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Fluorine-containing heterocycles: Part III. Synthesis of some new furo[2,3-b]-, pyrazolo[3,4-b]- and thieno[2,3-b]pyridines with anticipated biological activities
2nd Heterocyclic Update
*Corresponding author. Tel.: +20 1006670292
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This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Available online 18 June 2014
Peer review under responsibility of King Saud University.
Abstract
3-Cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-one (1) and its thiono analog 2 were prepared by the reaction of (2-thenoyl)-ω,ω,ω-trifluoroacetone with cyanoacetamide or cyanothioacetamide, respectively. Interaction of compound 1 with ethyl chloroacetate or chloroacetamide led to the regioselective formation of O-alkylated pyridines 3 and 10. The latter compounds underwent some successive reactions to furnish the promising furopyridines (4 and 7–9) and pyrazolopyridines (12–15). The reaction of 2 with chloroacetamides or chloroacetonitrile furnished 2-functionalized 3-amino-6-(2-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridines (16a, b) which were used as key intermediates in the synthesis of the title thienopyridines. Structures of the newly synthesized compounds were established on the basis of their elemental and spectral (IR, 1H NMR and mass) analyses.
Keywords
Furopyridines
Pyrazolopyridines
Thienopyridines
Pyridothienopyrimidines
Pyridothienotriazines
Fluorine-containing compounds
1 Introduction
Organofluorine compounds, particularly heterocyclic ones, are very attractive targets both from a theoretical and synthetic point of view. They have attracted much attention especially in the last decade in biological and medicinal chemistry (Hudlicky, 1992). This is due to the unique features of fluorine compounds and foremost their high physiological activity (Filler and Kobayashi, 1981; Welch, 1987). The introduction of fluorine into organic compounds often permits dramatic modification of their chemical and pharmaceutical properties (Nenajdenko et al., 1997). On the other hand, many substituted furopyridines (Clive and Huang, 2002; Hoffman, 1989; Wishka et al., 1998), pyrazolopyridines (Barreiro et al., 2003; De Mello et al., 2004; Menezes et al., 2002) and thienopyridines (Arndts et al., 2000; Bompart et al., 1987; Cho et al., 1998) are reported to possess versatile applications as biologically active compounds. In view of this fact and as a continuation of our previous work on fluorine-containing pyridines (Abdel-Monem et al., 2001; Bakhite et al., 2005; Abdel-Rahman et al., 2005), the present project was planned to synthesize other new pyridine derivatives as well as their condensed heterocyclic derivatives and to study their reactions with a variety of reagents hoping to get novel compounds with anticipated biological activities.
2 Experimental
Starting materials were obtained from commercial suppliers and used without further purification. Melting points were determined on a Gallan-Kamp apparatus and are uncorrected. The IR spectra were recorded on a Shimadzu 470 IR-spectrophotometer (KBr; νmax in cm−1). The 1H-NMR spectra were taken on a Varian EM-390, 90 MHz spectrometer or on a Jeol LA 400 MHz FT-NMR spectrometer using TMS as internal standard. Chemical shifts are given in δ ppm and coupling constant (J) is given in Hz. Electron impact (EI) MS spectra were carried out on a JEOL JMS-600 spectrometer. Elemental analyses (C, H, N and S) were performed on an Elemental Analyses system GmbH VARIOEL V2.3 1998 CHNS Mode (Assiut University). The reactions were monitored by TLC.
2.1 Cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-one (1)
To a solution of (2-thenoyl)-ω,ω,ω-trifluoroacetone (4.44 g, 20 mmol) and cyanoacetamide (1.68 g, 20 mmol) in ethanol (50 mL), few drops of piperidine or triethylamine were added. The reaction mixture was refluxed for 4 h and left to cool. The solid which formed was collected and recrystallized from ethanol to give yellow needles of 1. Yield: 4.0 g (74%); m.p.: 250–251 °C. IR (cm−1): 3100–3000 (NH), 2200 (C≡N), 1650 (C⚌O). 1H NMR (DMSO-d6) (400 MHz): δ = 8.17–8.18 (d, J = 4 Hz, 1H, H-5 of thiophene), 7.90–7.91 (d, J = 4 Hz, 1H, H-3 of thiophene), 7.65 (s, 1H, CH pyridine), 7.24–7.25 (t, J = 4 Hz, 1H, H-4 of thiophene). Anal. Calcd. for C11H5F3N2OS (270.23): C, 84.89; H, 1.86; N, 10.37; S, 11.87%. Found: C, 85.92; H, 1.77; N, 10.19; S, 12.06%.
2.2 3-Cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2)
It was prepared according to our reported method (Abdel-Monem et al., 2001).
2.3 Ethyl [3-cyano-6-(2-thienyl)-4-trifluoromethyl-2-pyridyloxy]acetate (3)
Compound 1 (2.7 g, 10 mmol) was dissolved in dry acetone (40 mL). To this solution, ethyl chloroacetate (1.1 mL, 10 mmol), anhyd. potassium carbonate (2.8 g, 20 mmol) and sodium iodide (0.011 g) were added. The reaction mixture was heated at 60 °C for 4 h and then allowed to cool. The precipitate that formed was filtered, washed with water to remove the extra potassium carbonate and recrystallized from ethanol to give compound 3 in the form of white needles. Yield: 3.0 g (84%); m.p.: 126–127 °C. Anal. Calcd. for C15H11F3N2O3S (356.32): C, 50.56; H, 3.11; N, 7.86; S, 8.99%. Found: C, 50.28; H, 3.08; N, 7.91; S, 9.20%. IR (cm−1): 2200 (C≡N), 1740 (C⚌O). 1H NMR (CDCl3) (90 MHz): δ = 8.1 (d, 1H, H-5 of thiophene), 7.7 (d, 1H, H-3 of thiophene), 7.6 (s, 1H, CH pyridine), 7.2 (t, 1H, H-4 of thiophene), 5.0 (s, 2H, OCH2CO), 4.1–4.4 (q, 2H, OCH2), 1.2–1.5 (t, 3H, CH3).
2.4 Ethyl 3-amino-6-(2-thienyl)-4-trifluoromethylfuro[2,3-b]pyridine-2-carboxylate (4)
To a solution of compound 3 (3.5 g, 10 mmol) in dry N,N-dimethylformamide (40 mL), anhydrous potassium carbonate (1.4 g, 10 mmol) was added. The reaction mixture was heated for 3 h with stirring, maintaining the temperature at 110–120 °C. After cooling, it was poured into crushed ice. The separated solid product was filtered, washed with water, dried in air and crystallized from ethanol to give 4 as yellow crystals; yield: 2.7 g (76%); m.p.: 200–201 °C. Anal. Calcd. for C15H11F3N2O3S (356.32): C, 50.56; H, 3.11; N, 7.86; S, 8.99%. Found: C, 50.34; H, 3.06; N, 8.11; S, 9.32%. IR (cm−1): 3500, 3380 (NH2), 1660 (C⚌O). 1H NMR (CDCl3) (90 MHz): δ = 7.9 (m, 2H, H-5 of thiophene and CH pyridine), 7.6 (d, 1H, H-3 of thiophene), 7.2–7.4 (t, 1H, H-4 of thiophene), 5.4 (s, 2H, NH2), 4.4–4.7 (q, 2H, OCH2), 1.3–1.6 (t, 3H, CH3).
2.5 Effect of sodium ethoxide on the ester (3), formation of compound (5)
To a solution of the ester 3 (0.71 g, 2 mmol), in absolute ethanol (5 ml), sodium ethoxide solution (0.1 g sodium in 10 mL abs. ethanol) was added. The reaction mixture was refluxed for 2 h and then left to cool. On dilution with ice-water, the white solid which separated, was collected, dried in air and crystallized from ethanol. It was identified as 3-Cyano-2-ethoxy-6-(2-thienyl)-4-trifluoromethylpyridine (5). Yield: 0.4 g (67%); m.p.: 120–122 °C. Anal. Calcd. for C13H9F3N2OS (298.29): C, 52.35; H, 3.04; N, 9.39; S, 10.75%. Found: C, 52.76; H, 3.19; N, 9.27; S, 11.08%. IR (cm−1): 2210 (C≡N). 1H NMR (CDCl3) (90 MHz): δ = 7.9 (s, 1H, H-5 of thiophene), 7.6–7.8 (m, 2H, CH pyridine and H-3 of thiophene), 7.3–7.5 (t, 1H, H-4 of thiophene), 4.6–4.9 (q, 2H, OCH2), 1.5–1.7 (t, 3H, CH3).
2.6 [3-Cyano-6-(2-thienyl)-4-trifluoromethyl-2-pyridyloxy]acethydrazide (6)
A mixture of ester 3 (0.7 g, 2 mmol) and an equimolar quantity of hydrazine hydrate 99% (0.1 mL, 2 mmol) in ethanol (15 mL) was stirred at room temperature for 24 h. The precipitated product was collected and recrystallized from ethanol to give white crystals of 6. Yield: 0.6 g (87%); m.p.: 180–181 °C. Anal. Calcd. for C13H9F3N4O2S (342.30): C, 45.62; H, 2.65; N, 16.37; S, 9.37%. Found: C, 45.55; H, 2.48; N, 16.52; S, 9.16%. IR (cm−1): 3400, 3300, 3250 (NHNH2), 2200 (C≡N), 1665(C⚌O). 1H NMR (DMSO-d6) (90 MHz): δ = 9.5 (s, 1H, NH), δ 8.1 (d,1H, H-5 of thiophene), 7.9 (d, 1H, H-3 of thiophene), 7.5 (s, 1H, CH pyridine), 7.2 (t, 1H, H-4 of thiophene), 5.0 (s, 2H, OCH2), 4.5 (s, 2H, NH2).
2.7 3-Amino-6-(2-thienyl)-4-trifluoromethylfuro[2,3-b]pyridine-2-carbohydrazide (7)
A mixture of compound 4 (1.4 g, 4 mmol) and hydrazine hydrate 99% (0.5 mL, 10 mmol) in ethanol was heated under reflux for 3 h and then left to cool. The precipitated solid was collected and recrystallized from ethanol to give yellow needles of 7. Yield: 1.0 g (73%); m.p.: 236–237 °C. Anal. Calcd. for C13H9F3N4O2S (342.30): C, 45.62; H, 2.65; N, 16.37; S, 9.37%. Found: C, 45.32; H, 2.73; N, 16.70; S, 9.58%. IR (cm−1): 3420, 3300, 3150 (NH2, NHNH2), 1630 (C⚌O). 1H NMR (DMSO-d6) (90 MHz): δ = 9.2 (s, 1H, NH), 8.0 (d, 1H, H-5 of thiophene), 7.6 (m, 2H, H-3 of thiophene and CH pyridine), 7.1 (t, 1H, H-4 of thiophene), 6.0 (s, 2H, NH2), 4.6 (s, 2H, NH2).
2.8 N-(4-Methoxybenzylidene)-3-amino-6-(2-thienyl)-4-trifluoromethylfuro[2,3-b] pyridine-2-carbohydrazide (8)
A mixture of compound 7 (1.36 g, 4 mmol) and 4-methoxybenzaldehyde (0.5 mL, 4 mmol) in ethanol (20 mL) was refluxed for 4 h. The product was collected and recrystallized from ethanol to give 8 in the form of yellow needles. Yield: 1.5 g (81%); m.p.: 218–219 °C. Anal. Calcd. for C21H15F3N4O3S (460.43): C, 54.78; H, 3.28; N, 12.17; S, 6.96%. Found: C, 54.90; H, 3.33 N, 11.92; S, 6.70%. IR (cm−1): 3490, 3300, 3150 (NH2, NH), 1630 (C⚌O). 1H NMR (DMSO-d6) (90 MHz): δ = 9.1 (s, 1H, N⚌CH), 8.9 (s, 1H, CH pyrimidinone), 7.4–8.4 (m, 8H: 4 aromatic protons, 3 CH thiophene and CH pyridine), 5.6 (2H, 2H, NH2), 4.0 (s, 3H, OCH3).
2.9 3-(4-Methoxybenzylideneamino)-7-(2-thienyl)-9-trifluoromethylpyridio[3′,2′:4,5] furo[3,2-d]pyrimidine-4(3H)-one (9)
A mixture of 8 (0.9 g, 2 mmol) and triethyl orthoformate (1 mL) in redistilled acetic anhydride (15 mL) was heated under reflux for 3 h. The solid that formed on cooling was collected and recrystallized from an ethanol-chloroform mixture to give white crystals of 9, yield: 0.65 g (69%); m.p.: 293–294 °C. Anal. Calcd. for C22H13F3N4O3S (470.43): C, 56.17; H, 2.97; N, 11.91; S, 6.82%. Found: C, 56.11; H, 2.73; N, 12.03; S, 6.77%. IR (cm−1): 1670 cm−1 for (C⚌O).1H NMR (TFA) (90 MHz): δ = 9.0 (s, 1H, N⚌CH), 8.9 (s, 1H, CH pyrimidinone), 7.4–8.4 (m, 8H: 4 aromatic protons, 3 CH thiophene and CH pyridine), 4.0 (s, 3H, OCH3).
