NiH-catalyzed anti-Markovnikov hydroamidation of unactivated alkenes with 1,4,2-dioxazol-5-ones for the direct synthesis of N-alkyl amides

Bingnan Du; Chun-Ming Chan; Yuxin Ouyang; Kalok Chan; Zhenyang Lin; Wing-Yiu Yu

doi:10.1038/s42004-022-00791-4

NiH-catalyzed anti-Markovnikov hydroamidation of unactivated alkenes with 1,4,2-dioxazol-5-ones for the direct synthesis of N-alkyl amides

Commun Chem. 2022 Dec 22;5(1):176. doi: 10.1038/s42004-022-00791-4.

Authors

Bingnan Du¹, Chun-Ming Chan¹, Yuxin Ouyang¹, Kalok Chan², Zhenyang Lin³, Wing-Yiu Yu⁴

Affiliations

¹ State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
² Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, PR China.
³ Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, PR China. chzlin@ust.hk.
⁴ State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. wing-yiu.yu@polyu.edu.hk.

Abstract

The addition of a nitrogen-based functional group to alkenes via a direct catalytic method is an attractive way of synthesizing value-added amides. The regioselective hydroamidation of unactivated alkenes is considered one of the easiest ways to achieve this goal. Herein, we report the NiH-catalyzed anti-Markovnikov intermolecular hydroamidation of unactivated alkenes enabled by using 2,9-dibutylphenathroline (diBuphen) as the ligand. This protocol provides a platform for the direct synthesis of over 90 structurally diverse N-alkyl amides using dioxazolones, which can be easily derived from abundant carboxylic acid feedstocks. This method succeeds for both terminal and internal unactivated alkenes and some natural products. Mechanistic studies including DFT calculations reveal an initial reversible insertion/elimination of the [NiH] to the alkene, followed by the irreversible amidation to furnish the N-alkyl amides. By crossover experiments and deuterium labeling studies, the observed anti-Markovnikov regioselectivities are suggested to be controlled by the sterical environment of the coupling reaction.