Novel synthesis and reactions of pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinoline derivatives

Remon M. Zaki; Adel M. Kamal El Dean; Maisa I. Abd El Monem; Mohamed A. Seddik

doi:10.1515/hc-2015-0204

Article Open Access

Novel synthesis and reactions of pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinoline derivatives

Remon M. Zaki , Adel M. Kamal El Dean , Maisa I. Abd El Monem and Mohamed A. Seddik

Published/Copyright: February 29, 2016

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From the journal Heterocyclic Communications Volume 22 Issue 2

Abstract

Treatment of isoquinolinecarboxamide 4a with triethyl orthoformate, chloroacetyl chloride or carbon disulfide afforded the pyrimidinone 7, oxopyrimidinethione 12 and chloromethylpyrimidinone 18, respectively. These products were used as versatile starting materials for synthesis of other heterocyclic compounds. The heterocyclic hydrazide 6 was also obtained.

Keywords: pyrazolyl; tetrahydro isoquinoline; tetrahydrothieno isoquinoline

Introduction

Isoquinoline and its saturated derivatives have acquired considerable significance in heterocyclic chemistry [1, 2]. The tetrahydroisoquinoline ring system [3] is a basic structural component of many biologically active natural products [4, 5]. Tetrahydroisoquinoline is a common core structure of many alkaloids that show antitumor [6] and antimicrobial [7] activities. Thienopyrimidines have long been the subject of chemical and biological research. Some thienopyrimidines display analgesic [8], antipyretic [9, 10], anti-inflammatory [11–14] and anti-allergenic effects [15–17].

In the light of biological importance of tetrahydroisoquinolines and thienopyrimidines, we have synthesized many heterocyclic compounds containing morpholinyl-substituted tetrahydrothieno[2,3-c]isoquinoline fused to other rings [18–23]. In the present work we synthesized 1-(3,5-dimethylpyrazol-1-yl)-4-cyano-5,6,7,8-tetrahydroisoquinoline-3(2H)-thione (2) by the reaction of 1-hydrazino-4-cyano-5,6,7,8-tetrahydroisoquinoline-3(2H)-thione (1) with acetylacetone [20]. Compound 2 proved to be a versatile starting material for synthesis of other heterocyclic compounds.

Results and discussion

Alkylation of 2 with chloroacetamide and ethyl chloroacetate yielded sulfanyl acetamide 3a and ethyl sulfanyl acetate 3b, respectively. These compounds underwent Thorpe-Ziegler cyclization upon refluxing in ethanolic sodium ethoxide solution to give the respective substituted carboxamide 4a and substituted ethyl carboxylate 4b. The structures of 4a and 4b were elucidated by using elemental analysis and spectral data. Furthermore, hydrazinolysis of the ester group in compound 3b yielded the corresponding carbohydrazide compound 6 without isolation of the sulfanyl carbohydrazide intermediate product 5. On the other hand, the attempted reaction of amino ester compound 4b with hydrazine hydrate under the same conditions did not afford the expected amino carbohydrazide compound 6 and the starting material (amino ester) 4b was isolated (Scheme 1).

Scheme 1

Reaction of amino carboxamide compound 4a with triethyl orthoformate yielded the pyrimidinone 7 (Scheme 2). Treatment of compound 7 with phosphorus oxychloride afforded the chloropyrimidine 8. The latter compound was used in the synthesis of other pyrimidothienoisoquinolines 9–11. Nucleophilic substitution reaction of the chlorine atom in the chloropyrimidine derivative 8 by heating under reflux with aniline furnished the anilino-substituted pyrimidine 9. Thionation of the chloropyrimidine 8 with thiourea in ethanol yielded the pyrimidinethione 10 which was alkylated by treatment with α-halogenated carbonyl compounds in refluxing ethanol in the presence of sodium acetate to yield the S–alkylated products 11a–d.

Scheme 2

Reaction of amino carboxamide compound 4a with carbon disulfide in pyridine afforded the oxopyrimidinethione 12 which served as a versatile precursor to thiazolopyrimidothienoisoquinoline derivatives 13–16 by the reaction with α-halogenated alkylating agents. It is interesting to note that treatment of 12 with chloroacetone gave the sulfanyl derivative 16 instead of the expected product 17 (Scheme 3).

