This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α-imino esters. A highly diastereoselective tandem N-alkylation–Mannich reaction of α-imino esters was developed. A tandem N-alkylation–addition reaction of α-imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2-amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α-quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N-addition to β,γ-alkynyl α-imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N-alkylation–vinylogous aldol reaction of β,γ-alkenyl α-imino esters was discovered. N-Alkylation of α-iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four-component coupling reaction with methyl vinyl ketone. α-N-Acyloxyimino esters served as highly efficient substrates for the N,N,C-trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.

Nucleophilic addition of Grignard reagents to the iminium salts generated by the oxidation of cyclic amino ketene silyl acetals derived from pipecolic acid gave α-quaternary amino ester derivatives. Bicyclic compounds were prepared from N-allylated and homoallylated derivatives with vinylaion, allylation, or homoallylation followed by ring-closing metathesis. Application of this method to the synthesis of (±)-S22178, a potent 5-HT_1A agonist, was also described.

This report describes a one-pot synthesis of multisubstituted dihydroquinoxalin-2-ones using an umpolung N-alkylation followed by oxidation and C-alkylation reactions. Moreover, the synthesis of tricyclic compounds containing a dihydroquinoxaline skeleton was carried out by ring closing metathesis (RCM) of the resulting N,C-bis-addition products containing olefins.

Chiral β-lactam synthesis was achieved through the enantioselective reduction of iminocyclobutenones catalyzed by a chiral phosphoric acid and the subsequent thermal rearrangement of chiral aminocyclobutenones in the presence of appropriate amines.

Double nucleophilic addition reactions of dialkoxy ketenesilyl acetals proceeded with α,β-unsaturated imines to give 1,4- and 1,2-double addition products, and their subsequent transformations afforded multisubstituted pyrroles in good yields. Application of this procedure to the synthesis of an imidazole glycerol phosphate dehydratase inhibitor (IGPDI), a physiologically active 2,3,5-trisubstituted pyrrole, is also described.

Two practical methods have been developed for the preparation of N-allylideneamines 1b,c. One involves the isomerization of propargylamines and the other the dehydration of acrolein. N-Allylideneamines 1b,c thus prepared were used as efficient substrates for 1,4- and 1,2-double nucleophilic addition reactions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The synthesis of multi-substituted 2-iminopyridines by conjugate addition of ethyl cyanoacetate derivatives to alkynyl imines has been developed. The reaction of ethyl cyanoacetate derivatives with alkynyl imines provided multi-substituted 2-iminopyridines in good yields. Also described is the transformation of 2-iminopyridines into 2-aminopyridines by deprotection of the substituent on the nitrogen under acidic conditions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)