The First Example of a Diastereoselective Thio-Ugi Reaction:  A New Synthetic Approach to Chiral Imidazole Derivatives

Abstract

The first example of a diastereoselective thio-Ugi reaction with chiral alpha-methylbenzylamine is described. The reaction results in formation of two diastereomers of thioamides, the major of which was isolated. We have found that under similar conditions stereochemical results of the thio-Ugi reaction are opposite to stereochemical results of the Ugi reaction. Several chiral thioamides were synthesized. The reaction of thioamides with ammonia results in substituted amidines, which can be cyclized to imidazole derivatives in aqueous HCl. The synthesis of chiral imidazole derivatives was elaborated. Using certain approaches, both isomers of a key synthon in the synthesis of SB203386 (an orally bioactive HIV-1 protease inhibitor) were prepared. The scope, limitations, and stereochemistry of the approach are discussed.

Ammonia-Promoted One-Pot Tetrazolopiperidinone Synthesis by Ugi Reaction

“…Not surprisingly, few successful examples of ammonia Ugi reactions are known. 18−20 Thus, tritylamine as an ammonia surrogate was introduced in the Ugi MCR. 21 In this work, we wanted to perform the one-pot synthesis of tetrazolopiperidinones C using a suitable ammonia source in the Ugi tetrazole reaction and basic reaction conditions for postcyclization.…”

Synthesis of Some New 1,3,4,5‐tetrasubstituted‐1H‐imidazole‐2(3H)‐thiones Via a Facile One‐Pot Three‐Component Reaction in the Presence of Solvent and Heteropolyacids

“…There are many methods used for the synthesis of multisubstituted imidazoles. Some imidazoles have been prepared by Ugi reaction and Davidson cyclization or by reaction of imidazolium ylides and lithiated imidazoles . The multisubstituted imidazoles also synthesized by condensation of 1,2‐diketone or α‐hydroxy ketone with aldehyde and ammonium acetate on a solid support by microwave irradiation, by heterocyclic cope rearrangement, condensation of a 1,2‐diketone with an aryl nitrile and primary amine under microwave irradiation and N ‐alkylation of trisubstituted imidazoles .…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…151 As shown in Scheme 1.94, (S)-a-methylbenzylamine reacted with thiobenzoic acid, isobutyraldehyde, and an isocyanide to give the corresponding thioamide as a 2 : 1 mixture of two diastereomers from which the major (R)-product was separated by chromatography in 35% yield. Unexpectedly, the authors observed inversion of the stereoselectivity of the reaction upon replacement of thiobenzoic acid by benzoic acid, which furnished the corresponding (S)configured Ugi product as the major diastereomer in 80% yield and 55% de.…”