Jesús M. de Los Santos

This review provides an overview of recent advances in the use of azo compounds for cinnoline synthesis, highlighting metal-catalyzed C–H activation, cycloaddition reactions and classical methods (von-Richter, Widman–Stoermer or Borsche–Herbert).

Herein, an organocatalytic asymmetric synthesis of dihydroquinoline/hydantoin hybrids is described. The synthetic protocol involves a tandem reaction comprising a phosphoric acid–catalyzed initial Povarov dimerization of in situ generated imine/enamine mixtures under tautomeric equilibrium, followed by a Urech–Read reaction of the 1,2‐dihydroquinoline intermediates, which are amino acid derivatives.

Herein, we describe a novel azo-Povarov click reaction between N-carbonyl aryldiazenes and cis,trans-cycloocta-1,5-diene. This uncatalyzed [4 + 2] cycloaddition reaction enables the synthesis of a broad series of cinnoline derivatives at room temperature, in short reaction times and excellent yields (up to 98%). The functionality of the reaction has been also evidenced through the report of a high-yielding gram-scale synthesis as well as diverse transformations of the final cinnoline substrates. Furthermore, an activatable fluorogenic version of the reaction has been developed using quenched azo-fluorophores as starting materials.

Aziridines, structurally related to epoxides, are among the most challenging and fascinating heterocycles in organic chemistry due to their increasing applications in asymmetric synthesis, medicinal chemistry, and materials science. These three-membered nitrogen-containing rings serve as key intermediates in the synthesis of chiral amines, complex molecules, and pharmaceutically relevant compounds. This review provides an overview of recent progress in catalytic asymmetric aziridination, focusing on novel methodologies, an analysis of the scope and limitations of each approach, and mechanistic insights.

A previously unprecedented azo-Povarov reaction between N -carbonyl aryldiazenes and trans -cyclooctene derivatives has been developed.

A study on the reactivity of rigid 1-azadienes derived from methylene γ-lactams is reported. Through the functionalization of 1-amino α,β-unsaturated γ-lactam derivatives, easily available from a multicomponent reaction of amines, aldehydes, and pyruvates, it is possible to in situ generate rigid 1-azadienes locked by a γ-lactam core. The 4π-electron system of those rigid 1-azadienes can behave as both diene and dienophile species through a spontaneous cyclodimerization reaction or exclusively as dienes or dienophiles if they are trapped with imines or cyclopentadiene, respectively. The use of chiral rigid 1-azadienes as dienophiles in the cycloaddition reaction with cyclopentadiene leads to the formation of spiro-γ-lactams bearing four stereogenic centers in a highly stereospecific manner, reporting the first example of the use of methylene-γ-lactams in the synthesis of spirocycles.

A previously undescribed azo-Povarov reaction between N-carbonyl aryldiazenes with trans-cyclooctene is developed. The participation of these aryldiazenes in the uncatalysed [4 + 2] annulation reaction has been applied to the construction of a variety of appealing fused cinnoline derivatives in yields ranging from 34 to 91% for substrates over a broad scope. The starting materials are cost-effective and easily accessible, while the reaction conditions and procedures are simple, requiring no external catalysts. Moreover, the synthetic significance of this methodology has been evidenced by a gram-scale azo-Povarov reaction and further derivatizations of the resulting N-containing heterocycles.

A study on the reactivity of rigid 1-azadienes derived from methylene γ-lactams is reported. Through the functionalization of 1-amino α,β-unsaturated γ-lactam derivatives, easily available from a multicomponent reaction of amines, aldehydes and pyruvates it is possible to in situ generate rigid 1-azadienes locked by a γ-lactam core. The 4π-system of those rigid 1-azadienes can behave as both diene and dienophile species, through a spontaneous cyclodimerization reaction, or exclusively as dienes or dienophiles if they are trapped with imines or cyclopentadiene, respectively. The use of chiral rigid 1-azadienes as dienophiles in the cycloaddition reaction with cyclopentadiene leads to the formation of γ-spirolactams bearing four stereogenic centers in a highly stereospecific manner, reporting the first example of the use of methylene-γ-lactams in the synthesis of spirocycles.

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted N-acylaziridines based on a one-pot ZnCl₂-catalyzed Joullié–Ugi three-component reaction of phosphorylated 2H-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of N-acylaziridines in moderate-to-good yields and up to 98:2 dr for substrates over a wide scope. The relevance of this synthetic methodology was achieved via a gram-scale reaction and the further derivatization of the nitrogen-containing three-membered heterocycle. The diastereo- and regioselective ring expansion of the obtained N-acylaziridines to oxazole derivatives was accomplished in the presence of BF₃·OEt₂ as an efficient Lewid acid catalyst.