Synthesis of Mono- and Dibromo-Derivatives of 1-Phenylpyrazol-3-ol

Abstract

Dependent on the reaction conditions, 1-phenylpyrazol-3-ol and bromine give either 4-bromo-1-phenylpyrazol-3-ol (2a) or 4-bromo-1-(4-bromophenyl)pyrazol-3-ol (2b). Treatment of 2a or 2b with refluxing acetic anhydride leads to the corresponding O-acetyl derivatives 3a and 3b, respectively. Detailed spectroscopic data (¹H NMR, ¹³C NMR, ¹⁵N NMR, MS, IR) for 2b, 3a and 3b are presented.

In the course of investigations regarding Pd-catalyzed cross coupling reactions with halopyrazoles [1], we prepared 4-bromo-1-phenylpyrazol-3-ol (2a) via reaction of 1-phenylpyrazol-3-ol (1) with one equivalent of bromine in high yield similarly to a previously described procedure [2]. In this respect it seemed interesting for us, if treatment of 1 with an excess of Br₂ would lead to a dibromination product (introduction of a bromo atom also into the phenyl ring) and thus to a synthon with two different targets for further C–C bond formation. Such a behaviour was reported in a related case, namely in the bromination of 1-phenylpyrazole, where the use of excess bromine together with severe reaction conditions was found to give 15% 4-bromo-1-(4-bromphenyl)pyrazole besides the main product 4-bromo-1-phenylpyrazole (65%) [3].

We found that treatment of 1 with 3 equivalents of bromine in a solution of boiling carbon tetrachloride gave the dibromination product 2b in 82% yield (Scheme 1). The structure of 2b was unambiguously determined by spectroscopic methods (¹H, ¹³C, and ¹⁵N NMR, MS) and CHN analysis. Furthermore, treatment of 2a and 2b with boiling acetic anhydride afforded the corresponding O-acetyl products 3a and 3b in high yield (Scheme 2).

4-Bromo-1-(4-bromophenyl)-1H-pyrazol-3-ol (2b)

To a well stirred solution of hydroxypyrazole 1 [4] (1 g, 6.25 mmol) in carbon tetrachloride (30 mL) a solution of bromine (0.32 mL, 6.25 mmol) in carbon tetrachloride (8 mL) was added dropwise during 1 h, and stirring was continued for 2 h at room temperature. Then the reaction temperature was increased to reach reflux temperature within 1 h while adding a second equivalent of bromine (0.32 mL, 6.25 mmol) in carbon tetrachloride (8 mL). After the addition was complete, stirring was continued for further 5 h at reflux temperature. Then another equivalent of bromine (0.32 mL, 6.25 mmol) in carbon tetrachloride (8 mL) was added dropwise during 1 h, and stirring was continued for further 9 h at reflux temperature. The reaction mixture was then allowed to cool to room temperature; the precipitated solid was filtered off, washed with carbon tetrachloride (15 mL), and recrystallized from aqueous ethanol to afford 1.63 g (82%) of pure 2b.

Melting point: 199–201 °C, yellowish crystals.

¹H NMR (300 MHz, DMSO-d₆) [6]: δ (ppm) 11.07 (s, 1H, OH), 8.54 (s, 1H, H-5), 7.62 (m, 4H, Ph H-2,3,5,6).

¹³C NMR (75 MHz, DMSO-d₆) [6]: δ (ppm) 159.6 (C-3, ³J(C-3,H-5) = 8.8 Hz), 138.5 (Ph C-1), 132.2 (Ph C-3,5), 128.7 (C-5, ¹J = 195.0 Hz), 118.6 (Ph C-2,6), 117.3 (Ph C-4), 82.7 (C-4, ²J(C-4,H-5) = 5.0 Hz).

¹⁵N NMR (50 MHz, DMSO-d₆) [7]: δ (ppm) −119.4 (N-2), −189.4 (N-1).

MS (m/z, %) [8]: 320 (M⁺, 49), 318 (M⁺, 100), 316 (M⁺, 45), 239 (22), 237 (21), 157 (23), 157 (23), 155 (19).

Elemental Analysis: Calculated for C₉H₆Br₂N₂O (317.96): C, 34.00%; H, 1.90%; N, 8.81%. Found: C, 34.24%; H, 1.95%; N, 8.64%.

