHeme 9.9



Other Ru Complexes with Bidentate Ligands Other well-defined ruthenium complexes used as catalysts for the transfer hydrogenation are listed here: ruthenium complexes bearing (N,O)-chelating Schiff base ligands [17a] and ruthenium complexes bearing (p,S)-chelating ligands (Scheme 9.10) [17b].

Ru and Os Complexes with bis-Bidentate LigandsRu Complexes with (N,N)(p,p)-Chelating Ligands Several ruthenium comp-lexes (28) bearing aminomethylpyridine and diphosphine ligands have been synthesized and used as catalysts for the transfer hydrogenation of ketones with 2-propanol [18a]. The reactions were carried out with low catalytic loading (0.05 mol%) in the presence of NaOH. Some examples are shown in Table 9.27. Among the complexes examined, the cis-dichloro complex 28c exhibited the highest activity (TOF = up to 300,000 h−1), whereas the complex 28d having two monophosphine

NRu

O COL1

L2Cl

CHArAr = Ph, 4-MeOC6H4

L2 = PPh3, AsPh3, C5H5NL1 = PPh3, AsPh3

SRu

P CO

Cl

CO

Cl S

P

OPh2 P=S

OPh2P=S PPh2PPh2

=

sCHeme 9.10

R1COR2Cat. 28 (0.05 mol%), NaOH (2 mol%)

R1CH(OH)R2

Entry Cat. TOF (h–1)a

123456

28a28b28c28d28c28c

35,000220,000300,000

5200400,000280,000

989797989994


Conversion(%)

iPrOH, 82 °C

Ru

PPh2

Ph2PN

NH2

Cl

Cl

28a

RuPPh3

PPh3N

Cl

Cl

NH2

28d

RuPPh2

Ph2PN

Cl

Cl

NH2

28b

RuPPh2

Ph2PN

Cl

Cl

NH2

28c

Time (min)

1011

701

10

Ketone

PhCOMePhCOMePhCOMePhCOMe

CyclohexanoneCH2=CHCH2CH2COMe


ligands showed much lower activity. It should noted that the C = C double bond was not reduced at all. The asymmetric version was also mentioned.

Ru Complexes with (N,p)(p,p)- and (N,p)(N,p)-Chelating Ligands Ruthenium complexes (29) bearing aminophosphine and diphosphine ligands have been synthe-sized and used for the transfer hydrogenation of acetophenone with 2-propanol [18b]. The reactions were conducted in the presence of tBuOK. A few examples are shown in Scheme 9.11.

Ru Complexes with (N,N)(C,p)-Chelating Ligands A cyclometalated ruthe-nium complex (30) bearing aminomethylpyridine and (2-phosphinomethyl)phenyl ligands has been synthesized and used as a catalyst for the transfer hydrogenation of ketones with 2-propanol [18c]. The reactions were conducted with a very low catalytic loading (0.05 mol%) in the presence of NaOH. A few examples are shown in Table 9.28. The complex 30 exhibited very high catalytic activity and TOF reached up to 63,000 h−1. It should be noted that the C = C double bond remained intact.

Ru Complexes with (N,N)(C,C)-Chelating Ligands A cyclometalated ruthe-nium complex (31) bearing aminomethylpyridine and N-heterocyclic carbene (NHC) ligands has been synthesized and used as a catalyst for the transfer hydrogenation of

PhCOMeCat. 29 (0.5 mol%), tBuOK (2.5 mol%)

iPrOH/C6H6 (1 : 1), 60 °CPhCH(OH)Me

29a: Conversion = ~95% at 2 h29b: Conversion = ~55% at 4 h29c: Conversion = ~95% at 4 h

P

H2N

Ph2P

PPh2Ph2

Ru

Cl

Cl

RR

P

H2N

H2N

PPh2 Ph2

Ru

Cl

Cl

29a: R = H29b: R = Me

29c

sCHeme 9.11


R1CH(OH)R2

Entry TOF (h–1)a

1234

60,00063,00030,00033,600

98999599


Conversion(%)

iPrOH, 82 °C

30

Time (min)

5101010

Ketone

PhCOMeC4H9COMe

CH2=CHCH2CH2COMeCyclopentanone

Ru

COCl

NH2

N PPh2




ketones with 2-propanol [18d]. Examples are shown in Table 9.29. The complex 31 exhibited the extremely high catalytic activity in the presence of NaOH and TOF reached up to 120,000 h−1. It should be noted that the C = C double bond remained intact.

Os Complexes with (N,N)(p,p)-Chelating Ligands Several osmium complexes (32) bearing aminomethylpyridine and diphosphine ligands have been synthesized and used as catalysts for the transfer hydrogenation of ketones with 2-propanol [18e]. The reactions were carried out in the presence of iprONa. Some examples are shown in Table 9.30. Among the complexes, a mixture of the complexes 32a/32b exhibited the highest activity and TOF reached up to 570,000 h−1, which was greater than the analogous ruthenium complex 28a. The hydrogen transfer reactions of other ketones


R1CH(OH)R2

Entry TOF (h–1)a

1234

110,000120,000100,000

50,000

99989996


Conversion(%)

iPrOH, 82 °C

RuPPh3

N

ClNH2

31

Time (min)

525

15

Ketone

PhCOMe3,5-(MeO)2C6H3COMe

CyclohexanoneCH2=CHCH2CH2COMe

N

N

N

Ph

Ph


R1COR2Cat. 32 (0.05 mol%), iPrONa (2 mol%)

R1CH(OH)R2

Entry Cat. TOF (h–1)a

12345

32a/32b (1:3)32c32d

32a/32b (1:3)32a/32b (1:3)

570,00014,00086,000

320,00017,000

9894989698


Conversion(%)

iPrOH, 82 °C

Os

PPh2

Ph2PN

NH2

Cl

Cl32a

OsPPh3

PPh3N

Cl

Cl

NH232d

OsPPh2

Ph2PN

Cl

Cl

NH2

32b

Time (min)

30 (s)105230

Ketone

PhCOMePhCOMePhCOMe

CH2=CHCH2CH2COMeMe3CCOCPh

Os

PPh2

Ph2PN

NH2

Cl

Cl32c


catalyzed by the complexes 32c/32d also proceeded very well. It should noted that the C = C double bond was not reduced at all.

Ru and Rh Complexes with Tridentate LigandsRu Complexes with (N,N,p)-Chelating Ligands Several ruthenium complexes (33) bearing tridentate aminomethylpyridine–phosphine ligands have been synthe-sized and used as catalysts for the transfer hydrogenation of ketones with 2-propanol [19a]. The reactions were carried out in the presence of iprONa. Several examples are shown in Table 9.31. The trans-dichloro complexes 33a and 33b exhibited high catalytic activities and were more active than the cis-dichloro and cis-chloro-hydride complexes 33c and 33d. The hydrogen transfer reactions of ketones catalyzed by the complex 33b also proceeded very well. TOF reached up to 250,000 h−1.

(Arene)Ru Complexes with (S, N, S)-, (S, N, Se)-, and (S, N, Te)-Chelating Ligands A series of cationic (C

6H

6)Ru complexes (34) bearing tridentate [S, N, E

(E = S, Se. Te)]-type ligands were synthesized and used as catalysts for the transfer hydrogenation of ketones with 2-propanol [19b]. The reactions were carried out with very low catalytic loading (0.001 mol%) in the presence of KOH. Some examples are shown in Table 9.32. Among the complexes, 34c and 34f exhibited higher activities, probably due to the Te ligand having an electron-donating methoxy group.

R1COR2Cat. 33 (0.1 mol%), iPrONa (4 mol%)

R1CH(OH)R2

Entry Catalyst TOF (h–1)a

123456

33a33b33c33d33b33b

190,000185,00021,00016,000

250,00054,000

989898969999


Yield (%)

iPrOH, 82 °C

RuPPh2

PPh2N

N

Cl

Cl

33a

Time (min)

22

151514

Ketone

PhCOMePhCOMePhCOMePhCOMe

3-ClC6H4COMeCyclohexanone

RuPPh2

PPh2N

N

Cl

Cl Ru

Cl

PPh2N

Cl

N

PPh3

33b 33c

RuPPh2

PPh2N

N

H

Cl

33d




Ru Complex with (p,p,p)-Chelating Ligand A ruthenium complex (35) bearing tridentate meC(CH

2pph

2)

3 (triphos) ligand has been synthesized and used as a cata-

lyst for the transfer hydrogenation of ketones and an aldehyde with 2-propanol in the presence of NaOH [19c]. A few examples are shown in Table 9.33.

Rh Complexes with (N,C = C,C = C)-Chelating Ligands Cationic rhodium complexes (3) bearing novel tridentate (trop)

2NH ligand (see Subsection “Rh

Complexes with (N,C = C,C = C)-Chelating Ligands” in Section 9.2) have been synthesized and used for the transfer hydrogenation with ethanol [19d]. The reactions of ketones were carried out with a very low catalyst loading in the

R1COR2Cat. 34 (0.001 mol%). KOH (4 mo%)

R1CH(OH)R2iPrOH, re�ux, 5 – 7 h

Ru

C6H6

NS

MeE

C6H4R-4 Ru

C6H6

NHS

MeE

C6H4R-4

34a: E = S, R = H34b: E = Se, R = H34c: E = Te, R = OMe

34d: E = S, R = H34e: E = Se, R = H34f: E = Te, R = OMe

Entry Ketone

123

PhCOMeCyclopentanone

EtCOMe

a Reaction time was 5 h for 34a–34c and 7 h for 34d–34f.

938785

Conversion (%)a

959088

979388

928884

958987

989390

[PF6]2 [PF6]2

34a 34b 34c 34d 34e 34f


R1COR2Cat. 35 (1 mol%), NaOH (24 mol%)

R1CH(OH)R2

Entry

123

85100

98

Conversion (%)

iPrOH, 82 °C, 24 h

RuPPh2

Ph2PCl

Cl

CO

Ph2P

Substrate

PhCOMeCyclohexanone

PhCHO 35


presence of base. A few examples are shown in Table 9.34. The reactions proceeded with extremely high TOF even at room temperature. Electron-poor aromatic ketones were reduced smoothly using the complex 3e at 40 °C and nitro group was tolerated.

Treatment of the complexes 3c–3e with tBuOK gave the neutral amide complexes 3f and 3 g, respectively, which were converted to the hydride complexes 3 h and 3i by reaction with methanol or ethanol accompanied by formation of esters. These exper-imental results suggest that the conversion of the complexes 3f and 3 g to the complexes 3 h and 3i with ethanol is essential in the catalytic cycle (Scheme 9.12). mechanistic studies and DET calculations were performed to support the metal–ligand cooperative hydrogen transfer.

R1COR2Cat. 3, base (1 mol%)

R1CH(OH)R2 + 1/2 MeCO2Et

Entry Cat. (mol%) TOF (h-1)a

1234

3c or 3d (0.001)3c or 3d (0.001)

3e3e

(0.001)(0.005)

a TOF after 50% conversion.

Ketone

MeCOMeCylcohexanone

2-PyCOMe4-NO2C6H4COMe

EtOH, rt –40 °C

Base

tBuOK

tBuOK

K2CO3

K2CO3

500,000750,000300,000

25,000

trop2NH

3c: R = Ph, X = OTf

3d: R = Ph, X = BArf4

3e: R = OPh, X = OTf

=

N

Rh

PR3

[X]

H NH

(Arf = 3,5-(CF3)2C6H3)


3f, 3g 3h, 3i3c–3eBase

EtOH 1/2 MeCO2Et

R1CH(OH)R2 R1COR2 3f: R = Ph3g: R = OPh

3h: R = Ph3i: R = OPh

N

Rh

PR3

N

Rh

PR3H

H

sCHeme 9.12



Ru Complex with (C,N,N)(P,P)-Chelating Ligand A cyclometalated ruthenium com-plex (36a) bearing 2-(aminomethyl)-6-(tolyl)pyridine and bis-1,4-(diphenylphosphino)butane ligands has been synthesized and used as a catalyst for the transfer hydrogenation of ketones with 2-propanol [20a]. The reactions were carried out using very low cata-lyst loading (0.005 mol%) in the presence of NaOH. Several examples are shown in Table 9.35. The complex 36a exhibited the extremely high catalytic activity, and TOF reached up to 2,500,000 h−1. The C = C double bond remained intact.

It was found that the reaction of 36a with iprONa gave a Ru alkoxide species 36b, which was converted to a Ru hydride complex 36c and acetone through β-hydrogen elimination (Scheme 9.13, the 1st equation) [20a, 20b]. The complex 36c reacted with an equimolar amount of benzophenone, resulting in the insertion of the carbonyl group to the Ru–H bond to produce another Ru alkoxide complex, 36d. The subsequent addition of diphenylmethanol to 36d led to the formation of an alk-oxide–alcohol adduct 36d · HOCH

2ph (Scheme 9.13, the 2nd equation). These

results support a stepwise mechanism via the complex 36b and, then, the complex 36c. Thus, the insertion of a carbonyl group to the Ru–H bond of 36c produces a

R1COR2Cat. 36a (0.005 mol%), NaOH (2 mol%)

R1CH(OH)R2

Entry TOF (h–1)a

1234

1,100,0002,500,0001,500,000

700,000

98999797


Conversion.(%)

iPrOH, 82 °C

RuPPh2

Ph2PN

ClNH2

36a

Time (min)

512

10

Ketone

PhCOMe3-ClC6H4COMeCyclohexanone

CH2=C(Me)CH2CH2COMe

table 9.35 Transfer hydrogenation of ketones catalyzed by 36a.

36c

36a + iPrONa +

RuPPh2

Ph2PN

iPrONH236b

36c +

RuPPh2

Ph2PN

HNH2

RuPPh2

Ph2PN

ONH2

Ph

Ph

36d

Ph2CHOH36d •HOCH2Ph

O

Ph

O

Ph

sCHeme 9.13

Ru–alkoxide such as 36d, which is replaced with 2-propanol to give an alcohol along with the starting active species 36b.

Fe Complexes with Various Polydentate LigandsFe Complexes with (N,N)-, (N,N,p)-, (O,N,N,O)-, and (p,N,N,p)-Chelating Ligands Several iron complexes (37) bearing polydentate iminophosphorane (N = p) ligands have been synthesized and used as catalysts for the transfer hydroge-nation with 2-propanol [21a]. The reactions were carried out with low catalytic load-ing (0.1 mol%) in the presence of iprONa. Some examples are shown in Table 9.36. Among the complexes, 37a and 37c showed higher catalytic activities.

Fe Complexes with (p,N,N,p)-Chelating Ligands A series of iron complexes (38) bearing tetradentate diimine–diphosphine ligands have been synthesized and used as catalysts for the transfer hydrogenation of acetophenone with 2-propanol [21b–21d]. The reactions were conducted in the presence of tBuOK (Table 9.37). A few examples are shown in Table 9.37. While the complexes 38a and 38b were inactive, 38c showed moderate catalytic activity [21b] and the complex 38d exhib-ited the higher activity [21c]. A treatment of 38c with tBuOK produced a neutral amide complex 38e, which showed the comparable catalytic activity without a base

PPh2

NPh2P NFe

PPh2

Ph2P O

NPh2P N

OFe

PPh2

PPh2

PPh2

Cl

Cl

37b

NPh2P NFe

PPh2

PPh2

37a

PPh2

S

Cl

Cl

S

Cl[Cl]

37c

PPh2

NPh2P NFe

PPh2

37d

PPh2

Cl [BF4]

PPh2

NPh2P

NFe

PPh2

37e (R = tBu)

PPh2

CNR

CNR

PhCOMeCat. 37 (0.1 mol%), iPrONa (4 mol%)

iPrOH, 82 °CPhCH(OH)Me

Entry Cat. Time (h) Conversion (%)

12345

37a37b37c37d37e

88688

9180897578

[BF4]2




to that of 38c in the presence of tBuOK [21d]. Asymmetric transfer hydrogenation catalyzed by analogous iron complexes bearing chiral tetradentate ligands was also reported [21d, 21e].

Other Catalyst Systems Other intriguing complexes and catalyst combinations for the transfer hydrogenation with 2-propanol are added: (arene)Ru complexes bearing a rigid diphosphine (2-diphenylphosphino-5,6-dimethyl-7-phenyl-7-phosphabicyclo- [2.2.1]hept-5-ene) ligand [22a], a catalyst combination of Fe

3(CO)

12/terpyridine

(2,2′:6′,2″-terpyridine)/pph3 [22b], and biomimetic transfer hydrogenation of var-

ious ketones catalyzed by catalyst combinations of Fe3(CO)

12/porphyrin or FeCl

2/

porphyrin [22c, 22d].

9.2.2 Hydrogenation of esters and lactones

While there have been tremendous amounts of reports on catalytic hydrogenation and transfer hydrogenation reductions of ketones and aldehydes to alcohols (Section 9.2.1), a limited number of catalytic hydrogenation of esters and lactones using well-defined complexes have been reported, because of the less electrophilicity and, therefore, less reactivity of their carbonyl groups toward metal hydride species.

9.2.2.1 Cp*Ru Complexes with (N,N)-Chelating Ligands A Cp*Ru complex (39) bearing 2-(aminomethyl)pyridine ligand has been synthesized and used for hydrogenation of lactones [23]. At first, screening of various (N,p)- and

PhCOMeCat. 38, tBuOK

iPrOH, 50 °C, 1 hPhCH(OH)Me

12a

3

38c (0.2)38d (0.017)

38e (0.5)

PR2

N N

PR2

Fe

CO[BPh4]

38a: R = Cy

38b: R = iPr

38c: R = Et

38d: R = PhBr

47

~68c

14582100b

a The reaction temperature was 28 °C.b TOF at 15% conversion.c Conversion at 40 min.

PEt2

N N

PEt2

Fe

CO

38e

Entry Cat. (mol%)Conversion

(%) TOF (h–1)tBuOK (mol%)

1.60.13

0

table 9.37 Transfer hydrogenation of acetophenone using 38.

(N,N)-chelating ligands revealed that 2-(aminomethyl)pyridine gave the best result. Hydrogenation of various lactones was carried out in the presence of tBuOK. Several examples are shown in Table 9.38. Various 5- and 6-membered lactones were hydro-genated to give diols in good to high yields. The complex 39 also catalyzed hydroge-nation of lactams and amides. In addition, asymmetric hydrogenative DKR was mentioned.

9.2.2.2 Ru Complexes with (N,P)(N,P)-Chelating Ligands It has been reported that ruthenium complexes (1a and 40) bearing amino- and iminophosphine ligands are used as catalysts for hydrogenation of esters and lactones [24]. The complexes 1a and 40 exhibited high catalytic activity, whereas ruthenium complexes having diamine and diphosphine ligands showed almost no activity. Hydrogenation of benzoate esters was carried out with very low catalyst loading (0.01–0.05 mol%) in the presence of meONa. Several examples are shown in Table 9.39. The catalytic hydrogenation of various benzoate esters proceeded very smoothly to give benzyl alcohol in excellent yields. In the case of isopropyl benzoate, low H

2 pressure (10 bar)

or low catalyst loading (0.01 mol%) did not decrease the yield.Various esters and lactones were smoothly hydrogenated using 1a or 40a to give

the corresponding alcohols and diols in high yields, respectively. Some examples are shown in Table 9.40. The hydrogenation of unsaturated esters catalyzed by the com-plex 40a was also conducted to give unsaturated alcohols chemoselectively. However, the competitive hydrogenation of alkene moiety of methyl cinnamate occurred to give saturated alcohols as a major product.

9.2.2.3 Ru Complex with (N,N)(P,P)-Chelating Ligand It has been reported that a dihydride ruthenium complex (41a) bearing diamine and diphosphine ligands cat-alyzes hydrogenation of esters and lactones under low pressure of H

2 (4 atm) at low

temperature (30 °C) [25]. The reactions were carried out in the presence of tBuOK. Several examples are shown in Table 9.41. It should be noted that the catalytic

Cat. 39 (1 mol%), tBuOK (25 mol%)

H2 (5 MPa), iPrOH, 100 °C

Entry

12345

Ph4-CF3C6H4

HPhH

8281738781

n

O

O

R1

R2

HOOH

R1 R2

n

R1 R2 n

HH

C5H11

HMe

11122

Time (h)

612141215

Yield (%)

N NH2

Ru

Cp* Cl

39

table 9.38 Hydrogenation of lactones catalyzed by 39.



Cat. 1a or 40, MeONa (5 mol%)

H2, THF, 100 °C

Entry

12345

1a (0.05)40a (0.05)40b (0.05)1a (0.05)1a (0.01)

9999969999

Cat. (mol%) Time (h)

11144

Yield (%)

40a1a

PPh2

N NRu

PPh2

Cl PPh2

N NRu

PPh2

Cl

ClCl

PPh2

H2N

H2N

RuPPh2

Cl

Cl

PhCO2R PhCH2OH

40b

H2 (bar)

5050501050

R

MeMeMeiPriPr

table 9.39 Hydrogenation of benozate esters catalyzed by 1a or 40.

OO R3HO

OH

R3

n

Cat. 1a or 40a (0.05 mol%), MeONa (5 mol%)

H2 (50 bar), THF, 100 °C

R1CO2R2

n

R1CH2OH

or or

Entry

12

3b

4b

5

6

40a1a

40a

1a

40a

40a

a The ratio of unsaturated alcohol/saturated alcohol.b The reaction was carried out in the presence of MeOK in toluene.

8394

91

93

93

87

Cat. Time (h)

2.52.5

4

4

2.5

2.5

Yield (%)Substrate

PhCH2CO2MeC7H15CO2Me

OO C5H11

OO C5H11

C5H11CO2Et

PhCO2Me

Ratioa

99 : 1

12 : 88

table 9.40 Hydrogenation of esters and lactones catalyzed by 1a or 40a.

intermediate 41b was directly observed in the stoichiometric reaction of 41a with γ-butyrolactone at −80 °C in the presence of tBuOK.

9.2.2.4 Ru Complex with (N,N,P)-Chelating Ligand A ruthenium complex (42) bearing a tridentate diamine–phosphine ligand has been synthesized and used as the catalyst for hydrogenation of esters [26]. methyl heptafluorobutanoate and dimethyl phthalate were hydrogenated in the presence of LiHBEt

3 at high temperature

(Scheme 9.14).

9.2.2.5 Other Catalyst Combination It has been reported that catalyst combina-tions generated in situ from Ru(acac)

3 with tridentate tripodal phosphine

[meC(CH2pph

2)

3 and N(CH

2pph

2)

3] and tripodal sulfur [meC(CH

2SBu)

3] ligands

catalyze hydrogenation of dimethyl oxalate and esters under high H2 pressure

(80–100 bar) at 100–120 °C [27].

Entry Substrtate

123

4

5

PhCO2MePhCO2

iPrPhCH=CHCO2Me

10091100

100

92

Yield (%)

Cat. 41a (1–2 mol%), tBuOK (18 mol%)

H2 (4 atm), THF, 30–500 °C, 3–4 h

Ru

PPh2

Ph2P H

L

H2N

NH2

Ester or lactone Alcohol or diol

O O

O

O

O

41b: L = OO

H

41a: L = H

table 9.41 Hydrogenation of esters and lactones catalyzed by 41a.

Cat. 42 (0.5 mol%)MeOH, LiHBEt3 (1.5 mol%)

C3F7CO2Me C3F7CH2OH

Y = 100% NH2

RuNH

PPh2

Cl

Cldmso

42

H2 (50 bar), 140 °C, 24 h

CO2Me

CO2Me

Cat. 42 (0.5 mol%),MeOH, LiHBEt3 (1.5 mol%)

H2 (60 bar), 150 °C, 60 h

CH2OH

CH2OH

O

O

+

Y = 34%Y = 54%

sCHeme 9.14



9.2.3 Hydrogenation of amides and imides

Since carbonyl groups of amides and imides are less electron deficient and, therefore, less reactive than those of esters. Thus, only a handful of catalytic hydrogenation of amides and imides using well-defined complexes has been reported.

9.2.3.1 Cp*Ru Complexes with (N,P)-Chelating Ligands It has been reported that a Cp*Ru complex (43) bearing an aminophosphine ligand catalyzes the hydro-genation of imides very effectively [28a]. The reactions were carried out in the presence of tBuOK in 2-propanol. A variety of 5- and 6-membered cyclic imides were hydrogenated to give the corresponding hydroxyamide products exclusively in high to quantitative yields. Some examples are shown in Table 9.42. While N-pivaloyl group was exclusively removed, the sterically less hindered amide group was hydro-genated exclusively. Furthermore, enantioselective hydrogenative desymmetrization of prochiral glutarimides and bicyclic imides has been accomplished with Cp*Ru complexes having chiral ligands [28a, 28b].