2.10 [3-Cyano-6-(2-thienyl)-4-trifluoromethyl-2-pyridyloxy]acetamide (10)
Compound 1 (2.7 g, 10 mmol) was dissolved in dry acetone (30 mL). To the homogeneous solution, chloroacetamide (0.94 g, 10 mmol), anhydrous potassium carbonate (2.8 g, 20 mmol) and a pinch of sodium iodide (0.011 g) were added. The reaction mixture was refluxed for 6 h at 60 °C and cooled to room temperature. The separated salt was filtered off and washed with acetone (30 mL). The total filtrate was concentrated under vacuum and the residue treated with water. The separated white solid was filtered, dried in air and crystallized from ethanol to give white crystals of 10. Yield: 2.8 g (85%); m.p.: 264–265 °C. Anal. Calcd. for C13H8F3N3O2S (327.28): C, 47.71; H, 2.46; N, 12.84; S, 9.80%. Found: C, 47.93; H, 2.75; N, 11.98; S, 9.60%. IR (cm−1): 3400, 3200 (NH2), 2180 (CN), 1660 (C⚌O). 1H NMR (DMSO-d6) (400 MHz): δ = 8.22–8.23 (d, J = 4 Hz, 1H, H-5 of thiophene), 8.07 (s, 1H, CH pyridine), 7.91–7.92 (d, J = 4 Hz, 1H, H-3 of thiophene), 7.63 (s, 1H, NH of NH2), 7.31 (s, 1H, NH of NH2), 7.24–7.26 (t, J = 4 Hz, 1H, H-4 of thiophene), 4.93 (s, 2H, OCH2).
2.11 3-Amino-6-(2-thienyl)-4-trifluoromethyl-lH-pyrazolo[3,4-b]pyridine (12)
2.11.1 Method (A)
Compound 10 (1.6 g, 5 mmol) was suspended in excess of hydrazine hydrate (8 mL) and the reaction mixture was refluxed for 6 h. It was then cooled to room temperature, poured onto crushed ice and the separated solid was filtered, washed with water, dried in air and crystallized from ethanol to give 12 in the form of yellow plates. Yield: 1.3 g (91%); m.p: 231–232 °C. Anal. Calcd. for C11H7F3N4S (284.26): C, 46.48; H, 2.48; N, 19.71; S, 11.28%. Found: C, 46.37; H, 2.54; N, 19.89; S, 11.17%. IR (cm−1): 3480, 3320, 3200 (NH2, NH). 1H NMR (CDCl3) (90 MHz): δ = 12.4 (s,1H, NH), 7.9 (d, 1H, H-5 of thiophene), 7.7 (m, 2H, H-3 of thiophene and CH pyridine), 7.2–7.4 (t, 1H, H-4 of thiophene), 4.4 (s, 2H, NH2). MS: 284 (M+, 4%), 283 (M−1)+, 100%).
2.11.2 Method (B)
Compound 13 (1.5 g, 5 mmol) in excess amount of hydrazine hydrate (2 mL, 40 mmol) was heated under reflux for 4 h. The reaction mixture was triturated with ethanol (10 mL) and left to cool. The precipitated solid was collected and recrystallized from ethanol to give yellow needles of 12. Yield: 1.35 g (95%). This product was identical in all aspects to that described in method A.
2.12 3-Cyano-2-methylthio-6-(2-thienyl)-4-trifluoromethylpyridine (13)
A mixture of 2 (1.43 g, 5 mmol), methyl iodide (5 mmol) and sodium acetate trihydrate (0.75 g, 5 mmol) in ethanol (15 mL) was heated under reflux for 1 h. The precipitate that formed on cooling was collected and recrystallized from ethanol as fine white needles of 13. Yield: 1.4 g (93%); m.p. 147–148 °C. Anal. Calcd. for C12H7F3N2S2 (300.33): C, 47.99; H, 2.35; N, 9.33; S, 21.35%. Found: C, 47.82; H, 2.53; N, 9.55; S, 21.29%. IR (cm−1): 2200 (C≡N).1H NMR (CDCl3) (90 MHz): δ = 7.9 (d, 1H, H-5 of thiophene), 7.7 (m, 2H, H-3 of thiophene and CH pyridine), 7.2–7.4 (t, 1H, H-4 of thiophene), 2.7 (s, 3H, SCH3).
2.13 2,4-Dimethyl-8-(2-thienyl)-10-trifluoromethylpyridio[2′,3′:3,4]pyrazolo[1,5-a] pyrimidine (14)
A mixture of 12 (0.85 g, 3 mmol) and acetylacetone (0.3 mL, 3 mmol) in glacial acetic acid (10 mL) was refluxed for 4 h and then allowed to cool. The precipitate that formed was collected and recrystallized from ethanol to give 14 in the form of pale yellow crystals. Yield: 0.8 g (76%); m.p.: 205–206 °C. Anal. Calcd. for C16H11F3N4S (348.35): C, 55.17; H, 3.18; N, 16.08; S, 9.21%. Found: C, 55.32; H, 3.13; N, 16.19; S, 9.45%. IR (cm−1): 1600 (C⚌N).1H NMR (CDCl3) (400 MHz): δ = 7.85–7.86 (d, J = 4 Hz, 1H, H-5 of thiophene), 7.82 (s, 1H, CH pyridine), 7.52–7.53 (s, J = 4 Hz, 1H, H-3 of thiophene), 7.15–7.17 (t, J = 4 Hz, 1H, H-5 of thiophene), 7.07 (s, 1H, CH pyrimidine), 2.95 (s, 3H, CH3 at C-2), 2.73 (s, 3H, CH3 at C-4).
2.14 2-Methyl-8-(2-thienyl)-10-trifluoromethylpyridio[2′,3′:3,4]pyrazolo[1,5-a] pyrimidine-4(1H)-one (15)
A mixture of 12 (0.85 g, 3 mmol) and ethyl acetoacetate (0.4 mL, 5 mmol) in glacial acetic acid (10 mL) was refluxed for 5 h. The solid product that formed after cooling was collected and recrystallized from dioxane as orange crystals of 15. Yield: 0.9 g (85%); m.p.: 213–214 °C. Anal. Calcd. for C15H9F3N4OS (350.32): C, 51.43; H, 2.59; N, 15.99; S, 9.15%. Found: C, 51.38; H, 2.71; N, 16.18; S, 9.21%. IR (cm−1): 3200 (NH), 1700 (C⚌O).1H NMR (CDCl3) (400 MHz): δ = 7.86–7.87 (d, J = 4 Hz, 1H, H-5 of thiophene), 7.85 (s, 1H, CH pyridine), 7.52–7.54 (d, J = 4 Hz, 1H, H-3 of thiophene), 7.17–7.20 (t, J = 4 Hz, 1H, H-4 of thiophene), 7.10 (s, 1H, CH pyrimidine), 3.2 (s, 3H, CH3).
