2,6-dichloro-4-methylphenol

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sol. of 2,6-dichloro-p-cresol (0.55 mmol; 97 mg) in toluene (4.8 mL) was treated with compound E9 (0.37 mmol; 250 mg) followed by azodicarboxylic dipiperidide (0.73 mmol; 184 mg) and PBu3 (1.28 mmol; 0.27 mL). The reaction mixture was stirred at 80° C. After 1 h, the reaction mixture was allowed to cool to rt, diluted with Et2O (50 mL), filtrated, and the filtrate was washed with NaOH 1M (50 mL) and brine (50 mL). The org. extract was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.23 g, 76%). LC-MS: tR=1.25 min; ES+: 843.29. to cool to rt filtrated the filtrate was washed with NaOH 1M (50 mL) and brine (50 mL) extract was dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 30:70)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sol. of 2,6-dichloro-p-cresol (0.55 mmol; 97 mg) in toluene (4.8 mL) was treated with compound E9 (0.37 mmol; 250 mg) followed by azodicarboxylic dipiperidide (0.73 mmol; 184 mg) and PBu3 (1.28 mmol; 0.27 mL). The reaction mixture was stirred at 80° C. After 1 h, the reaction mixture was allowed to cool to rt, diluted with Et2O (50 mL), filtrated, and the filtrate was washed with NaOH 1M (50 mL) and brine (50 mL). The org. extract was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.23 g, 76%). LC-MS: tR=1.25 min; ES+: 843.29. to cool to rt filtrated the filtrate was washed with NaOH 1M (50 mL) and brine (50 mL) extract was dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 30:70)

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

Procedure: A mixture of 2-(thiazol-2-yloxy)ethanol (6.39 g, 44.0 mmol), 2,6-dichloro-p-cresol (15.6 g, 88.0 mmol), azodicarboxylic-dipiperidide (22.2 g, 88.0 mmol) and PBu3 (85%, 38.3 mL, 132 mmol) in toluene (325 mL) was heated to reflux for 30 min. The mixture was allowed to cool to rt, filtered, and the precipitate was washed thoroughly with toluene. The filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and washed with aq. 1M NaOH (4×). The org. phase was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:19→1:9→1:4) yielded the title compound as a colourless solid (9.24 g, 69%). LC-MS: tR=1.06 min, ES+: 304.05. was heated to reflux for 30 min filtered the precipitate was washed thoroughly with toluene The filtrate was evaporated under reduced pressure The residue was diluted with EtOAc washed with aq. 1M NaOH (4×) phase was dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the crude by FC (EtOAc/heptane 1:19→1:9→1:4)

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

Procedure: 4-Methyl-2,6-dichlorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield the titled compound (4.66 g, 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3H) 3.70 (d, J=7.20 Hz, 2H) 4.29 (d, J=7.20 Hz, 2H) 7.11 (s, 2H).

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

Procedure: 4-Methyl-2,6-dichlorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield the titled compound (4.66 g, 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3H) 3.70 (d, J=7.20 Hz, 2H) 4.29 (d, J=7.20 Hz, 2H) 7.11 (s, 2H).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of compound 4-[4-(2-Hydroxyethoxy)phenyl]piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (5.50 g, 15 mmol), 2,6-dichloro-p-cresol (3.08 g, 18 mmol), azodicarboxylic dipiperidine (7.31 g, 29 mmol) and PBu3 (14 mL, 58 mmol) in toluene (150 mL) was heated to 50° C. for 16 h. The mixture was allowed to cool to rt, filtered, and the precipitate was washed with toluene. The filtrate was diluted with EtOAc, and washed with water (2×) and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 0:1→1:9→2:8) yielded the compound as a colorless oil (7.3 g, 90%). LC-MS: tR=1.18 min, ES+=538.34. to cool to rt filtered the precipitate was washed with toluene The filtrate was diluted with EtOAc washed with water (2×) and brine layer was dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the crude by FC (EtOAc/heptane 0:1→1:9→2:8)

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

Procedure: 12 g (67 mmol) of 2,6-dichloro-4-methylphenol are dissolved in 25 ml of 2-propanol followed by the addition of 10.5 g (76 mmol) of potassium carbonate and 12.8 g (70 mmol) of 2-chloro-N-(4-methylphenyl)acetamide. The mixture is refluxed for 4 h. At this time, the formation of A: 2-(2′,6′-dichloro-4′-methylphenoxy)-N-(4-methylphenyl)acetamide is completed. 13.6 ml of sodium methylate solution 30% in methanol are slowly added and the temperature is increased to about 85° C. by distilling 25 ml of solvent. The mixture is stirred 2 h more to complete the formation of B. 25 ml of water are added at 70° C. to obtain a 2 phases solution. The lower layer is discarded. The upper layer is diluted with 20 ml of heptane-fraction and washed with 2×20 ml of water. The organic phase is separated and concentrated in vacuo to obtain N-(2′,6′-dichloro-4′-methylphenyl)-4-methylaniline as a crude oil. GC/MS: 265 (100, M+), 195 (130). The mixture is refluxed for 4 h by distilling 25 ml of solvent 25 ml of water are added at 70° C. to obtain a 2 phases solution washed with 2×20 ml of water The organic phase is separated concentrated in vacuo

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

Procedure: 12 g (67 mmol) of 2,6-dichloro-4-methylphenol are dissolved in 25 ml of 2-propanol followed by the addition of 10.5 g (76 mmol) of potassium carbonate and 12.8 g (70 mmol) of 2-chloro-N-(4-methylphenyl)acetamide. The mixture is refluxed for 4 h. At this time, the formation of A: 2-(2′,6′-dichloro-4′-methylphenoxy)-N-(4-methylphenyl)acetamide is completed. 13.6 ml of sodium methylate solution 30% in methanol are slowly added and the temperature is increased to about 85° C. by distilling 25 ml of solvent. The mixture is stirred 2 h more to complete the formation of B. 25 ml of water are added at 70° C. to obtain a 2 phases solution. The lower layer is discarded. The upper layer is diluted with 20 ml of heptane-fraction and washed with 2×20 ml of water. The organic phase is separated and concentrated in vacuo to obtain N-(2′,6′-dichloro-4′-methylphenyl)-4-methylaniline as a crude oil. GC/MS: 265 (100, M+), 195 (130). The mixture is refluxed for 4 h by distilling 25 ml of solvent 25 ml of water are added at 70° C. to obtain a 2 phases solution washed with 2×20 ml of water The organic phase is separated concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Bromophenyl)ethanol (1 eq.) and 2,6-dichloro-4-methylphenol (1.5 eq.) were taken up in freshly deoxygenated toluene (0.1 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. The reaction mixture was cooled to RT washed with 1 N aq. NaOH The aqueous wash was back extracted with ether the combined organic extracts were dried over MgSO4 Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloro-4-methylphenol (1 eq.), ethylene carbonate (1 eq.) and imidazole (0.5% loading) were combined and heated at 150° C. for 4 h to afford the title compound as a brown oil.