Preparation of 3,4-dihydro-2,1-benzothiazine 2,2-dioxides with polymer-supported hypervalent iodine reagents

Radical cyclization and ionic cyclization onto the aromatic rings of 2-arylethanesulfonamides with polymer-supported hypervalent iodine reagents were examined, where the reactivities appear to be dependent on the substituent bonded to the nitrogen atom of 2-arylethanesulfonamides to obtain the corresponding 3,4-dihydro-2,1-benzothiazine 2,2-dioxides.


Introduction
Extensive study on organohypervalent iodine compounds has been carried out and these compounds have been widely used for organic synthesis. 13][4] As one important synthetic application with organohypervalent iodine reagents, we have been studying the preparation of heterocyclic compounds via radical reaction mechanism with (diacetoxyiodo)arene in the presence of iodine. 5Among them, 3,4-dihydro-2,1-benzothiazine 2,2-dioxide derivatives have potent biological activities such as lipoxygenase inhibition and as drugs for heart diseases (Fig. 1).Therefore, active studies for the synthetic development of benzothiazine derivatives have been carried out.However, methods i ~ iv require many preparative steps, and quite acidic or basic conditions; moreover, the yields of cyclization products are generally not so high.On the other hand, method v provides the corresponding cyclization products in good yields under mild conditions.Based on this method v, we planned to develop the preparation of 3,4-dihydro-2,1-benzothiazine 2,2dioxides from 2-arylethanesulfonamides with polymer-supported hypervalent iodine reagents.

Cyclization of N-methyl-2-arylethanesulfonamides via radical pathway
Based on the direct preparation of N-methyl-3,4-dihydro-2,1-benzothiazine 2,2-dioxides from Nmethyl-2-arylethanesulfonamides with (diacetoxyiodo)benzene (DIB) in the presence of iodine under photochemical conditions 5e , the same radical cyclization with poly{4-(diacetoxyiodo)styrene} (PSDIB) in the presence of iodine was carried out.Thus, irradiation of a mixture of N-methyl-2-arylethanesulfonamides with PSDIB 3a (3.0 eq.) in the presence of iodine (1.0 eq.) in 1,2-dichloroethane with a tungsten lamp (500W) was carried out at room temperature, and the results are shown in Table 1 and Scheme 1.In spite of the heterogeneous solution, the photolytic radical reaction proceeds effectively to provide the corresponding cyclization products in good yields via sulfonamidyl radicals, with 2phenyl-, 2-naphthyl-, and 2-indolylethanesulfonamides.When poly{4-[hydroxy(tosyloxy)iodo]styrene} (PSHTIB) 4f was used instead of PSDIB under the same conditions, the yield of cyclization product was decreased (entry 5).The same photolytic treatment of N-methoxy-2-arylethanesulfonamides with PSDIB in the presence of iodine did not proceed at all.

Cyclization of N-methoxy-2-arylethanesulfonamides via ionic pathway
Then, ionic cyclization of 2-arylethanesulfonamides with PSDIB and PSHTIB was carried out as shown in Table 2.The cyclization of N-methyl-2-phenylethanesulfonamides with PSDIB (entry 1) and PSHTIB did not proceed at all, and the starting materials were recovered.However, treatment of N-methoxy-2-arylethanesulfonamides with PSHTIB in acetonitrile gave the corresponding cyclization products, N-methoxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxides in good to moderate yields at room temperature (entries 2-5).As shown in Table 2, electrondonating groups on the aromatic ring increase the yield, and electron-withdrawing groups on the aromatic ring reduce the yield of the cyclization products.This suggests that the reaction proceeds through an electrophilic pathway onto the aromatic ring of N-methoxy-2arylethanesulfonamides.The same treatment of N-methoxy-2-phenylethanesulfonamides with PSDIB, which has a less polarized iodine center than that of PSHTIB, did not generate any cyclization product (entry 6).When N-methoxy-2-(4'-methoxyphenyl)ethanesulfonamide, which has an electron-rich aromatic ring, was used, this reaction provides the corresponding spiro sultam (Scheme 2).Thus, under the ionic conditions, the N-methoxy group in N-methoxy-2-arylethanesulfonamides plays an important role for the formation of an N-I bonded hypervalent iodine intermediate, and the subsequent electrophilic cyclization onto the aromatic ring by the electrophilic nitrogen atom proceeds smoothly to generate N-methoxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide, together with the formation of poly(4-iodostyrene) and p-toluenesulfonic acid.The recovered poly(4iodostyrene) can be converted to PSDIB and PSHTIB, and reused for the same reactions (Table 2, entry 2).

