Fast and efficient solvent-free Passerini reaction

A Passerini three component condensation between a carboxylic acid, an aldehyde, and an isocyanide at high temperature under solvent-free conditions was developed. This methodology allows the formation of a broad range of α-acyloxyamides in excellent yields in short reaction times.     

Convergent synthesis of dendrimers via the Passerini three-component reaction

Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer products from precursor dendrons in reasonable yields. This proof-of-principle experiment opens the door to making surface-triblock dendrimers.     

Solid-phase synthesis of modified oligopeptides via Passerini multicomponent reaction

A Passerini multicomponent reaction of N-protected-α-aminoaldehydes, carboxylic acids and solid-supported isocyanides has been successfully performed on Lantern™. The initially formed N-protected-β-amino-α-acyloxyamides gave, by piperidine-promoted deprotection and concomitant acyl migration, β-acylamino-α-hydroxyamides which, by OH-oxidation and cleavage off the solid support, provided β-acylamino-α-oxoamides. Formation and disappearance of the isocyano group has been followed using photoacoustic IR spectroscopy, a fast, reliable and non-disruptive technique that has been successfully applied for the first time to macroscopic solid supports.     

Solvent-free synthesis of azulene derivatives via Passerini reaction by grinding

An efficient and convenient approach to the synthesis of azulene derivatives bearing a carboxamide unit based on solvent-free Passerini reaction, using grinding is described. This method provides several advantages such as high efficiency, operational simplicity, and mild conditions.     

New synthetic technology for the synthesis of hindered alpha-diazoketones via acyl mesylates

[formula: see text] A mild and reliable one-pot protocol for the elaboration of sterically demanding carboxylic acids into alpha-diazoketones via acyl mesylates has been developed. Aside from delineating the reaction parameters which render this strategy quite general for hindered carboxylic acids, we have directly proven the existence of the fleeting acyl mesylate group as the reactive species in these reactions and shed light onto the differing mechanisms which are operative in the activation of hindered and simple carboxylic acids with methanesulfonyl chloride.     

Stereochemical control of the Passerini reaction

A catalytic asymmetric Passerini reaction using tridentate indan (pybox) Cu(II) Lewis acid complex 4 with substrates capable of bidentate coordination has been achieved. The reaction occurs via ligand-accelerated catalysis.     

Passerini reactions for the efficient synthesis of 3,3-disubstituted oxetanes

Three-component reactions of oxetan-3-ones with isocyanides and carboxylic acids produce 3,3-disubstituted oxetanes in good yields. Good levels of diastereocontrol (dr = 4:1) can be achieved in these Passerini reactions when the oxetane nucleus possesses a bulky cyclohexyl substituent at C–2. The (2S¹,3R¹)-stereochemistry of the major diastereomer was confirmed by X-ray crystallography after ester hydrolysis, and a possible mechanism to account for the diastereofacial selectivity is presented.     

The 100 facets of the Passerini reaction

This perspective aims at celebrating the 100th anniversary of the discovery of the Passerini three component reaction. After being nearly neglected for many years, now this reaction has become quite popular, thanks to the achievements of the last 30 years, which have revealed several chances of exploitation in organic synthesis. Though not being comprehensive, this review means to show the various ways that have been used in order to expand the utility of the Passerini reaction. Post-MCR transformations to give heterocycles or peptidomimetics, variants through single component replacement, stereochemical issues, and applications in total syntheses will be especially covered.

This perspective aims at celebrating the 100th anniversary of the discovery of the Passerini three component reaction.     

Organocatalytic synthesis of amides from nitriles via the Ritter reaction

A simple, inexpensive, environmentally friendly, and efficient route for the synthesis of a wide variety of amides in high yields via the Ritter reaction of alcohols with nitriles has been demonstrated. Pentafluorophenyl ammonium triflate (PFPAT) is used as an organocatalyst and is air-stable, cost-effective, easy to handle, and easily removed from the reaction mixtures.     

