HETEROCYCLES

Paper | Regular issue | Vol. 87, No. 12, 2013, pp. 2577-2587
Received, 8th October, 2013, Accepted, 30th October, 2013, Published online, 6th November, 2013.
DOI: 10.3987/COM-13-12855

■ A Convenient Synthesis of 9H-Thioxanthen-9-ones and Their Aza-Analogues

Kazuhiro Kobayashi,* Toshihide Komatsu, Kazuhiro Nakagawa, Erika Hara, and Shohei Yuba

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

Abstract

An efficient method for the preparation of 9H-thioxanthen-9-ones and their three aza-analogues has been developed. The reaction of (2-fluorophenyl)(2-halophenyl)methanones, derived from 1-bromo-2-fluorobenzens and 2-halobenzaldehydes by an easy two-step sequence, with Na2S·9H2O in DMF at 60 °C gives 9H-thioxanthen-9-ones. This procedure can be applied to the synthesis of 5H-[1]benzothiopyrano[2,3-b](or [2,3-c])pyridin-5-ones or 10H-[1]benzothiopyrano[3,2-c]pyridin-10-ones starting from 2-, 3- or 4-chloropyridines, respectively.

INTRODUCTION
A literature survey of the utility of 9H-thioxanthen-9-one derivatives indicated that a number of compounds having this skeleton exhibit a variety of biological activities,1 and that some compounds are useful for photosensitive materials.2 While 9H-thioxanthen-9-ones have been commonly prepared by the intramolecular Friedel-Crafts acylation of 2-(arylsulfanyl)benzoic acids under harsh conditions,2,3 few other general methods have been developed. We envisioned that the reaction of (2-fluorophenyl)(2-halophenyl)methanones, which have been easily prepared from 1-bromo-2-fluorobenzenes and 2-halobenzaldehydes and used for the preparation of 10-substituted acridin-9(10H)-ones,4 with Na2S·9H2O under mild conditions would provide 9H-thioxanthen-9-ones.5 In this paper, we wish to describe the results of our investigation, which show that 9H-thioxanthen-9-ones (2) can be prepared by the reaction of (2-fluorophenyl)(2-halophenyl)methanones (1) with Na2S·9H2O in DMF at 60 °C. We also report that this method is applicable to the synthesis of three types of their aza-analogues, 5H-[1]benzothiopyrano[2,3-b](or [2,3-c])pyridin-5-ones (6) (or 10) or 10H-[1]benzothiopyrano[3,2-c]-pyridin-10-ones (14). These [1]benzothiopyranopyridinone derivatives are also of biological,6 material scientific,7 and synthetic interests.8

RESULTS AND DISCUSSION
The precursor (2-fluorophenyl)(2-halophenyl)methanones (1) were prepared by the reaction of 1-fluoro-2-lithiobenzenes, generated from 1-bromo-2-fluorobenzenes according to the previously reported method,9 with 2-halobenzaldehydes, followed by the PCC oxidation of the resulting alcohols, as described previously.4 When these compounds (1) were treated with Na2S·9H2O in DMF at 60 °C, substitution of the two halogens with the sulfur atom proceeded smoothly and cleanly to afford, after addition of water followed by recrystallization of the precipitated crude products, the corresponding 9H-thioxanthen-9-ones (2) in good to excellent yields, as shown in Scheme 1.

Encouraged by the above results we applied this method to the synthesis of three aza-analogues of 9H-thioxanthen-9-ones, 5H-[1]-benzothiopyrano[2,3-b](or [2,3-c])pyridin-5-ones (6) (or 10) or 10H-[1]benzothiopyrano[3,2-c]pyridine-10-ones (14) from 2-, 3- or 4-chloropyridines (3, 7, or 11), respectively. We first conducted the synthesis of 5H-[1]benzothiopyrano[2,3-b]pyridin-5-ones (6) as illustrated in Scheme 2. Thus, commercially available 2-chloropyridine (3) was treated with LDA in THF at –78 °C according to the reported procedure10 to generate 2-chloro-3-lithiopyridine, which was allowed to react with 2-halobenzaldehydes to give (2-chloropyridin-3-yl)(2-halophenyl)methanols (4) in fair to good yields. The lower yield of 4c is likely due to the steric encumbrance of the two adjacent chloro groups. Then, these alcohols were oxidized with PCC in CH2Cl2 at room temperature to give (2-chloropyridin-3-yl)-(2-halophenyl)methanones (5) in satisfactory yields. The final step, treatment of 5 with Na2S·9H2O, was carried out applying the same conditions described above to afford the desired products (6) in excellent yields.
Next, the synthesis of 5H-[1]benzothiopyrano[2,3-c]pyridin-5-ones (10) from commercially available 3-chloropyridine (7) was similarly carried out under the same conditions, as depicted in Scheme 3. The precursor (3-chloropyridin-4-yl)(2-halophenyl)methanones (9) were also prepared in good yields from 7, via the corresponding alcohols (8), by the same sequence used for the preparation of 5. However, when compounds (9) were treated with Na2S·9H2O in the same way as described above, the expected products (10) were obtained in somewhat diminished yields compared to those of 6 as summarized in Scheme 3 as well. These disappointing results are presumably due to the low reactivity of the 3-chloro substituent of the pyridine ring of 9 compared to the 2-chloro substituent of the pyridine ring of 5.

Finally, the preparation of 10H-[1]benzothiopyrano[3,2-c]pyridin-10-ones (14) was also similarly achieved as illustrated in Scheme 4. The reaction of 3-chloro-4-lithiopyridine,10 generated from 4-chloropyridine (11), with 2-halobenzaldehydes to furnish the corresponding alcohols (12) in good yields, the PCC oxidation of which gave (4-chloropyridin-3-yl)(2-halophenyl)methanones (13). However, these ketones proved to be rather unstable under isolation conditions by SiO2 chromatography. So, these compounds were not isolated and were subjected, after filtration through a small pad of SiO2, to the treatment with Na2S·9H2O under the same reaction conditions described above to afford the desired products (14) in moderate overall yields from 12.

In conclusion, we have developed an efficient synthetic approach for the construction of 9H-thioxanthen-9-ones via the reaction of (2-fluorophenyl)(2-halophenyl)methanones with Na2S·9H2O under mild conditions. Their three aza-analogues were also synthesized starting with the respective chloropyridines by an application of this sequence.

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 Spectrum65 FTIR spectrophotometer. 1H NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz or JEOL LA400 FT NMR spectrometer operating at 400 MHz. 13C NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. Low-resolution MS spectra (EI, 70 eV) were measured by a JEOL JMS AX505 HA spectrometer. High-resolution MS spectra (DART, positive) were measured by a Thermo Scientific Exactive spectrometer. 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-Fluorophenyl)(2-halophenyl)methanones (1a-1d) were prepared as described previously.4 n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially available.
(2-Bromo-4,5-dimethoxyphenyl)(5-chloro-2-fluorophenyl)methanone (1e): prepared from 1-bromo-5-chloro-2-fluorobenzene and 2-bromo-4,5-dimethoxybenzaldehyde, via (2-bromo-4,5-dimethoxyphenyl)(5-chloro-2-fluorophenyl)methanol, under the conditions reported for the preparation of 1a-1d.4
(2-Bromo-4,5-dimethoxyphenyl)(5-chloro-2-fluorophenyl)methanol: yield: 62%; a colorless oil; Rf 0.20 (AcOEt/hexane 1:5); IR (neat) 3469, 1604 cm–1; 1H NMR (500 MHz) δ 2.42 (d, J = 3.4 Hz, 1H), 3.85 (s, 3H), 3.88 (s, 3H), 6.32 (d, J = 3.4 Hz, 1H), 7.02 (s, 1H), 7.05 (s, 1H), 7.09–7.12 (m, 2H), 7.20 (dd, J = 8.6, 8.0 Hz, 1H). Anal. Calcd for C15H13BrClFO3: C, 47.96; H, 3.49. Found: C, 47.81; H, 3.74.
1e: yield: 62%; a colorless oil; Rf 0.29 (AcOEt/hexane 1:5); IR (neat) 1669, 1604 cm–1; 1H NMR (500 MHz) δ 3.88 (s, 3H), 3.94 (s, 3H), 7.01 (s, 1H), 7.05 (s, 1H), 7.15 (dd, J = 9.7, 1.1 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H). Anal. Calcd for C15H11BrClFO3: C, 48.22; H, 2.97. Found: C, 48.34; H, 2.87.
Typical Procedure for the Preparation of 9H-Thioxanthen-9-ones (2). 9H-Thioxanthen-9-one (2a).11 A mixture of 1a (0.12 g, 0.49 mmol) in DMF (4 mL) containing Na2S·9H2O (0.12 g, 0.49 mmol) was heated at 60 °C until TLC analyses (SiO2; AcOEt/hexane 1:8) had revealed complete consumption of 1a (ca. 1 h). The mixture was cooled to rt and H2O (20 mL) was added. The precipitate was collected by filtration and recrystallized to give 2a (0.10 g, 94%); a white solid; mp 219–221 °C (hexane/CHCl3) (lit.,3 mp 219–220 °C). The spectral (IR and 1H-NMR) data for this compound were identical to those reported previously.3
2-Chloro-9H-thioxanthen-9-one (2b);12 a white solid; mp 150–151 °C (hexane/CH2Cl2) (lit.,12b mp 150–151.5 °C); IR (KBr) 1635 cm–1; 1H NMR (400 MHz) δ 7.49–7.55 (m, 2H), 7.58–7.61 (m, 2H), 7.65 (ddd, J = 8.3, 6.8, 1.4 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.62 (dd, J = 7.3, 1.4 Hz, 1H).
3-Chloro-9H-thioxanthen-9-one (2c): a white solid; mp 171–173 °C (hexane/CH2Cl2) (lit.,13 168–172 °C); IR (KBr) 1645 cm–1; 1H NMR (500 MHz) δ 7.43 (ddd, J = 8.7, 1.8, 0.9 Hz, 1H), 7.50 (td, J = 7.3, 0.9 Hz, 1H), 7.56–7.58 (m, 2H), 7.64 (dd, J = 8.7, 6.9 Hz, 1H), 8.54 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 7.3 Hz, 1H).
3-Chloro-6,7-dimethoxy-9H-thioxanthen-9-one (2d); a white solid; mp 218–220 °C (hexane/CH2Cl2). IR (KBr) 1626 cm–1; 1H NMR (500 MHz) δ 4.01 (s, 3H), 4.02 (s, 3H), 6.92 (s, 1H), 7.42 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 8.55 (d, J = 8.7 Hz, 1H); 13C NMR δ 56.18, 56.35, 106.54, 110.06, 122.98, 125.00, 126.78, 127.03, 130.66, 131.25, 138.25, 138.37, 148.87, 153.59, 177.85; MS m/z 306 (M+, 100). Anal. Calcd for C15H11ClO3S: C, 58.73; H, 3.61. Found: C, 58.80; H, 3.69.
2-Chloro-6,7-dimethoxy-9H-thioxanthen-9-one (2e): a white solid; mp 218–220 °C (hexane/CH2Cl2). IR (KBr) 1626 cm–1; 1H NMR (500 MHz) δ 4.015 and 4.022 (2s, combined 6H), 6.93 (s, 1H), 7.43 (dd, J = 8.6, 2.3 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 8.56 (d, J = 8.6 Hz, 1H); 13C NMR δ 56.22, 56.38, 106.54, 110.07, 122.99, 125.03, 126.77, 127.04, 130.66, 131.25, 138.26, 138.37, 148.88, 153.59, 177.86; MS m/z 306 (M+, 100). Anal. Calcd for C15H11ClO3S: C, 58.73; H, 3.61. Found: C, 58.64; H, 3.85.

