Synthesis of 4 , 4 '-( Cyclohexane-1 , 1-diyl ) bis ( 1-methyl-1 H-pyrazol-5-ol )

Methyl (2E)-3-methoxyacrylate and excess methylhydrazine yield crude 1methyl-2-pyrazolin-5-one which is reacted with cyclohexanone to obtain the title compound in 86% yield. Detailed spectroscopic data (H NMR, C NMR, N NMR, and MS) are presented.


Introduction
During our ongoing research on pyrano [2,3-c]pyrazol-4(1H)-ones [1][2][3][4][5] we were interested in the not yet commercially available methylpyrazolone 1.Although dozens of patents and journal articles deal with its synthesis, most of them include multi-step reactions or seem to be less suited for laboratory scale preparations.Thus, we chose to follow a patent protocol, which starts from alkoxyacrylic alkyl esters and alkylhydrazines [6].Recently, we have successfully applied that procedure to yield the unsubstituted pyrazolone [7].Unfortunately, no work up for the crude methylpyrazolone 1 is published in the original patent (only GC/MS analysis is carried out).When we tried to find a proper solvent to precipitate the desired methylpyrazolone from the oily reaction syrup, we found that ketones -such as acetone or cyclohexanone -readily react and give colourless precipitates as the analysis of such a precipitate revealed.A representative procedure with cyclohexanone is presented in the experimental part [Scheme 1].It should be noted that according to NMR data in DMSO-d 6 solution, we presume a rather unsymmetrical conformation as outlined in Scheme 2. Consistent with this suggestion, we achieved no intramolecular cyclization to the corresponding pyrano[2,3-c:6,5-c']dipyrazole upon treatment with conc.sulfuric acid or polyphosphoric acid, that would be expected if the hydroxy groups were spatially close.
Scheme 2. Proposed conformation of compound 2 in DMSO solution [8] strong NOE weak NOE

Experimental
Melting points were determined on a Reichert-Kofler hot-stage microscope and are uncorrected.Mass spectra were obtained on a Shimadzu QP 1000 instrument (EI, 70 eV).Elemental analysis was performed at the Microanalytical Laboratory, University of Vienna. 1 H and 13 C NMR spectra were recorded on a Varian UnityPlus 300 spectrometer at 28 °C (299.95MHz for 1 H, 75.43 MHz for 13 C) or on a Bruker Avance 500 spectrometer at 293 K (500.13MHz for 1 H, 125.77MHz for 13 C).The centre of the solvent signal was used as an internal standard which was related to TMS with δ = 7.26 ppm ( 1 H in CDCl 3 ), δ = 2.49 ppm ( 1 H in DMSO-d 6 ), δ = 77.0ppm ( 13 C in CDCl 3 ), and δ = 39.5 ppm ( 13 C in DMSO-d 6 ).The digital resolutions were 0.2 Hz/data point in the 1 H and 0.4 Hz/data point in the 1 Hcoupled 13 C-NMR spectra (gated decoupling). 15N NMR spectra were obtained on a Bruker Avance 500 instrument with a 'directly' detecting broadband observe probe and were referenced against external nitromethane (coaxial capillary).
Molbank 2008 CAUTION: Methylhydrazine is a potentially highly toxic compound and must be used with great care under a well-ventilated hood.
To a well stirred solution of methyl 3-methoxyacrylate (50 mmol, 5.80 g) in dry MeOH (5 mL) methylhydrazine (75 mmol, 3.46 g) was added dropwise and the mixture was stirred at room temperature for 3 h.Then the excess solvent and reagents were distilled off using a rotary evaporator to obtain the crude methylpyrazolone 1 as a yellowish honey-like mass [9].Cyclohexanone (25 mmol, 2.45 g) was added to the residue and the mixture was refluxed for 5 min.The formed precipitate was filtered off and washed subsequently with petroleum ether and acetone to yield the pure title compound 2 (5.91 g, 86%).