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

C. Loukou, N. Patel, V. Foucher, K. Hemming

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

LanguageEnglish
Pages455-479
Number of pages25
JournalJournal of Sulfur Chemistry
Volume26
Issue number6
DOIs
Publication statusPublished - 1 Dec 2005

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Thiazines
Amino Alcohols
sulfoxide
Oxides
Triazenes
Cyclization
Sulfonamides
Ketones
Hydrolysis
Esters
Nitrogen
Alcohols
Oxidation

Cite this

Loukou, C. ; Patel, N. ; Foucher, V. ; Hemming, K. / The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from 1,2-thiazine 1-oxides. In: Journal of Sulfur Chemistry. 2005 ; Vol. 26, No. 6. pp. 455-479.
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The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from 1,2-thiazine 1-oxides. / Loukou, C.; Patel, N.; Foucher, V.; Hemming, K.

In: Journal of Sulfur Chemistry, Vol. 26, No. 6, 01.12.2005, p. 455-479.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from 1,2-thiazine 1-oxides

AU - Loukou, C.

AU - Patel, N.

AU - Foucher, V.

AU - Hemming, K.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - 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.

AB - 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.

KW - 1,2-Thiazine 1-oxide

KW - Allylic sulfoxide

KW - Azide

KW - Benzodiazepine

KW - Benzothiadiazepine

KW - N-sulfinylamine

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U2 - 10.1080/17415990500473827

DO - 10.1080/17415990500473827

M3 - Article

VL - 26

SP - 455

EP - 479

JO - Journal of Sulfur Chemistry

T2 - Journal of Sulfur Chemistry

JF - Journal of Sulfur Chemistry

SN - 1741-5993

IS - 6

ER -