Cobaltaelectro-Catalyzed C–H Annulation with Allenes for Atropochiral and P-Stereogenic Compounds: Late-Stage Diversification and Continuous Flow Scale-Up

Abstract

The 3d metallaelectro-catalyzed C–H activation has been identified as an increasingly viable strategy to access valuable organic molecules in a resource-economic fashion under exceedingly mild reaction conditions. However, the development of enantioselective 3d metallaelectro-catalyzed C–H activation is very challenging and in its infancy. Here, we disclose the merger of cobaltaelectro-catalyzed C–H activation with asymmetric catalysis for the highly enantioselective annulation of allenes. A broad range of C–N axially chiral and P-stereogenic compounds were thereby obtained in good yields of up to 98% with high enantioselectivities of up to >99% ee. The practicality of this approach was demonstrated by the diversification of complex bioactive compounds and drug molecules as well as decagram scale enantioselective electrocatalysis in continuous flow.

Nickel-electrocatalyzed enantioselective C–H activations for chemo-divergence

“…The enantioselective desymmetrization strategy encompassed a broad scope (Fig. 2b), yielding the desired carboacylation products 5-16 in high yields and excellent enantiomeric control, including substrates bearing thioether (8), cyano (9), or carboxylic ester (10,11,14) groups, among others.…”

Enantioselective C–H bond functionalization under Co(iii)-catalysis

“…The synthetic potential was further extended to a continuous flow reactor setup without any supporting electrolyte yielding the same stereo-electronic product with a slight modification of the reaction conditions (Scheme 12c). 53…”

Nickel-Catalyzed Atroposelective C–H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands

“…In light of the growing significance of atropisomerism in both fundamental research and industrial applications, , there is an urgent demand for developing new atropisomeric frameworks , coupled with efficient and sustainable methodologies. While the past years have witnessed great progress in the enantioselective synthesis of optically pure atropisomers, , especially C–N axially chiral skeletons, , these heavily rely on precious and potentially toxic transition metals, constraining the development of this approach. − Recently, the synthesis of C–N axially chiral compounds was successfully achieved utilizing earth-abundant cobalt catalyst through de novo construction of aryl rings in an atroposelective fashion − or atroposelective C–H functionalization of pre-existing biaryl substrates. , However, the use of other earth-abundant and less toxic 3d metals to achieve atroposelective C–H functionalization remains unexplored yet highly desirable.…”

“…Based on our continued interest in the development of HASPO preligands ,− and 3d metal-catalyzed atroposelective C–H functionalization, ,, we report herein the unprecedented, nickel-catalyzed atroposelective C–H alkylation to deliver C–N axially chiral benzimidazole derivatives with high enantioselectivities (Figure c). Salient features include the first example of nickel-catalyzed atroposelective C–H activation, the design of novel chiral HASPO preligands for enantioselective catalysis, and ample scope.…”