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 1­hydrazino­4­cyano­5,6,7,8­tetrahydroisoquinoline­3(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 Thorpe­Ziegler 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], anti­inflammatory [11–14] and anti­allergenic (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[2,3­c]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(3,5­dimethylpyrazol­1­yl)­4­cyano­5,6,7,8­tet­ of the chloropyrimidine 8 with thiourea in ethanol yielded rahydroisoquinoline­3(2H)­thione (2) by the reaction of the pyrimidinethione 10 which was alkylated by treat­ ment with α­halogenated 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, ∆ O 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 α­halogenated 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 cm­1 (C = S); 1H­NMR (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); EI­MS: 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[2,3­c] 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, H­NMR (400 MHz, CDCl3): δ 1.67–1.99 (m, 4H, 2CH2, cyclohexene), ­1 1 aliphatic), 2220 (CN), 1674 (C = O), 1620 cm (C = N); H­NMR (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.