2,4-dihydroxy-6-methylbenzaldehyde

Conditions: temp:22.01; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250-mL round-bottom flask were placed a solution of 2,4-dihydroxy-6-methylbenzaldehyde (2.0 g, 13.16 mmol, 1.00 equiv) in dichloromethane (50 mL), 3,4-dihydro-2H-pyran (1.65 g, 19.64 mmol, 1.49 equiv) and pyridinium p-toluenesulfonate (330 mg, 1.31 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature. Then it was diluted with 100 mL of dichloromethane and washed with 3×20 mL of 1 M sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.8 g (52%) of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde as a yellow oil. Into a 250-mL round-bottom flask were placed washed with 3×20 mL of 1 M sodium carbonate solution The organic layer was dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 1.8 g (52%) of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde as a yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A light yellow suspension of 2,4-dihydroxy-6-methyl-benzaldehyde (4.90 g, 24.98 mmol) in DCM (400 mL) was treated with 3,4-dihydro-2H-pyran (3.5 mL, 38.61 mmol) followed by pyridinium-p-toluenesulfonate (0.20 g, 0.80 mmol). The suspension slowly cleared to a yellow solution. The solution was stirred at rt overnight then diluted with water and washed with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (4.60 g, 70%), as a light yellow liquid. 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 1H), 10.09 (s, 1H), 6.45 (d, J=2 Hz, 1H), 6.08 (d, J=2 Hz, 1H), 5.49-5.40 (m, 1H), 3.90-3.80 (m, 1H), 3.65-3.60 (m, 1H), 2.52 (s, 3H), 2.10-1.40 (m, 6H). washed with saturated NaHCO3 The organic layer was dried (Na2SO4) filtered concentrated to a yellow oil The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2,4-dihydroxy-6-methyl-benzaldehyde (6.37 g, 37.88 mmol) in dichloromethane (150 mL) was added 3,4-dihydro-2H-pyran (4.78 g, 56.82 mmol) and pyridium p-toluenesulfonic acid (1.90 g, 7.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours then quenched by adding saturated NaHCO3 at 0° C. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:3) to give pure product (8.78 g, 98.1%). 1H NMR (400 MHz, CDCl3) δ ppm 12.33 (s, 1H), 10.11 (s, 1H), 6.47 (s, 1H), 6.39 (s, 1H), 5.49 (t, J=3.13 Hz, 1H), 3.78-3.90 (m, 1H), 3.52-3.72 (m, 1H), 2.54 (s, 3H), 1.77-2.03 (m, 3H), 1.53-1.70 (m, 3H); MS (ESI) m/z=285 [M+H]+. then quenched by adding saturated NaHCO3 at 0° C The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Dihydroxy-6-methylbenzaldehyde (91 mg, 0.60 mmol) described in M. M. Joullie et al., J. Org. Chem., 50, 3997 (1985), dodecanal (133 mg, 0.72 mmol) and calcium chloride dihydrate (59 mg, 0.40 mmol) were stirred in a 0.4 M potassium hydroxide methanol solution (2 ml) at 0° C. for 24 hours. The reaction mixture was made acidic with 1 M hydrochloric acid. After extractive workup with ethyl acetate, the crude product was purified by silica gel thin-layer chromatography (hexane:ethyl acetate=3:1) to obtain 2,4-dihydroxy-3-(1-hydroxydodecyl)-6-methylbenzaldehyde (58 mg, yield 28%). After extractive workup with ethyl acetate, the crude product was purified by silica gel thin-layer chromatography (hexane:ethyl acetate=3:1)