1-(4-chloro-2,6-dimethylphenyl)ethanone

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 4-ethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol) and Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (6.0 g) as yellow oil in 82% yield: 1H NMR (500 MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 2 H), 6.93 (d, J=8.5 Hz, 2 H), 6.63 (s, 2 H), 2.64 (q, J=7.5 Hz, 2 H), 2.47 (s, 3 H), 2.21 (s, 6 H), 1.25 (t, J=7.5 Hz, 3 H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.00 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3-methoxyphenol (4.08 g, 32.9 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.4 g) as yellow oil in 73% yield: 1H NMR (500 MHz, CDCl3) δ 7.24 (m, 1 H), 6.68-6.66 (m, 3 H), 6.57-6.56 (m, 2 H), 3.79 (s, 3 H), 2.48 (s, 3 H), 2.22 (s, 6 H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3,5-dimethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (6.3 g) as yellow solids in 86% yield: 1H NMR (500 MHz, CDCl3) δ 6.76 (s, 1 H), 6.63 (s, 2 H), 6.62 (s, 2 H), 2.48 (s, 3 H), 2.29 (s, 6 H), 2.22 (s, 6 H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), sesamol (4.54 g, 32.9 mmol) in toluene (54.8 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was recrystallized in MeOH to give 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)ethanone (4.80 g) as white solids in 62% yield: 1H NMR (500 MHz, CDCl3) δ 6.77 (d, J=8.5 Hz, 1 H), 6.59 (s, 2 H), 6.56 (s, 1 H), 6.48 (m, 1 H), 5.98 (s, 2 H), 2.46 (s, 3 H), 2.21 (s, 6 H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was recrystallized in MeOH

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (4.50 g, 24.6 mmol), K3PO4 (10.5 g, 49.3 mmol), 4-fluorophenol (3.31 g, 29.5 mmol) in toluene (49.3 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (314 mg, 0.74 mmol), Pd(OAc)2 (233 mg, 1.04 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (100 mL), and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(4-Fluorophenoxy)-2,6-dimethylphenyl)ethanone (4.40 g) as yellow oil in 68% yield: 1H NMR (500 MHz, CDCl3) δ 7.03 (m, 2 H), 6.98 (m, 2 H), 6.60 (s, 2 H), 2.47 (s, 3 H), 2.22 (s, 6 H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (100 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (4.50 g, 24.6 mmol), K3PO4 (10.5 g, 49.3 mmol), and phenol (2.78 g, 29.5 mmol) in toluene (49.3 mL) was added 2-(di-tert-butylphosphino)biphenyl (221 mg, 0.74 mmol) and Pd(OAc)2 (233 mg, 1.04 mmol). The reaction was heated at 100° C. for 2.0 h under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl-4-phenoxyphenyl)ethanone as a yellow oil in 68% yield: 1H NMR (500 MHz, CDCl3) δ 7.35 (t, J=8.0 Hz, 2 H), 7.12 (t, J=7.5 Hz, 1 H), 7.00 (d, J=7.5 Hz, 2 H), 6.65 (s, 2 H), 2.48 (s, 3 H), 2.22 (s, 6 H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) the combined filtrate was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

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

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27 mmol) in acetonitrile (54.8 mL) was added tetrabutylammoniumtribromide (TBABr3, 13.2 g, 27.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-chloro-2,6-dimethylphenyl)ethanone (7.2 g), which was used directly for the next step without further purification. The solution was concentrated under reduced pressure added with water extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous MgSO4(s) concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous copper(II) chloride (98.9 g, 0.74 mol) was mixed with tert-butyl nitrite (94.8 g, 0.83 mol) in acetonitrile (1.02 L). The solution was cooled to 0° C. and slowly added with 1-(4-amino-2,6-dimethylphenyl)ethanone (100 g, 0.61 mol) in a period of 5.0 min. After the addition was completed, the reaction mixture was warmed to room temperature, and was poured into an aqueous hydrochloric acid solution (20%, 1.0 L). The solution was extracted with EtOAc (800 mL), and the organic layer was separated, washed with H2O (1.0 L), dried over MgSO4 (s), and concentrated under reduced pressure. The liquid was distilled to give 1-(4-chloro-2,6-dimethylphenyl)ethanone (85.0 g) as yellow oil in 76% yield: 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 2 H), 2.45 (s, 3 H), 2.22 (s, 6 H). After the addition the reaction mixture was warmed to room temperature The solution was extracted with EtOAc (800 mL) the organic layer was separated washed with H2O (1.0 L) dried over MgSO4 (s) concentrated under reduced pressure The liquid was distilled

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 4-ethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol) and Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (6.0 g) as yellow oil in 82% yield: 1H NMR (500 MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.63 (s, 2H), 2.64 (q, J=7.5 Hz, 2H), 2.47 (s, 3H), 2.21 (s, 6H), 1.25 (t, J=7.5 Hz, 3H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.00 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3-methoxyphenol (4.08 g, 32.9 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.4 g) as yellow oil in 73% yield: 1H NMR (500 MHz, CDCl3) δ 7.24 (m, 1H), 6.68-6.66 (m, 3H), 6.57-6.56 (m, 2H), 3.79 (s, 3H), 2.48 (s, 3H), 2.22 (s, 6H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3,5-dimethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (6.3 g) as yellow solids in 86% yield: 1H NMR (500 MHz, CDCl3) δ 6.76 (s, 1H), 6.63 (s, 2H), 6.62 (s, 2H), 2.48 (s, 3H), 2.29 (s, 6H), 2.22 (s, 6H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), sesamol (4.54 g, 32.9 mmol) in toluene (54.8 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was recrystallized in MeOH to give 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)ethanone (4.80 g) as white solids in 62% yield: 1H NMR (500 MHz, CDCl3) δ 6.77 (d, J=8.5 Hz, 1H), 6.59 (s, 2H), 6.56 (s, 1H), 6.48 (m, 1H), 5.98 (s, 2H), 2.46 (s, 3H), 2.21 (s, 6H). The solution was cooled to room temperature filtered through a small pad of Celite The cake was washed with ethyl acetate (50 mL) was concentrated under reduced pressure The residue was recrystallized in MeOH