Harnessing the Versatile Reactivity of Propargyl

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Apr 15, 2015 - Scheme 1 Reaction pathways of unsaturated and propargyl alcohol substrates with ..... a Nazarov cyclization yielding 2,4a-dihydro-1H-fluorene.
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Harnessing the Versatile Reactivity of Propargyl Alcohols and their Derivatives for Sustainable Complex Molecule Synthesis Gold Catalysis

R2

H

R3

R3 O

X

R2

N Ts

N

R1

OH

R4

BzO R

O

OH

I

OEt R2

R1OCO R2

Ph R1

N Ts

R4

R2

R4

R2

chemistry is the efficient and selective assembly of complex molecular structures, especially carbo- and heterocycles, from readily accessible starting materials. With this has arisen the development of tandem reaction processes, which permit multiple transformations in a single synthetic step and that have often provided elegant routes to complex target scaffolds from simple precursors. Propargyl alcohols and their derivatives have become increasingly attractive starting materials for such processes owing to their reactivity in the presence of a Brønsted or Lewis acid catalyst as well as halogenation reagents. This account describes our recent efforts in the field, and demonstrates how propargyl alcohols and their derivatives can be transformed into a diverse range of highly functionalized acyclic, carbocyclic and heterocyclic structures, which are of importance as synthetic building blocks and as motifs in functional materials and bioactive compounds. 1 Introduction 2 Acyclic Conjugated Enynes 3 Carbocycles 3.1 Indenes 3.2 Dihydrofluorenes 3.3 Cyclopentenes, Cyclobutenes and Cyclopenta[b]naphthalenes 3.4 ortho-Phenolic Esters 4 Heterocycles with One Heteroatom 4.1 Indoles 4.2 Piperidines, Azepines and Pyrrolidines 4.3 Pyrroles 4.4 Furans 4.5 Benzo[b]oxepines and Benzo[b]azepines 5 Heterocycles with Two Heteroatoms 5.1 Thiazoles and Oxazoles 5.2 Dioxolanes 6 Conclusion

Key words alkynes, carbocycles, heterocycles, homogeneous cataly-

R1

R1

N Ts

N R2

R2

R3

R1

R3 R2

R3

SO2Ar' I

R4

R4

R1

R5

R3

R4

R1

R3

N R1 I

R2

R2 O

R1

R5

O N Ts

R4

1

Ar

N R2

OH

XR5 I O

O

Ar

N

CHO

O

O

Abstract One of the major challenges faced in modern synthetic

R3

R1

R4 Propargyl Alcohols, Carbonates, Esters, and Ethers

R3

R4

R3 O R2

Received: 18.11.2014 Accepted after revision: 27.01.2015 Published online: 15.04.2015 DOI: 10.1055/s-0034-1380402; Art ID: st-2014-a0952a

R1 N R4

R2

N Ts

OR1

H N Ts

R3

R3

O

R3 X

R2 3 R

Nu N Ts

OH

Lewis or Brønsted Acid Catalysis

R2

N R1

Ar

R2

R4 R3

R1

R2

Ar

Ar' OCOR1

SO2R5 R2

R1

R2

N Ts

R3

C(O)R1

R1

R3

R1

O

OCOR1

R2

H

R4

R3

R4

R2

BzO

a

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore b School of Chemistry, Monash University, Clayton 3800, Victoria, Australia [email protected] c Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK [email protected]

O

R2

Ar TsN

R1

Silver Catalysis R3

R1OCO ( ) n

N R1 Metal-Free Processes

R2 R3

O

R4

Introduction

The search for straightforward and efficient methods to establish complex molecular scaffolds from readily accessible precursors is one of the major and most enduring challenges in synthetic organic chemistry. In pursuit of this objective, tandem reaction processes comprising multiple structural transformations in a single step are highly attractive, and many proceed with excellent regioselectivity and stereoselectivity.1 Recently, highly Lewis acidic complexes of late transition metals have been shown to catalyze unconventional transformations due to their unique carbophilic reactivity; most notably in inducing cycloisomerization of alkenyl, allenyl and alkynyl π-bonds (Scheme 1, eq. 1).2–4 In particular, catalysis by gold and silver complexes of substrates bearing a propargyl alcohol motif has demonstrated great versatility, leading to diverse carbocyclic and heterocyclic products (Scheme 1, eq. 2).3,4 Additionally, under activation by oxophilic catalysts, propargyl alcohols may be regarded as pro-electrophiles and are susceptible to nucleophilic attack (Scheme 1, eq. 3).5 This account describes our contributions to the field which have led to the development of novel pathways from propargyl alcohols and their derivatives to functionalized acyclic, carbocyclic and heterocyclic targets of potential biological or materials interest. For a more comprehensive perspective, we would like to refer the reader to recent reviews detailing significant results in the field achieved by other research groups from around the globe.1–5

2 Acyclic Conjugated Enynes

sis, tandem reactions

Our work in this field commenced with the establishment of two methods for the regioselective synthesis of

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Benjamin James Ayersa Philip Wai Hong Chan*a,b,c

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[M]+

[M]+

Nu–

[M]

[M] (1)

or Nu

Nu

O O

O R3

R3

[Au]+

O

products

R1 vinyl carbenoid

(2)

O R1

R1

R2

R2

[Au]+

O O

1,3-shift

R3 R2

R3COX

HO

R1

[cat]+

products

R1 R

products

[Au]+ allene

2

HO

(3) R1

[cat]+

[cat]+

R2

+

R1

products

R1

products

R2

HO R1 R2

– [cat]–OH +

R2

Scheme 1 Reaction pathways of unsaturated and propargyl alcohol substrates with Lewis and Brønsted acids

Biographical Sketches

Benjamin James Ayers received his Masters in Chemistry (Honours) degree from the University of Oxford, UK, in 2008, and under the supervision of Professor George W. J. Fleet was awarded his D.Phil. degree in or-

ganic chemistry from the same institution, in 2013. After his postgraduate studies, he worked as a Wellcome Trust postdoctoral fellow in the group of Professor Caroline Springer at the Institute of Cancer Re-

search, London, UK. In 2014, he moved to Nanyang Technological University, Singapore as a postdoctoral fellow in the group of Professor Philip Wai Hong Chan.

Philip Wai Hong Chan received his Bachelor of Science (Honours) degree in chemistry from the University of Bristol, UK, in 1995, and was awarded his D.Phil. degree in organic chemistry from the University of Oxford, UK, in 1998, under the supervision of Professor Mark G. Moloney. After completing his postgraduate studies, he spent two years working as a JSPS postdoctoral fellow in the group of Professor Yoshinori Yamamoto at Tohoku Universi-

ty, Japan, followed by a year as an ARC postdoctoral fellow in the group of Professor Craig A. Hutton at The University of Sydney, Australia, and then four years as an AoE postdoctoral fellow in the group of Professor Chi-Ming Che at The University of Hong Kong. In 2006, he joined the faculty of the Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore, as an Assistant Professor. He is currently the Monash-Warwick Alli-

ance Chair Professor of Sustainable Chemistry at Monash University, Australia and the University of Warwick, UK, a joint appointment between the two institutions as part of the Monash-Warwick Alliance. His research interests lie within the broad area of sustainable synthetic organic chemistry and its applications to the synthesis of natural products and functional materials.

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O

1,2-shift

R3 [Au]+

R2

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argyl alcohols 1 and alcohols 4 (Scheme 2, eq. 2).7 Remarkably, this latter reaction was found to be effective at an exceptionally low catalyst loading of 0.01 mol%, achieving a product turnover of 10,000. In both reactions, it was thought that the pathway proceeded by respective Lewis or Brønsted acid mediated ionization of the alcohol moiety in 1, with anticipated formation of the tertiary carbocation intermediate 7 (Scheme 2, eq. 3). Subsequent opening of the cyclopropyl ring by attack of the amine or alcohol nucleophile then furnished the respective conjugated 1,3-enyne products 3 and 5. With regard to the excellent product regio-

conjugated 1,3-enynes from 1-cyclopropyl-2-propyn-1ols.5–7 The inspiration for this initial research arose from the pioneering work in the laboratories of Nishibayashi and Liang,8 along with the evident utility of conjugated 1,3enynes as building blocks for the preparation of compounds of biological and materials interest.9 In the first approach, we reported the formation of conjugated 1,3-enynes 3 from 1-cyclopropyl-2-propyn-1-ols 1 and sulfonylamines 2 under catalysis by ytterbium(III) triflate [Yb(OTf)3] (5 mol%) (Scheme 2, eq. 1).6 The second approach involved the triflic acid (TfOH) catalyzed formation of 1,3-enynes 5 from prop-

R1

OH

Yb(OTf)3 (5 mol%)

R2

NH2SO2Ar 2, PhMe 4 Å MS, 100 °C, 1.5–12 h

NHSO2Ar (1)

R

1

1

R2 3 R4

OH

TfOH (0.01 mol%)

R3 R4 R

R2

1

R3

R1

R5OH 4, Δ 10–30 min

OH

R4 R1

(2)

R2 5

1

R3

OR5

R3 R4

Yb(OTf)3 = [Yb] or

Nu

R1

TfO– + H+

TfOH

R2 1

R2 3, Nu = NHSO2Ar 5, Nu = OR5

(3)

NuH 2, Nu = NHSO2Ar 4, Nu = OR5

R2

[Yb]/H+

R3

OH R3 R4

R1

R2

R1

R4 7

6

H+ [Yb]–OH or H2O

[Yb] + H2O

Selected examples: Ph Ph

NHTs

4-FH4C6 3a, 70%

NHTs

H3C(H2C)5

Ph 3b, 73%

Ph

OEt

Ph

OEt

t-Bu 5a, 98%

Scheme 2 Lewis and Brønsted acid catalyzed formation of conjugated enynes

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5b, 92%

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selectivity, it was postulated that this arose from the carbonium species 7 adopting the conformation shown in Scheme 2, which minimized unfavorable steric interactions. Both catalytic systems also proved general in scope, affording efficient access to this challenging conjugated 1,3-enyne scaffold.

3

nucleophiles was used to elicit inter- and intramolecular formation of functionalized carbocycles in tandem reaction processes.

3.1

Indenes

In view of their interesting biological properties and synthetic utility, we reasoned and subsequently demonstrated that the reaction of propargyl alcohol 8 and phenol 9, catalyzed by Yb(OTf)3, would afford a new method for the assembly of indenol 10 (Scheme 3, eq. 1).10,11 Mechanistically, it was speculated that the Lewis acidic catalyst led to ionization of the substrate to afford the tertiary carbocation 11, or its mesomeric equivalent allenic carbocation 11′. Friedel–Crafts alkylation at the acetylenic carbon center of 11, or the allenic carbocation center of 11′ with phenol 9,

Carbocycles

Building on this initial work, we envisaged that suitable modification of this synthetic strategy would permit access to functionalized carbocyclic scaffolds from simple propargyl alcohol and derivative precursors. In the following section, the replacement of heteroatomic with carbon-based

R4 OH

OH R4

+

R1 2 R

Yb(OTf)3 (10 mol%)

R5

R5

MeNO2, 80 °C, 24 h

R3

(1)

R1

R3

8 R4

OH

R2

9

10

OH OH R5

Yb(OTf)3 = [Yb]

R1

R2

R1

R3

R3

R2 10

8

H2O R4

OH H+

R5

[Yb]–OH R1

R1

R3

(2) R1

+

R2

R2

R2

[Yb]

+

R3

13

R4

R3

11

R1

11'

OH

OH R4

R2 [Yb]

R5

R5 R3 9

12 Selected examples: Me

OH

Me Me

Ph

10a, 92%

Me Me

C6H4-4-F Ph

OH

Ph

C6H4-4-CN Ph 10b, 99%

OH

OH Me

Ph

C6H4-4-Br C6H4-4-Br

Ph 4-ClH4C6

10c, 98%

10d, 53%

Scheme 3 Lewis acid catalyzed tandem Friedel–Crafts alkylation/hydroarylation of propargyl alcohols with phenols

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Ph

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and subsequent ytterbium(III)-mediated hydroarylation of intermediate 12, was thought to afford the indenyl–ytterbium complex 13. The subsequent protodemetalation yielded the indenol product 10. This tandem Friedel–Crafts/hydroarylation sequence proved to be both high yielding and tolerant of a diverse range of propargyl alcohol substrates. In analogy to our prior acyclic work, TfOH was demonstrated to be capable of mediating the process. However, lower yields with TfOH, and the milder conditions offered by Yb(OTf)3 catalysis, led to the latter process being a more attractive synthetic approach. Additionally, the utility of this protocol was illustrated by converting three indenols 10e–g into their respective bioactive indendione derivatives 14e– g (Scheme 4). Me

OH

Me

O

Me

Me O2

Ph

CHCl3, 2.5 d

Ph

Ph Ph

3.2

O R 10e, R = H 10f, R = Cl 10g, R = Me

Pleasingly, these alkynol approaches complemented existing metal-free methods for indene synthesis that employed the analogous unsaturated substrates with allylic, benzylic, propargylic and, more recently, homoallylic motifs.14,15 In the case of the latter, we had delineated the approach to indene 25 from homoallylic alcohol 24 by p-toluenesulfonic acid monohydrate (p-TsOH·H2O) catalysis (Scheme 6, eq. 1).15 It was proposed that the reaction proceeded by Brønsted acid mediated ionization of homoallylic alcohol 24 forming cationic species 26 (Scheme 6, eq. 2). Deprotonation of this adduct gave the conjugated 1,3-diene 27, with reprotonation furnishing the internal allylic cation 28. Subsequent Friedel–Crafts reaction of this intermediate was assumed to form the indene 25, following rearomatization of the Wheland intermediate 29. The diene 27 was isolated in a control reaction at room temperature (Scheme 6, eq. 3). On resubmission to the reaction conditions, the indene adduct 25 was formed, supporting the involvement of the diene intermediate 27 in the reaction pathway.

