An Efficient Synthesis of Substituted Pyrazoles from One-Pot Reaction of Ketones, Aldehydes, and Hydrazine Monohydrochloride

Abstract

An efficient, one-pot and metal-free process for the preparation of 3,5-disubstituted and 3,4,5-trisubstituted pyrazoles on multi-gram scale was developed. One-pot condensation of ketones, aldehydes and hydrazine monohydrochloride readily formed pyrazoline intermediates under mild conditions. Oxidation of pyrazolines, in situ, employing bromine afforded a wide variety of pyrazoles. The methodology offers a fast, and often chromatography-free protocol for the synthesis of 3,4,5-substituted pyrazoles in good to excellent yields. Alternatively, a more benign oxidation protocol affords 3,5-disubstituted or 3,4,5-trisubstituted pyrazoles by simply heating pyrazolines in DMSO under oxygen.

Key words

heterocyclic compounds - pyrazoles - pyrazolines - ketones - aldehydes - oxidation of pyrazolines - oxygen - bromine

• References and Notes


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• 15 General Procedure for One-Pot, Three-Component Coupling, and Subsequent Oxidation by Bromine for the Synthesis of Pyrazoles 14a–p and 7A suspension of hydrazine hydrochloride (6.85 g, 0.1 mol, 1 equiv) in MeOH (30 mL) was warmed under argon atmosphere to 55 °C. Ketone (0.1 mol, 1.0 equiv) and neat aldehyde (0.1 mol, 1.0 equiv) were added sequentially dropwise over 30 min to the stirred suspension. After 10 min of stirring the resulting orange solution was cooled to 0 °C over 1 h. Bromine (20.8 g, 0.13 mol, 1.3 equiv) was added dropwise to the reaction mixture with stirring, keeping the reaction temperature below 10 °C. After 30 min of stirring at 0 °C, the reaction was quenched with dropwise addition of 30 wt% aqueous solution of NaOH (53.3 g, 0.4 mol, 4 equiv) over 1 h. The resulting heterogeneous mixture was warmed briefly to 45–55 °C and then cooled to 25 °C. The reaction mixture was stirred overnight to afford a suspension which was filtered. The collected solid was washed with water (60 mL) to afford crude product as wet solids. The wet solid in EtOH (35 mL) was heated at reflux for 30 min, cooled to 25 °C, stirred at this temperature for 1 h, and filtered. The collected solid was washed with EtOH (4–6 mL) and dried for 24 h at 65 °C under vacuum (2 mbar) to afford pyrazoles 14 or 7.Analytical Data for Compound 14a ¹H NMR (600 MHz, CDCl₃): δ = 8.42 (br s, 1 H, 1). 7.72 (dt, J = 7.0, 1.2 Hz, 2 H, 2′ phenyl), 7.44 (tt, J = 7.2, 1.1 Hz, 2 H, 3′ phenyl), 7.39 (tt, J = 7.4, 1.2 Hz, 1 H, 4′ phenyl), 2.72 (t, J = 6.1 Hz, 2 H, 4), 2.70 (t, J = 6.2 Hz, 2 H, 7), 1.87–1.80 (m, 4 H, 6 and 5). ¹³C NMR (150 MHz, CDCl₃): δ = 145.0 (7a), 143.2 (3), 129.2 (4′ phenyl), 129.1 (1′ phenyl), 129.0 (3′ phenyl), 127.4 (2′ phenyl), 114.0 (3a), 22.9 (5), 21.9 (6), 21.7 (7), 21.5 (4). MS (LR-APCI⁺): m/z calcd for C₁₃H₁₄N₂: 198.1; found: 199.0 [M + H]⁺.Procedure for the Synthesis of 3,5-Substituted Pyrazole 17a by Catalytic Reduction of 4-Bromopyrazol 17bA suspension of hydrazine hydrochloride (6.85 g, 0.1 mol, 1 equiv) in MeOH (30 mL) is warmed under argon atmosphere to 55 °C. Acetone (5.80 g, 0.1 mol, 1 equiv) is mixed with the stirred suspension, then, within 30 min neat benzaldehyde (10.61 g, 0.1 mol, 1 equiv) is added dropwise to the reaction mixture. After 10 min of stirring the resulting orange solution is cooled to 0 °C. Bromine (31.96 g, 0.2 mol, 2 equiv) is added dropwise to the reaction mixture while stirring at temperature lower than 15 °C. After more than 30 min of the continuing stirring at 0–5 °C the reaction is quenched by slowly (over 1 h) adding of the 30% aqueous NaOH solution (53.33 