A Mild Strategy for the Preparation of Phenols via the Ligand-Free Copper-Catalyzed O-Arylation of para-Toluenesulfonic Acid

Abstract

A facile and simple ligand-free copper-catalyzed reaction to synthesize substituted phenols is reported. The reaction presumably proceeds via an O-arylsulfonate intermediate that is hydrolyzed to afford good to excellent yields of up to 88%. This protocol provides an alternative to existing reports which use strong hydroxide salts as the direct hydroxylation partner. Demonstrating a wide substrate scope and functional group tolerance, this protocol can also be applied to inexpensive and commercially available carboxylic acids to yield phenols.

Key words

phenol - copper - ligand-free - water - p-toluenesulfonic acid

• References and Notes


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• 16 General Procedure for the Synthesis of Substituted Phenols via O-Arylation of p-Toluenesulfonic Acid: A mixture of Cu₂O (Sigma-Aldrich, 99.99% purity, 0.147 mmol), Cs₂CO₃ (2.94 mmol), distilled H₂O (0.2 mL), aryl halide (1.47 mmol) and p-toluenesulfonic acid (TsOH) solution (0.3 mL, 2.45 mol/dm³) were added to a reaction vial and a screw cap was fitted to it. The reaction mixture was stirred under air in a closed system at 120 °C for 24 h, following which the heterogeneous mixture was cooled to r.t. and diluted with CH₂Cl₂. The combined organic extracts were dried with anhyd Na₂SO₄ and the solvent was removed under reduced pressure. The crude product was loaded onto the silica gel column using minimal amounts of CH₂Cl₂ and was purified by silica gel column chromatography to afford the N-arylated product. Phenol (2a): Following the general procedure using p-toluenesulfonic acid solution (0.3 mL, 2.45 mol/dm³) and iodobenzene (0.165 mL, 1.47 mmol), the product (122 mg, 89% yield) was obtained as a colorless oil after purification by flash chromatography (hexane–EtOAc, 80:20). ¹H NMR (400 MHz, CDCl₃): δ = 7.23 (t, J = 8.6 Hz, 2 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 2 H), 5.67 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.3, 129.7, 120.9, 115.3. GC–MS: t _R = 4.91 min, M/Z = 94. HRMS: m/z [M⁺] calcd for C₆H₆O: 95.0495; found: 95.0500. 2-Fluorophenol (2b): Following the general procedure using p-toluenesulfonic acid solution (0.3 mL, 2.45 mol/dm³) and 2-fluoroiodobenzene (0.172 mL, 1.47 mmol), the product (66 mg, 40% yield) was obtained as a colorless oil after purification by flash chromatography (hexane–EtOAc, 80:20). ¹H NMR (400 MHz, CDCl₃): δ = 7.02–7.17 (m, 3 H), 6.85–6.90 (m, 1 H), 5.59 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 151.1 (J = 236.2 Hz), 143.4 (J = 14.5 Hz), 124.8 (J = 3.1 Hz), 120.9 (J = 6.1 Hz), 117.4 (J = 2.2 Hz), 115.5 (J = 17.5 Hz). HRMS: m/z [M⁺] calcd for C₆H₅OF: 113.0400; found: 113.0393. 2′-Hydroxyacetophenone (2c): Following the general procedure using p-toluenesulfonic acid solution (0.3 mL, 2.45 mol/dm³) and 2′-iodoacetophenone (0.210 mL, 1.47 mmol), the product (140 mg, 70% yield) was obtained as a colorless oil after purification by flash chromatography (hexane–EtOAc, 90:10). ¹H NMR (400 MHz, CDCl₃): δ = 12.26 (br s, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.45 (t, J = 8.4 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.89 (t, J = 8.0 Hz, 1 H), 2.61 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.5, 162.3, 136.4, 130.7, 119.7, 118.9, 118.3, 26.6. HRMS: m/z [M⁺] calcd for C₈H₈O₂: 137.0600; found: 137.0598. O-Cresol (2d): Following the general procedure using p-toluenesulfonic acid solution (0.3 mL, 2.45 mol/dm³) and 2-methyliodobenzene (0.188 mL, 1.47 mmol), the product (48 mg, 30% yield) was obtained as a colorless oil after purification by flash chromatography (hexane–EtOAc, 85:15). ¹H NMR (400 MHz, CDCl₃): δ = 7.09–7.17 (m, 2 H), 6.89 (t, J = 7.2 Hz, 1 H), 6.79 (d, J = 7.6 Hz, 1 H), 4.88 (br s, 1 H), 2.28 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.7, 131.0, 127.1, 123.8, 120.8, 114.9, 15.7. HRMS: m/z [M⁺] calcd for C₇H₈O: 109.0651; found: 109.0655.