HETEROCYCLES

Note | Special issue | Vol. 82, No. 1, 2010, pp. 867-880
Received, 7th June, 2010, Accepted, 6th July, 2010, Published online, 7th July, 2010.
DOI: 10.3987/COM-10-S(E)47

■ A Convenient Approach to the Synthesis of Furo- and Thieno-[3,2-c]pyridine Derivatives

Hiroshi Maruoka,* Fumi Okabe, Keishi Yamasaki, Eiichi Masumoto, Toshihiro Fujioka, and Kenji Yamagata

Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

The title compounds were prepared from 4,5-dihydro-3-furan- and -3-thiophene-carbonitriles having an active methylene group at C-2 position 1, 2, 7, and 8 as key starting materials. Compounds 1 and 2 condensed with N,N-dimethylformamide dimethyl acetal to give the corresponding enamines 3 and 4. This condensation was followed by exchange reaction of amines and subsequent intramolecular cyclization reaction in the presence of ammonium acetate to lead the corresponding furo- and thieno-[3,2-c]pyridines 5 and 6. On the other hand, the reactions of compounds 7 and 8 with amines such as aqueous ammonium hydroxide and benzylamine afforded the intermediate acetamide derivatives A, without isolation of them, which underwent intramolecular cyclization reaction in the presence of sodium methoxide to yield the corresponding furo- and thieno-[3,2-c]pyridin-6(2H)-ones 9−12.

In many biologically active compounds, the pyridine core is a privileged substructure. Pyridines are basic structural motifs found in numerous products with interesting medicinal properties such as antimicrobial, myasthenia gravis, multiple sclerosis, spinal cord injuries, botulism, antibacterial, and antifungal.1−6 Among pyridine derivatives, fused analogues are often of much greater interest biologically than the corresponding monocyclic compounds. Some heterocyclic compounds containing condensed pyridines such as furo- and thieno-[3,2-c]pyridines possess a wide spectrum of pharmacological action.7−12 Hence, the preparation and biological properties of new substituted furo- and thieno-[3,2-c]pyridines are of interest.13−21 The preparation of furo[3,2-c]pyridines was first described by Herz and Tocker, who applied Bischler-Napieralski reaction to N-acyl derivatives of β-(2-furyl)ethylamine.22 In addition, thieno[3,2-c]pyridines were mentioned for the first time by Steinkopf and Lützkendorf using Skraup reaction starting from 2-aminothiophene.23
Although many synthetic methods for such furo- and thieno-[3,2-c]pyridines have been reported, there are relatively few methods in the literature describing the preparation of partially hydrogenated furo- and thieno-[3,2-c]pyridines.24−29 Interestingly, hydrogenated heterobicycles are also an important class of natural products and have potential uses in many fields. For example, it is known that the partially hydrogenated furo[2,3-b]furan ring is embodied in large number of natural products, particularly in some insect antifeeding compounds such as clerodin and azadirachtin.30−33 In this context, the preparation and biological properties of new partially hydrogenated heterobicycles such as furo- and thieno- [3,2-c]pyridines continues to attract attention and provides an interesting challenge. In the course of our investigation of the synthesis of heterobicycles,34−37 we have shown the synthesis of fused thiopyranthione and thiophene derivatives from 4,5-dihydro-3-furan- and -3-thiophene-carbonitriles having an active methylene group at C-2 position 1, 2, 7, and 8 as versatile starting materials.38 To further extend the utility of them, we herein describe a convenient procedure for the synthesis of furo- and thieno-[3,2-c]pyridine derivatives 5, 6, and 9−12 from key starting materials 1, 2, 7, and 8.

Initially, we examined condensation reaction of 3-cyano-4,5-dihydro-2-furan- and -2-thiophene- acetonitriles 1a−d and 2a−c with N,N-dimethylformamide dimethyl acetal39−42 (DMFDMA). Compounds 1a−d and 2a−c were easily prepared by Wittig reaction of tetrahydro-2-oxo-3-furan- and -3-thiophene- carbonitriles with (triphenylphosphoranylidene)acetonitrile according to our previous procedure.38 The reaction of compounds 1a−d and 2a−c with DMFDMA resulted in the formation of enamines 3a−d and 4a−c with 48−65% isolated yields (Scheme 1 and Table 1). Treatment of 3a−d and 4a−c with ammonium acetate39 followed by exchange reaction of amines effected intramolecular cyclization reaction to lead the corresponding furo- and thieno-[3,2-c]pyridines 5a−d and 6a−c in moderate yields (Scheme 1 and Table 2). Elemental analyses, MS spectra, 1H and 13C NMR spectra of compounds 3−6 are consistent with the assigned structures (see experimental section). For example, the IR spectra of 3 and 4 display bands in the range of 2205−2170 cm-1 due to two conjugated cyano groups. The 1H NMR spectra of 3 and 4 exhibit a signal near δ 7.4 attributable to the olefin proton of the (dimethylamino)methylene. The 13C NMR spectra of 3 and 4 show a signal near δ 153 due to the olefin carbon of the (dimethylamino)methylene. The IR spectra of 5 and 6 display bands in the range of 3450−3105 cm-1 due to a primary amino group. The 1H NMR spectra of 5 and 6 exhibit a D2O exchangeable signal near δ 6.7 attributable to the primary amino protons.

In the next step, we also attempted aminolysis/cyclization reaction of methyl 3-cyano-4,5-dihydro-2- furan- and -2-thiophene-acetates 7a−d and 8a−c38 with amines (Scheme 2). First the aminolysis parameters were optimized and second the base sodium methoxide was investigated because of its ease of handling. As a consequence, the reaction of compound 7a with aqueous ammonium hydroxide and/or benzylamine in MeOH at room temperature for 24 h led to the corresponding acetamide derivatives 13 (68%) and 14 (73%). Treatment of 13 and 14 with sodium methoxide in MeOH at room temperature for 1 h caused intramolecular cyclization reaction to give the corresponding furo[3,2-c]pyridin-6(2H)-ones 9a (59%) and 11a (90%). On the basis of these results, we have tried to directly construct furo- and thieno- [3,2-c]pyridin-6(2H)-ones 9−12 starting from 7 and/or 8 and amines in a one-pot process, without isolation of the intermediate acetamide derivatives A. The best results are shown in Table 3. Indeed, when a mixture of 7a−d and/or 8a−c and aqueous ammonium hydroxide and/or benzylamine in MeOH was stirred at room temperature for 24 h and then the reaction mixture was treated with sodium methoxide at room temperature for 1 h, the desired furo- and thieno-[3,2-c]pyridin-6(2H)-ones 9a−d, 10a−c, 11a−d, and 12a−c were obtained in moderate yields.
