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Enolization rates control mono- versus di-fluorination of 1,3-dicarbonyl derivatives

Rozatian, Neshat; Beeby, Andrew; Ashworth, Ian W.; Sandford, Graham; Hodgson, David R.W.

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Authors

Neshat Rozatian

Ian W. Ashworth

Graham Sandford



Abstract

Fluorine-containing 1,3-dicarbonyl derivatives are essential building blocks for drug discovery and manufacture. To understand the factors that determine selectivity between mono- and di-fluorination of 1,3-dicarbonyls systems, we have performed kinetic studies of keto-enol tautomerism and fluorination processes. Photoketonization of 1,3-diaryl-1,3-dicarbonyl derivatives and their 2-fluoro analogues is coupled with relaxation kinetics to determine enolization rates. Reaction additives such as water accelerate enolization processes, especially of 2-fluoro-1,3-dicarbonyl systems. Kinetic studies of enol fluorination with Selectfluor™ and NFSI reveal the quantitative effects of 2-fluorination upon enol nucleophilicity towards reagents of markedly different electrophilicity. Our findings have important implications for the synthesis of α,α-difluoroketonic compounds, providing valuable quantitative information to aid in the design of fluorination and difluorination reactions.

Citation

Rozatian, N., Beeby, A., Ashworth, I. W., Sandford, G., & Hodgson, D. R. (2019). Enolization rates control mono- versus di-fluorination of 1,3-dicarbonyl derivatives. Chemical Science, 10(44), 10318-10330. https://doi.org/10.1039/c9sc04185k

Journal Article Type Article
Acceptance Date Sep 16, 2019
Online Publication Date Sep 16, 2019
Publication Date Nov 28, 2019
Deposit Date Sep 16, 2019
Publicly Available Date Jan 8, 2020
Journal Chemical Science
Print ISSN 2041-6520
Electronic ISSN 2041-6539
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 10
Issue 44
Pages 10318-10330
DOI https://doi.org/10.1039/c9sc04185k

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