HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 12, 2009, pp. 2993-3000
Received, 3rd August, 2009, Accepted, 11th September, 2009, Published online, 15th September, 2009.
DOI: 10.3987/COM-09-11810

■ One-Pot Synthesis of Three Types of 2,3-Disubstituted Thienopyridines from Halopyridinyl Ketones

Kazuhiro Kobayashi,* Taketoshi Kozuki, and Hisatoshi Konishi

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

Abstract

This report describes a one-pot synthesis of three types of thienopyridine derivatives from the respective halopyridinyl ketones. Thus, the reaction of 2-bromopyridin-3-yl ketones, derived from 2-bromopyridine, with sodium sulfide followed by successive treatment BrCH2EWG’s and sodium hydride afforded 2,3-disubstituted thieno[2,3-b]pyridines. Similar one-pot sequences starting from aryl 3-bromopyridin-4-yl ketones and aryl 4-chloropyridin-3-yl ketones could also be readily performed to afford 2,3-disubstituted thieno[2,3-c]pyridines and 2,3-disubstituted thieno[3,2-c]pyridines, respectively.

INTRODUCTION
Thienopyridines are present in a large number of molecules of pharmaceutical and biological interest.1,2,3 Although several efficient methods for the preparation of thieno[2,3-b]pyridine derivatives have been reported,4 there have been only a few reports on the synthesis of thieno[2,3-c]pyridine and thieno[3,2-c]pyridine derivatives.5 For example, 2-substituted thieno[2,3-c]pyridines have been prepared by cyclization of the Schiff bases between thiophene-2-carboxaldehydes and aminoacetaldehyde dimethyl acetal.5a Recently, two routes to 3-substituted 4-aminothieno[3,2-c]pyridines from 4-bromothiophene-3- carboxylic acid have been reported by Engstrom and co-workers.5d We therefore embarked on the research for developing a procedure which is applicable to the synthesis of all these thienopyridine systems. In this paper we disclose a one-pot sequence using the respective halopyridinyl ketones, sodium sulfide, and BrCH2EWG’s (EWG = electron withdrawing group; CN, CO2t-Bu, COPh) that provides a new entry for the synthesis of 2,3-disubstituted thieno[2,3-b]pyridine, thieno[2,3-c]pyridine, and thieno[3,2-c]pyridine derivatives.

RESULTS AND DISCUSSION
First, we investigated conditions for the one-pot synthesis of 2,3-substituted thieno[2,3-b]pyridines (4) from 2-bromopyridin-3-yl ketones (1), which could be easily prepared from commercially available 2-bromopyridine via 2-bromo-3-lithiopyridine6 (see Experimental section). We found that the synthesis of 2,3-substituted thieno[2,3-b]pyridines (4) could be conducted as illustrated in Scheme 1. The starting materials (1) were allowed to react with sodium sulfide nonahydrate in DMF at 70 ˚C, and the resulting sodium thiolate intermediates (2) were treated with BrCH2EWG’s at room temperature to give 2-sulfenylated pyridn-3-yl ketones (3), which were then treated with sodium hydride at 0 ˚C to give, after the usual workup and subsequent purification by recrystallization or column chromatography on silica gel, the desired thieno[2,3-b]pyridine derivatives (4). It is notable that sodium hydride works well in the presence of water derived from disodium sulfide nonahydrate. The results are summarized in Table 1, which indicates that the yields of the products were fair-to-good in general.

To demonstrate the generality of the present one-pot transformation, we decided to prepare 2,3-disubstituted thieno[2,3-c]pyridine derivatives (6) from aryl 3-bromopyridin-4-yl ketones (5), which was readily prepared from commercially available 3-bromopyridine via a reaction of 3-bromo-4-lithiopyridine6 with N,N-dimethylbenzamides. We found that when compounds 5 was successively treated with disodium sulfide, BrCH2EWG’s, and sodium hydride under conditions similar to those for the preparation of 4, the corresponding desired products (6) were obtained, as shown in Scheme 2. The reaction of 5 with sodium sulfide proceeded more smoothly at lower reaction temperature than those of 1. Unfortunately, however, rather complicated mixtures of the products were formed after addition of sodium hydride and we were unable to obtain 6 in satisfactory yields. This may be ascribed to the formation of the products arising from bispyridinylation of disodium sulfide in the first step.

