Pyrimidinethione as a building block in heterocyclic synthesis: synthesis of pyrano[2,3-d]pyrimidine, chromeno[2,3-d]pyrimidine, pyrido[3′,2′:5,6]pyrano[2,3-b]pyridine, and pyrimido[5′,4′:5,6]pyrano[2,3-d]pyrimidine derivatives

Mohamed Ahmed Mahmoud Abdel Reheim; Ibrahim Saad Abdel Hafiz; Mohamed Ahmed Elian

doi:10.1515/hc-2016-0039

Article Open Access

Pyrimidinethione as a building block in heterocyclic synthesis: synthesis of pyrano[2,3-d]pyrimidine, chromeno[2,3-d]pyrimidine, pyrido[3′,2′:5,6]pyrano[2,3-b]pyridine, and pyrimido[5′,4′:5,6]pyrano[2,3-d]pyrimidine derivatives

Mohamed Ahmed Mahmoud Abdel Reheim , Ibrahim Saad Abdel Hafiz and Mohamed Ahmed Elian

Published/Copyright: November 5, 2016

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From the journal Heterocyclic Communications Volume 22 Issue 6

Abstract

New heterocyclic compounds with expected biological activity have been prepared by reactions of 6-phenyl-2-thioxo-2,3-dihydropyrimidine-4(5H)-one (4) and 7- amino-5-(4-chlorophenyl)-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (8b) in the presence of an electrophilic or a nucleophilic reagent.

Keywords: pyranopyridine; pyranopyrimidine; 4H-pyrans; thioxopyrimidine

Introduction

Pyrimidinethiones have been found to possess antimicrobial [1], [2], antitubercular [3], antitumor [4], and hypoglycemic activity [5]. However, 4H-pyrans are spasmolytic, diuretic, anticoagulant, anticancer, and antianaphylactic agents [6], [7], [8], [9]. In addition, 4H-pyrans are useful intermediates for synthesis of fused pyranopyridines [10] and pyranopyrimidines [11]. Also, various pyranopyrimidines exhibit antimicrobial [12], antibacterial [13], antigenotoxic [14], antifungal [15], [16], [17], antithrombotic [18], analgesic, anti-inflammatory, and antiphologistic activity [19], [20]. In this paper we report the synthesis of new pyranopyrimidinethiones and chromenopyrimidinethiones.

Results and discussion

The reaction of ethyl benzoylacetate (1) with thiourea yielded a mixture of pyrimidinethione 4 as a major product and its tautomer 5 as a minor product [21], apparently through intermediates 2 and 3 (Scheme 1). Products 4 and 5 were isolated by silica gel chromatography but the mixture was used for the transformations described below. The mixture is referred to as compound 4.

Scheme 1

The active methylene group in compound 4 was exploited to synthesize novel heterocyclic compounds by reactions with electrophilic reagents. Thus, the pyrano[2,3-d]pyrimidine-6-carbonitriles 8a–e were synthesized in an excellent yield upon treatment of 4 with arylidenemalononitriles 6a–e in the presence of a catalytic amount of piperidine. The structures of compounds 8a–e were established based on analytical and spectral data. Products 8a–e are apparently formed via a Michael type addition of the active methylene group in pyrimidinethione 4 to the activated double bond in arylidenemalononitriles 6a–e followed by intramolecular cyclization of the intermediate adducts 7 [21], [22], [23] (Scheme 2). The alternative products 9 were not found. In a similar manner, the reaction of 4 with α, β-unsaturated ketones 10a–c in the presence of a catalytic amount of piperidine may result in the formation of the intermediate adducts 11, which are precursors to the final pyranopyrimidinethiones 12a–c [24].

