Cellulose Sulfuric Acid as an Eco-Friendly Catalyst for Novel Synthesis of Pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones

Abstract

A novel synthesis of a series of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones has been developed from reactions of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-arylprop-2-en-1-ones and 7-amino-1,3-disubstituted[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones in dioxane under thermal conditions, using cellulose sulfuric acid as an eco-friendly acid catalyst. The reaction mechanism was proposed and the structures of the newly synthesized compounds were established on the basis of spectral data (mass spectrometry, infrared, ¹H and ¹³C nuclear magnetic resonance) and elemental analyses.

cellulose sulfuric acid; chalcone; annelated heterocyclic ring system

Introduction

Numerous elegant methods have been recently published to demonstrate the construction of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines, such as: (i) treatment of 2-hydrazinopyrido[2,3-d]pyrimidines^1-3 with various reagents, such as, triethyl orthoformate, ethyl chloroformate, chloroacetyl chloride, acetic anhydride, carbondisulfide, formic acid, and ammonium isothiocyanate; (ii) oxidative cyclization of hydrazino derivatives¹ in bromine-acetic acid mixture; (iii) reaction of 2-thioxopyrido[2,3-d]pyrimidines or its methylthio derivatives^4,5 with hydrazonoyl halides; (iv) treatment of hydrazino derivatives with aldohexose sugar followed by acetylation.⁶ The curiosity for the synthetic strategy of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines is due to their biological activities. For example, some derivatives of the former ring system exhibit antitumor,¹ analgesic,² anti-inflammatory,² ulcerogenic,^2,6 and antimicrobial^4-6 activities.

Recently, the direction of science and technology has been shifting more towards eco-friendly, natural product resources and reusable catalysts.⁷ Thus, cellulose sulfuric acid, as a promising biopolymeric solid supported acid catalyst, is an attractive candidate for acid-catalyzed reactions.^8-11 On the basis of these precedents, we attempted to report a new and efficient method for the synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines using cellulose sulfuric acid as an eco-friendly biopolymeric solid supported acid catalyst.

Experimental

All melting points were determined on an electrothermal Gallenkamp apparatus and are uncorrected. Solvents were generally distilled and dried by standard literature procedures prior to use. The infrared (IR) spectra were measured on a Pye-Unicam SP300 instrument in potassium bromide discs. The ¹H and ¹³C-nuclear magnetic resonance (NMR) spectra were recorded on a Varian Mercury VXR-300 spectrometer (300 MHz for ¹H-NMR and 75 MHz for ¹³C NMR) and the chemical shifts were related to that of the solvent deuterated dimethyl sulfoxide (DMSO-d₆). The mass spectra were recorded on a GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers, the ionizing voltage was 70 eV. Elemental analyses were carried out at the Microanalytical Centre of Cairo University, Giza, Egypt. Cellulose sulfuric acid,¹⁰1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-arylprop-2-en-1-one (1),¹²7-amino-1,3-disubstituted[1,2,4]triazolo [4,3-a]pyrimidin-5(1H)-ones (2),^13,14 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (7),¹⁵ and N-phenyl 2-oxopropanehydrazonoyl chloride (9)¹⁶ were prepared as previously reported in the respective literature.

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one derivatives 6a-s

To a mixture of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-arylprop-2-en-1-one (1) (1 mmol) and 7-amino-1,3-disubstituted[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones (2) (1 mmol) in dioxane (15 mL) cellulose sulfuric acid (0.05 g) was added. The mixture was refluxed for 8 h then cooled to ambient temperature and cellulose sulfuric acid was filtered off. The filtrate was concentrated to dryness, and the crude solid product was crystallized from appropriate solvent to afford the pure products 6a-s.

3-Acetyl-1,6-diphenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6a)

Yellowish-white microcrystals; IR (KBr) ν_max/cm^-11702, 1650 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.60 (s, 3H, CH₃), 3.31 (s, 3H, COCH₃), 7.43-8.05 (m, 16H, Ar-H + pyridine-H), 8.61 (s, 1H, pyrazole-H); ¹³C NMR (75 MHz, DMSO-d₆) ∆ 23.1, 30.5, 123.9, 124.2, 124.5, 125.9, 126.4, 126.5, 128.2, 128.8, 129.1, 129.4, 129.8, 139.8, 142.2, 143.9, 147.4, 147.7, 148.8, 152.4, 153.3, 155.3, 159.1, 159.3, 168.1, 176.4; MS m/z (%) 537 (M⁺, 65), 511 (100), 494 (58), 377 (52), 77 (59); anal. calcd. for C₃₂H₂₃N₇O₂ (537.19): C, 71.50; H, 4.31; N, 18.24; found: C, 71.31; H, 4.43; N, 18.39%.

N3,1,6-Triphenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxamide (6b)

Yellowish-white microcrystals; IR (KBr) ν_max/cm^-13310 (NH), 1691, 1653 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆2.61 (s, 3H, CH₃), 7.43-8.13 (m, 21H, Ar-H + pyridine-H), 8.59 (s, 1H, pyrazole-H), 11.12 (s, 1H, NH); MS m/z (%) 614 (M⁺, 77), 494 (58), 377 (52), 119 (100), 77 (53); anal. calcd. for C₃₇H₂₆N₈O₂ (614.22): C, 72.30; H, 4.26; N, 18.23; found: C, 72.41; H, 4.33; N, 18.33%.

3-Acetyl-6-(4-chlorophenyl)-1-phenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6c)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 1703, 1652 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.60 (s, 3H, CH₃), 3.31 (s, 3H, COCH₃), 7.52-7.93 (m, 15H, Ar-H + pyridine-H), 8.63 (s, 1H, pyrazole-H); ¹³C NMR (75 MHz, DMSO-d₆) ∆ 23.5, 31.1, 123.8, 124.7, 125.2, 125.9, 126.4, 126.8, 128.2, 128.8, 129.1, 129.4, 130.7, 138.9, 142.1, 143.9, 147.4, 147.7, 148.8, 152.4, 153.3, 155.3, 159.7, 160.2, 168.1, 176.7; MS m/z (%) 573 (M⁺+ 2) (17), 571 (M⁺, 56), 528 (50), 160 (96), 77 (100); anal. calcd. for C₃₂H₂₂ClN₇O₂(571.15): C, 67.19; H, 3.88; N, 17.14; found: C, 67.31; H, 4.03; N, 17.39%.

3-Acetyl-1,6-bis-(4-chlorophenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidin-5-one (6d)

Yellowish-white microcrystals; IR (KBr) ν_max/cm^-11698, 1653 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.63 (s, 3H, CH₃), 3.29 (s, 3H, COCH₃), 7.52-8.03 (m, 14H, Ar-H + pyridine-H), 8.64 (s, 1H, pyrazole-H); MS m/z (%) 607 (M⁺+ 2) (14), 605 (M⁺, 55), 494 (100), 111 (71), 77 (65); anal. calcd. for C₃₂H₂₁Cl₂N₇O₂ (605.11): C, 63.37; H, 3.49; N, 16.17; found: C, 63.51; H, 3.33; N, 16.29%.

3-Acetyl-6-(4-chlorophenyl)-1-(4-methylphenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6e)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 1702, 1653 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.38 (s, 3H, Ar-CH₃), 2.60 (s, 3H, CH₃), 3.32 (s, 3H, COCH₃), 7.52-7.89 (m, 14H, Ar-H + pyridine-H), 8.60 (s, 1H, pyrazole-H); MS m/z (%) 587 (M⁺ +2) (5), 585 (M⁺, 12), 322 (21), 91 (8), 77 (100); anal. calcd. for C₃₃H₂₄ClN₇O₂(585.17): C, 67.63; H, 4.13; N, 16.73; found: C, 67.51; H, 4.03; N, 16.59%.

3-Acetyl-6-(4-chlorophenyl)-1-(4-methoxyphenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6f)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 1703, 1652 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.59 (s, 3H, CH₃), 3.30 (s, 3H, COCH₃), 3.64 (s, 3H, OCH₃), 7.52-7.92 (m, 14H, Ar-H + pyridine-H), 8.63 (s, 1H, pyrazole-H); MS m/z (%) 603 (M⁺ + 2) (5), 601 (M⁺, 17), 547 (87), 189 (100), 87 (82); anal. calcd. for C₃₃H₂₄ClN₇O₃(601.16): C, 65.83; H, 4.02; N, 16.29; found: C, 65.61; H, 4.09; N, 16.39%.

Ethyl 6-(4-chlorophenyl)-1-phenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydro-5-oxo-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (6g)

Pale yellow microcrystals; IR (KBr) ν_max/cm^-1 1723, 1653 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 1.44 (t, 3H, J7.0 Hz, CH₃), 2.59 (s, 3H, CH₃), 4.57 (q, 2H, J7.0 Hz, CH₂), 7.51-7.92 (m, 15H, Ar-H + pyridine-H), 8.63 (s, 1H, pyrazole-H); ¹³C NMR (75 MHz, DMSO-d₆) ∆ 30.6, 35.6, 122.9, 124.1, 124.8, 125.7, 126.6, 126.9, 127.9, 128.4, 128.9, 129.3, 129.8, 129.9, 139.5, 142.7, 143.9, 147.7, 147.9, 148.8, 152.9, 153.8, 155.4, 159.6, 160.2, 168.1, 176.7; MS m/z (%) 603 (M⁺ + 2) (8), 601 (M⁺, 22), 322 (57), 229 (100), 120 (90); anal. calcd. for C₃₃H₂₄ClN₇O₃ (601.16): C, 65.83; H, 4.02; N, 16.29; found: C, 65.71; H, 4.11; N, 16.41%.

Ethyl 1,6-bis-(4-chlorophenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydro-5-oxo-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (6h)

Pale yellow microcrystals; IR (KBr) ν_max/cm^-1 1720, 1651 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 1.43 (t, 3H, J7.0 Hz, CH₃), 2.61 (s, 3H, CH₃), 4.53 (q, 2H, J7.0 Hz, CH₂), 7.51-7.97 (m, 14H, Ar-H + pyridine-H), 8.61 (s, 1H, pyrazole-H); MS m/z (%) 637 (M⁺+ 2) (15), 635 (M⁺, 43), 250 (58), 120 (30), 77 (100); anal. calcd. for C₃₃H₂₃Cl₂N₇O₃ (635.12): C, 62.27; H, 3.64; N, 15.40; found: C, 62.31; H, 3.71; N, 15.49%.

Ethyl 6-(4-chlorophenyl)-1-(4-methylphenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydro-5-oxo-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (6i)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 1722, 1655 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 1.42 (t, 3H, J7.0 Hz, CH₃), 2.38 (s, 3H, Ar-CH₃), 2.59 (s, 3H, CH₃), 4.53 (q, 2H, J7.0 Hz, CH₂), 7.53-7.90 (m, 14H, Ar-H + pyridine-H), 8.62 (s, 1H, pyrazole-H); MS m/z (%) 617 (M⁺+ 2) (8), 615 (M⁺, 22), 558 (40), 185 (55), 77 (100); anal. calcd. for C₃₄H₂₆ClN₇O₃(615.18): C, 66.29; H, 4.25; N, 15.91; found: C, 66.31; H, 4.11; N, 15.81%.

N3,1-Diphenyl-6-(4-chlorophenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxamide (6j)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 3318 (NH), 1689, 1650 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.59 (s, 3H, CH₃), 7.38-7.92 (m, 20H, Ar-H + pyridine-H), 8.63 (s, 1H, pyrazole-H), 11.14 (s, 1H, NH); MS m/z (%) 650 (M⁺+ 2) (20), 648 (M⁺, 60), 410 (95), 119 (100), 77 (51); anal. calcd. for C₃₇H₂₅ClN₈O₂ (648.18): C, 68.46; H, 3.88; N, 17.26; found: C, 68.41; H, 4.73; N, 17.33%.

N3-Phenyl-1-(4-methylphenyl)-6-(4-chlorophenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,5-dihydro pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxamide (6k)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 3314 (NH), 1689, 1654 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.39 (s, 3H, Ar-CH₃), 2.61 (s, 3H, CH₃), 7.38-7.98 (m, 19H, Ar-H + pyridine-H), 8.60 (s, 1H, pyrazole-H), 11.18 (s, 1H, NH); MS m/z (%) 664 (M⁺+ 2) (20), 662 (M⁺, 60), 351 (100), 119 (92), 77 (51); anal. calcd. for C₃₈H₂₇ClN₈O₂(662.19): C, 68.83; H, 4.10; N, 16.90; found: C, 68.61; H, 4.01; N, 17.03%.

3-Acetyl-6-(4-methylphenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6l)

Yellow microcrystals; IR (KBr) v_max/cm^-1 1705, 1651 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.39 (s, 3H, Ar-CH₃), 2.62 (s, 3H, CH₃), 3.34 (s, 3H, COCH₃), 7.41-8.15 (m, 15H, Ar-H + pyridine-H), 8.57 (s, 1H, pyrazole-H); MS m/z (%) 551 (M⁺, 95), 525 (60), 262 (100), 91 (66), 77 (93); anal. calcd. for C₃₃H₂₅N₇O₂ (551.21): C, 71.86; H, 4.57; N, 17.78; found: C, 71.61; H, 4.43; N, 17.69%.

Ethyl 6-(4-methylphenyl)-1-phenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydro-5-oxo-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (6m)

Pale yellow microcrystals; IR (KBr) ν_max/cm^-1 1727, 1651 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 1.34 (t, 3H, J7.0 Hz, CH₃), 2.35 (s, 3H, Ar-CH₃), 2.60 (s, 3H, CH₃), 4.51 (q, 2H, J 7.0 Hz, CH₂), 7.51-7.92 (m, 15H, Ar-H + pyridine-H), 8.60 (s, 1H, pyrazole-H); MS m/z (%) 581 (M⁺, 22), 389 (100), 91 (50), 77 (58); anal. calcd. for C₃₄H₂₇N₇O₃ (581.22): C, 70.21; H, 4.68; N, 16.86; found: C, 70.11; H, 4.51; N, 16.71%.

N3,1–Diphenyl-6-(4-methylphenyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxamide (6n)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 3310 (NH), 1689, 1649 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.39 (s, 3H, Ar-CH₃), 2.60 (s, 3H, CH₃), 7.38-7.98 (m, 20H, Ar-H + pyridine-H), 8.58 (s, 1H, pyrazole-H), 11.18 (s, 1H, NH); MS m/z (%) 628 (M⁺, 50), 488 (90), 343 (100), 91 (40), 77 (70); anal. calcd. for C₃₈H₂₈N₈O₂ (628.23): C, 72.60; H, 4.49; N, 17.82; found: C, 72.41; H, 4.73; N, 17.63%.

3-Acetyl-6-[4-(N, N-dimethylamino)phenyl]-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-1,5-dihydropyrido[2,3-d][1,2,4] triazolo[4,3-a]pyrimidin-5-one (6o)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 1707, 1655 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.60 (s, 3H, CH₃), 3.11 (s, 6H, N(CH₃)₂), 3.36 (s, 3H, COCH₃), 7.41-8.15 (m, 15H, Ar-H + pyridine-H), 8.58 (s, 1H, pyrazole-H); MS m/z (%) 580 (M⁺, 90), 262 (60), 118 (100), 77 (75); anal. calcd. for C₃₄H₂₈N₈O₂ (580.23): C, 70.33; H, 4.86; N, 19.30; found: C, 70.18; H, 4.73; N, 19.59%.

Ethyl 6-[4-(N, N-dimethylamino)phenyl]-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-1,5-dihydro-5-oxo-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (6p)

Yellowish-white microcrystals; IR (KBr) ν_max/cm^-11723, 1650 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆1.29 (t, 3H, J7.0 Hz, CH₃), 2.60 (s, 3H, CH₃), 3.11 (s, 6H, N(CH₃)₂), 4.31 (q, 2H, J7.0 Hz, CH₂), 7.51-7.97 (m, 15H, Ar-H + pyridine-H), 8.62 (s, 1H, pyrazole-H); MS m/z (%) 610 (M⁺, 22), 118 (100), 77 (75); anal. calcd. for C₃₅H₃₀N₈O₃(610.24): C, 68.84; H, 4.95; N, 18.35; found: C, 68.75; H, 4.81; N, 18.41%.

3-Acetyl-6-(2-thienyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6q)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 1705, 1651 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.62 (s, 3H, CH₃), 3.34 (s, 3H, COCH₃), 7.41-8.15 (m, 14H, Ar-H + pyridine-H), 8.61 (s, 1H, pyrazole-H); MS m/z (%) 543 (M⁺, 61), 384 (90), 77 (100); anal. calcd. for C₃₀H₂₁N₇O₂S (543.15): C, 66.28; H, 3.89; N, 18.04; S, 5.90; found: C, 66.39; H, 4.03; N, 18.14; S, 5.83%.

Ethyl 6-(2-thienyl)-1-phenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydro-5-oxo-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (6r)

Pale yellow microcrystals; IR (KBr) ν_max/cm^-1 1728, 1647 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 1.32 (t, 3H, J7.0 Hz, CH₃), 2.61 (s, 3H, CH₃), 4.53 (q, 2H, J7.0 Hz, CH₂), 7.51-7.95 (m, 14H, Ar-H + pyridine-H), 8.61 (s, 1H, pyrazole-H); MS m/z (%) 573 (M⁺, 58), 168 (88), 148 (92), 80 (100), 77 (89); anal. calcd. for C₃₁H₂₃N₇O₃S. (573.16): C, 64.91; H, 4.04; N, 17.09; S, 5.59; found: C, 65.11; H, 4.15; N, 16.91; S, 5.36%.

N3,1-Diphenyl-6-(2-thienyl)-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxamide (6s)

Yellow microcrystals; IR (KBr) ν_max/cm^-1 3310 (NH), 1689, 1649 (2CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.60 (s, 3H, CH₃), 7.38-7.98 (m, 19H, Ar-H + pyridine-H), 8.60 (s, 1H, pyrazole-H), 11.21 (s, 1H, NH); MS m/z (%) 620 (M⁺, 77), 440 (100), 168 (88), 80 (94), 77 (50); anal. calcd. for C₃₅H₂₄N₈O₂S (620.17): C, 67.73; H, 3.90; N, 18.05; S, 5.17; found: C, 67.51; H, 4.03; N, 18.16; S, 5.11%.

Synthesis of 5-phenyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (8)

To a mixture of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenylprop-2-en-1-one (1) (1 mmol) and 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (7) (0.143 g, 1 mmol) in dioxane (15 mL) was added cellulose sulfuric acid (0.05 g). The mixture was refluxed for 8 h, then cooled to ambient temperature and cellulose sulfuric acid was filtered off. The filtrate was concentrated to dryness, and the crude solid product was crystallized from dioxane to afford the pure product 8.

Yield 75%, (0.31 g); pale yellow microcrystals; mp 247-249 °C (DMF/EtOH); IR (KBr) ν_max/cm^-1 3414, 3252 (2 NH), 1665 (CO); ¹H NMR (300 MHz, DMSO-d₆) ∆ 2.61 (s, 3H, CH₃), 6.91-8.02 (m, 11H, Ar-H + pyridine-H), 8.63 (s, 1H, pyrazole-H), 11.82 (s, 1H, br, NH), 12.36 (s, 1H, br, NH); MS m/z (%) 411 (M⁺, 100), 380 (92), 325 (81), 77 (50); anal. calcd. for C₂₃H₁₇N₅OS (411.12): C, 67.13; H, 4.16; N, 17.02; S, 7.79; found: C, 67.26; H, 4.27; N, 16.88; S, 7.83%.

Alternative synthesis of 3-acetyl-1,6-diphenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d][1,2,4] triazolo[4,3-a]pyrimidin-5-one (6a)

To a mixture of equimolar amounts of 8 (0.411 g, 1 mmol) and N-phenyl 2-oxopropanehydrazonoyl chloride (9) (0.196 g, 1 mmol) in dioxane (15 mL) was added triethylamine (0.14 mL, 1 mmol). The reaction mixture was refluxed till all of the starting materials had disappeared and hydrogen sulfide gas ceased to evolve (8 h, monitored by thin layer chromatography). The solvent was evaporated and the residue was treated with methanol. The solid formed was filtered and recrystallized from dimethylformamide (DMF) to give compound 6a as authentic sample.

Results and Discussion

We initiated our study with the investigation of the nature of solvent and amount of acid catalyst on the optimization of the product yields. Thus, treatment of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenylprop-2-en-1-one (1) with 3-acetyl-7-amino-1-phenyl[1,2,4]triazolo[4,3-a] pyrimidin-5(1H)-one (2) in different solvents under thermal condition, in presence of catalytic amount of cellulose sulfuric acid, led to formation of novel annelated heterocyclic ring system, namely, pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one 6a (Scheme 1, Table 1).

Scheme 1
Proposed mechanism for the synthesis of pyridotriazolopyrimidinone 6a.

Table 1
Effect of solvent and amount of acid-catalyst on the product yields

Run	Solvent	Amount of catalyst / g	Yield / %	Run	Solvent	Amount of catalyst	Yield / %
1	Benzene	0.05	43	7	Dioxane	0.01	40
2	Toluene	0.05	48	8	Dioxane	0.02	51
3	Xylene	0.05	47	9	Dioxane	0.03	65
4	Acetonitrile	0.05	62	10	Dioxane	0.04	71
5	DMF	0.05	70	11	Dioxane	0.05	75
6	Dioxane	0.05	75	12	Dioxane	0.06	66

We have found that, in non-polar aprotic solvents (benzene, toluene, and xylene) the product yields are low (runs 1-3). On the other hand, by using polar aprotic solvent (acetonitrile, DMF, and dioxane) the product yields improve (runs 4-6). Thus, dioxane was found to be the most suitable solvent for the formation of product 6a. The relationship between the yields of annelated product 6a and the amount of acid-catalyst was investigated. As shown in Table 1, the yield of 6a increased with an increase of the amount of catalyst (0.01 g up to 0.05 g) (runs 7-11) and then the yield decreased (run 12).

The efficiency of the cellulose sulfuric acid reagent compared to various acidic catalysts was also examined (Table 2). In this study, it was found that cellulose sulfuric acid is more efficient and superior catalyst (run 1) over other acidic catalysts (runs 2-4) with respect to the percent yield of the desired product. It was also observed that the yield of the product was only 10% in the absence of the cellulose sulfuric acid reagent (run 5).

Table 2
Effect of acid-catalysts on the product yields

Run	Catalyst	Amount of catalyst / mmol	Yield / %
1	Cellulose sulfuric acid	0.05	75
2	p-Toluenesulfonic acid	0.1	52
3	Acetic acid	0.1	60
4	Sulfuric acid in acetic acid	0.1	62
5	No catalyst	None	10

To account for the formation of product 6a, we proposed the mechanism shown in Scheme 1. Condensation of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenylprop-2-en-1-one (1) with 3-acetyl-7-amino-1-phenyl[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one (2a) afforded non-isolable intermediate 3a. Intramolecular cyclization with concurrent auto-oxidation^17,18 of intermediate 3a gave the respective pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one 6a as end product.

Having established the feasibility of the reaction of 1 with 2a, attention was directed to extend the scope of this reaction on 1,3-disubstituted[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones. Thus, refluxing of 1 with 2a-s in dioxane, containing 0.05 g of cellulose sulfuric acid afforded 1,3,6,8-tetrasubstituted pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one 6a-s (Scheme 2, Table 3).

