Cobalt(II)-Catalyzed C-H Alkylation of N-Heterocycles with 1,4-Dihydropyridines

The rapid incorporation of alkyl and acyl groups into C-H bonds of N-heterocycles is in demand for the development of lead candidates in drug discovery. Herein, we report the 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 a 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 drug candidates as well as the gram-scale synthesis of bioactive molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

Automated summary

In this study, a cobalt(II)-catalyzed method for C-H alkylation and acylation of N-heterocycles using 1,4-dihydropyridines (DHPs) as alkylating and acylating agents was reported. The combination of KBrO3 and a Co(II) catalyst successfully generated alkyl and acyl radicals from DHPs. This method was applicable to various heterocycles and demonstrated selectivity in modifying drug candidates and synthesizing bioactive molecules on a gram scale.