Electrochemically driven cross-electrophile coupling of alkyl halides

Abstract

Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp³ carbons—those bonded to four other atoms—in drug candidates and their improved success rate in clinical trials. As such, the development of robust and selective methods for the construction of carbon(sp³)–carbon(sp³) bonds remains a critical problem in modern organic chemistry. 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. 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(sp³)–carbon(sp³) 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.

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