ethyl 2-(4-bromophenyl)propanoate

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

Procedure: 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.3 mL, 9.0 mmol) was added to a mixture of ethyl 2-(4-bromophenyl)propanoate (1.3 g, 5.0 mmol), bis(acetonitrile)palladium(II) chloride (26 mg, 0.10 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (160 mg, 0.40 mmol) and triethylamine (2.1 mL, 15 mmol) in 1,4-dioxane (3.0 mL) and then the mixture was evacuated under reduced pressure and then refilled with nitrogen thrice. The reaction was then heated at 110° C. for 4 h. The mixture was cooled to r.t. and filtered through a short pad of silical gel and then washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (0-10%) to afford the desired product. the mixture was evacuated under reduced pressure refilled with nitrogen thrice The mixture was cooled to r.t. filtered through a short pad of silical gel washed with ethyl acetate The solvent was removed under reduced pressure The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (0-10%)

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

Procedure: 2.0 M LDA in heptane/THF/ethylbenzene (6.0 mL, 12 mmol) was slowly added to a solution of ethyl (4-bromophenyl)acetate (2.43 g, 10.0 mmol) in THF (20 mL) at −78° C. and then the mixture was stirred for 30 min. Methyl iodide (0.93 mL, 15 mmol) was added at −78° C. and then the reaction was stirred for an additional 30 min. Saturated NH4Cl aq. was added to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-10%) to afford the desired product (2.0 g). the reaction was stirred for an additional 30 min to quench the reaction The mixture was extracted with ethyl acetate The combined organic layers were washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-10%)

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

Procedure: To a solution of 73A (3.06 g, 11.9 mmol) in 50 mL CH2Cl2 at −78° C., was added a solution of diisobutylaluminum hydride (35.7 mL, 35.7 mmol, 1M in hexanes). The mixture was removed from the cooling bath, stirred 1 h, then recooled to −50° C. and quenched with EtOAc (2 mL). The reaction mixture was diluted with H2O, then extracted with EtOAc (3×). The combined organic extract washed with brine, dried (Na2SO4), filtered through a 1″ pad of SiO2, then concentrated to afford 2.34 g of 73B as a colorless oil. MS (ESI) m/z 197.1 (M-OH)+. The mixture was removed from the cooling bath recooled to −50° C. quenched with EtOAc (2 mL) The reaction mixture was diluted with H2O extracted with EtOAc (3×) The combined organic extract washed with brine dried (Na2SO4) filtered through a 1″ pad of SiO2 concentrated

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

Procedure: To a solution of 73A (3.06 g, 11.9 mmol) in 50 mL CH2Cl2 at −78° C., was added a solution of diisobutylaluminum hydride (35.7 mL, 35.7 mmol, 1M in hexanes). The mixture was removed from the cooling bath, stirred 1 h, then recooled to −50° C. and quenched with EtOAc (2 mL). The reaction mixture was diluted with H2O, then extracted with EtOAc (3×). The combined organic extract washed with brine, dried (Na2SO4), filtered through a 1″ pad of SiO2, then concentrated to afford 2.34 g of 73B as a colorless oil. MS (ESI) m/z 197.1 (M-OH)+. The mixture was removed from the cooling bath recooled to −50° C. quenched with EtOAc (2 mL) The reaction mixture was diluted with H2O extracted with EtOAc (3×) The combined organic extract washed with brine dried (Na2SO4) filtered through a 1″ pad of SiO2 concentrated

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

Procedure: To a solution of LDA (8.66 mL, 2M in heptane/THF/ethylbenzene, 17.3 mmol) in 30 mL THF at −78° C., was added a solution of ethyl 4-bromophenylacetate (4.00 g, 16.5 mmol) in 20 mL THF. The mixture was stirred at −78° C. for 30 min, then a solution of iodomethane (10.7 mL, 2M in methyl tert-butyl ether, 21.5 mmol) was added. The mixture was stirred for 10 min at −78° C., then was removed from the cooling bath and stirred for 30 min. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc. The organic phase washed with water, sat. Na2SO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 3.07 g of 73A as a colorless oil. MS (ESI) m/z 257.1, 259.1 (M+H)+. The mixture was stirred for 10 min at −78° C. was removed from the cooling bath stirred for 30 min The reaction was quenched with sat. NH4Cl diluted with EtOAc The organic phase washed with water, sat. Na2SO3 and brine dried (Na2SO4) concentrated The crude product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient)

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

Procedure: Prepared according to the procedure described in Example 17, Step 2 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-fluoro-phenyl)-ethyl ester, 2-(4-bromo-phenyl)-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride; purification by preparative HPLC, followed by silica gel chromatography, was utilized. Prepared purification by preparative HPLC

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

Procedure: Prepared according to the procedure described in Example 17, Step 2 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-fluoro-phenyl)-ethyl ester, 2-(4-bromo-phenyl)-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride; purification by preparative HPLC, followed by silica gel chromatography, was utilized. Prepared purification by preparative HPLC

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

Procedure: To ethyl 4-bromophenylacetate (2.137 g, 8.8 mmol) in THF (20 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1M in hexane; 11.4 mL, 11.4 mmol), and the solution was stirred for 1 hour at −78° C. Iodomethane (0.71 mL, 11.4 mmol) in THF (5 mL) was added, and the reaction was warmed to room temperature. The mixture was quenched with water and concentrated. The residue was dissolved in EtOAc and washed three times with water and once with brine. The organic layer was dried and concentrated, and the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give 2-(4-bromo-phenyl)-propionic acid ethyl ester. the reaction was warmed to room temperature The mixture was quenched with water concentrated The residue was dissolved in EtOAc washed three times with water The organic layer was dried concentrated the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes)

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

Procedure: 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.3 mL, 9.0 mmol) was added to a mixture of ethyl 2-(4-bromophenyl)propanoate (1.3 g, 5.0 mmol), bis(acetonitrile)palladium(II) chloride (26 mg, 0.10 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (160 mg, 0.40 mmol) and triethylamine (2.1 mL, 15 mmol) in 1,4-dioxane (3.0 mL) and then the mixture was evacuated under reduced pressure and then refilled with nitrogen thrice. The reaction was then heated at 110° C. for 4 h. The mixture was cooled to r.t. and filtered through a short pad of silical gel and then washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (0-10%) to afford the desired product. the mixture was evacuated under reduced pressure refilled with nitrogen thrice The mixture was cooled to r.t. filtered through a short pad of silical gel washed with ethyl acetate The solvent was removed under reduced pressure The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (0-10%)