Scheme 3

Treatment of 4a with chloroacetyl chloride in dioxane afforded product 19, apparently through intermediary of 18. Compound 19 underwent nucleophilic displacement reaction upon treatment with aniline to afford the aniline derivative 20 (Scheme 4).

Scheme 4

Conclusion

The newly synthesized pyrazolyltetrahydrothieno[2,3-c]isoquinolines were used as a versatile precursors for synthesis of other heterocyclic compounds.

Experimental

1-(3,5-Dimethylpyrazol-1-yl)-3-sulfanyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (2)

A mixture of thione 1 (1 g, 4.5 mmol) and acetylacetone (20 mmol) was gently heated under reflux for 1 h and then treated with absolute ethanol (20 mL). The mixture was heated under reflux for an additional 2 h and then cooled. The resultant solid product was filtered, dried and crystallized from dioxane; yield 1.13 g (88%) of yellow crystals; mp >300^oC; IR (KBr): ν_max 3446 (NH), 2950, 2820 (CH, aliphatic), 2226 (CN), 1568 (C=N), 1279 cm^-1 (C=S); ¹H-NMR (90 MHz, CF₃CO₂D): δ 2.05 (m, 4H, 2CH₂, cyclohexene), 2.50, 2.70 (2s, 6H, 2CH₃ pyrazole), 2.60 (m, 2H, CH₂, cyclohexene), 3.20 (m, 2H, CH₂ cyclohexene), 6.60 (s, 1H, CH, pyrazole); EI-MS: m/z 284.02. Anal. Calcd for C₁₅H₁₆N₄S: C, 63.35; H, 5.67; N, 19.70; S, 11.27. Found: C, 63.50: H, 5.55; N, 19.83; S, 11.40.

Alkylation of 1-(3,5-dimethylpyrazol-1-yl)-3-sulfanyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (2)

A mixture of thione 2 (0.58 g, 2 mmol), an alkylating agent (2 mmol) and fused sodium acetate (0.75 g, 8.5 mmol) in ethanol (20 mL) was heated under reflux for 2 h. The solid product which precipitated upon cooling was filtered, washed with water, dried and crystallized.

2-(4-Cyano-1-(3,5-dimethylpyrazol-1-yl)-5,6,7.8-tetrahydroisoquinolin-3-ylsulfanyl) acetamide (3a)

This compound was obtained by the reaction of 2 with chloroacetamide; yield 0.52 g (79%); mp 222–224^oC; IR (KBr): ν_max 3469, 3380 (NH₂), 2940, 2850 (CH, aliphatic), 2220 (CN), 1674 (C=O), 1620 cm^-1 (C=N); ¹H-NMR (90 MHz, CDCl₃): δ 1.75–1.78 (m, 4H, 2CH₂, cyclohexene), 2.20 and 2.25 (2s, 6H, 2CH₃, pyrazole), 2.65–2.70 (m, 2H, CH₂, cyclohexene), 2.97 (m, 2H, CH₂, cyclohexene), 3.80 (s, 2H, CH₂CO), 6.10 (s, 1H, CH, pyrazole), 6.70 (s, 2H, NH₂). Anal. Calcd for C₁₆H₁₉N₅OS: C, 58.70; H, 5.23; N, 21.39; S, 9.79. Found: C, 58.88; H, 5.34; N, 21.25; S, 9.60.

Ethyl (4-cyano-1-(3,5-dimethyl pyrazol-1-yl)-5,6,7,8-tetrahydroisoquinolin-3-ylsulfanyl) acetate (3b)

This compound was obtained by the reaction of 2 with ethyl chloroacetate; yield 0.56 g (75%) of white crystals; mp 146–148^oC; IR (KBr): ν_max 2950, 2838 (CH, aliphatic), 2222 (CN), 1751 (C=O, ester), 1565 cm^-1 (C=N); ¹H-NMR (90 MHz, CDCl₃): δ 1.15 (t, 3H, J = 7 Hz, CH₃), 1.80–1.85 (m, 4H, 2CH₂, cyclohexene), 2.35–2.40 (2s, 6H, 2CH₃), 2.77–2.80 (m, 2H, CH₂, cyclohexene), 3.00–3.10 (m, 2H, CH₂, cyclohexene), 4.00 (s, 2H, CH₂CO), 4.30 (q, 2H, CH₂, J = 7 Hz, ester), 6.20 (s, 1H, CH, pyrazole). Anal. Calcd for C₁₉H₂₂N₄O₂S: C, 61.60; H, 5.99; N, 15.12; S, 8.64. Found: C, 61.74; H, 5.76; N, 15.44; S, 8.55.

