3-chloro-5-methoxyphenol

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:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-3,5-dimethoxy-benzene (1.72 g, 10 mmol) in 10 mL of CH2Cl2 was cooled to −78° C., followed by 1.0 M BBr3 in toluene (10 mL, 10 mmol) added dropwise. The solution was stirred at −78° C. for 1 hour, and then allowed to warmed to room temperature over 2 hours. The reaction was quenched with water, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried, and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes to give 0.51 g of the title compound. MS (APCI) m/e 159 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.88 (s, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 6.28 (m, 1H), 3.70 (s, 3H). added dropwise allowed to warmed to room temperature over 2 hours The reaction was quenched with water the aqueous layer was extracted with additional CH2Cl2 The combined organic layers were washed with brine dried concentrated under pressure The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-3,5-dimethoxy-benzene (1.72 g, 10 mmol) in 10 mL of CH2Cl2 was cooled to −78° C., followed by 1.0 M BBr3 in toluene (10 mL, 10 mmol) added dropwise. The solution was stirred at −78° C. for 1 hour, and then allowed to warmed to room temperature over 2 hours. The reaction was quenched with water, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried, and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes to give 0.51 g of the title compound. MS (APCI) m/e 159 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.88 (s, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 6.28 (m, 1H), 3.70 (s, 3H). added dropwise allowed to warmed to room temperature over 2 hours The reaction was quenched with water the aqueous layer was extracted with additional CH2Cl2 The combined organic layers were washed with brine dried concentrated under pressure The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-3,5-dimethoxy-benzene (1.72 g, 10 mmol) in 10 mL of CH2Cl2 was cooled to −78° C., followed by 1.0 M BBr3 in toluene (10 mL, 10 mmol) added dropwise. The solution was stirred at −78° C. for 1 hour, and then allowed to warmed to room temperature over 2 hours. The reaction was quenched with water, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried, and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes to give 0.51 g of the title compound. MS (APCI) m/e 159 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.88 (s, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 6.28 (m, 1H), 3.70 (s, 3H). added dropwise allowed to warmed to room temperature over 2 hours The reaction was quenched with water the aqueous layer was extracted with additional CH2Cl2 The combined organic layers were washed with brine dried concentrated under pressure The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium methanethiolate (12.32 g, 173.80 mmol) was added 1-methyl-2-pyrrolidine (75 mL) followed by 1-chloro-3,5-dimethoxy-benzene (20.00 g, 115.87 mmol) and the reaction heated in a 140° C. bath for 2.5 hours then stirred at room temperature over night. The 1-methyl-2-pyrrolidine was removed under reduced pressure and the material partitioned between ethyl acetate/water/1N hydrochloric acid. The organic layer was washed with twice with 1N hydrochloric acid, once with aqueous saturated sodium chloride, dried over magnesium sulfate and solvent removed under reduced pressure to give a yellowish solid. The solid was chromatographed on 400 mL plug of silica gel eluting with dichloromethane. The combined purified fractions were removed of solvent to give the title compound as a yellow solid (16.62 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ 6.43 (t, J=2.0 Hz, 1 H), 6.40 (t, J=1.9 Hz, 1 H), 6.28 (t, J=2.1 Hz, 1 H), 3.71 (s, 3 H); MS (APCI+) m/z 159 [M+1]+; tR=2.04 min. The 1-methyl-2-pyrrolidine was removed under reduced pressure the material partitioned between ethyl acetate/water/1N hydrochloric acid The organic layer was washed with twice with 1N hydrochloric acid once with aqueous saturated sodium chloride, dried over magnesium sulfate and solvent removed under reduced pressure to give a yellowish solid The solid was chromatographed on 400 mL plug of silica gel eluting with dichloromethane The combined purified fractions were removed of solvent

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

Procedure: A mixture of 372 mg (2.346 mmol) of 3-chloro-5-methoxyphenol (B-1), 947 mg (4.692 mmol) of 5-bromopyridine-3-boronic acid (13-1), 426 mg (2.346 mmol) of copper (II) acetate and 4.0 g of freshly activated powdered 4A molecular sieves was stirred in 20 mL of DCM in a screw top glass sealed tube. The reaction was then treated with 1.635 mL (11.73 mmol) of triethylamine and the vessel was loosely capped. The mixture was vigorously stirred at room temperature for 48 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to a black residue. The residue was purified on a CombiFlash silica column eluted with an ethyl acetate:hexanes gradient to give the desired product 13-2 as an oil (Rf=0.7, EtOAc:hexanes 1:4). MS: M+1=314. 1H NMR(CDCl3): 3.79 (s, 3H), 6.47 (m, 1H), 6.61 (m, 1H), 6.74 (m, 1H), 7.46 (m, 1H), 8.33 (d, 1H), 8.46 (d, 1H). sealed tube the vessel was loosely capped The mixture was filtered through a pad of celite the filtrate was concentrated in vacuo to a black residue The residue was purified on a CombiFlash silica column eluted with an ethyl acetate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-3,5-dimethoxy-benzene (1.72 g, 10 mmol) in 10 mL of CH2Cl2 was cooled to −78° C., followed by 1.0 M BBr3 in toluene (10 mL, 10 mmol) added dropwise. The solution was stirred at −78° C. for 1 hour, and then allowed to warmed to room temperature over 2 hours. The reaction was quenched with water, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried, and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes to give 0.51 g of the title compound. MS (APCI) m/e 159 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.88 (s, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 6.28 (m, 1H), 3.70 (s, 3H). added dropwise allowed to warmed to room temperature over 2 hours The reaction was quenched with water the aqueous layer was extracted with additional CH2Cl2 The combined organic layers were washed with brine dried concentrated under pressure The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes