DEPARTMENT OF CHEMISTRY, UNIVERSITY OF JYVÄSKYLÄ RESEARCH REPORT No. 175

REMOTE β’-FUNCTIONALIZATION OF β-KETO ESTERS

BY

Mikko V. Leskinen

Academic Dissertation for the Degree of Doctor of Philosophy

To be presented, by permission of the Faculty of Mathematics and Science of the University of Jyväskylä, for public examination in Auditorium KEM4, on February 28th,

2014 at 12 noon.

Copyright ©, 2014 University of Jyväskylä

Jyväskylä, Finland ISBN 978-951-39-5619-6

ISSN 0357-346X

Title page 1 (produced by the Publishing Unit)

Title page 2 (produced by the Publishing Unit)

ABSTRACT

Leskinen, Mikko Remote β’-functionalization of β-keto esters Jyväskylä: University of Jyväskylä, 2014, 116 p. Department of Chemistry, University of Jyväskylä, Research Report Series ISSN 0357-346X ISBN 978-951-39-5619-6 The research described in this thesis focuses on the remote catalytic oxidative functionalization of sp3 C−H bonds. The goal of the work was to develop a new method for the cross-dehydrogenative coupling of β-keto esters and indoles. The basic aims of the study were successfully realized, and a new oxidative remote sp3 β’-C−H functionalization platform was created. The reactions were found to work under benign conditions at room temperature. Cross-dehydrogenative coupling

reactions between -keto esters and electron-rich arenes, such as indoles,

proceed with high regiochemical fidelity with a range of -keto esters and

indoles. The mechanism of the reaction between a prototypical -keto ester, ethyl 2-oxocyclopentanonecarboxylate and N-methylindole, has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The coupling is completed in cycle B, the C–C bond formation cycle, which is catalyzed by Pd(II) and also by trifluoroacetic acid. Keywords: Remote functionalization, Dehydrogenative cross-coupling,

Oxidative coupling, C−H functionalization, Palladium, -keto esters, Indole

Author’s address Mikko V. Leskinen Department of Chemistry P.O. Box 35 40014 University of Jyväskylä Finland mikko.v.leskinen@jyu.fi, mikko.v.leskinen@gmail.com Supervisors Professor Petri Pihko Department of Chemistry University of Jyväskylä

Reviewers Professor Olivier Baudoin

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires Université Claude Bernard Lyon 1 Lyon, France

Professor Olafs Daugulis Department of Chemistry University of Houston Houston, USA Opponents Professor Thorsten Bach

Technische Universität München Lehrstuhl für Organische Chemie I Lichtenbergstraße 4 85747 Garching Germany

ACKNOWLEDGEMENTS

Haluaisin aloittaa tämän kirjan kiittämällä kaikkia niitä, jotka ovat osaltaan olleet vaikuttamassa tämän kirjan syntyyn, tai ovat ylipäätään olleet vaikuttamassa siihen että olen päätynyt tätä kirjaa kirjoittamaa. Väitöskirjatyöni on suoritettu 06/2009−02/2014 innovaatiorahoituskeskus Tekesin, Suomen akatemian ja Jyväskylän yliopiston rahoituksella, joten kiitos myös näille tahoille. Ensimmäiseksi haluaisin tietenkin kiittää professori Petri Pihkoa, jonka ohjauksessa olen saanut toteuttaa väitöskirjatyöni. Kiitos kaikista niistä ajatuksia herättävistä keskusteluista mitä olen kanssasi saanut käydä ja menttoroinnista mitä olet suonut. Tietenkin isot kiitokset menevät porukalle, joiden kanssa olen saanut läheisesti työskennellä ja jotka ovat olleet ystäviä niin ylä- kuin alamäissä. Eeva, Sanna, Antti P., Antti N., Sakari, Melarto ja Jatta. Teitte kaikesta helpompaa. Big thanks goes also to Post-Docs Billy, Roshan, Aurelie, Nicolas, Sahoo, Hasibur, Meryem and Syam. Opiskelijat jotka ovat helpottaneet raadantaa labrassa Aini, Minna ja Laura. Kiitos! Kiitos myös kaikille, joiden kanssa olen saanut työskennellä. Haluaisin myös kiittää niitä ihmisiä ja firmoja joita ilman en varmaan olisi koskaan päätynyt tänne asti. Heikki Hassila Pharmatory, kiitos menttoroinnista ja siitä että näin mitä kemia on oikeasti. Hormos Medical Leena ja Maire, kiitos mukavasta vuodesta. Orion, kiitos kokoporukalle, mutta erityisesti Antti Pohjakalliolle ja Sirpa Raskulle, jotka auttoivat minua suurenmoisesti pääsemään sisälle hommiin. Ystävät KIITOS! Kiitos perheelleni kaikesta Jouko, Anne, Otto ja Kalle olette rakkaita. Kiitos rakkaimmalleni Leenalle yhteisistä vuosista, ilman sinua en olisi tässä. Rakkaudella, Jyväskylässä 10.2.2014 Mikko Leskinen

LIST OF ORIGINAL PUBLICATIONS

This thesis is based on the following original publications, which in the text are referred to by their Roman numerals. I Mikko V. Leskinen, Kai-Tai Yip, Arto Valkonen, and Petri M. Pihko,

Palladium-Catalyzed Dehydrogenative β‘-Functionalization of β-Keto Esters with Indoles at Room Temperature, J. Am. Chem. Soc. 2012, 134, 5750−5753.

II Kai-Tai Yip, Roshan Y. Nimje, Mikko V. Leskinen, and Petri M.

Pihko, Palladium-Catalyzed Dehydrogenative β’-Arylation of β -Keto Esters under Aerobic Conditions: Interplay of Metal and Brønsted Acids, Chem. Eur. J. 2012, 18, 12590 – 12594.

III Roshan Y. Nimje, Mikko V. Leskinen, and Petri M. Pihko, A Three-

Component Palladium-Catalyzed Oxidative C−C Coupling Reaction: A Domino Process in Two Dimensions, Angew. Chem. Int. Ed. 2013, 52, 4818 –4822.

IV Mikko V. Leskinen, Ádám Madarász, Kai-Tai Yip, Aini Vuorinen,

Imre Pápai, and Petri M. Pihko, Cross-Dehydrogenative Couplings between Indoles and β-Keto Esters: Ligand-Related Kinetic Isotope Effects and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II), Manuscript.

Author’s contribution In paper I, the author conceived and initiated the study and performed the screening of the conditions, explored the substrate scope, and wrote the paper together with the co-authors. In paper II, the author conceived the studies together with the co-authors and contributed to the control experiments necessary for the mechanistic study. The paper was written together with the co-authors. In paper III, the author conceived and initiated the study, carried out the kinetic experiments and wrote the paper together with the co-authors. In paper IV, the author conceived and initiated the study, carried out the kinetic experiments, expanded the substrate scope of the reaction, co-supervised one of the co-authors (A.V.), and wrote the paper together with the co-authors.

ABBREVIATIONS

Ac Acetyl AQ 8-Aminoquinoline BG Bulky group Bn Benzyl Boc tert-Butyloxycarbonyl B-Pin Boronic acid pinacol ester BQ Benzoquinone Bz Benzoyl Cat. Catalyst cod (1Z,5Z)-cycloocta-1,5-diene coe Cyclooctene de Diastereometric excess DCE 1,2-Dichloroethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DFT Density functional theory DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dr Diastereometric ratio ee Enantiometric excess

esp α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid EWG Electrons withdrawing group IBX 2-Iodoxybenzoic acid KIE Kinetic isotope effect Lauroyl peroxide Dodecanoic peroxyanhydride mep N,N’-dimethyl- N,N’-bis(2-pyridylmethyl-ethane Me4phen 3,4,7,8-Tetramethyl-1,10,-phenanthroline nbe Norbornen NMP 1-Methyl-2-pyrrolidone NPhth Phtalimidyl Ns 4-Nitrobenzenesulfonyl Ms Methanesulfonyl Oxone Potassium peroxymonosulfate, K2S2O8 PDP 2-({(S)-2-[(S)-1-(pyridine-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1-

}methyl)pyridine PG Removable protecting group

Ph-BOX (−)-2,2′-Isopropylidenebis[(4S)-4-phenyl-2-oxazoline] Piv Pivalic PivOH Pivalic acid RedG Nonhaem iron-dependent dioxygenase Selectfluor 1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane

ditetrafluoroborate Me3tacn 1,4,7-trimethyl-1,4,7-triazacyclononane TBDPS tert-Butyldiphenylsilyl TBS tert-Butyldimethylsilyl TcBoc 2,2,2-Trichloro-tert-butyloxycarbonyl TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxy Tf Trifluoromethanesulfonyl

TFA Trifluoroactetic acid THF Tetrahydrofuran tetramethylTHF 2,2,5,5-Tetramethyltetrahydrofuran tpa Triphenylacetate Ts p-Toluenesulfonyl

CONTENTS

ABSTRACT

PREFACE

LIST OF ORIGINAL PUBLICATIONS

ABBREVIATIONS

TABLE OF CONTENTS

1 REVIEW OF LITERATURE .............................................................................. 13

1.1 Introduction ............................................................................................... 13

1.1.1 Selective catalytic oxidative remote functionalization of

aliphatic sp3 C−H bonds ............................................................... 13

1.2 Oxidative C-C bond formation reactions .............................................. 18

1.2.1 β-C-C Bond formation reactions ................................................. 18

1.2.2 γ-C-C Bond formation reactions ................................................. 33

1.3 Oxidative hydroxylations and alkoxylations ....................................... 34

1.3.1 β-Hydroxylations and β-alkoxylations ....................................... 34

1.3.2 γ-Hydroxylations and γ-alkoxylations ....................................... 42

1.4 Aminations ................................................................................................ 56

1.4.1 β- and δ-Aminations ...................................................................... 56

1.5 Oxidative halogenations .......................................................................... 71

1.6 Organocatalytic approach ....................................................................... 71

1.7 Conclusion ................................................................................................. 74

2 RESULTS AND DISCUSSION ......................................................................... 76

2.1 Aims and background of the work ........................................................ 76

2.2 Dehydrogenative α-coupling reactions with β-keto esters ................. 78

2.2.1 Development of racemic α-functionalization of β-keto esters 78

2.2.2 Enantioselective α-functionalization of β-keto esters ............... 82

2.3 Dehydrogenative cross-coupling at remote β-position ....................... 84

2.3.1 Dehydrogenative β’-functionalization of β-keto esters with

indoles ............................................................................................. 84

2.3.2 Dehydrogenative β’-arylation of β-keto esters .......................... 89

2.3.3 A three-component palladium-catalyzed oxidative C−C

coupling reaction ........................................................................... 91

2.4 The reaction mechanism of the β’-functionalization of β-keto esters

with indoles ............................................................................................... 95

3 SUMMARY AND CONCLUSIONS .............................................................. 103

REFERENCES ............................................................................................................. 106

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1 REVIEW OF LITERATURE

1.1 Introduction

1.1.1 Selective catalytic oxidative remote functionalization of aliphatic sp3 C−H bonds

The catalytic functionalization of C−H bonds1-20profoundly changed how we

think about using them in synthetic chemistry and has the potential to revolu-

tionize the synthesis of complex molecules.21-30 In particular, the functionaliza-

tion of C−H bonds has plenty of unreleased potential in the late-state function-

alization31-33 of complex molecules as well as for the streamlining of large-scale

manufacturing in pharmaceutical, fine-chemical and agricultural industries.34-36

At the C−H functionalization, the direct oxidations of the C−H bonds allows for

the use of simple (i.e., less functionalized) reagents and often reduces the num-

ber of steps it takes for the target molecule to produce better atomy-, redox- and

step-economies. With late-state functionalization, it is possible to add function-

alities to drug candidates and create new analogues without a need for going

back to the beginning of the sequence with pre-functionalized starting materials.

The benefit of this kind of strategy includes fewer laborious operations that lead

to lower costs and improvements of waste and environmental profiles.

14

Figure 1. Activated vs. unactivated positions.

The thermodynamics of making a new bond (e.g. C−C bond) with a loss of hy-

drogen is typically unfavorable and thus requires an external driving force,

namely, an appropriate sacrificial oxidant. Other challenges include overcom-

ing the low reactivity of C−H bonds, achieving a site selective functionalization

of one C−H bond in the presence of all others, and outcompeting dimerization.

A classic problem in the field is how to selectively functionalize an sp3 C−H

bond, which is not adjacent to a heteroatom or π system (i.e., α-position). By

contrast, there are a lot of tools that can be used for the functionalization of sp2

and for the α-positions of functional groups. However, the sp3 C−H bond func-

tionalization of these remote positions is still elusive (Figure 1).37

The stoiciometric amounts of expensive metal-salts are commonly used in the

functionalization of C−H as an oxidizer. For catalytic purposes, the replacement

of metal-salts by using inexpensive and environmentally friendly oxidants such

as air and oxygen will dramatically improve the practicality of using C−H cou-

pling reactions. As a result, this offers attractive academic and industrial pro-

spects in the synthetic chemistry.38-47

15

Scheme 1. Proposed biosynthesis scheme for butyl-meta-cycloheptylprodiginine by dehydrogenative macrocyclization between sp3 and sp2 C−H bonds.

In nature, region- and stereoselective C−H bond functionalizations under ambi-

ent reaction conditions come from fundamental transformations catalyzed by

enzymes.48,49 For example, cytochrome P450 mono-oxygenases catalyse (among

other oxidative reactions) the O2-mediated alkyl C−H bond hydroxylation of

complex molecules, which is critical for the drug metabolizing and biosynthesis

of secondary metabolites.50-52 In Nature, new C−C bonds are also formed

through the oxidative coupling of remote sp3 C−H bonds (See Scheme 1).53,54

Reactions such as these can inspire chemists to go beyond biosynthetic path-

ways by creating new kinds of reactions. Besides the reactions that mimic natu-

ral, biosynthetic pathways, chemists can also design new kinds of reactions

through metal catalysis, via pathways that are not accessible in Nature

Figure 3. Definition of positions in this review.

The aim of this review is to bring attention to the current state of the field of

remote selective catalytic oxidative functionalization of sp3 C−H bonds. Remote

16

position is defined as all other positions compared to the α-position of the func-

tional group or to the sp/sp2 carbon (Figure 3). It should be noted that halogen-

ated reagents do not need an external oxidant for C−H bond functionalization

reactions, hence they are not covered in this review (Scheme 2).

Scheme 2. Halogenated reagents can be used for direct C−H bond functionalization reac-tions without the need of an external oxidant.

There are two activation modes available for remote sp3 C−H bond

functionalizations; directed and selective (Scheme 3). Directed intramolecular

sp3 C−H activation is facilitated by heteroatom-assisted coordination of the

transition metal. The selectivity is controlled by the electronics, sterics and

strain release.55 It must be noted that for sp3 C−H bonds, pKa and bond dissocia-

tion energies do not vary in aliphatic systems to the extent that they do in aro-

matic, bencylic or allylic systems. As a result, this makes it harder to distinguish

between C−H bonds in an aliphatic system (Scheme 4). 56 , 57 The activation

modes are covered in more detail in later chapters.

It should be noted that oxidative addition through Pd(IV) is unprecedented and

extremely unlikely (Scheme 3).

17

Scheme 3. Indicates activation modes for remote sp3 C−H bond functionalization.

Scheme 4. Selected bond dissociation energies and the pKa for C−H bonds.

18

1.2 Oxidative C-C bond formation reactions

1.2.1 β-C-C Bond formation reactions

In 2006, Chen, Goodhue and Yu reported the seminal example of palladium(II)-

catalyzed alkylations of remote β-sp3 C−H bonds with either methylboroxine

(Scheme 5) or boronic acids (Scheme 6) using pyridine as a directing group.58

Using an organometallic reagent in C−H activation is challenging because

Pd(II)-catalyzed homocoupling might be faster than C−H activation.59

In the alkylation reaction of sp3 C−H bonds with methylboroxine, the research-

ers used Cu(OAc)2 as a co-oxidant together with benzoquinone (BQ). Benzo-

quinone is also important for the reductive elimination step.60 However, in the

alkylation of β-sp3 C−H bonds with boronic acid Ag2O and had to be used as a

co-oxidant because Cu(OAc)2 severely suppressed the coupling reaction. Ag2O

plays a dual role as a co-oxidant and also promotes transmetallation61. It is

noteworthy that Ag2O was able to replace Cu(OAc)2 as an oxidant in the cou-

pling reaction with methylboroxines (Scheme 5). A major limitation for using

Ag(I) salts as the stoichiometric oxidant is that its use is not practical on a larger

scale.

19

Scheme 5. Pyridine-directed alkylation of β-sp3 C−H bonds with methylboroxine (3).58

Scheme 6. Pyridine-directed alkylation of sp3 C−H bonds with alkylboronic acid.58

20

Scheme 7. Enantioselective alkylation of sp3 C−H bonds with alkylboronic acid.62

Later, in 2008, Yu and coworkers reported the first example of a catalytic

asymmetric sp3 C−H coupling reaction. They presented only one example of the

C−C coupling of a butylboronic acid (17) with a primary C−H bond, which af-

forded only a modest yield and enantioselectivity (Scheme 7).62

Yu and coworkers have also investigated the use of a more practical directing

group (carboxylic acid) for an oxidative β-sp3 functionalization reaction.63 The

actual directing-group in this transformation is the in-situ formed carboxylate

where K2HPO4 is used as a base in the reaction. The yields and scope of the oxi-

dative β-sp3-arylation reaction were modest (Scheme 8).

21

Scheme 8. Carboxylic acid-Directed arylation of β-sp3 bonds with phenylboronate (19).63

In 2008, Yu and coworkers reported that O-methyl hydroxamic acids, readily

available from carboxylic acids, were also viable directing groups in β-C−H ac-

tivation via Pd-catalysis.64 Thus, β-arylation of the methyl group proceeded

smoothly by stirring the substrate with 0.5 equiv of benzoquinone, 2 equiv of

Ag2O, 2 equiv. of K2CO3, 1.6 equiv. of arylboronic acid, and 10 mol % of

Pd(OAc)2 in tert-BuOH at 70 °C for 18 hours (Scheme 9).

22

Scheme 9. β-Arylation of O-methyl hydroxyamic acids.64

However, the coupling of substrates with a alkylboronic acids under conditions

identical to those used with arylboronic acids, (Scheme 9), did not produce any

desired product. This is presumably due to β-hydride elimination. Yu speculat-

ed that the undesired β-hydride elimination could be suppressed by using a

sterically hindered ligand along with a meticulous choice of a good solvent.65,66

Following this hypothesis, they found that the presence of sterically hindered

ligand prevented the reaction, but the use of 2,2,5,5-tetramethyltetrahydrofuran

as a solvent allowed for the coupling of a β-sp3 C−H bond with alkylboronic

acids (Scheme 10).

23

Scheme 10. β-Alkylation of O-methyl hydroxyamic acids.64

Yu and coworkers also demonstrated the potential for their protocol by alkylat-

ing substrate 38, derived from dehydroabietic acid, with alkylboronic acid 39

Scheme 11). Dehydroabietic acid is identified as a natural product and as an

efficient BK channel opener.67

.

Scheme 11. β-Alkylation of dehydroabietic acid derivative 38.64

While aryl C−H olefination has been extensively explored in recent years, the

olefination of an unactive sp3 alkyl C−H bond has been a more elusive task

(Scheme 12). The first aryl C−H olefination was published by Fujiwara and

24

Moritani as early as 1967,68,69 whereas the first olefination of an unactive sp3

C−H bond was not published until the Yu’s group reported success in this area

in 2010.70

Scheme 12. Aryl and sp3 C−H olefination.

As established in previous reports, the N-arylamide (CONHAr) directing group

was highly efficient in a Pd(II)-catalyzed sp3 C−H activation. This was especially

true for electron-withdrawing substituents in an N-aryl group (CF3, F, and NO2)

that enhanced the reactivity of the coupling reactions.71 By optimizing the di-

recting group, they were able to identify two optimal aryl groups in the

olefination of a β-sp3 C−H bond (Ar1 and Ar2 in Scheme 13).

Scheme 13. Directing group optimization.70

25

The choice of solvents was also crucial for their reactivity. Polar and strongly

coordinating amide solvents, such as NMP, DMA, and DMF, produced superior

results. With the optimized conditions at hand, they β-olefinated a wide variety

of amides with their corresponding products (Scheme 14).

Scheme 14. Amide-directed olefination of sp3 β-C−H bond.70

Remarkably, their olefination protocol was also found to be effective for the β-

olefination of cyclopropane substrates (49, 50 and 51). With substrates 50 and 53

serving as a side reaction, the ortho-olefination of the aryl groups also took place

(Scheme 15 and Scheme 16).

26

Scheme 15. Amide-directed olefination of cyclopropane 50 sp3 β-C−H bond.70

Scheme 16. Amide-directed olefination of cyclopropane 53 sp3 β-C−H bond70.

Despite recent landmark developments of the Pd(II)-catalyzed carbonylation of

aryl sp2 C−H bonds72-77, achieving Pd(II)-catalyzed sp3 C−H carbonylation has

been a more challenging task. By following Fujiwara’s78-80 early footsteps for the

carbonylation of a small alkane sp3 C−H bond, Yoo, Wasa and Yu established

the amide-directed carbonylation of a sp3 β-C−H bond.81

Scheme 17. Amide-directed carbonylation of sp3 β-C−H bond81.

27

They demonstrated the power of their β-carbonylation method with a wide

range of different substrates (Scheme 18). Substrates bearing a quaternary α-

center provided products with good to excellent yields. It is also intriguing that

substrates bearing hydrogen at the α-carbon gave the succinimide products in

good yields.

Scheme 18. Amide-directed carbonylation of an sp3 β-C−H bond81.

Applications of catalytic sp3 C−H bond functionalization reactions with low-

valent late transition metals are rare. However, Chatani and coworkers have

recently demonstrated the use of a low-valent late transition metal catalyst,

Ru(CO)12, as a catalyst for the regioselective carbonylation of unactivated β sp3

C−H bonds of aliphatic amides (Scheme 19).82,83 Interestingly, they use ethylene

as an oxidizer in the reaction. Furthermore, they clearly demonstrate a role of

the pyridine directing group in the reaction. Hence, a product was not formed

in the reaction if the pyridine directing group was replaced by a non-chelating

phenyl group.

28

Scheme 19. Amide-pyridine-directed carbonylation of a sp3 β-C−H bond.82,83

Sanford and coworkers published in 2011 a new method for the

Pd/polyoxometalate-catalyzed aerobic olefination of unactivated β-sp3 bonds.84

Their strategy involved a sequence of a β-olefination of sp3 C−H bond followed

by a reversible intramolecular Michael addition, which protects the

monoalkylated product from over functionalization (Scheme 20).

Scheme 20. β-Olefination followed by a reversible Michael addition.84

The reaction is executed under similar conditions reported by Obora and Ishii

for the Pd/polyoxometalate cocatalyzed aerobic olefination of benzene. 85

Molybdovanadophosporic acid (H4[PMo11VO40]) is serving as reoxidant of the

29

reduced Pd0 to PdII during the reaction course.84,85 A variety of pyridines could

be used as substrates in this β-olefination and cyclization sequence with moder-

ate yields (Scheme 21).84

Scheme 21. β-Olefination and cyclization between various pyridines and alkenes.84

In 2011, Yu and coworkers made a breakthrough in the enantioselective C−H

activation. After laborious screening, they demonstrated the first examples of

an enantioselective β-C−H activation of cyclopropanes through a systematic

tuning of the mono-N-protected amino acid ligand and the reaction conditions

(Scheme 22).86

30

Scheme 22. Asymmetric cyclopropane C−H activation.86

To establish the optimal reaction conditions, they first screened the reaction

conditions for the racemic reaction for the β-coupling of cyclopropanes and

organoboron reagents (Scheme 23). Building on their earlier success of utilizing

acidic N-arylamides (Scheme 22, Ar) as weakly coordinating directing groups

for a diverse range of alkyl and aryl C−H functionalization reactions,70,71,81,87-89

they chose amide 81 as a test substrate for a coupling reaction with

phenylboronic acid pinacol ester. Extensive screening revealed the need to use

four different reaction conditions and two different organoboron reagents (B-

Pin and BF3K) in order to obtain optimal yields.

31

Scheme 23. Racemic cross-coupling of cyclopropyl C−H bonds with organoboron rea-gents.86

Subsequently, they started to screen optimal ligands for an effective

enantioselective coupling reaction. Initially, they focused on screening mono-N-

protected L-leucine derivatives and found that carbamate groups gave superior

ee and mono selectivity compared with an amide group (Scheme 22, PG).

Among the various carbamate protecting groups that were tested, 2,2,2-

trichloro-tert-butyloxycarbonyl (TcBoc) gave the best ee (78%) and yield (47%).

They subsequently investigated the effect of the amino acid backbone and

found that having an aryl group on the amino acid side chain was crucial for

obtaining a high ee (Scheme 22, R3). After a slight modification of the carbamate

protecting group, they finally discovered that amino acid ligand 89 afforded the

best ee. This ligand afforded moderate yields and a good ee (Scheme 24). It is

also noteworthy that the reagents were added into two batches, using a 5 mol%

32

catalyst and a 10 mol% ligand 89 for each batch to afford the optimal yield and

ee. The addition of the reactants in a single batch resulted in inferior and incon-

sistent results.

Scheme 24. Enantioselective cross-coupling of cyclopropyl C−H bonds with organoboron reagents.86

Liègault and Fagnou reported the first example of an intramolecular

dehydrogenative coupling between sp2 and β-sp3 C−H bonds.90 They demon-

strate the dehydrogenative intramolecular β-coupling reaction by using

Pd(OAc)2 as a catalyst and air as the terminal oxidant, which showed moderate

scope and efficiency (Scheme 25).

33

Scheme 25. Intramolecular dehydrogenative β-coupling reaction.90

1.2.2 γ-C-C Bond formation reactions

Recently in 2013, Pierre and Baudoin disclosed a method for an intramolecular

γ-coupling reaction between sp2 and γ-sp3 C−H bonds. This paper showed that

the synthesis of fused thiophene-cyclopentanes by PdII-catalyzed

dehydrogenative sp2 and γ-sp3 C−H coupling is feasible, with modest yields

(Scheme 26). Therefore, they also gave a statement that the reaction, “is current-

ly much less efficient than a two-step sequence composed of electrophilic halo-

genations and Pd(0)-catalyzed sp3 C−H arylation, and thus, it cannot be consid-

ered as synthetically competitive alternative yet”.91

34

Scheme 26. Intramolecular dehydrogenative γ-coupling reaction.91

1.3 Oxidative hydroxylations and alkoxylations

1.3.1 β-Hydroxylations and β-alkoxylations

Sanford and coworkers reported the first acetoxylation of benzylic C−H

bonds,92 and they also extended this methodology to primary unactivated β-sp3

C−H bonds with O-methyl oxime or pyridine as a directing group (Scheme

28).93 The reactivity and selectivity observed in these reactions arise from the

chelating groups, which are both directing and activating the β-sp3 C−H bond

(Scheme 27).

35

Scheme 27. Chelate-directed β-oxidation of an O-methyl oxime.93

Scheme 28. Oxime-directed β-acetoxylation of an sp3 C−H bond.93

Removal of the oxime ether directing group from the β-functionalized products,

as seen in Scheme 28, is challenging. Therefore, Sanford and coworkers devel-

oped a more practical method for the β-acetoxylation of an sp3 C−H bond. They

used simple unprotected oximes, which are surrogate to the ketone, as a re-

movable directing group (Scheme 29). While the regeneration of a ketone from

the corresponding oxime is plausible, in this case, the feasibility of the oxime

hydrolysis was demonstrated in only 5 examples and the yields over two steps

were only modest (18-64%).94

36

Scheme 29. Hydroxyl oxime-directed acetoxylation of an sp3 C−H bond.94

The development of a metal catalyst for the oxidation of sp3 C−H bonds into

C−O bonds using oxygen as an oxidant is still a major challenge. Notably, the

oxidants used in these reactions are typically reagents such as PhI(OAc)2, perox-

ides, IOAc, or K2S2O8, which have significant disadvantages including high cost,

poor atom economy and the formation of waste byproducts. Therefore, more

sophisticated methods for the acetoxylation of sp3 C−H bonds is needed. To ad-

dress these problems, Sanford and coworkers reported, in 2012, a method for

the aerobic Pd-catalyzed oxidation of unactivated sp3 C–H bonds.95 Their paper

demonstrates the use of a combination of Pd(OAc)2 and NaNO3 or NaNO2, as

the co-catalyst, to catalyze the aerobic β-acetoxylation of an sp3 C−H bond

(Scheme 30). They also demonstrated that an oxygen atom in the product origi-

nates from acetic acid and not from O2 by carrying out a reaction in the atmos-

phere of 18O2.

Scheme 30. β-Acetoxylation of sp3 C−H bond using air or O2 as an oxidant.95

37

In 2005, Yu and coworkers reported the β-acetoxylation of sp3 C−H bonds using

oxazoline as a directing group (Scheme 31).96 The use of acetic anhydride in this

reaction is crucial for catalytic turnover. If acetic anhydride is not used in the

reaction, then the yields do not exceed the molar amount of the catalyst. Also,

based on a previous characterization of isolated Pd(IV) species formed by the

oxidative addition of benzoyl peroxide or an aryl transfer from

diphenyliodonium triflate to a 2,2’-bipyridine-coordinated Pd(II) and Pt(II) cen-

ters, the researchers concluded that Pd(IV) intermediates might be in involved

in the catalytic cycle.97-99

Scheme 31. Oxazoline-directed β-acetoxylation of an sp3 C−H bond.96

In 2012, Houk, Yu and coworkers published a study on the origin of the

diastereoselectivity at Pd(II)-catalyzed sp3 C−H bond iodination and

acetoxylation reactions. They based their conclusions on the characterization of

38

a trinuclear chiral C−H insertion intermediate by X-ray and DFT calculations.

The solid-state structure revealed that the new (S) chiral center which is gener-

ated after the C−H cleavage is determinate by t-Bu groups on the oxazoline and

carboxyclic moieties of the substrates which are remaining in anti-position to

each other (Figure 2). The DFT calculations revealed that t-Bu substituent in

oxazolene ligand is essential to achieve high reactivity. Repleacing the t-Bu sub-

stituent with the smaller i-Pr group leads to a stable resting

[bis(oxazoline)]Pd(OAc)2 complex before the C−H activation and increases the

overall activation barrier an therefore lowering the reactivity.100

Figure 2. X-ray structure of the trinuclear chiral C−H insertion intermediate.101

More recently, in 2012, Sahoo and coworkers used a new removable pyridyl-

sulfoximine-directing group β-acetoxylation of sp3 C−H bonds.102 They were

able to demonstrate the efficiency of their new ligand with several examples

(Scheme 32). Also, the removal and recovery of the directing group could be

achieved (Scheme 33).

39

Scheme 32. Pyridyl-sulfoximine-directed β-acetoxylation of a sp3 C−H bond.102

Scheme 33. Recovery of a pyridyl-sulfoximine-directing group.102

Synthesis of 1,2-diols directly from monoalcohols via the catalytic oxidation of a

sp3 C−H bond is a more challenging problem than the β-oxidation of

monoalcohols to 1,3-diols. Compared to the β-position that gives 1,3-diols, the

β-position of an alcohol is relatively electron-deficient due to the inductive ef-

40

fect of oxygen and is, thus, less reactive toward electrophilic C−H activation.

Dong and coworkers developed a β-acetoxylation of sp3 C−H bonds of alcohols

by using an exo-directing group (Figure 3).103 In an exo-palladacycle, formed

through the coordination of oxime nitrogen to Pd(II), the π-bond of the direct-

ing group is outside of the metallocycle, whereas in an endo-palladacycle, the π-

bond of the directing group is inside of the metallocycle (Figure 3).

Figure 3. endo-Metalation vs exo-metalation.103

The yields of the reaction are good with numerous substrates. However, the

substrate scope seems to be quite limited: there are no examples of any other

functional groups than the directing group in the substrates (Scheme 34).

41

Scheme 34. β-Acetoxylation of sp3 C−H bond via exo-directing group103

Corey and coworkers have contributed to the development of methods for the

β-acetoxylation of sp3 C−H bonds104. They reported, in 2006, a diastereoselective

β-acetoxylation of α-amino acid derivatives using 8-aminoquinone as a direct-

ing group (Scheme 35).

42

Scheme 35. β-Acetoxylation of α-amino acid derivatives.104

1.3.2 γ-Hydroxylations and γ-alkoxylations

The strategy used by Simmons and Hartwig for the γ-functionalization of

unactivated aliphatic C−H bonds directed by a hydroxyl group is outlined be-

low (Scheme 36):105

Scheme 36. Strategy for the hydroxyl-directed γ- functionalization of C−H bonds.105

In this strategy, dihydrosilane attaches to the oxygen atom of an alcohol 159 or

ketone 160 by forming a (hydrido)silyl ether 161 to direct the γ-C−H bond func-

tionalization. The (hydrido)silyl ether 161 is formed through a dehydrogenative

coupling with alcohol or by hydrosilylation of the ketone. The Si-H unit of silyl

ether undergoes an Ir-catalyzed dehydrogenative functionalization of a primary

C−H bond without the isolation of an intermediate 161. This is followed by a

43

Fleming-Tamao oxidation106-112 of the oxasilolane 162 which yields the 1,3-diol

163 (Scheme 36).

Selected products for the γ-functionalization of alcohols and ketones are pre-

sented in Scheme 37 and Scheme 38, respectively. Both tertiary and secondary

alcohols undergo a primary aliphatic C−H bond functionalization with compa-

rable efficiency. Reactions of phenol 168 also occurred under this condition in a

good yield. The reaction was insensitive to the stereochemistry of cyclic trans-

and cis-2-methylcyclohexanol (165). However, the reaction with an acyclic ke-

tone, which possesses a diastereotopic methyl group, provided 174 as a major

product with good diastereoselectivity (82:18 dr).

44

Scheme 37. Hydroxyl-directed γ-oxygenation of alcohols.105

45

Scheme 38. Hydroxyl-directed γ-oxygenation of ketones.105

Because the Ir-catalyzed γ-functionalization tolerates this kind of auxiliary func-

tionality and is highly selective for primary C−H bonds, Simmons and Hartwig

were also able to demonstrate the robustness of their reaction with natural

product substrates. As an example, (+)-fenchol was oxidized smoothly at the

methyl group, affording the oxidized product 183 (Scheme 39).

46

Scheme 39. Directed aliphatic C−H functionalization of (+)-fenchol.105

Furthermore, direct γ-functionalization of (+)-camphor via exo-selective

hydrosilylation followed by C−H functionalization resulted in 185 with a 57%

yield (Scheme 40).

Scheme 40. Direct γ-functionalization of (+)-camphor.105

Finally, they conducted the selective C−H functionalization on a pair of

triterpenoid saponin aglycons. Triterpenoid saponin aglycons exhibit a range of

biological activities e.g. anti-inflammatory, anti-fungal and anti-tumor proper-

ties. They also possess strong haemolytic activities, and consequently, are inter-

esting synthetic targets. 113 The selective C−H functionalization of methyl

olenate resulted in methyl hederagenin (187) in one step (Scheme 41).

47

Scheme 41. Hydroxyl-directed γ-functionalization of methyl olenate.105

Despite the significant advances in Pd-catalyzed sp3 C−H acetoxylation reac-

tions by the Sanford and Yu laboratories, the corresponding alkoxylation reac-

tions are rare. As an example of such a reaction, Chen and coworkers reported a

highly efficient method for the synthesis of alkyl ether via a Pd-catalyzed,

picolinamide directed γ-alkoxylation of sp3 and sp2 C−H bonds for remote alco-

hols.114 In summary, they have developed a highly efficient method for the syn-

thesis of alkyl ethers via Pd-catalyzed γ-alkoxylation of a wide range of amides

(Scheme 42 and Scheme 43).

Scheme 42. Picolinamide-directed γ-alkoxylation of sp3 C−H bond with alcohols.114

48

Scheme 43. Substrate scope of picolinamides and alcohols at γ-oxidation reaction.114

Altough ruthenium tetraoxide was first prepared by Claus115 in 1860, its use as

an unselective oxidant for organic compounds did not begin until 1953 by

Djerassi and Engle.116 However, in 1985, Hasegawa, Niwa and Yamada pub-

lished their groundbreaking report on the selective oxidation of sp3 C−H bonds

with RuCl3 for ketone functionalities.117 They present the ruthenium-catalyzed

direct oxidation of a sp3 C−H bond adjacent to a cyclopropane ring that results

in the corresponding ketones (Scheme 44).

49

Scheme 44. Ruthenium-catalyzed oxidation of sp3 C−H bond.117

A seminal report of the selective hydroxylation of alkenes tertiary sp3 C−H

bonds with RuCl3 was disclosed in 1989 by Tenaglia, Terranova and Waegel.118

They showed that the combination of RuCl3, which forms a catalytically active

species (RuO4) under the reaction conditions, and NaIO4 as a oxidizer in a ter-

nary solvent mixture is capable of hydroxylating the natural product cedrane

and a small number of related substrates (Scheme 45).

50

Scheme 45. Ruthenium-catalyzed hydroxylation of tertiary C−H bonds.118

The catalytically active species, RuO4, is formed in-situ in reaction conditions by

the oxidation of a lower-valent ruthenium precursor, RuCl3. Subsequently,

formed catalytic quantities of RuO4 are involved in concerted asynchronous [3 +

2] cycloaddition of the substrates where a C−H bond is transformed to an alco-

hol (Scheme 46).119-126

Scheme 46. Proposed transition state for the Ruthenium-catalyzed hydroxylation of tertiary C−H bonds.

In 2010, MacNeill and Du Bois presented an efficient protocol for the selective

hydroxylation of unactivated tertiary C−H bonds.127 The combination of catalyt-

ic RuCl3 and pyridine with KBrO3 as the oxidant was shown to promote the

hydroxylation of substrates possessing different polar functional groups. This

protocol produces the tertiary alcohol products in moderate yields (Scheme 47).

51

Scheme 47. Ruthenium-catalyzed oxidation of tertiary C−H bonds.127

Needless to say, proper ligands are needed in order to efficiently advance and

tune these catalysts or steer the catalyst to react enantioselectively. Studies by

Che and coworkers 128 , 129 inspired McNeill and Du Bois to examine (1,4,7-

trimethyl-1,4,7-triazacyclononane) ruthenium(III) trichloride, [(Me3tacn)RuCl3]

221, as an oxidation precatalyst. They found that a [(Me3tacn)RuCl3]-precatalyst

combined with AgClO4 and (NH4)2Ce(NO3)6 efficiently hydroxylated tertiary

C−H bonds in a number of structurally diverse substrates (Scheme 48). They

also proposed a mechanism, based on chemoselectivity trends and kinetic iso-

tope effect data, that involves a stepwise radical-rebound C−H abstraction

pathway.130

52

Scheme 48. Ru-catalyzed oxidation of tertiary C−H bonds.130

In 2007, based on the work of Lawrence Que’s group131-135 and others136-140 on

non-heme iron catalysts, Chen and White presented a pioneering publication

for the selective hydroxylation of tertiary sp3 C−H bonds. 141 They reported that

an iron-based small molecule catalyst, Fe(S,S-PDP) 227, used hydrogen perox-

ide to hydroxylate a broad range of the substrates bearing tertiary sp3 C−H

bonds (Scheme 49). It is noteworthy that the hydroxylation reaction occurred

with the complete retention of stereochemistry (232 and 233).

53

Scheme 49. Fe(S,S-PDP)-catalyzed hydroxylation of tertiary sp3 C−H bonds.141

Earlier, in 2001, White, Doyle and Jacobsen have used a similar bulky iron-

catalyst, [Fe(II)(mep)(MeCN)2]142,143 240, for preparative epoxidations of ole-

fins.144 Increasing the flexibility of the ligand results in a weaker binding of the

54

ligand, which increases the decomposition of the catalyst. Unselective oxida-

tions with nonheme iron-catalysts are often attributed to catalyst decomposi-

tion.145 Hence, to improve the site selectivity of the Fe catalyst, Chen and White

added more rigidity to the ligand (241 in Scheme 50).

Scheme 50. Fe(S,S-PDP)-Catalyst has more rigid ligand compared to [Fe(II)(mep)(MeCN)2].

They also propose a model for the site-selectivity of C−H hydroxylation. There

are three modes of selectivity:141

1. Due to an electrophilic nature of the oxidant generated with Fe(S,S-

PDP) and H2O2, hydroxylation preferentially occurs at the most elec-

tron-rich tertiary C−H bond.

2. Hydroxylation occurs at the least sterically hindered and most elec-

tron-rich tertiary C−H bond.

3. Hydroxylation is also directed by a free carboxylic acid.

Chen and White demonstrate the value of their protocol through the late-stage

hydroxylation of the antimalarial drug artemisin (242). On the basis of the selec-

tivity rules outlined above, they were able to identify the most reactive tertiary

55

C−H bond, which reacted as predicted in the hydroxylation reaction. By recy-

cling the unreacted starting material two times, they were able to isolate the

selectively hydroxylated, diastereomerically pure 243 in a 56% overall yield

(Scheme 51). Similar yields were also possible to achieve by slowly adding cata-

lyst Fe(S,S-PDP) and hydrogen peroxide simultaneously over 45 or 60 min via a

syringe pump.146 Chen and White have also used the same catalyst, Fe(S,S-PDP),

in unselective methylene oxidations.147

Scheme 51. Selective hydroxylation of antimalarial drug artemisinin.141

In 2013, Gormisky and White introduced a new modification of Fe(S,S)-PDP),

which shows that a catalyst control of site-selectivity in aliphatic C−H oxidation

is possible, without the need of a specific match between one catalyst and one

substrate (245 in Scheme 52). The improved site selectivity achieved with this

catalyst is based on the steric blocking of larger C−H sites through non-binding

bulky ortho-CF3-aryl rings. However, the examples that were presented are still

unselective. The authors also disclosed a quantitative mathematical model that

relates each the site selectivities of each catalyst with the properties of the sub-

strate.148

56

Scheme 52. Fe(S,S-PDP) and its derivative Fe(S,S-CF3-PDP).148

1.4 Aminations

1.4.1 β- and δ-Aminations

In 2009, Kuwano and coworkers presented the first example of an

intramolecular nickel-catalyzed one-step coupling between a β-sp3 C−H bond

and an amine, which is followed by a β-hydride elimination to form β-amino

substituted unsaturated ketones (enaminones).149 They used Ni(cod)2 as a cata-

lyst, PMe3 as a ligand, PhCl as an oxidizer and K3PO4 as a base in dioxane at

elevated temperatures (Scheme 53).

57

Scheme 53. Nickel-catalyzed sequential β-amination and β-hydride elimination.149

Che and coworkers disclosed an intramolecular protocol for the β-amidation of

sp3 C−H bonds.150 This protocol enables oxime-directed amidation of some al-

kene substrates by using Pd(OAc)2 as a catalyst and oxone as an oxidizer in

dichloroethane at 80 °C (Scheme 54). Their method is also applicable to the β-

amidation of sp2 C−H bonds.

58

Scheme 54. Oxime-directed β-coupling between amines and sp3 C−H bonds.150

By treading on Barton’s151, Breslow’s152, and Corey’s153 footsteps on the func-

tionalization of C−H bonds in the terpenoid skeleton, Baran and coworkers

have made important contributions to the β-amidation of sp3 C−H bonds in

terpenes. Improving the methodology reported by Banks and coworkers,154

Baran and coworkers were able to conduct a Ritter-type amination of β-sp3 C−H

bonds (Scheme 56).155 The methodology is based on two steps: First, the β-

aminated cyclic imidate 258 is formed by using Selectfluor as the oxidizer and

acetonitrile as the amine source. The imidate 258 is then hydrolyzed in a second

step for a β-aminated product 259 in one-pot (Scheme 55). The method is also

capable for the nonselective mono-amination of hydrocarbon substrates.

59

Scheme 55. β-Amination of an sp3 C−H bond followed by hydrolysis.155

Scheme 56. Scope of β-amination of sp3 C−H bonds for alcohols and ketones.155

In 2009, Glorius and coworkers reported the intramolecular β-amidation of ani-

lines.156 They synthesized indolines through a Pd-catalyzed oxidative cycliza-

tion of amide substrates by using AgOAc as an oxidizer and K2CO3 as a base at

high temperature (Scheme 57). A wide range of substrates could be used, but

only trace amounts of the product was detected when anything else than the N-

acetyl group, such as -pivaloyl, -benzoyl, -trifluoroacetyl, or N-tosyl group, was

used.

60

Scheme 57. Intramolecular β-Amination of sp3 C−H bonds.156

Chen and coworkers recently (2012) disclosed an efficient method for synthesiz-

ing azetidines, pyrrolidines, and indolines via a Pd-catalyzed intramolecular

amination of sp3 C−H bonds at the γ and δ positions of picolinamide (Scheme 58

and Scheme 59).157 In a palladium-catalyzed intramolecular amination of γ-sp3

C−H bonds, it was found that the use of a typical PhI(OAc)2 oxidizer, in normal

conditions, is effective. Pd(OAc)2 and PhI(OAc)2 are commonly used in sp3 C-H

61

hydroxylation and alkoxylation rections. Hence, it is not surprising that the

primary by-products of the coupling reactions are γ- and δ-

acetoxypicolinamides.

Scheme 58. Synthesis of azetidines via an intramolecular amination of γ-sp3 C−H bonds.157

62

Scheme 59. The synthesis of pyrrolidines via an intramolecular amination of δ-sp3 C−H bonds.157

In 2013, Chen and coworkers introduced a synthesis of pyrrolidones by the pal-

ladium-catalyzed intramolecular amination of δ-sp3 C−H bonds, using 8-

aminoquinoline (AQ) or pyridine as the directing group (Scheme 60 and

Scheme 61).158 In this method, they used the same conditions as in their earlier

pyrrolidine synthesis,157 where Pd(OAc)2 served as a catalyst and PhI(OAc)2 as

an oxidizer in toluene at elevated temperatures. They also used two different

directing groups with the same substrates that had similar results (Scheme 60

and Scheme 61).

63

Scheme 60. Intramolecular aminoquinoline-directed γ-amination.158

Scheme 61. Intramolecular pyridine-directed γ-amination.158

Nadres and Daugulis have published a method for the formation of five-

membered heterocycles via a palladium-catalyzed picolinic acid-directed δ-sp3

C−H/C-N coupling. 159 They used commonly employed conditions, i.e.

Pd(OAc)2, as a catalyst and PhI(OAc)2 as an oxidizer in toluene at 80-120 °C, to

64

synthesize a range of the pyrrolidines (Scheme 62). The cyclization method was

also found to be effective for sp2 as well as for benzylic sp3 C−H bonds.

