4-chloro-3,5-dimethylphenol

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:; See reaction.notes.procedure_details.

Procedure: This compound is prepared from compound E6 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.33 min, ES+: 933.35.

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

Procedure: This compound is prepared from compound E2 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.27 min, ES+: 821.24.

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

Procedure: This compound is prepared from compound E2 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.27 min, ES+: 821.24.

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

Procedure: To a 1 L round-bottom flask 4-chloro-3,5-dimethylphenol 63 (20 g, 127.7 mmol) and acetone (500 mL, 0.2 M) was placed. To this solution were added potassium carbonate (35.3 g, 255.4 mmol) and iodomethane (63.44 g, 447 mmol). The reaction was stirred and heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 4-chloro-3,5-dimethylphenyl methyl ether 64 (16.88 g, 77%). 1HNMR (300 MHz, CDCl3): δ 2.41 (s, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 3.82 (s, 3H), 4.06 (s, 3H), 4.11 (s, 2H), 5.97 (d, 1H), 6.44 (s, 1H), 6.70 (s, 1H), 7.15 (d, 1H), 8.41 (brd, 1H), 10.31 (brd, 1H), APCI-MS m/z 468.2 (M+H)+. heated to reflux for 3 hours extracted with ethyl acetate The separated organic layer was washed with brine dried over magnesium sulfate concentrated The crude product was purified by silica gel chromatography eluted with hexane

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

Procedure: To a 1 L round-bottom flask 4-chloro-3,5-dimethylphenol 63 (20 g, 127.7 mmol) and acetone (500 mL, 0.2 M) was placed. To this solution were added potassium carbonate (35.3 g, 255.4 mmol) and iodomethane (63.44 g, 447 mmol). The reaction was stirred and heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 4-chloro-3,5-dimethylphenyl methyl ether 64 (16.88 g, 77%). 1HNMR (300 MHz, CDCl3): δ 2.41 (s, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 3.82 (s, 3H), 4.06 (s, 3H), 4.11 (s, 2H), 5.97 (d, 1H), 6.44 (s, 1H), 6.70 (s, 1H), 7.15 (d, 1H), 8.41 (brd, 1H), 10.31 (brd, 1H), APCI-MS m/z 468.2 (M+H)+. heated to reflux for 3 hours extracted with ethyl acetate The separated organic layer was washed with brine dried over magnesium sulfate concentrated The crude product was purified by silica gel chromatography eluted with hexane

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

Procedure: The general procedure described in Example 3 was used with 4-chloro-3,5-dimethyl-phenol (156 mg, 1.00 mmol), 4-phenoxathiineboronic acid (293 mg, 1.20 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (3.0 mL), 12 h, 100° C. The product was isolated as a colorless oil (277 mg, 85%), which became a white solid upon standing. Mp=116° C. 1H NMR (400 MHz, CDCl3) δ: 7.20 (m, 2H), 7.01-7.16 (m, 3H), 6.96 (d, 1H, J=7.6 Hz), 6.73 (m, 3H), 5.64 (s, 1H), 2.04 (s, 6H). 13C NMR (125 MHz, CDCl3) δ: 154.6, 152.6, 149.9, 138.3, 130.2, 129.9, 129.5, 127.8, 126.8, 126.1, 124.7, 124.6, 121.2, 121.1, 118.2, 114.2, 20.9. IR (neat, cm−1): 3367, 1593, 1471, 1419, 1311, 1265, 1223, 1154, 1026, 752. Anal. Calcd for C20H16O2S: C, 74.97; H, 5.03. Found: C, 74.88; H, 4.99.

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-chloro-3,5-dimethylphenol (16 g, 0.1 mole) in dichloromethane (100 ml) was stirred and cooled to 2° C. in an ice bath. Titanium tetrachloride (35 g, 0.18 mole) was added dropwise over a period of 10 minutes and dichloromethylmethyl ether (11.5 g, 0.1 mole) was added slowly to the dark red solution, the temperature being kept below 10° C. throughout. After the solution had been stirred at 5° C. for 30 minutes the temperature was allowed to rise and to remain at 20° C. for 30 minutes. Finally the solution was warmed at 35° C. for 15 minutes and then poured into ice water (200 ml). The mixture was shaken vigorously until almost colourless and then the dichloromethane layer was separated and the aqueous phase was extracted with more dichloromethane (2×50 ml). The combined organic layers were washed with water thoroughly (4×200 ml) and then dried over anhydrous magnesium sulphate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure using a rotary evaporator. The product, 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde was isolated as a white solid (13 g, 70%), mp 89°-90° C. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.40 (3H, s); 2.64 (3H, s); 6.71 (1H, s); 10.23 (1H, s); 11.91 (1H, s). being kept below 10° C. to remain at 20° C. for 30 minutes Finally the solution was warmed at 35° C. for 15 minutes was separated the aqueous phase was extracted with more dichloromethane (2×50 ml) The combined organic layers were washed with water thoroughly (4×200 ml) dried over anhydrous magnesium sulphate The drying agent was removed by filtration the filtrate was concentrated under reduced pressure a rotary evaporator

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-3,5-dimethyl-phenol (20.0 g, 128 mmol) was dissolved in glacial acid (150 ml) and the solution was cooled to 5° C. Then nitric acid 65% (12.4 g, 128 mmol) was added dropwise while temperature was kept below 20° C. by external cooling. After the addition was complete stirring was continued for 1 hour at ambient temperature. The reaction mixture was poured into ice/water (1:1, 500 g) whereupon an orange solid precipitated. The solid was filtered off, washed with water and dried. Yield: 23.2 g (90.1%). 1H-NMR (DMSO-d6): δ=11.0 (s, 1H); 6.9 (s, 1H); 2.3 (s, 3H); 2.2 ppm (s, 3H). was kept below 20° C. by external cooling After the addition precipitated The solid was filtered off washed with water dried

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-3,5-dimethyl-phenol (20.0 g, 128 mmol) was dissolved in glacial acid (150 ml) and the solution was cooled to 5° C. Then nitric acid 65% (12.4 g, 128 mmol) was added dropwise while temperature was kept below 20° C. by external cooling. After the addition was complete stirring was continued for 1 hour at ambient temperature. The reaction mixture was poured into ice/water (1:1, 500 g) whereupon an orange solid precipitated. The solid was filtered off, washed with water and dried. Yield: 23.2 g (90.1%). 1H-NMR (DMSO-d6): δ=11.0 (s, 1H); 6.9 (s, 1H); 2.3 (s, 3H); 2.2 ppm (s, 3H). was kept below 20° C. by external cooling After the addition precipitated The solid was filtered off washed with water dried