Thereafter, we tried to prepare 2,3-disubstituted thieno[3,2-c]pyridine derivatives (8) from aryl 4-chloropyridin-3-yl ketones (7), which was readily prepared from commercially available 4-chloropyridine via a reaction of 4-chloro-3-lithiopyridine6 with N,N-dimethylbenzamides, using similar one-pot conditions. The one-pot sequence starting with 7 under conditions as described above proceeded more cleanly and smoothly compared to those for the preparation of products (4) and (6) to result in the formation of the corresponding products (8) in relatively good yields, as shown in Scheme 3.

In conclusion, we have demonstrated that the one-pot sequence from halopyridinyl ketones provides a new and facile entry to three types of 2,3-disubstituted thienopyridine derivatives. Because the methodology starts with readily available and inexpensive materials and was performed under operationally simple conditions, it may be of value in organic synthesis. Further research addressing the applicability of this methodology to the synthesis of related heterocycles is currently under investigation in our laboratory.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were determined with a Shimadzu FTIR-8300 spectrophotometer. The 1H NMR spectra were determined in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz or a JEOL LA400 FT NMR spectrometer operating at 400 MHz. The 13C NMR spectra were determined 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. TLC was carried out on a Merck Kieselgel 60 PF254. Column chromatography was performed using Merck Kieselgel 60 (0.063–0.200 mm). All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. 1-(2-Bromopyridin-3-yl)propan-1-one (1a)7 and (2-bromopyridin-3-yl)- phenylmethanone (1b)4b were prepared according to the reported methods. N,N-Dimethylbenzamides were prepared from the respective benzoyl chloride and dimethylamine. All other chemicals used in this study were commercially available.
Aryl Halopyridinyl Ketones (1c), (5a), (5b), (7a), and (7b). These compounds were prepared by the reaction of 2-bromo-3-lithiopyridine, 3-bromo-4-lithiopyridines, or 4-chloro-3-lithiopyridine, generated by treating the respective halopyridines with LDA according to the previously reported procedure,6 with N,N-dimethylbenzamides in THF at –78 ˚C.
(2-Bromopyridin-3-yl)(4-methoxyphenyl)methanone (1c): in 56% yield; a yellow oil; Rf 0.25 (2:5 THF–hexane); IR (neat) 1668 cm–1; 1H NMR (500 MHz) δ 3.90 (s, 3H), 6.97 (d, J = 8.7 Hz, 2H), 7.40 (dd, J = 7.3, 4.6 Hz, 1H), 7.64 (dd, J = 7.3, 1.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 8.51 (dd, J = 4.6, 1.8 Hz, 1H). Anal. Calcd for C13H10BrNO2: C, 53.45; H, 3.45; N, 4.79. Found: C, 53.49; H, 3.58; N, 4.66.
(3-Bromopyridin-4-yl)phenylmethanone (5a): in 52% yield; a pale-yellow solid; mp 70–71 ˚C (hexane–Et2O); IR (KBr) 1676 cm–1; 1H NMR (500 MHz) δ 7.27 (d, J = 5.0 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.80 (d, J = 7.3 Hz, 2H), 8.67 (d, J = 5.0 Hz, 1H), 8.85 (s, 1H). Anal. Calcd for C12H8BrNO: C, 54.99; H, 3.08; N, 5.34. Found: C, 54.83; H, 3.17; N, 5.24.