2.15 2-Methyl-7-(2-thienyl)-9-trifluoromethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4-(3H)-one (17)
Compound 16a (1.71 g, 5 mmol) in acetic anhydride (15 mL) was heated under reflux for 3 h. The product that formed on cooling was collected and recrystallized from ethanol to give 17 in the form of white crystals. Yield: 1.0 g (55%), m.p.: >360 °C. Anal. Calcd. for C15H8F3N3OS2 (367.37): C, 49.04; H, 2.19; N, 11.44; S, 17.46%. Found: C, 49.28; H, 2.17; N, 11.36; S, 17.82%. IR (cm−1): 3500–3200 (NH), 1660 (C⚌O).1H NMR (TFA) (90 MHz): δ = 8.5 (s, 1H, CH pyridine), 8.3 (d, 1H, CH thiophene), 8.0 (d, 1H, CH thiophene), 7.5 (t, 1H, CH thiophene), 3.1 (s, 3H, CH3).
2.16 2-Chloromethyl-7-(2-thienyl)-9-trifluoromethylpyrido[3′,2′:4,5]thieno[3,2-d] pyrimidine-4-(3H)-one (18)
Compound 16a (1.71 g, 5 mmol) in chloroacetyl chloride (10 mL) was heated on a water bath for 3 h. The product that formed on cooling was collected and recrystallized from ethanol to give 18 in the form of white crystals. Yield: 1.8 g (89%), m.p.: >360 °C. Anal. Calcd. for C15H7ClF3N3OS2 (401.82): C, 44.84; H, 1.76; N, 10.46; S, 15.96%. Found: C, 45.01; H, 1.52; N, 10.26; S, 16.07%. IR (cm−1): 3500–3200 (NH), 1660 (C⚌O). 1H NMR (TFA) (90 MHz): δ = 8.6 (s, 1H, CH pyridine), 8.4 (d, 1H, CH thiophene), 8.1 (d, 1H, CH thiophene), 7.6 (t, 1H, CH thiophene), 4.5 (s, 2H, CH2Cl).
2.17 Reaction of compound 16a with aromatic aldehydes, formation of tetrahydro-pyridothienopyrimidinones (19a-d)
A mixture of 16a (0.68 g, 2 mmol) and the respective aldehyde (2 mmol) in ethanol (15 mL) containing few drops of HCl was heated under reflux for 3 h. The product that formed on cooling was collected and recrystallized from acetic acid as yellow needles of 19a–d.
2.17.1 2-(4-Hydroxyphenyl)-4-oxo-7-(2-thienyl)-9-trifluoromethyl-1,2,3,4-tetrahydro-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine (19a)
Prepared by using 4-hydroxybenzaldehyde. Yield: 87%; m.p.: 325–326 °C. Anal. Calcd. for C20H12F3N3OS2 (431.46): C, 55.68; H, 2.80; N, 9.74; S, 14.86%. Found: C, 55.72; H, 2.91; N, 9.55; S, 14.50%. IR (cm−1): 3400, 3200 (2NH), 1650 (C⚌O). 1H NMR (TFA) (90 MHz): δ = 8.3–8.5 (m, 2H, CH pyridine and CH thiophene), 8.1 (d, 1H, CH thiophene), 7.3–7.6 (m, 3H: 2H aromatic and CH thiophene), 7.0–7.2 (d, 2H, aromatic), 6.3 (s, 1H, CH of tetrahydropyrimidine).
2.17.2 2-(3,4-Dihydroxyphenyl)-4-oxo-7-(2-thienyl)-9-trifluoromethyl-1,2,3,4-tetra-hydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine (19b)
Prepared by using 3,4-dihydroxybenzaldehyde. Yield: 80%; m.p.: 319–320 °C. Anal. Calcd. for C20H12F3N3O3S2 (463.46): C, 51.83; H, 2.61; N, 9.07; S, 13.84%. Found: C, 51.68; H, 2.73; N, 8.95; S, 13.63%. IR (cm−1): 3400, 3200 (2NH), 1650 (C⚌O). 1H NMR (TFA) (90 MHz): δ = 8.4–8.6 (m, 2H, CH pyridine and CH thiophene), 8.3 (d, 1H, CH thiophene), 7.5 (t, 1H, CH thiophene), 7.4 (s, 1H, aromatic proton), 7.1–7.2 (d, 2H, aromatic protons), 6.3 (s, 1H, CH of tetrahydropyrimidine).
2.17.3 2-(3-Hydroxy-4-methoxyphenyl)-4-oxo-7-(2-thienyl)-9-trifluoromethyl-1,2,3,4-tetrahydropyrido[3′,2′:4,5]thieno [3,2-d]pyrimidine (19c)
Prepared by using 3-hydroxy-4-methoxybenzaldehyde. Yield: 78%; m.p.: 307–308 °C. Anal. Calcd. for C21H14F3N3O3S2 (477.48): C, 52.82; H, 2.96; N, 8.80; S, 13.43%. Found: C, 52.90; H, 2.78; N, 8.95; S, 13.25%. IR (cm−1): 3400, 3200 (2NH), 1650 (C⚌O). 1H NMR (TFA) (90 MHz): δ 8.5–8.6 (m, 2H, CH pyridine and CH thiophene), 8.3 (d, 1H, CH thiophene), δ 7.6 (t, 1H, CH thiophene), δ 7.4 (s, 1H, aromatic), 7.2–7.3 (d, 2H, aromatic), 6.4 (s, 1H, CH of tetrahydropyrimidine), 4.0 (s, 3H, OCH3).
2.17.4 2-(3,4-Methylenedioxyphenyl)-4-oxo-7-(2-thienyl)-9-trifluoromethyl-1,2,3,4-tetrahydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine (19d)
Prepared by using piperonal. Yield 83%; m.p.: 316–317 °C. Anal. Calcd. for C21H12F3N3O3S2 (475.47): C, 53.05; H, 2.54; N, 8.84; S, 13.49%. Found: C, 53.15; H, 2.42; N, 8.64; S, 13.40%. IR (cm−1): 3400, 3200 (2NH), 1650 (C⚌O). 1H NMR (TFA) (90 MHz): δ 8.2–8.4 (m, 2H, CH pyridine and CH thiophene), 8.1 (d, 1H, CH thiophene), 7.4 (t, 1H, CH thiophene), 6.8–7.2 (m, 3H, aromatic), 6.2 (s, 1H, CH of tetrahydropyrimidine), 5.9 (s, 2H, OCH2O).
2.18 4-Amino-7-(2-thienyl)-9-trifluoromethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine (20)
Compound 16b (0.65 g, 2 mmol) in formamide (10 mL) was heated under reflux for 4 h. The solid that formed while hot was collected and recrystallized from an ethanol-chloroform mixture to give white crystals of 20.Yield: 0.58 g (83%); m.p.: 309–310 °C. Anal. Calcd. for C14H7F3N4S2 (352.36): C, 47.72; H, 2.00; N, 15.90; S, 18.20%. Found: C, 47.63; H, 2.13; N, 15.84; S, 18.43%. IR (cm−1): 3190, 3100 (NH2), 1640 (C⚌N). 1H NMR (DMSO-d6) (90 MHz): δ = 8.8 (s, 1H, CH pyrimidine), 8.0 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.5 (m, 3H: NH2 and CH thiophene), 7.2 (m, 1H, CH thiophene), MS: 352.4 (M+, 100%).
2.19 4-Imino-3-phenyl-1,2,3,4-tetrahydro-7-(2-thienyl)-2-thioxo-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno [3,2-d]pyrimidine (21)
A mixture of compound 16b (0.65 g, 2 mmol) and phenyl iso-thiocyanate (0.25 ml, 2 mmol) in pyridine (10 mL) was gently heated under reflux for 6 h. The solid that formed on cooling was collected and recrystallized from acetic acid to give orange crystals of 21. Yield: 0.83 g (90%); m.p.: > 360 °C. Anal. Calcd. for C20H11F3N4S3 (460.52): C, 52.16; H, 2.41; N, 12.17; S, 20.89%. Found: C, 51.85; H, 2.35; N, 12.28; S, 20.71%. IR (cm−1): 3380, 3200 (2NH), 1600 (C⚌N). 1HNMR (DMSO-d6) (90 MHz): δ = 10.0 (s, 1H, NH), 8.3 (s, 1H, CH pyridine), 8.0 (d, 1H, CH thiophene), 7.7 (d, 1H, CH thiophene), 7.2–7.5 (m, 6H, aromatic protons and CH thiophene).
2.20 3-Amino-2-(Δ1-imidazolin-2-yl)-6-(2-thienyl)-4-trifluoromethylthieno[2,3-b]pyridine (22)
To a suspension of 16b (1.62 g, 5 mmol) in ethylene diamine (5 mL), carbon disulfide (0.2 mL) was added drop wise. The reaction mixture was heated on a water bath for 2 h and then triturated with ethanol (10 mL). The solid that formed was collected and recrystallized from an ethanol-chloroform mixture to give yellow crystals of 22. Yield: 1.6 g (87%); m.p.: 200–201 °C. Anal. Calcd. for C15H11F3N4S2 (368.40): C, 48.90; H, 3.01; N, 15.21; S, 17.41%. Found: C, 48.76; H, 3.11; N, 15.32; S, 17.30%. IR (cm−1): 3500–3250 (NH and NH2), 1600 (C⚌N). 1H NMR (CDCl3) (90 MHz): δ = 8.0 (s, 1H, CH pyridine), 7.8 (d, 1H, CH thiophene), 7.5 (d, 1H, CH thiophene), 7.2 (t, 1H, CH thiophene), 6.7 (s, 2H, NH2), 3.7 (s, 4H, (CH2)2). MS: 368.0 (M+, 100%).
2.21 3-Amino-2-(3,4,5,6-tetrahydropyrimidin-2-yl)-6-(2-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridine (23)
It was prepared from 16b and propylenediamine in analogy to the above procedure. It was recrystallized from chloroform to give yellow needles of 23. Yield: 1.5 g (78%); m.p.: 190–191 °C. Anal. Calcd. for C16H13F3N4S2 (382.43): C, 50.25; H, 3.43; N, 14.65; S, 16.77%. Found: C, 50.45; H, 3.29; N, 14.56; S, 16.90%. IR (cm−1): 3500, 3400 (NH2), 3100 (NH), 1600 (C⚌N). 1H NMR (CDCl3) (90 MHz): δ = 7.9 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.6 (m, 1H, CH thiophene), 7.2 (t, 1H, CH thiophene), 6.7 (s, 2H, NH2), 3.4–3.7 (t, 4H, 2NCH2), 1.8 (m, 2H, CH2). MS: 382.25 (M+, 100%).
2.22 3-Amino-2-(1H-tetrazol-5-yl)-6-(2-thienyl)-4-trifluoromethylthieno[2,3-b] pyridine (24)
A solution of compound 16b (1.62 g, 5 mmol), sodium azide (0.4 g, 6 mmol) and ammonium chloride (0.32 g, 6 mmol) in DMF (15 mL) was heated on a water bath for 5 h. The reaction mixture was cooled, diluted with water and acidified with dilute acetic acid. The solid that formed was collected and crystallized from ethanol to give yellow crystals of 24. Yield: 1.55 g (84%); m.p.: 255–256 °C. Anal. Calcd. for C13H7F3N6S2 (368.36): C, 42.39; H, 1.92; N, 22.81; S, 17.41%. Found: C, 42.70; H, 2.25; N, 22.99; S, 17.57%. IR (cm−1): 3500–3300 (NH, NH2), 1620 (C⚌N). 1H NMR (DMSO-d6) (90 MHz): δ = 8.9 (s, 1H, NH), δ 7.4–8.4 (m, 8H: 4 aromatic protons, 3CH thiophene and CH pyridine), 6.1 (s, 1H, CH), 5.1 (s, 2H, CH2), 4.5 (s, 2H, CH2). MS: 368.0 (M+, 100%).
2.23 2,3-Dihydro-9-(2-thienyl)-7-trifluoromethyl-imidazo[1″,2″-c]pyrido[3′,2′:4,5] thieno[2,3-e]pyrimidine (25)
Compound 22 (0.73 g, 2 mmol) in triethyl orthoformate (10 ml) was heated under reflux for 3 h. The precipitate that formed while hot was collected and recrystallized from acetic acid to give white needles of 25. Yield: 0.7 g (92%); m.p.: 307–308 °C. Anal. Calcd. for C16H9F3N4S2 (378.40): C, 50.79; H, 2.40; N, 14.81; S, 16.95%. Found: C, 50.58; H, 2.22; N, 14.75; S, 17.08%. IR (cm−1): 1630 (C⚌N). 1H NMR (TFA) (90 MHz): δ = 8.8 (s, 1H, CH pyrimidine), 8.0 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.5 (m, 1H, CH thiophene), 7.2 (m, 1H, CH thiophene), 5.1 (s, 2H, CH2), 4.5 (s, 2H, CH2). MS: 378.1 (M+, 28%).
