Gold Vinylidenes as Useful Intermediates in Synthetic ...Chemistry Fabien Gagosz* 0-02-02614 95...

1087

F. Gagosz Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2019, 51, 1087–1099short reviewen

Gold Vinylidenes as Useful Intermediates in Synthetic Organic ChemistryFabien Gagosz* 0000-0002-0261-4925

Department of Chemistry and Biomolecular Sciences, University of Ottawa, K1N 6N5, Ottawa, [email protected]

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

AuL

AuL

AuL

Gold Vinylidene

E

NuNu

E

HH

•

Received: 02.12.2018Accepted: 05.12.2018Published online: 10.01.2019DOI: 10.1055/s-0037-1611647; Art ID: ss-2018-z0809-sr

License terms:

Abstract Gold vinylidenes have recently emerged as useful intermedi-ates in synthetic organic chemistry. These species, which can principallybe accessed by a 1,2-migration process from a gold-activated alkyne orby dual gold catalysis on a diyne substrate, can react with nucleophilicpartners or by C–H insertion to produce a variety of functionalized (po-ly)cyclic compounds. This short review covers the synthetic approachesdeveloped so far to access gold vinylidenes and the different reactivitiesthese species can exhibit.1 Introduction2 1,2-Migration Processes3 Dual Gold Catalysis4 Other Processes5 Conclusion

Key words vinylidene, reactive intermediate, gold, catalysis, dual ca-talysis, nucleophilic trapping, C–H insertion

1 Introduction

Since its emergence more than 15 years ago, homoge-neous gold catalysis has developed into a very active area ofresearch.1 The straightforward access to various gold com-plexes, their ease of use and general high stability, allied tothe variety of selective and unusual transformations theycan allow, have enabled homogenous gold catalysis to be-come a synthetic tool of choice for the generation of molec-ular diversity and structural complexity. Since gold cata-lysts are electrophilic in nature and particularly prone toactivate carbon–carbon systems, a large number of the syn-thetic transformations reported to date involve cationic in-

termediates, whose reactivity can be modulated, to someextent, by the presence of the gold moiety. Gold carbenes oftype 1, for instance, have been intensively studied (Scheme1).1,2 They can be accessed from a variety of substrates, un-der different reaction conditions and following a range ofmechanistic pathways. In sharp contrast, and while theirfirst appearance in the literature as potential intermediatesin a synthetic transformation dated from 2004, gold vi-nylidenes species 2 have comparatively attracted less atten-tion.3 Such a situation can probably be imputed to a long-standing lack of synthetic processes to access them in aneasy and selective manner.

Fabien Gagosz was born in France in 1974. He obtained his Ph.D. de-gree in 2002 under the guidance of Prof. Samir Zard at Ecole Polytech-nique, Palaiseau, France. After postdoctoral studies in the group of Prof. William B. Motherwell at University College, London, he returned to Ecole Polytechnique in 2004 to start his independent career as Chargé de Recherche, CNRS. He was promoted to Directeur de Recherche in 2012. In 2016, he moved to the University of Ottawa where he is cur-rently Professor in the Department of Chemistry and Biomolecular Sci-ences. His research program focuses on the design of new catalytic tools and the development of synthetic methods in general, with a spe-cial interest for late transition-metal-catalyzed reactions and a predilec-tion for homogeneous gold catalysis.

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1087–1099

http://orcid.org/0000-0002-0261-4925

1088


The context changed in 2012 when the groups of Hash-mi and Zhang discovered that arenediyne substrates couldbe used for the generation of gold vinylidenes, and thatthese species demonstrated interesting reactivities. Sincethen, more attention has been focused onto the field and avariety of synthetic transformations based on their involve-ment as key reactive species have been reported.

The aim of this short review is to give the reader anoverview of the synthetic approaches developed so far toaccess gold vinylidenes and the various reactivities thesespecies can exhibit. It is organized by means of gold vi-nylidene generation: 1) 1,2-migration processes, 2) dualgold catalysis, and 3) other unrelated processes. The reac-tivities of gold vinylidenes are illustrated for each transfor-mation by a short selection of representative examples.

2 1,2-Migration Processes

The treatment of an alkyne substrate 3 bearing either ahalogen atom (Br, I) or a trialkylsilyl (SiR3) substituent withan electrophilic gold species is probably the most straight-forward manner to generate vinylidene gold species(Scheme 2). Indeed, upon activation of the C≡C bond bygold, the X group can perform a 1,2-migration to deliver avinylidene gold intermediate 4 that can then react via nuc-leophilic trapping or C–H bond insertion.

Scheme 2 Generation of gold vinylidene species from alkynes by 1,2-migratory process

The very first example of such a reactivity (and involve-ment of a vinylidene gold species in a synthetic process)was reported by Fürstner and co-workers in 2004.4 Whileworking on the synthesis of substituted phenanthrene bycycloisomerization of o-alkynylbiaryl derivatives, they ob-served that bromo- and iodoalkynes 5Br and 5I were rear-ranged selectively into phenanthrene 6Br and 6I in the pres-ence of AuCl (Scheme 3). This reactivity was attributed tothe involvement of a vinylidene gold species 7 that cyclizesonto the pendant aryl motif. DFT studies performed by So-

riano and Marco-Contelles brought support to the proposedmechanism.5 Interestingly, the use of InCl3 as the catalystled to a divergent reactivity with the selective formation ofthe regioisomeric 10-halophenanthrenes 8.

Scheme 3 Synthesis of halophenanthrenes from haloalkynes

The same concept of 1,2-halogen migration was exploit-ed by the group of González for the formation of dehydro-iodoquinolines from iodopropargyl amide derivatives 9(Scheme 4).6 The authors found that the selectivity was de-pendent on the nature of the gold(I) complex employed.The use of [(IPr)Au]NTf2 (13) as the catalyst favored the io-dine migration product 11, while a phosphite-based goldcomplex 14 led majorly to the product of direct cyclization12. This divergence in selectivity was explained by consid-ering the difference of electrophilicity between the twocatalysts and the ability of NHC-based gold complexes tomore favorably stabilize the vinylidene gold intermediate10.7 The reaction was shown to be particularly selective inthe case of substrates possessing electron-withdrawing arylsubstituents, as the competitive direct cyclization wasslowed down in such cases. The same authors also reportedthat the 1,2-iodine migration process could also be em-ployed for the selective synthesis of 3-iodo-2H-chromenes(Scheme 4).8

More recently, González and co-workers demonstratedthat aryliodoalkynes 15 could also be employed as sub-strates for the synthesis of functionalized indenes 17.9 Inthis case, the intermediate gold iodovinylidene species 16cyclizes following a concerted C–H bond insertion at thebenzylic position of the substrate (Scheme 5). This proce-dure represents a particularly efficient entry to iodoin-denes.

The group of Hashmi also proposed the involvement ofsimilar gold iodovinylidene intermediates in a synthesis of1,3-diodonaphthalenes 20 from 1,2-bis(iodoethyl)arenes 18(Scheme 6).10 In this transformation, the electrophilic spe-cies 19 was proposed to cyclize onto the pendant iodo-alkyne thus inducing the nucleophilic addition of benzene.This process could also be applied to enediyne or bro-moalkyne derivatives.

Scheme 1 Gold carbene and gold vinylidene species

AuL AuLAuL

1 2

AuL

Gold vinylideneGold carbene

well developed, rich chemistry

intensely studied

various accesses

−

−

−

considerable recent interest−

highly reactive species−

L: ligand

• •

XRAuL

XR

AuL

1,2-migration•

R

X

AuL

X = Br, I, SiR3 (SnR3, GeR3)

3 4

5Br X = Br

X

AuCl(20 mol%)

toluene80 °C, 20 h9

10

5I X = I

X

AuCl

10

9

AuClH

X

X

10

9

10

9

6Br X = Br: 77%

6I X = I: 76%

InCl3(100 mol%)

toluene80 °C, 16 h

X

8Cl X = Cl: 95%

5Cl X = Cl

10

9

8Br X = Br: 7%

7

•


1089


Besides halogen atoms, it was also reported that silylgroups could undergo 1,2-migration upon activation of a si-lylalkyne with an electrophilic gold species. However, ex-

amples of such a reactivity remain rare. Seregin and Gevor-gyan reported in 2006 that 2-propargylpyridine 21 could berearranged into indolizine 23 when treated with AuBr3 intoluene at 50 °C (Scheme 7).11 This process was shown to beapplicable to a series of other heterocyclic motifs. A mecha-nism involving the nucleophilic addition of the pyridine ni-trogen atom onto an intermediate gold vinylidene 22 wasinitially proposed to explain the formation of 23. DFT calcu-lations conducted later on by Li and Gevorgyan led to ques-tion the likelihood of such a mechanism while not ruling itout, though.12

A more recent and unambiguous example of 1,2-silylgroup migration was reported by the group of Barriault.13

During their studies on the total syntheses of biologicallyactive polyprenylated polycyclic acylphloroglucinols,14 theauthors isolated an intriguing organogold complex 25 thatwas produced when ynone 24 was reacted with a catalyticamount of [(JohnPhos)Au(NCMe)]SbF6 (Scheme 8). In-trigued by the structure of 25 and the relative position ofthe TBS group/the gold residue, the authors made a seriesof experiments which showed that: a) the process could beapplied to other trialkylsilyl groups and b) alkenyl gold spe-cies of type 28 could be generated and isolated in the pres-ence of various gold complexes. To explain this reactivity, amechanism involving a gold vinylidene species 27, interme-diately produced by 1,2-migration of the silyl group on thegold-activated C≡C, was proposed. Interestingly, the use ofdi- and triphenylsilyl groups prevents the migration thusScheme 4 Synthesis of 3-iododehydroquinolines and -2H-chromenes

9

NTs

INTs

ILAu

NTs

I

+

[Au] (3 mol%)

DCE, r.t., 24 hNTs

I

1,2-migration

11 12

10

[(IPr)Au]NTf2 85% 14 : 1

(ArO)3PAuCl/AgSbF6

64% 1 : 1.4

Ar:

t-Bu

t-Bu

NTs

I

NTs

I

+

NTs

I

R = Cl

[(IPr)Au]NTf2(3 mol%)

DCE, r.t., 24 h

R = C(O)Me

80%

72%

99 : 1

23 : 1

O

I

O

I

+

O

I

R = CN, R' = H


1,4-dioxane, 100 °C

R = F, R' = Cl

91%

90%

14 : 1

1 : 0

(13)

(14)

R

R'

R R R

R

R' R'

R

•

Scheme 5 Synthesis of 2-iodoindenes via gold iodovinylidene interme-diates


DCE, 80 °C22–97%

IR1

R2

R1

R2

AuL

I

H

R3

H

I

R2R3

R1

R3

I

OO

79%

I

OMe

89%

Cl

I

90%

15 16 17

•

Scheme 6 Synthesis of 1,3-diiodonaphthalenes


benzene, 60 °C36–85%

IR R

AuL

IR

69% 74%

18 19 20

I I

I

Ph

I

MeO

MeO

Ph

I

I

I

I

Ph

53%

Ph

Br

Br

with AuCl(20 mol%)

•

Scheme 7 Postulated gold-mediated 1,2-silyl migration in the formation of fused pyrrole-containing heterocycles

NAuBr3

(2 mol%)

toluene50 °C, 1.5 h

21 22

OTBS

SiMe3

N

OTBS

[Au]

SiMe3

N

[Au]

TBSOH

SiMe3

N

OTBS

SiMe3

23

N

N

OTBS

SiMe3

63%87%

N

OTBS

SiMe3

56%

S


1090


leading to the formation of the regioisomeric organogoldcomplex. The authors also demonstrated that 28 could beefficiently demetalated in the presence of electrophilic spe-cies thus allowing the formation of further functionalizedcompound 29.

Scheme 8 Isolation of organogold complexes through 1,2-silyl group migration

While gold vinylidene species can be conveniently ac-cessed by 1,2-migration from iodo- or silylalkynes, and sub-sequently involved in synthetically useful transformations,examples of such a reactivity remain rare in the literature.The migration process generally competes with the directnucleophilic functionalization or with the dehalogena-tion/desilylation of the gold-activated alkyne.