Cyclization of 3-substituted sulfanyl-1-(3,5-dimethyl pyrazol-1-yl)-5,6,7,8-tetrahydroiso-quinoline-4-carbonitriles 3a,b

A solution of the substituted sulfanyl tetrahydroisoquioline carbonitrile 3a,b (0.01 mol) in absolute ethanol (20 mL) containing a few drops of sodium ethoxide solution [prepared from 0.5 g of finely divided sodium metal and absolute ethanol (20 mL)] was heated under reflux for 20 min. The precipitated solid 4a,b which formed on cooling was filtered off, dried and crystallized from a proper solvent.

1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxamide (4a)

The product was crystallized from ethanol/dioxane mixture (1:1); pale yellow crystals; yield 0.46 g (89); mp 268-270^oC; IR (KBr): ν_max 3463, 3389, 3300, 3126 (2NH₂), 2939, 2850 (CH, aliphatic), 1659 cm^-1 (C=O, amide); ¹H-NMR (400 MHz, CDCl₃): δ 1.79–1.95 (m, 4H, 2CH₂, cyclohexene), 2.24 and 2.32 (2s, 6H, 2CH₃, pyrazole), 2.66 (m, 2H, CH₂, cyclohexene), 3.38–3.41 (m, 2H, CH₂, cyclohexene), 5.38 (s, 1H, CH, pyrazole), 6.01 (s, 2H, NH₂, thiophene), 6.51 (s, 2H, NH₂, amide). Anal. Calcd for C₁₇H₁₉N₅OS (341.44): C, 59.80; H, 5.61; N, 20.51; S, 9.39. Found: C, 59.94; H, 5.47; N, 20.38; S, 9.51.

Ethyl 1-amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-4-carboxylate (4b)

The product was crystallized from ethanol; pale yellow crystals; yield 0.44 g (80%); mp 186–188^oC; IR (KBr): ν_max 3401, 3200 (NH₂), 2935, 2850 (CH, aliphatic), 1674 (C=O, ester), 1614 cm^-1 (C=N); ¹H-NMR (90 MHz, CDCl₃): δ 1.55 (t, 3H, J = 7 Hz, CH₃, ester), 1.96 (m, 4H, 2CH₂, cyclohexene), 2.40 and 2.45 (2s, 6H, CH₃, pyrazole), 2.70–2.78 (m, 2H, CH₂, cyclohexene), 3.42 (m, 2H, CH₂, cyclohexene), 4.60 (q, 2H, J = 7 Hz, CH₂, ester), 6.20 (s, 1H, CH, pyrazole), 6.4 (s, 2H, NH₂). Anal. Calcd for C₁₉H₂₂N₄O₂S (370.48): C, 61.60; H, 5.99; N, 15.12; S, 8.65. Found: C, 61.51; H, 5.83; N, 15.26; S, 8.78.

1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-4-carbohydrazide (6)

A mixture of amino ester 3b (1 g, 2.7 mmol) and hydrazine hydrate (10 mL, 0.3 mol) was heated under reflux for 15 min, then treated with ethanol (10 mL) and heated for an additional 2 h. The precipitated solid was filtered off, dried and crystallized from ethanol as yellow crystals; yield 0.73 g (80%); mp 212–214^oC; IR (KBr): ν_max 3421, 3317, 3249 (NH₂, NH), 2931, 2856 (CH aliphatic), 1658 (CO), 1599 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.67–1.99 (m, 4H, 2CH₂, cyclohexene), 2.13 and 2.16 (2s, 6H, 2CH₃, pyrazole), 2.31 (m, 4H, 2CH₂, cyclohexene), 3.55 (s, 2H, NH₂, carbohydrazide), 5.78 (s, 2H, NH₂, thiophene), 6.40 (s, 1H, CH, pyrazole), 11.90 (s, 1H, NH). Anal. Calcd for C₁₈H₂₀N₄OS (340.45): C, 63.50; H, 5.92; N, 16.46; S, 9.40. Found: C, 63.62; H, 5.83; N, 16.59; S, 9.26.

