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Paper | Regular issue | Vol 94, No. 6, 2017, pp.1063-1073
Published online, 8th May, 2017
DOI: 10.3987/COM-17-13705
Short Synthesis of 5-Substituted-2,3,4,5-tetrahydro-Benzo[f][1,4]thiazepines by Using a Modified Pictet-Spengler Reaction

Toshiaki Saitoh, Michikazu Kitabatake, Yuuko Sugihara, Yuuki Ono, Yoshie Horiguchi, and Kunihiko Mohri*

*Department of Pharmaceutical Sciences, Showa Pharmaceutical University, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan


5-Substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6) were synthesized using a modified Pictet-Spengler reaction of N-formyliminium ion (4) as the key step. The cyclization of 4 was found to be affected by the acidity of the reaction media, which depended on the structure of the benzene ring. The cyclization of the substrates (4a-g) lacking an electron-donating substituent at the benzene ring proceeded smoothly by using a mixed acid catalyst of trifluoroacetic acid and a small amount of trifluoromethanesulfonic acid, thus giving N-formylbenzothiazepines (5a-g) in good yields. On the other hand, in the case of substrates (4h-j) with the OMe group at the benzene ring, although the cyclization proceeded by use of trifluoroacetic acid as the sole catalyst to give the products (5h-j), the mixed acid catalyst did not induce the cyclization reaction to any extent. The modified Pictet-Spengler reaction, which constitutes imination of 2-(phenylthio)ethanamine (1a) with aldehydes (2), and formylation of the resulting imines (3), followed by the acid-catalyzed cyclization of N-formyliminium ion (4), could be carried out as a one-pot procedure, thus providing a convenient methodology for synthesizing various 5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6).