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Electrochemically driven cross-electrophile coupling of alkyl halides

Zhang, Wen and Lu, Lingxiang and Zhang, Wendy and Wang, Yi and Ware, Skyler D. and Mondragon, Jose and Rein, Jonas and Strotman, Neil and Lehnherr, Dan and See, Kimberly A. and Lin, Song (2022) Electrochemically driven cross-electrophile coupling of alkyl halides. Nature, 604 (7905). pp. 292-297. ISSN 0028-0836. doi:10.1038/s41586-022-04540-4. https://resolver.caltech.edu/CaltechAUTHORS:20211213-518504000

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-022-04540-4DOIArticle
https://rdcu.be/cHx09PublisherFree ReadCube access
https://doi.org/10.26434/chemrxiv-2021-c2hd6-v2DOIDiscussion Paper
https://pubs.acs.org/doi/10.1021/cen-10009-scicon3Featured Inc&en : Synthesis
ORCID:
AuthorORCID
Zhang, Wen0000-0002-0704-3463
Lu, Lingxiang0000-0001-9168-6121
Ware, Skyler D.0000-0002-3249-1946
Rein, Jonas0000-0001-8237-6519
Strotman, Neil0000-0002-5350-8735
Lehnherr, Dan0000-0001-8392-1208
See, Kimberly A.0000-0002-0133-9693
Lin, Song0000-0002-8880-6476
Additional Information:© The Author(s), under exclusive licence to Springer Nature Limited 2022. Received 10 October 2021. Accepted 10 February 2022. Published 21 February 2022. Financial support was provided by NIGMS (R01GM134088; to S.L.), NSF Center for Synthetic Organic Electrochemistry (CHE-2002158; to K.A.S.), and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S.L. is grateful to the Research Corporation for Science Advancement for a Cottrell Scholar Award. This study made use of the NMR facility supported by the NSF (CHE-1531632). XPS data were collected at the Molecular Materials Research Center in the Beckman Institute of the California Institute of Technology. We thank C. Yang for providing propargylic chloride substrates. Data availability: All data supporting the findings of this work are available within the paper and its Supplementary Information. Contributions: S.L. and K.A.S. supervised the project. N.S. and D.L. provided guidance on the project. Wen Zhang and S.L. conceived the work. Wen Zhang, L.L., N.S., D.L. and S.L. designed the experiments. Wen Zhang. and L.L. conducted the synthetic experiments and mechanism studies. Wendy Zhang, S.D.W. and K.A.S. conducted the analysis of electrode passivation. Y.W., J.M. and J.R. conducted the density functional theory calculations. Wen Zhang, L.L., Wendy Zhang, K.A.S. and S.L. wrote the manuscript. N.S., D.L. and S.D.W. edited the manuscript. The authors declare no competing interests. Peer review information: Nature thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.
Funders:
Funding AgencyGrant Number
NIHR01GM134088
NSFCHE-2002158
Merck Sharp and DohmeUNSPECIFIED
Cottrell Scholar of Research CorporationUNSPECIFIED
NSFCHE-1531632
Subject Keywords:Electrochemistry; Synthetic chemistry methodology
Issue or Number:7905
DOI:10.1038/s41586-022-04540-4
Record Number:CaltechAUTHORS:20211213-518504000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211213-518504000
Official Citation:Zhang, W., Lu, L., Zhang, W. et al. Electrochemically driven cross-electrophile coupling of alkyl halides. Nature 604, 292–297 (2022). https://doi.org/10.1038/s41586-022-04540-4
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112372
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:13 Dec 2021 23:25
Last Modified:14 Apr 2022 19:56

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