(3-Bromopyridin-4-yl)(3-chlorophenyl)methanone (5b): in 60% yield; a pale-yellow solid; mp 79–80 ˚C (hexane); IR (KBr) 1682 cm–1; 1H NMR (500 MHz) δ 7.26 (d, J = 4.6 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.63 (dd, J = 7.8, 1.8 Hz, 2H), 7.79 (t, J = 1.8 Hz, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.86 (s, 1H). Anal. Calcd for C12H7BrClNO: C, 48.60; H, 2.38; N, 4.72. Found: C, 48.59; H, 2.41; N, 4.63.
(4-Chloropyridin-3-yl)phenylmethanone (7a):8 in 69% yield; a pale-yellow oil; Rf 0.29 (1:3 THF–hexane). The spectral (IR and 1H NMR) data for this compound were identical those reported previously.8
(4-Chloropyridin-3-yl)(3-methylphenyl)methanone (7b): in 59% yield; a pale-yellow oil; Rf 0.33 (1:5 THF–hexane); IR (neat) 1668, 1603 cm–1; 1H NMR (500 MHz) δ 2.42 (s, 3H), 7.38 (dd, J = 7.8, 7.3 Hz, 1H), 7.45 (d, J = 5.5 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 8.60 (s, 1H), 8.64 (d, J = 5.5 Hz, 1H). Anal. Calcd for C13H10ClNO: 67.39; H, 4.35; N, 6.05. Found: C, 67.34; H, 4.31; N, 6.01.
Typical Procedure for the Preparation of Thieno[2,3-b]pyridines (4). 3-Ethylthieno[2,3-b]pyridine- 2-carbonitrile (4a). A stirred mixture of 1a (0.21 g, 0.96 mmol) and Na2S nonahydrate (0.23 g, 0.96 mmol) in DMF (3.5 mL) was heated at 70 ˚C for 1 h. After cooling to rt, 2-bromoacetonitrile (0.12 g, 0.96 mmol) was added and the mixture was stirred for 10 min at the same temperature. Then NaH (60% in oil; 38 mg, 0.96 mmol) was added at 0 ˚C, and stirring was continued for an additional 10 min at the same temperature before water (15 mL) was added. The organic materials were extracted with AcOEt three times (10 mL each), and the combined extracts were washed with water and then brine, and then dried over anhydrous Na2SO4. After evaporation of the solvent, the resulting residual solid was recrystallized from hexane–CH2Cl2 to give 4a (0.11g, 60%); a pale-yellow solid; mp 108–109 ˚C; IR (KBr) 2218 cm–1; 1H NMR (500 MHz) δ 1.37 (t, J = 7.3 Hz, 3H), 3.09 (q, J = 7.3 Hz, 2H), 7.44 (dd, J = 7.8, 4.6 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 8.74 (dd, J = 4.6, 1.8 Hz, 1H); 13C NMR δ 14.46, 22.04, 105.45, 113.73, 120.29, 130.30, 131.18, 149.15, 150.09, 162.25; MS m/z 188 (M+, 43), 173 (100). Anal. Calcd for C10H8N2S: C, 63.80; H, 4.28; N, 14.88. Found: C, 63.71; H, 4.11; N, 14.66.
3-Phenylthieno[2,3-b]pyridine-2-carbonitrile (4b): a pale-yellow solid; mp 137–138 ˚C (hexane–Et2O); IR (KBr) 2218 cm–1; 1H NMR (500 MHz) δ 7.44 (dd, J = 8.2, 4.6 Hz, 1H), 7.54–7.63 (m, 5H), 8.16 (dd, J = 8.2, 1.4 Hz, 1H), 8.78 (dd, J = 4.6, 1.4 Hz, 1H); MS m/z 236 (M+, 100). Anal. Calcd for C14H8N2S: C, 71.16; H, 3.41; N, 11.86. Found: C, 71.02; H, 3.42; N, 11.63.
1,1-Dimethylethyl 3-Phenylthieno[2,3-b]pyridine-2-carboxylate (4c): a white solid; mp 115–116 ˚C (hexane); IR (KBr) 1693 cm–1; 1H NMR (500 MHz) δ 1.37 (s, 9H), 7.28 (dd, J = 8.2, 4.6 Hz, 1H), 7.36 (dd, J = 8.2, 1.4 Hz, 2H), 7.43–7.50 (m, 3H), 7.78 (dd, J = 8.2, 1.4 Hz, 1H), 8.68 (dd, J = 4.6, 1.4 Hz, 1H); MS m/z 311 (M+, 22), 255 (100). Anal. Calcd for C18H17NO2S: C, 69.43; H, 5.50; N, 4.50. Found: C, 69.36; H, 5.52; N, 4.50.
Phenyl(3-phenylthieno[2,3-b]pyridin-2-yl)methanone (4d): pale-yellow needles; mp 130–131 ˚C (hexane–CH2Cl2); IR (KBr) 1653 cm–1; 1H NMR (500 MHz) δ 7.20 (dd, J = 7.8, 7.3 Hz, 1H), 7.21–7.28 (m, 6H), 7.36 (tt, J = 7.3, 1.4 Hz, 1H), 7.38 (dd, J = 8.2, 4.6 Hz, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 2H), 8.07 (dd, J = 8.2, 1.4 Hz, 1H), 8.73 (dd, J = 4.6, 1.4 Hz, 1H); MS m/z 315 (M+, 93), 314 (100). Anal. Calcd for C20H13NOS: C, 76.16; H, 4.15; N, 4.44. Found: C, 76.15; H, 4.17; N, 4.47.
3-(4-Methoxyhenyl)thieno[2,3-b]pyridine-2-carbonitrile (4e): a white solid; mp 182–184 ˚C (hexane–CH2Cl2); IR (KBr) 2214, 1616 cm–1; 1H NMR (500 MHz) δ 3.91 (s, 3H), 7.10 (d, J = 8.7 Hz, 2H), 7.43 (dd, J = 8.2, 4.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 8.16 (dd, J = 8.2, 1.8 Hz, 1H), 8.76 (dd, J = 4.6, 1.8 Hz, 1H); 13C NMR δ 55.47, 105.07, 114.45, 114.81, 120.72, 123.93, 130.44 (2C), 132.80, 146.05, 150.28, 160.77, 161.99; MS m/z 266 (M+, 100). Anal. Calcd for C15H10N2OS: C, 67.65; H, 3.78; N, 10.52. Found: C, 67.42; H, 3.77; N, 10.43.
1,1-Dimethylethyl 3-(4-Methoxyhenyl)thieno[2,3-b]pyridine-2-carboxylate (4f): a pale-yellow solid; mp 183–184 ˚C (hexane–CH2Cl2); IR (KBr) 1715, 1609 cm–1; 1H NMR (500 MHz) δ 1.43 (s, 9H), 3.88 (s, 3H), 7.02 (d, J = 8.7 Hz, 2H), 7.28 (dd, J = 8.2, 4.6 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.82 (dd, J = 8.2, 1.4 Hz, 1H), 8.67 (dd, J = 4.6, 1.4 Hz, 1H); MS m/z 341 (M+, 27), 285 (100). Anal. Calcd for C19H19NO3S: C, 66.84; H, 5.61; N, 4.10. Found: C, 66.91; H, 5.63; N, 4.01.
Typical Procedure for the Preparation of Thieno[2,3-c]pyridines (6). 3-(3-Chlorophenyl)thieno[2,3- c]pyridine-2-carbonitrile (6b). A stirred mixture of 5b (0.25 g, 0.83 mmol) and Na2S nonahydrate (0.22 g, 0.91 mmol) in DMF (3.5 mL) was heated at 40 ˚C for 30 min. After cooling to rt, 2-bromoacetonitrile (0.11 g, 0.91 mmol) was added and the mixture was stirred for 20 min at the same temperature. Then NaH (60% in oil; 36 mg, 0.91 mmol) was added 0 ˚C and stirring was continued for an additional 15 min at the same temperature. After workup similar to that described for the preparation of 4a, the crude product was purified by column chromatography on silica gel to afford 6b (0.10 g, 45%); a pale-yellow solid; mp 187–189 ˚C (hexane–CH2Cl2); IR (KBr) 2222 cm–1; 1H NMR (400 MHz) δ 7.50–7.56 (m, 3H), 7.60 (t, J = 1.5 Hz, 1H), 7.72 (dd, J = 5.5, 1.1 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 9.26 (d, J = 1.1 Hz, 1H); 13C NMR δ 111.64, 113.42, 118.15, 127.39, 129.05, 130.16, 130.76, 132.56, 135.39, 136.85, 141.64, 144.81, 145.38, 145.61; MS m/z 270 (M+, 100). Anal. Calcd for C14H7ClN2S: C, 62.11; H, 2.61; N, 10.35. Found: C, 61.97; H, 2.75; N, 10.58.
Phenyl(3-phenylthieno[2,3-c]pyridin-2-yl)methanone (6a): colorless crystals; mp 143–145 ˚C (hexane–CH2Cl2); IR (KBr) 1647 cm–1; 1H NMR (500 MHz) δ 7.20–7.31 (m, 7H), 7.39 (t, J = 7.3 Hz, 1H), 7.66 (d, J = 7.3 Hz, 2H), 7.69 (d, J = 5.5 Hz, 1H), 8.59 (d, J = 5.5 Hz, 1H), 9.27 (s, 1H); MS m/z 315 (M+, 100). Anal. Calcd for C20H13NOS: C, 76.16; H, 4.15; N, 4.44. Found: C, 76.08; H, 4.18; N, 4.60.
