A New Versatile Route to the Synthesis of a Novel Series of Highly Substituted 1,1′-Carbonylbispyrazole Derivatives

Abstract

The reaction of 1H-pyrazole-1-carbohydrazide with various α,β-unsaturated nitriles under suitable conditions leads to a cyclocondensation reaction, thereby providing a novel route for the synthesis of a series of highly substituted 1,1′-carbonylbispyrazole derivatives.

Key words

1H-pyrazole-1-carbohydrazide - pyrazoles - α,β-unsaturated nitriles - carbonylbispyrazoles - cyclizations - heterocycles

• References and Notes

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• 26 General Procedure for the Synthesis of Pyrazoles 2 A mixture of 4 (82 mmol) and hydrazinecarboxylic acid ethyl ester (1, 8.52 g, 81 mmol) was stirred under reflux in abs. EtOH (120 mL) for 4 h. After cooling in the refrigerator overnight, the precipitate was filtered and washed with cold Et₂O to afford 2 as colorless needles. Ethyl 5-Amino-4-cyano-1H-pyrazole-1-carboxylate (2a) Yield 12.4 g (84%); mp 165–167 °C. IR: ν_max = 3493, 3280, 3214, 3128–3156, 2219, 1771, 1628 cm^–1. ¹H NMR (100 MHz, CDCl₃): δ = 1.48 (t, 3 H, CH₃), 4.54 (q, 2 H, CH₂), 6.32 (s, 2 H, NH₂), 7.57 (s, 1 H, CH). Ethyl 5-Amino-4-cyano-3-methyl-1H-pyrazole-1-carboxylate (2b) Yield 12.7 g (81%); mp 180–181 °C. IR: ν_max = 3406, 3320, 3247, 2990, 2213, 1736, 1646, 1563, 1471, 1332, 1256, 1021 cm^–1. ¹H NMR (100 MHz, CDCl₃): δ = 1.43 (t, 3 H, CH₃), 2.25 (s, 3 H, CH₃), 4.48 (q, 2 H, CH₂), 6.48 (s, 2 H, NH₂). Anal. Calcd for C₈H₁₀N₄O₂: C, 49.48; H, 5.19; N, 28.85. Found: C, 49.38; H, 5.11; N, 28.78.
• 27 General Procedure for the Synthesis of 1H-Pyrazole-1-carbohydrazides 3 Hydrazine monohydrate (10 mL, 206 mmol) was added to a solution of 2 (55 mmol) in abs. EtOH (60 mL), and the mixture was refluxed for 3 h. The excess of solvent was distilled off, and the crude product obtained was poured into ice water. After cooling in the refrigerator overnight, the solid residue was filtered and washed with cold water and dried to give 3 as a white solid. 5-Amino-4-cyano-1H-pyrazole-1-carbohydrazide (3a) Yield 8.2 g (90%); mp 175 °C. IR: ν_max = 3416, 3341, 3284, 3240, 3178, 2956, 2238, 1646, 1570, 1034 cm^–1. ¹H NMR (100 MHz, DMSO-d ₆): δ = 6.82 (s, 4 H, 2 NH₂), 7.72 (s, 1 H, CH), 12.09 (s, 1 H, NH). Anal. Calcd for C₅H₆N₆O: C, 36.15; H, 3.64; N, 50.58. Found: C, 36.08; H, 3.58; N, 50.49. 5-Amino-4-cyano-3-methyl-1H-pyrazole-1-carbohydrazide (3b) Yield 7.9g (80%); mp 125–127 °C. IR: ν_max = 3403, 3341, 3284, 3242, 2994, 2217, 1660, 1298 cm^–1. ¹H NMR (100 MHz, CD₃COCD₃): δ = 2.20 (s, 3 H, CH₃), 5.35 (s, 4 H, 2 NH₂), 11.19 (s, 1 H, NH). Anal. Calcd for C₆H₈N₆O: C, 40.00; H, 4.48; N, 46.65. Found: C, 39.01; H, 4.41; N, 46.60.
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• 34 Synthesis of 1,1′-Carbonylbis(5-amino-1H-pyrazole-4-carbonitrile) (5a) Compound 4a (0.62 g, 5 mmol) was added to a stirring solution of 3a (0.82 g, 5 mmol) in EtOH (10 mL). The contents were stirred at r.t. for a further 30 min and then refluxed for 3 h. After the completion of the reaction [monitoring by TLC using CHCl₃–MeOH (4:1, v:v) as eluent], the white solid was filtered under suction and washed with cold EtOH (1.1g, 93%); mp >300 °C (dec.). IR: ν_max = 3321, 3277, 3126, 2235, 1688, 1610, 1570, 1487, 1338, 1329, 1262 cm^–1. ¹H NMR (100 MHz, DMSO-d ₆): δ = 8.54 (s, 1 H, arom.), 8.72 (s, 1 H, arom.), 9.37 (br, 4 H, NH₂, D₂O exchangeable). Anal. Calcd for C₉H₆N₈O: C, 44.63; H, 2.50; N, 46.27. Found: C, 44.54; H, 2.55; N, 46.12. Synthesis of 5-Amino-1-(5-amino-4-cyano-1H-pyrazole-1-carbonyl)-3-methyl-1H-pyrazole-4-carbonitrile (5b) Compounds 4b (0.54 g, 4 mmol) and 3a (0.66 g, 4 mmol) were added to a solution of Na of NaOEt prepared by adding (0.21 g, 9 mmol) to abs. EtOH (10 mL). The mixture was stirred at r.t. for 30 min and then heated to reflux for 3 h. After the completion of the reaction [monitoring by TLC using CHCl₃–MeOH (3:1, v/v) as eluent], the mixture was cooled to r.t. H₂O (5 mL) was added, and the mixture was neutralized by HCl. The collected solid was recrystallized from MeOH (0.81 g, 81%); mp >300 °C (dec.). IR: ν_max = 3340, 3310, 3248, 3180, 3116, 2232, 2221, 1650, 1594 cm^–1. ¹H NMR (100 MHz, DMSO-d ₆): δ = 2.52 (s, 3 H, CH₃), 8.67 (s, 1 H, arom.), 9.25 (br, 4 H, NH₂, D₂O exchangeable). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 24.3, 77.4, 81.1, 113.9, 115.5, 147.9,150.6, 150.9, 164.6. Anal. Calcd for C₁₀H₈N₈O: C, 46.88; H, 3.15; N, 43.73. Found: C, 46.78; H, 3.04; N, 43.60.
• 35 General Procedure for the Synthesis of 1,1′-Carbonylbispyrazole Derivatives 5c–f A mixture of of 4c–e (4 mmol) and 3 (4 mmol) in pyridin (5 mL) was heated to reflux for 4 h, then poured onto ice water and the mixture neutralized with concd HCl. The precipitated solid was filtered, washed with H₂O, and crystallized from an appropriate solvent. 5-Amino-1-(5-amino-4-cyano-1H-pyrazole-1-carbonyl)-3-(methylthio)-1H-pyrazole-4-carbonitrile (5c) Yield 0.89 g (78%, DMF); mp >300 °C. IR: ν_max = 3353, 3304, 3027, 3186, 2240, 2218, 1659, 1607, 1567, 1384, 1342, 1291 cm^–1. ¹H NMR (100 MHz, DMSO-d ₆): δ = 2.64 (s, 3 H, SCH₃), 8.37 (s, 1 H, arom.), 9.03 (br, 4 H, NH₂, D₂O exchangeable). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.2, 74.6, 80.9, 113.9, 114.3, 147.7, 150.1, 150.4, 166.5. Anal. Calcd for C₁₀H₈N₈OS: C, 41.66; H, 2.80; N, 38.87; S, 11.12. Found: C, 41.56; H, 2.46; N, 38.57; S, 11.04. 5-Amino-1-[4-amino-5-cyano-3-(ethylthio)-1H-pyrazole-1-carbonyl]-1H-pyrazole-4-carbonitrile (5d) Yield 1.05g (87%, EtOH); mp >300 °C (dec.). IR: ν_max = 3350, 3320, 3252, 3187, 3101, 2994, 2941, 2217, 1657, 1597, 1563, 1534, 1465, 1380, 1339, 1286, 1248 cm^–1. ¹H NMR (100 MHz, DMSO-d ₆): δ = 1.26–1.41 (t, 3 H, SCH₂CH₃), 3.11–3.30 (q, 2 H, SCH₂CH₃), 8.62 (s, 1 H, arom.), 9.19 (br, 4 H, NH₂, D₂O exchangeable). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 15.7, 25.8, 75.8, 81.9, 115.3, 148.8, 151.4, 151.6, 167.2. Anal. Calcd for C₁₁H₁₀N₈OS: C, 43.70; H, 3.33; N, 37.07; S, 10.61. Found: C, 51.64; H, 3.29; N, 37.42; S, 10.55. Ethyl 1-(5-Amino-4-cyano-1H-pyrazole-1-carbonyl)-5-methyl-3-(methylthio)-1H-pyrazole-4-carboxylate (5e) Yield 1.09g (82%, n-hexane); mp 128–129 °C. IR: ν_max = 3351, 3313, 3250, 3219, 3184, 2239, 2217, 1658, 1607, 1566, 1534, 1462, 1384, 1342, 1278 cm^–1. ¹H NMR (100 MHz, CDCl₃): δ = 1.38–1.52 (t, 3 H, OCH₂CH₃), 2.65 (s, 3 H, CH₃), 2.88 (s, 3 H, SCH₃), 4.33–4.56 (q, 2 H, OCH₂CH₃), 8.29 (s, 1 H, arom.). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.1, 14.2, 15.3, 62.8, 81.9, 112.9, 115.4, 146.6, 147.4, 149.0, 164.1, 164.6. Anal. Calcd for C₁₃H₁₄N₆O₃S: C, 46.70; H, 4.22; N, 25.14; S, 9.59. Found: C, 46.62; H, 4.15; N, 25.09; S, 9.59. 5-Amino-1-(4-amino-5-cyano-3-methyl-1H-pyrazole-1-carbonyl)-1H-pyrazole-4-carbonitrile (5f) Yield 0.87g (81%, MeOH). IR: ν_max = 3327, 3277, 3120, 2234, 1680, 1609, 1565, 1485, 1335 cm^–1. ¹H NMR (100 MHz, DMSO-d ₆): δ = 2.47 (s, 3 H, CH₃), 2.52 (s, 3 H, CH₃), 9.13 (br, 4 H, 2 NH₂, D₂O exchangeable). ¹H NMR (100 MHz, CD₃COCD₃): δ = 2.49 (s, 3 H, CH₃), 2.59 (s, 3 H, CH₃), 8.40 (br, 4 H, 2 NH₂, D₂O exchangeable). Anal. Calcd for C₁₁H₁₀N₈O: C, 48.89; H, 3.73; N, 41.46. Found: C, 48.81; H, 3.69; N, 41.40.