Typical Procedure for the Preparation of Compounds (4, 8, and 12). (2-Chlorophenyl)(2-chloropyridin-3-yl)methanol (4a). To a stirred solution of 2-chloro-3-lithiopyridine (10 mmol), generated according to the reported method,10 in THF (30 mL) at –78 °C was added dropwise 2-ClC6H4CHO (1.7 g, 12 mmol). After 5 min, water (20 mL) was added, and the mixture was extracted with AcOEt (3 × 20 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on SiO2 to give 4a (1.9 g, 75%); a yellow oil; Rf 0.30 (AcOEt/hexane 1:3); IR (neat) 3345 cm–1; 1H NMR (500 MHz) δ 2.82 (d, J = 4.1 Hz, 1H), 6.48 (d, J = 4.1 Hz, 1H), 7.26–7.33 (m, 4H), 7.39 (m, 1H), 7.76 (dd, J = 7.8, 1.8 Hz, 1H), 8.34 (dd, J = 4.6, 1.8 Hz, 1H). Anal. Calcd for C12H9Cl2NO: C, 56.72; H, 3.57; N, 5.51. Found: C, 56.70; H, 3.78; N, 5.70.
(2-Bromo-5-methoxyphenyl)(2-chloropyridin-3-yl)methanol (4b): a white solid; mp 135–137 °C (hexane/CH2Cl2); IR (KBr) 3185 cm–1; 1H NMR (500 MHz) δ 2.74 (d, J = 4.1 Hz, 1H), 3.77 (s, 3H), 6.37 (d, J = 4.1 Hz, 1H), 6.77 (dd, J = 8.7, 2.8 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 7.25 (dd, J = 7.8, 4.6 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 7.8, 1.8 Hz, 1H), 8.35 (dd, J = 4.6, 1.8 Hz, 1H). Anal. Calcd for C13H11BrClNO2: C, 47.52; H, 3.37; N, 4.26. Found: C, 57.58; H, 3.60; N 4.10.
(2-Chloropyridin-3-yl)(2,3-dichlorophenyl)methanol (4c): a pale-yellow solid; mp 157–158 °C (hexane/Et2O); IR (KBr) 3213 cm–1; 1H NMR (500 MHz) δ 2.22 (s, 1H), 6.48 (s, 1H), 7.23–7.31 (m, 3H), 7.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.68 (dd, J = 7.4, 1.7 Hz, 1H), 8.36 (dd, J = 4.6, 1.7 Hz, 1H). Anal. Calcd for C12H8Cl3NO: C, 49.95; H, 2.79; N, 4.85. Found: C, 59.83; H, 2.83; N, 4.71.
(2-Chlorophenyl)(3-chloropyridin-4-yl)methanol (8a): a white solid; mp 140–141 °C (hexane/Et2O); IR (KBr) 3104 cm–1; 1H NMR (500 MHz) δ 2.75 (d, J = 4.0 Hz, 1H), 6.48 (d, J = 4.0 Hz, 1H), 7.19 (dd, J = 7.4, 1.7 Hz, 1H), 7.24–7.31 (m, 2H), 7.42 (dd, J = 7.4, 1.7 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.55 (s, 1H). Anal. Calcd for C12H9Cl2NO: C, 56.72; H, 3.57; N, 5.51. Found: C, 56.78; H, 3.60; N, 5.32.
(2-Bromo-5-chlorophenyl)(3-chloropyridin-4-yl)methanol (8b): a white solid; mp 164.5–165 °C (hexane/Et2O); IR (KBr) 3153 cm–1; 1H NMR (500 MHz) δ 2.99 (d, J = 4.0 Hz, 1H), 6.37 (d, J = 4.0 Hz, 1H), 7.20 (dd, J = 8.6, 2.3 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H). Anal. Calcd for C12H8BrCl2NO: C, 43.28; H, 2.42; N, 4.21. Found: C, 43.37; H, 2.66; N, 4.08.
(2-Bromo-5-methoxyphenyl)(3-chloropyridin-4-yl)methanol (8c): a white solid; mp 128–129 °C (hexane/CH2Cl2); IR (KBr) 3186 cm–1; 1H NMR (500 MHz) δ 3.03 (d, J = 4.0 Hz, 1H), 3.74 (s, 3H), 6.37 (d, J = 4.0 Hz, 1H), 6.76–6.78 (m, 2H), 7.41 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.54 (s, 1H). Anal. Calcd for C13H11BrClNO2: C, 47.52; H, 3.37; N, 4.26. Found: C, 47.37; H, 3.50; N, 4.19.
(2-Chlorophenyl)(4-chloropyridin-2-yl)methanol (12a): a pale-yellow solid; mp 147–149 °C (hexane/CH2Cl2) (lit.,14 mp 151 °C); IR (KBr) 3089 cm–1; 1H NMR (400 MHz) δ 2.80 (s, 1H), 6.54 (s, 1H), 7.29–7.34 (m, 3H), 7.39–7.43 (m, 2H), 8.45 (d, J = 5.4 Hz, 1H), 8.57 (s, 1H).
(4-Chloropyridin-2-yl)(2,3-dichlorophenyl)methanol (12b): a pale-yellow solid; mp 161–163 °C (hexane/CH2Cl2); IR (KBr) 3091 cm–1; 1H NMR (400 MHz) δ 2.85 (br, 1H), 6.54 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 4.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 7.8, 2.0 Hz, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.49 (s, 1H). Anal. Calcd for C12H8Cl3NO: C, 49.95; H, 2.79; N, 4.85. Found: C, 49.90; H, 2.88; N, 4.73.
