Regioselective N1-Alkylation for the Synthesis of Antitumor Evodiamine Analogs via a Hydrogen-Borrowing Strategy

2026-06-24

PRE

Qiming Cheng

Liangfeng Wang

Yi-Fan Geng

Xu Tang

Mulan Gong

Fangjiang Cui

Jun-Cheng Su *

Guixia Wang *

Xiangfei Kong *

DOI：10.1002/ajoc.70458

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The N1 alkylation of the indole moiety was achieved via a hydrogen borrowing strategy using an inexpensive nickel catalyst, [(PPh3)2NiCl2], 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.

Keywords:

antitumor activities

evodiamine analogs

hydrogen-borrowing

nickel catalyst

Regioselective N1-Alkylation for the Synthesis of Antitumor Evodiamine Analogs via a Hydrogen-Borrowing Strategy

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