Scheme 2

A mixture of formaldehyde and malononitrile was allowed to react with compound 4 in refluxing ethanol in the presence of a catalytic amount of piperidine to give 14 [25], [26]. It can be suggested that compound 14 is formed by the addition of the active methylene group in 4 to the π-deficient center in an intermediate alkylidenenitrile followed by cyclization of the resultant intermediate adducts 13 (Scheme 3). Pyranopyrimidines 16a,b were synthesized by cyclocondensation of compound 4 with ethoxymethylenemalononitrile and ethyl 2-cyano-3-ethoxyacrylate, respectively, in refluxing ethanol in the presence of a catalytic amount of piperidine. Adducts 15 are the suggested intermediate products (Scheme 3). The given structures of 16a,b are fully consistent with elemental analysis and spectral data. In a similar manner, cyclization of 2-(benzylidene)cyclohexanones with substrate 4 in ethanol at reflux in the presence of piperidine produced the corresponding chromenopyrimidinethiones 18a–d [27]. Again, the formation of 18a–d can be understood in terms of the Michael type addition of the active methylene group in the substrate 4 to the activated double bond in the unsaturated cyclohexanone followed by cyclization of the resultant intermediate adducts 17a–d.

Scheme 3

The utility of the pyranopyrimidines 8 in the synthesis of tricyclic fused heterocyclic compounds is illustrated in Schemes 4 and 5 by transformations of the selected compound 8b. First, compound 8b was allowed to react with chloroacetyl chloride in refluxing dioxane for 3 h to afford 2-chloroacetimide derivative 19. A subsequent melting of compound 19 in the presence of ammonium acetate [28], [29] furnished the fused tricyclic product 22. It can be suggested that the intermediate product 20 undergoes cyclization to 21, which is transformed into the final product 22 by Dimroth rearrangement. However, the reaction of 8b with chloroacetyl chloride in dioxane under reflux for 24 h gave the pyranopyrimidine 22 directly (Scheme 4).

Scheme 4

Scheme 5

Compound 8b was also allowed to react with benzylidenemalononitrile 6a in ethanol in the presence of a catalytic amount of piperidine under reflux to give the pyrido[3′,2′:5,6]pyrano[2,3-d]pyrimidine-7-carbonitrile 23 (Scheme 5). The formation of compound 23 is believed to involve an initial Michael addition of the amino function group in compound 8b to the double bond of benzylidenemalononitrile followed by intramolecular cyclization of the resultant adduct. The infrared (IR), ¹H-nuclear magnetic resonance (¹H-NMR) and mass spectra of compound 23 fully support the proposed structure [26]. However, condensation of 8b with dimethylformamide-dimethylacetal (DMF-DMA) yielded substituted formamidine 24. Treatment of 24 with ammonium acetate in acetic acid gave the tricyclic fused compound 25. The same product 25 was obtained directly from 8b by treatment with formamide. The structure of compound 25 was established by spectral analysis [30], [31], [32] (Scheme 5).

Conclusion

Compounds 4 and 8b were used as starting materials for the efficient synthesis of new heterocyclic compounds.

Experimental

Melting points were determined using a Büchi apparatus and are uncorrected. IR spectra were recorded in KBr pellets on a Bruker-Vector 22 instrument. ¹H NMR spectra (300 MHz) and ¹³C NMR spectra (75 MHz) were recorded on a Varian Gemini spectrometer with tetramethylsilane (TMS) as the internal reference. Electron impact (EI)-mass spectra were recorded on an HP D5988 A instrument. Elemental analyses were performed at the Microanalytical Centre at the Faculty of Science, Cairo University, Egypt.

General procedure for the preparation of compounds 4 and 5

A mixture of thiourea (0.76 g, 0.01 mol) and ethyl benzoylacetate (1.92 g, 0.01 mol) was stirred without solvent for 24 h at room temperature. The progress of the reaction was monitored by thin-layer chromatography (TLC). The solid mixture of 4 and 5 was filtered off, washed with diethyl ether, and separated by preparative TLC on silica gel 60 F-254 (Merk) eluting with toluene/acetone (10:4 v/v). Individual components were crystallized from ethanol. A mixture of 4 and 5 was used for the transformations described below.

6-Phenyl-2-thioxo-2,3-dihydropyrimidine-4(5H)-one (4)

White crystals; yield 83%; mp 245–247°C; IR: 3207 (NH), 3076 (CH-arom), 1669 (C=O) cm⁻¹; ¹H NMR (DMSO-d₆): δ 4.17 (s, 2H, CH₂), 7.02–7.57 (m, 6H, aromatic, and NH); MS: m/z 205 (M⁺+1). Anal. Calcd for C₁₀H₈N₂OS (204): C, 58.80; H, 3.95; N, 13.72; S, 15.70. Found: C, 58.82; H, 3.97; N, 13.73; S, 15.69.

