(1-bromo-3-chloropropan-2-yl)oxymethylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a stirred slurry of 4.6 g (0.19 mol) sodium hydride in 115 mL of dry dioxane was added dropwise 30.4 (0.10 mol) of diethyl malonate over a 30 min period. After this addition was complete, 50.0 g (0.19 mol) of 1-chloro-2-benzyloxy-3-bromopropane 3 was added dropwise in 30 min (St mixture was heated at reflux for 44 hr, cooled to room ##STR5## temperature, and 4.6 g (0.19 mol) of sodium hydride in 50 mL of dioxane was added in portions. The mixture was heated at reflux for an additional 120 hr. The solvent was partially removed under reduced pressure and the mixture was treated with 100 mL of water. The organic layer was extracted into ether. The ether extracts were dried and concentrated and the residue was distilled under reduced pressure. Distillation through a 12-in Vigreux column yielded 49.0 g (85%) of diethyl 3-benzyloxycyclobutane-1, 1-dicarboxylate 4 bp 174°-176° C. (0.9 mm); 1H NMR(CDCl3) δ1.23 (t, J=7 Hz, 6H, CH3), 4.0-4.7 (m, 1H OCH), 4.34 (s, 2H OCH2), 4.13 (q, J=7 Hz, 4H, OCOCH2), 7.23 (s, 5H, phenyl). After this addition was heated at reflux for 44 hr was added in portions The mixture was heated at reflux for an additional 120 hr The solvent was partially removed under reduced pressure the mixture was treated with 100 mL of water The organic layer was extracted into ether The ether extracts were dried concentrated the residue was distilled under reduced pressure Distillation through a 12-in Vigreux column

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

実験手順: Compound 1 was prepared according to the literature procedures of Avram, M., Nenitzescu, C. D. and Maxim, C. D. (1957) Chem. Ber., 90:1424 and Safanda, J. and Sobotka, P. (1982) Collect. Czech. Chem. Commun. 47:2440 with minor improvements. Malonic acid diethyl ester (258.6 ml, 1.703 moles) was added neat over a two hours period to a suspension of sodium hydride (51.10 g, 1.703 moles, Fluka N° 71614: 80% NaH in oil) in dioxane (1000 ml). This solution was stirred 90 min at room temperature. 1-Bromo-2-benzyloxy-3-chloro-propane (500 g, 1.789 moles) was added neat over a one hour period. The mixture was stirred for one hour at room temperature, followed by 24 hours at 125° C. After slow cooling to room temperature, a like quantity of sodium hydride was added neat in 5 g portions over one hour. The suspension was slowly heated to 125° C. and mechanically stirred for 120 hours at this temperature. The workup was as described in the literature references. Thus, compound 1 was first purified by distillation 172° C. at 0.6 Torr, followed by flash chromatography (tertiobutylmethylether/hexane=1/99 to 2/8) to afford 1: 382.5 g, 73.3% as a colourless oil. (1982) Collect The mixture was stirred for one hour at room temperature followed by 24 hours at 125° C After slow cooling to room temperature The suspension was slowly heated to 125° C. mechanically stirred for 120 hours at this temperature Thus, compound 1 was first purified by distillation 172° C. at 0.6 Torr to afford 1

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

実験手順: To a stirred slurry of 4.6 g (0.19 mol) sodium hydride in 115 mL of dry dioxane was added dropwise 30.4 (0.10 mol) of diethyl malonate over a 30 min period. After this addition was complete, 50.0 g (0.19 mol) of 1-chloro-2-benzyloxy-3-bromopropane 3 was added dropwise in 30 min (St mixture was heated at reflux for 44 hr, cooled to room ##STR5## temperature, and 4.6 g (0.19 mol) of sodium hydride in 50 mL of dioxane was added in portions. The mixture was heated at reflux for an additional 120 hr. The solvent was partially removed under reduced pressure and the mixture was treated with 100 mL of water. The organic layer was extracted into ether. The ether extracts were dried and concentrated and the residue was distilled under reduced pressure. Distillation through a 12-in Vigreux column yielded 49.0 g (85%) of diethyl 3-benzyloxycyclobutane-1, 1-dicarboxylate 4 bp 174°-176° C. (0.9 mm); 1H NMR(CDCl3) δ1.23 (t, J=7 Hz, 6H, CH3), 4.0-4.7 (m, 1H OCH), 4.34 (s, 2H OCH2), 4.13 (q, J=7 Hz, 4H, OCOCH2), 7.23 (s, 5H, phenyl). After this addition was heated at reflux for 44 hr was added in portions The mixture was heated at reflux for an additional 120 hr The solvent was partially removed under reduced pressure the mixture was treated with 100 mL of water The organic layer was extracted into ether The ether extracts were dried concentrated the residue was distilled under reduced pressure Distillation through a 12-in Vigreux column

