# Synthesis of New Pyrazolo[1,5-a]pyrimidine, Triazolo[4,3-a]pyrimidine Derivatives, and Thieno[2,3-b]pyridine Derivatives from Sodium 3-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate

Authors: Abdou O. Abdelhamid; Sobhi M. Gomha
Journal: Journal of Chemistry
 (2013)

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## Abstract

Condensation of sodium 3-oxo-3-(1-phenyl-1H-pyrazol-4-yl)prop-1-en-1-olate (2) with several heterocyclic amines, cyanoacetamide, cyanothioacetamide, and 2-cyanoacetohydrazide gives pyrazolo[1,5-a]pyrimidines (5a–d), pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9), benzo[4,5]imidazo[1,2-a]pyrimidine (10), [1,2,4]triazolo[1,5-a]pyrimidine (11), and pyridine derivatives (12–14). Also, thieno[2,3-b]pyridines (15–18) were synthesized via pyridinethione (13) with α-halo ketones and α-halo ester. Structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data, alternative synthetic routes, and chemical transformation whenever possible.


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## Body

## 1. Introduction

Several pyrazole derivatives received great attention due to their biological and pharmacological activities not only as potential inhibitors of HIV-1 [1], pesticides [2], fungicides [3], antihypertensive agents [4], and anticancer activity [5], but also as important and useful starting materials for the synthesis of other fused heterocyclic systems. Furthermore, compounds containing the pyrimidine nucleus are of significant biological importance and are used as antibacterial [6–9], antifungal [10, 11], antitumour [12, 13], antiviral [13–17], anti-inflammatory [18, 19], and antihypertensive [20–22] agents. In this work, we synthesized some new pyrazolo[1,5-a]pyrimidine, triazolo[4,3-a]pyrimidine, and thieno[2,3-b]pyridine derivatives.


## 2. Experimental

Melting points were measured on Electrothermal IA 9000 series digital melting point apparatus and are uncorrected. The IR spectra were recorded in potassium bromide discs on a Pye Unicam SP 3300 and Shimadzu FT IR 8101 PC infrared spectrophotometer.1H NMR and 13C NMR spectra were recorded in DMSO-d6 using a Varian Gemini 300 NMR spectrometer (300 MHz for 1H NMR and 75 MHz for 13C NMR). Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV. Elemental analysis was carried out at the Microanalytical Centre of Cairo University, Giza, Egypt. All reactions were followed by TLC (Silica gel, Merck). 1-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)ethanone [23] was prepared as reported in the literature.


### 2.1. Synthesis of Sodium 3-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2)

A mixture of (0.01 mol) 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone 1 (2.0 g, 10 mmol) and ethyl formate (0.74 g, 10 mmol) was dropped over a solution of sodium methoxide (0.54 g, 10 mmol) in 20 mL dry ether with stirring. The formed solid product was collected and used directly in the following reactions.


### 2.2.  Synthesis of5a–d and 9–14

Method A (General Procedure). A mixture of sodium 3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2) (2.5 g, 10 mmol) and the appropriate 3-amino-5-methylpyrazole 3a, 3-amino-5-phenylpyrazole 3b, 3-amino-4-cyanopyrazole 3c, 3-amino-4-methyl-5-phenylpyrazole 3d, 4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-amine, 2-aminobenzimidazole, 4H-1,2,4-triazol-3-amine, cyanoacetamide, cyanothioacetamide, and 2-cyanoacetohydrazide (10 mmol) and few drops of acetic acid was grinded for 10–20 min (monitored by TLC). The solid products collected by filtration and recrystallized from the suitable solvent gave the respective products 5a–dand9–14in an excellent yield.Method B (General Procedure). A solution of sodium 3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2) (2.5 g, 10 mmol), the appropriate 3-amino-5-methylpyrazole 3a, 3-amino-5-phenylpyrazole 3b, 3-amino-4-cyanopyrazole 3c, 3-amino-4-methyl-5-phenylpyrazole 3d, 4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-amine, 2-aminobenzimidazole, 4H-1,2,4-triazol-3-amine, cyanoacetamide, cyanothioacetamide, 2-cyanoacetohydrazide (10 mmol), and piperidine acetate (1 mL) in water (3 mL) was refluxed for 10 min. After completion of the reaction, the hot reaction mixture was neutralized with acetic acid (1.5 mL) and then cooled and the solid products collected by filtration and recrystallized from the suitable solvent gave products 5a–dand9–14in a good yield, which were identical in all aspects (m.p., mixed m.p., and spectra) with those obtained from Method A.


#### 2.2.1. 2-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (5a)

Yield 91%; yellow crystals; mp 202–204°C (from acetic acid) (Lit. mp 202–204°C [24]).


#### 2.2.2. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (5b)

Yield 90%; yellow crystals; m.p. 218-219°C (from acetic acid) (Lit. M.p. 216–218°C [24]).


#### 2.2.3. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (5c)

Yield 92%; yellow crystals; m.p. 230–232°C (from acetic acid); IR (KBr):v1594 (C=N), 2231 (CN) cm−1; 1H NMR (DMSO-d6): δ 2.56 (s, 3H, CH3), 6.38 (d, 1H, J=4 Hz, pyrimidine H-5), 6.86 (s, 1H, pyrazole H-3), 7.28–7.66 (m, 5H, ArH’s), 8.24 (s, 1H, pyrazole H-3), 8.71 (d, 1H, J=4 Hz, pyrimidine H-4); 13C NMR (DMSO-d6): δ 9.42 (CH3), 83.11, 105.21, 111.88, 112.76, 121.87, 125.74, 128.72, 130.11, 139.88, 140.15, 128.55, 152.37, 155.18; MS m/z(%): 301(M+ + 1, 14), 300(M+, 41), 211(32), 84(76), 63(100). Anal. Calcd for C17H12N6 (300.32): C, 67.99; H, 4.03; N, 27.98; Found C, 67.69; H, 4.08; N, 27.68%.


