Versatile Synthesis of 4-Methylidenepyrazolidin-3-ones Using a Horner–Wadsworth–Emmons Approach

Abstract

A new, versatile method for the synthesis of, so far unknown, variously substituted 4-methylidenepyrazolidin-3-ones as potential cytotoxic agents is described. Target compounds were synthesized from the corresponding 4-diethoxyphosphorylpyrazolidin-3-ones which were used as Horner–Wadsworth–Emmons ­reagents for the olefination of formaldehyde. 4-Phosphorylpyrazolidin-3-ones were, in turn, obtained starting from the sodium salt of ethyl 2-diethoxyphosphoryl-3-hydroxy-2-propenoate, ethyl 2-acyl-2-diethoxyphosphorylacetates, or 3-methoxy-2-diethoxyphosphorylacrylate and monosubstituted or 1,2-disubstituted hydrazines.

Key words

alkylation - antitumor agents - heterocycles - lactams - Michael addition - olefination

• References and Notes

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• 10 General Procedure for the N-Methylation: Synthesis of 2-Aryl-4-diethoxyphosphoryl-1-methyl-1,2-dihydro-3H-pyrazol-3-ones 12a–e and 2-Aryl-4-diethoxyphosphoryl-1-methyl-1,2-dihydro-3H-pyrazol-3-ones 17a–gA solution of the corresponding pyrazolol 11a–e (5 mmol) and (MeO)₂SO₂ (0.57 mL, 6 mmol) in DCE (50 mL) was heated at 80 °C for 18 h. The solvent was evaporated, and the crude product was purified by column chromatography (eluent: EtOAc–MeOH, 9:1). With the pyrazolols 16a–g the reaction was performed with CF₃SO₃Me (1.64 g, 10 mmol) at 80 °C for 2 h.Diethyl [1-Methyl-3-oxo-2-(p-tolyl)-2,3-dihydro-1H-pyrazol-4-yl]phosphonate (12c)Pale-yellow oil. IR (film): 3035, 1655, 1509, 1258, 1029, 758, 542 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 1.25 [t, ³ J _H–H = 7.1 Hz, 6 H, (CH ₃CH₂O)₂P(O)], 2.28 (s, 3 H, CH₃), 3.27 (s, 3 H, CH₃), 4.06–4.14 [m, 4 H, (CH₃CH ₂O)₂P(O)], 7.09 (d, ³ J _H–H = 8.2 Hz, 2 H, 2 × HAr), 7.18 (d, ³ J _H–H = 8.2 Hz, 2 H, 2 × HAr), 7.84 (d, ³ J _H–P = 4.4 Hz, 1 H, H-5). ¹³C NMR (62.9 MHz, CDCl₃): δ = 16.0 [d, ³ J _C–P = 6.9 Hz, (CH₃CH₂O)₂P(O)], 20.8 (s, CH₃), 36.9 (s, CH₃), 62.0 [d, ² J _C–P = 5.6 Hz, (CH₃ CH₂O)₂P(O)], 93.8 (d, ¹ J _C–P = 222.2 Hz, C-4), 126.3 (s, 2 × CAr), 129.8 (s, 2 × CAr), 130.0 (s, CAr), 138.6 (s, CAr), 147.1 (d, ² J _C–P = 18.8 Hz, C5), 162.9 (d, ² J _C–P = 14.0 Hz, C3). ³¹P NMR (101 MHz, CDCl₃): δ = 12.51. Anal. Calcd for C₁₅H₂₁N₂O₄P: C, 55.55; H, 6.53. Found: C, 55.42; H, 6.60.