Dihydrofluorenes

R 14e, R = H, 96% 14f, R = Cl, 73% 14g, R = Me, 64%

Scheme 4 Oxidation of indene products to give indendiones

While investigating the reactivity of aryl-substituted propargyl alcohols 15, we discovered their unexpected dimerization into highly conjugated indenes 16 and 17 in the presence of a catalytic amount of iron(III) chloride (FeCl3) (Scheme 5, eq. 1).11,12 Propargyl alcohols have been shown to be suitable precursors for the formation of indenes,13 however, the synthesis of dimers 16 and 17 was unprecedented. The mechanism was believed to involve FeCl3-mediated ionization of the starting alcohol followed by alkoxylation at the acetylenic carbocation center of 18, or the allenic carbon center of 18′ with propargyl alcohol 15 to furnish the intermediate 19. Subsequent intramolecular Friedel–Crafts rearrangement was believed to yield the propargyl alcohol 20, with a second ionization process furnishing the putative carbocation intermediate 21. Ensuing indene ring formation and 1,3-alkyl migration was surmised to result in the formation of indenyl carbocation 22, with deprotonation furnishing the indene adduct 16. Alternatively, 1,4-migration of the aryl moiety in 22 would give rise to the isomeric indene product 17 via intermediate 23 (Scheme 5, eq. 2). The use of enantioenriched starting materials supported the possible participation of carbocation intermediates. While the underlying rationale remained unclear, we were led to hypothesize that the complete regioselectivity observed for substrates bearing an isopropyl (iPr) or phenyl (Ph) group or a terminal C=C bond resulted from the minimization of unfavorable steric interactions between this group and the migratory group in 22.

It was envisaged that gold-catalyzed cycloisomerization of propargyl alcohols and their derivatives bearing a tethered electrophilic or nucleophilic moiety might provide ready access to a diverse range of functionalized targets.3 Indeed, a representative example has been the number of elegant methods concerning 1,n-enyne and 1,n-diyne ester substrates 30, featuring 1,2- or 1,3-acyloxy migrations to reactive gold–allene and gold–carbenoid intermediates 33 and 35, respectively (Scheme 7).16,17 Subsequent reaction of the tethered unsaturated alkene or alkyne moieties in a tandem process led to the formation of carbocyclic scaffolds. It was apparent that for the less well-explored 1,n-diyne ester substrate class, a tandem process initiated by a 1,2acyloxy migration had not been realized. This led our group to describe the first procedure of this type, furnishing 2,4adihydro-1H-fluorenes 38 from 1,6-diyne esters and carbonates 36 by treatment with 5 mol% of gold(I)-phosphine catalyst 37 (Scheme 8, eq. 1).17d,18 The reaction was proposed to proceed by way of a 1,2-acyloxy shift in alkynyl–gold(I) complex 39 to furnish the putative gold(I)–carbenoid 40, with subsequent trapping by the pendant alkyne moiety to give the cyclopropene intermediate 41 (Scheme 8, eq. 2). The documented formation of a cyclopropene motif in the field of gold catalysis has been exceedingly rare.19 Cycloreversion of the intermediate 41 was postulated to ensue, affording the gold(I)–carbenoid intermediate 42, followed by a Nazarov cyclization yielding 2,4a-dihydro-1H-fluorene 38, after protodeauration. This procedure proved to be efficient, furnishing the target dihydro-1H-fluorenes, such as 38a–c, in good yields. Control experiments demonstrated that dual activation of the ester-containing alkyne was not operative,20 and that the origin of the proton involved in de-

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R3 R1

OH FeCl3 (5 mol %)

R2 R3

R1

R2

R2

R1

+

R3

CH2Cl2, r.t., 0.5 h

R1

R2 (1)

R1 R3

15

17

16

OH

R1

R2

R3

R2

R3

R3

R3 R3

R2

R3 R2

R2

FeCl3 = [Fe]

R1

R2

R1 R1

15

R1 H2O

R1 23

22

21 H+

R3 HO

R

R1

2

[Fe]–OH (2)

R2

R1

R3 R3

R2

R3

R2

R3

R3

R1

R2

R1

R2

R3

R2

R1

R2

R3

20

R2

H

R1

R1

R3

18' OH

16 R1

R2

R3

R3

R1

R2 R1

R3

18

R2

O

R1 17

R1

15

19

Selected examples: EtO

O

Ph

O

Ph

O

O

Ph

Ph O

Et

Bn

Me

Ph Ph

Ph

Me

O O

Ph

EtO O

Ph

Ph Et

Ph 16a, 65%

16b, 43%

16c, 71%

17a, 7%

17b, 35%

Scheme 5 Iron(III) chloride catalyzed dimerization of 1,1,3-trisubstituted prop-2-yn-1-ols to give highly conjugated indenes

auration arose from an intramolecular 1,3-proton shift (Scheme 9). Following this work, Hashmi and co-workers described the analogous gold(I)-catalyzed synthesis of β-

naphthol derivatives by an initial 1,2-acyloxy migration of a 1,6-diyne substrate.17e

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R2 R3

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R2

R2 OH

p-TsOH⋅H2O (5 mol%)

R4 R1

R1

(CH2Cl)2, Δ, 0.5–24 h

R3 24

R4

25 R2

R2 OH R1

R2 R3

H+

R4

R1

R3

(1)

R3

R3 R1

– H+

– H2O R4

24

R4

26

27 H+

(2)

R2

R2

R2

R3 R

1

R

R1

3

R3

+

– H+ H

R4 25

+

R1

R4

R4

29

28

OMe

Selected examples: Ph

Ph

Me Me

Me

Ph Br

Me

Me

Me

CO2Me

MeO Me 25a, 99%

25b, 82%

25c, 73%

25d, 72%

Ph Ph

OH

Ph

p-TsOH⋅H2O (5 mol%) +

Me

Ph

(CH2Cl)2, r.t., 1 h 79%, 25a/27a, 1:3

Me

(3)

Ph Me

Me 25a

24a

27a p-TsOH⋅H2O (5 mol%) (CH2Cl)2, Δ, 0.5 h 85%

Scheme 6 Brønsted acid catalyzed synthesis of highly conjugated indene derivatives

R1

O 1,3-shift

O

R3 ≠ H OCOR1

n

OCOR1

[Au]

n

R2

R3 30

R2

3 R2 R 33

32 [Au]+

O

31

O+

1,2-shift 3

R =H R2

[Au]

OCOR1 R2

34

OCOR1

n

R1

R3

products

[Au]+

R3

R2

n

[Au]+

n

n

[Au]+ 35

Scheme 7 Gold-catalyzed 1,3- and 1,2-acyloxy shifts in 1,n-diyne substrates

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1305–1339

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t-Bu t-Bu P Au NCMe R4

R3

R2

+ SbF – 6

OCOR1

OCOR1

R2 37 (5 mol%)

(1) R3

R4 38

36

R4

R2

R3

R4

OCOR1

R2

R3

OCOR1

[Au]+

[Au]+

R4

R3

R2

1,2-shift

OCOR1 [Au]

36

39

+

40 − [Au]+

OCOR1

R2

OCOR1

R2

R2

(2)

OCOR1

[Au]+ − [Au]+

R3

R4

R3 R4

R3 R4

[Au]+

[Au]+ 42

38

41

Selected examples: OBz

Ph

Ph

OBz

Ph

OBz

S Me 38a, 80%

38b, 72%

Me 38c, 93%

Scheme 8 Gold-catalyzed cycloisomerization of 1,6-diyne carbonates and esters to give 2,4a-dihydro-1H-fluorenes

Ph

OBz

t-Bu t-Bu P Au NCMe

+ SbF – 6

Ph

3.3 Cyclopentenes, Cyclobutenes and Cyclopenta[b]naphthalenes OBz

D

D

37 (5 mol%) D

D

D

CH2Cl2, r.t., 2 h D

D

D d5-36a 100% D-content

Ph

D

t-Bu t-Bu P Au NCMe

D

d5-38a 75% yield, 80% D-content + SbF – 6

OPNB 37 (5 mol%)

Ph

OPNB D

CH2Cl2, r.t., 6 h Ph

D d1-38d 75% yield, 94% D-content

d1-36d 94% D-content

Scheme 9 Deuterium labeling experiments

In contrast, it was surmised that an internal acetate alkyne moiety would render 1,6-diyne esters and carbonate starting materials prone to a 1,3-acyloxy migration. The outcome of gold-catalyzed cycloisomerizations of such substrates 43 was shown to be dependent on the steric and electronic properties of both the substrate and catalyst, affording three structurally diverse products (Scheme 10, eq. 1).17a It was found that cyclopenta[b]naphthalenes 45 were formed chemoselectively with an N-heterocyclic carbene (NHC) gold(I) catalyst 44, while gold(III) complex 46 gave cyclopentene 47.21 Switching the acetate alkyne substituent from aryl to vinyl resulted in the formation of the cyclobutene product 48, which was found to be optimal when gold(I)-phosphine catalyst 37 was employed.22 Following initial gold-catalyzed 1,3-acyloxy migration, it was proposed that subsequent activation of the pendent alkyne group in allenyl adduct 50 would trigger a 5-exo-dig cy-

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CH2Cl2, r.t., 2–24 h

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+

i-Pr O N O

N

O

R2

R2

Au

i-Pr

NCPh 44 (5 mol%)

46 (5 mol%)

1

N

i-Pr Au

OCOR1

Cl

Cl

Ar

SbF6–

i-Pr

Ar

R2

CH2Cl2, r.t. 10 min–24 h R3 = Ar

CH2Cl2, r.t. 10 min–24 h R3 = Ar

R3

43

47

t-Bu t-Bu P Au NCMe

+

(1)

45

SbF6–

R4

R2

OCOR1 37 (5 mol%) CH2Cl2, 4 Å MS r.t., 2–24 h 48

R3 = R4 R2

O OCOR1

R2

R2 OCOR1 1,3-shift

R3

3

R

R3

Ar

R2

O

[Au] 51 path c

path a

R1 O Ar

R3

c

50 O

R2

a

O R1

49

43

O

b

[Au]+

[Au]+

R1

+

R2

[Au]+

R3 =

R3 = Ar

R4

H path b bond rotation

– [Au]+ – R1CO2H

+

52

45

[Au] 55

O R1

Ar

+

R2

Ar

O

C(O)R1 [Au]

O

54

Selected examples

Ar O

O

R1

[Au]

47

R2

O

+

– [Au]+

– [Au]+

+

O 48

R1 [Au]

53

Ph Ph

++

R2

Ar

(2)

OAc

[Au] R2

R4

R2

51' O Ph

Ph Br

C(O)Me

Ph

n-Pent OAc Ph

S 45a, 81%

47b, 74%

48c, 68%

Scheme 10 Gold-catalyzed cycloisomerization of 1,6-diyne esters to give 1H-cyclopenta[b]naphthalenes, cis-cyclopenten-2-yl δ-diketones, and bicyclo[3.2.0]hepta-1,5-dienes

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Cy Cy P Au NTf 2 i-Pr i-Pr

O

i-Pr 57 (5 mol%)

OEt

HO

OH

OEt AcOH (1 equiv), (CH2Cl)2, 80 °C, air, 20 h

R2 R3

R2

R3

[Au]+, H+

OH

O

O

O

OEt

HO

OEt

HO

R2

R3

R2 R3

[Au]+

[Au]

59

60 OH

O

OEt

AcOD-d3 (10 equiv) (CH2Cl)2, 80 °C, air, 20 h

i-Pr Ph

i-Pr

O

Ph

OH

O

57 (5 mol%)

OEt

HO

(2)

D d1-58a 60% yield, 40% D-content

56a

O

O

57 (5 mol%)

OEt

HO

(1)

58

56

O

O

OEt (3)

AcOH (1 equiv), D2O (20 equiv), (CH2Cl)2, 80 °C, air, 20 h

BnO Ph 56b

BnO

Ph D d1-58b 49% yield, 40% D-content

Selected examples: OH

O

OH OEt

BnO

Ph 58b, 70%

OH

O

O OEt

OEt Ph

Ph 58c, 79%

2-MeH4C6

Ph

58d, 76%

Scheme 11 Gold-catalyzed benzannulation of 5-hydroxy-3-oxoalk-6-ynoate esters to give ortho-phenolic esters

clization to form intermediate 51. At this juncture, the pathway was postulated to diverge, being dependent on the nature of the catalyst and substrate. A Friedel–Crafts cyclization of intermediate 51 and subsequent elimination of the carboxylic acid gave cyclopenta[b]naphthalenes 45 (Scheme 10, eq. 2, path a).21 On the other hand, the less sterically encumbered gold(III) catalyst 46 was suggested to permit bond rotation of the oxonium side chain in intermediate 51 to give 51′. This latter intermediate possessed an orbital overlap, which allowed backside attack of the vinyl

gold moiety to the carbonyl carbon center.23 Deauration of the resultant intermediate 54 formed the cyclopentene product 47 (Scheme 10, eq. 2, path b). Alternatively, when R3 was a vinyl substituent in the intermediate 51, the larger spatial volume of this group hindered both bond rotation and Friedel–Crafts processes, which allowed for a competitive Prins-type [2+2]-cyclization to proceed. Deauration of intermediate 55 furnished the cyclobutene adduct 48 (Scheme 10, eq. 2, path c).22

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OCOR1

OCOR1

[Au]+

X

X

heterocycles

(1)

+

[Au] 62 [cat] OH

HO Lewis or Brønsted acid R1

( )n

catalyst

R1

( )n

X

X 64

63

[Au]+ OCOR2

heterocycles

(2)

1,3-shift OCOR2

OCOR2 [Au]+

( )n

[Au]+

R1

X 67

R1

( )n X

R1

( )n X

65

66

OCOR2 1,2-shift R1 = H

( )n

[Au]+

X 68

Scheme 12 Strategies toward heterocycle synthesis by gold-catalyzed C–C and C–X bond formation

3.4

ortho-Phenolic Esters

We became interested in the potential gold-catalyzed cyclization of propargyl alcohols tethered with a β-ketoester functionality. In due course, we reported the synthesis of ortho-phenolic esters 58 from 5-hydroxy-3oxoalk-6-ynoate esters 56 with gold(I)-phosphine catalyst 57 (5 mol%) in the presence of acetic acid (Scheme 11, eq. 1).24 The ortho-phenolic ester structural motif in these carbolic acid adducts is found in a plethora of bioactive natural and synthetic products.25,26 Previously, the group of Fürstner had described a two-step approach to ortho-phenolic ester products via a gold(I)-catalyzed alkyne hydroarylation.27 Our interest in this product class culminated in the development of a single-step protocol involving carbophilic activation of the substrate 56 by the [Au]+ catalyst 57, and tautomerization facilitated by acetic acid, affording enol complex 59 (Scheme 11, eq. 1). Ensuing intramolecular hydroarylation then furnished the intermediate 60. It was postulated that aromative dehydration may precede protodeauration to yield the ortho-phenolic ester products 58. This supposition was supported by the lack of product formation in the absence of the gold(I) catalyst, hinting that the role of the acetic acid was limited to the promotion of the keto–enol tautomerization, protodeauration and dehydration processes. Furthermore, the outcome of control experiments with 56a and 56b in the presence of deuterated acetic acid (AcOD-d3) and deuterium oxide (D2O), respec-

tively, further supported this conclusion (Scheme 11, eqs. 2 and 3). The reaction proved to be applicable to a range of 5hydroxy-3-oxoalk-6-ynoate esters 56, furnishing potentially valuable functionalized carbolic acid derivatives 58 in good yields.

4 Heterocycles with One Heteroatom In concert with the preceding sections, our target scope expanded to include the synthesis of heterocycles. This involved methods that established either carbon–carbon or carbon–heteroatom bonds under catalytic conditions. In the case of the former, our substrates possessed a heteroatom located between the propargyl alcohol and tethered groups (Scheme 12, eq. 1). For the latter, the combination of nucleophilic pendant nitrogen or oxygen atoms and electrophilic intermediate complexes of propargyl alcohols or their derivatives, led to straightforward assembly of heterocyclic products (Scheme 12, eq. 2). Described below are a variety of methods developed in our laboratory for the synthesis of functionalized heterocycles.

4.1

Indoles

Indoles are privileged heterocyclic structures that serve as synthetic building blocks in both functional materials and bioactive compounds.28,29 This utility affords para-

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AuCl/AgOTf (5 mol%)

R1 OH

NHTs

R2

H R1 O

CaSO4, toluene Δ, 2 h

R1 [Au]+ R2

NHTs 70

69

[Au]+ OH

Ar

R

R1 = Ph R2 = Ar

OH R1

[Au]+ OH

OH

R2

N Ts

Ar

1

N Ts

H+

R1

N Ts 74

[Au] R2

N Ts 71 – [Au]+

N Ts 75

OH

72 [Au]+ [Au]+ OH

R2 = H

R1

77 R1 Nu

N Ts 76

NuH (Nu = OR3, Ar)

N Ts 73

N Ts

R2 = CHR4R5

78 R1

N Ts

R2

[Au]+ OH

R4 R5

80

N Ts

R1

H R5 R4

79

Scheme 13 Gold-catalyzed cycloisomerization of 2-tosylaminophenylprop-1-yn-3-ols into indoles

mount importance to efficient and versatile processes that furnish these structures from readily available precursors. Our interest in this field began with the demonstration that gold(I) chloride/silver triflate (AuCl/AgOTf) activation of 2tosylaminophenylprop-1-yn-3-ols 69 resulted in intramolecular hydroamination of complex 70 and the formation of indole and related products, via the putative enamide– gold(I) intermediate 71 (Scheme 13).30 Ensuing protodeauration gave the intermediate 72, with subsequent activation of the hydroxy group in 73 and Friedel–Crafts alkylation, when R2 = Ar, forming the indenyl-fused indole 75. Alternatively, for a more reactive primary vinyl gold species when R2 = H, a 1,3-allylic alcohol isomerization (AAI) pathway was found to furnish the indole 77. In contrast, the presence of a strong nucleophile led to preferential SN2′ displacement and formation of indole 78. Lastly, it was found that for R2 = CHR4R5, a simple dehydration step furnished 2-vinyl-1H-indoles 80. The cationic gold(I) complex was determined to be the active species by contrast with the catalytic activities of AgOTf and TfOH in analogous reactions. The present reaction also occurred with complete substrate structuredependent regioselectivity, and a broad scope.

While illustrating the crucial activity of the gold(I) complex for the reactions to proceed, a control reaction in the presence of AgOTf (5 mol%) resulted in the fortuitous isolation of (Z)-2-methylene-1-sulfonylindolin-3-ol 72a in 45% yield (Scheme 14, eq. 1).31 We were keen to pursue this interesting reaction given the presence of this scaffold in bioactive natural products, and its versatility toward further functionalization. Added to this was the fact that, in comparison with indoles, the synthesis of indolin-3-ols 72 had been less well-explored. It was found that treatment of a range of substrates 69 with silver(I) acetate (AgOAc) (5 mol%) furnished the indolin-3-ols 72 in excellent yields of up to 99% (Scheme 14, eq. 1). Furthermore, the utility of these indolin-3-ols 72 as synthetic building blocks was exemplified by further derivatization by 1,3-AAI, nucleophilic substitution, oxidation, and rearrangement reactions to afford an array of targets 81–84 (Scheme 14, eq. 2). Following these studies, the scope of the indole-forming process was expanded to encompass related starting materials, such as 1,n-propargyl diol substrates. Up to this point, the Lewis and Brønsted acid mediated chemistry of this chemical class had been used solely to furnish oxygen het-

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Ph

OH

AgOTf (5 mol%)

R1

R1 OH

AgOAc (5 mol%)

OH (1)

Ph

R2

NHTs

72a, 45%

MeCN, r.t., 1–3 h

R2

N Ts

69

72

Selected examples: Me

Ph

N Ts

N Ts

OH

OH

N Ts

S

72b, 96%

R1

Ph

OH

OH

72c, 99%

Ph

72d, 99%

p-TsOH⋅H2O (5 mol%)

NIS (2 equiv)

MeCN r.t., 3 h

MeCN Δ, 1 h

R1

I

O R2

N Ts 81, 90% R = R2 = Ph

R1

82, 87% R1 = Ph, R2 = H

OH

1

N Ts

R1 F N Ts

R2

DAST (5 equiv) CH2Cl2 –78 °C to r.t., 4 h

83, 56% R1 = Ph, R2 = H

72

N Ts

(2)

R2 O

NIS (2 equiv) MeCN Δ, 1 h

N Ts

R2

84, 71% R1 = H, R2 = Ph

Scheme 14 Silver(I) acetate catalyzed hydroamination of 1-[2-(sulfonylamino)phenyl]prop-2-yn-1-ols to give (Z)-2-methylene-1-sulfonylindolin-3-ols

erocycles (Scheme 15, eq. 1).32 To complement these works, we realized the AgOTf-mediated tandem heterocyclization/alkynylation of propargyl diols 88 to give 2-alkynyl indoles 89 (Scheme 15, eq. 2).33 Mechanistically, it was postulated that the reaction proceeded with activation of the distal hydroxy group in complex 90 (Scheme 15, eq. 3). It was thought that this then led to intramolecular hydroamination and the formation of allenamide 91. At room temperature, and when R1 = R2 = Ph and R3 = R4 = H, the intermediate allenamide 91 was isolated in 30% yield. Subsequent activation of the remaining hydroxy group in complex 92 by the silver catalyst initiated deprotonation of the allene moiety and formed the 2-alkynyl indole 89. Previous methods employed to access 2-alkynyl indoles have hitherto required challenging cross-coupling reactions.34 In order to achieve an alternative reaction outcome, it was apparent that replacing the allenyl proton with an aryl moiety in the allenamide intermediate 91 would preclude the dehydrative pathway in Scheme 15. Consequently, it was demonstrated that for tertiary propargyl alcohols 93, AgOTf-mediated cycloisomerization afforded the spirocyclic indene-fused indolin-3-ones 94 by a tandem hydroamination/Friedel–Crafts reaction.35 The reaction pathway was

reasoned to proceed by hydroamination to afford allenamide 95 (Scheme 16, eq. 2). Subsequent silver(I)-activation of the enamide alkene group in complex 96 resulted in an intramolecular Friedel–Crafts reaction and the formation of spirocycles 94, after rearomatization and protodemetalation of the Wheland intermediate 97. The reaction proved robust, high yielding, and tolerant toward a range of substrates to afford the novel spirocyclic products, with the notable exception of N-tosyl reagents. While allyl, benzyl and methyl substituents were observed to have no influence on the outcome of the reaction, the steric demands imposed by the tosyl group in complex 96 prevented the formation of a spirocyclic product. In this latter instance, the N-tosyl allenamide 95 was the sole isolated product. With this caveat aside, the reaction provided convenient access to compounds of potential pharmacological interest bearing both the privileged indene and indolin-3-one scaffolds. In tandem with this work, an alternative approach to access other classes of functionalized indole derivatives was also considered. Particularly intriguing was the possibility of trapping the putative vinyl gold intermediate 71, proposed earlier in Scheme 13, by a method other than protodeauration. Previous work has demonstrated that vinyl gold

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N Ts

PhMe, Δ, 17 h R1 = R2 = Ph

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OH

OH

Lewis or Brønsted acid catalysis

or

( )n

O

OH HO 85

( )n 86

87

R1 OH

R1 R4

AgOTf (5 mol%)

R4 OH R3

(1)

( ) n + H 2O

NHTs

(2)

R2 + 2H2O

PhMe, 70 °C, 2 h

N Ts

R3

R2

88

89 R1 OH

R1 R4

R4 AgOTf = [Ag]+

R2 N Ts

R3

OH R3

H2O

NHTs

89 H+

[Ag]+ HO

R1

R4 R3

R2

88

N Ts

[Ag]–OH (3) H R1 OH

R2

[Ag]+

R4

92

OH R3 HO [Ag]+

R4

R

R2

90

1

R2

N Ts

R3

NHTs

91 Selected examples: Ph

Ph C6H4-4-Br

N Ts 89a, 89%

Ph N Ts 89b, 92%

Cl C6H4-4-MeO N Ts 89c, 91%

Scheme 15 Silver triflate catalyzed tandem heterocyclization/alkynylation of but-2-yn-1,4-diols into 2-alkynyl indoles

intermediates can be trapped by N-iodosuccinimide (NIS) to generate vinyl iodides.36,37 It was envisaged that the reaction of intermediate 71 with NIS would lead to vinyl iodide 98, with subsequent reactions affording a range of synthetically useful building blocks (Scheme 17). With this concept in mind, we were able to demonstrate the formation of indole 2-carbaldehydes 101 in yields of 70–98%, from a broad range of propargyl alcohols 99 in the presence of gold(I) catalyst 57 and two equivalents of NIS at 55 °C (Scheme 18, eq. 1).38 Interestingly, at –40 °C to room temperature, the (E)-2-(iodomethylene)indolin-3-ol 100 was formed chemoselectively in 80–99% yield. Following this discovery, the intermediacy of the vinyl iodide species 100 was supported by its treatment with gold(I) catalyst 57

at 55 °C, which led to the formation of indole 2-carbaldehydes 101. From these results, it was suggested that the putative vinyl gold intermediate 71 was trapped by NIS to form vinyl iodide 100, with the Lewis acidic gold complex catalyzing the ensuing 1,3-AAI to furnish the carbaldehyde 101 (Scheme 18, eq. 2). The 1,3-AAI process was shown to occur in an intramolecular manner by conducting an analogous reaction in the presence of H218O (Scheme 18, eq. 3). In the preceding synthesis, the gold(I) catalyst was necessary for both the initial hydroamination step and also the subsequent 1,3-AAI process. An analogous reaction in the absence of the gold catalyst did not afford a product. However, by increasing the number of equivalents of NIS from two to three, and by changing the solvent to nitromethane

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R3 R3

AgOTf (10 mol%)

R2 NHR1

O (1)

PhMe, r.t., 15 h HO

R2

R4

N R1 94

93

R4

R3 O

R3

R2

[Ag]+ – H2O

NHR1

4 HO R

R3 [Ag]+

O

O

R2

R2 R4

N R1 95

93

R4

N + R1[Ag] 96

R1 = Ts

(2)

R3

R3 O H

O R2 – [Ag]+

R2 N R1 94

N R1

R4

R4

[Ag]

97

Selected examples: MeO O

O

O S

O

Me N

N Bn

+ S

N

Ph

N

Ph

OMe 94a, 94%

94b, 84%

94c, 94c' 85% (2:1.1)

Scheme 16 Silver triflate-catalyzed tandem hydroamination/hydroarylation of 1-(2-allylamino)phenyl-4-hydroxy-but-2-yn-1-ones into 1′-allylspiro[inden-1,2′-indolin]-3′-ones

(MeNO2), a subsequent study demonstrated the formation of 2- and 3-oxindole products 104 and 105 from propargyl alcohols 103 by an iodoaminocyclization (Scheme 19, eq. 1).39,40 The reactions of alkenes, alkynes and allenes with an amine nucleophile and an halogenating reagent for the formation of heterocycles have received growing interest.41,42 The work of Liang and Hessian in accessing 2-acyl-1Hindoles and 3-iodoquinolines, respectively, from internal propargyl alcohols when treated with molecular iodine are particularly noteworthy.42 Complementing this methodology, our work constituted the first example of this principal applied to terminal propargyl alcohols. Mechanistically, NIS promoted the iodoaminocyclization of substrate 103 to form the vinyl iodide intermediate 106 (Scheme 19, eq. 2). Further reaction with NIS was thought to lead to the diiodo

compound 107. For tertiary alcohols (R2 ≠ H), a 1,2-hydroxy shift to give 108 preceded the 1,2-alkyl migration to 109, with 2-oxindole 104 afforded upon deprotonation (Scheme 19, path a). Alternatively, for secondary alcohols (R2 = H), a 1,2-hydrogen shift furnished the oxocarbenium species 110, with deprotonation and elimination of hydrogen iodide (HI) giving 3-oxindoles 105 (Scheme 19, path b). R1

N Ts

OH

R1 [Au]

NIS

R2

71

N Ts

OH

I

indole derivatives

R2

98

Scheme 17 Strategies from vinyl gold intermediates to give indole derivatives by iododeauration with NIS

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Uniting both this work and the NIS/gold(I)-mediated method described in Scheme 18,38,39 it was discovered that treatment of 1-phenyl-1-[2-(tosylamino)phenyl]prop-2yn-1-ol (99h) with NIS in undistilled MeNO2 led to 2-carbaldehyde 101h as the major adduct, rather than the gemdiiodo-2-oxindole 104h (Scheme 20, eq. 1).43 This outcome

was in contrast to the analogous gold(I)-catalyzed system, where reaction in undistilled acetone and in the absence of the catalyst led to substrate recovery.38 Subsequent optimization permitted chemoselective preparation of N-tosyland 1H-indole 2-carbaldehydes 101 from sulfonamide and acetamide substrates 99, respectively (Scheme 20, eq. 2),

Cy Cy P Au NTf 2

R

OH

I

–40 °C to r.t.

i-Pr i-Pr

N Ts

i-Pr 57 (5 mol %) NIS (2 equiv)

R OH

100, 80–99% (1) 57, 55 °C

acetone 0.25–2 h

NHTs

R

99 R = H, alkyl, aryl heteroaryl

55 °C CHO N Ts 101, 70–98%

R OH

R

[Au]+

R

OH

[Au]

– [Au]+

N Ts 71

NHTs 99

OH

NIS

I

N Ts 100 [Au]+

(2)

1,3-AAI R

R

O H CHO – HI

N Ts

N Ts

101 Selected examples: Ph R

102

R

OH

Me CHO

N Ts

N Ts 101a, R = Me, 75% 101b, R = OMe, 70%

Ph I

Cl

O CHO

I

CHO O

101c, R = 4-MeC6H4, 75% 101d, R = 4-BrC6H4, 87% 101e, R = 2-naphthalenyl, 90%

N Ts

N Ts

101f, 84%

100g, 98%

Cy Cy P Au NTf 2 i-Pr i-Pr Ph

OH

i-Pr 57 (5 mol%) NIS (2 equiv)

Ph CHO

NHTs 99h

18O

H2 (1 equiv) acetone, Δ, 16 h

N Ts 101h 0% 18O-content

Scheme 18 Gold-catalyzed cycloisomerization of 1-[2-(tosylamino)phenyl]prop-2-yn-1-ols into 1H-indole-2-carbaldehydes

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R2

I

NIS (3 equiv)

I O

MeNO2, Δ, 1 h R2 ≠ H

R2 OH

N R1 104

103 R1 = Ac, Ts

O

NIS (3 equiv)

I

MeNO2, r.t., 3 h R2 = H

R2 OH

R2

NIS – NHS

N R1 106

NHR1 103

I

OH

+

R2 I

N R1

N R1

path a 1,2-OH shift

I

I

H O

108

I

I

I I OH

– H+

N R1 104

110

(2)

R2 I O

I

H

1,2-alkyl shift

OH

– H+ – HI

I

N R1 107

R2 = H path b 1,2-H shift

I

105

R2 R2 ≠

+

+

O

N R1

R2

NIS

OH

N R1 105

N R1 109

+

Scheme 19 1-(2′-Anilinyl)prop-2-yn-1-ol rearrangement to give oxindoles

with the 1H-indole formed by in situ cleavage of the acetamide moiety. The utility of the indole building block was also illustrated by the large scale formal synthesis of the bioactive indole alkaloid, (R)-calindol (113) (Scheme 20, eq. 3).43,44 In a recent development, we described the preparation of 3,3-disubstituted 2-oxindoles 116 by base-mediated 1,2addition of readily available alkynes to ketones 114, followed by silica gel promoted cycloisomerization of the resulting crude mixture of propargyl alcohol 115 (Scheme 21, eq. 1).45 This methodology comprised a tandem hydroamination/semipinacol rearrangement induced by the weak Brønsted acidity of silica gel. The mechanism for this transformation was proposed to commence with the activation of the in situ formed propargyl alcohol adduct 115, forming the enammonium intermediate 118. Isomerization into the iminium species 119 and a subsequent 1,2-hydroxy shift was thought to form the carbocation 121. The 3,3-disubstituted 2-oxindole 116 was furnished upon 1,2-alkyl migration and deprotonation of the resultant cationic species 122. No incorporation of isotopically labeled oxygen was observed when an analogous control reaction was conducted in the presence of H218O. This indicated that the reaction proceeded via an intramolecular 1,2-hydroxy shift. The present protocol was found to proceed well under benign,

ambient conditions, and was scalable to provide gram quantities, and the silica gel could be successfully reused in multiple runs.

4.2

Piperidines, Azepines and Pyrrolidines

In tandem with our gold-catalyzed approaches to carbocyclic products, we were interested in developing related methods to explore the synthesis of heterocyclic compounds. Our initial work in this area demonstrated the synthesis of piperidine-containing azabicyclo[4.2.0]oct-5-enes 124 by gold(I)-phosphine complex 37 catalyzed tandem 1,3-migration/[2+2] cycloaddition of 1,7-enyne benzoates 123 (Scheme 22, eq. 1).16d,46 Following an initial gold-mediated 1,3-acyloxy shift to give the allene 126 via complex 125, the crucial stage in this synthesis was the selective activation of the tethered alkene moiety to form the complex 128 (Scheme 22, eq. 2). The preferential coordination of gold catalysts to the allene moiety over the alkene group was disfavored here due to the steric demands of the substrate and the catalyst. Subsequent 6-exo-trig cyclization afforded alkyl–gold(I) intermediate 129, with a formal [2+2] cycloaddition completed on attack of the oxocarbenium moiety by the Au–C(sp3) bond, furnishing the target azabicyclo[4.2.0]oct-5-enes 124, regio- and stereoselectively,

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Ph

NIS (3 equiv) CHO MeNO2, Δ, 24 h

N R2

99

N Ts

101 R2 = SO2R3, 51–91% R2 = H, 52–72%

NaBH4 (3 equiv) +

(3)

HN H2 N

101i

(2)

CHO

H2O–acetone (25:1, v/v), Δ, 24 h

R1 = H, alkyl, aryl R2 = SO2R3, Ac

CHO

104h, 22%

R1

NIS (2.2 equiv)

NHR2

(1)

N Ts

101h, 61% R1 OH

I O

+

N Ts

NHTs 99h

I

Ph

Ph

OH

Me

111

MeOH, r.t. 3.5 h

Me N Ts 112, 90% yield ref. 44

HN Me N H 113, (R)-calindol

Scheme 20 NIS-mediated synthesis of 1H-indole-2-carbaldehydes, and a formal synthesis of (R)-calindol

in good overall yields. This represented the first example of a tandem process involving 1,3-acyloxy migration and subsequent selective coordination of the gold catalyst to an alkene moiety, and constituted a novel transformation in the field of 1,n-enyne ester cycloisomerizations.16 The intermediacy of the allene 126 was demonstrated by its isolation and resubmission to the reaction conditions to afford the bicyclic piperidine 124. On examination of the gold-catalyzed cycloisomerization of related 1,7-diyne benzoate esters 130 possessing a pendent alkyne moiety, an alternative mode of reactivity was observed (Scheme 23, eq. 1).17f,47 Treatment of the starting 1,7-diyne benzoate 130, bearing a terminal pendent alkyne (R4 = H), with gold(I) catalyst 37 resulted in the intriguing formation of the indeno[1,2-c]azepine 131. On the other hand, the analogous reaction of internal alkyne 130 (R4 ≠ H) resulted in the formation of azabicyclo[4.2.0]octa-1(8),5-diene 132. In the case of the latter process, it was surmised that the mechanism proceeded in close analogy to that for the 1,7-enynes 123 discussed above, where a gold(I)-mediated 1,3-acyloxy shift afforded

allene intermediate 136 (Scheme 23, eq. 2). Preferential pendent alkyne activation was thought to result in the piperidine-forming cyclization and the putative vinyl gold complex 138. This was followed by Prins-type [2+2]-cyclization and deauration furnishing the piperidines 132. For the azepine-forming reaction, it was surmised that coordination to the terminal alkyne would be sterically favored over complexation of the hindered acetate alkyne moiety, culminating in a concerted Friedel–Crafts/alkenylation process to afford the indeno[1,2-c]azepines 131 via the Wheland intermediate 134. This concerted 5-endo-dig/7endo-dig process initiated by nucleophilic attack of an appropriately placed aryl group constituted a novel mode of reactivity in the cycloisomerization of 1,n-diyne esters.17 This work also demonstrated that complete regioselective control of product formation was possible by exploiting the steric interactions between the substrate alkyne moieties and the gold(I) catalyst. Following these studies, we set out to build on the concept of driving product selectivity by fine-tuning the steric interactions between the substrate and gold catalyst. In

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Syn lett

1323

Account

B. J. Ayers, P. W. H. Chan

R4CCH (3.5 equiv) LDA (3.5 equiv)

O R1

R NHR

3

THF, –78 °C to r.t. 3 h, aq work-up

2

NHR

2

R3

i) R4CCLi ii) SiO2

O R3 NHR

HO R3

N R2

R1

114

HO R3 R1

R1 +

R4

NHR2

2

116 HO R3

H+

(1)

O

(1:20 v/v), r.t. 1–18 h

R4

R4

R1

115

114

R1

SiO2 (100 equiv) EtOAc–n-hexane

HO R3 R1

+

R2

H R2 118

117

R4

N

R4

N

119 (2)

R3

R3

O

R4

R1

R4

R1

R3 R1

+

+

R1

OH

H

O

OH

– H+

N

N R2

R4

N R2

R4

N

R2

122

116

R3

+

R2

121

120

Selected examples: Ph

Bn

Br

O N Me 116a, 96%

Ph

Bn

CF3

116b, 91%

Bn O

O

O N Me

Ph

N Me 116c, 98%

N Bn 116d, 88%

Scheme 21 Silica gel mediated hydroamination/semipinacol rearrangement for the synthesis of 2-oxindoles from alkynes and 1-(2-aminophenyl)ketones

Scheme 22, treatment of 1,7-enyne benzoates 123 with gold(I)-phosphine catalyst 37 was shown to lead to the formation of cyclobutane-fused piperidines 124. In contrast, we revealed that for 1,7-enyne esters 140 possessing terminal alkene and aliphatic ester motifs, treatment with NHCgold(I) catalyst 44 resulted in the formation of piperidine diketones 141, whereas treatment with gold(I)-phosphine catalyst 37 furnished the piperidines 142 (Scheme 24, eq. 1).16b As previously, we proposed that both reactions were initiated by gold(I)-mediated 1,3-acyloxy migration to form the allene 143 (Scheme 24, eq. 2). Owing to the steric encumberment of the allenic moiety, preferential gold(I) coordination to the tethered alkene in complex 145 resulted in a 6-exo-dig cyclization and the formation of the piperidine 146. In instances where gold(I)-phosphine catalyst 37 was used, the chemoselective formation of piperidines 142 was observed (Scheme 24, eq. 2, path b). In accord with earlier work, this observation might be due to the increased rate of protodeauration in such gold(I)-phosphine complexes.48 In examples where NHC-gold(I) catalyst 44 was employed, the slower rate of protodeauration might permit bond rotation to give intermediate 147, and subsequent unprecedented 1,5-acyl migration to the Au–C(sp3) bond forming the diketone 141 (Scheme 24, eq. 2, path a).23 This rationale was

supported by an analogous reaction with NHC-gold(I) catalyst 44 in the presence of water (2 equiv), where diketone 141 remained the major product (141, 51% yield, 142, 21% yield). Up to this point, our research on gold catalysis had focused on the cycloisomerization of 1,n-enyne and 1,n-diyne substrates. Recently, we sought to extend this field of chemistry to encompass related starting materials, such as 1,n,mdienyne substrates. This work culminated in the gold(I)phosphine complex 37 catalyzed formation of cis-cyclohepta-4,8-dienes 150 from 1,6,8-dienyne carbonates and esters 149 (Scheme 25, eq. 1).49,50 The reaction mechanism was proposed to proceed by initial gold(I)-catalyzed 1,2-acyloxy migration to give gold–carbenoid species 151, which may adopt two possible conformations (151′ and 151′′) for the ensuing cyclopropanation reaction (Scheme 25, eq. 2). The reactive conformation 151′′ was suggested to be preferred owing to fewer unfavorable steric interactions, and would lead to the formation of 152. Subsequent Cope rearrangement of the intermediate 152 furnished the azepine-fused pyrrolidine product 150. During the assessment of the scope of this protocol, a substrate–structure dependence on the mode of reactivity was revealed. While all the starting 1,6,8-dienyne esters underwent the tandem 1,2-acyloxy

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Syn lett

1324

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B. J. Ayers, P. W. H. Chan

t-Bu t-Bu P Au NCMe

BzO R1

+

SbF6–

BzO

R3

R2

37 (5 mol%) N Ts

R4

R2 R1

N Ts

123

R

BzO

124

R3

2

[Au]+

(1)

H

(CH2Cl)2, 4 Å MS 80 °C, 15–24 h

R4

R3

BzO

[Au]+

OBz

R3

R2

1,3-shift

R2

+ R4 – [Au]

R1

[Au]+

R3

OBz R3

R2

[Au]+ R1

R1

R4

N Ts

N Ts

123

R4

N Ts

125

R1

126

R4

N Ts 127

(2) BzO

R3 R4

R2 H R1

R2 R4

R1 – [Au]+

O

R2

Ph

R3

R3

TsN

N Ts

OBz

O +

H

124

H [Au]

R1

129

R4

N Ts

[Au]+

128

Selected examples: BzO

BzO

Ph

S

BzO

BzO

Ph

Ph

Ph Et H i-Bu

N Ts

124a, 82%

Et

Et

H

H i-Bu

N Ts 124b, 77%

Ph Me

i-Bu

N Ts

H n-Pr

124c, 90%

N Ts 124d, 83%

Scheme 22 Gold-catalyzed tandem 1,3-migration/[2+2] cycloaddition of 1,7-enyne benzoates to give azabicyclo[4.2.0]oct-5-enes

migration/cyclopropanation/Cope rearrangement sequence, substrates bearing a pendant terminal diene or terminal alkenyl phenyl moiety were observed to undergo a competitive, but reversible 1,3-acyloxy migration to afford the isolable allenes 153 prior to the tandem cyclization process. Resubmission of these allenes to the reaction conditions resulted in the successful formation of the pyrrolidine targets 150. This reaction provided rare experimental evidence for the reversible interconversion of allene and carbenoid organogold species generated in the opening step of this tandem process.

4.3

Pyrroles

In Scheme 22, the gold(I)-phosphine complex 37 catalyzed synthesis of cyclobutane-fused piperidines 124 from 1,7-enyne ester and carbonate substrates 123 was de-

scribed. During the course of this study, the cycloisomerization of 1,7-enyne ester 123a catalyzed by NHC-gold(I) complex 44 resulted in the isolation of pyrrole 154a in 20% yield (Scheme 26).16d This fortuitous result may have arisen from a pathway involving a deaurative 1,3-sulfonyl migration step. With this intriguing result, and to our knowledge, the only two examples of such a deaurative process having been reported by the groups of Shin and Nakamura,51 we set out to investigate the C–S bond-forming process. On investigation of the related propargyl alcohol substrate 155, NHC-gold(I) complex 44 was observed to be the optimum catalyst for the transformation, furnishing the pyrrole 154 in 70% yield (Scheme 27, eq. 1).52,53 The reaction was reasoned to proceed by gold(I)-mediated hydroamination of complex 156 to form the ammonium intermediate 157 (Scheme 27, eq. 2, path a). Dehydration of this species followed by deaurative 1,3-sulfonyl migration

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Syn lett

1325

Account

B. J. Ayers, P. W. H. Chan

t-Bu t-Bu P Au NCMe

R2

BzO

R2

R3 R4

R1

37 (5 mol%)

N Ts

37 (5 mol%) (1)

R1

N Ts

132

R3

[Au]+

BzO N Ts

R3

R1

N Ts

R1

R3

R2

R3

R2

+

[Au] –[Au]+

BzO

BzO

N Ts

R1 [Au]+

133

[Au]+

BzO

131

N Ts

R4

130

R1

134

N Ts

131

R4 ≠ H R2

R2

R3

R2

OBz R3

1,3-shift

BzO

OBz R3

[Au]+

(2)

[Au]+ R1

R4

concerted process

BzO

R4 ≠ H

R1

PhMe, 4 Å MS 80 °C, 24 h R4 = H

130 R2

R2

R3

R2

R3

BzO

PhMe, r.t., 15 h R4 ≠ H

+ SbF – 6

t-Bu t-Bu P Au NCMe

+ SbF – 6

– [Au]+

N Ts

R1

R1

N Ts

R4

R4

135

N Ts [Au]+

136

R4

137 R2

BzO

R2

BzO R3

R2

R3

O

R4

Prins-type [Au] cyclization

R4 +

– [Au]+ R1

R1

N Ts 132

R1

+

O

Ph

R3

TsN R4

N Ts

[Au]

139

138

Selected examples: Ph

BzO

BzO

Ph Ph

Ph

Ph

Ph

BzO Bn

N Ts

131a, 70%

BzO N Ts 131b, 60% Bn

Bn

Ph

N Ts 132c, 80%

TBSO

N Ts 132d, 80%

Scheme 23 Gold-catalyzed cycloisomerization of 1,7-diyne benzoates into indeno[1,2-c]azepines and azabicyclo[4.2.0]octa-1(8),5-dienes

resulted in the formation of target pyrrole 154. Alternatively, 1,3-sulfonyl migration may precede dehydration in yielding the product 154 by an equivalent route (Scheme 27, eq. 2, path b). This methodology provides efficient and high

yielding access to highly functionalized pyrrole derivatives, as well as adding to the rare examples of catalyst regenerating sulfonyl-migratory deauration.

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+

i-Pr

SbF6–

i-Pr + SbF – 6

N

N

R3

O Ph R1

37 (5 mol%) H2O (2 equiv)

Me

R2OCO

(CH2Cl)2 80 °C, 24 h

N Ts 142

R1

NCPh 44 (10 mol%)

R3

Ph

4 Å MS

N Ts

R2

R1

R3

141

N Ts

R1

R1

N Ts 143

140

R3

Ph

R3

Ph

R2

O

R2

O

[Au]+

[Au]+

R3

Ph

O

O R2

O

[Au]+

(1)

O

N Ts

140

Ph

R1

R3

O Ph

(CH2Cl)2 80 °C, 24 h

O R2OCO

i-Pr

Au

i-Pr

R1

N Ts

N Ts

144

[Au]+

145

O Ph

R1

+

O R2

TsN H [Au]

Ph

R1

R3

+

O R2

TsN H

O

148

path a

R3

[Au]

H

O

Ph

O

Me

R1

O

O

141a, 77%

N Ts 142

Ph

O

Ph

n-C5H11 N Ts

R3

O

Selected examples: O Ph

Bn

– [Au]+

path b

141

Ph

(2)

146

R2 N Ts

R2

[Au]

147

Ph

O R3

R3

O

+

TsN

– [Au]+

R1

Ph

R1

TBSO

Ph

Ph N Ts 141b, 66%

O

Et

O Ph

Me N Ts

Ph

MeO2S

142a, 97%

( )2

Me N Ts

142b, 87%

Scheme 24 Gold-catalyzed cycloisomerization of 1,7-enyne esters into cis-1,2,3,6-tetrahydropyridin-4-yl ketones

It was later envisaged, and successfully shown, that the 2-vinyl pyrrole adduct 162 was accessible by intermolecular reaction of propargyl 1,4-diol 160 with sulfonamide 161 in the presence of Yb(OTf)3 (Scheme 28, eq. 1).54 Up to this point, the cycloisomerization reactions of this class of substrate had only extended to stoichiometric electrophilic halocyclizations furnishing 3,4-dihalodihydrofurans,55

