A one-step synthesis of pyrazolone

Abstract

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%.