2,2-diethoxyethoxymethylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Prepared by a modification of the literature procedure reported in Croat. Chim. Acta, 1966, 235. Phosphorus pentachloride (0.13 mol) was added to benzyloxyacetaldehyde diethyl acetal (0.13 mol) at 20-30° C. The reaction mixture was heated at 60° C. for 75 min and then cooled to 0° C. The reaction mixture was treated with DMF (0.39 mol) and stirred at room temperature for four days. The reaction mixture was diluted with 1.0N HCl(aq) (200 ml) and ether (200 ml). The ether layer was discarded and the aqueous layer was basified with 8N NaOH(aq). The aqueous layer was extracted with ethyl acetate and ether and the combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The resulting black oil was purified by column chromatography to give the product as a brown solid (0.06 mol, 43%). δH (250 MHz; CDCl3) 8.62 (1H, s), 7.44-7.26 (5H, m), 6.18 (1H, s), 4.96 (2H, s), 3.04 (6H, s). Prepared by a modification of the literature procedure cooled to 0° C The aqueous layer was extracted with ethyl acetate and ether the combined organic extracts were dried (MgSO4) filtered evaporated in vacuo The resulting black oil was purified by column chromatography

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

Procedure: [(2,2-Diethoxyethoxy)methyl]benzene (8.30 g, 37.0 mmol) stirred under ice cooling was added with phosphorus pentachloride (8.09 g, 38.8 mmol) over 15 minutes. The mixture was stirred at the same temperature for 15 minutes, and then heated and stirred on an oil bath at 75° C. for 75 minutes. The reaction mixture was cooled by stirring at room temperature for 20 minutes, cooled, and then added with anhydrous N,N-dimethylformamide (8.6 mL, 111 mmol) at the same temperature, and the mixture was stirred at room temperature for 3 days. The reaction mixture was added with 8 M aqueous sodium hydroxide on an ice bath until pH became 8 or higher, and then the mixture was diluted with water, and extracted with ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=4:1→2:1) to obtain 2-(benzyloxy)-3-(dimethylamino)acrylaldehyde (4.05 g, 53%) as brown oil. heated stirred on an oil bath at 75° C. for 75 minutes The reaction mixture was cooled by stirring at room temperature for 20 minutes cooled the mixture was stirred at room temperature for 3 days extracted with ether The organic layer was washed successively with water and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography (hexane:acetone=4:1→2:1)

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

Procedure: POCl3 (12.9 ml, 141.2 mmol) was added to DMF (10.9 ml, 141.2 mmol) at 0° C. The reaction was immediately warmed to ambient temperature and stirred for 30 minutes. ((2,2-diethoxyethoxy)methyl)benzene (10.6 g, 47.1 mmol) was added as a solution in 80 mL of chloroform. The solution was stirred at 75° C. for 3.5 hours. The solution was cooled, poured over ice water, and neutralized with Na2CO3. The residue was extracted with chloroform and the organic layer was dried with Na2SO4 and concentrated. The residue was re-dissolved in MeOH (450 mL). NaOMe (25% in MeOH, 58 ml, 253 mmol) was added followed by 2-hydrazinylethanol (10.6 g, 139 mmol). The reaction stirred overnight at ambient temperature. The material was concentrated in vacuo followed by dilution with saturated NH4Cl solution. The material was extracted with EtOAc, dried (Mg2SO4), and concentrated. Flash chromatography gave 2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 13% yield). The solution was stirred at 75° C. for 3.5 hours The solution was cooled The residue was extracted with chloroform the organic layer was dried with Na2SO4 concentrated The residue was re-dissolved in MeOH (450 mL) The reaction stirred overnight at ambient temperature The material was concentrated in vacuo The material was extracted with EtOAc dried (Mg2SO4) concentrated

