Reaction of 2-Methoxy-3H-azepine with NBS:  Efficient Synthesis of 2-Substituted 2H-Azepines

• Published in: Journal of organic chemistry Vol. 70; no. 9; pp. 3425 - 3436
• Main Authors: Cordonier, Christopher E. J, Satake, Kyosuke, Atarashi, Mikihiko, Kawamoto, Yousuke, Okamoto, Hideki, Kimura, Masaru
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.04.2005; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; BENZENE; MECHANISM; CHEMILUMINESCENCE; NUCLEAR-MAGNETIC-RESONANCE; 4H-AZEPINES; IONS; 3H-AZEPINES; 1H-AZEPINE; EXCHANGE; AZEPINE DERIVATIVES; Ether; Regioselectivity; Nitrogen heterocycle; Alkylamine; Alkanethiol; Organic bromine compounds; Etherification; N-Bromosuccinimide; Electrophilic substitution; Nucleophilic substitution; Chemical synthesis; Hydrogen bromide; Nucleophile
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0500232

The reaction of 2-methoxy-3H-azepines, in the presence or absence of a nucleophile, with N-bromosuccinimide (NBS) gave a regioselective 1,4-adduct from which the corresponding 2H-azepine derivatives were formed via base-promoted hydrogen bromide elimination, generally in moderate to quantitative yield. Competitive formation of 4-bromo-2-methoxy-3H-azepine by electrophilic substitutuion or 3H-azepin-2-yl 2H-azepin-2-yl ether by transetherification was minimized at lower reaction temperatures. Quantitative substitution of 2-(2‘,4‘,6‘-trichlorophenoxy)-2H-azepine derivatives, formed in moderate yield from the respective 3H-azepine and NBS in the presence of 2,4,6-trichlorophenol (TCP), by various nucleophiles gave the corresponding 2-substituted 2H-azepine. Among these nucleophiles were alkanethiol and alkylamine that are not tolerated in the reaction of 3H-azepine and NBS.