Scheme 62. Intramolecular cyclization of alkyl picolinamides.159

In 2001, based on Breslow’s pioneering study’s160-162 Espino and Du Bois dis-

closed a rhodium-catalyzed intramolecular oxidative cyclization reaction of

carbamates to oxazolidinones.163 Several carbamates were used to illustrate the

potential value of their β-C−H bonds amination reaction (a, Scheme 63). Later in

2003, Hinman and Du Bois employed the same protocol in a stereoselective to-

tal synthesis of (-)-Tetrodotoxin (b, Scheme 63).164

65

Scheme 63. Intramolecular rhodium-catalyzed oxidative cyclization of carbamates to oxalzolidinones.163,164

Also in 2001, Du Bois and co-workers introduced a similar method for the oxi-

dative cyclization of sulfamate esters. 165 A combination of sulfamate with

66

PhI(OAc)2 and a commercial dirhodium catalyst, Rh4(OAc)4 or Rh2(oct)4, result-

ed in a γ-aminated product with good yields (a, Scheme 64). Wehn and Du Bois

also applied the same methodology to the intramolecular γ-amination of sp3

C−H bonds in the enantioselective synthesis of the alkaloid manzacidin A (b,

Scheme 64). 166

67

Scheme 64. Intramolecular rhodium-catalyzed γ-amination of sp3 C−H bonds.165,166

68

In order to improve the scope and efficiency of the amination of sp3 C−H bonds,

efforts have also focused on the design of new catalysts. Du Bois and coworkers

have developed a more robust and efficient rhodium(II)-catalyst, Rh2(esp)2,

which shows a superior catalytic activity for intramolecular C−H oxidation

with sulfamate, sulfamide and urea substrates (Figure 4).167 It is noteworthy

that Rh2(esp)2 is also commercially available.168

Figure 4. Rh2(esp)2, Bis[rhodium(α, α, α′, α′-tetramethyl-1,3-benzenedipropionic acid)].167,168

Zalatan and Du Bois have also suggested that high performance displayed by

Rh2(esp)2 for catalytic C−H amination is due to the kinetic stability of the cata-

lyst dimer when it comes to oxidative decomposition. Furthermore, remarkably,

the carboxylic acid generated as a byproduct under these conditions serves a

critical role as a reducting agent to return a mixed-valent Rh2+/Rh3+ dimer to a

catalytically active neutral form (Scheme 65).169-171Zare group, the researchers

have also confirmed and identified these reactive transiently dirhodium inter-

mediates by using a high-resolution desorption electrospray ionization mass

spectrometry.172

69

Scheme 65. Reduction of inactive [Rh2(esp)2]+ by a carboxylic acid.167-169

By using this new efficient catalyst, Rh2(esp)2, Fiori and Du Bois reported suc-

cess in the intermolecular amination of benzylic and tertiary C−H bonds.173 The

reaction was conducted with several substrates by using

trichloroethylsulfamate as a nitrene precursor in good yields. However, if the

reaction was conducted with substrates bearing remote sp3 C−H bonds the

yields were found to be modest (Scheme 66).

Scheme 66. Rhodium-catalyzed intermolecular amination of tertiary C−H bonds.173

70

In 2013, Roizen, Zalatan and Du Bois reported a more general method for the

selective intramolecular amination of tertiary C−H centers (Scheme 67).174 The

influence of different nitrogen sources compared to the efficiency of the reaction

was dramatic. While most of the sulfonamides produced low yields in the reac-

tion, the sulfamate prepared from 2,6-difluorophenol, DfsNH2 318, provided a

much better yield. A carboxylic acid additive, PhMe2CCO2H, served as an effec-

tive reducing agent for the mixed-valent Rh2+/Rh3+ dimer to neutral species

and improved catalyst turnover numbers (Scheme 65). It was also observed that

the enantiospecific insertion into an optically active tertiary substrate is possible

without the loss of enantiopurity (324).

Scheme 67. Rhodium-catalyzed intermolecular amination of tertiary C−H bonds.174

71

1.5 Oxidative halogenations

Yu and co-workers used an oxazoline-directing group tactic in order to achieve

the iodination of a β-sp3 C−H bond (Scheme 68).175 Oxazoline, a chelating chiral

auxiliary, was also effective for the asymmetric β-iodination of (331 and 332).

Scheme 68. Oxazoline-directed β-iodination of sp3 C−H bond.175

1.6 Organocatalytic approach

In 2005, Brodsky and Du Bois presented the first organocatalytic oxaziridine-

based hydroxylation of tertiary sp3 C−H bonds.176 They found that bis(3, 5-bis

(trifluoromethyl) phenyl) diselenide, (Ar2Se2), reacted with urea-hydrogen per-

oxide to give perselenic acid, which acts as an oxidizer. They were able to

hydroxylate tertiary sp3 C−H bonds for a modest number of substrates with

72

moderate yields (Scheme 69). The disadvantage of the method was the use of a

toxic and expensive diselenide.

Scheme 69. Organocatalytic benzoaxathiazine-catalyzed sp3 C−H bond hydroxylation.176

The oxaziridine intermediate is generated in-situ by using a terminal oxidant.

Subsequently, the formed oxaziridine intermediate hydroxylates the C−H bond

(Scheme 70). An oxaziridine-mediated O-atom transfer to the C−H bond likely

occurs through a concerted, asynchronous process.177-179

Scheme 70. Benzoaxathiazine-catalyzed sp3 C−H bond hydroxylation.176

In 2009, Du Bois and co-workers published an improved organocatalytic proto-

col for the benzoxathiazine-catalyzed sp3 C−H bond hydroxylation process. 180

73

They were able to improve the catalytic activity by systematically exploring the

influence of an electronic substitution on catalysts aromatic ring. Moreover,

they suggest that aquous H2O2 conditions promotes the kinetically slow C−H

hydroxylation events throught the hydrophobic aggregation of catalyst and

substrate. With the more active catalyst 338 in their hands, they were able to use

only H2O2 as a terminal oxidant. Additionally, they employed their protocol to

a number of architecturally diverse substrates that resulted in good yields

(Scheme 71).

Scheme 71. Benzoaxathiazine-catalyzed sp3 C−H bond hydroxylation by using aqueous hydroperoxide as an oxidizer.180

In 2011, Wang and co-workers proposed a new organocatalytic strategy for the

enantioselective β-functionalization of aldehydes (Scheme 72).181 Their oxidative

74

enamine catalysis strategy is based on the oxidation of enamine A to the un-

saturated iminium ion B. Subsequently, the resulting iminium ion B species

undergoes an enantioselective conjugation addition to a new chiral product.

Scheme 72. Strategy for organocatalytic access to the β-functionalization of aldehydes.181

They demonstrate the efficiency of their protocol with several examples where

the β-position of an aldehyde is also a benzylic position. However, there is only

one example with an aliphatic aldehyde 345 (Scheme 73).

Scheme 73. Organocatalytic enantioselective cascade oxidation-Michael reaction.181

1.7 Conclusion

The reactions discussed above enable the direct, selective and efficient activa-

tion of remote sp3 C−H bonds to form C−C, C−O, C−N and C−I bonds and can

be used to generate molecular complexity in the three dimensions. However,

although there are plenty of examples of efficient oxidative functionalization of

75

remote sp3 C−H bonds, selective dehydrogenative cross-couplings reactions are

still rare and their mechanistic investigations are yet elusive.

The utilization of the remote functionalization of the sp3 C−H bonds beholds

great potential to construct the molecular diversity by efficient and “economical”

manners. To be sure, in the future the increasing demand of more economical,

novel and resourceful reactions to achieve the remote functionalization of sp3

C−H bonds will keep the field vibrant.

76

2 RESULTS AND DISCUSSION

2.1 Aims and background of the work

The design of a new drug, which is at the heart of commercialization of biologi-

cal targets, starts with chemical synthesis. The complexity of the active pharma-

ceutical ingredients (API) has grown during the years, mostly due to an in-

creased amount of disease pathways (i.e. biological targets) and new regulatory

requirements (Figure 5).182 Today, the number of chemical entities needed from

concept to product is enormous and is growing, and the preclinical and clinical

studies also need increasing quantities of candidates for testing.

Figure 5. The evolving chemical structural landscape of the pharmaceutical industry.

The development of new complex pharmaceuticals is critically dependent on

our ability to synthesize an active molecular species in an efficient manner. The

77

competitive environment of the pharmaceutical industry continues to undergo

dramatic changes. What the pharmaceutical and fine chemicals industry needs

in order to survive in this environment is both new products — i.e. new mole-

cules, and fast, robust, innovative technologies to access the ever more difficult

target molecules. This can be achieved by developing more efficient, novel syn-

thetic methodologies, which will help us to synthesize new molecules faster and

more cost efficiently by using sustainable chemistry. One of the most promising

technologies that will answer these requirements are catalytic dehydrogenative

cross-coupling reactions (CDC) where two C−H bonds are oxidized by using an

external sacrificial oxidant to form a new C−C bond (Scheme 74).183-185

Scheme 74. Catalytic dehydrogenative cross-coupling reaction.

As a part of the Pharma programme of Tekes,186 a consortium project titled

“Enabling Synthesis Technologies − Key Technologies for Enhancing the Com-

petitiveness of Pharmaceutical and Fine Chemical Industry in Finland and Re-

moving the Bottlenecks in Synthesis” was launched in 2008. The industrial con-

sortium behind this project identified the following reaction types as particular-

ly acute problems within the pharmaceutical industry:

1) Redox reactions: Organo- and organometallic catalysis for C=O or

C=N reduction/alcohol oxidation.

2) Coupling chemistry: Catalytic C−C, C−N bond formation reactions,

especially asymmetric coupling reactions.

3) Quaternaries: Synthesis of quaternary stereocenters, especially all-

carbon quaternary centers.

78

The asymmetric synthesis of molecules bearing quaternary carbon stereocenters

represents a remarkably challenging and dynamic area in organic synthesis.

The construction of molecules containing these centers with the right catalytic

enantioselective manners is particularly demanding and important.187-192 In or-

der to respond to the problems given above, the project initiated an investiga-

tion of the oxidative formation of quaternary centers. The initial idea of this

study was to develop an enantioselective oxidative α-functionalization method

for β-keto esters to form quaternary stereocenters (Scheme 75).

Scheme 75. Initial idea for oxidative α-functionalization of β-keto esters.

2.2 Dehydrogenative α-coupling reactions with β-keto esters

2.2.1 Development of racemic α-functionalization of β-keto esters

Indole is the third most popular ring system found in bioactive molecules193

and consists of a common core of over 3000 natural products194. Because of the

central place of heterocycles, especially indole, in medicinal chemistry, the orig-

inal aim of this study developed an oxidative coupling reaction between indoles

and β-keto esters.

This study was initiated by examining the optimal metal-catalyst for the reac-

tion of cyclic β-keto esters 349 and 1-methylindole (350) with t-BuOOH (in 2,2,4-

trimethylpentane, 5.5 M) as an oxidant without any additional solvent. The α-

coupled product (351) was then obtained in moderate yields with copper-salts

79

as a catalyst (Table 1, entries 1-12) and similar results were obtained with

Mn(OAc)2 and FeCl2. However, the use of Pd(OAc)2 and (Ph3P)3RuCl did not

provide for a α-coupling product. The most active copper-catalyst Cu(OAc)2 ∙

H2O was chosen to use for further achiral screenings.

Table 1. Screen of transition metal catalyst in the oxidative α-functionalization of β-keto estersa

Entry [M] (10 mol%) Yieldb

1 Cu(OAc)2 59% 2 Cu(OAc)2 ∙ H2O 60% 3 CuBr 47% 4 CuBr2 42% 5 CuCl 52% 6 CuCl2 49%

10 Cu(II) 2-Ethylhexanoate 55% 11 Cu(BF4)2 ∙ xH2O nd 12 CuI 25% 13 Pd(OAc)2 nd 14 Mn(OAc)2 61% 15 FeCl3 25% 16 (Ph3P)3RuCl nd 17 InCl3 12% 18 - nd

a) To the mixture of indole 350 (24 mg, 0.2 mmol, 100 mol%), β-ketoester 349 (62 mg, 0.4 mmol, 200 mol%). Additionally, a transition metal catalyst (10 mol%) was added to tBuOOH in 2,2,4-trimethylpentane (45 μl, 0.25 mmol, 125 mol%, 5.5 M) and the reaction mixture was stirred 1h at 70 °C under Ar. b) GC yield. Tetradecane was used as an internal standard.

Subsequently, the effect of an additional solvent was investigated. A survey of

different solvents revealed that none of the co-solvents were beneficial for the

reaction yields (Table 2).

80

Table 2. Screen of the solvents in an oxidative α-functionalization of β-keto estersa

Entry Solvent Yieldb

1 DCE 37% 2 CHCl3 28% 3 Toluene 43% 4 ACN 35% 5 THF nd 6 Hexane 39% 7 DMF nd 8 MeOH 12% 9 H2O 28%

a) To the solution of indole 350 (24 mg, 0,2 mmol, 100 mol%), β-ketoester 349 (62 mg, 0,4 mmol, 200 mol%) and Cu(OAc)2 ∙ H2O (4 mg, 0,02 mmol, 10 mol%) in solvent (0.5 ml) was added tBuOOH in 2,2,4-trimethylpentane (45 μl, 0,25 mmol, 125 mol%, 5,5 M), and the re-action mixture was stirred 3h at 70 °C under Ar. b) GC yield. Tetradecane was used as an internal standard.

The effect of ligand was also studied. Cu(II) was by far the best cation and

triflate was the counteranion of choice in the ligand screens. This is due to the

weakly nucleophilic character and weak coordination ability of the triflate

ion.195 The reaction was conducted in CH2Cl2 under an O2 atmosphere. All of

the tested ligands gave low (<5%) yields (Table 3). The screen of the achiral lig-

ands revealed that ligands could not improve the yields in the racemic reaction.

81

Table 3. Screen of the ligands in an oxidative α-functionalization of β-keto esters.a

Entry Ligand Entry Ligand

1

7

2

8

3

9

4

10

5

11

6

a) To the solution of Cu(OTf)2 (12 mg, 0.03 mmol, 50 mol%) and Ligand (51 mol%) in CH2Cl2 (0.5ml) was added indole 350 (8 mg, 0,07 mmol, 100 mol%) and β-ketoester 349 (11 mg, 0,07 mmol, 100 mol%), and the reaction mixture was stirred at rt under O2 (balloon).

82

2.2.2 Enantioselective α-functionalization of β-keto esters

As mentioned in the introduction, the ultimate goal of the project was to devel-

op an enantioselective dehydrogenative α-coupling reaction in order to form

chiral quaternary centers. To achieve this goal, several chiral ligands were ex-

amined.

It was found that additional bases could also increase the conversion of the α-

coupling product. The most effective bases were triethylamine and iPr2NEt. A

stoichiometric amount of base inhibited the reaction, and ca. 20 mol% of the

base was optimal. For enantioselectivity screens, several chiral ligands were

employed (Table 4). The bis(oxazoline) ligands gave the best selectivities in the

enantioselective reaction (Table 4), affording the product at up to 63% ee. How-

ever, the yield and enantioselectivities were only modest with all of the ligands.

Some of the more hindered bis(oxazoline) ligands were ineffective for the reac-

tion due to either the stability or the inhibition of the catalyst. Furthermore, the

yields were generally lower than the amount of the catalyst, indicating that the

catalytic cycle was not working.

83

Table 4. Screen of the ligand in the enantioselective oxidative α-functionalization of β-keto esters.a

Entry Ligand mol% Base

(mol%) Reaction time Yield eed

1

120 - 18h 37% 50%

2

50 15b 47h 36% 44%

3

30 10c 42h 30% 44%

4

50 - 24h 20% 63%

5

50 16b 18h 7% 40%

6

50 20c 20h 28% 44%

7

50 - 20h 10% 32%

8e

<5% -

84

9e

<5% -

10e

<5% -

11e

<5% -

a) Conditions: To a solution of Cu(OTf)2 and ligand in CH2Cl2 (0.5ml) was added indole 350 (24 mg, 0,2 mmol, 100 mol%) and β-ketoester 349 (62 mg, 0,4 mmol, 200 mol%), and the reaction mixture was stirred at rt under an O2 (balloon). b) iPr2NEt c) Et3N d) Determined by HPLC (Chiralcel IA column). e) Several conditions were screened.

2.3 Dehydrogenative cross-coupling at remote β-position

2.3.1 Dehydrogenative β’-functionalization of β-keto esters with indoles

When different oxidizers were tested for the enantioselective α-coupling reac-

tion between β-keto ester 349 and indole (350), it was found that 2,3-dichloro-

5,6-dicyano-1,4-benzoquinone (DDQ) resulted in the formation of a new prod-

uct (Scheme 76). After characterization, the newly formed product was identi-

fied as the unexpected β-coupling product 352.

85

Scheme 76. First example of an intermolecular dehydrogenative cross-coupling reaction at β’-Position between the sp3 and sp2 C−H bonds.196

After this new and exciting discovery of a dehydrogenative cross-coupling reac-

tion that took place at the β-position, further efforts concentrated on developing

this reaction. It should be noted that, if the ligand is omitted from the reaction

with Cu(OTf)2, no product is formed. The screen of the various ligands revealed

the superiority of the Ph-BOX ligand. All other ligands showed lower yields

and achiral ligands. In order to overcome the problem with low yields, several

copper sources were screened. However, none of them improved the yields.

Attention was then switched to other metal salts. To our delight, the use of

Pd(OAc)2 gave a significantly improved yield. Instead of indole (350), 1-

methylindole (353) was selected as a model compound for further screening as

it was easier to add to the reaction media via a syringe.

Further screens indicated that Pd(TFA)2 was a more active catalyst than

Pd(OAc)2.I 1,4-Dioxane and 2-propanol mixed with AcOH gave similar results

in the reaction. However, 2-propanol was determined to be the solvent of choice

to use due to its lower price, better environmental profile and suitability for in-

86

dustrial scale reactions.197,198 Additionally, with the 2-propanol/AcOH solvent

system, the undesired side reaction, a homocoupling of indole 353,199 could be

minimized.200 While a wide variety of oxidants gave reasonable conversions at

room temperature, tert-butyl perbenzoate (tBuOOBz) afforded superior results.

It should be noted that in addition to the peroxide oxidant, oxygen was also a

synthetically useful oxidant. Furthermore, the reaction is really robust and can

be conducted with an open vessel without the need of dry solvents. More im-

portantly, the regioselectivity was excellent for both coupling partners and no

indole regioisomers could be detected in any of the reactions with the Pd(II)

catalyst. These results are presented in full in paper I.

The substrate scope of the dehydrogenative β-coupling reaction was found to be

wide. Both unsubstituted 355 as well as N-substituted indoles (356 and 358)

provided good product yields.I N-Benzyl protected indole 357 also supplied a

good product yield.IV The reaction is highly tolerant of the substituent with dif-

ferent electronic properties in the indole nucleus, which allowed for further op-

portunities to conduct synthetic transformations. Furthermore, bulky indoles

360 and 359 bearing an aromatic group for position 3 provided high yields.IV

The substrate scope with β-keto esters was also wide. The substrates bearing 6-

and 7-membered ring (365 and 366), and ester groups (361-364) were reacting

smoothly in the reaction with good yields.I,IV Acyclic β-keto esters and lactones

were also seen to be compatible substrates (367 and 368).I

The diastereoselective synthesis of the β-coupling products were also possible.

The use of an enantiopure menthyl-derived ester enabled β-functionalization in

a diastereoselective fashion (369, dr = 3:1 for two trans isomers). The

regiochemical identity of both isomers was confirmed by 2D NMR experi-

ments.I Later, it was found that higher diastereomeric ratios were achieved by

using enantiopure 2-phenyl-menthyl-derived esters as a starting material

(dr >20:1).IV

87

Scheme 77. Scope of dehydrogenative coupling with different indoles.I,IV

88

Scheme 78. Scope of dehydrogenative coupling with different β-keto esters.I,IV

A more practical and economic option was achieved when a combined reaction

of Pd(OAc)2 and trifluoroacetic acid was used instead of Pd(TFA)2 under nor-

89

mal conditions. This provided comparable reaction rates and yields compared

to Pd(TFA)2.IV

Table 5. Effect of added trifluoroacetic acid to the coupling reaction catalyzed by Pd(OAc)2.a,IV

Entry TFA Rate 354 (mM min-1)b

1c 0 mol% 1.7 2 0 mol% 0.1 3 10 mol% 1.7 4 20 mol% 2.3 5 30 mol% 2.6 6 40mol% 2.6

a) The rates were obtained by monitoring the temporal progress of the coupling by 1H NMR spectroscopy. Reaction conditions: TFA, [349]0= 0.476 M, [353]0= 0.318 M, [tBuOOBz]0= 0.413 M, 10 mol% Pd(OAc)2, 4:1 [D8]-Dioxane/AcOH, 300 K. b) Max rate. c) Used Pd(TFA)2 instead of Pd(OAc)2.

2.3.2 Dehydrogenative β’-arylation of β-keto esters

The expansion to these substrates was carried out by Drs. Kai-Tai Yip and

Roshan Nimje at this laboratory. After realizing that indoles could react with β-

keto esters it was also postulated that electron-rich aromatics could also react

with β-keto esters. After screening the reaction conditions, it was found that by

carefully choosing to use a Pd catalyst and a Brønsted acid co-catalyst, electron-

rich arenes (Scheme 79) and a variety of phenols (Scheme 80) could undergo a

highly regioselective dehydrogenative coupling at room temperature with β-

keto esters in the β’-position. The acidic co-catalyst prevented problems associ-

ated with the overoxidation or degradation of the product. These result are pre-

sented more detailed in paper II.

90

Scheme 79. A dehydrogenative coupling of electron-rich arenes and β-keto esters.II

Scheme 80. Dehydrogenative coupling between phenols and β-keto esters.II

Interestingly enough, the β’-arylation of β-keto esters also proceeded with

iodobenzene by using AgOAc as the iodide scavenger in TFA to directly pro-

vide for the β’-arylation product 371 (Scheme 81).II This direct arylation reaction

was discovered at an early stage of the studies in 2012, but we were not able to

realize this reaction with good yields and a wider substrate scope. However, in

2013, Huang and Dong published a similar catalytic direct β-arylation reaction

of simple ketones with aryl iodides. They cited our single example and expand-

ed the concept through a careful optimization of the reaction conditions and

ligands.201

Scheme 81. Direct arylation of the β’-position of β-keto esters.II

91

2.3.3 A three-component palladium-catalyzed oxidative C−C coupling reac-tion

In 2012, I also found that aryl boronic acids could couple at the β’-position of β-

keto esters with modest yields (Scheme 82).

Scheme 82.The direct arylation of β’-position of β-keto esters with a phenylboronic acid.

Subsequently, during the competition reaction between indole 353 and

phenylboronic acid (372) with β-keto ester 349 it was serendipitously discov-

ered that all three components of the reaction could react together (Scheme

83).III After this invention, it was easy to rationalize the novelty and the poten-

tial of this reaction. Laborious screening revealed that the original reaction con-

ditions were most optimal for the three component reactions. The scope of the

reaction, as probed by Dr. Roshan Nimje, turned out to be very wide. Even very

hindered atropisomers could be synthesized.III

Scheme 83. A novel palladium-catalyzed oxidative three component reaction.III

92

The most interesting aspect of the newly developed reaction was its mechanism.

Theoretically, each of the components could react in a homo- or heterocoupling

with another component. Typically, multicomponent reactions are considered

to proceed in a linear domino mode: in the first stage, components (A) and (B)

give rise to a reactive intermediate (AB) which then reacts with a third compo-

nent (C), and so on, until the sequence is terminated. In these classical multi-

component reactions, the reactivity order is controlled largely by the functional

groups present.

By contrast, in an oxidative coupling, the three components (A), (B), and (C)

could react with each other in any order. Such three-component domino reac-

tions (3CR) could proceed through an alternative two dimensional split domino

process. In such a process, there are two kinetic alternatives that result in the

final (ABC) product, via the (AB) or (BC) intermediates. If the steps are irre-

versible, the efficiency of the process could be compromised if one of the path-

ways leads to a dead end. Alternatively, unwanted homocoupling or

heterocoupling reactions between the components could also jeopardize the

projected 3CR process.

93

Figure 6. Monitoring of the temporal progress of the 3CR by 1H NMR spectroscopy.III

In order to probe whether the 3CR reaction could proceed through either (A+B)

or (B+C) pathways, or whether one of the pathways was dominating, the tem-

poral progress of the reaction was followed by 1H NMR (Figure 6) and each of

the binary coupling reactions was also monitored separately in control experi-

ments. The experiments revealed that in the major pathway, indole 353 and bo-

ronic acid 372 were coupled first, forming species BC (375). Subsequently, BC

(375) reacted with enone 374, generated from -ketoester 349, to give the prod-

uct 376 (ABC). These results are presented in full in paper III.

94

Scheme 84. The dominating reaction pathway of a palladium-catalyzed oxidative three component reaction.III

95

2.4 The reaction mechanism of the β’-functionalization of β-keto esters with indoles

Figure 7. Monitoring of the temporal progress of the coupling by 1H NMR spectroscopy.IV

The reaction mechanism was investigated comprehensively by online 1H NMR

methods, which allowed the simultaneous monitoring of several species and

also enabled the study of kinetic isotope effects via deuterium labeling of the

substrates (Figure 7). In summary, kinetic experiments revealed that the reac-

tion likely proceeded in two stages, via an enone intermediate 374. A proposed

96

mechanism thus involves two catalytic cycles, the dehydrogenation step (Cycle

A) and the C-C coupling step (Cycle B) (Scheme 85).IV

Scheme 85. Schematic catalytic cycles for the dehydrogenation and the C-C bond formation steps.IV

Key evidence for the roles of each component in the cycle is summarized below.