These products 9−12 gave satisfactory elemental analyses and spectroscopic data (IR, 1H NMR, 13C NMR, and MS) consistent with their assigned structures (see experimental section). For example, the IR spectra of 9−12 display bands in the range of 3480−3180 cm-1 due to a primary amino and amido groups. The 1H NMR spectra of 9−12 exhibit two D2O exchangeable signals near δ 5.9 and 10.0 attributable to the primary amino and amido protons. The 13C NMR spectra of 9−12 show a signal near δ 162 due to the amido carbonyl carbon. In addition, furo[3,2-c]pyridin-6(2H)-ones 9a and 11a were identical with authentic samples prepared by intramolecular cyclization reaction of acetamide derivatives 13 and 14 with sodium methoxide.

In conclusion, we have developed a convenient method for the synthesis of furo- and thieno- [3,2-c]pyridine derivatives 5, 6, and 9−12 from 4,5-dihydro-3-furan- and -3-thiophene-carbonitriles having an active methylene group at C-2 position 1, 2, 7, and 8. It is also worth noting that compounds 1, 2, 7, and 8 are versatile building blocks for the synthesis of new heterobicycles. This methodology offers significant advantages with regard to the simplicity of operation. Functionalized fused pyridine derivatives are important synthons in organic synthesis and for the preparation of biologically active compounds with interest in medicinal chemistry.

EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a JASCO FT/IR-4100 spectrometer. The 1H and 13C NMR spectra were measured with a JEOL JNM-A500 spectrometer at 500.00 and 125.65 MHz, respectively. The 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) relative to TMS as internal standard. Positive FAB MS spectra were obtained on a JEOL JMS-700T spectrometer. Elemental analyses were performed on YANACO MT-6 CHN analyzer. The starting compounds 1, 2, 7, and 8 were prepared in this laboratory according to our previous procedure.38
General procedure for the preparation of enamines 3 and 4 from 1 and/or 2 and DMFDMA.
A mixture of 1a−d and/or 2a−c (10 mmol) and DMFDMA (1.43 g, 12 mmol) was stirred at 80 °C for 2 h. After removal of MeOH in vacuo, the residue was purified by column chromatography on alumina with CH2Cl2 as the eluent to give 3a−d and 4a−c.
3-Cyano-4,5-dihydro-α-[(dimethylamino)methylene]-2-furanacetonitrile (3a)
Colorless prisms (1.07 g, 98%), mp 110−111 °C (acetone/petroleum ether); IR (KBr): 2203, 2185 (CN) cm-1; 1H NMR (CDCl3): δ 2.95 (t, J = 9.2 Hz, 2H, 4-H), 3.10−3.45 [m, 6H, N(CH3)2], 4.45 (t, J = 9.2 Hz, 2H, 5-H), 7.42 (s, 1H, olefin H); 13C NMR (CDCl3): δ 31.4 (C-4), 38.5, 47.7 [N(CH3)2], 68.4 [C=CHN(CH3)2], 70.8 (C-5), 72.4 (C-3), 116.5, 117.8 (CN), 152.9 [C=CHN(CH3)2], 165.3 (C-2); MS: m/z 190 [M+H]+. Anal. Calcd for C10H11N3O: C, 63.48; H, 5.86; N, 22.21. Found: C, 63.49; H, 5.83; N, 22.37.
3-Cyano-4,5-dihydro-α-[(dimethylamino)methylene]-4-phenyl-2-furanacetonitrile (3b)
Colorless prisms (1.53 g, 58%), mp 181−182 °C (acetone/petroleum ether); IR (KBr): 2201, 2186 (CN) cm-1; 1H NMR (CDCl3): δ 3.10−3.45 [m, 6H, N(CH3)2], 4.35 (dd, J = 6.4, 11.4 Hz, 2H, 4- and 5-H), 4.77 (t, J = 11.4 Hz, 1H, 5-H), 7.22−7.37 (m, 5H, aryl H), 7.53 (s, 1H, olefin H); 13C NMR (CDCl3): δ 38.6, 47.7 [N(CH3)2], 49.7 (C-4), 68.3 [C=CHN(CH3)2], 78.2 (C-3), 78.4 (C-5), 116.4, 117.4 (CN), 127.1, 127.7, 129.0, 140.8 (C aryl), 153.2 [C=CHN(CH3)2], 165.6 (C-2); MS: m/z 266 [M+H]+. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.43; H, 5.76; N, 15.81.
3-Cyano-4,5-dihydro-5-methyl-α-[(dimethylamino)methylene]-2-furanacetonitrile (3c)
Colorless prisms (1.64 g, 62%), mp 163−164 °C (acetone/petroleum ether); IR (KBr): 2204, 2181 (CN) cm-1; 1H NMR (CDCl3): δ 1.39 (d, J = 6.4 Hz, 3H, 5-CH3), 2.55 (dd, J = 7.6, 13.4 Hz, 1H, 4-H), 3.05 (dd, J = 9.5, 13.4 Hz, 1H, 4-H), 3.10−3.45 [m, 6H, N(CH3)2], 4.77−4.83 (m, 1H, 5-H), 7.40 (s, 1H, olefin H); 13C NMR (CDCl3): δ 21.2 (5-CH3), 38.3 (C-4), 38.6, 47.6 [N(CH3)2], 68.6 [C=CHN(CH3)2], 71.8 (C-3), 79.7 (C-5), 116.6, 118.0 (CN), 152.9 [C=CHN(CH3)2], 164.4 (C-2); MS: m/z 204 [M+H]+. Anal. Calcd for C11H13N3O: C, 65.01; H, 6.45; N, 20.67. Found: C, 65.00; H, 6.42; N, 20.71.
3-Cyano-4,5-dihydro-α-[(dimethylamino)methylene]-5-phenyl-2-furanacetonitrile (3d)
Colorless prisms (1.64 g, 62%), mp 163−164 °C (acetone/petroleum ether); IR (KBr): 2205, 2190 (CN) cm-1; 1H NMR (CDCl3): δ 2.96 (dd, J = 8.5, 14.0 Hz, 1H, 4-H), 3.10−3.45 [m, 7H, 4-H and N(CH3)2], 5.61 (dd, J = 8.5, 10.1 Hz, 1H, 5-H), 7.26−7.41 (m, 5H, aryl H), 7.43 (s, 1H, olefin H); 13C NMR (CDCl3): δ 38.6 [N(CH3)2], 39.4 (C-4), 47.6 [N(CH3)2], 68.4 [C=CHN(CH3)2], 72.1 (C-3), 83.9 (C-5), 116.4, 117.4 (CN), 125.7, 128.6, 128.8, 140.0 (C aryl), 153.0 [C=CHN(CH3)2], 164.3 (C-2); MS: m/z 266 [M+H]+. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.38; H, 5.76; N, 15.75.
3-Cyano-4,5-dihydro-α-[(dimethylamino)methylene]-2-thiopheneacetonitrile (4a)
Pale yellow needles (0.99 g, 48%), mp 104−105 °C (acetone/petroleum ether); IR (KBr): 2174 (CN) cm-1; 1H NMR (CDCl3): δ 3.05−3.09 (m, 2H, 4-H), 3.13−3.40 [m, 8H, 5-H and N(CH3)2], 7.35 (s, 1H, olefin H); 13C NMR (CDCl3): δ 31.7 (C-4), 38.0 (C-5), 39.2, 47.2 [N(CH3)2], 71.5 [C=CHN(CH3)2], 90.1 (C-3), 117.2, 117.5 (CN), 153.4 [C=CHN(CH3)2], 157.3 (C-2); MS: m/z 206 [M+H]+. Anal. Calcd for C10H11N3S: C, 58.51; H, 5.40; N, 20.47. Found: C, 58.55; H, 5.31; N, 20.71.
3-Cyano-4,5-dihydro-α-[(dimethylamino)methylene]-4-phenyl-2-thiopheneacetonitrile (4b)
Colorless prisms (1.83 g, 65%), mp 150−151 °C (acetone); IR (KBr): 2198, 2185 (CN) cm-1; 1H NMR (CDCl3): δ 3.10−3.50 [m, 7H, 5-H and N(CH3)2], 3.67 (dd, J = 9.1, 11.4 Hz, 1H, 5-H), 4.47 (dd, J = 7.0, 9.1 Hz, 1H, 4-H), 7.28−7.38 (m, 5H, aryl H), 7.48 (s, 1H, olefin H); 13C NMR (CDCl3): δ 38.9 [N(CH3)2], 39.5 (C-5), 47.4 [N(CH3)2], 55.8 (C-4), 71.5 [C=CHN(CH3)2], 94.6 (C-3), 117.3, 117.7 (CN), 127.3, 127.9, 129.0, 140.2 (C aryl), 153.4 [C=CHN(CH3)2], 158.0 (C-2); MS: m/z 282 [M+H]+. Anal. Calcd for C16H15N3S: C, 68.30; H, 5.37; N, 14.93. Found: C, 68.26; H, 5.49; N, 14.74.
3-Cyano-4,5-dihydro-5-methyl-α-[(dimethylamino)methylene]-2-thiopheneacetonitrile (4c)
Colorless prisms (1.10 g, 50%), mp 79−81 °C (acetone/petroleum ether); IR (KBr): 2200, 2182 (CN) cm-1; 1H NMR (CDCl3): δ 1.40 (d, J = 6.7 Hz, 3H, 5-CH3), 2.73 (dd, J = 5.8, 15.0 Hz, 1H, 4-H), 3.10−3.40 [m, 7H, 4-H and N(CH3)2], 3.77−3.82 (m, 1H, 5-H), 7.34 (s, 1H, olefin H); 13C NMR (CDCl3): δ 21.4 (5-CH3), 39.7 [N(CH3)2], 43.6 (C-5), 45.7 (C-4), 47.5 [N(CH3)2], 71.6 [C=CHN(CH3)2], 88.8 (C-3), 117.4, 117.5 (CN), 153.4 [C=CHN(CH3)2], 156.5 (C-2); MS: m/z 220 [M+H]+. Anal. Calcd for C11H13N3S: C, 60.24; H, 5.97; N, 19.16. Found: C, 60.30; H, 5.98; N, 19.17.
General procedure for the preparation of furo- and thieno-[3,2-c]pyridines 5 and 6 from 3 and/or 4 and ammonium acetate.
A mixture of 3a−d and/or 4a−c (5 mmol) and ammonium acetate (0.77 g, 10 mmol) in DMF (5 mL) was stirred at 100 °C for 5 h. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, dried, and recrystallized from an appropriate solvent to yield 5a−d and 6a−c.
4-Amino-2,3-dihydrofuro[3,2-c]pyridine-7-carbonitrile (5a)
Pale red prisms (0.54 g, 67%), mp >300 °C (DMF/H2O); IR (KBr): 3381, 3332, 3125 (NH), 2228 (CN) cm-1; 1H NMR (DMSO-d6): δ 2.97 (t, J = 8.9 Hz, 2H, 3-H), 4.72 (t, J = 8.9 Hz, 2H, 2-H), 6.77 (br s, 2H, NH2), 8.08 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 25.8 (C-3), 73.3 (C-2), 81.5 (C-7), 102.3 (C-3a), 115.9 (CN), 152.3 (C-6), 158.7 (C-4), 166.9 (C-7a); MS: m/z 162 [M+H]+. Anal. Calcd for C8H7N3O: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.50; H, 4.47; N, 26.00.
4-Amino-2,3-dihydro-3-phenylfuro[3,2-c]pyridine-7-carbonitrile (5b)
Pale yellow prisms (0.95 g, 80%), mp 202−203 °C (acetone/petroleum ether); IR (KBr): 3433, 3302, 311 (NH), 2225 (CN) cm-1; 1H NMR (DMSO-d6): δ 4.55 (dd, J = 3.7, 9.2 Hz, 1H, 2-H), 4.62 (dd, J = 3.7, 9.2 Hz, 1H, 3-H), 5.03 (t, J = 9.2 Hz, 1H, 2-H), 6.48 (br s, 2H, NH2), 7.15−7.18 (m, 2H, aryl H), 7.30−7.34 (m, 2H, aryl H), 7.23−7.27 (m, 1H, aryl H), 8.19 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 43.5 (C-3), 81.4 (C-2), 81.8 (C-7), 105.6 (C-3a), 115.7 (CN), 127.0, 127.1, 128.6, 141.0 (C aryl), 153.2 (C-6), 158.5 (C-4), 166.9 (C-7a); MS: m/z 238 [M+H]+. Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.92; H, 4.77; N, 17.62.
4-Amino-2,3-dihydro-2-methylfuro[3,2-c]pyridine-7-carbonitrile (5c)
Pale red prisms (0.50 g, 57%), mp 221−222 °C (acetone/petroleum ether); IR (KBr): 3408, 3327, 3145 (NH), 2218 (CN) cm-1; 1H NMR (DMSO-d6): δ 1.43 (d, J = 6.4 Hz, 3H, CH3), 2.55 (dd, J = 7.2, 15.3 Hz, 1H, 3-H), 3.13 (dd, J = 9.2, 15.3 Hz, 1H, 3-H), 5.10−5.18 (m, 1H, 2-H), 6.73 (br s, 2H, NH2), 8.08 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 21.4 (CH3), 33.0 (C-3), 81.4 (C-7), 82.6 (C-2), 102.0 (C-3a), 116.0 (CN), 152.4 (C-6), 158.7 (C-4), 166.1 (C-7a); MS: m/z 176 [M+H]+. Anal. Calcd for C9H9N3O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.78; H, 5.25; N, 24.01.
4-Amino-2,3-dihydro-2-phenylfuro[3,2-c]pyridine-7-carbonitrile (5d)
Pale yellow needles (0.85 g, 72%), mp 239−240 °C (acetone/petroleum ether); IR (KBr): 3431, 3317, 3105 (NH), 2212 (CN) cm-1; 1H NMR (DMSO-d6): δ 2.90−2.96 (m, 1H, 3-H), 3.46−3.52 (m, 1H, 3-H), 6.05 (dd, J = 7.5, 9.9 Hz, 1H, 2-H), 6.83 (br s, 2H, NH2), 7.36−7.45 (m, 5H, aryl H), 8.16 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 34.1 (C-3), 81.3 (C-7), 86.0 (C-2), 101.6 (C-3a), 115.8 (CN), 125.8, 128.4, 128.7, 140.4 (C aryl), 152.7 (C-6), 158.6 (C-4), 166.1 (C-7a); MS: m/z 238 [M+H]+. Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.77; H, 4.80; N, 17.56.
4-Amino-2,3-dihydrothieno[3,2-c]pyridine-7-carbonitrile (6a)
Pale red prisms (0.67 g, 76%), mp 283−284 °C (DMF/H2O); IR (KBr): 3404, 3310, 3134 (NH), 2216 (CN) cm-1; 1H NMR (DMSO-d6): δ 3.12 (t, J = 8.3 Hz, 2H, 3-H), 3.50 (t, J = 8.3 Hz, 2H, 2-H), 6.80 (br s, 2H, NH2), 8.13 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 31.7 (C-3), 32.1 (C-2), 90.6 (C-7), 115.8 (C-3a), 117.6 (CN), 151.8 (C-6), 154.9 (C-7a), 156.6 (C-4); MS: m/z 178 [M+H]+. Anal. Calcd for C8H7N3S: C, 54.22; H, 3.98; N, 23.71. Found: C, 54.20; H, 4.08; N, 23.68.
4-Amino-2,3-dihydro-3-phenylthieno[3,2-c]pyridine-7-carbonitrile (6b)
Colorless prisms (1.12 g, 89%), mp 253−255 °C (acetone/petroleum ether); IR (KBr): 3449, 3288, 3138 (NH), 2214 (CN) cm-1; 1H NMR (DMSO-d6): δ 3.26−3.30 (m, 1H, 2-H), 4.04 (dd, J = 8.9, 11.6 Hz, 1H, 2-H), 4.82 (dd, J = 1.8, 8.9 Hz, 1H, 3-H), 6.57 (br s, 2H, NH2), 7.15−7.18 (m, 2H, aryl H), 7.23−7.33 (m, 3H, aryl H), 8.24 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 41.2 (C-2), 48.3 (C-3), 90.8 (C-7), 117.6 (CN), 118.0 (C-3a), 127.0, 127.1, 128.4, 140.3 (C aryl), 152.7 (C-6), 155.9 (C-7a), 156.7 (C-4); MS: m/z 254 [M+H]+. Anal. Calcd for C14H11N3S: C, 66.38; H, 4.38; N, 16.59. Found: C, 66.49; H, 4.50; N, 16.59.
4-Amino-2,3-dihydro-2-methylthieno[3,2-c]pyridine-7-carbonitrile (6c)
Colorless prisms (0.63 g, 66%), mp 228−229 °C (acetone); IR (KBr): 3415, 3326, 3122 (NH), 2209 (CN) cm-1; 1H NMR (DMSO-d6): δ 1.40 (d, J = 7.0 Hz, 3H, CH3), 2.82 (dd, J = 5.6, 16.0 Hz, 1H, 3-H), 3.23−3.29 (m, 1H, 3-H), 4.15−4.20 (m, 1H, 2-H), 6.79 (br s, 2H, NH2), 8.14 (s, 1H, 6-H); 13C NMR (DMSO-d6): δ 22.4 (CH3), 40.0 (C-3), 44.7 (C-2), 90.6 (C-7), 114.8 (C-3a), 117.6 (CN), 151.8 (C-6), 154.1 (C-7a), 156.8 (C-4); MS: m/z 192 [M+H]+. Anal. Calcd for C9H9N3S: C, 56.52; H, 4.74; N, 21.97. Found: C, 56.58; H, 4.79; N, 21.89.
General procedure for the preparation of furo- and thieno-[3,2-c]pyridin-6(2H)-ones 9−12 from 7 and/or 8 and amines in the presence of sodium methoxide.
A mixture of 7a−d and 8a−c (5 mmol) and 28% aqueous ammonium hydroxide (5 mL, 0.128 mol) and/or benzylamine (5 mL, 45.8 mmol) in MeOH (5 mL) was stirred at rt for 24 h. To the obtained reaction mixture was added a solution of sodium (0.12 g, 5 mmol) in anhydrous MeOH (3 mL) with stirring and then the resulting mixture was stirred at rt for 1 h. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, dried, and recrystallized from an appropriate solvent to afford 9a−d, 10a−c, 11a−d, and 12a−c.
4-Amino-3,5-dihydrofuro[3,2-c]pyridin-6(2H)-one (9a)
Colorless prisms (0.41 g, 54%), mp >300 °C (CHCl3/MeOH); IR (KBr): 3403, 3319, 3195 (NH), 1678 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.75 (t, J = 8.2 Hz, 2H, 3-H), 4.48 (t, J = 8.2 Hz, 2H, 2-H), 4.83 (s, 1H, 7-H), 5.81 (br s, 2H, NH2), 9.78 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 24.4 (C-3), 72.5 (C-2), 81.4 (C-7), 86.0 (C-3a), 146.0 (C-4), 163.7 (CO), 172.4 (C-7a); MS: m/z 153 [M+H]+. Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.09; H, 5.35; N, 18.26.
