1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Organic & Supramolecular Chemistry Synthesis, Alkylation and Reduction of 4-Aryl-2H-1,2,3- benzothiadiazine 1,1-dioxides Márta Porcs-Makkay, [a] Imre Gyűjtő, [a, b] Gyula Lukács, [a] Anna Komáromi, [a] Gábor Tóth, [a, b] Zsófia Garádi, [a, b] Gyula Simig, [a] and Balázs Volk* [a] ortho-(2-Aryl-1,3-dioxolan-2-yl)benzenesulfonyl chlorides ob- tained 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 benzothiadia- zine 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 sup- ported the structure elucidation of the compounds. Introduction Biological efficacy of compounds exhibiting a phthalazinone [1–5] (1, Figure 1) skeleton and reports demonstrating that the sulfone moiety may function as a carbonyl isostere [6,7] prompted us to start intensive efforts for the synthesis of compounds possessing the structurally related benzothiadia- zine dioxide (2H-1,2,3-benzothiadiazine 1,1-dioxide) skeleton (2, Figure 1). Certain representatives of this latter family act as antago- nists of the prostaglandin D 2 receptor exhibiting an antiasth- matic effect, [2] or as cyclin-dependent kinase 4 (CDK4) inhibitors with anticancer properties. [8,9] Other members of this family show antibacterial [10–12] or hypotensive activity, [13] while 4-aryl derivatives 3 (Figure 1) are intermediates of potential moth- proofing agents and pickling inhibitors. [14] The literature on the synthesis of this compound family is rather scarce. Parent compound 2 was prepared starting from sodium 2-formylbenzenesulfonate (4) via hydrazone 5 with erratic reproducibility and low yields (Scheme 1, route A). Better results were obtained by changing the order of the two steps, i.e. by transformation of the sulfonate salt 4 to 2-formylbenze- [a] Dr. M. Porcs-Makkay, I. Gyűjtő, Dr. G. Lukács, Dr. A. Komáromi, Prof. G. Tóth, Z. Garádi, Prof. G. Simig, Dr. B. Volk Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, Hungary E-mail: volk.balazs@egis.hu [b] I. Gyűjtő, Prof. G. Tóth, Z. Garádi Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szent Gellért tér 4, 1111 Budapest, Hungary Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201901212 Figure 1. Phthalazinone (1) derivatives, the structurally related benzothiadia- zine dioxide skeleton (2), and a family of bioactive benzothiadiazine dioxides (3). Scheme 1. Synthetic routes of benzothiadiazine dioxides described in the literature. Full Papers DOI: 10.1002/slct.201901212 8295 ChemistrySelect 2019, 4,8295–8300 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim