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Journal of Chemistry
Volume 2013 (2013), Article ID 765243, 15 pages
http://dx.doi.org/10.1155/2013/765243
Research Article

Thioxopyrimidine in Heterocyclic Synthesis I: Synthesis of Some Novel 6-(Heteroatom-substituted)-(thio)pyrimidine Derivatives

Department of Creative Fashion Design, Taoyuan Innovation Institute of Technology, Jhongli 32091, Taiwan

Received 27 June 2012; Revised 30 August 2012; Accepted 16 October 2012

Academic Editor: Filomena Conforti

Copyright © 2013 Yuh-Wen Ho and Maw Cherng Suen. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A series of novel N-cycloalkanes, morpholine, piperazines, pyrazole, pyrimidine, benzimidazolo[1,2-a]pyrimidine, 1,2,3,4-tetrazolo[1,5-a]pyrimidine, azopyrazolo[1,5- a]pyrimidine, pyrimido[4', 5' :3,4]pyrazolo[1,5-a]pyrimidines and pyridine derivatives incorporating a 5-cyano-4-methyl-2-phenyl-(thio)pyrimidine moiety were obtained by the intramolecular cyclization of 6-methylthio-pyrimidine, 6-(benzoylmethyl)thio- pyrimidine and 2-[(5-cyano-4-methyl-2-phenylpyrimidin-6-yl)thio]-3-dimethyl- amino-1-phenyl-prop-2-en-1-one with appropriate amines and enaminone compounds, respectively. The structure of all new synthesized compounds was established from their spectral data, elemental analysis and the X-ray crystal analysis.

1. Introduction

Pyrimidine derivatives attracted organic chemists very much due to their biological and chemotherapeutic importance. Pyrimidine derivatives and related fused heterocycles are important classes of heterocyclic compounds that exhibit a broad spectrum of biological activities such as anticancer [15], antiviral [6], antibacterial [7, 8], antioxidant [9, 10], anxiolytic [11], and antidepressant activities [12]. Furthermore, they possess anti-inflammatory [1319] and analgesic activities that are well documented in the literature [2022]. The incorporation of two moieties increases biological activity of both and thus it was of value to synthesize some new heterocyclic derivatives having two moieties in the same molecules. The course of our researches was devoted to the development of new classes of pyrimidines substituted at position-6 with different fused heterocycles moiety in the hope that they may be biologically active. In preceding papers [2325] we have described the synthesis of a series of novel 5-(1-pyrrolyl)-4-methyl-2-phenylthieno[2,3-d]pyrimidine derivatives containing chalcones, pyridines, pyridin-2(1H)-ones, 2H-pyran-2-one, pyrazoles, pyrimidines imidazolpyrimidines, pyrazolopyrimidines, and 1,3,4-oxadiazoles moiety. In continuation of our studies, we report herein the use of thioxopyrimidine 1 for the synthesis of various N-cycloalkanes, morpholine, piperazines, pyridines, pyrazole, pyrimidine, benzimidazolo[1,5-a]pyrimidine, 1,2,3,4-tetrazolo[1,5-a]pyrimidine, azopyrazolo[1,5-a]pyrimidine, and pyrimido[4′,5′:3,4]pyrazolo[1,5-a]pyrimidine incorporating a (thio)pyrimidine moiety. The structure of the new compounds was verified by spectroscopic methods and the X-ray crystal structure of compound 13 is also discussed.

2. Experimental

All melting points are uncorrected and in °C. IR spectra were recorded on a JASCO FTIR-3 spectrometer (KBr); 1H-NMR spectra were obtained on a Bruker AM-300 WB FI-NLR spectrometer, and chemical shifts are expressed in ppm using TMS as an internal standard. Electron impact mass spectra were obtained at 70 eV using a Finingan Mat TSQ-46C spectrometer. Microanalyses for C, H, and N were performed on a Perkin-Elmer 240 elemental Analyzer. Enaminone derivatives 14a–f, 5-amino-4-phenylazo-3-methyl-1H-pyrazole 26, and 3-amino-4-methyl-6-phenyl-pyrazolo-[3,4-d]pyrimidine 28 were prepared following the methods in the literature [24, 26, 27].

2.1. 5-Cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine (1)

To a suspension of ammonium thiocyanate (7.60 g, 0.1 mol) in dry dioxane (100 mL), benzoyl chloride (14 g, 0.1 mol) was added. The reaction mixture was refluxed for 5 min.,then treated with 3-aminocrotononitrile (8.20 g, 0.1 mol). The reaction mixture was refluxed for 2 h and poured into ice water. The solid product was collected by filtration, washed with water, and recrystallized from ethanol to give 17 g of yellow needle crystals (74% yield), mp 212°C; IR: 2225 (CN), 1200 (C S) cm−1; 1H-NMR (DMSO- ): 2.50 (3H, s, CH3), 2.90 (1H, s, NH), 7.66–7.51, 8.11–8.08 (5H, m, phenyl-H); : 227 ( ). Anal. Calcd. for : C, 63.43; H, 3.96; N, 18.50. Found: C, 63.40; H, 4.00; N, 18.60%.

2.2. 5-Cyano-4-methyl-2-phenyl-6-methylthio-pyrimidine (2)

A mixture of compound 1 (0.23 g, 1 mmol) in methanol (10 mL) and sodium methoxide (0.08 g, 1.5 mmol) and methyl iodide (0.17 g, 1.2 mmol) were added. After stirring at room temperature for 4 h, the resulting solid product was collected by filtration, washed with water, and recrystallized from THF to give 0.21 g of pale yellow crystals (87% yield), mp 144°C; IR: 2207 (C N) ; 1H-NMR (CDCl3): 2.70 (3H, s, CH3), 2.75 (3H, s, SCH3), 8.49–8.47, 7.55–7.49 (5H, m, phenyl-H); MS ( , %): 241( ,100), 227(4), 195(4), 153(14), 138(9), 111(3), 104(17), 244(2), 77(10), 51(6). Anal. Calcd. for : C, 64.73; H, 4.56; N, 17.42. Found: C, 64.88 H, 4.54; N, 17.55%.

2.3. 5-Cyano-4-formyl-2-phenyl-6-methylthio-pyrimidine (3)

A mixture of 5-cyano-4-methyl-2-phenyl-6-methylthio-pyrimidine 2 (0.24 g, 1 mmol) and selenium oxide (0.11 g, 1 mmol) in dioxane (10 mL) was refluxed for 1 h. After cooling, the mixture was filtered. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (light petroleum ether/ethyl acetate 7 : 3 v/v as eluent) to give 0.2 g of reddish brown needles (78% yield), mp 164°C; IR: 2218 (C N), 1689 (C O) cm−1; 1H-NMR (DMSO- ): 2.74 (3H, s, SCH3), 8.40, 7.61–7.52 (5H, m, phenyl-H), 9.85 (1H, s, CHO); MS ( , %): 255( , 18), 241(100), 277(61), 200(22), 138(10), 104(12), 97(5). Anal. Calcd. for : C, 61.17; H, 3.52; N, 16.47. Found: C, 61.13; H, 3.72; N, 16.45%.

2.4. 6-Substituted-5-cyano-4-methyl-2-phenyl-pyrimidine Derivatives (4a,b and 5a–f) General Procedure

A mixture of compound 2 (0.24 g, 1 mmol) and excess secondary amines (pyrrolidine, piperidine, morpholine, N-methylpiperazine, N-ethylpiperazine, ethyl 1-piperazinecarboxylate, 1-phenylpiperazine, and 1-(2-pyrimidyl)piperazine) (5 mmol) was refluxed for 10 h and poured into ice-water, and the precipitated product was collected by filtration, washed with water, and the crude product recrystallized from chloroform/THF. The physical constants and spectral data of compounds 4a,b and 5a–f are recorded in Tables 1 and 2.

tab1
Table 1: Physical and analytical data of 6-substituted-pyrimidine derivatives (4a, b and 5af).
tab2
Table 2: Spectral data of 6-substituted-pyrimidine derivatives (4a, b and 5af).
2.5. 4-[(4-N,N-Dimethylamino)-2-phenylvinyl)]-6-piperidinyl-5-cyano-2-phenyl-pyrimidine (6)

A mixture of 6-piperidinyl-4-methyl-pyrimidine 4b (0.28 g, 1 mmol) and N,N-dimethylaminobenzaldehyde (0.15 g, 1 mmol) in dioxane (10 mL) in the presence of catalytic amount of piperidine was refluxed for 8 h. After cooling, the resulting solid product was collected by filtration and washed with water, and the crude product recrystallized from ethanol/glacial acetic acid to give 0.15 g of pale yellow needles (37% yield), mp 103°C; IR: 2212 (C N) cm−1; 1H-NMR (CDCl3): 3.07–2.96, 1.75–1.62 (10H, m, piperidinyl-H), 3.09 (6H, s, CH3), 6.70 (1H, d, J = 2.0 Hz, –CH ), 7.74 (1H, d, J = 2.0 Hz, CH–), 8.57–8.55, 7.52–7.44 (9H, m, phenyl-H); MS ( , %): 409( , 100), 381(9), 366(3), 326(5), 289(7), 222(4), 205(6), 195(8), 190(5), 104(7), 85(5). Anal. Calcd. for : C, 76.28; H, 6.60; N, 17.11. Found: C, 76.01; H, 6.42; N, 17.31%.

2.6. 6-Cyanopropylthio-5-cyano-4-methyl-2-phenyl-pyrimidin (8)

A mixture of 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 1 (2.27 g, 0.01 mol), sodium ethoxide (1.36 g, 0.02 mol), and 4-chlorobutyronitrile (1.03 g, 0.01 mol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 4 h and then diluted with cold water (50 mL) was collected by filtration, washed with water, and recrystallized from DMF/ethanol to give 2.88 g of yellow needles (98% yield), mp 144°C; IR: 2220 (C N) cm−1; 1H-NMR (CDCl3): 2.21 (2H, t, J = 2.54 Hz, CH2), 2.58–2.56 (2H, m, CH2), 2.71 (3H, s, CH3), 3.54 (2H, t, J = 2.27 Hz, CH2), 8.47-8.46, 7.55–7.49 (5H, m, phenyl-H); MS ( , %): 294( ,22), 254(60), 241(100), 227(28), 194(9), 153(31), 104(15), 77(16). Anal. Calcd. for : C, 65.30; H, 4.76; N, 19.04. Found: C, 65.23; H, 4.70; N, 19.13%.

2.7. 5-Amino-6-benzoyl-4-methyl-2-phenylthieno[2,3-d]pyrimidine (10)

A mixture of 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 1 (2.27 g, 0.01 mol), 2-bromoacetophenone 9 (1.99 g, 0.01 mol), and sodium ethoxide (1.36 g, 0.02 mol) in DMF (50 mL) was stirred at room temperature for 4 h and then diluted with cold water (50 mL). The resulting solid product was collected by filtration, washed with water, and recrystallized from DMF/ethanol to give 3.17 g of yellow needles (92% yield), mp 236°C; IR: 3421, 3288 (NH2), 1663 (C O) cm−1; 1H-NMR (DMSO- ): 2.56 (3H, s, CH3), 3.71 (2H, br, NH2), 8.39–8.37, 7.95–7.72 (10H, m, phenyl-H); MS ( , %): 345( ,100). Anal. Calcd. for : C, 69.56; H, 4.34; N, 12.17. Found: C, 69.71; H, 4.50; N, 12.43%.

2.8. 6-Benzoyl-4-methyl-5-(1-pyrrolyl)-2-phenylthieno [2,3-d]pyrimidine (11)

A mixture of 5-amino-6-benzoyl-4-methyl-2-phenylthieno[2,3-d]pyrimidine 10 (0.34 g, 1 mmol) and 2,5-dimethoxytetrahydrofuran (0.13 g, 1 mmol), in glacial acetic acid (20 mL) was refluxed for 12 h. After cooling, the resulting solid product was collected by filtration and washed with water, and the crude product recrystallized from ethanol/glacial acetic acid to give 0.18 g of brown needles (46% yield), mp 130°C; IR: 1663 (C O) cm−1; 1H-NMR (CDCl3): 2.31 (3H, s, CH3), 6.10 (2H, m, 3,4-H of pyrrolyl), 6.71 (2H, m, 2,5-H of pyrrolyl), 8.59–8.57, 7.69–7.31 (10H, m, phenyl-H); MS ( , %): 395( ,100). Anal. Calcd. for : C, 72.91; H, 4.30; N, 10.63. Found: C, 73.01; H, 4.42; N, 10.67%.

2.9. 5-(1,2,3,4-Tetrazol-1-yl)-6-benzoly-4-methyl-2-phenylthieno[2,3-d]pyrimidine (12)

A mixture of 5-amino-6-benzoyl-4-methyl-2-phenylthieno[2,3-d]pyrimidine  10 (0.34 g, 1 mmol), sodium azide (0.065 g, 1 mmol), and triethyl orthoformate (8 mL) was refluxed in acetic anhydride (15 mL) for 4 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and washed with water, and the crude product recrystallized from DMF/glacial acetic acid to give 0.31 g of orange yellow needles (78% yield), mp 196°C; IR: 1662 (C O) cm−1; 1H-NMR (CF3COOD): 2.61 (3H, s, CH3), 8.83 (1H, s, 5-H of tetrazoly), 8.64–8.62, 8.21–7.96 (10H, m, phenyl-H); MS ( , %): 398( ,10), 367(13), 344(100), 268(3), 240(10), 211(2), 105(5). Anal. Calcd. for : C, 63.31; H, 3.51; N, 21.10. Found: C, 63.45; H, 3.66; N, 21.31%.

2.10. 6-[(Benzoylmethyl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine (13)

A mixture of 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 1 (2.27 g, 0.01 mol), sodium ethoxide (0.68 g, 0.01 mol), and 2-bromoacetophenone 9 (1.99 g, 0.01 mol) in DMF (50 ml). The reaction mixture was stirred at room temperature for 4 h and then diluted with cold water (50 mL) was collected by filtration, washed with water, and recrystallized from chlorofrom/ethanol to give 3.1 g of pale yellow needles (90% yield), mp 169°C; IR: 2220(C N), 1679 (C O) cm−1; 1H-NMR (CDCl3): 2.67 (3H, s, CH3), 4.77 (2H, s, SCH2), 8.11–8.06, 7.70–7.22 (10H, m, phenyl-H); MS ( , %): 345( ,85), 319(15), 312(30), 242(3), 240(30), 134(10), 105(100), 77(4). Anal. Calcd. for : C, 69.56; H, 4.34; N, 12.17. Found: C, 69.68; H, 4.40; N, 12.33%.

