HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 10, 2016, pp. 1810-1821
Received, 13th July, 2016, Accepted, 6th September, 2016, Published online, 12th September, 2016.

■ Synthesis of 2-Alk(or Aryl)oxy- and 2-(Alkyl(or Aryl)sulfanyl)-4H-3,1-benzothiazine Derivatives Carrying a (Z)-Halomethylidene Substutuent at the 4-Position

Kazuhiro Kobayashi* and Takashi Nogi

Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

2-Alk(or aryl)oxy-4-(Z)-(halomethylidene)-4H-3,1-benzothiazines were synthesized by the reaction of 2-(2,2-dihaloethenyl)phenyl isothiocyanates with sodium alk(or aryl)oxides. Similar treatment of the 2-(2,2- dibromoethenyl)phenyl isothiocyanates with sodium thiolates gave the corresponding 2-(alkyl(or aryl)sulfanyl)-4-(Z)-(bromomethylidene)-4H-3,1- benzothiazines. The above 2-aryloxybenzothiazine derivative underwent clean conversion to 2-aryloxy-4-(Z)-[(arylsulfanyl)methylidene]-4H-3,1-benzothiazines on treatment with sodium arenethiolates. 2-(Arylsulfanyl)-4-(Z)- [(arylsulfanyl)methylidene]-4H-3,1-benzothiazines were also synthesized by the reaction of 2-(2,2-dibromoethenyl)phenyl isothiocyanates with two equivalents of sodium arenethiolates.

INTRODUCTION
The compounds based on the 4H-3,1-benzothiazine skeleton have recently aroused widespread interest among synthetic chemists, because some members of this family have been shown to possess a variety of biological activities.1 Therefore, a number of interesting methods have been reported to prepare this class of compounds.2 Several routes to 2-alk(or aryl)oxy-3,4 or 2-(alkyl(or aryl)sulfanyl)-4H-3,1- benzothiazines3-7 have also been reported. However, we became aware that to date no syntheses of their 4-halomethylidene derivatives have been achieved,8 though Ding et al. have prepared 4-(Z)-(arylmethylidene)-2-(arylsulfanyl)-4H-3,1-benzothiazines by the reaction 2-(2- arylethynyl)benzenamines with carbon disulfide followed by copper-catalyzed S-arylation with aryl bromides,6 and a synthesis of 2-alkoxy-4-(1-iodopentylidene)-4H-3,1-benzothiazines based the reaction of 2-(hex-1-ynyl)phenyl isothiocyanate with sodium alkoxides followed by iodocyclization has been reported by Sashida et al.5 On the other hand, we previously reported that 2-(2,2-dihaloethenyl)phenyl isothiocyanates (1) reacted with secondary amines and the resulting thiourea derivatives were treated with sodium hydride to afford N,N-dialkyl-4-(Z)-(halomethylidene)-4H-3,1-benzothiazin-2-amines.9a These prompted us to explore the possibility of the formation of 2-alk(or aryl)oxy-4-(Z)-(halomethylidene)- 4H-3,1-benzothiazines (2) or 2-(alkyl(or aryl)sulfanyl)-4-(Z)-(halomethylidene)-4H-3,1-benzothiazines (3) by the reaction of these isothiocyanates (1) with sodium alk(or aryl)oxides or sodium thiolates. We now wish to report the achievement of these transformations and the synthesis of 2-aryloxy-4-(Z)-[(arylsulfanyl)methylidene]-4H-3,1-benzothiazine (5) and 2-(arylsulfanyl)-4-(Z)- [(arylsulfanyl)methylidene]-4H-3,1-benzothiazine derivatives (6).

RESULTS AND DISCUSSION
As shown in Scheme 1, we began our study by investigating reactions of 2-(2,2-dihaloethenyl)phenyl isothiocyanates (1) with alkoxides, generated from alcohols and sodium hydride, in DMF, in expectation of the formation of 2-alk(or aryl)oxy-4-(Z)-(halomethylidene)-4H-3,1-benzothiazines (2) through addition of alk(or aryl)oxides to the carbon atom of the isothiocyanate moiety followed by the intramolecular cyclization of the resulting thiocarbamate anion intermediates and elimination of a halide anion, as proposed in the previous paper.9a As expected, the reactions gave the desired products under the conditions summarized in Table 1, in which the yields of the products are also compiled. These data indicate that while the reactions using dibromoethenyl derivatives 1a, 1c, and 1d proceeded smoothly at 0 ˚C to give the products generally in good yields, those using dichloroethenyl derivatives 1b required an elevated temperature and an extended reaction time and the yields of the products considerably decreased. The alkoxide of an aliphatic alcohol, such as benzyl alcohol, was less reactive compared to aryloxides. As can be seen from Entry 2, the reaction of 1a with sodium benzyloxide required a prolonged reaction time and the yield of the product 2b was moderate-to fair. These reactions were highly Z selective affording each of these products as the sole isomer. The assignments of the stereochemistry of the products prepared in this study are based on NOE experiments as described in the previous report.9a

Subsequently, we examined the reactions of 1 with sodium thiolates, generated in situ from thiols and sodium hydride (Scheme 2). It was found that using 2-(2,2-dibromoethenyl)phenyl isothiocyanate (1a) and 4-chloro-2-(2,2-dibromoethenyl)phenyl isothiocyanate (1c), a similar sequence proceeded smoothly at room temperature to afford the corresponding 2-(alkyl(or aryl)sulfanyl)-4-(Z)-(bromomethylidene)-4H- 3,1-benzothiazines 3 in generally good yields as the sole stereoisomer (Table 2).

