Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐Aminoacetonitrile with Ketimines

Abstract

Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Brønsted base cooperative catalyst allows for an efficient stereoselective coupling of N-alkylidene-a-aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra-and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading. Scheme 1. Background for this work.(diphenylthiophosphinoyl)ketimines has been developed. Ketimines bearing sp 3 substituents on the imine carbonyl group were generally used with high diastereo-and enantioselectivity. The use of the soft Lewis basic ketimine was the key to promoting the reaction with a soft Lewis acid/hard Brønsted base cooperative catalyst.

Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds

“…Owing to the readily accessible feedstocks, simple manipulation, and privileged product formation, the Mannich reaction is well suited for diversity-oriented synthesis (DOS) applicable in drug discovery, and its utility is demonstrated in alkaloid synthesis and the development of the antiulcer drug Ranitidine [4][5][6][7][8][9][10][11] . Recently, the asymmetric version of Mannich reaction has attracted much interests [12][13][14][15][16][17][18][19][20][21][22] . Despite these advances, the nucleophilic components of the Mannich reaction rely on Brønsted-acidic carbonyl C(sp 3 )−H bonds (Fig.…”

Catalytic Enantioselective Reaction of α‐Aminoacetonitriles Using Chiral Bis(imidazoline) Palladium Catalysts

“…[7] During the preparation of this manuscript, Shibasaki, Kumagai, and co-workers reported the highly antiselective enantioselective reaction of N-fluorenylidene-aaminoacetonitrile with N-thiophosphinoyl ketimines derived from dialkyl ketones (83-95 % ee). [8] Despite the pioneering progress achieved in the catalytic enantioselective reaction of a-aminoacetonitriles with imines,t he development of novel catalyst systems with wide substrate tolerance and acceptable catalytic activity for enantioselective reactions of a-aminoacetonitrile still remains am ajor challenge. [9] Recently,w e developed the highly enantioselective reaction of nitrile compounds with imines using palladium pincer complexes with 1,3-bis(imidazolin-2-yl)benzene (Phebim).…”

Catalytic Enantioselective Reaction of α‐Aminoacetonitriles Using Chiral Bis(imidazoline) Palladium Catalysts

“…[5] One of the solutions for this problem is to use an electron-withdrawing group for the amino group.T here are only three reports on the catalytic enantioselective reaction of a-cyano carbanions of N-protected a-aminoacetonitriles. [8] Despite the pioneering progress achieved in the catalytic enantioselective reaction of a-aminoacetonitriles with imines,t he development of novel catalyst systems with wide substrate tolerance and acceptable catalytic activity for enantioselective reactions of a-aminoacetonitrile still remains am ajor challenge. [6] Recently, Kobayashi and co-workers reported the catalytic enantioselective reaction of N-fluorenylidene-a-aminoacetonitrile with N-diphenylphosphinoylimineu sing chiral guanidine as as trong basic organocatalyst to afford ap roduct with 73 % ee.…”