Novel Synthesis and Reactions of Pyrazolyl- Substituted Tetrahydrothieno[2,3-C]Isoquinoline Derivatives

Heterocycl. Commun. 2016; 22(2): 103–109

Remon M. Zaki*, Adel M. Kamal El Dean, Maisa I. Abd El Monem and Mohamed A. Seddik Novel synthesis and reactions of pyrazolyl- substituted tetrahydrothieno[2,3-c]isoquinoline derivatives

DOI 10.1515/hc-2015-0204 1-hydrazino-4-cyano-5,6,7,8-tetrahydroisoquinoline-3(2H)- Received September 25, 2015; accepted November 7, 2015; previously thione (1) with acetylacetone [20]. Compound 2 proved to published online February 29, 2016 be a versatile starting material for synthesis of other het erocyclic compounds. Abstract: Treatment of isoquinolinecarboxamide 4a with triethyl orthoformate, chloroacetyl chloride or carbon disulfide afforded the pyrimidinone 7, oxopy rimidinethione 12 and chloromethylpyrimidinone 18, Results and discussion respectively. These products were used as versatile start ing materials for synthesis of other heterocyclic com Alkylation of 2 with chloroacetamide and ethyl chloro pounds. The heterocyclic hydrazide 6 was also obtained. acetate yielded sulfanyl acetamide 3a and ethyl sulfanyl acetate 3b, respectively. These compounds underwent Keywords: pyrazolyl; tetrahydro isoquinoline; tetra Thorpe-Ziegler cyclization upon refluxing in ethanolic hydrothieno isoquinoline. sodium ethoxide solution to give the respective substi tuted carboxamide 4a and substituted ethyl carboxy late 4b. The structures of 4a and 4b were elucidated by Introduction using elemental analysis and spectral data. Furthermore, hydrazinolysis of the ester group in compound 3b yielded Isoquinoline and its saturated derivatives have acquired the corresponding carbohydrazide compound 6 without considerable significance in heterocyclic chemistry [1, 2]. isolation of the sulfanyl carbohydrazide intermediate The tetrahydroisoquinoline ring system [3] is a basic product 5. On the other hand, the attempted reaction of structural component of many biologically active natural amino ester compound 4b with hydrazine hydrate under products [4, 5]. Tetrahydroisoquinoline is a common core the same conditions did not afford the expected amino structure of many alkaloids that show antitumor [6] and carbohydrazide compound 6 and the starting material antimicrobial [7] activities. Thienopyrimidines have long (amino ester) 4b was isolated (Scheme 1). been the subject of chemical and biological research. Reaction of amino carboxamide compound 4a Some thienopyrimidines display analgesic [8], antipy with triethyl orthoformate yielded the pyrimidinone 7 retic [9, 10], anti-inflammatory [11–14] and anti-allergenic (Scheme 2). Treatment of compound 7 with phosphorus effects [15–17]. oxychloride afforded the chloropyrimidine 8. The latter In the light of biological importance of tetrahydroiso compound was used in the synthesis of other pyrimi quinolines and thienopyrimidines, we have synthesized dothienoisoquinolines 9–11. Nucleophilic substitution many heterocyclic compounds containing morpholinyl- reaction of the chlorine atom in the chloropyrimidine substituted tetrahydrothieno[2,3-c]isoquinoline fused derivative 8 by heating under reflux with aniline fur to other rings [18–23]. In the present work we synthe nished the anilino-substituted pyrimidine 9. Thionation sized 1-(3,5-dimethylpyrazol-1-yl)-4-cyano-5,6,7,8-tet of the chloropyrimidine 8 with thiourea in ethanol yielded rahydroisoquinoline-3(2H)-thione (2) by the reaction of the pyrimidinethione 10 which was alkylated by treat ment with α-halogenated carbonyl compounds in reflux *Corresponding author: Remon M. Zaki, Chemistry Department, ing ethanol in the presence of sodium acetate to yield the Faculty of Science, Assiut University, 71516, Assiut, Egypt, S–alkylated products 11a–d. e-mail: [email protected]; [email protected] Adel M. Kamal El Dean, Maisa I. Abd El Monem and Reaction of amino carboxamide compound 4a with Mohamed A. Seddik: Chemistry Department, Faculty of Science, carbon disulfide in pyridine afforded the oxopyrimi Assiut University, 71516, Assiut, Egypt dinethione 12 which served as a versatile precursor to 104 R.M. Zaki et al.: Pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinolines

O O CN CN

H2N EtOH, ∆ N N N S N N S H H H XY 1 2 X = Cl, Br AcONa, EtOH

CN for 3b CN

N a: Y = CONH2 N H2NNH2, ∆ N N SCH2CONHNH2 N N SY b: Y = CO Et EtOH 2 5 3a, b

EtOH, EtONa

NH2 NH2 for 4b NHNH2 Y N N N S N N S N O H2NNH2, ∆ EtOH 6 4a, b

Scheme 1

N XY N X = Cl, Br N N N NH N N S AcONa, EtOH, ∆ N N S S Y S 11a–d 10

11a: Y = CO2Et H NCSNH 11b: Y = COMe 2 2 11c: Y = COPh EtOH, ∆ 11d: Y = CONHPh-Me-p

N N POCl3 N NH N N N N S N N S O 8 Cl 7

PhNH2 HC(OEt)3, AcOH EtOH, ∆

4a N

N N N N S NHPh 9

Scheme 2 R.M. Zaki et al.: Pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinolines 105

S CN N N NH N 2 N N S O 13

BrCH(CN)2

EtOH, K2CO3, ∆

S HN S NH N CS2 ClCH2CO2Et N 4a N O N O pyridine N N S EtOH, K CO , ∆ N N S 2 3 O 12 14

ClCH2COMe PhCOCH2Br EtOH, K2CO3, ∆ EtOH, K2CO3, ∆

S S S N N N N NH N Ph

N N N O N N S O N N S O N N S

17 16 15

Scheme 3

O Cl H N HN Cl N N Ph NH NH2 NH ClCH COCl PhNH2 2 N N O N 4a N N S O N N S N N S O dioxane EtOH, ∆ 18 19 20

Scheme 4 thiazolopyrimidothienoisoquinoline derivatives 13–16 by Experimental the reaction with α-halogenated alkylating agents. It is interesting to note that treatment of 12 with chloroacetone 1-(3,5-Dimethylpyrazol-1-yl)-3-sulfanyl-5,6,7,8-tetrahydroisoqui- gave the sulfanyl derivative 16 instead of the expected noline-4-carbonitrile (2) A mixture of thione 1 (1 g, 4.5 mmol) and product 17 (Scheme 3). acetylacetone (20 mmol) was gently heated under reflux for 1 h and then treated with absolute ethanol (20 mL). The mixture was heated Treatment of 4a with chloroacetyl chloride in dioxane under reflux for an additional 2 h and then cooled. The resultant solid afforded product 19, apparently through intermediary of product was filtered, dried and crystallized from dioxane; yield 1.13 g o 18. Compound 19 underwent nucleophilic displacement (88%) of yellow crystals; mp > 300 C; IR (KBr): νmax 3446 (NH), 2950, reaction upon treatment with aniline to afford the aniline 2820 (CH, aliphatic), 2226 (CN), 1568 (C = N), 1279 cm-1 (C = S); 1H-NMR (90 MHz, CF CO D): δ 2.05 (m, 4H, 2CH , cyclohexene), 2.50, 2.70 (2s, derivative 20 (Scheme 4). 3 2 2 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: Conclusion H, 5.55; N, 19.83; S, 11.40.

Alkylation of 1-(3,5-dimethylpyrazol-1-yl)-3-sulfanyl-5,6,7,8- The newly synthesized pyrazolyltetrahydrothieno[2,3-c] tetrahydroisoquinoline-4-carbonitrile (2) A mixture of thione 2 isoquinolines were used as a versatile precursors for syn (0.58 g, 2 mmol), an alkylating agent (2 mmol) and fused sodium ace thesis of other heterocyclic compounds. tate (0.75 g, 8.5 mmol) in ethanol (20 mL) was heated under reflux for 106 R.M. Zaki et al.: Pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinolines

2 h. The solid product which precipitated upon cooling was filtered, mixture of amino ester 3b (1 g, 2.7 mmol) and hydrazine hydrate washed with water, dried and crystallized. (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 2-(4-Cyano-1-(3,5-dimethylpyrazol-1-yl)-5,6,7.8-tetrahydroiso- solid was filtered off, dried and crystallized from ethanol as yellow o quinolin-3-ylsulfanyl) acetamide (3a) This compound was crystals; yield 0.73 g (80%); mp 212–214 C; IR (KBr): νmax 3421, 3317, -1 obtained by the reaction of 2 with chloroacetamide; yield 0.52 g 3249 (NH2, NH), 2931, 2856 (CH aliphatic), 1658 (CO), 1599 cm (C = N); o 1 (79%); mp 222–224 C; IR (KBr): νmax 3469, 3380 (NH2), 2940, 2850 (CH, H-NMR (400 MHz, CDCl3): δ 1.67–1.99 (m, 4H, 2CH2, cyclohexene), -1 1 aliphatic), 2220 (CN), 1674 (C = O), 1620 cm (C = N); H-NMR (90 MHz, 2.13 and 2.16 (2s, 6H, 2CH3, pyrazole), 2.31 (m, 4H, 2CH2, cyclohexene),

