Research Projects

Owing to low cost and commercial feedstock, acyl hydrazides have long been acclaimed as valuable substrates in organic reactions largely in the synthesis of nitrogen-containing heterocycles. The submitted proposal will explore in situ generation of various unprecedented reactive free radicals from different hydrazides via oxidative denitrogenation, their reactivity towards amines with polarity matched or radical polar-crossover by virtue of their global electro- or nucleophilicity, and translational potential to pharmaceuticals synthesis. In our previous study, unexplored pyridine acyl radicals were generated in situ from their corresponding pyridine carbohydrazides via denitrogenation, and subsequently reacted with polarity-matched coupling partners (various amines) to form pyridine carboxamides (Org. Chem. Front., 2022, 9, 6902-6908). Recently, we demonstrated oxidative denitrogenation of formohydrazide (as a source of formyl group) for regioselective N-formylation of various amines and also in the synthesis of N-heterocycles and a Production linked incentive (PLI) scheme drug Chlorothiazide (Org. Lett. 2024, 26, 10013-10019). Subsequently, we developed regioslective acetylation of various amines using acetohydrazide as a novel acetyl radical source via oxidative denitrogenative. The broad scope of the method was demonstrated in the synthesis of pharmaceuticals, drug intermediates, natural products and late-stage functionalization of bioactive molecules (J. Org. Chem.2025, 90, 6392-6406). Based on our previous work on radical functionalizations using acyl hydrazides, we propose whether arylacetohydrazides as radical precursors of arylacetyl radical could undergo coupling with amines via denitrogenation. Unlike conventional amidation, we plan to develop a denitrogenative radical amidation approach for the synthesis of arylacetamides that are otherwise difficult to prepare by conventinonal methods. The investigation will attempt to identify an optimized condition especially under transition-metal-free condition, utilizing a cheap, green and nontoxic reagent under room temperature condition. The wide substrate scope and more importantly, its translational potential to gram-scale synthesis of pharmaceuticals including Efaproxiral and Atenolol will be demonstrated. The generation of arylacetylradical via oxidative denitrogenation of arylacetohydrazides will be attempted to unveil the electronic nature and subsequent reactivity of these radicals via computational tools, CV and EPR studies. Secondly, radical carbamoylation of various amines using semicarbazide as a carbamoyl radical source for synthesizing ureas under mild, aqueous, oxidative denitrogenative conditions will be investigated. Mechanistic study to unveil the involvement of a radical pathway will also be investigated. In this investigation, new process development of anticancer drugs including Sorafenib, Regorafenib, Tivozanib, and Linifanib will be explored. Thirdly, carbonyl insertion into amines forming symmetrical ureas/thioureas using a novel, bench-stable carbonyl/thiocarbonyl surrogates, carbohydrazide and thiocarbohydrazide, respectively via double oxidative denitrogenation will be investigated. The scope including pharmaceutical synthesis and mechanistic study will also be a part of this investigation. Subsequently, we will study an unexplored radical cyanoacetylation of various amines for synthesizing cyanoacetamides and the best-selling drug Teriflunomide using cyanoacetohydrazide as a novel cyanoacetyl radical precursor. Mechanistic studies involving both experimental and computational could help establish the generation of unprecedented cyanoacetyl radical via oxidative denitrogenation, which then could react with amines to produce cyanoacetamides. Subsequent to successive realization of N-functionalizations with all radicals, a key challenge to C-functionalization of aromatic (heteroaromatic) compounds with all these radicals will also be explored.