Selectivity, Speciation, and Substrate Control in the Gold-Catalyzed Coupling of Indoles and Alkynes

TY - JOUR

T1 - Selectivity, Speciation, and Substrate Control in the Gold-Catalyzed Coupling of Indoles and Alkynes

AU - Epton, Ryan G.

AU - Unsworth, William P.

AU - Lynam, Jason M.

N1 - Funding Information: We are grateful to the University of York (Ph.D. studentship to R.G.E. and the provision of an Eleanor Dodson Fellowship to W.P.U.) and the EPSRC (EP/H011455/1 and EP/K031589/1) for funding computational equipment used in this study. We thank Dr. Michael James (University of York) for insightful comments on this manuscript. We are grateful to Dr. Adrian Whitwood for the single crystal X-ray structure of 37 . Publisher Copyright: © 2022 American Chemical Society.

PY - 2022/2/28

Y1 - 2022/2/28

N2 - A convenient and mild protocol for the gold-catalyzed intermolecular coupling of substituted indoles with carbonyl-functionalized alkynes to give vinyl indoles is reported. This reaction affords 3-substituted indoles in high yield, and in contrast to the analogous reactions with simple alkynes which give bisindolemethanes, only a single indole is added to the alkyne. The protocol is robust and tolerates substitution at a range of positions of the indole and the use of ester-, amide-, and ketone-substituted alkynes. The use of 3-substituted indoles as substrates results in the introduction of the vinyl substituent at the 2-position of the ring. A combined experimental and computational mechanistic study has revealed that the gold catalyst has a greater affinity to the indole than the alkyne, despite the carbon-carbon bond formation step proceeding through an η2(π)-alkyne complex, which helps to explain the stark differences between the intra- and intermolecular variants of the reaction. This study also demonstrated that the addition of a second indole to the carbonyl-containing vinyl indole products is both kinetically and thermodynamically less favored than in the case of more simple alkynes, providing an explanation for the observed selectivity. Finally, a highly unusual gold-promoted alkyne dimerization reaction to form a substituted gold pyrylium salt has been identified and studied in detail.

AB - A convenient and mild protocol for the gold-catalyzed intermolecular coupling of substituted indoles with carbonyl-functionalized alkynes to give vinyl indoles is reported. This reaction affords 3-substituted indoles in high yield, and in contrast to the analogous reactions with simple alkynes which give bisindolemethanes, only a single indole is added to the alkyne. The protocol is robust and tolerates substitution at a range of positions of the indole and the use of ester-, amide-, and ketone-substituted alkynes. The use of 3-substituted indoles as substrates results in the introduction of the vinyl substituent at the 2-position of the ring. A combined experimental and computational mechanistic study has revealed that the gold catalyst has a greater affinity to the indole than the alkyne, despite the carbon-carbon bond formation step proceeding through an η2(π)-alkyne complex, which helps to explain the stark differences between the intra- and intermolecular variants of the reaction. This study also demonstrated that the addition of a second indole to the carbonyl-containing vinyl indole products is both kinetically and thermodynamically less favored than in the case of more simple alkynes, providing an explanation for the observed selectivity. Finally, a highly unusual gold-promoted alkyne dimerization reaction to form a substituted gold pyrylium salt has been identified and studied in detail.

UR - http://www.scopus.com/inward/record.url?scp=85124870563&partnerID=8YFLogxK

U2 - 10.1021/acs.organomet.2c00035

DO - 10.1021/acs.organomet.2c00035

M3 - Article

AN - SCOPUS:85124870563

SN - 0276-7333

VL - 41

SP - 497

EP - 507

JO - Organometallics

JF - Organometallics

IS - 4

ER -