Scheme 2
Synthesis of pyridotriazolopyrimidinone derivatives 6a-s.

Table 3
Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones 6a-s

Compound No.	Ar1	R	Ar2	Solvent of crystalization	Melting point / °C	Yield/%
6a	C6H5	COCH3	C6H5	DMF	236-238	75
6b	C6H5	CONHPh	C6H5	DMF	252-254	75
6c	4-ClC6H4	COCH3	C6H5	DMF	216-218	80
6d	4-ClC6H4	COCH3	4-ClC6H4	DMF	226-228	70
6e	4-ClC6H4	COCH3	4-CH3C6H4	DMF/EtOH	243-245	75
6f	4-ClC6H4	COCH3	4-CH3OC6H4	DMF/EtOH	254-256	66
6g	4-ClC6H4	COOC2H5	C6H5	EtOH	206-208	75
6h	4-ClC6H4	COOC2H5	4-ClC6H4	EtOH	213-215	70
6i	4-ClC6H4	COOC2H5	4-CH3C6H4	EtOH	218-220	70
6J	4-ClC6H4	CONHPh	C6H5	DMF	262-264	70
6k	4-ClC6H4	CONHPh	4-CH3C6H4	DMF/EtOH	231-233	65
6l	4-CH3C6H4	COCH3	C6H5	DMF/EtOH	244-246	80
6m	4-CH3C6H4	COOC2H5	C6H5	EtOH	189-191	75
6n	4-CH3C6H4	CONHPh	C6H5	DMF	263-265	65
6o	4-N(CH3)2C6H4	COCH3	C6H5	DMF	244-246	65
6P	4-N(CH3)2C6H4	COOC2H5	C6H5	EtOH	203-205	60
6q	2-thienyl	COCH3	C6H5	DMF/EtOH	238-240	70
6r	2-thienyl	COOC2H5	C6H5	EtOH	213-214	70
6s	2-thienyl	CONHPh	C6H5	DMF	267-269	70

The structures of the products 6a-s were established by elemental analyses and spectral data. The IR spectra showed in each case one absorption band at v= 1647-1655 cm^-1, assignable to (CO-amide). ¹H NMR revealed a singlet signal at ∆ = 7.56-7.62 ppm, assignable to pyridine-H on fused pyridine ring¹⁹ and another singlet signal at ∆= 8.57-8.64 ppm, corresponding to pyrazole (H-3).²⁰ Further, ¹³C NMR of the products confirmed the presence of [1,2,4]triazolo[4,3-a]pyrimidine ring by exhibiting signal at ∆ = 168.1 ppm corresponding to (C=O) group attached to sp³ nitrogen atom.¹³

The assigned structure and the proposed mechanism were further confirmed by alternate synthesis of 6a as a typical example of the series prepared. Thus, treatment of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenylprop-2-en-1-one (1) with 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (7) in dioxane in the presence of catalytic amount of cellulose sulfuric acid under reflux afforded the respective 2-thioxopyrido[2,3-d]pyrimidine-4-one (8) (Scheme 3). Heating of compound 8 with N-phenyl 2-oxopropanehydrazonoyl chloride (9) in dioxane, in the presence of triethylamine, furnished 3-acetyl-1,6-diphenyl-8-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (6a) as authentic product (Scheme 3). The conversion of 8 into product 6a proceeded through S-alkylation²¹ to give S-alkylated product (intermediate 10) followed by Smiles rearrangement,²² affording intermediate 11, which eliminated hydrogen sulfide gas to give the desired product6a.

Scheme 3
Alternative synthesis of 6a.

Conclusions

A series of novel annelated heterocyclic ring system, namely, pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones 6a-s were prepared via reaction of chalcone with amino[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones in the presence of catalytic amount of cellulose sulfuric acid as eco-friendly acid catalyst.

• Supplementary Information
  Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file

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Publication Dates

• Publication in this collection
  May 2015

History

• Received
  18 Sept 2014
• Accepted
  06 Mar 2015