17

Introduction to Homogeneous Gold Catalysis

1.1 General Introduction

Gold has been present in the collective conscience of mankind since the beginning of

known history. It always exerted a deep fascination, being associated with beauty, wealth and

authority probably due to its collective and unique properties such as high density, softness,

malleability, ductility and most aesthetically pleasing property such as glittery. Particularly,

there is special significance of gold in Indian culture; religious and societal. The importance of

gold can be understood in the saying “all glitters are not gold”. Gold in free elemental form

does not get oxidized by air or water as evident by its occurrence as nuggets or grains in rocks,

in veins and in alluvial deposits.[1] Such high stability of gold in the nature might have created

the misconceptions amongst the scientific community that the metal is extremely inert and

therefore its salts could not be used as catalysts for organic reactions. This could be the reason

why gold has lived in the shadow of other metals for a long time.

In the beginning of the 1970's several examples in the area of heterogeneous catalysis

have appeared.[2] Some of the great examples of industrial importance include

hydrochlorination of ethyne to vinyl chloride[3] and the low temperature oxidation of CO to

CO2.[4] Similarly, gold nano particals played an important role in the development of this

discipline.[5] Homogeneous gold catalysis have several advantages over the heterogeneous

catalysis in terms of many aspects such as yields, enantioselectivity, much better substrate

tolerance and most importantly the use of low temperature and pressure which makes reaction

to be conducted under mild conditions. The main benefit of the homogeneous gold catalysis is

that the specific modification of the catalyst structure may influence the reaction paths in a

controlled and predictable manner. In recent years, homogeneous gold catalysis has attracted

much attention and a lot of powerful new reaction cascades for the rapid construction of

molecular complexity, starting from simple key precursors, have been explored.[6] An early

18

example of enantioselective gold catalyzed reaction is the Aldol reaction of isocyano

acetates/amides with aldehydes.[7] In fact this is one of the rarest phenomenons in organic

chemistry; wherein the enantioselective reaction was discovered first before the discovery of

relatively simple reactions took place. In general, the basic principle involved in gold-catalyzed

reactions is the coordination of catalysts to C-C multiple bonds which then becomes

electrophilic rendering susceptible for the attack of nucleophiles.

In the past 15 years homogeneous gold catalysis have grown explosively to become

one of the most exciting research for rapid construction of molecular complexity in one pot

with high atom economy.[8] The Gold catalyzed reactions currently focused in redox reactions

and nucleophilic additions to π systems. The extraordinary catalytic activity of gold species can

be explained in terms of basic principles in frontier orbitals, π-acidity and relativistic effects.

1.2 Lewis Acidity of Gold - Relativistic Effects

Gold has an electronic configuration of [Xe] 4f14 5d

10 6s1 6p

0. The oxidation states of

gold range from −1 to +5, but Au(I) and Au(III) complexes dominates the chemistry. These

cationic gold complexes are exceptionally potent and superior Lewis acids that have a high

affinity for π bonds of alkenes, alkynes and allenes. The unusual catalytic properties and

reactivity of gold catalysts can be rationalized in terms of relativistic effects.[9] The strong

relativistic contractions of the 6s and 6p orbitals (LUMO) makes the electrons closer to the

nucleus.[10] This contraction explains the increased ionization energy of Au when compared to

other group 11 elements, Cu and Ag, or Pt (group 10) (Figure 1.1), this ultimately accounts for

a greater Lewis acidity of Au(I) cationic complexes. This conclusion also correlates with the

strong electronegativity of gold (2.4 for Au, compared to Ag 1.9). Thus relativistic effects can

also explain the expansion of d and f orbitals, being electrons occupying the outer orbitals of 5d

and 4f orbitals (HOMO) are better shielded by the electrons in the contracted s and p orbitals.

Hence there will be a weaker nuclear attraction for 5d and 4f orbitals, which results the soft

Lewis acidic nature of gold(I) species reacting preferentially with "soft" species (such as π-

systems) and being less oxophilic. These relativistic effects are also observed for elements

heavier than the lanthanides.[11] Thus relative effects are particularly helpful in explaining the

reactivity and reactive pathways of the gold.