The complex 43 also catalyzed the hydrogenation of electron-deficient N-acylcarbamates and N-acylsulfonamides [28c]. The reactions were conducted in the presence of tBuOK under H

2 (3 mpa) in tBuOH at 80 °C. Some examples are shown in Table 9.43. N-Boc,

N-mesyl, N-tosyl, N-ester, and sulfonamide groups remained intact, and the acyl groups of cyclic carboxamides were exclusively hydrogenated to afford the hydroxy-amine and -sulfonamide products, respectively, in excellent yields.

9.2.3.2 Cp*Ru Complex with (N,N)-Chelating Ligand A Cp*Ru complex bearing 2-(aminomethyl)pyridine ligand (39), an effective catalyst for the hydroge-nation of lactones (Section 9.2.2.1), also exhibited catalytic activity for the hydrogenation of lactams and amides [23]. The reactions were carried out using relatively high catalyst loading of 39 (10 mol%). Several examples are shown in Table 9.44. The various N-aryllactams and amides were hydrogenated in good to high yields.

Cat. 43 (1 or 5 mol%), tBuOK (1 or 5 mol%)

H2 (3 MPa), iPrOH, 80 °C, 18 h

a δ-Lactam was formed exclusively by removal of pivaloyl group.b HOCH2CH2CH2C(Me)2CONHBn was formed exclusively.

H2N PPh2

Ru

Cp* Cl

43

N

O

R

O

NH

OH

R

N–Ph

O

O

N–Bn

O

O

N

OO

tBu

Y > 99% Y > 99% Y > 99%a (2 h) Y > 99%b

N–Bn

O

O

O

table 9.42 Hydrogenation of various imides catalyzed by 43.

9.2.3.3 Ru Complexes with (N,N)(P,P)-Chelating Ligands A dihydride ruthe-nium complex (41a) bearing diamine and diphosphine ligands, which showed the high catalytic activity for hydrogenation of esters (Section 9.2.2.3), also catalyzed the hydrogenation of cyclic imides under low pressure of H

2 (4 atm) at low temperature

(30 °C) [29]. The reactions were carried out in the presence of tBuOK in THF. A few examples are shown in Table 9.45. While the hydrogenation of N-methylsuccinimide gave exclusively dihydrogenated hydroxy-amide product (b), that of N-substituted phthalimide derivatives affords monohydrogenated hydroxy lactams (a) selectively. Enantioselective monohydrogenation of meso-cyclic imides using a chiral complex was also described.

9.2.3.4 Ru Complexes with (N,P)(N,P)-Chelating Ligands Cationic (allyl)Ru complexes (44) bearing bis-aminophosphine ligands have been synthesized as a mix-ture of regioisomers, and they exhibited high catalytic activity for the hydrogenation of lactams and amides [30]. Hydrogenation of lactams was conducted using 44 pre-pared in situ in the presence of (me

3Si)

2NK. A few examples are shown in Table 9.46.

N–Z

O

Z = Boc: 2 mol%, 36 hZ = Ms: 1 mol%, 2 h

N–Ts

O

N

O

BocSO2

N–Bn

O

N-CO2Me

O

Cat. 43 / tBuOK (1:1)

H2 (3 MPa), tBuOH, 80 °CN

O

Z

OH

NH ZR R

Y > 99%

10 mol%, 48 h 5 mol%, 24 h 2 mol%, 24 h 10 mol%, 24 h

Substrate, Cat. mol%, time

table 9.43 Hydrogenation of N-acylcarbamates and N-acylsulfonamides catalyzed by 43.


H2 (5 MPa), iPrOH, 100 °C, 24–72 hN

O

Ar

OH

NH Ar

N–Ph N–Ph N–Ph

O O

N

O

Ph

O

Ph

O

NMe

Ph

Y = 83% Y = 73% Y = 96% Y = 60% Y = 73%

table 9.44 Hydrogenation of lactams and amides catalyzed by 39.



This catalytic system is also applicable to the hydrogenation of amides. Some examples are shown in Table 9.47. The order of reactivity between tertiary amides is RCO–Nph

2 ~ RCO–N(ph)me > RCO–Nme

2.

It should be noted that the complex 44 and the analogous complex 1a (see Section 9.2.21, Table 9.1 and Section 9.2.2.3, Table 9.39) very efficiently catalyze the hydro-genation of N-phenyl-γ-butyrolactam with low catalyst loading (0.01 mol%) and TONs reach up to 7120 and 6760, respectively [30].

9.2.3.5 Other Catalyst Systems It is worth noting that tetranuclear [(p-cymene)4Ru

4H

6]-

Cl2 and [(p-cymene)RuCl

2]

2 catalyze the monohydrogenation of cyclic imides to lac-

tams under H2 (60 bar) at 90 °C in water [31a]. It should be also noted that a catalyst

combination of Ru(acac)3/meC(CH

2pph

2)

3 (triphos) catalyzes the hydrogenation of

Cat. 41a (1 mol%), tBuOK (9 mol%)

H2 (4 atm), THF, 30 °C, 3 h

Entry A: Yield (%)

1

23

N

O

O

R

Substrate

N–R

O

O

NMe

O

O

0

7066

N

OH

O

R NH

OH

O

R+

R = MeR = Bn

AB

100

00

B: Yield (%)

table 9.45 Hydrogenation of imides catalyzed by 41.

Cat. 44 (0.1 mol%), (Me3Si)2NK (5 mol%)

H2 (50 atm), THF, 100 °C, 24 hN

O

R

OH

NH

N–Ph N–Ph

O O

Z

N–H

O

RuPPh2

PPh2

H2N

H2N

[BF4]

RuNH2

NH2

Ph2P

Ph2P

[BF4]

(91%) (9%)

+

44

Y = 100% Y = 100% Y = 23%

table 9.46 Hydrogenation of lactams catalyzed by 44.

HYDROGENATION AND TRANSFER HYDROGENATION OF ImINES 263

amides in the presence of aq. NH3 under H

2 (40 bar) at 164 °C in THF to give primary

amines selectively [31b].

9.3 Hydrogenation and transfer Hydrogenation of imines and related CompoUnds

Reduction of carbon–nitrogen unsaturated bonds producing amines has been a fundamental and important transformation in organic synthesis as well as industrial chemistry, and great numbers of methods have been developed for reduction of C=N double bonds including reductive amination of carbonyl compounds. This section describes the recent development of catalytic hydrogenation and transfer hydrogenation of imines including reductive amination as well as that of nitrogen heteroaromatics in which molecular hydrogen (H

2), 2-propanol, and formic acid (or

sodium formate) are used as greener hydrogen sources [32]. Although tremendous amounts of ruthenium, rhodium, and iridium complexes bearing chiral diphos-phine, diamine, amine–phosphine, and amine–alcohol ligands have been developed for the asymmetric hydrogenation and transfer hydrogenation of imines, reductive amination, and nitrogen heteroaromatics [33], asymmetric reactions are not discussed here, as mentioned earlier. This section is focused on hydrogenation and transfer hydrogenation catalyzed by well-defined metal complexes bearing bidentate and miscellaneous ligands.

9.3.1 Hydrogenation and transfer Hydrogenation of imines

9.3.1.1 Hydrogenation of Imines with H2

Ru Complexes with (N,P)(N,P)-Chelating Ligands Ruthenium complexes (1) bearing bis-aminophosphine ligands, which have been used as catalysts for the hydrogenation of ketones (see Section 9.2.1.1, Table 9.1), also exhibited high

Cat. 44 (0.1 mol%), (Me3Si)2NK (4 mol%)

H2 (50 atm), THF, 100 °C, 24 h

Entry Yield (%)

12345

Ph –(CH2)5–Ph Ph HMe Ph PhMe Ph MeMe Me Me

8250

100100

50

R1 N

O

R2

R3

R1 OH + HNR2

R3

R1 R2 R3

table 9.47 Hydrogenation of acylcic amides catalyzed by 44.


catalytic activities for hydrogenation of imines [5]. The reactions were carried out in the presence of tBuOK at room temperature with or without solvent. Several exam-ples are shown in Table 9.48. Various imines were reduced with low catalyst loading under low pressure of H

2 (3 atm).

Ir and Rh Complexes with (P or N,C = C,C = C)-Chelating Ligands Cationic iridium complexes (45) bearing tridentate troppR (R = ph, Cy) {(5-H-dibenzo[a,d]cyclohepten-5-yl)phosphine} ligands have been synthesized and used as catalysts for the hydrogenation of imines [34]. The reactions were conducted with low catalyst loading (0.1 mol%) in THF. Examples are shown in Table 9.49. The high TOFs were observed in the hydrogenation of an aldimine, while catalytic activities decreased very much in the hydrogenation of a ketimine due to a marked steric effect. The asymmetric version was also described.

It should be added that the rhodium complex (3a) bearing trop2N ligand, which is

used as a catalyst for hydrogenation of ketones (see Section 9.2.1.1, Table 9.3), also catalyzes hydrogenation of an aldimine (Scheme 9.15) [7].

Cat. 1, tBuOK (1 : tBuOK = 1 : 3 – 5)

H2 (3 atm), C6D6 or no solvent, rt

12345

PhPhPh

Me2CHPh

Cat. (mol%)

1a (0.024)1b (0.27)1a (0.056)1a (0.05)1a (0.2)

R1 R2

NR3

R1 R2

HNR3

Conversion = 100%

Entry R1 R2 R3

HH

MeMeMe

PhPhBnPhBu

Time (h)

124

121236

P

H2N

H2N

PPh2Ph2

Ru

L

Cl

1a: L = Cl1b: L = H

Solvent

C6D6C6D6NoNo

C6D6

table 9.48 Hydrogenation of imines catalyzed by 1.

Entry Cat TOF (h–1)

1234

45a45b45a45b

>2000>6000

8276

45a: R = Ph45b: R = Cy

HH

MeMe

Cat. 45 (0.1 mol%), H2 (50 bar)

THF, 50 °C, R1 Ph

NPh

R1 Ph

HNPh

[OTf]R1 PR2

troppR

PR2 =

PR2

Ircod

table 9.49 Hydrogenation of imines catalyzed by 45.

Other Catalyst Systems It has been reported that the hydrogenation of imines is catalyzed by a catalyst combination of [Cp*RuCl]

4 and 2-aminomethylpyridine in the

presence of tBuOK, in which formation of Cp*Ru complex bearing 2-pyridylmethyl-amide ligand (a) is proposed [35a]. The reactions were carried out under H

2 (100 bar)

in 2-propanol at room temperature (Scheme 9.16).It should be noted that CpRuH(dppe) and CpRuH(dppm) complexes catalyze the

hydrogenation of iminium cations [35b].

9.3.1.2 Transfer Hydrogenation of IminesCp*Rh Complexes with (N,N)-Chelating Ligands A couple of unsaturated 16-electron Cp*Rh complexes bearing 1,2-benzenediamido ligands (46) have been synthesized and used as catalysts for transfer hydrogenation of a cyclic imine [36]. The reactions were carried out with HCO

2H-Et

3N (5 equiv) at 27 °C. Among the complexes, 46a showed

higher catalytic activities (Scheme 9.17).

Cp*Ir Complexes with (C,N)-Chelating Ligands It has been reported that cyclo-metalated Cp*Ir complexes (47) bearing imido-phenyl ligands, easily prepared by treatment of aromatic ketimines with [Cp*IrCl

2]

2, exhibit high catalytic activities for

Cat. 3b (1 mol%), H2 (100 bar)

THF, 25 °C, 16 h

3a

N

Rh

PPh2TolPh Me

NPh

Ph Me

HNPh

Conversion >97%

sCHeme 9.15

Cat. [Cp*RuCl]4/2-PyCH2NH2/tBuOK (1 mol%/Ru)

H2 (100 bar), iPrOH, rt, overnightR1 R2

NR3

R1 R2

HNR3

NHNRuCp*

AConversion = 38– 99%

sCHeme 9.16

Cat. 46 (1 mol%), HCO2H-Et3N

CD3OD, 27 °CN

MeO

MeONH

MeO

MeO

NRh

NX

Xʹ

Cp*46a: X = H, Xʹ = Ts46b: X = Xʹ = Ts46c: X = Xʹ = H

46a: TOF = 94 (h–1)

Catalytic activities:46a > 46b ~ 46c

sCHeme 9.17



the transfer hydrogenation of various imines [37]. Since the complex 47a showed the highest activity, the transfer hydrogenation of various imines was conducted using 47a as a catalyst with an excess of an azeotropic mixture of HCO

2H · Et

3N as a hydrogen

source in CF3CH

2OH. A few examples are shown in Table 9.50. Aliphatic ketimines

were reduced very smoothly within 2 h to give the corresponding amines in high yields. Aromatic ketimines were less reactive. An aldimine was reduced very rapidly. The complex 47a also exhibited high catalytic activity for reductive amination.

9.3.2 reductive amination of Carbonyl Compounds and amines

9.3.2.1 Reductive Amination with H2 Since the main side reaction in the reductive

amination is formation of an alcohol by hydrogenation of a carbonyl compound, it is important to note not only catalytic efficiency but also selectivity of amine formation.

Rh Complexes with (P,P)-Chelating Ligands It has been reported that cationic rho-dium complexes bearing diphosphine ligands (48) catalyze reductive amination of aldehydes and secondary amines under H

2 [38]. The reactions were carried out in

methanol at room temperature. Some examples are shown in Table 9.51 [38b]. It is apparent that the complex 48b, which is formed from 48a by prehydrogenation in meOH for 10 min, increases the selectivity very much. Basicity and steric bulkiness of secondary amines influenced the selectivity.

Other Catalyst Systems There have been several reports on reductive amination in water using catalyst combinations, [Rh(cod)Cl]

2/TppTS (p(3-C

6H

4SO

3Na)

3) [39a],

pd(phCN)2Cl

2/BQC (dipotassium 2,2′-biquinoline-4,4′-dicarboxylate) [39b], and

Cat. 47a (0.1 mol%), HCO2H•Et3N

CF3CH2OH, 80 ˚C

1234

C5H11C6H13

PhPh

R1 R2

NR3

R1 R2

HNR3

Entry R1 R2 R3

MeEtMeH

4-MeOC6H44-MeOC6H4

4-MeOC6H4

PhCH2

Time (h)

0.525

0.3

N Ir4-MeOC6H4 4-MeOC6H4

X

Cp*

Cl

Yield (%)

97949296

HN Ir

OMe

Cp*

Cl

47c47a: X = CN47b: X = OMe

table 9.50 Transfer hydrogenation of imines catalyzed by 47.

FeSO4/EDTA-Na

2 [39c]. It is worth noting that simple cationic [Ir(cod)

2][BF

4] and

Fe3(CO)

12 catalyze reductive amination of ketones and aldehydes [39d, 39e].

9.3.2.2 Reductive Amination by Transfer Hydrogenation with Formic Acid or FormateCp*Ir Complexes with (N,N)-Chelating Ligand It has been reported that water-soluble cationic Cp*Ir complexes bearing 2,2′-bipyridine ligands 9a and 9b, effective catalysts for the transfer hydrogenation of ketones in water (see Section 9.2.1.2, Table 9.10), also efficiently catalyze the reductive amination of α-keto acids with HCO

2NH

4 or aq. NH

3/HCO

2Y (Y = Na or H) in water to give α-amino acids [40a].

The reactions were carried out using 9a[SO4] or the isolated hydride complex 9b[pF

6]

as a catalyst with a large excess of HCO2NH

4 or NH

3 aq./HCO

2Y (Y = Na or H) in

water. Some examples are shown in Table 9.52. It was found that the reactions were pH dependent and α-amino acids were selectively produced in high yields at pH = 5–7. Thus, alanine was produced selectively at pH = 5, while lactic acid was formed selectively at pH = 3. Other nonpolar and uncharged polar α-amino acids were also obtained selectively in high yields (>90%) at pH = 5. In the cases of charged polar α-amino acids, the optimum pH was 6.5.

A possible mechanism for the pH-dependent reductive amination of α-keto acid with NH

3 and HCO

2− is proposed (Scheme 9.18). The first step is nucleophilic

addition of NH3 to the carbonyl carbon to produce α-imino acid intermediate, and

this step cannot proceed under acidic conditions (pH < ca. 4) due to formation of NH

4+. The resulting α-imino acid intermediate subsequently reacts with the Ir–H

Cat. 48 (0.2 mol%), H2 (50 bar)

MeOH, rt, 20 h

Entry

12345

R

Product ratio

Ph4-HOC6H4

C7H15

PhPh

1.427.012.0

2.90.4

4.7>99

>99.5>99.5

0.7

Rh(cod)PPh2

PPh2

[BF4]Rh(MeOH)2

PPh2

PPh2

[BF4]H2 (50 bar)

MeOH, 10 min

48a 48b

RCHO + R1R2NH + RCH2OH

Cat. 49aAmin/Alcohol

Cat. 49bAmin/Alcohol

N

R2

R1

RCH2

R1R2NH (pKa)

Piperidine (11.02)PiperidinePiperidine

Pyrrolidine (11.27)Dimethylamine (10.73)

Conversion >99%

table 9.51 Reductive amination of aldehydes and amines catalyzed by 48.



species 9b generated by the reaction of the Ir–OH2 species 9a with HCO

2− at pH = ca.

4–7. Thus, the selective reductive amination of α-keto acid to α-amino acid with NH3

and HCO2

− can be achieved at the optimized pH = 5 or 6.5.

Cp*Rh Complexes with Tethered (N)-Ligating Ligands Cp*Rh complexes (49) bearing tethered amine ligand have been synthesized and used as catalysts for the reductive amination of an aldehyde and amine · formic acid [40b]. The reactions of p-methoxybenzaldehyde with (phCH

2)

2NH · HCO

2H were carried out in meOH at

70 °C. Examples are shown in Table 9.53. The reactions using the complexes 49a and 49b (n = 2) proceeded quantitatively with the high selectivity (96%), while the selectivity decreased when the dimethylamino-tethered complex 49c and the com-plex 49d having longer chain length (n = 3) were used, indicating that the effective Rh/NH bifunctional catalysis is operating in the cases of 49a and 49b.

Cp*Ir Complexes with (N,C)-Chelating Ligands The cyclometalated Cp*Ir complexes 47, the effective catalysts for the transfer hydrogenation of imines (see Section 9.3.1.2, Table 9.50), also exhibited high catalytic activity for reduc-tive amination of various aldehydes and ketones by transfer hydrogenation [37]. Since it was found that the complex 47b was more active than the complex 47a,

RCOCO2H +Cat. 9a[SO4] or 9b[PF6] (0.5 mol%)

H2O, pH = 5.0 or 6.5, 80 °C, 6 hRCH(NH3

+)CO2–

Entry Cat.

12345

9b[PF6]9a[SO4]

9a[SO4]9a[SO4]9a[SO4]

9496969794

N N

Ir

Cp* L

9a: L = OH29b: L = H

HCO2NH4or

NH3 aq/HCO2Y

Ammonia andhydride source

HCO2NH4HCO2NH4

HCO2NH4

HCO2NH4

NH3/HCO2H

HHH

iPr4-HOC6H4CH2

R Yield (%)2+

table 9.52 pH-Dependent reductive amination of α-keto acids catalyzed by 9 in water.

NH4+ NH3

R CO2H

O

R CO2H

NH

pH = ca. 4 – ca. 7

9b 9a

HCO2–CO2

R CO2–

NH3+H2O

–H+

H+

–H+pH < ca. 4

sCHeme 9.18

the reactions were carried out using 47b with an excess amount of an azeotropic mixture of HCO

2H · Et

3N as a hydrogen source in meOH to give amines very

selectively. Some examples are shown in Table 9.54. The reactions of various aliphatic ketones and amines afforded the corresponding amines in high to excellent yields. The C = C bond remained intact. d-Glucose and an amino acid can be used as substrates (Entry 5). The reactions of less reactive aromatic ketones required higher catalytic loading (0.5 mol%) and longer reaction time (12 h) (Entries 6–9).

Entry Cat. Amine : Alcohol

1

2

3

4

49a

49b

49c

49d

96 : 4

96 : 4

75 : 25

56 : 44

Rh NR2

ClCl

n

49a: R,R = H, n = 149b: R,R = H, Me, n = 149c: R,R = Me, n = 149d: R,R = H, n = 2

4-MeOC6H4CHO+

(PhCH2)2NH•HCO2H

Cat. (1 mol%)

MeOH, 70 °C, 24 h

4-MeOC6H4CH2N(CH2Ph)2+

4-MeOC6H4CH2OH

Converion > 99%

table 9.53 Reductive amination of an aldehyde catalyzed by 49.

Cat. 47b (0.1 or 0.5 mol%), HCO2H•Et3N

MeOH, 80 °C

1234

5

6789

R1 R2

O

R1 R2

HNR3

Entry Substrate Amines

4-MeOC6H4NH2

Pyrrolidine4-MeOC6H4NH2

4-MeOC6H4NH2

(S)-PhCH2CHNH2

4-MeOC6H4NH2

4-MeOC6H4NH2

4-MeOC6H4NH2

4-MeOC6H4NH2

Time (h)

1511

5

12121212

Yield (%)a

98969690

65

92879581

+ R3–NH2

C5H11COMe3,4-(OCH2O)C6H3(CH2)2COMe

CH2=CH(CH2)2COMePhCH=CHCHO

PhCOMe2-MeOC6H4COMe4-CNC6H4COMe

PhCOCO2Me

OH

HO

H

HO

H

OHOHHH

OH

CO2H

table 9.54 Redcutive amination of ketones and aldehydes catalyzed by 47b.



primary amines were also synthesized by the similar reductive amination of ketones with HCO

2NH

4. A few examples are shown in Table 9.55. The reactions

of a variety of ketones proceed smoothly to give the corresponding amines in high yields.

Other Catalyst Systems It should be noted that simple [Cp*RhCl2]

2 catalyzes

reductive amination of ketones and α-keto acids with HCO2NH

4 [40c].

9.3.3 Hydrogenation and transfer Hydrogenation of nitrogen Heteroaromatics

9.3.3.1 Hydrogenation of Nitrogen HeteroaromaticsRh Complexes with (P,P,P)-Chelating Ligand It has been reported that rhodium complexes (50) bearing triphos ligand [meC(CH

2pph

2)

3] catalyze hydrogenation of

quinoline [41a]. The reactions were carried out in THF at 80 °C to give 1,2,3,4-tetra-hydroquinoline (THQ) selectively. A few examples are shown in Table 9.56. Addition of TfOH (5–20 equiv) lowered the reaction temperature, though the conversion

Cat. 47b (0.5 mol%)

MeOH, 80 °C

12

3

R1 R2

O

R1 R2

NH2


8580

93

+ HCO2NH4

PhCOMe1-Tetralone

PhCOCO2Me

512

5

table 9.55 Redcutive amination of ketones with HCO2NH

4

catalyzed by 47b.

Cat. 50 (1 mol%), H2 (30 bar)

THF, 1 h

1

2

3

4

50a

50a

50a

50b

Entry Catalyst TfOH (equiv.) Temp (°C)

0

5–20

100

20

60

40

40

60

Conv. (%)

98

98

30

98

RhP

Ph2

Ph2

PPPh2

CO2Me

CO2Me [PF6]

RhPPh2

Ph2P

PPh2

50a

50b

N NH

S

table 9.56 Hydrogenation of quinoline catalyzed by 50.

decreased by addition of too much acid. The neutral complex 50b was a poor catalyst; however, addition of TfOH (20 equiv) made it as efficient as 50a.

There have been a couple of reports on the hydrogenation of nitrogen heteroaro-matics, such as quinoline, isoquinoline, acridine, etc., catalyzed by catalyst combina-tions of [mCl(coe)

2]

2/triphos (m = Rh and Ir) [41b, 41c].

Other Catalyst Systems Water-soluble ruthenium complexes bearing TppTS [p(m-C

6H

4SO

3Na)

3] or TppmS [p(m-C

6H

4SO

3Na)ph

2] ligands catalyzed the hydrogenation

of quinoline [41d]. RuH2 complexes with phosphine ligands also catalyzed the hydro-

genation of quinoline, isoquinoline, and pyridines [41e]. It should be noted that a catalyst combination of [(p-cymene)RuCl

2]

2/I

2 exhibited high catalytic activity of the

selective hydrogenation of various quinolines to 1,2,3,4-tetrahydroquinolines [41f].

9.3.3.2 Transfer Hydrogenation of Nitrogen HeteroaromaticsRh Complex with (N,N)(N,N)-Chelating Ligands It has been reported that a rhodium complex (51) bearing two bipyridine ligands in cis-fashion catalyzes the transfer hydrogenation of quinoline with 2-propanol [42a]. A few examples are shown in Table 9.57. While the conversions were generally low, the reaction under H

2 improved

the conversion, suggesting that the hydrogenation was more favorable than the transfer hydrogenation. The similar transfer hydrogenation of pyridine and 2-methylpyridine gave piperidine and 2-methylpiperidine in 51 and 25% conversions, respectively.

Other Catalyst Systems It has been reported that simple [Cp*IrCl2]

2 efficiently

catalyzes the transfer hydrogenation of a variety of quinolones with 2-propanol in the presence of HClO

4 to give 1,2,3,4-tetrahydroquinolines regio- and chemoselec-

tively [42b]. Simple [Cp*RhCl2]

2 also catalyzed the transfer hydrogenation of various

N-alkylisoquinolinium salts with an azeotropic mixture of HCO2H · Et

3N (5:2) to

afford N-alkyl-1,2,3,4-tetrahydroisoquinolines in high yields [42c]. A catalyst combination of [Cp*IrCl

2]

2/monotosylated ethylenediamine efficiently catalyzed

Cat. 51 (1 mol%), NaOH

iPrOH, 3 h

1234

Entry Conversion (%)

23548122

51

N N

Temperature(°C)

90110100100

Rh

Cl

ClN

N

N

N

[Cl]

•2H2O

Conditions Selec. (%)

N2

N2

H2 (1 atm)N2 + H2O (5%)

94859198

NH

+

table 9.57 Transfer hydrogenation of quinoline catalyzed by 51.



transfer hydrogenation of a variety of quinoxalines with HCO2Na in HOAc/NaOAc

buffer solution (pH = 5.5) to give 1,2,3,4-tetrahydroquinoxalines in good to excel-lent yields [42d]. It is worth noting that [Cp*RhCl

2]

2 in the presence of KI effi-

ciently catalyzes the transfer hydrogenation of various quinolines, isoquinolines, and quinoxalines with an azeotropic mixture of HCO

2H · Et

3N (5:2), indicating that

iodide ion greatly accelerates the catalytic reactions [42e].

9.3.4 Hydrogenation of nitrile Compounds

Reduction of nitrile compounds to primary amines has been an important transfor-mation in organic synthesis. However, the catalytic hydrogenation suffers from the formation of side products such as dimeric imines and dimeric secondary amines (Scheme 9.19).

9.3.4.1 Ru Complexes with (C,N)-Chelating Ligand It has been reported that the bis(dihydrogen) ruthenium complex RuH

2(H

2)

2(pCyp

3)

2 (52a) (Cyp = cyclopentyl)

catalyzes the selective hydrogenation of benzonitrile to benzylamine under mild conditions [43a]. Furthermore, it was revealed that cyclometalated ruthenium complexes 52b and 52c, which were readily produced by treatment of 52a with 2 and 1 equiv of benzonitrile, respectively, also catalyzed the hydrogenation very effectively. A few examples are shown in Table 9.58. The reactions were carried out at room temperature to give benzylamine with high selectivity. The complexes 52b and 52c were more active than 52a, substantiating the experimental evidence for trapping of the imine intermediate.

9.3.4.2 Ru Complexes with (P,N,N,P)-Chelating Ligands Ruthenium complexes (5) bearing tetradentate diaminodiphosphine ligands, the effective catalysts for hydrogenation of ketones (see Section 9.2.1.1, Table 9.6), also cata-lyzed the hydrogenation of benzonitrile [43b]. The reactions were carried out using 5 g in the presence of base (tBuOK or KH) to give benzylamine selectively in excellent conversions. Some examples are shown in Table 9.59. Since water severely inhibited the hydrogenation, use of KH improved the rate of conversion due to removal of a trace amount of water. The complex 5 g was more active

R CNCat. [M], H2

R C=NHCat. [M], H2

R CH2NH2

R C=NH

R NH

R

NH2

R N RR NH

RCat. [M], H2

NH3

sCHeme 9.19

than the known catalyst RuH2(H

2)

2(pCy

3)

3. A catalyst combination of 5 g and

RuH2(H

2)

2(pCy

3)

3 was more effective and reduced the H

2 pressure to 7 atm. The

bulky methylated backbone of 5d decreased the catalytic activity. mechanistic investigations including DFT calculations were also performed and supported the similar mechanism to that of the hydrogenation of ketones (see Section 9.2.1.1, Scheme 9.1).

9.3.4.3 Catalyst Combination of Ru Complex and Phosphine A catalyst combination of (allyl)

2Ru complex and phosphine ligand exhibited high catalytic

activity for the hydrogenation of nitriles to give primary amines in a highly selective manner [43c, 43d]. Among many ruthenium complexes and phosphines examined, a catalyst combination of (methallyl)

2Ru(cod) and pph

3 or DppF

Cat. 52 (0.5 mol%), H2 (3 bar)

THF, 22 °C

123

Entry

566868

Ratio of A : B

96 : 496 : 498 : 2

52a52b52c

2 h 24 h

99 : 199 : 199 : 1

RuH H

PCyp3

PCyp3 PCyp3

H

H H

H RuH

NH

H

H H

2PhCNRu

PhCN

H

NH

Cyp3P Cyp3P

PCyp3

H

52b 52c

PhCN

52a

PhCH2NH2 + PhCH=NCH2PhPhCN

Cat.Conversion (%)

2 h 24 h

969796

A B

THF, rtTHF, rt

table 9.58 Hydrogenation of benzonitrile catalyzed by 52.

PhCNCat. 5 (0.5 mol%), base (5 mol%)

H2 (14 atm), toluene, 20 °CPhCH2NH2

Entry Cat.

1234a

5

5g5g

RuH2(H2)2(PCy3)25g + RuH2(H2)2(PCy3)25d + RuH2(H2)2(PCy3)2

Base

tBuOK

tBuOKtBuOK

tBuOK/KHNone

Time (h)

<183–6503

22

Conversion.(%)

100100

96100

995g

PPh2 Ph2

N N

PRu

Cl

HH H

a 0.25 mol% of each catalyst was used under H2 (7 atm).

table 9.59 Hydrogenation of benzonitrile catalyzed by 5.



(1,1′-diphenylphosphinoferrocene) gave the best results. The reactions were carried out in the presence of tBuOK in toluene (Scheme 9.20). A variety of aromatic, heterocyclic, and aliphatic nitriles were hydrogenated to give the corresponding primary amines selectively in good to excellent yields. It should be noted that DppF is superior to pph

3 as the additive ligand.

referenCes

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Cat. Ru(cod)(methallyl)2 (0.5 mol%),PPh3 (1 mol%) or DPPF (0.5 mol%), tBuOK (10 mol%)

H2 (50 bar), toluene, 80 or 140 °C6 h (PPh3) or 1–2 h (DPPF)

R–CN R–CH2NH2

Y = 65–99%

sCHeme 9.20

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[22] (a) Ghebreyessus KY, Nelson JH. J Organomet Chem 2003;669:48. (b) Enthaler S, Hagemann B, Erre G, Junge K, Belle m. Chem Asian J 2006;1:598. (c) Enthaler S, Erre G, Tse mK, Junge K, Beller m. Tetrahedron Lett 2006;47:8095. (d) Enthaler S, Spilker B, Erre G, Junge K, Tse mK, Beller m. Tetrahedron 2008;64:3867.

[23] Ito m, Ootsuka T, Watari R, Shiibashi A, Himizu A, Ikariya T. J Am Chem Soc 2011;133:4240.

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278

Bond-Forming reactions Based on Hydrogen transFer catalyzed By Well-deFined transition metal complexes Bearing Bidentate and miscellaneous ligands

10

10.1 introduction

Bond formation is one of the most important chemical transformations in organic synthesis. The main subjects discussed in this chapter are carbon–carbon, carbon–nitrogen, and carbon–oxygen bond-forming reactions via hydrogen transfer process catalyzed by well-defined homogeneous transition metal complexes. These catalytic systems are cascade or domino reactions that generally consisted of three steps: (1) dehydrogenation (β-hydrogen elimination) step to generate electrophilic active species such as C=O or C=N double bonds and a metal hydride species ([MH

2] or [MH]), (2) bond-forming step by condensation of the active species

with nucleophiles to produce unsaturated intermediates, and (3) hydrogenation (hydrometalation) step of the resulting unsaturated intermediate with the transient metal hydride species to furnish a bond-forming product (Scheme 10.1). In the catalytic cycle, the hydrogen atom of a substrate is firstly transferred to a metal catalyst generating a transient metal hydride species. After the bond formation, the hydride of the metal hydride species is retransferred to the unsaturated species to afford a final product accompanied by regeneration of the starting metal catalyst. Thus, these catalytic systems are termed as “borrowing hydrogen,” “hydrogen autotransfer,” or “redox-neutral” protocol [1]. Since no oxidant or reductant is necessary and only water (when Y is O) is produced as a coproduct, these catalytic

CARBON–CARBON BOND-FORMING REACTIONS BASED ON HYDROGEN TRANSFER 279

protocols have been recently attracting much attention from atom-economical and environmental points of view.

While this chapter is focused on the bond-forming reactions by well-defined transition metal complexes, there have been a great number of the transformations using catalyst combinations of metal complexes and ligands. Accordingly, these catalytic systems are also referred briefly.

10.2 carBon–carBon Bond-Forming reactions Based on Hydrogen transFer

Alkylation of nucleophilic organometallic reagents such as enolate anions with elec-trophilic alkyl halides has been widely used as one of the most popular carbon–carbon bond-forming reactions, although this process has apparent disadvantages such as use of harmful alkyl halides and formation of equimolar amount of halide waste. The use of less harmful alcohols as the alkylating agents is environmentally superior and increases the atom efficiency because water is produced as coproduct. However, alcohols are very poor electrophilic alkylating agents because of much higher energy of heterolysis of a C–O bond than that of an O–H bond. On the other hand, carbonyl compounds derived from alcohols by dehydrogenative oxidation are good electro-philes. Thus, a number of catalytic systems in which alcohols are tentatively converted to carbonyl compounds via hydrogen transfer processes have been developed [1, 2].

10.2.1 α-alkylation of carbonyl and related compounds with primary alcohols

The overall catalytic cycle of this transformation is shown in Scheme 10.2. At first, the metal-catalyzed dehydrogenation of a primary alcohol produces an aldehyde and a metal hydride species. Aldol condensation of the resulting aldehyde with a ketone proceeds in the presence of base to give an α,β-unsaturated ketone (and water), which

R1 YH

Y

R2–XH2 (X = CCOR, N)

R1 XR2

XH

Cat. [M]

Cat. [MH2] or [MH]

2) Bond-forming step

Active species Unsaturated species

(Y = O, NH) –YH2

H HR2–XH2(X = CCOR, N)

3) Hydrogenation(hydrometalation)

1) Dehydrogenation(β-hydrogen elimination)

+ YH2

R1R2

R1

scHeme 10.1

280 BOND-FORMING REACTIONS

is subsequently hydrogenated or hydrometalated by the transient metal hydride species to afford a β-alkylated ketone and regenerate the starting metal catalyst. Thus, the metal-catalyzed hydrogen transfer process plays a fundamental role in the overall catalytic cycle and water is only a coproduct.

There have been tremendous numbers of reports on the alkylation of ketones with primary alcohols catalyzed by metal complexes in the presence of base (Scheme 10.3). However, in almost all cases, various catalyst combinations of simple metal complex with or without ligand have been used. Therefore, brief summaries of the catalyst systems are described in the following.

10.2.1.1 Alkylation of Ketones with Alcohols The representative catalyst combinations of simple metal complex/base are RuCl

2(PPh

3)

3/KOH [3a–3c],

RuCl2(dmso)

4/KOH [3d, 3e], [Ir(cod)Cl]

2/PPh

3/KOH [3f–3 h], and [Cp*IrCl

2]

2/

KOH [3i] (Scheme 10.3).

10.2.1.2 Alkylation of Esters, Amides, and Nitriles with Primary Alcohols The alkylation of esters with primary alcohols is carried out using a catalyst combination of [Ir(cod)Cl]

2/PPh

3/tBuOK (Scheme 10.4, the 1st equation) [4a]. The similar

reactions of oxindole with alcohols are catalyzed by catalyst combinations of

R1 O R1

Cat. [M]

Cat. [MH2] or [MH]

Base

R1 OH

H

R2

OR2

O

R1 R2

OH

–H2O

H2O

R2

O

Cat. [M], base

Dehydrogenation(β-hydrogen elimination)

Hydrogenation(hydrometalation)

Aldol condensation

scHeme 10.2

R1 OHR1 R2

O

R2

O

+ H2O+Cat. [M], base

Cat. [M], baseRuCl2(PPh3)3, KOH in dioxane at 80 °C, 20–40 h

RuCl2(dmso)4, KOH in dioxane at 80 °C, 24 h[IrCl(cod)]2/PPh3, KOH at 100 °C, 4 h

[Cp*IrCl2]2, KOH in toluene at 110 °C under MW, 30–40 min

scHeme 10.3


RuCl3 · xH

2O/PPh

3/NaOH [4b] and [Cp*IrCl

2]

2/KOH [4c] (the 2nd equation) without

solvent. Furthermore, it has been shown that the catalyst combinations of [Cp*IrCl2]

2/

KOH and [Ir(cod)Cl]2/Cs

2CO

3 are effective for the alkylation of arylacetonitriles and

acetonitrile with various primary alcohols under microwave (MW) irradiation, respectively (the 3rd and 4th equations) [4d, 4e].

10.2.1.3 Alkylation of Active Methylene Compounds with Alcohols Active methylene compounds are another possible and promising substrates for the C–C bond-forming reaction involving Knoevenagel-type transformation. The alkylation of 1-cyano-3,3-dimethyl-2-propanone with benzylic alcohols was carried out by a catalyst combination of [Ir(cod)Cl]

2/DPPF/K

2CO

3/piperidinium acetate [5a]. A cata-

lyst combination of RuH2(CO)(PPh

3)

3/Xantphos/piperidinium acetate improved the

reaction. A ruthenium complex (1) was characterized and showed the high catalytic activity (Scheme 10.5) [5b, 5c].

The alkylation of alkyl cyanoacetates with various primary alcohols and diols was achieved using a catalyst combination of [Ir(cod)Cl]

2/PPh

3 without base (Scheme 10.6)

[5d, 5e]. A catalyst combination of [Cp*IrCl2]

2/KOH was also effective for the alkyl-

ation of tert-butyl cyanoacetate with benzylic alcohols without solvent [5f].The decarboxylative alkylation of ethyl malonate with primary alcohols was

conducted using a catalyst combination of Ru(PPh3)

3Cl

2/KOH/pyrrolidine/2-propa-

nol to give homologated esters (Scheme 10.7, the 1st equation) [5 g]. It has been also reported that the alkylation of malonic half-esters or nitroalkane with primary alcohols was carried out using a catalyst combination of RuH

2(CO)(PPh

3)

3/Xantphos/

pyrrolidine or RuH2(CO)(PPh

3)

3/Xantphos/piperidinium acetate in the presence of

crotononitrile as a hydrogen acceptor to give α,β-unsaturated esters or nitroalkenes (the 2nd and 3rd equations) [5 h].

R OH ROtBu+ CO2

tBuO

tBuOH, 100 °C, 15 h

R OH +NH

ONH

O

RRuCl3•xH2O (2 mol%), PPh3 (4 mol%),NaOH (10 mol%), 110 °C, 20 h

[Cp*IrCl2]2 (2.5 mol%)KOH (20 mol%), 110 °C, 20 h

R OH RAr CN+CN

Ar

[Cp*IrCl2]2 (2.5 mol%), KOH (15 mol%)

R OH R+ CH3CNCN

180 °C, 40 min under MW

100 °C, 12–17 hor 110 °C, 10 min under MW

[Ir(cod)Cl]2 (2 mol%), Cs2CO3 (20 mol%)

or

Y = 70–95%

Y = 71–92% or 64–99%

Y = 67–99%

Y = 30–90%

[Ir(cod)Cl]2 (5 mol%), PPh3 (15 mol%)tBuOK (200 mol%)

scHeme 10.4


The alkylation of 1,3-dimethylbarbituric acid with primary alcohols was cata-lyzed by a catalyst combination of [Cp*IrCl

2]

2/KOH under MW irradiation

(Scheme 10.8) [5i].Furthermore, the alkylation of 4-hydroxy-2-quinolones and 4-hydroxycoumarin

with primary alcohols was achieved using the similar catalyst combination of [Cp*IrCl

2]

2/KOH (Scheme 10.9) [5j].

R OHToluene, re�ux, 4 h

RuH2(CO)(PPh3)3 (0.5–5 mol%)Xantphos (0.5–5 mol%)

Piperidinium acetate (5 mol%)

OPPh3 PPh3

Xantphos

RuOC

P H

H

P

PPh3

P

P=

1

tBu+ NC

O

tBu

O

CN

R

Y = 31–89%

scHeme 10.5

R OH + NCOR

O

OR

O

CN

Ror

Y = 43–99% or 52–86%

[Cp*IrCl2]2 (2.5 mol%)KOH (15–20 mol%), 100 °C, 4 h

[IrCl(cod)]2 (5 mol%), PPh3 (20 mol%)p-Xylene, 130 °C, 15 h

scHeme 10.6

R OH +OEt

O

OEt

O

RHO

O

R1 OH +OR2

O

HO

O

OR2

O

R1

R1 OH + R2 NO2 Crotononitrile (150 mol%)Toluene, re�ux, 8 h

Crotononitrile (150 mol%)Toluene, re�ux, 2 h

R1NO2

R2

Y = 71–100%

Y = 71–95%

Y = 62–100%

RuH2(CO)(PPh3)3 (2.5 mol%)Xantphos (2.5 mol%)

Pyperidine acetate (20 mol%)

RuH2(CO)(PPh3)3 (2.5 mol%)Xantphos (2.5 mol%)Pyrrolidine (30 mol%)

RuCl2(PPh3)3 (2.5 mol%)KOH (6.25 mol%)

Pyrrolidine (30 mol%)

Me2CHOH (20 mol%)Toluene, re�ux, 24 h

scHeme 10.7


10.2.2 β-alkylation of secondary alcohols with primary alcohols

A general cascade of the catalytic cycle is similar to that of α-alkylation of ketones with primary alcohols (Scheme 10.10). Firstly, both secondary and primary alcohols are doubly dehydrogenated by metal catalysts to generate ketones and aldehydes as well as metal hydride species. Aldol condensation followed by double hydrogenation or hydrometalation of alkene and ketone moieties with metal hydride species furnishes β-alkylated alcohols.

10.2.2.1 Ru Complexes The β-alkylation of secondary alcohols with primary alcohols is carried out using a catalyst combination of RuCl

2(PPh

3)/KOH in the presence

of a large excess of 1-decene (hydrogen acceptor) in dioxane (hydrogen donor) (Scheme 10.11) [6a]. The reactions are also catalyzed by a catalyst combination of RuCl

2(dmso)

4/KOH in dioxane [6b].

CpRu and Ru Complexes with (N,N,N)- and (N,N)(N,N)-Chelating Ligands It has been reported that several ruthenium complexes (2a–2f) bearing Cp, Tp [hydrotris (pyr-azolyl)borate], and 6,6′-dichloro-2,2′-bipyridine ligands catalyze the β-alkylation of

R OH +

N

NO

O

ON

NO

O

OR

Y = 74–91%

110 °C, 10 min under MW

[Cp*IrCl2]2 (2.5 mol%)KOH (15 mol%)

scHeme 10.8

R OH +


110 °C, 48 hX O

OH

X O

OH

R

X = NMe, NH, O Y = 68–94%

scHeme 10.9

R1 OH

R1 OR1baseR2

O

R2

O

R1 R2

OH

R2

OH+

+

H2O

Cat. [M]

Cat. [M], base

Aldole condensation



–H2O

Cat. [MH2] or [MH]

scHeme 10.10


secondary alcohols with primary alcohols [6c]. The reactions were carried out in the presence of KOH without solvent. Some examples are shown in Table 10.1. The half-reduced products, ketones, were also produced to some extents. Among the complexes, the dicationic bipyridine complex 2f generally exhibited higher activity than others.

R1 OH +RuCl2(dmso)2 (2 mol%)

KOH (200 mol%), 100 °C, 7 d

RuCl2(Pph3)3 (5 mol%), KOH (300 mol%),1-Dodecene (500 mol%)

Dioxane, 80 °C, 40 h

R2

OH

R2

OH

R1or

Y = 34–90% or 48–90%

scHeme 10.11

R1 OH +R2

OH

R2

OH

R1

Cat. 2 (0.4 mol%),NaOH (20 mol%)

120 °C, 24 h

Cp

RuPh3P

PPh3

NCMe

Cp

RuPh3P

PPh3

Cl

[BF4] Cp

Ru

Ph2P PPh2

Cl

N

N

N

NN

N

Ru

B

H

ClPPh3

Ph3P

N

N

N

NN

N

Ru

B

H

ClPPh2

Ph2P

NN

Cl

Cl

NN Cl

Cl RuOH2

OH2

2a 2b 2c

2d 2e 2f

Entry2c2b

123456

71 (3)84 (6)66 (2)48 (5)60 (20)72 (0)

a Values in parenthesis are conversions for the ketone.

2a

88 (7)77 (6)61 (3)65 (9)78 (12)75 (0)

R1 R2

Ph2-MeOC6H4

4-FC6H4PhCH2CH2

PhPh

PhPhPhPh

4-MeOC6H44-ClC6H4

2f2e2d

Catalyst/conversion (%)a

94 (3)81 (7)71 (2)57 (0)74 (17)87 (4)

73 (13)74 (10)77 (9)60 (4)70 (25)93 (3)

74 (13)78 (8)77 (9)56 (5)68 (20)92 (6)

92 (8)89 (11)86 (9)88 (9)64 (29)86 (10)

R2

O

R1+

[BF4] [OTf]2



(C6H

6)Ru Complexes with (C,N)-Chelating Ligands A series of cyclometalated

(C6H

6)Ru complexes (3a–3d) bearing (C,N)-chelating aminomethylphenyl ligands

have been synthesized and used as catalysts for the β-alkylation of secondary alcohols with primary alcohols [6d]. The reactions were conducted in the presence of tBuONa at 110 °C in toluene. Some examples are shown in Table 10.2. Among the complexes, 3a exhibited the highest catalytic activity. The reactions between aromatic alcohols gave better conversions and selectivity compared to those between aliphatic and aro-matic alcohols.

10.2.2.2 Ir Complexes It has been reported that [Cp*IrCl2]

2 efficiently catalyzes

the β-alkylation of secondary alcohols with primary alcohols in the presence of an equimolar amount of base [7a]. A variety of aromatic and aliphatic alcohols are used as the substrates (Scheme 10.12).

The self-condensation of primary aliphatic alcohols, known as the Guerbet reac-tion, was catalyzed by [Cp*IrCl

2]

2 in the presence of 1,7-octadiene and tBuOK [7b].

The reaction of various aliphatic primary alcohols gave β-alkylated dimer alcohols (Scheme 10.13). It has been also reported that selective formation of butanol by the

R1 OH +R2

OH

R2

OH

R1

Cat. 3 (1 mol%),tBuONa (100 mol%)


C6H6

Ru

NR1R2NCMe

[PF6]

3a: R1 = R2= H3b: R1 = H, R2= Me3c: R1 = R2= Me

Entry

123456

Cat.

3a3b3c3d3a3a

R1 R2

PhPhPhPh

C4H9Ph

PhPhPhPhPh

4-ClC6H4

Conversion (%)

R2

O

R1+

C6H6

Ru

NH2

NCMe

[PF6]

3d

Alcohol : Ketone

969684994092

97 : 376 : 2496 : 450 : 5080 : 2098 : 2


R1 OH +

[Cp*IrCl2]2 (0.5–2.0 mol%)tBuONa or NaOH (100 mol%)

Toluene, 110 °C, 17 hR2

OH

R2

OH

R1

Y = 58–88%

scHeme 10.12


Guerbet reaction of ethanol is catalyzed by a catalyst combination of [Ir(acac)(cod)]/dppp in the presence of 1,7-octadiene and EtONa [7c].

Cp*Ir Complexes with (N)-Monoligating and (N,N)-Chelating Ligands Cp*Ir complexes (4a and 4b) bearing N-monoligating formamidine and (N,N)-chelating for-mamidate ligands have been synthesized and used as the catalysts for the β-alkylation of 1-phenylethanol with primary alcohols [7d]. The reactions were carried out in the presence of KOH in toluene at 100 °C. A few examples are shown in Table 10.3. The monoligating complex 4a was more active than the (N,N)-chelating complex 4b.

Cp*Ir Complex with (S, S, S)-Chelating Ligand A Cp*Ir complex (5) bearing a tridentate thioether–dithiolate (tpdt=S(CH

2CH

2S−)

2) ligand catalyzes the β-alkylation

of 1-arylethanol with primary alcohols [7e]. The reactions were conducted in the presence of tBuOH at 110 °C in toluene. Several examples are shown in Table 10.4. The catalyst loading was relatively low (0.1 mol%). Some amounts of ketone prod-ucts were formed in the reactions of aliphatic primary alcohols, decreasing the yield.

OH p-Xylene, 120 °C, 4 hOHR

R

RY = 43–98%

[Cp*IrCl2]2 (1 mol%), 1,7-Octadiene (10 mol%)tBuOK (40 mol%)

scHeme 10.13

R OH +Ph

OH

Ph

OH

R

Cat. 4 (1 mol%)KOH (100 mol%)

Toluene, 100 °C

Entry

123a

4

a 2 equiv of primary alcohol was used.

Cat.

4a4b4a4a

R

PhPh

C3H73-ClC6H4

Alcohol (%)

Ph

O

R+

Ketone (%)

90729193

923

84

Ir

Cp*

N ClCl

NH

Ir

Cp*

N NCl

4a 4b

Time (h)

3386

taBle 10.3 β-Alkylation of 1-phenylethanol with primary alcohols catalyzed by 4.


10.2.2.3 Other Catalyst Systems Other than ruthenium and iridium catalysts, a couple of catalyst combinations of metal/base have been reported: Ni(OAc)

2(H

2O)

4/

KOH [8a], Cu(OAc)2(H

2O)/KOH [8b], and CpFe(η5-C

5H

4CHO)/NaOH [8c].

10.2.3 related alkylation reactions with primary alcohols via Hydrogen transfer

It has been reported that indoles are alkylated with primary alcohols using a catalyst combination of [Cp*IrCl

2]

2/KOH to give 3-substituted indoles (Scheme 10.14) [9a].

The alkylation of the benzylic position of 2-amino-4-methylpyrimidines with primary alcohols has been achieved by using a catalyst combination of [Ir(cod)- Cl]/Py

2NP(iPr)

2 in the presence of tBuOK (Scheme 10.15) [9b]. The reaction was

applicable to 4-methylpyrimidine, 2-methylpyrazine, 3-methylpyridazine, and 2-picoline, although the yield was getting lower with decreasing acidity of the methyl proton.

R1 OH +R2

OH

R2

OH

R1

Cat. 5 (0.1 mol%), tBuONa (100 mol%)


Ir

Cp*

SS

S

5

Entry

12345

R1 R2

PhPhPh

C4H9C3H7

Ph4-MeOC6H4

4-ClC6H4CH3Ph

Yield (%)

9082855085


R1 OH110 °C, 24 h

R2

NH

R2

NH

R1

+

Y = 35–84%


scHeme 10.14

R1 OHtBuOK (110 mol%)

Diglyme, 110 °C, 24 h

+N N

NHR2

N N

NHR2

R1

Y = 62–98%

[IrCl(cod)]2 (1 mol%)Py2NP(iPr)2 (2 mol%)

scHeme 10.15


10.2.4 n-Heterocyclization through the alkylation of alcohols with primary alcohols

The Friedländer reaction has provided the classical but convenient methods for synthesis of quinoline ring systems. The Friedländer reaction is the annulation reaction that consists of a base- or acid-promoted aldol condensation of 2-amino-substituted aromatic carbonyl compounds with carbonyl compounds containing reactive methylene moiety followed by cyclodehydration [10a]. Recently, there have been many reports on various catalytic Friedländer reactions (so-called modified Friedländer reaction) in which the key steps are the aforementioned catalytic carbon–carbon bond-forming reactions using primary alcohols as alkylating reagents [10b].

There have been many reports on the modified Friedländer reaction of 2- aminobenzyl alcohol with a variety of ketones to afford quinolines (Scheme 10.16, the 1st equation). Two catalytic cycles are proposed: (path 1) metal-catalyzed dehydroge-nation of 2-aminobenzyl alcohols generating 2-aminobenzaldehyde, base-promoted cross-aldol condensation with ketones, and cyclodehydration between amino and carbonyl moieties and (path 2) imine formation, metal-catalyzed dehydrogenation, and base-promoted aldol-type cyclocondensation. Many catalyst combinations for this

OH

NH2R1

O

R2+Cat. [M], base

N R1

R2

O

NH2

R1

O

R2

OH

NR1

R2

NH2

OR1

R2

O

NR1

R2

Aldol-typecondensation

Cat. [M]

Cross aldolecondensation

Cat. [M]

Dehydrogenation

Imineformation

Cyclo-dehydration

O

NH2R3

OH

R4+Cat. [M], base

Cat. [M], base

N R3

R4

R2

R1 R1

R2

OH

NH2R1

OH

R2+

N R1

R2

Dehydrogenation

Path 1Path 2

scHeme 10.16


transformation have been reported: RuCl2(PPh

3)

3/KOH in dioxane [11a], RuCl

2-

(dmso)4/KOH/Ph

2CO in dioxane [3d, 3e], RhCl(PPh

3)

3/KOH in dioxane [11b],

[IrCl(cod)]2/PPh

3/KOH [11c], Pd(OAc)

2/PEG-2000/KOH in toluene [11d], and

CuCl2/KOH under O

2 in dioxane [11e, 11f].

The similar modified Friedländer reactions of 2-aminophenyl ketones and alcohols (the 2nd equation) have been also carried out using a catalyst combination of RuCl

2(dmso)

4/tBuOK/Ph

2CO [11 g]. It has been also reported that the modified

Friedländer reactions of 2-aminobenzyl alcohol with various alcohols (the 3rd equation) are conducted using catalyst combinations of RuCl

2(PPh

3)

3/KOH/1-

dodecene in dixoane [11 h], RuCl2(dmso)

4/KOH/Ph

2CO in dioxane [6b], and

RuCl2(dmso)

4/tBuOK/Ph

2CO [11 g].

10.2.5 transfer Hydrogenative c–c Bond-Forming coupling between alcohols and unsaturated c–c Bond-containing compounds

It has been reported that unsaturated compounds such as allenes, 1,3-dienes, 1,3-enynes, and alkynes can be coupled with primary alcohols to give homoallylic, homopropargylic, and allylic alcohols (Scheme 10.17) [12a–12c]. In these protocols, metal-catalyzed dehydrogenative oxidation of primary alcohols takes place to give aldehydes with concomitant formation of metal hydride species, which then give organometallic species through hydrometalation of unsaturated compounds. The subsequent addition of allylic, allenic, and vinylic metal nucleophiles to the resulting

R•

R+

Cat. [M]

Cat. [M]

Cat. [M]

Cat. [M]

Cat. [M]

Cat. [M]

RR+

OH

RR+

OHOH

OH

R

O

[M]

R

O+

R

O

[M]+

OH OH

[M]

H

H

H

H

H

H

+ [H–M]•

R

O+ Carbonyl

addition

Carbonyladdition

Carbonyladdition

Dehydrogenation

R

O+ [H–M]

R

O+ [H–M]

Hydro-metalation

Hydro-metalation

Hydro-metalation

Dehydrogenation

Dehydrogenation

scHeme 10.17


aldehyde electrophiles affords carbon–carbon bond-forming coupling products without any coproducts. Thus, these protocols are initiated by dehydrogenative oxidation of alcohols and require no oxidant or hydrogen donor.

It should be noted that the analogous carbon–carbon bond-forming coupling of aldehydes and the unsaturated C–C bond-containing compounds, so-called hydroac-ylation, has been also achieved under H

2 or in the presence of an excess amount of

2-propanol as a hydrogen source in all of aforementioned transformations [12d, 12e], though these protocols are not discussed here.

10.2.5.1 Transfer Hydrogenative C–C Bond-Forming Coupling of Primary Alcohols and AllenesIr Complex with (P,P)-Chelating Ligand It has been reported that a cationic iridium complex (6) bearing diphosphine [BIPHEP, 2,2′-bis(diphenylphosphino)biphenyl] ligand catalyzes transfer hydrogenative coupling of primary alcohols and allenes [13a]. The reactions were carried out in the presence of Cs

2CO

3. Several examples

are shown in Table 10.5. 1,1-Dimethylallene and 1-methylallene reacted with primary alcohols at more hindered positions to give reverse prenylation and crotylation prod-ucts in good to high yields.

(Allyl)Ir Complex with (C,O)- and (P,P)-Chelating Ligands The transfer hydroge-native C–C coupling of methanol and allenes has been achieved by using cyclometa-lated (π-allyl)Ir complexes (7) bearing (C,O)-chelating benzoate and diphosphine ligands [13b]. The reactions of methanol (15 equiv) with 1,1′-disubstituted allenes were conducted without any base in toluene. Some examples are shown in Table 10.6. Among the complexes, 7d exhibited the highest catalytic activity. The coupling reac-tion of methanol and various 1,1′-disubstituted allenes afforded the corresponding homoallylic neopentyl alcohols in modest yields.

Cat. 6 (5–10 mol%),Cs2CO3 (5–10 mol%)

ClCH2CH2Cl/EtOAc (1:1), 75 °C

Entry

12345

a PhthN = phtalimido.

R1

4-NO2C6H4Ph

PhthNCH2a

4-NO2C6H44-MeOC6H4

Yield (%)

9290848272

Time (h)

1516.5151414

•R1

+OH R2

R3 R1

OH

R2 R3

PPh2

PPh2

Ir(cod)

[BArf4]

(Arf = 3,5-(CF3)2C6H3)

6

R2 R3

MeMeMeMeMe

MeMeMeHH

taBle 10.5 Transfer hydrogenative coupling of primary alcohols and allenes catalyzed by 6.


A possible mechanism is proposed for the transfer hydrogenative coupling of methanol and allenes (Scheme 10.18) [13b]. The catalytic cycle would start by meth-anolysis of the π-allyl moiety of the complex 7d to form an Ir methoxide complex with concomitant release of 1-propene. β-Hydrogen elimination of the complex could produce a transient Ir hydride complex and formaldehyde. Hydrometalation of allene with the Ir hydride complex would produce an Ir-allyl species, which subse-quently adds to formaldehyde to give an 18-electron Ir homoallylalkoxide complex. Finally, the alkoxide moiety could be replaced with methanol to generate the starting catalytic species. Deuterium-labeling experiments suggest that the dehydrogenative oxidation of methanol is the turnover-limiting step in the present catalytic cycle.

Cat. 7 (5 mol%)


Entry

1

2

3

4

5

6

a PhthN = phtalimido.

Yield (%)

39

37

44

67

64

70

•+R1 OH

R1

7a: BIPHEP7b: BIPHEP7c: BIPHEP7d: DPPF

R2

Me

Me

Me

Me

C3H7

Me

Cat.

7a

7b

7c

7d

7d

7d

CH3OHR2

R2Ir

P

PO

O

X

NO2

P P XH

OMeClCl

R1

4-MeOC6H4CH2O

4-MeOC6H4CH2O

4-MeOC6H4CH2O

4-MeOC6H4CH2O

4-MeOC6H4CH2O

PhthNa

taBle 10.6 Transfer hydrogenative coupling of methanol and 1,1-disubstituted allenes catalyzed by 7.

•R

RR R

OIr

O

P POCH3

NO2

ClO

Ir

O

P P H

NO2

Cl

OIr

O

P P

NO2

Cl

R

ROIr

O

P P

NO2

Cl

OR

R18-electron complex

7d

OH

HOH

Hydrometallation

Carbonyl addition

CH3OH

CH3OH


scHeme 10.18


Asymmetric version of the transfer hydrogenative C–C coupling of primary alcohols and allenes has been also accomplished by using a similar cyclometalated (π-allyl)iridium complex bearing chiral diphosphine ligands [13c].

Other Catalyst Systems It has been reported that the transfer hydrogenative C–C coupling of primary alcohols and allenamides is catalyzed by a catalyst combination of RuHCl(CO)(PPh

3)

3/DPPF in THF [13d].

10.2.5.2 Transfer Hydrogenative C–C Bond-Forming Coupling of Primary Alcohols and 1,3-Dienes and 1,3-Enynes It has been reported that coupling of pri-mary alcohols and 1,3-butadienes is carried out using a catalyst combination of RuHCl(CO)(PPh

3)

3/(4-MeOC

6H

4)

3P or rac-BINAP/Me

2CO/3-NO

2C

6H

4CO

2H to give

homoallylic alcohols (Scheme 10.19) [14a]. In the reaction with isoprene, the cou-pling occurred at the less the hindered C∙C double bond.

The transfer hydrogenative coupling of ethanol and 2-substituted 1,3-butadienes was conducted using a catalyst combination of RuH

2(PPh

3)/DPPB/C

7F

15CO

2H to

afford more crowded homoallylic alcohols having quaternary carbon centers selec-tively (Scheme 10.20) [14b]. It should be also noted that the anti-selectivity is high (>17:1) in most of the reactions.

It has been also reported that β,γ-unsaturated ketones are obtained in the transfer hydrogenative coupling of primary alcohols and 1,3-butadienes when a catalyst combination of RuH

2(CO)(PPh

3)

3/CF

3CO

2H is employed (Scheme 10.21) [14c].

Similarly, the transfer hydrogenative coupling of primary alcohols and 4-substi-tuted 1-buten-3-yne derivatives is catalyzed by a catalyst combination of RuHCl(CO)-(PPh

3)

3/DPPF to give homopropargylic alcohols (Scheme 10.22) [14d].

It has been reported that the transfer hydrogenative coupling of primary alcohols and 1,3-cyclohexadiene is conducted using a catalyst combination of [Ir(cod)Cl]

2/

R+

OH

OH

R1

R2

RuHCl(CO)(PPh3)3 (5 mol%)(4-MeOC6H4)3P (15 mol%) or

rac-BINAP (5 mol%)

Y = 61–93%

R2R1

R1Me2CO (2.5 mol%)

3-NO2C6H4CO2H (2.5 mol%)THF, 95–110 °C

scHeme 10.19

+OHR

R(Solvent)

MajorY = 58–78%

High anti-selectivity

OH R+

Minor

OHRuH2(CO)(PPh3)3 (5 mol%)DPPB (5 mol%)

C7F15CO2H (5 mol%)EtOH-Me2CO (1:1)

80–100 °C

scHeme 10.20


BIPHEP/Bu4NI to give regioselectively homoallylic alcohols as single diastereomers

(Scheme 10.23) [14e].

(Allyl)Ir Complexes with (C,O)- and (P,P)-Chelating Ligands The transfer hydro-genative C–C coupling of primary alcohols and 1,3-butadienes has been achieved by using the cyclometalated (π-allyl)Ir complexes 7a–7c, which are employed in the coupling reaction of alcohols and allenes (Section 10.2.5.1, Table 10.6) [14f]. The reactions were carried out in the presence of equimolar amount of base. Some examples are shown in Table 10.7. Among the complexes and bases examined, 7b exhibited the highest catalytic activity in the presence of NaOAc. Although the regio-selectivity was very high in each case, mixtures of syn- and anti-diastereomers were produced.

10.2.5.3 Transfer Hydrogenative C–C Bond-Forming Coupling of Primary Alcohols and α,β-Unsaturated Aldehydes It has been reported that the carbon–carbon bond-forming coupling of primary alcohols and α,β-unsaturated aldehydes is achieved by using RuHCl(CO)(PPh

3)

3 as a catalyst in the presence of catalytic

amount of the corresponding aldehydes to give 2-hydroxymethyl ketones (Scheme 10.24) [14 g].

R+

O

R OHR1 R2

R1

R2

Toluene, 110 °C

Y = 62–98%

RuH2(CO)(PPh3)3 (5 mol%)CF3CO2H (5 mol%)

scHeme 10.21

R+

OH

R OH

RuHCl(CO)(PPh3)3 (5 mol%)DPPF (5 mol%)

THF, 95 °C

R1R1

Y = 42–94%

scHeme 10.22

+R OH R

OH

R

OH

+

Major Minor

[Ir(cod)Cl]2 (3.75 mol%)BIPHP (7.5 mol%)

Bu4NI (10 mol%)ClCH2CH2Cl, 65 °C

Y = 61–95%Major : Minor = 5–15 : 1

syn : anti >95 : 5

scHeme 10.23


10.2.5.4 Transfer Hydrogenative C–C Bond-Forming Coupling of Primary Alcohols and Alkynes The carbon–carbon bond-forming coupling of primary alcohols and alkynes has been catalyzed by RhH(O

2CCF

3)

2(CO)(PPh

3)

2 in the

presence of 2-propanol to give allylic alcohols selectively (Scheme 10.25, the 1st equation) [15a]. On the other hand, the reactions without 2-propanol predominately afford hydroacylation products, α,β-unsaturated ketones (the 2nd equation) [15b].

It has been reported that the carbon–carbon bond-forming coupling of primary alcohols and 1-aryl-1-propynes is conducted using a catalyst combination of [Ir(OH)(cod)]

2/P(C

8H

17)

3 to give anti-isomeric homoallylic alcohols exclusively

(Scheme 10.26, the 1st equation) [15c]. The terminal methyl group is indispensable

Cat. 7 (5 mol%), base (100 mol%)


Entry

123456

Yield (%)

576280828664

+

R

NaHCO3NaHCO3NaOAcNaOAcNaOAcNaOAc

Cat.

7a7b7b7b7b7b

Base

4-MeOCOC6H44-MeOCOC6H44-MeOCOC6H44-MeCOC6H4

4-CF3C6H4PhCH = CH

R

OH OH

R

taBle 10.7 Transfer hydrogenative coupling of primary alcohols and 1,3-butadiene catalyzed by 7.

+R1 OH Benzene, re�ux, 2 hR2 H

O

R1

O OH

R2Y = 30–72%

RuHCl(CO)(PPh3)3 (10 mol%)R1CHO (10 mol%)

scHeme 10.24

OH R3 +

+ R2

+ R2R1

OHR1 R3

THF, 110 °C, 30 hY = 70–99%

Y = 61–81%

R1 R3

OH

R2R1 R3

O

R2

Y = 1–14%

R1 R3

O

R2

Ru(O2CCF3)(CO)(PPh3)2 (5 mol%)

Ru(O2CCF3)(CO)(PPh3)2(5 mol%)

2-Propanol (200 mol%)THF, 95 °C, 9–18 h

scHeme 10.25


for the reaction to proceed. Similar reactions using a catalyst combination of [Ir(cod)Cl]

2/P(C

8H

17)

3 give hydroacylation products in highly regioselective manner

(the 2nd equation) [15d].

10.2.5.5 Transfer Hydrogenative C–C Bond-Forming Coupling of Primary Alcohols and Allyl Acetate It has been reported that the C–C bond-forming cou-pling of benzylic alcohols and allyl acetates is achieved using a catalyst combination of [Ir(cod)Cl]

2/BIPHP in the presence of Cs

2CO

3 and 3-NO

2C

6H

4CO

2H to afford

homoallylic alcohols (Scheme 10.27) [16a, 16c]. The asymmetric coupling reactions of a variety of primary alcohols with allylic acetates have been also extensively studied using chiral diphosphine ligands [16].

10.2.6 alkylation of cyclic amines with aldehydes and alcohols

Ru Complexes with (P,O)-Chelating Ligands It has been reported that (p-cymene)-Ru complexes (8a and 8b) bearing bidentate phosphinobenzenesulfonate ligands catalyze alkylation of cyclic tert-amines with aldehydes to afford C(3)-substituted cyclic amines [17a]. Since the complex 8b was superior to 8a in the selectivity, the reactions were carried out using 8b as the catalyst in the presence of camphorsul-fonic acid (CSA) and, then, HCO

2H was added as hydrogen source to complete

transfer hydrogenation. Examples are shown in Table 10.8. Various cyclic 5-, 6-, and 7-membered amines were alkylated with aldehydes at the C3-positions to give the alkylated products in good to high yields.

The complex 8b also catalyzed the alkylation of cyclic amines with primary alcohols to afford N- and C(3)-dialkylated cyclic amines [17b]. The reactions were

R OH + Ar

+R1 OH R2 Me

Me

Y = 34–94%

Y = 65–100%

R

OH

Ar



R1

O

R2

[Ir(cod)Cl]2 (5 mol%)P(C8H17)3 (20 mol%)

[Ir(OH)(cod)]2 (5 mol%)P(C8H17)3 (30 mol%)

scHeme 10.26

Ar OH +

Y = 80–85%

Ar

OHOAc

R RCs2CO3 (20 mol%)

3-NO2C6H4CO2H (10 mol%)THF, 100 °C, 20 h

[Ir(cod)Cl]2 (2.5 mol%)BIPHEP (5 mol%)

scHeme 10.27


conducted in the presence of CSA in toluene at 150 °C for 16 h. A few examples are shown in Table 10.9. When the complex 8a was used, the N-alkylated product was formed selectively.

10.3 carBon–nitrogen Bond-Forming reactions Based on Hydrogen transFer

Carbon–nitrogen bond-forming reactions have been extensively studied in organic synthesis since nitrogen-containing organic compounds such as amines, amides, and sulfonamides, etc. are key functional groups in biomolecules, biologically active compounds, pharmaceuticals, agrochemicals, and a variety of industrial chemicals. There have been many synthetic methods for carbon–nitrogen bond formation, for example, alkylation of amines with alkyl halides or sulfonates, reductive amination of carbonyl compounds, coupling reactions of amines with alkyl halides or sulfonates, etc. Recently, carbon–nitrogen bond-forming reactions based on hydrogen transfer process (so-called redox neutral, borrowing hydrogen, or hydrogen autotransfer)

+N

R1

R2CHON

R1

R21) Cat. 8b (2 mol%), CSA (6–10 mol%), Toluene, 140 °C, 16 h

2) HCO2H (1.5 equiv), 140 °C, 1 h

NBn

Ph

NBn

Ph

NBn

PhNBn

C6H13

NCH2Bn

O

p-cymene

RuP O

Cl

SO2

Y = 89%Y = 88%

Y = 72% Y = 70% Y = 86%

Ph

R

8a: R = Ph8b: R = tBu

taBle 10.8 C(3)-Alkylation of cyclic tertiary amines with aldehydes catalyzed by 8b.

+

N

H

ArCH2OHN

CH2Ar

ArCat. 8b (1.5 mol%)CSA (20–40 mol%)


N

CH2Ph

N

CH2Ph

NPh

CH2Ph CH2Ph CH2PhY = 80% Y = 71% Y = 68%

taBle 10.9 N- and C(3)-Dialkylation of cyclic amines with benzylic alcohols catalyzed by 8b.

CARBON–NITROGEN BOND-FORMING REACTIONS 297

have been attracting considerable attention from environmental points of view and green chemistry, and many reviews on these subjects have appeared [1, 10b, 18].

10.3.1 n-alkylation of amines with alcohols

General catalytic cycle for the N-alkylation of amines with alcohols via hydrogen transfer process consists of the three cascade reactions: (1) [M]-catalyzed dehydro-genation (or β-hydrogen elimination) of an alcohol to give a carbonyl compound and a metal hydride species ([MH

2] or [MH]), (2) formation of an imine (or an

iminium ion) by condensation of the carbonyl compound and an amine, and (3) hydrogenation (or hydrometalation) of the imine (or the iminium ion) by the tran-siently generated metal hydride species (Scheme 10.28). Thus, any oxidant or reductant is not required (the metal catalyst [M] carries out hydrogen transfer two times, i.e., accepts and donates hydrogen). Thus, this protocol avoids using harmful alkyl halides as alkylating agent and produces only water as coproduct, providing environmentally benign and highly atom-economical synthetic methods for amines.