CDCl3): δ 1.75–1.78 (m, 4H, 2CH2, cyclohexene), 2.20 and 2.25 (2s, 6H, 3.55 (s, 2H, NH2, carbohydrazide), 5.78 (s, 2H, NH2, thiophene), 6.40

2CH3, pyrazole), 2.65–2.70 (m, 2H, CH2, cyclohexene), 2.97 (m, 2H, (s, 1H, CH, pyrazole), 11.90 (s, 1H, NH). Anal. Calcd for C18H20N4OS

CH2, cyclohexene), 3.80 (s, 2H, CH2CO), 6.10 (s, 1H, CH, pyrazole), 6.70 (340.45): C, 63.50; H, 5.92; N, 16.46; S, 9.40. Found: C, 63.62; H, 5.83;

(s, 2H, NH2). Anal. Calcd for C16H19N5OS: C, 58.70; H, 5.23; N, 21.39; S, N, 16.59; S, 9.26. 9.79. Found: C, 58.88; H, 5.34; N, 21.25; S, 9.60. 5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrim- Ethyl (4-cyano-1-(3,5-dimethyl pyrazol-1-yl)-5,6,7,8-tetrahy- ido[4′,5′:4,5]thieno[2,3-c]isoquin-olin-8(9H)-one (7) A mix droisoquinolin-3-ylsulfanyl) acetate (3b) This compound ture of compound 4a (2 mmol), triethyl orthoformate (2 mL) and a was obtained by the reaction of 2 with ethyl chloroacetate; yield few drops of glacial acetic acid was heated under reflux for 30 min. o 0.56 g (75%) of white crystals; mp 146–148 C; IR (KBr): νmax 2950, The solid precipitate was filtered off, dried and crystallized from 2838 (CH, aliphatic), 2222 (CN), 1751 (C = O, ester), 1565 cm-1 (C = N); ethanol as pale yellow crystals; yield 0.52 g (72%); mp > 360oC; 1 -1 H-NMR (90 MHz, CDCl3): δ 1.15 (t, 3H, J = 7 Hz, CH3), 1.80–1.85 (m, IR (KBr): νmax 3450 (NH), 2929, 2850 (CH aliphatic), 1651 cm (C = O 1 4H, 2CH2, cyclohexene), 2.35–2.40 (2s, 6H, 2CH3), 2.77–2.80 (m, 2H, pyrimide); H-NMR (400 MHz, DMSO-d6): δ 1.76–1.88 (m, 4H, 2CH2,

CH2, cyclohexene), 3.00–3.10 (m, 2H, CH2, cyclohexene), 4.00 (s, 2H, cyclohexene), 2.20, 2.21 (2s, 6H, 2CH3, pyrazole), 2.51–2.61 (m, 4H,

CH2CO), 4.30 (q, 2H, CH2, J = 7 Hz, ester), 6.20 (s, 1H, CH, pyrazole). 2CH2, cyclohexene), 6.10 (s, 1H, CH, pyrazole), 8.38 (s, 1H, CH,

Anal. Calcd for C19H22N4O2S: C, 61.60; H, 5.99; N, 15.12; S, 8.64. Found: pyrimidine), 12.90 (s, 1H, NH). Anal. Calcd for C18H19N5OS (351.43): C, 61.74; H, 5.76; N, 15.44; S, 8.55. 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. Cyclization of 3-substituted sulfanyl-1-(3,5-dimethyl pyrazol- 1-yl)-5,6,7,8-tetrahydroiso-quinoline-4-carbonitriles 3a,b A 8-Chloro-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrim- solution of the substituted sulfanyl tetrahydroisoquioline carboni ido[4′,5′:4,5]thieno[2,3-c]isoquinoline (8) A mixture of pyrimi trile 3a,b (0.01 mol) in absolute ethanol (20 mL) containing a few dinone 7 (0.75 g, 2.1 mmol) and phosphorus oxychloride (3 mL) was drops of sodium ethoxide solution [prepared from 0.5 g of finely heated under reflux for 2 h, then cooled, poured in an ice-water and divided sodium metal and absolute ethanol (20 mL)] was heated neutralized with diluted sodium carbonate solution. The precipitated under reflux for 20 min. The precipitated solid4a,b which formed on solid was filtered off, dried and crystallized from ethanol as white o cooling was filtered off, dried and crystallized from a proper solvent. crystals; yield 0.64 g, 80%; mp 260-262 C; IR (KBr): νmax 2944, 2931, -1 1 2867 (CH aliphatic), 1567 cm (C = N); H-NMR (400 MHz, DMSO-d6):