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

実験手順: To a stirred slurry of 4.6 g (0.19 mol) sodium hydride in 115 mL of dry dioxane was added dropwise 30.4 (0.10 mol) of diethyl malonate over a 30 min period. After this addition was complete, 50.0 g (0.19 mol) of 1-chloro-2-benzyloxy-3-bromopropane 3 was added dropwise in 30 min (St mixture was heated at reflux for 44 hr, cooled to room ##STR5## temperature, and 4.6 g (0.19 mol) of sodium hydride in 50 mL of dioxane was added in portions. The mixture was heated at reflux for an additional 120 hr. The solvent was partially removed under reduced pressure and the mixture was treated with 100 mL of water. The organic layer was extracted into ether. The ether extracts were dried and concentrated and the residue was distilled under reduced pressure. Distillation through a 12-in Vigreux column yielded 49.0 g (85%) of diethyl 3-benzyloxycyclobutane-1, 1-dicarboxylate 4 bp 174°-176° C. (0.9 mm); 1H NMR(CDCl3) δ1.23 (t, J=7 Hz, 6H, CH3), 4.0-4.7 (m, 1H OCH), 4.34 (s, 2H OCH2), 4.13 (q, J=7 Hz, 4H, OCOCH2), 7.23 (s, 5H, phenyl). After this addition was heated at reflux for 44 hr was added in portions The mixture was heated at reflux for an additional 120 hr The solvent was partially removed under reduced pressure the mixture was treated with 100 mL of water The organic layer was extracted into ether The ether extracts were dried concentrated the residue was distilled under reduced pressure Distillation through a 12-in Vigreux column

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a stirred slurry of 4.6 g (0.19 mol) sodium hydride in 115 mL of dry dioxane was added dropwise 30.4 (0.10 mol) of diethyl malonate over a 30 min period. After this addition was complete, 50.0 g (0.19 mol) of 1-chloro-2-benzyloxy-3-bromopropane 3 was added dropwise in 30 min (Step 2). The mixture was heated at reflux for 44 hr, cooled to room temperature, and 4.6 g (0.19 mol) of sodium hydride in 50 mL of dioxane was added in portions. The mixture was heated at reflux for an additional 120 hr. The solvent was partially removed under reduced pressure and the mixture was treated with 100 mL of water. The organic layer was extracted into ether. The ether extracts were dried and concentrated and the residue was distilled under reduced pressure. Distillation through a 12-in Vigreux column yielded 49.0 g (85%) of diethyl 3-benzyloxycyclobutane-1,1-dicarboxylate 4 bp 174°-176° C. (0.9 mm); 1H NMR(CDCl3) δ 1.23 (t, J=7 Hz, 6H, CH3), 4.0-4.7 (m, 1H OCH), 4.34 (s, 2H OCH2), 4.13 (q, J=7 Hz, 4H, OCOCH2), 7.23 (s, 5H, phenyl). After this addition The mixture was heated at reflux for 44 hr The mixture was heated at reflux for an additional 120 hr The solvent was partially removed under reduced pressure the mixture was treated with 100 mL of water The organic layer was extracted into ether The ether extracts were dried concentrated the residue was distilled under reduced pressure Distillation through a 12-in Vigreux column

