Utility of Styrylpyrazoloformimidate in the Synthesis of Fused Heterocyclic Compounds

Hamdi M. Hassaneen^*, Zakaria Ahmed Gomaa

Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.

DOI: 10.4236/ijoc.2015.54021                

Abstract

Refluxing of (E)-5-amino-1-phenyl-3-styryl-1H-pyrazole-4-carbonitrile 2 with triethylor-thoformate in acetic anhydride afforded the corresponding formimidate 3. Treatment of 3 with hydrazine hydrate in ethanol afforded amino imino compound 4. Reaction of 4 with diethyl dicarbonate at reflux gave (E)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 7. Refluxing of 4 with hydrazine hydrate afforded (E)-4-hydrazinyl-1-phenyl-3-styryl-1H-pyrazolo[3,4-d] pyrimidine 8. Treatment of the latter compound 8 with aldehydes in boiling ethanol in the presence of acetic acid afforded the corresponding hydrazone 10. Oxidative cyclization of the hydrazone 10 led to the formation of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11. The latter products re-arranged to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines 13. The structures of the new products were established on the basis of elemental analysis and spectral data.

Keywords

(Z)-N'-Phenylcinnamohydrazonoyl Chloride, (E)-5-Amino-1-Phenyl-3-Styryl-1H-Pyrazole-4-Carbonitrile, Formimidate, Dimroth Rearrangement

1. Introduction

The chemistry of hydrazonoyl halides has attracted the interest of many research groups as they have proved to be useful organic synthesis [1] - [10] . In continuation of our long standing interest for the utility of nitrilimines derived from hydrazonoyl halides in the synthesis of heterocycles [11] - [14] , we are interested in (Z)-N'-phenyl- cinnamohydrazonoyl chloride 1 to study the effect of C=C double bond on the cycloaddition reactions [15] - [17] . We wish to report herein a simple and convenient route for the synthesis of pyrazolo[3,4-d]pyrimidine, pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and its isomeric pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivative via Dimroth rearrangement. Such compounds have been used as a new pharmacological test for characterization of human A₃ adenosine receptors [18] - [20] .

2. Results and Discussion

Compound (E)-5-amino-1-phenyl-3-styryl-1H-pyrazole-4-carbonitrile 2 was prepared from our laboratory via reaction of (Z)-N'-phenylcinnamohydrazonoyl chloride 1 with malononitrile in ethanolic sodium ethoxide solution (Scheme 1) [21] . Refluxing of compound 2 with triethylorthoformate in acetic anhydride afforded ethyl N-(4-cyano-1-phenyl-3-((E)-styryl)-1H-pyrazol-5-yl)formimidate 3 (Scheme 1). The structure of compound 3 was established on the basis of elemental analysis and spectral data. The IR spectrum of 3 revealed the absence of amino group, while it showed a characteristic band at υ 2215 cm⁻¹ assignable to cyano group. Its ¹H NMR data showed signals at δ, 1.29 (t, 3H, CH₃), 4.32 (q, 2H, CH₂), 7.15 - 7.69 (m, 12H, Ar H), and 8.60 (s, 1H, NCH). Also, its ¹³C-NMR spectrum showed 17 carbon atoms. Moreover, the mass spectrum showed molecular ion peak as a base peak at m/z 342 (100%). Reaction of 3 with hydrazine hydrate in ethanol at room temperature yielded a product 4 which analyzed correctly for C₁₉H₁₆N₆ (Scheme 1). The IR spectrum of 4 showed the absence of cyano group and it showed bands at υ 3351, 3309, 3177 cm⁻¹ assignable to amino and imino groups. Also, the mass spectrum revealed a base peak at m/z 328 (100%) corresponding to its molecular ion peak. On the basis of elemental analysis and spectral data, the product is (E)-4-imino-1-phenyl-3-styryl-1H-pyrazolo [3,4-d]pyrimidin-5(4H)-amine 4.

When compound 4 was refluxed with diethyl dicarbonate a single product was obtained, its mass spectrum and elemental analysis are consistent with the molecular formula C₂₃H₁₈N₆O₂ (Scheme 2). Two possible structures were proposed for the isolated product 5a and 5b. The identity of the isolated product was confirmed to be (E)-ethyl-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate 5b. Thus, sapo- nification of the reaction product obtained 5b gave the intermediate acid 6 which decarboxylated to a pro- duct identical to all respects (m.p., mixed m.p., IR) with (E)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazo- lo[1,5-c]pyrimidine 7. The latter product 7 was also confirmed via its alternative synthesis by treatment of compound 4 with triethylorthoformate or formic acid. Structure of 5a was accordingly discarded. In addition, structure 5b was further substantiated by IR and ¹H NMR spectra. Its IR spectrum exhibits a carbonyl band at υ 1743 cm⁻¹ and ¹H NMR spectrum showed signals at: δ 1.42 (t, J = 7 Hz, 3H), 4.49 (q, J = 7 Hz, 2H), 7.37-8.78 (m, J = 7 Hz, 12H), and 9.84 (s, 1H, pyrimidine-CH).

Scheme 1. Synthesis of formimidate 3 and amino imino compound 4.

Scheme 2. Synthesis of pyrazolotriazolopyrimidine 7.

Refluxing of compound 4 with hydrazine hydrate in ethanol, gave (E)-4-hydrazinyl-1-phenyl-3-styryl-1H- pyrazolo[3,4-d]pyrimidine 8, via Dimroth type rearrangement, which has not been reported hitherto (Scheme 3 and Scheme 4). This is consistent with a similar rearrangement that was reported recently [22] . The structure of 8 was confirmed by elemental and spectral data (see experimental) and its reaction described below.

Thus, treatment of hydrazine derivative 8 with the appropriate aldehydes 9a-i in refluxing ethanol in the presence of acetic acid led to the formation of the new condensation products, 4-(2-arylhydrazinyl)-1-phenyl -3-styryl-1H-pyrazolo[3,4-d]pyrimidine 10a-i. The structures of 10a-i were confirmed by their elemental analysis and spectral data. For example their IR spectra showed the characteristic band for NH at υ 3199 - 3352 cm⁻¹. Also, their ¹H NMR spectra revealed in each case, a signal in the region 11.97 - 12.13 assignable to NH proton which disappeared upon shaking its DMSO solution with D₂O.

Oxidative cyclization of hydrazone 10a-h led to the formation of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyri- midine derivatives 11a-h (Scheme 3 and Scheme 5). Thus, stirring of 10a-h with 4 equivalent of Fe(ΙΙΙ) chloride in ethanol overnight gave, in each case, a single product as evidenced by TLC analysis. Mass spectra revealed that, each product has 2 hydrogen atoms less than that of the respective hydrazone. Also, IR and ¹H NMR revealed the absence of NH band and CH=N proton, respectively.

Compounds 11a,e were isomerized to the thermodynamically more stable pyrazolo[4,3-e][1,2,4]triazo- lo[1,5-c]pyrimidine derivatives 13a,e through tandem ring opening and ring closure reactions via heating of 11a,e in ethanol in the presence of sodium acetate (Scheme 3). This rearrangement is consistent with those reported in earlier reports [23] . The structures of 13a,e were established by elemental and spectral analysis (see experimental). Also, the structures of 13a,e were confirmed via their alternative synthesis. Thus, treatment of 4 with acid chlorides 12a,e in refluxing pyridine gave a products identical in all respects (m.p., mixed m.p., IR and ¹H NMR spectra) with those obtained above from base-catalyzed rearrangement of 11a,e (Scheme 3). Also,

Scheme 3. Synthesis of hydrazinylpyrazolo pyrimidine 8, arylhydrazinylpyrazolopyrimidine 10 and pyrazolotriazolopyrimidine derivatives 11, 13.

Scheme 4. Synthesis of (E)-4-hydrazinyl-1-phenyl-3-styryl-1H-pyrazolo [3,4-d]pyrimidine.

Scheme 5. Synthesis of (E)-2-alkyl-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidine.

compound 4 reacted with 12j,k,l to give the corresponding 13j,k,l. The latter compounds 13j,k,l were confirmed by elemental and spectral analysis.

3. Experimental

3.1. General

All melting points were determined on an electrothermal GallenKamp melting point apparatus and are uncorrected. The IR spectra were recorded as KBr Pellets on a Jasco FTIR-460 plus Fourier transform infrared spectrophotometer. ¹H and ¹³C NMR spectra were recorded at (300 MHz) and (75 MHz) respectively on Varian EM-300 MHz spectrometer. Chemical shifts (δ) are given from TMS (ppm) as internal standard for ¹H NMR and ¹³C NMR. Mass spectra were recorded on AEI MS 30 mass spectrometer operating at 70 eV. The elemental analyses were performed at the Microanalytical Center of Cairo University. Compound 2 was prepared as previously described [18] .

3.2. Preparation of Ethyl N-(4-Cyano-1-Phenyl-3-((E)-Styryl)-1H-Pyrazol-5-yl)Formimidate 3

To a solution of the compound (E)-5-amino-1-phenyl-3-styryl-1H-pyrazole-4-carbonitrile 2 (1.43 g, 5 mmol) in acetic anhydride (5 mL), triethylorthoformate (0.74 g, 5 mmol) was added. The reaction mixture was refluxed for 5 h and the solvent was evaporated under reduced pressure. The solid product was collected and crystallized from acetonitrile to afford the compound 3. Yellow crystals; m.p: 170˚C - 171˚C; yield (82%); IR (KBr): υ = 2215 (CN) cm⁻¹; ¹H NMR (DMSO-d6): δ = 1.29 (t, 3H, CH₂CH₃), 4.32 (q, 2H, CH₃CH₂), 7.15 - 7.69 (m, 12H, Ar H), 8.60 (s, 1H, NCH); ¹³C NMR (DMSO-d6): δ = 13.74, 64.07, 79.46, 114.46, 117.78, 123.78, 126.88, 128.00, 128.74, 128.85, 128.97, 132.88, 135.58, 137.46, 149.57, 151.51, 162.46. MS: m/z (%) = 342 (M⁺, 100), 313 (31), 285 (45), 77 (41). Anal. for C₂₁H₁₈N₄O: Calcd. C, 73.67; H, 5.30; N, 16.36. found C, 73.31; H, 5.03; N, 16.11.

3.3. Preparation of (E)-4-Imino-1-Phenyl-3-Styryl-1H-Pyrazolo[3,4-d]Pyrimidin-5(4H)-Amine 4

To a solution of the compound 3 (17.1 g, 50 mmol) in ethanol (250 mL), hydrazine hydrate (2.5 mL, 50 mmol) was added. The reaction mixture was stirred for 5 h at room temperature; the solid product was collected and crystallized from dioxane to afford the compound 4. Yellow crystals; m.p. 200˚C - 202˚C; yield (91%); IR (KBr): υ = 3351 & 3309 (NH₂), 3177 (NH) cm⁻¹. MS: m/z (%) = 328 (M⁺, 100), 313 (29), 77 (30). Anal. for C₁₉H₁₆N₆: Calcd. C, 69.50; H, 4.91; N, 25.59. found C, 69.07; H, 4.72; N, 25.39.

3.4. Preparation of (E)-9-Styryl-7H-Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine-2-Carboxylate Ethyl 7-Phenyl 5b

A solution of the compound 4 (1.64 g, 5 mmol) in diethyl dicarbonate (10 mL) was refluxed for 4 h. and then cooled. The solid product was filtered off, dried and finally crystallized from acetic acid to give 5b. Yellow crystals; m.p. 212˚C - 214˚C; yield (88%); IR (KBr): υ = 1743 (CO) cm⁻¹; ¹H NMR (DMSO-d6): δ = 1.42 (t, 3H, CH₂CH₃), 4.49 (q, 2H, CH₃CH₂), 7.37 - 8.78 (m, 12H, Ar H), 9.84 (s, 1H, NCH). MS: m/z (%) = 410 (M+, 96), 409 (50), 77 (100). Anal. for C₂₃H₁₈N₆O₂: Calcd. C, 67.31; H, 4.42; N, 20.48. found C, 67.02; H, 4.37; N, 20.25.

3.5. Preparation of (E)-7-Phenyl-9-Styryl-7H-Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine 7

A solution of the compound 4 (1.64 g, 5 mmol) in triethylorthoformate or formic acid (10 mL) was refluxed for 4 h. left to cool and the solid product was filtered, dried and finally crystallized from acetic acid to afford 7. Pale yellow crystals; m.p. 198˚C - 200˚C (acetic acid); yield (86%); ¹H NMR (DMSO-d6): δ = 6.98 - 8.56 (m, 12H, Ar H), 9.77 (s, 1H, NCH), 9.79 (s, 1H, NCH). MS: m/z (%) = 338 (M⁺, 98), 337 (100), 77 (30). Anal. for C₂₀H₁₄N₆: Calcd. C, 70.99; H, 4.17; N, 24.84. found C, 70.65; H, 4.12; N, 24.61.

3.6. Preparation of (E)-4-Hydrazinyl-1-Phenyl-3-Styryl-1H-Pyrazolo[3,4-d]Pyrimidine 8

A solution of the compound 4 (16.4 g, 50 mmol) in ethanol (250 mL) and hydrazine hydrate (10 mL) was refluxed for 5 h. The solvent was evaporated; the solid product was collected, dried and finally crystallized from acetonitrile to afford 8. Yellow crystals; m.p. 202˚C - 204˚C; yield (90%); IR (KBr): υ = 3310 (NH), 3351 & 3309 (NH₂) cm⁻¹; ¹H NMR (DMSO-d6): δ = 4.86 (s, 2H, NH₂), 7.31-8.41 (m, 13H, Ar H), 9.25 (s, 1H, NH). MS: m/z (%) = (M⁺, 38), 313 (30), 297 (80), 77 (100). Anal. for C₁₉H₁₆N₆: Calcd. C, 69.50; H, 4.91; N, 25.59. found C, 69.22; H, 4.81; N, 25.33.

3.7. General Method for Preparation (E)-4-(2-Arylhydrazinyl)-1-Phenyl-3-Styryl-1H-Pyrazolo[3,4-d]Pyrimidine 10a-i

To a mixture of compound 8 (1.64 g, 5 mmol) in ethanol (30 mL), the appropriate aldehyde 9a-i (5 mmol) was added. The reaction mixture was refluxed for 2 h and the solvent was evaporated. The solid product formed was collected, dried and finally crystallized from suitable solvent to afford 10a-i.

4-((Z)-2-Benzylidenehydrazinyl)-1-phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidine 10a:

Yellow crystals; m.p. 188˚C - 189˚C (acetonitrile); yield (87%); IR (KBr): υ = 3205 (NH) cm⁻¹, ¹H NMR (DMSO-d6): δ = 7.15 - 8.58 (m, 19H, Ar H), 12.04 (s, 1H, NH). MS: m/z (%) = 416 (M⁺, 14), 415 (42), 313 (43), 236 (41), 77 (100). Anal. for C₂₆H₂₀N₆: Calcd. C, 74.98; H, 4.84; N, 20.18. found C, 74.37; H, 4.71; N, 19.73.

4-((Z)-2-(3-Methylbenzylidene)hydrazinyl)-1-phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidine 10b:

Yellow crystals; m.p. 192˚C - 194˚C (acetonitrile); yield (81%); IR (KBr): υ = 3352 (NH) cm⁻¹, ¹H NMR (DMSO-d6): δ = 2.36 (s, 3H, CH₃), 7.24-8.52 (m, 18H, Ar H), 12.01 (s, 1H, NH); ¹³C NMR (DMSO-d6): δ = 20.83, 99.47, 119.11, 121.83, 125.20, 126.783, 128.18, 128.41, 128.76, 129.01, 130.57, 132.80, 136.52, 137.80, 138.19, 147.89, 153.98. MS: m/z (%) = 430 (M⁺, 79), 339 (52), 312 (100), 236 (79), 77 (80). Anal. for C₂₇H₂₂N₆: Calcd. C, 75.33; H, 5.15; N, 19.52. found C, 75.06; H, 4.92; N, 19.36.

N,N-Dimethyl-4-((Z)-(2-(1-phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hydrazono)methyl)aniline 10c:

Yellow crystals; m.p. 242˚C - 244˚C (dimethylformamide); yield (77%); IR (KBr): υ = 3199 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 2.99 (s, 6H, N(CH₃)₂), 6.75-8.43 (m, 18H, Ar H), 11.87 (s, 1H, NH). MS: m/z (%) = 459 (M⁺, 34), 457 (62), 312 (100), 236 (65), 145 (60), 77 (91). Anal. for C₂₈H₂₅N₇: Calcd. C, 73.18; H, 5.48; N, 21.34. found C, 72.55; H, 5.23; N, 20.84.

4-((Z)-(2-(1-Phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hydrazono)methyl)phenol 10d:

Yellow crystals; m.p. 270˚C - 272˚C (acetonitrile); yield (83%); IR (KBr): υ = 3324 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 6.99 - 8.68 (m, 18H, Ar H), 11.98 (s, 1H, NH), 13.02 (s, 1H, OH). MS: m/z (%) = 432 (M⁺, 82), 312 (100), 77 (93). Anal. for C₂₆H₂₀N₆O: Calcd. C, 72.21; H, 4.66; N, 19.43. found C, 71.76; H, 4.51; N, 19.11.

4-((Z)-2-(4-Chlorobenzylidene)hydrazinyl)-1-phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidine 10e:

Yellow crystals; m.p. 230˚C - 232˚C (dimethylformamide); yield (84%); IR (KBr): υ = 3205 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 7.02 - 8.70 (m, 18H, Ar H), 12.11 (s, 1H, NH). MS: m/z (%) = 450 (M⁺, 100), 77 (72). Anal. for C₂₆H₁₉ClN₆: Calcd. C, 69.25; H, 4.25; Cl, 7.86; N, 18.64. found C, 68.76; H, 4.03; Cl, 7.65; N, 18.23.

4-((Z)-2-(4-Fluorobenzylidene)hydrazinyl)-1-phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidine 10f:

Yellow crystals; m.p. 192˚C - 194˚C (acetonitrile); yield (87%); IR (KBr): υ = 3199 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 7.04 - 8.71 (m, 18H, Ar H), 12.13 (s, 1H, NH). MS: m/z (%) = 434 (M⁺, 87), 339 (32), 312 (100), 236 (79), 77 (56). Anal. for C₂₆H₁₉FN₆: Calcd. C, 71.88; H, 4.41; F, 4.37; N, 19.34. found C, 71.51; H, 4.30; F, 4.29; N, 19.03.

1-Phenyl-3-((E)-styryl)-4-((Z)-2-(thiophen-2-ylmethylene)hydrazinyl)-1H-pyrazolo[3,4-d]pyrimidine 10g:

Yellow crystals; m.p. 186˚C - 188˚C (acetonitrile); yield (83%); IR (KBr): υ = 3337 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 7.01 - 8.71 (m, 17H, Ar H), 12.01 (s, 1H, NH). MS: m/z (%) = 422 (M⁺, 100), 312 (88), 236 (61), 77 (42). Anal. for C₂₄H₁₈N₆S: Calcd. C, 68.23; H, 4.29; N, 19.89; S, 7.59. found C, 67.81; H, 4.20; N, 19.64; S, 7.50.

1-Phenyl-4-((Z)-2-(pyridin-4-ylmethylene)hydrazinyl)-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidine 10h:

Yellow crystals; m.p. 284˚C - 286˚C (dimethylformamide); yield (84%); IR (KBr): υ = 3322 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 6.89 - 8.64 (m, 18H, Ar H), 11.97 (s, 1H, NH). MS: m/z (%) = 417 (M⁺, 54), 312 (71), 77 (100). Anal. for C₂₅H₁₉N₇: Calcd. C, 71.93; H, 4.59; N, 23.49. found C, 71.58; H, 4.24; N, 23.11.

4-((Z)-2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-1-phenyl-3-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidine 10i:

Yellow crystals; m.p. 214˚C - 216˚C (acetonitrile); yield (82%); IR (KBr): υ = 3341 (NH) cm⁻¹; ¹H NMR (DMSO-d6): δ = 6.09 (s, 2H, CH₂), 6.97 - 8.47 (m, 17H, Ar H), 12.01 (s, 1H, NH). MS: m/z (%) = 460 (M⁺, 54), 312 (100), 236 (63), 77 (92). Anal. for C₂₇H₂₀N₆O₂: Calcd. C, 70.42; H, 4.38; N, 18.25. found C, 70.01; H, 4.30; N, 18.11.

3.8. General Method for Preparation of 7H-Pyrazolo[4,3-e][1,2,4]Triazolo[4,3-c]Pyrimidine 11a-h

To a solution of an appropriate arylhydrazinyl compound 10a-h (5 mmol) in ethanol (20 mL), ferric chloride (4 mL, 2 M) was added, and the reaction mixture was stirred for 24 h. The solid that separated was collected, dried and finally crystallized from dimethylformamide to afford the corresponding 7H-pyrazolo[4,3-e][1,2,4]triazo- lo[4,3-c]pyrimidine 11a-h.

(E)-3,7-Diphenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11a:

White crystals; m.p. 276˚C - 278˚C; yield (87%); ¹H NMR (DMSO-d6): δ = 7.37 - 8.81 (m, 17H, Ar H), 9.32 (s, 1H, NCH). MS: m/z (%) = 414 (M⁺, 100), 77 (80). Anal. for C₂₆H₁₈N₆: Calcd. C, 75.35; H, 4.38; N, 20.28. found C, 75.03; H, 4.32; N, 20.01.

(E)-7-Phenyl-9-styryl-3-(m-tolyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11b:

White crystals; m.p. 182˚C - 184˚C; yield (86%); ¹H NMR (DMSO-d6): δ = 2.23 (s, 3H, CH₃), 7.31 - 8.47 (m, 16H, Ar H), 9.08 (s, 1H, NCH). MS: m/z (%) = 428 (M⁺, 100), 77 (26). Anal. for C₂₇H₂₀N₆: Calcd. C, 75.68; H, 4.70; N, 19.61. found C, 75.22; H, 4.410; N, 19.15.

(E)-N,N-Dimethyl-4-(7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-3-yl)aniline 11c:

Yellow crystals; m.p. 222˚C - 224˚C; yield (85%); ¹H NMR (DMSO-d6): δ = 3.02 (s, 6H, N(CH₃)₂), 6.89 - 8.41 (m, 16H, Ar H), 9.24 (s, 1H, NCH). MS: m/z (%) = 457 (M⁺, 47), 77 (100). Anal. for C₂₈H₂₃N₇: Calcd. C, 73.50; H, 5.07; N, 21.43. found C, 73.21; H, 4.98; N, 21.24.

(E)-4-(7-Phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-3-yl)phenol 11d:

Pale green crystals; m.p. 284˚C - 286˚C; yield (88%); ¹H NMR (DMSO-d6): δ = 6.93 - 8.45 (m, 16H, Ar H), 9.28 (s, 1H, NCH), 13.11 (s, 1H, OH). MS: m/z (%) = 430 (M^+, 18), 77 (100). Anal. for C₂₆H₁₈N₆O: Calcd. C, 72.55; H, 4.21; N, 19.52. found C, 72.31; H, 4.16; N, 19.39.

(E)-3-(4-Chlorophenyl)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11e:

Yellow crystals; m.p. 250˚C - 252˚C; yield (80%); ¹H NMR (DMSO-d6): δ = 7.33 - 8.12 (m, 16H, Ar H), 8.66 (s, 1H, NCH). MS: m/z (%) = 448 (M⁺, 100), 77 (48). Anal. for C₂₆H₁₇ClN₆: Calcd. C, 69.56; H, 3.82; Cl, 7.90; N, 18.72. found C, 69.14; H, 3.75; Cl, 7.78; N, 18.59.

(E)-3-(4-Fluorophenyl)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11f:

White crystals; m.p. 228˚C - 230˚C; yield (81%); ¹H NMR (DMSO-d6): δ = 7.34 - 8.14 (m, 16H, Ar H), 8.81 (s, 1H, NCH). MS: m/z (%) = 432 (M⁺, 100), 77 (21). Anal. for C₂₆H₁₇FN₆: Calcd. C, 72.21; H, 3.96; F, 4.39; N, 19.43. found C, 71.43; H, 3.90; F, 4.32; N, 19.31.

(E)-7-Phenyl-9-styryl-3-(thiophen-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11 g:

Green crystals; m.p. 262˚C - 264˚C; yield (84%); ¹H NMR (DMSO-d6): δ = 7.33 - 8.73 (m, 15H, Ar H), 9.48 (s, 1H, NCH); ¹³C NMR (DMSO-d6): δ = 98.57, 118.90, 122.25, 126.39, 126.81, 127.59, 128.51, 128.88, 129.24, 129.72, 135.62, 136.38, 137.73, 138.69, 142.28, 144.87, 145.56. MS: m/z (%) = 420 (M⁺, 100), 77 (18). Anal. for C₂₄H₁₆N₆S: Calcd. C, 68.55; H, 3.84; N, 19.99; S, 7.63. found C, 68.01; H, 3.80; N, 19.51; S, 7.52.

(E)-7-Phenyl-3-(pyridin-4-yl)-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11 h:

Orange crystals; m.p. 268˚C - 270˚C; yield (83%); ¹H NMR (DMSO-d6): δ = 6.91 - 8.68 (m, 16H, Ar H), 9.36 (s, 1H, NCH). MS: m/z (%) = 415 (M⁺, 100), 77 (41). Anal. for C₂₅H₁₇N₇: Calcd. C, 72.28; H, 4.12; N, 23.60. found C, 71.74; H, 4.06; N, 23.31.

3.9. General Methods for Preparation of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives 13

Method A: To a solution of the appropriate 11a,e (1 mmol) in absolute ethanol (30 mL), sodium acetate (0.16 g, 2 mmol) was added and the mixture was refluxed for 8 h. The precipitated solid after cooling was filtered, washed with water, dried and finally crystallized from suitable solvent to give the respective products 13a,e.

Method B: To a solution of the compound 4 (1.64 g, 5 mmol) in pyridine (20 mL), the appropriate acid chloride 12a,e,j,k,l (5 mmol) was added. The reaction mixture was refluxed for 4 h, then cooled and poured over crushed ice containing hydrochloric acid (10%) with stirring. The solid product was filtered, washed with water, dried and finally crystallized from suitable solvent to afford 13a,e,j,k,l.

(E)-2,7-Diphenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 13a:

Pale brown crystals; m.p. 210˚C - 212˚C (dimethylformamide); yield (80%); ¹H NMR (DMSO-d6): δ = 6.66 - 8.75 (m, 17H, Ar H), 9.78 (s, 1H, NCH). MS: m/z (%) = 414 (M⁺, 100), 77 (28). Anal. for C₂₆H₁₈N₆: Calcd C, 75.35; H, 4.38; N, 20.28. found C, 74.98; H, 4.18; N, 19.89.

(E)-2-(4-Chlorophenyl)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 13e:

Pale yellow crystals; m.p. 268˚C - 270˚C (dimethylformamide); yield (87%); ¹H NMR (DMSO-d6): δ = 6.68 - 8.84 (m, 16H, Ar H), 9.81 (s, 1H, NCH). MS: m/z (%) = 448 (M⁺, 100), 447 (68), 77 (54). Anal. for C₂₆H₁₇ClN₆: Calcd C, 69.56; H, 3.82; Cl, 7.90; N, 18.72. found C, 69.31; H, 3.66; Cl, 7.69; N, 18.40.

(E)-2-Methyl-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 13j:

White crystals; m.p. 186˚C - 187˚C (acetic acid); yield (92%); ¹H NMR (DMSO-d6): δ = 2.57 (s, 3H, CH₃), 7.32 - 8.59 (m, 12H, Ar H), 9.50 (s, 1H, NCH); ¹³C NMR (DMSO-d6): δ = 14.28, 118.81, 122.05, 126.82, 127.37, 128.54, 128.88, 129.22, 135.60, 136.37, 137.87, 140.16, 144.17, 164.41. MS: m/z (%) = 352 (M⁺, 98), 351 (100), 77 (35). Anal. for C₂₁H₁₆N₆: Calcd. C, 71.58; H, 4.58; N, 23.85. found C, 71.01; H, 4.33; N, 23.52.

(E)-2-(4-Bromophenyl)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 13k:

Pale yellow crystals; m.p. 290˚C - 292˚C (dimethylformamide); yield (85%); ¹H NMR (DMSO-d6): δ = 6.71 - 8.80 (m, 16H, Ar H), 9.84 (s, 1H, NCH). MS: m/z (%) = 492 (M⁺, 100), 491 (75), 206 (30), 102 (29), 77 (81). Anal. for C₂₆H₁₇BrN₆: Calcd C, 63.30; H, 3.47; Br, 16.20; N, 17.03. found C, 63.01; H, 3.39; Br, 16.03; N, 16.86.

(E)-2-(Furan-2-yl)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 13l:

Pale yellow crystals; m.p. 264˚C - 266˚C (dimethylformamide); yield (86%); ¹H NMR (DMSO-d6): δ = 6.75 - 8.77 (m, 15H, Ar H), 9.62 (s, 1H, NCH). MS: m/z (%) = 404 (M⁺, 100), 403 (65), 77 (53). Anal. for C₂₄H₁₆N₆O: Calcd C, 71.28; H, 3.99; N, 20.78. found C, 70.79; H, 3.63; N, 20.47.

NOTES

^*Corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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