A sustainable one-pot three step approach for the synthesis of 3,5-disubstituted 1,2,4-triazines as versatile pharmacological tools.

1,2,4-Triazines are an important class of six-membered aromatic heterocycles which have demonstrated a wide range of pharmacological applications, showcasing properties that extend to anticonvulsant, antithrombotic, antibacterial, antimalarial, antiviral, anti-inflammatory, and anticancer activities.1,2 While various strategies for synthesizing 1,2,4-triazines have been reported, they often require multiple steps/purifications, harsh reaction conditions, activation by toxic metals/oxidants, longer reaction times, use of complex synthetic precursors, and sometime lead to the formation of multiple regioisomers.2 We report herein the first microwave-assisted one-pot three-step metal-free [4+2] procedure for the synthesis of 3-hydrazinyl-1,2,4-triazine directly from commercially available aromatic and heteroaromatic ketones (1). The optimized protocol allowed us to quickly generate substituted 5-aryl/heteroaryl-3-hydrazineyl-1,2,4-triazines (5) in good overall yields which were further elaborated by a µW-assisted condensation with a wide range of aldehydes/ketones to provide a collection of hydrazone-derivatives (7). The developed synthetic approach proceeds under mild conditions, with good functional group compatibility and represent a versatile, rapid, and efficient tool for the generation of new highly functionalized 1,2,4-triazines derivatives of potential biological interest.3