A Mild Procedure for the Preparation of 3-Aryl-4-formylpyrazoles

Abstract

A variety of 3-aryl-4-formylpyrazoles can be easily prepared in good yields from the corresponding methyl ketones, upon treatment with 2,4,6-trichloro[1,3,5]triazine in N,N-dimethyl form­amide at room temperature. This kind of pyrazole can constitute new building blocks for combinatorial chemistry.

methylketones - cyanuric acid - pyrazoles

References

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16

All solvents and reagents were used as obtained from commercial source. Standard ¹H NMR and ¹³C NMR were recorded at 300 and 75.4 MHz from CDCl₃ solutions. All runs were conducted at least in duplicate. General Preparation of 4-Formylpyrazoles. The procedure for 1,3-diphenyl-4-formylpyrazole (Table [1] , run 1) is representative for all cases. 2,4,6-Trichloro-[1,3,5]-triazine (1.83 g, 10.0 mmol) was added to DMF (2 mL), maintained at 25 °C. After the formation of a white solid, the reaction was monitored (TLC) until complete disappearance of TCT, then the phenylhydrazone of acetophenone (1.00 g, 5.0 mmol) in DMF (15 mL) was added. After the addition, the mixture was stirred at r.t., monitored (TLC) until completion (16 h). A 15% solution of Na₂CO₃ (20 mL) was added then the organic phase extracted twice with 15 mL of Et₂O. The organic layer was dried (Na₂SO₄) and the solvent evaporated to yield 1,3-diphenyl-4-formylpyrazole that was recovered without other purifications (1.12 g, 90%): mp 145 °C. ¹H NMR: δ = 10.12 (s, 1 H), 8.55 (s, 1 H), 7.86-7.74 (m, 5 H), 7.54-7.44 (m, 5 H) ppm. ¹³C NMR: δ = 185.5, 158.1, 139.7, 136.5, 129.7, 129.1, 128.5, 127.3, 127.0, 126.5, 118.8, 106.3 ppm.
All new compounds were identified through their elemental analyses and spectroscopic data. Preparation of 4-(Dimethoxymethyl)-1,3-diphenyl-1 H -pyrazole. To a solution of 1,3-diphenyl-4-formylpyrazole (0.50 g, 2.01 mmol) in dry MeOH (20 mL) was added of NH₄Cl (0.01 g) and of 0.50 g of molecular sieves (4 Å). The mixture was refluxed under argon atmosphere for 10 h, and then concentrated in vacuo. The organic residue washed with H₂O (20 mL), aq Na₂CO₃ (20 mL), dried on Na₂SO₄, and filtered on Celite. After evaporation of the solvent 4-(di-methoxymethyl)-1,3-diphenyl-1H-pyrazole was recovered (0.59 g, 100%): ¹H NMR: δ = 8.15 (s, 1 H), 7.90 (d, 2 H), 7.80 (d, 2 H), 7.47 (t, 4 H), 7.39 (t, 1 H), 7.25 (t, 1 H), 5.61 (s, 1 H), 3.38 (s, 6 H) ppm. ¹³C NMR: δ = 150.7, 139.8, 132.9, 129.3, 129.1, 128.7, 128.4, 128.0, 127.9, 127.6, 127.3, 126.3, 120.2, 118.8, 112.3, 98.3, 52.1 ppm. Anal. Calcd for C₁₈H₁₈N₂O₂ (294.35): C, 73.45; H, 6.16; N, 9.52. Found: C, 73.45; H, 6.12; N, 9.50. Preparation of 1,3-Diphenyl-1 H -pyrazole-4-carboxylic acid. The reported procedure is representative for all experiments. An aq 15% solution of NaHCO₃ (15 mL) was added to a solution of 1-phenyl-3-p-tolyl-1H-pyrazole-4-carbaldehyde (0.34 g, 1.3 mmol) in acetone (20 mL), stirred and maintained at 0 °C, followed by solid NaBr (0.05 g, 0.5 mmol) and TEMPO (0.015 g, 0.1 mmol). Trichloroisocyanuric acid (0.58 g, 2.5 mmol) was then slowly added within 10 min, at 0 °C. After the addition, the mixture was warmed to r.t., stirred for the required time until completion, then i-PrOH (1 mL) was added. The mixture was filtered on Celite, concentrated under vacuum and treated with 15 mL of a sat. solution of Na₂CO₃. The aqueous phase was washed with portions of EtOAc, treated with 1 N HCl and extracted twice with EtOAc. The organic layer were dried (Na₂SO₄), and the solvent evaporated to yield 1-phenyl-3-p-tolyl-1H-pyrazole-4-carboxylic acid that was recovered without other purifications (0.35 g, 97%): ¹H NMR: δ = 10.95 (s, 1 H), 8.00 (s, 1 H), 7.62 (d, 2 H) 7.42 (m, 5 H), 7.25 (d, 2 H), 2.40 (s, 3 H) ppm. ¹³C NMR: δ = 172.0, 147.4, 140.3, 129.8, 129.6, 129.2, 114.1, 21.4 ppm. Anal. Calcd for C₁₇H₁₄N₂O₂ (278.31): C, 73.37; H, 5.07; N, 10.07. Found: C, 73.35; H, 5.12; N, 10.04. 1-Phenyl-3-(4-chlorophenyl)-1 H -pyrazole-4-carboxylic acid: ¹H NMR: δ = 11.00 (s, 1 H), 8.10 (s, 1 H), 7.52 (d, 2 H) 7.43 (d, 2 H), 7.30-7.22 (m, 5 H) ppm. ¹³C NMR: δ = 170.0, 149.4, 139.7, 134.4, 131.2, 129.6, 129.2, 126.3, 120.2, 114.3 ppm. Anal. Calcd for C₁₆H₁₁ClN₂O₂ (298.72): C, 64.33; H, 3.71; Cl, 11.87; N, 9.38. Found: C, 64.35; Cl, 11.82; N, 9.34.
Preparation of [3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methanol. To a solution of 3-(4-chloro-phenyl)-1-phenyl-1H-pyrazole-4-carbazole (0.23 g, 0.8 mmol) in dry THF (30 mL) was added LiAlH₄ (0.03 g, 0.8 mmol), and refluxed for 45 min. The mixture was then left at r.t. for 1 h, hydrolyzed with HCl 1 N (10 mL), added with H₂O (50 mL), extracted with portions (15 mL) of Et₂O. The extracts were washed with 15 mL of a sat. solution of Na₂CO₃ (20 mL), dried on Na₂SO₄, filtered on Celite and concentrated under vacuum to give [3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]methanol (0.23 g, 100%): ¹H NMR: δ = 9.95 (s, 1 H), 8.65 (s, 1 H), 7.62 (d, 2 H) 7.42 (d, 2 H), 7.28 (m, 5 H), 2.37 (s, 3 H) ppm. ¹³C NMR: δ = 152.2, 140.4, 134.3, 130.8, 129.6, 129.2, 126.3, 123.1, 117.1, 54.4 ppm. Anal. Calcd for C₁₆H₁₃ClN₂O (284.74): C, 67.49; H, 4.60; N, 9.84. Found: C, 67.49; H, 4.62; N, 9.93.