Gold-Catalyzed Intermolecular Alkyne Oxyarylation for C3 Functionalization of Benzothiophenes

Paige A Rist,Richard S Grainger,Paul W Davies

doi:10.1021/acs.orglett.0c03596

Abstract

C3-selective C-C bond formation on benzothiophenes is challenging, and few direct functionalization methods are available. A gold-catalyzed reaction of alkynes with benzothiophene S-oxides provides regioselective entry into C3-alkylated benzothiophenes with the C7-alkylated isomer as the minor product. This oxyarylation reaction works with alkyl and aryl alkynes and substituted and unsubstituted benzothiophenes. Mechanistic studies identify that sulfoxide inhibits the catalyst [DTBPAu(PhCN)]SbF6, which also degrades and forms the unreactive complex [(DTBP)2Au]SbF6.

Highlights

C3-selective C−C bond formation on benzothiophenes is challenging, and few direct functionalization methods are available
The vinylgold carbenoid intermediate B should evolve through a [3,3]-sigmatropic rearrangement and onto C3 rather than the C7 benzenoid position (Scheme 1b)
Rearrangement must occur before the electrophilic organogold species reacts with a second equivalent of sulfoxide.8c Our interest in gold-catalyzed reactions with sulfoxides[9] led us to investigate the potential of oxyarylation for C3 benzothiophene elaboration

Summary

Corresponding Authors

The alternative carbene formation and electrophilic aromatic substitution pathway can be ruled out from the results of the crossover experiments and the ready formation of compounds 26 and 27 bearing a deactivating ester group at C2. Sulfoxide inhibition of the reaction is seen, as are direct interactions between sulfoxide 1 and the gold complex. Gold-catalyzed reactions between readily accessed benzothiophene S-oxides and terminal alkynes provide efficient and selective access to C3-alkylated benzothiophenes bearing a useful carbonyl group for subsequent exploitation. The approach is compatible with a variety of electron-rich and electron-deficient aromatic and aliphatic alkynes as well as reactive functionalities including carboxylic esters, tertiary amines, phthalimide, and alkyl and aryl halides. The highest regioselectivities are seen with aryl alkynes. The reactions are straightforward to perform and do

■ ACKNOWLEDGMENTS

■ REFERENCES