Arenes participate in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes

• Published in: Nature chemistry Vol. 15; no. 6; pp. 764 - 772
• Main Authors: Aggarwal, Shubhangi, Vu, Alexander, Eremin, Dmitry B., Persaud, Rudra, Fokin, Valery V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2023; NATURE PORTFOLIO; Nature Publishing Group
• Subjects: 639/638/403/933; 639/638/549/933; Analytical Chemistry; Aromatic compounds; Azides (organic); Benzene; Biochemistry; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Cycloaddition; Dipoles; Hydrocarbons; Inorganic Chemistry; Lithium; Organic Chemistry; Physical Chemistry; Physical Sciences; Science & Technology; Sulfonamides; AZIDES; SMILES REARRANGEMENT; ACETYLIDES; AMIDE; LIGATION; SULFONYL; ALKYNE; TRUCE
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-023-01188-z

The venerable 1,3-dipolar cycloaddition has been widely used in organic synthesis for the construction of various heterocycles. However, in its century-long history, the simple and omnipresent aromatic phenyl ring has remained a stubbornly unreactive dipolarophile. Here we report 1,3-dipolar cycloaddition between aromatic groups and diazoalkenes, generated in situ from lithium acetylides and N -sulfonyl azides. The reaction results in densely functionalized annulated cyclic sulfonamide-indazoles that can be further converted into stable organic molecules that are important in organic synthesis. The involvement of aromatic groups in the 1,3-dipolar cycloadditions broadens the synthetic utility of diazoalkenes, a family of dipoles that have been little explored so far and are otherwise difficult to access. The process described here provides a route for the synthesis of medicinally relevant heterocycles and can be extended to other arene-containing starting materials. Computational examination of the proposed reaction pathway revealed a series of finely orchestrated bond-breaking and bond-forming events that ultimately lead to the annulated products. 1,3-Dipolar cycloadditions are well-known transformations in organic synthesis. However, the reactivity of benzene rings in these processes is underexplored. In situ-generated diazoalkenes have now been shown to undergo intramolecular 1,3-dipolar cycloadditions with aromatic rings. The transformation results in an unaromatized benzene ring that enables the synthesis of functionalized heterocycles.