Continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles via consecutive β-azidation of α,β-unsaturated carbonyl compounds and CuAAC reactions

Abstract

We herein report a multi-step flow protocol for the synthesis of 1,4-disubstituted 1,2,3-triazoles starting from α,β-unsaturated carbonyls. Best results, both in terms of chemical productivity and sustainability, were obtained using a sequential combination of two flow reactors: one packed with a tailor-made POLITAG-F organocatalytic system and a copper tube apparatus. Moreover, the use of aqueous acetonitrile azeotrope led to excellent catalytic performances in both the developed processes while affording a waste-minimized multi-step protocol. Indeed, the azide intermediates subsequently reacted without the need for an additional purification step, and the aqueous acetonitrile azeotrope could be largely recovered/reused at the end of the process. 1,4-disubstituted β-keto 1,2,3- triazoles were obtained with high yields, which can be associated with low E-factor values. Finally, the green metrics evaluation of the process is also given to quantify the advantages associated with the use of our flow strategy.