2.11. 6-[(4,5,6-Trisubstituted-2-phenyl-pyridin-3-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine (16a–f) General Procedure

A mixture of compound 13 (0.35 g, 1 mmol) and enaminone derivatives 14a–f (1 mmol) and ammonium acetate (2 mmol) was refluxed in glacial acetic acid (10 mL) for 11 h. After cooling, the resulting solid product was collected by filtration, washed with water, and recrystallized from ethanol/glacial acetic acid. The physical constants and spectral data of compounds 16a–f are recorded in Tables 6 and 7.

2.12. 2-[(5-Cyano-4-methyl-2-phenylpyrimidin-6-yl)thio]-3-dimethylamino-1-phenyl-prop-2-en-1-one (17)

A mixture of compound 13 (0.35 g, 1 mmol) and N,N-dimethylformamide dimethylacetal (1 mmol) was refluxed in xylene (5 mL) for 5 h. After cooling, the resulting solid product was collected by filtration, washed with water, and recrystallized from ethanol/glacial acetic acid afforded 0.26 g of yellow crystals (66% yield), mp 185°C; IR: 2214 (C N), 1654 (C O) cm−1; 1H-NMR (CF3COOD): 2.94 (6H, s, N(CH3)), 3.43 (3H, s, CH3), 7.47 (1H, s, CH–N), 8.27–8.23, 7.81–7.57 (10H, m, phenyl-H); MS ( , %): 400( ,10), 344(100). Anal. Calcd. for : C,69.00; H, 5.00; N, 14.00. Found: C, 59.93; H, 5.23.; N, 14.33%.

2.13. 6-[(4-Phenyl-pyrimidin-5-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine (21)

A mixture of compound 17 (0.40 g, 1 mmol) and formamide/formic acid (1 : 1, 1 mmol) 20and ammonium acetate (2 mmol) was refluxed for 7 h. After cooling, the resulting solid product was collected by filtration, washed with water, and recrystallized from ethanol/glacial acetic acid to give 0.21 g of yellow needles (56% yield), mp 258°C; IR: 2209 (C N) cm−1; 1H-NMR ( ): 3.84 (3H, s, CH3), 8.21 (1H, s, 6-H of pyrimidinyl), 8.26 (1H, s, 2-H of pyrimidinyl), 8.70–8.69, 8.24–8.02 (10H, m, phenyl-H); MS ( , %): 381(54), 345(100), 280(16), 256(8), 210(1), 121(2), 105(22), 98(6), 57(4). Anal. Calcd. for : C, 69.29; H, 3.93; N, 18.37. Found: C, 69.38; H, 4.01; N, 18.44%.

2.14. 6-[(Substituted)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine Derivatives (19, 23, 25, 27 and 29) General Procedure

A mixture of compound 17 (0.40 g, 1 mmol) and phenylhydrazine 18, 2-amino-benzimidazole 22, 5-amino-1H-tetrazole 24, and 5-amino-pyrazoles 26, 28 (1 mmol) in the presence of glacial acetic acid (5 mL) was refluxed for 7 h. After cooling, the resulting solid product was collected by filtration, washed with water, and the crude product recrystallized from DMF/glacial acetic acid.

2.15. 6-[(1,5-Diphenyl-1H-pyrazol-4-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine (19)

Yield 38%, mp 240°C; IR: 2201 (C N) cm−1; 1H-NMR ( ): 3.34 (3H, s, CH3), 7.76 (1H, s, 3-H of pyrazole), 8.25–8.23, 7.81–7.79, 7.70–7.57 (15H, m, phenyl-H); MS ( , %): 445( ,7), 422(6), 355 (4), 344(100), 268(3), 93(2). Anal. Calcd. for : C, 72.80; H, 4.26; N, 15.73. Found: C, 72.91; H, 4.47; N, 15.89%.

2.16. 6-[(4-Phenyl-benzimidazolo[1,2-a]pyrimidinyl-3-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine (23)

Yield 54%, mp 232°C; IR: 2204 (C N) (C N) cm−1; 1H-NMR (CF3COOD): 2.51 (3H, s, CH3), 8.53 (1H, s, 2-H of benzimidazolo- pyrimidinyl), 8.09-8.08, 7.98-7.86 (14H, m, benzimidazolyl-H and phenyl-H); MS ( , %): 470(11), 430(2), 367(2), 355(30), 345(100), 276(2), 227(8), 105(4). Anal. Calcd. for : C, 71.48; H, 3.82; N, 17.87. Found: C, 71.39; H, 3.99; N, 17.98%.

2.17. 6-[(4-Phenyl-1,2,3,4-tetrazolo[1,5-a]pyrimidinyl-3-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine (25)

Yield 50%, mp 233°C; IR: 2206 (C N) cm−1; 1H-NMR (CF3COOD): 2.63 (3H, s, CH3), 8.65 (1H, s, 2-H of tetrazolopyrimidinyl), 8.22–8.17, 8.11–7.99 (10H, m, phenyl-H); MS ( , %): 422(6), 344(100), 292(2), 212(5), 105(3). Anal. Calcd. for : C, 62.55; H, 3.32; N, 26.54. Found: C, 62.74; H, 3.45; N, 26.66%.

2.18. 6-[(5-Cyano-6-methyl-2-phenylpyrimidin-4-yl)thio]-2-methyl-3-phenylazo-7-phenyl-pyrazolo[1,5-a]pyrimidine (27)

Yield 67%, mp 230°C; IR: 2200 (C N) cm−1; 1H-NMR ( ): 2.62 (3H, s, CH3), 2.91 (3H, s, CH3), 8.00 (1H, s, 5-H of pyrazolopyrimidinyl), 8.28-8.27, 7.84–7.61 (15H, m, phenyl-H); MS ( , %): 538(15), 461(8), 344(100), 316(10), 240(4), 182(1), 124(1), 93(2). Anal. Calcd. for : C, 69.14; H, 4.08; N, 20.81. Found: C, 69.26; H, 4.22; N, 20.66%.

2.19. 7-[(5-Cyano-6-methyl-2-phenylpyrimidin-4-yl)thio]-4-methyl-2,8-diphenyl-pyrimido[4′,5′:3,4]pyrazolo[1,5-a]pyrimidine (29)

Yield 65%, mp 289°C; IR: 2201 (C N) cm−1; 1H-NMR ( ): 2.37 (3H, s, CH3), 3.52 (3H, s, CH3), 7.67 (1H, s, 6-H of pyrimidopyrazolopyrimidinyl), 8.41–8.39, 7.95–7.72 (15H, m, phenyl-H); MS (m/z, %): 562(15), 460(1), 418(2), 316(10), 368(100), 344(20), 249(4), 225(16), 197(10), 153(12), 104(13), 77(17), 51(4). Anal. Calcd. for C33H22N8S: C, 70.46; H, 3.91; N, 19.92. Found: C, 70.66; H, 4.12; N, 20.16%.

2.20. X-Ray Structure Study of Compound 13

The diffraction data of compound 13 was collected on a Siemens CCD diffractometer, which was equipped with graphite-monochromated Mo-Kα (Kα = 0.71073 Å) radiation. Data reduction was carried by standard methods with use of well-established computational procedures [28, 29]. A pale yellow crystal of compound 13 was mounted on the top of a glass fiber with epoxy cement. The hemisphere data collection method was used to scan the data points at 3.34 2 52.02°. The structure factors were obtained after Lorentz and polarization correction. The final residuals of the final refinement were , . The crystallographic data of compound 13 has been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC 752301. Copy of this information may be obtained free of charge via http://www.ccdc.cam.ac.uk or from The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +441223/336–033; email: deposit@ccdc.cam.ac.uk).

3. Results and Discussion

All relevant reactions are depicted in Schemes 1, 2, 3, and 4. The required compound 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 1 was prepared by treating benzoylisothiocyanate with 3-aminocrotononitrile in refluxing dioxane [26]. Several pyrimidines substituted at position-6 with different heterocyclic residues were obtained via treatment of thioxopyrimidine 1 with different reagents. Thus, reaction of thioxopyrimidine 1 with methyl iodide in the presence of sodium methoxide to yield the 6-methylthio-4-methyl-2-phenyl-pyrimidine 2, which reacted with selenium oxide in dioxane afforded the 4-formyl-6-methylthio-2-phenyl-pyrimidine 3 (Scheme 1). The IR spectra of compound 3 showed the characteristic absorption bands at 1689 cm−1 for the HC O group and 2218 cm−1 for the C N group. In addition, the 1H NMR spectra (DMSO- ) of compound 3 revealed two singlets at 2.74 (3H, s) and 9.85 (1H, s), which were readily assigned to the SCH3 and HC O groups, respectively. On the other hand, a series of novel 6-substituted-pyrimidine derivatives 4a,b and 5a–f were also obtained by the condensation reaction of compound 2 with appropriate secondary amines such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, N-ethylpiperazine, ethyl 1-piperazinecarboxylate, 1-phenyl-piperazine and 1-(2-pyrimidyl)piperazine, (Scheme 1). Compounds 4a,b and 5a–f were obtained generally in 28–89% yields. The structures of 4a,b and 5a–f were verified by elemental analysis and by spectroscopic methods. Physical and spectral data of compounds 4a,b and 5a–f are recorded in Tables 1 and 2, respectively. Typical assignments for 5f by 1H-NMR are shown in Figure 1. These structures get further support from mass spectroscopy. The mass fragmentation pattern of compound 5d showed the presence of the ion peaks [M–CH3]+ at 336, [M–CH2CH3]+at 322, [M–OCH2CH3]+ at 306 and [M–COOCH2CH3]+ at 278. Also, it has been observed that electron impact (EI) spectral has many common features. Compounds 5a–f exhibited 249, 236, 223, 194 and 153 piece peaks. The possible mass fragmentation pathways of compounds 5a–f are shown in Figure 5.

