(5-formyl-2-methoxyphenyl)boronic acid

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: A solution of 5-formyl-2-methoxybenzeneboronic acid (1 g, 5.6 mmol), 2-methyl-5-bromobenzoxazole (1 g, 4.72 mmol) and K2CO3 (1.63 g, 11.8 mmol) in ethanol (20 mL) and toluene (40 mL) was degassed prior to addition of Pd(Ph3)4 (55 mg, 0.047 mmol). The mixture was refluxed for 20 hours then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, extracted with ethyl acetate, washed with water and the organic layer dried over sodium sulphate. The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4) to give 1.13 g of title compound. The mixture was refluxed for 20 hours then cooled filtered through diatomaceous earth The filtrate was concentrated in vacuo extracted with ethyl acetate washed with water the organic layer dried over sodium sulphate The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4)

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

Procedure: A solution of 5-formyl-2-methoxybenzeneboronic acid (1 g, 5.6 mmol), 2-methyl-5-bromobenzoxazole (1 g, 4.72 mmol) and K2CO3 (1.63 g, 11.8 mmol) in ethanol (20 mL) and toluene (40 mL) was degassed prior to addition of Pd(Ph3)4 (55 mg, 0.047 mmol). The mixture was refluxed for 20 hours then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, extracted with ethyl acetate, washed with water and the organic layer dried over sodium sulphate. The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4) to give 1.13 g of title compound. The mixture was refluxed for 20 hours then cooled filtered through diatomaceous earth The filtrate was concentrated in vacuo extracted with ethyl acetate washed with water the organic layer dried over sodium sulphate The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4)

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

Procedure: The intermediate 3-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methoxybenzaldehyde was prepared in a manner similar to the procedure described in Example 1b using 4-bromo-2,6-di-t-butylphenol (0.50 g, 1.75 mmol), 2-methoxy-5-formylphenyl boronic acid (0.315 g, 1.75 mmol), tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.175 mmol), K2CO3 (0.95 g, 7.0 mmol), dimethoxyethane (15 mL) and H2O (1 mL); 367 mg, 61% yield.

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

Procedure: A mixture of 2-methoxy-5-formylphenylboronic acid (2.3 g, 12.80 mmol), 6-bromo-1,1,4,4,7pentamethyl1,2,3,4-tetrahydronaphthalene (3.0 g, 10.66 mmol) and potassium carbonate (5.89 g, 42.64 mmol) in 1,2-dimethoxyethane (100 mL) and water (5 mL) was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.13 mmol) was added and the mixture heated at reflux under argon for 8 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: 0% to 25% ethyl acetate in hexane) to give 3.43 g (95%) of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde. 1H NMR (500 MHz; CDCl3): δ1.26 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 3.89 (s, 3H); 7.06 (d, J=8.5 Hz, 1H); 7.09 (s, 1H); 7.16 (s, 1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=8.5 Hz, J2=2.0 Hz 1H), 9.91 (s, 1H). was degassed with argon for 15 minutes the mixture heated at reflux under argon for 8 hours washed successively with water and brine dried over anhydrous magnesium sulfate filtered evaporated The residue was chromatographed on silica gel (eluent: 0% to 25% ethyl acetate in hexane)

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

Procedure: A mixture of 7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (469 mg, 1.51 mmol), 2-methoxy-5-formylphenylboronic acid (407 mg, 2.26 mmol), potassium carbonate (834 mg, 6.03 mmol) and water (2.5 mL) in anhydrous 1,2-dimethoxyethane (30 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium (0) (349 mg, 0.30 mmol). The reaction mixture was heated under reflux for 8.5 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), saturated aqueous NH4Cl (100 mL), saturated aqueous NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40S cartridge, eluting with 10% ethyl acetate/90% hexane. The title compound was isolated as bright yellow solid (315 mg, 57%). was degassed with argon for 15 minutes The reaction mixture was heated under reflux for 8.5 hours extracted with ethyl acetate (2×100 mL) The organic extracts were successively washed with water (100 mL), saturated aqueous NH4Cl (100 mL), saturated aqueous NaCl (100 mL) dried over MgSO4 filtered Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography eluting with 10% ethyl acetate/90% hexane