5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquin-olin-8(9H)-one (7)

A mixture of compound 4a (2 mmol), triethyl orthoformate (2 mL) and a few drops of glacial acetic acid was heated under reflux for 30 min. The solid precipitate was filtered off, dried and crystallized from ethanol as pale yellow crystals; yield 0.52 g (72%); mp >360^oC; IR (KBr): ν_max 3450 (NH), 2929, 2850 (CH aliphatic), 1651 cm^-1 (C=O pyrimide); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.76–1.88 (m, 4H, 2CH₂, cyclohexene), 2.20, 2.21 (2s, 6H, 2CH₃, pyrazole), 2.51–2.61 (m, 4H, 2CH₂, cyclohexene), 6.10 (s, 1H, CH, pyrazole), 8.38 (s, 1H, CH, pyrimidine), 12.90 (s, 1H, NH). Anal. Calcd for C₁₈H₁₉N₅OS (351.43): C, 61.52; H, 4.88; N, 19.93; S, 9.12. Found: C, 61.63; H, 4.75; N, 19.84; S, 9.24.

8-Chloro-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinoline (8)

A mixture of pyrimidinone 7 (0.75 g, 2.1 mmol) and phosphorus oxychloride (3 mL) was heated under reflux for 2 h, then cooled, poured in an ice-water and neutralized with diluted sodium carbonate solution. The precipitated solid was filtered off, dried and crystallized from ethanol as white crystals; yield 0.64 g, 80%; mp 260-262^oC; IR (KBr): ν_max 2944, 2931, 2867 (CH aliphatic), 1567 cm^-1 (C=N); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.76–1.88 (m, 4H, 2CH₂, cyclohexene), 2.20 and 2.21 (2s, 6H, 2CH₃, pyrazole), 2.51–2.61 (m, 4H, 2CH₂, cyclohexene), 6.10 (s, 1H, CH, pyrazole), 9.28 (s, 1H, CH, pyrimidine). Anal. Calcd for C₁₈H₁₈ClN₅S (369.88): C, 58.45; H, 4.36; Cl, 9.59; N, 18.93; S, 8.60. Found: C, 58.56; H, 4.23; Cl, 9.71; N, 18.80; S, 8.73.

5-(3,5-Dimethylpyrazol-1-yl)-8-anilino-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinoline (9)

A mixture of chloropyrimidine derivative 8 (0.25 g, 0.67 mmol) and aniline (2 mmol) was gently heated for 5 min and then treated with ethanol (10 mL). The mixture was heated under reflux for 2 h and the resultant solid precipitate was filtered off, dried and crystallized from ethanol as brown crystals; yield 0.64 g (75%); mp 224–226^oC; IR (KBr): ν_max 3420 (NH), 3040 (CH aromatic) 2927, 2867 (CH aliphatic), 1610 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.84–1.98 (m, 4H, 2CH₂, cyclohexene), 2.27 and 2.34 (2s, 6H, 2CH₃, pyrazole), 2.73 (m, 4H, 2CH₂, cyclohexene), 6.04 (s, 1H, CH, pyrazole), 7.43 (m, 5H, 5CH, aromatic), 7.67 (s, 1H, CH, pyrimidine), 8.89 (s, 1H, NH). Anal. Calcd for C₂₄H₂₂N₆S (426.55): C, 67.58; H, 5.20; N, 19.70; S, 7.52. Found: C, 67.69; H, 5.33; N, 19.56; S, 7.65.

5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]iso-quinolin-8(9H)-thione (10)

A mixture of chloropyrimidine derivative 6 (1 g, 2.7 mmol) and thiourea (1 g, 0.013 mol) in ethanol was heated under reflux for 4 h. The resultant solid precipitate was filtered off and crystallized from dioxane to afford yellow crystals; yield 0.74 g (75%); mp 290–292^oC; IR (KBr): ν 3420 (NH), 2934, 2860 (CH aliphatic), 1291 (C=S), 1574 cm^-1 (C=N); ¹H NMR (DMSO-d₆): δ = 1.74–1.80 (m, 4H, 2CH₂, cyclohexene), 2.20, 2.30 (2s, 6H, 2CH₃, pyrazole), 2.51–2.61 (m, 4H, 2CH₂, cyclohexene), 6.20 (s, 1H, CH, pyrazole), 8.50 (s, 1H, CH, pyrimidine), 12.70 (s, 1H, NH). Anal. Calcd for C₁₈H₁₇N₅S₂ (367.50): C, 58.83; H, 4.66; N, 19.06; S, 17.45. Found: C, 58.71; H, 4.78; N, 19.19; S, 17.34.

Alkylation of compound 10

A mixture of pyrimidinethione 10 (0.5 g, 1.3 mmol), an alkylating agent (2 mmol) and fused sodium acetate (0.75 g, 8.5 mmol) in ethanol (20 mL) was heated under reflux for 2 h. The solid product which formed on cooling was filtered off, washed with water, dried and crystallized from a proper solvent.

Ethyl (5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8-ylsulfanyl)acetate (11a)

This compound was obtained from 10 and ethyl chloroacetate as white crystals; yield 0.50 g, (82%); mp 122–124^oC; IR (KBr): ν_max 2980, 2850 (CH aliphatic), 1740 (C=O), 1620 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.32 (t, 3H, J = 7 Hz, CH₃, ester), 1.86–2.08 (m, 4H, 2CH₂, cyclohexene), 2.30 and 2.35 (2s, 6H, 2CH₃, pyrazole), 2.77 (m, 4H, 2CH₂, cyclohexene), 3.77 (s, 2H, CH₂CO), 4.27 (q, 2H, J = 7 Hz, CH₂, ester), 6.07 (s, 1H, CH, pyrazole), 9.09 (s, 1H, CH, pyrimidine). Anal. Calcd for C₂₂H₂₃N₅O₂S₂ (453.59): C, 58.26; H, 5.11; N, 15.44; S, 14.14. Found: C, 58.39; H, 5.25; N, 15.55; S, 14.03.

1-(5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8-yl sulfanyl) acetone (11b)

This compound was obtained from 10 and chloroacetone as white crystals; yield 0.45 g, (79%); mp 164–168^oC; IR (KBr): ν_max 2979, 2860 (CH aliphatic), 1716 (C=O), 1568 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.87–2.01 (m, 4H, 2CH₂, cyclohexene), 2.31, 2.36 and 2.43 (3s, 9H, 3CH₃), 2.78 (m, 2H, CH₂, cyclohexene), 3.76 (m, 2H, CH₂, cyclohexene), 4.28 (s, 2H, CH₂ CO), 6.08 (s, 1H, CH, pyrazole), 9.06 (s, 1H, CH, pyrimidine). Anal. Calcd for C₂₁H₂₁N₅OS₂ (423.56): C, 59.55; H, 5.00; N, 16.53; S, 15.14. Found: C, 59.41; H, 5.14; N, 16.41; S, 15.29.

2-(5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]iso-quinolin-8-ylsulfanyl)acetophenone (11c)

This compound was obtained from 10 and phenacyl bromide as white crystals; yield 0.39 g, (60%); mp 142–144^oC; IR (KBr): ν_max 3055 (CH aromatic), 2928, 2854 (CH aliphatic), 1694 (C=O unsaturated), 1567 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.86–2.02 (m, 4H, 2CH₂, cyclohexene), 2.31, 2.38 (2s, 6H, 2CH₃, pyrazole), 2.80 (m, 2H, CH₂, cyclohexene), 3.78 (m, 2H, CH₂, cyclohexene), 5.01 (s, 2H, CH₂ CO), 6.10 (s, 1H, CH, pyrazole), 7.53–8.14 (m, 5H, ArH), 9.03 (s, 1H, CH, pyrimidine). Anal. Calcd for C₂₆H₂₃N₅OS₂ (485.63): C, 64.31; H, 4.77; N, 14.42; S, 13.21. Found: C, 64.43; H, 4.53; N, 14.29; S, 13.35.

2-(5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8-ylsulfanyl)-N-(4-methoxyphenyl)acetamide (11d)

This compound was obtained from 10 and p-methylchloroacetanilide as white crystals; yield 0.52 g (75%); mp 222–224^oC; IR (KBr): ν_max 3243 (NH), 3040 (CH aromatic), 2992, 2943 (CH aliphatic), 1651 (C=O), 1594 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.88–2.02 (m, 4H, 2CH₂ cyclohexene), 2.32 (s, 3H, CH₃p-methylacetanilide), 2.34 and 2.36 (2s, 6H, 2CH₃, pyrazole), 2.79–2.82 (m, 2H, CH₂, cyclohexene), 3.77 (m, 2H, CH₂, cyclohexene), 4.16 (s, 2H, CH₂), 6.10 (s, 1H, CH of pyrazole), 7.11–7.41 (dd, 4H, ArH p-substituted), 9.20 (s, 1H, CH, pyrimidine), 9.40 (s, 1H, NH). Anal. Calcd for C₂₇H₂₆N₆OS₂ (514.68): C, 63.01; H, 5.09; N, 16.33; S, 12.46. Found: C, 63.12; H, 5.21; N, 16.47; S, 12.56.

