4,4,4-trifluorobutanoyl chloride

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:0.00; pressure:0.00; stir:

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 20.35 g of magnesium (turning) and 148 ml of ethanol, 0.1 ml of carbon tetrachloride was added and heated to 55° C. To the mixture, a mixed solution of 197 ml of ethanol, 700 ml of diethyl ether and 168 g of diethyl malonate was added dropwise over one hour. After 2 hours, the reaction solution was cooled to -5° C. under a nitrogen flow and 112 g of 4,4, 4-trifluorobutyryl chloride was added. After the temperature was returned to ambient temperature over one hour, the reaction was further conducted for 12 hours. The reaction solution was poured into an aqueous 5% ice-cooled hydrochloric acid, and extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated 20 saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 179 g of 4,4,4-trifluorobutyryl-malonic acid diethyl ester (b.p.: 125°-134° C., 15 mmHg) (yield: 90%). 1H-NMR (CDCl3, internal standard TMS); δ value (ppm): 1.32 (t, 3H), 2.50 (m, 2H), 2.95 (t, 2H), 4.29 (q, 2H), 4.50 (s, 1H) was added was added After the temperature was returned to ambient temperature over one hour the reaction was further conducted for 12 hours extracted three times with diethyl ether the combined ether layer was washed twice with saturated 20 saline dried over anhydrous magnesium sulfate Then, the solvent was distilled off under reduced pressure

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

Procedure: To a mixture of 131 g of 4,4,4-trifluorobutyric acid and 1 liter of pentane, 101 ml of oxalyl chloride and 0.1 ml of dimethylformamide were added, and the mixture was heated at reflux for 3 hours. The reaction solution was distilled at normal pressure to give 112 g of 4,4,4-trifluorobutyryl chloride (b.p. 103° C., 760 mmHg) (yield: 76%). were added the mixture was heated at reflux for 3 hours The reaction solution was distilled at normal pressure

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

Procedure: 4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH2Cl2 (80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0 mmol, 5.85 g). The mixture was cooled to 0° C., then treated with pyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (200 ml), then washed with brine(2×50 ml). Solvent was removed from the volatile product by simple distillation at atmospheric pressure to provide 20 g of 4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used without further purification. 1H NMR (CDCl3) δ3.70 (3H, s), 3.19 (3H, s), 2.78-2.65 (2H, m), 2.57-2.40 (2H, m). to warm to room temperature overnight washed with brine(2×50 ml) Solvent was removed from the volatile product by simple distillation at atmospheric pressure

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

Procedure: Method 5 General Experimental: 4,4,4-Trifluorobutyric acid (70.0 mmol, 10.0 g) in CH2Cl2 (190 ml) was treated with oxalyl chloride (140 mmol, 12.3 ml) and DMF (1 drop), then heated to reflux for 1 h. Solvent and excess oxalyl chloride were removed from the volatile product by simple distillation of the reaction mixture at atmospheric pressure to provide crude 4,4,4-trifluorobutyric acid chloride (6.4 g). 1H NMR (CDCl3) δ3.20 (2H, t, J=7.2), 2.65-2.45 (2H, m). heated to reflux for 1 h Solvent and excess oxalyl chloride were removed from the volatile product by simple distillation of the reaction mixture at atmospheric pressure

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

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.1 ml of carbon tetrachloride was added to a mixture of 20.35 g of magnesium(turnings) and 148 ml of ethanol and then heated at 55° C. A mixed solution of 197 ml of ethanol, 700 ml of diethyl ether and 168 g of diethyl malonate was added to the reaction mixture over 1 hour. Two hours later the reaction solution was cooled to -5° C. and 112 g of 4,4,4-trifluorobutyryl chloride was added to the solution under an atmosphere of nitrogen, then the resultant reaction mixture was left at an ambient temperature for 1 hour. Then the mixture was allowed to react further 12 hours. After completion of the reaction, the reaction solution was poured into a 5% hydrochloric acid solution and extracted three times with diethyl ether. The ether layers were combined and washed twice with brine and dried over anhydrous magnesium sulfate. The filtered ether solution was evaporated under reduced pressure. The obtained residue was distilled under reduced pressure to yield 179 g of the desired 4,4,4-trifluoro-butyrylmalonic acid diethyl ester in a yield of 90%. Two hours later the reaction solution was cooled to -5° C. the resultant reaction mixture to react further 12 hours After completion of the reaction extracted three times with diethyl ether washed twice with brine dried over anhydrous magnesium sulfate The filtered ether solution was evaporated under reduced pressure The obtained residue was distilled under reduced pressure