Abstract
Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp(3) carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials(1). As such, the development of robust and selective methods for the construction of carbon(sp(3))-carbon(sp(3)) bonds remains a critical problem in modern organic chemistry(2). Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective(3-5). Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp(3))-carbon(sp(3)) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.