6-Hydroxy-4-phenylpyrimidine-2(1H)-thione (5)

Yellow crystals; yield 5%; mp 240–242°C; IR: 3380 (OH), 3275 (NH) cm⁻¹; ¹H NMR (DMSO-d₆): δ 6.07 (s, 1H, CH), 7.48–7.70 (m, 6H, aromatic, and NH), 12.49 (s, 1H, OH); ¹³C NMR (DMSO-d₆): δ 179.3, 163.4, 154.6, 133.1, 131.02, 129.1, 129.1, 128.7, 128.7, 59.01; MS: m/z 205 (M⁺+1). Anal. Calcd for C₁₀H₈N₂OS (204): C, 58.80; H, 3.95; N, 13.72; S, 15.70. Found: C, 58.81; H, 3.96; N, 13.74; S, 15.69.

General procedure for the preparation of pyranopyrimidines 8a–e

A mixture of compound 4 (2.04 g; 0.01 mol) and arylidenemalononitrile 6a–e (0.01 mol) in ethanol (50 mL) containing a catalytic amount of piperidine (0.25 mL) was heated under reflux for 12 h. The mixture was cooled, poured into crushed ice, and acidified with HCl. The separated solid of 8a–e was filtered off, washed with water, and crystallized from ethanol.

7-Amino-4,5-diphenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (8a)

White crystals; yield 82%; mp 108–110°C; IR: 3329, 3203 (NH₂), 3050 (CH-arom), 2934 (CH-aliph), 2185 (CN) cm⁻¹; ¹H NMR (DMSO-d₆): δ 4.97 (s, 1H, 4H-pyrane), 6.13 (s, 2H, NH₂), 7.05–7.39 (m, 5H, aromatic), 7.42–7.79 (m, 5H, aromatic), 9.73 (s, 1H, NH); ¹³C NMR (DMSO-d₆): δ 179.2, 162.9, 162.01, 159.1, 144.08, 133.2, 131.01, 129.1, 129.1, 128.6, 128.6, 128.5, 128.5, 127.6, 127.6, 125.6, 119.09, 75.01, 58.1, 34.7; MS: m/z 359 (M⁺+1). Anal. Calcd for C₂₀H₁₄N₄OS (358): C, 67.02; H, 3.94; N, 15.63; S, 8.95. Found: C, 67.02; H, 3.95; N, 15.65, S, 8.93.

7-Amino-5-(4-chlorophenyl)-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (8b)

Yellow crystals; yield 84%; mp 186–188°C; IR: 3471, 3332 (NH₂), 3226 (NH), 2924 (CH), 2218 (CN) cm⁻¹; ¹H NMR (DMSO-d6): δ 5.02 (s, 1H, 4H-pyrane), 6.15 (s, 2H, NH₂), 7.00–7.29 (m, 4H, aromatic), 7.26–7.84 (m, 6H, aromatic, and NH); MS: m/z 393 (M⁺+1). Anal. Calcd for C₂₀H₁₃ClN₄OS (392): C, 61.14; H, 3.34; N, 14.26; Cl, 9.02; S, 8.16. Found: C, 61.15; H, 3.36; N, 14.27; Cl, 9. 01; S, 8.15.

7-Amino-5-(2-nitrophenyl)-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (8c)

Pale yellow crystals; yield 78%; mp 150–152°C; IR: 3336, 3200 (NH₂), 2936 (CH-aliph), 2191 (CN) cm⁻¹; ¹H NMR (CDCl₃): δ 4.38 (s, 1H, 4H-pyrane), 6.62 (s, 2H, NH₂), 6.95–7.49 (m, 4H, aromatic), 7.58–8.54 (m, 5H, aromatic), 9.28 (s, 1H, NH); MS: m/z 403 (M⁺). Anal. Calcd for C₂₀H₁₃N₅O₃S (403): C, 59.55; H, 3.25; N, 17.36; S, 7.95. Found: C, 59.56; H, 3.27; N, 17.37; S, 7.94.

