Enantioselective Copper-Catalyzed Radical Cyanation of Propargylic C–H Bonds: Easy Access to Chiral Allenyl Nitriles

Abstract

The first enantioselective copper-catalyzed cyanation of propargylic C−H bonds via radical relay was established using novel Box OTMS ligands, providing an efficient and straightforward tool for the construction of structurally diverse chiral allenyl nitriles in good yields with excellent enantioselectivities. This reaction features high functional group tolerance and mild conditions. In addition, the chiral allene products can be readily converted to other chiral compounds via axis-to-center chirality transfer.

Copper-catalyzed radical relay in C(sp3)–H functionalization

“…Very recently, interesting enantioselective propargylic (aryl) C–H cyanations were reported to deliver various enantiomerically enriched allenylnitriles efficiently, but there was no observation of chiral propoarylic nitriles. 91 Although an unactivated C(sp 3 )–H bond could be converted into carbon radicals via HAT, there is still no general method to intercept unstabilized carbon radicals asymmetrically via copper catalysis. In addition, due to the bulky chiral ligands which are required for enantioselective control, asymmetric tertiary C(sp 3 )–H bond functionalization via a copper catalyst is less developed.…”

Radical transformations for allene synthesis

“… 14 In 2021, G. Liu, Lin, and coworkers discovered, for the first time, an approach for the synthesis of chiral allenes 32 directly from enantioselective copper-catalyzed cyanation of propargylic C–H bonds. 52 A new type of box OTMS ligands L6 was designed and the structurally diverse chiral allenyl nitriles can be obtained in good yields and with excellent enantioselectivities. The chiral allenes can be smoothly converted into other enantioenriched organic compounds via axis-to-center chirality transfer.…”

Recent advances in the metal-catalyzed asymmetric synthesis of chiral allenes

“…Enantioselective cyanation of benzyl alkynes via a copper-catalyzed radical relay was disclosed by Liu and co-workers in 2021, leading to chiral allenyl nitriles 205 in good yields with high enantioselectivity under mild conditions. 48 On the basis of DFT calculations and experimental results, a possible reaction pathway was proposed, as depicted in Scheme 32. Initially, Cu-NCR species 206 was formed through CuOAc, L28 and TMSCN, which went through hydrogen-atom-transfer to deliver allenyl radical 208 along with copper species 209 .…”