3-chloro-2,6-difluorobenzaldehyde

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

Procedure: (S,E)-N-(3-Chloro-2,6-difluorobenzylidene)-2-methylpropane-2-sulfinamide: To a stirred suspension of 3-chloro-2,6-difluorobenzaldehyde (0.615g, 3.48 mmol) and Cs2CO3 (1.702 g, 5.23 mmol) in DCM (20 mL) was added a solution of (S)-2-methylpropane-2-sulfinamide (0.422 g, 3.48 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred at rt overnight. After overnight stirring, the reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product (0.98 g, 100%) as yellow oil. MS (ESI) m/z: 282.0 (M+H)+. After overnight stirring washed with brine (3×20 mL) The combined organic layers were dried over MgSO4 concentrated in vacuo

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

Procedure: (S,E)-N-(3-Chloro-2,6-difluorobenzylidene)-2-methylpropane-2-sulfinamide: To a stirred suspension of 3-chloro-2,6-difluorobenzaldehyde (0.615g, 3.48 mmol) and Cs2CO3 (1.702 g, 5.23 mmol) in DCM (20 mL) was added a solution of (S)-2-methylpropane-2-sulfinamide (0.422 g, 3.48 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred at rt overnight. After overnight stirring, the reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product (0.98 g, 100%) as yellow oil. MS (ESI) m/z: 282.0 (M+H)+. After overnight stirring washed with brine (3×20 mL) The combined organic layers were dried over MgSO4 concentrated in vacuo

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

Procedure: 1-(6-Bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 6-bromo-3-chloro-2-fluorobenzaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.33-7.41 (m, 2H), 6.64 (dd, J=17.6, 10.2 Hz, 1H), 6.25 (d, J=10.7 Hz, 1H), 6.07 (d, J=17.6 Hz, 1H).

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

Procedure: To a 100 mL dry round bottom flask containing vinylmagnesium bromide (1 M in THF) (24 mL, 24.00 mmol) under Ar at 0° C. was added 3-chloro-2,6-difluorobenzaldehyde (3.2 g, 18.13 mmol) in THF (10 mL) dropwise. The reaction was stirred for 1 h and quenched with 1 N HCl to pH 2. The mixture was extracted with Et2O (3×). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to yield the desired product (3.71 g, 100%) as pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.34 (ddd, J=8.9, 8.1, 5.8 Hz, 1H), 6.90 (td, J=9.2, 1.7 Hz, 1H), 6.23 (dddt, J=17.2, 10.4, 5.8, 1.2 Hz, 1H), 5.60 (dd, J=7.6, 6.7 Hz, 1H), 5.40-5.31 (m, 1H), 5.28 (dt, J=10.2, 1.2 Hz, 1H), 2.38 (dt, J=8.3, 1.9 Hz, 1H). To a 100 mL dry round bottom flask quenched with 1 N HCl to pH 2 The mixture was extracted with Et2O (3×) The combined organic layer was washed with brine dried over MgSO4 filtered concentrated

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

Procedure: 1-(6-Bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 6-bromo-3-chloro-2-fluorobenzaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.33-7.41 (m, 2H), 6.64 (dd, J=17.6, 10.2 Hz, 1H), 6.25 (d, J=10.7 Hz, 1H), 6.07 (d, J=17.6 Hz, 1H).

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

Procedure: To a 100 mL dry round bottom flask containing vinylmagnesium bromide (1 M in THF) (24 mL, 24.00 mmol) under Ar at 0° C. was added 3-chloro-2,6-difluorobenzaldehyde (3.2 g, 18.13 mmol) in THF (10 mL) dropwise. The reaction was stirred for 1 h and quenched with 1 N HCl to pH 2. The mixture was extracted with Et2O (3×). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to yield the desired product (3.71 g, 100%) as pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.34 (ddd, J=8.9, 8.1, 5.8 Hz, 1H), 6.90 (td, J=9.2, 1.7 Hz, 1H), 6.23 (dddt, J=17.2, 10.4, 5.8, 1.2 Hz, 1H), 5.60 (dd, J=7.6, 6.7 Hz, 1H), 5.40-5.31 (m, 1H), 5.28 (dt, J=10.2, 1.2 Hz, 1H), 2.38 (dt, J=8.3, 1.9 Hz, 1H). To a 100 mL dry round bottom flask quenched with 1 N HCl to pH 2 The mixture was extracted with Et2O (3×) The combined organic layer was washed with brine dried over MgSO4 filtered concentrated

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

Procedure: 1H-Benzoimidazol-5-ylamine (1 mmol) and 3-Chloro-2,6-difluorobenzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2 ml of a solution of KOCN (KSCN) (2 mmol) and Pyridinehydrochloride (2 mmol) in MeOH is added was added. Finally 3-Isocyano-2,2-dimethyl-butane (1 mmol) is added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. was added After evaporation of the solvent the residue was purified with chromatographic methods

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

Procedure: 1H-Benzoimidazol-5-ylamine (1 mmol) and 3-Chloro-2,6-difluorobenzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2 ml of a solution of KOCN (KSCN) (2 mmol) and Pyridinehydrochloride (2 mmol) in MeOH is added was added. Finally Isocyano-cyclohexane (1 mmol) is added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. was added After evaporation of the solvent the residue was purified with chromatographic methods

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

Procedure: 1H-Benzoimidazol-5-ylamine (1 mmol) and 3-Chloro-2,6-difluorobenzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2 ml of a solution of KOCN (KSCN) (2 mmol) and Pyridinehydrochloride (2 mmol) in MeOH is added was added. Finally 1-Isocyano-1,2,3,4-tetrahydro-naphthalene (1 mmol) is added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. was added After evaporation of the solvent the residue was purified with chromatographic methods

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of prop-1-en-2-ylmagnesium bromide (0.5M in THF) (2 mL, 1.000 mmol) was added 3-chloro-2,6-difluorobenzaldehyde (136 mg, 0.769 mmol) in THF (1 mL) dropwise at 0° C. under Ar and stirred at 0° C. for 15 mins. The reaction mixture was quenched with sat. aq.NH4Cl and extracted with ether. The organic phase was washed with sat. aq.NH4Cl and brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography to yield 73A as colorless oil (87 mg, 52%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.36-7.28 (m, 1H), 6.91-6.83 (m, 1H), 5.48 (d, J=9.2 Hz, 1H), 5.12-5.06 (m, 1H), 5.04-4.99 (m, 1H), 2.56 (dt, J=9.2, 2.2 Hz, 1H), 1.75 (s, 3H). The reaction mixture was quenched with sat. aq NH4Cl and extracted with ether The organic phase was washed with sat. aq NH4Cl and brine, dried over MgSO4 filtered concentrated Purification by flash chromatography

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

Procedure: 1-(3-Chloro-2-fluoro-6-methoxyphenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 3-chloro-2-fluoro-6-methoxybenzaldehyde. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.43-7.36 (m, 1H), 6.75-6.56 (m, 2H), 6.13-6.03 (m, 2H), 3.80 (s, 3H).

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

Procedure: 1-(6-Bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 6-bromo-3-chloro-2-fluorobenzaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.33-7.41 (m, 2H), 6.64 (dd, J=17.6, 10.2 Hz, 1H), 6.25 (d, J=10.7 Hz, 1H), 6.07 (d, J=17.6 Hz, 1H).