4-Amino-3,5-dihydro-3-phenylfuro[3,2-c]pyridin-6(2H)-one (9b)
Colorless prisms (0.83 g, 73%), mp >300 °C (CHCl3/MeOH); IR (KBr): 3482, 3375 (NH), 1652 (CO) cm-1; 1H NMR (DMSO-d6): δ 4.29 (dd, J = 3.4, 8.9 Hz, 1H, 2-H), 4.39 (dd, J = 3.4, 8.9 Hz, 1H, 3-H), 4.80 (t, J = 8.9 Hz, 1H, 2-H), 4.95 (s, 1H, 7-H), 5.56 (br s, 2H, NH2), 7.15−7.17 (m, 2H, aryl H), 7.19−7.23 (m, 1H, aryl H), 7.28−7.32 (m, 2H, aryl H), 9.90 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 42.5 (C-3), 80.8 (C-2), 81.6 (C-7), 90.3 (C-3a), 126.6, 126.9, 128.5, 142.8 (C aryl), 146.6 (C-4), 163.9 (CO), 172.4 (C-7a); MS: m/z 229 [M+H]+. Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.49; H, 5.38; N, 12.20.
4-Amino-3,5-dihydro-2-methylfuro[3,2-c]pyridin-6(2H)-one (9c)
Colorless plates (0.33 g, 39%), mp >300 °C (CHCl3/MeOH); IR (KBr): 3386, 3184 (NH), 1691 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.32 (d, J = 6.9 H, 3H, CH3), 2.33 (dd, J = 6.8, 14.0 Hz, 1H, 3-H), 2.92 (dd, J = 8.5, 14.0 Hz, 1H, 3-H), 4.81 (s, 1H, 7-H), 4.83−4.90 (m, 1H, 2-H), 5.78 (br s, 2H, NH2), 9.80 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 21.6 (CH3), 31.9 (C-3), 81.2 (C-2), 81.3 (C-7), 86.1 (C-3a), 146.0 (C-4), 163.7 (CO), 171.7 (C-7a); MS: m/z 167 [M+H]+. Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.86; H, 6.10; N, 16.77.
4-Amino-3,5-dihydro-2-phenylfuro[3,2-c]pyridin-6(2H)-one (9d)
Colorless prisms (0.66 g, 58%), mp >300 °C (CHCl3/MeOH); IR (KBr): 3391, 3187 (NH), 1688 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.68 (dd, J = 6.7, 14.3 Hz, 1H, 3-H), 3.28 (dd, J = 9.2, 14.3 Hz, 1H, 3-H), 4.95 (s, 1H, 7-H), 5.80 (dd, J = 6.7, 9.2 Hz, 1H, 2-H), 5.87 (br s, 2H, NH2), 7.30−7.34 (m, 3H, aryl H), 7.37−7.41 (m, 2H, aryl H), 9.90 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 33.2 (C-3), 81.4 (C-7), 85.0 (C-2), 85.4 (C-3a), 125.5, 128.0, 128.5, 141.6 (C aryl), 146.1 (C-4), 163.9 (CO), 171.8 (C-7a); MS: m/z 229 [M+H]+. Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.38; H, 5.37; N, 12.23.
4-Amino-3,5-dihydrothieno[3,2-c]pyridin-6(2H)-one (10a)
Colorless needles (0.32 g, 38%), mp >300 °C (CHCl3/MeOH); IR (KBr): 3377, 3328, 3184 (NH), 1672 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.86 (t, J = 7.6 Hz, 2H, 3-H), 3.28 (t, J = 7.6 Hz, 2H, 2-H), 5.36 (s, 1H, 7-H), 5.76 (br s, 2H, NH2), 10.05 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 29.6 (C-3), 32.3 (C-2), 94.4 (C-7), 96.9 (C-3a), 145.2 (C-4), 159.8 (C-7a), 161.3 (CO); MS: m/z 169 [M+H]+. Anal. Calcd for C7H8N2OS: C, 49.98; H, 4.79; N, 16.65. Found: C, 49.75; H, 4.79; N, 16.41.
4-Amino-3,5-dihydro-3-phenylthieno[3,2-c]pyridin-6(2H)-one (10b)
Green prisms (0.81 g, 66%), mp >300 °C (CHCl3/MeOH); IR (KBr): 3436, 3357, 3297 (NH), 1613 (CO) cm-1; 1H NMR (DMSO-d6): δ 3.04 (dd, J = 1.7, 11.3 Hz, 1H, 2-H), 3.84 (dd, J = 8.2, 11.3 Hz, 1H, 2-H), 4.57 (dd, J = 1.7, 8.2 Hz, 1H, 3-H), 5.45 (s, 1H, 7-H), 5.53 (br s, 2H, NH2), 7.18−7.23 (m, 3H, aryl H), 7.27−7.31 (m, 2H, aryl H), 10.13 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 41.8 (C-2), 46.2 (C-3), 94.5 (C-7), 99.7 (C-3a), 126.6, 127.0, 128.2, 142.6 (C aryl), 145.9 (C-4), 160.3 (C-7a), 161.5 (CO); MS: m/z 245 [M+H]+. Anal. Calcd for C13H12N2OS • 0.1H2O: C, 63.44; H, 5.00; N, 11.38. Found: C, 63.39; H, 4.97; N, 11.33.
4-Amino-3,5-dihydro-2-methylthieno[3,2-c]pyridin-6(2H)-one (10c)
Brown prisms (0.33 g, 36%), mp >300 °C (EtOH); IR (KBr): 3385, 3192 (NH), 1671 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.34 (d, J = 6.7 Hz, 3H, CH3), 2.52 (dd, J = 6.3, 14.3 Hz, 1H, 3-H), 3.01 (dd, J = 7.6, 13.4 Hz, 1H, 3-H), 3.90−3.97 (m, 1H, 2-H), 5.32 (s, 1H, 7-H), 5.73 (br s, 2H, NH2), 10.06 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 22.2 (CH3), 37.9 (C-3), 44.7 (C-2), 94.5 (C-7), 96.3 (C-3a), 145.4 (C-4), 159.3 (C-7a), 161.3 (CO); MS: m/z 183 [M+H]+. Anal. Calcd for C8H10N2OS: C, 52.72; H, 5.53; N, 15.37. Found: C, 52.58; H, 5.58; N, 15.15.
