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.

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The site-selective modification of quinolines and their analogs has emerged as a pivotal topic in medicinal chemistry and drug discovery. Herein, we describe the rhodium­(III)-catalyzed C8-alkylation of quinoline N-oxides with maleimides as alkylating agents, resulting in the formation of bioactive succinimide-containing quinoline derivatives. The reaction proceeds under mild conditions with complete functional group tolerance.

The straightforward and rapid incorporation of a thiazolidinedione scaffold into prefunctionalized (hetero)aromatic compounds is in demand for the development of antidiabetic glitazones and other pharmaceuticals. Herein, we report the unprecedented N- and O-directed C–H alkylation of various (hetero)arenes with methylene thiazolidinediones under rhodium(III) catalysis. The applicability of the developed protocol in challenging contexts is exhibited by the late-stage installation of a methylene thiazolidinedione moiety on the C–H bond of commercially available drug molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.