1,1-Dimethylethyl 3-(3-Chlorophenyl)thieno[2,3-c]pyridine-2-carboxylate (6c): a pale-yellow solid; mp 97–99 ˚C (hexane); IR (KBr) 1695 cm–1; 1H NMR (400 MHz) δ 1.40 (s, 9H), 7.25 (ddd, J = 7.8, 7.3, 1.5 Hz, 1H), 7.37 (s, 1H), 7.38 (dd, J = 5.9, 1.1 Hz, 1H), 7.43–7.45 (m, 2H), 8.51 (d, J = 5.9 Hz, 1H), 9.20 (d, J = 1.1 Hz, 1H); MS m/z 345 (M+, 19), 289 (100). Anal. Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05. Found: C, 62.32; H, 4.76; N, 4.01.
Typical Procedure for the Preparation of Thieno[3,2-c]pyridines (8). 3-Phenylthieno[3,2-c]pyridine- 2-carbonitrile (8a). A stirred mixture of 7a (0.27 g, 1.3 mmol) and Na2S nonahydrate (0.33 g, 1.4 mmol) in DMF (3.5 mL) was heated at 50 ˚C for 2 h. After cooling to rt, 2-bromoacetonitrile (0.17 g, 1.4 mmol) was added and the mixture was stirred for 5 min at the same temperature. Then NaH (60% in oil; 55 mg, 1.4 mmol) was added at 0 ˚C and stirring was continued for an additional 5 min at the same temperature. After workup similar to that described for the preparation of 4a, the crude product was purified by recrystallization from hexane–CH2Cl2 to afford 8a (0.24 g, 82%); a pale-yellow solid; mp 172–173 ˚C (hexane–CH2Cl2); IR (KBr) 2214 cm–1; 1H NMR (500 MHz) δ 7.56–7.63 (m, 3H), 7.67 (dd, J = 7.8, 1.4 Hz, 2H), 7.85 (dd, J = 5.5, 0.9 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 9.17 (d, J = 0.9 Hz, 1H); MS m/z 236 (M+, 100). Anal. Calcd for C14H8N2S: C, 71.16; H, 3.41; N, 11.86. Found: C, 70.93; H, 3.52; N, 11.83.
1,1-Dimethylethyl 3-Phenylthieno[3,2-c]pyridine-2-carboxylate (8b): pale-yellow crystals; mp 92–93 ˚C (hexane); IR (KBr) 1694 cm–1; 1H NMR (500 MHz) δ 1.36 (s, 9H), 7.41 (dd, J = 7.8, 0.9 Hz, 2H), 7.45–7.52 (m, 3H), 7.79 (d, J = 5.9 Hz, 1H), 8.54 (d, J = 5.9 Hz, 1H), 8.78 (s, 1H); MS m/z 311 (M+, 54), 255 (100). Anal. Calcd for C18H17NO2S: C, 69.43; H, 5.50; N, 4.50. Found: C, 69.27; H, 5.55; N, 4.42.
Phenyl(3-phenylthieno[3,2-c]pyridin-2-yl)methanone (8c): pale-yellow crystals; mp 117–118 ˚C (hexane–CH2Cl2); IR (KBr) 1630 cm–1; 1H NMR (500 MHz) δ 7.18 (dd, J = 7.8, 7.3 Hz, 2H), 7.23–7.27 (m, 3H), 7.30–7.32 (m, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.61 (dd, J = 7.8, 1.4 Hz, 2H), 7.87 (dd, J = 5.5, 0.9 Hz, 1H), 8.60 (d, J = 5.5 Hz, 1H), 9.05 (d, J = 0.9 Hz, 1H); 13C NMR δ 117.13, 127.96, 128.50, 128.57, 129.61, 130.21, 132.80, 132.82, 135.36, 136.84, 138.37, 140.34, 144.65, 147.64, 147.82, 191.06; MS m/z 315 (M+, 95), 314 (100). Anal. Calcd for C20H13NOS: C, 76.16; H, 4.15; N, 4.44. Found: C, 76.15; H, 4.20; N, 4.34.
3-(3-Methylphenyl)thieno[3,2-c]pyridine-2-carbonitrile (8d): a pale-yellow solid; mp 135–137 ˚C (hexane–CH2Cl2); IR (KBr) 2218 cm–1; 1H NMR (500 MHz) δ 2.49 (s, 3H), 7.38 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.50 (dd, J = 7.8, 7.3 Hz, 1H), 7.84 (dd, J = 6.0, 0.9 Hz, 1H), 8.66 (d, J = 6.0 Hz, 1H), 9.17 (d, J = 0.9 Hz, 1H); MS m/z 250 (M+, 100). Anal. Calcd for C15H10N2S: C, 71.97; H, 4.03; N, 11.19. Found: C, 72.04; H, 4.15; N, 11.15.

ACKNOWLEDGEMENTS
The authors would like to thank Mrs. Miyuki Tanmatsu of this university for determining mass spectra and performing combustion analyses.

References

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