It should be mentioned that the reaction of 2-(2,2-dichloroethenyl)phenyl isothiocyanate (1b) or 2-(2,2-dibromoethenyl)-4-methoxyphenyl isothiocyanate (1d) with sodium benzenethiolate under the same conditions gave the corresponding 2-(Z)-[2-halo-2-(phenylsulfanyl)ethenyl]phenyl isothiocyanates (4) and the desired benzothiazine derivatives did not obtained at all, as shown in Scheme 3. It may be assumed that the α-position of the dihaloethenyl moiety of 1b is much more electrophilic toward benzenethiolate than that of 1a due to the difference of the electron withdrawing properties between chlorine and bromine. For 1d, the electron donating methoxy substituent may lower the electrophilicity of the isothiocyanate carbon toward benzenethiolate.

We next turn attention to substitution of the bromo group of 2 for an arylsulfanyl group. In fact, treatment of 2j with sodium thiolates in DMF at room temperature led smoothly to the formation of the corresponding 4-(Z)-[(arylsulfanyl)methylidene]-6-methoxy-2-(4-methylpheoxy)-4H-3,1-benzothiazines (5) in good yields, as depicted in Scheme 4. However, all attempts at similar replacement with an alkoxy group were unsuccessful. The reactions gave considerably intractable mixtures of products.

We then tried to convert 2-(2,2-dibromoethenyl)phenyl isothiocyanates (1a) and (1c) into 2-arylsulfanyl-4-(Z)-[(arylsulfanyl)methylidene]-4H-3,1-benzothiazines (6) in one-pot. The conversion was accomplished by exposure of the starting materials to two equivalents of sodium arenethiolates in DMF at 0 ˚C to room temperature, as shown in Scheme 5. The yields were moderate to fair.

In conclusion, we have developed a convenient procedure for the preparation of novel 4-(Z)-(halomethylidene)-4H-3,1-benzothiazine derivatives. The procedure is useful because of its efficiency, the ready availability of the starting materials and the ease of operations, and its applicability to the synthesis of 4-(Z)-[(arylsulfanyl)methylidene]-4H-3,1-benzothiazine derivatives.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Perkin–Elmer Spectrum 65 FTIR spectrophotometer. 1H NMR and 13C NMR spectra were recorded using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 and 125 MHz, respectively. High-resolution MS spectra were measured by a JEOL JMS-T100GCV spectrometer　(EI, TOF; 70eV). Elemental analyses were performed with an Elementar Vario EL II instrument. TLC was carried out on Merck Kieselgel 60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. 2-(2,2-Halomethylidene)-1-isothiocyanatobenzenes (1) were prepared according to the reported method.9 All other chemicals used in this study were commercially available.
General Procedure for the Preparation of 2-Alk(or aryl)oxybenzothiazines (2) and 2-(Alkyl(or aryl)sulfanyl)benzothiazines (3). To a stirred suspension of NaH (60% in mineral oil; 40 mg, 1.0 mmol) in DMF (3 mL) at 0 ˚C was added a solution of an alcohol or a thiol (1.0 mmol) in DMF (1 mL). After evolution of H2 gas had ceased, a solution of 1 (1.0 mmol) in DMF (1 mL) was added. Stirring was then continued at the temperature and for the period indicated in Schemes 1 or 2 and Tables 1 or 2, respectively. Saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with H2O (3 × 15 mL) and brine (15 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on silica gel (CHCl3/hexane 3: 1) to give the desired product.
