Editorial for the Special Issue on Cycloaddition Reactions at the Beginning of the Third Millennium

Cycloadditions are among the most efficient chemical processes because they combine atom economy and high levels of selectivity—particularly regio- and stereoselectivity—with the ability to generate molecular complexity in a single step [1]. The application of this methodology in various chemical fields remains highly relevant and effective [2], as substantiated by this Special Issue, which comprises eight experimental articles and three reviews addressing this subject.

The Diels–Alder reaction, the most famous [4+2] cycloaddition [3], continues to evolve as a powerful tool in organic synthesis [4]. Its intriguing mechanism has been thoroughly investigated [5]. Nishiwaki et al., at Kochi University of Technology in Japan, explored Diels–Alder reactions using various dienes and α-nitrocinnamate, as an excellent dienophile, producing highly functionalized cyclohexenes and cyclohexanones under mild conditions [Contribution 1]. In addition, Pineda-Contreras et al., of various Mexican universities, applied the Diels–Alder cycloaddition of azobenzene-based maleimide and furan to synthesise new exo-N-azobenzene oxanorbornene dicarboximides [Contribution 2]. [1+2+2] Cycloadditions are reported by Fedushkin et al., of the G. A. Razuvaev Institute of Organometallic Chemistry of the Russian Academy of Sciences, in a study on the reactivity of a low-valent gallium(I) complex with various heteroalkenes, such as 1,2-dibenzylidenehydrazine [Contribution 3].

1,3-Dipolar cycloadditions (1,3-DC) [6] represent a valuable and efficient tool in the design of five-membered heterocycles [7]. Greener synthetic protocols for creating isoxazolidines as crucial intermediates for biologically relevant glycomimetics were developed by Pratesi and Matassini, of the University of Florence, exploiting 1,3-DC of carbohydrate-derived nitrones and levoglucosenone as a dipolarophile. Operating in solvent-free conditions, often in combination with microwave irradiation or orbital shaking, generally results in shorter reaction times and higher yields and selectivity [Contribution 4]. Feng et al., of the College of Science at Sichuan Agricultural University of Ya’an (China), have successfully addressed the challenging synthesis (due to enthalpic and entropic limitations) of eight-membered cyclic diaryl sulfides via a one-pot procedure starting with 1,3-DC of an aryne and 2-methylenebenzothiophene-3-ones [Contribution 5]. The same approach, involving the microwave-assisted reactions of aldoximes and dimethyl-2-methylene glutarate, was applied by Denton et al., at Medgar Evers College (City University of New York), to access bioactive isoxazoline dicarboxylic acids [Contribution 6]. Moreover, the regioselective synthesis of new spiro-2-pyrazoline derivatives via 1,3-DC of nitrilimines and thioaurones has been described by Bakhouch and Bahsis, of various Universities of Morocco in collaboration with the University of Cergy Paris [Contribution 7].

The organocatalyzed eco-friendly production of cyclic carbonates via formal cycloaddition of epoxides with CO₂ has been described by Lara-Sánchez and Martínez from various Universities of Chile, in collaboration with the University of Castilla-La Mancha (Spain) [Contribution 8].

Concerning the reviews, Fedeli et al., of Friedrich Schiller University of Jena and University of Massachusetts Amherst, focused on the bioorthogonal click cycloadditions [8], presenting an insight into the strategies to modify nanostructured biomedical scaffolds inside living systems [Contribution 9]. The contributions are organised according to the three main mechanisms of “click” cycloadditions: strain-promoted sydnone-alkyne, tetrazine ligation, and strain-promoted [3+2] azido-alkyne. Colorado-Peralta et al., from Universidad Veracruzana of Veracruz (Mexico), reviewed the anticancer activity of platinum complexes with 1,4-disubstituted-1H-1,2,3-triazoles, evidencing the importance of the copper-catalyzed azide-alkyne cycloadditions (CuAAC) approach [Contribution 10]. An update on the synthesis of 2-azetidinones (privileged structures for applications as potential drugs and versatile intermediates in organic synthesis) via cycloaddition was accomplished by Cordero, Giomi, and Machetti of University of Florence and National Research Council of Italy. The Staudinger [2+2] cycloaddition [9] remains the most widely used approach for their preparation and emerging research areas include the use of photocatalysis in Staudinger synthesis from diazo compounds and the application of asymmetric catalysts in the Kinugasa reaction [10,11,12] for enantioselective β-lactam synthesis [Contribution 11].

Finally, the guest editors would like to thank all the authors and reviewers who provided invaluable support in making this Special Issue possible. Special thanks must also be given to the Reactions Editorial Office, who devoted time to reaching out to a large number of colleagues in the field and helping to edit the Special Issue. Thank you all for generously giving your time, passion, experience, and knowledge to this Special Issue.