4-methylbenzene-1,3-diol

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

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

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

Procedure: A solution of 2,4-dihydroxytoluene (10.0 g) in ethylacetoacetate (12 ml) was poured in small portion into conc. H2SO4 (26 ml), chilling in an ice bath. After the addition was completed the solid obtained was separated by filtration, washed several times with water up to neutrality of the washings, dried and crystallized from MeOH, yielding 4,6-dimethyl-7-hydroxycoumarin (III) (10.64 g; m.p. 273° C.). ##STR9## chilling in an ice bath After the addition obtained was separated by filtration washed several times with water up to neutrality of the washings dried crystallized from MeOH

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

Procedure: The starting material 2,4-dihydroxytoluene was prepared by adding boron tribromide (3.1 ml, 3.2 mmol) to a solution of 2,4-dimethoxytoluene (1 g, 6.5 mmol) in pentane (10 ml) at −70° C. The reaction mixture was allowed to warm to ambient temperature and the mixture stirred for a further 2 hours. Ice water and ethyl acetate were then added and the aqueous layer basified to pH9.5 with 2M aqueous sodium hydroxide solution. After stirring for 10 minutes, the organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/ethyl acetate (9/1) to give 2,4-dihydroxytoluene (759 mg, 94%) as a white solid. The starting material 2,4-dihydroxytoluene was prepared After stirring for 10 minutes the organic layer was separated the aqueous layer extracted with ethyl acetate The combined organic extract was washed with brine dried (MgSO4) the solvent removed by evaporation The residue was purified by flash chromatography eluting with methylene chloride/ethyl acetate (9/1)

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

Procedure: The starting material 2,4-dihydroxytoluene was prepared by adding boron tribromide (3.1 ml, 3.2 mmol) to a solution of 2,4-dimethoxytoluene (1 g, 6.5 mmol) in pentane (10 ml) at −70° C. The reaction mixture was allowed to warm to ambient temperature and the mixture stirred for a further 2 hours. Ice water and ethyl acetate were then added and the aqueous layer basified to pH9.5 with 2M aqueous sodium hydroxide solution. After stirring for 10 minutes, the organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/ethyl acetate (9/1) to give 2,4-dihydroxytoluene (759 mg, 94%) as a white solid. The starting material 2,4-dihydroxytoluene was prepared After stirring for 10 minutes the organic layer was separated the aqueous layer extracted with ethyl acetate The combined organic extract was washed with brine dried (MgSO4) the solvent removed by evaporation The residue was purified by flash chromatography eluting with methylene chloride/ethyl acetate (9/1)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Methylresorcinol (25.8 g, 0.208 mol) and succinic anhydride (20.8 g, 0.208 g) were placed in a round bottom flask and the flask was purged with nitrogen. Methanesulfonic acid (150 mL) was added and the solution heated under nitrogen to 65° C. for 2 hours. The solution was added dropwise to 1 L of rapidly stirred, ice-cooled water with the simultaneous addition of 50% aq sodium hydroxide to maintain the pH at 2.25+/-0.25. The product was collected by centrifugation and washed with water (3×) and acetone (2×). The solid was air-dried, then vacuum-dried at 110° C. to afford a brick-red powder (24.1 g, 74%). the flask was purged with nitrogen Methanesulfonic acid (150 mL) was added The solution was added dropwise to 1 L ice-cooled water with the simultaneous addition of 50% aq sodium hydroxide to maintain the pH at 2.25+/-0.25 The product was collected by centrifugation washed with water (3×) and acetone (2×) The solid was air-dried vacuum-dried at 110° C.

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

Procedure: 2,4-Dihydroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3 L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3 mL) and the mixture was sparged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson, J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), and 9.008 (s, OH). fitted with a gas inlet and a bubbler outlet the mixture was sparged with nitrogen the catalyst was removed by filtration was added The solution was washed with 4×200 mL of water the combined water extracts back-extracted with ethyl acetate washed the combined organic layers dried over sodium sulfate

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

Procedure: 2,4-Dihydroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3 L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3 mL) and the mixture was sparged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson, J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), and 9.008 (s, OH). fitted with a gas inlet and a bubbler outlet the mixture was sparged with nitrogen the catalyst was removed by filtration was added The solution was washed with 4×200 mL of water the combined water extracts back-extracted with ethyl acetate washed the combined organic layers dried over sodium sulfate

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

Procedure: Alkylation of 4-methylbenzene-1,3-diol using (bromomethyl)cyclohexane following the method used in Example 154 gave 5-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. Yield (0.15 g, 8.5%): 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.4 Hz, 1H), 6.36-6.41 (m, 2H), 3.68 (d, J=6.4 Hz, 2H), 2.16 (s, 3H), 1.64-1.89 (m, 6H), 1.14-1.34 (m, 3H), 0.96-1.08 (m, 2H).

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Methylresorcinol (25.8 g, 0.208 mol) and succinic anhydride (20.8 g, 0.208 g) were placed in a round bottom flask and the flask was purged with nitrogen. Methanesulfonic acid (150 mL) Was added and the solution heated under nitrogen to 65° C. for 2 hours. The solution was added dropwise to 1 L of rapidly stirred, ice-cooled water with the simultaneous addition of 50% aq sodium hydroxide to maintain the pH at 2.25±0.25. The product was collected by centrifugation and washed with water (3×) and acetone (2×). The solid was air-dried, then vacuum-dried at 110° C. to afford a brick-red powder (24.1 g, 74%). the flask was purged with nitrogen Methanesulfonic acid (150 mL) Was added The solution was added dropwise to 1 L ice-cooled water with the simultaneous addition of 50% aq sodium hydroxide to maintain the pH at 2.25±0.25 The product was collected by centrifugation washed with water (3×) and acetone (2×) The solid was air-dried vacuum-dried at 110° C.

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

Procedure: 2,4-Dihydroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3 L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3 mL) and the mixture was sparged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson, J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), and 9.008 (s, OH). fitted with a gas inlet and a bubbler outlet the mixture was sparged with nitrogen the catalyst was removed by filtration was added The solution was washed with 4×200 mL of water the combined water extracts back-extracted with ethyl acetate washed the combined organic layers dried over sodium sulfate

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

Procedure: Alkylation of 4-methylbenzene-1,3-diol using (bromomethyl)cyclohexane following the method used in Example 154 gave 5-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. Yield (0.15 g, 8.5%): 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.4 Hz, 1H), 6.36-6.41 (m, 2H), 3.68 (d, J=6.4 Hz, 2H), 2.16 (s, 3H), 1.64-1.89 (m, 6H), 1.14-1.34 (m, 3H), 0.96-1.08 (m, 2H).