Cycle A:

- The reaction proceeds smoothly with stoichiometric amount of Pd(TFA)2

without a oxidizer under the Ar → The reaction is Pd(II) catalyzed (Pa-

per I).

- Deuterium labeling of an indole at the C2 position accelerates the for-

mation of enone 374 compared to a non-deuterated indole → Indole is π-

coordinated to Pd center (Paper IV, Figure 2).

97

- Control experiments with 1,3-dimethylindole accelerates formation of

enone 374 compared to the reaction without indole 353 → Indole is π co-

ordinated to Pd center (Paper IV)

- Intramolecular competition experiment202 with mono-β’-D-labeled β-keto

ester: no kinetic isotope effect (KIE) observed. → Rupture of β’-H bond is

not turnover-determining in cycle A (Paper IV, Scheme 6 and Scheme 87).

Cycle B:

- Cycle B: control experiments with enone under either Pd(TFA)2 or TFA

catalysis indicated that only Pd(TFA)2 catalysis afforded rates compara-

ble to the standard reaction conditions → Cycle B is likely Pd(II) cata-

lyzed (Paper IV, Scheme 3).

Although TFA alone was an inefficient catalyst, when Pd(OAc)2 was used as a

catalyst with added TFA the formation rate of the enone 374 (Cycle A) as well

as the formation rate of the product 354 (Cycle B) was comparable to the reac-

tion rates with Pd(TFA)2 (Paper IV, Table 1). These results indicate that TFA

plays a crucial role at the dehydrogenation step (Cycle A) as well as at the C−C

bond formation step (Cycle B).

A KIE experiment was also conducted with a deuterium-labelled β-keto ester

D6-349 (Paper IV, Figure 3). In this case, unfortunately, the formation of the cor-

responding enone could not be reliably monitored. Although the rate of con-

sumption of D6-349 appears to display an inverse KIE, possible initial H/D ex-

change and/or differences in the rates of the formation of PdII(D6-349)(2a)Ln or

PdII(D6-349)2Ln complexes could also account for this observation (Cycle A).

Indeed, the overall rate of the reaction did not exhibit any KIE (354: kH/kD =

0.98), and the initial rate of the consumption of the oxidant indicated a small

normal KIE (kH/kD = 1.07). Since the consumption of the oxidant is likely corre-

lated with the concentration of the enone, thus the rate of formation of enone

98

D5-374 is likely lower with deuterated β-keto ester D6-349. This might be due

the formation of more stable complex PdII(D6-349)(353)Ln or/and PdII(D6-

349)2Ln compared to the corresponding non-deuterated complexes. As a result

of the higher stability of the O-bounded D6-349 enolate-Pd(II) complex, the

formation of C-bound enolate-Pd(II) complex would be slower compared to

non-deuterated β-keto ester (Cycle A). If this is true, the formation rate of the

product D5-354 from the deuterated-enone D5-374 would be faster than the

formation rate of the product 354 from the enone 374 (Cycle B), indeed the con-

centration of deuterated enone D5-374 is likely lower than concentration of non-

deuterated enone 374 (tBuOOBz: kH/kD = 1.07) whereas the overall rate exhibits

small KIE (354: kH/kD = 0.98). Furthermore, in the competition reaction between

349 and D6-349, the non-deuterated 349 reacts faster than the deuterated D6-349

(Article IV, Scheme 5). This result also suggests that formation rate of enone D5-

374 derived from D6-349 is slower than formation of enone 374. However, to

substantiate this hypothesis the monitoring of the concentrations of deuterated

enone D5-374 would be essential.

99

Scheme 86. Intermolecular competition between D6-349 and 349 in the coupling process.IV

Interestingly, the competition reaction between 349 and D6-349 produced three

products, instead of two. The products were: non-deuterated 354, D5-354 bear-

ing five deuteriums, and D4-354 bearing four deuteriums, with the product dis-

tribution 57:32:10, respectively (Paper IV, Scheme 5 and Scheme 86 above). This

result may indicate that the dehydrogenation step is reversible to some extent,

leading to H/D exchange and the formation of D4-354.

To obtain further insight into the reaction mechanism, the KIEs were also as-

sayed via additional competition studies. The competition reaction between

substrates 353 and D-353, gives a product distribution kH/kD 1:1.22 (Paper IV,

Scheme 4). If indole 353 is not dissociated from Pd after the first stage of the

reaction (formation of enone 374, Cycle A), then the observed KIE could be ex-

100

plained by the more rapid rate of enone formation with D-353. However, the

fact that a significant concentration of free enone 374 can be observed during

the reaction suggests that the catalytic cycle for the final product formation (Cy-

cle B) is separate from the first dehydrogenation cycle that produces enone 374

(Cycle A). Therefore the observed KIE could be related to the C−C bond for-

mation step (Cycle B).

Scheme 87. Intramolecular competition studies with β’-monodeuterated D1-349.IV

An intramolecular competition experiment, the mono-β’-deuterated D1-354 was

gave rise to product 354 that exhibited a 48.6:51.4 H/D ratio (Scheme 87). The

absence of a KIE in this experiment suggests that the β’-H bond cleavage is not

turnover-limiting for the dehydrogenation cycle The fact that no 1° KIE is ob-

served even under these conditions can be rationalized by the fact that the dif-

ferent hydrogen isotopes are not in an equal environment after the turnover-

limiting step (i.e. TSrearr). The choice between ’-H vs. ’-D abstraction has al-

ready been made in the turnover-determining ligand rearrangement step which

leads to the formation of C-bound enolate int3 (Scheme 88). The effect of deuter-

ium substitution in the ’ position of the ligand on the ligand rearrangement

step is expected to be small, resulting in a negligible 1° KIE.IV

101

Scheme 88. Explanation of the product distribution from intramolecular competition study.IV

The effect of the electron-withdrawing alkyl ester was studied using β-keto es-

ter 375 bearing a CF3CH2O ester group. Under the standard conditions, the re-

action between 375 and 353 was significantly slower than the standard reaction

between 349 and 353. (0.52 mM min-1 with 375 vs. 1.7 mM min-1 with 349). This

rate difference was also confirmed by an intermolecular competition between

349 and 375 (P354/P376 = 3) (Paper IV, Figure 2 and Scheme 89). These results

indicate that the electron density of the β-keto ester contributes to the reaction

rate.

Scheme 89. Intermolecular competition between 375 and 349 in the coupling process.IV

102

The use of C3 deuterated 1-methylindole in KIE experiments would have given

more detailed mechanistic information on C−C bond formation step (Cycle B).

Unfortunately, under the reaction conditions, the exchange rate of deuterium to

hydrogen at position 3 was much faster than the formation rate of the product

354 (rate of D/H exchange: 5.53 mM min-1 vs. rate of formation of 354: 1.7 mM

min-1) (see paper IV, SI).

A more thorough picture of the mechanism is emerging from the computational

studies carried out by Imre Pápai and Ádám Madarász. In brief, the computa-

tions reinforce the view that indole is an active ligand in the dehydrogenation

step and the dehydrogenation step likely proceed via a proton-assisted electron

transfer (PCET) process involving proton migration to TFA in concert with an

electron transfer to the Pd(II) center.203,204

The mechanism for the second step, the formation of the C−C bond, is still elu-

sive. The experimental evidence provides two possibilities for the formation of

a C−C bond from enone. Starting from enone 374, the C−C bond formation pro-

ceeds via both acid catalysis as well as via a Pd(II) catalysis. However, the

Pd(II)-catalyzed reaction is significantly faster. While several different scenarios

for the Pd(II)-catalyzed mechanism could be proposed (see paper IV), at present,

an unequivocal mechanism cannot be proposed for the role of Pd(II) in the C−C

bond formation stage.

103

3 SUMMARY AND CONCLUSIONS

The basic aims of the study were successfully realized, and a new oxidative re-

mote sp3 β’-C−H functionalization platform was created. The platform enables

the Pd(II)-catalyzed cross-dehydrogenative coupling between β-ketoester and β-

ketolactones and electro-rich aromatics, such as indoles, in a highly chemo- and

regioselective manners under mild conditions with a range of -keto esters and

indoles. (Scheme 90). Mechanistic investigations, using online NMR monitoring,

revealed that the reaction proceeds in two stages, via an enone intermediate.

Surprisingly, the formation of enone was assisted by the second substrate,

indole, and the role of indole was confirmed by kinetic isotope effect studies.

Furthermore, the proposed mechanism is also supported by DFT calculations.

The results of this thesis contribute to the general knowledge of

dehydrogenative cross-coupling reactions and especially a palladium-catalyzed

dehydrogenative cross-coupling between remote sp3 β-C−H and sp2 C−H bonds

were achieved by using an external oxidant.

104

Scheme 90. Novel oxidative sp3 β’-C−H functionalization reactions.

It should be noted that technology invented in this project was also successfully

applied to synthesize real discovery intermediates during my three month re-

searcher visit (23.4.2012-26.7.2012) to the Orion Corporation’s Medicinal Chem-

istry department.

While the α-position of carbonyl compounds can readily be functionalized

through palladium-catalyzed chemistry and the technology is widely applied in

the industry,205-208 the corresponding β-C−H functionalization chemistry is still

elusive. This is particularly true when it comes to dehydrogenative β-C−H func-

tionalization coupling reactions. The methodology developed in this thesis, will

therefore, provide new possibilities for synthesizing new kinds of chemical enti-

ties, which have earlier been demanding and burdensome to synthesize. Fur-

thermore, this mechanistic based series of studies highlights that it is possible to

105

employ indoles as alternative ligands in the dehydrogenation of carbonyl com-

pounds instead of using DMSO as the ligand. Understanding the mechanistic

aspects of the dehydrogenative β-coupling reaction might also help to invent

new types of dehydrogenative β-coupling reactions.

106

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ORIGINAL PAPERS

I

THE PALLADIUM-CATALYZED DEHYDROGENATIVE

β’-FUNCTIONALIZATION OF β-KETO

ESTERS WITH INDOLES AT ROOM TEMPERATURE

by

Mikko V. Leskinen, Kai-Tai Yip, Arto Valkonen, and Petri M. Pihko

J. Am. Chem. Soc. 2012, 134, 5750−5753.

Reprinted with permission from J. Am. Chem. Soc. 2012, 134, 5750−5753. Copyright

2012 American Chemical Society.

Palladium-Catalyzed Dehydrogenative β′-Functionalization of β-KetoEsters with Indoles at Room TemperatureMikko V. Leskinen, Kai-Tai Yip, Arto Valkonen, and Petri M. Pihko*

Department of Chemistry and NanoScience Center, University of Jyvaskyla, FI-40014 JYU, Finland

*S Supporting Information

ABSTRACT: The dehydrogenative β′-functionalization ofα-substituted β-keto esters with indoles proceeds with highregioselectivities (C3-selective for the indole partner andβ′-selective for the β-keto ester) and good yields undermild palladium catalysis at room temperature with a varietyof oxidants. Two possible mechanisms involving either lateor early involvement of indole are presented.

Direct cross-coupling reactions where new carbon−carbonbonds are generated via the oxidation of C−H bonds are

highly desirable transformations from the atom-economic pointof view. It is therefore not surprising that these reactions, alsocalled cross-dehydrogenative coupling (CDC) reactions, haveattracted significant attention in the past few years.1 Theselectivity challenges associated with such processes areformidable, since the C−H functionalization could potentiallytake place at several different sites.2 As an example,regioselective coupling at the β-position of carbonyl com-pounds would be a desirable alternative to the classicalconjugate addition reactions3 (Scheme 1) since saturated, less

functionalized precursors would be required. However,dehydrogenative β-functionalization reactions of carbonylcompounds4 are rare and typically involve the use of directinggroups5 or auxiliary amine catalysts.6 In the case of esters,amides, and β-dicarbonyl compounds, CDCs afford productsfunctionalized at the α-position instead of the β-position.7

Because of the central place of heterocycles, especiallyindoles, in medicinal chemistry, we recently initiated a programdirected toward oxidative functionalizations of indoles andβ-keto esters. Indole is the third most popular ring system foundbioactive molecules8 and a common core of over 3000 naturalproducts.9 Known dehydrogenative coupling methods currently

allow the union of indoles with tertiary amines, alkenes, arenes,and heteroarenes.9,10 Herein we describe a simple protocol forthe oxidative coupling of α-substituted β-keto esters and indolesat the remote β′ position of the β-keto ester (Scheme 2).

We initiated our screen by examining the reaction ofN-methylindole (2a) with cyclic β-keto ester 1a (Table 1). WithMn(OAc)2 and t-BuOOH as the oxidant, we obtained theα-coupled product 4a in poor yield, and similar results wereobtained with Cu(OAc)2. However, the use of Pd(OAc)2 gave asignificantly improved yield, and more importantly, the site ofthe coupling had switched to the β′ position to give 3a. Furtherscreens indicated that Pd(TFA)2 was a more active catalystthan Pd(OAc)2 and that dioxane as well as the mixed solvent2-propanol/AcOH were optimal solvents. With the i-PrOH/AcOH solvent system,11 the undesired side reaction, homo-coupling of 1a,12 could be minimized. Although a wide varietyof oxidants gave reasonable conversions at room temperature,tert-butyl perbenzoate (t-BuOOBz) afforded superior results(entry 18), and these conditions were then selected for furtherexploration. It should be noted that in addition to peroxideoxidants, MnO2, AgOAc, and oxygen were also syntheticallyuseful oxidants (entries 6, 9, and 12). Significantly, theregioselectivity was excellent on both coupling partners, andno 4a or no indole regioisomers could be detected in reactionswith PdII catalysts.Schemes 3 and 4 summarize the results obtained with a range

of indoles and β-keto esters. Both unsubstituted as well asN-substituted indoles give good product yields (3a−h), andthe reaction is highly tolerant of substituents with different

Received: January 20, 2012Published: March 16, 2012

Scheme 1. Roadmap of β-Functionalization of CarbonylDerivatives

Scheme 2. Regioselective Functionalization of β-Keto Esterswith Indoles

Communication

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electronic properties in the indole nucleus (3d−h) (Scheme 3),allowing further opportunities for synthetic transformations.Furthermore, β-keto esters with different steric demands (seeproducts 3i−l) are readily engaged in the coupling reaction(Scheme 4). All cyclic products exhibited trans stereochemistry,13

and the use of an enantiopure menthyl-derived ester enablesthe β-functionalization in a diastereoselective fashion (3m, dr =3:1 for the two trans isomers). Other β-keto ester scaffolds,including cycloheptanone (3n) and γ-butyrolactone (3o−p)systems, are also compatible. Notably, a pendant olefinic unit in3q remains intact, reflecting the mildness of the reaction con-ditions and the orthogonal reactivity to Heck-type reactions.14

In addition, acyclic β-keto esters can also be β-functionalized(3r and 3s).15

Mechanistically, the β-arylation is likely to proceed via a Pd0/PdII catalytic manifold instead of the oxidant-dependent PdII/PdIV cycle16 because (1) the reaction could proceed with avariety of oxidants (Table 1) and (2) a reasonable product yield(66%) was obtained when the reaction was performed with astoichiometric amount of Pd(TFA)2 in the absence of anexternal oxidant under an argon atmosphere.To provide insight into the reaction mechanism, the fol-

lowing kinetic experiments were performed. The rate of thedehydrogenative coupling between 1a and 2a displays a satu-ration dependence on β-keto ester 1a.17 The effect of indole 2ais more complex (Figure 1): at low [2a], the rate exhibits apseudo-first-order dependence (the rate rises to maximum at1 equiv of 2a), while inhibition kinetics appears when [2a] isincreased from 1 to 8 equiv.17 Furthermore, the reaction rate isnot dependent on the oxidant concentration, and the reaction is0.7th order with respect to [Pd(TFA)2].

17

At least two different mechanistic scenarios are consistentwith the above data (Scheme 5). The first scenario involves aSaegusa oxidation18 of 1a to enone intermediate A followed bya Friedel−Crafts-type or Pd-catalyzed conjugate addition ofindole 2a. In this “late indole” mechanism, the pseudo-first-order kinetics at low concentrations of 2a could be rationalized

Table 1. Optimization of Reaction Conditionsa

entry catalyst oxidizer product (%)b

1c Mn(OAc)2 t-BuOOHd 4a (<10)2c Cu(OAc)2 t-BuOOHd 4a (12)3 Pd(OAc)2 t-BuOOH 3a (43)4 Pd(TFA)2 t-BuOOH 3a (67)5 Pd(TFA)2 H2O2 3a (46)6 Pd(TFA)2 O2 (1 atm) 3a (64)7 Pd(TFA)2 DDQ 3a (<2)8 Pd(TFA)2 oxone 3a (35)9 Pd(TFA)2 AgOAc 3a (42)10 Pd(TFA)2 Na2S2O8 3a (45)11 Pd(TFA)2 K2S2O8 3a (59)12 Pd(TFA)2 MnO2 3a (58)13 Pd(TFA)2 t-BuOOt-Bu 3a (26)14 Pd(TFA)2 PhCMe2OOH 3a (57)15 Pd(TFA)2 (PhCMe2O)2 3a (34)16 Pd(TFA)2 t-BuOOAc 3a (72)17 Pd(TFA)2 BzOOBz 3a (37)18 Pd(TFA)2 t-BuOOBz 3a (82)19 Pd(TFA)2 t-BuOOBz 3a (66)e

aUnless otherwise indicated, reactions were carried out with 0.4 mmolscale of 2a for 15−18 h. bDetermined by 1H NMR analysis usingdibenzyl ether as the internal standard. cNeat at 70 °C. d5.3 M in iso-octane. Addition of a polar cosolvent inhibited the reaction completely(see the Supporting Information for further solvent screens). eIn 20%AcOH/H2O.

Scheme 3. Scope of Dehydrogenative Coupling withDifferent Indolesa

aIsolated yields of pure products are reported. Conditions, unlessotherwise indicated: 1 (1.5 equiv), 2 (0.4 mmol, 1.0 equiv), t-BuOOBz(1.3 equiv), Pd(TFA)2 (0.1 equiv), i-PrOH/AcOH (4:1, 0.5 mL) at25 °C. bOpposite enantiomer shown.

Scheme 4. Scope of Dehydrogenative Coupling withDifferent β-Keto Estersa

aIsolated yields of pure products are reported. Conditions, unlessotherwise indicated: β-keto ester (1.5 equiv), indole (0.4 mmol, 1.0 equiv),t-BuOOBz (1.3 equiv), Pd(TFA)2 (0.1 equiv), i-PrOH/AcOH (4:1, 0.5 mL)at 25 °C. bSlow addition of indole over 10 h. c4.5 equiv of 1r was used.dOpposite enantiomer shown.

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if the Saegusa oxidation is faster than the conjugate addition atlow [2a]. The catalytic cycle would be completed by theregeneration of PdII from Pd0 in the presence of tert-butylperbenzoate.19

Alternatively, an “early indole” scenario in which a palladatedindole species B is involved in the dehydrogenation step couldalso be envisioned. The reaction might then proceed viaintermediates C and D-1 or D-2. This mechanism would alsobe consistent with the kinetic behavior of indole if the rate issuppressed at high [2a] by the formation of Pd(indole)2species. Literature precedents supporting this mechanistic

alternative include the following: (a) indoles are known tobe palladated and homocoupled at C3;12 (b) α-arylpalladiumspecies derived from β-dicarbonyl compounds are known toundergo slow reductive eliminations, suppressing the competingα-arylation;20 and (c) a similar mechanism for the β-arylationsof preformed ester enolates with heteroaryl and aryl halideswas recently proposed on the basis of kinetic and computa-tional studies.21

Further kinetic experiments with preformed enone 5i orβ-ketoester 1i did not fully resolve the issue. Under the standardconditions, the reaction between 5i and 2a (eq 1a or 1b) was

ca. 2−3 times faster than the standard reaction between 1i and2a (eq 2). Under acid catalysis (20 mol % TFA) or with 4:1i-PrOH/AcOH alone, the reaction between 5i and 2a wassignificantly slower (initial rate of 0.003 or 0.001 M min−1,respectively).17 These data suggest that if 5i is an intermediate(Saegusa pathway), the conjugate addition step is unlikely to beacid-catalyzed. Interestingly, in a control experiment with 1abut without indole 2a, only very slow formation of enone wasobserved (12% conversion to 5a after 14 h, rate of formation of5a = 0.00025 M min−1).17 Therefore, although neither mechanisticpathway can be completely ruled out at present, in practice thereaction appears to require the presence of indole to engage theβ-keto ester partner fully.In summary, we have presented a novel dehydrogenative

coupling method for constructing C(sp2)−C(sp3) bonds byconnecting the C3 position of indoles and the β′-position ofβ-keto esters under mild reaction conditions and with excellentregioselectivities. Two possible mechanisms have been presented: aSaegusa-type mechanism (“late indole”) and an indole-assisteddehydrogenation mechanism (“early indole”). Efforts to advancethe understanding of the reaction mechanism and generalize theconcept of dehydrogenative β′-functionalization are ongoing.

■ ASSOCIATED CONTENT

*S Supporting InformationExperimental details and spectroscopic data for new com-pounds. This material is available free of charge via the Internetat http://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding AuthorPetri.Pihko@jyu.fi

NotesThe authors declare no competing financial interest.

Figure 1. Plot of the initial rate of dehydrogenative coupling of β-ketoester 1a with varying concentrations of 1-methylindole 2a: [1a] =0.484 M, [2a] = 0.0323−2.583 M, [Pd(TFA)2] = 0.032 M,[t-BuOOBz] = 0.424 M at 25 °C. The inset displays a linear least-squares fit for [2a] ranging from 0.0323 to 0.323 M.

Scheme 5. Plausible Mechanisms for PdII-CatalyzedDehydrogenative β′-Functionalization of β-Keto Esters

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■ ACKNOWLEDGMENTS

We thank Mr. Esa Haapaniemi and Ms. Mirja Lahtipera forNMR and mass spectrometric assistance and Prof. KariRissanen and Mr. Antti Neuvonen for assistance with theX-ray studies. Financial support was provided by Tekes, Orion,CABB, Hormos Medical, PCAS Finland, Fermion, Pharmatory,and AB Enzymes (all under the auspices of the PharmaProgram of Tekes). A.V. thanks Academy Professor KariRissanen for funding through Academy of Finland (KR projectNos. 130629, 122350, and 140718). We also thank the refereesfor their constructive comments.

