1,1,1,2,2,3,3-heptafluoro-3-iodopropane

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: To 20 ml of an acetonitrile solution of 1.25 g of 4-aminothiophenol and 1.11 g of triethylamine, 5.91 g of 1-iodoheptafluoro-n-propane was added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ether, washed with an aqueous solution of 1N sodium hydroxide and purified by silica gel column chromatography (eluent:hexane:ethyl acetate=4:1) to give 1.85 g (yield 63%) of the title compound. washed with an aqueous solution of 1N sodium hydroxide purified by silica gel column chromatography (eluent:hexane:ethyl acetate=4:1)

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

Procedure: To 20 ml of an acetonitrile solution of 1.25 g of 4-aminothiophenol and 1.11 g of triethylamine, 5.91 g of 1-iodoheptafluoro-n-propane was added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ether, washed with an aqueous solution of 1N sodium hydroxide and purified by silica gel column chromatography (eluent:hexane:ethyl acetate=4:1) to give 1.85 g (yield 63%) of the title compound. washed with an aqueous solution of 1N sodium hydroxide purified by silica gel column chromatography (eluent:hexane:ethyl acetate=4:1)

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

Procedure: A solution of heptafluoropropyl iodide (14.58 g, 49.2 m.mole) in diethylether (65 ml) was stirred and cooled to -70°. A solution of phenylmagnesium bromide in diethylether (15.75 ml of a 3 molar solution; 47.25 m.mole) was then added dropwise at such a rate that the temperature of the reaction mixture did not exceed -65°. When the addition was complete, stirring was continued for 15 minutes and a solution of 1,3-dichloroacetone (5 g, 39.4 m.mole) in diethylether was then added dropwise, again at such a rate that the temperature of the reaction mixture did not exceed -65°. When the addition was complete, stirring was continued at -70° for 1 hour and then a saturated aqueous solution of ammonium chloride (50 ml) was added. The reaction mixture was allowed to warm to room temperature, water (25 ml) was added, and the aqueous layer was separated and extracted with diethylether (2×25 ml). The combined diethylether extracts were dried (MgSO4) and evaporated to give a pale yellow liquid which was immediately added to a stirred mixture of 1,2,4-triazole (2.7 g, 39.4 m.mole), anhydrous potassium carbonate (10.8 g, 78.75 m.mole) and dimethylformamide (DMF) (125 ml). Stirring was continued for 2.5 hours at room temperature and the reaction mixture was then poured into a mixture of diethylether (250 ml) and brine (800 ml). The aqueous layer was separated and extracted with diethylether (2×50 ml) and the combined diethylether extracts were dried (MgSO4) and evaporated. The residue was then flash chromatographed on silica (230-400 mesh), eluting with ethyl acetate to give, as a pale brown solid, 2-heptafluoropropyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (240 mg), which was used immediately in the next step. cooled to -70° mole) was then added dropwise at such a rate that the temperature of the reaction mixture did not exceed -65° When the addition did not exceed -65° When the addition stirring was continued at -70° for 1 hour the aqueous layer was separated extracted with diethylether (2×25 ml) The combined diethylether extracts were dried (MgSO4) evaporated to give a pale yellow liquid which Stirring was continued for 2.5 hours at room temperature The aqueous layer was separated extracted with diethylether (2×50 ml) the combined diethylether extracts were dried (MgSO4) evaporated flash chromatographed on silica (230-400 mesh) eluting with ethyl acetate

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

Procedure: To a solution composed of 20 ml of DMF and 2.24 g (12 mmol) of 2-mercaptobiphenyl was added 481 mg (12 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 1.73 ml (12 mmol) of perfluoropropyl iodide was added dropwise. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 days. The white precipitate formed in the reaction solution was removed by filtration. Water was addd to the filtrate, and the mixture was extracted with hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography (ethyl acetate:hexane=1:30) to give 3.46 g (87.3%) of 2-(heptafluoropropylthio)biphenyl as a colorless oil. The properties of the product were as shown below. was slowly elevated to room temperature the mixture was stirred for 2 days The white precipitate formed in the reaction solution was removed by filtration the mixture was extracted with hexane The organic layer was washed with water dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure to give a brown oil It was purified by silica gel column chromatography (ethyl acetate:hexane=1:30)

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

Procedure: To a solution composed of 20 ml of DMF and 2.24 g (12 mmol) of 2-mercaptobiphenyl was added 481 mg (12 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 1.73 ml (12 mmol) of perfluoropropyl iodide was added dropwise. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 days. The white precipitate formed in the reaction solution was removed by filtration. Water was addd to the filtrate, and the mixture was extracted with hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography (ethyl acetate:hexane=1:30) to give 3.46 g (87.3%) of 2-(heptafluoropropylthio)biphenyl as a colorless oil. The properties of the product were as shown below. was slowly elevated to room temperature the mixture was stirred for 2 days The white precipitate formed in the reaction solution was removed by filtration the mixture was extracted with hexane The organic layer was washed with water dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure to give a brown oil It was purified by silica gel column chromatography (ethyl acetate:hexane=1:30)

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

Procedure: To 20 ml of an acetonitrile solution of 1.25 g of 4-aminothiophenol and 1.11 g of triethylamine, 5.91 g of 1-iodoheptafluoro-n-propane was added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ether, washed with an aqueous solution of 1N sodium hydroxide and purified by silica gel column chromatography (eluent:hexane:ethyl acetate=4:1) to give 1.85 g (yield 63%) of the title compound. washed with an aqueous solution of 1N sodium hydroxide purified by silica gel column chromatography (eluent:hexane:ethyl acetate=4:1)

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

Procedure: Heptafluoropropyliodide (5 g, 6.9 mmole) was stirred at -78° C. in dry diethylether (20 ml). A solution of phenylmagnesium bromide in ethyl ether (10 ml of a 1.88 M solution) was added over a half-hour period. When this addition was complete, the reaction mixture was stirred at -20° C. for one hour. To this solution was added, at -78° C., 1,3-dichloroacetone (3.25 g, 25.6 mmole) in dry diethylether (20 ml) dropwise, keeping the temperature below -65° C. The mixture was then stirred four hours between -20° and -50° C. Glacial acetic acid (3 ml) in diethylether (5 ml) was added slowly followed by water (15 ml). The mixture was allowed to warm to 5° C. and then the phases were separated. The aqueous phase was washed with ether (2×25 ml). The ethereal extracts were combined, dried (MgSO4) and evaporated to give crude 1,3-dichloro-2-(heptafluoropropyl)propan-2-ol, which was used directly in the next step. When this addition To this solution was added, at -78° C. the temperature below -65° C The mixture was then stirred four hours between -20° and -50° C to warm to 5° C. the phases were separated The aqueous phase was washed with ether (2×25 ml) dried (MgSO4) evaporated

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

Procedure: Heptafluoropropyliodide (5 g, 6.9 mmole) was stirred at -78° C. in dry diethylether (20 ml). A solution of phenylmagnesium bromide in ethyl ether (10 ml of a 1.88 M solution) was added over a half-hour period. When this addition was complete, the reaction mixture was stirred at -20° C. for one hour. To this solution was added, at -78° C., 1,3-dichloroacetone (3.25 g, 25.6 mmole) in dry diethylether (20 ml) dropwise, keeping the temperature below -65° C. The mixture was then stirred four hours between -20° and -50° C. Glacial acetic acid (3 ml) in diethylether (5 ml) was added slowly followed by water (15 ml). The mixture was allowed to warm to 5° C. and then the phases were separated. The aqueous phase was washed with ether (2×25 ml). The ethereal extracts were combined, dried (MgSO4) and evaporated to give crude 1,3-dichloro-2-(heptafluoropropyl)propan-2-ol, which was used directly in the next step. When this addition To this solution was added, at -78° C. the temperature below -65° C The mixture was then stirred four hours between -20° and -50° C to warm to 5° C. the phases were separated The aqueous phase was washed with ether (2×25 ml) dried (MgSO4) evaporated

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

Procedure: Add perfluoropropyl iodide (6.6 mL, 48.0 mmol, from Aldrich, stabilized with Cu) dropwise, under N2, to a -78° C. solution of Boc-Val-Pro-Val-OCH3 ] (3.89, 9.0 mmol) in anhydrous diethyl ether (100 mL). Add methyllithium-lithium bromide complex (28.5 mL, 42.0 mmol) at a rate which maintains an internal reaction temperature below -70° C. Stir the reaction mixture at -78° C. for 1 hour, then remove the cold bath and continue stirring for 5 minutes. Pour the reaction mixture into H2O (100 mL) and acidify the aqueous phase with 1N HCl. Extract the aqueous phase with additional diethyl ether (100 mL) and dry (MgSO4) the combined ethereal extracts. Remove the solvent in vacuo and purify the resultant yellow foam by flash chromatography (4.0×25 cm column eluted with 3:1 Et2O-hexane) to yield the title compound as a white foam. (Yield: 654 mg, 13%). FT-IR (KBr) 3423, 3292, 2972, 2937, 2879, 2823, 2771, 2739, 2253, 1755, 1687, 1635, 1525, 1444, 1392, 1367, 1348, 1313, 1232, 1178, 1126, 1041, 1018, 966, 922, 910, 877, 837, 798, 756, 736, 667, 650, 632, 596 cm-1 ; 1H NMR (300 MHz, CDCl3)δ 7.63 (d, 1H, J=8.2 Hz, NH), 5.44 (d, 1H, J=9.2 Hz, NH), 5.02 (dd, 1H, J=7.8, 4.5 Hz, CH of Val), 4.64 (dd, 1H, J=8.0, 3.0 Hz, CH of Pro), 4.30 (dd, 1H, J=9.2, 6.8 Hz, α-CH of Val), 3.80-3.74 and 3.66-3.60 (pr m, 2H, CH2N), 2.31-1.92 (series of m, 6H, β-CH of Val, CH2CH2), 1.44 (s, 9H, t-Bu), 1.02 (d, 3H, J=7.0 Hz, CH3), 0.98,(d, 3H, J=6.9 Hz, CH3), 0.94 (d, 3H, J=6.7 Hz, CH3), 0.88 (d, 3H, J=6.9 Hz, CH3); 13C NMRδ 193.3, 193.0, 192.7, 172.9, 171.1, 155.7, 118.7, 115.8, 111.3, 108.9, 108.6, 108.2, 105.9, 79.6, 77.3, 77.2, 76.9, 76.6, 59.7, 59.3, 56.8, 47.8, 31.4, 29.0, 28.3, 26.9, 25.1, 19.9, 19.8, 19.7, 19.5, 19.4, 17.5, 17.4, 16.3, 16.1; 19F NMR (376.3 MHz, CDCl3)δ -80.91 (t, CF3), -119.03 and -120.43 (AB quartet, J=297 Hz, CF2), -126.62 (s, CF2), MS (CI/CH4) m/z (rel. intensity) 566 (MH+, 100). HRMS (C23H34F7N3O5) (M+) calcd 566.2492, obsd 566.2475. to a -78° C. an internal reaction temperature below -70° C remove the cold bath continue stirring for 5 minutes Pour the reaction mixture into H2O (100 mL) Extract the aqueous phase with additional diethyl ether (100 mL) dry (MgSO4) the combined ethereal extracts Remove the solvent in vacuo purify the resultant yellow foam by flash chromatography (4.0×25 cm column eluted with 3:1 Et2O-hexane)

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

Procedure: To an acetonitrile solution (20 ml) of 4-aminothiophenol (1.25 g, 9.98 mmol) and triethylamine (1.11 g, 11.0 mmol) was added 1-iodoheptafluoro-n-propane (5.91 g, 19.9 mmol), and the resultant mixture was stirred at room temperature for 3 hours. The mixture was diluted with ether, and washed with a 1N sodium hydroxide aqueous solution. Then, the product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.85 g (yield 63%) of the title compound. washed with a 1N sodium hydroxide aqueous solution Then, the product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1)