5-(3,5-Dimethylpyrazol-1-yl)-8-oxo-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-10(11H)-thione (12)

A mixture of compound 4a (1 g, 2.9 mmol) and carbon disulfide (3.5 mL, 0.046 mmol) in pyridine (5 mL) was heated under reflux on water bath for 4 h. The resultant solid product was filtered, dried and crystallized from dioxane as brilliant yellow crystals; mp 310–312°C; yield 0.95g (85%); IR (KBr): ν 3371, 3130 (2NH), 2928, 2820 (CH aliphatic), 1666 (C=O), 1250 cm^-1 (C=S); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.70–1.82 (m, 4H, 2CH₂ cyclohexene), 2.20 and 2.25 (2s, 6H, 2CH₃ pyrazole), 2.58 (m, 4H, 2CH₂ cyclohexene), 6.15 (s, 1H, CH pyrazole), 8.50 (s, 1H, CH pyrimidine), 12.80 (s, 1H, NH). Anal. Calcd for: C₁₈H₁₇N₅OS₂ (383.50) C, 56.38; H, 4.47; N, 18.26; S, 16.72. Found: C, 56.23; H, 4.59; N, 18.38; S, 16.59.

Synthesis of compounds 13–16

A mixture of the thione 12 (0.5 g, 1.3 mmol) and an alkylating agent (4 mmol) in the presence of anhydrous potassium carbonate (0.5 g, 3.6 mmol) in ethanol (20 mL) was heated under reflux for 2 h. The solid product which was formed on cooling was filtered off, washed with water, dried and crystallized from a proper solvent.

10-Amino-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydrothiazolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-11-carbonitrile (13)

This compound was obtained from 12 and bromomalononitrile as yellow crystals; yield 0.37 g (65%); mp 228–230^oC; IR (KBr): ν_max 3490, 3324 (NH₂), 2930, 2850 (CH aliphatic), 2201 (CN), 1691 cm^-1 (C=O); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.75–1.87 (m, 4H, 2CH₂ cyclohexene), 2.19 and 2.21 (2s, 6H, 2CH₃ pyrazole), 2.51–2.57 (m, 4H, 2CH₂ cyclohexene), 6.09 (s, 1H, CH pyrazole), 4.08 (s, 2H, NH₂). Anal. Calcd for C₂₁H₁₇N₇OS₂ (447.54): C, 56.36; H, 3.83; N, 21.91; S, 14.33. Found: C, 56.48; H, 3.71; N, 21.79; S, 14.48.

5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydrothiazolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-10(11H)-one (14)

This compounds was obtained from 12 and ethyl chloroacetate as white crystals; yield (0.41 g (75%); mp 248–250^oC; IR (KBr): ν_max 2935, 2885 (CH aliphatic), 1725, 1631 (2C=O), 1548 cm^-1 (C=N); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.74–1.85 (m, 4H, 2CH₂ cyclohexene), 2.15, 2.20 (2s, 6H, 2CH₃ pyrazole), 2.62 (m, 4H, 2CH₂ cyclohexene), 3.62 (s, 2H, CH₂), 6.06 (s, 1H, CH pyrazole). Anal. Calcd for C₂₀H₁₇N₅O₂S₂ (423.52): C, 56.45; H, 4.50; N, 16.46; S, 15.07. Found: C, 56.56; H, 4.38; N, 16.59; S, 15.19.

5-(3,5-Dimethylpyrazol-1-yl)-10-phenyl-1,2,3,4-tetrahydrothiazolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinoline (15)

This compound was obtained from 12 and phenacyl bromide as white crystals; yield 0.38 g (68%); mp 240–242^oC; IR (KBr): ν_max 3431 (NH), 2929, 2875 (CH aliphatic), 1686 (C=O), 1540 cm^-1 (C=N); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.43–1.45 (m, 4H, 2CH₂ cyclohexene), 2.14, 2.17 (2s, 6H, 2CH₃ pyrazole), 2.42 (m, 4H, 2CH₂ cyclohexene), 5.02 (s, 1H, CH₂), 6.06 (s, 1H, CH pyrazole), 7.59–8.14 (m, 5H, ArH). Anal. Calcd for C₂₆H₂₁N₅OS₂ (483.62): C, 64.57; H, 4.38; N, 14.48; S, 13.26. Found: C, 64.39; H, 4.24; N, 14.61; S, 13.40.