■ REFERENCES(1) For recent reviews of cross-dehydrogenative coupling, see:(a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.(b) Scheuermann, C. J. Chem.Asian J. 2010, 5, 436. (c) Li, C.-J. Acc.Chem. Res. 2009, 42, 335.(2) (a) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50,3362. (b) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.Res. 2012, DOI: 10.1021/ar200194b. (c) For a thematic issue on“Selective Functionalization of C−H Bonds” (Crabtree, R. H., Ed.),see: Chem. Rev. 2010, 110, 575−1211. (d) Godula, K.; Sames, D.Science 2006, 312, 67.(3) For general approaches to stereoselective conjugate reactionswith α,β-unsaturated carbonyls, see: (a) Catalytic AsymmetricConjugate Reactions; Co rdova, A., Ed.; Wiley-VCH: Weinheim,Germany, 2010. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem.Rev. 2007, 107, 5416.(4) For a Ni-catalyzed dehydrogenative coupling that providesoveroxidized enaminone products, see: Ueno, S.; Shimizu, R.;Kuwano, R. Angew. Chem., Int. Ed. 2009, 48, 4543.(5) For selected examples of catalytic β-functionalization withdirecting groups, see: (a) Desai, L. V.; Hull, K. L.; Sanford, M. S.J. Am. Chem. Soc. 2004, 126, 9542. (b) Wasa, M.; Engle, K. M.; Yu,J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (c) Daugulis, O.; Do, H.;Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. For recent reviews ofdirected C−H functionalization, see: (d) Lyons, T. W.; Sanford, M. S.Chem. Rev. 2010, 110, 1147. (e) Chen, X.; Engle, K. M.; Wang, D.-H.;Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.(6) Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang,W. Nat. Commun. 2011, 2, 211. (b) Hayashi, Y.; Itoh, T.; Ishikawa, H.Angew. Chem., Int. Ed. 2011, 50, 3920.(7) For selected examples of catalytic dehydrogenative couplings ofβ-dicarbonyl compounds in the α-position, see: (a) Zhang, Y.; Li, C.-J.Angew. Chem., Int. Ed. 2006, 45, 1949. (b) Liu, L.; Floreancig, P. Org.Lett. 2009, 11, 3152. (c) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z.Angew. Chem., Int. Ed. 2010, 49, 5558. Also see ref 1a.(8) Ertl, P.; Jelfs, S.; Muhlbacher, J.; Schuffenhauer, A.; Selzer, P.J. Med. Chem. 2006, 49, 4568.(9) For recent reviews of indoles and their functionalization, see:(a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, pr215−pr283.(b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.(c) Bartoli, G.; Bencivenni, G.; Daipozzo, R. Chem. Soc. Rev. 2010, 39,4449.(10) For selected examples, see: With alkenes: (a) Ferreira, E. M.;Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (b) Liu, C.;Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250. (c) Grimster,N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int.Ed. 2005, 44, 3125. (d) García-Rubia, A.; Arrayas, R. G.; Carretero,J. C. Angew. Chem., Int. Ed. 2009, 48, 6511. With arenes: (e) Deprez,N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,128, 4972. (f) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.(g) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007,129, 12072. (h) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;DeBoef, B. Org. Lett. 2007, 9, 3137. With amines: (i) Li, Z.; Li, C.-J.J. Am. Chem. Soc. 2005, 127, 6968. (j) Liu, P.; Zhou, C.-Y.; Xiang, S.;Che, M.-C. Chem. Commun. 2010, 46, 2739. With heteroarenes:

(k) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int. Ed.2011, 50, 5365.(11) The beneficial role of acetic acid is also attributed to itsassistance with palladium-catalyzed C−H bond functionalization ofarenes. See: (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res.2001, 34, 633. (b) Ackermann, L. Chem. Rev. 2011, 111, 1315.(12) For examples of homocoupling of N-alkylindoles, see: (a) Li,Y.; Wang, W.-H.; Yang, S.-D.; Li, B.-J.; Feng, C.; Shi, Z.-J. Chem.Commun. 2010, 46, 4553. (b) Liang, Z.; Zhao, J.; Zhang, Y. J. Org.Chem. 2010, 75, 170. (c) Liu, Q.; Li, G.; Yi, H.; Wu, P.; Liu, J.; Lei, A.Chem.Eur. J. 2011, 17, 2353.(13) The relative stereochemistry of the products was assigned onthe basis X-ray diffraction of 3b, 3n, and 3p as well as by comparisonof the 1H NMR 3JHα−Hβ′ coupling constants (see the SupportingInformation).(14) For overviews, see: (a) The Mizoroki−Heck Reaction; Oestreich,M., Ed.; Wiley: Chichester, U.K., 2009. (b) Link, J. T. Org. React. 2002,60, 157.(15) Under these conditions, 3-methylindole and 2-acetylcyclopen-tanone were not viable coupling partners. Studies to expand the scopeare underway.(16) (a) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010,110, 824. (b) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew.Chem., Int. Ed. 2011, 50, 1478.(17) See the Supporting Information for details.(18) For an overview, see: Ito, Y.; Suginome, M. In Handbook ofOrganopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;Wiley: New York, 2002; Vol. 2, p 2873.(19) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.Chem. Rev. 2007, 107, 5318.(20) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.(b) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.(c) Wolkowski, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41,4289. (d) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am.Chem. Soc. 2000, 122, 1360.(21) For an early example of β-arylation of ester enolates, see:(a) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F.J. Am. Chem. Soc. 2002, 124, 12557. For recent β-arylation studieswith aryl halides, see: (b) Renaudat, A.; Jean-Gerard, L.; Jazzar, R.;Kefalidis, C. E.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49,7261. (c) Larini, P.; Kefalidis, C. E.; Jazzar, R.; Renaudat, A.; Clot, E.;Baudoin, O. Chem.Eur. J. 2012, 18, 1932.

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II

PALLADIUM-CATALYZED DEHYDROGENATIVE β’-ARYLATION

OF β-KETO ESTERS UNDER AEROBIC CONDITIONS: INTERPLAY

OF METAL AND BRØNSTED ACIDS

by

Kai-Tai Yip, Roshan Y. Nimje, Mikko V. Leskinen, and Petri M. Pihko

Chem. Eur. J. 2012, 18, 12590 – 12594.

Reproduced with kind permission by 2012 WILEY-VCH Verlag GmbH & Co. KGaA,

Weinheim.

DOI: 10.1002/chem.201201988

Palladium-Catalyzed Dehydrogenative b’-Arylation of b-Keto Esters underAerobic Conditions: Interplay of Metal and Brønsted Acids

Kai-Tai Yip, Roshan Y. Nimje, Mikko V. Leskinen, and Petri M. Pihko*[a]

In chemical synthesis, methods that enable the rapid buildup of complexity from simple precursors are highly valuablefrom an atom and redox economic point of view. In thisregard, catalytic dehydrogenative cross-couplings betweentwo different molecules are particularly attractive, sincethey do not require any pre-functionalization of the sub-strate.[1,2] The challenges associated with such processes areformidable—the catalysts will need to activate both compo-nents chemo- and regioselectively, while avoiding potentialhomocoupling reactions between either of the two couplingpartners. For example, electron-rich arenes and phenols areknown to undergo oxidative homocoupling reactions undercatalytic oxidative conditions.[3,4] Another serious problemassociated with these reactions is the potential for furtheroxidation of the product, especially when prolonged reac-tion times and/or forcing conditions, such as heating, are re-quired to promote the reactions.

Here we show that by a careful choice of Pd catalyst anda Brønsted acid co-catalyst,[5] electron-rich arenes and a va-riety of phenols can undergo a highly regioselective cross-dehydrogenative coupling at room temperature with b-ketoesters in the b’-position, overcoming problems associatedwith the overoxidation or degradation of the product. Previ-ously, regioselective arylation in the b-position of esters hasbeen successful only with prefunctionalized aryl halides.[6]

In contrast to our recently reported cross-dehydrogenativeb’-functionalization of b-keto esters with indoles,[7] in our in-itial screens with electron-rich arenes we encountered signif-icant challenges associated with expanding the scope of thereaction, including the generally lower reactivity of arenescompared to indoles, and the competing overoxidation ordegradation of the product. In our initial screens with 1,3,5-trimethoxybenzene (2 a) and b-keto ester 1 a (Table 1), thereaction was feasible only at elevated temperatures (80 8C)when tert-butyl perbenzoate (tBuOOBz) was used as the ox-idant. Owing to the inherent hazards associated with pro-longed heating of high concentrations of peroxides, weturned to oxygen gas as a mild alternative.[8] Although [Pd-

ACHTUNGTRENNUNG(tfa)2] (tfa= trifluoroacetate) was an active catalyst at 50 8C,its use also resulted in significant overoxidation to enones4 a and also 6 a (enone derived from 1 a) when O2 was usedas the terminal oxidant.

Instead of trying to control the reaction by limiting theoxygen supply, we observed that the activity of a milder cat-alyst, PdACHTUNGTRENNUNG(OAc)2, could be boosted by the addition of catalyt-ic amounts of acids,[9] especially when acetic acid was alsoused as a co-solvent.[10] A survey of different acid co-cata-lysts revealed that diphenyl phosphate was particularly ef-fective, affording the desired product 3 a in 82 % yield andminimizing the formation of overoxidation product 4 a(entry 8). When 50 mol% diphenyl phosphate was used, 3 awas isolated in 87 % yield. The rate of b-arylation in thepresence of 50 mol % (PhO)2P(O)OH was approximately14-fold faster when compared to the rate without the acidadditive (Scheme 1).

[a] K.-T. Yip, R. Y. Nimje, M. V. Leskinen, P. M. PihkoDepartment of Chemistry and Nanoscience CenterUniversity of Jyv�skyl�P. O. B. 35, F40014 JYU (Finland)E-mail : Petri.Pihko@jyu.fi

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201201988.

Table 1. Screen of Brønsted acid additive and solvent.[a]

Entry Brønstedacid

pKaACHTUNGTRENNUNG(H2O)[b] Yield [%]

of 3a[c]Yield [%]of 4a[c]

1[d] – – 8 02[e,f,g] – – 44 293[f,h] TFA (excess) �0.3 17 154[h] TFA (excess) �0.3 40 155[d] TsOH·H2O ca. �3 complex mixture6[e] Cl3CCOOH 0.7 42 07[e] HIO3 0.8 37 <38[d] ACHTUNGTRENNUNG(PhO)2P(O)OH ca. 1 82 (87)[i] 5 (3)[i]

9[e] Cl2CHCOOH 1.3 74 510[e] o-NO2-BzOH 2.2 13 <311[e] ClCH2COOH 2.9 19 612[d] p-NO2-BzOH 3.4 N.D.[j] <313[e] IBX 2.4 complex mixture

[a] Reaction conditions: 1a (0.6 mmol), 2a (0.4 mmol), acid additive(0.08 mmol), Pd ACHTUNGTRENNUNG(OAc)2 (0.04 mmol) in 0.5 mL solvent under an oxygen-filled balloon at 25 8C for 24 h. [b] For a comparison of pKa values, seeSupporting Information. [c] Determined by 1H NMR spectroscopy usingan internal standard. [d] 4:1 AcOH/DCE. [e] 1:1 AcOH/DCE.[f] 10 mol % of [Pd ACHTUNGTRENNUNG(tfa)2] were used instead of Pd ACHTUNGTRENNUNG(OAc)2. [g] At 50 8C.[h] TFA/DCE (4:1) as solvent. [i] Isolated yield; 50 mol % diphenyl phos-phate used. [j] N.D.=not detected.

� 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 12590 – 1259412590

With the optimized conditions in hand, the scope of thecoupling between different arenes and b-keto esters wasthen explored (Scheme 2). Among cyclic b-keto esters ex-plored, 5-membered cyclic b-keto esters system furnishescoupling products (3 a–e) with 2 a in high yields (75–87 %)regardless of the steric bulkiness of ester group. Even amoderately diastereoselective arylation (3 e of d.r. 2.3:1) canbe achieved by (�)-menthyl ester. Seven-membered rings(3 f) and g-lactones (3 g) are also viable partners for the b-arylation, and variations in substituent and substitution pat-tern of the aryl component can also be tolerated. For exam-ple, coupling of 1 a with triethoxylated arene yielded 3 h in72 % yield. Interestingly, some regioselectivity in the aryla-tion process can be achieved by altering the arene substitu-ent. For instance, a bulky TIPS-substituted arene led to se-lective formation of para-regioisomer of 3 i of 2.3:1 ratio,while the use of benzylated arene resulted in the reverseratio in the formation of 3 j (para/ortho = 1:2.2). Further-more, the coupling of 1 a with 1,2,3-trimethoxybenzene,under modified conditions, afforded 3 k as the exclusiveisomer. Finally, acyclic b-keto ester-derived products canalso be obtained by slow addition of the b-keto ester (3 l).

Although arenes bearing two donor groups, such as 1,3-di-methoxybenzene, were insufficiently reactive, we were de-lighted to find that unprotected phenols can be successfullyused as the reaction partners when the reaction is conductedunder modified conditions.[10] The scope of these reactions issummarized in Scheme 3. In general, b-arylation reactionsare highly para-selective to phenolic systems, even in thecase of simple phenol (3 m and 3 n), which is known to bereactive at both para- and ortho-positions.[11] In addition, thereactions are remarkably tolerant to the steric crowdingfrom the substitution(s) at the ortho-position(s) (3 o–u). Inparticular, product 3 q can be efficiently obtained from thecoupling with 2,6-di-tert-butylphenol. An electronically de-activated phenol can also be used, although with somewhatreduced yield (3 u). Besides the cyclic b-keto esters, phenolsare also capable of b-coupling to a b-keto lactone system(3 v–x) without a competitive ring opening. Finally, success-ful dehydrogenative coupling between an a-methyl-b-ketoester and either an electron-rich arene (to give 3 l inScheme 2) or unprotected phenols (to give 3 y–3 za inScheme 3) demonstrates that oxidative coupling can be usedas an alternative disconnection to the conventional benzyla-tion of b-keto esters.

The practicability of dehydrogenative b’-arylation wasalso demonstrated by the gram-scale syntheses of 3 a(Scheme 2) and 3 s (Scheme 3) with a reduced loading(5 mol%) of PdII catalyst and oxygen gas as the sole oxi-dant.

In line with the previously reported b’-arylation of b-ketoesters with indoles,[7] two major mechanistic pathways forthe reaction can be presented (Scheme 4): an “early-aryla-tion” pathway in which the arene is palladated prior to itsengagement with the b-keto ester, and a “late-arylation”pathway in which the b-keto ester is first oxidized to anenone species and then undergoes a conjugate addition-typeprocess with the arene. The early arene pathway might in-volve migratory insertion to give D-1/D-2 and subsequent

Scheme 1. Diphenyl phosphate accelerated PdII-catalyzed dehydrogena-tive coupling.

Scheme 2. Scope of diphenyl phosphate/PdII co-catalyzed dehydrogena-tive coupling of 1 with different aromatics. Yields of isolated productsare reported. Reaction conditions, unless otherwise indicated: 1(0.6 mmol, 1.5 equiv), 2 (0.4 mmol, 1.0 equiv), diphenyl phosphate(50 mol %), Pd ACHTUNGTRENNUNG(OAc)2 (10 mol %), AcOH/DCE (DCE =dichloroethane;4:1, 0.5 mL) under an oxygen-filled balloon at 25 8C. [a] X-ray structureof 3 a is available [CCDC 879905], see the Supporting Information.[17]

[b] 1 (1.33 g, 1.4 equiv), 2 (1.00 g, 1.0 equiv), diphenyl phosphate(25 mol %), Pd ACHTUNGTRENNUNG(OAc)2 (5 mol %), AcOH/DCE (4:1, 15 mL) under anoxygen-filled balloon at 25 8C. [c] 1.2 equiv of 1e used. [d] Isomeric ratiodetermined by 1H NMR spectroscopy from a crude mixture. [e] Single re-gioisomer obtained exclusively. [f] 10 mol % of [Pd ACHTUNGTRENNUNG(tfa)2] in TFA/DCE(4:1, 0.5 mL) were used instead of Pd ACHTUNGTRENNUNG(OAc)2 in AcOH/DCE. [g] In theabsence of diphenyl phosphate. [h] 10 mol % of [Pd ACHTUNGTRENNUNG(tfa)2] were used in-stead of Pd ACHTUNGTRENNUNG(OAc)2. [i] Slow addition of b-keto ester 1 over 10 h.

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COMMUNICATION

reductive elimination that results in the formation of the C�C bond at the b’-position.

In control experiments with tBuOOBz (130 mol %) andPd ACHTUNGTRENNUNG(OAc)2 (10 mol %) but without arene 2 a, the enone 6 aderived from b-keto ester 1 a is generated only very slowly

(4.3 �10�5mmin�1; <6 % conversion to enone 6 a after

13 h).[12] Conducting the same experiment in the presence of50 mol % (PhO)2P(O)OH reveals that the rate of formationof enone is similarly slow (6.6 � 10�5

m min�1; 2 % conversionto enone 6 a after 3.5 h, after which time the concentrationof 6 a remains essentially constant). However, control ex-periments with preformed enone 6 b and arene 2 a indicatethat conversion to the product 3 b is essentially complete in30 min with diphenyl phosphate (50 mol %), and the rate isindependent of the presence of 10 mol % Pd ACHTUNGTRENNUNG(OAc)2. Assuch, although the “late-arylation” pathway is feasible ifenough enone is available, the slow formation of enone maylimit the overall reaction rate.[13] The higher observed rateof the overall reaction (6.7 �10�4

mmin�1, Scheme 1)[14] maybe more consistent with the “early-arylation” pathway inwhich the dehydrogenation of the b-keto ester 1 a takesplace with the involvement of the aryl–Pd species B. Impor-tantly, our preliminary studies revealed that PdII-catalyzeddehydrogenation of 1 a can be accelerated by the presenceof electron-rich carbon ligands [Eq. (1)],[15] pointing towardsearly involvement of the electron-rich arene in the reactionpathway.

In view of the above, the role of acid co-catalyst (diarylphosphate) in these reactions most likely is to promote theformation of the arylpalladium species B. Previously, Fuji-wara and co-workers have reported the use of acids, such as

Scheme 3. Scope of PdII-catalyzed dehydrogenative coupling of 1 withdifferent phenols. Yields of isolated products are reported. Reaction con-ditions: 1 (0.6 mmol, 1.5 equiv), 2 (0.4 mmol, 1.0 equiv), [Pd ACHTUNGTRENNUNG(tfa)2](10 mol %), TFA/DCE (4:1, 0.5 mL) under an oxygen-filled balloon at20–25 8C. [a] 1 (2.34 g, 1.4 equiv), 2 (1.08 g, 1.0 equiv), [Pd ACHTUNGTRENNUNG(tfa)2](5 mol %), TFA/DCE (4:1, 12.5 mL) under an oxygen-filled balloon at20 8C. [b] X-ray structure of 3v is available [CCDC 880392], see the Sup-porting Information.[17]

Scheme 4. Plausible reaction mechanism of dehydrogenative b-arylation of 1a with 2a.

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P. M. Pihko et al.

trifluoroacetic acid as solvent in promoting electrophilic pal-ladation of arenes at room temperature.[9] Alternatively, theacid co-catalyst might promote the conjugate addition stepin the “late-arylation” scenario. However, no enantioselec-tivity could be obtained when a variety of sterically bulkychiral diaryl phosphates were screened instead of diphenylphosphate.[10] Of course, such a result does not completelyrule out the “late-arylation” pathway, since the stereochem-istry could already be set in the planar-chiral complex Abefore the C�C bond formation. In the “early-arylation”scenario, the chiral Brønsted acid might be dissociatedbefore the engagement of 1 a to generate complex C, thusleading to racemic product.

Although we cannot fully exclude either mechanism withthese experiments, we have nevertheless obtained additionalindirect evidence for the feasibility of the “early-arylation”pathway in a control experiment with iodobenzene.[16] Thereaction proceeds with the use of AgOAc as the iodide scav-enger to give direct b-arylation product 3 zb in 55 % yieldunder acidic and phosphine-free conditions [Eq. (2)].

In conclusion, we have developed a PdII/Brønsted acid co-catalyzed dehydrogenative b’-arylation of b-keto esters witharenes and phenols at room temperature using molecularoxygen (1 atm) as the sole oxidant. Notable features of thereaction include 1) mild, ambient reaction conditions, 2) tol-erance of different substituent patterns, and 3) high regiose-lectivity. A possible mechanism involving acid-assisted palla-dation of arene and subsequent engagement of the b-ketoester is proposed on the basis of control experiments. Thetunability and cooperativity of PdII/Brønsted acid systemshould play a pivotal role to broaden the scope of this trans-formation even further.

Acknowledgements

We thank Mr. Esa Haapaniemi and Ms. Mirja Lahtiper� for NMR andmass spectrometric assistance, and Prof. Kari Rissanen and Mr. AnttiNeuvonen for assistance with the X-ray studies. Financial support hasbeen provided by Tekes, Orion, CABB, Hormos Medical, PCAS Finland,Fermion, Pharmatory and AB Enzymes (all under the auspices of thePharma program of Tekes) and the Academy of Finland (Projects 138854and 139046).

Keywords: arylation · Brønsted acids · C�Hfunctionalization · oxidation · palladium catalysis

[1] For recent reviews on dehydrogenative cross-coupling, see: a) C. S.Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; b) C. J. Scheuer-

mann, Chem. Asian J. 2010, 5, 436; c) C.-J. Li, Acc. Chem. Res. 2009,42, 335.

[2] For recent examples of catalytic dehydrogenative Csp3�Csp2 bond for-mation involving arenes, see: a) K.-T. Yip, D. Yang, Org. Lett. 2011,13, 2134; b) P. Gandeepan, K. Parthasarathy, C.-H. Cheng, J. Am.Chem. Soc. 2010, 132, 8569; c) J. E. M. N. Klein, A. Perry, D. S.Pugh, R. J. K. Taylor, Org. Lett. 2010, 12, 3446; d) Y.-Z. Li, B.-J. Li,X.-Y. Lu, S. Lin, Z.-J. Shi, Angew. Chem. 2009, 121, 3875; Angew.Chem. Int. Ed. 2009, 48, 3817; e) K. C. Nicolaou, R. Reingruber, D.Sarlah, S. Br�se, J. Am. Chem. Soc. 2009, 131, 2086; f) J. C. Conrad,J. Kong, B. N. Laforteza, D. W. C. MacMillan, J. Am. Chem. Soc.2009, 131, 11640; g) C. E. Houlden, C. D. Bailey, J. G. Ford, M. R.Gagn�, G. C. Lloyd-Jones, K. I. Booker-Milburn, J. Am. Chem. Soc.2008, 130, 10066; h) G. Deng, L. Zhao, C.-J. Li, Angew. Chem. 2008,120, 6374; Angew. Chem. Int. Ed. 2008, 47, 6278; i) Z. Li, C.-J. Li, J.Am. Chem. Soc. 2005, 127, 6968; j) H. Zhang, E. M. Ferreira, B. M.Stoltz, Angew. Chem. 2004, 116, 6270; Angew. Chem. Int. Ed. 2004,43, 6144.

[3] For an overview, see: a) J. Hassan, M. S�vignon, C. Gozzi, E.Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359. For arenes, see:b) Y. Rong, W. Lu, Organometallics 2007, 26, 4376; c) K. L. Hull,E. L. Lanni, M. S. Sanford, J. Am. Chem. Soc. 2006, 128, 14047; forphenolic compounds, see: d) H. Egami, T. Katsuki, J. Am. Chem.Soc. 2009, 131, 6082; e) X. Li, B. Hewgley, C. A. Mulrooney, J.Yang, M. C. Kozlowski, J. Org. Chem. 2003, 68, 5500; f) A. S. Hay,H. S. Blanchard, G. F. Endres, J. W. Eustance, J. Am. Chem. Soc.1959, 81, 6335; g) H. Finkbeiner, A. S. Hay, H. S. Blanchard, G. F.Endres, J. Org. Chem. 1966, 31, 549.

[4] For selected examples of dehydrogenative heterocoupling with re-giocontrol, see: a) T. W. Lyons, K. L. Hull, M. S. Sanford, J. Am.Chem. Soc. 2011, 133, 4455; b) H. Egami, K. Matsumoto, T. Oguma,T. Kunisu, T. Katsuki, J. Am. Chem. Soc. 2010, 132, 13633; c) D. R.Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129,12072; d) K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129,11904; e) D. R. Stuart, K. Fagnou, Science 2007, 316, 1172; f) T. A.Dwight, N. R. Rue, D. Charyk, R. Josselyn, B. DeBoef, Org. Lett.2007, 9, 3137; g) R. Li, L. Jiang, W. Lu, Organometallics 2006, 25,5973; h) E. M. Beck, N. P. Grimster, R. Hatley, M. J. Gaunt, J. Am.Chem. Soc. 2006, 128, 2528; i) N. P. Grimster, C. Gauntlett, C. R. A.Godfrey, M. J. Gaunt, Angew. Chem. 2005, 117, 3185; Angew. Chem.Int. Ed. 2005, 44, 3125; j) M. Smrcina, S. Vyskocil, B. M�ca, M.Pol�Sek, T. A. Claxton, A. P. Abbott, P. Kocovsky, J. Org. Chem.1994, 59, 2156; for an example of direct arylation with unique regio-control, see: k) R. J. Phipps, M. J. Gaunt, Science 2009, 323, 1593.

[5] For overviews, see: a) H. Yamamoto, K. Futatsugi in Acid Catalysisin Modern Organic Synthesis Vol. 1 (Eds.: H. Yamamoto, K. Ishi-hara), Wiley-VCH, 2008, 1– 34; b) C. H. Cheon, H. Yamamoto,Chem. Commun. 2011, 47, 3043; c) M. Rueping, R. M. Koenigs, I.Atodiresei, Chem. Eur. J. 2010, 16, 9350; d) C. Zhong, X. Shi, Eur. J.Org. Chem. 2010, 2999; e) M. Terada, Chem. Commun. 2008, 4097;f) T. Akiyama, Chem. Rev. 2007, 107, 5744; g) H. Yamamoto, K. Fu-tatsugi, Angew. Chem. 2005, 117, 1958; Angew. Chem. Int. Ed. 2005,44, 1924. For selected examples, see: h) Z. Chai, T. J. Rainey, J. Am.Chem. Soc. 2012, 134, 3615; i) M. Hatano, K. Moriyama, T. Maki, K.Ishihara, Angew. Chem. 2010, 122, 3911; Angew. Chem. Int. Ed.2010, 49, 3823; j) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129,11336; k) M. Rueping, C. Azap, Angew. Chem. 2006, 118, 7996;Angew. Chem. Int. Ed. 2006, 45, 7832.

[6] For an early example of b-arylation of ester enolates, see: a) M. Jør-gensen, S. Lee, X. Liu, J. P. Wolkowski, J. F. Hartwig, J. Am. Chem.Soc. 2002, 124, 12557; for recent b-arylation studies with aryl halides,see: b) A. Renaudat, L. Jean-G�rard, R. Jazzar, C. E. Kefalidis, E.Clot, O. Baudoin, Angew. Chem. 2010, 122, 7419; Angew. Chem. Int.Ed. 2010, 49, 7261; c) P. Larini, C. E. Kefalidis, R. Jazzar, A. Renau-dat, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932.

[7] M. V. Leskinen, K.-T. Yip, A. Valkonen, P. M. Pihko, J. Am. Chem.Soc. 2012, 134, 5750.

[8] For recent reviews, see: a) A. N. Campbell, S. S. Stahl, Acc. Chem.Res. 2012, 45, 851; b) Z. Shi, C. Zhang, C. Tang, N. Jiao, Chem. Soc.

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Rev. 2012, 41, 3381; c) T. Punniyamurthy, S. Velusamy, J. Iqbal,Chem. Rev. 2005, 105, 2329; d) S. S. Stahl, Angew. Chem. 2004, 116,3480; Angew. Chem. Int. Ed. 2004, 43, 3400.

[9] For a pioneering study on the effect of acidic medium on PdII-cata-lyzed arene functionalization reactions, see: a) C. Jia, T. Kitamura,Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633; b) C. Jia, D. Piao, J.Oyamada, W. Lu, T. Kitamura, Y. Fujiwara, Science 2000, 287, 1992.

[10] See the Supporting Information for detailed screens.[11] a) X. Guo, R. Yu, H. Li, Z. Li, J. Am. Chem. Soc. 2009, 131, 17387;

b) K. M. Bogle, D. J. Hirst, D. J. Dixon, Org. Lett. 2007, 9, 4901;c) R. B. Bedford, S. J. Coles, M. B. Hursthouse, M. E. Limmert,Angew. Chem. 2003, 115, 116; Angew. Chem. Int. Ed. 2003, 42, 112;d) K. Kobayashi, M. Arisawa, M. Yamaguchi, J. Am. Chem. Soc.2002, 124, 8528.

[12] See Supporting Information for details.

[13] It should be noted that the “early- and late-arylation” pathways arenot necessarily exclusive.

[14] Due to the instability of enone derived from 1a and the proton–deu-terium exchange of arene 2 a in [D4]acetic acid, the kinetics ofenone formation experiments and dehydrogenative couplings werestudied under slightly different, but comparable conditions.

[15] Detailed studies and the mechanistic implications of the acceleratedeffect of dehydrogenation of 1a will be reported in due course.

[16] These reactions would take place via oxidative addition pathways, asin reference [6].

[17] CCDC-879905 (3 a) and CCDC-880392 (3v) contain the supplemen-tary crystallographic data for this paper. These data can be obtainedfree of charge from The Cambridge Crystallographic Data Centrevia www.ccdc.cam.ac.uk/data_request/cif.

Received: June 5, 2012Published online: August 22, 2012

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III

A THREE-COMPONENT PALLADIUM-CATALYZED OXIDATIVE

C-C COUPLING

REACTION: A DOMINO PROCESS IN TWO DIMENSIONS

by

Roshan Y. Nimje, Mikko V. Leskinen, and Petri M. Pihko

Angew. Chem. Int. Ed. 2013, 52, 4818 –4822.

Reproduced with kind permission by 2013 WILEY-VCH Verlag GmbH & Co. KGaA,

Weinheim.

Multicomponent ReactionsDOI: 10.1002/anie.201300833

A Three-Component Palladium-Catalyzed Oxidative C�C CouplingReaction: A Domino Process in Two Dimensions**Roshan Y. Nimje, Mikko V. Leskinen, and Petri M. Pihko*

In multicomponent reactions (MCRs), three or more reac-tants combine in a single chemical step to give a product thatcontains nearly all the atoms of the individual reactants.Compared with multistep reaction routes, MCRs are highlyattractive in terms of step economy.[1, 2] Typical MCRs proceedin a linear domino mode: in the first stage, the components Aand B (Scheme 1a) give rise to a reactive intermediate (AB)which then reacts with a third component (C), and so on, untilthe sequence is terminated. Very often, the first steps arereversible, and only the terminating steps are irreversible(type I or type II MCRs).[3, 4]

In contrast, if three components A, B, and C could reactwith each other in any order, such three-component dominoreactions (3CR) could proceed through an alternative two-dimensional split domino process (Scheme 1b). In sucha process, there are two kinetic alternatives to give the finalABC product, via the AB or the BC intermediates. If the stepsare irreversible, the efficiency of the process could becompromised if one of the pathways leads to a dead end(see the box in Scheme 1b). Alternatively, unwanted homo-coupling or heterocoupling reactions between the compo-nents could also jeopardize the projected 3CR process. Giventhese constraints, it is not surprising that nearly all knownMCRs and domino reactions proceed in a strict linear fashion,with the functionalities of the individual components deter-mining the order of events.[5]

Herein, we describe a successful two-dimensional 3CRthat proceeds through a mild Pd-catalyzed oxidative couplingbetween b-ketoesters (component A), indoles (componentB), and aryl boronates (component C ; Scheme 1c). This 3CRcould theoretically proceed via both AB and BC intermedi-ates, and we demonstrate herein that both pathways are

viable. To the best of our knowledge, catalytic oxidative 3CRshave not been reported in the literature.[6] The 3CR generatesdensely functionalized 2,3-disubstituted indoles directly fromthe three components.[7]

We hypothesized that the reaction conditions of ourpreviously reported[8] cross-dehydrogenative coupling reac-tion between b-ketoesters and indoles could also enable otheroxidative coupling reactions at the free 2-position of theindole. Two-component oxidative couplings between indolesat the 2-position and arylboronates have previously beenreported, by the groups of Shi,[9a] Zhang,[9b] and Studer.[10]

However, direct oxidative 2,3-difunctionalization reactions ofindoles have not been developed, and we were concerned thatowing to the increased steric requirements of such a processa CuII co-catalyst might be required,[9a,b] and this couldcompromise the regioselectivity for the b-ketoester.[8a] How-ever, we anticipated that the use of the more-electrophilic PdII

precursor Pd(TFA)2, might overcome these problems, as thiscatalyst was shown to be superior to other PdII sources in thecross-dehydrogenative coupling reactions.[8a]

Scheme 1. The difference between a) linear and b) two-dimensionalmulticomponent sequences. Bz = benzoyl, TFA = trifluoroacetate

[*] Dr. R. Y. Nimje, M. V. Leskinen, Prof. Dr. P. M. PihkoDepartment of Chemistry and NanoScience CenterUniversity of Jyv�skyl�P. O. B. 35, 40014 JYU (Finland)E-mail: petri.pihko@jyu.fiHomepage: http://tinyurl.com/pihkogroup

[**] We thank the Academy of Finland (projects 138854 and 139046),Tekes, Orion Pharma, Hormos Medical, and AB Enzymes forfinancial support. We also thank Mirja Lahtiper� and Esa Haapa-niemi for assistance with mass spectrometry and NMR spectros-copy, respectively. Antti Neuvonen and Dr. K.-T. Yip are acknowl-edged for assistance with the X-ray and kinetic analysis, respectively.Author contributions: M.V.L. conceived and initiated the study andperformed the kinetic experiments. R.Y.N. explored the scope of thereaction. P.M.P. supervised the project and wrote the papertogether with the co-authors.

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/anie.201300833.

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To our delight, when the three components b-ketoester1a, indole 2a, and phenylboronic acid 3 (Table 1) weresubjected to our reaction conditions with 2.5 equivalents ofthe oxidant (tBuOOBz), the reaction proceeded cleanly togive the ABC product 4a (83% conversion, 76% yield uponisolation). Further studies (Table 1) indicated that phenyl-boronic acid was indeed the optimal coupling partner. Otheroxidants, acid additives, and solvents were also screened (seethe Supporting Information) but these generally turned out tobe inferior to the optimal conditions.

The scope of the reaction turned out to be very wide.Scheme 2 summarizes the exploration of the scope withdifferent arylboronates and indoles. Both electron-donatingand electron-withdrawing groups are tolerated on the boro-nate (products 4 c–4 i), as well as on indole (4k–4n). With o-tolylboronic acid, the product 4 i was obtained as a 1:1 mixtureof two atropisomers. Even compound 4j, derived from o-isopropylphenylboronic acid, was obtained in good yield andthe two diastereomeric atropisomers could readily be sepa-rated and characterized (see the Supporting Informa-tion).[11, 12] These experiments also attest to the high sterictolerance of the 3CR process.

Different b-ketoesters are also tolerated (Scheme 3). 3CRproducts derived from b-keto lactones (4 p–4 q), 7-memberedb-ketoesters (4r), fused b-ketoesters (4s), and even open-chain b-ketoesters (4t) can be accessed with remarkable easeby this oxidative three-component coupling reaction. Finally,the use of a menthyl ester provides the product with moderatebut promising diastereoselectivity (4u ; 3:1 d.r.), and evenmore remarkably, with o-tolylboronic acid, the reaction givesonly two major products in a 1.8:1 ratio (4v ; presumably the

atropisomeric products) instead of the expected statisticalmixture of four diastereomers.

These investigations underline the high tolerance of thereaction to steric effects and suggest that some level of controlfor the diastereoselectivity should also be possible. Thereaction proceeds under very mild reaction conditions, atroom temperature, with benign solvents (AcOH + iPrOH ordioxane).

In all cases, the reactions proceeded with high regiochem-ical fidelity: the arylboronate 3 was selectively coupled at the2-position of indole, and the cross-dehydrogenative couplingof b-ketoester was fully regioselective for the b’ position ofthe b-ketoester and the 3-position of the indole compo-nent.[8–10] What was more remarkable, however, was that thedehydrogenative conditions of the reaction did not result inunwanted coupling between the b-ketoester 1 and theboronate 3 (A + C coupling). Indeed, even in a controlexperiment with 1a and 3a but no indole component, the rateof the formation of 8 a (A + C product) was very low(Scheme 4).

To probe whether the 3CR could proceed through bothA + B and B + C pathways, or whether one of the pathwayswas dominating, we carried out the following experiments.First, monitoring the reaction progress (Figure 1a) by1H NMR spectroscopy indicated that the formation of 5

Table 1: Screening of various aryl sources for the 3CR.[a]

Entry X t [h] Yield [%][a]

1 20 83

2 24 11

3 24 59

4 48 0

5 48 0

6 48 0

7 24 0

[a] Reaction conditions: 1a (0.6 mmol, 1.5 equiv), 2a (0.4 mmol,1 equiv), 3 (0.8 mmol, 2 equiv), Pd(TFA)2 (0.04 mmol, 10 mol%), andtBuOOBz (1.0 mmol, 2.5 equiv) in iPrOH/AcOH 4:1 (0.5 mL).[b] Determined by 1H NMR analysis using dibenzyl ether as an internalstandard.

Scheme 2. Oxidative domino cross-couplings with various arylboronateand indole components. The yields of the products after purificationare reported. Reaction conditions, unless otherwise indicated:1 (1.5 equiv), 2 (0.4 mmol, 1.0 equiv), 3 (0.8 mmol, 2.0 equiv),tBuOOBz(2.5 equiv), Pd(TFA)2 (0.1 equiv), iPrOH/AcOH (4:1; 0.5 mL)at 25 8C. [a] Dioxane/AcOH (4:1; 0.5 mL) used as a solvent. [b] 2(3 equiv) used in two installments. [c] 1:1 mixture of atropisomers. Thecombined yield of two atropisomers is given.

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(A + B coupling) was slower than the formation of 6 (B + C)under the 3CR conditions, with a more than 20-fold initialrate difference between these two competing processes.

Each coupling step of the process was then examinedindividually by two-component coupling (2CR) experimentsunder otherwise identical reaction conditions. The initialcoupling reactions between 1a + 2 a (A + B) and 2a + 3 (B +

C) were studied first. These experiments revealed that theboronate indole coupling (2a + 3 ; B + C) proceeded at nearlyidentical rates in the 3CR (5.5 mmmin�1) and in the 2CR(5.1 mmmin�1; Figure 1c). In stark contrast, the cross-dehy-drogenative coupling between b-ketoester 1a and indole 2a

(A + B) proceeded nearly an order of magnitude faster underthe 2CR conditions (1.5 mmmin�1) compared to the 3CRconditions (0.2 mmmin�1; see Figure 1a). The difference inthe rates of the individual 2CRs A + B and B + C, thusappears to be amplified in the 3CR.

The second step of the 3CR was studied next. Althoughthe rate of the formation of the AB product 5 was marginalunder the 3CR conditions, the AB + C control experimentdemonstrated that 5 readily reacted with 3 (C) under

Scheme 3. Oxidative domino cross-couplings with different b-keto-esters. Yields of pure products are reported and the X-ray crystallo-graphic structure of 4q is shown.[15] Reaction conditions, unlessotherwise indicated: 1 (1.5 equiv), 2 (0.4 mmol, 1.0 equiv), 3(0.8 mmol, 2.0 equiv), tBuOOBz (2.5 equiv), Pd(TFA)2 (0.1 equiv),iPrOH/AcOH (4:1; 0.5 mL) at 25 8C. [a] Combined yield of diastereo-mers.

Scheme 4. Control experiment to probe the possibility of the formationof the A+ C coupling product.

Figure 1. a) Monitoring of the temporal progress of the three-componentA + B + C (1a + 2a + 3a) coupling by 1H NMR spectroscopy. b) Monitoringof the temporal progress of the A+ B (1a + 2a) two-component couplingby 1H NMR spectroscopy. c) Initial rate kinetics of the B + C (2a + 3) two-component coupling. Reaction conditions: [1a]0 = 0.44m, [2a]0 = 0.29m,[3]0 = 0.58m, [tBuOOBz]0 = 0.73m, 10 mol% Pd(TFA)2, 4:1 [D8]dioxane/AcOH, 300 K. In the three-component coupling, [7] could not be reliablymonitored in the early stages of the reaction (see the SupportingInformation).

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otherwise identical reaction conditions to give 4 (ABCproduct).[12] Thus, the AB + C!ABC pathway, althoughslower than the A + BC pathway, was nevertheless shown tobe productive. In turn, a competition experiment with 1a (A)and equimolar concentrations of 2a (B) and 6 (BC) indicatedthat these two competing cross-dehydrogenative couplingreactions to give 5 (AB) and 4 (ABC) proceed at nearlyidentical rates.[12] These experiments confirmed that the 3CRproceeds predominantly through the “B + C, then A” path-way, with the dominance established by the faster B + Ccoupling relative to the A + B coupling. However, bothpathways are viable routes to the product.

The suppression of the A + B coupling relative to the B +

C coupling under the 3CR conditions could be due topartitioning of the catalyst between the A + B and B + Ccatalytic cycle, as both reactions are competing for the samePd catalyst pool. However, the reactions are also competingfor the same substrate, indole 2a (B). The sigmoidal shape ofthe curve for [5] in the two-component A + B coupling ischaracteristic of a consecutive reaction and suggests thatenone 7 is an intermediate (see Figure 1b).[13] The initialdelay, inherent in the consecutive nature of the A + Bcoupling, gives this reaction a serious kinetic disadvantagecompared to the B + C coupling; by the time the concen-tration of the intermediate (e.g. enone 7) reaches its peak,most of the indole 2a (B) has already been consumed.Consequently, the reaction will be diverted towards the A +

BC pathway, possibly with 6 (BC) competing with 2 a (B) forenone 7. Although the rate differences between the two-component A + B and B + C experiments is small, thesedifferences are amplified in the three-component A + B + Creaction because the A + B reaction is a consecutive reactionwith an induction period, whereas the B + C reaction starts toconsume indole 2a (B) without detectable delay.[14]

Such kinetic amplifications could be useful in designingselective reactions and MCR processes, or for probing theinduction periods of reactions. For example, two competingreactions with similar initial rates but different inductionperiods should display significant rate differences in a com-petition experiment for the same substrate, even in caseswhere the intermediates themselves would escape detection.

In summary, palladium-catalyzed oxidative three-compo-nent coupling between b-ketoesters, indoles, and arylboronicacids proceeds under very mild reaction conditions withexcellent regioselectivity for the products. Even very hin-dered compounds, such as atropisomeric products 4j and 4v,can be accessed in good yields. Indole couples faster with thearylboronic acid than the b-ketoester, and this rate differenceis significant under the three-component reaction conditions,possibly because the coupling with b-ketoester involves anenone intermediate. Further implications of this study on themechanism of both oxidative coupling reactions are beingstudied and will be reported separately.

Received: January 30, 2013Published online: April 2, 2013

.Keywords: homogeneous catalysis · kinetics ·multicomponent reactions · oxidative couplings · palladium

[1] a) “Towards the ideal synthesis”: P. A. Wender, S. T. Handy,D. L. Wright, Chem. Ind. 1997, 765; For a more recentperspective, see: b) T. Gaich, P. S. Baran, J. Org. Chem. 2010,75, 4657.

[2] For selected reviews, see: a) E. Ruijter, R. Scheffelaar, R. V. A.Orru, Angew. Chem. 2011, 123, 6358; Angew. Chem. Int. Ed.2011, 50, 6234; b) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr.Opin. Chem. Biol. 2010, 14, 371; c) G. Guillena, D. J. Ram�n, M.Yus, Tetrahedron: Asymmetry 2007, 18, 693; d) A. Dçmling,Chem. Rev. 2006, 106, 17; e) Multicomponent Reactions (Eds.: J.Zhu, H. Bienaym�), Wiley-VCH, Weinheim, 2005.

[3] A. Dçmling, I. Ugi, Angew. Chem. 2000, 112, 3300; Angew.Chem. Int. Ed. 2000, 39, 3168.

[4] L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions inOrganic Synthesis, Wiley-VCH, Weinheim, 2006.

[5] During the preparation of this manuscript, Enders and co-workers described an organocatalytic branched (i.e. split)domino sequence: X. Zenge, Q. Ni, G. Raabe, D. Enders,Angew. Chem. 2013, 125, 3050; Angew. Chem. Int. Ed. 2013, 52,2977.

[6] Oxidative domino cross-couplings have been previously de-scribed, but typically these reactions involve only two compo-nents. For selected examples, see: a) S. Hajdok, J. Conrad, U.Beifuss, J. Org. Chem. 2012, 77, 445; b) K. Hackeloer, G.Schnakenburg, S. R. Waldvogel, Org. Lett. 2011, 13, 916; fora rare example with three components, see: c) L. Jiangsheng, C.Feifei, L. Zhiwei, X. Yuan, C. Chao, L. Weidong, C. Zhong, Chin.J. Chem. 2012, 30, 1699.

[7] Reactions that achieve the formation of two C�C bonds at theindole nucleus in a single operation are rare. For an example ofa cross-dehydrogenative coupling where the 2,3-disubstitutedproducts were generated in trace amounts, see: a) D. R. Stuart,E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129, 12072; foran example of a stoichiometric 2,3-difunctionalization, see:b) M. Ishikura, H. Kato, M. Ohnuki, Chem. Commun. 2002, 220;c) M. Ishikura, H. Kato, Tetrahedron 2002, 58, 9827; forexamples of 2,3-difunctionalizations involving annulations, see:d) G. Zhang, X. Huang, G. Li, L. Zhang, J. Am. Chem. Soc. 2008,130, 1814; e) R. Liu, J. Zhang, Adv. Synth. Catal. 2011, 353, 36;f) X. Han, H. Li, R. P. Hughes, J. Wu, Angew. Chem. 2012, 124,10536; Angew. Chem. Int. Ed. 2012, 51, 10390; for a review ofcatalytic functionalization of indoles, see: g) M. Bandini, A.Eichholzer, Angew. Chem. 2009, 121, 9786; Angew. Chem. Int.Ed. 2009, 48, 9608.

[8] a) M. V. Leskinen, K.-T. Yip, A. Valkonen, P. M. Pihko, J. Am.Chem. Soc. 2012, 134, 5750; b) K.-T. Yip, R. Y. Nimje, M. V.Leskinen, P. M. Pihko, Chem. Eur. J. 2012, 18, 12590.

[9] a) S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi,Angew. Chem. 2008, 120, 1495; Angew. Chem. Int. Ed. 2008, 47,1473; for an alternative protocol with aryltrifluoroborates, see:b) J. Zhao, Y. Zhang, K. Cheng, J. Org. Chem. 2008, 73, 7428.

[10] S. Kirchberg, R. Frçhlich, A. Studer, Angew. Chem. 2009, 121,4299; Angew. Chem. Int. Ed. 2009, 48, 4235.

[11] For examples of atropisomers derived from indoles, see:a) T. D. W. Claridge, J. M. Long, J. M. Brown, D. Hibbs, M. B.Hursthouse, Tetrahedron 1997, 53, 4035; for a related benzimi-dazole-derived atropisomer, see: b) A. Figge, H. J. Altenbach,D. J. Brauer, P. Tielmann, Tetrahedron: Asymmetry 2002, 13, 137;for atropisomers derived from 1,2,3-trisubstituted pyrroles, see:c) S. Le Gac, N. Monnier-Benoit, L. D. Metoul, S. Peti, I. Jabin,Tetrahedron: Asymmetry 2004, 15, 139; d) J. L. A. Webb, J. Org.Chem. 1953, 18, 1413.

[12] See the Supporting Information for details.[13] In a three-component control experiment where 250 mol % of

enone 7 was used in lieu of b-ketoester 1a but no additionaloxidant was used, the reaction gave exclusively the A + B

AngewandteChemie

4821Angew. Chem. Int. Ed. 2013, 52, 4818 –4822 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

coupling product 5 (see the Supporting Information). Thisexperiment indicates that enone 7 may not be capable ofreoxidizing Pd0 in the catalytic cycle (in order to sustain the B +

C oxidative coupling) and suggests that the concentration of 7controls the rate of the A + B coupling. For a previous discussionof the mechanism of the indole-b-ketoester coupling, seeRef. [8a].

[14] We are aware that given the complexity of the system, otherfactors are likely to play a role as well. For example, most of the

species here (1a, 2a, 5, 6 and 7) could act as ligands for Pd. Forevidence of the involvement of indoles in the formation of 7, seeRef. [8b] (see the Supporting Information, p. S40).

[15] CCDC 917055 (4q) contains the supplementary crystallographicdata for this paper. These data can be obtained free of chargefrom The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

.AngewandteCommunications

4822 www.angewandte.org � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2013, 52, 4818 –4822

IV

CROSS-DEHYDROGENATIVE COUPLINGS BETWEEN INDOLES

AND β-KETO ESTERS: SCOPE, MECHANISM, AND EVIDENCE

FOR LIGAND-RELATED KINETIC ISOTOPE EFFECTS AND DE-

HYDROGENATION VIA A PROTON-ASSISTED ELECTRON

TRANSFER TO PD(II)

by

Mikko V. Leskinen, Ádám Madarász, Kai-Tai Yip, Aini Vuorinen, Imre Pápai, and

Petri M. Pihko

Manuscript

Mikko V. Leskinen,† Ádám Madarász,‡ Kai-Tai Yip,† Aini Vuorinen,† Imre Pápai,*,‡ Antti J. Neu-vonen,† and Petri M. Pihko*,†

†Department of Chemistry and NanoScience Center, University of Jyväskylä, FI-40014 JYU, Finland, and ‡Research Center for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri ut 59-67, H-1027, Budapest, Hungary

ABSTRACT: Cross-dehydrogenative coupling reactions between -ketoesters and electron-rich arenes, such as indoles,

proceed with high regiochemical fidelity with a range of -ketoesters and indoles. The mechanism of the reaction be-

tween a prototypical -ketoester, ethyl 2-oxocyclopentanonecarboxylate and N-methylindole, has been studied experi-mentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control exper-

iments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction pro-ceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the

-keto ester ligand from a O,O’-chelate to an C-bound Pd enolate. This ligand tautomerization event is assisted by the

-bound indole ligand. Subsequent scission of the ’-C–H bond takes place via a proton-assisted electron transfer mecha-nism where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally, and both were found to be viable routes for the coupling step.