AgOTf-catalyzed formation of 2-alkynylindoles (Scheme 15),33 and gold(I)-catalyst-induced spiroketalization.56 It was proposed that the present procedure proceeded by way of ytterbium(III)-mediated ionization of the allylic alcohol moiety in complex 163 to furnish the alkynyl carbocation species 164 (Scheme 28, eq. 2). Subsequent nucleophilic attack by the amine 161 at the sterically least hindered car-

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t-Bu t-Bu P Au NCMe

1327

Account

B. J. Ayers, P. W. H. Chan

t-Bu t-Bu P Au NCMe

+ SbF – 6

R1OCO

R1OCO 37 (2 mol%)

( )n R2

TsN

TsN H

[Au]+

[Au]+

TsN

R1

R1

O R2

O R3

R3 R2

O ( )n O

R3

149

151

151' disfavored

151'' favored

1,3-shift

– [Au]+

R1OCO [3,3]

( )n R2

H

TsN

R2 TsN

OCOR1 R2

(2) ( )n

R1OCO

( )n

TsN

[Au]+

R2

[Au]+

TsN

R3

[Au]+

R3

( )n

TsN

( )n

( )n R2 1,2-shift

TsN

(1)

150 R1OCO

R1OCO

( )n R2

PhMe, 80 °C, 24 h

R3

149

H

R3

H

H

R3 150

152

R3

153

Selected examples: AcO Me Me Me

TsN

Me H

TsN

H H 150a, 99%

AcO

AcO

AcO

TsN

TsN

H

H

H 150c, 83%

H 150b, 82%

n-Bu

150d, 81%

Scheme 25 Gold-catalyzed cycloisomerization of 1,6,8-dienyne carbonates and esters into cis-cyclohepta-4,8-diene-fused pyrrolidines

bon was surmised to provide the amino alcohol adduct 165. Activation of the remaining propargyl alcohol moiety by the Yb(OTf)3 catalyst was suggested to give the putative intermediate 166, which underwent intramolecular iminocyclization to form the 2-vinyl pyrrole 162. This proposed re-

action mechanism was supported by the isolation of 1,3enyne intermediate 165e in an analogous reaction at 0 °C, with resubmission of this intermediate to the optimized conditions at 100 °C furnishing the pyrrole 162e (Scheme 28, eq. 3).

+ SbF – 6

i-Pr i-Pr N i-Pr

BzO

Ph

Et

N Au

i-Pr Et

NCPh 44 (5 mol%)

Et +

i-Bu

N Ts 123a

PhMe, 4 Å MS 80 °C, 15 h

i-Bu

N

154a, 20%

BzO

OBz Ph

Ts

Ph

Et

+

H

Ph i-Bu

N Ts

i-Bu

126a, 29%

124a, 0%

Scheme 26 Pyrrole by-product formation by NHC-gold-catalyzed cycloisomerization of a 1,7-enyne ester substrate © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1305–1339

N Ts

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B. J. Ayers, P. W. H. Chan

+SbF – 6

i-Pr i-Pr

i-Pr HO R3

R5O2S

Au

i-Pr R3

NCPh 44 (5 mol%)

R2 N

N

R4

R1

SO2R5

R2

PhMe, 80 °C, 18 h

R1 154

155 HO R3

R5O

2S

N

R1

HO R3

[Au]+

R2

(1)

R4

N

R4

R2 R5O2S

N

R1

R3

[Au]+

[Au]+

R2

R4

R2

R4

N

R5O

– H 2O

R1

2S

158 1,3-sulfonyl migration

– [Au]+

SO2R5

R3

SO2R5

R3

N

R4

R2

– H 2O

Bn

N

Ph

Ph

Bn

Ts

N

Ph

Bn

Ts

N

R1

R1 154

Ph Ph

N

159 Selected examples: Ts

R1

– [Au]+

HO R2

R4

N

R 5 O 2S

157 path b 1,3-sulfonyl migration

Ph

[Au]

path a

156

155

R3

[Au]

HO

Bn

O

(2)

R4

O S

OMe

Ph

N

Me 154b, 70%

154c, 93%

154d, 98%

154e, 67%

Scheme 27 Gold-catalyzed tandem aminocyclization/1,3-sulfonyl migration of N-substituted N-sulfonylaminobut-3-yn-2-ols to give 1-substituted 3sulfonyl-1H-pyrroles

4.4

Furans

Functionalized furans are of significant importance in heterocyclic chemistry, owing to their prevalence in bioactive natural and pharmaceutical products.57,58 It became apparent that it might be possible to access furan derivatives from propargyl 1,4-diols under Brønsted acid catalysis, and gratifyingly, this principal was successfully realized (Scheme 29). 59 Mediated by the Brønsted acid catalyst, p-TsOH·H2O, the tandem alkylation/cycloisomerization of propargyl 1,4-diols 168 with 1,3-dicarbonyl compounds 169 afforded tetrasubstituted furans 170 (Scheme 29, eq. 1). In the course of this work, it was observed that the pTsOH·H2O-catalyzed dehydrative rearrangement of the substrate also gave 2,3,5-trisubstituted furans 171. It was proposed that in both reactions protonation and ionization of

the tertiary alcohol provided intermediates 173 and 173′. In the presence of 1,3-dicarbonyl compound 169, nucleophilic attack of the acetylenic carbon center of 173 or the allenic carbocation center of 173′ furnished the tetrasubstituted furan 170, following protonation and dehydrative cyclization (Scheme 29, eq. 2, path a). At 80 °C, deprotonation of intermediate 173 or 173′ was postulated to yield allenyl ketone 178 via cumulene 177 (Scheme 29, eq. 2, path b). From here, a possible 1,2-aryl migration either preceded or succeeded by protonation (routes i and ii, respectively) provided the trisubstituted furan 171. We found that complete product chemoselectivity was possible by varying both the temperature and solvent; ambient conditions and nitromethane afforded tetrasubstituted furan 170, while at 80 °C and in the presence of 1,2-dichloroethane gave the trisubstituted adduct 171.

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N

1329

Account

B. J. Ayers, P. W. H. Chan

OH R2 R3

Ar'SO2NH2 Ar + HO 160

R3

R2

R3

162

OH

OH

OH

R2 R3

[Yb]

R1 [Yb]

Ar 160

+

R1

HO

R1

Ar

R2 R3

Ar

+

– [Yb]–OH HO

SO2Ar'

161 R2

(1)

Ar

N

PhMe, air, 100 °C 1–24 h

R1

R3

OH

R1

R2

Yb(OTf)3 (10 mol%)

R1

Ar

163

164

164' (2) Ar'SO2NH2 161

R2

HO

R1

R1

R3

H Ar

R2

Ar

N

N R3

SO2Ar' 162

H+

[Yb] SO2Ar

R3

R1

C6H4-4-Cl

165

C6H4-4-Me

N Ph

Ph

Ts 162c, 94%

Ph

Me

Ph

C6H4-4-Cl

N

N

Ts

162d, 72% Yb(OTf)3 (10 mol%) TsNH2 161a

OH Ph HO 160e

Me

Ph

SO2C6H4-4-MeO

162b, 65%

4-ClH4C6 4-ClH4C6

Ar

R3

Me

4-ClH4C6

Ph

SO2Ar HN

R1

4-ClH4C6

Ts 162a, 70%

[Yb]

166

Selected examples: Me Ph N

OH R2

– [Yb]–OH

SO2Ar'

167

Ph

Ar

HN

R2

OH 4-ClH4C6 4-ClH4C6

TsHN

Ph

PhMe, air, 0 °C, 5 h Me 165e, 79% Yb(OTf)3 (10 mol%) (3)

PhMe, air 100 °C, 1 h

4-ClH4C6

Me

4-ClH4C6 N

Ph

Ts 162e, 70%

Scheme 28 Ytterbium(III) triflate catalyzed annulation of propargylic 1,4-diols with aryl sulfonamides to afford highly substituted pyrrole derivatives

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O

O

R4 O

R1

R

5

R2 R3

R1

R2

R1

OH

R2

p-TsOH⋅H2O (10 mol%)

R2 R1

MeNO2 r.t., 6 h

R4

O 170

OH

R3

+

R1

OH2

+

R2

R2

R1

R2

R1

+

168

R3

OH

OH

H

172

H

173

R3

path a

R3

R3

O 171

169

R3 H

R1

(CH2Cl)2 80 °C, 1 h

168

– H 2O OH

(1)

OH

H+

R3 H

R2

R5

HO

OH

R4

O

173'

H+

O

H

R2

R1

R3

O

H

R5

H2O +

R4

O

174

175 – H 2O

path b

R2

ii

i O

R1

R2 R5

R1

R3 178

H+

O

R1

R3

O R5

O

R4

R3

170

O

R4

176 (2)

R2

+

OH

R1

R3

179

R2 H+

H

177

OH

R1

R3

181

182

1,2-shift

1,2-shift

H

R2

R2 R1

R3

OH

route ii R2

R2

R1

R2

R3

route i

O

R1

H+

+

O 180

R3 – H + R1

R2 +

O

R3

R3 – H + R1

171

OH

183

Scheme 29 Brønsted acid catalyzed cycloisomerization of but-2-yn-1,4-diols with 1,3-dicarbonyl compounds to give tri- and tetra-substituted furans

4.5 Benzo[b]oxepines and Benzo[b]azepines Benzo[b]oxepines are an important class of heterocycle that occur in many bioactive natural compounds.60 This has aroused much scientific interest in the preparation of derivatives of this scaffold,61 and led us to consider the potential of a synthetic approach from propargyl alcohol derivatives. Consequently, it was demonstrated that in the presence of gold(I) complex 37 (5 mol%) and 1.2 equivalents of benzyl alcohol (BnOH), benzo[b]oxepin-3(2H)-ones 185 were furnished from O-propargylated salicylaldehydes 184 by a tandem intramolecular heterocyclization/Petasis–Ferrier rearrangement (Scheme 30, eq. 1).62 The reaction was found to

proceed excellently under mild conditions that did not require the exclusion of air or moisture. Subsequently, it was proposed that the reaction was initiated by the nucleophilic addition of BnOH to the aldehyde moiety of 184a′ under Lewis acidic conditions (Scheme 30, eq. 2). Ensuing activation of the alkyne moiety in hemiacetal 186a by the gold(I) catalyst was suggested to trigger an intramolecular 7-exodig heterocyclization to give the benzo[e][1,4]dioxepinesubstituted vinyl gold species 187a. Petasis–Ferrier rearrangement of this cyclic species via the enolic gold complex 188a, and debenzoxylative deauration or protodeauration of alkyl gold adduct 189a provided the benzo[b]oxepin3(2H)-one product. The by-product 190a was also formed

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t-Bu t-Bu P Au NCMe

i)

37 (5 mol%) BnOH (1.2 equiv) CH2Cl2, air, r.t., 1–24 h

CHO R1

+ SbF – 6

R2

R3 R1

O R3

(1)

O

ii) p-TsOH⋅H2O (20 mol%) 40 °C, 6 h

O

184

R2

185 BnO

Br

CHO

Br

CHO

Br

Br O +

O

O

H

Br

Br H

H

184a unfavored

Br

H + BnOH

184a' favored

+

O Br

190a

185a

p-TsOH⋅H2O

H+

[Au]+ BnO

OBn Br

O

O

[Au]

Br

OH

(2)

O O

O Br 189a

[Au]+

Br 186a

– H+ BnO +

Br

BnO +

H

O

Br

HO

[Au]

O

[Au]

O

Br

Br 187a

188a

Selected examples: Me Br

O2N

Br

O

O

O

O

Br

O Me

O

O

O

NO2

185a, 99%

185b, 99%

CH18O

Br

O Br 184a-18O 50% content

i) 37 (5 mol%) BnOH (1.2 equiv) CH2Cl2, air, r.t., 1 h

iI) p-TsOH⋅H2O (20 mol%) 40 °C, 6 h

Br 185c, 21%

185d, 62%

Br 18O

O Br 185a-18O 51% yield 43% incorporation

Scheme 30 Gold-catalyzed heterocyclization/Petasis–Ferrier rearrangement to afford benzo[b]oxepin-3(2H)-ones

