Cu(â… )-Catalyzed Transannulation Of N-Heteroaryl Aldehydes Or Ketones With Alkylamines Via C(sp~3)-H Amination

Imidazo[1,5-α]pyridines represent an important class of heterocyclic compunds because Imidazo[1,5-α]pyridine derivatives are widely utilized as key buiding blocks in both pharmacuetical industries and material chemistry. Based on the traditional Vilsmeier-type protocol, alternative synthetic methods have been successfully developed to construct Imidazo[1,5-α] N-heterocycles in which an excess amount of activating reagents such as iodine, S8, etc. were employed.We have developed the Cu(Ⅰ)-catalyzed direct Csp3-H amination of 2-acylpyridines with aliphatic amines to construct multifunctional imidazo[1,5-α]pyridines. We screened the reaction conditions for the temperature, catalyst, reaction time and solvent, etc. and finally found that CuBr(20.0 mol %) as catalyst, N-Heteroaryl aldehydes or ketones (0.1 mmol), alkylamines (0.1 mmol) as reagents in acetonitrile (2.0 mL) at 80℃ for 12 h could afford a moderate to good yield of imidazo[1,5-α]pyridines. On the basis of these promising screening results we next investigated the scope of the current procedure by testing various pyridine derivatives and amine derivatives via the Cu(Ⅰ)-catalyzed one-pot C(sp3)-H amination/cyclization amination/cyclization.21 Imidazo[1,5-α]pyridine derivateds were obtained and characterized by IR, HRMS and NMR.To further investigate the primary mechanism of the present Cu(Ⅰ)-catalyzed C(sp3)-H amination, several controlled reactions were carried out. Based on relevant reactions regarding the Cu(Ⅰ)-dioxygen catalytic system, we depict a plausible catalytic cycleWe herein have developed the first Cu(Ⅰ)-catalyzed direct C(sp3)-H amination of 2-acylpyridines with aliphatic amines to construct multifunctional imidazo[1,5-α]pyridines via a onepot tandemprocess employing aerial oxygen as the green oxidant, in which N-heteroarenes were used as amine sources.