1,2,4,5-tetrafluorobenzene

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:

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

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

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium in hexane (1.6 M, 62.5 ml) was added dropwise to a well stirred solution of 1,2,4,5-tetrafluorobenzene (15.0 g) in dry tetrahydrofuran (150 ml) maintained at a temperature of -60° C. under an atmosphere of dry argon. When the addition was complete the mixture was stirred at -45° C. for 2 hours and then methyl iodide (14.2 g) was added dropwise whilst the temperature was kept at -45° C. After a period of 30 minutes the mixture was allowed to warm to the ambient temperature, poured into distilled water and the mixture extracted with diethyl ether (2×50 ml), and the extracts dried over anhydrous magnesium sulphate. After filtering the solution was concentrated by evaporation of the solvents at atmospheric pressure. The residual oil was distilled and the fraction boiling in the range 115°-122° C. at atmospheric pressure (6.2 g) collected, identified by n.m.r. and gas chromatographic analysis as consisting of ca. 95% of the required 2,3,5,6-tetrafluorotoluene and ca. 5% of 2,3,5,6-tetrafluoro-1,4-xylene. When the addition was kept at -45° C After a period of 30 minutes the mixture was allowed to warm to the ambient temperature poured into distilled water the mixture extracted with diethyl ether (2×50 ml) the extracts dried over anhydrous magnesium sulphate After filtering the solution was concentrated by evaporation of the solvents at atmospheric pressure The residual oil was distilled boiling in the range 115°-122° C. at atmospheric pressure (6.2 g) collected

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-((R)-1-Hydroxypentyl)pyrrolidine-1-carboxylic acid t-butyl ester (40.0 mg, 155 μmol) was dissolved in DMF (100 mL, 12.9 mmol). While stirring, 60% sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 311 μmol) was slowly added, and the mixture was stirred for 15 minutes. 1,2,4,5-Tetrafluorobenzene (52.1 μL, 466 μmol) was added. The mixture was then heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL), and the solvent was removed under reduced pressure. 1.25M HCl in EtOH (2.0 mL, 2.5 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19.2 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H20F3NO, 288.15. found 288.2. the mixture was stirred for 15 minutes The reaction was quenched with MeOH (1 mL) the solvent was removed under reduced pressure the mixture was stirred overnight The product was concentrated purified by preparative HPLC

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: