Ugi Four-Component Reactions Using Alternative Reactants

Abstract

The Ugi four-component reaction (Ugi-4CR) undoubtedly is the most prominent multicomponent reaction (MCRs) that has sparked organic chemists’ interest in the field. It has been widely used in the synthesis of diverse heterocycle molecules such as potential drugs, natural product analogs, pseudo peptides, macrocycles, and functional materials. The Ugi-4CRs involve the use of an amine, an aldehyde or ketone, an isocyanide, and a carboxylic acid to produce an α-acetamido carboxamide derivative, which has significantly advanced the field of isocyanide-based MCRs. The so-called intermediate nitrilium ion could be trapped by a nucleophile such as azide, N-hydroxyphthalimide, thiol, saccharin, phenol, water, and hydrogen sulfide instead of the original carboxylic acid to allow for a wide variety of Ugi-type reactions to occur.β In addition to isocyanide, there are alternative reagents for the other three components: amine, isocyanide, and aldehyde or ketone. All these alternative components render the Ugi reaction an aptly diversity-oriented synthesis of a myriad of biologically active molecules and complex scaffolds. Consequently, this review will delve deeper into alternative components used in the Ugi MCRs, particularly over the past ten years.

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

“…A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces highly diverse peptidic structures A with up to four points of substitution ( Scheme 1 ) [ 26 – 27 ]. By replacing the carboxylic acid with a nucleophilic azide reagent XN 3 (generally TMSN 3 ), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1 H -tetrazoles (1,5-DS-1 H -Ts) B .…”

Advances in Isocyanide‐Based Multicomponent Synthesis of Quinoxaline Scaffolds

“…Different review articles relating to the synthesis of quinoxalines [10,25–36] . have appeared in the literature, but in these review articles the update information relating to the synthetic methods involving isocyanide based multicomponent reactions have not been addressed, although some representative methods have been included up to some extent.…”

“…[15] Different review articles relating to the synthesis of quinoxalines. [10,[25][26][27][28][29][30][31][32][33][34][35][36] have appeared in the literature, but in these review articles the update information relating to the synthetic methods involving isocyanide based multicomponent reactions have not been addressed, although some representative methods have been included up to some extent. The present review article includes update information on the synthetic methods involving isocyanide based multicomponent reactions in the construction of structurally diverse heterocyclic scaffolds, quinoxalines and fused quinoxalines.…”

Exploring Phthalimide as the Acid Component in the Passerini Reaction

“…However, the utilization of carboxylic acids could also be considered as a limitation of the reactions due to a finite number of readily available variations. Besides carboxylic acids, very few alternative acids were described 6,7 El Kaim et al reported some notable examples by using Oarylative compounds as a replacement of carboxylic acids in both Passerini and Ugi reactions to access α-aryloxy-amides, 8 as well as O-and N-arylamides 9 (Figure 1c). Subsequently, the use of other starting materials instead of carboxylic acids has been reported (Figure 1A).…”

“…However, the utilization of carboxylic acids could also be considered as a limitation of the reactions due to a finite number of readily available variations. Besides carboxylic acids, very few alternative acids were described , …”