HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 6, 2014, pp. 1491-1501
Received, 19th March, 2014, Accepted, 16th April, 2014, Published online, 17th April, 2014.

■ An Efficient Method for the Preparation of 4-Alkoxy-substituted Thieno[2,3-b]pyridines

Keiji Saito, Satoru Naito, and Tsuyoshi Shinozuka*

Department of Chemistry, Daiichi Sankyo India Pharma Private Limited, Village Sehroul, Sector-18, Udyog Vihar Industrial Area, Gurugaon, 122 015, India

Abstract

An efficient method for the preparation of 4-alkoxy-substituted thieno[2,3-b]pyridines is described. The key intermediates, 4-alkoxy-2-chloro-3-cyanopyridines, were synthesized from a variety of alcohols by nucleophilic substitution with 3-cyano-2,4-dichloropyridine or by Mitsunobu reaction with 2-chloro-4-hydroxynicotinonitrile. Subsequent reaction of 4-alkoxy-2-chloro-3-cyanopyridines with 2-(acetylthio)acetamide under basic conditions provided 4-alkoxy-substituted thieno[2,3-b]pyridines in fair to good yields.

During the course of a project directed at the synthesis of antiosteoporotic compounds,1 the need arose for a general route for the synthesis of 4-alkoxy-substituted thieno[2,3-b]pyridine derivatives 3 (Scheme 1). Since thieno[2,3-b]pyridines 3 can be synthesized from chloropyridines 1 and thiols 2 in the presence of a base,2,3 4-alkoxy-2-chloro-3-cyanopyridines 1 are thought to be the straightforward precursors. It is known that 4-alkoxy-substituted chloropyridines 1 can be prepared from malononitrile.4 However, only methoxy and ethoxy groups are introduced as the C4 substituent of chloropyridines 1. Although there is another precedent exploiting the O-alkylation of 3-cyano-2-halo-4-hydroxypyridines with alkylhalides, only a limited number of primary alkyl groups are incorporated with moderate yields.5 Using our method, a variety of alkoxy groups derived from the corresponding primary and secondary alcohols can be installed efficiently and effectively. Herein, we report a general procedure for the preparation of 4-alkoxy-substituted 2-chloro-3-cyanopyridines 1, followed by syntheses of 4-alkoxy-substituted thieno[2,3-b]pyridines 3.

Given that nucleophilic substitution of 2,4-dichloropyridine occurs selectively at the 4-position,6 our initial approach to 4-alkoxy-2-chloro-3-cyanopyridines 1 was nucleophilic substitution of 3-cyano-2,4-dichloropyridines (4)7 with sodium alkoxides, as summarized in Table 1. The regiochemistry of the products 1 was determined by comparison with the 1H NMR spectrum of the authentic sample 1a (R = Me, Table 1).4a Several products precipitated after the addition of water to the reaction mixture, and subsequent filtration, provided the desired products in moderate (1a, 1b and 1c) to good (1d) yields. As cyclohexyl derivative 1e and cycloheptyl derivative 1f were oily products, typical workup and purification by column chromatography were performed. As N-methylpiperidine derivative 1h is water-soluble, the reaction mixture was concentrated, and the following purification provided 1h in an excellent yield of 94%.

Due to its relatively high water solubility, the isolated yields of 1a, 1b and 1c are not better than the yield of 1e and 1f, because compounds 1e and 1f were chromatographically purified. When dichloropyridine 4 was reacted with ethyl glycolate 5g, the precipitate obtained was not desired 1g, but 2-alkoxyl compound 6,8 which was isolated in 63% yield. The reason for the changes in regioselectivity is unclear. However, even in polar solvent, like DMF, sodium mediated interaction between the carbonyl oxygen of ethyl glycolate 5g and the nitrogen of pyridine 4 seems to affect the regioselectivity greatly.9
Next, we envisioned an alternative synthetic approach to 4-alkoxy-2-chloro-3-cyanopyridines 1 because 4-alkoxypyridine 1g needed to be synthesized. The alternative approach includes Mitsunobu reaction10 of 4-hydroxypyridine 7 as shown in Table 2. Using this method, compound 1g was successfully obtained in 59% yield, and the regiochemistry of 1b–1g was reconfirmed by the comparison of 1H NMR spectra. Simple alcohols such as ethyl, isopropyl, and benzyl alcohol provided 4-alkoxypyridines 1 in excellent yields. Interestingly, the reaction of 4-hydroxypyridine 7 with cyclohexyl alcohol (5e) provided 4-alkoxypyridine 1e in poor yield and a large amount of starting 7 was recovered, whereas the reaction with cycloheptyl alcohol (5f) provided 4-alkoxypyridine 1f in quantitative yield. Since the reaction with alcohol 5h also provided a trace amount of 4-alkoxypyridine 1h, saturated six-membered-ring-substituted alcohols are not suitable in these reaction conditions.11

Since 4-alkoxy-2-chloro-3-cyanopyridines 1 were on hand, the ring closure reaction was examined. Although thioglycolamide 2 (Scheme 1; R2 = NH2) is known to react with 2-chloro-3-cyanopyridine 1 to provide thieno[2,3-b]pyridine-2-carboxamide 3,3 thioglycolamide was found to be unstable and dimerized in several days even under a nitrogen atmosphere. Moreover, thioglycolamide can be purchased only in alcoholic ammonia solution. On the other hand, 2-(acetylthio)acetamide 8 (Table 3) is commercially available and deacetylation of 8 proceeds smoothly to provide thioacetamide 2 quantitatively. Therefore, one-pot reaction was performed as indicated in Table 3. The product 3 precipitated after the addition of water to the reaction mixture. The exception was carboxylic acid 3g, which precipitated upon the addition of 1 M HCl. 4-Isopropoxythieno[2,3-b]pyridine 3c, 4-(benzyloxy)thieno[2,3-b]pyridine 3d, 4-(cyclohexyloxy)thieno[2,3-b]pyridine 3e, 4-(cycloheptyloxy)thieno[2,3-b]pyridine 3f, and 4-[(1-methylpiperidin-4-yl)oxy]thieno[2,3-b]pyridine 3h were isolated in good to excellent yields. On the other hand, the reaction with 4-methoxythieno[2,3-b]pyridine 3a and 4-ethoxythieno[2,3-b]pyridine 3b showed moderate yields due to its relatively high water solubility. In particular, the yield of acid 3g was only 42% because of its higher water solubility.

In summary, an efficient method for the preparation of 4-alkoxy-substituted thieno[2,3-b]pyridines 3 has been established. The regioselective nucleophilic substitution of alkoxide takes place in the 4-position of 3-cyano-2,4-dichloropyridine (4) in most cases to provide 4-alkoxy-2-chloro-3-cyanopyridines 1. Mitsunobu reaction of 2-chloro-3-cyano-4-hydroxypyridines 7 also provides 4-alkoxy-2-chloro-3-cyanopyridines 1 in good yields with the secured regiochemistry. The reaction of 4-alkoxy-2-chloro-3-cyanopyridines 1 with 2-(acetylthio)acetamide 8 under basic conditions affords 4-alkoxy-substituted thieno[2,3-b]pyridines 3 in fair to excellent yields.

EXPERIMENTAL
Melting points are uncorrected. IR absorption spectra were recorded on a Jasco FT/IR-830 spectrophotometer. NMR spectra were recorded on a VARIAN Mercury 400 (400 MHz) or VARIAN Inova 500 (500 MHz) instrument using tetramethylsilane as an internal reference. Low-resolution MS and HRMS were recorded on a JEOL JMS-AX505H. Elemental analyses were performed by the Institute of Science and Technology, Inc. TLC analysis was performed on 60 F254 plate (Merck, art. 5715). Separation of the compounds by column chromatography was carried out with silica gel 60 (Merck, 230–400 mesh ASTM).
2-Chloro-4-methoxynicotinonitrile (1a).