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

Procedure: POCl3 (12.9 ml, 141.2 mmol) was added to DMF (10.9 ml, 141.2 mmol) at 0° C. The reaction was immediately warmed to ambient temperature and stirred for 30 minutes. ((2,2-diethoxyethoxy)methyl)benzene (10.6 g, 47.1 mmol) was added as a solution in 80 mL of chloroform. The solution was stirred at 75° C. for 3.5 hours. The solution was cooled, poured over ice water, and neutralized with Na2CO3. The residue was extracted with chloroform and the organic layer was dried with Na2SO4 and concentrated. The residue was re-dissolved in MeOH (450 mL). NaOMe (25% in MeOH, 58 ml, 253 mmol) was added followed by 2-hydrazinylethanol (10.6 g, 139 mmol). The reaction stirred overnight at ambient temperature. The material was concentrated in vacuo followed by dilution with saturated NH4Cl solution. The material was extracted with EtOAc, dried (Mg2SO4), and concentrated. Flash chromatography gave 2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 13% yield). The solution was stirred at 75° C. for 3.5 hours The solution was cooled The residue was extracted with chloroform the organic layer was dried with Na2SO4 concentrated The residue was re-dissolved in MeOH (450 mL) The reaction stirred overnight at ambient temperature The material was concentrated in vacuo The material was extracted with EtOAc dried (Mg2SO4) concentrated

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

Procedure: Prepared by a modification of the literature procedure reported in Croat. Chim. Acta, 1966, 235. Phosphorus pentachloride (0.13 mol) was added to benzyloxyacetaldehyde diethyl acetal (0.13 mol) at 20-30° C. The reaction mixture was heated at 60° C. for 75 min and then cooled to 0° C. The reaction mixture was treated with DMF (0.39 mol) and stirred at room temperature for four days. The reaction mixture was diluted with 1.0N HCl(aq) (200 ml) and ether (200 ml). The ether layer was discarded and the aqueous layer was basified with 8N NaOH(aq). The aqueous layer was extracted with ethyl acetate and ether and the combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The resulting black oil was purified by column chromatography to give the product as a brown solid (0.06 mol, 43%). δH (250 MHz; CDCl3) 8.62 (1H, s), 7.44-7.26 (5H, m), 6.18 (1H, s), 4.96 (2H, s), 3.04 (6H, s). Prepared by a modification of the literature procedure cooled to 0° C The aqueous layer was extracted with ethyl acetate and ether the combined organic extracts were dried (MgSO4) filtered evaporated in vacuo The resulting black oil was purified by column chromatography

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

Procedure: Prepared by a modification of the literature procedure reported in Croat. Chim. Acta, 1966, 235. Phosphorus pentachloride (0.13 mol) was added to benzyloxyacetaldehyde diethyl acetal (0.13 mol) at 20-30° C. The reaction mixture was heated at 60° C. for 75 min and then cooled to 0° C. The reaction mixture was treated with DMF (0.39 mol) and stirred at room temperature for four days. The reaction mixture was diluted with 1.0N HCl(aq) (200 ml) and ether (200 ml). The ether layer was discarded and the aqueous layer was basified with 8N NaOH(aq). The aqueous layer was extracted with ethyl acetate and ether and the combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The resulting black oil was purified by column chromatography to give the product as a brown solid (0.06 mol, 43%). δH (250 MHz; CDCl3) 8.62 (1H, s), 7.44-7.26 (5H, m), 6.18 (1H, s), 4.96 (2H, s), 3.04 (6H, s). Prepared by a modification of the literature procedure cooled to 0° C The aqueous layer was extracted with ethyl acetate and ether the combined organic extracts were dried (MgSO4) filtered evaporated in vacuo The resulting black oil was purified by column chromatography

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

Procedure: A stirring mixture of 100 g of benzyloxyacetaldehyde diethyl acetal, 500 ml of tetrahydrofuran and 400 ml of 2N sulfuric acid is heated at reflux temperature for 45 minutes. The resulting solution is cooled to room temperature, concentrated in vacuo to 400 ml volume and diluted with 1000 ml of chloroform. The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride and dried. The filtrate is evaporated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 59.0 g of the desired product as a colorless oil. is heated at reflux temperature for 45 minutes concentrated in vacuo to 400 ml volume diluted with 1000 ml of chloroform The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride dried The filtrate is evaporated in vacuo

