Regioselective Synthesis of Highly Functionalized 2H‑Pyrroles via Dearomative Chlorination of 1H‑Pyrroles

• Published in: Journal of organic chemistry 2024-08, Vol.89 (16), p.11394-11407
• Main Authors: Shambalova, Victoria E., Larkovich, Roman V., Aldoshin, Alexander S., Lyssenko, Konstantin A., Nechaev, Mikhail S., Nenajdenko, Valentine G.
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/acs.joc.4c01099

An efficient protocol was developed for the synthesis of highly functionalized 2H-pyrroles. This synthetic approach involves the in situ generation of highly reactive 2,5-dichloro-substituted 2H-pyrroles through dearomative chlorination of the corresponding 1H-pyrroles. The resulting reaction mixture is then treated with various amines, leading to the formation of 2,5-diaminated 2H-pyrroles. Subsequent nucleophilic substitution of fluorine with different N-, O-, and S-nucleophiles allows us to introduce additional functionality into a 2H-pyrrole core. The overall outcome of this reaction sequence is the triple nucleophilic modification of pyrroles. All steps of the sequence were found to be highly efficient, regioselective in the preparation of desired di- and trisubstituted derivatives in up to 96% overall yield. In addition, the computational study of this reaction sequence was carried out using density functional theory (DFT). The results of calculations are in perfect agreement with experimental observations.