19

Figure 1.1: The Relativistic (R) and Nonrelativistic (NR) Orbital Energies of [AgH] and [AuH]

Molecules (a.u. is atomic units) (figure extracted from ref 10b)

The next section describes a selection of most representative examples which show the

diversity of the gold catalyzed homogenous transformations. These transformations classified

on the basis of nucleophile and mechanism.

1.3 Gold Catalyzed Organic Transformations

1.3.1 Gold Catalyzed Additions to C-C Multiple Bonds

In homogeneous catalysis, gold complexes are usually activates C-C multiple bonds of

alkynes, allene and olefins towards various nucleophilic addition and cyclization reactions,

leading to the formation of C-C, C-O, C-N and C-S bonds (Figure 1.2).

•

[Au] [Au] [Au]

•

[Au]

H Nu

H [Au]

H Nu

[Au]

Nu

HH

⁄⁄⁄⁄ ⁄⁄⁄⁄

⁄⁄⁄⁄ ⁄⁄⁄⁄⁄⁄⁄⁄ ⁄⁄⁄⁄

H

H Nu

H H

H Nu

H

Nu

HH⁄⁄⁄⁄ ⁄⁄⁄⁄ [Au]

NuHNuH = C, N, O and S

Figure 1.2: Gold Catalyzed Nucleophilic Additions to C-C Multiple Bonds

20

1.3.1.1 C-C Bond Formation

The first representative example of C-C bond formation by gold(I) catalyst for enyne

cyclization reaction was developed by Echavarren and coworkers.[12,13] In this reaction, the C-C

triple bond of 1 is activated by gold to form the alkyne-gold complex 2 followed by

nucleophilic attack by alkene. The resulting intermediate 3 is undergo intramolecular

cyclopropanation to form 4 which is converted in to 7 via 5 and 6 (Scheme 1.1). These results

suggests that gold(I) complexes are active catalysts for the cyclization of enynes.

Scheme 1.1: Gold(I) Catalyzed C-C Bond Formation in Enyne Cyclization

PhO2S

PhO2S

PhO2SPhO2S

PhO2S

PhO2S

PhO2S

PhO2S

(Ph3P)Au

PhO2S

PhO2S HH

(Ph3P)Au

H

PhO2S

PhO2SHH

(Ph3P)Au

PhO2S

PhO2S

(Ph3P)Au

H

2 mol% Ph3PAuCl2 mol% AgSbF6

CH2Cl2, rt5 h, 100%

[Au(PPh3)]-[Au(PPh3)]

1

2

3 4 5

6

7

[Au(PPh3)]

exo-dig

Toste research group examined the triphenylphosphinegold(I)triflate catalyzed 5-exo-dig

addition of β-ketoesters to alkynes.[14] In these transformations 1,3-dicarbonyl compounds act as

carbon nucleophiles in addition to tethered alkynes 8 and 10 to give

methylenecyclopentanecarboxylates 9 and cyclopentenecarboxylates11; respectively, in excellent

yields (Scheme 1.2a and 1.2b). Similarly, Sawamura et al.[15] developed the gold(I) catalyzed

intramolecular carbon nucleophile addition reactions of alkynes 12 to afford

methylenecyclohexanecarboxylates 13 (Scheme 1.2c). Later, the research groups of Kozmin,[16]

and Zhang[17] reported similar type of reactions. Echavarren observed intresting catalyst

dependent intramolecular hydroarylation of alkynes with indoles (14). The 7-exo-dig cyclized

product 15 was observed when Au(I) catalyst used, in contrast, Au(III) catalyst was used for 8-

endo-dig cyclized product 16 (Scheme 1.3).[18,19]

21

Scheme 1.2: Au(I) Catalyzed Intramolecular Addition of β-Ketoesters to Alkynes

CO2R2CO2R21 mol% Ph3PAuOTf

CH2Cl2, rtup to 99%

CO2R4

R5 1 mol% Ph3PAuOTf

CH2Cl2, rtup to 99%

R5

CO2R4

CO2MeO

CO2MeO

1 mol% Ph3PAuNTf2

CH2Cl2, rtup to 99%

(a)

(b)

(c)

8

10

12

9

11

13

R1

O

R3

O

OR1

OR3

Scheme 1.3: Gold Catalyzed Intramolecular Addition of Indoles to Alkynes

NH

N

NH

NH

N

N

PG

NH

N PG

R2 5 mol% AuCl3CH2Cl2,

rt to 50 oC75-87%

5 mol%P(tBu)2(o-biphenyl)]AuSbF6

CH2Cl2,

rt to 50 oC65-82%

PG

PG

R2

R2

14 15

14 16

R1

R1

R1

R1

R2

Michelet et al. reported gold(I) catalyzed tandem Friedel-Crafts

addition/carbocyclization between enynes 17 and electron-rich arenes 18 to afford 20.[20] As per

mechanism the enyne cyclization occurs to give a transient carbenic intermediate 19 which is

subsequently attacked by the electron-rich arene (Scheme 1.4). A similar system was also

reported simultaneously by Echavarren research group.[21] Hashmi et al. discovered gold(III)

promoted procedure for the addition of 2-methylfuran (21) with vinyl ketones 22 to get

substituted furans 23. If an alkyne group is tethered with the vinyl ketone 24, a tandem reaction

takes place to afford phenol products 25.[22] Research group of He et al. demonstrated the

reaction of heterocycles (cf. 29 and 32) and electron-rich arenes 26 with electron-deficient

olefins 27 or alkynes 30 in the presence of gold(III) catalyst.[23] Dual addition products of

22

heterocycles (cf. 28, 31 and 33) were observed when electron-deficient alkynes and

heterocycles were used as substrates. This suggests that electron-deficient olefins are more

reactive than corresponding alkynes in this reaction (Scheme 1.5).

Scheme 1.4: Gold(I) Catalyzed Friedel-Crafts Addition/Carbocyclization between Enynes and

Arenes

X

R2R1

R2R1

X

HR3

3 mol%Ph3PAuSbF6

Et2O, rtup to 91%

+

XR2

R1H

+Au

R3+

X = O, C(CO2Me)2, C(SO2Ph)2

R3

17

19

2018

Scheme 1.5: Gold(III) Catalyzed Intermolecular Addition of Heterocycles to

Electron-deficient Olefins

O OR1

R2

O

R2

O

R1

+1 mol% AuCl3

CH3CN, rtup to 74%

O O

R3

O

R3

OH

5 mol% AuCl3

CH3CN, rtup to 54%

+

Arene +R5

O

R4 5 mol% AuCl3

CH3CN,50 oC, up to 99%

R5

O

Ar

R4

O

NMe

CO2Et

CO2Et

5 mol% AuCl3

CH3CN, rt58%

5 mol% AuCl3

CH3CN, rt63%

O

NMe

CO2Et

CO2Et

2

2

+

+

21 22 23

21 24 25

27 28

29 30 31

32 30 33

26

23

Che and Zhou described an intramolecular addition of β-ketoamide to unactivated

alkenes 34 catalyzed by 5 mol% of Au(I) in toluene to furnish substituted lactams 35 (Scheme

1.6a). This method can also apply for the synthesis of spirolactams 37 from 36 up to 99% yield

(Scheme 1.6b).[24]

Scheme 1.6: Gold(I) Catalyzed Intramolecular Carbon Nucleophile Addition to Alkenes

NBn

O O5 mol%

(tBu)2(o-biphenyl)AuCl5 mol% AgOTf

toluene, 50 oC99%

NBn

O

O

NBn

O5 mol%

(tBu)2(o-biphenyl)AuCl5 mol% AgOTf

toluene, 50 oCup to 99%

O

NO

OBn

n = 1, 2

(a)

(b)

34 35

36 37

( ) ( )n n

The research groups of Widenhoefer[25] and Nelson[26] independently reported gold(I)

catalyzed intramolecular hydroarylation of allenes. In these reactions allene (38 or 40) is

activated by cationic gold complex followed by nucleophilic attack of the indole[25] or

pyrrole[26] ring delivered the products 39 and 41 respectively in excellent yields (Scheme 1.7).