#### 2.2.4. 3-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (5d)

Yield 90%; yellow crystals; m.p. 226°C (from acetic acid) (Lit. m.p. 226–228°C [25]).


#### 2.2.5. 8,10-Dimethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl) pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9)

Yield 93%; yellow crystals; m.p. 290–292°C (from acetic acid); IR (KBr):v1588 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.49 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.74 (s, 3H, CH3), 6.08 (d, 1H, J=4 Hz, pyrimidine H-5), 6.85 (s, 1H, pyridine H), 7.50–7.59 (m, 5H, ArH’s), 8.01 (s, 1H, pyrazole H-3), 8.24 (d, 1H, J=4 Hz, pyrimidine H-4); 13C NMR (DMSO-d6): δ 8.44 (CH3), 19.21 (CH3), 21.47 (CH3), 104.19, 110.12, 112.85, 117.11, 120.78, 122.13, 126.88, 129.45, 133.12, 135.48, 139.89, 140.46, 148.74, 150.12, 151.78, 165.15; MS m/z(%): 355(M+ + 1, 41), 354(M+, 63), 262(45), 214(31), 119(28), 77(100). Anal. Calcd for C21H18N6 (354.41): C, 71.17; H, 5.12; N, 23.71; Found C, 71.31; H, 5.06; N, 23.56%.


#### 2.2.6. 4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)benzo[4,5] imidazo[1,2-a]pyrimidine (10)

Yield 94%; yellow crystals; m.p. 203°C (from acetic acid) (Lit. m.p. 196-197°C [24]).


#### 2.2.7. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (11)

Yield 94%; yellow crystals; m.p. 180°C (from acetic acid) (Lit. m.p. 179-180°C [25]).


#### 2.2.8. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12)

Yield 91%; yellow crystals; m.p. 266–268°C (from ethanol); IR (KBr):v1614 (C=N), 2213(CN), 3393(NH) cm−1; 1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 6.97 (d, 1H, J=8.0 Hz, pyridine H-5), 7.53–7.73 (m, 6H, ArH’s and pyrazole H-3), 8.18 (d, 1H, J=8.0 Hz, pyridine H-4), 10.21 (s, br., 1H, NH); MS m/z(%): 276(M+, 100), 231(34), 164(36), 118(54), 77(78). Anal. Calcd for C16H12N4O (276.29): C, 69.55; H, 4.38; N, 20.28; Found C, 69.45; H, 4.23; N, 20.21%.


#### 2.2.9. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (13)

Yield 93%; yellow crystals; m.p. 236–238°C (from ethanol); IR (KBr):v1621 (C=N), 2218 (CN), 3420 (NH) cm−1; 1H NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 6.93 (d, 1H, J=7.8 Hz, pyridine H-5), 7.52–7.62 (m, 6H, ArH’s and pyrazole H-3), 8.12 (d, 1H, J=7.8 Hz, pyridine H-4), 14.01 (s, 1H, NH); MS m/z(%): 293(M+ + 1, 38), 292(M+, 100), 264(16), 181(16), 118(26), 77(82). Anal. Calcd for C16H12N4S (292.36): C, 65.73; H, 4.14; N, 19.16; Found C, 65.67; H, 4.10; N, 19.02%.


#### 2.2.10. 1-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (14)

Yield 92%; yellow crystals; m.p. 238–140°C (from ethanol); IR (KBr):v1603 (C=N), 2214 (CN), 3148, 3427 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.52 (s, 3H, CH3), 7.37 (d, 1H, J=8.1 Hz, pyridine H-5), 6.88 (s, br., 2H, NH2), 7.50–7.56 (m, 5H, ArH’s), 7.83 (s, 1H, pyrazole H-3), 8.09 (d, 1H, J=8.1 Hz, pyridine H-4); 13C NMR (DMSO-d6):δ 10.89 (CH3), 105.22, 110.46, 113.21, 118.24, 120.58, 126.87, 128.57, 128.89, 136.78, 139.25, 143.22, 146.57, 150.27; MS m/z(%): 292(M+ + 1, 38), 291(M+, 100), 118(11), 77(61). Anal. Calcd for C16H13N5O (291.31): C, 65.97; H, 4.50; N, 24.04; Found C, 65.78; H, 4.54; N, 23.94%.


### 2.3. 3-Amino-2-substituted-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]-pyridine Derivatives (15–18)

Method A. A mixture of 13 (0.29 g, 1 mmol) and the appropriate ethyl chloroacetate, chloroacetone, ω-bromoacetophenone or chloroacetonitrile (1 mmol), and 3–5 drops of acetic acid was grinded for 15 min. The resulting solid was collected and recrystallized from ethanol to give the respective compounds, 15–18, in excellent yields.Method B. A mixture of 13 (0.29 g, 1 mmol) and potassium hydroxide (0. 0.056 g, 1 mmol) in N,N-dimethylformamide (10 mL) was stirred for 2 h at room temperature. The appropriate ethyl chloroacetate, chloroacetone, ω-bromoacetophenone, or chloroacetonitrile (1 mmol each) was added and stirring was continued for 2 h. The resulting solid was collected and recrystallized from ethanol to give 15–18, respectively.