A solution of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (7.38 g, 49.2 mmol) in POCl3 (50 mL) was refluxed for 1 h. The excess POCl3 was removed under reduced pressure. The residue was diluted with a slurry of ice and water (100 mL). The resulting suspension was made basic with a saturated aqueous solution of NaHCO3 (100 mL). The white crystal was collected to provide 1a (7.67 g, 93%). Mp 175–176 °C; IR (KBr): 2232, 1580, 1554, 1482, 1432, 1394, 1312, 1039, 843 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (1H, d, J = 4.3 Hz), 7.40 (1H, d, J = 4.3 Hz), 4.05 (3H, s); 13C NMR (125 MHz, DMSO-d6) δ 166.1, 154.0, 152.3, 112.6, 107.9, 98.6, 57.8; MS (EI): m/z = 168 [M+], 139, 138, 107, 103, 92, 75, 64, 63; HRMS-EI m/z [M+] calcd for C7H5N2OCl: 168.0091; found: 168.0087. Anal. Calcd for C7H5N2OCl•0.11H2O: C, 49.29; H, 3.09; N, 16.42; Cl, 20.78. Found: C, 49.40; H, 2.94; N, 16.59, Cl, 20.88.
General Procedure for the Preparation of 1 from 4
To a slurry of sodium hydride (48 mg, 1.1 mmol) in anhydrous THF (1.0 mL) was added alcohol 5 (1.1 mmol). This sodium alkoxide solution was added to a stirred solution of 4 (173 mg, 1.0 mmol) in DMA (1.0 mL) at 0 °C. After stirring for 1 h at 0 °C, water (5 mL) was added to the reaction mixture. In the cases of 1b, 1c, and 1d, the precipitate was filtered and washed with water (10 mL) and Et2O (1 mL) to provide 1b, 1c, or 1d. In the cases of 1e and 1f, the mixture was extracted with AcOEt (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), concentrated, and purified by column chromatography to provide 1e or 1f.
2-Chloro-4-methoxynicotinonitrile (1a): Compound 1a was synthesized in 10-mmol scale, and exhibited an identical 1HNMR spectrum to authentic sample.
2-Chloro-4-ethoxynicotinonitrile (1b): White crystal; Mp 91–93 °C; IR (KBr): 2995, 2925, 1579, 1556, 1468, 1395, 1317, 1257, 1038, 965, 815, 843 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.39 (1H, d, J = 5.9 Hz), 6.85 (1H, d, J = 5.9 Hz ), 4.27 (2H, q, J = 6.8 Hz), 1.53 (3H, t, J = 6.8 Hz); 13C NMR (125 MHz, CDCl3) δ 168.4, 154.4, 153.2, 112.3, 106.5, 100.5, 66.3, 14.2; MS (EI): m/z = 182 [M+], 154, 137, 126, 119, 93, 76, 64; HRMS-EI m/z [M+] calcd for C8H7N2OCl 182.0247; found: 182.0241. Anal. Calcd for C8H7N2OCl: C, 52.62; H, 3.86; N, 15.34. Found: C, 52.74; H, 3.93; N, 15.19.
2-Chloro-4-isopropoxynicotinonitrile (1c): White powder; Mp 87–88 °C; IR (KBr): 3096, 2985, 2235, 1580, 1550, 1469, 1390, 1316, 1262, 1102, 985, 840 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (1H, d, J = 6.4 Hz), 7.43 (1H, d, J = 6.4 Hz), 4.99 (1H, quint., J = 5.9 Hz), 1.36 (6H, d, J = 5.9 Hz); 13C NMR (125 MHz, DMSO-d6) δ 167.5, 153.8, 152.6, 112.7, 108.7, 99.1, 73.8, 21.2; MS (EI): m/z = 196 [M+], 181, 154, 145, 126, 119, 111, 93, 71, 57, 44; HRMS-EI m/z [M+] calcd for C9H9N2OCl 196.0404; found: 196.0401. Anal. Calcd for C9H9N2OCl: C, 54.97; H, 4.61; N, 14.25; Cl, 18.03. Found: C, 54.83; H, 4.48; N, 14.14; Cl, 18.14.
