Selectivity Control in Gold-Catalyzed Hydroarylation of Alkynes with Indoles: Application to Unsymmetrical Bis(indolyl)methanes

McLean, Euan B.; Cutolo, Francesca M.; Cassidy, Orla J.; Burns, David J.; Lee, Ai‐Lan

doi:10.1021/acs.orglett.0c02526

Cited by 29 publications

(15 citation statements)

References 81 publications

(13 reference statements)

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“…Lee's group discussed a synthetic pathway of gold-catalyzed hydroarylation of alkynes 174 with indoles 171 (Scheme 76). 97 The reaction took place between alkynes and different substituted indoles derivatives 171 to prepare the desired products 243 in up to 96% yields under the optimized reaction conditions of 2 mol% PPh 3 AuNTf 2 catalyst and acetonitrile at 30 °C for 24 h. Both electron-withdrawing and electron-donating groups at different positions of the aryl ring of indole furnished excellent yields of the corresponding product. Generally, N -alkylation of indole gave a high yield (96%); however, in the presence of the electron-withdrawing Boc group the yield of the reaction decreased (<5%) due to the nucleophilic nature of indole.…”

Section: Intermolecular Hydroarylation Reactionmentioning

confidence: 99%

Gold-catalyzed hydroarylation reactions: a comprehensive overview

2022

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Section: Intermolecular Hydroarylation Reactionmentioning

confidence: 99%

Gold-catalyzed hydroarylation reactions: a comprehensive overview

2022

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“…To drive selectivity toward the diarylated product, addition of a Brønsted acid in a second step (Scheme 21, reaction (a)) results in the complete conversion to the diarylated product in minutes, which can be put to advantage in the production of double hydroarylation products bearing two different heteroaryl substituents. Very recently, it has been established by the group of Lee that in the case of 2,3 or 4-substituted indoles the gold-catalyzed hydroarylation reaction of arylacetylenes conveniently stops at the monohydroarylation stage using a defect of indole [122]. Steric effects are invoked to explain the lack of further reactivity.…”

Section: Selectivity: Monoarylation Versus Diarylationmentioning

confidence: 99%

Gold-Catalyzed Intermolecular Alkyne Hydrofunctionalizations—Mechanistic Insights

2020

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An overview of the current state of mechanistic understanding of gold-catalyzed intermolecular alkyne hydrofunctionalization reactions is presented. Moving from the analysis of the main features of the by-now-generally accepted reaction mechanism, studies and evidences pointing out the mechanistic peculiarities of these reactions using different nucleophiles HNu that add to the alkyne triple bond are presented and discussed. The effects of the nature of the employed alkyne substrate and of the gold catalyst (employed ligands, counteranions, gold oxidation state), of additional additives and of the reaction conditions are also considered. Aim of this work is to provide the reader with a detailed mechanistic knowledge of this important reaction class, which will be invaluable for rapidly developing and optimizing synthetic protocols involving a gold-catalyzed alkyne hydrofunctionalization as a reaction step.

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“…Recently, Lee and co-workers have shown that vinyl indoles can be prepared in excellent yield from the reaction of 2-substituted indoles with an excess of alkyne at low gold catalyst loadings, although with indole itself, bis indolemethanes were still generated. 32 While this could be circumvented through the use of a 2-boryl-substituted indole and subsequent deprotection, the selective monoalkenylation of unsubstituted indole remains an unsolved challenge.…”

Section: Introductionmentioning

confidence: 99%

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

2022

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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 bis indolemethanes, 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 η 2 (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.

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Selectivity Control in Gold-Catalyzed Hydroarylation of Alkynes with Indoles: Application to Unsymmetrical Bis(indolyl)methanes

Cited by 29 publications

References 81 publications

Gold-catalyzed hydroarylation reactions: a comprehensive overview

Gold-catalyzed hydroarylation reactions: a comprehensive overview

Gold-Catalyzed Intermolecular Alkyne Hydrofunctionalizations—Mechanistic Insights

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

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