Scheme 1.7: Gold(I) Catalyzed Hydroarylation of Allenes

MeN

CO2MeMeO2C

• MeN

CO2MeMeO2C

N

•H

RO2C

Et

N

EtRO2C

5 mol%Ph3PAuOTf

CH2Cl2, rt, 17 h92%

5 mol%P(tBu)2(o-biphenyl)AuOTf

toluene, −10 °C, 17 h99%

38 39

40 41

Corma research group first time shown the application of Au(I) catalyst for

Sonogashira cross-coupling reaction. In this transformation phenyl acetylene (43) reacts with

iodo benzene (42) in the presence of gold(I) salt and base gave the product 44. Interestingly

they found the homocoupling product 45 in the presence of Au(III) complex (Scheme 1.8).[27]

24

Scheme 1.8: Gold Catalyzed Sonogashira Cross-Coupling Reactions

Ph I

+Ph

Ph Ph

Ph Ph

K3PO4

o-xylene,130 oC

NH

N OAu

Cl

tBu

HN

NAuPPh3

AuPPh3

O

tBu

AuPPh3

Au(III)Au(I)

Au(I)

90%

Au(III)

90%

42

43

44

45

1.3.1.2 C-N Bond Formation

Gold catalyzed C–N bond formation, first time reported by Utimoto research group in

1987. Gold(III) catalyzed intramolecular hydroamination of alkynes in the presence of 5 mol%

NaAuCl4, amino alkynes 46 and 48 underwent 6-exo-dig cyclization to afford

tetrahydropyridines 47 and (±)-Solenopsin A (49); respectively (Scheme 1.9).[28,29] The first

intermolecular version of hydroamination of alkynes was demonstrated by Tanaka research

group. They used the combination of Ph3PAuMe and acidic promoters for this transformation

(Scheme 1.10).[30]

Scheme 1.9: Gold(III) Catalyzed Intramolecular Hydroamination of Alkynes

NH2npent N

npent

NH2

nundec

N nundec

5 mol% NaAuCl4

CH3CN, reflux71%

5 mol% NaAuCl4

CH3CN, reflux90% ± solenopsin

(a)

(b)

46 47

48 49

Scheme 1.10: Gold(I) Catalyzed Intermolecular Hydroamination of Alkynes

R2R1 R3H2N

0.01-0.5 mol%Ph3PAuMe,

acidic promoter

neat, 70οCup to 99%

R1R1

NR3

NR3

R2R2

++

Che et al. disclosed a gold(I) catalyzed tandem hydroamination-hydroarylation of

alkynes for the synthesis of dihydroquinolines 54 (Scheme 1.11a) and tetrahydroquinolines 56

(Scheme 1.11b) from aromatic amines (cf. 50 and 55) and terminal alkynes.[31] They proposed a

25

mechanism in which a gold catalyzed hydroamination of the alkyne gives an enamine

intermediate 51, which tautomerizes to ketimine 52. This ketimine intermediate reacts with

another molecule of alkyne to yield propargylic amine 53, which then undergoes an

intramolecular hydroarylation to afford the product 54. Both primary and secondary aromatic

amines gave good yields in this reaction.

Scheme 1.11: Gold(I) Catalyzed Tandem Hydroamination-Hydroarylation of Alkynes

+

R1

NH2

HN

R1

5 mol%P(tBu)2(o-biphenyl)AuOTf

15 mol% NH4PF6

CH3CN,150 οC, MWup to 94%

R1

N

R1

HN

NH

R2+ N

R25 mol% IPrPAuOTf

CH3NO2, rt.up to 95%

(a)

(b)

50

51 5352

54

55 56

R1

HN R1

R1

R2

Toste and coworkers[32] reported a dinuclear bisphosphine (dppm)Au2Cl2 activated with

AgSbF6 as the most effective catalyst system for the synthesis of pyrroles through C-N bond

formation. They proposed a mechanism in which a gold catalyzed hydroamination of the

alkyne 57 occurs first to gives an enamine intermediate 59. The gold backbonds the electron

Scheme 1.12: Au(I) Catalyzed Acetylenic Schmidt Reaction

N N

Au

N2

Au+

N3

R3

R2

MG

R1 HNR1

R3

MGR2

2.5 mol%(dppm)(AuSbF6)2

CH2Cl2, rtup to 93%

MG = OTBS,CH2CH2R2

59 60

57 58

R1

R2

MG

R1

R2

MG

R3 R3

26

density to the substrate expelling N2 to form gold carbene intermediate 60. Then subsequent

migration of the neighbouring group takes place to afford products 58 (Scheme 1.12).