765243.sch.001
Scheme 1
765243.sch.002
Scheme 2
765243.sch.003
Scheme 3
765243.sch.004
Scheme 4
765243.fig.001
Figure 1: Structural assignment of typical protons in 5f by 1H NMR.

Next, treatment of 6-piperidinyl-4-methyl-pyrimidine 4b with N,N-dimethyl-aminobenzaldehyde in refluxing dioxane in the presence of catalytic amount of piperidine yielded the 4-[(4-N,N-dimethylamino)-2-phenylvinyl)]-6-piperidinyl-5-cyano-2-phenyl-pyrimidine 6. The 1H-NMR spectra (CDCl3) of compound 6 revealed a sharp singlet at 3.09 (6H, s) assigned to the –N(CH3)2 protons and at 6.70 (1H, d) and 7.74 (1H, d) assigned to the –CH CH– of 4-dimethylaminophenylethylene moiety, two multiplets at 3.07–2.96, 1.75–1.62 (10H, m) assigned to the piperidinyl protons and a multiplet at 8.57–7.44 (9H, m) assigned to the phenyl protons, were also confirmed by the mass spectrum m/z 409( ). However, reaction of compound 2 with benzhydrazide did not produce the desired compound 7, but led only to the recovery of starting material. On the other hand, the 6-cyanopropylthio-pyrimidine 8 was also obtained by treatment of compound 1 with 4-chlorobutyronitrile in DMF at room temperature in the presence of sodium ethoxide in a molar ratio of 1 : 2 (Scheme 2). Nevertheless, under same reaction conditions, treatment of compound 1 with 2-bromoacetophenone 9 formed the nonisolable S-alkylated intermediate, which via nucleophilic substitution and intramolecular cyclocondensation afforded the corresponding 5-amino-6-benzoly-4-methyl-2-phenylthieno[2,3-d]pyrimidine 10, which when reacted with 2,5-dimethoxy-tetrahydrofuran in glacial acetic acid produced the 5-(1-pyrrolyl)-6-benzoly-4-methyl-2-phenylthieno[2,3-d]pyrimidine 11. Also, reaction of compound 10 with sodium azide and triethyl orthoformate in acetic anhydride afforded the corresponding 5-(1,2,3,4-tetrazol-1-yl)-6-benzoly-2-phenyl-thieno[2,3-d]pyrimidine 12 (Scheme 2). The structure of compounds 10–12 was established on the basis of their elemental analysis and spectral data. The IR spectra of compounds 11 and 12 indicated the complete disappearance of NH2 and showed the characteristic absorption band at 1663-1662 cm−1 for the C O group. The 1H-NMR spectra (CDCl3) of compound 11 revealed two multiplets at 6.10 (2H, m) and 6.71 (2H, m), which were readily assigned to the hydrogen of the pyrrolyl ring. Moreover, compound 12 showed a singlet at 8.83 (1H, s) assigned to the hydrogen attached at C5 of the tetrazolyl ring.

On the other hand, treatment of compound 1 with 2-bromoacetophenone 9 in the presence of sodium ethoxide in a molar ratio of 1:1 afforded the open-chain product 6-(benzoylmethyl)thio-2-phenyl-pyrimidine 13 in 90% yield (Scheme 2). The IR spectra of compound 13 indicated the characteristic absorption bands at 1679 cm−1 for the C O group and 2220 cm−1 for the C N group. In particular, the 1H-NMR spectrum (CDCl3) of compound 13 revealed a singlet at 4.77 (2H, s) assigned to the SCH2CO protons. The structure of 13 was unambiguously confirmed by X-ray crystallography. The suitable single crystals of compound 13 were obtained by slow crystallization from chloroform/DMF at room temperature. Perspective view and the numbering of the atoms are depicted in Figure 2. This drawing clearly establishes the structural formula and also shows the conformation of the molecule. The packing diagram (Figure 3) in the solid state by intermolecular hydrogen bonding between C–H of the –S–CH2 group and C O atom (C−H–-O 2.261 Å, C−H–-O 145.5°). The relevant crystallographic date and structure refinement are recorded in Table 3. The selected bond lengths and bond angles are listed in Table 4. The hydrogen atoms were refined isotropically in idealized positions riding on the atom to which they are attached. The crystal system of compound 13 is monoclinic, the space group is P 21/n and data was collected in the range 2.60 to 26.01°. Details of the intensity collection are recorded in Table 3.

tab3
Table 3: Crystal data and structure refinement for compound 13.
tab4
Table 4: Selected bond lengths [Å] and angles [°] for compound 13a.
765243.fig.002
Figure 2: Perspective view of compound 13 with atomic numbering.
fig3
Figure 3: (a) Packing diagram for 13 showing the C−H–-O hydrogen bonds (C−H–-O = 2.261 Å, C−H–-O = 145.5°). (b) Packing diagram for 13 showing the interactions between the layers.

