Laurence Grimaud

Challenging 50 Years of Established Views on Ugi Reaction: A Theoretical Approach

The Ugi reaction is one of the most famous multicomponent couplings, and its efficiency is still explained by the original mechanism suggested by Ugi in the 60s. This article aims to present a thorough theoretical study of this reaction. It describes how the imine is activated and how the new stereogenic center is formed. Our calculations strongly suggest alternatives to some commonly accepted features, such as the reversibility of the intermediate steps, and temper the nature of the driving force of the reaction.

Transition‐Metal‐Free α‐Arylation of Enolizable Aryl Ketones and Mechanistic Evidence for a Radical Process

The α-arylation of enolizable aryl ketones can be carried out with aryl halides under transition-metal-free conditions using KOtBu in DMF. The α-aryl ketones thus obtained can be used for step- and cost-economic syntheses of fused heterocycles and Tamoxifen. Mechanistic studies demonstrate the synergetic role of base and solvent for the initiation of the radical process.

New MCR−Heck−Isomerization Cascade toward Indoles

The use of ortho-iodonitrophenol in Ugi-Smiles reaction coupled with Heck cyclization gives new access to indole scaffolds. The sequence can be performed in a one-pot reaction if the residual isocyanide is neutralized prior to the addition of the palladium catalyst.

Isocyanide-based two-step three-component keteneimine formation.

The addition of isocyanides to acyl chlorides (Isocyanide-Nef reaction) leads to imidoyl chlorides which can later be treated with trialkylphosphites to afford new keteneimines in a Perkow-type reaction. The whole sequence may be performed without any solvent, and the resulting keteneimine may easily be converted to phosphorylated tetrazoles and triazoles.

Three‐Component Metal‐Free Arylation of Isocyanides

Though the efficiency of isocyanides as strong ligands for transition metals was recognized very early, the disclosure of metal-catalyzed arylation of isocyanides has only been explored quite recently. In most of these studies, the formation of a metal/aryl complex starting from aryl iodide or bromide is followed by isocyanide insertion and trapping of the metal/imidoyl complex with various nucleophiles (Scheme 1). These three-component couplings are mostly

New palladium-catalyzed aerobic oxidative cleavage and cyclization of N-aryl peptide derivatives.

Oxidative cleavage and cyclization cascades of N-aryl peptides have been achieved under palladium catalysis with air as the sole stoichiometric oxidant.

Three-component strategy toward 5-membered heterocycles from isocyanide dibromides

A three-component strategy starting from isocyanides allows a straightforward synthesis of five-membered ring heterocycles. New cascades were developed involving the addition of a nitrogenated nucleophile-an azide or a tetrazole-on isocyanide dibromides, an electrocyclization, and a Suzuki coupling, which afford new accesses to tetrazole and triazole scaffolds.

Ugi–Smiles couplings: new entries to N-aryl carboxamide derivatives

The scope of the Ugi reaction has been extended by the use of phenols as carboxylic acid surrogates to afford N-aryl carboxamides. A Smiles rearrangement occurs as the last step of the mechanism instead of the classical final Mumm process. Various parameters concerning the nature of these inputs have been studied: the use of heteroaromatic derivatives, the substitution of the hydroxyl moiety by a thio entity (to afford functionalized thioamides), as well as the influence of the nature and position of substituents on the phenol. A three-component version (Passerini–Smiles) of this coupling has been developed as well. Following these couplings, various post-condensation transformations have been performed to reach more complex heteroaromatic fused systems. The easy functionalizations of phenols offer many opportunities for cyclization strategies: the reduction of the nitro group allows the formation of o-phenylenediamine derivatives, which, in turn, can be transformed into quinoxalines, benzotriazoles, and benzimidazoles. Various organometallic reactions of the Ugi–Smiles adducts have been successfully carried out, either from iodophenols (Heck couplings to give indoles, Ullmann reaction to form quinoxalines), or from allyl pyrimidines (azepine formation by RCM strategy) as starting phenol inputs. Finally, a new palladium-mediated oxidative cyclization led to the formation of tricyclic systems.

Smiles Cascades toward Heterocyclic Scaffolds

Two different Smiles rearrangements can be combined to afford a multicomponent formation of isoquinolinones and isoindolinones from nitro methyl salicylate. After a Ugi-Smiles four-component coupling, the base-triggered cyclization of the resulting adduct is followed by a ring contraction via a Truce-Smiles rearrangement.

Toward pyrrolo[2,3-d]pyrimidine scaffolds.

Herein, we present a new route to highly substituted pyrrolo[2,3-d]pyrimidines featuring a Ugi-Smiles/Sonogashira cascade followed by an efficient base-catalyzed intramolecular cyclization. When formaldehyde is chosen as input in the Ugi-Smiles step, aromatic fused systems are eventually obtained through the isomerization of an exo-alkylidene intermediate.