Working Paper
Authors
- Song Lin
Cornell University ,
- Wen Zhang Cornell University ,
- Lingxiang Lu Cornell University ,
- Wendy Zhang California Institute of Technology ,
- Jose Mondragon Cornell University ,
- Skyler Ware California Institute of Technology ,
- Jonas Rein Cornell University ,
- Neil Strotman Merck & Co., Inc. ,
- Dan Lehnherr Merck & Co., Inc. ,
- Kimberly See California Institute of Technology
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.
Version notes
Corrected typo in the funding information.
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