Molecules 2015, 20
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amount of the starting material (5.6%). 4-Hydroxy-2-methylbenzaldehyde (5): Appearance: White
solid. Mp = 106–108 °C. TLC: Rf = 0.1 (hexane/AcOEt, 9:1). HPLC (H2O/MeCN from 95:5 to 0:100
1
over 8 min): tR = 4.1 min. H-NMR (C3D6O) δ 10.1 (1H, s), 9.21 (1H, s), 7.71 (1H, d, J = 8.4 Hz),
13
6.86–6.81 (1H, m), 6.78–6.74 (1H, m), 2.58 (4H, s) ppm. C-NMR (C3D6O) δ 191.3, 162.9, 144.0,
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135.7, 128.3, 119.1, 114.1, 19.7 ppm. IR (ATR, Smart orbit): v = 3118.7, 1657.5, 1556.0, 1307.4
(max) cm−1.
3.3.3. Entry 3
Reaction of 3-methoxyphenol (352 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl methyl
ether (320 μL, 3.54 mmol) and DCM (10 mL) gave an orange solid. The mixture of regioisomers was
chromatographed on SiO2 (hexane/AcOEt, 8:2) to yield 4-hydroxy-2-methoxy- benzaldehyde (8)
(81.1 mg, 17%) and a mixture of inseparable products: 6-hydroxy-2-methoxy- benzaldehyde (6) and
1
2-hydroxy-4-methoxybenzaldehyde (7) in a 1:3.2 ratio determined by H-NMR (212.7 mg of the
mixture was obtained, 44% yield of the formylation reaction). 4-Hydroxy-2-methoxybenzaldehyde (8):
Appearance: White solid. Mp = 155–157 °C. TLC: Rf = 0.1 (hexane/AcOEt, 8:2). HPLC (H2O/MeCN
from 95:5 to 0:100 over 8 min): tR = 4.4 min. 1H-NMR (C3D6O) δ 10.2 (1H, s), 9.35 (1H, s), 7.64 (1H,
d, J = 8.5 Hz), 6.57 (1H, d, J = 2.1 Hz), 6.53 (1H, ddd, J = 8.5, 2.1, 0.6 Hz), 3.91 (3H, s) ppm.
13C-NMR (C3D6O) δ 186.4, 164.7, 164.1, 129.7, 118.1, 108.2, 98.8, 55.2 ppm. IR (ATR, Smart orbit):
v = 3137.8, 1654.3, 1634.6, 1569.3 (max) cm−1.
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3.3.4. Entry 4
Reaction of 3,5-dimethylphenol (395.8 mg, 3.24 mmol), TiCl4 (790 μL, 7.21 mmol), dichloromethyl
methyl ether (330 μL, 3.65 mmol) and DCM (10 mL) gave an orange solid which was
chromatographed on SiO2 (hexane/AcOEt, 9:1) to yield 2-hydroxy-4,6-dimethylbenzaldehyde (9)
(318.2 mg, 65%) and 4-hydroxy-2,6-dimethylbenzaldehyde (10) (61.7 mg, 13%). The ratio of the
products 9:10 was 5:1 and the global yield 78%. 2-Hydroxy-4,6-dimethylbenzaldehyde (9):
Appearance: Pale yellow solid. Mp = 48–50 °C. TLC: Rf = 0.77 (hexane/AcOEt, 8:2). HPLC
(H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 5.1 min. 1H-NMR (CDCl3) δ 11.9 (1H, m), 10.2 (1H, m),
6.62 (1H, s), 6.53 (1H, m), 2.55 (3H, s), 2.30 (3H, s) ppm. 13C-NMR (100 MHz, CDCl3) δ 194.7, 163.6,
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149.4, 142.0, 123.3, 116.7, 116.3, 77.5, 77.2, 76.8, 22.3, 18.1 ppm. IR (ATR, Smart orbit): v = 2879.8,
1640.8, 1625.6 (vmax), 1567.2 cm−1. 4-Hydroxy-2,6-dimethylbenzaldehyde (10): Appearance: White
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solid. Mp = 195–197 °C. TLC: Rf = 0.23 (hexane/AcOEt, 8:2). HPLC (H2O/MeCN from 95:5 to 0:100
over 8 min): tR = 6.9 min. 1H-NMR (C3D6O) δ 10.4 (1H, s), 6.60 (2H, s), 2.54–2.53 (6H, m). 13C-NMR
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(C3D6O) δ 206.1, 191.7, 145.3, 126.2, 117.2, 21.0 ppm. IR (ATR, Smart orbit): v = 3138.5, 1649.9,
1602.3, 1555.7, 1313.9, 1151.3 (v max) cm−1.
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3.3.5. Entry 5
Reaction of 3,5-dimethoxyphenol (502.8 mg, 3.26 mmol), TiCl4 (790 μL, 7.21 mmol),
dichloromethyl methyl ether (330 μL, 3.65 mmol) and DCM (10 mL) afforded an orange solid, which
was chromatographed on SiO2 (hexane/AcOEt, 9:1) to yield 6-hydroxy-2,4-dimethoxybenzaldehyde