Synthesis of 4-methyl-2H-1,2,3-benzothiadiazine 1,1-dioxides and their further transformation via alkylation and reduction steps

Abstract

Ortho lithiation of acetophenone ketals followed by introduction of the chlorosulphonyl group and subsequent ring closure with hydrazine monohydrate or acetohydrazide gave rise to the formation of variously substituted 4-methyl-1,2,3-benzothiadiazine 1,1-dioxides. N(2)-Alkylation and reduction of the C=N double bond were carried out successfully to give N(2)-alkyl-4-methyl-3,4-dihydro-1,2,3-benzothiadiazine 1,1-dioxides. Finally, N(3)-alkylation was accomplished by reductive alkylation with aldehydes. Certain unsaturated and also some 3,4-dihydro derivatives exhibited a significant anxiolytic effect in vivo. Detailed NMR studies and DFT calculations supported the structure elucidation of the compounds.

Graphical Abstract

Keywords:

• Alkylation
• DFT calculation
• lithiation
• NMR studies
• reduction

Acknowledgements

The authors deeply thank Dr András Dancsó, Dr. Judit Halász and Mr Péter Kővágó for their assistance with the NMR and IR spectra, Ms Mónika Mezővári for the MS measurements, and Mrs Mária Tóthné Lauritz and Ms Dóra R. Németh for the HRMS data. The work was supported by the Varga József and Pro Progressio Foundations.