1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9- δ 1.76–1.88 (m, 4H, 2CH2, cyclohexene), 2.20 and 2.21 (2s, 6H, 2CH3, tetrahydrothieno[2,3-c]isoquinoline-2-carboxamide (4a) The pyrazole), 2.51–2.61 (m, 4H, 2CH2, cyclohexene), 6.10 (s, 1H, CH, product was crystallized from ethanol/dioxane mixture (1:1); pale yel pyrazole), 9.28 (s, 1H, CH, pyrimidine). Anal. Calcd for C18H18ClN5S o low crystals; yield 0.46 g (89); mp 268-270 C; IR (KBr): νmax 3463, 3389, (369.88): C, 58.45; H, 4.36; Cl, 9.59; N, 18.93; S, 8.60. Found: C, 58.56; -1 3300, 3126 (2NH2), 2939, 2850 (CH, aliphatic), 1659 cm (C = O, amide); H, 4.23; Cl, 9.71; N, 18.80; S, 8.73. 1 H-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, cyclohex 5-(3,5-Dimethylpyrazol-1-yl)-8-anilino-1,2,3,4-tetrahydropyrim- ene), 3.38–3.41 (m, 2H, CH2, cyclohexene), 5.38 (s, 1H, CH, pyrazole), ido[4′,5′:4,5]thieno[2,3-c]isoquinoline (9) A mixture of chloro

6.01 (s, 2H, NH2, thiophene), 6.51 (s, 2H, NH2, amide). Anal. Calcd for pyrimidine derivative 8 (0.25 g, 0.67 mmol) and aniline (2 mmol)

C17H19N5OS (341.44): C, 59.80; H, 5.61; N, 20.51; S, 9.39. Found: C, 59.94; was gently heated for 5 min and then treated with ethanol (10 mL). H, 5.47; N, 20.38; S, 9.51. The mixture was heated under reflux for 2 h and the resultant solid precipitate was filtered off, dried and crystallized from ethanol as o Ethyl 1-amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahydro brown crystals; yield 0.64 g (75%); mp 224–226 C; IR (KBr): νmax 3420 thieno[2,3-c]isoquinoline-4-carboxylate (4b) The product was (NH), 3040 (CH aromatic) 2927, 2867 (CH aliphatic), 1610 cm-1 (C = N); 1 crystallized from ethanol; pale yellow crystals; yield 0.44 g (80%); mp H-NMR (400 MHz, CDCl3): δ 1.84–1.98 (m, 4H, 2CH2, cyclohexene), o 186–188 C; IR (KBr): νmax 3401, 3200 (NH2), 2935, 2850 (CH, aliphatic), 2.27 and 2.34 (2s, 6H, 2CH3, pyrazole), 2.73 (m, 4H, 2CH2, cyclohex -1 1 1674 (C = O, ester), 1614 cm (C = N); H-NMR (90 MHz, CDCl3): δ 1.55 (t, ene), 6.04 (s, 1H, CH, pyrazole), 7.43 (m, 5H, 5CH, aromatic), 7.67

3H, J = 7 Hz, CH3, ester), 1.96 (m, 4H, 2CH2, cyclohexene), 2.40 and 2.45 (s, 1H, CH, pyrimidine), 8.89 (s, 1H, NH). Anal. Calcd for C24H22N6S

(2s, 6H, CH3, pyrazole), 2.70–2.78 (m, 2H, CH2, cyclohexene), 3.42 (m, (426.55): C, 67.58; H, 5.20; N, 19.70; S, 7.52. Found: C, 67.69; H, 5.33;

2H, CH2, cyclohexene), 4.60 (q, 2H, J = 7 Hz, CH2, ester), 6.20 (s, 1H, CH, N, 19.56; S, 7.65. 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. 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 1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9- mixture of chloropyrimidine derivative 6 (1 g, 2.7 mmol) and thio tetrahydrothieno[2,3-c]isoquinoline-4-carbohydrazide (6) A urea (1 g, 0.013 mol) in ethanol was heated under reflux for 4 h. The R.M. Zaki et al.: Pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinolines 107

resultant solid precipitate was filtered off and crystallized from diox (400 MHz, CDCl3): δ 1.88–2.02 (m, 4H, 2CH2 cyclohexene), 2.32 (s, o ane to afford yellow crystals; yield 0.74 g (75%); mp 290–292 C; IR 3H, CH3 p-methylacetanilide), 2.34 and 2.36 (2s, 6H, 2CH3, pyrazole), -1 (KBr): ν 3420 (NH), 2934, 2860 (CH aliphatic), 1291 (C = S), 1574 cm 2.79–2.82 (m, 2H, CH2, cyclohexene), 3.77 (m, 2H, CH2, cyclohexene), 1 (C = N); H NMR (DMSO-d6): δ = 1.74–1.80 (m, 4H, 2CH2, cyclohexene), 4.16 (s, 2H, CH2), 6.10 (s, 1H, CH of pyrazole), 7.11–7.41 (dd, 4H, ArH

2.20, 2.30 (2s, 6H, 2CH3, pyrazole), 2.51–2.61 (m, 4H, 2CH2, cyclohex p-substituted), 9.20 (s, 1H, CH, pyrimidine), 9.40 (s, 1H, NH). Anal. ene), 6.20 (s, 1H, CH, pyrazole), 8.50 (s, 1H, CH, pyrimidine), 12.70 (s, Calcd for C27H26N6OS2 (514.68): C, 63.01; H, 5.09; N, 16.33; S, 12.46.

1H, NH). Anal. Calcd for C18H17N5S2 (367.50): C, 58.83; H, 4.66; N, 19.06; Found: C, 63.12; H, 5.21; N, 16.47; S, 12.56. S, 17.45. Found: C, 58.71; H, 4.78; N, 19.19; S, 17.34. 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 Alkylation of compound 10 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 A mixture of pyrimidinethione 10 (0.5 g, 1.3 mmol), an alkylating crystallized from dioxane as brilliant yellow crystals; mp 310–312°C; agent (2 mmol) and fused sodium acetate (0.75 g, 8.5 mmol) in etha yield 0.95g (85%); IR (KBr): ν 3371, 3130 (2NH), 2928, 2820 (CH ali nol (20 mL) was heated under reflux for 2 h. The solid product which phatic), 1666 (C = O), 1250 cm-1 (C = S); 1H-NMR (400 MHz, DMSO-d ): δ formed on cooling was filtered off, washed with water, dried and 6 1.70–1.82 (m, 4H, 2CH cyclohexene), 2.20 and 2.25 (2s, 6H, 2CH pyra crystallized from a proper solvent. 2 3 zole), 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: C H N OS Ethyl (5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrim- 18 17 5 2 (383.50) C, 56.38; H, 4.47; N, 18.26; S, 16.72. Found: C, 56.23; H, 4.59; ido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8-ylsulfanyl)acetate N, 18.38; S, 16.59. (11a) This compound was obtained from 10 and ethyl chloroac etate as white crystals; yield 0.50 g, (82%); mp 122–124oC; IR (KBr): -1 1 νmax 2980, 2850 (CH aliphatic), 1740 (C = O), 1620 cm (C = N); H-NMR Synthesis of compounds 13–16 (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, A mixture of the thione 12 (0.5 g, 1.3 mmol) and an alkylating agent ester), 6.07 (s, 1H, CH, pyrazole), 9.09 (s, 1H, CH, pyrimidine). Anal. (4 mmol) in the presence of anhydrous potassium carbonate (0.5 g,

Calcd for C22H23N5O2S2 (453.59): C, 58.26; H, 5.11; N, 15.44; S, 14.14. 3.6 mmol) in ethanol (20 mL) was heated under reflux for 2 h. The Found: C, 58.39; H, 5.25; N, 15.55; S, 14.03. solid product which was formed on cooling was filtered off, washed with water, dried and crystallized from a proper solvent. 1-(5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8-ylsulfanyl)acetone 10-Amino-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydrothi- (11b) This compound was obtained from 10 and chloroacetone as azolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin- o ν white crystals; yield 0.45 g, (79%); mp 164–168 C; IR (KBr): max 2979, 11-carbonitrile (13) This compound was obtained from 12 and -1 1 2860 (CH aliphatic), 1716 (C = O), 1568 cm (C = N); H-NMR (400 MHz, bromomalononitrile as yellow crystals; yield 0.37 g (65%); mp 228– CDCl ): δ 1.87–2.01 (m, 4H, 2CH , cyclohexene), 2.31, 2.36 and 2.43 (3s, o 3 2 230 C; IR (KBr): νmax 3490, 3324 (NH2), 2930, 2850 (CH aliphatic), 2201 9H, 3CH ), 2.78 (m, 2H, CH , cyclohexene), 3.76 (m, 2H, CH , cyclohex -1 1 3 2 2 (CN), 1691 cm (C = O); H-NMR (400 MHz, DMSO-d6): δ 1.75–1.87 (m, ene), 4.28 (s, 2H, CH CO), 6.08 (s, 1H, CH, pyrazole), 9.06 (s, 1H, CH, 2 4H, 2CH2 cyclohexene), 2.19 and 2.21 (2s, 6H, 2CH3 pyrazole), 2.51–2.57 pyrimidine). Anal. Calcd for C H N OS (423.56): C, 59.55; H, 5.00; N, 21 21 5 2 (m, 4H, 2CH2 cyclohexene), 6.09 (s, 1H, CH pyrazole), 4.08 (s, 2H, 16.53; S, 15.14. Found: C, 59.41; H, 5.14; N, 16.41; S, 15.29. 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. 2-(5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]iso-quinolin-8-ylsulfanyl)acetophe- 5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydrothia- none (11c) This compound was obtained from 10 and phenacyl zolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin- o bromide as white crystals; yield 0.39 g, (60%); mp 142–144 C; IR 10(11H)-one (14) This compounds was obtained from 12 and ethyl o (KBr): νmax 3055 (CH aromatic), 2928, 2854 (CH aliphatic), 1694 (C = O chloroacetate as white crystals; yield (0.41 g (75%); mp 248–250 C; unsaturated), 1567 cm-1 (C = N); 1H-NMR (400 MHz, CDCl ): δ 1.86– 3 IR (KBr): νmax 2935, 2885 (CH aliphatic), 1725, 1631 (2C = O), 1548 2.02 (m, 4H, 2CH , cyclohexene), 2.31, 2.38 (2s, 6H, 2CH , pyrazole), -1 1 2 3 cm (C = N); H-NMR (400 MHz, DMSO-d6): δ 1.74–1.85 (m, 4H, 2CH2 2.80 (m, 2H, CH , cyclohexene), 3.78 (m, 2H, CH , cyclohexene), 5.01 2 2 cyclohexene), 2.15, 2.20 (2s, 6H, 2CH3 pyrazole), 2.62 (m, 4H, 2CH2 (s, 2H, CH CO), 6.10 (s, 1H, CH, pyrazole), 7.53–8.14 (m, 5H, ArH), 2 cyclohexene), 3.62 (s, 2H, CH2), 6.06 (s, 1H, CH pyrazole). Anal. Calcd 9.03 (s, 1H, CH, pyrimidine). Anal. Calcd for C H N OS (485.63): C, 26 23 5 2 for C20H17N5O2S2 (423.52): C, 56.45; H, 4.50; N, 16.46; S, 15.07. Found: C, 64.31; H, 4.77; N, 14.42; S, 13.21. Found: C, 64.43; H, 4.53; N, 14.29; 56.56; H, 4.38; N, 16.59; S, 15.19. S, 13.35. 5-(3,5-Dimethylpyrazol-1-yl)-10-phenyl-1,2,3,4-tetrahydrothi- 2-(5-(3,5-Dimethylpyrazol-1-yl)-1,2,3,4-tetrahydropyrim- azolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinoline ido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8-ylsulfanyl)-N-(4-meth- (15) This compound was obtained from 12 and phenacyl bromide as oxyphenyl)acetamide (11d) This compound was obtained from o white crystals; yield 0.38 g (68%); mp 240–242 C; IR (KBr): νmax 3431 10 and p-methylchloroacetanilide as white crystals; yield 0.52 g (NH), 2929, 2875 (CH aliphatic), 1686 (C = O), 1540 cm-1 (C = N); 1H-NMR (75%); mp 222–224oC; IR (KBr): ν 3243 (NH), 3040 (CH aromatic), max (400 MHz, DMSO-d6): δ 1.43–1.45 (m, 4H, 2CH2 cyclohexene), 2.14, 2.17 2992, 2943 (CH aliphatic), 1651 (C = O), 1594 cm-1 (C = N); 1H-NMR (2s, 6H, 2CH3 pyrazole), 2.42 (m, 4H, 2CH2 cyclohexene), 5.02 (s, 1H, 108 R.M. Zaki et al.: Pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinolines

CH2), 6.06 (s, 1H, CH pyrazole), 7.59–8.14 (m, 5H, ArH). Anal. Calcd [4] Kametani, T. The Total Syntheses of Isoquinoline Alkaloids. for C26H21N5OS2 (483.62): C, 64.57; H, 4.38; N, 14.48; S, 13.26. Found: C, In The Total Synthesis of Natural Products. ApSimon, J., Ed. 64.39; H, 4.24; N, 14.61; S, 13.40. John Wiley: New York, 1977, Vol. 3, pp. 1–272. [5] Gozler, B.; Brossi, A. The Alkaloids. Chapter 7 Pavine and (5-(3,5-Dimethylpyrazol-1-yl)-8-oxo-1,2,3,4-tetrahydrothia- Isopavine Alkaloids Chemistry and Pharmacology, Academic: zolo[2″,3″:2′,1′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin- London, 1987, Vol. 31, 317–389. 10ylsulfanyl) acetone (16) This compound was obtained from [6] Scott, J. D.; Williams, R. M. Chemistry and biology of the 10 and chloroacetone as white crystals; yield 0.42 g (75%); mp196– tetrahydroisoquinoline antitumor antibiotics. Chem. Rev. 2002, o 198 C; IR (KBr): νmax 3480 (NH), 2928, 2855 (CH aliphatic), 1719, 1663 102, 1669–1730. -1 1 (2C = O), 1548 cm (C = N); H-NMR (400 MHz, DMSO-d6): δ 1.87 (m, 4H, [7] Iwasa, K.; Moriyasu, M.; Tachibana, Y.; Kim, H.; Wataya, Y.;

2CH2 cyclohexene), 2.07 (s, 3H, CH3), 2.18 and 2.20 (2s, 6H, 2CH3 pyra Wiegrebe, W.; Bastow, K. F.; Cosentino, L. M.; Kozukaand, M.; zole), 2.30 (m, 4H, 2CH2 cyclohexene), 4.30 (s, 2H, CH2 CO), 6.11 (s, 1H, Lee. K. Simple isoquinoline and benzylisoquinoline alkaloids

CH pyrazole), 13.39 (s, 1H, NH). Anal. Calcd for C21H21N5O2S2 (439.56): as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV C, 57.38; H, 4.82; N, 15.93; S, 14.59. Found: C, 57.25; H, 4.93; N, 15.79; agents. Bioorg. Med. Chem. 2001, 9, 2871–2884. S, 14.72. [8] Dave, C. G.; Shah, P. R.; Dave, K. C.; Patel, V. J. Synthesis and biological activity of pyrido[3’, 2’: 4, 5]thieno[3, 2-d]pyrimi- 10-Chloromethyl-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4-tetrahy- dines. J. Indian Chem. Soc. 1989, 66, 48–50. dropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinoline-8(9H)-one [9] Bousquet, E.; Romero, G.; Guerrera, F.; Caruso, A.; Roxas, M. A. (19) A mixture of aminocarboxamide 4a (0.5 g, 1.4 mmol) and Synthesis and analgesic activity of 3-substituted derivatives of chloroacetyl chloride (0.2 mL) in dioxane (5 mL) was heated on pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-(3H)-one. Farmaco, water bath at 70–80°C for 2 h, then cooled, poured in an ice-water Ed. Sci. 1985, 40, 869–874. and neutralized by diluted sodium carbonate solution. The result [10] Bousquet, E.; Guerrera, F.; Siracusa, N. A.; Caruso, A.; Roxas, ant solid was filtered off, dried and crystallized from ethanol as M. A. Synthesis and pharmacological activity of 3-substituted o white crystals; yield 0.46 g (80%); mp 278–280 C; IR (KBr): νmax pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones. Farmaco, 3391 (NH), 2937, 2850 (CH aliphatic), 1659 (C = O), 1568 cm-1 (C = N); Ed. Sci. 1984, 39, 110. 1 H-NMR (400 MHz, CDCl3): δ 1.72–1.84 (m, 4H, 2CH2 cyclohexene), [11] Rodinovskaya, L. A.; Sharanin, Yu. A.; Shestopalov, A. M.;

2.16, 2.37 (2s, 6H, 2CH3 pyrazole), 2.55–2.60 (m, 4H, 2CH2 cyclohex Litvinov, V. P. Cyclization reactions of nitrils. 29. Regioselec- ene), 3.56–3.59 (s, 2H, CH2Cl), 6.18 (s, 1H, CH pyrazole), 10.56 (s, tive synthesis of 6-aryl-3-cyano-2(1H)-pyridinethiones and

1H, NH). Anal. Calcd for C19H18ClN5OS (399.91): C, 57.07; H, 4.54; the corresponding selenones and their characteristics.Chem. Cl, 8.87; N, 17.51; S, 8.02. Found: C, 57.29; H, 4.42; Cl, 8.72; N, 17.64; Heterocycl. Compd. 1988, 24, 658–665. S, 8.16. [12] Leistner, S.; Wagner, G.; Guetscharo, M.; Glusa, E. Synthesis of 7-benzyl-5,6,7,8-tetrahyro-pyrido[4′,3′:4,5]thieno[2,3-d] 10-Phenylaminomethyl-5-(3,5-dimethylpyrazol-1-yl)-1,2,3,4- pyrimidin-4-(3H)-ones with alkylthioether groups in position 2 tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolin-8(9H)- and examination of their platelet aggregation inhibiting activity. one (20) A mixture of chloromethylpyrimidine derivative 19 (0.5 Pharmazie 1986, 41, 54–55. g, 1.2 mmol) and aniline (2 mmol) was gently heated under reflux [13] Vieweg, H.; Leistner, S.; Wagner, G.; Boehm, N.; Krasset, U.; for 5 min, then treated with ethanol (10 mL) and heated for an Gruppe, R.; Lohmann, D.; Loban, G. East Germ. Pat. DD 257, additional 2 h. The precipitated solid was filtered off, dried and 830 (1988); Chem. Abstr. 1988, 110, 95262. crystallized from dioxane as white crystals; yield 0.48 g (75%); mp [14] Vieweg, H.; Leistner, S.; Wagner, G.; Boehm, N.; Krasset, U.; o 298–300 C; IR (KBr): νmax 3420, 3309 (2NH), 3040 (CH aromatic), Gruppe, R.; Lohmann, D.; Loban, G.;East Germ. Pat. DD 258, 2927, 2867 (CH aliphatic), 1660 (C = O), 1605 cm-1 (C = N); 1H-NMR 234 (1988); Chem.Abstr. 1989, 110, 95263.

