Divergent, Stereospecific Mono‐ and Difluoromethylation of Boronic Esters

Abstract

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH2F and CHF2 groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α‐fluoro‐boronic esters. These unique intermediates can be readily transformed into the corresponding mono‐ or difluoromethylated compounds through proto‐ or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2‐migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.

A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds

“…Aggarwal reported the synthesis of α-fluoro-boronic ester from fluoroiodomethyl lithium with boronic ester, while the instability of this reagent resulted in its poor performance in cross-coupling reaction. [37] Recently, monofluorocarboxylic acid has been utilized as a fluoroalkylating reagent in decarboxylative cross-coupling with organohalides reported by Koh whereas the scope has been largely restricted to sp 2 -C coupling partner. [38] Indeed, as the most widely used monofluoroalkyalting reagents so far, 1-bromo (or iodine)-1-fluoroalkane has recently been used for modular synthesis of monofluoroalkanes via nickel-catalyzed cross-coupling with alkyl and aryl metals or halides.…”