Oxidative cross-dehydrogenative coupling (CDC) -H bond functionalization:butyl peroxybenzoate (TBPB)-promoted regioselective direct C-3 acylation/benzoylation of 2-indazoles with aldehydes/benzyl alcohols/styrenes

An efficient, cost-effective, transition-metal-free, oxidative C-H cross-dehydrogenative coupling via a C-H bond functionalization protocol for the regioselective direct C-3 acylation/benzoylation of substituted 2H-Indazoles 1a-m with substituted aldehydes 2a-q/benzyl alcohols 5a-e/styrenes 6a-e is reported. The operationally simple protocol proceeds in the presence of tert-butyl peroxybenzoate (TBPB) as an oxidant in chlorobenzene (PhCl) as a solvent at 110 degrees C for 24 h under an inert atmosphere, which furnished a diverse variety of substituted 3-(acyl/benzoyl)-2H-indazoles 3a-q/4a-l in up to 87% yields. The reaction involves a free-radical mechanism and proceeds via the addition of an in situ generated acyl radical (from aldehydes/benzyl alcohols/styrenes) on 2H-indazoles. The functional group tolerance, broad substrate scope, control/competitive experiments and gram-scale synthesis and its application to the synthesis of anti-inflammatory agent 11 and novel indazole-fused diazepine 13 further signify the versatile nature of the developed methodology.

Automated summary

An efficient and cost-effective protocol for regioselective direct C-3 acylation/benzoylation of substituted 2H-Indazoles with substituted aldehydes/benzyl alcohols/styrenes via a transition-metal-free oxidative C-H bond functionalization has been developed. The reaction proceeds via a free-radical mechanism and shows versatile nature with good functional group tolerance and gram-scale synthesis capability, demonstrating potential applications in drug synthesis.