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. 2025 Jun 6;27(22):5720-5725.
doi: 10.1021/acs.orglett.5c01478. Epub 2025 May 21.

2-(Cyanomethyl)benzimidazole Derivatives as 1,3-Dicarbonyl Analogues for a Kinetically Controlled Diastereo- and Enantioselective Mannich-Type Reaction Catalyzed by Chiral Phosphoric Acid

Haiting Ye  1 , Linan Hou  1   2 , Akihiro Takeda  1 , Takuma Sato  1 , Jyothi Yadav  1 , Jun Kikuchi  1 , Ming Bao  2 , Masahiro Terada  1
Affiliations

2-(Cyanomethyl)benzimidazole Derivatives as 1,3-Dicarbonyl Analogues for a Kinetically Controlled Diastereo- and Enantioselective Mannich-Type Reaction Catalyzed by Chiral Phosphoric Acid

Haiting Ye et al. Org Lett. .

Abstract

An asymmetric Mannich-type reaction of N-protected 2-(cyanomethyl)benzimidazoles with N-benzoyl imines was developed by using chiral phosphoric acid as a chiral Brønsted acid catalyst. Products having vicinal trisubstituted carbon stereogenic centers were formed in a highly diastereo- and enantioselective manner, even though one of the stereogenic centers had an active methine proton. Comprehensive control experiments revealed that high stereoselectivity was achieved through a kinetically controlled process.

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Figures

1
1
Tautomerization of a pronucleophile and formation of a nucleophilic addition product. (a) 1,3-Dicarbonyl compound. (b) 2-Alkylbenzimidazole derivative having an EWG and a PG.
1
1. Diastereo- and Enantioselective Mannich-Type Reaction of 2-(Cyanomethyl)­benzimidazoles 1 with N-Benzoyl Imines 2 Catalyzed by CPA (R)-3
2
2. Control Experiments: (a) Monitoring the Reaction, (b) Retro Reaction, and (c) Solvent Effect
2
2
Energy diagram of the reaction of 1a with 2a catalyzed by (R)-3a. The relative free energy (kcal/mol) of the sum of 1a, 2a, and (R)-3a is set to zero.
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