Regioselective N1 ‐Alkylation for the Synthesis of Antitumor Evodiamine Analogs via a Hydrogen‐Borrowing Strategy
Qiming Cheng, Liangfeng Wang, Yi‐Fan Geng, Xu Tang, Mulan Gong, Fangjiang Cui, Jun‐Cheng Su, Guixia Wang, Xiangfei KongABSTRACT
The N1 alkylation of the indole moiety was achieved via a hydrogen borrowing strategy using an inexpensive nickel catalyst, [(PPh 3 ) 2 NiCl 2 ], with high regioselectivity. The reaction yield was higher under a nitrogen atmosphere than in air; however, the highest yield was achieved when the reaction was initiated under vacuum conditions. The proposed mechanism—comprising alcohol dehydrogenation, nucleophilic addition of the resulting aldehyde, and hydrogenation of the C═C double bond—was verified by LC‐MS analysis of reaction intermediates and density functional theory (DFT) calculations. This method enabled the straightforward synthesis of 26 evodiamine analogs in yields ranging from 43% to 91%. Preliminary biological evaluation indicated that several analogs exhibit potent in vitro antitumor activity.