3-(1,1-difluoroethyl)benzaldehyde

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

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

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

Procedure: 3-(1,1-difluoroethyl)benzonitrile was synthesized from 3-acetylbenzonitrile following the method described for 3-bromo-5-(1,1-difluoroethyl)pyridine. A solution of 3-(1,1-difluoroethyl)benzonitrile (1.6 g, 9.57 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. and was treated dropwise with a 1 M solution of DIBAL in hexanes (11.5 mL, 11.2 mmol). The mixture was allowed to slowly warm to room temperature. The reaction was monitored by TLC. After 3 h, the reaction mixture was poured into a beaker containing crushed ice and 6 N HCl. The mixture was stirred for about 1 h. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with aqueous NaHCO3 followed by water. The organic layer was dried (Na2SO4), concentrated, and silica chromatographed to afford 3-(1,1-difluoroethyl)benzaldehyde as a light yellow oil, which was used directly for next step without further purification and identification. the reaction mixture was poured into a beaker containing The layers were separated the aqueous phase was extracted with CH2Cl2 The combined organic layer was washed with aqueous NaHCO3 The organic layer was dried (Na2SO4) concentrated silica chromatographed

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

Procedure: Dissolve 3-(1,1-difluoro-ethyl)-benzonitrile (4.39 g, 26.26 mmol) in toluene (44 mL). Place the reaction under nitrogen, cool to −78° C. in a dry-ice bath, then add diisobutylaluminum hydride (52.5 mmol, 1 M solution in toluene) dropwise over 30 minutes with stirring. Stir the reaction in the dry-ice bath for 30 minutes, then add glacial HOAc (14 mL) dropwise to control foaming, followed by water (100 mL). Stir the reaction mixture overnight at room temperature. Separate the layers; extract the cloudy aqueous with toluene. Wash the toluene extracts with brine, dry the organics over magnesium sulfate, filter, and evaporate to afford 3-(1,1-difluoro-ethyl)-benzaldehyde as a pale yellow oil. (4.0 g, 90%). 1H NMR (400 MHz, CDCl3): δ 10.03 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 1.98-1.89 (m, 3H). the reaction under nitrogen Stir the reaction mixture overnight at room temperature Separate the layers extract the cloudy aqueous with toluene Wash the toluene dry the organics over magnesium sulfate filter evaporate

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

Procedure: Add a solution of [3-(1,1-Difluoro-ethyl)-phenyl]-methanol (3.47 mmol) in dichloromethane (10.5 mL) dropwise to a suspension of 3,3,3-triacetoxy-3-iodophthalide (3.64 mmol) in dichloromethane (10.5 mL) at room temperature. Stir for 30 minutes. Add diethyl ether (10 mL) and 5% aqueous sodium bicarbonate (10 mL) containing sodium thiosulfate (3 g). Mix well for 20 minutes. Separate the layers, and extract the aqueous with ethyl ether. Combine the organic layers, wash with brine, dry over sodium sulfate, filter, and evaporate to give a yellow solid. Purify over silica (40 g) eluting with 0 to 50% dichloromethane in hexanes. Evaporate until most solvent is removed being careful not to drive off the volatile product. Dry additionally by blowing a nitrogen stream over the product to give the title compound in 70% yield. 1HNMR (400.43 MHz, CDCl3): δ 10.03 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 1.98-1.89 (m, 3H). Mix well for 20 minutes Separate the layers extract the aqueous with ethyl ether wash with brine dry over sodium sulfate filter evaporate to give a yellow solid Purify over silica (40 g) eluting with 0 to 50% dichloromethane in hexanes Evaporate until most solvent is removed Dry additionally