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

Abstract

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.

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

“…Alkenes have been shown in some cases to coordinate more strongly than alkynes, but the trend depends on substitution pattern (alkynes can coordinate more strongly) [69]. A more recent study of alkyne activation demonstrates that esters coordinate relatively weakly compared to alkynes, while amides coordinate relatively strongly [70]. Analysis of 31 P chemical shift of the catalyst under reaction conditions does not provide strong conclusions about what is coordinating to gold in solution as chemical shifts vary only slightly compared to that of the original catalyst, but that does not preclude a kinetically effective catalyst cycle being initiated by gold coordination to functional groups in solution other than the alkene itself, thus deviating from classic π-activation.…”

Au(I)-catalysis Enables Regioselective Hydrogen Isotope Labeling of Indoles

“…1). 34 Liu also made the hypothesis that indoles intermediate may coordinate a Au(I) complex and form an indolyl-gold(I) species ii. 35 More importantly, Shi and Tang hypothesized the formation of indolyl intermediates iii with a C3-Au bond, 18 and indirectly evidenced this hypothesis by exposure to a deurated solvent under harsh conditions, resulting in a low deuteration incorporation though.…”

DFT Studies of Au(I) Catalysed Reactions: Anion Effects and Reaction Selectivity

“…In our own groups, we have used DFT to explore the selectivity of gold(I) coordination in a study exploring the formation of 3-vinylindole species using alkynes with electron-withdrawing functionalities. [32] First, the relative energy difference between coordination to indoles (35 and 36) and ynone (34) species were compared (Figure 24). Coordination to both the ketone (AA) and alkyne (AB) of the ynone was considered.…”