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DOI: 10.1055/a-1797-5298
Practical Synthesis of Variously Substituted 2,3,4-Benzothiadiazepine 2,2-Dioxides
Dedicated to the memory of the late Professor Ferenc Fülöp (1952–2021)
Abstract
The significant pharmacological activity of 2,3-benzodiazepine-4-ones led to an increased interest in this compound family. However, the literature of the closely related 2,3,4-benzothiadiazepine 2,2-dioxides is rather scarce. Earlier we elaborated a synthesis of 5-aryl congeners variously substituted at the aromatic ring. In the present study, a new synthetic route was investigated via highly versatile intermediates, to extend the reaction to a wider aromatic substitution pattern and to the preparation of 5-alkyl and 5-H derivatives. The essence of this approach is, starting from benzaldehyde acetals, acetophenone and benzophenone ketals, to synthesize ortho-formyl- and ortho-acyl-arylmethanesulfonyl chlorides, which are suitable precursors of the target compounds. The synthesis was implemented as follows: ortho-lithiation of the corresponding acetals and ketals and subsequent treatment with paraformaldehyde, or alternatively in two steps, with DMF or ethyl formate, followed by reduction with NaBH4, led to the corresponding hydroxymethyl derivatives. Reaction of these latter with methanesulfonyl chloride gave mesylates that were used to S-alkylate thiourea to afford S-alkylisothiouronium salts. The final steps of the synthesis were carried out in a telescoped reaction. Treatment of the S-alkylisothiouronium salts with N-chlorosuccinimide resulted in the corresponding arylmethanesulfonyl chlorides. Subsequent reaction with hydrazine hydrate followed by an acidic treatment gave 2,3,4-benzothiadiazepine 2,2-dioxides.
Key words
2,3,4-benzothiadiazepine 2,2-dioxides - lithiation - directed ortho-metalation - S-alkylisothiouronium salts - oxidative chlorination - ring closure - telescoped reactionSupporting Information
- Supporting Information for this article is available online at https://doi.org/10.1055/a-1797-5298. Included are synthetic procedures for the preparation of derivatives 16b,d,f,g,j,k, 17b,d–k, 19b,d–k, and 15c–g,i,j, and characterization thereof. In certain cases, mesylate intermediates 18b–f,h,j,k and ketal protected sulfonyl hydrazides 22c,k were isolated, purified and characterized, these are also described.
- Supporting Information
Publication History
Received: 16 February 2022
Accepted after revision: 14 March 2022
Accepted Manuscript online:
14 March 2022
Article published online:
09 May 2022
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