An efficient preparation of N-alkyl-2-benzazepine derivatives and investigation of their biological activity Akio Kamimura a, * , Masahiro So a , Tomohiro Kuratani a , Kenji Matsuura b , Makoto Inui b, * a Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan b Department of Pharmacology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505, Japan article info Article history: Received 26 December 2008 Revised 6 April 2009 Accepted 24 April 2009 Available online 3 May 2009 Keywords: 2-Benzazepines SAR studies HaCat cell Epithelial cell migration Promotion of skin wound Radical cyclization N-Alkylation abstract N-Alkyl-2-benzazepine derivatives are readily prepared through N-alkylation of secondary 2-benzaze- pines that are constructed via 7-endo selective cyclization of radical cyclization of N-boc-N-(2-bromo- 5-methoxyphenylmethyl) methacrylamides. The structure and activity relationship of these derivatives are examined. Ó 2009 Elsevier Ltd. All rights reserved. Benzazepines, containing seven-membered aza-heterocyclic ring fusing aromatic unit, are of interest due to their biological activity that would be expected as a potential drug candidate. 1 For example, this heterocyclic nucleus was applied in a part of pep- tide mimic of RGD motif, which was a well-known antagonist of integrin that engaged cell adhesion and signal transduction. 2 Re- cently, we found that 2-benzazepines structure showed an activity that promoted not only the epithelial cell migration in vitro but also the skin wound healing in vivo. This is a remarkable activity of 2-benzazepines promising new potential drug candidate. 3 Prep- aration of this structure used to require long steps. 2 2-Benazepines are readily prepared through a unique 7-endo selective cyclization of aryl radical. 4 To investigate structure and activity relationship of these compounds, we need to develop a quick method to derivatize 2-benzazepines. In this Letter, we disclose a convenient derivatiza- tion of benzazepines through the preparation of secondary 2-ben- zaepienes and subsequent N-alkylation. The biological activity of these compounds is also reported. Our strategy for the derivatization is based on the preparation of secondary 2-benzazepines 1 and following N-alkylation. To pre- pare compound 1, a dummy substituent should be introduced be- fore cyclization because any kind of cyclization from secondary amides should be reluctant to undergo due to dominant s-trans conformation of the amide unit. The dummy substituent should be readily introduced and removed in good yield under mild con- ditions. We chose N-carbamate derivatives such as N-boc as the suitable dummy substituents for this preparation. Preparation of 1 was carried out straightly from commercial available 2-bromo-5-methoxybenzoic acid 2. The acid was re- duced to corresponding benzyl alcohol then converted into azide 3 in 89% yield through chloride. Reductive treatment of azide 3 with Raney-Ni gave primary benzyl amine which underwent acyl- ation reaction with methacroyl chloride to give unsaturated amide 4 in 59% yield. N-protection of 4 with (boc) 2 O or ClCO 2 Me under standard conditions smoothly afforded precursor 5a and 5b in good yield (Scheme 1). The radical cyclization of 5 was carried out under standard rad- ical reaction conditions. Treatment of 5a and 5b with Bu 3 SnH with syringe pump technique resulted in the smooth conversion to de- sired 6a and 6b in 29% and 44%, respectively. Although the yield was moderate, the cyclization took place very selective because no regioisomeric product of 6 was observed in the reaction pot. This is a great advantage in the preparation because the radical cyclization from N-alkyl amides always contained small amounts of side products such as 6-exo products which was hard to be re- moved through usual chromatographic treatment. 4 The 7-endo selectivity might be enhanced by the presence of carbamate group such as N-boc. Compound 6 was readily purified by recrystalliza- tion so the present method was much advantageous to prepare 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.04.117 * Corresponding authors. E-mail address: ak10@yamaguchi-u.ac.jp (A. Kamimura). Bioorganic & Medicinal Chemistry Letters 19 (2009) 3193–3195 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl