Photoredox-enabled late-stage functionalization of pyrrolidines in batch and flow: rapid access to benzothiazole hybrids as a new class of cholinesterase inhibitors

Abstract

A visible-light-driven photoredox protocol for the α-amino C(sp³)–H heteroarylation of N-aryl pyrrolidines and piperidines with 2-chlorobenzothiazole derivatives in batch and in flow conditions is developed. The transformation proceeds under mild conditions using an iridium photocatalyst in the presence of water, providing efficient access to benzothiazole-amine hybrid structures. After initial optimization in batch, the reaction was successfully translated to microfluidic flow, where enhanced light utilization and improved mass and heat transfer enabled higher productivity and superior energy efficiency compared to batch procedures. The scope of the method encompasses a broad range of substituted N-aryl pyrrolidines and benzothiazoles, affording the desired products in generally good to excellent yields. In total, a diverse library of benzothiazole–pyrrolidine and –piperidine derivatives was synthesized. The obtained compounds were evaluated for their physicochemical properties and biological activity against acetyl- and butyrylcholinesterase enzymes. Several derivatives exhibited inhibition of these enzymes in the micromolar range, with few molecules showing selectivity towards butyrylcholinesterase. In silico ADME analysis indicated favorable lipophilicity and predicted blood–brain barrier permeability. The synergistic combination of photoredox catalysis and microflow technology allowed an efficient and sustainable approach to the late-stage functionalization of biologically relevant amines and the rapid generation of a neuroactive small-molecule library.