The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from 1,2-thiazine 1-oxides

Loukou, Christina, Hemming, Karl, Patel, N. and Foucher, V. (2005) The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from 1,2-thiazine 1-oxides. Journal of Sulfur Chemistry, 26 (6). pp. 455-479. ISSN 1741-5993

Abstract

This paper presents a new approach to the synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides, sulfonamide analogues of the 'privileged' 1,4-benzodiazepine pharmacophore. The key steps during this synthesis are the hetero Diels-Alder reaction of an N-sulfinylamine dienophile with a diene to give a 1,2-thiazine 1-oxide which is then converted into a N-(o-azidobenzenesulfonyl)-1,2-amino alcohol via a 2, 3-sigmatropic rearrangement involving an intermediate allylic sulfoxide and sulfenate ester. Staudinger reaction of the o-azido group and hydrolysis of the intermediate iminophosphorane gave the corresponding N-(o-aminobenzenesulfonyl)-1,2-amino alcohols. Fmoc protection at nitrogen, oxidation of the alcohol, and Fmoc deprotection furnished directly the 1,2,5-benzothiadiazepine 1,1-dioxides in 57-69% yield. An alternative method which uses triazene chemistry is also presented, but was consistently lower yielding. A second route to 1,2,5-benzothiadiazepine 1,1-dioxides using 2-nitrobenzenesulfonamide as the dienophile precursor proceeded without incident to give N-(o-nitrobenzenesulfonyl)-1,2-amino ketones which underwent reductive cyclisation to furnish the target heterocycle.

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