3‐Mono‐Substituted BINOL Phosphoric Acids as Effective Organocatalysts in Direct Enantioselective Friedel–Crafts‐Type Alkylation of N‐Unprotected α‐Ketiminoester

Abstract

Although BINOL-derived phosphoric acids are among the most widely used chiral Brønsted acid organocatalysts, their structures are mostly limited to 3,3'-disubstituted ones and simple 3-mono-substituted ones without any polar functionalities on the 3-substituent have not been used in highly enantioselective reactions. This work reports such 3-mono-substituted analogues as effective organocatalysts in direct highly enantioselective Friedel-Crafts-type alkylation of N-unprotected α-ketiminoester. The origin of the observed high enantioselectivity with the 3-mono-substituted catalyst is also discussed.

Organocatalytic Enantioselective Friedel‐Crafts Alkylation Reactions of Pyrroles

“…Ohshima and Morimoto developed an enantioselective aza‐FCA reaction with fluorinated N ‐unprotected α‐ketimino esters 78 catalyzed by chiral BINOL‐derived phosphoric acid XXX [57] . Initially developed for indoles, the process was further extended to pyrroles 1 , showing a clear drop in enantioselectivity (Scheme 37).…”

Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines

“…Bolm and co-workers studied indole additions to an N -Boc trifluoromethylpyruvate-derived imine with phosphoric acid 11 . Later, the Ohshima group utilized unsymmetrical chiral phosphoric acid 12 for indole and pyrrole additions to the unprotected imine of the same ketimino ester . The Akiyama laboratory has explored indole and pyrrole additions to unprotected aryl CF 3 imines with catalyst 11 …”

Enantioselective Aza-Friedel–Crafts Reaction of Indoles and Pyrroles Catalyzed by Chiral C1-Symmetric Bis(phosphoric Acid)

“…16 Very recently, Ohshima used highly reactive N-unprotected ethyl trifluoropyruvate imine as a sole substrate in the presence of 5 mol % of a chiral C 1 -symmetric phosphoric acid catalyst. 17,18 In their paper, pyrroles were also examined, but the enantioselectivities were moderate (ca. 60% ee).…”

“…Later, in 2012, Hu used acyclic α-ketimino esters in the presence of 5 mol % of another chiral C 2 -symmetric BINOL-derived phosphoric acid catalyst, and a variety of the corresponding products were obtained in high yields with high enantioselectivities, although a relatively long reaction time (24 h) was required . Very recently, Ohshima used highly reactive N -unprotected ethyl trifluoropyruvate imine as a sole substrate in the presence of 5 mol % of a chiral C 1 -symmetric phosphoric acid catalyst. , In their paper, pyrroles were also examined, but the enantioselectivities were moderate (ca. 60% ee).…”