4-(Benzyloxy)-2-chloronicotinonitrile (1d): White needle; Mp 140–142 °C; IR (KBr): 3092, 2231, 1578, 1459, 1387, 1307, 1003, 824, 757, 701 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.37 (1H, d, J = 5.9 Hz), 7.43–7.38 (5H, m), 6.91 (1H, d, J = 5.9 Hz), 5.31 (2H, s); 13C NMR (125 MHz, CDCl3) δ 168.1, 154.5, 153.2, 133.7, 129.0, 129.0, 127.2, 112.2, 107.1, 100.9, 71.8; MS (EI): m/z = 244 [M+], 91, 65; HRMS-EI m/z [M+] calcd for C13H9N2OCl 244.0404; found: 244.0405. Anal. Calcd for C13H9N2OCl: C, 63.81; H, 3.71; N, 11.45; Cl, 14.49. Found: C, 63.99; H, 3.64; N, 11.35; Cl, 14.26.
2-Chloro-4-(cyclohexyloxy)nicotinonitrile (1e): Colorless oil; IR (film): 2941, 2862, 2233, 1578, 1465, 1305, 1016, 987, 824 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.35 (1H, d, J = 6.4 Hz ), 6.84 (1H, d, J = 6.4 Hz), 4.56–4.50 (1H, m), 1.96–1.42 (10H, m); 13C NMR (125 MHz, CDCl3) δ 167.7, 154.6, 152.8, 112.5, 107.2, 101.1, 78.5, 30.9, 25.1, 23.0; MS (EI): m/z = 236 [M+], 207, 195, 181, 155, 119, 83, 67, 55, 42; HRMS-EI m/z [M+] calcd for C12H13N2OCl 236.0717; found: 236.0721. Anal. Calcd for C12H13N2OCl•0.12H2O: C, 60.34; H, 5.59; N, 11.73; Cl, 14.84. Found: C, 60.06; H, 5.85; N, 11.50; Cl, 15.24.
2-Chloro-4-(cycloheptyloxy)nicotinonitrile (1f): Colorless oil; IR (film): 2933, 2233, 1575, 1464, 1307, 998, 821 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.34 (1H, d, J = 6.3 Hz), 6.79 (1H, d, J = 6.3 Hz), 4.69–4.64 (1H, m), 2.05–1.47 (12H, m); 13C NMR (125 MHz, CDCl3) δ 167.7, 154.6, 152.9, 112.5, 107.3, 101.1, 81.4, 33.2, 28.1, 22.6; MS (EI): m/z = 250 [M+], 215, 172, 155, 137, 119, 97, 81, 55, 42; HRMS-EI m/z [M+] calcd for C13H15N2OCl 250.0873; found: 250.0880. Anal. Calcd for C13H15N2OCl•0.36H2O: C, 60.71; H, 6.16; N, 10.89. Found: C, 61.03; H, 6.51; N, 10.93.
2-Chloro-4-[(1-methylpiperidin-4-yl)oxy]nicotinonitrile (1h): White needle; Mp 119–122 °C; IR (KBr): 2943, 2804, 2229, 1578, 1550, 1465, 1314, 1138, 1041, 989, 847, 772 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.37 (1H, d, J = 5.9 Hz); 6.84 (1H, d, J = 5.9 Hz), 4.63–4.60 (1H, m), 2.67–2.62 (2H, m), 2.45–2.39 (2H, m), 2.33 (3H, s), 2.08–1.93 (4H, m); 13C NMR (125 MHz, CDCl3) δ 167.3, 154.7, 152.9, 112.3, 107.1, 101.2, 75.0, 51.6, 46.1, 30.2; MS (EI): m/z = 251 [M+], 216, 209, 154, 119, 98, 70, 55, 42; HRMS-EI m/z [M+] calcd for C12H14N3OCl 251.0786; found: 251.0839. Anal. Calcd for C12H14N3OCl•0.14H2O: C, 56.69; H, 5.66; N, 16.53; Cl, 13.94. Found: C, 56.63; H, 5.68; N, 16.46; Cl, 13.84.
Ethyl [(4-chloro-3-cyanopyridin-2-yl)oxy]acetate (6): Pale brown powder; Mp 167–169 °C; IR (KBr): 3500, 3395, 3081, 1721, 1626, 1418, 1386, 1282, 1263, 1142, 965, 840, 760 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.33 (1H, d, J = 5.9 Hz); 7.34 (1H, d, J = 5.9 Hz), 5.54 (2H, brs), 4.45 (2H, q, J = 7.3 Hz), 1.44 (3H, t, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 160.9, 159.3, 147.1, 144.7, 117.0, 107.9, 60.9, 29.8, 14.6; MS (EI): m/z = 240 [M+], 212, 194, 168, 138, 131, 103, 76, 51, 44; HRMS-EI m/z [M+] calcd for C10H9N2O3Cl 240.0302; found: 240.0302.
Ethyl [(2-chloro-3-cyanopyridin-4-yl)oxy]acetate (1g).
To a stirred solution of 7 (155 mg, 1 mmol), PPh3 (340 mg, 1.3 mmol), and ethyl glycolate (123 µL, 1.3 mmol) in THF (5.0 mL) was added the solution of DEAD in toluene (0.62 mL, 1.3 mmol) dropwise at 0 °C. After stirring at 0 °C for 20 h, i-Pr2O (5 mL) was added and the precipitate was removed. The residue was concentrated and purified by column chromatography (toluene/MeCN = 10:1) to provide 1g (142 mg, 59%) as a white needle. Mp 70–72 °C; IR (KBr): 2990, 2232, 1751, 1576, 1470, 1386, 1223, 1085, 814 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.40 (1H, d, J = 5.9 Hz), 6.73 (1H, d, J = 5.9 Hz), 4.85 (2H, s), 4.30 (2H, q, J = 7.3 Hz), 1.31 (3H, t, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 167.8, 166.9, 153.8, 152.5, 112.4, 108.6, 98.9, 66.0, 61.2, 13.9; MS (EI): m/z = 240 [M+], 195, 181, 167, 139, 103, 76; HRMS-EI m/z [M+] calcd for C10H9N2O3Cl 240.0309; found: 240.0299. Anal. Calcd for C10H9N2O3Cl•0.12H2O: C, 49.47; H, 3.84; N, 11.54. Found: C, 49.09; H, 3.92; N, 11.90.
General Procedure for the Preparation of 3
To a solution of 2-(acetylthio)acetamide 8 (112 mg, 0.84 mmol) in DMF (0.7 mL) was added 8 M aqueous solution of NaOH (0.42 mL, 3.4 mmol). After 5 min, a solution of 1 (0.70 mmol) in DMF (0.7 mL) was added. After stirring for 1 h, water (2 mL) was added. The precipitate was filtered and washed with water (10 mL) and EtOH (1 mL) to provide 3.
3-Amino-4-methoxythieno[2,3-b]pyridine-2-carboxamide (3a): Yellow powder; Mp 238–241 °C; IR (KBr): 3482, 3325, 3149, 1667, 1613, 1583, 1504, 1375, 1289, 1044 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (1H, d, J = 5.9 Hz); 7.05 (2H, brs), 6.98 (1H, d, J = 5.9 Hz), 6.95 (2H, brs), 4.01 (3H, s); 13C NMR (125 MHz, DMSO-d6) δ 166.9, 163.0, 159.7, 151.6, 146.1, 115.2, 101.9, 94.0, 56.1; MS (EI): m/z = 223 [M+], 205, 178, 150, 137, 122, 104, 77, 66, 45; HRMS-EI m/z [M+] calcd for C9H9N3O2S 223.0415; found: 223.0416. Anal. Calcd for C9H9N3O2S: C, 48.42; H, 4.06; N, 18.82; S, 14.36. Found: C, 48.11; H, 4.32; N, 18.76, S, 14.18.
