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.
Highlights
Fluorinated compounds have fundamental roles within the pharmaceutical, agrochemical and materials industries.[1,2,3,4] The presence of a uorine atom imparts profound effects upon the physical, chemical and biological properties of drugs and plant protection agents such as ProzacTM, Lipitor®, cipro oxacin and diclosulam.[5]
Our efforts towards the quanti cation of the factors which affect mono- versus di uorination are two-fold; in the rst instance, we focus on the effects of different reaction conditions on the keto–enol tautomerism of the 1,3-diaryl-1,3dicarbonyl derivatives 4a–d and 5a–d
We have shown through kinetics studies that the addition of water is a simple method for increasing the rate of enolization and increasing the rate of formation of 2,2-di uoro-1,3-dicarbonyl 6a
Summary
Fluorinated compounds have fundamental roles within the pharmaceutical, agrochemical and materials industries.[1,2,3,4] The presence of a uorine atom imparts profound effects upon the physical, chemical and biological properties of drugs and plant protection agents such as ProzacTM, Lipitor®, cipro oxacin and diclosulam.[5] Such compounds are o en synthesised from uorine-containing building blocks;[6] a key example is the antifungal agent voriconazole,[7] which is synthesised from a 5 uoropyrimidine intermediate that is prepared from a 2- uoro1,3-ketoester derivative In this context, nding selective and efficient routes towards the uorination of 1,3-dicarbonyl derivatives has been the subject of signi cant interest. The photochemistry and photophysics of 1,3-diaryl-1,3-dicarbonyl derivatives have been extensively studied.[40,41] In the 1970s, the groups of Markov[42,43] and Mazur[44,45,46] reported photoisomerization of 1,3-dicarbonyl compounds, whereby the keto–enol equilibrium was perturbed towards the keto tautomer upon irradiation This process reverses to attain the tautomeric equilibrium by a nonphotochemical reaction in darkness. We explore and discuss the kinetics of uorination of enols 4a–d and uoroenols 5a–d and the effects of solvent composition upon these processes
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