4-Amino-3,5-dihydro-5-(phenylmethyl)furo[3,2-c]pyridin-6(2H)-one (11a)
Colorless prisms (0.76 g, 63%), mp 217−218 °C (acetone); IR (KBr): 3458, 3310 (NH), 1672 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.82 (t, J = 8.2 Hz, 2H, 3-H), 4.50 (t, J = 8.2 Hz, 2H, 2-H), 5.05 (s, 1H, 7-H), 5.17 (br s, 2H, CH2Ph), 6.19 (br s, 2H, NH2), 7.15−7.17 (m, 2H, aryl H), 7.19−7.22 (m, 1H, aryl H), 7.26−7.30 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 25.4 (C-3), 42.7 (CH2Ph), 72.1 (C-2), 80.9 (C-7), 86.7 (C-3a), 126.48, 126.53, 128.1, 137.5 (C aryl), 146.8 (C-4), 162.9 (CO), 170.1 (C-7a); MS: m/z 243 [M+H]+. Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.46; H, 5.90; N, 11.57.
4-Amino-3,5-dihydro-3-phenyl-5-(phenylmethyl)furo[3,2-c]pyridin-6(2H)-one (11b)
Colorless prisms (1.37 g, 86%), mp 190−191 °C (acetone); IR (KBr): 3464, 3307, 3194 (NH), 1665 (CO) cm-1; 1H NMR (DMSO-d6): δ 4.29 (dd, J = 3.1, 8.5 Hz, 1H, 2-H), 4.46 (dd, J = 3.1, 8.5 Hz, 1H, 3-H), 4.81 (t, J = 8.5 Hz, 1H, 2-H), 5.02 (br d, J = 16.5 Hz, 1H CH2Ph), 5.17 (s, 1H, 7-H), 5.31 (br d, J = 16.5 Hz, 1H, CH2Ph), 5.94 (br s, 2H, NH2), 7.11−7.22 (m, 6H, aryl H), 7.26−7.31 (m, 4H, aryl H); 13C NMR (DMSO-d6): δ 42.7 (CH2Ph), 43.1 (C-3), 80.5 (C-2), 80.9 (C-7), 90.7 (C-3a), 126.3, 126.5, 126.6, 126.9, 128.1, 128.4, 137.3, 142.8 (C aryl), 147.4 (C-4), 163.0 (CO), 170.2 (C-7a); MS: m/z 319 [M+H]+. Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.42; H, 5.75; N, 8.79.
4-Amino-3,5-dihydro-2-methyl-5-(phenylmethyl)furo[3,2-c]pyridin-6(2H)-one (11c)
Colorless needles (1.07 g, 84%), mp 241−242 °C (acetone); IR (KBr): 3474, 3311, 3277, 3204 (NH), 1672 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.35 (d, J = 6.4 Hz, 3H, CH3), 2.39 (dd, J = 6.7, 13.9 Hz, 1H, 3-H), 2.99 (dd, J = 8.5, 13.9 Hz, 1H, 3-H), 4.86−4.91 (m, 1H, 2-H), 5.02 (s, 1H, 7-H), 5.15 (AB q, J = 16.2 Hz, 2H, CH2Ph), 6.13 (br s, 2H, NH2), 7.15−7.22 (m, 3H, aryl H), 7.26−7.30 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 21.6 (CH3), 32.8 (C-3), 42.7 (CH2Ph), 80.8 (C-2), 80.9 (C-7), 86.3 (C-3a), 126.5, 128.0, 137.5 (C aryl), 146.7 (C-4), 163.0 (CO), 169.4 (C-7a); MS: m/z 257 [M+H]+. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.19; H, 6.25; N, 10.95.
4-Amino-3,5-dihydro-2-phenyl-5-(phenylmethyl)furo[3,2-c]pyridin-6(2H)-one (11d)
Colorless prisms (1.05 g, 66%), mp 196−197 °C (acetone); IR (KBr): 3445, 3407, 3312, 3276 (NH), 1682 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.74 (dd, J = 6.9, 14.3 Hz, 1H, 3-H), 3.34 (dd, J = 9.3, 14.3 Hz, 1H, 3-H), 5.14 (br d, J = 15.3 Hz, 1H, CH2Ph), 5.15 (s, 1H, 7-H), 5.23 (br d, J = 15.3 Hz, 1H, CH2Ph), 5.81 (dd, J = 6.9, 9.3 Hz, 1H, 2-H), 6.24 (br s, 2H, NH2), 7.18−7.23 (m, 3H, aryl H), 7.27−7.42 (m, 7H, aryl H); 13C NMR (DMSO-d6): δ 34.1 (C-3), 42.8 (CH2Ph), 80.8 (C-7), 84.6 (C-2), 85.9 (C-3a), 125.5, 126.5, 126.6, 127.9, 128.1, 128.5, 137.4, 141.5 (C aryl), 146.8 (C-4), 163.0 (CO), 169.5 (C-7a); MS: m/z 319 [M+H]+. Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.48; H, 5.82; N, 8.77.
4-Amino-3,5-dihydro-5-(phenylmethyl)thieno[3,2-c]pyridin-6(2H)-one (12a)
Pale brown plates (0.67 g, 52%), mp 205−206 °C (acetone); IR (KBr): 3446, 3305, 3282 (NH), 1622 (CO) cm-1; 1H NMR (DMF): δ 2.93 (t, J = 7.6 Hz, 2H, 3-H), 3.29 (t, J = 7.6 Hz, 2H, 2-H), 5.20 (br s, 2H, CH2Ph), 5.54 (s, 1H, 7-H), 6.15 (br s, 2H, NH2), 7.16−7.18 (m, 2H, aryl H), 7.19−7.23 (m, 1H, aryl H), 7.27−7.31 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 30.9 (C-3), 31.8 (C-2), 43.0 (CH2Ph), 93.7 (C-7), 97.1 (C-3a), 126.5, 126.6, 128.1, 137.0 (C aryl), 145.5 (C-4), 157.7 (C-7a), 160.5 (CO); MS: m/z 259 [M+H]+. Anal. Calcd for C14H14N2OS: C, 65.09; H, 5.46; N, 10.84. Found: C, 65.12; H, 5.49; N, 10.76.