4-(Z)-(Bromomethylidene)-2-(4-methylphenoxy)-4H-3,1-benzothiazine (2a): a yellow solid; mp 87–89 ˚C (hexane/CH2Cl2); IR (KBr) 1635 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 6.83 (s, 1H), 7.11–7.15 (m, 3H), 7.17–7.20 (m, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3) δ 20.91, 100.53, 119.09, 121.35, 123.09, 126.90, 128.25, 129.85, 130.37, 133.48, 135.34, 141.69, 150.19, 157.99. HR-MS. Calcd for C16H12BrNOS (M): 344.9823. Found: m/z 344.9824. Anal. Calcd for C16H12BrNOS: C, 55.50; H, 3.49; N, 4.05. Found: C, 55.47; H, 3.47; N, 3.92.
4-(Z)-(Bromomethylidene)-2-(phenylmethoxy)-4H-3,1-benzothiazine (2b): a yellow solid; mp 69–70 ˚C (hexane); IR (KBr) 1627 cm–1; 1H NMR (CDCl3) δ 5.48 (s, 2H), 6.79 (s, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.22–7.42 (m, 6H), 7.45 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3) δ 69.93, 100.04, 119.11, 123.18, 126.39, 127.81, 128.36, 128.52, 128.68, 130.39, 133.71, 135.66, 142.07, 157.99. HR-MS. Calcd for C16H12BrNOS (M): 344.9823. Found: m/z 344.9832. Anal. Calcd for C16H12BrNOS: C, 55.50; H, 3.49; N, 4.05. Found: C, 55.51; H, 3.58; N, 4.01.
4-(Z)-(Bromomethylidene)-2-(4-chlorophenoxy)-4H-3,1-benzothiazine (2c): a beige solid; mp 160–161 ˚C (hexane/CH2Cl2); IR (KBr) 1636 cm–1; 1H NMR (CDCl3) δ 6.86 (s, 1H), 7.12 (dd, J = 8.0, 1.1 Hz, 1H), 7.18–7.23 (m, 3H), 7.33 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.47 (dd, J = 8.0, 1.1 Hz, 1H); 13C NMR (CDCl3) δ 100.84, 119.13, 123.07, 123.16, 127.21, 128.21, 129.37, 130.48, 130.97, 133.14, 141.32, 150.88, 157.61. HR-MS. Calcd for C15H9BrClNOS (M): 364.9277. Found: m/z 364.9271. Anal. Calcd for C15H9BrClNOS: C, 49.14; H, 2.47; N, 3.82. Found: C, 48.98; H, 2.49; N, 3.86.
4-(Z)-(Bromomethylidene)-2-(4-methoxyphenoxy)-4H-3,1-benzothiazine (2d): an orange solid; mp 124–126 ˚C (hexane/CH2Cl2); IR (KBr) 1630 cm–1; 1H NMR (CDCl3) δ 3.83 (s, 3H), 6.83 (s, 1H), 6.91 (d, J = 9.2 Hz, 2H), 7.13–7.20 (m, 4H), 7.31 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.46 (dd, J = 8.0, 1.1 Hz, 1H); 13C NMR (CDCl3) δ 55.59, 100.53, 114.30, 119.09, 122.58, 123.10, 126.90, 128.24, 130.38, 133.48, 141.70, 145.87, 157.18, 158.24. HR-MS. Calcd for C16H12BrNO2S (M): 360.9772. Found: m/z 360.9763. Anal. Calcd for C16H12BrNO2S: C, 53.05; H, 3.34; N, 3.87. Found: C, 52.77; H, 3.34; N, 3.85.
4-(Z)-(Chloromethylidene)-2-(4-methylphenoxy)-4H-3,1-benzothiazine (2e): a yellow solid; mp 72–74 ˚C (hexane); IR (KBr) 1634 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 6.67 (s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 7.15 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.18–7.21 (m, 3H), 7.30 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.43 (dd, J = 8.0, 1.1 Hz, 1H); 13C NMR (CDCl3) δ 20.91, 111.15, 117.82, 121.37, 122.92, 126.87, 128.31, 129.85, 130.30, 130.75, 135.35, 141.56, 150.20, 157.71. HR-MS. Calcd for C16H12ClNOS (M): 301.0328. Found: m/z 301.0339. Anal. Calcd for C16H12ClNOS: C, 63.68; H, 4.01; N, 4.64. Found: C, 63.63; H, 4.27; N, 6.37.
4-(Z)-(Chloromethylidene)-2-(4-chlorophenoxy)-4H-3,1-benzothiazine (2f): a pale-yellow solid; mp 147–149 ˚C (hexane/CH2Cl2); IR (KBr) 1635 cm–1; 1H NMR (CDCl3) δ 6.69 (s, 1H), 7.12 (dd, J = 7.4, 1.1 Hz, 1H), 7.17–7.22 (m, 3H), 7.32 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.44 (dd, J = 8.0, 1.1 Hz, 1H); 13C NMR (CDCl3) δ 111.45, 117.85, 122.98, 123.09, 127.16, 128.27, 129.37, 130.41, 130.98 (2 overlapped Cs), 141.17, 150.87, 157.33. HR-MS. Calcd for C15H9Cl2NOS (M): 320.9782. Found: m/z 320.9795. Anal. Calcd for C15H9Cl2NOS: C, 55.92; H, 2.82; N, 4.35. Found: C, 55.70; H, 2.79; N, 4.24.
4-(Z)-(Chloromethylidene)-2-(4-methoxyphenoxy)-4H-3,1-benzothiazine (2g): a yellow solid; mp 98–99 ˚C (hexane/CH2Cl2); IR (KBr) 1631 cm–1; 1H NMR (CDCl3) δ 3.82 (s, 3H), 6.67 (s, 1H), 6.91 (d, J = 9.2 Hz, 2H), 7.13–7.20 (m, 4H), 7.30 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H); 13C NMR (CDCl3) δ 55.59, 111.16, 114.29, 117.81, 122.59, 122.92, 126.85, 128.29, 130.31, 130.74, 141.56, 145.86, 157.19, 157.96. HR-MS. Calcd for C16H12ClNO2S (M): 317.0277. Found: m/z 317.0281. Anal. Calcd for C16H12ClNO2S: C, 60.47; H, 3.81; N, 4.41. Found: C, 60.43; H, 3.81; N, 4.36.
4-(Z)-(Bromomethylidene)-6-chloro-2-(4-methylphenoxy)-4H-3,1-benzothiazine (2h): a yellow solid; mp 146–147 ˚C (hexane/CH2Cl2); IR (KBr) 1626 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 6.85 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 8.6, 2.2 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H); 13C NMR (CDCl3) δ 20.91, 101.79, 120.38, 121.33, 123.02, 129.48, 129.89, 130.29, 132.11, 132.42, 135.54, 140.35, 150.06, 158.51. HR-MS. Calcd for C16H11BrClNOS (M): 378.9433. Found: m/z 378.9418. Anal. Calcd for C16H11BrClNOS: C, 50.48; H, 2.91; N, 3.68. Found: C, 50.56; H, 3.06; N, 3.59.
4-(Z)-(Bromomethylidene)-6-chloro-2-(naphthalen-2-yloxy)-4H-3,1-benzothiazine (2i): a pale-yellow solid; mp 173–174 ˚C (hexane/CH2Cl2); IR (KBr) 1622 cm–1; 1H NMR (THF-d8) δ 6.96 (d, J = 8.6 Hz, 1H), 7.25 (dd, J = 8.6, 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 (s, 1H), 7.40–7.46 (m, 2H), 7.68 (d, J = 1.7 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H); 13C NMR (THF-d8) δ 103.11, 118.46, 120.53, 121.37, 123.42, 125.69, 126.46, 127.61, 127.66, 129.12, 129.54, 130.24, 131.69, 131.72, 132.15, 134.04, 140.37, 150.34, 158.30. HR-MS. Calcd for C19H11BrClNOS (M): 414.9433. Found: m/z 414.9419. Anal. Calcd for C19H11BrClNOS: C, 54.76; H, 2.66; N, 3.36. Found: C, 54.55; H, 2.78; N, 3.21.
4-(Z)-(Bromomethylidene)-6-methoxy-2-(4-methylphenoxy)-4H-3,1-benzothiazine (2j): a pale-yellow solid; mp 104–105 ˚C (hexane/CH2Cl2); IR (KBr) 1636, 1600 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.81 (s, 3H), 6.83 (s, 1H), 6.89 (dd, J = 8.6, 2.9 Hz, 1H), 6.95 (d, J = 2.9 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3) δ 20.91, 55.59, 100.31, 107.60, 116.35, 119.67, 121.29, 129.50, 129.83, 133.69, 135.18, 135.28, 150,32, 155.95, 158.26. HR-MS. Calcd for C17H14BrNO2S (M): 374.9929. Found: m/z 374.9946. Anal. Calcd for C17H14BrNO2S: C, 54.27; H, 3.75; N, 3.72; S, 8.52. Found: C, 54.15; H, 3.80; N, 3.64; S, 8.51.