• 11 General Procedure for L-Selectride Reduction: Synthesis of 2-Aryl-4-diethoxyphosphoryl-1-methylpyrazolidin-3-ones 13a–e and 2-Aryl-4-diethoxyphosphoryl-1-methylpyrazolidin-3-ones 18a–gTo a cooled (–78 °C) solution of the corresponding pyrazolone 12a–e or 17a–g (1 mmol) in THF (15 mL) was added dropwise a THF solution of L-Selectride (1.25 mmol) under an argon atmosphere, and the mixture was stirred at this temperature for 1 h. Then, the mixture was allowed to slowly warm to r.t. and was stirred at r.t. overnight. The reaction mixture was concentrated to half the initial volume and quenched with 10% aq NH₄Cl. After extraction with CH₂Cl₂ (3 × 15 mL), the combined organic layers were washed with brine and dried over MgSO₄. After filtration and evaporation, the crude product was purified by column chromatography (eluent: EtOAc–MeOH, 9:1).Diethyl [1-Methyl-3-oxo-2-(p-tolyl)pyrazolidin-4-yl]phosphonate (13c)Pale-yellow oil. IR (film): 2982, 1689, 1614, 1508, 1354 1248, 1018, 963 cm^–1. ¹H NMR (250 MHz, DMSO-d ₆): δ = 1.24 [t, ³ J _H–H = 7.0 Hz, 3 H, (CH ₃CH₂O)P(O)], 1.27 [t, ³ J _H–H = 7.0 Hz, 3 H, (CH ₃CH₂O)P(O)], 2.25 (s, 3 H, CH₃), 2.57 (s, 3 H, CH₃), 3.56 (dd, ³ J _H–H = 9.2 Hz, ³ J _H–P = 14.5 Hz, 2 H, 2 × H-5), 3.84 (dt, ³ J _H–H = 9.2 Hz, ² J _H–P = 21.5 Hz, 1 H, H-4), 4.05–4.20 [m, 4 H, (CH₃CH ₂O)₂P(O)], 7.13–7.20 (m, 2 H, 2 × HAr), 7.48–7.55 (m, 2 H, 2 × HAr). ¹³C NMR (62.9 MHz, DMSO-d ₆): δ = 15.5 [d, ³ J _C–P = 5.6 Hz, (CH₃CH₂O)₂P(O)], 19.8 (s, CH₃), 40.4 (d, ¹ J _C–P = 146.9 Hz, C-4), 42.9 (s, CH₃), 51.7 (d, ² J _C–P = 1.8 Hz, C-5), 61.5 [d, ² J _C–P = 6.7 Hz, (CH₃ CH₂O)P(O)], 61.9 [d, ² J _C–P = 6.4 Hz, (CH₃ CH₂O)P(O)], 119.7 (s, 2 × CAr), 128.7 (s, 2 × CAr), 133.7 (s, CAr), 134.1 (s, CAr), 164.9 (d, ² J _C–P = 2.3 Hz, C-3). ³¹P NMR (101 MHz, DMSO-d ₆): δ = 23.13. Anal. Calcd for C₁₅H₂₃N₂O₄P: C, 55.21; H, 7.10. Found: C, 55.11; H, 7.23.
• 12 General Procedure for Methylidenation: Synthesis of 2-Aryl-1-methyl-4-methylidenepyrazolidin-3-ones 14a–e, 2-Aryl-1-methyl-4-methylidenepyrazolidin-3-ones 19a–g, and 4-Methylidene-1,2-diphenylpyrazolidin-3-ones 24a–eTo a solution of the corresponding pyrazolidinone 13a–e, 18a–g, or 23a–e (0.5 mmol) in THF (5 mL), NaH (14 mg, 0.6 mmol) was added, and the resulting mixture was stirred at r.t. for 30 min. Then, paraformaldehyde (75 mg, 2.5 mmol) was added in one portion. After 2 h the reaction mixture was quenched with brine (5 mL), the solvent was evaporated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The organic extracts were dried over MgSO₄, filtered, and the solvent was evaporated. The crude product was purified by column chromatography (eluent: CH₂Cl₂).1-Methyl-4-methylene-2-(p-tolyl)pyrazolidin-3-one (14c)Pale-yellow oil. IR (film): 2960, 2858, 1693, 1662, 1492, 1348, 822 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 2.32 (s, 3 H, CH₃), 2.56 (s, 3 H, CH₃), 3.52–3.88 (m, 1 H, 1 × H-5), 4.06–4.40 (m, 1 H, 1 × H-5), 5.49–5.51 (m, 1 H, HCH=), 6.14–6.16 (m, 1 H, HCH=), 7.15–7.20 (m, 2 H, 2 × HAr), 7.70–7.79 (m, 2 H, 2 × HAr). ¹³C NMR (62.9 MHz, CDCl₃): δ = 19.5 (s, CH₃), 45.9 (s, CH₃), 55.8 (s, C-5), 117.9 (s, CH₂=), 119.3 (s, 2 × CAr), 127.9 (s, 2 × CAr), 134.3 (s, CAr), 134.8 (s, CAr), 139.2 (s, C-4), 165.2 (s, C-3). Anal. Calcd for C₁₂H₁₄N₂O: C, 71.26; H, 6.98. Found: C, 71.09; H, 7.12.
