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

Herein 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])