#### 2.3.1. Ethyl 3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carboxylate (15)

Yield 88%; yellow crystals; m.p. 145-146°C; IR (KBr):v1720 (C=O), 3320, 3418 (NH2) cm−1; 1H NMR (DMSO-d6): δ 1.32 (t, J=7.5 Hz, 3H, CH3CH2), 2.49 (s, 3H, CH3), 4.16 (q, J=7.5 Hz, 2H, CH2CH3), 7.82 (d, 1H, J=8.4 Hz, pyridine H-5), 7.45–7.82 (m, 7H, ArH’s and NH2), 7.82 (s, 1H, pyrazole H-3), 8.48 (d, 1H, J=8.4 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ11.32, 14.58, 60.12, 105.42, 117.45, 122.57, 126.51, 126.89, 127.74, 128.48, 132.25, 136.75, 140.25, 143.11, 144.87, 148.28, 155.28, 165.78; MS m/z(%): 381(M+ + 1, 43), 380(M+, 21), 176(57), 148(57), 102(57), 71(86), 53(100). Anal. Calcd for C20H18N4O2S (378.45): C, 63.47; H, 4.79; N, 14.80; Found C, 63.49; H, 4.68; N, 14.65%.


#### 2.3.2. 1-(3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl) thieno[2,3-b]pyridin-2-yl)ethanone (16)

Yield 86%; yellow crystals; m.p. 137-138°C; IR (KBr):v1713 (CO), 3310, 3414 (NH2) cm−1; 1H NMR (DMSO-d6): δ2.12 (s, 3H, CH3), 2.38 (s, 3H, CH3), 7.38–7.62 (m, 8H, ArH’s, NH2 and pyridine H-5), 7.72 (s, 1H, pyrazole H-3), 8.59 (d, 1H, J=8.4 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ 11.38 (CH3), 31.25 (CH3), 117.28, 122.58, 126.24, 126.78, 127.34, 128.48, 132.57, 136.57, 140.38, 142.28, 144.37, 147.81, 156.37, 191.28; MS m/z(%): 349(M+ + 1, 21), 348(M+, 41), 292(32), 149(38), 105(32), 77(100), 64(77). Anal. Calcd for C19H16N4OS (348.42): C, 65.50; H, 4.63; N, 16.08; Found C, 65.43; H, 4.67; N, 15.87%.


#### 2.3.3.  (3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (17)

Yield 88%; yellow crystals; m.p. 127-128°C; IR (KBr):v1660 (CO), 3404 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 7.18–7.58 (m, 14H, ArH’s, NH2, pyrazole H-3 and pyridine H-5)), 8.54 (d, 1H, J=8.4 Hz, pyridine H-4); MS m/z(%): 411(M+ + 1, 3), 410(M+, 10), 293(13), 253(18), 105(100), 77(81). Anal. Calcd for C24H18N4OS (410.49): C, 70.22; H, 4.42; N, 13.65; Found C, 70.18; H, 4.32; N, 13.39%.


#### 2.3.4. 3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carbonitrile (18)

Yield 84%; yellow crystals; m.p. 196–198°C; IR (KBr):v1637 (C=N), 3200 (CN), 3343, 3410 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.29 (s, 3H, CH3), 7.48–7.60 (m, 7H, ArH’s, NH2 and pyrimidine H-5), 7.79 (s, 1H, pyrazole H-3), 8.88 (d, 1H, J=8.4 Hz, pyridine H-4); MS m/z(%): 331(M+, 10), 302(17), 179(11), 133(16), 84(100), 77(81). Anal. Calcd for C18H13N5S (331.39): C, 65.24; H, 3.95; N, 21.13; Found C, 65.12; H, 3.91; N, 20.83%.


### 2.4. 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-3-amine (19)

To a solution of the thione13 (0.29 g, 0.01 mol) in ethanol (10 mL) hydrazine hydrate was added (1 mL) and the mixture was heated under reflux for 12 h. The solution was poured over ice-water mixture and then neutralized by HCl. The solid product was filtered off, dried, and recrystallized from ethanol to afford compound 15. Yield 72%; yellow crystals; m.p. 204–206°C; IR (KBr): v1592 (C=N), 3190, 3322 (NH2 and NH) cm−1; 1H NMR (DMSO-d6): δ 2.89 (s, 3H, CH3), 5.94 (s, br., 3H, NH2 and NH), 6.92 (d, 1H, J=8.1 Hz, pyridine H-4), 7.48–7.56 (m, 5H, ArH’s), 8.14 (s, 1H, pyrazole H-3), 8.48 (d, 1H, J=8.1 Hz, pyridine H-4); MS m/z(%): 291(M+ + 1, 18), 290(M+, 31), 274(52), 224(30), 171(28), 118(42), 77(100). Anal. Calcd for C16H14N6  (290.32): C, 66.19; H, 4.86; N, 28.95; Found C, 66.08; H, 4.91; N, 28.76%.


### 2.5. 2,4-Dimethyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (20)

To a solution of19 (1.45 g, 5 mmol) and acetylacetone (0.5 g, 5 mmol), in acetic acid (20 mL) was refluxed for 10 min. The solid product was collected by filtration and recrystallized from acetic acid to afford compound 20. Yield 72%; yellow crystals; m.p. 206°C; IR (KBr): v1592 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.19 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.45 (s, 3H, CH3), 6.40 (s, 1H, pyrimidine H-5), 6.50 (d, 1H, J=8 Hz, pyridine H-5), 7.39–7.50 (m, 5H, ArH’s), 8.00 (s, 1H, pyrazole H-3), 8.40 (d, 1H, J=12 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ 10.15 (CH3), 15.68 (CH3), 19.36 (CH3), 104.60, 108.10, 118.00, 119.90, 122.65, 123.38, 126.00, 129.82, 134.65, 140.21, 142.95, 143.42, 146.00, 146.84, 161.10, 164.44; MS m/z(%): 355(M+ + 1, 1), 354(M+, 3), 211(12), 185(31), 157(36), 105(23), 80(100). Anal. Calcd for C21H18N6 (354.41): C, 71.17; H, 5.12; N, 23.71; Found C, 71.10; H, 5.19; N, 23.56%.


