(2,3,4,5,6-pentafluorophenyl)methanol

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

Procedure: A mixture of phosphorus tribromide (2.1 g) and toluene (1 cm3) was added dropwise to a solution of 2,3,4,5,6-pentafluorobenzylalcohol (3.4 g) and pyridine (0.21 g) in toluene (10 cm3) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, then at the ambient temperature (ca. 20° C.) for 75 minutes, and was then added to an excess of saturated sodium bicarbonate solution. The products were extracted into diethyl ether, and the combined ether layers dried and concentrated by evaporation under reduced pressure. The residual solution (still containing toluene) was passed through a plug of silica gel. at the ambient temperature (ca. 20° C.) for 75 minutes The products were extracted into diethyl ether the combined ether layers dried concentrated by evaporation under reduced pressure

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

Procedure: A mixture of pentafluorobenzyl alcohol (3.0 g) and dry methylene dichloride (50 ml) was cooled to a temperature of 0° C. in an ice-bath and 2-chloro-1-diethylamino-1,1,2-trifluoroethane (4.3 g) was slowly added to the cooled, stirred mixture over a period of ten minutes. After standing for a period of 18 hr at 0° C. the reaction mixture was poured into ice and the organic layer was separated and washed with IM aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation and the product was distilled under reduced pressure to give pentafluorobenzyl fluoride, b.p. 51° C. at 30 mm Hg. the reaction mixture was poured into ice the organic layer was separated washed with IM aqueous sodium carbonate solution The organic layer was dried over anhydrous sodium sulfate the solvent was removed by distillation the product was distilled under reduced pressure

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

Procedure: 38 g of sodium borohydride in 200 ml of dry dioxane are initially introduced into the apparatus at 20° C. and a solution of 86 g of pentafluorobenzoyl fluoride in 100 ml of dioxane is added dropwise, whilst stirring. When the addition has ended, the mixture is subsequently stirred at 20° C. for 2 hours and at 80° C. for 30 minutes and cooled and 75 ml of water are slowly added dropwise, followed by dilute hydrochloric acid until the mixture has a clearly acid reaction. After extraction with methylene chloride, the organic phase is distilled. 168 g of pentafluorobenzyl alcohol are obtained at a boiling point of 87° C./19 mbars. When the addition the mixture is subsequently stirred at 20° C. for 2 hours and at 80° C. for 30 minutes cooled a clearly acid reaction After extraction with methylene chloride the organic phase is distilled

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-δ-oxobenzenepentanoic acid (J. Org. Chem. 1948, 13, 284; J. Org. Chem. 1984, 49, 3170; 6.2 g, 23 mmol) was added to a solution of 1,3-diisopropylcarbodiimide (1.8 mL, 11.5 mmol) in tetrahydrofuran-dichloromethane (1:1, 40 mL) and the mixture was allowed to stand at room temperature for 20 min. The mixture was added to 4-sulfamylbenzoyl AM resin (Novabiochem, product no. 01-64-0121, 1.15 mmol/g loading; 2 g) in a 70 mL solid phase extraction cartridge equipped with a frit and stopcock. 4-Dimethylaminopyridine (138 mg, 1.1 mmol) was added and the mixture was allowed to stand overnight at room temperature. The resin was washed with tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×), dichloromethane (3×) and acetic acid (3×). A solution of (4-methylphenyl)hydrazine hydrochloride (3.2 g, 20 mmol) and zinc chloride (2.7 g, 20 mmol) in glacial acetic acid (40 mL) was added and the mixture was heated to 70° C. for 1 h. The mixture was vented, mixed manually and heated overnight at 70° C. The mixture was cooled and the resin was washed with acetic acid (3×), tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×) and tetrahydrofuran-dichloromethane (1:1, 4×). A solution of pentafluorobenzyl alcohol (2.3 g, 11.5 mmol), triphenylphosphine (3 g, 11.5 mmol) and diisopropyl azodicarboxylate (2.3 mL, 11.5 mmol) in tetrahydrofuran-dichloromethane (1:1, 40 mL) was added and the mixture was stirred at room temperature for 3 h. The resin was washed with tetrahydrofuran-dichloromethane (1:1, 4×), dimethylformamide (4×), tetrahydrofuran-dichloromethane (1:1, 4×), dichloromethane (4×) and ether (2×), then dried under a stream of nitrogen and transferred from the cartridge to a round bottom flask. A solution of 1-(2-methoxyphenyl)piperazine (884 mg, 4.6 mmol) in tetrahydrofuran (40 mL) was added and the mixture was left to stand at room temperature for 24 h. Scavenger resin (description 1, 2.4 g) and sufficient tetrahydrofuran to cover the additional swollen resin were added and the mixture was left to stand at room temperature for 24 h. The mixture was filtered and the resin washed with tetrahydrofuran. The combined filtrates were evaporated under reduced pressure and the residue was purified by medium pressure liquid chromatography on silica gel, eluting with hexane-ethyl acetate (1:1) to give the title compound (494 mg, 40%). 1H NMR (360 MHz, CDCl3) δ8.00 (1H, br s), 7.59-7.57 (2H, m), 7.45-7.32 (3H, m), 7.27-7.25 (1H, m), 7.06-7.00 (2H, m), 6.93-6.80 (3H, m), 3.85 (3H, s), 3.77 (2H, t, J 5.0 Hz), 3.43 (2H, t, J 5.0 Hz), 3.26 (2H, m), 2.93 (2H, t, J 5.0 Hz), 2.76 (2H, t, J 5.0 Hz), and 2.69 (2H, m). m/z (ES+) 532, 534 (M+1). The mixture was added to 4-sulfamylbenzoyl in a 70 mL solid phase extraction cartridge equipped with a frit and stopcock to stand overnight at room temperature The resin was washed with tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×), dichloromethane (3×) and acetic acid (3×) mixed manually heated overnight at 70° C The mixture was cooled the resin was washed with acetic acid (3×), tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×) and tetrahydrofuran-dichloromethane (1:1, 4×) The resin was washed with tetrahydrofuran-dichloromethane (1:1, 4×), dimethylformamide (4×), tetrahydrofuran-dichloromethane (1:1, 4×), dichloromethane (4×) and ether (2×) dried under a stream of nitrogen transferred from the cartridge to a round bottom flask the mixture was left to stand at room temperature for 24 h were added the mixture was left to stand at room temperature for 24 h The mixture was filtered the resin washed with tetrahydrofuran The combined filtrates were evaporated under reduced pressure the residue was purified by medium pressure liquid chromatography on silica gel eluting with hexane-ethyl acetate (1:1)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-δ-oxobenzenepentanoic acid (J. Org. Chem. 1948, 13, 284; J. Org. Chem. 1984, 49, 3170; 6.2 g, 23 mmol) was added to a solution of 1,3-diisopropylcarbodiimide (1.8 mL, 11.5 mmol) in tetrahydrofuran-dichloromethane (1:1, 40 mL) and the mixture was allowed to stand at room temperature for 20 min. The mixture was added to 4-sulfamylbenzoyl AM resin (Novabiochem, product no. 01-64-0121, 1.15 mmol/g loading; 2 g) in a 70 mL solid phase extraction cartridge equipped with a frit and stopcock. 4-Dimethylaminopyridine (138 mg, 1.1 mmol) was added and the mixture was allowed to stand overnight at room temperature. The resin was washed with tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×), dichloromethane (3×) and acetic acid (3×). A solution of (4-methylphenyl)hydrazine hydrochloride (3.2 g, 20 mmol) and zinc chloride (2.7 g, 20 mmol) in glacial acetic acid (40 mL) was added and the mixture was heated to 70° C. for 1 h. The mixture was vented, mixed manually and heated overnight at 70° C. The mixture was cooled and the resin was washed with acetic acid (3×), tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×) and tetrahydrofuran-dichloromethane (1:1, 4×). A solution of pentafluorobenzyl alcohol (2.3 g, 11.5 mmol), triphenylphosphine (3 g, 11.5 mmol) and diisopropyl azodicarboxylate (2.3 mL, 11.5 mmol) in tetrahydrofuran-dichloromethane (1:1, 40 mL) was added and the mixture was stirred at room temperature for 3 h. The resin was washed with tetrahydrofuran-dichloromethane (1:1, 4×), dimethylformamide (4×), tetrahydrofuran-dichloromethane (1:1, 4×), dichloromethane (4×) and ether (2×), then dried under a stream of nitrogen and transferred from the cartridge to a round bottom flask. A solution of 1-(2-methoxyphenyl)piperazine (884 mg, 4.6 mmol) in tetrahydrofuran (40 mL) was added and the mixture was left to stand at room temperature for 24 h. Scavenger resin (description 1, 2.4 g) and sufficient tetrahydrofuran to cover the additional swollen resin were added and the mixture was left to stand at room temperature for 24 h. The mixture was filtered and the resin washed with tetrahydrofuran. The combined filtrates were evaporated under reduced pressure and the residue was purified by medium pressure liquid chromatography on silica gel, eluting with hexane-ethyl acetate (1:1) to give the title compound (494 mg, 40%). 