3 Dual Gold Catalysis

A major breakthrough in the field of gold vinylidenechemistry was made when the group of Hashmi found in201215 that these reactive species could be convenientlygenerated by an intramolecular reaction between a nucleo-philic goldacetylide 30 and a gold-activated alkyne 31(Scheme 9). This important discovery paved the way to thedevelopment of a variety of dual gold-catalyzed processes16

which are based on the key generation of intermediate goldvinylidene species 32 from diyne substrates. These reac-tions are detailed in the following paragraphs.

The story started when Hashmi and co-workers studiedthe reaction of arenediyne 33 in the presence of the[(IPr)Au]NTf2 complex 13 in benzene (Scheme 10). When33 was treated with 15 mol% of 13 at 20 °C, benzene adduct34 was produced almost as a single product. It was pro-posed that 34 was formed by an initial diyne cyclization fol-lowed by the trapping of the resulting naphthyl cation by amolecule of solvent.10,17 Surprisingly, when the reactionwas conducted at reflux, another unexpected benzene ad-duct 35 was competitively formed. The authors discoveredthat the selectivity could even be completely shifted to-wards the formation of 35 in the presence of a basic addi-tive (Et3N). After an extensive and careful study of the influ-ence of reaction conditions (nature of catalyst and loading,additive, temperature), as well as D-labeling experiments,the group of Hashmi proposed that the unexpected adduct35 could be produced by an unusual mechanism involvingthe formation of an intermediate gold vinylidene species(Scheme 10).18

Scheme 10 Initial discovery by Hashmi and co-workers: gold vi-nylidene as an intermediate in the hydroarylating-aromatization of arenediynes

The transformation would be initiated by the formationof goldacetylide 37 from 36, a process that would be favoredin the presence of Et3N as an additive. A dual activation via38 would then induce the formation of key gold vinylideneintermediate 39, which would subsequently evolve into thegem-diaurated species 40 by a sequence of hydrogen trans-

24

OTBSO

TBS

[(L)Au(NCMe)]SbF6(5 mol%)

CH2Cl2, r.t.

O

O

TBS

AuLL = JohnPhos 25 3%

OTBSO

R3Si

(3.3 equiv)

[(L)Au(NCMe)]SbF6(1 equiv)

CH2Cl2, r.t.

O

O

R3Si

AuL

84%

L: JohnPhos

26 28

SiR3 = TBS

83%

30%TIPS

63%

L: IPr

SiR3 = TBS

OTBS

O

R3Si

AuL27

1,2-migration

O

O

R3Si

E

"E+"

E = Me 98%

E = I 98%

29

TES

•

Scheme 9 Generation of gold vinylidene species from diyne by dual gold catalysis

R3R2

AuL

Electrophile

R1

AuL

3132

AuLR1

Nucleophile

30

R3

R2

LAuR3R2

R1 H 2 AuL

– H

•

[(IPr)Au]NTf2 (13)

benzene

Ph

Ph

+

[Au] 20 °C 80% 99 1:

[Au] 80 °C 90% 67 33:

[Au]80 °C 91% 2 98:

Et3N 10 mol%

15 mol%

5 mol%

5 mol%

33 34 35

LAu

37

(Et3N)

AuL

– H

AuL

LAu

LAu

AuL

AuLAuL

LAu

H

RR R

RR

AuL

PhLAu

R H

Ph

AuL

AuL

R

LAu

R Ph

AuL

dual goldactivation

AuL

39

catalysttransfer

36

40

ringexpansion

"initiation"

36 38

PhR

41

•


1091


fer and ring expansion. The catalytic cycle would be closedby a catalyst transfer from 40 to 36 that would liberate thereaction product 41 and regenerate the di-gold complex 38.It is worth noting that 40 could be isolated and was foundto be catalytically active in the process.

By capitalizing on this result, and on the basis of theirmechanistic investigations, the Hashmi group subsequentlyreported that dibenzopentalenes 43 could be synthesizedby reacting diyne derivatives 42 in the presence of complex13 (Scheme 11).19 In this transformation, the intermediategold vinylidene 45, generated by dual gold catalysis, istrapped in an intermolecular manner by the pendant arylgroup. Interestingly, no compounds derived from an inter-molecular reaction of 45 with benzene (used as the solvent)was observed. The involvement of 45 in the process and theoverall mechanistic proposal were supported by a series ofcomputational studies.20 Of special interest is the catalysttransfer event, which was found to proceed between thegem-diaurated species 46 and 42 in a 3-step sequence com-prising an initial AuL+ transfer, followed by a proton transferand a second AuL+ transfer.20b

Scheme 11 Synthesis of dibenzopentalenes by dual gold catalysis

Since the gold activation of the diyne is a required stepprior to the formation of the gold vinylidene species (‘initia-tion’ step), Hashmi and co-workers designed a new class ofσ,π-acetylide digold complexes 47 derived from propyne,which could act as traceless dual-activation catalysts(TDACs) (Scheme 12).21 These complexes were shown par-ticularly active in a series of transformations as exemplifiedby the conversion of 48 into dibenzopentalene 49 (see addi-tional examples in the following paragraphs).

The replacement of the aryl moiety at the alkyne termi-nus of the substrate by a substituted allyl or benzyl groupallowed an easy access to fluorenes 51 and benzofluorenes52 (Scheme 13).22 The reaction should proceed in a similarmanner with the initial generation of gold vinylidene 50,which would then suffer a nucleophilic attack of the allyl orbenzyl moiety to ultimately deliver cyclized aromatic prod-

ucts. The nature of the final product depends on the substi-tution pattern at the allyl/benzylic position of the substratesince an additional aromatization step can take place whenthis position is not fully substituted.

Scheme 13 Synthesis of fluorene derivatives by dual gold catalysis

Besides undergoing nucleophilic trapping with carbon πsystems, gold vinylidenes generated by dual gold catalysiscan also be involved in C–H insertion processes. This reac-tivity was first demonstrated independently by the groupsof Zhang and Hashmi in 2012 (Scheme 14).23,24 Zhang andco-workers employed a combination of [(BrettPhos)Au]NTf2as the catalyst and a pyridine oxide as a basic additive toconvert arene diynes 53 into benzofulvene 57. While thereaction can be performed without this basic additive, itspresence was shown to positively affect both the rate andthe efficiency of the transformation. Hashmi and co-work-ers employed the catalytic system that was shown to be ac-tive in their previously reported synthesis of dibenzopen-talenes.19 DFT calculations as well as D-labelling experi-ments support a mechanism in which a dual gold-catalyzedprocess allows the formation of an intermediate gold vi-nylidene species 55 that subsequently undergo a C–H inser-tion. The nature of the C–H bond activation process wasstudied by Hashmi, Knizia, and Klein.25 The group of Hash-

[(IPr)Au]NTf2 (13)(5 mol%)

benzene, 80 °C42

43

AuL

LAu

AuL

AuL

R1

dual goldactivation

catalysttransfer

R1

R2

Ar

R1

R2

R1 R1

R2

R2

LAuAuL

AuL

nucleopghilictrapping

42

44

4645

"initiation"

54%

MeO

MeO 68% 20%

S

44

•

Scheme 12 σ,π-Acetylide digold complexes as traceless dual-activa-tion catalysts

"initiation"

Au(IPr)

Au(IPr) X

X = NTf2, OTf, SbF6, BF4, PF647TADCs

R

H

+

H

R

Au(IPr)

(IPr)Au

R

16 h, 73%[Au]

benzene, 80°C

R

[(IPr)Au]NTf2 (5 mol%)

Au(IPr)

Au(IPr) NTf2R = C4H9

(2.5 mol%) 2.5 h, 90%

48 49 47 (NTf2)

50

AuL

AuL

51

52% 94%

R RR

R

[(IPr)Au]NTf2 (5 mol%)or

47 (NTf2) (10 mol%)

benzene, 80 °C

(R ≠ H)

RR

52

or

LAu

R

R

AuL

F

44%

•


1092


mi was also able to isolate and characterize a gem-diauratedspecies 56 that might participate in the catalytic cycle bytransferring the Au moieties to the diyne substrate 53. Thetransformation proved to be applicable to a large variety ofsubstrates allowing C–H insertion not only in primary orsecondary C–H bonds but also in O–H and N–H bonds.

The same C–H bond activation process could be appliedto the cycloisomerization of iodoalkyne derivatives 58(Scheme 15).26 In this case, iodobenzofulvenes 59 were se-lectively obtained as the result of an iodine atom transferfrom the substrate 58 to the gem-diaurated species 60. Asdescribed above, this transfer might proceed in 3 steps:AuL+ transfer from 60 to 58, followed by the iodine atomtransfer, and a subsequent second AuL+ transfer. This trans-formation, which was shown to be relatively efficient, al-lows for further functionalization of the fulvene core bytransition-metal-catalyzed cross-coupling reactions.

With the very same substrate 33 that led to the initialdiscovery of gold vinylidene generation by dual gold cataly-sis (see Scheme 10), Hashmi and co-workers demonstratedthat intermolecular reactions of gold vinylidene 61 with al-kanes or alkenes was also accessible (Scheme 16).27 Reac-tions of 61 with cycloalkanes (employed as the solvent) ledto the isolation of substituted naphthalenes 62 in moderateyields. The mechanism for this transformation was not de-tailed. The reaction was more efficient when the trappingof 61 was performed in the presence of linear or cyclicalkenes. In this case, fused cyclobutene derivatives 64, de-rived from the gold-catalyzed rearrangement of the inter-mediate alkylidenecyclopropane 63 could be isolated.

Scheme 16 Intermolecular C–H activation and cyclopropanation with gold vinylidene species

Interestingly, while aryldiynes of type 65 were shown toundergo a dual gold-catalyzed 5-endo-dig cyclization lead-ing to the formation of gold vinylidene species 66, it wasdemonstrated by the Zhang group that the cyclization eventcould alternatively proceed following a 6-endo-dig modewhen the aryl group tethering the two alkyne moieties wasreplaced by an alkene 67 (Scheme 17).28 This shift in cy-clization mode lead to the formation of intermediate ortho-aurophenyl cations 68, which can also be regarded as car-benes 69. These species were shown to react via C–H acti-vation or with nucleophilic patterns to produce a variety ofaromatic compounds. The same observation was made bythe group of Hashmi with 2,3-dialkynylthiophene deriva-tives 70 (Scheme 17).29 Interestingly, the regioisomeric 3,4dialkynylthiophenes 71 react similarly to aryldiynes 65 fol-lowing 5-endo-dig cyclization process leading to gold vi-nylidene intermediates.30 Computational studies by Hashmiand co-workers showed that this divergence in selectivearises from electronic and not steric effect.

However, the presence of an unsaturated C=C motif be-tween the two alkyne units is not a structural requirementto enable the dual gold-catalyzed generation and selective

Scheme 14 Synthesis of benzofulvene derivatives by dual gold cataly-sis

53

AuL

AuL57 55

R1H

R2

[(BrettPhos)Au]NTf2 (5 mol%)2,6-Me2PyrO (50 mol%)

DCE, r.t.

Zhang

Hashmi

R1

H

R2

R2

H

R1

56

R2

R1 AuLLAu

dual goldactivation

catalysttransfer

C–Hactivation

5453

R1H

R2

AuL

LAu

H

A

B

H

OTHP

93% A

H

MeO

MeO 73% B

NTs

H

97% A

or

54

[(IPr)Au]NTf2 (5 mol%)benzene, 80 °C

•

Scheme 15 Synthesis of iodobenzofulvene by iodine atom transfer

47 (NTf2)(5 mol%)

1,4-dioxane50 °C

58

AuL

AuL

59

R1H

R2

R1

H

R2

R2

H

R1

60

R2

R1 AuLLAu

I and AuLtransfer

H

H

58%

H

MeO

MeO52% 86%

I

I

R2

R1

AuL

H

58

I

AuL

R1H

R2

+

AuL

LAu

I I

H

F

I

•

33

AuL

AuL61

64%

R( )n

C–H activation

n = 1, 3

62 (34–40%)

R

R

AuL

LAu

RR

R R

AuL

R

R

AuL

63 64

Cyclopropanation

81%

49%

with

Et

Et


[(IPr)Au]Ph(10 mol%)

80 °C

•


1093


reaction of gold vinylidenes. The group of Van der Eyckenhas reported for instance that diynamides 72, which can beobtained in a straightforward manner by an Ugi reaction,could be cyclized into cyclopentapyridone derivatives 74 inthe presence of a catalytic amount of [(IPr)Au]OTf in 1,2-di-chloroethane at 120 °C (Scheme 18).31 In this transforma-tion, the gold vinylidene species 73, produced intermedi-ately by a dual gold-catalyzed cyclization of diyne 72, in-serts into a primary or tertiary inactivated C–H bond togenerate a new five-membered fused cycle.

In the same vein, Hashmi, Fuji, and Ohno demonstratedthat dual gold catalysis could also be applied to the cyclo-

isomerization of substrates 75 possessing a simple two car-bon alkyl moiety tethering the two alkyne units (Scheme19).32 Depending on the substitution pattern of the sub-strate linker, the intermediate gold vinylidene species 76could evolve either via C–H activation or nucleophilic trap-ping. As for the reactivity trend, competition experimentsshowed that 1) the C–H activation pathway was more favor-able than the nucleophilic trapping by an aromatic ring and2) nucleophilic trapping by aromatics led preferentially tothe formation of a new 6-membered (as compared to a 5-membered one). In a recent article, the group of Hashmi re-ported another example of selective nucleophilic trappingusing polyarylated 1,5-hexadiyne substrates.33 Selected ex-amples of such transformations are given in Scheme 19.

Scheme 19 Selective reactivity of gold vinylidene species generated from variously functionalized 1,5-hexadiyne substrates

Gold vinylidene generated by dual gold catalysis alsoproved to be useful species for the synthesis of various ni-trogen containing heterocyclic motifs. For example, and byanalogy with the work performed with aryldiyne sub-strates, the group of Hashmi developed a procedure for thesynthesis of polyclic fused pyridines 80 from pyridiniumsubstrates 77 (Scheme 20).34 Initial tests showed that thecycloisomerization could not be directly performed fromthe ‘free’ pyridines, presumably due to their capacity tostrongly bind to gold catalysts. It is also interesting to notethat while simple methylpyridium salts exhibit a low tomoderate reactivity, the benzyl ones 77 bearing either a

Scheme 17 5-endo-dig versus 6-endo-dig cyclization pathways in dual gold catalysis of 1,5-diynes

65

AuL

AuL

R

AuL

5-endo-dig

67

R

AuL

6-endo-dig

R

R

RR'

R'

R'

AuL

R'

AuL

R

R

AuL

R'

AuL

R

Aryl

Alkene

71

AuL

AuL

AuL

5-endo-dig

R'

R'

S

S

70

AuL

6-endo-dig

R'

AuL

R'

AuL

AuL

R'

AuL

Thiophene

S S S

aryl cation68 carbene69

Thiophene

66

•

•

Scheme 18 C–H activation with gold vinylidenes using diyne sub-strates produced by an Ugi reaction

72R1 H

O

R2 N C

H2N

H

R3

HO2C

UGI-4CR

MeOH, 20 °C NR1

HN O

R2

OH

R3

NR1

HN O

R2

O R3

H

(IPr)AuCl/AgOTf(5 mol%)

DCE120 °C

74

NR1

HN O

R2

O73

H

R3

AuL

AuL

NPh

CyHN O

O

62%

N

t-BuHN O

O

90%

F

Cl

N

CyHN O

O

61%

O2N

•

47(PF6) or 47 (NTf2)(5 mol%)

toluene, 80 °C

75

AuL

AuL

R1

R2 R1

R2

AuL

AuL

R2

HR3

76

C–Hactivation

R2

HR3

AuL

AuL

R2

R3

n( )

R2

R3

n( )

Nucleophilictrapping

MeO

H

47 (PF6) (5 mol%)

toluene, 80 °C

H

MeO92%

C–Hactivation

MeO

80%

SelectiveArylation

MeO

F

92%

SelectiveArylation

FF

F

47 (PF6) (5 mol%)

toluene, 60 °C

47 (NTf2) (5 mol%)

toluene, 80 °C

•

• •


1094


PF6– or NTf2

– counteranion, could be readily and efficientlyconverted into 79 by treatment with [(IPr)Au]NTf2 at 55 °Cin dichloromethane. The transformation, which involvesthe C–H insertion of gold vinylidene 78 as the key step,could be employed for the synthesis of a variety of polycy-clic pyridinium 79. These salts could be subsequently hy-drogenated and debenzylated to liberate the correspondingfree pyridines 80. This protocol appears to be particularlyuseful as it allows a rapid access to structural motifs, whichare found in molecules described to possess insecticidal orantimicrobial properties.

Several synthetic procedures have also been reportedusing ynamide derivatives as substrates for the synthesis ofheterocyclic structures. Ohno, Hashmi, and Fuji have

demonstrated that N-propargyl ynamide of type 81 couldbe converted in moderate to goods yield into 3,4-disubsti-tuted polyclic pyrroles 83 and 84 (Scheme 21).35 The intro-duction of a nitrogen atom in the diyne tether does not af-fect the reactivity previously observed for substrates pos-sessing an all-carbon linker. The intermediate goldvinylidene 82 was found capable of performing either C–Hactivation or nucleophilic trapping to produce pyrrole de-rivative 83 or 84, respectively. The C–H activation turnedout to be generally more efficient than the arylation pro-cess. It is worth noting that the cyclization leading to 82proceeds by umpolung via the addition of the nucleophilicgoldacetylide to the carbon of the ynamide.

