# Thioxopyrimidine in Heterocyclic Synthesis II: Novel Synthesis of Some Triazoles and Triazepine Derivatives with a Pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine Skeleton

Authors: Yuh Wen Ho; Se Long Chou
Journal: Journal of Chemistry
 (2013)

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## Abstract

Condensation of ethoxymethyleneamino-thieno[2,3-d]pyrimidines 4 with appropriate amino compounds afforded the corresponding 7-substituted-8-imino-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidines 6a, 6b, and 7 and 2-substituted-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 9a, 9b, respectively. Also, hydrazinolysis of compound 4 in ethanol which yielded the key intermediate 7-amino-8-imino-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (10), which can be cyclized with appropriate isothiocyanates 14a–14g in refluxing pyridine, afforded the corresponding 2-(substituted-amino)-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyramidines 15a–15g. Furthermore, intramolecular cyclization of compound (10) with appropriate 1,3-dibromopropane and Mannich bases 18a–18c under the basic condition afforded the corresponding (tri)dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines 16 and 18a–18c, respectively. On the other hand, the 11-substituted-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines 21a–21e were also obtained by the intramolecular cyclization of compound (10) with appropriate enaminone derivatives 19a–19e under the acidic condition.


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## Body

## 1. Introduction

Pyrimidine and its derivatives are biologically important as antimicrobial [1, 2], antitumor [3], antihypertensive [4], and anti-inflammatory activities [5]. Among the derivatives of thieno[2,3-d]pyrimidines, substances have been observed that have antiviral, fungicidal, and insecticidal activity [6], antibacterial and antiplastic properties [7], antihypertensive [8] and anticonvulsant activity [9], and antihistaminic [10] action. Compounds with triazepine skeletons have attracted much attention as a result of their interesting biological properties [11, 12]. On the other hand, condensed heterocyclic 1,2,4-triazepines were found to have salidiuretic and renal vasodilator, antioxidant, and analgesic and immunomodulating activities [13–15]. Further, the fusion of pyrimidine with triazepine moiety shows enhanced pharmacological effects as antiviral, antifungal [16], and antidiabetic [17] and also acts as inhibitors [18] in cancer chemotherapy.Recently, it has been demonstrated that heterocycles attached to seven-membered rings show important biological activities [19–21]. Likewise, fused triazepine derivatives with a bridgehead nitrogen atom in the molecule exhibit interesting biological properties [22]. Various conventional methods for the synthesis of fused triazepines are exemplified in the literature [23, 24] using cycloaddition [25] and photochemical methods, but pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines are the least investigated group among the fused triazepines. Moreover, no general method is ever reported for the synthesis of the title compounds starting from 7-amino-8-imino-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (10). In view of these, it was considered of interest to synthesize some new triazoles and triazepine derivatives of structure fused to pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (PTP) ring in the hope that they may be biologically active. In preceding papers [26–29], we have described the synthesis of some new pyrimido[2,3:4,3]pyrazolo[1,5-a]- pyrimidines, 1,2,4-triazolo[1,5-a]pyrimidothieno[2,3-d]pyrimidine, and 1,3,4-oxadiazole-thieno[2,3-d]pyrimidines from 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6- thioxopyrimidine 1 [26], respectively. In continuation of our studies [26–30], we report herein the synthesis of some new pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]- triazolo[1,5-c]pyrimidines and pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine derivatives by making use of the key intermediate 7-amino-8-imino-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (10), easily obtained from the thioxopyrimidine 1. The substrate proved to be a versatile compound by virtue of its vicinal amino and imino functions, evaluating the reactivity in several cyclization reactions performed with the aim of obtaining new triazoles and triazepines with a conserved PTP core.


## 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-NMR spectrometer, and chemical shifts are expressed in δ ppm using TMS as an internal standard. Electron impact mass spectra were obtained at 70 eV using a Finnigan Mat TSQ-46C spectrometer. Microanalyses for C, H, and N were performed on a Perkin-Elmer 240 elemental analyzer. Commercially available reagents were purchased from Aldrich and used directly. Reactions were routinely monitored by thin layer chromatography (TLC (ethyl acetate and hexane (3:7))) on silica gel (precoated F245 Merck plates). Compounds 17a–17c [30, 31] and 19a–19e [26] were prepared according to known procedures.


### 2.1. 5-Amino-6-cyano-4-methyl-2-phenyl-thieno[2,3-d] pyrimidine (3)

A mixture of compound1 (2.27 g, 10 mmol), potassium carbonate anhydrous (2.76 g, 20 mmol), and chloroacetonitrile 2 (0.64 g, 10 mmol) 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 ethyl acetate/ethanol to give pale yellow needles. Yield 2.44 g (92%), mp 259°C; IR: ν 3511, 3359 (NH2), 2204 (CN) cm−1; 1H NMR (DMSO-d6): δ2.60 (3H, s, CH3), 6.23 (2H, br, NH2), 8.55–8.53, 7.53–7.48 (5H, m, phenyl-H); MS: 266(M+,100). Anal. Calcd. for C14H10N4S: C, 63.15; H, 3.75; N, 21.05. Found: C, 63.23; H, 3.80; N, 21.12%.


### 2.2. 6-Cyano-5-ethoxymethyleneamino-4-methyl-2-phenyl-thieno[2,3-d]pyrimidine (4)

A solution of compound3 (2.66 g, 10 mmol) and triethyl orthoformate (8 mL) was refluxed in acetic anhydride (15 mL) for 24 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and recrystallized from ethanol to furnish 4 as pale yellow crystals. Yield 2.67 g (83%), mp 150°C; IR: ν 2215 (CN), 1627 (N=C) cm−1; 1H NMR (CDCl3): δ 1.48 (3H, t, J = 1.42 Hz, CH3), 2.92 (3H, s, CH3), 4.50 (2H, q, J = 2.12 Hz, OCH2), 8.09 (1H, s, N=CH), 8.55–8.53, 7.52–7.50 (5H, m, phenyl-H); MS: 322(M+,100), 293(13), .277(32), 266(96), 250(4), 191(5), 163(33), 153(9), 104(18), 77(19). Anal. Calcd. for C17H14N4OS: C, 63.35; H, 4.34; N, 17.39. Found: C, 63.33; H, 4.40; N, 17.41%.


### 2.3. 7-Ethyl-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido [3,2:4,5]thieno[2,3-d]pyrimidine (6a)

To a solution of compound4 (0.322 g, 1 mmol) in ethanol (10 mL), ethylamine (10 mL) was added. The reaction mixture was refluxed for 4-5 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish 6a as pale yellow crystals. Yield 0.29 g (92%), mp 225°C; IR: ν 3307 (NH), 1614 (C=N) cm−1; 1H NMR (CDCl3): δ 1.47 (3H, t, J = 1.47 Hz, CH3), 3.13 (3H, s, CH3), 4.10 (2H, q, J = 2.15 Hz, CH2), 8.57–8.55, 7.52–7.50 (5H, m, phenyl-H), 7.90 (1H, s, 6-H); MS: 321 (M+,100). Anal. Calcd. for C17H15N5S: C, 63.55; H, 4.67; N, 21.80. Found: C, 63.65; H, 4.70; N, 21.97%.


### 2.4. 2,7-Diphenyl-8-imino-4-methyl-7,8-dihydropyrimido [3,2:4,5]thieno[2,3-d]pyrimidine (6b)

This compound was synthesized from compound4 (0.322 g, 1 mmol) and aniline (0.092 g, 1 mmol) in a similar way to that described for the preparation of 6a. It was recrystallized from acetic acid/DMF to furnish 6b as pale yellow crystals. Yield 0.33 g (90%), mp 249°C; IR: ν 3310 (NH), 1609 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.68 (3H, s, CH3), 8.87–8.85, 8.33–8.01 (10H, m, phenyl-H), 9.22 (1H, s, 6-H), 9.41 (1H, br, NH); MS: 369(M+,100), 265(12), 184(11), 153(2), 136(2), 104(9), 77(21). Anal. Calcd. for C21H15N5S: C, 68.29; H, 4.06; N, 18.97. Found: C, 68.49; H, 4.30; N, 19.19%.


### 2.5. 7-Formyl-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido [3,2:4,5]thieno[2,3-d]pyrimidine (7)

A mixture of compound4 (0.322 g, 1 mmol) and formamide (10 mL) was refluxed for 1 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish 7 as brown crystals. Yield 0.31 g (97%), mp 240°C; IR: ν 3305 (NH), 1678 (CO), 1616 (C=N) cm−1; 1H NMR (DMSO-d6): δ 3.10 (3H, s, CH3), 8.86 (1H, s, 6-H), 8.45-8.44, 7.54–7.47 (5H, m, phenyl-H), 8.33 (1H, br, NH), 8.54 (1H, s, CHO), MS: 321(M+,2), 293(100), 266(2), 190(22), 163(9), 136(2), 103(4), 77(2). Anal. Calcd. for C16H11N5OS: C, 59.81; H, 3.42; N, 21.80. Found: C, 59.95; H, 3.33; N, 21.92%.


### 2.6.2,9-Diphenyl-7-methyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (9a)

A mixture of compound4 (0.322 g, 1 mmol) and benzoylhydrazine 8a (0.136 g, 1 mmol) in 2-methoxyethanol (10 mL) was refluxed for 7 h. After cooling, the resulting solid product was collected by filtration and washed with water, and the crude product was recrystallized from ethanol/glacial acetic acid to furnish 9a as white crystals. Yield 0.34 g (87%), mp 306°C; IR: ν 1603 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.42 (3H, s, CH3), 8.43–8.40, 7.88–7.76 (10H, m, phenyl-H), 9.93 (1H, s, 5-H); MS: 394 (M+,100), 317(2), 290(20), 262(3), 197(10), 153(3), 118(10), 105(20), 77(24). Anal. Calcd. for C22H14N6S: C, 67.00; H, 3.55; N, 21.31. Found: C, 67.23; H, 3.42; N, 21.45%.


### 2.7. 2-(4-Pyridyl)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (9b)

This compound was synthesized from compound4 (0.322 g, 1 mmol) and isonicotinic acid hydrazide (0.137 g, 1 mmol) in a similar way to that described for the preparation of 9a. It was recrystallized from ethanol/DMF to furnish 9b as pale yellow crystals. Yield 0.32 g (83%), mp >340°C; IR: ν 1607 (C=N) cm−1; 1H NMR (CDCl3): δ 3.73 (3H, s, CH3), 7.87–7.82, 7.74–7.71 (5H, m, phenyl-H), 8.40 (2H, d, J = 1.00 Hz, 3,5-H of pyridyl), 8.85 (2H, d, J = 1.00 Hz, 4,6-H of pyridyl), 9.83 (1H, s, 5-H); MS: 395(M+,100), 317(2), 291(20), 267(4), 236(1), 197(10), 190(2), 103(4), 77(8). Anal. Calcd. for C21H13N7S: C, 63.79; H, 3.29; N, 24.81. Found: C, 63.98; H, 3.42; N, 24.99%.


### 2.8. 7-Amino-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (10)

A mixture of compound4 (0.322 g, 1 mmol) and hydrazine hydrate (8 mL, 80%) in ethanol (20 mL) was refluxed for 24 h. After cooling, the resulting solid product was collected by filtration and washed with water, and the crude product was recrystallized from ethanol/DMF to furnish (10) as pale yellow crystals. Yield 0.27 g (89%), mp 285°C; IR: ν 3315, 3247 (NH2, NH), 1603 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.21 (3H, s, CH3), 5.13 (2H, s, NH2), 8.11–8.07, 7.51–7.37 (5H, m, phenyl-H), 8.69 (1H, s, 6-H), 9.23 (H, s, NH); MS: 308(M+,100), 292(2), 278(38), 251(18), 225(2), 188(4), 176(10), 148(6), 120(4), 104(19), 77(16). Anal. Calcd. for C15H12N6S: C, 58.44; H, 3.89; N, 27.27. Found: C, 58.66; H, 3.82; N, 27.36%.


### 2.9. 8-(Acetylamino)-7-diacetylamino-4-methyl-2-phenyl-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (11)

A mixture of compound (10) (0.308 g, 1 mmol) and acetic anhydride (10 mL) was refluxed for 2 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish (11) as orange crystals. Yield 0.41 g (96%), mp 236°C; IR: ν 1718 (CO), 1639(C=N) cm−1; 1H NMR (CF3COOD): δ 2.32 (3H, s, COCH3), 2.56 (6H, s, (COCH3)2), 2.79 (3H, s, CH3), 8.47–8.44, 7.97–7.78 (5H, m, phenyl-H), 9.15 (1H, s, 6-H); MS: 434(M+,20), 393(40), 350(93), 308(100), 280(34), 251(12), 191(2), 176(6), 148(5), 120(4), 103(3). Anal. Calcd. for C21H18N6O3S: C, 58.06; H, 4.14; N, 19.35. Found: C, 58.26; H, 4.04; N, 19.48%.


### 2.10. 2,7-Dimethyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (12)

A mixture of compound (10) (0.308 g, 1 mmol) and glacial acetic acid (10 mL) was refluxed for 2 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish (12) as pale brown crystals. Yield 0.31 g (93%), mp 271°C; IR: ν 1615 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.06 (3H, s, CH3), 3.17 (3H, s, CH3), 8.51–8.49, 7.58–7.53 (5H, m, phenyl-H), 8.72 (1H, s, 5-H); MS: 332(M+,20), 318(6), 293(100), 278(11), 267(1), 229(5), 190(24), 163(9), 103(4). Anal. Calcd. for C17H12N6S: C, 61.44; H, 3.61; N, 25.30. Found: C, 61.69; H, 3.42; N, 25.55%.


### 2.11. 7-(4-Dimethylaminophenyl)azo-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (13)

A mixture of compound (10) (0.308 g, 1 mmol) and N,N-dimethyl-4-nitrosoaniline (0.15 g, 1 mmol) in glacial acetic acid (10 mL) was stirred at 70–80°C for 2 h. The reaction mixture was cooled and poured into ice-water; the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish 13 as brown crystals. Yield 0.28 g (64%), mp 247°C; IR: ν 3305 (NH), 1629 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.51 (6H, s, N(CH3)2), 3.61 (3H, s, CH3), 8.34–8.32, 7.86–7.67 (9H, m, phenyl-H), 8.66 (1H, s, 6-H); MS: 412(M+10), 397(3), 347(3), 332(8), 319(13), 308(10), 293(100), 278(9), 267(8), 215(5), 191(19), 163(10), 136(11), 121(8), 104(8), 77(12). Anal. Calcd. for C23H20N8S: C, 62.72; H, 4.54; N, 25.45. Found: C, 62.86; H, 4.64; N, 25.68%.


### 2.12. General Procedures for the Preparation of 2-(substituted-amino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines (15a–15g)

A mixture of compound (10) (0.308 g, 1 mmol) and appropriate isothiocyanates 14a–14g (1 mmol) in pyridine (10 mL) was refluxed for 7-8 h. The reaction mixture was cooled and poured into ice-water the precipitate was filtered and recrystallized from DMF/ethanol to furnish 15a–15g.


### 2.13. 2-(Methylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15a): Yellowish Brown Crystals

Yield 0.19 g (55%), mp 286°C; IR:ν 3309 (NH), 1612 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.35 (3H, s, CH3), 3.81 (3H, s, CH3), 8.53–8.45, 7.99–7.81 (5H, m, phenyl-H), 9.48 (1H, br, NH), 9.87 (1H, s, 5-H); MS: 347(M+,31), 332(10), 304(3), 293(12), 278(7), 174(1), 163(9), 79(4). Anal. Calcd. for C17H13N7S: C, 58.78; H, 3.74; N, 28.24. Found: C, 58.89; H, 3.82; N, 28.45%.


### 2.14. 2-(Ethylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]-triazolo[1,5-c]pyrimidine (15b)

Pale greenish yellow crystals. Yield 0.10 g (28%), mp 327°C; IR:ν 3303 (NH), 1614 (C=N) cm−1; 1H NMR (CF3COOD): δ 1.92 (3H, t, J = 1.50 Hz, CH3), 3.81 (3H, s, CH3), 4.92 (2H, q, J = 1.00 Hz, CH2), 8.55–8.49, 8.00–7.81 (5H, m, phenyl-H), 9.15 (1H, br, NH), 9.88 (1H, s, 5-H); MS: 361(M+,41), 350(84), 347(100), 332(8), 319(22), 304(4), 293(12), 278(16), 265(8), 215(18), 174(20), 147(9), 103(38), 77(10). Anal. Calcd. for C18H15N7S: C, 59.83; H, 4.15; N, 27.14. Found: C, 59.99; H, 4.35; N, 27.26%.


### 2.15. 2-(Phenylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15c): Greenish Yellow Crystals

Yield 0.20 g (49%), mp 295°C; IR:ν 3311 (NH), 1605 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.78 (3H, s, CH3), 8.46–8.45, 7.92–7.77 (10H, m, phenyl-H), 9.79 (1H, s, 5-H); MS: 409(M+,21), 350(100), 332(8), 304(15), 293(16), 278(8), 247(5), 201(10), 174(8), 147(3), 103(10), 77(4). Anal. Calcd. for C22H15N7S: C, 64.54; H, 3.66; N, 23.96. Found: C, 64.69; H, 3.88; N, 24.11%.


### 2.16. 2-(4-Chlorophenylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15d) Pale Greenish Yellow Crystals

Yield 0.27 g (62%), mp 266°C; IR:ν 3314 (NH), 1612 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.45 (3H, s, CH3), 7.68 (2H, d, J = 1.00 Hz, 3,5-H of phenyl-H), 7.78 (2H, d, J = 1.00 Hz, 2,6-H of phenyl-H), 8.65-8.64, 8.09–7.97 (5H, m, phenyl-H), 9.98 (1H, s, 5-H); MS: 443.5(M+,21), 407(2), 392(14), 350(100), 332(4), 319(5), 304(12), 293(30), 278(11), 255(13), 247(5), 213(16), 174(16), 147(40), 103(20), 91(31), 71(33). Anal. Calcd. for C22H14ClN7S: C, 59.52; H, 3.15; N, 22.09. Found: C, 59.69; H, 3.28; N, 22.21%.


### 2.17. 2-(Benzylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15e): Yellow Crystals

Yield 0.20 g (47%), mp 306°C; IR:ν 3314 (NH), 1601 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.60 (3H, s, CH3), 4.15 (2H, s, CH2), 8.80-8.79, 8.29–7.83 (10H, m, phenyl-H), 8.79 (1H, s, 5-H); MS: 422(M+,10), 350(100), 332(2), 308(20), 304(8), 293(9), 278(12), 265(6), 247(2), 201(4), 174(6), 153(4), 103(28), 91(14), 77(7). Anal. Calcd. for C23H16N7S: C, 65.40; H, 3.79; N, 23.22. Found: C, 65.49; H, 3.88; N, 23.36%.


### 2.18. 2-(2-Mthylphenylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15f): Greenish Yellow Crystals

Yield 0.18 g (43%), mp 285°C; IR:ν 3308 (NH), 1608 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.47 (3H, s, CH3), 2.54 (3H, s, CH3), 8.78–8.45, 8.24–7.79 (9H, m, phenyl-H), 9.78 (1H, s, 5-H); MS: 423(M+,6), 350(100), 332(12), 318(20), 304(8), 293(68), 278(7), 265(8), 247(3), 215(6), 201(5), 190(16), 174(6), 147(3), 103(6), 77(4). Anal. Calcd. for C23H17N7S: C, 65.24; H, 4.01; N, 23.16. Found: C, 65.36; H, 3.95; N, 23.25%.


### 2.19. 2-(1-Naphthylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15g): Greenish Yellow Crystals

Yield 0.23 g (51%), mp 282°C; IR:ν 3309 (NH), 1613 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.41 (3H, s, CH3), 8.58–8.55, 8.32–7.89 (12H, m, phenyl-H and naphthyl-H), 9.89 (1H, s, 5-H); MS: 459(M+,7), 396(4), 350(100), 332(18), 318(18), 304(11), 293(61), 278(6), 265(7), 247(5), 201(7), 174(8), 163(10), 147(6), 103(10), 77(7). Anal. Calcd. for C26H17N7S: C, 67.97; H, 3.70; N, 21.35. Found: C, 68.11; H, 3.88; N, 21.47%.


### 2.20. 4-Methyl-2-phenyl-8H-9,10,11-trihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (16)

There was a mixture of compound (10) (0.308 g, 1 mmol), potassium carbonate anhydrous (3.036 g, 2.2 mmol), and 1,3-dibromopropane (0.201 g, 1 mmol) in DMF (30 mL). The reaction mixture was stirred at 60°C for 9 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and neutralized with 10% hydrochloric acid. The solid formed was collected by filtration, washed with water, and recrystallized from acetic acid/ethanol to give reddish brown crystals. Yield 0.29 g (83%), mp 175°C; IR: ν 3308 (NH), 1611 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.32 (2H, m, 10-CH2), 2.92 (3H, s, CH3), 3.42 (2H, t, J = 1.60 Hz, 11-CH2), 4.42 (2H, t, J = 1.70 Hz, 9-CH2), 8.45–8.33, 7.84–7.81 (5H, m, phenyl-H), 9.84 (1H, s, 6-H), 10.12 (1H, br, NH); MS: 348(M+,11), 333(13), 318(89), 308(8), 293(39), 218(100), 263(3), 251(8), 215(9), 190(14), 175(38), 163(9), 121(10), 104(21), 77(22). Anal. Calcd. for C18H16N6S: C, 62.06; H, 4.59; N, 24.13. Found: C, 62.19; H, 4.65; N, 24.26%.


### 2.21. General Procedures for the Preparation of 9-substituted-4-methyl-2-phenyl-10,11-dihydro-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines (18a–18c)

A mixture of compound (10) (0.308 g, 1 mmol), Mannish base 17a–17c (N,N-dimethyl-2-benzolethylamine hydrochloride 17a, N,N-dimethyl-2-furoylethyl- amine hydrochloride 17b, and N,N-dimethyl-2-thenoylethylamine hydrochloride 17c) (1 mmol), and anhydrous potassium carbonate (0.304 g, 2.2 mmol) was refluxed in DMF (10 mL) for 8 h. After cooling, solid formed was collected by filtration and recrystallized from chloroform/ethanol.


### 2.22.2,9-Diphenyl-4-methyl-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (18a): Pale Brown Crystals

Yield 0.35 g (83%), mp 172°C; IR:ν 1609 (C=N) cm−1; 1H NMR (CDCl3): δ 3.11 (3H, s, CH3), 3.26 (2H, t, J = 1.00 Hz, 10-CH2), 4.21 (2H, t, J = 1.00 Hz, 11-CH2), 8.54–8.51, 7.57–7.41 (10H, m, phenyl-H), 8.72 (1H, s, 6-H); MS: 422(M+,38), 394(5), 345(4), 332(13), 318(96), 293(100), 278(36), 250(7), 214(10), 190(39), 163(22), 159(9), 115(10), 103(39), 77(61). Anal. Calcd. for C24H18N6S: C, 68.24; H, 4.26; N, 19.90. Found: C, 68.49; H, 4.45; N, 20.15%.


### 2.23. 9-(2-Furyl)-4-methyl-2-phenyl-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (18b): Brown Crystals

Yield 0.32 g (79%), mp 162°C; IR:ν 1615 (C=N) cm−1; 1H NMR (CDCl3): δ 3.16 (3H, s, CH3), 3.22 (2H, t, J = 1.00 Hz, 10-CH2), 4.19 (2H, t, J = 1.00 Hz, 11-CH2), 6.84 (1H, dd, J = 1.00, 1.00 Hz, 4-H of furyl), 7.59 (1H, d, J = 1.00 Hz, 3-H of furyl), 8.49–8.44, 7.54–7.49 (5H, m, phenyl-H), 8.54 (1H, d, J = 1.0 Hz, 5-H of furyl), 8.71 (1H, s, 6-H); MS: 412(M+,20), 384(5), 345(4), 332(3), 318(50), 293(100), 278(26), 250(4), 215(8), 190(39), 163(21), 153(7), 120(7), 103(28), 95(29), 77(30), 51(9). Anal. Calcd. for C22H16N6OS: C, 64.07; H, 3.88; N, 20.38. Found: C, 64.19; H, 3.98; N, 20.45%.


### 2.24. 9-(2-Thienyl)-4-methyl-2-phenyl-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (18c): Pale Yellow Crystals

Yield 0.35 g (82%), mp 154°C; IR:ν 1621 (C=N) cm−1; 1H NMR (CDCl3): δ 3.16 (3H, s, CH3), 3.28 (2H, t, J = 1.00 Hz, 10-CH2), 4.23 (2H, t, J = 1.00 Hz, 11-CH2), 7.08 (1H, dd, J = 1.00, 1.00 Hz, 4-H of thienyl), 8.57–8.40, 7.54–7.42 (6H, m, 3-H of thienyl and phenyl-H), 8.62 (1H, d, J = 1.00 Hz, 5-H of thienyl), 8.73 (1H, s, 6-H); MS: 428(M+,10), 400(5), 345(2), 332(6), 318(19), 293(100), 278(22), 250(4), 215(5), 190(40), 163(23), 153(9), 110(45), 103(32), 77(30), 51(10). Anal. Calcd. for C22H16N6S2: C, 61.68; H, 3.73; N, 19.62. Found: C, 61.78; H, 3.88; N, 19.80%.


### 2.25. 7-[1-(4-Pyridyl)prop-2-enone-3-yl]amino-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (20)

Method A: a mixture of compound (10) (0.308 g, 1 mmol) and 3-dimethylamino-1-(4-pyridyl)prop-2-enone 19e (0.176 g, 1 mmol) in glacial acetic acid (10 mL) was stirred at 80°C for 7 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and recrystallized from DMF/ethanol to give brownish yellow crystals. Yield 0.26 g (60%), mp 207°C; IR: ν 3215 (NH), 1668 (C=O), 1632 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.59 (3H, s, CH3), 4.00 (1H, d, J = 1.05 Hz, COCH=), 8.68 (2H, d, J = 1.00 Hz, 3,5-H of pyridyl), 8.78–8.74, 8.26–8.07 (6H, m, -NCH= and phenyl-H), 9.27 (2H, d, J = 1.00 Hz, 2,6-H of pyridyl), 9.53 (1H, s, 6-H); MS: 439(M+,20), 421(100), 394(14), 367(29), 333(20), 319(88), 308(58), 293(29), 278(27), 215(9), 210(16), 174(15), 121(10), 104(22), 77(23), 51(14). Anal. Calcd. for C23H17N7OS: C, 62.87; H, 3.87; N, 22.32. Found: C, 62.88; H, 3.98; N, 22.47%. Method B: a mixture of compound (10) (0.308 g, 1 mmol) and 19e (0.176 g, 1 mmol) in glacial acetic acid (10 mL) was stirred at 50–55°C for 3 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and recrystallized to obtain 20 (0.31 g, 70%).


### 2.26. General Procedures for the Preparation of 11-substituted-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines (21a–21d)

A mixture of compound (10) (0.308 g, 1 mmol) and appropriate 3-dimethyl-amino-1-(substituted)prop-2-enones 19a–19d (1 mmol) in glacial acetic acid (10 mL) was refluxed for 10 h. The reaction mixture was cooled and poured into ice-water; the precipitate was filtered and recrystallized from DMF/ethanol to obtain 21a–21d.


### 2.27. 2,11-Diphenyl-4-methyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21a): Pale Reddish Brown Crystals

Yield 0.29 g (70%), mp 194°C; IR:ν 1611 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.22 (3H, s, CH3), 7.08 (2H, d, J = 1.00 Hz, 10-H), 7.48 (2H, d, J = 1.00 Hz, 9-H), 8.03–7.68, 7.59–7.53 (10H, m, phenyl-H), 9.51 (1H, s, 6-H); MS: 420(M+,100), 387(12), 366(48), 318(23), 308(30), 293(45), 278(29), 263(8), 210(14), 190(19), 120(9), 105(38), 77(56). Anal. Calcd. for C24H16N6S: C, 68.57; H, 3.80; N, 20.00. Found: C, 68.69; H, 3.95; N, 20.25%.


### 2.28. 11-(2-Furyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21b): Greenish Yellow Crystals

Yield 0.26 g, (64%) mp 244°C; IR:ν 1619 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.23 (3H, s, CH3), 7.05 (2H, d, J = 1.00 Hz, 10-H), 6.60 (1H, dd, J = 1.00, 1.00 Hz, 4-H of furyl), 6.69 (1H, d, J = 1.00 Hz, 3-H of furyl), 7.91–7.81, 7.76–7.61 (6H, m, 9-H, and phenyl-H), 8.34 (1H, d, J = 1.00 Hz, 5-H of furyl), 9.53 (1H, s, 6-H); MS: 410(M+,100), 356(42), 319(82), 293(48), 278(42), 250(18), 229(10), 205(13), 190(23), 174(18), 163(14), 129(25), 104(44), 95(51), 77(42). Anal. Calcd. for C22H14N6OS: C, 64.39; H, 3.41; N, 20.48. Found: C, 64.49; H, 3.68; N, 20.55%.


### 2.29. 11-(2-Thienyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21c): Yellowish Brown Crystals

Yield 0.27 g (63%), mp 231°C; IR:ν 1623 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.24 (3H, s, CH3), 7.33 (2H, d, J = 1.00 Hz, 10-H), 7.84 (2H, d, J = 1.00 Hz, 9-H), 7.20 (1H, dd, J = 1.00, 1.00 Hz, 4-H of thienyl), 7.13 (1H, d, J = 1.00 Hz, 3-H of thienyl), 7.91–7.90, 7.31–7.29 (5H, m, phenyl-H), 8.11 (1H, d, J = 1.0 Hz, 5-H of thienyl), 9.54 (1H, s, 6-H); MS: 426(M+,10), 399(5), 333(7), 319(100), 279(13), 213(2), 190(7), 121(3), 111(77), 77(8). Anal. Calcd. for C22H14N6S2: C, 61.97; H, 3.28; N, 19.71. Found: C, 62.12; H, 3.38; N, 19.87%.


### 2.30. 11-(2-Pyrazinyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21d): Brown Crystals

Yield 0.22 g (53%), mp 240°C; IR:ν 1624 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.32 (3H, s, CH3), 6.71 (2H, d, J = 1.00 Hz, 10-H), 7.45 (2H, d, J = 1.00 Hz, 9-H), 8.24 (1H, d, J = 1.00 Hz, 6-H of pyrazinyl), 8.41–8.36, 7.93–7.77 (5H, m, phenyl-H), 8.49 (1H, d, J = 1.00 Hz, 5-H of pyrazinyl), 8.98 (1H, s, 3-H of pyrazinyl), 9.19 (1H, s, 6-H); MS: 422(M+,24), 395(9), 319(35), 293(100), 238(4), 215(10), 190(41), 163(22), 147(8), 104(19), 77(23). Anal. Calcd. for C22H14N8S: C, 62.55; H, 3.31; N, 26.54. Found: C, 62.74; H, 3.48; N, 26.78%.


### 2.31. 11-(4-Pyridyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21e)

Method A: this compound was synthesized from compound (10) (0.308 g, 1 mmol) in glacial acetic acid in a similar way to that described for the preparation of 21a–21d. It was recrystallized from DMF/ethanol to give pale brown crystals. Yield 0.29 g, (68%) mp 237°C; IR: ν 1622 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.19 (3H, s, CH3), 7.30 (2H, d, J = 1.0 Hz, 10-H), 7.97 (2H, d, J = 1.00 Hz, 3,5-H of pyridyl), 8.14–8.12, 7.50–7.38 (5H, m, phenyl-H), 8.16 (2H, d, J = 1.00 Hz, 9-H), 8.31 (1H, s, 6-H), 8.54 (2H, d, J = 1.00 Hz, 2,6-H of pyridyl); MS: 421(M+,100), 367(4), 333(8), 318(19), 308(44), 293(66), 278(42), 214(8), 198(10), 190(22), 163(12), 120(5), 104(22), 77(26). Anal. Calcd. for C23H15N7S: C, 65.55; H, 3.56; N, 23.27. Found: C, 65.74; H, 3.68; N, 23.48%. Method B: the filtrate from the above reaction 20 was poured into cold water (20 mL) and stirred for 15 min. The resulting precipitate was collected by filtration and recrystallized to give 21e (0.026 g, 6.3%). Method C: a mixture of 20 (0.439 g, 1 mmol) and glacial acetic acid (10 mL) was refluxed for 10 h. The reaction mixture was cooled and poured into ice-water; the precipitate was filtered and recrystallized to obtain 21e (0.202 g, 48%).


## 2.1. 5-Amino-6-cyano-4-methyl-2-phenyl-thieno[2,3-d] pyrimidine (3)

A mixture of compound1 (2.27 g, 10 mmol), potassium carbonate anhydrous (2.76 g, 20 mmol), and chloroacetonitrile 2 (0.64 g, 10 mmol) 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 ethyl acetate/ethanol to give pale yellow needles. Yield 2.44 g (92%), mp 259°C; IR: ν 3511, 3359 (NH2), 2204 (CN) cm−1; 1H NMR (DMSO-d6): δ2.60 (3H, s, CH3), 6.23 (2H, br, NH2), 8.55–8.53, 7.53–7.48 (5H, m, phenyl-H); MS: 266(M+,100). Anal. Calcd. for C14H10N4S: C, 63.15; H, 3.75; N, 21.05. Found: C, 63.23; H, 3.80; N, 21.12%.


## 2.2. 6-Cyano-5-ethoxymethyleneamino-4-methyl-2-phenyl-thieno[2,3-d]pyrimidine (4)

A solution of compound3 (2.66 g, 10 mmol) and triethyl orthoformate (8 mL) was refluxed in acetic anhydride (15 mL) for 24 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and recrystallized from ethanol to furnish 4 as pale yellow crystals. Yield 2.67 g (83%), mp 150°C; IR: ν 2215 (CN), 1627 (N=C) cm−1; 1H NMR (CDCl3): δ 1.48 (3H, t, J = 1.42 Hz, CH3), 2.92 (3H, s, CH3), 4.50 (2H, q, J = 2.12 Hz, OCH2), 8.09 (1H, s, N=CH), 8.55–8.53, 7.52–7.50 (5H, m, phenyl-H); MS: 322(M+,100), 293(13), .277(32), 266(96), 250(4), 191(5), 163(33), 153(9), 104(18), 77(19). Anal. Calcd. for C17H14N4OS: C, 63.35; H, 4.34; N, 17.39. Found: C, 63.33; H, 4.40; N, 17.41%.


## 2.3. 7-Ethyl-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido [3,2:4,5]thieno[2,3-d]pyrimidine (6a)

To a solution of compound4 (0.322 g, 1 mmol) in ethanol (10 mL), ethylamine (10 mL) was added. The reaction mixture was refluxed for 4-5 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish 6a as pale yellow crystals. Yield 0.29 g (92%), mp 225°C; IR: ν 3307 (NH), 1614 (C=N) cm−1; 1H NMR (CDCl3): δ 1.47 (3H, t, J = 1.47 Hz, CH3), 3.13 (3H, s, CH3), 4.10 (2H, q, J = 2.15 Hz, CH2), 8.57–8.55, 7.52–7.50 (5H, m, phenyl-H), 7.90 (1H, s, 6-H); MS: 321 (M+,100). Anal. Calcd. for C17H15N5S: C, 63.55; H, 4.67; N, 21.80. Found: C, 63.65; H, 4.70; N, 21.97%.


## 2.4. 2,7-Diphenyl-8-imino-4-methyl-7,8-dihydropyrimido [3,2:4,5]thieno[2,3-d]pyrimidine (6b)

This compound was synthesized from compound4 (0.322 g, 1 mmol) and aniline (0.092 g, 1 mmol) in a similar way to that described for the preparation of 6a. It was recrystallized from acetic acid/DMF to furnish 6b as pale yellow crystals. Yield 0.33 g (90%), mp 249°C; IR: ν 3310 (NH), 1609 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.68 (3H, s, CH3), 8.87–8.85, 8.33–8.01 (10H, m, phenyl-H), 9.22 (1H, s, 6-H), 9.41 (1H, br, NH); MS: 369(M+,100), 265(12), 184(11), 153(2), 136(2), 104(9), 77(21). Anal. Calcd. for C21H15N5S: C, 68.29; H, 4.06; N, 18.97. Found: C, 68.49; H, 4.30; N, 19.19%.


## 2.5. 7-Formyl-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido [3,2:4,5]thieno[2,3-d]pyrimidine (7)

A mixture of compound4 (0.322 g, 1 mmol) and formamide (10 mL) was refluxed for 1 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish 7 as brown crystals. Yield 0.31 g (97%), mp 240°C; IR: ν 3305 (NH), 1678 (CO), 1616 (C=N) cm−1; 1H NMR (DMSO-d6): δ 3.10 (3H, s, CH3), 8.86 (1H, s, 6-H), 8.45-8.44, 7.54–7.47 (5H, m, phenyl-H), 8.33 (1H, br, NH), 8.54 (1H, s, CHO), MS: 321(M+,2), 293(100), 266(2), 190(22), 163(9), 136(2), 103(4), 77(2). Anal. Calcd. for C16H11N5OS: C, 59.81; H, 3.42; N, 21.80. Found: C, 59.95; H, 3.33; N, 21.92%.


## 2.6.2,9-Diphenyl-7-methyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (9a)

A mixture of compound4 (0.322 g, 1 mmol) and benzoylhydrazine 8a (0.136 g, 1 mmol) in 2-methoxyethanol (10 mL) was refluxed for 7 h. After cooling, the resulting solid product was collected by filtration and washed with water, and the crude product was recrystallized from ethanol/glacial acetic acid to furnish 9a as white crystals. Yield 0.34 g (87%), mp 306°C; IR: ν 1603 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.42 (3H, s, CH3), 8.43–8.40, 7.88–7.76 (10H, m, phenyl-H), 9.93 (1H, s, 5-H); MS: 394 (M+,100), 317(2), 290(20), 262(3), 197(10), 153(3), 118(10), 105(20), 77(24). Anal. Calcd. for C22H14N6S: C, 67.00; H, 3.55; N, 21.31. Found: C, 67.23; H, 3.42; N, 21.45%.


## 2.7. 2-(4-Pyridyl)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (9b)

This compound was synthesized from compound4 (0.322 g, 1 mmol) and isonicotinic acid hydrazide (0.137 g, 1 mmol) in a similar way to that described for the preparation of 9a. It was recrystallized from ethanol/DMF to furnish 9b as pale yellow crystals. Yield 0.32 g (83%), mp >340°C; IR: ν 1607 (C=N) cm−1; 1H NMR (CDCl3): δ 3.73 (3H, s, CH3), 7.87–7.82, 7.74–7.71 (5H, m, phenyl-H), 8.40 (2H, d, J = 1.00 Hz, 3,5-H of pyridyl), 8.85 (2H, d, J = 1.00 Hz, 4,6-H of pyridyl), 9.83 (1H, s, 5-H); MS: 395(M+,100), 317(2), 291(20), 267(4), 236(1), 197(10), 190(2), 103(4), 77(8). Anal. Calcd. for C21H13N7S: C, 63.79; H, 3.29; N, 24.81. Found: C, 63.98; H, 3.42; N, 24.99%.


## 2.8. 7-Amino-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (10)

A mixture of compound4 (0.322 g, 1 mmol) and hydrazine hydrate (8 mL, 80%) in ethanol (20 mL) was refluxed for 24 h. After cooling, the resulting solid product was collected by filtration and washed with water, and the crude product was recrystallized from ethanol/DMF to furnish (10) as pale yellow crystals. Yield 0.27 g (89%), mp 285°C; IR: ν 3315, 3247 (NH2, NH), 1603 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.21 (3H, s, CH3), 5.13 (2H, s, NH2), 8.11–8.07, 7.51–7.37 (5H, m, phenyl-H), 8.69 (1H, s, 6-H), 9.23 (H, s, NH); MS: 308(M+,100), 292(2), 278(38), 251(18), 225(2), 188(4), 176(10), 148(6), 120(4), 104(19), 77(16). Anal. Calcd. for C15H12N6S: C, 58.44; H, 3.89; N, 27.27. Found: C, 58.66; H, 3.82; N, 27.36%.


## 2.9. 8-(Acetylamino)-7-diacetylamino-4-methyl-2-phenyl-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (11)

A mixture of compound (10) (0.308 g, 1 mmol) and acetic anhydride (10 mL) was refluxed for 2 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish (11) as orange crystals. Yield 0.41 g (96%), mp 236°C; IR: ν 1718 (CO), 1639(C=N) cm−1; 1H NMR (CF3COOD): δ 2.32 (3H, s, COCH3), 2.56 (6H, s, (COCH3)2), 2.79 (3H, s, CH3), 8.47–8.44, 7.97–7.78 (5H, m, phenyl-H), 9.15 (1H, s, 6-H); MS: 434(M+,20), 393(40), 350(93), 308(100), 280(34), 251(12), 191(2), 176(6), 148(5), 120(4), 103(3). Anal. Calcd. for C21H18N6O3S: C, 58.06; H, 4.14; N, 19.35. Found: C, 58.26; H, 4.04; N, 19.48%.


## 2.10. 2,7-Dimethyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (12)

A mixture of compound (10) (0.308 g, 1 mmol) and glacial acetic acid (10 mL) was refluxed for 2 h. After cooling, the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish (12) as pale brown crystals. Yield 0.31 g (93%), mp 271°C; IR: ν 1615 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.06 (3H, s, CH3), 3.17 (3H, s, CH3), 8.51–8.49, 7.58–7.53 (5H, m, phenyl-H), 8.72 (1H, s, 5-H); MS: 332(M+,20), 318(6), 293(100), 278(11), 267(1), 229(5), 190(24), 163(9), 103(4). Anal. Calcd. for C17H12N6S: C, 61.44; H, 3.61; N, 25.30. Found: C, 61.69; H, 3.42; N, 25.55%.


## 2.11. 7-(4-Dimethylaminophenyl)azo-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (13)

A mixture of compound (10) (0.308 g, 1 mmol) and N,N-dimethyl-4-nitrosoaniline (0.15 g, 1 mmol) in glacial acetic acid (10 mL) was stirred at 70–80°C for 2 h. The reaction mixture was cooled and poured into ice-water; the precipitate was filtered and recrystallized from acetic acid/ethanol to furnish 13 as brown crystals. Yield 0.28 g (64%), mp 247°C; IR: ν 3305 (NH), 1629 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.51 (6H, s, N(CH3)2), 3.61 (3H, s, CH3), 8.34–8.32, 7.86–7.67 (9H, m, phenyl-H), 8.66 (1H, s, 6-H); MS: 412(M+10), 397(3), 347(3), 332(8), 319(13), 308(10), 293(100), 278(9), 267(8), 215(5), 191(19), 163(10), 136(11), 121(8), 104(8), 77(12). Anal. Calcd. for C23H20N8S: C, 62.72; H, 4.54; N, 25.45. Found: C, 62.86; H, 4.64; N, 25.68%.


## 2.12. General Procedures for the Preparation of 2-(substituted-amino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines (15a–15g)

A mixture of compound (10) (0.308 g, 1 mmol) and appropriate isothiocyanates 14a–14g (1 mmol) in pyridine (10 mL) was refluxed for 7-8 h. The reaction mixture was cooled and poured into ice-water the precipitate was filtered and recrystallized from DMF/ethanol to furnish 15a–15g.


## 2.13. 2-(Methylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15a): Yellowish Brown Crystals

Yield 0.19 g (55%), mp 286°C; IR:ν 3309 (NH), 1612 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.35 (3H, s, CH3), 3.81 (3H, s, CH3), 8.53–8.45, 7.99–7.81 (5H, m, phenyl-H), 9.48 (1H, br, NH), 9.87 (1H, s, 5-H); MS: 347(M+,31), 332(10), 304(3), 293(12), 278(7), 174(1), 163(9), 79(4). Anal. Calcd. for C17H13N7S: C, 58.78; H, 3.74; N, 28.24. Found: C, 58.89; H, 3.82; N, 28.45%.


## 2.14. 2-(Ethylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]-triazolo[1,5-c]pyrimidine (15b)

Pale greenish yellow crystals. Yield 0.10 g (28%), mp 327°C; IR:ν 3303 (NH), 1614 (C=N) cm−1; 1H NMR (CF3COOD): δ 1.92 (3H, t, J = 1.50 Hz, CH3), 3.81 (3H, s, CH3), 4.92 (2H, q, J = 1.00 Hz, CH2), 8.55–8.49, 8.00–7.81 (5H, m, phenyl-H), 9.15 (1H, br, NH), 9.88 (1H, s, 5-H); MS: 361(M+,41), 350(84), 347(100), 332(8), 319(22), 304(4), 293(12), 278(16), 265(8), 215(18), 174(20), 147(9), 103(38), 77(10). Anal. Calcd. for C18H15N7S: C, 59.83; H, 4.15; N, 27.14. Found: C, 59.99; H, 4.35; N, 27.26%.


## 2.15. 2-(Phenylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15c): Greenish Yellow Crystals

Yield 0.20 g (49%), mp 295°C; IR:ν 3311 (NH), 1605 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.78 (3H, s, CH3), 8.46–8.45, 7.92–7.77 (10H, m, phenyl-H), 9.79 (1H, s, 5-H); MS: 409(M+,21), 350(100), 332(8), 304(15), 293(16), 278(8), 247(5), 201(10), 174(8), 147(3), 103(10), 77(4). Anal. Calcd. for C22H15N7S: C, 64.54; H, 3.66; N, 23.96. Found: C, 64.69; H, 3.88; N, 24.11%.


## 2.16. 2-(4-Chlorophenylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15d) Pale Greenish Yellow Crystals

Yield 0.27 g (62%), mp 266°C; IR:ν 3314 (NH), 1612 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.45 (3H, s, CH3), 7.68 (2H, d, J = 1.00 Hz, 3,5-H of phenyl-H), 7.78 (2H, d, J = 1.00 Hz, 2,6-H of phenyl-H), 8.65-8.64, 8.09–7.97 (5H, m, phenyl-H), 9.98 (1H, s, 5-H); MS: 443.5(M+,21), 407(2), 392(14), 350(100), 332(4), 319(5), 304(12), 293(30), 278(11), 255(13), 247(5), 213(16), 174(16), 147(40), 103(20), 91(31), 71(33). Anal. Calcd. for C22H14ClN7S: C, 59.52; H, 3.15; N, 22.09. Found: C, 59.69; H, 3.28; N, 22.21%.


## 2.17. 2-(Benzylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15e): Yellow Crystals

Yield 0.20 g (47%), mp 306°C; IR:ν 3314 (NH), 1601 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.60 (3H, s, CH3), 4.15 (2H, s, CH2), 8.80-8.79, 8.29–7.83 (10H, m, phenyl-H), 8.79 (1H, s, 5-H); MS: 422(M+,10), 350(100), 332(2), 308(20), 304(8), 293(9), 278(12), 265(6), 247(2), 201(4), 174(6), 153(4), 103(28), 91(14), 77(7). Anal. Calcd. for C23H16N7S: C, 65.40; H, 3.79; N, 23.22. Found: C, 65.49; H, 3.88; N, 23.36%.


## 2.18. 2-(2-Mthylphenylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15f): Greenish Yellow Crystals

Yield 0.18 g (43%), mp 285°C; IR:ν 3308 (NH), 1608 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.47 (3H, s, CH3), 2.54 (3H, s, CH3), 8.78–8.45, 8.24–7.79 (9H, m, phenyl-H), 9.78 (1H, s, 5-H); MS: 423(M+,6), 350(100), 332(12), 318(20), 304(8), 293(68), 278(7), 265(8), 247(3), 215(6), 201(5), 190(16), 174(6), 147(3), 103(6), 77(4). Anal. Calcd. for C23H17N7S: C, 65.24; H, 4.01; N, 23.16. Found: C, 65.36; H, 3.95; N, 23.25%.


## 2.19. 2-(1-Naphthylamino)-7-methyl-9-phenyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (15g): Greenish Yellow Crystals

Yield 0.23 g (51%), mp 282°C; IR:ν 3309 (NH), 1613 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.41 (3H, s, CH3), 8.58–8.55, 8.32–7.89 (12H, m, phenyl-H and naphthyl-H), 9.89 (1H, s, 5-H); MS: 459(M+,7), 396(4), 350(100), 332(18), 318(18), 304(11), 293(61), 278(6), 265(7), 247(5), 201(7), 174(8), 163(10), 147(6), 103(10), 77(7). Anal. Calcd. for C26H17N7S: C, 67.97; H, 3.70; N, 21.35. Found: C, 68.11; H, 3.88; N, 21.47%.


## 2.20. 4-Methyl-2-phenyl-8H-9,10,11-trihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (16)

There was a mixture of compound (10) (0.308 g, 1 mmol), potassium carbonate anhydrous (3.036 g, 2.2 mmol), and 1,3-dibromopropane (0.201 g, 1 mmol) in DMF (30 mL). The reaction mixture was stirred at 60°C for 9 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and neutralized with 10% hydrochloric acid. The solid formed was collected by filtration, washed with water, and recrystallized from acetic acid/ethanol to give reddish brown crystals. Yield 0.29 g (83%), mp 175°C; IR: ν 3308 (NH), 1611 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.32 (2H, m, 10-CH2), 2.92 (3H, s, CH3), 3.42 (2H, t, J = 1.60 Hz, 11-CH2), 4.42 (2H, t, J = 1.70 Hz, 9-CH2), 8.45–8.33, 7.84–7.81 (5H, m, phenyl-H), 9.84 (1H, s, 6-H), 10.12 (1H, br, NH); MS: 348(M+,11), 333(13), 318(89), 308(8), 293(39), 218(100), 263(3), 251(8), 215(9), 190(14), 175(38), 163(9), 121(10), 104(21), 77(22). Anal. Calcd. for C18H16N6S: C, 62.06; H, 4.59; N, 24.13. Found: C, 62.19; H, 4.65; N, 24.26%.


## 2.21. General Procedures for the Preparation of 9-substituted-4-methyl-2-phenyl-10,11-dihydro-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines (18a–18c)

A mixture of compound (10) (0.308 g, 1 mmol), Mannish base 17a–17c (N,N-dimethyl-2-benzolethylamine hydrochloride 17a, N,N-dimethyl-2-furoylethyl- amine hydrochloride 17b, and N,N-dimethyl-2-thenoylethylamine hydrochloride 17c) (1 mmol), and anhydrous potassium carbonate (0.304 g, 2.2 mmol) was refluxed in DMF (10 mL) for 8 h. After cooling, solid formed was collected by filtration and recrystallized from chloroform/ethanol.


## 2.22.2,9-Diphenyl-4-methyl-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (18a): Pale Brown Crystals

Yield 0.35 g (83%), mp 172°C; IR:ν 1609 (C=N) cm−1; 1H NMR (CDCl3): δ 3.11 (3H, s, CH3), 3.26 (2H, t, J = 1.00 Hz, 10-CH2), 4.21 (2H, t, J = 1.00 Hz, 11-CH2), 8.54–8.51, 7.57–7.41 (10H, m, phenyl-H), 8.72 (1H, s, 6-H); MS: 422(M+,38), 394(5), 345(4), 332(13), 318(96), 293(100), 278(36), 250(7), 214(10), 190(39), 163(22), 159(9), 115(10), 103(39), 77(61). Anal. Calcd. for C24H18N6S: C, 68.24; H, 4.26; N, 19.90. Found: C, 68.49; H, 4.45; N, 20.15%.


## 2.23. 9-(2-Furyl)-4-methyl-2-phenyl-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (18b): Brown Crystals

Yield 0.32 g (79%), mp 162°C; IR:ν 1615 (C=N) cm−1; 1H NMR (CDCl3): δ 3.16 (3H, s, CH3), 3.22 (2H, t, J = 1.00 Hz, 10-CH2), 4.19 (2H, t, J = 1.00 Hz, 11-CH2), 6.84 (1H, dd, J = 1.00, 1.00 Hz, 4-H of furyl), 7.59 (1H, d, J = 1.00 Hz, 3-H of furyl), 8.49–8.44, 7.54–7.49 (5H, m, phenyl-H), 8.54 (1H, d, J = 1.0 Hz, 5-H of furyl), 8.71 (1H, s, 6-H); MS: 412(M+,20), 384(5), 345(4), 332(3), 318(50), 293(100), 278(26), 250(4), 215(8), 190(39), 163(21), 153(7), 120(7), 103(28), 95(29), 77(30), 51(9). Anal. Calcd. for C22H16N6OS: C, 64.07; H, 3.88; N, 20.38. Found: C, 64.19; H, 3.98; N, 20.45%.


## 2.24. 9-(2-Thienyl)-4-methyl-2-phenyl-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (18c): Pale Yellow Crystals

Yield 0.35 g (82%), mp 154°C; IR:ν 1621 (C=N) cm−1; 1H NMR (CDCl3): δ 3.16 (3H, s, CH3), 3.28 (2H, t, J = 1.00 Hz, 10-CH2), 4.23 (2H, t, J = 1.00 Hz, 11-CH2), 7.08 (1H, dd, J = 1.00, 1.00 Hz, 4-H of thienyl), 8.57–8.40, 7.54–7.42 (6H, m, 3-H of thienyl and phenyl-H), 8.62 (1H, d, J = 1.00 Hz, 5-H of thienyl), 8.73 (1H, s, 6-H); MS: 428(M+,10), 400(5), 345(2), 332(6), 318(19), 293(100), 278(22), 250(4), 215(5), 190(40), 163(23), 153(9), 110(45), 103(32), 77(30), 51(10). Anal. Calcd. for C22H16N6S2: C, 61.68; H, 3.73; N, 19.62. Found: C, 61.78; H, 3.88; N, 19.80%.