10.3.1.1 Formation of Secondary and Tertiary Amines by the Intermolecular N-AlkylationSimple Ru Complexes There have been many reports on the ruthenium-catalyzed N-alkylation of amines with alcohols before 2000 under relatively harsh reaction conditions (see reviews), and after 2000, various catalyst combinations of Ru complexes/ligands have been used in almost all cases. Therefore, a brief summary of the catalytic systems is described in the following (Scheme 10.29). The catalyst combinations of Ru complexes/ligands are [(p-cymene)RuCl

2]

2/DPPF/K

2CO

3, 3 Å

MS [19a], [(p-cymene)RuCl2]

2/DPPF, MS 3 Å [19b], [(p-cymene)RuCl

2]

2/DPPF or

DPEphos (bis(2-diphenylphosphinophenyl)ether) [19c,19d], [(p-cymene)RuCl2]

2/

DPEphos under MW without solvent [19e], Ru3(CO)

12/P(1-adamantyl)

2Bu or P(2-

MeC6H

4)

3 [19f], Ru

3(CO)

12/CataCXium® PCy (N-phenyl-2-(dicyclohexylphosphino)

R1 OH

R1 R1

R1

R2

R2

O N

NH

Cat. [M]

Cat. [MH2] or [MH]



Condensation

Carbonylcompounds

Imines

H H

R2–NH2

R2 – NH2

H2O

–H2O

scHeme 10.28


pyrrole) without or with solvent [19 g–19i], and Ru3(CO)

12/DCPE (DCPE = 1,2-bis(d

icyclohexylphosphino)ethane) [19j].It has been also reported that CpRuCl(PPh

3)

2 catalyzes the N-methylation of

amines using methanol as a solvent at 100 °C [19 k] and that [RuCl(PPh3)

2(CH

3CN)

3]

[BPh4] catalyzes the selective monoalkylation of anilines with primary alcohols used

as solvents in the presence of K2CO

3 [19 l]. It should be noted that a catalyst

combination of RuCl3 · 3H

2O/DPPF catalyzes N-alkylation of aliphatic tert-amines

with alcohols in chlorobenzene at 145 °C [19 m].

Ru Complex with (P,O)-Chelating Ligand The (p-cymene)Ru complex (8a) bearing bidentate phosphinobenzenesulfonate ligands (Section 10.2.6, Table 10.8) has been reported to catalyze reductive N-alkylation of amines with allylic alcohols in the presence of HCO

2H as a hydrogen donor [20]. The reactions were carried out in the

presence of slight excess of HCO2H to give N-alkylated amines. Several examples

are shown in Table 10.10. It should be noted that the isolated C = C bond was hydro-genated in less than 10% yield.

R1 OH

Cat. [Ru]/ligand

Cat. [Ru]/ligand

R2

R1 NR3 + H2O

R2

R4

+ HNR3

R4

NPh

PCy2

[(p-cymene)RuCl2]2/DPPF/K2CO3, MS, 3Å re�ux, 24 h in toluene[(p-cymene)RuCl2]2/DPPF or DPEphos, re�ux, 24 h in toluene

[(p-cymene)RuCl2]2/DPEphos, 115 °C, 90 min, under MWRu3(CO)12/P(1-adamantyl)2Bu or P(2-MeC6H4)3, 110 °C, 24 h

Ru3(CO)12/CataCXium® PCy, 110–120 °C, 24 hRu3(CO)12/CataCXium® PCy, 120–140 °C, 24 h in t-amyl alcohol

Ru3(CO)12/DCPE, 160 °C, 24 h in t-amyl alcohol

CataCXium® PCy

scHeme 10.29

+ R2R3NH

Cat. 8a (5 mol%)HCO2H (1.1 equiv)

Toluene, 150 °C, 15 hR1 OH R1 NR2R3

Ph N Ph N Ph NPh NEtPh

NEtPh

Y = 82% Y = 59% Y = 77%Y = 87%

Y = 64%Y = 57%

N

taBle 10.10 N-Alkylation of amines with allylic alcohols catalyzed by 8a.


Simple Ir Complexes Since a catalyst combination of [Cp*IrCl2]

2/base was found

to be very effective for the N-alkylation of amines with alcohols, many reactions using this catalyst combination have been reported (Scheme 10.30). Firstly, a cata-lyst combination of [Cp*IrCl

2]

2/K

2CO

3 was used for the N-alkylation of primary

amines with primary and secondary alcohols [21a]. Later, more effective combination of [Cp*IrCl

2]

2/NaHCO

3 was developed for the N-alkylation of various primary and

secondary amines with various primary and secondary alcohols [21b]. The N-alkylation of carbohydrate amines with carbohydrate alcohols for aminosugar synthesis was achieved by a catalyst combination of [Cp*IrCl

2]

2/CsCO

3 [21c]. A

catalyst combination of [Cp*IrCl2]

2/NaHCO

3 in the presence of H

2O was used for

the kilogram-scale synthesis of a GlyT1 inhibitor, and catalyst combinations of [Cp*IrCl

2]

2/tert-amines (such as N-methylpyrrolidine, 1,4-dimethylpiperazine,

TMEDA, and DABCO) were also effective for the usual N-alkylation [21d]. Direct N-alkylation of aminoazoles with primary alcohols was conducted by using a cata-lyst combination of [Cp*IrCl

2]

2/NaOH without solvent [21e]. Furthermore, che-

moselective N-alkylation of 2′-aminoacetophenones with primary alcohols was achieved by a catalyst combination of [Cp*IrCl

2]

2/K

2CO

3 under MW irradiation [3i].

It was also reported that [Cp*IrCl2]

2 catalyzed the N-alkylation of amines with

alcohols under MW irradiation without base [21f]. The N-alkylation of amines with alcohols was also conducted by a catalyst combination of [Ir(cod)Cl]

2/DPPF [21 g].

It has been reported that the N-alkylation of amines with alcohols in H2O is cata-

lyzed by [Cp*IrI2]

2 without base [21 h]. The catalytic systems were mainly effective

for the N-alkylation of the primary amines to give the secondary amines (Scheme 10.31, the 1st equation). When the secondary amines were used as the sub-strates, use of an ionic liquid [BMIM]PF

6 (BMIM = 1-butyl-3-methylimidazolium)

as a solvent gave the better results (the 2nd equation) [21i].Mechanistic investigations on the [Cp*IrCl

2]

2-catalyzed N-alkylation of amines

with alcohols have been also reported. DFT studies have suggested that Cp*Ir(CO3),

generated by reaction of [Cp*IrCl2]

2 with K

2CO

3, is the active species for the dehy-

drogenation of alcohols and the hydrogenation of imines and that dissociation of amine to regenerate the active species is the rate-determining step [21j]. The kinetic experiments and DFT calculations have indicated that the entire catalytic cycle

R1 OH

R2

R1 NR3 + H2O

R2

R4

+ HNR3

R4

Cat. [Cp*IrCl2]2/base[Cp*IrCl2]2/K2CO3, 90–110 °C, 17–48 h in toluene

[Cp*IrCl2]2/NaHCO3, 110 °C, 17 h in toluene[Cp*IrCl2]2/Cs2CO3, 120 °C, 24–48 h in toluene[Cp*IrCl2]2/tert-amine, 115 °C, 16 h in toluene

[Cp*IrCl2]2/NaOH, 150 °C, 12 h[Cp*IrCl2]2/K2CO3, 140 °C, 1 h under MW

Cat. [Cp*IrCl2]2/base

scHeme 10.30


(dehydrogenation of an alcohol, formation of an imine, and hydrogenation of the imine) takes place within the coordination sphere of the metal center [21 k].

Ir Complexes with (P,N)-Chelating Ligands It has been reported that iridium complexes (9) bearing N-phosphino-2,2′-dipyridylamine ligands are synthesized and catalyze the N-alkylation of aromatic amines with primary alcohols [22a]. The com-plex 9b exhibited higher catalytic activity than 9a. The reactions were conducted using 9b prepared in situ in the presence of an equimolar amount of tBuOK in diglyme. Some examples are shown in Table 10.11. The reactions of anilines and aminopyridines with various primary alcohols proceeded in good to excellent yields.

The same catalytic system was effective for the N,N′-dialkylation of 2,6-diamino-pyridine with benzylic and aliphatic primary alcohols (Scheme 10.32) [22b].

The N-alkylation of 2-aminopyridine or anilines with a variety of amino alcohols was also achieved by the similar catalytic system as the aforementioned except for the use of tBuONa to give diamine products (Scheme 10.33) [22c].

It has been reported that iridium(I) complexes (10) bearing anionic N-phosphino-2-amidopyridine ligands are synthesized and used as catalysts for the N-alkylation

R1 OH

R2

R1 NH

R3 + H2O

R2

+ R3–NH2

Y = 60–98%

Y = 38–100%

R1 OH R1 NR2

R3

+ HNR2

R3 [BMIM]PF6, 110 °C3–24 h

[Cp*IrI2]2 (1 mol%)

[Cp*IrI2]2 (1 mol%)

H2O, 115 °C, 10 h

+ H2O

scHeme 10.31

R1 OH +

[Ir(cod)Cl]2 (1 mol%)Py2 NP(iPr)2 (2 mol%)

tBuOK (110 mol%)

Diglyme, 110 °C, 17 h X

Y

HN R1

XY

NH2R2 R2

N N NR2P Ir(cod)Cl

9a: R = Cy9b: R = iPr

X = C; Y = C, NX = N; Y = C

Product Yield (%) Product

92979697

71

63

Yield (%)

PhNHCH2Ph4-MeOC6H4NHCH2Ph

3-ClC6H4NHCH2Ph3-PyNHCH2Ph

2-PyHN

O

2-PyNHMe

taBle 10.11 N-Alkylation of aromatic amines with primary alcohols catalyzed by 9b prepared in situ.


of anilines with primary alcohols under mild conditions [22d]. The shorter Ir–N and P–N bond lengths observed in the X-ray analysis of 10a than those of the sim-ilar neutral complex 9b indicate that anionic charge is delocalized over the P–N–C–N backbone. The reactions were carried out using the most active complex 10c in the presence of an equimolar amount of tBuOK at 70 °C. A few examples are shown in Table 10.12, and the complex 10c exhibited much higher activity than the complex 9b.

The complex 10c also catalyzed the N,N′-dialkylation of diaminobenzenes and 4,4′-sulfonyldianiline with a variety of primary alcohols (Scheme 10.34) [22e].

Cp*Ir Complex with (S, S, S)-Chelating Ligand The Cp*Ir complex 5, which exhibited the high catalytic activity for the β-alkylation of 1-phenylethanol with pri-mary alcohols (Section 10.2.2.2, Table 10.4), also catalyzed the N-alkylation of amines with primary alcohols [7e]. The reactions were conducted in the presence of

R1 OH+

NH2N NH2

NNH

NH

R1R1

Y = 82–97%

[Ir(cod)Cl]2 (0.3–0.7 mol%)Py2NP(iPr)2 (0.6–1.4 mol%)

tBuOK (220 mol%)

Diglyme, THF 70 °C, 48 h

scHeme 10.32

NH2

NH

NH

Y = 70–93%

2-Py

Py-2

R2R1

NH2

R1 R2

+RC6H5NH2

RC6H4 NH2

Y = 63–86%

NH2

HO

HO

HO

+2-PyNH2

Y = 71–91%

NH2(n = 0, 1, 4)

n

NH2nDiglyme, THF110 °C, 24 h

Diglyme, THF110 °C, 24 h

Diglyme, THF110 °C, 24 h

[Ir(cod)Cl]2 (0.5 mol%)Py2NP(iPr)2 (1.0 mol%)

tBuONa (110 mol%)

[Ir(cod)Cl]2 (2–2.5 mol%)Py2NP(iPr)2 (4–5 mol%)

tBuONa (110 mol%)

[Ir(cod)Cl]2 (0.5 mol%)Py2NP(iPr)2 (1.0 mol%)

tBuONa (110 mol%)+

2-PyNH2

NH

scHeme 10.33


equimolar amount of KOH, although the major products were the corresponding imines, except for the reaction of aniline (Scheme 10.35).

Cp*Ir Complexes with Tri(NH3) Ligands It has been reported that cationic Cp*Ir

complexes (11) bearing triammine ligands effectively catalyze the N-alkylation of amines with alcohols in H

2O without base [22f]. The complexes 11 were originally

synthesized and utilized for the N-alkylation of aqueous ammonia with alcohols (Section 10.3.3.1, Table 10.14). The reactions were carried out by using the most active complex 11c in H

2O under reflux. Some examples are shown in Table 10.13. A variety

of primary and secondary amines were alkylated with various primary and secondary alcohols to give the corresponding secondary and tertiary amines in good to high yields.

R1 OH +Cat. 10c, tBuOK (110 mol%)

Diglyme, 70 °C, 24 h R2C6H4

HN R1

N NR1

2P Ir(cod)

10a: R1 = iPr, R2 = H10b: R1 = Ph, R2 = H10c: R1 = Ph, R2 = Me10d: R1 = Ph, R2 = Cl

Product Yield (%)

PhNHCH2Ph4-MeCO6H4NHCH2Ph

4-ClC6H4NHCH2PhPhNH(CH2)4CH3

R2

Entry Cat. 10c (mol%)

1234

0.10.20.050.2

92929898

R2C6H4NH2

taBle 10.12 N-Alkylation of anilines with primary alcohols catalyzed by 10c.

Y = 42–99%

O2S

HN NH

CH2R RCH2Y = 50–98%

RCH2NHC6H4NHCH2R

RCH2OH + (4-NH2C6H4)2SO2

RCH2OH + C6H4(NH2)2Diglyme, 70 °C, 24 h

Diglyme, 70 °C, 48 h

Cat. 10c (1–3 mol%)tBuOK (220 mol%)

Cat. 10c (1–4 mol%)tBuOK (220 mol%)

scHeme 10.34

R1 OH NR1Toluene, 110 °C, 45 h

++ R2–NH2R2

NH

R1R2

MajorMinor

Y = 36–85%

Cat. 5 (1 mol%)KOH (100 mol%)

scHeme 10.35


Furthermore, recycle use of the complex 11c was also achieved by a simple phase separation and the reactions proceeded at least three times in high yields (Scheme 10.36).

Other Catalytic Systems Several catalyst combinations of metal salts and bases have been reported: Cu(OAc)

2/tBuOK [23a, 23b], CuCl

2/NaOH [23c], and Pd(OAc)

2/

CsOH [23d].

10.3.2 synthesis of nitrogen Heterocycles through n-alkylation of amines with alcohols

This section is focused on the recent development of synthesis of nitrogen heterocy-clic compounds through N-alkylation of amines with alcohols [10b].

10.3.2.1 N-Heterocyclization of Amino Alcohols It has been reported that the intramolecular N-alkylation of a variety of amino alcohols is catalyzed by [Cp*IrCl

2]

2/

K2CO

3 to give indoles, 1,2,3,4-tetrahydroquinolines, and 2,3,4,5-tetrahydro-1-ben-

zazepine, respectively, in good to excellent yields (Scheme 10.37, the 1st and 2nd equations) [24a]. It is worth noting that the N-alkylation of 2-aminophenethyl alcohols catalyzed by [Cp*IrCl

2]

2/KOH in the presence of primary alcohols affords

3-substituted indoles through the intramolecular cyclization followed by the

R1 OH+

Cat. 11c (1.0–3.0 mol%)R2

R1 NR3

R2

R4

IrH3N

Cp*

NH3

NH3

11a: X = Cl11b: X = Br11c: X = I

H2O, re�ux, 6–24 h

Entry

1234567

R1

Ph2-MeOC6H4

4-BrC6H4C7H15

C6H13C5H11

92909089939382

Time (h)

666666

14

R2 R3 R4 Yield (%)

HHHH

MeH

PhPhPhPhPh

4-MeOC6H4C6H13

HHHHHH

C6H13

R3HN

R4

–(CH2)5–

[X]2

taBle 10.13 N-Alkylation of amines with alcohols catalyzed by 11c in H2O.

R1 OH +Cat. 11c (1.0 mol%)

R1 NH

R2

H2O, re�ux, 6 hR2–NH2

R1 = Ph, R2 = PhR1 = 4-MeOC6H4, R2 =Ph

Y = 98% (1st), 95% (2nd), 90% (3rd)Y = 96% (1st), 92% (2nd), 88% (3rd)

scHeme 10.36


intermolecular C–C bond formation of the resulting indoles with primary alcohols (see Section 10.2.3) (the 3rd equation) [9a].

N-Heterocyclization of anilino alcohols was catalyzed by [Cp*IrCl2]

2/K

2CO

3 to

give 1,2,3,4-tetrahydroquinoxalines (Scheme 10.38, the 1st equation) [24b]. The seven-membered diazepine derivative was also prepared. It has been reported that N-alkylative homocoupling of N-benzylethanolamines is catalyzed by [Cp*IrCl

2]

2/

NaHCO3 to give N,N′-dibenzylpiperazines in moderate yields (the 2nd equation) [24c].

10.3.2.2 N-Heterocyclization of Primary Amines with Diols When 1,4-, 1,5-, and 1,6-diols are employed in the N-alkylation of primary amines, successive inter- and intramolecular N-alkylations proceed to afford 5-, 6-, and 7-membered nitrogen heterocycles.

Ru Complexes A couple of catalyst combinations of Ru complex/ligand used in the intermolecular N-alkylation (Section 10.3.1.1) have been also employed in the

[Cp*IrCl2]2 (2.5 mol%)K2CO3 (10 mol%)


Y = 73–99%

Y = 54–96%

OH

R1

R2

NH2NH

R1R2

R1

NH2

OH

R2

n

[Cp*IrCl2]2 (2.5 mol%)K2CO3 (10 mol%)

Toluene, re�ux, 20 hR1

NH

n

R2(n = 1, 2)



R2

R1

NH2NH

R1OH R3 OH+

R3

R2

Y = 53–75%

scHeme 10.37

Y = 42–84%

MeN

R1

NH2

OH[Cp*IrCl2]2 (20 mol%)

K2CO3 (20 mol%)

Toluene, 110 °C, 1–3 days

MeN

R1

NH

R2 R2

R2

R2

Y = 45–66%

HN

OH

[Cp*IrCl2]2 (2.5 mol%)NaHCO3 (15 mol%)


ArN N

Ar

Ar

scHeme 10.38


N-heterocyclization: [(p-cymene)RuCl2]

2/DPPF/K

2CO

3 [19a], [(p-cymene)RuCl

2]

2/

DPEphos/Et3N [19c], and [(p-cymene)RuCl

2]

2/DPEphos under MW [19e]

(Scheme 10.39).N-Heterocyclization of primary amines with 1,4-alkynediols has been accom-

plished by a catalyst combination of RuH2(CO)(PPh

3)

3/Xantphos to afford various

2,6-disubstituted pyrroles in moderate to high yields (Scheme 10.40) [25].

Ir Complexes Catalyst combinations of [Cp*IrCl2]

2/base have been employed for

the N-heterocyclization of primary amines with diols (Scheme 10.41). A variety of 5-, 6-, and 7-membered nitrogen heterocycles were synthesized by a catalyst combination of [Cp*IrCl

2]

2/NaHCO

3 [26a, 26b]. Similarly, the reactions of optically

active 1-phenylethylamine with 1-substituted 1,5-pentanediol were conducted by a catalyst combination of [Cp*IrCl

2]

2/KOAc to afford 2-substituted piperidines

Cat. [Ru]/ligandN R2 + 2H2O

n

R1

(n = 1–3)

Cat. [Ru]/ligand[(p-cymene)RuCl2]2/DPPF, K2CO3, MS 3Å, re�ux, 24 h in toluene

[(p-cymene)RuCl2]2/DPEphos, Et3N, re�ux, 24 h in toluene[(p-cymene)RuCl2]2/DPEphos,135 °C, 90 min, under MW

OH

OHn

R1 + H2N R2

scHeme 10.39

+ H2N–R3HO

OHR1

R2

NR1 R2

R3



Y = 62–100%

scHeme 10.40

[Cp*IrCl2]2 (0.5–2.5 mol%)NaHCO3 (1–5 mol%)

+ N R2

n

R1

(n = 1–3)

OH

OHn

R1 H2N R2


[Cp*IrCl2]2 (1.5 mol%)KOAc (6 mol%)

+OHToluene, 100–110 °C, 17 h

OH

Ar

NH2

PhNAr

PhY = 76, 72% (92, 90% de)

Y = 63–94%

scHeme 10.41


with high diastereoselectivity [26a, 26c]. In addition, the N-heterocyclization of benzylamines with diols was catalyzed by [Cp*IrCl

2]

2 under MW without base

[21f], and the N-heterocyclization of tryptamine with diols was catalyzed by a cata-lyst combination of [Ir(cod)Cl]

2/DPPF [21 g].

Furthermore, the N-heterocyclization of primary amines with diols in water has been accomplished by using [Cp*IrI

2]

2 or [Cp*Ir(NH

3)

3]I

2 (11c) (Scheme 10.42) [21i, 22f].

10.3.2.3 N-Heterocyclization of Diamines with 1,2-Diols or α-Hydroxy Ketones Synthesis of quinoxalines was performed by the Pd(OAc)

2-catalyzed

N-heterocyclization of 1,2-diaminobenzenes with α-hydroxy ketones in the presence of Et

3N and THF under air (Scheme 10.43, the 1st equation) [27a]. It was also

reported that RuCl2(PPh

3)

3 with excess amounts of KOH (400 mol%) and benzalac-

etone (200 mol%) catalyzed N-heterocyclization of 1,2-diaminobenzenes with 1,2-diols to give a variety of quinoxalines (the 2nd equation) [27b]. A catalyst combination

[Cp*IrI2]2 (1 mol%)+ N

n

R1

(n = 1–3)

OH

OHn

R1

H2O, 115 °C, 15 h

Ph

Y = 56–95%

H2N

Ph

Cat. 11c (1–3 mol%)+ N

n

R1

(n = 1 – 3)

OH

OHn

R1

H2O, re�ux, 24 hPh

Y = 74–94%

H2NPh

11c =[Cp*Ir(NH3)3][I]2

scHeme 10.42

Pd(OAc)2 (2 mol%)Et3N, THF

+

OH

O

Toluene, re�ux, air, 3 h

Y = 57–91%

R1

R2

H2N

H2N N

N

R3

R1

R2

R3

RuCl2(PPh3)3 (4 mol%)KOH (400 mol%)

Benzalacetone (200 mol%)+

OH

OH

Diglyme, re�ux, 20 h

Y = 63–84%

R1

R2

H2N

H2N N

N

R3

R1

R2

R3


+

OH

OH

Toluene or H2O, 100–140 °C, 6 h

Y = 54–100%

R1

R2

R3HN

R3HN N

NR1

R2

R4 R4

R3

R3

scHeme 10.43


of [Cp*IrCl2]

2/NaHCO

3 catalyzed the N-heterocyclization of 1,2-diamines with 1,2-

diols to afford piperazines (the 3rd equation) [27c].

10.3.2.4 Other N-Heterocyclization through the N-Alkylation as a Key Step N-Heterocyclization of 1-naphthylamines with 1,2-diols and 1,3-diols was conducted by a catalyst combination of IrCl

3 · 3H

2O/BINAP/Na

2CO

3 under air to

afford the corresponding 6,7-benzoindoles and 7,8-benzoquinolines, respectively (Scheme 10.44) [28a].

N-Heterocyclization of anilines with 1,2-diols was catalyzed by [Cp*IrCl2]

2/

methanesulfonic acid (MsOH) or RuCl3 · xH

2O/PPh

3 or Xantphos to give indoles

(Scheme 10.45, the 1st equation) [28b]. Similarly, N-heterocyclization of anilines with 1,3-diols was catalyzed by RuCl

3 · xH

2O/PPh

3/MgBr

2 · OEt

2 to afford quinolines

(the 2nd equation) [28c].N-Heterocyclization of 1,2-diaminobenzene with primary alcohols was accom-

plished by a catalyst combination of RuH2(CO)(PPh

3)

3/Xantphos/piperidinium

acetate in the presence of crotononitrile as a hydrogen acceptor to give benzimid-azoles (Scheme 10.46) [28d].