Recently, our group reported that structurally similarynamide substrates 85 possessing a longer linker betweenthe two alkyne units could similarly react to produce a vari-ety of N-containing aromatic heterocycles 88 (Scheme22).36 The use of [(RuPhos)Au]NTf2 in refluxing chloroformwas found to be a set of optimal catalytic conditions to per-form the transformation. The use of a pyridine additive wasobserved to increase the reaction rates and in some cases tosignificantly improve the yields. In contrast to the previous-ly reported dual gold-catalyzed reactions that proceed by 5-endo-dig cyclization, the given transformation singularly in-volves either a 5-, 6-, or 7-exo-dig cyclization. This processallows for the generation of a key gold vinylidene interme-diate 86, which subsequently reacts in an intramolecularmanner with a nucleophilic alkenyl or aryl moiety to pro-duce a new substituted phenyl or naphthyl motif. Overall,this transformation can be regarded as an intramoleculargold-catalyzed formal dehydro-Diels–Alder reaction be-tween an enyne and an alkyne. We also performed a seriesof D-labeling experiments and kinetic studies that supportthe involvement of a dual gold catalysis mechanism withspecies 86 and 87. The very same type of transformationwas reported very recently by the group of Zi using[(IPr)Au]NTf2 in combination with DIPEA.37

Scheme 22 Involvement of gold vinylidene species in formal dehydro-Diels–Alder reactions of ynamide derivatives

Scheme 20 Access to polycyclic pyridinium salts and pyridines by dual gold catalysis

N


CH2Cl255 °C

77

N

AuL

AuL78

H

R2

H

R2

N

R2H

PhBn

PF6

Bn

79

PF6

R1

N

R2

80

R1 H

H

R1

R1C–H

activation

N

RR'

insecticidalproperties H2

Pd/C

45–95%N

Pyr

CNantimicrobialcompound

N

Bn PF6

Et

95%N

Bn PF6

95%

N

53%(from 77)

H

H H

H

•

Scheme 21 Synthesis of pyrrole derivatives by C–H activation or nucle-ophilic trapping of gold vinylidene species

47 (PF6) (5 mol%)

toluene, 80 °C TsN

AuL

AuL 82

H

R3

C–Hactivation

TsN

81R2

R1

R1

TsN

AuL

AuL

R1

R3

or

Arylation

TsN

R1

R3TsN

R1R3

TsN

R1

H

R3

AuL

TsN

R1

R3

AuL

LAu

LAu

8483

NTs

β

OMe

75%

NTs

S

NTs

50%68%

NTs

H

H

44%

• •

CHCl3, 65°CNTs

AuL

86

(5 mol%)Nucleophilic

trapping

77%

[(RuPhos)Au]NTf2

(3,5-Br2Pyr)NTs

R1

R2n( ) R2

n( )

85

n( )

AuL

NTs

R1

R2

n( )N

R1

R2

LAu AuLTs88 87

NTs

NTs

NTs

S

60%

NTs

80%

NTs

88%

•


1095


In a very recent article, Hyland and Pyne described anunusual cycloisomerization of an enediyne motif 89 thatproduces isoindolinones 94 (Scheme 23).38 The singularityof this process lies in the fact that the dual catalyzed cy-clization event involves the initial addition of a nucleophilicgoldacetylide on the alkene moiety of the gold-activatedenyne (see 90 → 91). The resulting gold vinylidene species91 subsequently cyclizes onto the allenylgold moiety to de-liver a new gold carbene intermediate 92. The rearrange-ment of 92 into a six-membered cycle 93 followed by aro-matization of the system finally produce 94. This mecha-nism was supported by a combination of D-labelingexperiments and DFT calculations. An alternative directpathway leading to 93 from 91 was also suggested. Thistransformation was found to perform best with the oxo[(Ph3PAu)3O]BF4 gold complex in toluene at reflux to delivera variety of isoindolinones 94 in high yields. Interestingly,the propiolamide substrates 89 could be easily obtainedfrom the corresponding protected amino aldehydes 95 withhigh enantiopurity, and the gold-catalyzed transformationwas found to retain this level of purity.

Scheme 23 Gold vinylidenes as intermediates in the synthesis of isoin-dolinones by dual gold catalysis

Besides performing C–H activation or undergoing nucle-ophilic trapping with C-nucleophiles, gold vinylidene spe-cies have also been demonstrated to react with oxygen-based nucleophiles. As reported by the group of Hashmi,39 agold vinylidene 97 intermediately generated by dual goldcatalysis from an aryldiyne substrate 96 can, for instance,react with water (Scheme 24). This nucleophilic trappinggenerates an aurated enol 98 which then tautomerizes tothe gold acyl species 99. A subsequent CO extrusion pro-duces the alkylgold 100, which ultimately yield the indaneproduct 101 either by protodemetalation or by catalyst

transfer with substrate 96. The CO loss was confirmed byGC/MS spectrometry measurements using either 18O-la-beled water or a substrate 13C-labeled at the alkyne carbonbeing removed by CO extrusion. Since the trapping of thevinylidene intermediate with water proceeds in an inter-molecular fashion, a specific design of the substrate is re-quired to prevent (or limit) any competitive intramolecularC–H activation or nucleophilic trapping. The reaction wasshown to be the most efficient when it was performed withthe [(IPr)Au]NTf2 as the catalyst in THF at room tempera-ture with only 5 equivalents of water. The efficiency was,however, shown to be strongly dependent on the substratesubstitution pattern.

Scheme 24 Reaction of gold vinylidene species with water

Intramolecular transfers of alkoxy groups to gold vi-nylidene species is also feasible as reported by the Zhanggroup.40 When aryl diynes 102 possessing a methoxy groupat the propargylic position were reacted with a catalyticamount of [(IPr)Au]NTf2 in a t-BuOH/DCE mixture at 70 °C,various polyclic fused cylopentenones 106 could be ob-tained (Scheme 25). To explain their formation, the authorsproposed that a transfer of the methoxy group from the al-lylic position to the gold vinylidene moiety could proceed inthe intermediately formed species 103. A subsequent isom-erization of the resulting carbocation 104 would allow aNazarov-type cyclization that would ultimately lead to theformation of 106 after hydrolysis of cyclopentadiene 105.

