Pyrrolidine/Azepane Ring Expansion via Intramolecular Ullmann-Type Annulation/Rearrangement Cascade: Synthesis of Highly Functionalized 1 H-Benzazepines

Polina M Ivantcova; Anna A Kirsanova; Vladimir I Polshakov; Konstantin A Lyssenko; Konstantin V Kudryavtsev

doi:10.1021/acs.orglett.3c03030

Pyrrolidine/Azepane Ring Expansion via Intramolecular Ullmann-Type Annulation/Rearrangement Cascade: Synthesis of Highly Functionalized 1 H-Benzazepines

Org Lett. 2023 Oct 20;25(41):7573-7577. doi: 10.1021/acs.orglett.3c03030. Epub 2023 Oct 6.

Authors

Polina M Ivantcova¹, Anna A Kirsanova², Vladimir I Polshakov³, Konstantin A Lyssenko⁴, Konstantin V Kudryavtsev⁵

Affiliations

¹ Sirius University of Science and Technology, Olympic Ave 1, 354340 Sochi, Russian Federation.
² Department of Chemistry, City University of Hong Kong, Tat Chee Ave 83, Kowloon Tong, Hong Kong.
³ Faculty of Fundamental Medicine, Lomonosov Moscow State University, Lomonosovsky Ave 31/5, 119991 Moscow, Russian Federation.
⁴ Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russian Federation.
⁵ Institute of Pharmacy and Medicinal Chemistry, Pirogov Russian National Research Medical University, Ostrovityanova Street 1, 117997 Moscow, Russian Federation.

PMID: 37801732
DOI: 10.1021/acs.orglett.3c03030

Abstract

5-Arylpyrrolidine-2-carboxylates with an ortho-halogen substituent at 5-aryl and an electron-withdrawing group at the C⁴ position of the pyrrolidine ring were transformed into 1H-benzo[b]azepine-2-carboxylates under Cu(I) promotion and microwave activation. Reaction promoter copper(I) thiophene-2-carboxylate has been generated in situ in the reaction's environment from Cu₂O and thiophene-2-carboxylic acid. Functionalized 1H-benzo[b]azepine-2-carboxylates were obtained in racemic and optically active forms in 67-89% yields. Subsequent stereoselective 1,3-dipolar cycloaddition and an Ullmann-type annulation/rearrangement cascade (UARC) ensure a synthetic route to oligomeric optically active benzazepine species with a well-defined 3D-structure.