4-(Z)-(Bromomethylidene)-6-methoxy-2-(quinolin-8-oxy)-4H-3,1-benzothiazine (2k): a pale-yellow solid; mp 167–168 ˚C (hexane/CH2Cl2); IR (KBr) 1630 cm–1; 1H NMR (CDCl3) δ 3.78 (s, 3H), 6.79 (dd, J = 9.2, 2.9 Hz, 1H), 6.84 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.95 (d, J =2.9 Hz, 1H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 7.56 (dd, J = 8.0, 7.4 Hz, 1H), 7.61 (dd, J = 7.4, 1.1 Hz, 1H), 7.74 (dd, J = 8.0, 1.7 Hz, 1H), 8.19 (dd, J = 8.0, 1.7 Hz, 1H), 8.91 (dd, J = 4.0, 1.7 Hz, 1H); 13C NMR (CDCl3) δ 55.54, 100.19, 107.48, 116.23, 119.80, 121.67, 121.70, 125.66, 126.12, 129.38, 129.52, 133.85, 135.37, 135.90, 141.34, 148.93, 150.55, 156.83, 158.15. HR-MS. Calcd for C19H13BrN2O2S (M): 411.9881. Found: m/z 411.9897. Anal. Calcd for C19H13BrN2O2S: C, 55.22; H, 3.17; N, 6.78; S, 7.76. Found: C, 55.06; H, 3.24; N, 6.53; S, 7.90.
4-(Z)-(Bromomethylidene)-6-methoxy-2-(phenylmethoxy)-4H-3,1-benzothiazine (2l): a yellow solid; mp 110–112 ˚C (hexane/CH2Cl2); IR (KBr) 1636 cm–1; 1H NMR (CDCl3) δ 3.82 (s, 3H), 5.45 (s, 2H), 6.78 (s, 1H), 6.94–6.96 (m, 2H), 7.24 (d, J = 9.2 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.44 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3) δ 55.61, 69.72, 99.83, 107.61, 116.53, 119.63, 128.29, 128.45, 128.50, 128.97, 133.93, 135.74, 135.82, 156.11, 157.88. HR-MS. Calcd for C17H14BrNO2S (M): 374.9929. Found: m/z 374.9941. Anal. Calcd for C17H14BrNO2S: C, 54.27; H, 3.75; N, 3.72; S, 8.52. Found: C, 53.95; H, 3.77; N, 3.54; S, 8.92.
4-(Z)-(Bromomethylidene)-2-(phenylsulfanyl)-4H-3,1-benzothiazine (3a): a yellow solid; mp 88–90 ˚C (hexane/CH2Cl2); IR (KBr) 1603, 1542 cm–1; 1H NMR (CDCl3) δ 6.71 (s, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.43–7.49 (m, 3H), 7.67 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3) δ 100.89, 119.35, 123.21, 127.46, 127.94, 128.60, 129.25, 130.13, 130.41, 132.73, 135.83, 142.04, 159.62. HR-MS. Calcd for C15H10BrNS2 (M): 346.9438. Found: m/z 346.9451. Anal. Calcd for C15H10BrNS2: C, 51.73; H, 2.89; N, 4.02; S, 18.41. Found: C, 51.58; H, 3.09; N, 3.86; S, 18.75.
4-(Z)-(Bromomethylidene)-2-[(4-chlorophenyl)sulfanyl]-4H-3,1-benzothiazine (3b): a yellow solid; mp 123–124 ˚C (hexane/CH2Cl2); IR (KBr) 1605, 1546 cm–1; 1H NMR (CDCl3) δ 6.74 (s, 1H), 7.23–7.26 (m, 2H), 7.36–7.39 (m, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 101.79, 119.46, 123.30, 126.02, 128.12, 128.59, 129.48, 130.47, 132.46, 136.54, 136.90, 141.88, 158.65. HR-MS. Calcd for C15H9BrClNS2 (M): 380.9048. Found: m/z 380.9060. Anal. Calcd for C15H9BrClNS2: C, 47.08; H, 2.37; N, 3.66. Found: C, 47.27; H, 2.56; N, 3.49.
4-(Z)-(Bromomethylidene)-2-[(4-methoxyphenyl)sulfanyl]-4H-3,1-benzothiazine (3c): a yellow solid; mp 132–135 ˚C (hexane/CH2Cl2); IR (KBr) 1588, 1542 cm–1; 1H NMR (CDCl3) δ 3.87 (s, 3H), 6.69 (s, 1H), 6.97 (d, J = 8.6 Hz, 2H), 7.21 (td, J = 7.4, 1.7 Hz, 1H), 7.28 (dd, J = 7.4, 1.1 Hz, 1H), 7.35 (dd, J = 7.4, 1.7 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 55.42, 100.61, 114.87, 117.38, 119.07, 123.13, 127.78, 128.56, 130.41, 132.90, 138.05, 142.12, 161.38, 161.46. HR-MS. Calcd for C16H12BrNOS2 (M): 376.9544. Found: m/z 376.9544. Anal. Calcd for C16H12BrNOS2: C, 50.80; H, 3.20; N, 3.70. Found: C, 50.94; H, 3.20; N, 3.64.
