2-[2-(4-bromophenyl)ethoxy]oxane

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Magnesium turnings (0.97 g, 39.9 mmol) were weighed into a 250 mL 3-neck RB flask which was then suba-sealed (side-arm), connected to a 100 mL pressure-equalising addition funnel (centre-socket), connected to a double-layer coil condenser (side-arm) which in turn was connected to a nitrogen-vacuum manifold and the apparatus purge-filled with nitrogen three times. Separately 2d (9.50 g, 33.3 mmol) was weighed into a 100 mL RB flask which was then attached to a nitrogen-vacuum manifold and purge-filled with nitrogen before THF (anhydrous, 60 mL) was cannula-transferred into the flask forming a colourless solution. This solution was then cannula transferred into the pressure-equalising addition funnel. Ethyl bromide (0.274 mL) was then “dripped” over the magnesium turnings in the reaction flask using a 1.0 mL Hamilton gastight syringe. The 2d/THF solution was then added dropwise to the reaction mixture and after about 5 mL had added the reaction flask was continually heated by means of a silicone heating oil bath (bath T: 85° C.) until reflux started. After the completion of the addition of 2d/THF (about 30-45 minutes) the reflux was maintained by means of the silicone heating oil bath for a period of 75 minutes before the reaction mixture was allowed to cool to room temperature. After this period the reaction mixture consisted of a deep orange solution containing some residual flakes of magnesium. The reaction flask was then surrounded with a water-ice/methanol-water cooling mixture and the reaction mixture chilled for a period of 5 minutes prior to DMF (anhydrous, 3.00 mL) being added to the reaction mixture in a single portion via a 5 mL Hamilton gastight syringe. The reaction mixture in the cooling bath was then stirred whilst being allowed to warm slowly to room temperature overnight. Next day the (melted) cooling bath was removed and the reaction mixture was allowed to stir at room temperature under nitrogen for a further 24 hours. After 24 hours the reaction mixture was quenched by dropwise addition of 60 mL of saturated aqueous NH4Cl, which initially caused the deposition of a dense white precipitate (magnesium hydroxides) which then dissolved as the addition continued. Post quenching the reaction mixture consisted of a lower nearly colourless aqueous layer and an upper deep yellow organic layer together with a few shards of magnesium turning. This mixture was then filtered directly into a 250 mL-separating funnel and the layers partitioned and separated. The aqueous layer was then extracted with 100 mL of Et2O and these extracts combined with the organic layer from the reaction mixture. The organic extracts were then dried over anhydrous MgSO4 for a period of 90 minutes before the drying mixture was filtered and the collected solid washed with 3×25 mL portions of Et2O. The filtrate and washings were then combined and stripped to dryness in vacuo (rotary evaporator) to yield a pale yellow oil. A small aliquot of the crude product was analysed by TLC (silica-gel TLC plates, 20% EtOAc/80% n-hexane elution mixture) against the 2d starting material which indicated that all of the starting material had reacted to form a new highly tailed major spot with an Rf of 0.52 with additional minor spots at Rf values of 0.09 and 0.0 (baseline). The crude product was then pre-loaded onto 11.0 g of Merck 60 (15-40 μm) silica gel purified by dry column flash chromatography: (i) Sinter size: 80 mm diameter/column packed to a depth of 55 mm with Merck and crude product/silica amalgam packed on top of this; (ii) time per fraction: 3.00 minutes; (iii) Fraction size: 100 mL; (iv) Elution gradient: % Volume n-hexane: 100-62% in 2% increments/% Volume EtOAc: 0-38% in 2% increments (20 fractions in total). After elution of the column fractions' 10-17 were analysed by TLC (20% EtOAc/80% n-hexane) which indicated that most of the product was contained within fractions' 11-14 but fractions' 10 and 15 also contained some material (product highly tailed on the column, common property of aldehyde containing compounds) therefore fractions' 10-15 were combined and stripped to dryness in vacuo (rotary evaporator) to yield a pale yellow liquid which was then further dried in vacuo (oil immersion pump) at room temperature for a period of 4 hours. Yield: 5.878 g (75.3%, yellow liquid). 1H NMR (CDCl3) δ 1.40-1.87 (m, 6H, [3×—CH2—]pyran), 2.98 (t, 2H, ArCH2), 3.45 (m, 1H, [OCHaHb-]pyran), 3.70 (q+m, 2H, —OpyranCHaHb— & [OCHaHb-]pyran), 3.97 (q, 1H, —OpyranCHaHb), 4.58 (m, 1H, [—OCHO-]pyran), 7.41 (d, 2H, ArH), 7.82 (d, 2H, ArH), 9.98 (s, 1H, ArCHO). was then suba-sealed (side-arm) connected to a 100 mL pressure-equalising addition funnel (centre-socket) connected to a double-layer coil condenser the apparatus purge-filled with nitrogen three times forming a colourless solution cannula transferred into the pressure-equalising addition funnel after about 5 mL had added the reaction flask until reflux to cool to room temperature After this period the reaction mixture consisted of a deep orange solution the reaction mixture chilled for a period of 5 minutes to warm slowly to room temperature overnight Next day the (melted) cooling bath was removed to stir at room temperature under nitrogen for a further 24 hours After 24 hours the reaction mixture was quenched by dropwise addition of 60 mL of saturated aqueous NH4Cl, which then dissolved as the addition Post quenching the reaction mixture This mixture was then filtered directly into a 250 mL- separating funnel the layers partitioned separated The aqueous layer was then extracted with 100 mL of Et2O The organic extracts were then dried over anhydrous MgSO4 for a period of 90 minutes before the drying mixture was filtered the collected solid washed with 3×25 mL portions of Et2O stripped to dryness in vacuo (rotary evaporator) to yield a pale yellow oil A small aliquot of the crude product was analysed by TLC (silica-gel TLC plates, 20% EtOAc/80% n-hexane elution mixture) against the 2d had reacted to form a new highly tailed major spot with an Rf of 0.52 with additional minor spots at Rf values of 0.09 and 0.0 (baseline) pre-loaded onto 11.0 g of Merck 60 (15-40 μm) silica gel purified by dry column flash chromatography 3.00 minutes (iv) Elution gradient After elution of the column fractions' 10-17 stripped to dryness in vacuo (rotary evaporator) to yield a pale yellow liquid which was then further dried in vacuo (oil immersion pump) at room temperature for a period of 4 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into 30 mL of CH2Cl2 in a 150 mL RB flask was dissolved 4-bromophenethyl alcohol (7.00 g, 34.80 mmol) and 3,4-dihydro-2H-pyran (3.80 mL, 41.61 mmol). To this solution was added a few crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was then stirred at room temperature under a blanket of nitrogen overnight. Overnight the reaction mixture changed colour again to a deep brown colour. The reaction mixture was transferred to a 250 mL separating funnel and extracted with 150 mL of saturated NaHCO3(aq) solution during which time the brown colouration in the organic layer faded to an orange colour. The layers were separated and the organic layer was extracted again with 150 mL of brine. The organic layer was then separated and dried over anhydrous MgSO4 for 1 hour at room temperature. The mixture was then filtered and the collected solid washed with 3×30 mL portions of CH2Cl2. The filtrate and washings were combined and stripped to dryness on a rotary evaporator to yield an orange oil. Column chromatographic conditions for the remainder of the crude product were determined by TLC analysis (10% EtOAc/90% n-hexane eluant) which indicated a major spot at Rf 0.5 with a few minor spots on and around the baseline. The crude product was then purified by dry column flash chromatography using a sinter of 80 mm diameter and 80 mm depth packed to a depth of 5.5 cm with Merck 60 (15-40 μm) silica gel, time per fraction: 4.00 minutes, crude product pre-loaded onto 12.5 g of Merck 60 (15-40 □m) and this loaded on top of the column. n-Hexane/EtOAc elution in 100 mL fractions with the EtOAc component increasing in 1% increments from 0% (fraction 1) to 15% (fraction 16). Fractions' 9 & 10 “foamed” on leaving the column and TLC (10% EtOAc/90% n-hexane) of fractions' 8-15 indicated pure product was contained in fractions' 9-12 and these were combined and stripped to dryness on a rotary evaporator before being further dried in vacuo (oil immersion pump) overnight at room temperature. Yield: 9.821 g (98.9%, colourless liquid). 1H NMR (CDCl3) δ 1.40-1.88 (m, 6H, [3×—CH2—]pyran), 2.86 (t, 2H, ArCH2—), 3.45 (m, 1H, [OCHaHb-]pyran), 3.58 (q, 1H, —OpyranCHaHb—), 3.73 (m, 1H, [OCHaHb-]pyran), 3.92 (q, 1H, —OpyranCHaHb—), 4.57 (m, 1H, [—OCHO-]pyran), 7.10 (d, 2H, ArH), 7.40 (d, 2H, ArH). Overnight separating funnel extracted with 150 mL of saturated NaHCO3(aq) solution during which time the brown colouration in the organic layer The layers were separated the organic layer was extracted again with 150 mL of brine The organic layer was then separated dried over anhydrous MgSO4 for 1 hour at room temperature The mixture was then filtered the collected solid washed with 3×30 mL portions of CH2Cl2 stripped to dryness on a rotary evaporator to yield an orange oil The crude product was then purified by dry column flash chromatography 4.00 minutes, crude product n-Hexane/EtOAc elution in 100 mL fractions with the EtOAc component increasing in 1% increments from 0% (fraction 1) to 15% (fraction 16) Fractions' 9 & 10 “foamed” on leaving the column and TLC (10% EtOAc/90% n-hexane) of fractions' 8-15 indicated pure product stripped to dryness on a rotary evaporator before being further dried in vacuo (oil immersion pump) overnight at room temperature

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Magnesium (1.31 g, 53.90 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene (14.00 g, 49.09 mmol) in tetrahydrofuran (20 ml). Then dibromoethane (0.1 ml) was added under an atmosphere of nitrogen gas, and the mixture was stirred under room temperature for 1 hour. After cooling to ice-cooling temperature, 2M-ethylene oxide/tetrahydrofuran solution (49.09 ml, 98.18 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl alcohol (6.00 g, 42%) . After cooling to ice- was added the mixture was stirred at room temperature for 2 hours The mixture was extracted with ethyl ether dried over magnesium sulfate After evaporation of the solvent the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: p-Toluenesulfonic acid (0.30 g) was added to a solution of 4-bromophenethyl alcohol (9.50 g, 47.24 mmol) in methylene chloride (50 ml), and the mixture was stirred under ice-cooling. To the mixture was added 3,4-dihydropyran (5.53 g, 65.74 mmol). After stirring under ice-cooling for 20 minutes, a saturated aqueous solution of sodium bicarbonate (40 ml) was added to the reaction mixture. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene was obtained (13.40 g, 99%). cooling After stirring under ice- cooling for 20 minutes The resulting mixture was extracted with methylene chloride dried over magnesium sulfate After evaporation of the solvent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: p-Toluenesulfonic acid (0.30 g) was added to a solution of 4-bromophenethyl alcohol (9.50 g, 47.24 mmol) in methylene chloride (50 ml), and the mixture was stirred under ice-cooling. To the mixture was added 3,4-dihydropyran (5.53 g, 65.74 mmol). After stirring under ice-cooling for 20 minutes, a saturated aqueous solution of sodium bicarbonate (40 ml) was added to the reaction mixture. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene was obtained (13.40 g, 99%). cooling After stirring under ice- cooling for 20 minutes The resulting mixture was extracted with methylene chloride dried over magnesium sulfate After evaporation of the solvent

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 11.3 g of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene and 100 ml of tetrahydrofuran was cooled to −78° C., to which 25.9 ml of 1.56 M solution of n-butyl lithium in n-hexane was added dropwise over 15 minutes. After stirring at −78° C. for 1 hour, 4.2 ml of N,N-dimethylformamide was added dropwise at the same temperature over 15 minutes. After further stirring at −78° C. for 1 hour, 100 ml of saturated aqueous ammonium chloride solution was added, and the stirring was further continued until the reaction mixture came to room temperature. The reaction mixture was extracted twice with 200 ml of ethyl acetate, and the ethyl acetate layers were combined, washed three times with saturated aqueous ammonium chloride solution, and washed with saturated aqueous sodium chloride solution. The combined ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. This residue was subjected to silica gel chromatography, which afforded 7.20 g (yield, 78%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-benzaldehyde, nD24.5 1.5311. was added dropwise over 15 minutes After further stirring at −78° C. for 1 hour came to room temperature The reaction mixture was extracted twice with 200 ml of ethyl acetate washed three times with saturated aqueous ammonium chloride solution washed with saturated aqueous sodium chloride solution The combined ethyl acetate layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure to give a residue

