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 reaction

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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