Abstract
A continuous flow approach to access α-trifluoromethylthiolated esters and amides using commercially available arylacetic acids and N-(trifluoromethylthio)phthalimide as the electrophilic reagent is described. The experimental protocol involves the in-flow conversion of the carboxylic acid into N-acylpyrazole followed by the α-trifluoromethylthiolation in a PTFE coil reactor and final reaction with primary or secondary amines, or alcohols, to afford in a telescoped process α-substituted SCF3 amides and esters, respectively, in good overall yield and short reaction times.
Highlights
The growing interest in academia and industrial context, toward effective and large-scale syntheses of intermediates and active pharmaceutical ingredients (APIs), has seen the flourishing of flow chemistry as a powerful enabling technology
We recently reported the α-trifluoromethylthiolation of Nacyl pyrazoles using N,N,N’,N’-tetramethyl-1,8-naphthalenediamine as a catalytic base and N(trifluoromethylthio)phthalimide as the electrophilic source
N-Acylpyrazoles are readily available carboxylic acid surrogates,7 which were suitable for undergoing α-functionalization via enolate formation under mild basic conditions (Scheme 1)
Summary
The growing interest in academia and industrial context, toward effective and large-scale syntheses of intermediates and active pharmaceutical ingredients (APIs), has seen the flourishing of flow chemistry as a powerful enabling technology.1 An efficient optimization of the single transformations of a multistep synthesis, under better controlled and mild conditions, may lead to the development of telescoped processes, avoiding isolation of intermediates and maximizing efficiency, practicality, and environmental impact.2.
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