2,3,4,5,6-Pentafluorobenzonitrile

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

Procedure: A solution of 44.8 g (0.83 mole) of sodium methoxide in 1.6 liters of methanol was added dropwise at room temperature to a solution of 160.0 g (0.83 mole) of pentafluorobenzonitrile (XVIII) in 2.5 liters of methanol, whilst stirring. When the addition was complete, the mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was shaken with a mixture of water and toluene. The toluene layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residual solid was washed with hexane to afford 160.7 g of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX) as colorless needles. When the addition At the end of this time, the solvent was removed by evaporation under reduced pressure the residue was shaken with a mixture of water and toluene The toluene layer was separated washed with water dried over anhydrous sodium sulfate the solvent was then removed by evaporation under reduced pressure The residual solid was washed with hexane

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

Procedure: A mixture of 0.76 g of dl-5-chloro-6-ethyl-4-(αethyl-4-hydroxybenzylamino)pyrimidine, 0.5 g of pentafluorobenzonitrile, 0.4 g of anhydrous potassium carbonate and 20 ml of 1,3-dimethyl-2-imidazolidinone (DMI) was heated under stirring at 70 .C for 8 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and then toluene was evaporated under reduced pressure. The oily product obtained was isolated by column chromatography (Wako gel C-200, eluted with toluene:ethyl acetate=10:1) to give 0.8 g of the desired product as a colorless oily product. was heated After completion of the reaction extracted with toluene The extract was washed with water dried over anhydrous sodium sulfate toluene was evaporated under reduced pressure The oily product obtained

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

Procedure: A mixture of 0.76 g of dl-5-chloro-6-ethyl-4-(αethyl-4-hydroxybenzylamino)pyrimidine, 0.5 g of pentafluorobenzonitrile, 0.4 g of anhydrous potassium carbonate and 20 ml of 1,3-dimethyl-2-imidazolidinone (DMI) was heated under stirring at 70 .C for 8 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and then toluene was evaporated under reduced pressure. The oily product obtained was isolated by column chromatography (Wako gel C-200, eluted with toluene:ethyl acetate=10:1) to give 0.8 g of the desired product as a colorless oily product. was heated After completion of the reaction extracted with toluene The extract was washed with water dried over anhydrous sodium sulfate toluene was evaporated under reduced pressure The oily product obtained

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (78.63 g, 0.3 mol, Aldrich Chemical Co., Milwaukee, Wis.), 1-fluoro-2,4-dinitrobenzene (18.6 g, 0.10 mmol), triethyl amine (42 mL, 0.3 mol) and acetone (100 mL) was heated to 80° C. for 1.5 hr. After aqueous workup the excess hexanediol removed by Kugelrohr distillation and the dimer by-product was removed by crystallization. The residual oil was treated with pentafluorobenzonitrile (19.3 g, 0.10 mol), triethyl amine (15.3 mL, 0.11 mol) and acetone (100 mL) and heated to reflux for 4 h. Aqueous workup followed by extraction gave 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octafluorohexyloxy]-2,3,5,6-tetrafluorobenzonitrile as an orange oil. After aqueous workup the excess hexanediol removed by Kugelrohr distillation the dimer by-product was removed by crystallization heated to reflux for 4 h Aqueous workup followed by extraction

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (78.63 g, 0.3 mol, Aldrich Chemical Co., Milwaukee, Wis.), 1-fluoro-2,4-dinitrobenzene (18.6 g, 0.10 mmol), triethyl amine (42 mL, 0.3 mol) and acetone (100 mL) was heated to 80° C. for 1.5 hr. After aqueous workup the excess hexanediol was removed by Kugelrohr distillation and the dimer by-product was removed by crystallization. The residual oil was treated with pentafluorobenzonitrile (19.3 g, 0.10 mol), triethyl amine (15.3 mL, 0.11 mol) and acetone (100 mL) and heated to reflux for 4 h. Aqueous workup followed by extraction gave 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluorobenzonitrile as an orange oil. After aqueous workup the excess hexanediol was removed by Kugelrohr distillation the dimer by-product was removed by crystallization heated to reflux for 4 h Aqueous workup followed by extraction

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (78.63 g, 0.3 mol, Aldrich Chemical Co., Milwaukee, Wis.), 1-fluoro-2,4-dinitrobenzene (18.6 g, 0.10 mmol), triethyl amine (42 mL, 0.3 mol) and acetone (100 mL) was heated to 80° C. for 1.5 hr. After aqueous workup the excess hexanediol was removed by Kugelrohr distillation and the dimer by-product was removed by crystallization. The residual oil was treated with pentafluorobenzonitrile (19.3 g, 0.10 mol), triethyl amine (15.3 mL, 0.11 mol) and acetone (100 mL) and heated to reflux for 4 h. Aqueous workup followed by extraction gave 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluorobenzonitrile as an orange oil. After aqueous workup the excess hexanediol was removed by Kugelrohr distillation the dimer by-product was removed by crystallization heated to reflux for 4 h Aqueous workup followed by extraction

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

Procedure: A solution of 44.8 g (0.83 mole) of sodium methoxide in 1.6 liters of methanol was added dropwise at room temperature to a solution of 160.0 g (0.83 mole) of pentafluorobenzonitrile (XVIII) in 2.5 liters of methanol, whilst stirring. When the addition was complete, the mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was shaken with a mixture of water and toluene. The toluene layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residual solid was washed with hexane to afford 160.7 g of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX) as colorless needles. When the addition At the end of this time, the solvent was removed by evaporation under reduced pressure the residue was shaken with a mixture of water and toluene The toluene layer was separated washed with water dried over anhydrous sodium sulfate the solvent was then removed by evaporation under reduced pressure The residual solid was washed with hexane

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

Procedure: A solution of 44.8 g (0.83 mole) of sodium methoxide in 1.6 liters of methanol was added dropwise at room temperature to a solution of 160.0 g (0.83 mole) of pentafluorobenzonitrile (XVIII) in 2.5 liters of methanol, whilst stirring. When the addition was complete, the mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was shaken with a mixture of water and toluene. The toluene layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residual solid was washed with hexane to afford 160.7 g of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX) as colorless needles. When the addition At the end of this time, the solvent was removed by evaporation under reduced pressure the residue was shaken with a mixture of water and toluene The toluene layer was separated washed with water dried over anhydrous sodium sulfate the solvent was then removed by evaporation under reduced pressure The residual solid was washed with hexane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (78.63 g, 0.3 mol, Aldrich Chemical Co., Milwaukee, Wis.), 1-fluoro-2,4-dinitrobenzene (18.6 g, 0.10 mmol), triethyl amine (42 mL, 0.3 mol) and acetone (100 mL) was heated to 80° C. for 1.5 hr. After aqueous workup the excess hexanediol removed by Kugelrohr distillation and the dimer by-product was removed by crystallization. The residual oil was treated with pentafluorobenzonitrile (19.3 g, 0.10 mol), triethyl amine (15.3 mL, 0.11 mol) and acetone (100 mL) and heated to reflux for 4 h. Aqueous workup followed by extraction gave 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octafluorohexyloxy]-2,3,5,6-tetrafluorobenzonitrile as an orange oil. After aqueous workup the excess hexanediol removed by Kugelrohr distillation the dimer by-product was removed by crystallization heated to reflux for 4 h Aqueous workup followed by extraction

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

Procedure: A solution of sodium methoxide (18 g, 83 mmol, 25% in methanol) is added dropwise to a solution of pentafluorobenzonitrile (7.72 g, 40 mmol) in 60 mL methanol over 15 min. The reaction is heated to reflux for 3 hours, cooled to room temperature and then poured into 150 mL ice water. The product is then extracted with diethyl ether (100 mL×2), and the combined organic layers are washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is then chromatographed on silica gel, eluting with hexane:ethyl acetate (97:3 to 88:12 gradient) to yield 6.18 g (71%) of Compound 43 as a colorless oil. 1H-NMR (CDCl3) 4.16 (s, 3H); 4.10 (s, 3H). 19F NMR (CDCl3) 134.39 (dd, J=10.1 and 20.3 Hz, 1F); 150.80 (d, J=7.1 Hz, 1F); 158.00 (d, J=21.4 Hz, 1F). Anal. calc. for C9H6F3NO2: C, 49.78; H, 2.78; N, 6.45. Found: C, 49.71; H, 2.78; N, 6.56. A second product, 3,5-difluoro-2,4,6-trimethoxybenzonitrile, is also isolated from the reaction mixture as a colorless solid (1.09 g; 12%). 1H-NMR (CDCl3) 4.12 (s, 3H); 4.07 (s, 6H). 19F-NMR (CDCl3) 152.11 (s). The reaction is heated to reflux for 3 hours The product is then extracted with diethyl ether (100 mL×2) the combined organic layers are washed with brine (50 mL) dried over magnesium sulfate concentrated in vacuo The residue is then chromatographed on silica gel eluting with hexane:ethyl acetate (97:3 to 88:12 gradient)

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

Procedure: A solution of sodium methoxide (18 g, 83 mmol, 25% in methanol) is added dropwise to a solution of pentafluorobenzonitrile (7.72 g, 40 mmol) in 60 mL methanol over 15 min. The reaction is heated to reflux for 3 hours, cooled to room temperature and then poured into 150 mL ice water. The product is then extracted with diethyl ether (100 mL×2), and the combined organic layers are washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is then chromatographed on silica gel, eluting with hexane:ethyl acetate (97:3 to 88:12 gradient) to yield 6.18 g (71%) of Compound 43 as a colorless oil. 1H-NMR (CDCl3) 4.16 (s, 3H); 4.10 (s, 3H). 19F-NMR (CDCl3) 134.39 (dd, J=10.1 and 20.3 Hz, 1 F); 150.80 (d, J=7.1 Hz, 1 F); 158.00 (d, J=21.4 Hz, 1 F). Anal. calc. for C9H6F3NO2 : C, 49.78; H, 2.78; N, 6.45. Found: C, 49.71; H, 2.78; N, 6.56. A second product, 3,5-difluoro-2,4,6-trimethoxybenzonitrile, is also isolated from the reaction mixture as a colorless solid (1.09 g; 12%). 1H-NMR (CDCl3) 4.12 (s, 3H); 4.07 (s, 6H). 19F-NMR (CDCl3) 152.11 (s). The reaction is heated to reflux for 3 hours The product is then extracted with diethyl ether (100 mL×2) the combined organic layers are washed with brine (50 mL) dried over magnesium sulfate concentrated in vacuo The residue is then chromatographed on silica gel eluting with hexane:ethyl acetate (97:3 to 88:12 gradient)

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

Procedure: A mixture of 0.76 g of dl-5-chloro-6-ethyl-4-(αethyl-4-hydroxybenzylamino)pyrimidine, 0.5 g of pentafluorobenzonitrile, 0.4 g of anhydrous potassium carbonate and 20 ml of 1,3-dimethyl-2-imidazolidinone (DMI) was heated under stirring at 70 .C for 8 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and then toluene was evaporated under reduced pressure. The oily product obtained was isolated by column chromatography (Wako gel C-200, eluted with toluene:ethyl acetate=10:1) to give 0.8 g of the desired product as a colorless oily product. was heated After completion of the reaction extracted with toluene The extract was washed with water dried over anhydrous sodium sulfate toluene was evaporated under reduced pressure The oily product obtained