3-Amino-4-ethoxythieno[2,3-b]pyridine-2-carboxamide (3b): Pale yellow powder; Mp 241–243 °C; IR (KBr): 3446, 3331, 1645, 1584, 1506, 1375, 1294, 1046 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (1H, d, J = 5.9 Hz), 7.03 (2H, brs), 6.95 (1H, d, J = 5.9 Hz), 6.84 (2H, brs), 4.30 (2H, q, J = 7.1 Hz), 1.44 (3H, t, J = 7.1 Hz); 13C NMR (125 MHz, DMSO-d6) δ 166.8, 162.2, 159.9, 151.5, 146.1, 115.1, 102.5, 94.2, 64.6, 14.0; MS (EI): m/z = 237 [M+], 219, 205, 192, 176, 164, 148, 137, 120, 104; HRMS-EI m/z [M+] calcd for C10H11N3O2S 237.0572; found: 237.0574. Anal. Calcd for C10H11N3O2S: C, 50.62; H, 4.67; N, 17.71; S, 13.51. Found: C, 50.62; H, 4.69; N, 17.97, S, 13.52.
3-Amino-4-isopropoxythieno[2,3-b]pyridine-2-carboxamide (3c): White powder; Mp 238–240 °C (Dec.); IR (KBr): 3485, 3322, 3137, 1672, 1616, 1582, 1506, 1378, 1287, 1107, 995 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (1H, d, J = 5.9 Hz), 7.02 (2H, brs), 6.98 (1H, d, J = 5.9 Hz), 6.83 (2H, brs), 4.94 (1H, quint, J = 6.3 Hz), 1.40 (6H, d, J = 6.3 Hz); 13C NMR (125 MHz, DMSO-d6) δ 166.8, 161.4, 160.2, 151.4, 146.2, 115.5, 103.1, 94.1, 71.6, 21.3, 21.2; MS (EI): m/z = 251 [M+], 209, 192, 180, 164, 137, 120, 103, 92, 66, 52, 42; HRMS m/z [M+] calcd for C10H13N3O2S 251.0728; found: 251.0742. Anal. Calcd for C11H13N3O2S: C, 52.57; H, 5.21; N, 16.72; S, 12.76. Found: C, 52.20; H, 5.20; N, 16.71; S, 12.41.
3-Amino-4-(benzyloxy)thieno[2,3-b]pyridine-2-carboxamide (3d): White powder; Mp 216–221 °C; IR (KBr): 3490, 3324, 3151, 1651, 1580, 1502, 1370, 1290, 1039, 741 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (1H, d, J = 5.5 Hz), 7.55–7.36 (5H, m), 7.07 (2H, brs), 7.04 (1H, d, J = 5.5 Hz), 6.89 (2H, brs), 5.44 (2H, s); 13C NMR (125 MHz, DMSO-d6) δ 166.8, 161.9, 159.9, 151.4, 145.9, 135.6, 129.0, 128.6, 128.2, 127.7, 126.0, 115.4, 103.2, 94.5, 69.9; MS (FAB): m/z = 299 [M+], 283, 273, 257, 200, 193, 165, 91, 65; HRMS-FAB m/z [M+] calcd for C15H13N3O2S 299.0728; found: 299.0730. Anal. Calcd for C15H13N3O2S•0.12H2O: C, 59.75; H, 4.43; N, 13.94; S, 10.63. Found: C, 60.09; H, 4.36; N, 13.63; S, 10.26.
3-Amino-4-(cyclohexyloxy)thieno[2,3-b]pyridine-2-carboxamide (3e): White powder; Mp 206–208 °C; IR (KBr): 3492, 3330, 3159, 2935, 1654, 1580, 1504, 1368, 1286, 1041, 1020, 992 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (1H, d, J = 5.9 Hz), 7.04 (2H, brs), 7.02 (1H, d, J = 5.9 Hz), 6.81 (2H, brs), 4.76–4.70 (1H, m), 2.03–1.94 (2H, m), 1.77–1.28 (8H, m); 13C NMR (125 MHz, DMSO-d6) δ 166.8, 161.2, 160.2, 151.4, 146.1, 115.6, 103.2, 94.2, 76.0, 30.5, 24.7, 22.9; MS (EI): m/z = 291 [M+], 209, 192, 164, 137, 120, 55, 41; HRMS-EI m/z [M+] calcd for C14H17N3O2S 291.1041; found: 291.1040. Anal. Calcd for C14H17N3O2S•0.36H2O: C, 56.45; H, 6.00; N, 14.11; S, 10.76. Found: C, 56.75; H, 5.74; N, 14.07; S, 10.46.