7-Amino-5-(4-methoxyphenyl)-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (8d)

Green crystals; yield 70%; mp 180–182°C; IR: 3401, 3214 (NH₂), 2933 (CH-aliph), 2197 (CN) cm⁻¹; ¹H NMR (DMSO-d₆): δ 3.71 (s, 3H, OCH₃), 3.84 (s, 1H, 4H-pyrane), 7.061–7.088 (d, 2H, aromatic, J=8.1 Hz), 7.437–7.464 (d, 2H, aromatic, J=8.1 Hz), 7.30–7.85 (m, 8H, aromatic, NH, and NH₂); MS: m/z 388 (M⁺). Anal. Calcd for C₂₁H₁₆N₄O₂S (388): C, 64.93; H, 4.15; N, 14.42; S, 8.25. Found: C, 64.94; H, 4.16; N, 14.44; S, 8.23.

7-Amino-5-methyl-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (8e)

Pale green crystals; yield 78%; mp 170–172°C; IR: 3349, 3228 (NH₂), 2932 (CH), 2193 (CN) cm⁻¹; ¹H NMR (DMSO-d₆): δ 2.27 (s, 3H, CH₃), 4.09 (s, 1H, 4H-pyrane), 6.22 (s, 2H, NH₂), 6.39–8.04 (m, 6H, aromatic, and NH); MS: m/z 296 (M⁺). Anal. Calcd for C₁₅H₁₂N₄OS (296): C, 60.79; H, 4.08; N, 18.91; S, 10.82. Found: C, 60.80; H, 4.09; N, 18.93; S, 10.81.

General procedure for the preparation of pyranopyrimidinethiones 12a–c

A mixture of compound 4 (2.04 g; 0.01 mol) and chalcone 10a–c (0.01 mol) in ethanol (30 mL) containing a catalytic amount of piperidine (0.25 mL) was heated under reflux for 24 h. After cooling, the mixture was poured into crushed ice, and then acidified with HCl. The separated solid of 12a–c was filtered off, washed with water, and crystallized from ethanol.

4,5,7-Triphenyl-1H-pyrano[2,3-d]pyrimidine-2(5H)-thione (12a)

Pale yellow crystals; yield 88%; mp 100–102°C; IR: 3447 (NH), 2930 (CH) cm⁻¹; ¹H NMR (DMSO-d₆): δ 5.12 (d, 1H, CH, J=7.8 Hz), 5.39 (d, 1H, 4H-pyrane, J=5.1 Hz), 6.78–7.51 (m, 5H, aromatic), 7.52–7.73 (m, 5H, aromatic), 7.92–8.53 (m, 5H, aromatic), 9.88 (s, 1H, NH); MS: m/z 394 (M⁺). Anal. Calcd for C₂₅H₁₈N₂OS (394): C, 76.12; H, 4.60; N, 7.10; S, 8.13. Found: C, 76.13; H, 4.62; N, 7.11; S, 8.11.

5-(4-Chlorophenyl)-4,7-diphenyl-1H-pyrano[2,3-d]pyrimidine-2(5H)-thione (12b)

Pale yellow crystals; yield 82%; mp 104–106°C; IR: 3444 (NH), 3063 (CH), 2922 (CH) cm⁻¹; ¹H NMR (DMSO-d₆): δ 5.14 (d, 1H, CH, J=7.8 Hz), 5.39 (d, 1H, 4H-pyrane, J=7.8 Hz), 7.03–7.75 (m, 4H, aromatic), 7.85–8.16 (m, 5H, aromatic), 8.23–8.43 (m, 5H, aromatic), 10.00 (s, 1H, NH); MS: m/z 428 (M⁺). Anal. Calcd for C₂₅H₁₇ClN₂OS (428): C, 70.00; H, 3.99; N, 6.53; Cl, 8.27; S, 7.48. Found: C, 69.99; H, 3.97; N, 6.52; Cl, 8.26; S, 7.47.

5-(4-Methoxyphenyl)-4,7-diphenyl-1H-pyrano[2,3-d]pyrimidine-2(5H)-thione (12c)

Pale yellow crystals; yield 72%; mp 98–100°C; IR: 3272 (NH), 3050 (CH) cm⁻¹; ¹H NMR (DMSO-d₆): δ 3.84 (s, 3H, OCH₃), 5.33 (d, 1H, CH, J=4.8 Hz), 5.38 (d, 1H, 4H-pyrane, J=4.8 Hz), 6.97–7.04 (m, 4H, aromatic), 7.21–7.36 (m, 5H, aromatic), 7.64–8.70 (m, 5H, aromatic), 9.65 (s, 1H, NH); ¹³C NMR (DMSO-d₆): δ 179.3, 162.9, 162.01, 157.5, 140.3, 136.1, 133.08, 131.01, 130.2, 130.02, 130.01, 129.2, 129.1, 128.7, 128.7, 128.5, 128.5, 127.7, 125.09, 125.09, 114.3, 114.1, 91.4, 75.02, 55.8, 37.3; MS: m/z 425 (M⁺+1). Anal. Calcd for C₂₆H₂₀N₂O₂S (424): C, 73.56; H, 4.75; N, 6.60; S, 7.55. Found: C, 73.57; H, 4.76; N, 6.61; S, 7.53.

7-Amino-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (14)

A mixture of dihydropyrimidinone derivative 4 (0.01 mol) and formaldehyde/malononitrile (0.01 mol) in ethanol (50 mL) containing a catalytic amount of piperidine (0.25 mL) was heated under reflux for 24 h. After cooling, the mixture was poured into crushed ice then acidified with HCl. The resultant solid product 14 was filtered off, washed with water, and crystallized from ethanol: Brown crystals; yield 73%; mp 258–260°C; IR: 3330, 3180 (NH₂), 2926 (CH), 2203 (CN) cm⁻¹; ¹H NMR (DMSO-d₆): δ 4.12 (s, 2H, CH₂), 6.01 (s, 2H, NH₂), 7.21–7.91 (m, 5H, aromatic), 12.00 (hump, 1H, NH); MS: m/z 283 (M⁺+1). Anal. Calcd for C₁₄H₁₀N₄OS (282): C, 59.56; H, 3.57; N, 19.85; S, 11.36. Found: C, 59.55; H, 3.55; N, 19.84; S, 11.34.

General procedure for the preparation of carbonitriles 16a,b

A mixture of compound 4 (0.01 mol), 2-(ethoxymethylene)malononitrile (0.01 mol) or ethyl 2-cyano-3-ethoxyacrylate (0.01 mol) in ethanol (50 mL) containing a catalytic amount of piperidine (0.25 mL) was heated under reflux for 24 h. The mixture was cooled, poured into crushed ice, and acidified with HCl. The resultant solid of 16a,b was filtered off, washed with water, and crystallized from ethanol.

7-Imino-4-phenyl-2-thioxo-2,7-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (16a)

Brown crystals; yield 78%; mp 288–290°C; IR: 3420, 3339 (2NH), 2924 (CH), 2210 (CN) cm⁻¹; ¹H NMR (DMSO-d₆): δ 7.25–8.20 (m, 7H), 13.80 (s, 1H, NH); MS: m/z 280 (M⁺). Anal. Calcd for C₁₄H₈N₄OS (280): C, 59.99; H, 2.88; N, 19.99; S, 11.44. Found: C, 60.00; H, 2.89; N, 20.01; S, 11.42.

7-Oxo-4-phenyl-2-thioxo-2,7-dihydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (16b)

Yellow crystals; yield 83%; mp 108–110°C; IR: 3333 (NH), 2932 (CH), 2214 (CN), 1689 (C=O) cm⁻¹; ¹H NMR (DMSO-d₆): δ 7.26–8.18 (m, 6H), 13.80 (s, 1H, NH); MS: m/z 281 (M⁺). Anal. Calcd for C₁₄H₇N₃O₂S (281): C, 59.78; H, 2.51; N, 14.94; S, 11.40. Found: C, 59.79; H, 2.53; N, 14.95; S, 11.39.