Sperger research group disclosed hydroamination and cycloisomerization reaction for

the synthesis of fused bicyclic compound 62 from 1,6-diyne 61 by using Et3PAuNTf2 as a

catalyst (Scheme 1.13).[33] The key for this cyclization is the isomerization of enamine 63 into

64, under the reaction conditions, which undergo subsequent cycloisomerization to afford 62 in

72% yield.

Scheme 1.13: Gold(I) Catalyzed Hydroamination and Cycloisomerization

Me

Me

PhN

H

Ts

MeH Me

2.5 mol% Et3PAuCl2.5 mol% AgNTf2

CH2Cl2, rt, 2h, 72%

NTsPh

MeMeH

NTsPh

MeMe

NHTs61 62

63 64

Ph

Li and co-workers demonstrated the double hydroamination of 2-alkynylanilines 65

with terminal alkynes catalyzed by AuCl with AgOTf as a cocatalyst (Scheme 1.14).[34] The

corresponding N-vinylindoles 67 were obtained up to 82% yield at room temperature in the

absence of solvent. Mechanistic studies revealed that intermolecular hydroamination of alkyne

took place to produce intermediate 66 which delivered the product 67.

Scheme 1.14: Gold(I) Catalyzed Double Hydroamination Strategy

NH2

R1

+ R2

5 mol%AuCl/AgOTf

rt, 17-82% N

R2

R1

R1

N

R2

65

66

67

27

Krause research group developed gold(III) catalyzed intramolecular hydroamination of

allenes 68 to afford the derivatives 69 (Scheme 1.15a).[35] Similarly, Yamamoto research group

disclosed intermolecular hydroamination of allenes 70 catalyzed by gold(III) complexes to

afford the product 71 (Scheme 1.15b).[36]

Scheme 1.15: Gold(III) Catalyzed Hydroamination of Allenes

H •

R1

Me

H2NOR2 N

HR1

Me

OR2

•

H

Ph H

Me

NHPh

Ph Me

10 mol%AuBr3

PhNH2, THF,rt, 64%

2 mol% AuCl3

CH2Cl2up to 95%

68 69

70 71

(a)

(b)

Like allenes, conjugated dienes tend to be more reactive toward transition-metal

complexes than simple alkenes. He and coworkers developed gold(I) catalyzed protocol for the

intermolecular hydroamination of 1,3-dienes with carbamates to form allylamines.[37] For

example, treatment of a 1:1.2 mixture of benzyl carbamate 73 and 3-methyl- 1,3-pentadiene

(72) with a catalytic 1:1 mixture of Ph3PAuCl and AgOTf in dichloromethane at room

temperature afforded benzyl (1,2-dimethyl-2-butenyl)carbamate (74) in 86% yield (Scheme

1.16).

Scheme 1.16: Gold(I) Catalyzed Hydroamination of Conjugated Dienes

Me

MeOH2N

O

Me

Me

Me

NHCbz5 mol% Ph3PAuCl

5 mol% AgOTf

CH2Cl2, rt86%

+

72 73 74

Widenhoefer research group developed Au(I) catalyzed intramolecular hydroamination

of alkenyl carbamates to form protected nitrogen heterocycles. Electron-rich phosphines such

as P(tBu)2(o-biphenyl) was particularly effective ligand for intramolecular hydroamination of

olefin 75 to get 76. (Scheme 1.17).[38] The carbobenzyloxy (Cbz) group can easily remove from

the product, and the reaction is thus an efficient method to prepare allylic amines.

28

Scheme 1.17: Gold(I) Catalyzed Hydroamination of Olefins

NHCbz

Ph

Ph

N

PhPh

Me

5 mol% R3PAuCl5 mol% AgOTf

1,4 dioxane,100 οC,24 h, 98%75 76

R = P(tBu)2(o-biphenyl)

Cbz

1.3.1.3 C-O Bond Formation

Similar to C-C bond formation, gold complexes are able to activate C-C multiple bonds

for hydroalkoxylation, leading to the formation of new C-O bonds. The first reaction of this

type was developed by Utimoto et al. by using 2 mol% Na(AuCl4) as the catalyst and alcohols

and water as nucleophiles (Scheme 1.18).[38] The addition of water or alcohols to alkynes 77

could be achieved in an intermolecular manner to furnish ketones 78 or ketals 79.

Scheme 1.18: Gold(III) Catalyzed Hydroalkoxylation of Alkynes

R1R1

R1 R1 R1 R1

OR2

R2O

R1 R1

R2O

O

R1 = H

+

77

78

79

2 mol%Na(AuCl4)

R2OH

Michelet and coworkers[40] reported the intramolecular double hydroxylation of alkynes

80 to furnish high yields of bicyclic ketals 81 under mild conditions with either AuCl or AuCl3

(Scheme 1.19a). Krause and coworkers[41] demonstrated gold and Brønsted acid co-catalyzed

tandem cycloisomerization-hydroalkoxylation of 82 to 83 in Scheme 1.19b. The research group

of Barluenga also reported similar type of results (Scheme 1.19c). If the substrate contains a

pendant olefin instead of an alcohol, for instance substrate 84, product 85 was obtained.[42]

Gevorgyan research group reported first representative examples of gold catalyzed

isomerization of haloallenyl ketones (86 and 89) to furnish halofurans (87, 88 and 90) (Scheme

1.20).[43] The regioselectivity in this transformation depends on the oxidation state of the metal.

Gold(III) bind to the oxygen because of its higher Lewis acidity, whereas the softer gold(I)

preferentially binds the allenes.

29

Scheme 1.19: Gold Catalyzed Double Hydroxylation of Alkynes

R

HO

OH

n

2 mol% AuCl orAuCl3

MeOH, rtup to 99%n = 1, 2

O

R

n

R1

R3

OH

R2

O

R4OR1

R2

R3

2 mol% Ph3PAuBF410 mol% TsOH

R4OH, rtup to 72%

OH

2 mol% AuCl3

MeOH, rt94%

OMe

O

(a)

(b)

(c)

80 81

82 83

84 85

O

Scheme 1.20: Gold(I) Catalyzed Haloallenyl Ketone Isomerization to Halofurans

•R2

X R3

R4

O

O

X R3

R4R2

X = Cl, Br, I

1-3 mol% AuCl3

toluene, rtup to 97%

•Br

R1

O

O

Br

R1

•Br

R1

O

OR1 Br1 mol% Et3PAuCl

toluene, rt> 99% selectivity

1 mol% AuCl

toluene, rt> 95% selectivity

86

86 87

88

89

90

Representative examples of hydroalkoxylation was reported by the research group of

He.[44] Intermolecular anti Markovnikov addition of phenols 91 (Scheme 1.21a) and carboxylic

acids 94 (Scheme 1.21b) to unactivated alkenes 92 and 95 in the presence of Ph3PAuX afforded

hydroalkoxylation products 93 and 96 respectively in good yields. This is the first example of a

gold(I) mediated activation of inert alkenes toward nucleophilic addition.

Li and Yao reported gold(I) catalyzed addition and cyclization process for the synthesis

of isochromenes 98. 2-Alkynylbenzaldehydes 97 react with terminal alkynes in the presence of

gold catalyst and base gave 1-alkynyl-1H-isochromene products 98 (Scheme 1.22).[45] This

reaction was dually promoted by an electron-donating phosphine ligand and water.

30

Scheme 1.21: Gold(I) Catalyzed Hydroalkoxylation of Unactivated Alkenes

O

O

O

COOH

OH

OMeOMe

OMe

OMe

+

2 mol% Ph3PAuCl2 mol% AgOTf

toluene, 85 οC84%

5 mol% Ph3PAuCl5 mol% AgNO3

toluene, 85 οC84%

(a)

(b)

91 92 93

94 9695

+

Scheme 1.22: Gold(I) Catalyzed Addition/Cyclization of Terminal Alkynes with 2-Alkynyl

Benzaldehydes

O

R1

O

R2

R2

R1

+

5 mol% Me3PAuCliPr2NEt

water/toluene

70 °C, 24 hup to 89%

97 98

H

1.3.1.4 C-S Bond Formation

There are relatively few reports on the use of gold catalysts for the formation of C-S

bonds. Nakamura’s group first time reported the gold(I) catalyzed intramolecular

carbothiolation of alkynes 99 to afford 100 (Scheme 1.23).[46] This reaction proceed through the

nucleophilic addition of sulfur atom to alkynes followed by migration of α-alkoxyl alkyl group.

Scheme 1.23: Gold(I) Catalyzed Intramolecular Carbothiolation of Alkynes

R1

S

R2O R3

2 mol% AuCl

toluene, 25 οCup to 99%

SR1

R3

OR2

99 100

Krause and coworkers demonstrated the gold(I) catalyzed intramolecular

hydrothiolation of α-thioallenes 101 to get 2,5-dihydrothiophene 102 (Scheme 1.24a).[47] He’s

research group disclosed Ph3PAuOTf catalyzed intermolecular hydrothiolation of 1,3-dienes

103 to afford 104 in high yields (Scheme 1.24b).[48]

31

Scheme 1.24: Gold(I) Catalyzed Hydrothioalation

•

iPr 5 mol% AuCl

CH2Cl2, 20 οC86%

H

Me

S CH2OBniPr

Me

+ RSH

5 mol%Ph3PAuOTf

CH2Cl2, rtup to 100%

SR

(a)

(b)

101 102

103 104

HSCH2OBn

1.3.2 Gold Catalyzed Oxidation Reactions

The homogeneous gold catalyzed oxidation reaction of alcohols has more rarely been

reported. Research group of She demonstrated the gold catalyzed highly selective aerobic

oxidation of benzyl alcohol (105) to benzaldehyde (106) in 99% yield (Scheme 1.25).[49]

Scheme 1.25: Gold Catalyzed Oxidation of Alcohols

OH O

air, toluene,90 οC, 24 h

99%

N NAu

iPr

iPr

iPr

iPr

105 106

Sundermeyer et al.[50] reported gold catalyzed oxidations using (Me3Si)2O2. They

observed that 5 mol% of gold(III) complexes were active catalysts for the Baeyer-Villiger

oxidation of ketones 107 to 108[51] (Scheme 1.26).

Scheme 1.26: Gold(III) Catalyzed Baeyer-Villiger Oxidation of Ketones

O

OO

5 mol%AuCl3[OP(nC12H25)3]

5 mol% AgSbF6[(H3C)3Si]2O2

72%

107 108

1.3.3 Miscellaneous Reactions

Asao and coworkers reported gold catalyzed benzannulation between 2-

alkynyl(oxo)benzene 109 and benzenediazonium 2-carboxylates in good to high yields of

32

anthracene derivatives. This reaction proceeds through the [4+2] cycloaddition between

benzyne (111) and benzopyrylium auricate complex 110 (Scheme 1.27).[52]

Scheme 1.27: Gold(I) Catalyzed Benzannulation of 2-Alkynyl(oxo)benzene

O

R2

R1O

O2C

N2O

R2

R1

AuR1

+

+

10 mol% AuClClCH2CH2Cl

40-60 οC,up to 87%109

110 111

112

R2

Prim et al. described NaAuCl4 mediated direct amination and azidation of benzylic

alcohols 113. The reaction of benzylic alcohols with amines or azides under mild and

environmentally benign conditions provided various benzylic amines 114 or benzylicazide

derivatives 115 respectively in good yields (Scheme 1.28).[53]

Scheme 1.28: Gold(III) Catalyzed Amination and Azidation of Benzylic Alcohols

Ar R1

OH+

R2NH2

TMSN3Ar R1

NHR2

Ar R1

N35 mol% NaAuCl4

CH2Cl2, rtup to 100%

oror

113 114 115

Zhang et al.[54] reported gold(I) catalyzed facile rearrangement of propargylic acetates

116 in the presence of NIS to get iodoenones 117. If aliphatic substitutions on the substrates,

selectively Z-configuration products 117 were generated, while aromatic substitutions diminish

Scheme 1.29: Gold(I) Catalyzed Rearrangement Reactions

R3 R1 O

IR3R2AcO

R2R1

2 mol%Ph3PAuNTf2

acetone/H2ONIS, 0 οC75-97%

OSiEt3

Ph

10 mol%Ph3PAuCl10 mol%

AgSbF6NIS, CH2Cl2,

rt, 48%

CHO

H

I

Ph

116 117

118 119

(a)

(b)

33

the selectivity (Scheme 1.29a). Similarly, Kirsch research group reported gold(I) catalyzed

tandem cyclization/pinacol rearrangement of 3-silyloxy-1,5-enynes 118 to iodo-aldehydes 119 [55] (Scheme 1.29b).

1.3.4 Enantioselective Gold Catalyzed Reactions

The concept of asymmetric catalysis is one of the great challenges in organic synthesis.

Asymmetric gold catalyzed reactions have emerged as a powerful synthetic tool in modern

organic synthesis. Enantiomerically pure gold-phosphine complexes of the form P–Au–X (P =

phospine, X = anionic ligand or counterion) have been effective in achieving high

enantioselectivities.[56]

Research group of Ito first time reported the gold(I) catalyzed asymmetric Aldol

reaction[57] between isocyanoacetates 121 and aldehydes 120 to afford the mixtures of

oxazolines 122 and 123 with highly variable enantioselectivity (Scheme 1.30). This reaction

employs a chiral ferrocenyl bis(phosphine) ligand 124 to introduce selectivity.

Scheme 1.30: Gold Catalyzed Asymmetric Aldol Reaction

RO +

NC

CO2CH3

O NO N

CO2CH3RR CO2CH3

1 mol%Au(o-C6H11-NC)2BF4

chiral diphosphanylferrocene 124

CH2Cl2, 0 °C, 100 h83% yield dr 9:1, 96% ee (trans)

+

FePPh2PPh2

Me

H

NMe

N

124120 121 122 123

Czekelius[58] and Hashmi[59] research groups independently reported gold(I) catalyzed

asymmetric desymmetrization cyclization process involving an amide and a furanyl carbon

Scheme 1.31: Enantioselective Gold(I) Catalyzed Hydroamination and Hydroalkoxylation

O∗

NHTsNTsO

∗

OH

OHO

23% yield60% ee

99% yield55% ee

OH

10 mol%(R)-4-MeO-3,5-

(tBu)2BIPHEP(AuCl)2

10 mol% AgBF4toluene, rt, 16 h

10 mol%(R)-4-MeO-3,5-

(tBu)2BIPHEP(AuCl)2

10 mol% AgBF4

CH2Cl2, 24 h

133

135

134

136

34

nucleophile respectively. The diynamide 133 was cyclized in the presence of 10 mol% chiral

gold complex delivered the enamide 134 in modest 23% yield and 60% ee.[58] The

furyldialkyne 135 was cyclized in the presence of 10 mol% of chiral gold complex to phenol

adduct 136 in 99% yield and 55% ee (Scheme 1.31). [59]

Echavarren and coworkers reported (R)-tol-BINAP(AuCl)2/AgSbF6 catalyzed

alkoxycyclizations of 1,6-enyne 137 to cyclic ether 138 in 52% yield, with 94% ee (scheme

1.32).[60] In this reaction, insitu generated (R)-tol-BINAP(AuSbF6)2 is responsible for the

enantioselective cyclization.

Scheme 1.32: Chiral Gold(I) Catalyzed Enantioselective Alkoxycyclization

PhO2S

PhO2S

PhO2S

PhO2S

Ph

Ph1.5 mol%

(R)-tol-BINAP(AuCl)22 mol% AgSbF6

CH2Cl2, rt, MeOH168 h

OMe

52% yield94% ee

137 138

1.4 Conclusions

Gold catalysis has numerous applications in organic synthesis. Gold homogeneous

reactions have been developed in the last 15 years. Gold catalysis of organic reactions now has

become a highly active field. Most of the reactivities are based on the addition of nucleophiles

to alkynes, alkenes and allenes. The other reactivity patterns such as oxidation, C-H activation

are the important fields. Currently gold catalyzed asymmetric synthesis is hot spot in synthetic

organic chemistry.[61]

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