Scale-Up and Optimization of a Continuous Flow Carboxylation of N-Boc-4,4-difluoropiperidine Using s-BuLi in THF

Abstract

We report a large-scale carboxylation of N-Boc-4,4-difluoropiperidine (1) enabled by a continuous flow process. The flow process involved N-Boc-directed α-deprotonation using s-BuLi in THF and subsequent trapping with CO2 gas. Flow chemistry enabled the safe and scalable preparation of 400 g of carboxylic acid 2 over the course of a day to support our medicinal chemistry research program.

Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles

“…51, Despite these advantages, generation of organolithium species in flow is dominated by halogen-lithium exchanges, with C-H metalations (and particularly Csp 3 -H metalations) comparatively underexplored. 24,[80][81][82][83][84][85][86] Recently, we reported a continuous flow lithiation-substitutions of alkyl-1,3,4-oxadiazoles with a 1.3 s reactor residence time for lithiation before in-flow electrophilic trapping. 24 Quantitative yields were obtained at rt which were not replicable under comparable conditions in a batch reactor, and we were therefore inspired to investigate C-H functionalisations of 5-alkyltetrazoles in flow.…”