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

Procedure: A mixture of 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Example 66, 50 mg; 0.0858 mmol), 5-formyl-2-methoxyphenyl boronic acid (46 mg; 0.257 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg; 0.0103 mmol), and sodium carbonate (74 mg) in benzene/ethanol/water (2.8/0.4/1.2 mL) was heated at reflux for 60 h. The reaction was diluted with EtOAc (30 mL) and washed successively with H2O (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 2′-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-carbaldehyde as a yellow oil. LCMS=592.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 9.98 (s, 1 H), 7.99-7.96 (m, 1 H), 7.90 (s, 1 H), 7.75 (s, 2 H), 7.69-7.64 (m, 2 Hz), 7.53 (s, 1 H), 7.41-7.38 (m, 1 H), 7.17-7.14 (m, 1 H), 5.37 (t, J=8.2 Hz, 1 H), 4.59 (d, J=15.3 Hz, 1 H), 4.37 (d, J=15.6 Hz, 1 H), 3.92 (s, 3 H), 3.67-3.64 (m, 1 Hz), 3.19-3.16 (m, 1 H). was heated at reflux for 60 h washed successively with H2O (10 mL) and brine (10 mL) dried over MgSO4 filtered concentrated in vacuo The crude product was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient)

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

Procedure: A round bottom flask was charged with 6.0 g of Compound 1A (20.3 mmol), 5.5 g of 2-methoxy-5-formylphenylboronic acid (30.4 mmol) and tetrakis(triphenylphosphine)palladium(0), (1.17 g, 0.10 mmol). The flask was sealed and 100 mL of toluene and 30 mL of ethanol was added. The resulting solution was stirred to dissolve the reactants and then 21 mL of 2M K2CO3 was added via syringe. The reaction mixture was heated to 80° C. for 4 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (200 mL) and water (75 mL). The water layer was further extracted (2×100 mL) and the combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%) to give 7.05 g (99%) of product Compound 1B as a foamy solid. MS (electrospray): mass calculated for C22H25NO3, 351.18; m/z found 352.4, [M+H]+. 1HNMR (300 MHz, CDCl3): 9.94 (s, 1H), 7.93 (dd, J=2.1, 8.6 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 2.52 (s, 2H), 2.10 (s, 3H), 1.33 (s, 6H), 1.23 (t, J=6.9 Hz, 3H). The flask was sealed to dissolve the reactants After cooling the reaction mixture was partitioned between ethyl acetate (200 mL) and water (75 mL) The water layer was further extracted (2×100 mL) the combined organic layers were washed with water (50 mL) dried over magnesium sulfate filtered excess solvent removed on the rotary evaporator The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%)

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

Procedure: A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.50 g, 0.84 mmol), 5-formyl 2-methoxy phenyl boronic acid (0.22 g, 1.25 mmol), tetrakis(triphenylphosphine) palladium (48 mg, 5% mol) and sodium carbonate (0.19 g, 1.84 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/3:7 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 9.95 (s, 1H), 7.62-7.98 (m, 6H), 7.42 (m, 1H), 7.17 (m, 2H), 5.65 (d, J=8 Hz, 0.5H), 5.20 (d, J=8 Hz, 0.5H), 4.96 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=16.5 Hz, 0.5H), 3.85-4.10 (m, 2H), 3.98 (s, 1.5H), 3.92 (s, 1.5H), 0.59 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=6 Hz, 1.5H). was heated to reflux for 4 h The solvents were removed Water (30 ml) was added The organic was extracted with methylene chloride (3×40 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate

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

Procedure: A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.50 g, 0.84 mmol), 5-formyl 2-methoxy phenyl boronic acid (0.22 g, 1.25 mmol), tetrakis(triphenylphosphine) palladium (48 mg, 5% mol) and sodium carbonate (0.19 g, 1.84 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/3:7 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 9.95 (s, 1H), 7.62-7.98 (m, 6H), 7.42 (m, 1H), 7.17 (m, 2H), 5.65 (d, J=8 Hz, 0.5H), 5.20 (d, J=8 Hz, 0.5H), 4.96 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=16.5 Hz, 0.5H), 3.85-4.10 (m, 2H), 3.98 (s, 1.5H), 3.92 (s, 1.5H), 0.59 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=6 Hz, 1.5H). was heated to reflux for 4 h The solvents were removed Water (30 ml) was added The organic was extracted with methylene chloride (3×40 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate