Solvent Dependent Competitive Mechanisms for the Ugi Multicomponent Reaction: A Joint Theoretical and Experimental Study in the α-Acyl Aminocarboxamides vs α-Amino Amidines Formation

Abstract

A synthetic protocol for the preparation of α-acyl aminocarboxamides and α-amino amidines is proposed. The selectivity toward each of these two possible products was tuned by simple modifications of the reaction conditions. A broad scope is presented, allowing access to the desired products in up to 87% (Ugi adduct) and 93% (α-amino amidine). Theoretical calculations were carried out, and the analysis led to the proposal of a new mechanistic pathway for the Ugi reaction, in which methanol acts not only as the solvent but also as a reagent. High-resolution (tandem) mass spectrometry experiments allowed the detection and characterization of the key intermediate associated with this new and alternative reaction pathway, thus supporting the theoretical proposal.

Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects

“…To address the limitation of low yield encountered in the previous method of lipid generation using the 3-CR-Ugi reaction, we conducted an investigation into various catalysts, including p -toluenesulfonic acid, phosphoric acid, boric acid, and phenylphosphinic acid for boosting the reaction efficiency ( 27 – 31 ). Remarkably, phenylphosphinic acid (20% mol) emerged as the most effective catalyst, increasing the reaction yield from 10 to 70% ( SI Appendix , Fig.…”

Revisiting Biginelli-like reactions: solvent effects, mechanisms, biological applications and correction of several literature reports

“…As an illustration, we have recently demonstrated that a simple change in solvent, such as using methanol, can modulate the mechanism of the Ugi 4-component MCR, directing it towards an alternative catalytic cycle. 16…”

Stereoselective Synthesis of 12-Tetrazolyl Substituted (E)-5H-Quinazolino[3,2-a]quinazolines via Sequential Ugi-Azide/Staudinger/aza-Wittig/Addition/Ag(I)-Catalyzed Cyclization

“…The isocyanide based multicomponent reactions (I-MCRs), especially Ugi four-component reactions, have played a vital role in organic and medicinal chemistry due to their efficient construction of small-molecule libraries in a mild one-pot fashion. , The Ugi-azide reactions have also provided a powerful method for synthesis of 1,5-disubstituted tetrazoles, as the carboxylic acid component is changed to hydrazoic acid (produced in situ from NaN 3 or TMS-N 3 ). − In recent years, the sequence of Ugi reaction and other organic reactions has been successfully applied in the synthesis of many heterocyclic compounds. − For example, the tandem post-Ugi cyclization and Gold­(I)-catalyzed regioselective annulation were utilized in the preparation of densely functionalized pyrrolo­[1,2- a ]­pyrazine-3,6­(2 H ,4 H )-diones in good to excellent yields . Diverse benzazepinoindoles were assembled in a step-economical, chemo- and regioselective fashion by an Ugi/gold-catalyzed alkyne hydroarylation/Michael addition sequence .…”