3-Methyl-1-phenyl-1H-pyrazol-5-yl 2-Bromo-3-furan-carboxylate

Abstract

The reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one and 2-bromo-3-furoyl chloride in the presence of Ca(OH)₂ in 1,4-dioxane gave the title compound. The latter was also obtained in much higher yield upon reaction of the starting materials in the system dichloromethane / triethylamine. Detailed spectroscopic data (¹H NMR, ¹³C NMR, ¹⁵N NMR, IR, MS) are presented.

In a series of papers we recently described a short and efficient approach to novel heterocyclic systems containing a pyrano[2,3-c]pyrazol-4(1H)-one substructure via reaction of 2-pyrazolin-5-ones 1 with o-haloheteroarenecarbonyl chlorides 2 under the conditions of the ‘Jensen’-reaction (calcium hydroxide, refluxing 1,4-dioxane) and subsequent cyclization of the thus obtained 4-aroylpyrazol-5-ols 3 into the target compounds 4 (Scheme 1) [1,2,3,4,5,6].

In the course of these investigations we were also interested in furo[3’,2’:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones (4, Het = furane). The synthesis of a corresponding representative 4a (R¹ = Ph, R³ = Me) should be carried out similarly as outlined in Scheme 1, i.e. by reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one (1a) and 2-bromo-3-furoyl chloride (2a) under ‘Jensen’-conditions [7] followed by cyclization of the key intermediate 3a (Scheme 2).

However, the reaction of 1a and 2a in the presence of Ca(OH)₂ in refluxing 1,4-dioxane did not afford the expected C-aroyl product 3a but resulted in a complex reaction mixture, from which the ester 5 was isolated as the main component. Compound 5 could be easily identified considering its characteristic spectral data. Thus, the ¹H-NMR spectrum of 5 exhibits a singlet signal of pyrazole H-4 at δ 6.25 ppm, the corresponding pyrazole C-4 resonance (δ 95.8 ppm) shows a dublet structure in the ¹H-coupled ¹³C NMR spectrum (¹J = 181.7 Hz). Moreover, the carbonyl absorption at 1752 cm^-1 in the IR spectrum is typical for an ester-carbonyl moiety and definitely rules out a diaryl ketone substructure with intramolecular hydrogen bond as present in 3a. For the C=O absorption in the latter a much smaller value (~ 1620 cm^-1) for ν_C=O has to be expected [3].

Expectedly, reaction of 1a and 2a in dichloromethane in the presence of triethylamine according to ref. [8] afforded the title compound 5 as the sole product in high yields (82% after purification by column chromatography).

Experimental

Mass spectrum: Shimadzu QP 1000 instrument (EI, 70 eV). IR spectrum: Perkin-Elmer FTIR Spectrum 1000 instrument (KBr-disc). The 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). 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), and δ = 77.0 ppm (¹³C in CDCl₃). 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 (50.69 MHz for ¹⁵N) with a ‘directly’ detecting broadband observe probe and were referenced against external nitromethane. The reactants 1a and 2a are commercially available.

3-Methyl-1-phenyl-1H-pyrazol-5-yl 2-bromo-3-furancarboxylate (5)

(a) To a mixture of 3-methyl-1-phenyl-2-pyrazolin-5-one (1a) (87 mg, 0.5 mmol) and Ca(OH)₂ (74 mg, 1 mmol) in 4 mL of dry 1,4-dioxane was slowly added a solution of 2-bromo-3-furoyl chloride (2a) (105 mg, 0.5 mmol) in 1,4-dioxane (1 mL) and the whole was heated to reflux for 3 h. After cooling to rt, 2N HCl (2 mL) was added and the mixture was stirred for 15 min before it was poured onto H₂O (30 mL). The aqueous phase was extracted with EtOAc (4 × 20 mL), the combined organic phases were washed with H₂O, dried (Na₂SO₄) and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel, eluent: petroleum ether – EtOAc, 5:1). The main component (least retarded fraction) turned out to be compound 5. Yield: 35 mg (20%) of a yellowish oil which slowly solidified on standing.

(b) A mixture of 1a (174 mg, 1 mmol), 2a (230 mg, 1 mmol) and triethylamine (1 mL) in CH₂Cl₂ (20 mL) was refluxed for 3 h. Then solid products were filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, eluent: petroleum ether – EtOAc, 5:1) to afford 283 mg (82%) of 5.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.57 (m, 2H, Ph H-2/6), 7.48 (d, ³J = 2.2 Hz, 1H, furane H-5), 7.43 (m, 2H, Ph H-3/5), 7.32 (m, 1H, Ph H-4), 6.76 (d, ³J = 2.2 Hz, 1H, furane H-4), 6.25 (s, 1H, pyrazole H-4), 2.35 (s, 3H, Me).

¹³C NMR (75 MHz, CDCl₃): δ (ppm) 156.9 (C=O), 149.1 (pyrazole C-3, ²J(C3,3-Me) = 6.7 Hz, ²J(C3, H4) = 4.1 Hz), 144.9 (furane C-5, ¹J = 210.3 Hz, ²J(C5,H4) = 9.7 Hz), 143.8 (pyrazole C-5, ²J(C5,H4) = 4.7 Hz), 138.0 (Ph C-1), 131.6 (furane C-2, ³J(C2,H4) = 8.4 Hz, ³J(C2,H5) = 8.4 Hz), 129.0 (Ph C-3/5), 127.3 (Ph C-4), 123.5 (Ph C-2/6), 115.7 (furane C-3, ²J(C3,H4) = 3.0 Hz, ³J(C3,H5) = 5.8 Hz), 112.6 (furane C-4, ¹J = 182.7 Hz, ²J(C4,H5) = 12.9 Hz), 95.8 (pyrazole C-4, ¹J = 181.7 Hz, ³J(C4,3-Me) = 3.5 Hz), 14.5 (Me, ¹J = 127.7 Hz).

¹⁵N NMR (50 MHz, CDCl₃): δ (ppm) −183.6 (pyrazole N-1), −96.7 (pyrazole N-2).

IR (KBr) ν (cm⁻¹): 1752 (C=O).

MS (m/z, %): 348 (M⁺, 4), 346 (M⁺, 4), 173 (100).

Elemental Analysis: Calculated for C₁₅H₁₁BrN₂O₃ (347.16): C, 51.90%; H, 3.19%; N, 8.07%. Found: C, 51.90%; H, 3.26%; N, 7.77%.