3-Amino-4-(cycloheptyloxy)thieno[2,3-b]pyridine-2-carboxamide (3f): White powder; Mp 179–180 °C; IR (KBr): 3491, 3329, 3163, 2927, 1654, 1582, 1504, 1371, 1288, 1012 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (1H, d, J = 5.5 Hz), 7.03 (2H, brs), 6.94 (1H, d, J = 5.5 Hz), 6.81 (2H, brs), 4.89-4.83 (1H, m), 2.08–2.01 (2H, m), 1.90–1.81 (2H, m), 1.70–1.46 (8H, m); 13C NMR (125 MHz, DMSO-d6) δ 166.8, 161.2, 160.2, 151.4, 146.1, 115.6, 103.3, 94.1, 78.8, 32.6, 27.7, 22.1; MS (EI): m/z = 305 [M+], 209, 192, 164, 120, 97, 55, 41; HRMS-EI m/z [M+] calcd for C15H19N3O2S 305.1198; found: 305.1197. Anal. Calcd for C15H19N3O2S: C, 58.99; H, 6.27; N, 13.76; S, 10.50. Found: C, 58.81; H, 6.33; N, 13.60; S, 10.30.
{[3-Amino-2-(aminocarbonyl)thieno[2,3-b]pyridin-4-yl]oxy}acetic acid 0.67 HCl (3g): Yellow powder; Mp 180–182 °C (Dec.); IR (KBr): 3462, 3336, 3195, 1735, 1649, 1613, 1518, 1474, 1380, 1263, 1076 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (1H, d, J = 5.4 Hz), 7.09 (2H, brs), 6.95 (1H, d, J = 5.4 Hz), 4.99 (2H, s), 3.91 (2H, brs); 13C NMR (125 MHz, DMSO-d6) δ 168.8, 166.5, 162.6, 157.6, 149.7, 145.6, 116.1, 103.3, 94.8, 65.2; MS (FAB): m/z = 267 [M+], 251, 205, 187, 69, 55; HRMS-FAB m/z [M+] calcd for C10H9N3O4S 267.0314; found: 267.0325. Anal. Calcd for C10H9N3O4S•0.67HCl•3H2O: C, 34.75; H, 4.57; N, 12.16; Cl, 6.84; S, 9.28. Found: C, 35.06; H, 4.76; N, 12.04; Cl, 6.85; S, 9.46.
3-Amino-4-[(1-methylpiperidin-4-yl)oxy]thieno[2,3-b]pyridine-2-carboxamide (3h): White powder; Mp 204–206 °C; IR (KBr): 3479, 3331, 3165, 2935, 2790, 1662, 1582, 1504, 1371, 1287, 1040, 992 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.41 (1H, d, J = 5.9 Hz), 6.86 (2H, brs), 6.65 (1H, d, J = 5.9 Hz), 5.22 (2H, brs), 4.68–4.63 (1H, m), 2.66–2.60 (2H, m), 2.45–2.39 (2H, m), 2.33 (3H, s), 2.16–2.09 (2H, m), 2.03–1.96 (2H. m); 13C NMR (125 MHz, CDCl3) δ 167.4, 161.6, 161.2, 151.6, 147.6, 116.5, 102.5, 94.0, 73.4, 52.2, 46.2, 30.4; MS (ESI): m/z = 307 [M+H]+; HRMS-ESI m/z [M+H]+ calcd for C14H19N4O2S 307.1229; found: 307.1240. Anal. Calcd for C14H18N4O2S•0.1H2O: C, 54.56; H, 5.95; N, 18.18. Found: C, 54.35; H, 5.98; N, 18.36.

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