ortho‐(2‐Aryl‐1,3‐dioxolan‐2‐yl)benzenesulfonyl chlorides obtained from benzophenone ketals by directed ortho‐lithiation chemistry were cyclized either with hydrazine monohydrate or with acetohydrazide to furnish variously substituted 4‐aryl‐2H‐1,2,3‐benzothiadiazine 1,1‐dioxides. Alkylation of benzothiadiazine dioxides with alkyl iodides under basic conditions was elaborated, revealing significant differences compared to the reactivity of 4‐unsubstituted ones. Hydrogenation of the C=N double bond in the presence of platinum(IV) oxide is also described. Detailed NMR studies and DFT calculations supported the structure elucidation of the compounds.
The base-induced (
t
-BuOK) rearrangement reactions
of 3,4-dihydro-2
H
-1,2,3-benzothiadiazine 1,1-dioxides
result in a ring opening along the N–N bond, followed by ring
closure with the formation of new C–N bonds. The position of
the newly formed C–N bond can selectively be tuned by the amount
of the base, providing access to new, pharmacologically interesting
ring systems with high yield. While with 2 equiv of
t
-BuOK 1,2-benzisothiazoles can be obtained in a
diaza
-[1,2]-Wittig reaction, with 6 equiv of the base 1,2-benzothiazine
1,1-dioxides can be prepared in most cases as the main product, in
a
diaza
-[1,3]-Wittig reaction. DFT calculations and
detailed NMR studies clarified the mechanism, with a mono- or dianionic
key intermediate, depending on the amount of the reactant base. Also,
the role of an enamide intermediate formed during the workup of the
highly basic (6 equiv of base) reaction was clarified. The substrate
scope of the reaction was also explored in detail.
2H‑1,2,3‑Benzothiadiazine 1,1-dioxides are a class of compounds of pharmacological interest. After earlier studies carried out at our laboratory on various transformations (alkylation, acylation, reduction) at the hetero ring, the present manuscript focuses on the transformation of substituents at the aromatic carbocycle, including nucleophilic substitution of chlorine atoms and demethylation of the methoxy group with amines. The new methods described here allow the introduction of versatile functional groups on the aromatic ring, making these compounds useful building blocks for organic and medicinal chemistry applications.
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