INTRODUCTION– Dehydrogenative cross-couplings, or cross-dehydrogenative couplings between two partners with C–H bonds, constitute an attractive strategy in chemical synthesis.1 In particular, when the reaction part-ners include sp3 C–H bonds, the reactions can be used to generate molecular complexity in three dimensions, and at the same time allow functionalization in remote posi-tions. Although there have been significant advances in this field in recent years,2,3 dehydrogenative functionaliza-tion reactions involving remote sp3 C–H groups are still rare.4 In part, this might be due to the fact that the mech-anisms of dehydrogenative cross-couplings are only par-tially understood.

Herein, we present a full account on the mechanistic investigation and the scope of the selective Pd(II)-catalyzed dehydrogenative cross-coupling reaction be-tween indoles and β-keto esters.5 This reaction is an ex-ample of a cross-dehydrogenative coupling between sp3 and sp2 C−H bonds, and besides indoles, the reaction also accepts electron-rich aromatics and phenols as the cou-pling partner,6 and also allows for a three-component coupling between arylboronates, indoles and β-keto es-ters (Scheme 1).7

Scheme 1. Development of Dehydrogenative β’−C(sp3)−H C(sp2)−H Coupling Reaction

Results and Discussion

In our initial communication, we presented two possi-ble mechanistic scenarios for this reaction (Scheme 2). The first, a “late indole”, scenario involves a Saegusa oxi-dation8 of 1a to enone intermediate A followed by a

Friedel-Crafts-type Pd-catalyzed conjugate addition of indole 2a. The second, an “early indole”, scenario starts with the well-established C3-palladation of indole9 in which a C3-palladated indole species B is involved in the dehydrogenation step, followed by reductive elimination. Our early mechanistic investigations5 could not distin-guish between these two mechanistic possibilities. The key initial observations were: 1) Isolated enone 4a also afforded the coupling product with indole 2a, at a rate that was comparable to the overall reaction rate, and 2) without indole 2a, only very slow formation of enone 4a was observed. These observations suggested that if enone 4a was an intermediate, its formation might be depend-ent on the assistance of indole.

Scheme 2. Palladium-Catalyzed Dehydrogenative β′-Functionalization of β-Keto Ester with Indole and Orginally Proposed Reaction Mechanism

In our early studies, the progress of the reaction was monitored by withdrawing aliquots from the reaction mixture.5 In this work, we envisioned that the use of online NMR methods to monitor the temporal progress of the reaction would be most beneficial to reveal any fleet-ing intermediates, and to allow the simultaneous moni-toring of several species, including the oxidant.10

Kinetic Studies. Initially, the standard reaction of β-keto ester 1a with 1-methylindole (2a) was monitored by 1H NMR spectroscopy (Figure 1). The results show that [4a] builds up and decays during the initial stage of the reaction, and product formation ([3a]) follows a sigmoidal curve. The consumption of indole 2a also plots a reverse sigmoidal curve. These results strongly suggested that enone 4a is an intermediate, and indeed the rate of for-mation of 3a peaks close to the concentration peak of 4a.11 The sigmoidal shape of the curve for [4a] is characteristic of a delay caused by the buildup of the intermediate in a consecutive reaction. The initial rate for the consumption of β-keto ester 1a (-5.7 mM min-1) is also close to the ini-

tial rate of the consumption of the oxidizer tBuOOBz (-5.1 mM min-1).

Figure 1. Monitoring of the temporal progress of the cou-pling by 1H NMR spectroscopy. Reaction conditions: [1a]0= 0.476 M, [2a]0= 0.318 M, [tBuOOBz]0= 0.413 M, 10 mol% Pd(TFA)2, 4:1 [D8]-Dioxane/AcOH, 300 K. The reported rates are averages of three experiments. Rate0 and rate53 refer to the initial rate and the rate at t = 53 min, respectively.

Using separately prepared enone 4a, the reaction be-tween enone 4a and indole 2a was investigated under two sets of conditions. The initial concentration of 4a was set to 0.12 M, close to the peak concentration of 4a obtained under the standard oxidative coupling conditions (Figure 1). With Pd(TFA)2 as the catalyst, the reaction between 2a and 4a (Scheme 3) progresses at a rate comparable to the peak rate obtained under the standard conditions (1.7 mM min–1 for both cases). In contrast, TFA alone as the cata-lyst allowed the reaction to proceed, but at a significantly slower rate (1.7 mM min-1 with Pd(TFA)2 vs. 0.26 min-1 with TFA, see Scheme 3). These results indicated that Pd(II) also plays a role in the second coupling step, with a possible acid-catalyzed background reaction.

Scheme 3. Reactions of Indole 2a and Enone 4a

Table 1. Effect of TFA on the Reaction Ratea

Entry TFA Rate 3ab

(mM min-1)

Rate 4ac

(mM min-1)

1 0 mol% 0.1 0.1

2 10 mol% 1.7 2.9

3 20 mol% 2.3 3.6

4 40 mol% 2.6 3.3

aThe rates were obtained by monitoring the temporal pro-gress of the coupling by 1H NMR spectroscopy. Reaction conditions: 10-40 mol% TFA, [1a]0= 0.476 M, [2a]0= 0.318 M, [tBuOOBz]0= 0.413 M, 10 mol% Pd(OAc)2, 4:1 [D8]-Dioxane/AcOH, 300 K.b Max rate c Initial rate.

Interestingly, although TFA alone was an inefficient catalyst, the effect of additional TFA to the overall reac-tion rate was beneficial (Table 1). With added TFA, the reaction proceeded at a reasonable rate even when using Pd(OAc)2 as the Pd(II) source.

Kinetic Isotopic Effects and Deuterium Labeling. Although the above experiments established that enone 4a is indeed a viable intermediate for the reaction, control experiments without indole 2a clearly demonstrated that enone formation is very slow in the absence of indole.5 The reaction progress method allowed us to obtain kinet-ic isotope effect (KIE) data for all key reaction compo-nents, using deuterium-labeled starting materials.12

The first KIE experiment involved a comparison of C2-H vs C2-D-labeled indole (Figure 2 a).13 All reaction com-ponents displayed significant inverse KIEs in this experi-ment (Figure 2). These results indicate that D-2a acceler-ates the formation of the enone 4a. The increased rate of product formation (3a) might be due to increased rate of the formation of the intermediate.

A second set of KIE experiment was conducted with

deuterium-labelled -keto ester D6-1a (Figure 2 b). In this case, unfortunately, the formation of the corresponding enone could not be reliably monitored. Although the rate of consumption of D6-1a appears to display an inverse KIE, possible initial H/D exchange and/or differences in the rates of the formation of the Pd(II) complexes of 1a could also account for this observation. Indeed, the over-all rate of the reaction did not exhibit any KIE (3a: kH/kD = 0.98), and the initial rate of the consumption of the oxi-dant indicated a small normal KIE (kH/kD = 1.07). Since the consumption of the oxidant is most likely correlated with the concentration of the enone 4a, these results suggest that the dehydrogenative reaction that produces 4a is unlikely to exhibit a KIE, although this step must involve the breaking of the β’-H bond of 1a.

Figure 2. Temporal progress of the coupling by 1H NMR spectroscopy with deuterated starting materials. Reaction conditions: a): [1a]0= 0.476 M, [D-2a]0= 0.318 M, b) : [D6-1a]0 = 0.476 M, [2a]0= 0.318 M. For both experiments: [tBuOOBz]0= 0.413 M, 10 mol% Pd(TFA)2, 4:1 [D8]-Dioxane/AcOH, 300 K. Rates and kH/kD are averages of three experiments (a) or two experiments (b). Rate0 and ratexx refer to the initial rate and the rate at t = xx min, respectively.

Competition Studies. To obtain further insight into the reaction mechanism, the KIEs were also assayed via competition studies.12 As shown in Scheme 4, an intermo-lecular competition reaction between substrates 2a and D-2a, starting with 1a, gives a product distribution PH/PD 1:1.22. If 2a is not dissociated from Pd after the first stage of the reaction (formation of enone 4a), then the ob-served KIE could be explained by the more rapid rate of enone formation with D-2a. However, the fact that a significant concentration of free enone can be observed during the reaction (Figure 1) suggests that the catalytic cycle responsible for the coupling of enone 4a and indole 2a is at least partially separated from the first dehydro-genation cycle that produces enone 4a. Therefore, the observed KIE in Scheme 4a could be related to the C–C formation step. To assay this possibility, intermolecular competition experiments with 2a and D-2a were con-ducted using enone 4a as the substrate. These experi-ments gave a PH/PD that was much closer to unity under both Pd(II) catalysis and TFA catalysis (Scheme 4b), sug-gesting that the KIE observed with 1a (Scheme 4a) origi-nates from the dehydrogenation step and that 4a may not be fully dissociated from the Pd complex that eventually leads to the product 3a.

Scheme 4. Competition Studies between 2a and D-2a

In the competition reaction between 1a and D6-1a, the non-deuterated 1a reacts faster than the deuterated D6-1a (Scheme 5). This result is in agreement with the small normal KIE observed for oxidant consumption with D6-1a in the parallel experiment (Figure 2 b), suggesting that D6-1a is dehydrogenated at a slower rate than 1a. Interest-ingly, some deuterium leakage takes place in this experi-ment, producing D4-3a (Scheme 5).

Scheme 5. Intermolecular Competition Between D6-1a and 1a in the Coupling Process

Finally, in an intramolecular competition experiment, the mono-β’-deuterated D1-1a gave rise to product 3a that exhibited a 48.6:51.4 H/D ratio (Scheme 6). The absence of a KIE in this experiment suggests that the β’-H bond cleavage is not turnover-limiting for the dehydrogenation cycle (see below for further discussion).

Scheme 6. Intramolecular Competition Studies with

’-Monodeuterated D1-1a

Scheme 7. Intermolecular Competition Between 1a and 1b in the Coupling Process

The effect of the electron-withdrawing alkyl ester was

studied using -keto ester 1b. Under the standard condi-tions, the reaction between 1b and 2a was significantly slower than the standard reaction between 1a and 2a. (0.52 mM min-1 with 1b vs. 1.7 mM min-1 with 1a). This rate

difference was also confirmed by an intermolecular com-petition between 1a and 1b (P3a/P3b value of 3, see Scheme 7). These rates reflect the measured rates of the dehydro-genation step (rate of formation of enone: 1.6 mM min-1 for 4b vs. 4.4 mM min-1 for 4a).13

In summary, these kinetic experiments revealed that 1) the reaction likely proceeds in two stages, via an enone intermediate (4a), 2) the formation of enone is dependent on indole, and 3) the C–C bond formation step can pro-ceed under both acid catalysis as well as under Pd(II) catalysis. In parallel with these experiments, the intimate details of the mechanism were subjected to a computa-tional study.

Computational Studies and Revision of the Mech-anism. Based on our experimental findings, we envi-sioned that the Pd-catalyzed dehydrogenative cross-coupling reaction between β-ketoester 1a and indole 2a takes place via two distinct catalytic cycles (Scheme 8) corresponding to the formation of the enone intermediate (cycle A) followed by the C–C bond formation process with indole (cycle B). As indicated in Scheme 8, the Pd(TFA)2(2a) species may represent a common interme-diate of the two cycles. We carried out DFT calculations with the main aim at identifying and characterizing the key elementary steps of these cycles.15

Scheme 8. Schematic view of Catalytic Cycles for the Dehydrogenation and the C–C bond Formation Steps

Dehydrogenation: Cycle A. In accordance with previous studies on Pd-catalyzed dehydrogenation reactions, we

considered a sequence of C–H-activation/-hydride elim-ination steps in cycle A. The assistance of indole was clearly demonstrated in our experiments, therefore we assumed that 2a acts as a co-ligand along the entire reac-tion pathway.

The calculations indicate that the deprotonation of 1a

at the -carbon atom can occur easily via a tetracoordinate Pd(II) complex involving two TFA ligands and both substrates bound to the metal center (interme-diate Pd(TFA)2(1a)(2a)). This complex is predicted to be

at -0.1 kcal/mol with respect to Pd(TFA)2(2a) + 1a.16 The transition state identified for the deprotonation is depict-ed in Figure 3a and it represents only a small activation barrier (9.9 kcal/mol). It is apparent that the C–H bond of 1a is activated by a neighboring TFA ligand resulting in a Pd-enolate intermediate, which is stabilized by the disso-ciation of the TFAH molecule. This latter reaction inter-mediate (int1 in Figure 3b) lies slightly below the refer-ence level (at –3.4 kcal/mol), and it is characterized by chelating coordination of the enolate ligand through the

two carbonyl moieties (2(O,O') complex).17

For the -hydride elimination step, the ’-hydrogen should be accessible by the metal center, therefore, ligand rearrangement is expected as a next step along the reac-tion pathway. The simplest transformation would be an internal rearrangement of the bonding between Pd and enolate preserving the same stoichiometry, but other pathways (including various dissociation/association steps) are also feasible. Our attempts to explore these transformations pointed to several transition states lying higher in free energy than TSdepr. For instance, the transi-

tion state connecting int1 with an 3-Pd-enolate interme-diate (i.e. displacement of the ester group from the coor-dination sphere, see TSrear and int2 in Figure 4) is predict-ed to be at 16.9 kcal/mol, giving rise to a barrier of 20.3 kcal/mol (relative to int1).

18

Figure 3. Transition state located for the substrate deprotonation step of cycle A (a) and the corresponding product state intermediate (b). Relative Gibbs free energies (in kcal/mol, with respect to Pd(TFA)2(2a) + 1a) are shown in parenthesis. Metal-ligand bonds are indicated by dashed lines. For clarity of figures, hydrogen atoms are omitted, except those involved in dehydrogenation.

Figure 4. Decoordination of the ester group in intermediate int1: a) transition state, b) product state of rearrangement.

TSdepr (9.9) int1 (-3.4)

a) b)

HHH

a) b)

TSrear (16.9) int2 (7.0)

HH

Additional ligand rearrangement can lead to an inter-

mediate involved directly in the -hydride elimination step (see int3 in Figure 5). In this species, the enolate is

bound covalently to Pd via the -carbon atom (1(C)

complex) and it displays characteristic -agostic interac-tions with the metal center. This complex is computed to be at +3.2 kcal/mol on the free energy scale. Surprisingly, the Pd-mediated C–H bond cleavage does not yield the expected palladium-hydride species, because the located transition state (TSPCET in Figure 5) describes a direct hydrogen migration to the free oxygen of the TFA ligand without the formation of a palladium-hydride intermedi-ate (PdH species could only be identified computationally as very unstable structures).11

Figure 5. The proton-coupled electron transfer (PCET) tran-sition state of cycle A and the corresponding reactant and product state intermediates.

The population analysis carried out for the transition state and the corresponding intermediates reveals that this elementary step can be characterized as a concerted proton-coupled electron transfer (PCET) process involv-ing proton migration to TFA occurring in concert with 2e- electron transfer to the metal center.19,20, This reaction step results in a Pd(0)(TFAH)(2a)(4a) complex as an in-termediate (int4 in Figure 5) lying at 6.4 kcal/mol. The computed activation barrier of the PCET step is 16.9 kcal/mol with respect to the low-lying int1 intermediate, i.e. much lower than that of the ligand rearrangement. After this step, the catalytic cycle involves the oxidation process and the elimination of the enone molecule. These transformations were not examined computationally in the present work.

The Gibbs free energy diagram of the reaction route ex-plored for the dehydrogenation process is depicted in Figure 6. These results point towards a reasonable mech-anism for the dehydrogenation process, however, they

indicate that the 2(O,O') to 1(C) rearrangement of the

enolate ligand, and not the PCET step, might be rate-determining in cycle A.

Figure 6. Gibbs free energy diagram computed for the dehy-drogenation process.

Indole-Assisted Dehydrogenation. To assess the role of indole in the dehydrogenation cycle, we examined analogous reaction pathways using a model with a TFAH co-ligand replacing the indole. We find that the activation barriers are notably higher than those presented above. The largest difference was obtained for the ester decoordination step (the barrier increased to 24.2 kcal/mol) indicating that indole coordination is clearly beneficial in terms of the reaction rate. Interestingly, the PCET mechanism of C-H bond cleavage is maintained in the absence of indole as well, although the barrier of this step is predicted to be slightly higher in this case (15.0 kcal/mol).

To rationalize the results of KIE experiments with 2a, we calculated the KIE values based on the relative barriers with the different isotopomers of 2a. With D-2a, the cal-culated KIE is 0.85 for the transformation from int1 into int2 via TSrear.

21,12. The calculated value is very close to the

experimental KIE (0.77-0.85, see Figure 2). The magnitude of the KIE is similar to cases where hybridization changes from C(sp2) to C(sp3),22 suggesting that the steric envi-ronment of C2 of 2a becomes significantly more crowded in the turnover-determining step. This result suggests that 2a assists the tautomerization step by coordinating

more tightly (primarily via its 2,3--bond) to Pd(II) in the transition state TSrear. The need for indole assistance in this step may result from increased electron deficiency of the Pd(II) center in TSrear due to decoordination of 1a.

To test this hypothesis, we also experimentally explored other electron-rich ligands which would not react with 4a but would nevertheless be able to withstand the oxidative conditions. In addition to sulfoxides (DMSO and PhSOMe),23 1,2,3-trimethylindole and 1,3-dimethylindole were able to significantly accelerate the dehydrogenation step.11

a) b)

TSPCET (13.5)int3 (3.2)

c)

int4 (6.4)

H H

H

-5

0

5

10

15

20

-5

0

5

10

15

20

-5

0

5

10

15

20

DG

(k

ca

l/mo

l)

TSdepr (9.9)

TSrear (16.9)

TSPCET (13.5)

int1 (-3.4)

Pd(TFA)2(2a)(1a)

(-0.1)

Pd(TFA)2(2a) + 1a

int2 (7.0)

int3 (3.2)

int4 (6.4)

If the PCET step, where the ’-H bond is cleaved, was the turnover-determining step in cycle A, a much larger KIE would be expected than that observed experimentally

with ’-deuterated 1a variants (close to 1, see Figure 3 and Scheme 6). The calculated KIE for the PCET step is quite large (7.06), and it is in sharp contrast with the value obtained from the intramolecular competition experi-ment (Scheme 6) which is expected to be most sensitive to any KIE in the product-determining step. The fact that no 1° KIE is observed even under these conditions can be rationalized by the fact that the different hydrogen iso-topes are not in an equal environment after the turnover-

limiting step (i.e. TSrearr).24 The choice between ’-H vs.

’-D abstraction has already been made in the turnover-determining ligand rearrangement step which leads to the formation of C-bound enolate int3, The effect of deuteri-

um substitution in the ’ position of the ligand on the ligand rearrangement step is expected to be small, result-ing in a negligible 1° KIE.

The finding that the turnover is determined by the lig-and tautomerization step (from a O,O’-chelate int1 to C-

bound int3) is interesting. -Substituted -dicarbonyl

compounds are known to be unproductive in -arylation reactions,25 and our results suggest that such low reactivi-ty might have a kinetic origin. Specifically, if the barrier for the formation of the C-bound enolate from the O,O’-chelate intermediate is too high, this would prevent both

dehydrogenation and -arylation reactions. In a control experiment, methyl dimethylmalonate (5), a very sluggish

substrate for -arylation,25a failed to give any coupling products with 2a under the standard reaction conditions.11 This result could be rationalized by the higher Lewis ba-sicity of the ester oxygens in 5, which might result in a O,O’-chelated intermediate that would be too stable to undergo the tautomerization to the C-bound enolate. Since ligands such as indole are able to assist the tautomerization step, we can speculate that perhaps more

efficient -donor ligands might overcome these limita-tions.

The C–C Coupling Process. According to the experi-mental evidence, the C–C coupling process (cycle B) could proceed either via acid catalysis or Pd(II) catalysis under acidic conditions. We therefore examined several possibilities, and plausible pathways were identified for both Pd(II)- and acid-catalyzed pathways. For brevity, only the most feasible Pd(II)-catalyzed pathway is pre-sented herein the details of the other pathways are dis-cussed in the SI.

The Pd(II)-catalyzed pathway may begin with the Pd(TFA)2(2a)(4a) complex, which involves both coupling partners (indole 2a and enone 4a). Although this complex lies fairly high in free energy (11.8 kcal/mol with respect to Pd(TFA)2(2a) + 4a), it can undergo C–H activation via transition state TSCH to yield intermediate intCH (Figure 7). The located transition state is computed to be at 19.7 kcal/mol, and the resulting intermediate is predicted to be at 8.9 kcal/mol.,In this latter complex, the indole is

covalently bound to Pd, whereas enone 4a is -coordinated.

Facile C–C bond formation may take place from intCH (Figure 8).The located transition state (TSCC) lies notably lower in free energy than TSCH. The product state of the coupling process (intCC) is a very stable species, wherein the adduct is bound by multiple bonds to the metal cen-ter. Protonation of the carbonyl oxygen followed by the dissociation of the enolic form of the product is found to be a reasonable scenario for the completion of the cycle, but other product elimination routes may exist too. Sev-eral other C–C bond formation pathways were examined as well, but based on the obtained barriers, they are less feasible than those described above.11

Figure 7. C–H activation of indole.

Figure 8. Pd-catalyzed C–C coupling.

The Resting State of the Catalyst. Although the com-putations give reasonable barriers for the C–C bond form-ing step starting from Pd(TFA)2, the stability of the prod-uct complex intCC suggests that recycling Pd(II) requires

further assistance, e.g. from the acidic solvent and/or -ketoesters. We were able to crystallographically charac-terize a dinuclear [Pd2(TFA)2(3a)2] complex from a reac-tion conducted with 100 mol% of Pd(TFA)2.11 This com-plex could also be characterized computationally, and the experimentally and computationally derived structures are presented in Figure 9. The isolability of this complex supports the computational evidence that Pd(II)-3a com-plexes are stable intermediates, and their decomplexation might even limit the turnover of the reaction.

a) b)

TSCH (19.7) intCH (8.9)

a) b)

TSCC (16.0) intCC (-17.5)

Figure 9. Structure of the Pd2(TFA)2(3a)2] complex: a) X-ray structure, b) overlay of X-ray (blue) and computed (red) structures.

As a test for this hypothesis, we found that addition of dimethyl methylmalonate 5 (50 mol%) to the reaction mixture results in a marked increase in the rate of for-mation of both 3a and 4a (Scheme 9), pointing towards a possible assistance of 5 in releasing Pd(II).26 Alternatively, 5 could act as a ligand for dehydrogenation, but we find

this scenario less likely as -ketoester 1a alone cannot effectively promote the dehydrogenation without the assistance from indole.5 We cannot, however, rule out a third possibility that 5 assists in cycle B as a co-ligand.

Scheme 9. Effect of Malonate Ester 5

Reaction Scope and Asymmetric Variants of the Coupling Reaction. Although clarifying the mechanistic picture of the coupling reaction was the main focus of this study, we also present here the full scope of the transfor-mation and an asymmetric variant of the reaction. As described in our original communication, the reaction readily tolerated electron-rich, electron-poor, and sterically demanding indole-substrates, and both free indole N-H as well as N-methyl and N-benzyl indoles are

tolerated. In addition, a range of -keto esters, including cyclic 5,-, 6-, and 7-membered β-keto esters, can be used. Additional substrates that were not described in the ini-tial communication are shown in Scheme 10. The full scope is presented as a Chart in the Supporting Infor-mation.

For the development of an asymmetric version of the reaction, we have focused on using a chiral ester auxiliary. Although the use of chiral acids and/or chiral anions might conceivably induce enantioselectivity via either the Pd(II)- or acid-catalyzed C-C bond formation pathways, our previous experiments with chiral acids and chiral Pd phosphates were not very encouraging.6 Instead, 9-

phenylmenthyl esters27 exhibited useful levels of diastereoselectivity.28

Scheme 10. Additional Substrates for the Indole - β-Keto Ester Oxidative Couplinga

a Isolated yields of pure products are reported. Conditions: 1 (1.5 equiv), 2 (0.4 mmol, 1.0 equiv), t-BuOOBz (1.3 equiv), Pd(TFA)2 (0.1 equiv), i-PrOH/AcOH (4:1, 0.5 mL) at 25 ˚C.

Scheme 11 presents the scope of the transformation with different 9-phenylmenthyl β-keto esters. In general, the diastereoselectivities were good. The exception was 3i, which afforded only moderate 2.2:1 dr. The reaction also tolerates bromine substituents in the indole nucleus (3h, 3i); this is a useful feature for further functionalization of the products.

Scheme 11. Scope of the Diastereoselective Dehydrogenative Coupling with 9-Phenylmenthyl β-Keto Estersa

a Isolated yields of pure products are reported. Conditions, unless otherwise indicated: 1 (1.5 equiv), 2 (0.4 mmol, 1.0 equiv), t-BuOOBz (1.3 equiv), Pd(TFA)2 (0.1 equiv), i-PrOH/AcOH (4:1, 0.5 mL) at rt.

a) b)

Scheme 12. Revised Catalytic Cycles

Krapcho decarboxylation of 3aj provided the corre-sponding ketone 5a in 82% yield (eq 1). Interestingly, in this step, the initial 20:1 diastereomer ratio improved to >99.5:<0.5 er, indicating that the different diastereomers might decarboxylate at different rates.

Conclusions. -Keto esters and indoles can be dehydrogenatively cross-coupled with a high regiochemical fidelity under very mild conditions with Pd(II) catalysis. With the combined information obtained from online NMR monitoring experiments, kinetic iso-tope effects, and computational studies, the previously proposed reaction mechanism was revised. The revised mechanism is presented in Scheme 12.

The reaction involves indole already at the early stage

of the catalytic process as a -bound ligand for Pd(II) that assists the O–to–C Pd tautomerization step, the turnover-determining step of the dehydrogenation cycle. The assis-tance of the indole is evident both from the secondary kinetic isotope effects observed for the rate of the dehy-drogenation with 2-deuterated N-methylindole and from

the computational studies. The dehydrogenation of the -keto ester is completed by a proton-assisted electron transfer reaction where Pd(II) is simultaneously reduced to Pd(0) and trifluoroacetate ligand accepts a proton from

the ’ carbon. No Pd hydride intermediate could be char-acterized by the computations. For the C–C bond forming step, two plausible pathways involving either acid cataly-sis or Pd(II) catalysis can be presented. Finally, the syn-thetic utility of the protocol was expanded to include

additional substrates, and an asymmetric version of the reaction could be realized with 9-phenylmenthyl esters.

The reaction between indoles and -ketoesters appears to be possible only because indoles can serve the double role of a substrate and a ligand in the ligand-assisted tautomerization step, the turnover-determining step of the dehydrogenation cycle. This finding should encourage researchers to look for similar effects in other dehydro-genation and cross-dehydrogenative coupling reactions.

Supporting Information. Experimental procedures, addi-tional experiments pertaining to the mechanism, characteri-zation data, computational details, and copies of NMR spec-tra and HPLC chromatograms.

papai.imre@ttk.mta.hu, petri.pihko@jyu.fi

We thank Dr. Elina Kalenius and Mr. Esa Haapaniemi for assistance with mass spectrometry and NMR spectroscopy, respectively, and Academy Prof. Kari Rissanen for assistance with X-ray crystallography. Financial support from Tekes, Academy of Finland (project 138854), Hungarian Scientific Research Fund (OTKA, grant K-81927), AB Enzymes, CABB, Fermion, Hormos, Orion, and University of Jyväskylä is gratefully acknowledged.

1. For review of catalytic dehydrogenative cross-couplings, see: Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.

2. For unselective examples of dehydrogenative arylations of sp3 C−H bonds, see: (a) Deng, G.; Zhao, L.; Li, C.-J.

Angew. Chem. Int. Ed. 2008, 47, 6278. (b) Guo, X.; Li, C.-J. Org. Lett. 2011, 13, 4977.

3. For selected reviews of catalytic oxidative functionalizations of sp3 C−H bonds, see: (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010, 16, 2654. (b) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191. (c) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 2. (d) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem. Int. Ed. 2014, 53, 74.

4. For intramolecular PdII-catalyzed dehydrogenative arylations of sp3 C−H bonds, see: (a) Liègault, B.; Fagnou, K. Organometallics 2008, 27, 4841. (b) Pierre, C.; Baudoin, O. Tetrahedron 2013, 69, 4473.

5. Leskinen, M. V.; Yip, K-T.; Valkonen, A.; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750.

6. Yip, K-T; Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Chem. Eur. J. 2012, 18, 12590.

7. Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Angew. Chem. Int. Ed. 2013, 52, 4818.

8. For an overview, see: Ito, Y.; Suginome, M. In Hand-book of Organopalladium Chemistry for Organic Syn-thesis; Negishi, E.-I., Ed.; Wiley: New York, 2002; Vol. 2, p. 2873.

9. (a) Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc., Perkin Trans. 1 1983, 1361. (b) Itahara, T.; Kawasaki, K.; Ouseto, F. Synthesis 1984, 236. (c) Yokoyama, Y.; Mat-sumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486. (d) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097. (e) Grimster, N. P.; Gauntlett, C.; God-frey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (f) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159.

10. For examples of online NMR monitoring in detection of several intermediates, see: (a) Ref 7. (b) Sahoo, G.; Rahaman, H.; Madarász, Á.; Pápai, I.; Melarto, M.; Val-konen, A.; Pihko, P. M. Angew. Chem. Int. Ed. 2012, 51, 13144.

11. See the Supporting Information for details. 12. (a) Gómez-Callego, M.; Sierra, M. A. Chem. Rev. 2011,

111, 4857. For an insightful essay, see: (b) Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

13. In principle, C3-labeled indole could also have been used. In practice, C3-deuterated 2a rapidly exchanged the deuterium label with AcOH, with and without Pd(TFA)2 catalyst. See the Supporting Information for details. In contrast, the deuterium label at C2 was pre-served with D-2a under the reaction conditions.

14. Tanaka, D.; Romeril, S. P.; Myers. A. G. J. Am. Chem. Soc. 2005, 127, 10323.

15. Most of the DFT calculations (geometry optimizations, vibrational analysis, estimation of solvent effects) were

carried out at B97X-D/SDDP level of theory. For each located structure, we carried out additional single-point energy calculations using the same functional, but a larger basis set (supplemented by diffusion func-tions). The reported energetics refers to relative solu-tion-phase Gibbs free energies. For further details, see Supporting Information..

16. The Pd(TFA)2(2a) + 1a state was arbitrarily chosen as a reference level for the estimation of relative Gibbs free energies since the experimental evidence indicated in-volvement of 2a in the dehydrogenation of 1a.

17. For an early review on coordination chemistry of -dicarbonyl compounds, see: Kawaguchi, S.; Coord Chem. Rev. 1986, 70, 51. For experimental studies of

Pd(II) enolates, see: (b) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398. (c) Wolkowski, J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2002, 41, 4289.

18. The computed barrier is consistent with those reported for analogous O-bound enolate to C-bound enolate isomerization processes of Ni- and Pd-enolate com-plexes: a) Cámpora, J.; Maya, C. M.; Palma, P.; Carmo-na, E.; Gutiérrez, E.; Ruiz, C.; Graiff, C.; Tiripicchio, A. Chem. Eur. J. 2005, 11, 6889; b) Oertel, A. M.; Ritleng, V.; Busiah, A.; Veiros, L. F.; Chetcuti, M. J. Organome-tallics 2011, 30, 6495.

19. For recent comprehensive reviews on proton-coupled electron transfer (PCET) reactions, see: (a) Huynh, M. H. V.; Meyer, T. J. Chem. Rev. 2007, 107, 5004; (b) Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C. F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.; McCafferty, D. G.; Meyer, T. J. Chem. Rev. 2012, 112, 4016.

20. For studies describing metal-catalyzed C–H bond cleavage reactions in terms of the PCET mechanism, see: (a) Seu, C. S.;Appel, A. M.; Doud, M. D.; DuBois, D. L.; Kubiak, C. P. Energy Environ. Sci., 2012, 5, 6480; (b) Nielsen, R. J.; Goddard III, W. A. J. Am. Chem. Soc. 2006, 128, 9651. Note that in the latter work, this

mechanism is referred to as reductive -hydride elimi-nation.

21. The identity of the catalyst resting state is uncertain. In the KIE calculations, it was assumed that the resting state does not involve 2a as the ligand. For more de-tails about the KIE calculations, see the SI.

22. Anslyn, E. V.; Dougherty, D. A. (2006). Modern Physi-cal Organic Chemistry. University Science Books. pp. 435–437. ISBN 1-891389-31-9.

23. (a) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566. (b) Diao, T.; Pun, D.; Stahl S. S. J. Am. Chem. Soc. 2013, 135, 8205.

24. The system studied herein is different to the scenarios discussed in ref 12b In the 5th scenario of this paper, the absence of KIE in an intramolecular competition

experiment is attributed to the reversibility of the C–H

bond cleavage step, since in this particular example the

C–H and C–D bonds would otherwise be equally ac-

cessible in the product-determining step. This is not the case in this mechanistic scenario.

25. For accounts describing the scope of -arylation with

-dicarbonyl compounds, see: (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. (b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360. For a discussion of ligand

effects on -arylation of -dicarbonyl compounds, see: ref 17c. The authors propose that bulky ligands assist in the reductive elimination step, but no mention is made of the ligand effects on the tautomerization step.

26. In addition to 5, addition of DMPU also increases the overall reaction rate (ratemax = 2.0 mM min–1 for 3a with 50 mol% of DMPU vs. 1.7 mM min–1 under the standard conditions).

27. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.

28. The diastereoselective version also tolerate cyclic 6-

membered -keto esters, but the products could not be obtained in pure form.

29. The absolute stereochemistry of the products was de-termined by X-ray analysis of 3aj. See the SI for details.

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85. Du, Jin: Derivatives of dextran: synthesis and applications in oncology. (48 pp.) 2001

86. Koivisto, Jari: Structural analysis of selected polychlorinated persistent organic pollutants (POPs) and related compounds. (88 pp.) 2001

87. Feng, Zhinan: Alkaline pulping of non-wood feedstocks and characterization of black liquors. (54 pp.) 2001

88. Halonen, Markku: Lahon havupuun käyttö sulfaattiprosessin raaka-aineena sekä havupuun lahontorjunta. (90 pp.) 2002

89. Falábu, Dezsö: Synthesis, conformational analysis and complexation studies of resorcarene derivatives. (212 pp.) 2001

90. Lehtovuori, Pekka: EMR spectroscopic studies on radicals of ubiquinones Q-n, vitamin K3 and vitamine E in liquid solution. (40 pp.) 2002

91. Perkkalainen, Paula: Polymorphism of sugar alcohols and effect of grinding on thermal behavior on binary sugar alcohol mixtures. (53 pp.) 2002

92. Ihalainen, Janne: Spectroscopic studies on light-harvesting complexes of green plants and purple bacteria. (42 pp.) 2002

93. Kunttu, Henrik, Kiljunen, Toni (Eds.): 4th International Conference on Low Temperature Chemistry. (159 pp.) 2002

94. Väisänen, Ari: Development of methods for toxic element analysis in samples with environmental concern by ICP-AES and ETAAS. (54 pp.) 2002

95. Luostarinen, Minna: Synthesis and characterisation of novel resorcarene derivatives. (200 pp.) 2002

96. Louhelainen, Jarmo: Changes in the chemical composition and physical properties of wood and nonwood black liquors during heating. (68 pp.) 2003

97. Lahtinen, Tanja: Concave hydrocarbon cyclophane Β-prismands. (65 pp.) 2003

98. Laihia, Katri (Ed.): NBC 2003, Symposium on Nuclear, Biological and Chemical Threats – A Crisis Management Challenge. (245 pp.) 2003

99. Oasmaa, Anja: Fuel oil quality properties of wood-based pyrolysis liquids. (32 pp.) 2003

100. Virtanen, Elina: Syntheses, structural characterisation, and cation/anion recognition properties of nano-sized bile acid-based host molecules and their precursors. (123 pp.) 2003

101. Nättinen, Kalle: Synthesis and X-ray structural studies of organic and metallo-organic supramolecular systems. (79 pp.) 2003

102. Lampiselkä, Jarkko: Demonstraatio lukion kemian opetuksessa. (285 pp.) 2003

103. Kallioinen, Jani: Photoinduced dynamics of Ru(dcbpy)2(NCS)2 – in solution and on nanocrystalline titanium dioxide thin films. (47 pp.) 2004

104. Valkonen, Arto (Ed.): VII Synthetic Chemistry Meeting and XXVI Finnish NMR Symposium. (103 pp.) 2004

105. Vaskonen, Kari: Spectroscopic studies on atoms and small molecules isolated in low temperature rare gas matrices. (65 pp.) 2004

106. Lehtovuori, Viivi: Ultrafast light induced dissociation of Ru(dcbpy)(CO)2I2 in solution. (49 pp.) 2004

107. Saarenketo, Pauli: Structural studies of metal complexing schiff bases , Schiff base derived

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DEPARTMENT OF CHEMISTRY, UNIVERSITY OF JYVÄSKYLÄ RESEARCH REPORT SERIES

N-glycosides and cyclophane π-prismands. (95 pp.) 2004

108. Paasivirta, Jaakko (Ed.): CEOEC’2004, Sixth Finnish-Russian Seminar: Chemistry and Ecology of Organo-Element Compounds. (147 pp.) 2004

109. Suontamo, Tuula: Development of a test method for evaluating the cleaning efficiency of hard-surface cleaning agents. (96 pp.) 2004

110. Güneş, Minna: Studies of thiocyanates of silver for nonlinear optics. (48 pp.) 2004

111. Ropponen, Jarmo: Aliphatic polyester dendrimers and dendrons. (81 pp.) 2004

112. Vu, Mân Thi Hong: Alkaline pulping and the subsequent elemental chlorine-free bleaching of bamboo (Bambusa procera). (69 pp.) 2004

113. Mansikkamäki, Heidi: Self-assembly of resorcinarenes. (77 pp.) 2006

114. Tuononen, Heikki M.: EPR spectroscopic and quantum chemical studies of some inorganic main group radicals. (79 pp.) 2005

115. Kaski, Saara: Development of methods and applications of laser-induced plasma spectroscopy in vacuum ultraviolet. (44 pp.) 2005

116. Mäkinen, Riika-Mari: Synthesis, crystal structure and thermal decomposition of certain metal thiocyanates and organic thiocyanates. (119 pp.) 2006

117. Ahokas, Jussi: Spectroscopic studies of atoms and small molecules isolated in rare gas solids: photodissociation and thermal reactions. (53 pp.) 2006

118. Busi, Sara: Synthesis, characterization and thermal properties of new quaternary ammonium compounds: new materials for electrolytes, ionic liquids and complexation studies. (102 pp.) 2006

119. Mäntykoski, Keijo: PCBs in processes, products and environment of paper mills using wastepaper as their raw material. (73 pp.) 2006

120. Laamanen, Pirkko-Leena: Simultaneous determination of industrially and environmentally relevant aminopolycarboxylic and hydroxycarboxylic acids by capillary zone electrophoresis. (54 pp.) 2007

121. Salmela, Maria: Description of oxygen-alkali delignification of kraft pulp using analysis of dissolved material. (71 pp.) 2007

122. Lehtovaara, Lauri: Theoretical studies of atomic scale impurities in superfluid 4He. (87 pp.) 2007

123. Rautiainen, J. Mikko: Quantum chemical calculations of structures, bonding, and spectroscopic properties of some sulphur and selenium iodine cations. (71 pp.) 2007

124. Nummelin, Sami: Synthesis, characterization, structural and retrostructural analysis of self-assembling pore forming dendrimers. (286 pp.) 2008

125. Sopo, Harri: Uranyl(VI) ion complexes of some organic aminobisphenolate ligands: syntheses, structures and extraction studies. (57 pp.) 2008

126. Valkonen, Arto: Structural characteristics and properties of substituted cholanoates and N-substituted cholanamides. (80 pp.) 2008

127. Lähde, Anna: Production and surface modification of pharmaceutical nano- and microparticles with the aerosol flow reactor. (43 pp.) 2008

128. Beyeh, Ngong Kodiah: Resorcinarenes and their derivatives: synthesis, characterization and complexation in gas phase and in solution. (75 pp.) 2008

129. Välisaari, Jouni, Lundell, Jan (Eds.): Kemian opetuksen päivät 2008: uusia oppimisympäristöjä ja ongelmalähtöistä opetusta. (118 pp.) 2008

130. Myllyperkiö, Pasi: Ultrafast electron transfer from potential organic and metal containing solar cell sensitizers. (69 pp.) 2009

131. Käkölä, Jaana: Fast chromatographic methods for determining aliphatic carboxylic acids in black liquors. (82 pp.) 2009

132. Koivukorpi, Juha: Bile acid-arene conjugates: from photoswitchability to cancer cell detection. (67 pp.) 2009

133. Tuuttila, Tero: Functional dendritic polyester compounds: synthesis and characterization of small bifunctional dendrimers and dyes. (74 pp.) 2009

134. Salorinne, Kirsi: Tetramethoxy resorcinarene based cation and anion receptors: synthesis, characterization and binding properties. (79 pp.) 2009

135. Rautiainen, Riikka: The use of first-thinning Scots pine (Pinus sylvestris) as fiber raw material for the kraft pulp and paper industry. (73 pp.) 2010

136. Ilander, Laura: Uranyl salophens: synthesis and use as ditopic receptors. (199 pp.) 2010

137. Kiviniemi, Tiina: Vibrational dynamics of iodine molecule and its complexes in solid krypton - Towards coherent control of bimolecular reactions? (73 pp.) 2010

138. Ikonen, Satu: Synthesis, characterization and structural properties of various covalent and non-covalent bile acid derivatives of N/O-heterocycles and their precursors. (105 pp.) 2010

139. Siitonen, Anni: Spectroscopic studies of semiconducting single-walled carbon nanotubes. (56 pp.) 2010

140. Raatikainen, Kari: Synthesis and structural studies of piperazine cyclophanes –

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DEPARTMENT OF CHEMISTRY, UNIVERSITY OF JYVÄSKYLÄ RESEARCH REPORT SERIES

Supramolecular systems through Halogen and Hydrogen bonding and metal ion coordination. (69 pp.) 2010

141. Leivo, Kimmo: Gelation and gel properties of two- and three-component Pyrene based low molecular weight organogelators. (116 pp.) 2011

142. Martiskainen, Jari: Electronic energy transfer in light-harvesting complexes isolated from Spinacia oleracea and from three photosynthetic green bacteria Chloroflexus aurantiacus, Chlorobium tepidum, and Prosthecochloris aestuarii.(55 pp.) 2011

143. Wichmann, Oula: Syntheses, characterization and structural properties of [O,N,O,X´] aminobisphenolate metal complexes. (101 pp.) 2011

144. Ilander, Aki: Development of ultrasound-assisted digestion methods for the determination of toxic element concentrations in ash samples by ICP-OES. (58 pp.) 2011

145. The Combined XII Spring Meeting of the Division of Synthetic Chemistry and XXXIII Finnish NMR Symposium. Book of Abstracts. (90 pp.) 2011

146. Valto, Piia: Development of fast analysis methods for extractives in papermaking process waters. (73 pp.) 2011

147. Andersin, Jenni: Catalytic activity of palladium-based nanostructures in the conversion of simple olefinic hydro- and chlorohydrocarbons from first principles. (78 pp.) 2011

148. Aumanen, Jukka: Photophysical properties of dansylated poly(propylene amine) dendrimers. (55 pp.) 2011

149. Kärnä, Minna: Ether-functionalized quaternary ammonium ionic liquids – synthesis, characterization and physicochemical properties. (76 pp.) 2011

150. Jurček, Ondřej: Steroid conjugates for applications in pharmacology and biology. (57 pp.) 2011

151. Nauha, Elisa: Crystalline forms of selected Agrochemical actives: design and synthesis of cocrystals. (77 pp.) 2012

152. Ahkola, Heidi: Passive sampling in monitoring of nonylphenol ethoxylates and nonylphenol in aquatic environments. (92 pp.) 2012

153. Helttunen, Kaisa: Exploring the self-assembly of resorcinarenes: from molecular level interactions to mesoscopic structures. (78 pp.) 2012

154. Linnanto, Juha: Light excitation transfer in photosynthesis revealed by quantum chemical calculations and exiton theory. (179 pp.) 2012

155. Roiko-Jokela, Veikko: Digital imaging and infrared measurements of soil adhesion and

cleanability of semihard and hard surfaces. (122 pp.) 2012

156. Noponen, Virpi: Amides of bile acids and biologically important small molecules: properties and applications. (85 pp.) 2012

157. Hulkko, Eero: Spectroscopic signatures as a probe of structure and dynamics in condensed-phase systems – studies of iodine and gold ranging from isolated molecules to nanoclusters. (69 pp.) 2012

158. Lappi, Hanna: Production of Hydrocarbon-rich biofuels from extractives-derived materials. (95 pp.) 2012

159. Nykänen, Lauri: Computational studies of Carbon chemistry on transition metal surfaces. (76 pp.) 2012

160. Ahonen, Kari: Solid state studies of pharmaceutically important molecules and their derivatives. ( 65 pp.) 2012

161. Pakkanen, Hannu: Characterization of organic material dissolved during alkaline pulping of wood and non-wood feedstocks (76 pp.) 2012

162. Moilanen, Jani: Theoretical and experimental studies of some main group compounds: from closed shell interactions to singlet diradicals and stable radicals. ( 80 pp.) 2012

163. Himanen, Jatta: Stereoselective synthesis of Oligosaccharides by De Novo Saccharide welding. (133 pp.) 2012

164. Bunzen, Hana: Steroidal derivatives of nitrogen containing compounds as potential gelators.(76 pp.) 2013

165. Seppälä, Petri: Structural diversity of copper(II) amino alcohol complexes. Syntheses, structural and magnetic properties of bidentate amino alcohol copper(II) complexes. (67 pp.) 2013

166. Lindgren, Johan: Computational investigations on rotational and vibrational spectroscopies of some diatomics in solid environment. (77 pp.) 2013

167. Giri, Chandan: Sub-component self-assembly of linear and non-linear diamines and diacylhydrazines, formulpyridine and transition metal cations. (145 pp.) 2013

168. Riisiö, Antti: Synthesis, Characterization and Properties of Cu(II)-, Mo(VI)- and U(VI) Complexes With Diaminotetraphenolate Ligands. (51 pp.) 2013

169. Kiljunen, Toni (Ed.): Chemistry and Physics at Low Temperatures. Book of Abstracts. (103 pp.) 2013

170. Hänninen, Mikko: Experimental and Computational Studies of Transition Metal Complexes with Polydentate Amino- and Aminophenolate Ligands: Synthesis, Structure, Reactivity and Magnetic Properties. (66 pp.) 2013

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DEPARTMENT OF CHEMISTRY, UNIVERSITY OF JYVÄSKYLÄ RESEARCH REPORT SERIES

171. Antila, Liisa: Spectroscopic studies of

electron transfer reactions at the photoactive electrode of dye-sensitized solar cells. (53 pp.) 2013

172. Kemppainen, Eeva: Mukaiyama-Michael reactions with α-substituted acroleins – a useful tool for the synthesis of the pectenotoxins and other natural product targets. (190 pp.) 2013

173. Virtanen, Suvi: Structural Studies Of Dielectric Polymer Nanocomposites. (49 pp.) (2013)

174. Yliniemelä-Sipari Sanna: Understanding The Structural Requirements for Optimal Hydrogen Bond Catalyzed Enolization – A Biomimetic Approach.(160 pp.) 2013

13.