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

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.