Transition-metal-catalyzed C–H bond functionalization has drawn prodigious attention of organic chemists as it is capable to expedite the introduction of structural diversity into N-heterocyclic frameworks compared to the conventional approaches relying on functional group manipulation. In this field, the 4d and 5d transition-metals such as Pd, Rh, Ru, and Ir have been extensively investigated. Recently, Co, an earth abundant 3d transition-metal, has emerged as a promising catalyst owing to its easy accessibility, affordability, and environmentally benign nature. The utmost significance of alkylated N-heterocycles is dictated by their ubiquitous occurrence in the core structures of pharmaceuticals and investigational candidates. The alkyl groups can play various roles in drug design and action, such as occupying hydrophobic pockets, changing binding properties of a basic nitrogen atom, protecting against oxidative metabolism as well as acting as linkers within molecules. Therefore, the selective installation of alkyl groups into N-heterocyclic lead candidates has the potential to dramatically alter their pharmacodynamic and pharmacokinetic properties. Herein, we report the unprecedented cobalt(II)-catalyzed C–H alkylation and acylation of N-heterocycles with 1,4-dihydropyridines (DHPs) as alkylating and acylating agents. Notably, a combination of KBrO3 and Co(II) catalyst was successfully employed for the generation of alkyl and acyl radicals from DHPs. A series of heterocycles including azauracils, quinoxalinones, pyrazinones, pyridones, quinolones, quinazolinones, xanthines, chromones, and azine N-oxides were compatible under the developed conditions. The applicability of the developed protocol in challenging contexts is highlighted by the selective modification of drugs candidates as well as the gram-scale synthesis of bioactive molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

C(sp2)–H alkylation of N-heterocycles using 1,4-dihydropyridines via cobalt(II)-catalyst

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