## 2.1. Synthesis of Sodium 3-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2)

A mixture of (0.01 mol) 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone 1 (2.0 g, 10 mmol) and ethyl formate (0.74 g, 10 mmol) was dropped over a solution of sodium methoxide (0.54 g, 10 mmol) in 20 mL dry ether with stirring. The formed solid product was collected and used directly in the following reactions.


## 2.2.  Synthesis of5a–d and 9–14

Method A (General Procedure). A mixture of sodium 3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2) (2.5 g, 10 mmol) and the appropriate 3-amino-5-methylpyrazole 3a, 3-amino-5-phenylpyrazole 3b, 3-amino-4-cyanopyrazole 3c, 3-amino-4-methyl-5-phenylpyrazole 3d, 4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-amine, 2-aminobenzimidazole, 4H-1,2,4-triazol-3-amine, cyanoacetamide, cyanothioacetamide, and 2-cyanoacetohydrazide (10 mmol) and few drops of acetic acid was grinded for 10–20 min (monitored by TLC). The solid products collected by filtration and recrystallized from the suitable solvent gave the respective products 5a–dand9–14in an excellent yield.Method B (General Procedure). A solution of sodium 3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2) (2.5 g, 10 mmol), the appropriate 3-amino-5-methylpyrazole 3a, 3-amino-5-phenylpyrazole 3b, 3-amino-4-cyanopyrazole 3c, 3-amino-4-methyl-5-phenylpyrazole 3d, 4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-amine, 2-aminobenzimidazole, 4H-1,2,4-triazol-3-amine, cyanoacetamide, cyanothioacetamide, 2-cyanoacetohydrazide (10 mmol), and piperidine acetate (1 mL) in water (3 mL) was refluxed for 10 min. After completion of the reaction, the hot reaction mixture was neutralized with acetic acid (1.5 mL) and then cooled and the solid products collected by filtration and recrystallized from the suitable solvent gave products 5a–dand9–14in a good yield, which were identical in all aspects (m.p., mixed m.p., and spectra) with those obtained from Method A.


### 2.2.1. 2-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (5a)

Yield 91%; yellow crystals; mp 202–204°C (from acetic acid) (Lit. mp 202–204°C [24]).


### 2.2.2. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (5b)

Yield 90%; yellow crystals; m.p. 218-219°C (from acetic acid) (Lit. M.p. 216–218°C [24]).


### 2.2.3. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (5c)

Yield 92%; yellow crystals; m.p. 230–232°C (from acetic acid); IR (KBr):v1594 (C=N), 2231 (CN) cm−1; 1H NMR (DMSO-d6): δ 2.56 (s, 3H, CH3), 6.38 (d, 1H, J=4 Hz, pyrimidine H-5), 6.86 (s, 1H, pyrazole H-3), 7.28–7.66 (m, 5H, ArH’s), 8.24 (s, 1H, pyrazole H-3), 8.71 (d, 1H, J=4 Hz, pyrimidine H-4); 13C NMR (DMSO-d6): δ 9.42 (CH3), 83.11, 105.21, 111.88, 112.76, 121.87, 125.74, 128.72, 130.11, 139.88, 140.15, 128.55, 152.37, 155.18; MS m/z(%): 301(M+ + 1, 14), 300(M+, 41), 211(32), 84(76), 63(100). Anal. Calcd for C17H12N6 (300.32): C, 67.99; H, 4.03; N, 27.98; Found C, 67.69; H, 4.08; N, 27.68%.


### 2.2.4. 3-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (5d)

Yield 90%; yellow crystals; m.p. 226°C (from acetic acid) (Lit. m.p. 226–228°C [25]).


### 2.2.5. 8,10-Dimethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl) pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9)

Yield 93%; yellow crystals; m.p. 290–292°C (from acetic acid); IR (KBr):v1588 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.49 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.74 (s, 3H, CH3), 6.08 (d, 1H, J=4 Hz, pyrimidine H-5), 6.85 (s, 1H, pyridine H), 7.50–7.59 (m, 5H, ArH’s), 8.01 (s, 1H, pyrazole H-3), 8.24 (d, 1H, J=4 Hz, pyrimidine H-4); 13C NMR (DMSO-d6): δ 8.44 (CH3), 19.21 (CH3), 21.47 (CH3), 104.19, 110.12, 112.85, 117.11, 120.78, 122.13, 126.88, 129.45, 133.12, 135.48, 139.89, 140.46, 148.74, 150.12, 151.78, 165.15; MS m/z(%): 355(M+ + 1, 41), 354(M+, 63), 262(45), 214(31), 119(28), 77(100). Anal. Calcd for C21H18N6 (354.41): C, 71.17; H, 5.12; N, 23.71; Found C, 71.31; H, 5.06; N, 23.56%.


### 2.2.6. 4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)benzo[4,5] imidazo[1,2-a]pyrimidine (10)

Yield 94%; yellow crystals; m.p. 203°C (from acetic acid) (Lit. m.p. 196-197°C [24]).


### 2.2.7. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (11)

Yield 94%; yellow crystals; m.p. 180°C (from acetic acid) (Lit. m.p. 179-180°C [25]).


### 2.2.8. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12)

Yield 91%; yellow crystals; m.p. 266–268°C (from ethanol); IR (KBr):v1614 (C=N), 2213(CN), 3393(NH) cm−1; 1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 6.97 (d, 1H, J=8.0 Hz, pyridine H-5), 7.53–7.73 (m, 6H, ArH’s and pyrazole H-3), 8.18 (d, 1H, J=8.0 Hz, pyridine H-4), 10.21 (s, br., 1H, NH); MS m/z(%): 276(M+, 100), 231(34), 164(36), 118(54), 77(78). Anal. Calcd for C16H12N4O (276.29): C, 69.55; H, 4.38; N, 20.28; Found C, 69.45; H, 4.23; N, 20.21%.


### 2.2.9. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (13)

Yield 93%; yellow crystals; m.p. 236–238°C (from ethanol); IR (KBr):v1621 (C=N), 2218 (CN), 3420 (NH) cm−1; 1H NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 6.93 (d, 1H, J=7.8 Hz, pyridine H-5), 7.52–7.62 (m, 6H, ArH’s and pyrazole H-3), 8.12 (d, 1H, J=7.8 Hz, pyridine H-4), 14.01 (s, 1H, NH); MS m/z(%): 293(M+ + 1, 38), 292(M+, 100), 264(16), 181(16), 118(26), 77(82). Anal. Calcd for C16H12N4S (292.36): C, 65.73; H, 4.14; N, 19.16; Found C, 65.67; H, 4.10; N, 19.02%.


### 2.2.10. 1-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (14)

Yield 92%; yellow crystals; m.p. 238–140°C (from ethanol); IR (KBr):v1603 (C=N), 2214 (CN), 3148, 3427 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.52 (s, 3H, CH3), 7.37 (d, 1H, J=8.1 Hz, pyridine H-5), 6.88 (s, br., 2H, NH2), 7.50–7.56 (m, 5H, ArH’s), 7.83 (s, 1H, pyrazole H-3), 8.09 (d, 1H, J=8.1 Hz, pyridine H-4); 13C NMR (DMSO-d6):δ 10.89 (CH3), 105.22, 110.46, 113.21, 118.24, 120.58, 126.87, 128.57, 128.89, 136.78, 139.25, 143.22, 146.57, 150.27; MS m/z(%): 292(M+ + 1, 38), 291(M+, 100), 118(11), 77(61). Anal. Calcd for C16H13N5O (291.31): C, 65.97; H, 4.50; N, 24.04; Found C, 65.78; H, 4.54; N, 23.94%.


## 2.2.1. 2-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (5a)

Yield 91%; yellow crystals; mp 202–204°C (from acetic acid) (Lit. mp 202–204°C [24]).


## 2.2.2. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (5b)

Yield 90%; yellow crystals; m.p. 218-219°C (from acetic acid) (Lit. M.p. 216–218°C [24]).


## 2.2.3. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (5c)

Yield 92%; yellow crystals; m.p. 230–232°C (from acetic acid); IR (KBr):v1594 (C=N), 2231 (CN) cm−1; 1H NMR (DMSO-d6): δ 2.56 (s, 3H, CH3), 6.38 (d, 1H, J=4 Hz, pyrimidine H-5), 6.86 (s, 1H, pyrazole H-3), 7.28–7.66 (m, 5H, ArH’s), 8.24 (s, 1H, pyrazole H-3), 8.71 (d, 1H, J=4 Hz, pyrimidine H-4); 13C NMR (DMSO-d6): δ 9.42 (CH3), 83.11, 105.21, 111.88, 112.76, 121.87, 125.74, 128.72, 130.11, 139.88, 140.15, 128.55, 152.37, 155.18; MS m/z(%): 301(M+ + 1, 14), 300(M+, 41), 211(32), 84(76), 63(100). Anal. Calcd for C17H12N6 (300.32): C, 67.99; H, 4.03; N, 27.98; Found C, 67.69; H, 4.08; N, 27.68%.


## 2.2.4. 3-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (5d)

Yield 90%; yellow crystals; m.p. 226°C (from acetic acid) (Lit. m.p. 226–228°C [25]).


## 2.2.5. 8,10-Dimethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl) pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9)

Yield 93%; yellow crystals; m.p. 290–292°C (from acetic acid); IR (KBr):v1588 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.49 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.74 (s, 3H, CH3), 6.08 (d, 1H, J=4 Hz, pyrimidine H-5), 6.85 (s, 1H, pyridine H), 7.50–7.59 (m, 5H, ArH’s), 8.01 (s, 1H, pyrazole H-3), 8.24 (d, 1H, J=4 Hz, pyrimidine H-4); 13C NMR (DMSO-d6): δ 8.44 (CH3), 19.21 (CH3), 21.47 (CH3), 104.19, 110.12, 112.85, 117.11, 120.78, 122.13, 126.88, 129.45, 133.12, 135.48, 139.89, 140.46, 148.74, 150.12, 151.78, 165.15; MS m/z(%): 355(M+ + 1, 41), 354(M+, 63), 262(45), 214(31), 119(28), 77(100). Anal. Calcd for C21H18N6 (354.41): C, 71.17; H, 5.12; N, 23.71; Found C, 71.31; H, 5.06; N, 23.56%.


## 2.2.6. 4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)benzo[4,5] imidazo[1,2-a]pyrimidine (10)

Yield 94%; yellow crystals; m.p. 203°C (from acetic acid) (Lit. m.p. 196-197°C [24]).


## 2.2.7. 7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (11)

Yield 94%; yellow crystals; m.p. 180°C (from acetic acid) (Lit. m.p. 179-180°C [25]).