2.24 5-(4-Chlorophenyl)-2,3,5,6-tetrahydro-9-(2-thienyl)-7-trifluoromethylimidazo [1″,2″-c]pyrido[3′,2′:4,5]thieno[2,3-e]pyrimidine (26)
To a mixture of compound 22 (0.73 g, 2 mmol) and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in ethanol (15 mL), few drops of piperidine were added. The reaction mixture was heated under reflux for 4 h. The solid that formed while hot was collected and recrystallized from dioxane to give yellow crystals of 26. Yield: 0.9 g (92%); m.p.: 224–225 °C. Anal. Calcd. for C22H14ClF3N4S2 (490.95): C, 53.82; H, 2.87; N, 11.41; S, 13.06%. Found: C, 53.98; H, 2.75; N, 11.52; S, 12.97%. IR (cm−1): 3330 (NH). 1H NMR (DMSO-d6) (90 MHz): δ = 8.8 (s, 1H, NH), 7.3–8.4 (m, 8H: 4 aromatic protons, 3CH thiophene and CH pyridine), 6.1 (s, 1H, CH), 4.2 (s, 2H, CH2), 3.7 (s, 2H, CH2). MS: 490 (M+, 4%).
2.25 2,3,5,6-Tetrahydro-9-(2-thienyl)-5-thioxo-7-trifluoromethyl-pyrimido[1″,2″-c] pyrido[3′,2′:4,5]thieno[2,3-e]pyrimidine (27)
A mixture of compound 22 (0.73 g, 2 mmol) and carbon disulfide (1 mL) in pyridine (10 mL) was heated under reflux on a water bath for 8 h. The solid that formed while hot was collected and recrystallized from DMF to give orange crystals of 27. Yield: 0.62 g (76%); m.p.: > 360 °C. Anal. Calcd. for C16H9F3N4S3 (410.46): C, 46.82; H, 2.21; N, 13.65; S, 23.44%. Found: C, 46.58; H, 2.52; N, 13.74; S, 23.21%. IR (cm−1): 3250 (NH), 1610 (C⚌N). 1H NMR (TFA) (90 MHz): δ = 8.0 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.5 (m, 1H, CH thiophene), 7.2 (m, 1H, CH thiophene), 5.1 (s, 2H, CH2), 4.5 (s, 2H, CH2). MS: 410 (M+, 100%).
2.26 2,3-Dihydro-9-(2-thienyl)-7-trifluoromethyl-imidazo[1″,2″-c]pyrido[3′,2′:4,5] thieno[2,3-e][1,2,3]triazine (28)
Sodium nitrite solution 10% (5 mL) was added to a solution of 22 (0.73 g, 2 mmol) in conc. H2SO4 (5 mL) and acetic acid (5 mL) at 0 °C during 5 min with stirring. The reaction mixture was allowed to stand at room temperature for 30 min. The solid that precipitated on dilution with water was collected and crystallized from ethanol to give white needles of 28. Yield: 0.65 g (85%); m.p.: 279–280 °C. Anal. Calcd. for C15H8F3N5S2 (379.39): C, 47.49; H, 2.13; N, 18.46; S, 16.90%. Found: C, 47.36; H, 2.02; N, 18.37; S, 17.08%. IR(cm−1): 1640 cm−1 for (C⚌N). 1H NMR (TFA) (90 MHz): δ = 8.8 (s, 1H, CH pyrimidine), 8.0 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.5 (m, 1H, CH thiophene), 7.2 (m, 1H, CH thiophene), 5.1 (s, 2H, CH2), 4.5 (s, 2H, CH2). MS: 380.21 (M+, 10%).
2.27 3,4-Dihydro-10-(2-thienyl)-8-trifluoromethyl-2H-pyrimido[1″,2″-c]pyrido[3’,2’: 4,5]thieno[2,3-e]pyrimidine (29)
Compound 23 (0.76 g, 2 mmol) in triethyl orthoformate (10 ml) was heated under reflux for 3 h. The precipitate that formed while hot was collected and recrystallized from acetic acid to give white needles of 29. Yield: 0.74 g (94%); m.p.: 309–310 °C. Anal. Calcd. for C17H11F3N4S2 (392.42): C, 52.03; H, 2.83; N, 14.28; S, 16.34%. Found: C, 52.25; H, 2.56; N, 14.20; S, 16.31%. IR (cm−1): 1630 (C⚌N).1H NMR (TFA) (90 MHz): δ = 8.8 (s, 1H, CH pyrimidine), δ 7.9 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.6 (m, 1H, CH thiophene), 7.2 (t, 1H, CH thiophene), 3.4–3.7 (t, 4H, 2NCH2), 1.8 (m, 2H, CH2). MS: 391.81 (M+, 100%).
2.28 6-(4-Chlorophenyl)-3,4,6,7-tetrahydro-10-(2-thienyl)-8-trifluoromethyl-2H-pyrimido[1″,2″-c]pyrido[3′,2′:4,5]thieno[2,3-e]pyrimidine (30)
To a mixture of compound 23 (0.76 g, 2 mmol) and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in ethanol (15 mL), few drops of piperidine were added. The reaction mixture was heated under reflux for 4 h. The solid that formed while hot was collected and recrystallized from dioxane to give yellow crystals of 30. Yield: 0.8 g (79%); m.p.: 249–250 °C. Anal. Calcd. for C23H16ClF3N4S2 (504.98): C, 54.70; H, 3.19; N, 11.09; S, 12.70%. Found: C, 54.53; H, 3.12; N, 11.27; S, 12.86%. IR (cm−1): 3330(NH).1H NMR (TFA) (90 MHz): δ = 8.8 (m, 1H, CH thiophene), 8.2–8.4 (m, 7H: 4 aromatic protons, 2CH thiophene and CH pyridine), 6.1 (s, 1H, CH), 3.5–3.8 (t, 4H, 2NCH2), 1.9 (m, 2H, CH2).
2.29 3,4,6,7-Tetrahydro-10-(2-thienyl)-6-thioxo-8-trifluoromethyl-2H-pyrimido[1″,2″-c]pyrido[3′,2′:4,5] thieno[2,3-e]pyrimidine (31)
A mixture of compound 23 (0.76 g, 2 mmol) and carbon disulfide (1 mL) in pyridine (10 mL) was heated under reflux on a water bath for 8 h. The solid that formed while hot was collected and recrystallized from DMF to give orange crystals of 31. Yield: 0.68 g (80%); m.p.: > 360 °C. Anal. Calcd. for C17H11F3N4S3 (424.49): C, 48.10; H, 2.61; N, 13.20; S, 22.66%. Found: C, 48.32; H, 2.75; N, 13.38; S, 22.56%. IR (cm−1): 3300 (NH), 1610 (C⚌N). 1H NMR (TFA) (90 MHz): δ = 7.9 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.6 (m, 1H, CH thiophene), 7.2 (t, 1H, CH thiophene), 3.4–3.7 (t, 4H, 2NCH2), 1.8 (m, 2H, CH2). MS: 424.04 (M+, 100%).