4-(Z)-(Bromomethylidene)-2-[(naphthalen-2-yl)sulfanyl]-4H-3,1-benzothiazine (3d): a yellow solid; mp 114–115 ˚C (hexane/CH2Cl2); IR (KBr) 1603, 1542 cm–1; 1H NMR (CDCl3) δ 6.71 (s, 1H), 7.20–7.25 (m, 2H), 7.33–7.37 (m, 2H), 7.53–7.59 (m, 2H), 7.68 (dd, J = 8.6, 1.7 Hz, 1H), 7.86–7.89 (m, 3H), 8.19 (d, J = 1.1 Hz, 1H); 13C NMR (CDCl3) δ 101.46, 119.46, 123.25, 124.91, 126.74, 127.50, 127.82, 127.98, 128.14, 128.61, 128.80, 130.41, 131.76, 132.71, 133.49, 133.59, 135.61, 142.05, 159.50. HR-MS. Calcd for C19H12BrNS2 (M): 396.9595. Found: m/z 396.9614. Anal. Calcd for C19H12BrNS2: C, 57.29; H, 3.04; N, 3.52. Found: C, 57.23; H, 3.08; N, 3.33.
4-(Z)-(Bromomethylidene)-2-[(phenylmethyl)sulfanyl]-4H-3,1-benzothiazine (3e): a yellow solid; mp 72–74 ˚C (hexane/CH2Cl2); IR (KBr) 1601, 1548 cm–1; 1H NMR (CDCl3) δ 4.50 (s, 2H), 6.75 (s, 1H), 7.24–7.41 (m, 9H); 13C NMR (CDCl3) δ 35.32, 101.15, 120.05, 123.55, 127.46, 127.57, 128.11, 128.58, 129.18, 130.42, 132.39, 136.87, 141.82, 157.70. HR-MS. Calcd for C16H12BrNS2 (M): 360.9595. Found: m/z 360.9613. Anal. Calcd for C16H12BrNS2: C, 53.04; H, 3.34; N, 3.87. Found: C, 52.90; H, 3.44; N, 3.89.
4-(Z)-(Bromomethylidene)-6-chloro-2-(phenylsulfanyl)-4H-3,1-benzothiazine (3f): a yellow solid; mp 120–121 ˚C (hexane/CH2Cl2); IR (KBr) 1598, 1547 cm–1; 1H NMR (CDCl3) δ 6.74 (s, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.43–7.51 (m, 3H), 7.67 (dd, J = 8.0, 1.7 Hz, 2H); 13C NMR (CDCl3) δ 102.18, 120.61, 123.16, 127.08, 129.33, 129.86, 130.33, 130.36, 131.67, 133.15, 135.94, 140.64, 160.50. HR-MS. Calcd for C15H9BrClNS2 (M): 380.9048. Found: m/z 380.9040. Anal. Calcd for C15H9BrClNS2: C, 47.08; H, 2.37; N, 3.66; 16.75. Found: C, 47.42; H, 2.63; N, 3.58; S, 16.83.
4-(Z)-(Bromomethylidene)-6-chloro-2-[(4-chlorophenyl)sulfanyl]-4H-3,1-benzothiazine (3g): an orange solid; mp 156–158 ˚C (decomp) (hexane/CHCl3); IR (KBr) 1599, 1550 cm–1; 1H NMR (CDCl3) δ 6.76 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 102.56, 120.72, 123.23, 125.66, 129.54, 129.84, 130.41, 131.41, 133.36, 136.75, 136.98, 140.47, 159.46. HR-MS. Calcd for C15H8BrCl2NS2 (M): 414.8659. Found: m/z 414.8665. Anal. Calcd for C15H8BrCl2NS2: C, 43.19; H, 1.93; N, 3.36. Found: C, 43.07; H, 1.99; N, 3.32.
1-(Z)-[Halo(phenylsulfanyl)methylidene]-2-isothiocyanatobenzenes (4). These compounds were obtained by treating 1b or 1d with NaSPh as described in General Procedure (0 ˚C to rt; 4 h).
1-(Z)-[Chloro(phenylsulfanyl)methylidene]-2-isothiocyanatobenzene (4b): yield: 60%; a pale-pink oil; Rf 0.40 (hexane); IR (neat) 2057 cm–1; 1H NMR (CDCl3) δ 7.25–7.38 (m, 7H), 7.41 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 7.4 Hz, 1H); 13C NMR (CDCl3) δ 126.82, 126.90, 128.10, 129.19 (2 overlapped Cs), 129.37, 129.97, 130.16, 131.13, 131.21, 131.24, 131.82, 132.69. HR-MS. Calcd for C15H10ClNS2 (M): 302.9943. Found: m/z 302.9933. Anal. Calcd for C15H10ClNS2: C, 59.30; H, 3.32; N, 4.61. Found: C, 59.13; H, 3.39; N, 4.43.
1-(Z)-[Bromo(phenylsulfanyl)methylidene]-2-isothiocyanato-5-methoxybenzene (4d): yield: 70%; a pale-yellow oil; Rf 0.28 (CHCl3/hexane); IR (neat) 2077, 1600 cm–1; 1H NMR (CDCl3) δ 3.77 (s, 3H), 6.84 (dd, J = 9.2, 2.9 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 7.33–7.41 (m, 5H), 7.50 (s, 1H); 13C NMR (CDCl3) δ 55.61, 114.53, 115.34, 120.68, 122.49, 127.92, 128.14, 129.22, 131.04 (2 overlapped Cs), 132.94, 133.06, 135.52, 157.94. HR-MS. Calcd for C16H12BrNOS2 (M): 376.9544. Found: m/z 376.9537. Anal. Calcd for C16H12BrNOS2: C, 50.80; H, 3.20; N, 3.70. Found: C, 50.71; H, 3.22; N, 3.60.
Typical Procedure for the Preparation of 2-Aryloxy-4-(Z)-[(arylsulfanyl)methylidene]-4H-3,1- benzothiazines (5). 6-Methoxy-2-(4-methylphenoxy)-4-(Z)-[(phenylsulfanyl)methylidene]-4H-3,1- benzothiazine (5a). To a stirred suspension of NaH (60% in mineral oil; 19 mg, 0.47 mmol) in DMF (2 mL) at 0 ˚C was added PhSH (52 mg, 0.47 mmol) dropwise. After evolution of H2 gas had ceased, a solution of 2j (0.18 g, 0.47 mmol) in DMF (2 mL) was added dropwise and the temperature was raised to rt. Stirring was continued for 2 h at the same temperature and the mixture was worked up and purified as described in the above General Procedure to give 5a (0.14 g, 74%); a yellow solid; mp 126–127 ˚C (hexane/CH2Cl2); IR (KBr) 1637, 1600 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.81 (s, 3H), 6.81 (s, 1H), 6.86 (dd, J = 9.2, 2.9 Hz, 1H), 6.99 (d, J = 2.9 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.40 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3) δ 20.91, 55.78, 107.99, 108.00, 115.64, 117.32, 117.33, 120.76, 121.33, 127.17, 129.25, 129.41, 129.81, 134.86, 134.97, 135.09, 150.43, 156.11, 158.20. HR-MS. Calcd for C23H19NO2S2 (M): 405.0857. Found: m/z 405.0874. Anal. Calcd for C23H19NO2S2: C, 68.12; H, 4.72; N, 3.45; S, 15.81. Found: C, 68.37; H, 4.73; N, 3.40; S, 15.92.
4-(Z)-{[(4-Chlorophenyl)sulfanyl]methylidene}-6-methoxy-2-(4-methylphenoxy)-4H-3,1-benzothia-
zine (5b): a yellow solid; mp 125–127 ˚C (hexane/CH2Cl2); IR (KBr) 1631, 1605 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.81 (s, 3H), 6.74 (s, 1H), 6.88 (dd, J = 8.6, 2.9 Hz, 1H), 6.99 (d, J = 2.9 Hz, 1H), 7.12 (d, J = 8.6 Hz, 3H), 7.18 (d, J = 8.6 Hz, 2H), 7.31 (s, 4H); 13C NMR (CDCl3) δ 20.91, 55.60, 108.01, 115.88, 115.94, 120.48, 121.31, 129.34, 129.37, 129.82, 130.46, 131.16, 133.21, 133.53, 134.94, 135.14, 150.40, 155.99, 158.22. HR-MS. Calcd for C23H18ClNO2S2 (M): 439.0467. Found: m/z 439.0478. Anal. Calcd for C23H18ClNO2S2: C, 62.79; H, 4.12; N, 3.18. Found: C, 62.67; H, 4.14; N, 3.13.
