methyl (E)-but-2-enoate

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an atmosphere of argon, potassium (25 g) was dissolved completely in dried tert-butyl alcohol (820 ml) by refluxing by heating for 3 hours. The solution was cooled to 20° C., to which was added ether (300 ml) and then slowly a solution of methyl crotonate (63.93 g) and tert-butyl 4-formylbenzoate (71.0 g) in tert-butyl alcohol-ether mixture (2:1, 300 ml) while keeping the inner temperature at 10° C. The mixture was stirred at the same temperature for 2 hours, and 1 N potassium hydrogen sulfate in water (750 ml) was added with cooling to adjust the pH to 4. After extraction with ether, the ether layer was washed with saturated sodium chloride solution and the solvent was evaporated off under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), to which was added 5% Pd-C (15 g: manufactured by Engelhard Co. Ltd.), and stirred vigorously at room temperature under hydrogen pressure of 4 kg/cm2 for 3 hours. The catalyst was filtered off, the solvent was evaporated off under reduced pressure, and dried methanol (200 ml), 4-(N,N-dimethylamino)pyridine (30 mg) and dichloromethane (250 ml) were added, to which a solution of 1,3-dicyclohexylcarbodiimide (132 g) in dichloromethane (250 ml) was added slowly dropwise at 0° C. After stirring at room temperature for 18 hours, the mixture was cooled to 0° C. Acetic acid (30 ml) was added and the mixture stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. The resulting precipitate was filtered off, the filtrate was concentrated to dryness under reduced pressure, and to the residue was added ethyl acetate (100 ml), which was left standing at 0° C. for 2 hours, and the resulting precipitate was again filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (carrier: silica gel, 500 g, ether-hexane, 1:15→1:5), to give the object compound (59.7 g). by refluxing by heating for 3 hours at 10° C with cooling After extraction with ether the ether layer was washed with saturated sodium chloride solution the solvent was evaporated off under reduced pressure The residue was dissolved in ethyl acetate (100 ml), to which was added 5% Pd-C (15 g: manufactured by Engelhard Co. Ltd.) stirred vigorously at room temperature under hydrogen pressure of 4 kg/cm2 for 3 hours The catalyst was filtered off the solvent was evaporated off under reduced pressure, and dried methanol (200 ml), 4-(N,N-dimethylamino)pyridine (30 mg) and dichloromethane (250 ml) were added, to which a solution of 1,3-dicyclohexylcarbodiimide (132 g) in dichloromethane (250 ml) was added slowly dropwise at 0° C After stirring at room temperature for 18 hours the mixture was cooled to 0° C Acetic acid (30 ml) was added the mixture stirred at 0° C. for 30 minutes at room temperature for 30 minutes The resulting precipitate was filtered off the filtrate was concentrated to dryness under reduced pressure to the residue was added ethyl acetate (100 ml), which was left standing at 0° C. for 2 hours the resulting precipitate was again filtered off The filtrate was concentrated under reduced pressure the residue was purified by column chromatography (carrier: silica gel, 500 g, ether-hexane, 1:15→1:5)

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

Procedure: Benzyl-methyl-amine (20 g, 165 mmol, 1.0 equiv) was added neat to methyl crotonate (19.8 g, 198 mmol, 1.2 equiv). The resulting solution was stirred at room temperature for 72 h. The excess crotonic ester was removed in vacuo to yield the desired product (40.3 g,˜100%) which was used without further purification; MS, m/z 222=M+1. The excess crotonic ester was removed in vacuo

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of potassium tert-butoxide (52 g) and tert-butanol (170 ml) was treated dropwise with a mixture of 3-methoxybenzaldehyde (30 g) and methyl crotonate (35 ml). The temperature of the reaction mixture rose to 80° C. during the addition and was then maintained for a further 3 hours at 65° C. The reaction mixture was cooled to room temperature, poured into ice/water and washed with diethyl ether. The aqueous phase was acidified with concentrated HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated under reduced pressure to yield an orange oil. Yield 53.2 g. Used directly in the next step. The temperature of the reaction mixture rose to 80° C. during the addition The reaction mixture was cooled to room temperature washed with diethyl ether extracted with ethyl acetate The organic phase was washed with brine dried (MgSO4) evaporated under reduced pressure to yield an orange oil

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

Procedure: A mixture of potassium tert-butoxide (68 g) and tert-butanol (130 ml) was treated dropwise with a mixture of 3-methylbenzaldehyde (33.8 g) and methyl crotonate (45 ml). The temperature of the reaction mixture rose to 65° C. during the addition and this was maintained for a further 3 hours. The reaction mixture was cooled to room temperature, poured into ice/water and washed with diethyl ether. The aqueous phase was acidified with concentrated HCl and extracted with diethyl ether. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by trituration with isohexane and filtration. The temperature of the reaction mixture rose to 65° C. during the addition this was maintained for a further 3 hours washed with diethyl ether extracted with diethyl ether The organic phase was washed with water dried (MgSO4) evaporated under reduced pressure Purification was by trituration with isohexane and filtration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 26.5 g (0.2 moles) of aluminum chloride in 50 cc of dichloroethane is added a solution of 13.5 g (0.1 moles) of hexanoyl chloride and 10.0 g (0.1 moles) of methyl crotonate. Over a period of 10 minutes the temperature rises from 25 to 60°C. The reaction mass is refluxed for 4 hours at a temperature of approximately 90°C. The resultant methyl-5-oxo-decenoate is formed only in a small amount (approximately 2-3%).