1H NMR (360 MHz, CDCl3) δ8.00 (1H, br s), 7.59-7.57 (2H, m), 7.45-7.32 (3H, m), 7.27-7.25 (1H, m), 7.06-7.00 (2H, m), 6.93-6.80 (3H, m), 3.85 (3H, s), 3.77 (2H, t, J 5.0 Hz), 3.43 (2H, t, J 5.0 Hz), 3.26 (2H, m), 2.93 (2H, t, J 5.0 Hz), 2.76 (2H, t, J 5.0 Hz), and 2.69 (2H, m). m/z (ES+) 532, 534 (M+1). The mixture was added to 4-sulfamylbenzoyl in a 70 mL solid phase extraction cartridge equipped with a frit and stopcock to stand overnight at room temperature The resin was washed with tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×), dichloromethane (3×) and acetic acid (3×) mixed manually heated overnight at 70° C The mixture was cooled the resin was washed with acetic acid (3×), tetrahydrofuran-dichloromethane (1:1, 3×), dimethylformamide (3×) and tetrahydrofuran-dichloromethane (1:1, 4×) The resin was washed with tetrahydrofuran-dichloromethane (1:1, 4×), dimethylformamide (4×), tetrahydrofuran-dichloromethane (1:1, 4×), dichloromethane (4×) and ether (2×) dried under a stream of nitrogen transferred from the cartridge to a round bottom flask the mixture was left to stand at room temperature for 24 h were added the mixture was left to stand at room temperature for 24 h The mixture was filtered the resin washed with tetrahydrofuran The combined filtrates were evaporated under reduced pressure the residue was purified by medium pressure liquid chromatography on silica gel eluting with hexane-ethyl acetate (1:1)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl bromide (9.6 g) in dry tetrahydrofuran (25 cm3) was added dropwise in a stirred mixture of magnesium turnings (5.0 g), dry tetrahydrofuran (50 cm3) and a small crystal of iodine at the ambient temperature (ca. 22° C.). When the addition was complete the mixture was stirred for a further 1 hour at the ambient temperature and the solution of methyl magnesium bromide thus formed was then added dropwise to a stirred solution to pentafluorobenzyl alcohol (17.8 g) in tetrahydrofuran (50 cm3) whilst the temperature was maintained at 30° C. When the addition was complete the mixture was stirred for a further 2 hours at the ambient temperature and for 3 hours at the reflux temperature. Water at 0° C. was added to the mixture, which was then acidified with dilute hydrochloric acid and extracted with diethyl ether (2×80 cm3). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (4.6 g) was shown by gas liquid chromatographic examination of a sample to consist of ca. 70% by weight of unreacted starting material and ca. 30% by weight of product. The oil was subjected to vigorous purification by column and thin-layer chromatography using a silica gel support and eluting with a mixture of diethyl ether and hexane (3:7 by volume), to obtain 2-methyl-3,4,5,6-tetrafluorobenzyl alcohol as a colourless oil. When the addition extracted with diethyl ether (2×80 cm3) washed with water dried over anhydrous magnesium sulphate concentrated by evaporation of the solvent under reduced pressure The oil was subjected to vigorous purification by column and thin-layer chromatography eluting with a mixture of diethyl ether and hexane (3:7 by volume)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl bromide (9.6 g) in dry tetrahydrofuran (25 cm3) was added dropwise in a stirred mixture of magnesium turnings (5.0 g), dry tetrahydrofuran (50 cm3) and a small crystal of iodine at the ambient temperature (ca. 22° C.). When the addition was complete the mixture was stirred for a further 1 hour at the ambient temperature and the solution of methyl magnesium bromide thus formed was then added dropwise to a stirred solution to pentafluorobenzyl alcohol (17.8 g) in tetrahydrofuran (50 cm3) whilst the temperature was maintained at 30° C. When the addition was complete the mixture was stirred for a further 2 hours at the ambient temperature and for 3 hours at the reflux temperature. Water at 0° C. was added to the mixture, which was then acidified with dilute hydrochloric acid and extracted with diethyl ether (2×80 cm3). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (4.6 g) was shown by gas liquid chromatographic examination of a sample to consist of ca. 70% by weight of unreacted starting material and ca. 30% by weight of product. The oil was subjected to vigorous purification by column and thin-layer chromatography using a silica gel support and eluting with a mixture of diethyl ether and hexane (3:7 by volume), to obtain 2-methyl-3,4,5,6-tetrafluorobenzyl alcohol as a colourless oil. When the addition extracted with diethyl ether (2×80 cm3) washed with water dried over anhydrous magnesium sulphate concentrated by evaporation of the solvent under reduced pressure The oil was subjected to vigorous purification by column and thin-layer chromatography eluting with a mixture of diethyl ether and hexane (3:7 by volume)