(5-(3,5-Dimethylpyrazol-1-yl)-8-oxo-1,2,3,4-tetrahydrothiazolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-10ylsulfanyl) acetone (16)

This compound was obtained from 10 and chloroacetone as white crystals; yield 0.42 g (75%); mp196–198^oC; IR (KBr): ν_max 3480 (NH), 2928, 2855 (CH aliphatic), 1719, 1663 (2C=O), 1548 cm^-1 (C=N); ¹H-NMR (400 MHz, DMSO-d₆): δ 1.87 (m, 4H, 2CH₂ cyclohexene), 2.07 (s, 3H, CH₃), 2.18 and 2.20 (2s, 6H, 2CH₃ pyrazole), 2.30 (m, 4H, 2CH₂ cyclohexene), 4.30 (s, 2H, CH₂ CO), 6.11 (s, 1H, CH pyrazole), 13.39 (s, 1H, NH). Anal. Calcd for C₂₁H₂₁N₅O₂S₂ (439.56): C, 57.38; H, 4.82; N, 15.93; S, 14.59. Found: C, 57.25; H, 4.93; N, 15.79; S, 14.72.

10-Chloromethyl-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinoline-8(9H)-one (19)

A mixture of aminocarboxamide 4a (0.5 g, 1.4 mmol) and chloroacetyl chloride (0.2 mL) in dioxane (5 mL) was heated on water bath at 70–80°C for 2 h, then cooled, poured in an ice-water and neutralized by diluted sodium carbonate solution. The resultant solid was filtered off, dried and crystallized from ethanol as white crystals; yield 0.46 g (80%); mp 278–280^oC; IR (KBr): ν_max 3391 (NH), 2937, 2850 (CH aliphatic), 1659 (C=O), 1568 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.72–1.84 (m, 4H, 2CH₂ cyclohexene), 2.16, 2.37 (2s, 6H, 2CH₃ pyrazole), 2.55–2.60 (m, 4H, 2CH₂ cyclohexene), 3.56–3.59 (s, 2H, CH₂Cl), 6.18 (s, 1H, CH pyrazole), 10.56 (s, 1H, NH). Anal. Calcd for C₁₉H₁₈ClN₅OS (399.91): C, 57.07; H, 4.54; Cl, 8.87; N, 17.51; S, 8.02. Found: C, 57.29; H, 4.42; Cl, 8.72; N, 17.64; S, 8.16.

10-Phenylaminomethyl-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8(9H)-one (20)

A mixture of chloromethylpyrimidine derivative 19 (0.5 g, 1.2 mmol) and aniline (2 mmol) was gently heated under reflux for 5 min, then treated with ethanol (10 mL) and heated for an additional 2 h. The precipitated solid was filtered off, dried and crystallized from dioxane as white crystals; yield 0.48 g (75%); mp 298–300^oC; IR (KBr): ν_max 3420, 3309 (2NH), 3040 (CH aromatic), 2927, 2867 (CH aliphatic), 1660 (C=O), 1605 cm^-1 (C=N); ¹H-NMR (400 MHz, CDCl₃): δ 1.29–1.98 (m, 4H, 2CH₂ cyclohexene), 2.28, 2.36 (2s, 6H, 2CH₃ pyrazole), 2.71–2.74 (m, 4H, 2CH₂ cyclohexene), 3.71 (s, 2H, CH₂), 6.14 (s, 1H, CH pyrazole), 6.70 (s, 1H, NHPh), 6.80–7.08 (m, 5H, ArH), 10.28 (s, 1H, NH pyrmidine). Anal. Calcd for C₂₄H₂₂N₆OS (442.55): C, 65.14; H, 5.01; N, 18.99; S, 7.20. Found: C, 65.25; H, 5.15; N, 18.83; S, 7.32.

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Received: 2015-9-25

Accepted: 2015-11-7

Published Online: 2016-2-29

Published in Print: 2016-4-1

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-2015-0204

Keywords for this article

pyrazolyl; tetrahydro isoquinoline; tetrahydrothieno isoquinoline

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