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Short Note

A one-step synthesis of pyrazolone

Gernot A. Eller
* and
Wolfgang Holzer
Department of Drug Synthesis, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria
Author to whom correspondence should be addressed.
Molbank 2006, 2006(1), M464;
Submission received: 3 January 2006 / Accepted: 4 January 2006 / Published: 22 January 2006


The fully unsubstituted pyrazolone (= 2-pyrazolin-5-one, which is tautomer to 1H-pyrazol-3-ol and 1H-pyrazol-5-ol) was prepared from hydrazine hydrate and methyl (2E)-3-methoxyacrylate in almost quantitative yield. Detailed spectroscopic data (1H NMR, 13C NMR, 15N NMR, MS) for this compound are presented.

Substituted 2-pyrazolin-5-ones play an important role as substructures of numerous pharmaceuticals, agrochemicals, dyes, pigments, as well as chelating agents and thus attract remarkable attention [1,2].
Recently, we investigated the synthesis of some N1-unsubstituted pyrazolones by use of the PMB (p-methoxybenzyl) protecting group [3,4]. Although this substituent proved to be conveniently removable from various 4-substituted pyrazolones upon treatment with refluxing trifluoroacetic acid only poor results were obtained when the parent 1-PMB-pyrazolone (= 2-(4-methoxybenzyl)-2,4-dihydro-3H-pyrazol-3-one [3]) was subjected to these conditions. Even prolonged heating (1 week instead of 1 day) did not effect full deprotection (1 day ~ 15%, 2 days ~ 35%, 7 days ~ 75%; monitored by mean of 1H NMR). Hence, there is need for other and more suitable methods for the synthesis of the unsubstituted pyrazolone 1.
With respect to the fact that other hitherto described syntheses of 1 are characterized by multi-step procedures and/or low yields [5,6], we report here an almost quantitative one-step preparation of the fully unsubstituted pyrazolone system from hydrazine hydrate and methyl (2E)-3-methoxyacrylate following an already known procedure for the synthesis of 1-alkyl pyrazolones [7] (Scheme 1).
A considerable number of studies deal with the prototropic tautomerism of pyrazolones [8].
Determination of the tautomeric composition of compound 1 is quite challenging as eight possible tautomeric forms have to be considered. This may also be a reason why in the Chemical Abstracts Service (CAS) references are cited for all possible tautomeric forms of compound 1 (Figure 1) except for form E. From the signal multiplicities in the carbon NMR spectra tautomeric forms B, C, F, G, and H can be excluded. Moreover, the 15N NMR chemical shifts found for compound 1 (–126.5 ppm and –192.0 ppm) rule out form A, as for this tautomer a much smaller chemical shift for the =CH–NH– atom has to be expected (for instance, in phenazone – 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one – which is structurally related to form A this atom exhibits a chemical shift of –245.1 ppm [9]). The differentiation between forms D and E is not a trivial task. However, from comparison of the 13C chemical shifts, the 15N chemical shifts, the 3J(H,H) coupling constants, and the different 13C,1H-coupling constants of 1 with those of the corresponding N-phenyl analogues (1-phenyl-1H-pyrazol-3-ol, 1-phenyl-1H-pyrazol-5-ol) [10,11] we assume that form D is predominating in DMSO-d6 solution. Nevertheless an additional contribution of other isomers (in minor amounts) can not be ruled out.
Compound 1: Under stirring, to a solution of 5.81 g (50 mmol) of methyl (2E)-3-methoxyacrylate in methanol (5 mL) was hydrazine hydrate (2.75 g, 55 mmol) added and the mixture was refluxed for 1h. Evaporation under reduced pressure to dryness gave 4.13 g (98%) of a slightly yellowish powder, pure according to 1H NMR spectroscopy.
Melting point: 160–162 °C, crystal modifications starting at ~140 °C, (lit. [12] 162–164 °C).
1H-NMR (300 MHz, DMSO-d6, 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 9.82 (br s, 2H, XH); 7.33 (d, 3J(H5,H4)= 2.3 Hz, 1H, H5); 5.43 (d, 3J(H4,H5)= 2.3 Hz, 1H, H4).
13C-NMR (75 MHz, DMSO-d6, 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 161.0 (C3, 2J(C3,H4)= 3.4 Hz, 3J(C3,H5)= 9.2 Hz); 130.1 (C5, 1J = 184.0 Hz, 2J(C5,H4)= 8.2 Hz); 89.3 (C4, 1J = 175.6 Hz, 2J(C4,H5)= 8.7 Hz).
15N-NMR (50 MHz, DMSO-d6, 294 K) [14]: δ= –126.5; –192.0.
MS (m/z, %) [15]: 84 (M+, 100); 55 (24).
Elemental Analysis: Calculated for C3H4N2O (84.08): C, 42.86%; H, 4.80%; N, 33.32%. Found: C, 42.75%; H, 4.65%; N, 33.15%.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

References and Notes:

  1. Elguero, J. Comprehensive Heterocyclic Chemistry: Pyrazoles and their Benzo Derivatives; Vol. 5, Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; pp. 167–303. [Google Scholar]
  2. Stanovnik, B.; Svete, J. Product class 1: Pyrazoles. Science of Synthesis 2002, 12, 15–225. [Google Scholar] [CrossRef]
  3. Eller, G. A.; Holzer, W. Heterocycles 2004, 63, 2537–2555.
  4. Becker, W.; Eller, G. A.; Holzer, W. Synthesis 2005, 2583–2589.
  5. Testa, E.; Fontanella, L. Farmaco 1971, 26, 1017–35.
  6. Dorn, H.; Zubek, A. J. Prakt. Chem. 1971, 313, 1118–24. [CrossRef]
  7. Maywald, V.; Steinmetz, A.; Rack, M.; Gotz, N.; Gotz, R.; Henkelmann, J.; Becker, H. Aiscar Bayeto, PCT Int. Appl. WO 0031042 A2 2000 (Chem. Abstr., 2000, 133, 4655).
  8. Holzer, W.; Hallak, L. Heterocycles 2004, 63, 1311–1334, and references cited therein.
  9. Cizmarik, J.; Lycka, A. Pharmazie 1988, 43, 794–795. [PubMed]
  10. Holzer, W.; Kautsch, C.; Laggner, C.; Claramunt, R. M.; Perez-Torralba, M.; Alkorta, I.; Elguero, J. Tetrahedron 2004, 60, 6791–6805.
  11. Sackus, A.; Holzer, W. manuscript in preparation.
  12. Lingens, F.; Schneider-Bernloehr, H. Liebigs Ann. Chem. 1965, 686, 134–144.
  13. The spectrum was obtained on a Varian UnityPlus 300 spectrometer (299.95 MHz for 1H, 75.43 MHz for 13C). The center of the solvent signal was used as an internal standard which was related to TMS with δ 2.49 ppm (1H NMR) and δ 39.5 ppm (13C NMR).
  14. The spectrum was obtained on a Bruker Avance 500 spectrometer and was referenced against neat, external nitromethane (coaxial capillary). The signals were not unequivocally assigned to the N atoms.
  15. The spectrum was obtained on a Shimadzu QP 1000 instrument (EI, 70eV).
  • Sample Availability: Available from MDPI.
Scheme 1. One-step procedure for the preparation of ‘pyrazolone’ 1.
Scheme 1. One-step procedure for the preparation of ‘pyrazolone’ 1.
Molbank 2006 m464 sch001
Figure 1. Possible tautomeric forms of ‘pyrazolone’ 1.
Figure 1. Possible tautomeric forms of ‘pyrazolone’ 1.
Molbank 2006 m464 g001

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Eller, G.A.; Holzer, W. A one-step synthesis of pyrazolone. Molbank 2006, 2006, M464.

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Eller GA, Holzer W. A one-step synthesis of pyrazolone. Molbank. 2006; 2006(1):M464.

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Eller, Gernot A., and Wolfgang Holzer. 2006. "A one-step synthesis of pyrazolone" Molbank 2006, no. 1: M464.

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