Aliphatic azo compounds as programmable nitrogen donors in alkyne-mediated heterocycle synthesis: Implications for medicinal chemistry

Clara Mañas, Estíbaliz Merino*

Nitrogen-containing heterocycles constitute the core of many approved drugs and clinical candidates, making efficient and predictable C–N bond construction a central objetive in medicinal chemistry. Aliphatic azo compounds, traditionally employed as radical initiators, have recently emerged as versatile programmable nitrogen donors, capable of transferring their nitrogen atoms directly into heterocyclic scaffolds. This review summarizes advances in the reactivity of azoaliphatic derivatives with alkynes, highlighting pathways where nitrogen atoms are retained in the final products and on their implications for drug delivery. Cycloaddition processes provide rapid access to privileged heterocycles such as pyrazoles and pyrroles, scaffolds that are well represented in marketed drugs and support early structure–activity relationship exploration. Complementary radical and carbenoid manifolds enable the formation of hydrazides, atropisomeric frameworks and rarer nitrogen–sulfur motifs, offering increased three-dimensionality and new vectors for tuning potency, selectivity and pharmacokinetic properties. Where available, representative case studies illustrate how these scaffolds have contributed to lead optimization, target selectivity or progression toward clinical evaluation. Beyond reactivity, this review critically evaluates scalability, operational robustness and sustainability to define when azo–alkyne methodologies are realistically applicable in medicinal chemistry workflows. Rather than presenting azo compounds as general-purpose reagents, we frame them as strategic nitrogen donors whose reactivity can be aligned with specific stages of the drug discovery pipeline. When used in this manner, azo–alkyne transformations enable efficient scaffold generation, late-stage diversification and access to underexplored chemical space relevant to modern medicinal chemistry.

Eur. J. Med. Chem. 2026
DOI: https://doi.org/10.1016/j.ejmech.2026.118648

Selective synthesis of 4,5-dihydropyrenes by a Brønsted acid-catalyzed cyclization cascade of biphenyl-embedded enynes

Jaime Tostado , Lucía Sánchez-Jiménez, and Manuel A. Fernández-Rodríguez *

A metal-free Brønsted acid-catalyzed cascade cyclization enables the selective synthesis of 4,5-dihydropyrenes from biphenyl-embedded trienynes. Proceeding under mild conditions with a low E-factor and broad substrate scope, it provides a sustainable approach to access these scarcely explored scaffolds.

Org. Biomol. Chem. 2026
DOI: https://doi.org/10.1039/D5OB01626F

Enantioselective copper(II) catalysed (4 + 1) cycloaddition of aza-o-quinone methides and bromomalonates. Facile access to enantioenriched indolines

Sergio Torres-Oya, Manuel A. Fernández-Rodríguez* and Mercedes Zurro*

Optically active indolines are valuable structural motifs present in numerous naturally occurring and biologically active molecules. Although several methodologies have been reported in the literature for the synthesis of chiral indolines, many of them rely on the hydrogenation of indoles using expensive metal catalysts. In this report, a copper(II)-catalysed enantioselective (4 + 1) cycloaddition of aza-o-quinone methides (aza-o-QMs) with bromomalonates to access indolines is described. The reactive aza-o-QMs are generated in situ from simple and easily accessible 2-chloromethyl arylsulfonamides under basic conditions, and subsequently undergo cyclization with the in situ formed bromomalonate anion to deliver diverse chiral indoline derivatives in up to 69% yields and 96:4 er. Scale up and further derivatizations occurred without erosion of enantioselectivity, showing the robustness of this methodology.

Org. Biomol. Chem. 2026
DOI: https://doi.org/10.1039/D6OB00091F 

Our recently published article Synthesis of Multisubstituted Pyridines by Heterocyclization of TosMIC Derivatives: Total Synthesis of Caerulomycins A and K by José A. García-García, José Luis Aceña, Patricia García-García and David Sucunza has been selected as issue cover in Organic Letters.
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DOI: https://pubs.acs.org/doi/10.1021/acs.orglett.5c04454

Divergent heterocycle synthesis enabled by switchable reaction of azobenzenes with alkynes

Clara Mañas, Estíbaliz Merino*

Azobenzenes are iconic photochromic molecules whose reversible light-induced E–Z isomerization underpins decades of applications in dyes, polymers, molecular switches, and therapeutic agents. Beyond this hallmark, their potential as synthetic building blocks has only recently emerged. In particular, the reactivity of azobenzenes with alkynes is unveiling a new frontier in heterocycle synthesis. Under metal-catalyzed, photocatalytic, or thermal conditions, these transformations provide streamlined access to indazoles, cinnolines, carbazoles, and related nitrogen heterocycles relevant to pharmaceuticals and materials science. This review discusses how distinct activation modes, transition-metal catalysis, photoredox processes, and thermal pathways enable divergent outcomes from common precursors, repositioning azobenzenes from passive chromophores to active scaffolds for functional molecular architectures.

Trends Chem. 2025
DOI: https://doi.org/ 10.1016/j.trechm.2025.12.003