Computational Studies towards the Optimization of the Synthesis of 1,2,4-Triazolo[1,5-a]pyridine-2-carboxylate: Advantages of Continuous Flow Processing

Several strategies to synthesize desired 1,2,4-triazolo[1,5-a]pyridine-2-carboxylate targets have been reported over the years. The most convenient way features the preparation of the precursor triazolopyridine-N-oxide through a condensation step between sulfilimines and a nitrile oxide species, followed by a deoxygenation step. This paper presents a detailed work on the synthesis of [1,2,4]triazolo[1,5-a]pyridine-2-carboxylate-N-oxide, featuring a synergistic experimental-theoretical approach. Herein, we report the development of an efficient and straightforward method to prepare ethyl [1,2,4]triazolo[1,5-a]pyridine-2-carboxylate 3-oxide in continuous flow. The transfer from batch to flow processing resulted in a significant boost in isolated yield (53 % vs. 31 %) and a decrease in the simultaneous presence of starting materials and product in the reaction media from 4 hours to 3.5 minutes. An in-depth mechanistic study of the reaction using density functional theory provided a deeper understanding of the whole reaction manifold and key indications on how to further improve the process in flow.