A sustainable metal-free microwave-assisted one-pot step [4+2] annulation for the synthesis of 3,5-disubstituted 1,2,4-triazines.

1,2,4-Triazines are an important class of six-membered aromatic heterocycles. Notably, 1,2,4-triazine derivatives have demonstrated a wide range of pharmacological applications, showcasing properties that extend to anticonvulsant, antithrombotic, antibacterial, antimalarial, antiviral anti- inflammatory, and anticancer activities.1 In addition to their wide pharmacological potential, 1,2,4-triazines and their analogs have also found applications as clickable bio-orthogonal probes,2 and as a starting material for the production of highly substituted pyridines via inverse electron demand hetero-Diels-Alder (IEDDA) cycloaddition reactions.3 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 or excess amounts of acid or base, longer reaction times, use of scarcely available or complex synthetic precursors, and sometime lead to the formation of multiple regioisomers.3 In the attempt to provide a more efficient, versatile, and environmentally friendly method to quickly explore the 1,2,4-triazine pharmacophore fragment, 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 one-pot 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 mW-assisted condensation with a wide range of aromatic or aliphatic aldehydes/ketones to provide a collection of hydrazone-derivatives of the 1,2,4-triazine scaffold (7). The developed synthetic approach proceeds under mild conditions, with good functional group compatibility and represent a versatile, rapid, and efficient tool for the rapid generation of new highly functionalized 1,2,4-triazines derivatives of potential biological interest.4