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

実験手順: To a stirred suspension of oil-free sodium hydride (10.7 g, 0.446 mol) in 270 ml of dry dioxane under nitrogen at room temperature was added over twenty minutes 69.1 g (0.432 mol) of diethyl malonate. After the addition, 1-chloro-2-benzyloxy-3-bromopropane (115 g, 0.437 mol) was added over 20 minutes, and the reaction was refluxed for 44 hours. The reaction was cooled to room temperature, and then a slurry of 10.7 g (0.446 mol) of oil-free sodium hydride in 100 ml of dioxane was cautiously added in portions. The mixture was refluxed for 120 hours and cooled to room temperature. The inorganics were removed by filtration, and the filtrate was concentrated in vacuo to an oil, which was partitioned between ether and water. The ether layer was dried (Na2SO4) and concentrated to an oil, which was distilled to give 58.8 g of desired product having a b.p. 142°-146°/0.3 mm. was added over 20 minutes the reaction was refluxed for 44 hours The mixture was refluxed for 120 hours cooled to room temperature The inorganics were removed by filtration the filtrate was concentrated in vacuo to an oil, which was partitioned between ether and water The ether layer was dried (Na2SO4) concentrated to an oil, which was distilled

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

実験手順: To a suspension of sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) in 1,4-dioxane (69 mL) was added diethyl malonate (17.7 mL, 0.117 mol) dropwise. The mixture was stirred for 1.5 hours at ambient temperature after complete addition. To this mixture was added [2-bromo-1-(chloromethyl)ethoxy]methylbenzene (prepared according to the procedure found in Organic Letters (2004), 6(11), pp. 1853-1856; 32.0 g, 0.121 mol) dropwise and the resulting mixture was stirred for 1 hour at ambient temperature, then heated at reflux for 16 hours. The mixture was cooled briefly in an ice bath and sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) was added portionwise. The mixture was heated to reflux for a further 24 hours. Upon cooling to room temperature, the mixture was poured into pH 7 buffer and brine, and the product was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 5-60% ethyl acetate in hexanes afforded product (26.9 g, 75%). after complete addition prepared 32.0 g, 0.121 mol) dropwise and the resulting mixture was stirred for 1 hour at ambient temperature heated at reflux for 16 hours The mixture was cooled briefly in an ice bath The mixture was heated to reflux for a further 24 hours Upon cooling to room temperature the mixture was poured into pH 7 buffer brine, and the product was extracted with three portions of ethyl acetate The combined extracts were washed with brine dried over sodium sulfate decanted concentrated Flash column chromatography, eluting with a gradient of 5-60% ethyl acetate in hexanes afforded product (26.9 g, 75%)

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

実験手順: Compound 1 was prepared according to the literature procedures of Avram, M., Nenitzescu, C. D. and Maxim, C. D. (1957) Chem. Ber., 90:1424 and Safanda, J. and Sobotka, P. (1982) Collect. Czech. Chem. Commun. 47:2440 with minor improvements. Malonic acid diethyl ester (258.6 ml, 1.703 moles) was added neat over a two hours period to a suspension of sodium hydride (51.10 g, 1.703 moles, Fluka N° 71614: 80% NaH in oil) in dioxane (1000 ml). This solution was stirred 90 min at room temperature. 1-Bromo-2-benzyloxy-3-chloro-propane (500 g, 1.789 moles) was added neat over a one hour period. The mixture was stirred for one hour at room temperature, followed by 24 hours at 125° C. After slow cooling to room temperature, a like quantity of sodium hydride was added neat in 5 g portions over one hour. The suspension was slowly heated to 125° C. and mechanically stirred for 120 hours at this temperature. The workup was as described in the literature references. Thus, compound 1 was first purified by distillation 172° C. at 0.6 Torr, followed by flash chromatography (tertiobutylmethylether/hexane=1/99 to 2/8) to afford 1: 382.5 g, 73.3% as a colourless oil. (1982) Collect The mixture was stirred for one hour at room temperature followed by 24 hours at 125° C After slow cooling to room temperature The suspension was slowly heated to 125° C. mechanically stirred for 120 hours at this temperature Thus, compound 1 was first purified by distillation 172° C. at 0.6 Torr to afford 1