(400 MHz, CDCl3): δ 1.29–1.98 (m, 4H, 2CH2 cyclohexene), 2.28, 2.36 [15] Elslager, E. F.; Jacob, P.; Leslie, M. W. Folate antago-

(2s, 6H, 2CH3 pyrazole), 2.71–2.74 (m, 4H, 2CH2 cyclohexene), 3.71 (s, nists. 6. Synthesis and anti-malarial effects of fused

2H, CH2), 6.14 (s, 1H, CH pyrazole), 6.70 (s, 1H, NHPh), 6.80–7.08 (m, 2,4-diaminothieno[2,3-d]pyrimidines. J. Heterocycl. Chem.

5H, ArH), 10.28 (s, 1H, NH pyrmidine). Anal. Calcd for C24H22N6OS 1972, 9, 775–782. (442.55): C, 65.14; H, 5.01; N, 18.99; S, 7.20. Found: C, 65.25; H, 5.15; [16] Chaykovsky, M.; Lin, M.; Rosowsky, A.; Modest, E. J. N, 18.83; S, 7.32. 2,4-Diamino-thieno [2,3d]pyrimidines as antifolates and anti- malarials. J. Med. Chem. 1973, 16, 188–191. [17] Madding, G. D.; Thompson, M. D. Regioselective syntheses of 2-amino-4,5-dialkylthiophene-3-carboxylates and their References conversion to 3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2- carboxylates. J. Het. Chem. 1987, 24, 581–587. [1] Chrzanowska, M.; Rozwadowska, M.D. Asymmetric [18] Kamal El-Dean, A. M.; Radwan, Sh. M.; Zaki, R. M. Synthesis of synthesis of isoquinoline alkaloids. Chem. Rev. 2004, Morphlinotetrahydro thieno[2,3-c]isoquinolines. J. Chin. Chem. 104, 3341–3370. Soc. 2008, 55, 1–10. [2] Bentley, K. W. β-Phenylethylamines and the isoquinoline alka- [19] Kamal, A. M.; Radwan, Sh. M.; Zaki, R. M. Reactions of loids. Nat. Prod. Rep. 2006, 23, 444–463. 1-Amino-5-morpholino-6,7,8,9-tetrahydrothieno[2,3-c] [3] Jacobs, J.; Deblander, J.; Kesteleyn, B.; Tehrani, K. A.; De isoquinoline-2-Carbonitrile. J. Chem. Res. 2010, 34, 596–602. Kimpe, N. Synthesis of N-substituted 1,2,3,4-tetrahydrobenz[g] [20] Kamal, A. M.; Radwan, Sh. M.; Zaki, R. M. Synthesis and isoquinoline-5,10-diones. Tetrahedron 2008, 64, 5345–5353. biological activity of Pyrazolothienotetrahydroisoquinoline and R.M. Zaki et al.: Pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinolines 109

[1,2,4]triazolo[3,4-a]thienotetrahydroisoquinoline derivatives. [22] Zaki, R. M.; Kamal El-Dean, A. M.; Radwan, Sh. M. Synthesis Eur. J. Med. Chem. 2011, 46, 567–578. and reactions of novel Thienotetrahydroisoquinoline com- [21] Zaki, R. M.; Radwan, Sh. M.; Kamal, A. M. Synthesis pounds. Afinidad LXVII 2012, 556, 1–11. and reactions of 1-Amino-5-morpholin-4-yl-6,7,8,9- [23] Zaki, R. M.; Kamal El-Dean, A. M.; Radwan, Sh. M. Synthesis and tetrahydrothieno[2,3-c]isoquinoline. J. Chin. Chem. Soc. 2011, reactions of some new morpholinylpyrrolyl tetrahydrothieno[2,3- 58, 544–554. c]isoquinoline. J. Adv. Chem. 2014, 10, 2512–2523.