• 13 Miller PC, Curtis JM, Molyneaux JM, Owen TJ. US 6,297,194 B1, 2001
• 14 General Procedure for the Synthesis of 1-Aryl-4-diethoxyphosphoryl-1H-pyrazol-5-ols 16f,g A mixture of ethyl 2-aroyl-2-diethoxyphosphorylacetate 15f,g (10 mmol), phenylhydrazine (11 mmol), and AcOH (0.6 g, 20 mmol) was refluxed in H₂O (50 mL) for 3 h. The reaction mixture was cooled and extracted with EtOAc (2 × 30 mL). The organic extracts were washed with brine, dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (eluent: EtOAc–hexane, 1:1).
• 15 Janecki T, Albrecht A, Koszuk JK, Modranka J, Słowak D. Tetrahedron Lett. 2010; 51: 2274
• 16 General Procedure for the Synthesis of 4-Diethoxy-phosphoryl-1,2-diphenylpyrazolidin-3-ones 23a–e To a solution of the 4-diethoxyphosphoryl-1,2-diphenyl-pyrazol-3-one 22 (2 mmol) in THF (15 mL) a solution of the corresponding Grignard reagent (2.4 mmol) was added dropwise, under an argon atmosphere at r.t., and the resulting mixture was refluxed for 2 h. After this time the reaction mixture was quenched with H₂O (5 mL), acidified to pH ca. 3 with 10% aq HCl solution, and extracted with CH₂Cl₂ (3 × 10 mL). The organic extracts were dried over MgSO₄, filtered, and the solvent was evaporated. The crude product was purified by column chromatography (eluent: CHCl₃–MeOH, 98:2). 4-Diethoxyphosphoryl-1,2,5-triphenylpyrazolidin-3-one (23e) Pale-yellow oil. IR (film): 2981, 1703, 1593, 1489, 1391, 1250, 1014, 964 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 1.07 [t, ³ J _H–H = 7.1 Hz, 3 H, (CH ₃CH₂O)P(O)], 1.30 [t, ³ J _H–H = 7.0 Hz, 3 H, (CH ₃CH₂O)P(O)], 3.30 (dd, ² J _H–P = 23.4 Hz, ³ J _H–H = 3.0 Hz, 1 H, H-4), 3.67–3.84 [m, 1 H, (CH₃CHO)P(O)], 3.91–4.04 [m, 1 H, (CH₃CHO)P(O)], 4.08–4.22 [m, 2 H, (CH₃CH ₂O)P(O)], 5.39 (dd, ³ J _H–P = 19.1 Hz, ³ J _H–H = 3.0 Hz, 1 H, H-5), 6.81–6.98 (m, 4 H, 4 × HAr), 7.10–7.24 (m, 3 H, 3 × HAr), 7.31–7.43 (m, 4 H, 4 × HAr), 7.50–7.53 (m, 2 H, 2 × HAr), 7.83–7.87 (m, 2 H, 2 × HAr). ¹³C NMR (62.9 MHz, CDCl₃): δ = 15.9 [d, ³ J _C–P = 5.4 Hz, (CH₃CH₂O)P(O)], 16.1 [d, ³ J _C–P = 6.1 Hz, (CH₃CH₂O)P(O)], 46.7 (d, ¹ J _C–P = 137.2 Hz, C-4), 62.9 [d, ² J _C–P = 6.9 Hz, (CH₃ CH₂O)P(O)], 63.3 [d, ² J _C–P = 6.6 Hz, (CH₃ CH₂O)P(O)], 68.6 (d, ² J _C–P = 0.9 Hz, C-5), 117.4 (s, 2 × CAr), 118.9 (s, 2 × CAr), 123.1 (s, CAr), 125.0 (s, CAr), 125.2 (s, 2 × CAr), 128.1 (s, CAr), 128.7 (s, 2 × CAr), 128.9 (s, 2 × CAr), 129.1 (s, 2 × CAr), 137.7 (s, CAr), 142.1 (d, ³ J _C–P = 12.1 Hz, CAr), 149.4 (s, CAr), 164.6 (d, ² J _C–P = 5.7 Hz, C-3). ³¹P NMR (101 MHz, CDCl₃): δ = 19.60. Anal. Calcd for C₂₅H₂₇N₂O₄P: C, 66.66; H, 6.04. Found: 66.49; H, 5.97.