(4-formyl-2-methoxyphenyl) trifluoromethanesulfonate

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

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

Procedure: To a mixture of 4-hydroxy-3-methoxybenzaldehyde (10.0 g, 65.7 mmol) and Et3N (13.0 g, 128.7 mmol) in anhydrous DCM (100 mL) was added Tf2O (28.0 g, 99.2 mmol) dropwise at room temperature and the reaction was stirred for 1 hour. The resulting mixture was quenched with water (100 mL) followed by a standard aqueous/EtOAc workup. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1) to give the product as a colorless oil (17.0 g, yield 91%). The resulting mixture was quenched with water (100 mL) The residue was purified by silica gel column chromatography (PE:EtOAc=20:1)

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

Procedure: To a mixture of 4-hydroxy-3-methoxybenzaldehyde (10.0 g, 65.7 mmol) and Et3N (13.0 g, 128.7 mmol) in anhydrous DCM (100 mL) was added Tf2O (28.0 g, 99.2 mmol) dropwise at room temperature and the reaction was stirred for 1 hour. The resulting mixture was quenched with water (100 mL) followed by a standard aqueous/EtOAc workup. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1) to give the product as a colorless oil (17.0 g, yield 91%). The resulting mixture was quenched with water (100 mL) The residue was purified by silica gel column chromatography (PE:EtOAc=20:1)

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

Procedure: To a solution of 4-hydroxy-3-(methoxy)benzaldehyde (0.760 g; 5.00 mmol) and Et3N (1.39 mL; 10.0 mmol) in anhyd CH2Cl2 (10 mL) at 0° C. was added Tf2O (0.92 mL; 5.5 mmol), dropwise over 2 min. The mixture was allowed to warm slowly to room temperature (overnight), diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.01 (s, 3H), 7.42 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2, 1.8 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 9.99 (s, 1H). washed (water, brine) dried over Na2SO4 concentrated in vacuo The residue was purified by flash chromatography (EtOAc/hexanes)

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

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution and cooled (20° C.) solution of 2 (5.0 g, 32.89 mmol) in CH2Cl2 (30 mL) was treated with pyridine (5.2 g, 65.82 mmol). After 15 min, Tf2O (11.13 g, 39.4 mmol) was added dropwise and stirred at −20° C. for 1 h. Reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL), brine (50 mL) and dried, Solvent was evaporated under reduced pressure and residue purified by column chromatography (Silica gel, 60-120 mesh, hexane:ethyl acetate 93:7) to give 3 (5.7 g, 61%) as a syrup. Reaction mixture The organic layer was washed with water (50 mL), brine (50 mL) dried Solvent was evaporated under reduced pressure and residue purified by column chromatography (Silica gel, 60-120 mesh, hexane:ethyl acetate 93:7)

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

Procedure: To a round-bottomed flask equipped with magnetic stir bar was charged 1a (3.0 g, 20 mmol), pyridine (4.7 g, 59 mmol, 3 equiv) and CH2Cl2 (25 mL). The mixture was cooled in a dry ice-acetone bath and Tf2O (6.6 mL, 11.1 g, 39 mmol, 2 equiv) was added dropwise over 30 min Afterwards, the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2×25 mL) followed by brine (25 mL). The organic phase was separated, dried over anhydrous MgSO4 and evaporated under reduced pressure leaving a brownish oil (5.12 g, 90%). The crude product could be further purified by short-path distillation at reduced pressure (0.1 ton) to give the product as colorless oil. However, the compound appears to be heat sensitive as there was a significant decomposition residue in the distillation pot. 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.51 (dd, J=8.2 and 1.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 3.99 (s, 3H); 13C NMR (CDCl3): δ 190.53, 152.49, 142.97, 137.06, 124.27, 123.45, 121.06, 118.92 (q, 1JCF=321.5 Hz), 112.06, 56.75; 19F {13C} NMR (CDCl3): δ −74.2. The product was used in the synthesis of compound 3a without further purification. To a round-bottomed flask equipped with magnetic stir bar The mixture was cooled in a dry ice-acetone bath The reaction mixture was washed with H2O (2×25 mL) The organic phase was separated dried over anhydrous MgSO4 evaporated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-formyl-2-methoxyphenyl trifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (61.0 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DMF (300 mL) were stirred at 110° C. for 8 h. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile. the organic layer was washed two times with water dried filtered concentrated The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which

