3-(phenylmethoxymethyl)cyclobutan-1-one

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 a diethyl ether (100 mL) solution of allyl benzyl ether (11.1 g, 75.0 mmol), was added zinc copper couple (74.5 g, 33.0 mmol) while stirring at room temperature, a dimethoxyethane (100 mL) solution of trichloroacetyl chloride (43.6 mL, 375 mmol) was added dropwise, and the mixture was stirred at mom temperature for six hours. The reaction mixture was poured into ice-cooled aqueous sodium hydrogencarbonate (500 mL), extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=15/1). The obtained dichloro product was dissolved in methanol (200 mL), ammonium chloride (20.0 g, 375 mmol) was added and zinc powder (30.0 g, 450 mmol) was added little by little while vigorously stirring. After the reaction was completed, the insoluble matters were filtered off with Celite, the filtrate was distilled off under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=15/1 then 12/1) to obtain the title compound (7.20 g, 37.9 mmol). the mixture was stirred at mom temperature for six hours The reaction mixture was poured into ice- extracted with ethyl acetate dried over anhydrous magnesium sulfate The mixture was filtered the solvent in the filtrate was distilled off under reduced pressure The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate The obtained dichloro product was dissolved in methanol (200 mL) while vigorously stirring the insoluble matters were filtered off with Celite the filtrate was distilled off under reduced pressure Water was added to the residue, which was extracted with ethyl acetate dried over anhydrous magnesium sulfate The mixture was filtered the solvent in the filtrate was then distilled off under reduced pressure The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate

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

Procedure: To a diethyl ether (100 mL) solution of allyl benzyl ether (11.1 g, 75.0 mmol), was added zinc copper couple (74.5 g, 33.0 mmol) while stirring at room temperature, a dimethoxyethane (100 mL) solution of trichloroacetyl chloride (43.6 mL, 375 mmol) was added dropwise, and the mixture was stirred at mom temperature for six hours. The reaction mixture was poured into ice-cooled aqueous sodium hydrogencarbonate (500 mL), extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=15/1). The obtained dichloro product was dissolved in methanol (200 mL), ammonium chloride (20.0 g, 375 mmol) was added and zinc powder (30.0 g, 450 mmol) was added little by little while vigorously stirring. After the reaction was completed, the insoluble matters were filtered off with Celite, the filtrate was distilled off under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=15/1 then 12/1) to obtain the title compound (7.20 g, 37.9 mmol). the mixture was stirred at mom temperature for six hours The reaction mixture was poured into ice- extracted with ethyl acetate dried over anhydrous magnesium sulfate The mixture was filtered the solvent in the filtrate was distilled off under reduced pressure The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate The obtained dichloro product was dissolved in methanol (200 mL) while vigorously stirring the insoluble matters were filtered off with Celite the filtrate was distilled off under reduced pressure Water was added to the residue, which was extracted with ethyl acetate dried over anhydrous magnesium sulfate The mixture was filtered the solvent in the filtrate was then distilled off under reduced pressure The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate

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: p-Toluene sulphonic acid (2.0 gm) was added to a solution of 3-[(benzyloxy)methyl]cyclobutanone (25.0 gm, 131.6 mmol) (step b) and 1,2-ethanediol (8.98 gm, 144.7 mmol) in benzene and the reaction mixture was refluxed with removal of water through dean-stark apparatus. After about 6 hours, the reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution, followed by water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get a crude product, which was purified by column chromatography. washed with saturated sodium bicarbonate solution The organic layer was dried over sodium sulphate concentrated under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 50 mL three-neck flask with t-BuOK (0.54 g, 4.8 mmol) and methyltriphenylphosphonium bromide (1.72 g, 4.8 mmol) inside, dry 1,4-dioxane was added under argon to give a yellow emulsion. This was heated to 40° C. for 30 min, after which time the mixture was cooled to 10° C. and a 1,4-dioxane solution of 3-(benzyloxymethyl)cyclobutanone (0.76 g, 4 mmol) was added drop by drop. The mixture was left stirring at 10° C. for 3 hr. Then the solvent was removed by rotary evaporator and the residue was dissolved in Et2O and H2O. The organic phase was separated and the aqueous phase was extracted with Et2O. The combined organic phase was dried over MgSO4 and the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane:EtOAc=3:1)). 1H NMR (CDCl3, 400 MHz): δ 2.36-2.48 (m, 2H), 2.52-2.64 (m, 1H), 2.72-2.84 (m, 2H), 3.48-3.50 (d, J=7.2, 2H), 4.53 (s, 1H), 4.74-4.77 (m, 2H), 7.2-7.4 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 29.82, 35.06, 73.26, 74.60, 106.52, 127.77, 127.88, 128.60, 147.34. MS (FAB): expected for C13H16O (M+H)+ 189.27. Found 189.12748. IR (neat) νmax 2921, 2853, 1720, 1676, 1453, 1272, 1113, 1071, 1027, 875, 737, 713, 698. to give a yellow emulsion after which time the mixture was cooled to 10° C. The mixture was left Then the solvent was removed by rotary evaporator the residue was dissolved in Et2O The organic phase was separated the aqueous phase was extracted with Et2O The combined organic phase was dried over MgSO4 the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane:EtOAc=3:1))

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 1 L flask charged with argon, dry THF 300 ml was added. This was cooled to −5° C., then n-BuLi (83 ml, 1.6M in hexane, 0.132 mol) was added. After mixing 5 min, diisopropylamine (18 ml, 0.132 mol) was added drop by drop. After stirring for 10 min, this solution was cooled to −78° C. Then a THF solution of 3-(benzyloxymethyl)-cyclobutanone (20 g, 0.11 mol) was added drop by drop at −78° C. After addition, replace the dry ice-acetone bath with ice-water bath. After stirring at 0° C. for 30 min, TMSCl (16 ml, 0.132 mol) was added dropwise, this was stirred at 0° C. for 1 hr and room temperature for 10 min. Then the solvents were removed and the residue was washed with dry pentane and filtered. The filtrate was concentrated to give crude product without further purification. 1H NMR (CDCl3, 600 MHz): δ 0.23 (s, 9H), 2.20 (dd, J=12.6, 1.2, 1H), 2.65 (m, 1H), 2.74 (dd, J=13.2, 4.2, 1H), 3.41 (m, 1H), 3.48 (m, 1H), 4.54 (s, 2H), 4.67 (s, 1H), 7.26-7.35 (m, 5H). 13C NMR (CDCl3, 150 MHz): δ 0.09, 32.70, 38.18, 73.26, 75.41, 93.69, 104.27, 127.70, 127.86, 128.55, 138.20. was added After mixing 5 min this solution was cooled to −78° C After addition After stirring at 0° C. for 30 min this was stirred at 0° C. for 1 hr and room temperature for 10 min Then the solvents were removed the residue was washed with dry pentane filtered The filtrate was concentrated to give crude product without further purification

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Zinc dust (93.5 g, 1.44 mol) was added to a solution of 3-(benzyloxymethyl)-2,2-dichlorocyclobutanone (124 g, 0.48 mol) in glacial acetic acid (800 ml) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in dichloromethane, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by column chromatography (Hexane:EtOAc=6:1). 1H NMR (CDCl3, 400 MHz): δ 2.70 (m, 1H), 2.84-2.92 (m, 2H), 3.08-3.18 (m, 2H), 3.59 (d, J=6.4, 2H), 4.56 (s, 2H), 7.28-7.38 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 23.88, 50.26, 73.11, 73.42, 127.88, 127.99, 128.68, 138.26, 207.22. were then filtered The residue was washed with diethyl ether the combined filtrate and washings were concentrated under reduced pressure The residue was dissolved in dichloromethane which was washed with saturated NaHCO3 twice The organic phase was dried over MgSO4 the solvent was evaporated to give an oily product, which was purified by column chromatography (Hexane:EtOAc=6:1)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 50 mL three-neck flask with t-BuOK (0.54 g, 4.8 mmol) and methyltriphenylphosphonium bromide (1.72 g, 4.8 mmol) inside, dry 1,4-dioxane was added under argon to give a yellow emulsion. This was heated to 40° C. for 30 min, after which time the mixture was cooled to 10° C. and a 1,4-dioxane solution of 3-(benzyloxymethyl)cyclobutanone (0.76 g, 4 mmol) was added drop by drop. The mixture was left stirring at 10° C. for 3 hr. Then the solvent was removed by rotary evaporator and the residue was dissolved in Et2O and H2O. The organic phase was separated and the aqueous phase was extracted with Et2O. The combined organic phase was dried over MgSO4 and the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 400 MHz): δ 2.36-2.48 (m, 2H), 2.52-2.64 (m, 1H), 2.72-2.84 (m, 2H), 3.48-3.50 (d, J=7.2, 2H), 4.53 (s, 1H), 4.74-4.77 (m, 2H), 7.2-7.4 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 29.82, 35.06, 73.26, 74.60, 106.52, 127.77, 127.88, 128.60, 147.34. MS (FAB): expected for C13H160 (M+H)+ 189.27. Found 189.12748. IR (neat) νmax 2921, 2853, 1720, 1676, 1453, 1272, 1113, 1071, 1027, 875, 737, 713, 698. to give a yellow emulsion after which time the mixture was cooled to 10° C. The mixture was left Then the solvent was removed by rotary evaporator the residue was dissolved in Et2O The organic phase was separated the aqueous phase was extracted with Et2O The combined organic phase was dried over MgSO4 the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane: EtOAc=3:1))

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 1 L flask charged with argon, dry THF 300 ml was added. This was cooled to −5° C., then n-BuLi (83 ml, 1.6M in hexane, 0.132 mol) was added. After mixing 5 min, diisopropylamine (18 ml, 0.132 mol) was added drop by drop. After stirring for 10 min, this solution was cooled to −78° C. Then a THF solution of 3-(benzyloxymethyl)-cyclobutanone (20 g, 0.11 mol) was added drop by drop at −78° C. After addition, replace the dry ice-acetone bath with ice-water bath. After stirring at 0° C. for 30 min, TMSCl (16 ml, 0.132 mol) was added dropwise, this was stirred at 0° C. for 1 hr and room temperature for 10 min. Then the solvents were removed and the residue was washed with dry pentane and filtered. The filtrate was concentrated to give crude product without further purification. 1H NMR (CDCl3, 600 MHz): δ 0.23 (s, 9H), 2.20 (dd, J=12.6, 1.2, 1H), 2.65 (m, 1H), 2.74 (dd, J=13.2, 4.2, 1H), 3.41 (m, 1H), 3.48 (m, 1H), 4.54 (s, 2H), 4.67 (s, 1H), 7.26-7.35 (m, 5H). 13C NMR (CDCl3, 150 MHz): δ 0.09, 32.70, 38.18, 73.26, 75.41, 93.69, 104.27, 127.70, 127.86, 128.55, 138.20. was added After mixing 5 min this solution was cooled to −78° C After addition After stirring at 0° C. for 30 min this was stirred at 0° C. for 1 hr and room temperature for 10 min Then the solvents were removed the residue was washed with dry pentane filtered The filtrate was concentrated to give crude product without further purification