TBHP-mediated denitrogenative synthesis of pyridine carboxamides from pyridine carbohydrazides and amines in water

Abstract

Isoniazid (isonicotinic acid hydrazide) is used as an antibiotic to treat tuberculosis and mechanistic studies indicate that the intermediately formed isonicotinoyl radical is the active form of the drug. However, the application of this and other pyridine acyl radicals in organic synthesis is largely unexplored. We have now studied the generation of these radicals and their subsequent reactivity with polarity-matched coupling partners. The radicals can be generated in situ through a tert-butyl hydroperoxide (TBHP)-mediated denitrogenation of the corresponding pyridine carbohydrazides. Those radicals then react with various amines yielding pyridine carboxamides in 50–93% yield. The key advantages of this synthetic method include the use of mild and metal-free reactions conditions, water as the solvent, a wide substrate scope, and an excellent functional-group tolerance, which was demonstrated in the synthesis of primary, secondary, and tertiary amides and pharmaceuticals. Further experimental studies revealed that this method is extendable to other acyl radicals and, thus, provides a complementary method to the available protocols. Computational studies further support the electronic nature and predicted reactivity of these pyridine acyl radicals.