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

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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-dicarbonyl 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.

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

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Publication details

The article was received on 21 Aug 2019, accepted on 16 Sep 2019 and first published on 16 Sep 2019


Article type: Edge Article
DOI: 10.1039/C9SC04185K
Chem. Sci., 2019, Advance Article
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    Enolization rates control mono- versus di-fluorination of 1,3-dicarbonyl derivatives

    N. Rozatian, A. Beeby, Ian W. Ashworth, G. Sandford and D. R. W. Hodgson, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC04185K

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