Synlett 2014; 25(1): 105-109
DOI: 10.1055/s-0033-1340071
letter
© Georg Thieme Verlag Stuttgart · New York

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

Jakub Modranka
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland   Fax: +48(42)6365530   Email: tjanecki@p.lodz.pl
,
Rafał Jakubowski
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland   Fax: +48(42)6365530   Email: tjanecki@p.lodz.pl
,
Tomasz Janecki*
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland   Fax: +48(42)6365530   Email: tjanecki@p.lodz.pl
› Author Affiliations
Further Information

Publication History

Received: 25 August 2013

Accepted after revision: 01 October 2013

Publication Date:
21 November 2013 (online)


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.

 
  • 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 11ae (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 16ag 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 12ae or 17ag (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 13ae, 18ag, or 23ae (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.