A Convenient Synthesis of Tri- and Tetramethylbenzaldehydes from Readily Available Phenols

Abstract

This letter describes a convenient synthesis of the six isomeric tri- and tetramethylbenzaldehydes, which are not readily available from major chemical suppliers. Formylation of readily available phenols via electrophilic aromatic substitution provides compounds containing the correct aromatic substitution pattern. ­Suzuki cross-coupling of the corresponding trifluoromethanesulfonates with methylboronic acid then provides the benzaldehydes as single isomers.

Key words

aldehydes - palladium - Suzuki - aromatic compounds - formylation

• References and Notes

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• 21 General Procedure for Formylation Aluminium trichloride (4.82 g, 36 mmol) was added to a solution of phenol (33 mmol) in anhydrous CH₂Cl₂ (50 mL) under argon, and the solution was stirred for 10 min. Dichloromethyl methyl ether (3.3 mL, 36 mmol) was added dropwise via a syringe pump (7.7 mL/h). The reaction was left to stir for a further 10 min before cold H₂O (200 mL) was added slowly. After stirring for a further 10 min, the organic layer was separated and washed with brine (100 mL) and H₂O (150 mL), dried over MgSO₄, filtered, and concentrated to give the aldehyde which was purified by column chromatography. 2-Hydroxy-3,5-dimethylbenzaldehyde (3) Brown viscous oil; R_f = 0.97 (EtOAc–PE, 1:1). IR: ν_max = 3201, 2921, 1646, 1467, 1260 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 11.09 (s, 1 H, OH), 9.81 (s, 1 H, CHO), 7.20 (br s, 1 H, ArH), 7.15 (s, 1 H, ArH), 2.29 (s, 3 H, Me), 2.23 (s, 3 H, Me). ¹³C NMR (150 MHz, CDCl₃): δ = 196.8 (CH), 158.0 (C_q), 139.1 (CH), 131.0 (CH), 128.6 (C_q), 126.6 (C_q), 119.9 (C_q), 20.3 (CH₃), 15.1 (CH₃). HRMS (EI): m/z calcd for C₉H₁₀O₂ [M]⁺: 150.0680; found: 150.0681.
• 22 General Procedure for Trifluoromethanesulfonate Synthesis Triethylamine (4.04 g, 40 mmol) was added to a solution of phenol (13 mmol) in anhydrous CH₂Cl₂ (13 mL) at –78 °C under argon, and the solution stirred for 30 min. Trifluoromethanesulfonic anhydride (2.5 mL, 15 mmol, 1.1 equiv) was added dropwise via a syringe pump (7.7 mL/h). The reaction was left to stir for a further 2 h. The reaction mixture was diluted with CH₂Cl₂ (15 mL) and washed with sat. NaHCO₃ (20 mL), brine (20 mL), and H₂O (20 mL), dried (MgSO₄), filtered, and concentrated to give the trifluoromethanesulfonate which was purified by column chromatography. 2-Formyl-4,6-dimethylphenyl trifluoromethane-sulfonate (4) Yellow viscous oil; R_f = 0.91 (EtOAc–PE, 1:1). IR: ν_max = 2883, 1701, 1598, 1407, 1207, 1136 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 10.19 (s, 1 H, CHO), 7.62 (d, 1 H, J = 2.0 Hz, ArH), 7.38 (d, 1 H, J = 2.0 Hz ArH), 2.42 (s, 3 H, Me), 2.40 (s, 3 H, Me). ¹³C NMR (150 MHz, CDCl₃: δ = 187.4 (CH), 145.9 (C_q), 139.1 (C_q), 138.8 (CH), 132.5 (C_q), 129.2 (C_q), 128.5 (CH), 118.4 (q, J = 321 Hz, C_q), 20.9 (CH₃), 16.5 (CH₃). HRMS (EI): m/z calcd for C₁₀H₉F₃O₄S [M]⁺: 282.0174; found: 282.0174.
• 23 General Procedure for Suzuki Cross-Coupling K₂CO₃ (397 mg, 3 mmol) and PdCl₂(dppf)·CH₂Cl₂ (116 mg, 10 mol%) were added to a solution of aryl trifluoromethane-sulfonate (1 mmol) in THF (25 mL) which was left to stir for 5 min. H₂O (HPLC grade, 1.25 mL) was added, followed by methylboronic acid (255 mg, 4 mmol). The reaction was heated at reflux overnight. EtOAc (7 mL) was added, and the organic layer was separated and washed with H₂O (2 × 10 mL), dried over MgSO₄, filtered, and concentrated to give the aldehyde which was purified by column chromatography.2,3,5-Trimethylbenzaldehyde (1a) Brown oil; R_f = 0.82 (EtOAc–PE, 1:1). IR: ν_max = 2923, 1692, 1478 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 10.28 (s, 1 H, CHO), 7.46 (s, 1 H, ArH), 7.20 (s, 1 H, ArH), 2.52 (s, 3 H, Me), 2.33 (s, 3 H, Me), 2.30 (s, 3 H, Me). ¹³C NMR (150 MHz, CDCl₃): δ = 193.5 (CH), 138.3 (C_q), 136.4 (CH), 136.3 (C_q), 135.4 (C_q), 134.3 (C_q), 130.1 (CH), 21.2 (CH₃), 20.2 (CH₃), 14.3 (CH₃). HRMS (EI): m/z calcd for C₁₀H₁₂O [M]⁺: 148.0888; found: 148.0876.