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

Abstract

Methyl (2E)-3-methoxyacrylate and excess methylhydrazine yield crude 1-methyl-2-pyrazolin-5-one which is reacted with cyclohexanone to obtain the title compound in 86% yield. Detailed spectroscopic data (¹H NMR, ¹³C NMR, ¹⁵N NMR, and MS) are presented.

1. 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-d₆ 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.

2. 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. ¹H and ¹³C NMR spectra were recorded on a Varian UnityPlus 300 spectrometer at 28 °C (299.95 MHz for ¹H, 75.43 MHz for ¹³C) or on a Bruker Avance 500 spectrometer at 293 K (500.13 MHz for ¹H, 125.77 MHz for ¹³C). The centre of the solvent signal was used as an internal standard which was related to TMS with δ = 7.26 ppm (¹H in CDCl₃), δ = 2.49 ppm (¹H in DMSO-d₆), δ = 77.0 ppm (¹³C in CDCl₃), and δ = 39.5 ppm (¹³C in DMSO- d₆). The digital resolutions were 0.2 Hz/data point in the ¹H and 0.4 Hz/data point in the ¹H-coupled ¹³C-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).

2.1. 4,4'-(Cyclohexane-1,1-diyl)bis(1-methyl-1H-pyrazol-5-ol) (2)

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%).

Mp: 186–191 °C, colourless powder.

¹H NMR (300 MHz, DMSO-d₆): δ (ppm) 13.77 (br s, 2H, OH), 7.16 (s, 2H, pyrazole H-3), 3.38 (s, 6H, NMe), 2.07 (m, 4H, cyclohexane H-2,6), 1.38 (m, 6H, cyclohexane H-3,4,5).

¹³C NMR (75 MHz, DMSO-d₆): δ (ppm) 156.0 (pyrazole C-5), 132.6 (pyrazole C-3, ¹J = 183.8 Hz), 110.9 (pyrazole C-4), 33.5 (cyclohexane C-1), 33.2 (cyclohexane C-2,6), 31.6 (NMe, ¹J = 140.0 Hz), 26.0 (cyclohexane C-4), 21.9 (cyclohexane C-3,5).

¹⁵N NMR (50 MHz, DMSO-d₆): δ (ppm) –210.0 (N-1); N-2 was not found.

MS (m/z, %): 276 (M⁺, 3), 179 (42), 178 (100), 163 (50), 149 (34), 135 (33), 124 (28), 111 (48), 99 (26), 98 (53), 79 (36), 55 (45), 43 (46).

Elemental Analysis: Calculated for C₁₄H₂₀N₄O₂ (276.33): C, 60.85%; H, 7.30%; N, 20.28%. Found: C, 60.66%; H, 7.24%; N, 20.34%.