The same group later reported that gold vinylidene 108derived from aryldiyne 107, could also react with 3,5-di-chloropyridine oxide to generate in situ a diaurated ketene109 (Scheme 26).41 This species could subsequently sufferan intra- or intermolecular nucleophilic attack of an alcoholor even water to produce indene derivatives 111 bearing ei-ther a lactone, an ester, or a carboxylic acid functionalgroup. The key oxidation step of 108 into 109 with the pyri-dine oxide was supported by DFT calculations, as well asthe involvement of the gem-digold species 110. This three-

77%

89

91

BocBnN

R1

O

H

95

BnN

O

R194

[(Ph3PAu)3O]BF4(2.5 mol%)

toluene, 110 °C

BnN

90

O

R1 R2

AuL

AuL

steps

BnN

O

R1

AuLR2

AuLBnN

O

R1

AuL

AuL

R2

BnN

O

R1

AuL

AuL

R2

R2

BnN

O

R1 R2

AuL

92

BnN

O

Bn 85%

BnN

O

S

65%

BnN

OF

93

•

•


H2O (5 equiv)THF, 20 °C

96

AuL

AuLR2

R2

97

R1

R1

dual goldactivation

CO extrusion

R2R1

AuL

LAu

R2

98R1

LAuOH

R2

101

R1

R2

99R1

LAuO

R2

100R1

AuL

OH

H

– AuL

– CO

CO2Me

CO2Me

85% 60%

Br

F

F

38%42%

•


1096


component reaction, which can be regarded as an oxidativecyclization of a diyne, was shown to be efficient and appli-cable to a large variety of substrates.

As seen from the different examples of reactions com-piled in this section, dual gold catalysis represents a partic-ularly efficient means of generating gold vinylidene speciesfrom diyne substrates. Depending on the nature of thelinker between the two alkyne units and the substitutionpattern of the substrate, these reactive electrophilic inter-mediates can undergo C–H insertion at a non-activated po-sition or react with carbon and oxygen nucleophiles to pro-duce a variety of polycyclic (aromatic) compounds.

4 Other Processes

Besides 1,2-migration of iodine or silyl groups from theterminal position of a gold-activated alkyne or dual gold ca-talysis of diynes, a few other processes have been reportedfor the generation and use of gold vinylidene intermediates.These alternative methods are described in the followingparagraphs.

The group of Zhang has reported in 2016 that TMS-pro-tected ynones 112 could be converted into 2-bromocyclo-pentenones 116 by treatment of 112 with a catalyticamount of (IPr)AuCl and AgSbF6 in the presence of N-bro-moacetamide (NBA) as the brominating agent (Scheme27).42 This transformation was shown to be high yielding,compatible with various commonly used functional groupsand, regio- and stereoselective. While the mechanism hasnot been completely elucidated, the authors have proposedon the basis of experimental studies that the reaction pro-ceeds via the intermediate formation of a bromovinylidenespecies 115. The latter can then undergo a C–H insertion ata non-activated position of a pendant alkyl group. As for thegeneration of 115, it was suggested that under the reactionconditions, the silylalkyne first converts into the golda-cetylide 113. Upon activation of the C=O bond in 113 by anacidic species (Ag+/TMS+), a gold allenylidene species 11443

would form and subsequently react with NBA to produce115. The corresponding bromoalkyne was demonstratednot to be an intermediate in this transformation, thus rul-ing out the possibility of a 1,2-migration process (see Sec-tion 2). The nature of the C–H insertion step was computa-tionally studied by Hashmi, Knizia, and Klein.25

Hashmi and co-workers also demonstrated that golda-cetylides 118, generated in situ by reaction between a ter-minal alkyne 117 and the gold pre-catalyst 119, could per-form a nucleophilic attack at a position bearing an aryl sul-

Scheme 25 Intramolecular migration of a methoxy group onto a gold vinylidene


tBuOH/DCE70 °C102

AuL

AuL103

R1

R1

OMe migration

105

70%

R3

R2

OMe

OMe

R3

R2 AuLR1

LAuOMe

R3

R2

AuLR1

LAuOMe

R3

R2

H

isomerization

R1

R2

R3

MeO– AuL

104

via Nazarov

106R1

R2

R3

Ohydrolyse

H2O

O

NTs

90%

O

F3C

O

82%

•

Scheme 26 Oxidation of gold vinylidene species to ketene and their intra-or intermolecular trapping

107

AuL

AuL

R2

R2

108

R1

R1

oxidation

111

– Pyr

83%

+N

O

Cl Cl

NO Cl

Cl

O

AuL

R2

R1

LAu

R2

R1

OR3O

HOR3

R2

R1

OR3O

LAuAuL

catalysttransfer

with 107

110 109

For esters or acids: DCE/R3OH (1:1), 70 °CFor lactones: DCE/tBuOH (1:1.5)


solvent, 70 °C

OR3O

Cl

60%

OHO

O

O

83%

OO

80%

•

•

Scheme 27 Generation of gold vinylidenes from goldacetylides under acidic conditions

(IPr)AuCl (5 mol%)AgSbF6 (10 mol%)

NBA (1.5 equiv)CH2Cl2, 20 °C

114116 115

112

91%

O

TMSH

Rn

O

AuLH

Rn

O

Br

H

Rn

O

H

Rn

Y

AuL

O

H

Rn

Br

AuL

C–Hinsertion

O

AuLH

Rn

Y

Y (Y: TMS, Ag)

NH

Br

O

113

allenylidene

vinylidene

O

Br

H

93%

O

Br

HH

65%, d.r. = 9:1

O

Br

H

73%

O

Br

H

Me

MeO2C

• ••


1097


fonate leaving group, thus allowing the formation of a goldvinylidene species 120 (Scheme 28).7,44 A subsequent attackof the sulfonate anion on 120 generates an aurated alkenylintermediate 121, which, in turn, undergoes a catalysttransfer with the substrate to deliver the alkenyl sulfonateproduct 122 and regenerate the goldacetylide 118. Both, 5and 6-membered cycles could be produced in moderate togood yields following this procedure. The efficiency of thetransformation was found to be dependent on the natureand substitution pattern of the chain tethering the alkynemoiety and the sulfonate group: geometrically restrictedsubstrates were observed to be more reactive. While thescope of this transformation remains so far limited, the easyaccess to the substrates and the usefulness of the alkenylsulfonate products makes this approach particularly attrac-tive from a synthetic point of view.

Scheme 28 Generation of gold vinylidenes by substitution of sulfonate leaving groups with a goldacetylide

Recently, Fürstner and Debrouwer reported anotherprotocol for the generation of gold vinylidene species by anintermolecular nucleophilic attack of a goldacetylide on anactivated aldehyde (Scheme 29).45 While this study was notdedicated to the development of a new synthetic transfor-mation, the described procedure undoubtably possessessome synthetic potential. The authors have shown that thetreatment of goldacetylide 124, generated by reaction ofthe TMS-alkyne 123 with a stoichiometric amount of(IPr)AuOH, with TBSOTf at –78 °C led to the formation of atransient gold vinylidene species 125.46 This process proba-bly involves the nucleophilic addition of the goldacetylidemoiety onto an O-silyloxocarbenium intermediate. Interest-ingly, 125 rapidly evolved at –78 °C via the formal transferof the oxygen residue from the benzylic position to the car-benic one to produce the HOTf·acylgold complex 126. At20 °C, 126 suffered an extrusion of CO that produced 127.Alternatively, its treatment with methanol delivered the

corresponding ester 128. Both intermediates 125 and 126could be detected using NMR spectrometry technics andthe structure of 126 was confirmed by X-ray analysis.

Scheme 29 Transient vinylidene species generated by reaction be-tween a goldacetylide and an oxocarbenium ion

Finally, Fensterbank, Gandon, and Gimbert have report-ed the involvement of intermediate gold vinylidene species132 in the gold-catalyzed selective conversion of 1,6-al-lenynes 129 into hydrindienes 133 (Scheme 30).47 The sin-gularity of the process, as compared to those presentedabove, lies in the mechanism leading to the formation of thegold vinylidene. The authors have proposed based on a se-ries of D-labeling experiments and computational studies,that the alkenylgold species 131, initially produced by nuc-leophilic attack of the allene in 130 on the gold-activatedalkyne moiety, could undergo a favorable 1,4-hydride shift.This unusual transfer would produce a gold vinylidene in-

119 (5 mol%)

benzene, 20°C

117

83% (E/Z = 4:1)

Rn

BsN

OS

Ar

O O

n( )

n = 0, 1

AuL

N N

i-Pr

i-Pr

118

AuL

Rn

OS

Ar

O O

n( )

L :

Rn

n( )AuL

OS

Ar

O O

120

Rn

n( )

OS

Ar

O O

AuL

121

catalysttransfer

118117Rn

n( )

OS

Ar

O O

H

122

OBs

O

OBs

82%53% (E/Z = 2.5:1)

O

OBs

OTs

49%

OBs : p-bromobenzene sulfonate

•

123

(IPr)AuOH(stoich.)

MeOH/EtOH60 °C

O

TMS124

O

AuIPr

O

AuIPr

TBS

OTBS

AuIPr

TfO

TfOTfO

O

IPrAu

TBSOTf

OIPrAuH

125

H2O

126

H

TBSOTfCH2Cl2

–78 °C

20 °C– CO

COOMe

MeOH20°C

127 128

•

Scheme 30 Generation of gold vinylidenes by hydride transfer from an intermediate alkenyl-gold species

131129

HX X

AuL

H

HH

HX

H

AuL

X

H

H

AuL

1,4-Hydrideshift

X

H

HC–H

insertion

132

X

H

H

134 133

[Au]: [(JohnPhos)Au]SbF6 [(IPr)Au]SbF6, AuCl3, AuCl

[(R3P)Au]SbF6

R = Ph, Et

130

H

H

MeO

MeO

83%

with [(JohnPhos)Au]SbF6

H

H

MeO2C

MeO2C85%

with AuCl3

N

H

H

71%

with [(JohnPhos)Au]SbF6

Ts

[Au] (1 mol%)

CH2Cl2, 20 °C

••

•


1098


termediate 132 which, in turn, could insert into a non-acti-vated C–H bond to deliver compound 133. Interestingly,while this process was found to be very efficient with goldcomplexes bearing bulky phosphine or NHC ligands [as wellas gold(I)/(III) halides], the use of gold(I) complexes pos-sessing less sterically demanding ligands (Et3P, Ph3P) led toa divergence in selectivity with the formation of Alder-enetype products 134.

5 Conclusion

While gold vinylidenes species have been proposed asreactive intermediates in synthetic processes as early as2004, the development of transformations based on theirefficient generation and selective reaction has only startedin 2012, after the groups of Hashmi and Zhang uncoveredthe synthetic potential of dual gold catalysis with diynesubstrates. Although gold vinylidenes can be accessed by a1,2-migration process from Au-activated halogeno- or silyl-alkynes (see Section 2), this route lacks generality. Depend-ing on the reaction conditions and the substitution patternof the substrate, the 1,2-migration pathway can be in com-petition with the direct nucleophilic functionalization ofthe alkyne and/or with the dehalogenation/desilylation ofthe gold-activated alkyne. In contrast, and as exemplified inSection 3, the use of dual gold catalysis with diyne sub-strates has been shown to be a far more robust and reliableway to produce gold vinylidenes. The reactivity principlelies in the possibility to generate in situ, from a terminalalkyne, a goldacetylide that would undergo an intramolecu-lar nucleophilic addition onto a second gold-activatedalkyne. The increased number of studies that have beenmade in the field of dual gold catalysis during the last 5years have already allowed enlightening some unique andunsuspected reactivities of gold vinylidenes. These specieshave been demonstrated to react, for instance, with carbonor oxygen-based nucleophiles, by oxidation or by C–H in-sertion at a non-activated center. If one considers that theregioselective reaction of an electrophilic species at the car-bon of a goldacetylide could theoretically generate a goldvinylidene species, the application of this simplistic reactiv-ity principle with various electrophiles should lead in thefuture to new exciting discoveries and consequently to anincreasing interest for the use of gold vinylidenes in syn-thetic organic chemistry.

Acknowledgment

The University of Ottawa and the Natural Sciences and EngineeringResearch Council are acknowledged for financial support, and Prof. P.Knochel for the kind invitation to contribute to this special issue.

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1099


(18) For a mass spectrometry study aimed at detecting intermedi-ates in this transformation, see: Greisch, J.-F.; Weis, P.; Brendle,K.; Kappes, M. M.; Haler, J. R. N.; Far, J.; De Pauw, E.; Albers, C.;Bay, S.; Wurm, T.; Rudolph, M.; Schulmeister, J.; Hashmi, A. S. K.Organometallics 2018, 37, 1493.

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Gold Vinylidenes as Useful Intermediates in Synthetic ...Chemistry Fabien Gagosz* 0-02-02614 95...

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