Coupling Isocyanide-Based Multicomponent Reactions with Aliphatic or Acyl Nucleophilic Substitution Processes

Abstract

This account summarizes the results of studies carried out by the authors during the last 10 years aimed at expanding the utility of the venerable Passerini and Ugi reactions. Particular emphasis is given to efforts that focus on coupling these processes with post-condensation, intramolecular, aliphatic nucleophilic substitution and acyl nucleophilic substitution reactions. The methodologies developed in these investigations serve as the basis for short sequences for the preparation of a diverse number of interesting drug-like structures.

Iron nitrate/TEMPO-catalyzed oxidative Passerini reaction of alcohols in air

“…[10][11][12][13][14][15][16] Of particular importance in this area is the Passerini three-component (3C) reaction that involves the reaction between an aldehyde or a ketone, an isocyanide and a carboxylic acid to afford an α-acyloxy amide. [17][18][19][20] As a consequence efforts have been directed toward developing alternatives to this important reaction.…”

Base-catalyzed cyclization of Ugi-adducts to substituted indolyl based γ-lactams

“…Using this method, Bruttomesso et al [16] prepared highly stereoselective steroidal 2,5-diketopiperazines. In this context, the Ugi multicomponent reaction, followed by intramolecular Mitsunobu cyclization, resulted in diazepane or diazocane systems [17,18]. Benzolactames were isolated from the cyclization of an Ugi adduct in the presence of Cs 2 CO 3 under microwave conditions [19].…”

Tandem Ugi MCR/Mitsunobu Cyclization as a Short, Protecting‐Group‐Free Route to Benzoxazinones with Four Diversity Points

“…[4][5][6] The most fruitful strategy directed towards this goal is probably represented by the combination of the Ugi reaction with postcondensation transformations. [7][8][9][10] Our group has been quite active in recent years in implementing this general strategy by coupling the Ugi reaction with metathesis processes, [11][12][13] other organometal-catalysed reactions, [14,15] acyl nucleophilic substitutions [16] and, last but not least, intramolecular or intermolecular aliphatic nucleophilic substitutions. [15,16] In particular, the introduction of an alcohol moiety and a suitable nucleophile (phenol, sulfonamide) into two of the four components of the U-MCR allows a post-condensation Mitsunobu [17] or Mitsunobu-like [18] cyclization, which can lead to a variety of oxaza or diaza heterocycles.…”