4-amino-2,6-difluorobenzaldehyde

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

Procedure: To a solid mixture of 4-amino-2,6-difluoro-benzaldehyde (6.5 g, 41.4 mmol, 1.0 equiv.) and (carbethoxymethylene)triphenylphosphorane (18.75 g, 53.8 mmol, 1.3 equiv.) at 23° C. was added ethanol (97 mL). After stirring for 25 min at 23° C., the reaction mixture was concentrated, pre-absorbed with silica gel and purified by flash column chromatography eluting with a gradient increasing in polarity from 0 to 30% ethyl acetate in hexane. Relevant fractions were combined to give the desired compound. the reaction mixture was concentrated pre-absorbed with silica gel purified by flash column chromatography eluting with a gradient increasing in polarity from 0 to 30% ethyl acetate in hexane

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

Procedure: A solution of 3,5-difluoroaniline (12.9 g, 0.1 mol) in anhydrous THF (400 mL) was cooled at −78° C. and treated with nbutyllithium (2.5 M in hexane, 84 mL, 0.21 mol, 2.1 equv.) dropwise over 25 min. After stirring at −78° C. for 30 min, trimethylsilyl chloride (1.0 M in THF, 210 mL, 0.21 mol, 2.1 equiv.) was added dropwise over 30 min. The temperature was allowed to rise to 23° C. and stirred overnight. After re-cooling to −78° C., additional n-butyllithium (2.5 M in hexane, 44 mL, 0.11 mol, 1.1 equiv.) was added dropwise over 20 min, and the reaction mixture was stirred at that temperature for 5 hours to form the anion. Then dimethylformamide (11.6 ml, 0.15 mol, 1.5 equiv.) was added dropwise over 20 min. The temperature was allowed to rise to 23° C. and stirred overnight. The mixture was cooled in an ice-bah and acidified to pH=1 by slow addition of aqueous HCl (1.0 M, 220 mL, 0.22 mol). After stirring 15 min, the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and evaporated to dry. The residue was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 50% ethyl acetate in hexane. Relevant fractions were combined to give the title compound. to rise to 23° C. stirred overnight After re-cooling to −78° C. the reaction mixture was stirred at that temperature for 5 hours to form the anion to rise to 23° C. stirred overnight After stirring 15 min the mixture was extracted with ethyl acetate (3×200 mL) The combined organic layers were washed (brine) dried (Na2SO4) filtered evaporated to dry The residue was purified by chromatography on a silica gel column eluting with a gradient increasing in polarity from 0 to 50% ethyl acetate in hexane