2.30 3,4-Dihydro-10-(2-thienyl)-8-trifluoromethyl-2H-pyrimido[1″,2″-c]pyrido[3′,2′: 4,5]thieno[2,3-e][1,2,3] triazine (32)
Sodium nitrite solution 10% (5 mL) was added to a solution of 23 (2 mmol) in conc. H2SO4 (5 mL) and acetic acid (5 mL) at 0 °C during 5 min with stirring. The reaction mixture was allowed to stand at room temperature for 30 min. The solid that precipitated on dilution with water was collected and crystallized from ethanol to give white needles of 32. Yield: 0.65 g (83%); m.p.: 252–253 °C. Anal. Calcd. for C16H10F3N5S2 (393.41): C, 48.85; H, 2.56; N, 17.80; S, 16.30%. Found: C, 48.72; H, 2.81; N, 17.63; S, 16.18% IR (cm−1): 1640 (C⚌N). 1H NMR (CDCl3) (90 MHz): δ = 7.9 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.6 (m, 1H, CH thiophene), 7.2 (t, 1H, CH thiophene), 3.4–3.7 (t, 4H, 2NCH2), δ 2.0 (m, 2H, CH2). MS: 393.86 (M+, 86%).
2.31 Reaction of 3-amino-2-(1H-tetrazol-5-yl)-6-(2-thienyl)-4-trifluoromethylthieno [2,3-b]pyridine (24) with triethyl orthoformate
Compound 24 (0.74 g, 2 mmol) in triethyl orthoformate (10 mL) was heated under reflux for 2 h. The precipitate that formed while hot was collected and recrystallized from ethanol to give white needles. This product was assigned as 4-azido-7-(2-thienyl)-9-trifluoromethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine (34). Yield: 0.65 g (86%); m.p.: 229–230 °C (dec.) Anal. Calcd. for C14H5F3N6S2 (378.36): C, 44.44; H, 1.33; N, 22.21; S, 16.95%. Found: C, 44.35; H, 1.48; N, 21.91; S, 17.12%. IR (cm−1): 2150 (N3). 1H NMR (TFA) (90 MHz): δ = 8.8 (s, 1H, CH pyrimidine), δ 8.0 (s, 1H, CH pyridine), 7.8 (d, 1H, CH thiophene), 7.5 (d, 1H, CH thiophene), 7.2 (t, 1H, CH thiophene). MS: 378 (M+, 54%).
2.32 5-(4-Chlorophenyl)-5,6-dihydro-9-(2-thienyl)-7-trifluoromethyltetrazolo[1″,5″-c] pyrido[3′,2′:4,5]thieno[2,3-e]pyrimidine (35)
To a mixture of compound 24 (0.74 g, 2 mmol) and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in ethanol (15 mL), few drops of piperidine were added. The reaction mixture was heated under reflux for 2 h. The solid that formed on cooling was collected and recrystallized from ethanol to give pale yellow crystals of 35.Yield: 0.8 g (81%); m.p.: 241–242 °C. Anal. Calcd. for C20H10ClF3N6S2 (490.91): C, 48.93; H, 2.05; N, 17.12; S, 13.06%. Found: C, 48.89; H, 2.26; N, 17.34; S, 12.96%. IR (cm−1): 3400 (NH). 1H NMR (DMSO-d6) (90 MHz): δ = 8.8 (s, 1H, NH), δ 7.3–8.4 (m, 8H: 4 aromatic protons, 3CH thiophene and CH pyridine), 6.1 (s, 1H, CH). MS: 490 (M+−1, 69%).
2.33 9-(2-Thienyl)-7-trifluoromethyltetrazolo[1″,5″-c]pyrido[3′,2′:4,5]thieno[2,3-e] [1,2,3]triazine (36)
Sodium nitrite solution 10% (5 mL) was added to a solution of 24 (0.74 g, 2 mmol) in conc. H2SO4 (5 mL) and acetic acid (5 mL) at 0 °C during 5 min with stirring. The reaction mixture was allowed to stand at room temperature for 30 min. The solid that precipitated on dilution with water was collected and crystallized from ethanol to give white needles of 36.Yield: 0.6 g (79%); m.p.: 179–180 °C (dec.). Anal. Calcd. for C13H4F3N7S2 (379.35): C, 41.16; H, 1.06; N, 25.85; S, 16.91%. Found: C, 41.25; H, 1.29; N, 25.61; S, 16.78%. IR(cm−1): 1600 (C⚌N).1H NMR (TFA) (90 MHz): δ = 8.0 (s, 1H, CH pyridine), 7.8 (m, 1H, CH thiophene), 7.5 (t, 1H, CH thiophene), 7.2 (m, 1H, CH thiophene). MS: 378 (M+−1, 0.5%).
3 Results and discussion
The wide synthetic utility of several 3-cyanopyridine-2(1H)-one (Kaigorodova et al., 2004; Litvinov et al., 1992; Wagner and Prantz, 1993) and 3-cyanopyridine-2(1H)-thione derivatives (Bakhite, 2003) promoted us to use 3-cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-one (1) and its thiono analog (2) as starting compounds in this investigation.
Thus, on treatment of (2-thenoyl)-ω,ω,ω-trifluoroacetone with cyanoacetamide in the presence of triethylamine or piperidine as a basic catalyst, a regioselective cyclo-condensation reaction occurred and 3-cyano-6-(2-thienyl-4-trifluoromethylpyridine-2(1H)-one (1) was obtained as a sole product. Under the same conditions, the reaction of (2-thenoyl)-ω,ω,ω-trifluoroacetone with cyanothioacetamide produced 3-cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2) (Abdel-Monem et al., 2001) (Scheme 1).
Synthesis of compounds 1 and 2.
When compound 1 was allowed to react with ethyl chloroacetate, in dry acetone containing slightly excess amount of anhyd. potassium carbonate and catalytic amount of sodium iodide for 4 h, ethyl (3-cyano-6-(2-thienyl)-4-trifluoromethyl-2-pyridyloxy)acetate (3) was obtained exclusively. This is in agreement with the earlier reports (Narsaiah et al., 1994; Von Gewald and Jgnsch, 1976) which state that when an o-substituent offers steric hindrance, only O-alkylation takes place and not N-alkylation. On heating of the open ester 3 in DMF containing anhyd. potassium carbonate at 110–120 °C, it underwent intramolecular Thorpe-Ziegler cyclization to give ethyl 3-amino-6-(2-thienyl)-4-trifluoromethylfuro[2,3-b]pyridine-2-carboxylate (4) (Scheme 2).
Synthesis of compounds 3–9.
An attempt to cyclize the open ester 3 to furopyridine 4, using sodium ethoxide as a basic catalyst in boiling ethanol, failed and instead, 3-cyano-2-ethoxy-6-(2-thienyl)-4-trifluoromethylpyridine (5) was obtained as a sole product. This may be due to the relatively high electrophilicity of the carbon atom number 2 of pyridine derivative 3 (Scheme 2). Treatment of ester 3 with hydrazine hydrate in ethanol at room temperature produced (3-cyano-6-(2-thienyl)-4-trifluoromethyl-2-pyridyloxy) acethydrazide (6) whereas the cyclized hydrazide, 3-amino-6-(2-thienyl)-4-trifluoromethylfuro[2,3-b]pyridine-2-carbohydrazide (7) was obtained via hydrazinolysis of the corresponding ester 4 using hydrazine hydrate in boiling ethanol. The direct condensation of 7 with an equimolar amount of 4-methoxy-benzaldehyde in boiling ethanol led to the formation of compound 8. Treatment of 8 with triethyl orthoformate in the presence of acetic anhydride furnished pyridofuropyrimidine derivative 9 (Scheme 2).
In the same manner, reaction of 3-cyanopyridine-2(1H)-one (1) with chloroacetamide, in dry acetone containing slightly excess amount of anhyd. potassium carbonate and catalytic amount of sodium iodide, resulted in the selective formation of (3-cyano-6-(2-thienyl)-4-trifluoromethyl-2-pyridyloxy)acetamide (10) (Scheme 3).
Synthesis of compounds 10–15.
An attempt to cyclize compound 10 into the corresponding furopyridine 11, by refluxing with hydrazine hydrate under neat conditions failed and instead, pyrazolo[3,4-b]pyridine 12 was obtained (Chandra Sheker Reddy et al., 1997). The structure of 12 was confirmed by an independent route via methylation of pyridinethione 2 followed by hydrazinolysis of the resulting 2-methylthiopyridine 13. Treatment of 12 with acetylacetone or ethyl acetoacetate in the presence of acetic acid led to the formation of pyridofuropyrimidine derivatives 14 and 15 respectively (Scheme 3).
On the other hand, 2-functionalized 3-amino-6-(2-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines 16a,b were obtained, by reacting 3-cyano-pyridine-2(1H)-thione 2 with chloroacetamide or chloroacetonitrile according to our reported procedures (Bakhite et al., 2005) (Scheme 4).
Synthesis of compounds 16a,b.
Compounds 16a,b were used as precursors for new pyridothienopyrimidines as well as pyridothienotriazines via some successive reactions.
Heating β-aminoamide 16a with acetic anhydride at reflux temperature led to the formation of pyridothienopyrimidine-4(3H)-one 17. In the same manner, the reaction of 16a with chloroacetyl chloride at 100 °C produced 2-chloromethyl derivative 18 in good yield. When compound 16a was allowed to react with some aromatic aldehydes of biological significance namely; 4-hydroxybenzaldehyde, 3,4-dihydroxybenz-aldehyde, vanillin or piperonal in ethanol containing few drops of conc. HCl, a cyclocondensation reaction occurred and the products which were obtained identified as 2-aryl-4-oxo-1,2,3,4-tetrahydro-7-(2-thienyl)-9-trifluoromethylpyrido[3′,2′:4,5] thieno[3,2-d]pyrimidines (19a–d) (Scheme 5).
Synthesis of compounds 17–19.
Refluxing of compound 16b in formamide yielded 4-aminopyrimidine derivative 20. The reaction of 16b with phenyl isothiocyanate in the presence of pyridine yielded tetrahydropyridothienopyrimidine 21 (Scheme 6).
Synthesis of compounds 20 and 21.
Incorporating imidazolinyl, tetrahydropyrimidinyl or tetrazolyl moiety into thienopyridine structure was successfully attempted by converting the nitrile group of 16b into imidazolinyl, tetrahydropyrimidinyl or tetrazolyl residue followed by some successive reactions.
Thus, the reaction of 16b with ethylenediamine in the presence of carbon disulfide gave 3-amino-2-(Δ1-imidazolin-2-yl)-6-(2-thienyl)-4-trifluoromethylthieno[2,3-b] pyridine (22) in a good yield. Similarly, the reaction of 16b with propylenediamine under the same (above) condition afforded 3-amino-2-(3,4,5,6-tetrahydropyrimidin-2-yl)-6-(2-thienyl)-4-trifluoro-methylthieno[2,3-b]pyridine (23). On treatment of 16b with sodium azide and ammonium chloride in hot DMF followed by acidification of the reaction mixture resulted in the formation of the tetrazolyl compound 24 (Scheme 7).
Synthesis of compounds 22–24.
The reaction of 22 with triethyl orthoformate, 4-chlorobenzaldehyde, and/ or carbon disulfide gave imidazo[1″,2″-c]pyrido[3′,2′:4,5]thieno[2,3-e]pyrimidine derivatives 25, 26 and 27 respectively. On treatment of 22 with nitrous acid, it underwent diazotization followed by self coupling to furnish heterocyclopyrido [3′,2′:4,5]thieno[2,3-e][1,2,3]triazine derivatives 28 in excellent yield (Scheme 8).
Synthesis of compounds 25–28.
By the same procedure, pyrimido[1″,2″-c]pyrido[3′,2′:4,5]thieno[2,3-e]pyrimidine derivatives 30, 31 and 32 were prepared starting from compound 23. On treatment of 23 with nitrous acid, it underwent diazotization followed by self coupling to give heterocyclopyrido[3′,2′:4,5]thieno[2,3-e][1,2,3]triazine derivatives 32 (Scheme 9).
Synthesis of compounds 29–32.
In contrast, the reaction of tetrazolyl derivative 24 with triethyl orthoformate produced the azidopyrimidine 34 rather than the expected tetrazolopyrimidine 33 (Scheme 10). When compound 24 was allowed to react with 4-chlorobenzaldehyde, the tetrazolo-pyridothienopyrimidine derivative 35 was obtained in high yield. The reaction of tetrazolyl derivative 24 with nitrous acid gave tetrazolotriazine 36. The latter compound does not isomerize to azidotriazine 37. (Scheme 10).
Synthesis of compounds 33–37.
The structure of all newly synthesized compounds was confirmed on the basis of their elemental analyses (experimental part) and spectral data.
4 Conclusion
In the present work, 3-cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-one (1) was prepared and used as a precursor for synthesizing the target fluorine-containing pyridines, furopyridines and pyrazolopyridines. Also, 2-functionalized 3-amino-6-(2-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines (16a,b) underwent several successive reactions to afford the desired thienopyridines and pyridothienopyrimidines bearing trifluoromethyl residue.
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