Formation of C-C Bonds from Unactivated C(sp3)-H Bonds of Hydrosilanes Derived from Common Functional Groups

University Of California Berkeley, Berkeley CA

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Abstract

PROJECT SUMMARY The process of developing novel therapeutics involves the synthesis of many analogs of bioactive compounds to optimize the efficacy, selectivity, and pharmacokinetic profile of potential drug candidates. The functionalization of C–H bonds can expedite this process by enabling the late-stage introduction of functional groups at the positions of typically inert C–H bonds and by eliminating wasteful functional group manipulations. In addition, new reactions at C–H bonds increase the number of potential retrosynthetic disconnections. Methods to form C–C bonds from unactivated C(sp3)–H bonds have been reported but are limited in the scope of suitable substrates, type of C–C bond formed, and ease of synthetic application. Hydrosilanes are readily available from ubiquitous alcohols, ketones, amines, and olefins and have been demonstrated to convert unactivated C(sp3)– H bonds to C–Si and C–B bonds with iridium and rhodium catalysis. However, hydrosilanes have not mediated the direct formation of C–C bonds from unactivated C–H bonds; the development of such transformations would address many of the limitations of current approaches to the functionalization of C–H bonds. This proposal outlines the development of a catalytic method to convert an unactivated C(sp3)–H bond to various C–C bonds by cross-coupling an organohalide electrophile with a C–H bond proximal to a hydrosilyl group. For example, the cross-coupling of an aryl halide with an unactivated C–H bond of a hydrosilyl ether would generate a γ-aryl alcohol derivative. This approach would combine the dehydrogenative silylation of an alcohol, functionalization of a C–H bond, and deprotection of the alcohol in one reaction vessel to effect γ- arylation of an alcohol. The development of this method with various electrophiles, such as aryl, heteroaryl, vinyl, acyl, allyl, benzyl, and alkyl halides, would lead to many categories of functionalized products. The accomplishment of these goals would expand the scope of substrates suitable for C–H bond functionalization, due to the diversity of functional groups that can be modified as hydrosilanes, including alcohols, ketones, amines, and olefins. In addition, this work would expand underdeveloped transformations, such as the heteroarylation, vinylation, acylation, and alkylation of unactivated C(sp3)–H bonds and achieve unreported transformations, such as the allylation of unactivated C(sp3)–H bonds. The scope of this type of C–H bond functionalization will be established for various silyl-modified functional groups, C–H bonds, and electrophiles, enabling regio- and stereoselective C–H functionalization at positions β, γ, and δ to the directing moiety. The application of this method to the late-stage modification of therapeutically relevant compounds is presented and would demonstrate the potential benefit of the proposed research to synthetic and medicinal chemists. Mechanistic experiments are planned to understand this novel C–H functionalization and to test the hypotheses by which this method is designed. The accomplishment of these goals will result in new methods for C–H bond functionalization and C–C bond formation, and access to products previously unavailable in direct fashion.