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 11.3 g of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene and 100 ml of tetrahydrofuran was cooled to −78° C., to which 25.9 ml of 1.56 M solution of n-butyl lithium in n-hexane was added dropwise over 15 minutes. After stirring at −78° C. for 1 hour, 4.2 ml of N,N-dimethylformamide was added dropwise at the same temperature over 15 minutes. After further stirring at −78° C. for 1 hour, 100 ml of saturated aqueous ammonium chloride solution was added, and the stirring was further continued until the reaction mixture came to room temperature. The reaction mixture was extracted twice with 200 ml of ethyl acetate, and the ethyl acetate layers were combined, washed three times with saturated aqueous ammonium chloride solution, and washed with saturated aqueous sodium chloride solution. The combined ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. This residue was subjected to silica gel chromatography, which afforded 7.20 g (yield, 78%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-benzaldehyde, nD24.5 1.5311. was added dropwise over 15 minutes After further stirring at −78° C. for 1 hour came to room temperature The reaction mixture was extracted twice with 200 ml of ethyl acetate washed three times with saturated aqueous ammonium chloride solution washed with saturated aqueous sodium chloride solution The combined ethyl acetate layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure to give a residue

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 15.67 g of 4-bromophenetyl alcohol, 6.88 g of 3,4-dihydro-2H-pyran, a catalytic amount of p-toluenesulfonic acid monohydrate, and 100 ml of tetrahydrofuran was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, which afforded 21.5 g (yield, 97%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene, m.p., 93.9° C. extracted twice with diethyl ether washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution in this order dried over anhydrous magnesium sulfate concentrated under reduced pressure, which

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 15.67 g of 4-bromophenetyl alcohol, 6.88 g of 3,4-dihydro-2H-pyran, a catalytic amount of p-toluenesulfonic acid monohydrate, and 100 ml of tetrahydrofuran was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, which afforded 21.5 g (yield, 97%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene, m.p., 93.9° C. extracted twice with diethyl ether washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution in this order dried over anhydrous magnesium sulfate concentrated under reduced pressure, which

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(4-bromophenethoxy)tetrahydro-2H-pyran (3.42 g, 12 mmol) in toluene (9.0 ml) and morpholine (1.22 g, 14 mmol) were added to a mixture of dry palladium acetate (32.3 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (86.0 mg, 0.29 mmol) and sodium t-butoxide (1.73 g, 18 mmol), and they were stirred at 70° C. for 16 hours. Water was added to the reaction mixture. After the extraction with ethyl acetate, the product was extracted from the organic layer with 1 M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was dried to obtain 4-morpholinophenethyl alcohol in the form of a light yellow solid (2.35 g, 95%). After the extraction with ethyl acetate the product was extracted from the organic layer with 1 M hydrochloric acid the product was extracted with ethyl acetate The organic layer was dried

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(4-bromophenethoxy)tetrahydro-2H-pyran (3.42 g, 12 mmol) in toluene (9.0 ml) and morpholine (1.22 g, 14 mmol) were added to a mixture of dry palladium acetate (32.3 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (86.0 mg, 0.29 mmol) and sodium t-butoxide (1.73 g, 18 mmol), and they were stirred at 70° C. for 16 hours. Water was added to the reaction mixture. After the extraction with ethyl acetate, the product was extracted from the organic layer with 1 M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was dried to obtain 4-morpholinophenethyl alcohol in the form of a light yellow solid (2.35 g, 95%). After the extraction with ethyl acetate the product was extracted from the organic layer with 1 M hydrochloric acid the product was extracted with ethyl acetate The organic layer was dried

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(4-bromophenethoxy)tetrahydro-2H-pyran (3.42 g, 12 mmol) in toluene (9.0 ml) and morpholine (1.22 g, 14 mmol) were added to a mixture of dry palladium acetate (32.3 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (86.0 mg, 0.29 mmol) and sodium t-butoxide (1.73 g, 18 mmol), and they were stirred at 70° C. for 16 hours. Water was added to the reaction mixture. After the extraction with ethyl acetate, the product was extracted from the organic layer with 1 M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was dried to obtain 4-morpholinophenethyl alcohol in the form of a light yellow solid (2.35 g, 95%). After the extraction with ethyl acetate the product was extracted from the organic layer with 1 M hydrochloric acid the product was extracted with ethyl acetate The organic layer was dried