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 26.5 g (0.2 moles) of aluminum chloride in 50 cc of dichloroethane is added a solution of 13.5 g (0.1 moles) of hexanoyl chloride and 10.0 g (0.1 moles) of methyl crotonate. Over a period of 10 minutes the temperature rises from 25 to 60°C. The reaction mass is refluxed for 4 hours at a temperature of approximately 90°C. The resultant methyl-5-oxo-decenoate is formed only in a small amount (approximately 2-3%).

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

Procedure: 2-(4-Chloro-phenylsulfanylmethyl)-1,3,4-trifluoro-benzene (Example 8, step 2, 1.0 g, 3.1 mmol) and methyl crotonate (1.55 g, 15.5 mmol) were dissolved in 50 mL of THF and potassium t-butoxide (1M in THF, 6.2 mL) was added. The reaction mixture was stirred at room temperature for five hours. 100 mL of water and 100 mL of EtOAc were added. The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hexane as the eluent (gradient from 0/100 to 50/50 in 40 min, 0.79 g, 60%). The product is a mixture of diastereomers. 1H NMR (CDCl3 400 MHz) δ 7.60 (m, 2H), 7.37 (m, 2H), 7.07 (m, 1H), 6.83 (m, 0.5H), 6.63 (m, 0.5H), 5.03 (t, J=10.2 Hz, 0.5H), 4.80 (d, J=10.2 Hz, 0.5H), 3.71 (s, 1.5H), 3.60 (s, 1.5H), 3.33 (m, 1H), 3.10 (m, 0.5H), 2.89 (m, 0.5H), 2.42 (m, 0.5H), 2.15 (m, 0.5H), 1.49 (t, J=6.6 Hz, 1.5H), 0.95 (dd, J=8.8 and 7.3 Hz, 1.5H). The organic layer was washed with brine (100 mL) dried over Na2SO4 concentrated The product was purified by column chromatography as the eluent (gradient from 0/100 to 50/50 in 40 min, 0.79 g, 60%) a mixture of diastereomers

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

Procedure: 2-(4-Chloro-phenylsulfanylmethyl)-1,3,4-trifluoro-benzene (Example 8, step 2, 1.0 g, 3.1 mmol) and methyl crotonate (1.55 g, 15.5 mmol) were dissolved in 50 mL of THF and potassium t-butoxide (1M in THF, 6.2 mL) was added. The reaction mixture was stirred at room temperature for five hours. 100 mL of water and 100 mL of EtOAc were added. The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hexane as the eluent (gradient from 0/100 to 50/50 in 40 min, 0.79 g, 60%). The product is a mixture of diastereomers. 1H NMR (CDCl3 400 MHz) δ 7.60 (m, 2H), 7.37 (m, 2H), 7.07 (m, 1H), 6.83 (m, 0.5H), 6.63 (m, 0.5H), 5.03 (t, J=10.2 Hz, 0.5H), 4.80 (d, J=10.2 Hz, 0.5H), 3.71 (s, 1.5H), 3.60 (s, 1.5H), 3.33 (m, 1H), 3.10 (m, 0.5H), 2.89 (m, 0.5H), 2.42 (m, 0.5H), 2.15 (m, 0.5H), 1.49 (t, J=6.6 Hz, 1.5H), 0.95 (dd, J=8.8 and 7.3 Hz, 1.5H). The organic layer was washed with brine (100 mL) dried over Na2SO4 concentrated The product was purified by column chromatography as the eluent (gradient from 0/100 to 50/50 in 40 min, 0.79 g, 60%) a mixture of diastereomers

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

Procedure: By a similar operation as in Reference Example 19 and using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g) and potassium tert-butoxide (76.7 g), the title compound was obtained as a pale-yellow solid (yield 16.8 g, 25%).

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

Procedure: By a similar operation as in Reference Example 19 and using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g) and potassium tert-butoxide (76.7 g), the title compound was obtained as a pale-yellow solid (yield 16.8 g, 25%).

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

Procedure: Benzyl-methyl-amine (20 g, 165 mmol, 1.0 equiv) was added neat to methyl crotonate (19.8 g, 198 mmol, 1.2 equiv). The resulting solution was stirred at room temperature for 72 h. The excess crotonic ester was removed in vacuo to yield the desired product (40.3 g, ˜100%) which was used without further purification; MS, m/z 222=M+1. The excess crotonic ester was removed in vacuo

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

Procedure: A mixture of 83 g (0.83 mol) of methyl crotonate (Aldrich Chemical Company) and 100 g (0.83 mol) of methyl thiolactate (Helvetica Chemica Acta, Vol. 45, pages 1750-1765, 1962) in 800 ml of toluene is added dropwise to a stirred suspension of 64.8 g (1.2 mol) of sodium methoxide (Aldrich Chemical Company) in 500 ml of toluene. The suspension is stirred and refluxed for four and one-half hours, cooled, 500 ml of water is added and the mixture is made acidic by the addition of glacial acetic acid. The aqueous solution is extracted with toluene. The toluene layer is separated, washed successively with 200 ml of water, 200 ml of saturated sodium bicarbonate solution and 200 ml of water, dried over anhydrous Na2SO4, and the solution evaporated to give 90 g of tetrahydro-2,5-dimethyl-4-oxo-3-thiophenecarboxylic acid, methyl ester; bp 78°-80° C./0.04 mm. refluxed for four and one-half hours cooled The aqueous solution is extracted with toluene The toluene layer is separated washed successively with 200 ml of water, 200 ml of saturated sodium bicarbonate solution and 200 ml of water dried over anhydrous Na2SO4 the solution evaporated