IrCl3•3H2O (5 mol%)BINAP (7.5 mol%)Na2CO3 (8 mol%)

Y = 66–99%

R2

NH2

HOOH

R1

or

HO OH

+

R2

HN R1

R2

NMesitylene, re�ux

under air or O2, 15 h

orY = 56–99%

scHeme 10.44

[Cp*IrCl2]2 (1 mol%)MsOH (5 mol%)170 °C, 2 days

Y = 20–61%

R2

NH2

HOOH

R1

HO OH

+ R2

R2

N

Y = 34–87%

R1

NH

R1

R1

or RuCl3•xH2O (1 mol%)

R2

NH2

+

RuCl3•xH2O (5 mol%)

Mesitylene, re�ux, 16 h

MgBr3•OEt2 (5 mol%)PBu3 (10 mol%)

170 °C, 24 hor Xantphos (1.5 mol%)

PPh3 (3 mol%)

scHeme 10.45


N-Heterocyclization of 2-aminobenzamides with primary alcohols was catalyzed by [Cp*IrCl

2]

2 to give quinazolinones in one-pot reaction (Scheme 10.47, the 1st equation)

[28e]. Several natural quinazolinones were synthesized by using this N-heterocyclization method to afford deoxyvasicinone and mackinazolinone as the representative examples (the 2nd equation) [28f]. The similar N-heterocyclization of 2-aminobenzamides and 2-aminobenzenesulfonamide with primary alcohols was catalyzed by RuH

2(CO)-

(PPh3)

3/Xantphos in the presence of crotononitrile (the 3rd equation) [28 g].

10.3.3 n-alkylation of ammonia and ammonium salts with alcohols

Ammonia (NH3) is the simplest, fundamental, and abundant nitrogen resource for a

wide variety of organic compounds containing nitrogen. Thus, the N-alkylation reaction using NH

3 or its salt as nitrogen source has been actively pursued in recent

years [29].

10.3.3.1 N-Alkylation of Ammonia (NH3) with Alcohols It has been reported

that N-alkylation of NH3 with secondary alcohols is catalyzed by a catalyst

+ R2

NH2

R2

Y = 43–85%

NH

N


Piperidinium acetate (15 mol%)NH2

R1 OHCH3CH=CHCN (2.2 equiv)


R1

scHeme 10.46

+ R2

NH2

R2

Y = 50–94%

[Cp*IrCl2]2 (2.5 mol%)R1 OH

Xylene, re�ux, 24–120 h

NH2

O

N

NH

O

R1

NH2

NH

O

OH

n

[Cp*IrCl2]2 (2.5 mol%)TfOH (10 or 20 mol%)

Xylene, re�ux, 24 or 36 h N

N

O

n

Deoxyvasicinone (n = 1): Y = 68%Mackinazolinone (n = 2): Y = 47%

NH2

+

X = CO: Y = 40–85%X = SO2: Y = 35–87%

X

R OHCH3CH=CHCN (2.5 equiv)


NH2

N

NHX

RX = COX = SO2

RuH2(CO)(PPh3)3 (5 mol%)Xantphos (5 mol%)

scHeme 10.47

combination of Ru3(CO)

12/CataCXium PCy (N-phenyl-2-(dicyclohexylphosphino)

pyrrole) in tert-amyl alcohol to give a variety of primary amines in moderate to excellent yields (Scheme 10.48, the 1st equation) [30a]. A large excess amount of NH

3 and the high reaction temperature (150–170 °C) were required to obtain the high

conversion and the high selectivity for the formation of primary amines. The similar catalytic reactions in cyclohexane at 140 °C were also reported, although the conversion and the selectivity were lower than those aforementioned (the 2nd equation) [30b]. More efficient catalytic system was developed by using a catalyst combination of RuHCl(CO)(PPh

3)

3/Xantphos in tert-amyl alcohol. Various primary

and secondary alcohols were converted to primary amines in good to excellent yields (the 3rd equation) [30c].

Cp*Ir Complexes with Tri(NH3) Ligands N-Alkylation of aq. NH

3 (28%) with

alcohols has been achieved by using the cationic Cp*Ir complexes (11) bearing tri-ammine ligands as catalysts [30d]. The complexes 11 are referred in the N-alkylation of amines with alcohols in water (Section 10.3.1.1, Table 10.13). Among the complexes, the iodide complex 11c exhibited the highest catalytic activity. The reactions with various primary alcohols were conducted without solvent at 140 °C to give the corresponding tert-amines in good to excellent yields. Several examples are shown in Table 10.14.

The similar reactions with secondary alcohols afforded secondary amines selec-tively, probably due to steric hindrance (Scheme 10.49, the 1st equation). It should be noted that the reaction with 1,5,9-nonanetriol furnished bicyclic quinolizidine in one-flask operation (the 2nd equation).

10.3.3.2 N-Alkylation of Ammonium Salts (NH4X) with Alcohols N-Alkylation

of ammonium salts (NH4X) with alcohols has been accomplished by using mainly

Cp*Ir catalysts. The N-alkylation of NH4X with alcohols was catalyzed by

[Cp*IrCl2]

2/NaHCO

3 without solvent to give tertiary amines or secondary amines

R1 OH+ NH3

Ru3(CO)12 (2 mol%)CataCXium PCy (6 mol%)

R2

R1 NH2

R2

CataCXium PCy

NPh

PCy2

tert-Amyl alcohol150–170 °C, 20 h Y = 58–93%

R1 OH+ NH3

RuHCl(CO)(PPh3)3 (3–6 mol%)Xantphos (3–6 mol%)

R2

R1 NH2

R2

tert-Amyl alcohol140–170 °C, 20 h Y = 70–97%

R1 OH+ NH3

Ru3(CO)12 (1 mol%)CataCXium PCy (6 mol%)

R2

R1 NH2

R2

Cyclohexane, 140 °C, 21 hY = 11–66%

scHeme 10.48



selectively, depending on the NH4X employed [30e, 30f]: tertiary amines were pro-

duced exclusively in the reactions of NH4OAc with primary alcohols (Scheme 10.50,

the 1st equation), while secondary amines were formed selectively in those of NH

4BF

4 (the 2nd equation), and the N-alkylation of NH

4BF

4 with secondary alcohols

afforded secondary amines exclusively due to steric hindrance (the 3rd equation). Furthermore, the N-alkylation of NH

4BF

4 with diols afforded 5- and 6-membered

cyclic secondary amines (the 4th equation).

Cp*Ir Complexes with (N)-Monoligating and (N,N)-Chelating Ligands It has been reported that the complexes 4a and 4b, which are used in the β-alkylation of 1-phenyl-ethanol with primary alcohols (Section 10.2.2.2, Table 10.3), also catalyze the N-alkylation of ammonium salts with alcohols [7d]. The reactions of NH

4OAc

without base proceeded more smoothly than those of NH4Cl with KOH to give

tertiary amines. Examples are shown in Table 10.15. The complex 4a was more active than 4b.

In addition, the N-alkylation of NH4OAc with benzyl alcohol was catalyzed by a

catalyst combination of [(p-cymene)RuCl2]

2/DPPF to give tribenzylamine [19b], and

the N-alkylation of NH4OAc with primary alcohols catalyzed by [Cp*IrCl

2]

2 was

carried out under MW to give tertiary amines exclusively [21f].

R OH +Cat. 11c

aq NH3 (28%)140 °C, 24 h

Entry

12345

R

Ph4-MeOC6H4

2-BrC6H44-MeOCOC6H4

C5H11

9495818996

Yield (%)

(RCH2)3N

Cat. 11c (mol%)

11221

IrH3N

Cp*

NH3NH3

[X]2

11a: X = Cl11b: X = Br11c: X = I

taBle 10.14 N-Alkylation of aq. NH3 (28%) with primary alcohols

catalyzed by 11c.

R1 OH+ aq NH3 (28%)

Cat. 11c (1–3 mol%)

140 °C, 24 h

R2

R1 NH

R2

R1

R2

Y = 63–89%

+ aq NH3 (28%)Cat. 11c (5.0 mol%)

140 °C, 24 hOH

OH OH

N

Y = 85%

scHeme 10.49

10.3.4 n-alkylation of sulfonamides and amides with alcohols

10.3.4.1 Ru Complexes A couple of catalyst combinations of Ru complex/phos-phine/base for N-alkylation of sulfonamides with primary alcohols have been reported: [(p-cymene)RuCl

2]

2/DPEphos or PPh

3/K

2CO

3 [19c, 19d] and [(p-cymene)

RuCl2]

2/DPEphos under MW without solvent [19e] (Scheme 10.51, the 1st equation).

N-Alkylation of amides with primary alcohols was also catalyzed by [(p-cymene)RuCl

2]

2/DPEphos under MW without solvent (the 2nd equation) [19e].

10.3.4.2 Ir Complexes It has been reported that N-alkylation of sulfonamides, amides, and carbamates is accomplished by catalyst combinations of Cp*Ir complex/base. The N-alkylation of sulfonamides with primary and secondary alcohols was

R OH +

[Cp*IrCl2]2 (0.5–2.5 mol%)NaHCO3 (2–30 mol%)

NH4OAc130 °C, 17 h Y = 55–92%

(RCH2)3N

R1 OH

+ NH4BF4

R2

R1 NH

R2

R1

R2

[Cp*IrCl2]2 (1–1.5 mol%)NaHCO3 (30 mol%)

140 °C, 17 hR OH

Y = 2–9%Y = 98–50%

(RCH2)2NH + (RCH2)3N

+ NH4BF4


140 °C, 17 hY = 54–86%

OHn

n = 1, 2

+ NH4BF4


140 °C, 17 h NH

PhHO

Ph n

Y = 62–85%

scHeme 10.50

Cat. 4, base

130 °CRCH2OH + NH4X R3N

Entry

12345

R

PhPhPh

4-MeC6H4C5H11

9760999990

Yield (%)Cat. (mol%)

4a (0.5)4b (0.5)4a (5)4a (1)4a (3)

X Base (mol%) Time (h)

OAcOAcCl

OAcOAc

––

KOH (100)––

1717391717

taBle 10.15 N-Alkylation of ammonium salts with alcohols catalyzed by 4.



accomplished by a catalyst combination of [Cp*IrCl2]

2/tBuOK (Scheme 10.52, the

1st equation) [31a]. It was revealed that a sulfonylimido-bridged unsaturated diirid-ium complex [(Cp*Ir)

2(μ-NTs)

2] is the key catalytic species. A catalyst combination

of [Cp*IrCl2]

2/NaOAc catalyzed the alkylation of amides and carbamates with pri-

mary alcohols without solvent (the 2nd and 3rd equations) [31b]. Furthermore, the N-alkylation of sulfonamides with primary alcohols in H

2O was conducted by a cat-

alyst combination of [Cp*IrI2]

2/NaOAc (the 4th equation) [21i].

10.3.4.3 Other Catalytic Systems There have been several catalyst combinations of metal salts and bases: Cu(OAc)

2/tBuOK [23a, 23b], Pd(OAc)

2/K

2CO

3 [23d], FeCl

2/

K2CO

3 [32a], and Cu(OAc)

2/K

2CO

3 under air [32b, 32c].

R1 OH + H2O+Cat. [Ru]/ligand

Cat. [Ru]/ligand[(p-cymene)RuCl2]2/DPEphos/K2CO3, 150 °C, 24 h in xylene

[(p-cymene)RuCl2]2/PPh3/K2CO3,150 °C, 24 h in xylene[(p-cymene)RuCl2]2/DPEphos, 165 °C, 2–3 h, under MW

R1 NH

SO2R2H2N–SO2R2

R1 OH + H2O+Cat. [Ru]/ligand

R1 NH

COR2H2N–COR2

scHeme 10.51

R1 OH+ H2O+

R1 NH

SO2R3

R2

H2N–SO2R3

+ H2OR1 NH

COR2

COOR2

H2N–COR2

Cat. [Cp*IrCl2]2/baseR2

Cat. [Cp*Ir]-complex/base[Cp*IrCl2]2/tBuOK, re�ux, 17 h in toluene or xylene

[Cp*IrCl2]2/NaOAc, 130 °C, 17 h[Cp*IrI2]2/K2CO3, 115 °C, 23 h in H2O



R1 OH

+ H2O

+

R1 NH

H2N–COOR2

+ H2OR1 NH

SO2R2H2N–SO2R2

Cat. [Cp*IrI2]2/baseR1 OH +

R1 OH +

scHeme 10.52

10.3.5 n-alkylation of nitro and nitrile compounds with alcohols

N-Alkylation of nitro and nitrile compounds with primary alcohols has been recently reported. These transformations consist of the following sequential reactions: (1) transfer hydrogenation of nitro and nitrile compounds with alcohols to produce amines and (2) N-alkylation of the resulting amines with alcohols. Thus, an excess of a reactant alcohol as a hydrogen source is required for reduction of nitro and nitrile groups. Catalyst combinations of [(p-cymene)RuCl

2]

2/DPPB/K

2CO

3 and Ru(acac)

2/

DPPE/KHCO3 were reported to catalyze N-alkylation of nitroarenes with primary

alcohols (Scheme 10.53, the 1st and 2nd equations) [33a, 33b]. Similarly, N-alkylation of arylnitriles with primary alcohols was conducted by a catalyst combination of RuCl

3/PPh

3/K

2CO

3 (the 3rd equation) [33a].

10.3.5.1 Ru Complex with (P,N)-Chelating Ligand It has been reported that a Ru(CO)

2Cl

2 complex (12) bearing 2-diphenylphosphinoaniline ligand catalyzes

N-alkylation of nitroarenes with primary alcohols [33c]. The reactions were carried out in the presence of tBuOK under H

2, and an excess amount of an alcohol (6 equiv)

was required to obtain high yields. Several examples are shown in Table 10.16.In addition, the N-alkylation of secondary amines with primary alcohols was also

conducted in the presence of NaB[3,5-(CF3)

2C

6H

3]

4 under H

2 (Scheme 10.54).

10.3.6 dehydrogenative n-acylation of amines with alcohols to produce amides

In addition to catalytic N-alkylation of amines with alcohols giving various amines and their derivatives, there is another pathway in which amides are produced through two dehydrogenation steps. This catalytic cycle consists of the following steps: (1) [M]-catalyzed dehydrogenation of an alcohol to give a carbonyl compound and a

R OH + R NH

ArAr–NO2

[(p-cymene)RuCl2]2 (2.5 mol%)DPPB (5 mol%), K2CO3 (15 mol%)

130 °C, 12–24 hY = 70–95%

R OH + R NH

ArAr–NO2

Ru(acac)2 (5 mol%)DPPE (7.5 mol%)

KHCO3 (100 mol%)

Chlorobenzene, 150 °C, 16 h

Y = 31–90%

R OH + R NH

Ar–CN

RuCl3 (5 mol%)PPh3 (5 mol%), K2CO3 (15 mol%)

140 °C, 9–24 hY = 81–95%

Ar

scHeme 10.53



metal hydride species ([MH2] or [MH]), (2) formation of aminals by addition of

amines to carbonyl compounds accompanied by generation of cat. [M] by release of H

2 from metal hydride species, and (3) further dehydrogenation of the resulting ami-

nals catalyzed by cat. [M] to furnish amides (Scheme 10.55). Since the intramolec-ular reaction reported in 1991 [34a], there have been many reports on this protocol in which metal complexes bearing carbene and pincer ligands have been widely employed as the catalysts (see Chapters 2 and 7) [1e, 1 h, 34b–34d].

Entry

12345

R

PhPhPh

4-MeC6H4C4H9

9710075

10082

Yield (%)

Ph4-BrC6H4

4-MeOC6H4PhPh

R OH + R NH

ArAr–NO2

Cat. 12 (1 mol%) , tBuOK (0.6 mol%)

H2 (1 atm), 110–120 °C, 24 h

NH2

Ru(CO)2Cl2

Ph2P

12

Ar

taBle 10.16 N-Alkylation of nitroarenes with primary alcohols catalyzed by 12.

Cat. 12 (1 mol%), NaBArf4 (2 mol%)

H2 (1 atm), 150 °C, 24 hR1CH2OH + NHR2R3

(Arf = [3,5-(CF3)2C6H3]4)

R1CH2NHR2R3

Y = 25–100%

scHeme 10.54

R1 OH

R1 O

Cat. [M]

Cat. [MH2] or [MH]

Carbonylcompounds

Hydrogen acceptor or –2H2

H

cat. [M]

Hydrogen acceptor or H2 3) Dehydrogenation(β-hydrogenelimination)

1) Dehydrogenation(β-hydrogenelimination)

Hydrogen acceptor or H2

cat. [MH2] or [MH]

R2–NH2

2) Addition of amine

R1 NH

R2

OH

Aminal

R1 NH

R2

OR2–NH2

scHeme 10.55

10.3.6.1 Catalytic Systems with Hydrogen Acceptors Several catalytic systems with hydrogen acceptors have been reported, because the liberation of H

2 from the

metal hydride species is generally an endothermic process and, therefore, hydrogen acceptors can make this process proceed more easily.

The intramolecular dehydrogenative N-acylation of amino alcohols has been accomplished using a catalyst combination of [Cp*RhCl

2]

2/K

2CO

3 in acetone that

serves as a hydrogen acceptor (Scheme 10.56, the 1st equation) [35a]. A variety of benzo-fused lactams including oxindoles were prepared in moderate to high yields. The intermolecular dehydrogenative N-acylation of amines with primary alcohols was conducted by using a catalyst combination of [(p-cymene)RuCl

2]

2/DPPB/

Cs2CO

3 with 3-methyl-2-butanone as a hydrogen acceptor in tBuOH to give amides

(the 2nd equation) [35b].It is worth noting that dehydrogenation of alcohols followed by formation of

oximes with hydroxylamine and the subsequent rearrangement to amides proceeds by using a catalyst combination of [Cp*IrCl

2]

2/Cs

2CO

3 with styrene as a hydrogen

acceptor to afford amides in one pot (Scheme 10.57) [35c].

Rh Complexes with (N,C = C,C = C)-Chelating Ligands It has been reported that a cationic rhodium complex (13b) bearing novel tridentate trop

2N (bis(5-H-dibenzo[a,d]-

OH

NH2

[Cp*RhCl2]2 (1.5–5 mol%)K2CO3 (10 mol%)

n

Acetone, re�ux or 100 °C8–30 h

R

n = 1–3

RNH

O

Y = 46–97%

n

R1 OH + H2N–R2

[(p-cymene) RuCl2]2 (2.5 mol%)DPPB (5 mol%), Cs2CO3 (10 mol%)

R1 NH

R2

O

(CH3)2CHCOCH3 (2.5 equiv)tBuOH, re�ux, 24 h Y = 31–73%

scHeme 10.56

R OH

1) [Cp*IrCl2]2 (2.5 mol%), Cs2CO3 (5 mol%)PhCH = CH2 (1.5 equiv)Toluene, re�ux, 24–36 h

R NH22) H2N–OH•HCl (1 equiv), reflux, 16 h

O

Y = 48–91%

R OH2N–OH

R NOH

Cat. [Ir]PhCH=CH2

Dehydrogenation [Ir]-catalyzedrearrangement

–H2O

scHeme 10.57



cyclohepten-5-yl)-amide) ligand very efficiently catalyzes dehydrogenative N-acylation of ammonia and primary amines with primary alcohols to afford various amides under extremely mild conditions (below room temperature) [36a]. The reactions were carried out with low catalyst loading of 13b (0.2 mol%), prepared by treatment of 13a with base, in the presence of methyl methacrylate (MMA) as a hydrogen acceptor to give a variety of amides in high yields. Some examples are shown in Table 10.17. The double bonds were not affected. The DFT theoretical cal-culations were also performed, suggesting the cooperative catalysis between Lewis acidic rhodium core (LUMO) and the Lewis basic amide N atom (HOMO) for the dehydrogenation steps.

Similarly, the dehydrogenative N-acylation of primary amines with polyalcohols and amino alcohols was accomplished by using 13b in the presence of MMA [36b]. Some examples are shown in Table 10.18. An excess amount of primary amines were required to obtain the amides in high yields in the intermolecular reactions. The intramolecular dehydrogenative N-acylation of amino alcohols also proceeded smoothly.

10.3.6.2 The Catalytic Systems without Hydrogen AcceptorRu Complexes with (N,N)(P,P)-Chelating Ligands It has been reported that a ruthe-nium complex (14a) bearing aminomethylpyridine and DPPB ligands catalyzes the intramolecular dehydrogenative N-acylation of 5-amino-1-pentanols without hydrogen acceptor to afford δ-valerolactams selectively [37a]. Among the bases

Cat. 13b (0.2 mol%), MMA (5 or 3 equiv)

THF, –20 or –30 °C (2 h), then rt (2 h)

13a

N

Rh

PPh3

=

R1 OH

NH3or

R2–NH2

+

Product Yield (%)

9494

82

9390

PhCONH2C7H15CONH2

PhCONH(iPr)BnNHCOCH2CONHBn

NH2

O

Entry Alcohol

PhCH2OHC7H15CH2OH

HOCH2CH2CH2OH

OH

12

3

45

H[OTf]

N

Rh

PPh3

13b Trop

base

R1–CONH2or

PhCH2OH

R1–CONHR2

taBle 10.17 Dehydrogenative N-acylation of ammonia or amines with primary alcohols catalyzed by 13b.

examined, KOH gave the highest selectivity of formation of amides. A few examples are shown in Table 10.19. DFT calculations were performed and indicated that, for amide to be formed, the key hemiaminal intermediate must remain to bind to ruthe-nium core and then eliminate H

2 to provide a vacant site for β-elimination forming a

carbonyl group.While the intermolecular reactions catalyzed 14a gave poor results, the similar

ruthenium complex (14b) bearing aminomethylpyridine and DPPF ligands exhibited the good catalytic activity for the intermolecular dehydrogenative N-acylation of amines with primary alcohols without hydrogen acceptor [37b]. The reactions were carried out in the presence of KOH without solvent to give amides. A few examples

Cat. 13b (0.2 mol%), MMA (3–6 equiv)

THF or no solvent, rt, 1–12 hR1 OH

R1 NHR2

OR2–NH2+

Product Yield (%)

9083

85a

92b

96b

a The reaction was carried out with BnNH (2 equiv), MMA (3 equiv), and MS 4 Å in DME.

Entry Alcohol

b The reaction was carried out with 13b (0.1 mol%) and MMA (2.5 equiv) in THF.

HOCH2CH(OH)CH2OHCH3CH(OH)CH2OH1

2

3

4

5

O

OH

OMe

HO OH

HO

CH3CH(OH)CONHBnBnHNCOCH(OH)CCONHBn

OBnHNCO

OH

OMe

HO OH

HONH2

NH

O

NH

O

HO NH2

taBle 10.18 Dehydrogenative N-acylation of primary amines with polyalcohols and amino alcohols catalyzed by 13b.

Cat. 14a (2.5 mol%), KOH (7 mol%)

Ru

Cl

Toluene, re�ux, 4 or 16 h

PPh2

Ph2P

Cl N

NH2

R

HN OH N R

14a

+ 2H2

Entry R Yield

1

2

3

H

Me2CHCH2

PhCH2

93

95

77

O

taBle 10.19 Dehydrogenative N-acylation of 5-amino-1-pentanols catalyzed by 14a.



are shown in Table 10.20. It was also mentioned that the complexes 14a and 14b exhibited the higher catalytic activity than the complexes 14c and 14d in the intra-molecular dehydrogenative N-acylation of N-butyl-5-amino-1-pentanol giving δ-valerolactam.

10.3.7 n-alkylation of amines with amines

Another protocol for carbon–nitrogen bond-forming reaction through hydrogen transfer process is N-alkylation of amines with amines. The catalytic cycle is very similar to that of the N-alkylation of amines with alcohols and consists of three cas-cade reactions (Scheme 10.58): (1) [M]-catalyzed dehydrogenation of an amine to

Cat. 14b (4 mol%), KOH (15 mol%)

125 °C, 3.5 h+ 2H2

Entry

R1 OH +R2

HN

R3R1 NR2R3

O

R1 R2 R3 Yield (%)

123

PhPh

PhCH2

–(CH2)5––(CH2)5–

748955

FeP

PPh2Cl

Ru Ru

Cl

PPh2H2

Ph2P

Ph2ClPh2N

Ph2Cl

Cl N

NN

H2

Cl FeP

PRu

NH

NH

14b 14c 14d

C6H13 H

taBle 10.20 Dehydrogenative N-acylation of amines with primary alcohols catalyzed by 14b.

