A Three-Step Preparation of 3-Isopropylcatechol

References

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• The preparation of 2-[2,3-dimethoxyphenyl]-propan-2-ol (5). To a solution of 10.3 g of veratrole (4) (74.6 mmol) in 50 mL of anhydrous THF cooled to −78 °C was slowly added 31.3 mL of n-BuLi (2.5 M in hexanes, 78.4 mmol). The mixture was stirred at 0 °C for a three-hour period. [A light yellow precipitate was observed.] The mixture was then cooled to −60 °C and anhydrous acetone (2.20 g, 37.7 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature over a three-hour period. The reaction was quenched with saturated aqueous ammonium chloride, followed by standard ethereal workup. Silica gel column chromatography [elution with hexanes: ether, 1:1, Rf (5) = 0.50, Rf (4) = 0.970] afforded 3.0 g of unreacted veratrole and 9.5 g (65%) of alcohol 5 which was homogeneous by TLC analysis: bp 100–102 °C at 0.50 mm of Hg; 1H NMR (250 MHz, CDCl3) δ 1.63 (s, 6 H), 3.87 (s, 3 H), 3.97 (s, 3 H), 6.86 (dd, 1 H, J=2 Hz), 6.93 (d, 1 H, J = 2 Hz), 7.02 (t, 1 H, J = 8Hz); 13C NMR (62.7 MHz, CDCl3) 30.7 (q), 55.7 (q), 60.9 (q), 72.7 (s), 111.6 (d), 117.9 (d), 123.6 (d), 141.1 (s), 146.7 (s), 152.6 (s) ppm; IR (film) 3447 cm−1; C, H analysis: Calculated for C11H16O3: C, 6.72; H, 8.22. Found: C, 67.33; H, 8.26 (Atlantic Microlabs, Atlanta, GA).
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• The preparation of 3-isopropylveratrole (2). A mixture of 9.5 g (48.5 mmol) of 5 dissolved in 50 mL of anhydrous ethanol, 5 mL of 85% phosphoric acid and 1 g of 5% Pd on active carbon was hydrogenated under three atmospheres of hydrogen at 60 °C for 6 hours using a Parr shaker. The catalyst was removed by filtration and the filtrate was concentrated. The residue was extracted with 200 mL of ether, washed with saturated aqueous sodium carbonate, dried over anhydrous magnesium sulfate, concentrated and chromatographed on silica gel [elution with hexanes:ether, 4:1] to afford 8.4g (97%) of 2 which was homogeneous by TLC analysis [hexanes: ether, 1:1; Rf(5) = 0.05, Rf(2) = 0.85]: bp 70–72 °C at 0.60 mm of Hg; 1H NMR (250 MHz, CDCl3) δ 1.24 (d, 6 H, J = 7 Hz), 3.36 (m, 1 H), 3.84 (s, 3 H), 3.90 (s, 3 H), 6.78 (d, 1 H, J = 1.5 Hz), 6.87 (d, 1 H, J = 1.5 Hz), 7.07 (t, 1 H, J = 8 Hz); 13C NRM (62.7 MHz, CDCl3) 23.5 (q), 26.6 (d), 55.6 (q), 60.8 (q), 109.6 (d), 118.2 (d), 124.0 (d), 142.5 (s), 146.2 (s), 152.6 (s) ppm; C, H analysis: Calculated for C11h16O2: C, 73.30; H, 8.95. Found: C, 73.01; H, 9.04 (Atlantic Microlabs, Atlanta, GA).
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• The preparation of 3-isopropylcatechol (1). A mixture of 1.1 g of 2, 10 mL acetic acid and 12 mL of HBr (48% aqueous) was refluxed for a four-hour period. The mixture was neutralized by the cautious addition of saturated aqueous sodium carbonate. The resulting mixture was extracted with ether (2 × 100 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield 0.97 g of crude residue. Purification of the crude catechol on silica gel afforded 0.64 g (96%) of 1 which was homogeneous by TLC analysis [hexanes: either, 1:1, Rf (1) = 0.65]: mp 44–49 °C; 1H NRM (250 MHz, CDCl3) δ 1.27 (d, 6 H, J = 7 Hz), 3.25 (heptet, J = 7 Hz), 5.30 (broad singlet), 6.62–6.90 (m, 3 H); 13C NMR (62.7 M Hz, CDCl3) 22.5 (q), 27.0 (d), 112.6 (d), 118.4 (d), 120.2 (d), 135.1 (s), 141.2 (s), 142.7 (s) ppm; IR (film) 3496 cm−1
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