(2-Bromo-5-methoxyphenyl)(4-chloropyridin-2-yl)methanol (12c): a pale-yellow solid; mp 162–163 °C (hexane/CH2Cl2); IR (KBr) 3100 cm–1; 1H NMR (500 MHz) δ 2.68 (d, J = 4.6 Hz, 1H), 3.78 (s, 3H), 6.43 (d, J = 4.6 Hz, 1H), 6.78 (dd, J = 8.6, 2.9 Hz, 1H), 7.01 (d, J = 2.9 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.50 (s, 1H). Anal. Calcd for C13H11BrClNO2: C, 47.52; H, 3.37; N, 4.26. Found: C, 47.40; H, 3.18; N, 4.19.
Aryl(chloropyridinyl)methanones (5, 9, and 13) were prepared by the oxidation of 4, 8, and 12, respectively, with PCC in CH2Cl2 as described previously.15 For compounds 13, after evaporation of the solvent the residue was filtered through a small pad of SiO2 using THF as an eluent. The solution was concentrated under reduced pressure and used in the next step without any other purification.
(2-Chlorophenyl)(2-chloropyridin-3-yl)methanone (5a): a pale-yellow oil; Rf 0.44 (AcOEt/hexane 1:3); IR (neat) 1682 cm–1; 1H NMR (500 MHz) δ 7.37–7.41 (m, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.50 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H), 7.60 (dd, J = 7.8, 1.4 Hz, 1H), 7.90 (dd, J = 7.8, 1.8 Hz, 1H), 8.54 (dd, J = 4.6, 1.8 Hz, 1H). Anal. Calcd for C12H7Cl2NO: C, 57.17; H, 2.80; N, 5.56. Found: C, 57.10; H, 2.91; N, 5.46.
(2-Bromo-5-methoxyphenyl)(2-chloropyridin-3-yl)methanone (5b): a pale-yellow oil; Rf 0.33 (AcOEt/ hexane 1:1); IR (neat) 1682 cm–1; 1H NMR (500 MHz) δ 3.83 (s, 3H), 6.95 (dd, J = 8.7, 3.2 Hz, 1H), 7.07 (d, J = 3.2 Hz, 1H), 7.37 (dd, J = 7.8, 4.6 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.90 (dd, J = 7.8, 1.8 Hz, 1H), 8.55 (dd, J = 4.6, 1.8 Hz, 1H). Anal. Calcd for C13H9BrClNO2: C, 47.81; H, 2.78; N, 4.29. Found: C, 47.66; H, 2.81; N, 4.25.
(2-Chloropyridin-3-yl)(2,3-dichlorophenyl)methanone (5c): a pale-yellow oil; Rf 0.23 (AcOEt/hexane 1:3); IR (neat) 1687 cm–1; 1H NMR (500 MHz) δ 7.34 (t, J = 8.0 Hz, 1H), 7.40 (dd, J = 8.0, 4.6 Hz, 1H), 7.45 (dd, J = 8.0, 1.7 Hz, 1H), 7.66 (dd, J = 8.0, 1.7 Hz, 1H), 7.94 (dd, J = 8.0, 1.7 Hz, 1H), 8.56 (dd, J = 4.6, 1.7 Hz, 1H). Anal. Calcd for C12H6Cl3NO: C, 50.30; H, 2.11; N, 4.89. Found: C, 50.08; H, 2.39; N, 4.85.
(2-Chlorophenyl)(3-chloropyridin-4-yl)methanone (9a): a pale-yellow oil; Rf 0.29 (AcOEt/hexane 1:5); IR (neat) 1687 cm–1; 1H NMR (500 MHz) δ 7.36–7.42 (m, 2H), 7.45–7.51 (m, 2H), 7.59 (dd, J = 7.4, 1.7 Hz, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.70 (s, 1H). Anal. Calcd for C12H7Cl2NO: C, 57.17; H, 2.80; N, 5.56. Found: C, 57.13; H, 3.01; N, 5.51.
(2-Bromo-5-chlorophenyl)(3-chloropyridin-4-yl)methanone (9b): a colorless oil; Rf 0.31 (AcOEt/ hexane 1:5); IR (neat) 1693 cm–1; 1H NMR (500 MHz) δ 7.38–7.40 (m, 2H), 7.48 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.72 (s, 1H). Anal. Calcd for C12H6BrCl2NO: C 43.54; H, 1.83; N, 4.23. Found: C, 43.47; H, 2.06; N, 4.13.
(2-Bromo-5-methoxyphenyl)(3-chloropyridin-4-yl)methanone (9c): a colorless oil; Rf 0.38 (AcOEt/hexane 1:2); IR (neat) 1686 cm–1; 1H NMR (400 MHz) δ 3.83 (s, 3 H), 6.97 (dd, J = 8.8, 2.9 Hz, 1H), 7.06 (d, J = 2.9 Hz, 1H), 7.37 (d, J = 4.9 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 4.9 Hz, 1H), 8.71 (s, 1H). Anal. Calcd for C13H9BrClNO2: C, 47.81; H, 2.78; N, 4.29. Found: C, 47.63; H, 2.88; N, 4.06.

