Beyond Amide Bond Formation: TCFH as a Reagent for Esterification
Nathaniel R. Luis, Kasey K. Chung, Matthew R. Hickey, Ziqing Lin, Gregory L. Beutner* and David A. Vosburg*
*Bristol Myers Squibb Company, New
Brunswick, New Jersey 08903; Harvey Mudd College, Claremont, California 91711, United States,
Email: gregory.beutner
bms.com, vosburghmc.edu
N. R. Luis, K. K. Chung, M. R. Hickey, Z. Lin, G. L. Beutner, D. A. Vosburg, Org. Lett., 2024, 26, 2045-2750.
DOI: 10.1021/acs.orglett.3c01611
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Abstract
The combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) or pyridine in DCM or MeCN enables the synthesis of esters and thioesters. Optimized conditions provide high yields and selectivity for a range of nucleophiles: from less nucleophilic alcohols to more reactive thiols.
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proposed reaction pathway
Details
The document discusses the use of N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) combined with N-methylimidazole (NMI) for esterification and thioesterification reactions. This method aims to provide a noncorrosive and efficient alternative to traditional acid chloride-based acylation processes. The study highlights the challenges of using less nucleophilic alcohols and more reactive thiols, leading to the identification of conditions that yield high selectivity and efficiency. The research focuses on optimizing reaction conditions using substrates like (S)-2-phenyl propionic acid and various alcohols, revealing that pyridine in dichloromethane (DCM) significantly improves yield and selectivity compared to NMI in acetonitrile (MeCN). The study also explores the scope of esterification and thioesterification reactions, demonstrating good-to-excellent yields across a range of substrates. Mechanistic studies suggest that anhydrides are intermediates in the pyridine-based esterification process, explaining the observed reactivity and selectivity. The findings support the broader adoption of TCFH as a preferred reagent for acylation reactions, offering a safer and more versatile alternative to traditional methods.
Key Words
ID: J54-Y2024