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

Procedure: In accordance with Scheme IV, benzyloxyacetaldehyde diethyl acetal is hydrolyzed with dilute sulfuric acid giving benzyloxyacetaldehyde, which is then reacted with allyl magnesium bromide to give 1-phenylmethoxy-4-penten-2-ol. This alcohol, is brominated with bromine in carbon tetrachloride or dichloromethane at -20° C. to 0° C. to give 4,5-dibromo-1-(phenylmethoxy)-2-pentanol. This dibromo alcohol, in aqueous methanol, is cyclized with calcium hydroxide in the presence of calcium bromide, to give a racemic mixture of trans and cis-4-bromo-2[(phenylmethoxy)methyl]tetrahydrofuran, IX and X respectively, which is separated by flash column chromatography using silica gel. The trans bromide, IX, is reacted with potassium thioacetate, in a dipolar aprotic solvent, to give cis-[5-[(phenylmethoxy)methyl]-3-tetrahydrofuranyl]ethanethioate, XI. The thioacetate, XI, is reacted with iodotrimethylsilane to give cis-[5-(hydroxymethyl)-3-tetrahydrofuranyl]ethanethioate, XIII. In the same manner, the cis bromide, X, is convened to the trans-[5-(hydroxymethyl)-3-tetra-hydrofuranyl]ethanethioate, XIV.

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

Procedure: A stirring mixture of 100 g of benzyloxyacetaldehyde diethyl acetal, 500 ml of tetrahydrofuran and 400 ml of 2N sulfuric acid is heated at reflux temperature for 45 minutes. The resulting solution is cooled to room temperature, concentrated in vacuo to 400 ml volume and diluted with 1000 ml of chloroform. The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride and dried. The filtrate is evaporated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 59.0 g of the desired product as a colorless oil. is heated at reflux temperature for 45 minutes concentrated in vacuo to 400 ml volume diluted with 1000 ml of chloroform The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride dried The filtrate is evaporated in vacuo

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

Procedure: In accordance with Scheme IV, benzyloxyacetaldehyde diethyl acetal is hydrolyzed with dilute sulfuric acid giving benzyloxyacetaldehyde, which is then reacted with allyl magnesium bromide to give 1-phenylmethoxy-4-penten-2-ol. This alcohol, is brominated with bromine in carbon tetrachloride or dichloromethane at -20° C. to 0° C. to give 4,5-dibromo-1-(phenylmethoxy)-2-pentanol. This dibromo alcohol, in aqueous methanol, is cyclized with calcium hydroxide in the presence of calcium bromide, to give a racemic mixture of trans and cis-4-bromo-2[(phenylmethoxy)methyl]tetrahydrofuran, IX and X respectively, which is separated by flash column chromatography using silica gel. The trans bromide, IX, is reacted with potassium thioacetate, in a dipolar aprotic solvent, to give cis-[5-[(phenylmethoxy)methyl]-3-tetrahydrofuranyl]ethanethioate, XI. The thioacetate, XI, is reacted with iodotrimethylsilane to give cis-[5-(hydroxymethyl)-3-tetrahydrofuranyl]ethanethioate, XIII. In the same manner, the cis bromide, X, is convened to the trans-[5-(hydroxymethyl)-3-tetra-hydrofuranyl]ethanethioate, XIV.

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

Procedure: POCl3 (12.9 ml, 141.2 mmol) was added to DMF (10.9 ml, 141.2 mmol) at 0° C. The reaction was immediately warmed to ambient temperature and was stirred for 30 minutes. ((2,2-Diethoxyethoxy)methyl)benzene (10.6 g, 47.1 mmol) was added as a solution in 80 mL of chloroform. The solution was stirred at 75° C. for 3.5 hours. The solution was cooled, poured over ice water, and neutralized with Na2CO3. The residue was extracted with chloroform and the organic layer was dried with Na2SO4 and concentrated. The residue was re-dissolved in MeOH (450 mL). NaOMe (25% in MeOH, 58 ml, 253 mmol) was added followed by 2-hydrazinylethanol (10.6 g, 139 mmol). The reaction was stirred overnight at ambient temperature. The material was concentrated in vacuo followed by dilution with saturated NH4Cl solution. The material was extracted with EtOAc, dried (MgSO4), and concentrated. Flash chromatography of the crude material gave 2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 13%). The solution was stirred at 75° C. for 3.5 hours The solution was cooled The residue was extracted with chloroform the organic layer was dried with Na2SO4 concentrated The residue was re-dissolved in MeOH (450 mL) The reaction was stirred overnight at ambient temperature The material was concentrated in vacuo The material was extracted with EtOAc dried (MgSO4) concentrated