g, 0.4 mol, 4 equiv). The resulting heterogeneous mixture is extracted with ethyl acetate (100 mL). From the separated organic layer solvent is removed. The residue, pyrazole 17b, is submitted to a catalytic hydrogenation at 4 bar/80 °C with 5% wet Pd on activated charcoal (3 g, 1.4 mmol, 0.014 equiv) in EtOH (50 mL). After 10–20 h of hydrogenation, the reaction mixture is cooled, filtered over Celite, the cake is washed with EtOH (50 mL), and from combined mother liquors containing the product solvent is removed in vacuo. The isolated material is hydrobromide salt of pyrazole 7a which is converted into free base by the basic extraction work-up in ethyl acetate/10% w/w aqueous solution of sodium carbonate.Analytical Data for Compound 17a ¹H NMR (600 MHz, CDCl₃): δ = 7.71 (d, J = 7.1 Hz, 2 H, 2′), 7.44 (t, J = 7.5 Hz, 2 H, 3′), 7.31 (tt, J = 7.4, 1.2 Hz, 1 H, 4′), 6.36 (s, 1 H, 4), 2.34 (d, J = 0.6 Hz, 3 H, CH₃-C5). ¹³C NMR (150 MHz, CDCl₃): δ = 128.7 (1′ and 3′), 127.9 (4′), 125.6 (2′), 102.1 (4), 11.8 (CH₃), C3 and C5 missing. MS (LR-APCI⁺): m/z calcd for C₁₀H₁₀N₂: 158.1; found: 158.9 [M + H]⁺.Analytical Data for Compound 17b ¹H NMR (600 MHz, CDCl₃): δ = 7.75 (dt, J = 7.0, 1.5 Hz, 2 H, 2′), 7.43 (tt, J = 7.1, 1.4 Hz, 2 H, 3′), 7.39 (tt, J = 7.3, 1.5 Hz, 1 H, 4′), 6.25 (br s, 1 H, 1), 2.27 (s, 3 H, CH₃-C5). ¹³C NMR (150 MHz, CDCl₃): δ = 145.4 (3), 143.8 (5), 130.4 (1′ phenyl), 128.7 (4′ phenyl), 128.6 (3′ phenyl), 127.4 (2′ phenyl), 92.8 (4), 11.3 (Me). MS (LR-APCI⁺): m/z calcd for C₁₀H₉BrN₂: 236.0; found: 236.8 [M + H]⁺, 238.8 [M + 2 + H]⁺.General Procedure for Preparation of Pyrazoles 7, 14a and 21a–o by Oxidation of Pyrazolines 13 and 20a–p with OxygenA solution of pyrazoline HCl salt 20 or 13 (2 mmol) in DMSO (10 mL) under 1 atm of pure O₂ gas was heated at 85 °C for 1–2 h or until the consumption of the starting material. The reaction solution was cooled to ambient temperature and poured into water (200 mL) with stirring to afford a suspension. The suspension was stirred at ambient temperature for 1 h, and solids were collected by filtration and washing with water. The solids were dried under vacuum at 45 °C overnight to afford pyrazoles 7, 14a, and 21.Analytical Data for Pyrazole 7 ¹H NMR (300 MHz, CDCl₃): δ = 13.33 und 13.00 (br s, NH two tautomers), 7.61–7.67 (m, 4 H, 2′, 3′, 5′, and 6′ phenyl), 4.55 (s, 2 H, 4), 3.63 (t, J = 5.7 Hz, 2 H, 7), 2.85–2.91 (m, 5 H, MeSO₂, and 6). ¹³C NMR (75 MHz, CDCl₃): δ = 142.37 (3), 141.21 (7a), 135.17 (1′ phenyl), 129.74 (q, J = 32.6 Hz, 4′ phenyl), 126.41 (2′ and 6′ phenyl), 125.85 (q, J = 3.9 Hz, 3′ and 5′ phenyl), 124.10 (q, J = 287.5 Hz, CF₃), 109.61 (3a), 43.09 (4), 42.86 (6), 36.93 (MeSO₂), 22.77 (7). ¹⁹F NMR (282 MHz, CDCl₃): δ = –62.60. MS (LR-APCI⁺): m/z calcd for C₁₄H₁₄F₃N₃O₂S: 345.1; found: 346.1 [M + H]⁺.Analytical Data for Pyrazoline 13 ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.87 (s, 2′, 3′ 5′, and 6′phenyl), 4.80 (br d, J = 10.27 Hz, 1 H, 3), 3.91 4.07 (m, 2 H, 4 and 6), 3.62–3.78 (m, 1 H, 3a), 3.08 (br t, J = 11.65 Hz, 1 H, 4), 3.01 (s, 3 H, MeSO₂), 2.85–3.01 (m, 2 H, 6), 2.65–2.79 (m, 2 H, 7). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 172.67 (7a), 138.98 (br s, 1′ phenyl), 130.01 (q, J = 31.7 Hz, 3′ and 5′ phenyl), 129.95 (2′ and 6′ phenyl), 126.90 (q, J = 3.3 Hz, 3′ and 5′ phenyl), 124.49 (q, J = 272.6 Hz, CF₃), 63.54 (3), 51.92 (3a), 49.01 (4), 44.82 (6), 37.34 (MeSO₂), 27.96 (7). MS (LR-APCI⁺): m/z calcd for C₁₄H₁₆N₃O₂S: 347.1; found: 348.1 [M + H]⁺; titration Cl^–: calcd for C₁₄H₁₆N₃O₂S·HCl: 9.25%; found: 9.79%.
• 16 Detailed procedures along with full analytical data are available in the Supporting Information.