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

Procedure: A mixture of pentafluorobenzyl alcohol (3.0 g) and dry methylene dichloride (50 ml) was cooled to a temperature of 0° C. in an ice-bath and 2-chloro-1-diethylamino-1,1,2-trifluoroethane (4.3 g) was slowly added to the cooled, stirred mixture over a period of ten minutes. After standing for a period of 18 hr. at 0° C. the reaction mixture was poured into ice and the organic layer was separated and washed with IM aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation and the product was distilled under reduced pressure to give pentafluorobenzyl fluoride, b.p. 51° C. at 30 mm Hg. at 0° C. the reaction mixture was poured into ice the organic layer was separated washed with IM aqueous sodium carbonate solution The organic layer was dried over anhydrous sodium sulfate the solvent was removed by distillation the product was distilled under reduced pressure

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4.12 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride was added at 0° C. to a mixture of 3 g of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylic acid, 30 ml of methylene chloride, 3.96 g of pentafluorobenzyl alcohol and 100 mg of 4-dimethylaminopyridine and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 hexane-ethyl acetate mixture yielded 4.78 g of pentafluorobenzyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-23° (c=0.5% in chloroform). was filtered The filtrate was evaporated to dryness under reduced pressure the residue was chromatographed over silica gel Elution with a 9-1 hexane-ethyl acetate mixture

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4.12 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride was added at 0° C. to a mixture of 3 g of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylic acid, 30 ml of methylene chloride, 3.96 g of pentafluorobenzyl alcohol and 100 mg of 4-dimethylaminopyridine and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 hexane-ethyl acetate mixture yielded 4.78 g of pentafluorobenzyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-23° (c=0.5% in chloroform). was filtered The filtrate was evaporated to dryness under reduced pressure the residue was chromatographed over silica gel Elution with a 9-1 hexane-ethyl acetate mixture

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

Procedure: A mixture of phosphorus tribromide (2.1 g) and toluene (1 cm3) was added dropwise to a solution of 2,3,4,5,6-pentafluorobenzylalcohol (3.4 g) and pyridine (0.21 g) in toluene (10 cm3) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, then at the ambient temperature (ca. 20° C.) for 75 minutes, and was then added to an excess of saturated sodium bicarbonate solution. The products were extracted into diethyl ether, and the combined ether layers dried and concentrated by evaporation under reduced pressure. The residual solution (still containing toluene) was passed through a plug of silica gel. at the ambient temperature (ca. 20° C.) for 75 minutes The products were extracted into diethyl ether the combined ether layers dried concentrated by evaporation under reduced pressure

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

Procedure: A mixture of pentafluorobenzyl alcohol (3.0 g) and dry methylene dichloride (50 ml) was cooled to a temperature of 0° C. in an ice-bath and 2-chloro-1-diethylamino-1,1,2-trifluoroethane (4.3 g) was slowly added to the cooled, stirred mixture over a period of ten minutes. After standing for a period of 18 hr at 0° C. the reaction mixture was poured into ice and the organic layer was separated and washed with IM aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation and the product was distilled under reduced pressure to give pentafluorobenzyl fluoride, b.p. 51° C. at 30 mm Hg. the reaction mixture was poured into ice the organic layer was separated washed with IM aqueous sodium carbonate solution The organic layer was dried over anhydrous sodium sulfate the solvent was removed by distillation the product was distilled under reduced pressure