Preparation of poly[4-(diacetoxyiodo)styrene] (PSDIB).
A mixture of 16 g (153 mmol) of polystyrene (Aldrich 33165-1), 18 g (71 mmol) of iodine, 7 g (21 mmol) of iodine pentoxide, 40 mL of carbon tetrachloride, and 35 mL of 50 % sulfuric acid in 200 mL of nitrobenzene was kept at 90 °C for 72 h.After the reactions were completed, the reaction mixture was diluted with 100 mL of chloroform and precipitation occurred upon the addition of methanol (1500 mL).The precipitates were collected by filtration to give poly(4-iodostyrene).IR peaks of 700 and 760 cm -1 in polystyrene disappeared, and a new peak at 820 cm -1 appeared in poly(4-iodostyrene).
Typical procedure for the radical cyclization of N-methyl-2-phenylethanesulfonamide with PSDIB PSDIB (1.5 mmol) was added to a solution of N-methyl-2-phenylethanesulfonamide (0.5 mmol) in 1,2-dichloroethane (5 mL), and then iodine (0.5 mmol) was added to the solution.The mixture was irradiated with a tungsten lamp (500 W) at 20-30 °C for 2 h under an argon atmosphere.
After the reaction, the reaction mixture was filtered.The filtrate was poured into a saturated aqueous sodium sulfite solution and extracted with chloroform thrice.The organic layer was dried over sodium sulfate.After removal of the solvent under reduced pressure, the residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 3 / 1).104.36 (t, J C-F = 27.9Hz), 120.15 (q, J C-F = 3.3 Hz), 139.20 (t, J C-F = 6.6, 2.5 Hz), 142.83 (q, J C-F = 9.0 Hz), 161.17 (q, J C-F = 244.Typical procedure for the ionic cyclization of N-methoxy-2-phenylethanesulfonamide with PSHTIB N-Methoxy-2-phenylethanesulfonamide (0.5 mmol) was added to a solution of PSHTIB (0.75 mmol) in acetonitrile (5 mL).The mixture was stirred at room temperature for 4 h under an argon atmosphere.After the reaction, diethyl ether (10 mL) was added to the reaction mixture and the mixture was filtered to remove poly(4-iodostyrene).The filtrate was poured into water and extracted with diethyl ether thrice.The combined organic layer was dried over sodium sulfate.After filtration, the solvent was removed and the residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 2 / 1).

Procedure for the ionic cyclization of N-methoxy-3-phenylpropionamide with PSHTIB
A mixture of N-Methoxy-3-phenylpropionamide (0.5 mmol) in acetonitrile (40 mL) was added dropwise to a solution of PSHTIB (0.75 mmol) in acetonitrile (10 mL).The mixture was stirred at room temperature for 5 h under an argon atmosphere.After the reaction, the reaction mixture was filtered to remove the polymer species.The filtrate was evaporated and the residue was extracted with water and diethyl ether thrice.The combined organic layer was dried over sodium sulfate.After filtration, the solvent was removed and the residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 2 / 1).

a
Starting material was quantitatively recovered.b Regenerated PSHTIB was used.cPSDIB was used instead of PSHTIB.

Table 2 .
Ionic cyclization of N-methoxy-2-arylethanesulfonamides IR-200 spectrometer.Mass spectra were measured with QMS (EI) and high-resolution mass spectra (HRMS) were measured with a 110A mass spectrometer.Microanalyses of polymers were performed with Perkin-Elmer 240B and 240 elemental analyzers at the Chemical Analysis Center of Tsukuba University.Silica Gel 60 (Kanto Kagaku Co.) was used for column chromatography, Kieselgel 60 F254 (Merck) was used for TLC, and Wakogel B-5F was used for preparative TLC.All reactions were carried out under an argon atmosphere.
1H NMR and13C NMR spectra were obtained on a JEOL-JMN-GSX 500 and a JEOL-JMN-GSX 400.Chemical shifts are expressed in parts per million from tetramethylsilane (TMS) in δ units.J values are given in hertz.IR spectra were recorded on a FT/