An Efficient One-Pot Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-dione Derivatives

Abstract

An efficient, three-component, one-pot condensation reaction between phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl cyanoacetate for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives in excellent yields is reported.

Key words

malononitrile - ethyl cyanoacetate - phthalhydrazide - pyrazolo[1,2-b]phthalazine-5-dione

References and Notes

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21

Typical Procedure for the Preparation of 3-Amino-5,10-dihydro-5,10-dioxo-1-phenyl-1 H -pyrazolo[1,2- b ]phthalazin-2-carbonitrile (7a)
A mixture of malononitrile (1 mmol), phthalhydrazide (1 mmol), benzaldehyde (1 mmol), PTSA (0.3 mmol), and [bmim]Br (0.30 g) was heated at 100 °C for 3 h (TLC). After cooling, the reaction mixture was washed with H₂O (15 mL) and residue recrystallized from MeOH to afford the pure product 7a. Yellow powder (94%); mp 276-278 °C. IR (KBr): ν_max = 3359, 3190, 2197, 1690, 1658 cm^-1. MS (EI, 70 eV): m/z (%) = 316 (20) [M⁺], 299 (42), 239 (100). ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.13 (1 H, s, CH), 7.29-7.47 (5 H, m, ArH), 7.93-8.26 (4 H, m, ArH), 8.09 (2 H, s, NH₂) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 62.4, 63.6, 116.1, 127.2, 127.3, 127.7, 128.7, 128.9, 129.2, 134.1, 135.1, 138.7, 151.2, 154.2, 157.1 ppm. Anal. Calcd (%) for C₁₈H₁₂N₄O₂: C, 68.35; H, 3.82; N, 17.71. Found: C, 68.41; H, 3.87; N, 17.78.

22

Selected Characterization Data
3-Amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1 H -pyrazolo[1,2- b ]phthalazine-2-carbonitrile (7b)
Yellow powder (88%); mp 259-262 °C. IR (KBr): ν_max = 3370, 3176, 2207, 1695, 1658 cm^-1. MS (EI, 70 eV): m/z
(%) = 350 (17) [M⁺], 333 (44), 239 (100). ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.46 (1 H, s, CH), 7.33-7.62 (4 H, m, ArH), 7.87-8.30 (4 H, m, ArH), 8.15 (2 H, s, NH₂) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 60.2, 61.0, 116.2, 127.2, 127.8, 128.3, 128.8, 129.2, 130.2, 130.4, 131.7, 134.3, 135.2, 135.8, 151.6, 154.0, 157.1 ppm. Anal. Calcd (%) for C₁₈H₁₁ClN₄O₂: C, 61.64; H, 3.16; N, 15.97. Found: C, 61.57; H, 3.11; N, 15.91.
3-Amino-1-(4-chlorophenyl)-5,10-dihydro-5,10-dioxo-1 H -pyrazolo[1,2- b ]phthalazine-2-carbonitrile (7c)
Yellow powder (91%); mp 270-272 °C. IR (KBr): ν_max = 3375, 3264, 2200, 1662, 1655 cm^-1. MS (EI, 70 eV): m/z
(%) = 350 (8) [M⁺], 333 (27), 239 (100). ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.15 (1 H, s, CH), 7.41-7.53 (4 H, m, ArH), 7.93-8.26 (4 H, m, ArH), 8.13 (2 H, s, NH₂) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 61.3, 62.7, 116.4, 127.1, 127.7, 128.9, 129.3, 133.3, 134.2, 135.1, 137.9, 151.2, 154.1, 157.1 ppm. Anal. Calcd (%) for C₁₈H₁₁ClN₄O₂: C, 61.64; H, 3.16; N, 15.97. Found: C, 61.56; H, 3.09; N, 15.92.
Ethyl 3-Amino-5,10-dihydro-1-(3-nitrophenyl)-5,10-dioxo-1 H -pyrazolo[1,2- b ]phthalazine-2-carboxylate (7k)
Yellow powder (93%); mp 239-240 °C. IR (KBr): ν_max = 3360, 3249, 1693, 1651, 1613 cm^-1. MS (EI, 70 eV): m/z
(%) = 408 (23) [M⁺], 286 (100), 240 (40), 162 (85). ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.99 (3 H, t, ³ J _HH = 9.2 Hz, CH₃), 3.94 (2 H, q, ³ J _HH = 7.8 Hz, OCH₂), 6.22 (1 H, s, CH), 7.56-8.30 (10 H, m, NH₂ and ArH), 8.26-8.27 ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 14.51, 59.19, 63.10, 81.12, 122.58, 123.12, 127.14, 127.69, 129.09, 129.49, 129.99, 134.17, 134.56, 135.05, 142.61, 147.95, 150.52, 153.93, 157.39, 164.31 ppm. Anal. Calcd (%) for C₂₀H₁₆N₄O₆: C, 58.82; H, 3.95; N, 13.72. Found: C, 58.88; H, 3.89; N, 13.66.
Ethyl 3-Amino-5,10-dihydro-1-(4-nitrophenyl )-5,10-dioxo-1 H -pyrazolo[1,2- b ]phthalazine-2-carboxylate (7l)
Yellow powder (95%); mp 241-243 °C. IR (KBr): ν_max = 3386, 3210, 1694, 1655, 1630 cm^-1. MS (EI, 70 eV): m/z
(%) = 408 (13) [M⁺], 286 (81), 240 (17), 162 (100). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.03 (3 H, t, ³ J _HH = 6.8 Hz, CH₃), 3.95 (2 H, q, ³ J _HH = 6.7Hz, OCH₂), 6.18 (1 H, s, CH), 7.73-8.29 (10 H, m, NH₂ and ArH) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 14.61, 59.27, 63.04, 81.18, 123.59, 125.58, 127.16, 127.73, 129.02, 129.25, 133.04, 134.22, 135.12, 147.34, 147.77, 153.81, 157.32, 164.26 ppm. Anal. Calcd (%) for C₂₀H₁₆N₄O₆: C, 58.82; H, 3.95; N, 13.72. Found: C, 58.75; H, 3.90; N, 13.78.
Ethyl 3-Amino-5,10-dihydro-5,10-dioxo-1-p-tolyl-1 H -pyrazolo[1,2- b ]phthalazine-2-carboxylate (7m)
Yellow powder (73%); mp 204-206 °C. IR (KBr): ν_max = 3447, 3333, 1706, 1658, 1624 cm^-1. MS (EI, 70 eV): m/z
(%) = 377 (27) [M⁺], 286 (100), 240 (25), 162 (10). ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.04 (3 H, t, ³ J _HH = 8.9 Hz, CH₃), 2.25 (3 H, s, CH₃), 3.96 (2 H, q, ³ J _HH = 9.0 Hz, OCH₂), 6.04 (1 H, s, CH), 7.07-7.38 (4 H, m, ArH), 7.69 (2 H, br s, NH₂), 7.92-8.27 (4 H, m, ArH). ¹³C NMR (75 MHz, DMSO-d ₆):
δ = 14.66, 21.17, 59.12, 63.45, 82.17, 127.11, 127.71, 128.93, 129.18, 129.34, 134.05, 135.11, 137.23, 137.26, 150.13, 153.49, 157.22, 164.55. Anal. Calcd (%) for C₂₁H₁₉N₃O₄: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.88; H, 5.01; N, 11.19.