2-chloro-6-methylphenol

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

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

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

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

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hexamethylenetetramine (19.60 g, 139.8 mmol) was added in portions to a solution of 2-chloro-6-methylphenol (20.00 g, 117.2 mmol) in trifluoroacetic acid (200 mL). There was a slight exotherm and effervescence was noted. The reaction mixture was heated in an oil-bath at 84-86° C. for 5 h, then it was cooled and evaporated (˜50° C., 0.2 mm). The residue was evaporated from hexane, then ice-water (500 mL) was added and the mixture was stirred for 20 min. Ether (100 mL) was added and the reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g). The resulting mixture was extracted with ether (2×250 mL), and the ether layers were washed with brine, dried (MgSO4), filtered and concentrated to about 100 mL. The mixture was then left to crystallize over the weekend to give a solid which was filtered off and washed with ice-cold ether to give 3-chloro-4-hydroxy-5-methylbenzaldehyde (6.9 g, 35%) as a yellow solid. The mother liquor was evaporated and dichloromethane (30 mL) was added. The yellow solid was filtered off (2.9 g, 14%). The remaining solution was purified by HPLC (7% ethyl acetate/hexanes) to give a yellow solid (7.8 g, 39%). The overall yield was 17.6 g (88%). it was cooled evaporated (˜50° C., 0.2 mm) The residue was evaporated from hexane ice-water (500 mL) was added Ether (100 mL) was added the reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g) The resulting mixture was extracted with ether (2×250 mL) the ether layers were washed with brine dried (MgSO4) filtered concentrated to about 100 mL The mixture was then left to crystallize over the weekend to give a solid which was filtered off washed with ice-cold ether

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

Procedure: 178.1 g (1.25 mol) 2-chloro-6-methylphenol and 80.5 g (0.5 mol) 4-chlorobenzyl chloride are dissolved in 300 ml dry chloroform. 40 g water-free, finely mortared ZnCl2 are subsequentlyadded.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 90.4 g (0.63 mol) 2-chloro-6-methylphenol are brought to reaction with 149.4 g (0.765 mol) 3,4-dichlorobenzylchloride and 2.4 g water-free, finely mortared ZnCL2 without solvent. After stirring 5-6 h at 60° C. the reaction mixture is subsequently worked up by washing three times, each with 100 ml water. by washing three times

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 85.8 g (0.6 mol) 2-chloro-6-methylphenol and 33.8 g (0.2 mol) 4-isopropylbenzyl chloride, dissolved in 160 ml chloroform, are reacted with 18 g water-free zinc chloride. At a bath temperature of 60° C. the reaction mixture is stirred 5-6 h, and then washed three times each with 150 ml water for the purpose of removing excess zinc chloride, dried across sodium sulfate and subjected to a driving-off of the solvent chloroform in a vacuum. washed three times each with 150 ml water for the purpose of removing excess zinc chloride dried across sodium sulfate

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-chloro-6-methyl phenol (5.0 g, 0.035 mol) in ethanol (25 mL) at room temperature was treated with dimethyl amine (3.95 mL of a 40% solution of dimethylamine in water, 0.035 mol) followed by formaldehyde (2.85 mL of a 37% solution of formaldehyde in water, 0.035 mol). The reaction was heated to reflux for 24 h. At this time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oil was diluted with water (200 mL) and acidified to pH=2 by addition of a 1N aqueous hydrochloric acid solution. The water layer was extracted with ethyl acetate (300 mL). The ethyl acetate layer was discarded. The water layer was made basic to pH=10 by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate (2×350 mL). The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was dried under high vacuum overnight to afford 2-chloro-4-dimethylaminomethyl-6-methyl-phenol (2b) (4.62 g, 66%) as an off-white solid; EI(+)-HRMS m/z calcd for C10H14ClNO (M+) 199.0764, found 199.0767. Molecular Weight=199.6822; Exact Mass=199.0764 The reaction was heated to reflux for 24 h concentrated under vacuum The resulting oil was diluted with water (200 mL) acidified to pH=2 by addition of a 1N aqueous hydrochloric acid solution The water layer was extracted with ethyl acetate (300 mL) The water layer was made basic to pH=10 by the addition of a 1N aqueous sodium hydroxide solution was extracted with ethyl acetate (2×350 mL) The organics were washed with a saturated aqueous sodium chloride solution dried with magnesium sulfate filtered concentrated under vacuum The resulting oil was dried under high vacuum overnight

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

Procedure: A solution of 2-chloro-6-methyl phenol (5.0 g, 0.035 mol) in ethanol (25 mL) at room temperature was treated with dimethyl amine (3.95 mL of a 40% solution of dimethylamine in water, 0.035 mol) followed by formaldehyde (2.85 mL of a 37% solution of formaldehyde in water, 0.035 mol). The reaction was heated to reflux for 24 h. At this time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oil was diluted with water (200 mL) and acidified to pH=2 by addition of a 1N aqueous hydrochloric acid solution. The water layer was extracted with ethyl acetate (300 mL). The ethyl acetate layer was discarded. The water layer was made basic to pH=10 by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate (2×350 mL). The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was dried under high vacuum overnight to afford 2-chloro-4-dimethylaminomethyl-6-methyl-phenol (2b) (4.62 g, 66%) as an off-white solid; EI(+)-HRMS m/z calcd for C10H14ClNO (M+) 199.0764, found 199.0767. Molecular Weight=199.6822; Exact Mass=199.0764 The reaction was heated to reflux for 24 h concentrated under vacuum The resulting oil was diluted with water (200 mL) acidified to pH=2 by addition of a 1N aqueous hydrochloric acid solution The water layer was extracted with ethyl acetate (300 mL) The water layer was made basic to pH=10 by the addition of a 1N aqueous sodium hydroxide solution was extracted with ethyl acetate (2×350 mL) The organics were washed with a saturated aqueous sodium chloride solution dried with magnesium sulfate filtered concentrated under vacuum The resulting oil was dried under high vacuum overnight