Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides

Abstract

Recent research in medicinal chemistry suggests a correlation between an increase in the fraction of sp3 carbons in drug candidates with their improved success rate in clinical trials. As such, the development of robust and selective methods for the construction of C(sp3)-C(sp3) bonds remains a critical problem in modern organic chemistry. Owing to the broad availability and synthetic accessibility of alkyl halides, their direct cross coupling—commonly known as cross-electrophile coupling (XEC)—provides a promising route toward this objective. However, achieving high selectivity in C(sp3)-C(sp3) XEC remains a largely unmet challenge. Herein, we employ 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 (SN2) to forge a new C–C bond. This transition-metal free protocol enables the efficient XEC of a variety of functionalized and unactivated alkyl electrophiles and exhibits substantially improved chemoselectivity versus existing methodologies.

Aliphatic Hydrosilanes via Nickel-Catalyzed Reductive Csp3–Si Coupling of Primary Alkyl Bromides and Chlorohydrosilanes

“…11 In 2022, our group reported a nickel-catalyzed reductive C−Si coupling between R 2 Si(H)Cl and Ar/Vinyl−X, where the Si− Cl bond was selectively cleaved (Scheme 1b-1, Shu 2022). 12 The carbon coupling partners were later expanded to Ar− OCO t Bu 13 and bromostyrenes 14 by Zeng and Ye groups using chromium and iron catalysts, respectively (Scheme 1b-1). However, these reactions have predominantly focused on Csp 2 −Si couplings.…”