Synthesis of puleganic amides via a catalytically efficient two-step approach

Puleganic amides display interesting insect-repellent properties. A new synthetic route to this type of amide was developed involving an organocatalytic cyclization and metal-catalyzed hydrogenation in a one-pot protocol. An eco-friendly oxidative amination provided the puleganic amides with only one purification step and acceptable yields.     

A new synthesis of β-keto amides by reduction of Passerini adducts

The Passerini reaction between glyoxals, isocyanides and acetic acid forms β-keto acyloxyamides, which are readily transformed in β-keto amides by reductive deacetoxylation with zinc. The versatility of this procedure, which allows introducing different groups both in position-3 and the amide nitrogen, makes it ideal for its use in diversity-oriented synthesis, in combination with subsequent complexity generation reactions.     

Highly efficient synthesis of amides via Ritter chemistry with ionic liquids

The utility of Brønsted-acidic imidazolium ionic liquid [BMIM(SO₃H)][OTf] as catalyst for the high yield synthesis of a wide variety of amides under mild conditions via the Ritter reaction of alcohols with nitriles has been demonstrated. As alternative methods for the carbocation generation step, NOPF₆ immobilized in [BMIM][PF₆] ionic liquid was used in the Ritter reaction of bromides with nitriles and for the synthesis of adamantyl amides from adamantane and nitriles.     

Iodine-catalyzed one-pot synthesis of amides from nitriles via Ritter reaction

Ritter reactions of alcohols and tert-butyl acetate with various nitriles were performed using iodine as a mild and effective catalyst under heating conditions to afford the corresponding amides in good to excellent yields.     

Mild and efficient one-pot synthesis of chiral β-chalcogen amides via 2-oxazoline ring-opening reaction mediated by indium metal

A simple and efficient procedure for the synthesis of β-seleno and β-thio amides via the ring-opening reaction of chiral 2-oxazolines in the presence of indium metal has been developed. Features of this method include the following: (i) easily and accessible starting materials; (ii) indium metal is more stable and less expensive then its respective salts; (iii) useful to excellent yields of β-chalcogen amides derivatives.     

Facile preparation of difluoromethyl- and monofluoromethyl-containing amides via Ritter reaction

Both secondary and tertiary difluoromethylated carbinols were found to readily react with acetonitrile under the catalysis of concentrated sulfuric acid to give the corresponding difluoromethylated acetamides in good yields, which is remarkably more efficient than the previously reported Ritter reactions with corresponding trifluoromethylated carbinols. Similarly, monofluoromethylated and (benzenesulfonyl)difluoromethylated carbinols have shown good reactivity in the Ritter reactions. Since the acetamides can be mildly deacetylated to give amines, the present methodology provides a convenient way for the synthesis of both difluoromethyl- and monofluoromethyl-containing amines starting from simple carbonyl compounds.     

New synthetic technology for the construction of N-hydroxyindoles and synthesis of nocathiacin I model systems

A new synthetic method providing expedient access to a wide range of polyfunctionalized N-hydroxyindoles (IV) is reported. These unique constructs are assembled by nucleophilic additions to in situ generated α,β-unsaturated nitrones (III) through carbon-carbon and carbon-heteroatom bond formation. The new synthetic technology was applied to the synthesis of nocathiacin I (1) model systems (2 and 3a-c) containing the N-hydroxyindole structural motif.     

New synthetic approach for the preparation of 2-aryl-thiazolo[4,5-b]pyridines via Liebeskind–Srogl reaction

The potentially bioactive 2-aryl-thiazolo[4,5-b]pyridines were synthesized via palladium-catalyzed desulfitative cross-coupling reaction between multisubstituted thiazolo[4,5-b]pyridine thioethers and boronic acids. Yields of [2_TD$IF]48%–94% were obtained with copper(I) thiophene-2-carboxylate in the system.     

Metal-promoted variants of the Passerini reaction leading to functionalized heterocycles

[reaction: see text]. The effect of replacing the Br?nsted acid in classic Passerini reactions with a mild Lewis acid has been studied. Triggered by metal-promoted silylation, condensations of aliphatic or aromatic carbonyl compounds with appropriately substituted isonitriles capable of neighboring group donation afford alpha-hydroxyamides, substituted oxazoles, and other useful heterocycles.