Photocatalyzed radical multicomponent alkylacylation of [1.1.1]propellane to synthesize 1,3-disubstituted BCP ketones

Abstract

Bicyclo[1.1.1]pentylketones (BCP ketones) are becoming increasingly significant in pharmaceutical chemistry as sp³-rich bioisosteres of aryl ketones. However, the limited availability of efficient synthetic methods for BCP ketones is impeding early-stages of drug discovery in pharmaceutical chemistry. In this study, we present a photoredox-enabled protocol for the facile synthesis of unsymmetrical 1,3-disubstituted BCP ketones. By utilizing a diverse range of hypervalent iodine salts as alkyl precursors and inexpensive aryl aldehydes as acyl precursors, we can readily convert [1.1.1]propellane into 1,3-disubstituted BCP ketones in moderate to good yields. This reaction proceeds at room temperature, is operationally simple, works under redox-neutral conditions, and exhibits a broad substrate scope with high functional group tolerance. Additionally, further transformation of BCP ketones into a variety of other BCP derivatives demonstrates the synthetic value of this developed method.