Facile synthesis of benzothiadiazine 1,1-dioxides, a precursor of RSV inhibitors, by tandem amidation/intramolecular aza-Wittig reaction

Summary Reaction of o-azidobenzenesulfonamides with ethyl carbonochloridate afforded the corresponding amide derivatives, which gave 3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxides through an intramolecular aza-Wittig reaction. The reaction was found to be general through the synthesis of a number of benzothiadiazine 1,1-dioxides. Acid-catalyzed hydrolysis of 3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxides furnished the 2-substituted benzothiadiazine-3-one 1,1-dioxides in good yields and high purity, which is the core moiety of RSV inhibitors.

Retrosynthetic analysis of the RSV inhibitors 5 and 6 relied on benzothiadiazine-3-one 1,1-dioxide 7, which can easily be obtained by simple hydrolysis of the benzothiadiazine 1,1dioxide derivative 8. Construction of this six-membered sultam 8 was thought to be achieved by intramolecular aza-Wittig reaction of the o-azido derivative 9. The following retrosynthetic analysis led us to the starting material o-azidobenzenesulfonic acid (11) for the synthesis of the intermediate 10 necessary for the synthesis of RSV inhibitors (Scheme 1).
We next conducted a series of reactions with the replacement of the solvent THF by other solvents, such as toluene, CH 2 Cl 2 , and CH 3 CN, but none of them afforded any cyclized product ( Table 1, entries 2-4,). Then the reaction conditions were modified through the use of a higher-boiling-point solvent, i.e., o-dichlorobenzene (DCB). The reaction was successful at higher temperature, affording the desired cyclized product 13b (54%) along with the by-product triphenylphosphine oxide (Table 1, entry 5).
Subsequently, we turned our attention to develop a simpler onestep procedure by heating the sulfonamide 10b with ethyl carbonochloridate, Et 3 N and PPh 3 in DCB at 135 °C for 6 h, which gave the cyclized product 13b in 78% yield ( Table 2, entry 1). The base Et 3 N was then replaced by Cs 2 CO 3 or K 2 CO 3 , but no better result was obtained ( Table 2, entries 2 and 3). Only DIPEA gave 69% yield of the product ( Table 2, entry 4). However, surprisingly the use of xylene as the solvent improved the yield of the cyclized product ( Table 2, entry 5). The replacement of NEt 3 by DIPEA as the base also gave a similar a All the reactions were carried out with 1 equiv 10b, 1.5 equiv ClCO 2 Et, 2 equiv base, and 1.5 equiv PPh 3 ; b isolated yields of 13b; c a smaller amount of 13b was isolated than the major product 14b. yield of the product ( Table 2, entry 6). The decomposition of the iminophosphorane intermediate into the corresponding amine derivative 14b was found to occur at higher temperature (150 °C) producing a low yield of the cyclized product (Table 2, entry 7). The reaction did not occur at all in the absence of a base ( Table 2, entry 8). The observations are summarized in Table 2.
It is notable that xylene appears to be a suitable solvent for this reaction. We then carried out the reactions with a variety of substrates 10a-i under the optimized conditions (ethyl carbonochloridate, PPh 3 , Et 3 N, xylene at 135 °C) in order to generalize the method, and the results are summarized in Table 3. The reactions of all the substrates having electron-deficient R-substituents at the 2-position proceeded smoothly, providing excellent yields, whereas the substrates having electron-donating R-substituents gave lower yields.
The proposed mechanism for the formation of the products 13 may involve amidation of SO 2 NH 2 by the reaction of nucleophilic sulfonamide 10 with ethyl carbonochloridate in the presence of Et 3 N to form the intermediates 9, which may then undergo intramolecular aza-Wittig reaction via the formation of iminophosphorane intermediate I. We have also demonstrated the conversion of the products 13 to the 2-substituted benzothiadiazine-3-one 1,1-dioxide 15 by hydrolysing 13 with ethanolic HCl. The benzothiadiazine-3-one 1,1-dioxide derivatives 15c,e,h were obtained in excellent yields from the compounds 13c,e,h (Scheme 4). These 2-substituted benzothiadiazine-3-one 1,1-dioxides may further be alkylated at the 4-position with suitable halides to yield the RSV inhibitors 5 and 6 by using the reported [13] procedure. Previously, Jung and Khazi [52] reported the synthesis of the benzothiadiazine 1,1-dioxide moiety from the reaction of o-aminobenzenesulfonamide with the costlier triphosgene, whereas in our case the synthesis of benzothiadiazine 1,1-dioxide derivatives was achieved from o-azidobenzenesulfonamides and required cheaper ethyl carbonochloridate as the reagent.

Conclusion
In conclusion, we have developed a simple and efficient method for the synthesis of 3-ethoxybenzothiadiazine 1,1-dioxide and benzothiadiazine-3-one 1,1-dioxide derivatives starting from an easy precursor, by the application of an intramolecular aza-Wittig reaction. The reaction procedure is very simple and gives good to excellent yields of the products. This benzothiadiazine-3-one 1,1-dioxide can further be alkylated at the 4-position, following a literature procedure, to give the bioactive RSV inhibitors.

Supporting Information
Supporting Information File 1 Experimental part.