ethyl (E)-4-diethoxyphosphorylbut-2-enoate

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

Procedure: To a solution of triethyl 4-phosphonocrotonate (5.53 g) in water (36 mL) was added a solution of potassium hydroxide (1.69 g) in water (36 mL) at room temperature, and the reaction solution was stirred for 3 hours. The resulting reaction solution was washed with dichloromethane, and the water layer was acidified to pH2 with concentrated hydrochloric acid and extracted with dichloromethane (550 mL). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 4.41 g of 4-diethylphosphonocrotonic acid as a colorless solid. The resulting reaction solution was washed with dichloromethane extracted with dichloromethane (550 mL) The combined organic layer was dried over anhydrous magnesium sulfate concentrated to dryness under reduced pressure

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

Procedure: Ethyl 4-bromocrotonate (7.0 mL) was added to triethylphosphite (9.9 mL) at 120 to 130° C. during 60 minutes periods. After the generation of ethyl bromide ceased, the reaction solution was stirred at the same temperature for 3 hours. After cooling, the resulting reaction solution was concentrated under reduced pressure. Then the residue was purified by distillation at 150 to 210° C. under reduced pressure (17 to 21 hPa) to give triethyl 4-phosphonocrotonate as colorless oil. After cooling the resulting reaction solution was concentrated under reduced pressure Then the residue was purified by distillation at 150 to 210° C. under reduced pressure (17 to 21 hPa)

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

Procedure: To a solution of lithium diisopropylamide (prepared from 3.8 ml of n-butyllithium in hexane and 0.84 ml of diisopropylamine) in 10 ml tetrahydrofuran at -70° C., is added 1.35 g of triethyl 4-phosphonocrotonate in a dropwise manner over a 15 minute period. On completion of the addition, 6.0 g of 5-(5-formylpentyl)imidazo[1,5-a]pyridine is added in a dropwise manner. The reaction mixture is allowed to stir at room temperature for 15 minutes. The reaction mixture is quenched with methanol and the solvent evaporated under reduced pressure to yield 5-(9-ethoxycarbonyl-nona-6,8-dienyl)-imidazo[1,5-a]pyridine as an oil. is added in a dropwise manner The reaction mixture is quenched with methanol the solvent evaporated under reduced pressure

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

Procedure: To a solution of lithium diisopropylamide (prepared from 3.8 ml of n-butyllithium in hexane and 0.84 ml of diisopropylamine) in 10 ml tetrahydrofuran at -70° C., is added 1.35 g of triethyl 4-phosphonocrotonate in a dropwise manner over a 15 minute period. On completion of the addition, 6.0 g of 5-(5-formylpentyl)imidazo[1,5-a]pyridine is added in a dropwise manner. The reaction mixture is allowed to stir at room temperature for 15 minutes. The reaction mixture is quenched with methanol and the solvent evaporated under reduced pressure to yield 5-(9-ethoxycarbonyl-nona-6,8-dienyl)-imidazo[1,5-a]pyridine as an oil. is added in a dropwise manner The reaction mixture is quenched with methanol the solvent evaporated under reduced pressure

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

Procedure: To a stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is added 550 mg of triethyl 4-phosphonocrotonate in a dropwise manner over a 10-minute period. The reaction mixture is maintained at 5° by cooling in an ice-water bath. On completion of the addition, 300 mg of 5-formylimidazol[1,5-a]pyridine is added to the reaction mixture which is then allowed to stir at room temperature for 1 hour. The reaction mixture is poured into 100 ml of ice water and extracted with 2×100 ml of ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate, filtered and evaporated to dryness to yield an oily residue. This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent under reduced pressure yields 5-(4-ethoxycarbonylbuta-1,3-dienyl)-imidazo[1,5-a]pyridine melting at 101°-103°. The reaction mixture is maintained at 5° by cooling in an ice-water bath is added to the reaction mixture which extracted with 2×100 ml of ethyl acetate dried over magnesium sulfate filtered evaporated to dryness to yield an oily residue This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate as eluent Evaporation of the solvent under reduced pressure

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

Procedure: To a stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is added 550 mg of triethyl 4-phosphonocrotonate in a dropwise manner over a 10-minute period. The reaction mixture is maintained at 5° by cooling in an ice-water bath. On completion of the addition, 300 mg of 5-formylimidazol[1,5-a]pyridine is added to the reaction mixture which is then allowed to stir at room temperature for 1 hour. The reaction mixture is poured into 100 ml of ice water and extracted with 2×100 ml of ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate, filtered and evaporated to dryness to yield an oily residue. This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent under reduced pressure yields 5-(4-ethoxycarbonylbuta-1,3-dienyl)-imidazo[1,5-a]pyridine melting at 101°-103°. The reaction mixture is maintained at 5° by cooling in an ice-water bath is added to the reaction mixture which extracted with 2×100 ml of ethyl acetate dried over magnesium sulfate filtered evaporated to dryness to yield an oily residue This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate as eluent Evaporation of the solvent under reduced pressure

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

Procedure: A stirred solution of 25.3 grams (0.230 mole) of potassium tert.-butoxide in 250 mL of tetrahydrofuran was cooled to 0 ° C., and a solution of 56.5 grams (0.230 mole) triethyl 4-phosphonocrotonate in 50 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature at about 0°-10 ° C. The complete addition required about 30 minutes. The reaction mixture was then stirred for one hour at 0°-5° C., and then 26.6 grams (0.180 mole) of 4-methoxyacetophenone was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was made acidic with an aqueous 2N hydrochloric acid solution and diluted with about 200 mL of water. The mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was taken up in 150 grams of silica gel, and the solvent was removed under reduced pressure. The silica gel mixture was placed on top of a column of silica gel, and the mixture was eluted with 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.9 grams of ethyl 5-(4-methoxyphenyl)-2,4-hexadienoate. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times. while maintaining the reaction mixture temperature at about 0°-10 ° C The complete addition required about 30 minutes Upon completion of addition stirred for about 18 hours The mixture was extracted with two 250 mL portions of diethyl ether The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride The organic layer was dried with magnesium sulfate filtered the solvent was removed under reduced pressure the mixture was eluted with 10% ethyl acetate in petroleum ether concentrated under reduced pressure

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

Procedure: 7.4 ml of 1.6M n-butyl lithium/hexane solution was dropwise added to a THF solution (30 ml) of 8.41 g of ethyl 4-diethylphosphonocrotonate below -50° C. and stirred for 15 minutes at --78° C. . To this was dropwise added 25 ml of a THF solution of 5.0 g of the above-mentioned 1-t-butyloxycarbonyl-4-piperidinone. This was stirred for 20 minutes at -78° C. and then for 2 hours at -10° C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with 1N HCl, saturated NaHCO3, brine (twice each) and dried with magnesium sulfate. The solvent was removed by distillation under a reduced pressure. Thus, 7.70 g of ethyl 4-(1-t-butyloxycarbonyl-4-piperidylidene)-2-butenoate was obtained as a white solid. This was stirred for 20 minutes at -78° C. for 2 hours at -10° C extracted three times with ethyl acetate The organic layer was washed with 1N HCl, saturated NaHCO3, brine (twice each) and dried with magnesium sulfate The solvent was removed by distillation under a reduced pressure

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

Procedure: 7.4 ml of 1.6M n-butyl lithium/hexane solution was dropwise added to a THF solution (30 ml) of 8.41 g of ethyl 4-diethylphosphonocrotonate below -50° C. and stirred for 15 minutes at --78° C. . To this was dropwise added 25 ml of a THF solution of 5.0 g of the above-mentioned 1-t-butyloxycarbonyl-4-piperidinone. This was stirred for 20 minutes at -78° C. and then for 2 hours at -10° C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with 1N HCl, saturated NaHCO3, brine (twice each) and dried with magnesium sulfate. The solvent was removed by distillation under a reduced pressure. Thus, 7.70 g of ethyl 4-(1-t-butyloxycarbonyl-4-piperidylidene)-2-butenoate was obtained as a white solid. This was stirred for 20 minutes at -78° C. for 2 hours at -10° C extracted three times with ethyl acetate The organic layer was washed with 1N HCl, saturated NaHCO3, brine (twice each) and dried with magnesium sulfate The solvent was removed by distillation under a reduced pressure

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

Procedure: To a suspension of 1.08 g (60% reagent, 27 mmol) of sodium hydride in 20 ml of tetrahydrofuran (THF), stirred in an ice bath, was added dropwise 6 ml (6.7 g, 27 mmol) of triethyl 4-phosphonocrotonate. The resulting mixture was stirred for an additional 1 hour in the cooling bath and a solution of 4.2 g (18 mmol) of 1-benzylindol-3-carboxaldehyde in 25 ml of water. This mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layer was washed with two 25 ml portions of brine, dried (magnesium sulfate) and concentrated on a rotary evaporator to give an oil. Purification on a dry column (25% ethyl acetate in hexane) followed by crystallization (acetone-ether) gave 3.7 g of product as orange crystals, m.p. 110-112. MS (EI): 331 (M+), 240 (M+--C7H7), 167 (M+--C7H7 --CO2C2H5). NMR spectrum (CDCl3) shows a triplet centered at δ1.26 (J=7 Hz), a singlet at δ5.21, a doublet centered at δ5.8 which is the signal of the olefinic proton adjacent to the carbonyl group. The remainder of the proton signals cluster around 7.25 ppm. The resulting mixture was stirred for an additional 1 hour in the cooling bath This mixture was transferred to a separatory funnel the layers were separated The aqueous layer was extracted with two 50 ml portions of ethyl acetate The combined organic layer was washed with two 25 ml portions of brine dried (magnesium sulfate) concentrated on a rotary evaporator to give an oil Purification on a dry column (25% ethyl acetate in hexane) followed by crystallization (acetone-ether)

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

Procedure: To a solution of 1.85 g (46.3 mmol) of a mineral oil containing 60% sodium hydride in dry tetrahydrofuran (100 ml) was added in an argon atmosphere 10.6 ml (47.8 mmol) of triethyl 4-phosphonocrotonate. The mixture was reacted at 0° C. for 1 hour, followed by addition of 4.86 g (32.3 mmol) of piperonal. The mixture was reacted at room temperature for 1.5 hours. Saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and subjected to silica gel column chromatography. There was obtained 7.23 g (29.6 mmol) of ethyl 5-(3,4-methylenedioxyphenyl)-2,4-pentadienoate. Spectrophotometric data of the product support the structure shown below. ##STR73## The mixture was reacted at 0° C. for 1 hour The mixture was reacted at room temperature for 1.5 hours the resulting mixture was extracted with ethyl acetate The organic layer was concentrated under reduced pressure

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

Procedure: To a suspension of 60% NaH in mineral oil (16 g) in 1 L THF was added triethyl 4-phosphonocrotonate (100 g). The resulting solution was stirred for 2 hr, and then a solution of 2,4-dichlorobenzaldehyde (54 g) in 200 mL THF was added thereto. The mixture was stirred at room temperature for 1 hr. The reaction was quenched by the addition of 1 L of aq. NH4Cl and the THF was evaporated. The mixture was extracted with 4×200 ml ethyl acetate and the combined organic layer washed with water, brine and dried over MgSO4 then evaporated to provide the crude product. This was purified by silica gel chromatography using 5% ethyl acetate-hexanes to give 25.9 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid ethyl ester. MS: m/e 271.04 (MH+) The mixture was stirred at room temperature for 1 hr The reaction was quenched by the addition of 1 L of aq. NH4Cl the THF was evaporated The mixture was extracted with 4×200 ml ethyl acetate the combined organic layer washed with water, brine dried over MgSO4 then evaporated to provide the crude product This was purified by silica gel chromatography