R1 NH2

R1 NH R1 NR2

R1 NH

R2

Cat. [M]

Cat. [MH2] or [MH]


3) Hydrogenation(hydrometalation)

2) N-Alkylimine formation

Imine N-Alkylimine

–NH3

H HR2–NH2

R2–NH2 NH3R1 NHR2

NH2

scHeme 10.58

give an imine and a metal hydride species ([MH2] or [MH]), (2) addition of another

amine to the imine followed by elimination of ammonia to give an N-alkylimine, and (3) hydrogenation of the N-alkylimine by the transiently generated metal hydride species.

10.3.7.1 N-Alkylation of Amines with Amines It has been reported that [Cp*IrI2]

2

exhibits high catalytic activity for the N-alkylation of aromatic, benzylic, and ali-phatic primary amines with alkylamines [38a]. The reactions were carried without any base in xylene at 155 °C. The reactions of anilines with various alkylamines gave the corresponding N-alkylated anilines in good to high yields, except for anilines with electron-withdrawing groups (CF

3 and NO

2) (Scheme 10.59, the 1st equation).

The reactions of benzylic and aliphatic amines with diisopropylamine resulted in high yields of the corresponding products (the 2nd and 3rd equations). The reaction of an unbranched amine with a branched amine also proceeded in good yield (the 4th equation). In addition, [Cp*IrCl

2]

2 catalyzed self-condensation of primary amines at

170 °C without solvent to give secondary amines (the 5th equation) [38b].

10.3.7.2 N-Heterocyclization of Amines with Amines and Amino Alcohols It has been reported that N-heterocyclization of anilines with trialkylamines is cata-lyzed by a catalyst combination of RuCl

3 · nH

2O/DPPM in the presence of SnCl

2 · 2H

2O

and 1-hexene as a hydrogen acceptor to give 2,3-disubstituted quinolines (Scheme 10.60, the 1st equation) [39a]. Similarly, a catalyst combination of PtBr

2/

Bu4PBr in the presence of 1-hexene catalyzed N-heterocyclization of aniline with

+

(iPr)2NH +

(iPr)2NH + H2NCHR1R2[Cp*IrI2]2 (1 mol%)

[Cp*IrI2]2 (1 mol%)

[Cp*IrCl2]2 (0.5 mol%)

[Cp*IrI2]2 (1 mol%)

[Cp*IrI2]2 (1 mol%)

Xylene, 155 °C, 10 h



Xylene, 155 °C, 10 hY = 79%

Y = 26–99%

Y = 97–99%

Y = 68–98%

R1R2CHNH2

or(R1R2CH)2NH

or

(R1R2CH)3N

R–NH2170 °C, 18–72 h

R2NH

Y = 70–83%

R1R2CH–NHC6H4RH2NC6H4R

H2NCH2C6H4R iPr–NHCH2C6H4R

iPr–NHCHR1R2

PhMeCHNH2 + H2NCH2CH2Ph PhMeCH–NHCH2CH2Ph

scHeme 10.59


320 Bond-Forming reactions

tributylamine to give 3-ethyl-2-propylquinoline (2nd equation) [39b]. Furthermore, the reactions of nitroarenes with trialkylamines were catalyzed by rucl

2(PPh

3)

2 in

the presence of sncl2 · 2H

2o to give 2,3-disubstituted quinolines (the 3rd equation)

[39c]. since no hydrogen acceptor was required, a nitro group served as a hydrogen acceptor and was reduced to an amino group.

n-Heterocyclization of anilines with tris(2-hydroxyethyl)ammonium chloride was conducted by using a catalyst combination of rucl

3 · 3H

2o/PPh

3 or

ruH2(PPh

3)

3 in the presence of sncl

2 · 2H

2o to give indoles (scheme 10.61, the

1st equation) [39d, 39e]. the similar n-heterocyclization of anilines with tris(3-hydroxypropyl)amine was catalyzed by a catalyst combination of rucl

3 · 3H

2o/

PPh3 in the presence of acetone as a hydrogen acceptor to give quinolines (the 2nd

equation) [39f].

RuCl3•nH2O (8 mol%)DPPM (12 mol%)

SnCl3•2H2O (100 mol%)

1-Hexene (10 equiv)Dioxane, 180 °C, 20 h

N(CH2CH2R1)3 + R2C6H4NH2

N(CH2CH2R1)3 + R2C6H4NO2

Y = 21–86%

RuCl2PPh3 (4 mol%)SnCl3•2H2O (100 mol%)

Toluene-H2O, 180 °C, 20 h

Y = 22–85%

R2

N

R1

R1

R2

N

R1

R1

+

PtBr2 (0.6 mol%)Bu4PBr (40 mol%)

1-Hexene (4.5 equiv)180 °C, 20 h

NBu3

Y = 50%N

Et

Pr

PhNH2

SCHEME 10.60

RuCl3•3H2O (10 mol%)PPh3 (30 mol%)

or RuH2(PPh3)3 (5 mol%)

Y = 16–169%

(HOCH2CH2)3N•HCl + RC6H4NH2NH

R

RuCl3•3H2O (5 mol%)PPh3 (15 mol%)

SnCl2•2H2O (100 mol%)

Acetone (10 equiv)Dioxane, 180 °C, 24 h

Y = 29–94%

RN

SnCl2•2H2O (100 mol%)H2O/dioxane (1/9)

180 °C, 20 h

(HOCH2CH2CH2)3N•HCl + RC6H4NH2

SCHEME 10.61

CARBON–OXYGEN BOND-FORMING REACTIONS BASED ON HYDROGEN TRANSFER 321

10.4 carBon–oxygen Bond-Forming reactions Based on Hydrogen transFer

The third interesting bond formation based on hydrogen transfer is the dehydro-genative carbon–oxygen bond-forming reactions of alcohols with alcohols or water to give esters and lactones or carboxylic acids. General catalytic cycle con-sists of the three cascade reactions (Scheme 10.62): (1) [M]-catalyzed dehydroge-nation of an alcohol to give a carbonyl compound along with a metal hydride species ([MH

2] or [MH]) from which the starting cat. [M] is regenerated by reac-

tion with a hydrogen acceptor or release of H2, (2) formation of a hemiacetal or a

gem-diol by nucleophilic addition of an alcohol or H2O, and (3) the second

[M]-catalyzed dehydrogenation of the hemiacetal or the gem-diol to give esters and lactones or carboxylic acids along with the metal hydride species from which the starting cat. [M] is regenerated again by reaction with the hydrogen acceptor or release of H

2.

Whereas there are closely related reactions such as Tishchenko dimerization of aldehydes to give esters [40] and oxidative esterification of aldehydes with alcohols [41], this section is focused on the recent development on dehydrogenative esterifi-cation and carboxylation of alcohols with alcohols and water [1].

10.4.1 dehydrogenative esterification and carboxylation of alcohols with Hydrogen acceptor

10.4.1.1 Ru Complexes While a few ruthenium complexes such as Ru3(CO)

12,

RuH2(PPh

3)

4, and Ru

2Cl

4 were reported to catalyze dehydrogenative esterification

of alcohols with alcohols at high temperature more than 25 years ago [42], more effi-cient catalytic systems under milder conditions have been recently developed.

R1 OH

R1 O R1 O–R2(H)

R1 O–R2(H)

Cat. [M]


2) Hemiacetal or gem-diol formation

Carbonylcompounds

Hydrogen acceptoror–2H2

H OR2–OH or H2O

R2–OH or H2O

OH

Cat. [M]

Hydrogen acceptor or H2 3) Dehydrogenation(β-hydrogenelimination)

Hydrogen acceptor or H2

cat. [MH2] or [MH]

Cat. [MH2] or [MH]

scHeme 10.62


Cp*Ru Complexes with (P,N)-Chelating Ligands It has been reported that a Cp*Ru complex (15a) bearing 2-aminoethyl(diphenyl)phosphine ligand exhibits the high catalytic activity for dehydrogenative lactonization of diols [43a]. The reactions were carried out by using 15a prepared in situ from Cp*RuCl(cod) and the ligand or 15a itself in the presence of tBuOK in acetone at 30 °C for a few hours. Some examples are shown in Table 10.21. A variety of 5-, 6-, and 7-membered lactones were obtained in excellent yields under extremely mild conditions, indicating that the cooperative metal/NH bifunctional catalysis works in both of the dehydrogenation steps.

The regioselective dehydrogenative lactonization of unsymmetrical 1,4-diols was also investigated by using many ruthenium complexes (15) bearing aminophosphine ligands including 15a [43b]. Among them, the complex 15b resulted in the highest regioselectivity for formation of the lactones through the dehydrogenation of steri-cally less hindered hydroxyl groups. A few examples are shown in Table 10.22.

Other Catalytic Systems Dehydrogenative methyl esterification of primary alcohols with methanol was conducted by using a catalyst combination of RuH

2(CO)-

Cp*RuCl(cod) (1 mol%)PPh2(CH2)2NH2 (1 mol%), tBuOK (1 mol%)

Acetone (0.5 M), 30 °C, 1–3 h

15a

O

O

O

O

O

O

H Me

Y >99% Y >99%

O

O

Y >99%

OO

Y = 93%

Ru

Cp*

ClH2NPPh2OH

OHnR

n = 1– 3

O

O

nR

or Cat. 15a (1 mol%), tBuOK (1 mol%)Acetone (0.5 M), 30 °C, 1–3 h

Y >99%

taBle 10.21 Dehydrogenative lactonization of diols catalyzed by 15a prepared in situ.

Cat. 15 (1 mol%), tBuOK (1 mol%)Acetone (0.5 M), 30 °C, 1 h

OH

OHO

O

ArO

O

Ar Ar+

Ph

Ph4-MeOC6H4

3-BnOC6H4

77 : 23

92 : 892 : 8

92 : 8

Conversion >99%

Cat. Ar

15a

15b15b

15b

RatioEntry

1

23

4

15b

Ru

Cp*

ClH2NPPh2

taBle 10.22 Regioselective dehydrogenative lactonization of 1,4-diols catalyzed by 15.


(PPh3)

3/Xantphos in the presence of crotononitrile as a hydrogen acceptor

(Scheme 10.63) [43c, 43d].

10.4.1.2 Ir ComplexesCp*Ir Complex with (N,O)-Chelating Ligand It has been reported that a Cp*Ir complex (16) bearing amido-alkoxo ligand, readily prepared by treatment of [Cp*IrCl

2]

2 with 2,2-diphenylglycinol in the presence of KOH, exhibits the high

catalytic activity for the dehydrogenative lactonization of diols using acetone as a hydrogen acceptor [44a]. The reactions were carried out with low catalyst loading (0.5 mol%) of 16 in acetone at room temperature. Several examples are shown in Table 10.23. A variety of 1,4- and 1,5-diols were converted to the corresponding lac-tones in excellent yields. The less hindered hydroxyl groups were oxidized selec-tively in the reactions of unsymmetrical diols. The asymmetric dehydrogenative lactonization using a chiral iridium complex was also reported [44b].

Similarly, the complex 16 effectively catalyzed the dehydrogenative esterification of primary alcohols [44c]. The reactions were conducted in the presence of K

2CO

3

using 2-butanone as a hydrogen acceptor at room temperature. Some examples are shown in Table 10.24. A variety of aliphatic and benzylic alcohols were transformed to the corresponding esters in good to high yields.

Cp*Ir Complex with (N,C)-Chelating Ligand It has been reported that a cyclometa-lated Cp*Ir complex (17) bearing 2-(aminodiphenylmethyl)phenyl ligand is synthe-sized and catalyzes the dehydrogenative esterification of primary alcohols [44d].

R OHR OMeToluene/MeOH (1:1), 110 °C, 24–48 h

ORuH2(CO)(PPh3)3 (5 mol%), Xantphos (5 mol%)

H2O (2 equiv), CH3CH=CHCN (3 equiv)

Y = 70–87%

scHeme 10.63

Cat. 16 (0.5 mol%)

OH

OHO 16

Ir

Cp*

HN O

Ph Ph

O

n nR R

Acetone, rt, 4–48 h

O

O

Y > 99%

O

O

Y = 98%

O

O

Y = 96% Y > 99%

O OO O

Y = 95%

(n = 1,2)

taBle 10.23 Dehydrogenative lactonization of diols catalyzed by 16.


The reactions were conducted in the presence of tBuOK under air as a hydrogen acceptor to give the corresponding esters. A few examples are shown in Table 10.25.

Ir Complex with (N,N,C = C,C = C)-Chelating Ligand A cationic iridium complex (18) bearing tetradentate trop

2dach {N,N-bis(5-H-dibenzo[a,d]cyclohepten-5-yl)-

1,2-diaminocyclohexane} ligand efficiently catalyzed the dehydrogenative lactoni-zation of 1,4-diols [44e]. The reactions were carried out with very low catalyst loading (0.01 mol%) in the presence of tBuOK using benzoquinone as a hydrogen acceptor to give the corresponding lactones in excellent yields (Scheme 10.64).

Other Catalytic Systems It has been reported that [IrCl(coe)]2 catalyzes the dehy-

drogenative esterification of primary alcohols with air as a hydrogen acceptor without base and solvent (Scheme 10.65, the 1st equation) [44f]. Furthermore, the dehydrogenative esterification of ethanol and methyl esterification of primary alcohols with methanol were accomplished by a catalyst combination of [Cp*IrCl

2]

2/

MeNH(CH2)

2OH/Cs

2CO

3 with acetone as a hydrogen acceptor (the 2nd and 3rd

equations) [44 g, 44 h].

Cat. 16 (2 mol%), K2CO3 (30 mol%)

2-Butanone, rt, 20–96 hR OH

R O

O

R

Entry R Yield (%)

1234

5

PhCH2CH2Ph

4-MeSC6H44-BrC6H4

89938791

67

Time (h)

20252624

96

taBle 10.24 Dehydrogenative estrification of primary alcohols catalyzed by 16.


17

IrCp* Cl

H2N

Ph Ph

Air (0.1 MPa), THF, 30 °CR OH

R O

O

R

Entry R Yield (%)Time (h)

3 4-MeC6H4

2 4-ClC6H4

1 Ph 64

62

64

18

3

18

taBle 10.25 Dehydrogenative estrification of primary alcohols catalyzed by 17.


10.4.1.3 Rh Complexes Rh Complexes with (N,C = C,C = C)-Chelating Ligands It has been reported that the rhodium complexes 13, which efficiently catalyze the dehydrogenative N-acylation of ammonia and primary amines with primary alcohols (see Section 10.3.6.1, Table 10.17), also exhibit the high catalytic activity for the dehydrogenative carboxylation and methyl esterification of primary alcohols to afford various carboxylic acids and methyl esters under mild conditions [36a]. The reactions were carried out by using 13b prepared in situ from 13a in the presence of cyclohexanone as a hydrogen acceptor with an excess amount of H

2O or MeOH to give the corresponding products in good to high yields.

Some examples are shown in Table 10.26. Employment of the isolated 13b and MMA increased the yields of methyl esters (Entries 4, 5).

Similarly, the dehydrogenative carboxylation of polyalcohols with H2O was accom-

plished by using 13a and NaOH in the presence of cyclohexanone to give a variety of hydroxycarboxylic acids in high yields [36b]. Examples are shown in Table 10.27.

It has been reported that a combination of 13a and Pd/SiO2 (supported Pd metal

nanoparticles) efficiently catalyzes the dehydrogenative carboxylation of primary alcohols with H

2O using a simple olefin as a hydrogen acceptor [45a]. The reactions

Cat. 18 (0.01 mol%), ,tBuOK (0.03 mol%)Benzoquione (2 equiv)

OH

OHR

PhCl, 80–100 °C, 5–10 minO

O

O

O

Yield >98%

=NH NH

Ir

18

O

O

R

[OTf]

Trop

scHeme 10.64

[IrCl(coe)2]2 (3 mol%)

Air, 95 °C, 15 hR OH

R O

O

R

Y = 50–94%

[Cp*IrCl2]2 (2 mol%), MeNH(CH2)2OH (6 mol%)Cs2CO3 (10 mol%)

[Cp*IrCl2]2 (2 mol%), MeNH(CH2)2OH (6 mol%)Cs2CO3 (10 mol%)

Acetone, rt, 24 h

Acetone, rt, 24 h

OHO

O

Y = 85%

R OH + MeOHR O

O

Y = 23–92%

scHeme 10.65


were conducted in the presence of NaOH and 1-hexene with H2O. A few examples

are shown in Table 10.28. In the reaction of cinnamyl alcohol, some amounts of sat-urated products were formed (Entry 5).

Cat. 13a (0.1 mol%), NaOH (1.2 equiv)Cyclohexanone (5 equiv), 25 °C, 2–12 h

R OH

H2Oor

MeOH+

Product Yield (%)

9496

89

91a

94a

PhCO2H2-PyCO2H

4-MeSC6H4CO2Me

a The reaction was carried out by using 13b (0.1 mol%) with MMA (3 equiv) at –30 to 25 °C.

Entry Alcohol

PhCH2OH2-PyCH2OH

4-MeSC6H4CH2OH

OH

12

3

4

5

OO

OH OO

CO2H

CO2Me

Cat. 13a (0.1 mol%), K2CO3 (5 mol%)Cyclohexanone (5 equiv), 0 °C, 0.3–4 h

RCO2Hor

RCO2Meor

taBle 10.26 Dehydrogenative carboxylation and methyl estrification of primary alcohols catalyzed by 13b prepared in situ.

Cat. 13a (0.1 mol%), NaOH (1.2 equiv)Cyclohexanone (2.5 equiv), rt, 2–18 h

2) HClR OH +

Product Yield (%)

99

98

97

66a

a The reaction was carried out at 40 °C with THF as the cosolvent.

Entry Alcohol

1

2

3

4O

OH

OMe

HO OH

HO OHO2C

OH

OMe

HO OH

HOCH2CH2OH

OHHOOH

OHPh

OH

NH2

HOCH2CO2H

HOCH2CH(OH)CO2H

CO2HPh

OH

NH2

H2O RCO2H

1)

taBle 10.27 Dehydrogenative carboxylation of polyalcohols catalyzed by 13a.


Furthermore, it has been reported that a cationic rhodium complex (13c) bear-ing tridentate trop

2NH and NHC ligands is synthesized and catalyzes the dehydroge-

native carboxylation of primary alcohols with H2O under aerobic conditions [45b].

The reactions were carried out in the presence of NaOH in DMSO/H2O/THF under

air to give the corresponding carboxylates (Na salts). Examples are shown in Table 10.29.

10.4.1.4 Other Catalyst Systems The dehydrogenative cross-esterification of various benzylic and heterobenzylic alcohols with aliphatic alcohols was accom-plished by a catalyst combination of Pd(OAc)

2/BuP(1-adamantyl)

2/AgPF

6 in the

presence of K2CO

3 using O

2 as a hydrogen acceptor (Scheme 10.66, the 1st equation)

[46a]. On the other hand, the dehydrogenative self-esterification of various benzylic and heterobenzylic alcohols was performed by a catalyst combination of Pd(OAc)

2/1,2-[(tBu)

2PCH

2]

2C

6H

4/AgPF

6 in the presence of K

2CO

3 under O

2 in tol-

uene (the 2nd equation) [46a]. Similarly, the dehydrogenative methyl esterification

Cat. 13a (0.1 mol%), Pd/SiO2 (0.1 mol%)NaOH (1.2 equiv), 1-hexene (10 equiv), rt, 12 h

R OH +

Product Yield (%)

Quant.997784

50a

PhCO2H2-MeOC6H4CO2H

4-BrC6H4CO2H3-FurylCO2H

PhCH=CHCO2H

a Ph(CH2)2CO2H (28%) and Ph(CH2)3OH (18%) were also produced.

Entry Alcohol

PhCH2OH2-MeOC6H4CH2OH

4-BrC6H4CH2OH3-FurylCH2OH

PhCH=CHCH2OH

12345

2) HClH2O RCO2H

1)

taBle 10.28 Dehydrogenative carboxylation of primary alcohols catalyzed by 13a and Pd/SiO

2.

Cat. 13c (1 mol%), NaOH (1.2 equiv)R OH

Product Yield (%)

647960

81

65

C7H15CO2NaPhCO2Na

4-MeSC6H4CO2Na

2-FurylCO2Na

Entry Alcohol

C7H15CH2OHPhCH2OH

4-MeSC6H4CH2OH

2-FurylCH2OH

123

4

5 13c

NRh

[OTf]

NN

H2O+

OH CO2Na

RCO2NaAir, DMSO-THF, rt, ca. 12 h

taBle 10.29 Dehydrogenative carboxylation of primary alcohols catalyzed by 13c.


of benzylic and heterobenzylic alcohols with methanol was achieved by a catalyst combination of PdCl

2(MeCN)

2/AgBF

4 in the presence of tBuONa using O

2 as a

hydrogen acceptor (the 3rd equation) [46b]. Furthermore, the dehydrogenative cross-esterification of various benzylic alcohols with aliphatic alcohols was conducted by a catalyst combination of PdCl

2(MeCN)

2/2-Ph

2PC

6H

4CH = CHCOPh/Ag

2CO

3 in the

presence of K3PO

4 under O

2 in hexane (the 4th equation) [46b].

10.4.2 dehydrogenative esterification of alcohols without Hydrogen acceptor

10.4.2.1 Ru Complexes The dehydrogenative lactonization of 1,4-butanediol catalyzed by various ruthenium complexes without a hydrogen acceptor has been investigated [47]. The reactions was carried out by using various RuH

2(PR

3)

2,

Ru(allyl)2(PR

3)

2, or RuCl

2(PR

3)

2(diamine) complexes at 205 °C without solvent. A

few examples are shown in Table 10.30. Among the complexes, cis-RuCl2(PMe

3)

2(eda)

(eda = ethylenediamine) exhibited the highest catalytic activity and TON that reached up to 17,000, suggesting the outer-sphere metal–ligand bifunctional mechanism.

It has been also reported that the dehydrogenative lactonization of 1,4-butanediol is catalyzed by the ruthenium complexes 14, which are used in the dehydrogenative N-acylation of alcohols with amines (Section 10.3.6.2, Tables 10.19 and 10.20) [37b]. The reactions were carried out in the presence of KOH without a hydrogen acceptor

Pd(OAc)2 (2–5 mol%)BuP(1-adamantyl)2 (4–5 mol%)

AgPF6(4–10 mol%), K2CO3 (50–120 mol%)

Y = 53–88%

Y = 55–89%

Pd(OAc)2 (5 mol%)1,2-[(tBu)2PCH2]2C6H4 (5 mol%)

AgPF6 (5 mol%), K2CO3 (120 mol%)

Y = 60–85%

PdCl2(MeCN)2 (5–10 mol%)AgBF4 (10–20 mol%), tBuONa (100 mol%)

O2 (1 bar), 50–80 °C, 20 h

Toluene, O2 (1 bar), 110 °C, 20 h

O2, 45 °C, overnight

Y = 40–84%

PdCl2 (MeCN)2 (10 mol%)2-Ph2PC6H4CH=CHCOPh (20 mol%)

Ag2CO3 (20 mol%), K3PO4 (450 mol%)

Hexane, O2, 60 °C, overnight

ArCO2RArCH2OH + ROH

ArCH2OH

ArCH2OH + ROH

ArCH2OH + MeOH

ArCO2CH2Ar

ArCO2Me

ArCO2R

scHeme 10.66


(Scheme 10.67). The complexes 14a and 14b exhibited higher catalytic activity than the complexes 14c and 14d.

10.4.2.2 Other Catalyst Systems It has been reported that the dehydrogenative esterification of primary alcohols without hydrogen acceptor is catalyzed by a simple ruthenium complex, Ru(OAc)

2(PPh

3)

2, and that addition of a catalytic amount of

TMEDA improves the yields [48] (Scheme 10.68, the 1st equation). On the other hand, the reaction catalyzed by Ru(SO

4)((PPh

3)

2(MeCN)

2 resulted in formation of

acetals in moderate yields (the 2nd equation).

Cat. [Ru] (0.023 mol%)

a 1,4-Butanediol (240 mmol) and the catalyst (0.0058 mol%) was heated for 48 h.

