Abstract
Electrophilic N-F fluorination agents underpin the introduction of fluorine in aliphatic systems across drug and academic research. The choice of N-F reagent is currently determined through empirical experimentation in the absence of quantitative values for electrophilicities. Here we report an experimentally-determined kinetic reactivity scale for ten N-F fluorinating reagents, including Selectfluor™, NFSI, Synfluor™ and several N-fluoropyridinium salts, in CH3CN. The reactivity scale, which covers eight orders of magnitude, employs para-substituted 1,3-diaryl-1,3-dicarbonyl derivatives to measure relative and absolute rate constants. The para-substituted 1,3-diaryl-1,3-dicarbonyl scaffold delivers a convenient, sensitive spectrophotometric reporter of reactivity that also led to the discovery of a unique form of tautomeric polymorphism.
Highlights
Organo uorine compounds have critically enabling roles in medicinal, agrochemical and material sciences due to the unique properties of the uorine atom.[1]
In order to capture the breadth of reactivities of commonly-used N–F reagents, we adopted the 1,3-diaryl-1,3-dicarbonyl derivatives 1a–m
NMR spectroscopy in CD3CN
Summary
Electrophilic N–F reagents such as Select uorTM,[4] N- uoropyridinium salts[5,6,7] and NFSI8 have been widely utilised by the pharmaceutical industry in both discovery and manufacturing processes. The choice of reagents for the uorination of a new scaffold at the discovery stage has generally been based on a “trial and error” approach rather than an understanding of reactivities of the electrophilic uorinating reagent and its nucleophilic substrate. Other fundamental transformations such as nitration, alkylation, halogenation, sulfonation and Friedel–Cra s processes have been studied extensively by kinetic approaches and predictive reactivity pro les for many reagents are well established.[9,10,11,12] Given the importance of uorination reactions in the chemical, pharmaceutical and materials industries, the lack of predictive reactivity data is surprising. An important eld of study that has emerged is the asymmetric a- uorination of carbonyl substrates, which has been explored with both chiral electrophilic uorinating agents and chiral catalysts.[32,33,34,35] Since the synthetic applications of N–F reagents are too numerous to cover in this paper, we refer to the excellent reviews from the recent literature to give an indication of topical uorination reactions.[36,37,38] in general, the uorination of 1,3dicarbonyl derivatives offers a convenient vehicle for the delivery of building blocks for the preparation of uoroaliphatic and -heteroaromatic systems[39] (e.g. voriconazole – a billion dollar drug marketed by P zer[40])
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