Tris(pentafluorophenyl)borane-Catalyzed Formal Cyanoalkylation of Indoles with Cyanohydrins

Despite the significant achievements related to the C3 functionalization of indoles, cyanoalkylation reactions continue to remain rather limited. We herein report on the formal C3 cyanoalkylation of indoles with cyanohydrins in the presence of a tris(pentafluorophenyl)borane (B(C6F5)(3)) catalyst. It is noteworthy that cyanohydrins are used as a cyanoalkylating reagent in the present reaction, even though they are usually used as only a HCN source. Mechanistic investigations revealed the unique reactivity of the B(C6F5)(3) catalyst in promoting the decomposition of a cyanohydrin by a Lewis acidic activation through the coordination of the cyano group to the boron center. In addition, a catalytic three-component reaction using indoles, aldehydes as a carbon unit, and acetone cyanohydrin that avoids the discrete preparation of each aldehyde-derived cyanohydrin is also reported. The developed methods provide straightforward, highly efficient, and atom-economic access to various types of synthetically useful indole-3-acetonitrile derivatives containing alpha-tertiary or quaternary carbon centers.

Automated summary

In this study, a method for the C3 cyanoalkylation of indoles using cyanohydrins in the presence of a B(C6F5)(3) catalyst was reported. Mechanistic investigations revealed the unique reactivity of the B(C6F5)(3) catalyst in promoting the decomposition of cyanohydrins. Additionally, a catalytic three-component reaction using indoles, aldehydes, and acetone cyanohydrin was developed for the synthesis of various types of indole-3-acetonitrile derivatives.