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

Abstract

AbstractSeveral 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.