The basal plane is formed by phenyl(C(15))-carbonylmethylthio(C(14)), carbonylmethylthio-pyrimidine(C(10)), and pyrimidine(C(7))-phenyl(C(6)) atoms, with bond lengths of 1.482(3), 1.7436(17), and 1.481(2) Å, respectively. The phenyl ring is in the cis (Z) configuration with respect to the S atom and the fused pyrimidine system (Figure 2). Moreover, the fused pyrimidine system is almost planar and due to the effect of carbonylmethyl-S moiety the phenyl group exhibit noticeable quinoid character that is demonstrated by the shortening of the C(17)–C(18) [1.353(5) Å], C(18)–C(19) [1.383(5) Å], C(19)–C(20) [1.385(4) Å], and C(16)–C(17) [1.374(3) Å] bond lengths compared to the standard distance of 1.397(1) Å [30]. In addition, the C(16)–C(17) phenyl and carbonyl group are in a staggered conformation with respect to the O atom giving rise to angular distortion at C(15) and C(14) [C(16)–C(15)–C(14)C(20)–C(15)–C(14)] (Table 4). The S–C(10) [1.7436(17) Å] bond is longer than the C(6)–C(7)[1.481(2) Å], which is probably due to electron withdrawing effect of the S atom. Also, the interesting torsion angles which entirely define the molecule conformation are selected and listed in Table 5. Moreover, the C(9)–C(10) [1.401(2) Å] and N(1)–C(7) [1.341(2) Å] bonds are longer than the N(2)–C(10) [1.334(19) Å]. The C(1)–C(2) phenyl ring has a dihedral angle with N(2)–C(10) pyrimidine ring of 171.1°, while the carbonylmethylthio’s dihedral angle with this pyrimidine is 101.0°. Furthermore, the C(16)–C(17) phenyl ring attached to the carbonylmethyl group and makes a dihedral angle of 112.2° with pyrimidine ring plane and the C(16)–C(17) phenyl ring has a dihedral angle with carbonylmethylthio group of 15.7°.

tab5
Table 5: Selected torsion angles for compound 13.
tab6
Table 6: Physical and analytical data of 6-[(4,5,6-trisubstituted-2-phenyl-pyridin-3-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine derivatives (16af).
tab7
Table 7: Spectral data of 6-[(4,5,6-trisubstituted-2-phenyl-pyridin-3-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine derivatives (16af).

On the other hand, the reaction of compound 13 with enaminone derivatives 14a–f was also investigated. Thus, it has been found that compound 13 with 3-dimethylamino-1-(phenyl)prop-2-enone 14a in refluxing glacial acetic acid in the presence of excess ammonium acetate gave a yellow product of molecular formula C29H20N4S (55% yield, mp 218°C). Spectroscopic analyses revealed that 6-[(2,6-diphenyl-pyridin-3-yl)thio]-5-cyano-4-methyl-2-phenylpyrimidine 16a was obtained (Scheme 3). The IR spectra of the reaction product indicated the absence of the C O group and showed the characteristic absorption band at 2203 cm−1 for the C N group. The 1H-NMR spectra (CF3COOD) of the reaction product showed additional two doublets at 8.44 (1H, d) and 8.76 (1H, d) assigned to the hydrogen attached at C5 and C4 of pyridine moiety, respectively, and at 8.54–8.52, 8.19–7.87 (15H, m) assigned to the phenyl protons. The structure of compound 16a was further confirmed by mass spectrum ( 456 ( )). The formation of compound 16a would involve an initial nucleophilic substitution of the exocyclic methylene group in compound 13 to the activated double bond in enaminone 14a to form the intermediate 15, which then undergoes amination and intramolecular cyclization via loss of water affording the final product 16a. Similarly, treatment of compound 13 with enaminone derivatives 14b–f, under similar reaction conditions, afforded the corresponding 6-[(4,5,6-trisubstituted-2-phenyl-pyridin-3-yl)thio]-5-cyano-4-methyl-2-phenyl-pyri-midines 16b–f (Scheme 3). Typical assignments for 16c and 16e by 1H-NMR are shown in Figure 4. The physical constants and spectral data of compounds 16a–f are recorded in Tables 6 and 7. These structures get further support from mass spectroscopy. The possible mass fragmentation pathway of compounds 16c is shown in Figure 6.

765243.fig.004
Figure 4: Structural assignment of typical protons in 16c and 16e by 1H NMR.
765243.fig.005
Figure 5
765243.fig.006
Figure 6

Furthermore, treatment of 6-(benzoylmethyl)thio-pyrimidine 13 with N,N-dimethylformamide dimethylacetal (DMFDMA) gave the enaminone derivative 2-[(5-cyano-4-methyl-2-phenylpyrimidin-6-yl)thio]-3-dimethylamino-1-phenylprop-2-en-1-one 17 (Scheme 4). The 1H NMR spectra (CF3COOD) of compound 17 revealed a sharp singlet at 2.94 (6H, s) assigned to the –N(CH3)2 protons and at 7.47 (1H, s) assigned to the –C CH–N, was also confirmed by the mass spectrum m/z 400 ( ). On the other hand, the study was extended to investigate the behavior of enaminone derivative 17 with different nucleophiles like amino compounds with a view to synthesizing various heterocyclic ring systems. Intramolecular cyclization of enaminone derivative 17 gave different products depending on reaction reagents. Thus, treatment of enaminone derivative 17 with phenylhydrazine 18 in the presence of glacial acetic acid afforded the 6-[(1,5-diphenyl-1H-pyrazol-4-yl)thio]-pyrimidine 19 (Scheme 4). The structure of pyrazole derivative 19 was established on the basis of their elemental analysis and spectral data. The IR spectra of compound 19 indicated the absence of the C O group and showed the characteristic absorption bands at 2201 cm−1 for the C N group. The 1H-NMR spectra (CF3COOD) of compound 19 revealed a sharp singlet at 7.76 (1H, s) assigned to the hydrogen attached at C3 of pyrazole ring and at 8.25–8.23, 7.81–7.79, 7.70–7.57 (15H, m) assigned to the phenyl protons, which was also confirmed by the mass spectrum m/z 445 ( ). The formation of compound 19 would involve an initial nucleophilic substitution of the amino group in phenylhydrazine 18 to the activated double bond in enaminone derivative 17, followed by deamination, to form the intermediate 19′, which then undergoes intramolecule cyclization via loss of water [31] affording the final product 19. Next, the bis-pyrimidine derivative 6-[(4-phenyl-pyrimidin-5-yl)thio]-5-cyano-4-methyl-2-phenyl-pyrimidine 21 was also obtained by the intramolecular cyclization of compound 17 with formamide/formic acid in the presence of excess ammonium acetate. The 1H-NMR spectra (CF3COOD) of compound 21 revealed additional two sharp singlets at 8.21 (1H, s) and 8.26 (1H, s) assigned to the hydrogen attached at C6 and C2 of pyrimidine ring and at 8.70-8.69, 8.24–8.02 (10H, m) assigned to the phenyl protons, which was also confirmed by the mass spectrum m/z 381 ( ).

Finally, intramolecular cyclization of the enaminone derivative 17 with 2-amino-bezimidazole 22, 5-amino-1H-tetrazole 24, 3-amino-4-phenylazo-pyrazole 26 and 3-amino-4-methyl-6-phenyl-pyrazolo[3,4-d]pyrimidine 28 under acid conditions afforded the corresponding benzimidazolo[1,2-a]pyrimidine 23, 1,2,3,4-tetrazolo[1,5-a]pyrimidine 25, azopyrazolo[1,5-a]pyrimidine 27, and pyrimido-[4′,5′ : 3,4]pyrazolo[1,5-a]pyrimidine 29, respectively (Scheme 4). The mechanisms of compounds 23, 25, 27, and 29 are similar to compound 19. The structures of compounds 23, 25, 27, and 29 were established on the basis of their elemental analysis and spectral data. For instance, the 1H NMR spectra of compounds 23 and 27 revealed a sharp singlet at 8.53 (1H, s) and at 8.00 (1H, s), which assigned to the hydrogen attached at C2 of benzimidazolopyrimidine and at C5 of pyrazolopyrimidine ring, respectively.

4. Conclusion

In conclusion, 6-methylthio-pyrimidine 2, 6-(benzoylmethyl)thio-pyrimidine 13 and 2-[(5-cyano-4-methyl-2-phenylpyrimidin-6-yl)thio]-3-dimethylamino-1-phenylprop-2-en-1-one 17 have been shown to be a useful building block for the synthesis of some new N-cycloalkanes, morpholine, piperazines, pyridines, pyrazole, pyrimidine, benzimidazolo[1,2-a]pyrimidine, 1,2,3,4-tetrazolo[1,5-a]pyrimidine, azopyrazolo[1,5-a]pyrimidine, and pyrimido[4′,5′ : 3,4]pyrazolo[1,5-a]pyrimidine, respectively. The structure of all newly synthesized compounds was established from their spectral data, elemental analysis, and the X-ray crystal analysis.

Acknowledgments

The authors are grateful to the highly valued instrument cent of National Taiwan Normal University for measuring the data of spectroscopy. They also want to thank National Science Council of Taiwan (NSC 97–2113-M-253–001) for their financial support.

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