Selective sp3 C–H alkylation via polarity-match-based cross-coupling

Using a triple catalytic approach, a selective sp3 C–H alkylation is demonstrated that is applicable in late-stage functionalization of pharmaceutical compounds. Given their ubiquity in organic molecules, the functionalization of C–H bonds is a long-standing pursuit in synthetic chemistry. Although numerous C(sp3)–C(sp2) coupling reactions have been developed, C(sp3)–C(sp3) bond formation under mild conditions remains a challenge. Here, David MacMillan and colleagues use a triple catalytic approach (photoredox, nickel and hydrogen-atom transfer) to alkylate C–H bonds next to heteroatoms. Such C–H activation typically requires strong lithium bases at low temperatures. When combined, this set of catalysts enables polarity reversal in the hydrogen-atom transfer, allowing the most hydridic C–H bond to be functionalized with alkyl bromides or tosylates. The potential of this chemistry for late-stage functionalization is highlighted by the alkylation of Prozac. The functionalization of carbon–hydrogen (C–H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence1. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C–H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl–alkyl fragment coupling. The sp3 C–H alkylation is highly selective for the α-C–H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.