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

Procedure: To a solution of vanillin (20.0 g, 131 mmol) in DMF (200 mL) at room temperature was added potassium carbonate (36 g, 263 mmol) and 4-nitrophenyl trifluoromethanesulfonate (54.0 g, 197 mmol) and the reaction mixture was stirred for 8 h. EtOAc (600 mL) was added to the reaction mixture and the organic layer was washed three times with water, dried, filtered, and concentrated. The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7) to provide 4-formyl-2-methoxyphenyl trifluoromethanesulfonate. the organic layer was washed three times with water dried filtered concentrated The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7)

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

Procedure: To a stirred solution of 4-hydroxy-3-methoxybenzaldehyde (2 g, 14.7 mmol) in dichloromethane (20 ml) was slowly added trifluoromethanesulfonic anhydride (4.5 g, 17.64 mmol) and pyridine (1.5 ml, 14.7 mmol) at 0° C. under nitrogen atmosphere. The solution was stirred for 16 h at ambient temperature, ice-water slurry added and then extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and the solvent evaporated. The residue was flash chromatographed over silica gel eluting with 4:1 heptane/ethyl acetate and the solvent evaporated to give trifluoromethanesulfonic acid-4-formyl-2-methoxy-phenyl ester (3.5 g) as colourless oil. To a stirred solution of trifluoromethanesulfonic acid-4-formyl-2-methoxy-phenyl ester (3.5 g, 12.3 mmol) in tetrahydrofuran (50 ml) was added 5-fluoro-2-methoxyphenyl boronic acid, lithium chloride (0.05 g, 1.18 mmol), 2M sodium carbonate (14 ml) and tetrakis(triphenylphosphine)palladium (0) (0.22 g, 0.18 mmol). The reaction mixture was refluxed for 5 days then concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and the solvent evaporated. The residue was flash chromatographed over silica gel eluting with 5:1 heptane/ethyl acetate and the solvent evaporated to give 5′-fluoro-2,2′-dimethoxy-biphenyl-4-carbaldehyde (2.65 g) as a yellow oil. To a stirred solution of 5′-fluoro-2,2′-dimethoxy-biphenyl-4-carbaldehyde (2.65 g, 9.16 mmol) in pyridine (50 ml) was added methoxylamine hydrochloride (0.474 g, 10.1 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h. Following evaporation of pyridine under reduced pressure, the residue was dissolved in dichloromethane, washed with water and dried over anhydrous sodium sulfate. Evaporation of solvent followed by purification on a SCX column eluting with methanol gave 5′-fluoro-2,2′-dimethoxy-biphenyl-4-carbaldehyde-O-methyl-oxime (1.05 g) as an oil. A stirred solution of 5′-fluoro-2,2′-dimethoxy-biphenyl-4-carbaldehyde-O-methyl-oxime (0.182 g, 0.63 mmol) and 10% palladium on activated carbon in ethanol (10 ml) and 2M hydrogen chloride (5 drops) was degassed at ambient temperature then purged with hydrogen at atmospheric pressure for 16 h in a sealed vessel. The reaction mixture was then filtered through dicalite and evaporated. The residue was basified to pH 11 with aqueous sodium carbonate, extracted with dichloromethane and dried over anhydrous sodium sulfate. Evaporation of solvent gave C-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-yl)-methylamine (0.27 g) as a gum. To a stirred solution of C-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-yl)-methylamine in dichloromethane (5 ml) was added 4-methoxybenzene sulfonyl chloride (0.03 g, 0.12 mmol) and triethylamine (0.034 ml, 0.24 mmol). The reaction mixture was stirred for 16 h. Water was added and the mixture was filtered through a hydrophobic filter, then flash chromatographed over a SCX column eluting with methanol. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (0.01 g) as gum: MS (ESI) m/z: 432.3 [M+H]+. The reaction mixture was refluxed for 5 days then concentrated under reduced pressure The concentrate was dissolved in ethyl acetate washed with water dried over sodium sulfate the solvent evaporated chromatographed over silica gel eluting with 5:1 heptane/ethyl acetate the solvent evaporated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol), 2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassium phosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) was degassed with nitrogen, whereupon a catalytic amount (0.285 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 120° C. for 5 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a plug of silica gel. Removal of the solvent provided the crude title compound (4.54 g) as an oil, which was used as such in the next step. was added extracted with ethyl acetate The combined extracts were washed with water dried over anhydrous magnesium sulfate filtered through a plug of silica gel Removal of the solvent

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol), 2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassium phosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) was degassed with nitrogen, whereupon a catalytic amount (0.285 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 120° C. for 5 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a plug of silica gel. Removal of the solvent provided the crude title compound (4.54 g) as an oil, which was used as such in the next step. was added extracted with ethyl acetate The combined extracts were washed with water dried over anhydrous magnesium sulfate filtered through a plug of silica gel Removal of the solvent