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

Basicity-Tuned Reactivity: diaza-[1,2]-Wittig versus diaza-[1,3]-Wittig Rearrangements of 3,4-Dihydro-2H-1,2,3-benzothiadiazine 1,1-Dioxides

“…Therefore, variously substituted benzothiadiazine 1,1-dioxides 1 were synthesized as starting materials (for synthetic methods, see the SI ) using the procedures described earlier. 26 , 38 The ring contraction of derivatives 1 to 1,2-benzisothiazoles 2 was conducted in the presence of 2 equiv of t -BuOK in THF ( Scheme 6 ), and in our standard procedure, the reaction mixture was quenched with water. Under these conditions, compounds 1a – j (i.e., substrates bearing various 2-alkyl substituents, various acyl or alkyl groups at position 3, and chlorine atoms both at positions 7 and 8) were transformed smoothly and effectively to 2a – j (in case of 1g , the hydrolysis of the trifluoroacetylamino group lowered the yield).…”

Transformation of 2H-1,2,3-benzothiadiazine 1,1-dioxides variously substituted at the aromatic ring, via nucleophilic substitution and demethylation reactions

“…Benzyl group seemed to be a protecting group promising to withstand the harsh conditions of the chlorine-amine exchange reaction. Reaction of 15 6 with benzylamine gave selectively 8benzylamino-7-chloro compound 16 bearing two benzyl groups (Scheme 4). The amino function at position 8 could be selectively deprotected at room temperature with trifluoromethanesulfonic acid (triflic acid, TfOH) resulting in compound 17, whereas double debenzylation occurred in one pot at 100 °C to give 18 in 32% yield.…”

“…1 Earlier, we published the synthesis of 4-unsubstituted (Fig. 1, R 4 =H), 2-4 4-phenyl (R 4 =Ph) 5 and 4-methyl (R 4 =Me) derivatives 6 and their 3,4-dihydro counterparts, and targeted N(2)and N(3)-alkylation 7,8 and acylation 9 reactions have also been elaborated. The in vivo anxiolytic effect of 4-unsubstituted BTDs 7 and in vitro positive AMPA modulator (PAM) activity of 4-aryl derivatives 5 was also studied.…”

Synthesis and Chemistry of 1,2,3-Benzothiadiazine 1,1-Dioxide Derivatives: A Comprehensive Overview

“…Removal of the 1,3-dioxolane protecting group, N-deacetylation and ring closure took place under strongly acidic conditions in one pot, giving rise to the formation of target compounds 1 [21,26] 5 [27] and 9 [25,26]. A widely applicable procedure, based on ortho-lithiation methodology, has been developed at our laboratory for the synthesis of a significant variety of 4-unsubstituted, 4-aryl-and 4-alkyl-BTDs (1, 5 and 9, Scheme 4), starting from variously substituted benzaldehydes (R = H) [21] benzophenones (R = aryl) [22] or acetophenones (R = Me) [23,24] of type 10 or 11, which were masked in the first step as 1,3-dioxolanes (12, 13, Scheme 4) using microwave technology [25]. Ortho-lithiation was carried out by exploiting the combined ortho-directing ability of the 1,3-dioxolan-2-yl group and another substituent of the aromatic ring, or by Br→Li exchange.…”

“…Alkylation of 4-methyl derivatives 9 with various alkylating agents (Scheme 9) in the presence of t-BuOK in DMF afforded the corresponding N(2)-alkylated derivatives 29 [24,30]. N( 2)-Haloalkylations enable the attachment of pharmacologically interesting ligands to the BTD core, as demonstrated by the alkylation of compound 5b with 1-bromo-4-chlorobutane (30) and the subsequent reaction with pharmacophore 31, resulting in compound 32, which was expected to exhibit serotonergic activity (Scheme 10) [27].…”