Entry Cat.

RuH2(PMe3)4RuH2(CO)(PMe3)3

cis-RuCl2(PMe3)2(eda)

123

205 °C, 40 hHO

OHO

O

+ 2H2

TON

378031704360 (17000)a

taBle 10.30 Dehydrogenative lactonization of 1,4-butanediol catalyzed by Ru complexes.

Cat. 14 (1 mol%), KOH (5 mol%)


Cat. 14a 14b 14c 14d

TOF (h–1) 10 12 5.0 5.0

HOOH O

O

+ 2H2

scHeme 10.67

R OH

R O

O

Y = 49–69%

R O

O

R

R

R

Ru(OAc)2(PPh3)2 (0.1 mol%)TMEDA (0.5–2 mol%)


+ 2H2157 °C, 48 h

R OHRu(SO4)(PPh3)2(MeCN)2 (0.1–0.29 mol%)

+ H2 + H2O

Y = 59–73%

scHeme 10.68


reFerences

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335


Index

acetalfrom dehydrogenative acetalization

of alcohol, 178, 329acetone

as hydrogen acceptor, oxidant, 3–7, 62–6, 133, 208

acridine-based pincer ligand, 165, 178aerobic oxidation

of alcohol, 7, 60–62, 133–6, 186–202

alcoholin aerobic oxidation, 7, 60–66,

133–6, 186–202as alkylating agent, 30–45, 88–90,

159–61, 165–72, 279–87, 297–303, 308–14

in amination of nitro compound, 313in β-alkylation, 28–36, 159–61,

283–7in C–C bond-forming coupling with

unsaturated compound, 289–95

in C–C bond-forming reaction, 27–36, 159–61, 279–96

in C–N bond-forming reaction, 37–46, 88–90, 161–73, 296–318

in C–O bond-forming reaction, 46, 47, 49, 97–102, 173–82, 321–9

in dehydrative etherification, 47in dehydrogenative acetalization,

178, 329in dehydrogenative amidation of

amine, 37–41, 161–5, 313–16in dehydrogenative carboxylation,

325–7in dehydrogenative esterification, 46,

49, 173–82, 323–6, 328in dehydrogenative oxidation, 10–12,

67, 128–33, 209–19as hydrogen donor, reductant, 14–21,

24, 75, 149, 152, 154, 155, 242–56

336 INdex

from hydrogenation of aldehyde, 12, 72–4, 141, 229–32

from hydrogenation of amide, 141, 260–263

from hydrogenation of carbamate, 141

from hydrogenation of ester, 21, 141, 154, 256–9

from hydrogenation of ketone, 12, 72–4, 141, 229–34

from transfer hydrogenation of aldehyde, 19–21, 77, 154, 238, 242, 243, 252

from transfer hydrogenation of ketone, 14–21, 75–8, 149, 152, 154, 155, 234–56

in imination of amine, 167, 302in imination of nitro compound, 45in kinetic resolution, 6, 9in N-alkylation of amide, 311in N-alkylation of amine, 37, 40,

43–5, 88–90, 169, 171, 297–303in N-alkylation of ammonia, 44,

165–8, 308–10in N-alkylation of ammonium salt,

90, 311in N-alkylation of sulfonamide, 312in Oppenauer-type oxidation, 3–7,

62–6, 133, 207–9in oxidation with chloroform, 67in oxidation with hydrogen peroxide,

133, 202–6in oxidation with silver oxide, 67in racemization, 6

aldehydein alkylation of cyclic amine, 295in hydroacylation, 47in hydrogenation, 12, 141,

230, 232from oxidation of primary alcohol,

5, 7, 10–12, 66, 67, 133, 186, 191, 196–208, 215–18

in transfer hydrogenation, 19–21, 76, 154, 238, 252

aldol condensation, 31, 34, 160, 280

alkanefrom alkane metathesis, 118–20in dehydroaromatization, 115–17in dehydrogenation, 121–6in transfer dehydrogenation, 109–20

alkane metathesis, 118–20alkene

from dehydrogenation of alkane, 121–6

from transfer dehydrogenation of alkane, 109–15

in transfer hydrogenation, 16alkene metathesis, 118–20α-alkylation

of carbonyl compound, 279–83of nitrile, 281

amidefrom dehydrogenative amidation of

amine with alcohol, 37–41, 161–5, 313–17

from dehydrogenative amidation of amine with ester, 163

in hydrogenation, 141, 260–263amine

in aerobic oxidation, 220–222as alkylating agent, 38, 42, 91–6,

172, 319in C–C bond-forming reaction,

102–4, 296in C–N bond-forming reaction,

37–45, 88–97, 161–5, 169, 171, 296–308

in dehydrogenative amidation with alcohol, 37–41, 161–5, 313–18

in dehydrogenative imidation of amine, 39

in dehydrogenative oxidation, 139, 220from hydrogenation of amide, 141,

260–263from hydrogenation of carbamate, 141from hydrogenation of imine, 79,

263–5from hydrogenation of nitrile, 13,

145, 272–4in imination with alcohol, 167, 302

INdex 337

in methylation with methanol, 169in mono-amination of diol, 171from N-alkylation of amine with

alcohol, 37, 40, 43–5, 89, 169, 171, 296–303

from N-alkylation of amine with amine, 38, 42, 91–6, 172, 318–20

from N-alkylation of ammonia with alcohol, 44, 165–8, 308–10

from N-alkylation of ammonium salt with alcohol, 90, 309–11

in N-alkylation with alcohol, 37, 40, 43–5, 88–90, 161–5, 169, 171, 297–303

in N-alkylation with amine, 38, 42, 91–6, 172, 319

in N-heterocyclization, 95, 303–8from reductive amination, 82–4,

266–70in transfer dehydrogenation, 68–70,

137–40from transfer hydrogenation of

imine, 15, 19, 20, 81, 149, 265from transfer hydrogenation of nitro

compound, 16amine-tethered NHC, 14amino alcohol

from hydrogenation of lactam, 260–262

from mono-amination of diol, 171in N-heterocyclization, 163, 168, 303

ammoniain N-alkylation with alcohol, 44,

165–8, 308–10ammonium salt

in N-alkylation with alcohol, 90, 309–11

anthraphos-type pincer ligand, 124aqueous ammonia

in N-alkylation with alcohol, 44, 310aromatic compound

from dehydroaromatization of alkane, 116

from dehydroaromatization of cycloalkane, 115

benzoquinoneas hydrogen acceptor, oxidant,

60–62, 69–71, 97, 209β-alkylation

of alcohol, 28–36, 159–61, 283–7β-amino alcohol

in dehydrogenative amidation, 163in imination, 168

bicarbonatein hydrogenation, 141

biomimetic catalyst, 61, 69bisphosphinite-based pincer ligand,

112borohydride Ru complex, 130, 141,

178borrowing hydrogen, 28, 31, 38, 165,

2782-butanone

as hydrogen acceptor, oxidant, 207, 208

tert-butylethyleneas hydrogen acceptor, 109–20,

137–40, 278

carbamatein hydrogenation, 141

carbon dioxidein hydrogenation, 23, 141, 145in transfer hydrogenation, 23

carboxylic acidfrom dehydrogenative carboxylation

of alcohol, 325–7catalysis

cooperative, 60, 208, 253, 316, 322catalyst

bifunctional, 195, 196, 214, 229, 246, 268, 322, 328

biomimetic, 60, 71, 98Shvo’s, 57, 87

C–C bond-forming reaction, 27–36, 102–4, 159–61, 279–96

C–N bond-forming reaction, 37–45, 88–97, 161–73, 296–320

C–O bond-forming reaction, 46–51, 97–102, 173–82, 321–9

338 INdex

chloroformas oxidant, 67

Co complexin aerobic oxidation of alcohol, 61,

62, 203in aerobic oxidation of amine, 71

cyano ylide, 28cyclic dipeptide

from dehydrogenative amidation of β-amino alcohol, 163

cycloalkanein dehydroaromatization, 115in dehydrogenation, 121–6in oligomerization based on alkane

metathesis, 119in transfer dehydrogenation, 109–15

cycloalkenefrom dehydrogenation of

cycloalkane, 121–6from transfer dehydrogenation of

cycloalkane, 109–15cyclohexanone

as hydrogen acceptor, oxidant, 63

dehydrative etherificationof alcohol, 47

dehydroaromatizationof alkane, 116of cycloalkane, 115

dehydrogenationof alcohol, 10–12, 67, 128–33of alkane, 121–6of aminal, 37of cyclic amine, 139, 222–4of cycloalkane, 121–6ligand-promoted, 211

dehydrogenative acetalizationof alcohol, 178, 329

dehydrogenative amidationof amine with alcohol, 37–41,

161–5, 313–19of amine with ester, 163of β-amino alcohol, 163of diamine with diol, 163

dehydrogenative cyclization

of amine with diol, 39dehydrogenative esterification

of alcohol, 46, 49, 101, 173–82, 322–5

dehydrogenative lactamizationof amino alcohol, 40, 315, 316

dehydrogenative lactonizationof diol, 46, 98–101, 178, 179,

321–5dehydrogenative oxidation

of alcohol, 10–12, 67, 128–33of amine, 220–222of primary alcohol, 10–12,

215–17of secondary alcohol, 10–12,

128–32, 209–15, 217–19diamine

from N-alkylation of amine with diol, 43

in N-alkylation with diol, 163, 306dibenzobarrelene-based pincer ligand,

131, 133, 179dimetallic Ru complex

in C–C bond-forming reaction, 31dinuclear Ru complex

in aerobic oxidation of amine, 222in dehydrogenative oxidation of

alcohol, 129, 209–11diol

in dehydrogenative imidation of amine, 39

in dehydrogenative lactonization, 46, 98–101, 178, 179, 321–5

from hydrogenation of lactone, 257–9

in mono-amination, 171in N-alkylation of amine, 43in N-heterocyclization of amine,

304–7dynamic kinetic resolution, 6

enaminefrom transfer dehydrogenation of

amine, 138enzyme catalyst, 6

INdex 339

esterin dehydrogenative amidation of

amine, 163from dehydrogenative esterification

of alcohol, 46, 49, 101, 173–82, 322–5, 328

in hydrogenation, 21, 141, 154, 256–9

ethanolas hydrogen donor, reductan, 253in hydrogen production, 130

etherfrom dehydrative etherification, 47

Fe complexin oxidation of alcohol with

hydrogen peroxide, 205, 206in transfer hydrogenation of ketone,

234, 255, 256Fe complex with cylopentadienone

ligandin dehydrogenative lactonization of

diol, 100in Oppenauer-type oxidation of

alcohol, 62, 65in reductive amination, 82, 83in transfer hydrogenation of

aldehyde and ketone, 76Fe complex with

hydroxycylopentadienyl ligandin dehydrogenative lactonization of

diol, 100in Oppenauer-type oxidation of

alcohol, 64formic acid

as hydrogen donor, reductant, 21, 77, 235–43, 265, 267, 270

from hydrogenation of bicarbonate, 141

from hydrogenation of carbon dioxide, 23, 141

from transfer hydrogenation of carbon dioxide, 23

Friedländer reaction, 288modified, 31, 288

heterodimetallic Ir-Pd complexin C–N bond formation, 45in imination of nitro compound with

alcohol, 45heterodimetallic Rh-Ru complex

in Oppenauer-type oxidation of alcohol, 208

hydroacylationof aldehyde, 47

hydrogen, H2

as hydrogen donor, reductant, 12–14, 21–4, 72–4, 80, 82–3, 141–9, 229–34, 256–65, 270–274

hydrogen auto-transfer, 278hydrogen peroxide

as hydrogen acceptor, oxidant, 133, 202–6

hydrogen productionfrom ethanol, 130from 2-propanol, 130

hydrogenationof aldehyde, 12, 72–4, 230, 232of amide, 141, 263of carbamate, 141of carbon dioxide, 23, 141of ester, 21, 141, 154, 258, 259of imide, 260, 262of imine, 15, 17, 20, 21, 80, 263–5of ketone, 12, 72–4, 141, 229–34of lactam, 261, 262of lactone, 256–9of N-heterocyclic compound, 21, 270of nitrile, 13, 145, 272–4

imidefrom dehydrogenative imidation of

diol with amine, 39in hydrogenation, 260, 262

iminein hydrogenation, 15, 17, 20, 21, 80,

263–5from imination of amine with

alcohol, 167, 301from imination of nitro compound

with alcohol, 45

340 INdex

imine (cont’d )from oxidation of amine, 222from oxidative homocoupling of

primary amine, 38from transfer dehydrogenation of

amine, 68–71, 137–40in transfer hydrogenation, 15, 19,

20, 81, 149, 265Ir complex

in aerobic oxidation of alcohol, 194–6

in alkylation of amine with alcohol, 300, 302, 303

in alkylation of ammonia with alcohol, 310

in β-alkylation of alcohol with alcohol, 286, 287

in C–C bond-forming coupling of alcohol and allene, 290, 291

in dehydrogenative esterfication of alcohol, 324

in dehydrogenative lactonization of diol, 323, 325

in dehydrogenative oxidation of alcohol, 210–218

in dehydrogenative oxidation of amine, 222–4

in hydrogenation of imine, 264in Oppenauer-type oxidation of

alcohol, 207in reductive amination, 268, 269in transfer hydrogenation of

aldehyde, 243in transfer hydrogenation of imine,

266in transfer hydrogenation of ketone,

236–8, 241, 244, 247

Janus-head complexin C–C bond-forming reaction, 31

ketonefrom aerobic oxidation of secondary

alcohol, 60–62, 133–6, 186–96, 200–202

in α–alkyalation with alcohol, 280in C–C bond-forming reaction of

2-aminobenzyl alcohol, 31, 288from dehydrogenative oxidation of

secondary alcohol, 10–12, 67, 128–33, 209–15, 217–19

in hydrogenation, 12, 72–4, 141, 229–34

from Oppenauer-type oxidation of secondary alcohol, 3–7, 62–6, 133, 208

from oxidation of alcohol with hydrogen peroxide, 133, 202–6

in transfer hydrogenation, 14–21, 75–8, 149, 152, 154, 155, 234–56

kinetic resolution, 6, 9Knoevenagel reaction, 28

lactamfrom dehydrogenative lactamization

of amino alcohol, 315, 317in hydrogenation, 261, 262

lactonefrom dehydrogenative lactonization

of diol, 46, 98–101, 178, 179, 322–5

in hydrogenation, 256–9

mechanisminner-sphere, 59, 72, 79outer-sphere, 59, 72, 76, 79, 208,

214, 232, 234, 328metallocene-based pincer ligand,

110methanol

in dehydrogenative esterfication of alcohol, 326

from hydrogenation of carbon dioxide, 145

in methylation of amine with methanol, 169

Mo alkylidene catalystin alkane metathesis, 118

INdex 341

Mo complexin hydrogenation of ketone, 231in oxidation of alcohol with

hydrogen peroxide, 204, 205MW (microwave) heating, 43, 75, 82,

298, 299, 305, 306, 311

N-alkylationof amine with alcohol, 37–45,

88–90, 169, 171, 297–303of amine with amine, 42, 91–6, 172,

318–20of ammonia with alcohol, 44, 165–8,

308–10of ammonium salt with alcohol, 90,

309–11N-heteroaromatic compound

in dehydrogenation reaction of cyclic amine, 139, 222–4

N-heterocyclic compoundin hydrogenation, 21, 270in transfer hydrogenation, 21

N-heterocyclizationof amine with alcohol, 303–8of amine with amine, 97, 319by modified Friedländer reaction,

31, 288NHC-Ir complex

in β-alkylation of alcohol, 32in C–C bond formation, 32in C–N bond formation, 40–46in dehydrative etherification of

alcohol, 47in dehydrogenative oxidation of

alcohol, 12in hydrogenation of aza-heterocyclic

compound, 21in N-alkylation of amine with

alcohol, 40–45in N-alkylation of aqueous ammonia

with alcohol, 44in Oppenauer-type oxidation, 4–7in racemization of secondary

alcohol, 6in reduction of carbon dioxide, 23

in transfer hydrogenation of aldehyde, 17–21

in transfer hydrogenation of alkene, 16in transfer hydrogenation of carbon

dioxide, 23in transfer hydrogenation of ketone,

16–21in transfer hydrogenation of nitro

compound, 16NHC-Ni complex

in C–O bond formation, 47in hydroacylation of aldehyde, 47in Tishchenko reaction, 47

NHC-Pd complexin aerobic oxidation of alcohol, 7–9in kinetic resolution of secondary

alcohol, 9NHC-Rh complex

in transfer hydrogenation of imine, 15

in transfer hydrogenation of ketone, 15NHC-Ru complex

in β-alkylation of alcohol, 30–32in C–C bond formation, 27–34in C–N bond formation, 37–41in C–O bond formation, 46, 49in dehydrogenative amidation of

amine with alcohol, 37–41in dehydrogenative esterification of

alcohol, 46, 49in dehydrogenative imidation of

amine with diol, 39in dehydrogenative oxidation of

alcohol, 10, 11in hydrogenation of aldehyde, 12in hydrogenation of ester, 21in hydrogenation of ketone, 12in hydrogenation of nitrile, 13in N-alkylation of nitro compound

with alcohol, 37in Oppenauer-type oxidation, 3in oxidative homocoupling of

primary amine, 38in transfer hydrogenation of

ketone, 14

342 INdex

nitrilein alkylation with alcohol, 281from dehydrogenative oxidation of

amine, 139, 220in hydrogenation, 13, 145, 272–4from transfer dehydrogenation of

amine, 138–40nitro compound

in alkylation with alcohol, 37, 45, 282

in imination with alcohol, 45in transfer hydrogenation, 16

nitroarenein C–N bond formation, 37, 45, 314

norborneneas hydrogen acceptor, 110, 112

oligomerizationof cycloalkane, 119

Oppenauer-type oxidation, 3–7, 62–6, 133, 207–9

Os complexin dehydrogenative oxidation of

alcohol, 218in hydrogenation of ketone, 230in transfer hydrogenation of ketone,

250oxidation

of alcohol, 59–67, 133–6, 185–209of amine, 68–71, 220–222

oxidative homocouplingof primary amine, 38

oxygen, O2

as hydrogen acceptor, oxidant, 7–9, 60–62, 71, 186–202, 220–222

Pd complexin aerobic oxidation of alcohol,

186–93phosphonium ylide, 27pincer Fe complex

in hydrogenation of aldehyde, 141in hydrogenation of bicarbonate, 141in hydrogenation of carbon

dioxide, 141

in hydrogenation of ketone, 141pincer Ir complex

in alkane metathesis, 118–20in β-alkylation of alcohol, 160in C–C bond formation, 160in dehydroaromatization of alkane,

115–17in dehydroaromatization of

cycloalkane, 115in dehydrogenation of alkane, 121–5in dehydrogenation of cyclic amine,

139in dehydrogenation of cycloalkane,

121–5in dehydrogenative esterification of

alcohol, 179in dehydrogenative lactonization of

diol, 179in dehydrogenative oxidation of

alcohol, 131–3in methylation of amine with

methanol, 169in mono-amination of diol, 171in N-alkylation of amine with amine,

172in oligomerization of cycloalkane,

119in Oppenauer-type oxidation, 133in transfer dehydrogenation of

alkane, 109–15in transfer dehydrogenation of

amine, 137–40in transfer dehydrogenation of

cycloalkane, 109–15in transfer hydrogenation of imine,

149in transfer hydrogenation of ketone,

149pincer Os complex

in dehydrogenative esterification of alcohol, 178

in N-alkylation of amine with alcohol, 169

pincer Pd complexin aerobic oxidation of alcohol, 133

INdex 343

pincer Ru complexin β-alkylation of alcohol, 159in C–C bond formation, 159in C–N bond formation, 161–9in C–O bond formation,

173–9, 180in dehydrogenation of cycloalkane,

125in dehydrogenative acetalization of

alcohol, 178in dehydrogenative amidation of

amine with alcohol, 161–3in dehydrogenative amidation of

amine with ester, 163in dehydrogenative amidation of

β-amino alcohol, 163in dehydrogenative esterification of

alcohol, 173–5, 180dehydrogenative lactonization

of diol, 178in dehydrogenative oxidation of

alcohol, 128–31in hydrogenation of amide, 141in hydrogenation of carbamate,

141in hydrogenation of carbon

dioxide, 145in hydrogenation of ester,

141, 154in hydrogenation of nitrile, 145in imination of amine with

alcohol, 167in N-alkylation of ammonia with

alcohol, 165–8in transfer dehydrogenation of

cycloalkane, 114in transfer hydrogenation of

aldehyde, 154in transfer hydrogenation of ketone,

152, 154, 155polyamide

from dehydrogenative amidation of diamine with diol, 163

polyketonein transfer hydrogenation, 244

2-propanolas hydrogen donor, reductant, 14–21,

24, 75–7, 81, 149, 152, 154, 155, 242–56

in hydrogen production, 130pyrazine

from imination of β-amino alcohol, 168

quinolinefrom C–C bond formation of

2-aminobenzyl alcohol with ketone, 31, 288

in hydrogenation, 270

racemizationof secondary alcohol, 6

Re complex with hydroxycylopentadienyl ligand

in transfer hydrogenation of imine, 82

in transfer hydrogenation of ketone, 76

redox-neutral, 278Rh complex

in dehydrogenative amidation of alcohol with ammonia and amine, 316, 317

in dehydrogenative carboxylation of alcohol, 325, 327

in dehydrogenative esterification of alcohol, 326

in dehydrogenative lactamization of amino alcohol, 317

in hydrogenation of ketone, 231in hydrogenation of quinoline, 270in reductive amination, 267,

270, 271in transfer hydrogenation of ketone,

236, 241, 243, 253, 265Rh, Ru complex with

cyclopentadienone ligandin Oppenauer-type oxidation of

alcohol, 66

344 INdex

Ru complexin aerobic oxidation of alcohol,

196–200in aerobic oxidation of amine, 220–222in alkylation of cyano ketone with

alcohol, 282in alkylation of cyclic amine with

aldehyde or alcohol, 296in alkylation of nitro compound with

alcohol, 314in β-alkylation of alcohol with

alcohol, 284–5in dehydrogenative amidation of

alcohol, 316–18in dehydrogenative lactamization of

amino alcohol, 317in dehydrogenative lactonization of

diol, 322, 329in dehydrogenative oxidation of

alcohol, 218in hydrogenation of amide and

imide, 260–262in hydrogenation of ester and

lactone, 257–9in hydrogenation of imine, 263–5in hydrogenation of ketone, 229,

232, 233in hydrogenation of nitrile, 272–74in transfer hydrogenation of

aldehyde, 238, 242, 243, 252in transfer hydrogenation of ketone,

235, 239–52, 254Ru complex with

hydroxycylopentadienyl ligandin C–C bond-forming reaction, 102–4in C–N bond-forming reaction,

88–97in C–O bond-forming reaction,

97–102in oxidation of alcohol, 59–67in oxidation of amine, 68–71in reduction of aldehyde and ketone,

72–4, 75, 77in reduction of imine, 79–82

silver oxide, AgO2

as oxidant, 67

silylalkynein C–C bond-forming reaction with

amine, 103

tethered NHC ligand, 14, 20tetrametallic Ru complex

in C–C bond formation, 31in Oppenauer-type oxidation of

alcohol, 208Tishchenko reaction, 47, 321transfer dehydrogenation

of alkane, 109–20of amine, 137–40of cycloalkane, 109–20

transfer hydrogenationof aldehyde, 19–21, 76, 154, 238, 242of alkene, 16of α,β-unsaturated ketone, 31, 160,

238of carbon dioxide, 23of imine, 15, 19, 20, 37, 42, 81, 82,

149, 265of ketone, 14–21, 75–8, 149, 152,

154, 155, 234–56of N-heterocyclic compound, 21of nitro compound, 16

trimethylamine oxide, Me3NO

as oxidant, 64, 65, 83

V complexin aerocic oxidation of alcohol,

200–202vinylsilane

as hydrogen acceptor, 27, 28

W alkylidene catalystin alkane metathesis, 118

W complexin oxidation of alcohol with

hydrogen peroxide, 205water, H

2O

as solvent, 43, 186–91, 201, 208, 217, 234–43, 262, 266, 267, 271, 303, 306, 310, 312

water-soluble complex, 12, 186, 217, 235–43, 303, 310

Wittig reaction, 28

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