1-bromo-3-(trifluoromethoxy)benzene

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

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

Conditions: temp:100.01; pressure:0.00; stir:

Procedure: The general procedure A was followed using 1-bromo-3-(trifluoromethoxy)benzene (73.5 uL, 0.5 mmol) and B2pin2 (126.9 mg, 0.5 mmol, 1.0 eq.) as starting material. The resulting mixture was allowed to stir 16 hours at 100 oC. 5g was obtained as colorless oil (183.0 mg, 100%) after purification by silica gel flash chromatography (EtOAc/PE=1:30 v/v).

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

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

Procedure: To a solution of 3-bromotrifluoromethoxybenzene (0.590 mL, 4.00 mmol) in THF (12 mL) at -78° C. was added t-butyl lithium (4.71 mL, of a 1.7M solution in pentane, 8.00 mmol. After 10 minutes zinc chloride(4.0 mL, of a 1M solution in diethylether, 4.00 mmol) was added. The reaction was stirred for 10 minutes at -78° C. and then allowed to warm to 0° C. and stirred for 30 minutes. This solution was added via cannula to a solution of 2-bromo-5-methyl pyridine and bis(triphenylphosphine) Nickel II chloride. The reaction stirred for 1 hour at 0° C. and then at ambient temperature for a furthur 1 hour. Saturated ammonium hydroxide solution (3 mL) was added and the mixture stirred until homogenous, extracted with Et2O and the organic extracts washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (Silica gel, 25-50% CH2Cl2 in hexanes). to warm to 0° C. stirred for 30 minutes The reaction stirred for 1 hour at 0° C. at ambient temperature for a furthur 1 hour the mixture stirred until homogenous, extracted with Et2O the organic extracts washed with saturated brine dried (MgSO4) evaporated in vacuo The residue was chromatographed (Silica gel, 25-50% CH2Cl2 in hexanes)

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

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

Procedure: The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-3-trifluoromethoxy-benzene. MS m/z 493 (M+1).

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

Procedure: The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 1-bromo-3-trifluoromethoxy-benzene. Light yellow solid. MS (ESI): 475.1 (MH+)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A multinecked flask as described in Example 1 was charged with 5.0 g (0.021 mol) of m-bromophenyl trifluoromethyl ether, 50 ml of dried, degassed triethylamine, 2.43 g (0.212 mol) of 3-aminophenylacetylene, 0.048 g (0.68 mmol) of bis(triphenylphosphine) palladium II chloride, 0.148 g (0.564 mmol) of triphenylphosphine, and 0.03 g (0.157 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromotography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product as a viscous orange-colored liquid. Short path distillation of the crude product under reduced pressure gave 5.1 g (0.018 mol, 86% yield) of the purified product as a colorless liquid. A multinecked flask as described in Example 1 of dried the reaction The product mixture was cooled to room temperature Filtration of the insoluble triethylamine hydrobromide salt by-product gave the crude product as a viscous orange-colored liquid Short path distillation of the crude product under reduced pressure

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A multinecked flask as described in Example 1 was charged with 5.0 g (0.021 mol) of m-bromophenyl trifluoromethyl ether, 50 ml of dried, degassed triethylamine, 2.43 g (0.212 mol) of 3-aminophenylacetylene, 0.048 g (0.68 mmol) of bis(triphenylphosphine) palladium II chloride, 0.148 g (0.564 mmol) of triphenylphosphine, and 0.03 g (0.157 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromotography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product as a viscous orange-colored liquid. Short path distillation of the crude product under reduced pressure gave 5.1 g (0.018 mol, 86% yield) of the purified product as a colorless liquid. A multinecked flask as described in Example 1 of dried the reaction The product mixture was cooled to room temperature Filtration of the insoluble triethylamine hydrobromide salt by-product gave the crude product as a viscous orange-colored liquid Short path distillation of the crude product under reduced pressure

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

Procedure: Add copper (I) iodide (45.0 mg, 0.24 mmol), bis(triphenylphosphine)palladium (II) dichloride (147.4 m g, 0.21 mmol) and triethylamine (2.37 mL, 16.8 mmol), to a solution of 1-bromo-3-trifluoromethoxybenzene (0.62 mL, 4.15 mmol) and trimethylsilylacetylene (0.78 mL, 5.4 mmol), in ethyl acetate (4 mL) and stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify by silica gel chromatography, eluting with hexanes to give the title compound (1.07 g, 100%). concentrate purify by silica gel chromatography eluting with hexanes

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

Procedure: To a solution of 1-bromo-3-(trifluoromethoxy)benzene (1.52 g, 6.3 mmol) in diethyl ether (50 mL) at −78° C. was added dropwise a solution of 1.6 M n-BuLi in hexane (4.2 mL, 6.6 mmol) and the reaction mixture was stirred at −78° C. for 30 min. A solution of 3-(trifluoromethoxy)benzonitrile (1.23 g, 6.6 mmol) in diethyl ether (5 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 h. 3N HCl (40 mL) was added and the reaction was allowed to warm to rt followed by stirring at rt for 1.5 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by a silica gel ISCO cartridge with elution at gradient 10% EtOAc/hexane to give bis(3-(trifluoromethoxy)phenyl)methanone (1.99 g, 90% yield) as a white solid. LCMS: RT=2.10 min [M+H] 351.3 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 7.46 (d, J=8.35 Hz 1 H), 7.54 (t, J=7.91 Hz, 1 H), 7.64 (s, 1 H), 7.70 (d, J=7.91 Hz, 1 H). the reaction mixture was stirred at −78° C. for 1.5 h to warm to rt by stirring at rt for 1.5 h extracted with EtOAc (3×75 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated under reduced pressure to yield a residue The residue was purified by a silica gel ISCO cartridge with elution at gradient 10% EtOAc/hexane