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competitively, suggesting the latter pathway was more likely, with the role of p-TsOH·H2O confined to promoting debenzoxylation and alcohol regeneration. Subsequently, 18Olabeling studies supported the proposed mechanism (Scheme 30, eq. 3). Remarkable rate enhancements were observed to correlate with the size of the substituent at the position ortho to the ethereal group on the salicylaldehyde ring of the substrate. It was postulated that this may be due to the adoption of preferred conformation 184a′, promoting intramolecular heterocyclization. As with benzo[b]oxepines, the analogous benzo[b]azepine class is also found in a range of pharmacologically relevant compounds,63 which has led to significant interest toward the synthesis of derivatives of this molecular architecture.64 By building on our earlier findings, we reasoned and successfully demonstrated that cycloisomerization of Npropargylated salicylaldehydes 191 under similar conditions would give benzo[b]azepin-3(2H)-ones 192 (Scheme 31).65 Mechanistically, the reaction was reasonably proposed to proceed by the same tandem heterocyclization/Petasis–Ferrier rearrangement pathway described in our approach to the benzo[b]oxepines. In this study, the presence of an ortho substituent relative to the ethereal group on the salicylaldehyde ring of the substrate was not required for good to excellent product yields to be obtained. t-Bu t-Bu P Au NCMe

i)

37 (5 mol%) BnOH (1.2 equiv) CH2Cl2, air or N2 (g) r.t., 1–24 h

CHO R1

R2 N Ts

+

SbF6–

R3 R1

O

ii) p-TsOH⋅H2O (20 mol%) air, 40 °C, 5 or 6 h

N Ts

R3

191

192

Selected examples:

O

O MeO

N Ts

N Ts 192b, 80%

192a, 81% Me

O

O N Ts 192c, 76%

N Ms 192d, 77%

Scheme 31 Gold-catalyzed heterocyclization/Petasis–Ferrier rearrangement to give benzo[b]azepin-3(2H)-ones

R2

5 Heterocycles with Two Heteroatoms 5.1

Thiazoles and Oxazoles

Heterocycles bearing two heteroatoms, such as thiazoles and oxazoles, are present as a privileged pharmacophore in a myriad of bioactive natural and synthetic compounds.66 Owing to their importance, methods that utilize mild conditions and permit the construction of highly functionalized, versatile derivatives of these motifs are highly sought after. Our interest in accessing these targets was sparked by the work of Zhan and Yoshimatsu, both of whom had described the assembly of thiazoles by treating propargyl alcohols and thioamides with Lewis acids to induce a [3+2] cycloaddition.67 While these methods were shown to be efficient, the major drawback was the formation of metal impurities, lessening the wider application and scalability of this procedure. We rationalized that this problem could be negated by employing Brønsted acid catalysts, and duly reported a thiazole-forming p-TsOH·H2O-catalyzed process in 2010 (Scheme 32, eq. 1).68 Likewise, the groups of Liu and Uemura described the synthesis of oxazoles from propargyl alcohols and amides under dual diruthenium(II,III)/gold(III) or ruthenium(III)/zinc(II) catalysis.69 Again, these methods were efficacious, but we envisaged the possible utilization of a single Lewis acid catalyst to effect the transformation. This led to the realization of an approach concerning the synthesis of oxazoles under Yb(OTf)3 catalysis (Scheme 32, eq. 1).70 Prior to this work, Zhan and co-workers had detailed a closely related Brønsted acid mediated oxazole synthesis, however, this protocol necessitated the use of a stoichiometric amount of p-TsOH·H2O.71 For both the thiazole 195 and oxazole 197 forming reactions, a catalyst loading of 5 mol% was found to be optimum, with the targets formed regioselectively and in good to excellent yields. A similar mechanism was proposed for the two reactions, which began with initial protonation/coordination of the tertiary alcohol moiety in propargyl alcohol 193 furnishing intermediate 198. Upon ionization, a mixture of the mesomeric propargyl and allenyl cationic species 199 was believed to be formed, with resultant regioselective nucleophilic attack by thioamide 194 or amide 196 at the acetylenic carbon/allenyl carbocation center. The putative allene intermediates 200 and 201 subsequently underwent 5-exo-trig cyclization to form the thiazole 195 and oxazole 197 targets, and regenerated the respective Brønsted or Lewis acid catalysts. These mild, catalytic procedures were shown to be applicable to a broad scope of substrates, and owing to opposing regioselectivity in the

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S R4

R

R1

S

R4

NH2 194 p-TsOH⋅H2O (5 mol%)

R2 3

O

N

OH R1

(CH2Cl)2, air, 100 °C 1.5–24 h

R4 195

NH2 196 Yb(OTf)3 (5 mol%)

R2

R2 R3 O

PhMe, air, 100 °C 5h

R3

R2

(1)

OH

R1

X

N R4 197

193

R3

R1

R1

Yb(OTf)3 = [Yb] or p-TsOH p-TsO– + H+

N R4

R2

R3 193

195, X = S 197, X = O

R2

H+/[Yb]

R4

HN

R1

X

[Yb]/H+

R1

R3

(2) R2

R3

198

200, X = S 201, X = O

R2 R1

+

R3

X R4

OH

H+ [Yb]–OH or H2O

R2

NH2

+

194, X = S 196, X = O

[Yb] + H2O

R1 R3 199

Selected examples: Ph Ph X

Ph

Ph Ph

N Me

195a, X = S, 90% 197a, X = O, 88%

Ph

C6H4-4-Cl

X

N Me

195b, X = S, 98% 197b, X = O, 88%

Ph S

C6H4-4-F C6H4-4-Cl

N

Ph O

C6H4-4-F N

C6H4-4-MeO

C6H4-2-Me

195c, 97%

197d, 70%

Scheme 32 Lewis and Brønsted acid catalyzed cyclization of tertiary propargyl alcohols with amides and thioamides to give oxazoles and thiazoles

formation of 2-aryloxazole products, are complementary to the existing dual metal and stoichiometric Brønsted acid procedures.

5.2

Dioxolanes

The intra- or inter-molecular trapping of gold–carbenoid intermediates with nucleophiles affords efficient methods for the assembly of complex scaffolds. In this account, examples have included the cycloisomerization of 1,6-diyne esters and carbonates to give 2,4a-dihydro-1H-fluorenes,

and of 1,6,8-dienyne esters and carbonates to afford ciscyclohepta-4,8-dienes (Schemes 8 and 25). The utility and scope of such transformations has sparked growing interest in this area, and in the case of ketone or aldehyde nucleophiles, has provided expedient approaches to oxaheterocyclic compounds.72 However, given that these reactions had mainly concerned cyclopropane-substituted gold–carbenoid intermediates derived from 1,n-enyne esters, the analogous cycloadditions from propargyl esters and carbonates remained unexplored. Given our interest in applying goldcatalyzed cycloisomerization chemistry to propargyl alcohol derived substrates, and the potentially different reactiv-

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ity mode of a vinyl gold–carbenoid species compared to a cyclopropyl–gold adduct, we were drawn to examining the cycloisomerization of 1,6-diyne esters and carbonates in the presence of an aldehyde. This led to the observation that treatment of substrates 202 with two equivalents of aldehyde 203 under catalysis by NHC-gold(I) complex 44, led to an unprecedented [2+2+1] cycloaddition and formation of 1,3-dioxolanes 204 (Scheme 33, eq. 1).17b This reactivity

mode had not been previously observed under gold catalysis. The approach proved efficient, even at a low 1 mol% catalyst loading, broad in scope, and afforded the synthetically useful 1,3-cyclohexadiene and 1,3-dioxolane motifs. Previously, in the absence of aldehyde nucleophiles, reactions of 1,6-diyne substrates proceeded via a putative gold(I)–carbenoid species to afford 2,4a-dihydro-1H-fluorenes as the product of a tandem Nazarov-type cyclization (Scheme 8).

+ SbF – 6

i-Pr i-Pr N

R

i-Pr

Au

i-Pr 2

N

R1OCO

NCPh 44 (5 mol%)

OCOR1 O

R2

+2 R4

H

R3 202

R4

R3 O

(1)

O

CH2Cl2, 4 Å MS 0 °C, 0.2–24 h

R4

203

204 R1

R3

OCOR1

R2

R2

[Au]+

R2

R1

O

R2

O O

+

OCOR1 O

R3

[Au]+

202

205 R4 R2

O

OCOR1

206

207

R4 R2

O H

H

OCOR1

[Au]+

203

R3 +

R3

[Au] R3

[Au]+

R2

OCOR1

[Au]+ (2)

R3

R1OCO

R3

[Au]

R3

[Au]+ R

211

2

210 – [Au]+

[2+2+1]

209

[3+2] OCOR1

R1OCO

R4

R3 O R2

208

R4

R2 O

O R4

R3 212 not observed

204

Selected examples: Ph PNBO

AcO Ph

n-Hex

O

Ph

O

Ph

BzO Cy

O Ph

O

O

n-Hex

Et

O

Ph Et

Cy 204a, 72%

204b, 78%

204c, 84%

Scheme 33 Gold-catalyzed [2+2+1] cycloaddition of 1,6-diyne carbonates and esters with aldehydes to give 4-(cyclohexa-1,3-dienyl)-1,3-dioxolanes

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It was suggested that the present procedure utilized a similar mechanism, with an initial 1,2-acyloxy shift of complex 205 affording the vinyl gold–carbenoid species 207. Ensuing cyclopropenation and cycloreversion resulted in the intermediate 210. In the presence of two aldehyde molecules 203, a [2+2+1] cycloaddition afforded the target 204. In our hands, we did not observe the potential competing [3+2] cycloaddition, and the adduct 212 was not isolated.

6

Conclusion

In this account, we have attempted to document comprehensively the developments and evolution of research in our laboratory with propargyl alcohols and their derivative substrates. The past few decades has witnessed an exponential growth in research with this substrate class, a trend that has paralleled the meteoric expansion of gold catalysis. In our studies, we have endeavored to broaden the scope of possible transformations and the utility of both propargyl alcohol substrates and catalysts. In particular, we have pursued research on two fronts: the robust and efficient assembly of complex, highly functionalized targets with synthetic, biological or materials relevance, from simple precursors, and the elucidation of novel tandem transformations, largely within the domain of gold catalysis.

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Acknowledgment This article and the research it covers were supported by Start-Up Grants from the School of Chemistry, Monash University, Department of Chemistry, the University of Warwick and College of Science, Nanyang Technological University, a Science and Engineering Research Council Grant (092 101 0053) and A*STAR-MSHE Joint Grant (122 070 3062) from A*STAR, a University Research Committee Grant (RG55/06), and a Tier 1 Grant (MOE2013-T1-002-035) and a Tier 2 Grant (MOE2013-T2-1-060) from the Ministry of Education of Singapore. All present and past members of the group whose names appear in the references are also thanked for their invaluable efforts in realizing these achievements.

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References (1) For selected reviews of tandem synthetic processes, see: (a) Domino Reactions; Tietze, L. F., Ed.; Wiley-VCH: Weinheim, 2014. (b) Behr, A.; Vorholt, A. J.; Ostrowski, K. A.; Seidensticker, T. Green Chem. 2014, 16, 982. (c) Pellìssier, H. Tetrahedron 2013, 69, 7171. (d) Fustero, S.; Sanchez-Rosello, M.; del Pozo, C. Pure Appl. Chem. 2010, 82, 669. (e) Moores, A. In Handbook of Green Chemistry; Anastas, P. T.; Crabtree, R. H., Eds.; Wiley-VCH: Weinheim, 2009, 1. (f) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45, 7134. (g) Hall, N. Science 1994, 266, 32. (2) For selected reviews concerning the reactivity of unsaturated substrates and transition metal complexes, see: (a) Yamamoto, Y. Chem. Soc. Rev. 2014, 43, 1575. (b) Gulevich, A. V.; Dudnik, A.

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(8) (a) Yamauchi, Y.; Onodera, G.; Sakata, K.; Yuki, M.; Miyake, Y.; Uemura, S.; Nishibayashi, Y. J. Am. Chem. Soc. 2007, 129, 5175. (b) Xiao, H.-Q.; Shu, X.-Z.; Ji, K.-G.; Qi, C.-Z.; Liang, Y.-M. New J. Chem. 2007, 31, 2041. (9) For selected reviews, see: (a) El-Shazly, M.; Barve, B. D.; Korinek, M.; Liou, J.-R.; Chuang, D.-W.; Cheng, Y.-B.; Hou, M.-F.; Wang, J.J.; Wu, Y.-C.; Chang, F.-R. Curr. Top. Med. Chem. 2014, 14, 1076. (b) Shirtcliff, L. D.; McClintock, S. P.; Haley, M. M. Chem. Soc. Rev. 2008, 37, 343. (c) Doucet, H.; Hierso, J.-C. Angew. Chem. Int. Ed. 2007, 46, 834. (d) Zeni, G.; Braga, A. L.; Stefani, H. A. Acc. Chem. Res. 2003, 36, 731. (10) Zhang, X.; Teo, W. T.; Chan, P. W. H. Org. Lett. 2009, 11, 4990. (11) For recent selected examples concerning indene synthesis, see: (a) Muthusamy, S.; Sivaguru, M. Org. Lett. 2014, 16, 4248. (b) Rosocha, G.; Batey, R. A. Tetrahedron 2013, 69, 8758. (c) Liu, L.; Fan, Y.; He, Q.; Zhang, Y.; Zhang-Negrerie, D.; Huang, J.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 3997. (d) Panteleev, J.; Huang, R. Y.; Lui, E. K. J.; Lautens, M. Org. Lett. 2011, 13, 5314. (e) Akagawa, K.; Sakamoto, S.; Kudo, K. Synlett 2011, 817. (f) Reddy, B. V. S.; Reddy, B. B.; Rao, K. V. R.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 5697. (g) Liu, C.-R.; Yang, F.-L.; Jin, Y.-Z.; Ma, X.-T.; Cheng, D.-J.; Li, N.; Tian, S.-K. Org. Lett. 2010, 12, 3832. (h) Yamazaki, S.; Yamamoto, Y.; Fukushima, Y.; Takebayashi, M.; Ukai, T.; Mikata, Y. J. Org. Chem. 2010, 75, 5216. (12) Rao, W.; Chan, P. W. H. Org. Biomol. Chem. 2010, 8, 4016. (13) (a) Maraval, V.; Duhayon, C.; Coppel, Y.; Chauvin, R. Eur. J. Org. Chem. 2008, 5144. (b) Feng, A.-H.; Chen, J.-Y.; Yang, L.-M.; Lee, G.-H.; Wang, Y.; Luh, T.-Y. J. Org. Chem. 2001, 66, 7922. (14) For selected examples, see: (a) Zhu, H.-T.; Ji, K.-G.; Yang, F.; Wang, L.-J.; Zhao, S.-C.; Ali, S.; Liu, S.; Liang, X.-Y.; Liang, Y.-M. Org. Lett. 2011, 13, 684. (b) Smith, C. D.; Rosocha, G.; Mui, L.; Batey, R. A. J. Org. Chem. 2010, 75, 4716. (c) Zhou, X.; Zhang, H.; Xie, X.; Li, Y. J. Org. Chem. 2008, 73, 3958. (d) Guo, S.; Liu, Y. Org. Biomol. Chem. 2008, 6, 2064. (e) Xi, Z.; Guo, R.; Mito, S.; Yan, H.; Kanno, K.-I.; Nakajima, K.; Takahashi, T. J. Org. Chem. 2003, 68, 1252. (15) Zhang, X.; Teo, W. T.; Rao, W.; Ma, D.-L.; Leung, C.-H.; Chan, P. W. H. Tetrahedron Lett. 2014, 55, 3881. (16) For selected examples of gold-catalyzed 1,n-enyne ester migrations, see: (a) Yu, Y.; Yang, W.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 7586. (b) Rao, W.; Sally; Koh, M. J.; Chan, P. W. H. J. Org. Chem. 2013, 78, 3183. (c) Hashmi, A. S. K.; Yang, W.; Yu, Y.; Hansmann, M. M.; Rudolph, M.; Rominger, F. Angew. Chem. Int. Ed. 2013, 52, 1329. (d) Rao, W.; Susanti, D.; Chan, P. W. H. J. Am. Chem. Soc. 2011, 133, 15248. (e) Garayalde, D.; Gómez-Bengoa, E.; Huang, X.; Goeke, A.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 4720. (f) Mauleón, P. J.; Krinsky, L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513. (g) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 3464. (h) Lemiére, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2009, 131, 2993. (i) Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056. (j) Zou, Y.; Garayalde, D.; Wang, Q.; Nevado, C.; Goeke, A. Angew. Chem. Int. Ed. 2008, 47, 10110. (k) Boyer, F.-D.; Le Goff, X.; Hanna, I. J. Org. Chem. 2008, 73, 5163. (l) Li, G.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 3740. (m) Moreau, X.; Goddard, J.-P.; Bernard, M.; Lemière, G.; López-Romero, J. M.; Mainetti, E.; Marion, N.; Mouriès, V.; Thorimbert, S.; Fensterbank, L.; Malacria, M. Adv. Synth. Catal. 2008, 350, 43. (n) Lemiére, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207. (o) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (p) Marion, N.; de Frémont, P.; Stevens, E. D.;

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Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem. Commun. 2006, 2048. (q) Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957. (r) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (s) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. (t) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654. For selected examples of gold-catalyzed 1,n-diyne ester migrations, see: (a) Li, D.; Rao, W.; Tay, G. L.; Ayers, B. J.; Chan, P. W. H. J. Org. Chem. 2014, 79, 11301. (b) Rao, W.; Chan, P. W. H. Chem. Eur. J. 2014, 20, 713. (c) Oh, C. H.; Kim, J. H.; Piao, L.; Yu, J.; Kim, S. Y. Chem. Eur. J. 2013, 19, 10501. (d) Rao, W.; Koh, M. J.; Li, D.; Hirao, H.; Chan, P. W. H. J. Am. Chem. Soc. 2013, 135, 7926. (e) Lauterbach, T.; Gatzweiler, S.; Nösel, P.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2013, 355, 2481. (f) Rao, W.; Koh, M. J.; Kothandaraman, P.; Chan, P. W. H. J. Am. Chem. Soc. 2012, 134, 10811. (g) Leboeuf, D.; Simonneau, A.; Aubert, C.; Malacria, M.; Gandon, V.; Fensterbank, L. Angew. Chem. Int. Ed. 2011, 50, 6868. (h) Zhang, D.-H.; Yao, L.-F.; Wei, Y.; Shi, M. Angew. Chem. Int. Ed. 2011, 50, 2583. (i) Luo, T.; Schreiber, S. L. J. Am. Chem. Soc. 2009, 131, 5667. (j) Oh, C. H.; Kim, A. Synlett 2008, 777. (k) Luo, T.; Schreiber, S. L. Angew. Chem. Int. Ed. 2007, 46, 8250. (l) Oh, C. H.; Kim, A. New J. Chem. 2007, 31, 1719. (m) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436. (n) Oh, C. H.; Kim, A.; Park, W.; Park, D. I.; Kim, N. Synlett 2006, 2781. For recent selected examples concerning dihydrofluorene synthesis, see: (a) Hashmi, A. S. K.; Hoffmann, J.; Shi, S.; Schütz, A.; Rudolph, M.; Lothschütz, C.; Wieteck, M.; Bührle, M.; Wölfle, M.; Rominger, F. Chem. Eur. J. 2013, 19, 382. (b) Garcia-Garcia, P.; Rashid, M. A.; Sanjuan, A. M.; Fernandez-Rodriguez, M. A.; Sanz, R. Org. Lett. 2012, 14, 4778. (c) Zhang, L.; Xie, X.; Liu, J.; Qi, J.; Ma, D.; She, X. Org. Lett. 2011, 13, 2956. (d) Chaudhuri, R.; Liao, H.-Y. M.; Liu, R. S. Chem. Eur. J. 2009, 15, 8895. (e) Gorin, J.; Watson, I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736. (f) Liu, W.; Buck, M.; Chen, N.; Shang, M.; Taylor, N. J.; Asoud, J.; Wu, X.; Hasinoff, B. B.; Dmitrienko, G. I. Org. Lett. 2007, 9, 2915. To our knowledge, only two prior reports have been described, see: (a) Briones, J. F.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134, 11916. (b) Witham, C. A.; Mauleón, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838. For illustrative examples of dual activation in gold catalysis, see: Braun, I.; Asiri, A. M.; Hashmi, A. S. K. ACS Catal. 2013, 3, 1902; and references cited therein. For recent selected examples concerning cyclopenta[b]naphthalenes, see: (a) Wang, X.-C.; Hu, J.; Sun, P.-S.; Zhong, M.-J.; Ali, S.; Liang, Y.-M. Org. Biomol. Chem. 2011, 9, 7461. (b) Kotha, S.; Halder, S. Synlett 2010, 337. (c) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kim, J. A.; Kim, H. M.; Kim, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Park, S. D.; Lee, J. M.; Lee, J. H.; Cheon, H. G.; Kim, S. S. Bioorg. Med. Chem. Lett. 2007, 17, 5239. (d) Scaglione, J. B.; Manion, B. D.; Benz, A.; Taylor, A.; DeKoster, G. T.; Rath, N. P.; Evers, A. S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. J. Med. Chem. 2006, 49, 4595. (e) Kim, K. R.; Lee, J. H.; Kim, S. J.; Rhee, S. D.; Jung, W. H.; Yang, S.-D.; Kim, S. S.; Ahn, J. H.; Cheon, H. G. Biochem. Pharmacol. 2006, 72, 446. For recent selected examples concerning bicyclo[3.2.0]hepta1,5-dienes, see: (a) Xin, X.; Wang, D.; Wu, F.; Wang, C.; Wang, H.; Li, X.; Wan, B. Org. Lett. 2013, 15, 4512. (b) Tam, W.; Jack, K.; Goodreid, J.; Cockburn, N. Adv. Org. Synth. 2013, 6, 59. (c) Dembitsky, V. M. J. Nat. Med. 2008, 62, 1. (d) Oh, C. H.; Gupta, A. K.; Park, D. I.; Kim, N. Chem. Commun. 2005, 5670. For examples of 1,5-acyl migrations in gold catalysis, see refs 16b, 17f, and 17g.

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(e) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010, 49, 2096. (f) Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868. (g) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75, 1764. (h) Besselièvre, F.; Piguel, S. Angew. Chem. Int. Ed. 2009, 48, 9553. (i) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem. Int. Ed. 2009, 48, 9346. (j) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156. (k) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (l) Gu, Y.; Wang, X. M. Tetrahedron Lett. 2009, 50, 763. (m) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (n) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955. Mothe, S. R.; Novianti, M. L.; Ayers, B. J.; Chan, P. W. H. Org. Lett. 2014, 16, 4110. See ref. 16q, and: (a) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst, T.; Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.; Rominger, F.; Frey, W.; Bats, J. W. Chem. Eur. J. 2010, 16, 956. (b) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147. (c) Kirsch, S. F.; Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.; Liébert, C.; Menz, H. Angew. Chem. Int. Ed. 2007, 46, 2310. (d) Buzas, A.; Gagosz, F. Synlett 2006, 2727. For a review comparing gold catalysis with iodonium activation of alkynes, see: Hummel, S.; Kirsch, S. F. Beilstein J. Org. Chem. 2011, 7, 847. Kothandaraman, R.; Mothe, S. R.; Toh, S. S. M.; Chan, P. W. H. J. Org. Chem. 2011, 76, 7633. Kothandaraman, P.; Koh, B. Q.; Limpanuparb, T.; Hirao, H.; Chan, P. W. H. Chem. Eur. J. 2013, 19, 1978. For recent selected reviews on 2- and 3-oxindole synthesis, see: (a) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247. (b) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (c) Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 327. (d) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821. (e) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003. For selected reviews on haloamination of unsaturated bonds, see: (a) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Chem. Eur. J. 2012, 18, 5460. (b) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937. (c) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075. (d) Mphahlele, M. J. Molecules 2009, 14, 4814. (e) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 1487. (f) Togo, H.; Iida, S. Synlett 2006, 2159. (g) Larock, R. C. In Acetylene Chemistry: Chemistry, Biology, and Material Science; Diederich, F.; Stang, P. J.; Tykwinski, R. R., Eds.; Wiley-VCH: New York, 2005, 51. (a) Ali, S.; Zhu, H.-T.; Xia, X.-F.; Ji, K.-G.; Yang, Y.-F.; Song, X.-R.; Liang, Y.-M. Org. Lett. 2011, 13, 2598. (b) Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243. Kothandaraman, P.; Lauw, S. J. L.; Chan, P. W. H. Tetrahedron 2013, 69, 7471. Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 7052. Susanti, D.; Ng, L. L. R.; Chan, P. W. H. Adv. Synth. Catal. 2014, 356, 353. For selected examples concerning azabicyclo[4.2.0]oct-5-enes, see: (a) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagashi, T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-Natschke, S. L.; Lee, K.-H. Tetrahedron 2001, 57, 1559. (b) Kurata, K.; Taniguchi, K.; Agatsuma, Y.; Suzuki, M. Phytochemistry 1998, 47, 363. (c) Crimmins, M. T.; Huang, S.; GuiseZawacki, L. E. Tetrahedron Lett. 1996, 37, 6519. (d) Piers, E.; Lu, Y.-F. J. Org. Chem. 1989, 54, 2267.

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