Asymmetric N-Alkylation of 1H-Indoles via Carbene Insertion Reaction

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N-H bond insertion reaction. N-Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both alpha-aryl and alpha-alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X-H (X=N, O, S et al.) and C-H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.

Automated summary

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed using a cooperative rhodium and chiral phosphoric acid catalyzed N-H bond insertion reaction. The reaction produces N-alkyl indoles with high yields and excellent enantioselectivities, even with both alpha-aryl and alpha-alkyl diazoacetates. This method requires only a small amount of rhodium catalyst and chiral phosphoric acid, and computational studies provide insights into the mechanism and selectivity.