5-chloro-2-(difluoromethoxy)benzaldehyde

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

Procedure: To a solution of potassium tert-butoxide (0.407 g, 3.63 mmol) in THF (10 mL) were added tert-butyl 2-(dimethoxyphosphoryl)acetate (0.528 mL, 2.66 mmol) and 5-chloro-2-(difluoromethoxy)benzaldehyde (0.50 g, 2.420 mmol) at 0° C. After 4 hrs, NH4Cl solution was added and the reaction mixture was diluted with EtOAc, washed with sat'd NH4Cl solution, sat'd NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. Intermediate 15A was obtained as a white solid 550 mg (74%). MS (ESI) m/z: 327.0 (M+Na)+. 19F NMR (376 MHz, CDCl3) δ: −81.11 (1F, s) ppm. washed with sat'd NH4Cl solution The organic phase was dried over Na2SO4 filtered concentrated The crude product was purified by normal phase chromatography

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

Procedure: Intermediate 16 was made in a similar manner as Intermediate 15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde for 5-chloro-2-(difluoromethoxy) benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.

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

Procedure: Intermediate 16 was made in a similar manner as Intermediate 15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde for 5-chloro-2-(difluoromethoxy) benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.

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

Procedure: Intermediate 16 was made in a similar manner as Intermediate 15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde for 5-chloro-2-(difluoromethoxy)benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.

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

Procedure: 5-Chloro-2-(difluoromethoxy)benzaldehyde (0.480 g, 2.324 mmol) was dissolved in dry THF (11.62 mL) and the reaction was cooled to −78° C. under argon. Vinyl magnesium bromide (3.49 mL, 3.49 mmol) was then added dropwise. After the reaction was complete, the ice bath was removed and reaction was allowed to warm to rt and stirred for an additional 2 h. The reaction was cooled to 0° C. and then carefully quenched with saturated ammonium chloride. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated to yield 1-(5-chloro-2-(difluoromethoxy)phenyl)prop-2-en-1-ol (561 mg, 103%) as a clear oil. MS (ESI) m/z: 236.9 (M+H, Chlorine isotope peak)+. the ice bath was removed reaction to warm to rt The reaction was cooled to 0° C. carefully quenched with saturated ammonium chloride The mixture was then diluted with water extracted with EtOAc (3×) The combined organic phases were dried over Na2SO4 filtered concentrated

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

Procedure: To a solution of potassium tert-butoxide (0.407 g, 3.63 mmol) in THF (10 mL) were added tert-butyl 2-(dimethoxyphosphoryl)acetate (0.528 mL, 2.66 mmol) and 5-chloro-2-(difluoromethoxy)benzaldehyde (0.50 g, 2.420 mmol) at 0° C. After 4 hrs, NH4Cl solution was added and the reaction mixture was diluted with EtOAc, washed with sat'd NH4Cl solution, sat'd NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. Intermediate 15A was obtained as a white solid 550 mg (74%). MS (ESI) m/z: 327.0 (M+Na)+. 19F NMR (376 MHz, CDCl3) δ: −81.11 (1F, s) ppm. washed with sat'd NH4Cl solution The organic phase was dried over Na2SO4 filtered concentrated The crude product was purified by normal phase chromatography

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

Procedure: Intermediate 16 was made in a similar manner as Intermediate 15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde for 5-chloro-2-(difluoromethoxy) benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.