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Enaminone in Heterocyclic Synthesis: Synthesis of New Pyrazolopyrazole Pyrazolothienooxazine and Pyrazolothienopyridine Derivatives.

Byline: Ibrahim Saad Abdel Hafiz Mohamed Ahmed Mahmoud Abdel ReheimSafaa Mohamed Baker and Mahmoud Mahfouz Ramiz

Summary: The chemical reactivity of enaminone 2 toward some nucleophilic and electrophilic reagents was investigated. Enaminone 2 was used as a key precursor for the synthesis of many important heterocyclic compounds. The synthesized compounds were characterized by IR 1H-NMR MS spectral and elemental analysis.

Keywords: Heterocycles Enaminone Pyrazole Pyrazolone Pyrazolothienooxazines Pyrazolothienopyridine.

Introduction

Heterocycles containing a pyrazole or pyrazolone ring system are found to exhibit a wide spectrum of biological activities including antibacterial and antifungal activities. Pyrazolone derivatives are an important class of heterocyclic compounds that occur in many drugs and synthetic products [1 2]. The derivatives of pyrazolone are important class of antipyretic and analgesic compounds [3-5]. In fact one of the first synthetic organic compounds to find use as an important drug was a pyrazolone (antipyrine) that first prepared in 1887 and used as antipyretic analgesic and anti- inflammatory [3]. Modifications in the pyrazolone nucleus led to the discovery of the well-known medicinal pyrazolone dipyrone that inhibit the activities in a dose-dependent manner of cyclooxygenase enzyme COX-1 and its variant COX- 3 [4 5].

It was found that pyrazolone derivatives exhibit remarkable analgesic [6] anti-tubercular [7] antifungal antibacterial [8] anti-inflammatory [9] antioxidant antitumor [10] insecticidal [11-13] and anticancer activities [14]. Numerous pyrazole derivatives are also used in dye industry [15]. Due to their easier preparation and rich biological activity pyrazolone framework plays an essential role and represents an interesting template for combinatorial and medicinal chemistry. This gave a great impetus to the search for potential pharmacologically active drugs carrying pyrazolone substituents.

In the last few years we have been involved in a program aimed at developing new efficient synthetic approaches for the synthesis of heterocyclic compounds of biological interest [16-19]. In previous studies we report here the utility of polyfunctionally substituted heterocycles in heterocyclic synthesis [20 21]. In continuation of this work and as apart of our biological chemistry program we report her the utility of 4-(dimethylamino)methylene)-13-diphenyl-1H- pyrazole-5(4H)-one (2) in the preparation of unique heterocyclic compounds.

Results and Discussion

Synthesis

Ethyl benzoylacetate was reacted with phenyl hydrazine to give pyrazolone 1 [22]. Similar to the behaviour of azolone toward DMF-DMA [23] pyrazolone 1 reacted with DMF-DMA to afford 4- (Dimethylamino)methylene)-13-diphenyl-1H- pyrazole-5(4H)-one (2) based on its spectral analysis. For example the 1H-NMR of 2 revealed the presence of a signal at = 3.07 ppm corresponding to the methyl functions a signal at = 6.96 ppm corresponding to olifinic proton a signal at = 7.21- 7.89 ppm corresponding to aromatic protons. The mass spectrum of the same product is in accordance with the proposed structure. Thus it showed the presence of the molecular ion peak at 291 and a number of fragments agree with the proposed structure (Scheme-1). Enaminone 2 used as a key precursor in the synthesis of new heterocyclic derivatives. Enaminone 2 was reacted with aniline (3a) 4-chloroaniline (3b) and piperidine (6) to give pyrazolone derivatives 5a

5b and 8 via intermediacy of 4a [16] 4b and 7 respectively. Establishing structures of 5a 5b and 8 was based on its elemental analyses and spectral data (Scheme-1). For example 1H-NMR of 5a revealed the presence of a signal at = 7.11-8.11 ppm corresponding to olifinic protons and aromatic protons and a signal at = 12 ppm corresponding to the amino function. The mass spectrum of the same product is in accordance with the proposed structure. Thus it showed the presence of the molecular ion peak at 339 and a number of fragments agree with the proposed structure (Scheme-1). In addition the behavior of enaminone 2 toward hydrazine derivatives was also investigated. When enaminone 2 was allowed to react with hydrazine (9a) on refluxing ethanol a compound with molecular formula C16H12N4 (Mr = 260) was obtained in a quantitative yield. This was considered to be pyrazolopyrazole 12 based on its spectral data. For example the IR spectrum of 12 revealed the absence of carbonyl group.

The 1H-NMR of the same product agrees with the proposed structure. Formation of 12 is believed to be formed via addition of hydrazine to the double bond system of enaminone2 to afford pyrazolone derivative 10a which then loses dimethylamine to give 11a which produces pyrazolopyrazole 12 after losing water (Scheme-2). Similarly phenylhydrazine was reacted with enaminone 2 to afford 11b via intermediacy of 10b. Establishing structure 11b was based on its elemental and spectral analysis. For example the 1H-NMR of 11b revealed the presence a signal at = 6.82 ppm corresponding to olifinic proton a signal at = 6.84- 8.18 ppm corresponding to aromatic and amino proton and a signal at = 6.82 ppm corresponding to amino proton. The mass spectrum of the same compound is in accordance with the proposed structure. Thus it showed the molecular ion peak at 354 and a base peak at 91 (Scheme-2). Furthermore the behaviour of enaminone 2 toward some activated azoles was also investigated. When 2 was allowed to react with pyrazolone 13a in refluxing ethanol 135-triphenyl-1H-pyrano[23- c:65-c']dipyrazole (17) was obtained [23] based on its elemental and spectral data. The formation of 17 is believed to be formed via addition of methylene group of 13a on the double bond system of enaminone 2 to afford the unstable intermediate 14a which loses readily dimethylamine to afford the non- isolable intermediate 15a which tautomerises into 16a that loses water to afford 17. Establishing structure 17 was based on its elemental and spectral data. The IR spectrum of compound 17 revealed the absence of carbonyl functions. The 1H-NMR of the same compound is in accordance with the proposed structure. Thus it showed a signal at = 7.36-7.95 ppm corresponding to olifinic proton and aromatic protons.

In a similar manner enaminone 2 was reacted with N-phenylpyrazolone 13b to give 15b via intermediacy of 14b (Scheme-3). Establishing structure 15b was based on its spectral data. For example the 1H-NMR of compound 15b revealed the presence of a signal = 7.36-7.94 corresponding to olifinic proton and aromatic protons and a signal at = 3.30 corresponding to sp3 proton. The mass spectrum of the same compound showed a very intense molecular ion peak at 482 (Scheme-3). Also imidazolidine-24-dione 18 reacted with 2 to give imidazopyranopyrazole 22 via intermediacy of 1921 (Scheme-3). Establishing compound 22 was based on its elemental and spectral data. For example the IR spectrum of compound 22 revealed the absence of carbonyl function. The mass spectrum of the same product agrees with the proposed structure. Thus it showed a molecular ion peak at 327 and a number of fragments agree with the proposed structure.

Scheme-3: The synthesis of derivatives (15b 17 22) The synthetic potentiality of 13-diphenyl- 1H-pyrazol-5(4H)-one (1) was also investigated by its reaction with a mixture of malononitrile and sulphur under reflux and a compound with molecular formula C18H12N4S (Mr = 316) was obtained. This was considered to be the thienopyrazole 26 based on its elemental and spectral analyses. Establishing of compound 26 was based on its elemental and spectral data. For example the IR spectrum of compound 26 revealed the presence of amino and cyano functions. The mass spectrum of the same compound is in accordance with the proposed structure. Thus it showed a molecular ion peak at 316 and fragments agree with the proposed structure. The formation of thienopyrazole 26 is believed to be formed from pyrazolone 1 malononitrile and elemental sulphur via Gewald synthesis [24]. Thienopyrazole 26 is used in many chemical transformations to prepare new heterocyclic compounds of expected biological activity [25-29].

Thus when thinopyrazole 26 is allowed to react with formic acid under reflux 13- diphenyl-1H8H-pyrazolo[3'4':45]thieno[23- d][13]oxazin-8-imine (28) is formed in quantitative Yield: via intermediacy of 27 (Scheme-4). The structure of compound 28 was proved using its spectral data. The IR spectrum of 28 revealed the absence cyano function indicating the addition of hydroxyl group on the triple bond system of cyano group. The 1H-NMR of the same product revealed the presence of a signal at = 6.01 ppm corresponding to olifinic proton a signal at = 7.21-7.91 ppm corresponding to aromatic and imino protons. The mass spectrum of the same product showed a very intense molecular ion peak at 344 and a base peak at 57.

Furthermore acylation of thienopyrazole 26 using acetic anhydride afforded N-(6-cyano-13- diphenyl-1H-thieno[32-c]pyrazol-5-yl)acetamide (29) based on its spectral data. For example The IR spectrum of 29 revealed the appearance of acyl carbonyl at 1719 cm-1. The 1H-NMR of the same compound revealed the presence of a signal at = 1.97 ppm corresponding to methyl function and a signal at = 7.18-7.88 corresponding to aromatic protons and NH proton. The mass spectrum of the same product agrees with the proposed structure. Treatment of 29 with a mixture of acetic acid and hydrochloric acid under reflux afforded thienooxazinimine 30. Thienooxazinimine 30 is obtained also from thienopyrazole 26 in a direct way by refluxing a mixture of 26 acetic acid and hydrochloric acid [30] (Scheme-4). Establishing compound 30 was based on its spectral data. For example The IR spectrum of compound 30 revealed the absence of carbonyl group and amidic NH group.

The mass spectrum of the same product showed a molecular ion peak at 358 and a base peak at 76. Scheme 4. The synthesis of derivatives (28-30) Also the reactivity of thienopyrazole 26 toward active methylene reagents was investigated. When 26 was allowed to react with ethyl acetoacetate (31a) in refluxing in ethanol containing catalytic amount of piperidine gave the acyclic product 32a. Trials to cyclize 32a under the same reaction condition failed [31]. Cyclization of 32a into pyridine derivative 33a took place on refluxing in dioxane containing a catalytic amount of piperidine for 5 hr. Establishing compound 33a was based on its elemental and spectral data. For example the IR spectrum of compound 33a revealed the absence of cyano function and appearance of amino function indicate the addition of methylene group on the triple bond system. The 1H-NMR revealed the presence of a signal at = 2.49 ppm corresponding to methyl function a signal at = 7.19-7.92 ppm corresponding to aromatic protons and amino protons and a signal at = 11.40 ppm corresponding to NH proton.

The mass spectrum of the same product is in accordance with the proposed structure. Similarly 26 reacted with ethyl benzoylacetate (31b) on refluxing in ethanol to afford 32b which cyclized into 33b in refluxing dioxane (Scheme-5). In the same way thienopyrazole 26 reacted with acetyl acetone (34) in refluxing ethanol to afford 35 (Scheme-5). Establishing compound 35 was based on its spectral data. For example the IR spectrum of compound 35 revealed the appearance of carbonyl group and methyl functions. The 1H-NMR of the same product is in accordance with proposed structure.

In continuation 13-diphenyl-1H-pyrazol- 5(4H)-one (1) reacted with benzylidine-malononitrile (36a) on refluxing in ethanol containing a catalytic amount of pipridine to give pyranopyrazole 40a rather than its isomeric 41a based on its elemental and spectral data [32]. Similarly arylidinemalononitrile 36b-d reacted with phenylpyrazolone 1 in the same reaction condition to give pyranopyrazole 40b-d (Scheme-6).

Scheme-6: The synthesis of derivatives (40a-d) The reaction of phenylpyrazolone (1) with aryldiazonium salts 42a-d resulted in the formation of hydrazo forms 44a-d according to their spectral analysis [33]. For example IR spectrum of compound 44a revealed the absence of aliphatic function and appearance of NH function. The 1H- NMR of compound 44a further support this as it revealed the presence a signal at = 13.83 ppm corresponding to NH group. The mass spectrum of the same product is in accordance with the proposed structure. Treatment of 44 with active methylene reagents afforded pyrazolopyridazines 48 (Scheme- 7). Formation of 48 from 44 and active methylene reagent is believed to proceed via initial addition of the active methylene reagents to the carbonyl group of 44 followed by cyclization and subsequent elimination of water. Establishing structure 48 was based on its elemental and spectral data.

For example the IR spectrum of compound 48a revealed the presence of amino function at 3425 cm-1 and cyano function at 2197 cm-1. The 1H-NMR and mass spectrum of the same product are in accordance with the proposed structure. Experimental Instruments

All melting points were measured using Akofler Block instrument and are uncorrected. IR spectra (KBr) were recorded on a FTIR 5300 spectrometer ( cm-1). The 1H NMR spectra were recorded in DMSO-d6 at 200 MHz on a Varian Gemini NMR. 1000 EX mass spectrometer at 70 ev. The purity of synthesized compounds was checked by thin layer chromatography TLC (aluminum sheets) using chloroform-methanol (9:1 V/V) eluent. Elemental analyses were carried out by the Microanalytical Research Center Faculty of Science Cairo University.

Preparation of 4-((dimethylamino)methylene)-13- diphenyl-1H-pyrazol-5(4H)-one (2)

To a solution of compounds 1 (0.01 mol) in dioxane (30 mL) DMF-DMA (0.01 mol) was added. The reaction mixture was refluxed for 6 hrs the solid product so formed Was collected by filtration and crystallized from ethanol to afford yellow crystals; Yield: 80 %; m.p.: 164166 oC; IR (KBr cm-1): 3047 (CH aromatic.) 2918 (CH aliphatic) and 1666 (C=O); 1H NMR (CDCl3): 7.89-6.96 (m 10H Ar H) 6.80 (s 1H olifinic proton) 3.07 (s 6H 2 CH3); MS (m/z): 291 (M+) Anal. Calcd. (%) for C18H17N3O: C 74.20; H 5.88; N 14.42. Found: C 74.40; H 5.84; N 14.40.

General procedure for synthesis of pyrazolone derivative (5a-b)

A mixture of enaminone 2 (0.01 mol) and aryl amine 3a b (0.01 mol) in ethanol (30 mL) containing a catalytic amount of piperidine (1.2 mL) was refluxed for 12 hrs. The reaction mixture was poured into cold water (30 mL) and acidified with hydrochloric acid (pH 3). The solid product so formed was collected by filtration and crystallized from ehanol to afford (5a-b). Scheme-7: The synthesis of pyrazolo[43-c]pyridazine (48a-g). 25-Diphenyl-4-[(phenylamino)methylidene]-24- dihydro-3H-pyrazol-3-one (5a)

It was obtained as brown crystals from ethanol; Yield: 63 % ; m.p.: 100102 oC; IR (KBr cm-1): 3429 (NH) 3090 (CH aromatic.) 2927 (CH aliphatic) 1663 (C=O); 1H NMR (DMSO-d6) 12.00 (s 1H NH) 8.11-7.11 (m 16H aromatic and olifinic proton); MS (m/z): 339 (M+) 247 (base peak); Anal. Calcd. (%) for C22H17N3O: C 77.86; H 5.05; N 12.38. Found: C 77.85; H 5.09; N 12.40.

4-{[(4-Chlorophenyl)amino]methylidene}-25- diphenyl-24-dihydro-3H-pyrazol-3-one (5b)

It was obtained as brown crystals from ethanol; Yield: 63 %; m.p.: 120122 oC; IR (KBr cm-1): 3442 (NH) 3056 (C-H aromatic) 2924 (CH aliphatic) 1654 (C=O); 1H NMR (DMSO-d6) 12.00 (s 1H NH) 8.53 -7.18 (m 15H aromatic and olifinic protons); MS (m/z): 373 (M+) 247 (base peak); Anal. Calcd. (%) for C22H16ClN3O: C 70.68; H 4.31; Cl 9.48; N 11.24. Found: C 70.72; H 4.33; Cl 9.52; N 11.27.

Preparation of 25-diphenyl-4-(piperidin-1-ylmethyl- idene)-24-dihydro-3H-pyrazol-3-one (8)

A mixture of enaminone 2 (0.01 mol) and piperidine 6 (1.2 mL) in ethanol (30 mL) was refluxed for 3 hr. The mixture was poured into cold water (30 mL) and acidified with HCl (pH 3). The solid product so formed was collected and crystallized from ethanol. It was obtained as pale yellow crystals; Yield: 77%; m.p.: 230-232 C; IR (KBr cm-1): 3050 (CH aromatic) 2924 (CH aliphatic); 1669 (C=O); 1H NMR (DMSO-d6) 8.55 - 7.28 (m 10H Ar-H) 6.04 (s 1H alkenyl-H) 4.47- 3.49 (br 6H 3 CH2) 1.64-1.10 (br 4H 2 CH2); MS (m/z): 332 (M+ + 1); Anal. Calcd. (%) for C21H21N3O: C 76.11; H 6.39 N 12.68. Found: C 76.14; H 6.36; N 12.65. General procedure for synthesis of hydrazine derivatives (11b 12)

Synthesis of 11b 12; Adjust A mixture of enaminone 2 (0.01 mol) hydrazine hydrate (9a) or phenyl hydrazine (9b) (0.01 mol) in ethanol (30 mL) was heated under reflux for 12 hrs. The reaction mixture was allowed to cool poured onto crushed ice and acidified with HCl (pH3). The solid product so formed was filtered off and crystallized from ethanol. 25-Diphenyl-4-[(2-phenylhydrazinyl)methylidene]- 24-dihydro-3H-pyrazol-3-one (11b)

It was obtained as brown crystals from ethanol; Yield: 61 %; m.p.: 100102 oC; IR (KBr cm-1): 3287 3425 (NH) 3060 (C-H aromatic) 2924 (CH aliphatic) 1719 (C=O); 1H NMR (DMSO-d6) 12.00 (s 1H NH) 8.18-6.84 (m 16H aromatic protons and NH) 6.82 (s 1H olifinic proton); MS (m/z): 354 (M+) 91 (base peak); Anal. Calcd. (%) for C22H18N4O: C 74.56; H 5.12; N 15.81. Found: C 74.59; H 5.15; N 15.83.

13-Diphenyl-15-dihydropyrazolo[34-c]pyrazole (12)

It was obtained as green crystals from ethanol; Yield: 69 %; m.p.: 110112 oC; IR (KBr cm-1): 3393 (NH) 3052 (C-H aromatic) 2955 (C-H aliphatic); 1H NMR (DMSO-d6) 11.85 (s 1H NH) 7.83-7.25 (m 10H aromatic protons) 6.02 (s 1H olifinic proton); MS (m/z): 262 (M++2) 77 (base peak); Anal. Calcd. (%) for C16H12N4 : C 73.83; H 4.65; N 21.52. Found: C 73.86; H 4.67; N 21.54.

General procedure for synthesis of compounds (15b 17 22)

A mixture of enaminone 2 (0.01 mol) activated azoles 13a-b or 18 (0.01 mol) in ethanol (30 mL) containing piperidine (1.2 mL) was refluxed for 15 hrs poured onto cold water (30 mL) and acidified with HCl (pH3). The solid product so formed was filtered and crystallized from ethanol to afford compounds 15b 17 and 22. '4-((5-Oxo-13-diphenyl-1H-pyrazol-4(5H)- ylidene)methyl)-13-diphenyl-1H-pyrazol-5(4H)-one (15b):

It was obtained as yellow crystals from ethanol; Yield: 77 %; m.p.: 236238 oC; IR (KBr cm-1): 3061 (CH aromatic) 2923 (CH aliphatic) 1660 (C=O); 1H NMR (DMSO-d6) 7.94-7.36 (m 21H olifinic and aromatic protons) 3.30 (s 1 H C H); MS (m/z): 482 (M+); Anal. Calcd. (%) for C31H22N4O2: C 77.16; H 4.60; N11.61. Found: C 77.17; H4.64; N 11.67. 135-Triphenyl-1H-pyrano[23-c:65-c']dipyrazole (17)

It was obtained as yellow crystals from ethanol; Yield: 77 %; m.p.: 240242 oC; IR (KBr cm-1): 3050 (CH aromatic); 1H NMR (DMSO-d6) 7.95-7.36 (m 16H aromatic and olifinic proton); MS (m/z): 390 (M++2) 77 (base peak); Anal. Calcd. (%) for C25H16N4O: C 77.30; H 4.15; N 14.42. Found: C 77.33; H 4.17; N 14.46.

13-Diphenyl-15-dihydro-6H imidazo[4'5':56]- pyrano[23-c]pyrazol-6-one (22)

It was obtained as brown crystals from ethanol; Yield: 70 %; m.p.: 200202 oC; IR (KBr cm-1): 3430 (NH) 3052 (CH aromatic) 1662 (C=O); 1H NMR (DMSO-d6) 8.04-7.36 (m 12H aromatic olifinic and NH protons); MS (m/z): 327 (M-1) 74 (base peak); Anal. Calcd. (%) for C19H12N4O2: C 69.51; H 3.68; N 17.06. Found: C 69.54; H 3.69; N 17.09.

Preparation of 5-amino-1 3-diphenyl-1H-thieno [3 2-c] pyrazole-6-carbonitrile (26)

Equimolar amounts of 1 (0.01 mol) malononitrile and elemental sulfur (0.01 mol) in ethanol (30 mL) containing piperidine (1.2 mL) were refluxed for 15 hrs poured onto cold water (30 mL) and acidified with HCl (pH 3). The solid product thus formed was filtered and crystallized from ethanol. It was obtained as pale yellow crystals; Yield: 86 %; m.p.: 290-292 C; IR (KBr cm-1): 3431 (NH2) 3062 (CH aromatic) 2209 (C=N); 1H NMR (DMSO-d6) 11.40 (s 2H NH2) 7.91-7.20 (m 10H aromatic protons); MS (m/z): 316 (M+); Anal. Calcd. (%) for C18H12N4S: C 68.33; H 3.82; N 17.71; S10.13. Found: C68.35; H 3.86; N 17.74; S10.16.

Preparation of 13-diphenyl-1H8H-pyrazolo [3'4':45]thieno[23-d][13]oxazin-8-imine (28)

To a suspension of 26 (0.01 mol) in methanol formic acid (10 mL) was added. The reaction mixture was refluxed for 8 hrs and left to stand. The solid product so formed was collected by filtration washed with water several times and crystallized from ethanol. It was obtained as brown crystals; Yield: 66 %; m.p.: 276-278 C; IR (KBr cm-1): 3408 (NH) 3061 (CH aromatic); 1H NMR (DMSO-d6) 7.91-7.21 (m 11H aromatic and imino protons) 6.01 (s 1H CH olifinic protons); MS (m/z): 343 (M+-1) 57 (base peak); Anal. Calcd. (%) for C19H12N4OS : C 66.26; H 3.51; N 16.27; S 9.31. Found: C 66.23; H 3.56; N 16.29; S 9.35.

Preparation of N-(6-cyano-13-diphenyl-1H- thieno[32-c]pyrazol-5-yl)acetamide (29)

To a suspension of 26 (0.01 mol) in ethanol acetic anhydride (10 mL) was added. The reaction mixture was refluxed for12 hrs and left to cool. The solid product so formed was collected by filtration and crystallized from ethanol. It was obtained as brown crystals; Yield: 71 %; m.p.: 140142 C; IR (KBr cm-1): 3445 (NH) 3062 (CH aromatic) 2926 (CH aliphatic) 2226 (C=N) 1719 (C=O); 1H NMR (DMSO-d6) 7.88-7.18 (m 11H aromatic and NH protons) 1.97 (s 3H CH3); MS (m/z): 358 (M+) 77 (base peak); Anal. Calcd. (%) for C20H14N4OS: C67.02; H 3.94; N 15.63; S8.95. Found: C 67.05; H 3.97; N 15.66; S 8.92.

Preparation of 6-methyl-13-diphenyl-1H8H- pyrazolo[3'4':45]thieno[23-d][13]oxazin-8-imine (30)

Method (A): A solution of 26 in glacial acetic acid (30 mL) and HCl conc. (3 mL) was heated under reflux for 8 hrs. The solid product which produced during reflux was collected by filtration and crystallized from ethanol to afford 30.

Method (B): A solution of compound 29 (0.01 mol) in glacial acetic acid (30 mL) containing HCl conc. (3 mL) was heated under reflux for 24 hrs. The solid product so formed was collected by filtration and crystallized from ethanol to afford 30. It was obtained as colourless crystals; Yield: 85 %; m.p.: 320322 C; IR (KBr cm-1): 3444 (NH) 3064 (CH aromatic) 2852 (CH aliphatic); 1H NMR (DMSO-d6) 10.71 (s 1 H NH) 7.92-7.20 (m 10H aromatic protons) 1.97 (s 3H CH3); MS (m/z): 355 (M+-3) 76 (base peak); Anal. Calcd. (%) for C20H14N4OS : C 67.02; H 3.94; N 15.63; S 8.95. Found: C 67.05; H 3.97; N15.66; S 8.93.

General procedure for synthesis of compounds (32a- b and 35)

A mixture of 26 (0.01 mol) and ethyl acetoacetate (31a) ethyl benzoylacetate (31b) or acetyl acetone (34) (0.01 mol) in ethanol (30 mL) containing catalytic amount of piperidine (1.2 mL) was refluxed for 2 hrs and poured onto cold water (30 mL). The solid product so formed was filtered and crystallized from ethanol.

N-(6-Cyano-1 3-diphenyl-1H-thieno [3 2-c]pyrazol- 5-yl)-3-oxobutanamide (32a)

It was obtained as white crystals from ethanol; Yield: 72 % ; m.p.: 140142 oC; IR (KBr cm-1): 3432 (NH) 3063 (CH aromatic) 2925 (CH aliphatic) 2223 (C=N) 1712 (C=O); 1H NMR (DMSO-d6) 7.91-7.24 (m 11H aromatic and NH protons) 4.10 (s 2H CH2) 1.23 (s 3H CH3); Anal. Calcd. (%) for C22H16N4O2S: C 65.98; H 4.03; N13.99; S 8.01. Found: C 65.95; H 4.08; N 13.93; S8.00.

N-(6-cyano-13-diphenyl-1H-thieno[32-c]pyrazol-5- yl)-3-oxo-3-phenylpropanamide (32b)

It was obtained as white crystals from ethanol; Yield: 81 %; m.p.: 148150 oC; IR (KBr cm-1): 3430 (NH) 3060 (CH aromatic) 2900 (CH aliphatic) 2220 (C=N) 1710 (C=O); Anal. Calcd. (%) for C27H18N4O2S : C70.11; H 3.92; N12.11; S 6.93. Found: C 70.15; H 3.90; N12.10; S6.90.

5{[-4-Oxopentan-2-ylidene]amino}-13-diphenyl-1H- thieno[32-c]pyrazole-6-carbonitrile (35)

It was obtained as brown crystals from ethanol; Yield: 79 % ; m.p.: 200202 oC; IR (KBr cm-1): 3064 (CH aromatic) 2923 (CH aliphatic) 2216 (C=N) 1698 (C=O); 1H NMR (DMSO-d6) 7.14-7.90 (m 10H aromatic protons ) 4.18 (s 2H CH2) 1.04 (s 3H CH3) 1.16 (s 3H CH3); MS (m/z): 396 (M+-2) 77 (base peak); Anal. Calcd. (%) for C23H18N4OS: C 69.32; H 4.55; N 14.06; S 8.05. Found: C 69.31; H 4.53; N 14.01; S 8.05%.

General procedure for synthesis of compounds (33a- b)

A solution of 32a-b (0.01 mol) in dioxane (30 mL) containing catalytic amount of piperidine (1.2 mL) was refluxed for 5 hrs and poured onto cold water (30 mL). The solid product so formed was filtered and crystallized from ethanol .7-Acetyl-8-amino-13-diphenyl-15-dihydro-6H- pyrazolo[3'4':45]thieno[23-b] pyridin-6-one (33a)

It was obtained as white crystals from ethanol; Yield: 55 %; m.p.: 306308 oC; IR (KBr cm-1): 3431 3400 (NH2) 3064 (CH aromatic) 2850 (CH aliphatic) 1700 (C=O); 1H NMR (DMSO-d6) 11.40 (s 1H NH) 7.92-7.19 (m 12H aromatic and NH2 protons) 2.49 (s 3H CH3); MS (m/z): 400 (M+) 57 (base peak); Anal. Calcd. (%) for C22H16N4O2S: C 65.98; H 4.03; N 13.99; S 8.01. Found: C 65.95; H 4.08; N13.93; S8.05.

8-Amino-7-benzoyl-13-diphenyl-1H- pyrazolo[3'4':45]thieno[23-b]pyridin-6(5H-one (33b)

It was obtained as white crystals from ethanol; Yield: 51 %; m.p.: 108110 oC; IR (KBr cm-1): 3444 3400 (NH2) 3058 (CH aromatic) 1733 1672 (C=O); 1H NMR (DMSO-d6) 7.27-7.93 (m 18H aromatic NH and NH2 protons); MS (m/z): 462 (M+) 77 (base peak); Anal. Calcd. (%) for C27H18N4O2S: C 70.11; H 3.92; N 12.11; S 6.39. Found: C 70.15; H 3.91; N 12.14; S 6.42.

General procedure for synthesis of pyrano[23- c]pyrazole (40a-d)

A mixture of pyrazolone 1 (0.01 mol) and arylidine malononitrile 36ad (0.01 mol) in ethanol (40 mL) containing catalytic amount of piperidine (1.2 mL) was refluxed for 6 hrs and poured onto cold water (30 mL) and acidified with HCl (pH 3). The solid product was collected and crystallized from ethanol to afford (40a-d). 6-Amino-1 3 4-triphenyl-1 4-dihydropyrano [2 3- c] pyrazole-5-carbonitrile (40a)

It was obtained as pale yellow crystals from ethanol; Yield: 81 %; m.p.: 238240 oC; IR (KBr cm-1): 3454 3384 (NH2) 3056 (CH aromatic) 2184 (C=N) 1H NMR (DMSO-d6) 8.08-7.18 (m 17H aromatic and NH2 protons) 5.22 (s 1H H-4 pyrane); MS (m/z): 390 (M+) 77 (base peak); Anal. Calcd. (%) for C25H18N4O: C 76.91; H 4.65; N 14.35. Found: C 76.93; H 4.67; N 14.39.

6-Amino-4-(4-chlorophenyl)-1 3-diphenyl-1 4 dihydropyrano[23-c]pyrazole-5-carbonitrile (40b)

It was obtained as white crystals from ethanol; Yield: 76 %; m.p.: 206208 oC; IR (KBr cm-1): 3449 3323 (NH2) 3061 (CH aromatic) 2199 (C=N) 1H NMR (DMSO-d6) 7.97-7.29 (m 16H aromatic and NH2 protons) 5.17 (s 1H H-4 pyran); MS (m/z): 424 (M+) 77 (base peak); Anal. Calcd. (%) for C25H17ClN4O: C 70.67; H 4.03; Cl 8.34; N13.19. Found: C 70.69; H 4.07; Cl 8.38; N13.16. 6-Amino-4-(4-nitrophenyl)-13-diphenyl-14- dihydropyrano[23-c]pyrazole-5-carbonitrile (40c)

It was obtained as pale yellow crystals from ethanol; Yield: 85 % ; m.p.: 216218 oC; IR (KBr cm-1): 3431 3326 (NH2) 3065 (CH aromatic) 2197 (C=N) 1H NMR (DMSO-d6) 8.10-7.29 (m 16H aromatic and NH2 protons) 5.40 (s 1H H-4 pyran); MS (m/z): 435(M+) 77 (base peak); Anal. Calcd. (%) for C25H17N5O3: C 68.96; H 3.94; N 16.08. Found: C 68.99; H 3.96; N16.05.

6-Amino-4-(24-dichlorophenyl)-13-diphenyl-14- dihydropyrano[23-c]pyrazole-5-carbonitrile (40d)

It was obtained as pale yellow crystals from ethanol; Yield: 76 %; m.p.: 202204 oC; IR (KBr cm-1): 3450 3324 (NH2) 3062 (CH aromatic) 2196 (C=N) 1H NMR (DMSO-d6) 7.93-7.20 (m 15H aromatic and NH2 protons ) 5.57 (s 1H H-4 pyran); MS (m/z): 458 (M+) 77 (base peak); Anal. Calcd. (%) for C25H16Cl2N4O: C 65.37; H 3.51; Cl15.44; N12.20. Found: C 65.36; H 3.53; Cl 15.48; N12.23.

General procedure for synthesis of compounds (44a- d)

To a stirred cold solution of aryldiazonium chlorides 42a-d (0.01 mol prepared by treating aniline derivatives (0.01 mol) with sodium nitrite (0.01 mol) in HCl ethanol (30 mL) and catalytic sodium acetate) the active methylene reagent 1 was added gradually. The stirring was continued for two hrs. The solid product so formed was filtered off washed with water several times dried and crystallized from ethanol to afford 44a-d.

25-Diphenyl-4-(2-phenylhydrazinylidene)-24- dihydro-3H-pyrazol-3-one (44a)

It was obtained as orange crystals from ethanol; Yield: 88 %; m.p.: 176178 oC; IR (KBr cm-1): 3450 (NH) 3010 (CH aromatic) 1660 (C=O); 1H NMR (DMSO-d6) 13.83 (s 1H NH) 8.02-7.03 (m 15H aromatic protons); MS (m/z): 340 (M+) 77 (base peak); Anal. Calcd. (%) for C21H16N4O: C 74.10; H 4.74; N 16.46. Found: C 74.13; H 4.76; N 16.42.

4-[2-(4-Methylphenyl)hydrazinylidene]-25-diphenyl- 24-dihydro-3H-pyrazol-3-one (44b)

It was obtained as orange crystals from ethanol; Yield: 76 %; m.p.: 196198 oC; (KBr cm-1): 3449 (NH) 3020 (CH aromatic) 1653 (C=O); 1H NMR (DMSO-d6) 13.87 (s 1H NH) 8.01-7.03 (m 14 H aromatic protons) 2.16 (s 3H CH3); MS (m/z): 354 (M+) 77 (base peak); Anal. Calcd. (%) for C22H18N4O: C 74.56; H 5.12; N 15.81. Found: C 74.57; H 5.10; N 15.85.

4-[2-(4-Chlorophenyl)hydrazinylidene]-25-diphenyl- 24-dihydro-3H-pyrazol-3-one (44c)

It was obtained as orange crystals from ethanol; Yield:76 %; m.p.: 222224 oC; IR (KBr cm- 1): 3423 (NH) 3015 (CH aromatic) 1650 (C=O); 1H NMR (DMSO-d6) 13.88 (s 1H NH) 8.05-7.10 (m 14H aromatic protons); MS (m/z): 374 (M+) 77 (base peak); Anal. Calcd. (%) for C21H15ClN4O: C 67.29; H 4.03; Cl 9.46; N 14.95. Found: C 67.25; H 4.00; Cl 9.50; N14.96.

4-[2-(4-Nitrophenyl)hydrazinylidene]-25-diphenyl- 24-dihydro-3H-pyrazol-3-one (44d)

It was obtained as brown crystals from ethanol; Yield: 87 %; m.p.: 250252 oC; IR (KBr cm-1): 3446 (NH) 3025 (CH aromatic) 1662 (C=O); 1H NMR (DMSO-d6) 14.04 (s 1H NH) 8.32-7.26 (m 14H aromatic protons); MS (m/z): 385 (M+) 77 (base peak); Anal. Calcd. (%) for 6-Imino-5-(4-methylphenyl)-13-diphenyl-56- dihydro-1H-pyrazolo[43-c]pyridazine-7-carbonitrile (48b)

It was obtained as brown crystals from ethanol; Yield: 67 %; m.p.: 155157 oC; IR (KBr cm-1): 3427(NH) 3061 (CH aromatic) 2206 (C=N); 1H NMR (DMSO-d6) 13.80 (s 1H NH) 8.18-7.24 (m 14H aromatic protons) 2.32 (s 3H CH3); MS (m/z): 402 (M+) 55 (base peak); Anal. Calcd. (%) for C25H18N6: C 74.61; H 4.51; N 20.88. Found: C 74.65; H 4.55; N 20.89. 5-(4-Chlorophenyl)-6-imino-13-diphenyl-56- dihydro-1H-pyrazolo[43-c]pyridazine-7-carbonitrile (48c)

It was obtained as brown crystals from ethanol; Yield: 67 %; m.p.: 180182 oC; IR (KBr cm-1): 3418 (NH) 3060 (CH aromatic) 2206 (C=N); 1H NMR (DMSO-d6) 13.80 (s 1H NH) 8.17-7.25 (m 14H aromatic protons); Anal. Calcd. (%) for C24H15ClN6: C 68.17; H 3.58; Cl 8.38; N19.87. Found: C 68.19; H 3.57; Cl 8.41; N19.85.

6-Imino-5-(4-nitrophenyl)-1 3-diphenyl-56-dihydro- 1H-pyrazolo[43-c]pyridazine-7-carbonitrile (48d)

It was obtained as brown crystals from o C21H15N5O3: C 65.45; H 3.92; N18.17. Found: C ethanol; Yield: 67 %; m.p.: 186187 C; IR (KBr 65.42; H 3.94; N18.20.

General procedure for synthesis of pyrazolo[43- c]pyridazine (48a-g)

A mixture of hydrazo pyrazolone 44a-d (0.01 mol) and active methylene reagents such as malononitrile (45a) or ethyl cyanoacetate (45b) (0.01 mol) in presence of ammonium acetate (2.0 g) was fused for 3.0 min in domestic microwave oven.

It was obtained as brown crystals from ethanol; Yield: 83 %; m.p.: 120122 oC; IR (KBr cm-1): 3061 (CH aromatic) 2214 (C=N) 1684 (C=O); 1H NMR (DMSO-d6) 8.05-7.24 (m 14H aromatic protons); MS (m/z): 424 (M+1) 55 (base peak); Anal. Calcd. (%) for C24H14ClN5O: C 68.01; H 3.33; Cl 8.36; N16.52. Found: C 68.05; H 3.36; Cl 8.33; N16.56.

Conclusion

In conclusion enaminone 2 was used as an efficient precursor for the synthesis of new heterocycles including the pyrazole moiety with expected biological activities.

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