## 2.2.8. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12)

Yield 91%; yellow crystals; m.p. 266–268°C (from ethanol); IR (KBr):v1614 (C=N), 2213(CN), 3393(NH) cm−1; 1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 6.97 (d, 1H, J=8.0 Hz, pyridine H-5), 7.53–7.73 (m, 6H, ArH’s and pyrazole H-3), 8.18 (d, 1H, J=8.0 Hz, pyridine H-4), 10.21 (s, br., 1H, NH); MS m/z(%): 276(M+, 100), 231(34), 164(36), 118(54), 77(78). Anal. Calcd for C16H12N4O (276.29): C, 69.55; H, 4.38; N, 20.28; Found C, 69.45; H, 4.23; N, 20.21%.


## 2.2.9. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (13)

Yield 93%; yellow crystals; m.p. 236–238°C (from ethanol); IR (KBr):v1621 (C=N), 2218 (CN), 3420 (NH) cm−1; 1H NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 6.93 (d, 1H, J=7.8 Hz, pyridine H-5), 7.52–7.62 (m, 6H, ArH’s and pyrazole H-3), 8.12 (d, 1H, J=7.8 Hz, pyridine H-4), 14.01 (s, 1H, NH); MS m/z(%): 293(M+ + 1, 38), 292(M+, 100), 264(16), 181(16), 118(26), 77(82). Anal. Calcd for C16H12N4S (292.36): C, 65.73; H, 4.14; N, 19.16; Found C, 65.67; H, 4.10; N, 19.02%.


## 2.2.10. 1-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (14)

Yield 92%; yellow crystals; m.p. 238–140°C (from ethanol); IR (KBr):v1603 (C=N), 2214 (CN), 3148, 3427 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.52 (s, 3H, CH3), 7.37 (d, 1H, J=8.1 Hz, pyridine H-5), 6.88 (s, br., 2H, NH2), 7.50–7.56 (m, 5H, ArH’s), 7.83 (s, 1H, pyrazole H-3), 8.09 (d, 1H, J=8.1 Hz, pyridine H-4); 13C NMR (DMSO-d6):δ 10.89 (CH3), 105.22, 110.46, 113.21, 118.24, 120.58, 126.87, 128.57, 128.89, 136.78, 139.25, 143.22, 146.57, 150.27; MS m/z(%): 292(M+ + 1, 38), 291(M+, 100), 118(11), 77(61). Anal. Calcd for C16H13N5O (291.31): C, 65.97; H, 4.50; N, 24.04; Found C, 65.78; H, 4.54; N, 23.94%.


## 2.3. 3-Amino-2-substituted-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]-pyridine Derivatives (15–18)

Method A. A mixture of 13 (0.29 g, 1 mmol) and the appropriate ethyl chloroacetate, chloroacetone, ω-bromoacetophenone or chloroacetonitrile (1 mmol), and 3–5 drops of acetic acid was grinded for 15 min. The resulting solid was collected and recrystallized from ethanol to give the respective compounds, 15–18, in excellent yields.Method B. A mixture of 13 (0.29 g, 1 mmol) and potassium hydroxide (0. 0.056 g, 1 mmol) in N,N-dimethylformamide (10 mL) was stirred for 2 h at room temperature. The appropriate ethyl chloroacetate, chloroacetone, ω-bromoacetophenone, or chloroacetonitrile (1 mmol each) was added and stirring was continued for 2 h. The resulting solid was collected and recrystallized from ethanol to give 15–18, respectively.


### 2.3.1. Ethyl 3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carboxylate (15)

Yield 88%; yellow crystals; m.p. 145-146°C; IR (KBr):v1720 (C=O), 3320, 3418 (NH2) cm−1; 1H NMR (DMSO-d6): δ 1.32 (t, J=7.5 Hz, 3H, CH3CH2), 2.49 (s, 3H, CH3), 4.16 (q, J=7.5 Hz, 2H, CH2CH3), 7.82 (d, 1H, J=8.4 Hz, pyridine H-5), 7.45–7.82 (m, 7H, ArH’s and NH2), 7.82 (s, 1H, pyrazole H-3), 8.48 (d, 1H, J=8.4 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ11.32, 14.58, 60.12, 105.42, 117.45, 122.57, 126.51, 126.89, 127.74, 128.48, 132.25, 136.75, 140.25, 143.11, 144.87, 148.28, 155.28, 165.78; MS m/z(%): 381(M+ + 1, 43), 380(M+, 21), 176(57), 148(57), 102(57), 71(86), 53(100). Anal. Calcd for C20H18N4O2S (378.45): C, 63.47; H, 4.79; N, 14.80; Found C, 63.49; H, 4.68; N, 14.65%.


### 2.3.2. 1-(3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl) thieno[2,3-b]pyridin-2-yl)ethanone (16)

Yield 86%; yellow crystals; m.p. 137-138°C; IR (KBr):v1713 (CO), 3310, 3414 (NH2) cm−1; 1H NMR (DMSO-d6): δ2.12 (s, 3H, CH3), 2.38 (s, 3H, CH3), 7.38–7.62 (m, 8H, ArH’s, NH2 and pyridine H-5), 7.72 (s, 1H, pyrazole H-3), 8.59 (d, 1H, J=8.4 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ 11.38 (CH3), 31.25 (CH3), 117.28, 122.58, 126.24, 126.78, 127.34, 128.48, 132.57, 136.57, 140.38, 142.28, 144.37, 147.81, 156.37, 191.28; MS m/z(%): 349(M+ + 1, 21), 348(M+, 41), 292(32), 149(38), 105(32), 77(100), 64(77). Anal. Calcd for C19H16N4OS (348.42): C, 65.50; H, 4.63; N, 16.08; Found C, 65.43; H, 4.67; N, 15.87%.


### 2.3.3.  (3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (17)

Yield 88%; yellow crystals; m.p. 127-128°C; IR (KBr):v1660 (CO), 3404 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 7.18–7.58 (m, 14H, ArH’s, NH2, pyrazole H-3 and pyridine H-5)), 8.54 (d, 1H, J=8.4 Hz, pyridine H-4); MS m/z(%): 411(M+ + 1, 3), 410(M+, 10), 293(13), 253(18), 105(100), 77(81). Anal. Calcd for C24H18N4OS (410.49): C, 70.22; H, 4.42; N, 13.65; Found C, 70.18; H, 4.32; N, 13.39%.


### 2.3.4. 3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carbonitrile (18)

Yield 84%; yellow crystals; m.p. 196–198°C; IR (KBr):v1637 (C=N), 3200 (CN), 3343, 3410 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.29 (s, 3H, CH3), 7.48–7.60 (m, 7H, ArH’s, NH2 and pyrimidine H-5), 7.79 (s, 1H, pyrazole H-3), 8.88 (d, 1H, J=8.4 Hz, pyridine H-4); MS m/z(%): 331(M+, 10), 302(17), 179(11), 133(16), 84(100), 77(81). Anal. Calcd for C18H13N5S (331.39): C, 65.24; H, 3.95; N, 21.13; Found C, 65.12; H, 3.91; N, 20.83%.


## 2.3.1. Ethyl 3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carboxylate (15)

Yield 88%; yellow crystals; m.p. 145-146°C; IR (KBr):v1720 (C=O), 3320, 3418 (NH2) cm−1; 1H NMR (DMSO-d6): δ 1.32 (t, J=7.5 Hz, 3H, CH3CH2), 2.49 (s, 3H, CH3), 4.16 (q, J=7.5 Hz, 2H, CH2CH3), 7.82 (d, 1H, J=8.4 Hz, pyridine H-5), 7.45–7.82 (m, 7H, ArH’s and NH2), 7.82 (s, 1H, pyrazole H-3), 8.48 (d, 1H, J=8.4 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ11.32, 14.58, 60.12, 105.42, 117.45, 122.57, 126.51, 126.89, 127.74, 128.48, 132.25, 136.75, 140.25, 143.11, 144.87, 148.28, 155.28, 165.78; MS m/z(%): 381(M+ + 1, 43), 380(M+, 21), 176(57), 148(57), 102(57), 71(86), 53(100). Anal. Calcd for C20H18N4O2S (378.45): C, 63.47; H, 4.79; N, 14.80; Found C, 63.49; H, 4.68; N, 14.65%.


## 2.3.2. 1-(3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl) thieno[2,3-b]pyridin-2-yl)ethanone (16)

Yield 86%; yellow crystals; m.p. 137-138°C; IR (KBr):v1713 (CO), 3310, 3414 (NH2) cm−1; 1H NMR (DMSO-d6): δ2.12 (s, 3H, CH3), 2.38 (s, 3H, CH3), 7.38–7.62 (m, 8H, ArH’s, NH2 and pyridine H-5), 7.72 (s, 1H, pyrazole H-3), 8.59 (d, 1H, J=8.4 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ 11.38 (CH3), 31.25 (CH3), 117.28, 122.58, 126.24, 126.78, 127.34, 128.48, 132.57, 136.57, 140.38, 142.28, 144.37, 147.81, 156.37, 191.28; MS m/z(%): 349(M+ + 1, 21), 348(M+, 41), 292(32), 149(38), 105(32), 77(100), 64(77). Anal. Calcd for C19H16N4OS (348.42): C, 65.50; H, 4.63; N, 16.08; Found C, 65.43; H, 4.67; N, 15.87%.


## 2.3.3.  (3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (17)

Yield 88%; yellow crystals; m.p. 127-128°C; IR (KBr):v1660 (CO), 3404 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.48 (s, 3H, CH3), 7.18–7.58 (m, 14H, ArH’s, NH2, pyrazole H-3 and pyridine H-5)), 8.54 (d, 1H, J=8.4 Hz, pyridine H-4); MS m/z(%): 411(M+ + 1, 3), 410(M+, 10), 293(13), 253(18), 105(100), 77(81). Anal. Calcd for C24H18N4OS (410.49): C, 70.22; H, 4.42; N, 13.65; Found C, 70.18; H, 4.32; N, 13.39%.


## 2.3.4. 3-Amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carbonitrile (18)

Yield 84%; yellow crystals; m.p. 196–198°C; IR (KBr):v1637 (C=N), 3200 (CN), 3343, 3410 (NH2) cm−1; 1H NMR (DMSO-d6): δ 2.29 (s, 3H, CH3), 7.48–7.60 (m, 7H, ArH’s, NH2 and pyrimidine H-5), 7.79 (s, 1H, pyrazole H-3), 8.88 (d, 1H, J=8.4 Hz, pyridine H-4); MS m/z(%): 331(M+, 10), 302(17), 179(11), 133(16), 84(100), 77(81). Anal. Calcd for C18H13N5S (331.39): C, 65.24; H, 3.95; N, 21.13; Found C, 65.12; H, 3.91; N, 20.83%.


## 2.4. 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-3-amine (19)

To a solution of the thione13 (0.29 g, 0.01 mol) in ethanol (10 mL) hydrazine hydrate was added (1 mL) and the mixture was heated under reflux for 12 h. The solution was poured over ice-water mixture and then neutralized by HCl. The solid product was filtered off, dried, and recrystallized from ethanol to afford compound 15. Yield 72%; yellow crystals; m.p. 204–206°C; IR (KBr): v1592 (C=N), 3190, 3322 (NH2 and NH) cm−1; 1H NMR (DMSO-d6): δ 2.89 (s, 3H, CH3), 5.94 (s, br., 3H, NH2 and NH), 6.92 (d, 1H, J=8.1 Hz, pyridine H-4), 7.48–7.56 (m, 5H, ArH’s), 8.14 (s, 1H, pyrazole H-3), 8.48 (d, 1H, J=8.1 Hz, pyridine H-4); MS m/z(%): 291(M+ + 1, 18), 290(M+, 31), 274(52), 224(30), 171(28), 118(42), 77(100). Anal. Calcd for C16H14N6  (290.32): C, 66.19; H, 4.86; N, 28.95; Found C, 66.08; H, 4.91; N, 28.76%.


## 2.5. 2,4-Dimethyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (20)

To a solution of19 (1.45 g, 5 mmol) and acetylacetone (0.5 g, 5 mmol), in acetic acid (20 mL) was refluxed for 10 min. The solid product was collected by filtration and recrystallized from acetic acid to afford compound 20. Yield 72%; yellow crystals; m.p. 206°C; IR (KBr): v1592 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.19 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.45 (s, 3H, CH3), 6.40 (s, 1H, pyrimidine H-5), 6.50 (d, 1H, J=8 Hz, pyridine H-5), 7.39–7.50 (m, 5H, ArH’s), 8.00 (s, 1H, pyrazole H-3), 8.40 (d, 1H, J=12 Hz, pyridine H-4); 13C NMR (DMSO-d6): δ 10.15 (CH3), 15.68 (CH3), 19.36 (CH3), 104.60, 108.10, 118.00, 119.90, 122.65, 123.38, 126.00, 129.82, 134.65, 140.21, 142.95, 143.42, 146.00, 146.84, 161.10, 164.44; MS m/z(%): 355(M+ + 1, 1), 354(M+, 3), 211(12), 185(31), 157(36), 105(23), 80(100). Anal. Calcd for C21H18N6 (354.41): C, 71.17; H, 5.12; N, 23.71; Found C, 71.10; H, 5.19; N, 23.56%.


## 3. Results and Discussion

The starting sodium 3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-olate (2) was prepared via reaction of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone [23] (1) with ethyl formate in the presence of sodium methoxide. Thus, condensation of 2 with 5-amino-3-methylpyrazole (3a) in acetic acid containing piperidine acetate or grinding afforded one isolable product formulated as 2-methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (5a) in good yield (Scheme 1). 1H NMR for the product revealed the signals at δ=2.61 (s, 3H, CH3), 2.69 (s, 3H, CH3), 6.36 (d, 1H, J=4 Hz, pyrimidine H-5), 6.78 (s, 1H, pyrazole H-4), 7.37–7.50 (m, 5H, ArH’s), 8.45 (s, 1H, pyrazole H-3), and 8.74 (d, 1H, J=4 Hz, pyrimidine H-4). The reaction seemed to be via the initial nucleophilic attack by the exocyclic amino group at the formyl group, which formed in situfrom 1 with water, followed by cyclization and elimination of one molecule of water leading to the formation of the product 5a (Scheme 1). The suggestion of the formation of the alternative isomeric product 7a is based on the initial attack of endocyclic amino group at the formyl group for the formation of 7a. As the spectroscopic data above does not allow one to distinguish between possible products 5a and 7a. The latter suggestion is excluded due to the higher nucleophilicity of the exocyclic primary amino group than the endocyclic amino group. Thus, the mechanism proposed in Scheme 1 seems to be acceptable. In order to establish unambiguously the structure of the product, the crystal structure of a similar previous work has been reported [26–29]. Also, product was obtained by an alternative synthesis route by reaction of 3-(dimethylamino)-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-one (8) [25] with 3a. Analogously, condensation of 3b–d with 2 gave corresponding 7-substituted pyrazolo[1,5-a]pyrimidines 5b–d, respectively.Scheme 1
Synthesis of pyrazolo[1,5-a]pyrimidines (5a–d).Treatment of2 with the appropriate 4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-amine, 2-aminobenzimidazole, 4H-1,2,4-triazol-3-amine, cyanoacetamide and 2-cyanothioacetamide, and 2-cyanoacetohydrazide gave 8,10-dimethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrido [2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9), 4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (10), 5-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyrimidine (11), 6(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12), 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (13), and 1-amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (14), respectively (Scheme 2). Structures 9–14 were confirmed by elemental analysis, spectral data, and chemical transformation whenever possible.Scheme 2
Synthesis of pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9), benzoimidazo[1,2-a]pyrimidine (10), triazolo[4,3-a]pyrimidine (11), and pyrimidinones (12–14).Thus, compound13 reacted with each of ethyl chloroacetate, chloroacetone, ω-bromoacetophenone, chloroacetonitrile and hydrazine hydrate, afforded ethyl 3-amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carboxylate (15), 1-(3-amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridin-2-yl)ethanone (16), (3-amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (17), 3-amino-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thieno[2,3-b]pyridine-2-carbonitrile (18), and 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (19), respectively (Scheme 3).Scheme 3
Synthesis of thieno[2,3-b]pyridines (15–18) and pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (20)Structures15–18 were elucidated by elemental analysis and spectral data. Also, compound 19 reacted with acetylacetone in acetic acid and gave 2,4-dimethyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (20). Structure of 20 was elucidated via elemental analysis and spectral data.


## 4. Conclusion

In summary, we have developed a simple, efficient procedure for the synthesis of pyrazolo[1,5-a]pyrimidine, pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine, [1, 2, 4]triazolo-[1,5-a]pyrimidine, pyridine, and thieno[2,3-b]pyridines derivatives.



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*Source: 327095-2013-11-10.xml*