General procedure for the preparation of chromenopyrimidinethiones 18a–d

A mixture of compound 4 (2.04 g; 0.01 mol) and 2-(benzylidene)cyclohexanone (0.01 mol) in ethanol (30 mL) containing a catalytic amount of piperidine (0.25 mL) was heated under reflux for 24 h. After cooling, the mixture was poured into crushed ice and acidified with HCl. The separated solid of 18a–d was filtered, washed with water, and crystallized from ethanol.

4,5-Diphenyl-6,7,8,9-tetrahydro-1H-chromeno[2,3-d]pyrimidine-2(5H)-thione (18a)

Pale yellow crystals; yield 84%; mp 105–107°C; IR: 3420 (NH), 3056 (CH), 2932 (CH) cm⁻¹; ¹H NMR (CDCl₃): δ 1.22–1.40 (m, 4H, 2CH₂), 1.43–3.33 (m, 4H, 2CH₂), 3.71 (s, 1H, 4H-pyrane), 6.95–7.22 (m, 5H, aromatic), 7.32–7.56 (m, 5H, aromatic), 7.81 (s, 1H, NH); ¹³C NMR (CDCl₃): δ 179.3, 162.9, 162.07, 144.08, 142.3, 133.1, 131.07, 129.1, 129.1, 128.7, 128.7, 128.5, 128.5, 127.6, 127.6, 125.7, 110.9, 75.0, 29.6, 26.1, 23.8, 23.4, 22.6; MS: m/z 372 (M⁺). Anal. Calcd for C₂₃H₂₀N₂OS (372): C, 74.16; H, 5.41; N, 7.52; S, 8.61. Found: C, 74.17; H, 5.42; N, 7.50; S, 8.60.

5-(4-Chlorophenyl)-4-phenyl-6,7,8,9-tetrahydro-1H-chromeno[2,3-d]pyrimidine-2(5H)-thione (18b)

Pale yellow crystals; yield 86%; mp 111–113°C; IR: 3434 (NH), 3050 (CH), 2923 (CH) cm⁻¹; ¹H NMR (CDCl₃): δ 0.75–1.97 (m, 4H, 2CH₂), 2.09–3.93 (m, 4H, 2CH₂), 4.37 (s, 1H, 4H-pyrane), 6.67–7.01 (m, 4H, aromatic), 7.26–8.01 (m, 5H, aromatic); 9.35 (s, 1H, NH); MS: m/z 407 (M⁺+1). Anal. Calcd for C₂₃H₁₉ClN₂OS (406): C, 67.89; H, 4.71; N, 6.88; Cl, 8.71; S, 7.88. Found: C, 67.90; H, 4.72; N, 6.90; Cl, 8.70; S, 7.87.

5-(4-Methoxyphenyl)-4-phenyl-6,7,8,9-tetrahydro-1H- chromeno[2,3-d]pyrimidine-2(5H)-thione (18c)

Yellow crystals; yield 81%; mp 140–142°C; IR: 3381 (NH), 2938 (CH) cm⁻¹; ¹H NMR (CDCl₃): δ 1.79–2.18 (m, 4H, 2CH₂), 2.92 (m, 4H, 2CH₂), 3.85 (s, 3H, OCH₃), 3.89 (s, 1H, 4H-pyrane), 6.94 (d, 2H, aromatic, J=8.4 Hz), 7.47 (d, 2H, aromatic, J=8.4 Hz), 7.26–7.78 (m, 6H, aromatic, and NH); MS: m/z 402 (M⁺). Anal. Calcd for C₂₄H₂₂N₂O₂S (402): C, 71.62; H, 5.51; N, 6.96; S, 7.97. Found: C, 71.61; H, 5.50; N, 6.94; S, 7.95.

5-(4-Hydroxyphenyl)-4-phenyl-6,7,8,9-tetrahydro-1H-chromeno [2,3-d]pyrimidine-2(5H)-thione (18d)

Pale yellow crystals; yield 80%; mp 102–104°C; IR: 3339 (NH), 3060 (CH), 2932 (CH) cm⁻¹; ¹H NMR (DMSO-d₆): δ 0.88–1.56 (m, 4H, 2CH₂), 1.90–2.40 (m, 4H, 2CH₂), 3.79 (s, 1H, 4H-pyrane), 6.65–7.12 (m, 4H, aromatic), 7.14–7.42 (m, 5H, aromatic), 8.25 (s, 1H, NH), 9.12 (s, 1H, OH); MS: m/z 388 (M⁺). Anal. Calcd for C₂₃H₂₀N₂O₂S (388): C, 71.11; H, 5.19; N, 7.21; S, 8.25. Found: C, 71.10; H, 5.18; N, 7.20; S, 8.24.