Typical Procedure for the Preparation of Benzothiopyranopyridinones (6, 10, and 14). 5H-[1]Benzothiopyrano[2,3-b]pyridin-5-one (6a): A solution of 5a (0.20 g, 0.79 mmol) and Na2S·9H2O (0.19 g, 0.79 mmol) in DMF (4 mL) was heated at 60 ˚C for 1 h under stirring. After cooling to rt, H2O (20 mL) was added and the precipitate was collected by filtration. Recrystallization of the crude product from hexane/CH2Cl2 gave 6a (0.15 g, 88%); a white solid; mp 232–234 °C (lit.,16 mp 234 °C); IR (KBr) 1651 cm–1; 1H NMR (500 MHz) δ 7.46 (dd, J = 7.3, 4.6 Hz, 1H), 7.53 (ddd, J = 7.8, 7.3, 0.9 Hz, 1H), 7.64–7.70 (m, 2H), 8.60 (dd, J = 7.8, 0.9 Hz, 1H), 8.80 (dd, J = 4.6, 1.8 Hz, 1H), 8.84 (dd, J = 7.8, 1.8 Hz, 1H).
7-Methoxy-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (6b): a yellow solid; mp 182–184 °C (hexane/ CHCl3); IR (KBr) 1634 cm–1; 1H NMR (500 MHz) δ 3.95 (s, 3H), 7.31 (dd, J = 8.7, 2.8 Hz, 1H), 7.44 (dd, J = 8.2, 4.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 8.80 (dd, J = 4.6, 1.8 Hz, 1H), 8.85 (dd, J = 8.2, 1.8 Hz, 1H); 13C NMR δ 55.73, 110.49, 121.41, 123.29, 125.71, 127.71, 129.30, 129.95, 137.84, 153.19, 158.72, 158.89, 180.34; MS m/z 243 (M+, 100). Anal. Calcd for C13H9NO2S: C, 64.18; H, 3.73; N, 5.76. Found: C, 64.14; H, 3.73; N, 5.71.
9-Chloro-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (6c): a pale-yellow solid; mp 194–196 °C (hexane/CH2Cl2); IR (KBr) 1645 cm–1; 1H NMR (500 MHz) δ 7.47–7.51 (m, 2H), 7.78 (dd, J = 7.4, 1.1 Hz, 1H), 8.56 (dd, J = 8.0, 1.1 Hz, 1H), 8.82 (dd, J = 8.0, 1.7 Hz, 1H), 8.85 (dd, J = 4.6, 1.7 Hz, 1H); 13C NMR δ 122.09, 125.49, 126.69, 128.42, 130.70, 130.85, 133.36, 136.86, 137.74, 153.67, 158.22, 180.40; MS m/z 247 (M+, 100). Anal. Calcd for C12H6ClNOS: C, 58.19; H, 2.44; N, 5.65. Found: C, 58.17; H, 2.57; N, 5.50.
5H-[1]Benzothiopyrano[2,3-c]pyridin-5-one (10a):16 a pale-yellow solid; mp 172–172.5 °C (hexane/ CH2Cl2); IR (KBr) 1652 cm–1; 1H NMR (500 MHz) δ 7.56 (dd, J = 8.0, 6.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.0, 6.9 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.98 (s, 1H).
7-Chloro-5H-[1]benzothiopyrano[2,3-c]pyridin-5-one (10b): a pale-yellow solid; mp 210–212 °C (hexane/CH2Cl2); IR (KBr) 1638 cm–1; 1H NMR (500 MHz) δ 7.62 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.6, 2.3 Hz, 1H), 8.33 (d, J = 4.6 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.71 (d, J = 5.2 Hz, 1H), 8.98 (s, 1H); 13C NMR δ 121.44, 128.18, 129.39, 130.01, 132.20, 133.33, 133.47, 133.50, 134.76, 146.69, 148.55, 178.12; MS m/z 247 (M+, 100). Anal. Calcd for C12H6ClNOS: C, 58.19; H, 2.44; N, 5.65. Found: C, 58.00; H, 2.69; N, 5.57.
