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Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184087
10.21203/rs.3.rs-3645899/v1
10.21203/rs.3.rs-3645899
preprint
1
Article
Enantioconvergent Copper-Catalysed Difluoromethylation of Alkyl Halides
Liu Wei
Ding Decai
Yin Lingfeng
Poore Andrew https://orcid.org/0009-0007-1650-0471

Ho Yeu-Shiuan
Cheng Yu-Ho
Hsieh Chi-Tien
Yachuw Stephen
Knieser Rachael
Krause Jeanette
Tian Shiliang https://orcid.org/0000-0002-9830-5480

Cheng Mu-jeng https://orcid.org/0000-0002-8121-0485

16 8 2024
rs.3.rs-3645899https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-3645899/v1
nihpp-rs3645899v1.pdf
Abstract

Stereochemical-controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF2H) groups at chiral centers are emerging as pivotal components in pharmaceuticals due to their distinct hydrogenbonding property. However, a general approach for introducing CF2H groups in an enantioselective manner remained elusive. Here, we show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a new strategy for constructing CF2H-containing stereocenters. This strategy is enabled by using copper catalysts bound with a chiral diamine ligand bearing electron-deficient phenyl groups, and a nucleophilic difluoromethyl-zinc reagent. This method allows for the high-yield conversion of a diverse range of alkyl halides into their alkyl-CF2H analogs with excellent enantioselectivity (up to 99% e.e.). Mechanistic studies, supported by DFT calculations, revealed a route involving asymmetric difluoromethylation of alkyl radicals and crucial non-covalent interactions in the enantio-determining steps.
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