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.

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
• Public URL: https://durham-repository.worktribe.com/output/1291566