4-Amino-3,5-dihydro-3-phenyl-5-(phenylmethyl)thieno[3,2-c]pyridin-6(2H)-one (12b)
Gray prisms (1.24 g, 74%), mp 224−226 °C (CHCl3/MeOH); IR (KBr): 3464, 3320 (NH), 1630 (CO) cm-1; 1H NMR (DMSO-d6): δ 3.03 (dd, J = 1.2, 11.3 Hz, 1H, 2-H), 3.86 (dd, J = 7.9, 11.3 Hz, 1H, 2-H), 4.67 (dd, J = 1.2, 7.9 Hz, 1H, 3-H), 5.06 (br d, J = 16.2 Hz, 1H, CH2Ph), 5.33 (br d, J = 16.2 Hz, 1H, CH2Ph), 5.64 (s, 1H, 7-H), 5.96 (br s, 2H, NH2), 7.11−7.13 (m, 2H, aryl H), 7.16−7.22 (m, 4H, aryl H), 7.26−7.30 (m, 4H, aryl H); 13C NMR (DMSO-d6): δ 41.5 (C-2), 43.0 (CH2Ph), 47.1 (C-3), 93.7 (C-7), 99.9 (C-3a), 126.3, 126.6, 127.0, 128.10, 128.12, 136.8, 142.3 (C aryl), 146.3 (C-4), 158.3 (C-7a), 160.6 (CO); MS: m/z 335 [M+H]+. Anal. Calcd for C20H18N2OS: C, 71.83; H, 5.42; N, 8.38. Found: C, 71.64; H, 5.55; N, 8.31.
4-Amino-3,5-dihydro-2-methyl-5-(phenylmethyl)thieno[3,2-c]pyridin-6(2H)-one (12c)
Colorless prisms (0.54 g, 40%), mp 196−197 °C (acetone); IR (KBr): 3466, 3312, 3202 (NH), 1672 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.36 (d, J = 6.7 Hz, 3H, CH3), 2.60 (dd, J = 6.4, 14.6 Hz, 1H, 3-H), 3.10 (dd, J = 7.8, 14.6 Hz, 1H, 3-H), 3.94−3.99 (m, 1H, 2-H), 5.19 (AB q, J = 16.0 Hz, 2H, CH2Ph), 5.50 (s, 1H, 7-H), 6.11 (br s, 2H, NH2), 7.16−7.23 (m, 3H, aryl H), 7.27−7.31 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 22.2 (CH3), 39.2 (C-3), 42.9 (C-2), 44.3 (CH2Ph), 93.7 (C-7), 96.5 (C-3a), 126.56, 126.63, 128.1, 137.0 (C aryl), 145.6 (C-4), 157.2 (C-7a), 160.5 (CO); MS: m/z 273 [M+H]+. Anal. Calcd for C15H16N2OS: C, 66.15; H, 5.92; N, 10.29. Found: C, 66.05; H, 5.96; N, 10.13.
The preparation of acetamide derivatives 13 and 14 from 7a and amines.
A mixture of 7a (0.84 g, 5 mmol) and 28% aqueous ammonium hydroxide (5 mL, 0.128 mol) and/or benzylamine (5 mL, 45.8 mmol) in MeOH (5 mL) was stirred at rt for 24 h. After removal of the solvent in vacuo, Et2O (in the case of the preparation of 13) or cold water (in the case of the preparation of 14) was added to the residue. The precipitate was isolated by filtration, washed with Et2O (in the case of the preparation of 13) or water (in the case of the preparation of 14), dried, and recrystallized from MeOH/Et2O (in the case of the preparation of 13) or acetone/petroleum ether (in the case of the preparation of 14) to give 13 and 14.
3-Cyano-4,5-dihydro-2-furanacetamide (13)
Colorless needles (0.52 g, 68%), mp 115−116 °C; IR (KBr): 3425, 3398, 3179 (NH), 2206 (CN), 1677 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.84−2.89 (m, 2H, 4-H), 3.20 (t, J = 1.3 Hz, 2H, CH2CO), 4.51 (t, J = 9.2 Hz, 2H, 5-H), 7.08, 7.48 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 29.4 (C-4), 34.7 (CH2CO), 71.9 (C-5), 83.6 (C-3), 116.5 (CN), 167.1 (CO), 168.6 (C-2); MS: m/z 153 [M+H]+. Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.16; H, 5.36; N, 18.23.
3-Cyano-4,5-dihydro-N-(phenylmethyl)-2-furanacetamide (14)
Colorless needles (0.89 g, 73%), mp 217−218 °C; IR (KBr): 3261, 3083 (NH), 2208 (CN), 1649 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.88 (t, J = 9.6 Hz, 2H, 4-H), 3.31 (s, 2H, CH2CO), 4.28 (d, J = 5.8 Hz, 2H, NHCH2), 4.52 (t, J = 9.6 Hz, 2H, 5-H), 7.22−7.27 (m, 3H, aryl H), 7.30−7.34 (m, 2H, aryl H), 8.57 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 29.4 (C-4), 34.9 (CH2CO), 42.4 (NHCH2), 71.9 (C-5), 83.7 (C-3), 116.4 (CN), 126.8, 127.1, 128.2, 138.8 (C aryl), 165.2 (CO), 168.4 (C-2); MS: m/z 243 [M+H]+. Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.54; H, 5.90; N, 11.59.
The preparation of furo- and thieno-[3,2-c]pyridin-6(2H)-ones 9a and 11a from 13 and 14 in the presence of sodium methoxide.
A mixture of 13 and/or 14 (3 mmol) in a solution of sodium (69 mg, 3 mmol) in anhydrous MeOH (3 mL) was stirred at rt for 1 h. After the same work-up as described above for the preparation of 9−12, 9a (0.27 g, 59%) and 11a (0.65 g, 92%) were obtained. The melting points and IR spectra of 9a and 11a coincided with those of authentic samples prepared from 7a and amines.

References

1. A. Fassihi, D. Abedi, L. Saghaie, R. Sabet, H. Fazeli, G. Bostaki, O. Deilami, and H. Sadinpour, Eur. J. Med. Chem., 2009, 44, 2145. CrossRef
2. S. R. Schwid, M. D. Petrie, M. P. McDermott, D. S. Tierney, D. H. Mason, and A. D. Goodman, Neurology, 1997, 48, 817.
3. J. L. Segal and S. R. Brunnemann, Pharmacotherapy, 1997, 17, 415.
4. K. M. McEvoy, A. J. Windebank, J. R. Daube, and P. A. Low, Engl. J. Med., 1989, 321, 1567.
5. F. S. Yates, ‘Comprehensive Heterocyclic Chemistry: Pyridines and their Benzo Derivatives: (vi) Applications,’ Vol. 2, ed. by A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, pp. 511−524.
6. L. C. Sellin, Med. Biol., 1981, 59, 11.
7. Y. Miyazaki, M. Nakano, H. Sato, A. T. Truesdale, J. D. Stuart, E. N. Nartey, K. E. Hightower, and L. Kane-Carson, Bioorg. Med. Chem. Lett., 2007, 17, 250. CrossRef
8. Z. Lu, J. Bohn, T. Rano, C. A. Rutkowski, A. L. Simcoe, D. B. Olsen, W. A. Schleif, A. Carella, L. Gabryelski, L. Jin, J. H. Lin, E. Emini, K. Chapman, and J. R. Tata, Bioorg. Med. Chem. Lett., 2005, 15, 5311. CrossRef
9. T. A. Engler, S. Malhotra, T. P. Burkholder, J. R. Henry, D. Mendel, W. J. Porter, K. Furness, C. Diefenbacher, A. Marquart, J. K. Reel, Y. Li, J. Clayton, B. Cunningham, J. McLean, J. C. O’Toole, J. Brozinick, E. Hawkins, E. Misener, D. Briere, R. A. Brier, J. R. Wagner, R. M. Campbell, B. D. Anderson, R. Vaughn, D. B. Bennett, T. I. Meier, and J. A. Cook, Bioorg. Med. Chem. Lett., 2005, 15, 899. CrossRef
10. W. S. Saari, J. S. Wai, T. E. Fisher, C. M. Thomas, J. M. Hoffman, C. S. Rooney, A. M. Smith, J. H. Jones, D. L. Bamberger, M. E. Goldman, J. A. O’Brien, J. H. Nunberg, J. C. Quintero, W. A. Schleif, E. A. Emini, and P. S. Anderson, J. Med. Chem., 1992, 35, 3792. CrossRef
11. C. Gachet, J.-P. Cazenave, P. Ohlmann, C. Bouloux, G. Defreyn, F. Driot, and J.-P. Maffrand, Biochem. Pharmacol., 1990, 40, 2683. CrossRef
12. J. S. New, W. L. Christopher, J. P. Yevich, R. Butler, R. F. Schlemmer. C. P. VanderMaelen, and J. A. Cipollina, J. Med. Chem., 1989, 32, 1147. CrossRef
13. A. R. Sherman, ‘Comprehensive Heterocyclic Chemistry III: Bicyclic 5-6 Systems: Two Heteroatoms 1:1,’ Vol. 10, ed. by A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, and R. J. K. Taylor, Elsevier, Oxford, 2008, pp. 263−337.
14. V. P. Litvinov, V. V. Dotsenko, and S. G. Krivokolysko, Adv. Heterocycl. Chem., 2007, 93, 117. CrossRef
15. S. Shiotani, Heterocycles, 1997, 45, 975. CrossRef
16. A. R. Sherman, ‘Comprehensive Heterocyclic Chemistry II: Bicyclic 5-6 Systems: Two Heteroatoms 1:1,’ Vol. 7, ed. by A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Elsevier, Oxford, 1996, pp. 167−227.
17. J. H. Wikel, M. L. Denney, and R. T. Vasileff, J. Heterocycl. Chem., 1993, 30, 289. CrossRef
18. J. B. Press and J. J. McNally, J. Heterocycl. Chem., 1988, 25, 1571. CrossRef
19. S. Hibino, S. Kano, N. Mochizuki, and E. Sugino, J. Org. Chem., 1984, 49, 5006. CrossRef
20. E. Bisagni, N. C. Hung, and J. M. Lhoste, Tetrahedron, 1983, 39, 1777. CrossRef
21. F. Eloy and A. Deryckere, Helv. Chim. Acta, 1970, 53, 645. CrossRef
22. W. Herz and S. Tocker, J. Am. Chem. Soc., 1955, 77, 3554. CrossRef
23. W. Steinkopf and G. Lützkendorf, Justus Liebigs Ann. Chem., 1914, 403, 45. CrossRef
24. S. Yamaguchi, E. Hamada, H. Yokoyama, Y. Hirai, and S. Shiotani, J. Heterocycl. Chem., 2002, 39, 335. CrossRef
25. S. Shiotani, M. Kurosaki, K. Taniguchi, and M. Moriyama, J. Heterocycl. Chem., 1997, 34, 941. CrossRef
26. N. B. Marchenko and V. G. Granik, Khim. Geterotsikl. Soedin., 1982, 68.
27. L. N. Yakhontov and E. I. Lapan, Khim. Geterotsikl. Soedin., 1970, 27.
28. E. M. Peresleni, M. Y. Uritskaya, V. A. Loginova, Y. N. Sheinker, and L. N. Yakhontov, Dokl. Akad. Nauk SSSR, 1968, 183, 1102.
29. L. N. Yakhontov, D. M. Krasnokutskaya, E. M. Peresleni, Y. N. Sheinker, and M. V. Rubtsov, Dokl. Akad. Nauk SSSR, 1967, 176, 613.
30. W. Kraus, M. Bokel, A. Klenk, and H. Pöhnl, Tetrahedron Lett., 1985, 26, 6435. CrossRef
31. D. Rogers, G. G. Ünal, D. J. Williams, and S. V. Ley, J. Chem. Soc., Chem. Comm., 1979, 97. CrossRef
32. J. V. Rodricks, J. Agr. Food Chem., 1969, 17, 457. CrossRef
33. I. C. Paul, G. A. Sim, T. A. Hamor, and J. M. Robertson, J. Chem. Soc., 1962, 4133. CrossRef
34. H. Maruoka, M. Yamazaki, and Y. Tomioka, J. Heterocycl. Chem., 2004, 41, 641. CrossRef
35. H. Maruoka, M. Yamazaki, and Y. Tomioka, J. Heterocycl. Chem., 2002, 39, 743. CrossRef
36. H. Maruoka, K. Yamagata, and M. Yamazaki, J. Heterocycl. Chem., 2001, 38, 269. CrossRef
37. H. Maruoka, K. Yamagata, and M. Yamazaki, Liebigs Ann. Chem., 1993, 1269. CrossRef
38. H. Maruoka, F. Okabe, K. Yamasaki, E. Masumoto, T. Fujioka, and K. Yamagata, Heterocycles, 2010, 81, 675. CrossRef
39. K. D. Khalil, H. M. Al-Matar, and M. H. Elnagdi, Heterocycles, 2009, 78, 2067. CrossRef
40. P. F. Schuda, C. B. Ebner, and T. M. Morgan, Tetrahedron Lett., 1986, 27, 2567. CrossRef
41. W. Kantlehner, E. Haug, and H. Hagen, Liebigs Ann. Chem., 1982, 298. CrossRef
42. E. E. Garcia and R. I. Fryer, J. Heterocycl. Chem., 1974, 11, 219 CrossRef