Post-Ugi Cyclization for the Construction of Diverse Heterocyclic Compounds: Recent Updates

Abstract

Multicomponent reactions (MCRs) have proved as a valuable tool for organic and medicinal chemist because of their ability to introduce a large degree of chemical diversity in the product in a single step and with high atom economy. One of the dominant MCRs is the Ugi reaction, which involves the condensation of an aldehyde (or ketone), an amine, an isonitrile, and a carboxylic acid to afford an α-acylamino carboxamide adduct. The desired Ugi-adducts may be constructed by careful selection of the building blocks, opening the door for desired post-Ugi modifications. In recent times, the post-Ugi transformation has proved an important synthetic protocol to provide a variety of heterocyclic compounds with diverse biological properties. In this review, we have discussed the significant advancements reported in the recent literature with the emphasis to highlight the concepts and synthetic applications of the derived products along with critical mechanistic aspects.

One‐Pot Construction of Bis‐Heterocycles through Isocyanide Based Multicomponent Reactions

“…In 2011, I. Akritopoulou-Zanze and co-workers reported the synthesis of indazoles bound imidazopyridines/pyrimidines/ pyrazines (28) and indazoles bound imidazothiazoles (29) via Sc(OTf) 3 catalyzed GBBR. [47] The products were obtained by reacting amidines with 1H-indazole-5-carbaldehyde, and isocyanides in the presence of Sc(OTf) 3 catalyst in methanol solvent at room temperature (Scheme 15).…”

“…The general reaction mechanism and that provide novel elements to one-pot IMCR based protocols are also discussed. However, the multistep synthesis of BHCs through post-IMCR modifications (reviewed elsewhere [28] ) is out of the scope of this review.…”

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

“…Dömling and co-workers, 2003 [37] (1 equiv) Ti(OiPr) 4 (1.35 equiv) THF (0.5 M), overnight 12-48 [32][33][34][35][36][37][38][39][40][41][42] Schreiber and co-workers, 2004 [38] (20 mol %) Cu(OTf) 2 ( [23,24] reactions that rely on the ability of organic isocyanides to participate in the nucleophilic attack onto the carbonyl or imine group are among the most studied MCRs. Accordingly, a wide range of post-MCR transformations have been elaborated allowing to upgrade the Passerini and Ugi adducts into potentially bioactive heterocycles [25][26][27][28][29][30][31][32]. While both Passerini and Ugi reactions proved to be quite robust towards different classes of substrates and possess broad functional group tolerance, the difficulties associated with controlling their stereochemical outcome [33][34][35] severely restrict their applicability in medicinal chemistry [36].…”

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

“…Among a wide variety of tandem strategies combination of an isocyanide-based multicomponent Ugi reaction with secondary transformations is one of the most powerful tools and provides access to a large number of diverse heterocyclic compounds [ 10 – 11 ]. Over the past decade, several cases of using an Ugi four-component reaction (Ugi-4CR) in combination with intramolecular azide–alkyne cycloaddition (IAAC) for the synthesis of 1,2,3-triazolobenzodiazepines were reported [ 3 , 7 , 12 – 14 ] ( Scheme 1 ).…”