7-Methoxy-5H-[1]benzothiopyrano[2,3-c]pyridin-5-one (10c): a yellow solid; mp 160–161 °C (hexane/ CH2Cl2); IR (KBr) 1630, 1604 cm–1; 1H NMR (500 MHz) δ 3.96 (s, 3H), 7.35 (dd, J = 8.8, 2.9 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 4.9 Hz, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.99 (s, 1H); 13C NMR δ 55.74, 110.21, 121.42, 123.72, 128.03, 128.47, 130.13, 132.84, 132.99, 146.02, 148.62, 158.88, 178.81; MS m/z 243 (M+, 100). Anal. Calcd for C13H9NO2S: C, 64.18; H, 3.73; N, 5.76. Found: C, 64.10; H, 3.79; N, 5.80.
10H-[1]Benzothiopyrano[3,2-c]pyridin-10-one (14a):16 a pale-yellow solid; mp 145–147 °C (hexane/ CH2Cl2); IR (KBr) 1643 cm–1; 1H NMR (500 MHz) δ 7.46 (d, J = 5.2 Hz, 1H), 7.56 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.69 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 8.63 (dd, J = 8.0, 1.1 Hz, 1H), 8.67 (d, J = 5.2 Hz, 1H), 9.69 (s, 1H).
6-Chloro-10H-[1]benzothiopyrano[3,2-c]pyridin-10-one (14b): a pale-yellow solid; mp 194–196 °C (hexane/CH2Cl2); IR (KBr) 1642 cm–1; 1H NMR (500 MHz) δ 7.52 (dd, J = 8.0, 7.4 Hz, 1 H), 7.54 (d, J = 4.9 Hz, 1H), 7.78 (dd, J = 7.4, 1.1 Hz, 1H), 8.58 (dd, J = 8.0, 1.1 Hz, 1 H), 8.71 (d, J = 4.9 Hz, 1H), 9.67 (s, 1H); 13C NMR δ 120.28, 123.01, 127.23, 128.27, 130.73, 132.04, 133.43, 135.28, 145.67, 150.61, 152.15, 179.01. HR MS. Calcd for C12H7ClNOS (M+H): 247.9937. Found: m/z 247.9927. Anal. Calcd for C12H6ClNOS: C, 58.19; H, 2.44; N, 5.65. Found: C, 58.02; H, 2.49; N, 5.37.
8-Methoxy-10H-[1]benzothiopyrano[3,2-c]pyridin-10-one (14c): a pale-yellow solid; mp 201–203 °C (hexane/CH2Cl2); IR (KBr) 1644, 1602 cm–1; 1H NMR (500 MHz) δ 3.96 (s, 3H), 7.32 (dd, J = 8.6, 2.9 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 2.9 Hz, 1H), 8.64 (d, J = 5.2 Hz, 1H), 9.70 (s, 1H); 13C NMR δ 55.78, 110.45, 119.82, 123.27, 127.58, 131.33, 146.29, 146.56, 149.75 (2C), 152.27, 159.16, 179.10. HR MS. Calcd for C13H10NO2S (M+H): 244.0432. Found: m/z 244.0416. Anal. Calcd for C13H9NO2S: C, 64.18; H, 3.73; N, 5.76. Found: C, 64.15; H, 3.76; N, 5.74.

ACKNOWLEDGEMENTS
The authors wish to thank Mrs. Miyuki Tanmatsu of our university for her support in recording mass spectra and performing combustion analyses.

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