## 2.25. 7-[1-(4-Pyridyl)prop-2-enone-3-yl]amino-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (20)

Method A: a mixture of compound (10) (0.308 g, 1 mmol) and 3-dimethylamino-1-(4-pyridyl)prop-2-enone 19e (0.176 g, 1 mmol) in glacial acetic acid (10 mL) was stirred at 80°C for 7 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and recrystallized from DMF/ethanol to give brownish yellow crystals. Yield 0.26 g (60%), mp 207°C; IR: ν 3215 (NH), 1668 (C=O), 1632 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.59 (3H, s, CH3), 4.00 (1H, d, J = 1.05 Hz, COCH=), 8.68 (2H, d, J = 1.00 Hz, 3,5-H of pyridyl), 8.78–8.74, 8.26–8.07 (6H, m, -NCH= and phenyl-H), 9.27 (2H, d, J = 1.00 Hz, 2,6-H of pyridyl), 9.53 (1H, s, 6-H); MS: 439(M+,20), 421(100), 394(14), 367(29), 333(20), 319(88), 308(58), 293(29), 278(27), 215(9), 210(16), 174(15), 121(10), 104(22), 77(23), 51(14). Anal. Calcd. for C23H17N7OS: C, 62.87; H, 3.87; N, 22.32. Found: C, 62.88; H, 3.98; N, 22.47%. Method B: a mixture of compound (10) (0.308 g, 1 mmol) and 19e (0.176 g, 1 mmol) in glacial acetic acid (10 mL) was stirred at 50–55°C for 3 h. The reaction mixture was cooled. The resulting solid product was collected by filtration and recrystallized to obtain 20 (0.31 g, 70%).


## 2.26. General Procedures for the Preparation of 11-substituted-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines (21a–21d)

A mixture of compound (10) (0.308 g, 1 mmol) and appropriate 3-dimethyl-amino-1-(substituted)prop-2-enones 19a–19d (1 mmol) in glacial acetic acid (10 mL) was refluxed for 10 h. The reaction mixture was cooled and poured into ice-water; the precipitate was filtered and recrystallized from DMF/ethanol to obtain 21a–21d.


## 2.27. 2,11-Diphenyl-4-methyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21a): Pale Reddish Brown Crystals

Yield 0.29 g (70%), mp 194°C; IR:ν 1611 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.22 (3H, s, CH3), 7.08 (2H, d, J = 1.00 Hz, 10-H), 7.48 (2H, d, J = 1.00 Hz, 9-H), 8.03–7.68, 7.59–7.53 (10H, m, phenyl-H), 9.51 (1H, s, 6-H); MS: 420(M+,100), 387(12), 366(48), 318(23), 308(30), 293(45), 278(29), 263(8), 210(14), 190(19), 120(9), 105(38), 77(56). Anal. Calcd. for C24H16N6S: C, 68.57; H, 3.80; N, 20.00. Found: C, 68.69; H, 3.95; N, 20.25%.


## 2.28. 11-(2-Furyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21b): Greenish Yellow Crystals

Yield 0.26 g, (64%) mp 244°C; IR:ν 1619 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.23 (3H, s, CH3), 7.05 (2H, d, J = 1.00 Hz, 10-H), 6.60 (1H, dd, J = 1.00, 1.00 Hz, 4-H of furyl), 6.69 (1H, d, J = 1.00 Hz, 3-H of furyl), 7.91–7.81, 7.76–7.61 (6H, m, 9-H, and phenyl-H), 8.34 (1H, d, J = 1.00 Hz, 5-H of furyl), 9.53 (1H, s, 6-H); MS: 410(M+,100), 356(42), 319(82), 293(48), 278(42), 250(18), 229(10), 205(13), 190(23), 174(18), 163(14), 129(25), 104(44), 95(51), 77(42). Anal. Calcd. for C22H14N6OS: C, 64.39; H, 3.41; N, 20.48. Found: C, 64.49; H, 3.68; N, 20.55%.


## 2.29. 11-(2-Thienyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21c): Yellowish Brown Crystals

Yield 0.27 g (63%), mp 231°C; IR:ν 1623 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.24 (3H, s, CH3), 7.33 (2H, d, J = 1.00 Hz, 10-H), 7.84 (2H, d, J = 1.00 Hz, 9-H), 7.20 (1H, dd, J = 1.00, 1.00 Hz, 4-H of thienyl), 7.13 (1H, d, J = 1.00 Hz, 3-H of thienyl), 7.91–7.90, 7.31–7.29 (5H, m, phenyl-H), 8.11 (1H, d, J = 1.0 Hz, 5-H of thienyl), 9.54 (1H, s, 6-H); MS: 426(M+,10), 399(5), 333(7), 319(100), 279(13), 213(2), 190(7), 121(3), 111(77), 77(8). Anal. Calcd. for C22H14N6S2: C, 61.97; H, 3.28; N, 19.71. Found: C, 62.12; H, 3.38; N, 19.87%.


## 2.30. 11-(2-Pyrazinyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21d): Brown Crystals

Yield 0.22 g (53%), mp 240°C; IR:ν 1624 (C=N) cm−1; 1H NMR (CF3COOD): δ 2.32 (3H, s, CH3), 6.71 (2H, d, J = 1.00 Hz, 10-H), 7.45 (2H, d, J = 1.00 Hz, 9-H), 8.24 (1H, d, J = 1.00 Hz, 6-H of pyrazinyl), 8.41–8.36, 7.93–7.77 (5H, m, phenyl-H), 8.49 (1H, d, J = 1.00 Hz, 5-H of pyrazinyl), 8.98 (1H, s, 3-H of pyrazinyl), 9.19 (1H, s, 6-H); MS: 422(M+,24), 395(9), 319(35), 293(100), 238(4), 215(10), 190(41), 163(22), 147(8), 104(19), 77(23). Anal. Calcd. for C22H14N8S: C, 62.55; H, 3.31; N, 26.54. Found: C, 62.74; H, 3.48; N, 26.78%.


## 2.31. 11-(4-Pyridyl)-4-methyl-2-phenyl-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine (21e)

Method A: this compound was synthesized from compound (10) (0.308 g, 1 mmol) in glacial acetic acid in a similar way to that described for the preparation of 21a–21d. It was recrystallized from DMF/ethanol to give pale brown crystals. Yield 0.29 g, (68%) mp 237°C; IR: ν 1622 (C=N) cm−1; 1H NMR (CF3COOD): δ 3.19 (3H, s, CH3), 7.30 (2H, d, J = 1.0 Hz, 10-H), 7.97 (2H, d, J = 1.00 Hz, 3,5-H of pyridyl), 8.14–8.12, 7.50–7.38 (5H, m, phenyl-H), 8.16 (2H, d, J = 1.00 Hz, 9-H), 8.31 (1H, s, 6-H), 8.54 (2H, d, J = 1.00 Hz, 2,6-H of pyridyl); MS: 421(M+,100), 367(4), 333(8), 318(19), 308(44), 293(66), 278(42), 214(8), 198(10), 190(22), 163(12), 120(5), 104(22), 77(26). Anal. Calcd. for C23H15N7S: C, 65.55; H, 3.56; N, 23.27. Found: C, 65.74; H, 3.68; N, 23.48%. Method B: the filtrate from the above reaction 20 was poured into cold water (20 mL) and stirred for 15 min. The resulting precipitate was collected by filtration and recrystallized to give 21e (0.026 g, 6.3%). Method C: a mixture of 20 (0.439 g, 1 mmol) and glacial acetic acid (10 mL) was refluxed for 10 h. The reaction mixture was cooled and poured into ice-water; the precipitate was filtered and recrystallized to obtain 21e (0.202 g, 48%).


## 3. Results and Discussion

Cyclization of thioxopyrimidine1 with chloroacetonitrile 2 in DMF in the presence of excess anhydrous potassium carbonate formed the nonisolable S-alkylated intermediate, which via nucleophilic substitution and intramolecular cyclocondensation afforded the 5-amino-6-cyanothieno[2,3-d]pyrimidine 3, and the latter reacted with triethyl orthoformate to give the 5-ethoxymethyleneamino-thieno[2,3-d]pyrimidines 4 (Scheme 1). Moreover, the reactivity of compound 4 towards amino compounds was also investigated. In treatment of 4 with phenylhydrazine in ethanol, an addition product formed, from which elimination of ethyl formate phenylhydrazone gave the compound 3 instead of the compound 3′, while with amino compounds 5a,5b, and formamide afforded the corresponding 7-substituted-8-imino-pyrimido[3,2: 4,5]thieno[2,3-d]pyrimidines 6a, 6b, and7, respectively (Scheme 2). The structure of compounds 6a,6b, and 7 was established on the basis of their elemental analysis and spectra data. The IR spectra of compounds 6a, 6b, and 7 showed the characteristic absorption band at 3310-3301 cm−1 for the NH group. In addition, the 1H NMR spectra (CDCl3) of compound 6a revealed a triplet at δ 1.47 (3H, s) and a quartet at 4.10 (2H, q), which were readily assigned to the ethyl group (CH2CH3) and a singlet at 7.90 (1H, s) which was assigned to the hydrogen attached at C6 of the pyrimidine ring, which was also confirmed by the mass spectrum m/z 321 (M+). Further, the 1H NMR spectra (DMSO-d6) of compound 7 revealed three singlets at δ 8.33 (1H, s), 8.54 (1H, s), and 8.86 (1H, s), which were readily assigned to the NH, HCO, and C6-H protons, respectively. Nevertheless, the compound 4 was cyclized with acid hydrazides 8a, 8b under different conditions to form a new tetracyclic compound. Thus, compound 4 with acid hydrazides 8a,8b in refluxing 2-methoxyethanol afforded the corresponding 2-substituted-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 9a,9b. The 1H NMR spectra (CF3COOD) of the compounds 9a,9b, which showed a singlet at δ 9.93 (1H, s) and 9.83 (6H, s), were readily assigned to the hydrogen attached at C6 of the pyrimidine ring, respectively. Hydrazinolysis of compound 4 in ethanol yielded the key intermediate (10) for the preparation of new triazoles and triazepines (Scheme 2). Moreover, the IR spectra of compound (10) showed the characteristic absorption band at 3315 and 3247 cm−1 for the NH2 and NH groups, respectively. The 1H NMR spectra (CF3COOD) of compound (10) revealed three singlets at δ 5.12 (1H, s), 9.23 (1H, s), and 8.69 (1H, s), which were readily assigned to the NH2, NH, and C6-H protons, respectively, which was also confirmed by the mass spectrum m/z 308(M+).Scheme 1Scheme 2Next, as described in Scheme3, several pyrimido[3,2:4,5]thieno[2,3-d]pyrimidines (PTP) substituted at positions 7 and 8 with different heterocyclic residues were obtained via treatment of compound (10) with different reagents. Thus, upon heating compound (10) in refluxing acetic anhydride, introduced three acetyl groups afforded the 8-(acetylamino)-7-diacetylamino-4-methyl-2-phenyl-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (11). Also, the compound (10) cyclized in glacial acetic acid at 70–80°C for 2 h afforded the 2,7-dimethyl-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (12). The structure of compounds (11),(12) was established on the basis of their elemental analysis and spectral data. The IR spectra of compounds (11),(12) indicated the complete disappearance of NH and NH2 groups. The 1H NMR spectra (CF3COOD) of the compound (11), which showed additional two signals at δ 2.32 (3H, s) and 2.56 (6H, s), which were assigned to the protons COCH3 attached at imino and amino groups of PTP moiety, respectively, were also confirmed by the mass spectrum m/z 434 (M+). Moreover, reaction of (10) with N,N- dimethyl-4-nitrosoaniline in refluxing glacial acetic acid afforded the 7-(4-dimethyl-aminophenyl)azo-8-imino-4-methyl-2-phenyl-7,8-dihydropyrimido[3,2:4,5]thieno[2,3-d]pyrimidine 13, because the molecular ion m/z 440 of compound13is unstable and could not be recorded in the electron impact mass spectra but showed the presence of the ion peaks m/z 412, m/z 397, m/z 319, and m/z 293. The possible mass fragmentation pathway of compound 13 is shown in Scheme 6. In addition, the structure of compound 13 was supported by the 1H NMR spectra, which showed a sharp singlet at δ 3.51 (6H, s) assigned to the N(CH3)2 protons.Scheme 3On the other hand, the 2-(substituted-amino)-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 15a–15g were obtained by intramolecular cyclization of compound (10) with appropriate isothiocyanates 14a–14g in refluxing pyridine (Scheme 3). Obviously this reaction proceeded via the thiourea intermediate 15′ with concomitant dehydrosulfurization. The structure of compounds 15a–15g was established on the basis of their elemental analysis and spectral data. The 1H NMR spectra of 15a–15g showed a singlet at δ 9.98-8.79 (1H, s) assigned to the hydrogen attached at C5 of the pyrimidotriazole ring. In addition, the 1H NMR spectra of compound 15b revealed a triplet at δ 1.92 (3H, s) and a quartet at 4.92 (2H, q), which were readily assigned to the ethyl group (CH2CH3) and a singlet at 9.15 (1H, br) which was assigned to the NH group. Also, it has been observed that electron impact (EI) spectral has many common features. Compounds 15a–15g exhibited m/z 332, m/z 304, m/z 293, m/z 278, and m/z 174 piece peaks. Next, cyclocondensation of compound (10) with 1,3-dibromopropane in DMF in the presence of excess anhydrous potassium carbonate at 60°C form the 9,10,11-trihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepine 16. In particular, the 1H NMR spectra of compound 16 revealed two additional triplets at δ 3.42 (2H, t) and 4.42 (2H, t), which were readily assigned to the hydrogen attached at C11 and C9 of the triazepine ring, respectively, a singlet at δ 10.12 (1H, br) assigned to the NH group, and a multiplet at δ 2.32 (2H, m) assigned to the hydrogen attached at C10 of the triazepine ring, which was also confirmed by the mass spectrum m/z 348 (M+).Work was further extended to study the behavior of compound (10) towards the different reagents with a view to synthesizing various heterocyclic ringsystems. Thus, treatment of compound (10) with Mannich bases [30, 31] 17a–17c in DMF in the presence of excess anhydrous potassium carbonate afforded the corresponding 9-substituted-10,11-dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines 18a–18c (Scheme 4). The mechanism involves the condensation of amino group in compound (10) with the carbonyl group, followed by dehydration and subsequent nucleophilic cyclization with loss of N,N-dimethylamine hydrochloride [26]. The 1H NMR spectra of compounds 18a–18c revealed two additional triplets at δ 3.22–3.28 (2H, t) and 4.19–4.23 (2H, t), which were readily assigned to the hydrogen attached at C10 and C11 of the triazepine ring, respectively. These structures get further support from mass spectroscopy. It has been observed that Electron Impact (EI) spectral has many common features. Compounds 18a–18c exhibited m/z 345, m/z 332, m/z 318, m/z 293, m/z 278, m/z 250, m/z 215, m/z 190, and m/z 163 piece peaks. The possible mass fragmentation pathway of compounds 18a–18c is shown in Scheme 7.Scheme 4Furthermore, the behavior of compound (10) with enaminone derivatives 19a–19e was also investigated (Scheme 5). To optimize the reaction temperature, the reaction of compound (10) and enaminone 19e was studied in glacial acetic acid, at different temperatures such as 50°C –55°C, 80°C, and reflux, respectively. It has been found that the treatment of compound (10) and enaminone 19e carried out at 50–55°C for 3h only afforded the open-chain product 20 in 70% yield, while at 80°C for 7h incomplete cyclocondensation was observed (as examined by TLC (ethyl acetate and hexane (3:7))); work-up of the reaction mixture yielded a mixture of two products 20 (60% yield)and 21e (6.3% yield)which were separated. Also, it was interesting to find that prolonging the reaction time (10h) and increasing the reaction temperature (reflux), the yield for compound 21e increased greatly from 6.3% to 68%.Scheme 5Scheme 6Scheme 7The structures of20 and 21e were established on the basis of microanalysis and spectra data as well as comparison (IR, mixed mp, TLC (ethyl acetate and hexane (3:7))). The IR spectra of the compound 20 showed the characteristic absorption band at 3215 cm−1 for the NH group and at 1668 cm−1 for the C=O group. The 1H NMR spectra of compound 20 showed a doublet at δ 4.00 (1H, d) assigned to the COCH= of 1-(4-pyridinyl)prop-2-enone moiety and a multiplet at δ 8.78–8.74, 8.26–8.07 (6H, m) assigned to the NCH= of 1-(4-pyridinyl)prop-2-enone moiety and phenyl protons. In addition, the IR spectra of compound 21e indicated the absence of the NH2 and NH groups. The 1H NMR spectra of compound 21e revealed two doublets at δ 7.52 (1H, d) and 8.16 (1H, d), which were readily assigned to the hydrogen attached at C10 and C9 of the triazepine ring, respectively. The structure of compound 21e was further confirmed via an independent synthesis of compound 21e by reaction of compound 20 in glacial acetic acid under reflux 10 h to afford a product identical in all respects (mp, mixed mp, TLC (ethyl acetate and hexane (3:7)) and spectra), with those of compounds 21e in 48% yield. Moreover, treatment of compound (10) with enaminones 19a–19d in glacial acetic acid under reflux afforded the corresponding 11-substituted-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines 21a–21d, respectively (Scheme 5). The formation of compound 21a–e would involve an initial Michael addition of the exocyclic amino group in compound (10) to the activated double bond in enaminone 19 to form the intermediate 20′, which then undergoes cyclization and aromatization via loss of both water and N,N-dimethylamine [26] affording the final product 21a–21e. The 1H NMR spectra of compounds 21a–21e revealed two additional doublets at δ 7.33–6.71 (1H, d) and 8.16–7.45 (1H, d), which were readily assigned to the hydrogen attached at C10 and C9 of the triazepine ring, respectively, and a singlet at δ 9.54–8.31 (1H, s) assigned to the hydrogen attached at C6 of the triazepine ring. These structures get further support from mass spectroscopy.


## 4. Conclusion

In conclusion, 7-amino-8-imino-pyrimido[3,2:4,5]thieno[2,3-d]pyrimidine (10) has been shown to be a useful building block for the synthesis of several novel 2-(substituted-amino)-pyrimido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 15a–15g, (tri)dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines 16 and 18a–18c. On the other hand, the 11-substituted-pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6-b][1,2,4]triazepines 21a–21e were also obtained from compound (10).



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*Source: 696579-2012-12-03.xml*