Regioselective Synthesis of Novel [1,2,4]Triazolo[1,5‐a]pyridine Derivatives

Abstract

AbstractHerein we report the reaction of 2‐(5‐aryl‐4H‐1,2,4‐triazol‐3‐yl)acetonitriles 1 a,b with appropriate Michael acceptors 2–4 to give novel [1,2,4]triazolo[1,5‐a]pyridines 5–8, whose antioxidant properties have been investigated. A plausible reaction mechanism, supported by DFT calculations, has been proposed to explain the total observed regioselective formation of [1,2,4]triazolo[1,5‐a]pyridine derivatives depending on the type of substituents on the Michael acceptor.Triazoles are well‐known agents exhibiting antimicrobial,[1] antitumor,[2] anti‐inflammatory,[3] antihypertensive,[4] anticonvulsant,[5] antiviral[6] and analgesic[7] biological activities. On the other hand, pyridine is the key core of heterocyclic derivatives showing a variety of pharmacological properties.[8–12] Several studies have revealed that a combination of different bioactive molecules, having different mechanisms of action, is a current strategy affording useful therapeutic agents.[13] This is the case of the [1,2,4]triazolo[1,5‐a] pyridine heterocyclic motif,[14] present in a number of bioactive compounds,[15] and largely used in materials chemistry.[16] Accordingly, diverse synthetic methods have been described for the synthesis of differently substituted [1,2,4]triazolo[1,5‐a]pyridines.[17–24] Our group has recently reported the ultrasound‐promoted facile and convenient “one‐pot” procedure for the synthesis of novel [1,2,4]triazolo[1,5‐a]pyridines in short reaction times and high yields, based on the reaction of 2‐(5‐aryl‐4H‐1,2,4‐triazol‐3‐yl)acetonitriles, malononitrile (or ethyl cyanoacetate) and aromatic aldehydes, in absolute ethanol, in the presence of IRA‐400.[25]