6-Methoxy-4-(Z)-{[(4-methoxyphenyl)sulfanyl]methylidene}-2-(4-methylphenoxy)-4H-3,1-benzo-
thiazine (5c): a yellow solid; mp 91–92 ˚C (hexane/CH2Cl2); IR (KBr) 1634 cm–1; 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 6.73 (s, 1H), 6.83 (dd, J = 9.2, 2.9 Hz, 1H), 6.89 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 2.9 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 9.2 Hz, 2H); 13C NMR (CDCl3) δ 20.90, 55.41, 55.55, 107.89, 114.89, 115.34, 119.99, 120.90, 121.32, 125.26, 126.56, 129.13, 129.79, 132.42, 134.71, 135.05, 150.45, 156.03, 158.16, 159.54. HR-MS. Calcd for C24H21NO3S2 (M): 435.0963. Found: m/z 435.0968. Anal. Calcd for C24H21NO3S2: C, 66.18; H, 4.86; N, 3.22; S, 14.72. Found: C, 66.39; H, 4.84; N, 3.16; S, 14.78.
Typical Procedure for the Preparation of 2-(Arylsulfanyl)-4-(Z)-[(arylsulfanyl)methylidene]-4H-3,1- benzothiazines (6). 2-(Phenylsulfanyl)-4-(Z)-[(phenylsulfanyl)methylidene]-4H-3,1-benzothiazine (6a). To a stirred suspension of NaH (60% in mineral oil; 40 mg, 1.0 mmol) in DMF (5 mL) at 0 ˚C was added PhSH (0.11 g, 1.0 mmol) dropwise. After evolution of H2 gas had ceased, a solution of 1a (0.32 g, 1.0 mmol) in DMF (2 mL) was added dropwise and the temperature was raised to rt. Stirring was continued for 2 h at the same temperature and the mixture was worked up and purified as described in the above General Procedure to give 6a (0.29 g, 76%); a yellow solid; mp 98–99 ˚C (hexane/CH2Cl2); IR (KBr) 1600, 1542 cm–1; 1H NMR (CDCl3) δ 6.71 (s, 1H), 7.20–7.26 (m, 3H), 7.30–7.35 (m, 5H), 7.39–7.48 (m, 4H), 7.67 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3) δ 118.46, 120.54, 123.53, 126.63, 127.14, 127.62, 127.72, 127.76, 128.30, 129.19, 129.44, 129.67, 129.96, 134.97, 135.71, 141.69, 159.78. HR-MS. Calcd for C21H15NS3 (M): 377.0367. Found: m/z 377.0384. Anal. Calcd for C21H15NS3: C, 66.81; H, 4.00; N, 3.71; S, 25.48. Found: C, 66.44; H, 3.95; N, 3.71; S, 25.37.
2-[(4-Methoxyphenyl)sulfanyl]-4-(Z)-{[(4-methoxyphenyl)sulfanyl]methylidene}-4H-3,1-benzothia-
zine (6b): yellow oil; Rf 0.28 (CH2Cl2/hexane 1:1); IR (neat) 1591, 1547 cm–1; 1H NMR (CDCl3) δ 3.80 (s, 3H), 3.86 (s, 3H); 6.62 (s, 1H), 6.86 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 7.17 (td, J = 7.4, 1.1 Hz, 1H), 7.24 (dd, J = 8.0, 1.1 Hz, 1H), 7.28–7.35 (m, 4H), 7.60 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 55.40 (2 overlapped Cs), 114.79, 114.83, 117.81, 120.40, 120.61, 123.35, 125.28, 125.38, 127.52, 128.19, 129.38, 132.37, 137.92, 141.64, 159.48, 161.30, 161.39. HR-MS. Calcd for C23H19NO2S3 (M): 437.0578. Found: m/z 437.0561. Anal. Calcd for C23H19NO2S3: C, 63.13; H, 4.38; N, 3.20. Found: C, 63.08; H, 4.44; N, 3.22.
6-Chloro-2-(phenylsulfanyl)-4-(Z)-[(phenylsulfanyl)methylidene]-4H-3,1-benzothiazine (6c): a yellow oil; Rf 0.36 (AcOEt/hexane 1:9); IR (KBr) 1594, 1540 cm–1; 1H NMR (500 MHz) δ 6.37 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.23–7.29 (m, 2H), 7.30–7.36 (m, 5H), 7.41–7.48 (m, 3H), 7.66 (dd, J = 8.0, 1.7 Hz, 2H); 13C NMR (125 MHz) δ 120.66, 121.90, 123.29, 125.11, 127.42, 127.47, 129.22, 129.28, 129.41, 129.51, 129.81, 130.11, 132.88, 134.48, 135.78, 140.19, 160.44. HR-MS. Calcd for C21H14ClNS3 (M): 410.9977. Found: m/z 410.9972. Anal. Calcd for C21H14ClNS3: C, 61.22; H, 3.43; N, 3.40. Found: C, 61.67; H, 3.44; N, 3.39.

ACKNOWLEDGEMENTS
We are indebted to Mrs. Miyuki Tanmatsu of our university for assistance in recording mass spectra and performing combustion analyses.

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