Synthesis of 2-chloro-N-(5-(4-chlorophenyl)-6-cyano-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-7-yl)acetamide (19)

A mixture of 8b (0.01 mol) and 2-chloroacetyl chloride (0.01 mol) in dioxane (30 mL) was heated under reflux for 3 h. The mixture was cooled and the separated solid of 19 was filtered, washed with cold ethanol, and crystallized from ethanol: Pale yellow crystals; yield 80%; mp 100–102°C; IR: 3330, 3212 (2NH), 3065 (CH), 2956 (CH), 2214 (CN), 1731 (CO) cm⁻¹; ¹H NMR (DMSO-d₆): δ 4.31 (s, 2H, CH₂), 5.23 (s, 1H, 4H-pyrane), 6.94–7.52 (m, 4H, aromatic), 7.54–8.29 (m, 5H, aromatic), 10.17 (s, 1H, NH), 11.76 (s, 1H, NH); ¹³C NMR (DMSO-d₆): δ 179.3, 162.9, 164.6, 162.01, 151.09, 142.4, 133.3, 131.2, 131.01, 130.3, 129.1, 128.9, 128.7, 119.1, 75.02, 60.2, 44.8, 34.5; MS: m/z 469 (M⁺). Anal. Calcd for C₂₂H₁₄Cl₂N₄O₂S (469): C, 56.30; H, 3.01; N, 11.94; Cl, 15.11; S, 6.83. Found: C, 56.29; H, 3.00; N, 11.93; Cl, 15.10; S, 6.82.

Synthesis of 8-(chloromethyl)-5-(4-chlorophenyl)-4-phenyl-2-thioxo-5,7-dihydro-1H-pyrano[2,3-d:6,5-d′]dipyrimidine-6(2H)-one (22)

Method A

A mixture of 8b (0.01 mol) and 2-chloroacetyl chloride (0.01 mol) in dioxane (50 mL) was heated under reflux for 24 h. After cooling, the separated solid of 22 was filtered, washed with cold ethanol, and crystallized from ethanol.

Method B

A mixture of 19 (0.01 mol) and ammonium acetate was fused for 6 h. After cooling and trituration with cold ethanol, the solid product 22 was filtered off, washed with water, and crystallized from ethanol.

Compound 22 was obtained in 71% yield (method A) and 70% yield (method B): Pale yellow crystals; yield; mp 320–322°C; IR: 3143 (NH), 3045 (CH), 2807 (CH), 1660 (CO) cm⁻¹; ¹H NMR (CDCl₃): δ 2.18 (s, 1H, NH), 3.50 (s, 2H, CH₂), 3.77 (s, 1H, 4H-pyrane), 7.17–7.27 (m, 4H, aromatic), 7.36–7.61 (m, 6H, aromatic, and NH); ¹³C NMR (CDCl₃): δ 179.3, 162.9, 164.03, 162.1, 162.02, 161.9, 142.5, 133.1, 131.2, 131.01, 130.3, 129.1, 128.9, 128.7, 100.7, 75.0, 49.5, 36.0; MS: m/z 469 (M⁺). Anal. Calcd for C₂₂H₁₄Cl₂N₄O₂S (469): C, 56.30; H, 3.01; N, 11.94; Cl, 15.11; S, 6.83. Found: C, 56.29; H, 3.00; N, 11.92; Cl, 15.10; S, 6.82.

Synthesis of 6-amino-5-(4-chlorophenyl)-4,8-diphenyl-2-thioxo-2,5-dihydro-1H-pyrido[3′,2′:5,6]pyrano [2,3-d]pyrimidine-7-carbonitrile (23)

A mixture of 8b (3.92 g; 0.01 mol) and 2-(benzylidene)malononitrile (6a, 0.01 mol) in ethanol (50 mL) containing a catalytic amount of piperidine (0.25 mL) was heated under reflux for 8 h. After cooling, the mixture was poured into crushed ice and acidified with HCl. The separated solid of 23 was filtered, washed with water, and crystallized from ethanol: Pale yellow crystals; yield 77%; mp 110–112°C; IR: 3331, 3203 (NH₂), 3087 (CH), 2933 (CH), 2190 (CN) cm⁻¹; ¹H NMR (CDCl₃): δ 4.06 (s, 1H, 4H-pyrane), 6.19 (s, 2H, NH₂), 7.31–7.50 (m, 4H, aromatic), 7.52–7.79 (m, 5H, aromatic), 7.80–7.96 (m, 5H, aromatic), 9.31 (s, 1H, NH); MS: m/z 520 (M⁺). Anal. Calcd for C₂₉H₁₈ClN₅OS (520): C, 66.98; H, 3.49; N, 13.47; Cl, 6.82; S, 6.17. Found: C, 66.97; H, 3.47; N, 13.46; Cl, 6.82; S, 6.17.

Synthesis of N′-(5-(4-chlorophenyl)-6-cyano-4-phenyl-2-thioxo-2,5-dihydro-1H-pyrano[2,3-d]pyrimidine-7-yl)-N,N-dimethylformimidamide (24)

A mixture of (8b, 0.01 mol) and DMF-DMA (0.01 mol) in xylene (30 mL) was heated under reflux for 6 h. After cooling, the separated solid of 24 was filtered, washed with cold ethanol, and crystallized from ethanol: Brown crystals; yield 81%; mp 210–212°C; IR: 3340 (NH), 2926 (CH), 2210 (CN) cm⁻¹; ¹H NMR (DMSO-d₆): δ 3.28 (s, 6H, 2CH₃), 4.27 (s, 1H, 4H-pyrane), 7.36–7.40 (m, 4H, aromatic), 7.42–7.61 (m, 7H, aromatic, N=CH, and NH); MS: m/z 447 (M⁺). Anal. Calcd for C₂₃H₁₈ClN₅OS (447): C, 61.67; H, 4.05; N, 15.63; Cl, 7.91; S, 7.16. Found: C, 61.68; H, 4.06; N, 15.64; Cl, 7.90; S, 7.14.

Synthesis of 6-amino-5-(4-chlorophenyl)-4-phenyl-1,5-dihydro-2H-pyrimido[5′,4′:5,6]pyrano[2,3-d]pyrimidine-2-thione (25)

Method A

A mixture of 8b (0.01 mol) and formamide (0.01 mol) in xylene (30 mL) was heated under reflux for 24 h, then cooled, and poured into crushed ice. The separated solid of 25 was filtered, washed with water, and crystallized from ethanol.

Method B

A mixture of 24 (0.01 mol), AcOH and AcONH₄ was heated under reflux for 12 h, then cooled, poured into crushed ice, and acidified with HCl. The separated solid of 25 was filtered, washed with water, and crystallized from ethanol: Yield 79% (method A) and 70% (method B); mp 150–152°C; IR: 3460, 3440 (NH₂), 3202 (NH), 2902 (CH) cm⁻¹; ¹H NMR (DMSO-d₆): δ 4.10 (s, 1H, 4H-pyrane), 6.04 (s, 2H, NH₂), 6.72 (s, 1H, pyrimidine), 6.99–7.31 (m, 4H, aromatic), 7.36–8.86 (m, 6H, aromatic, and NH); MS: m/z 421 (M⁺+2). Anal. Calcd for C₂₁H₁₄ClN₅OS (419): C, 60.07; H, 3.36; N, 16.68; Cl, 8.44; S, 7.64. Found: C, 60.08; H, 3.37; N, 16.70; Cl, 8.43; S, 7.63.

Acknowledgments

The authors are grateful to Prof. Dr. A. E. Khodair, Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt, for reviewing this manuscript.

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Received: 2016-3-13

Accepted: 2016-5-23

Published Online: 2016-11-5

Published in Print: 2016-12-1

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

https://doi.org/10.1515/hc-2016-0039

Keywords for this article

pyranopyridine; pyranopyrimidine; 4H-pyrans; thioxopyrimidine

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