4-Bromo-1-phenyl-1H-pyrazol-3-yl acetate (3a)

Bromopyrazole 2a (1.91 g, 8 mmol) – which had been prepared by treatment of hydroxypyrazole 1 with one equivalent of bromine at room temperature following a known procedure [2] – and excess acetic anhydride (25 mL) were heated to reflux for 30 min. Then, H₂O (15 mL) was added and the solution was stirred for further 30 min. The mixture was poured into ice-water (50 mL) and stirred for 30 min. Then the precipitate was filtered off, washed with H₂O, and dried to give 2.07 g (92%) of pure 3a.

Melting point: 82–85 °C, off-white crystals.

IR (KBr) [5]: 1758 cm⁻¹ (C=O).

¹H NMR (300 MHz, CDCl₃) [6]: δ (ppm) 7.90 (s, 1H, H-5), 7.57 (m, 2H, Ph H-2,6), 7.43 (m, 2H, Ph H-3,5), 7.29 (m, 1H, Ph H-4), 2.38 (s, 3H, CH₃).

¹³C NMR (75 MHz, CDCl₃) [6]: δ (ppm) 167.6 (CO, ²J(CO,CH₃) = 7.1 Hz), 154.0 (C-3, ³J(C-3,H-5) = 9.4 Hz), 139.2 (Ph C-1), 129.5 (Ph C-3,5), 128.4 (C-5, ¹J = 194.3 Hz), 127.0 (Ph C-4), 118.5 (Ph C-2,6), 87.7 (C-4, ²J(C-4,H-5) = 5.1 Hz), 20.4 (CH₃, ¹J = 131.0 Hz).

¹⁵N NMR (50 MHz, CDCl₃) [7]: δ (ppm) −177.0 (N-1); N-2 not found.

MS (m/z, %) [8]: 282 (M⁺, 6), 280 (M⁺, 6), 240 (100), 238 (99), 104 (49), 77 (84), 51 (30), 43 (52).

Elemental Analysis: Calculated for C₁₁H₉BrN₂O₂ (281.11): C, 47.00%; H, 3.23%; N, 9.97%. Found: C, 46.74%; H, 3.07%; N, 9.84%.

4-Bromo-1-(4-bromophenyl)-1H-pyrazol-3-yl acetate (3b)

Dibromopyrazole 2b (1.27 g, 4 mmol) and excess acetic anhydride (15 mL) were refluxed for 30 min. Then H₂O (10 mL) was added and the solution was stirred for further 30 min. The mixture was poured into ice-water (50 mL) and stirred for 30 min. Then the precipitate was filtered off, washed with H₂O, and dried to give 1.17 g (81%) of pure 3b.

Melting point: 77 °C, beige powder.

IR (KBr) [5]: 1780, 1761 cm⁻¹ (C=O).

¹H NMR (300 MHz, CDCl₃) [6]: δ (ppm) 7.87 (s, 1H, H-5), 7.55 (m, 2H, Ph H-3,5), 7.46 (m, 2H, Ph H-2,6), 2.38 (s, 3H, CH₃).

¹³C NMR (75 MHz, CDCl₃) [6]: δ (ppm) 167.5 (CO, ²J(CO,CH₃) = 7.1 Hz), 154.4 (C-3, ³J(C-3,H-5) = 9.4 Hz), 138.3 (Ph C-1), 132.6 (Ph C-3,5), 128.3 (C-5, ¹J = 194.3 Hz), 120.4 (Ph C-4), 120.0 (Ph C-2,6), 88.4 (C-4, ²J(C-4,H-5) = 5.0 Hz), 20.4 (CH₃, ¹J = 130.7 Hz).

¹⁵N NMR (50 MHz, CDCl₃) [7]: δ (ppm) −99.2 (N-2), −179.3 (N-1).

MS (m/z, %) [8]: 362 (M⁺, 1), 360 (M⁺, 3), 358 (M⁺, 1), 320 (28), 318 (60), 316 (28), 157 (26), 155 (25), 76 (29), 75 (30), 43 (100).

Elemental Analysis: Calculated for C₁₁H₈Br₂N₂O₂ (360.00): C, 36.70%; H, 2.24%; N, 7.78%. Found: C, 36.82%; H, 2.19%; N, 7.76%.