4-cyclopentyloxy-3-methoxybenzaldehyde

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

Procedure: A mixture of vanillin (10 g, 65.7 mmoles), cyclopentyl bromide (21.09 g, 196.7 mmoles), tetrabutylammonium bromide (211.8 mg, 0.675 mmoles) and K2CO3 (27.16 g, 199.48 mmoles) in tetrahydrofuran/water 8:2 (200 ml) was refluxed under nitrogen and vigorous stirring for 55 hours, then diluted with water, extracted with ethyl acetate, and the extract was washed with water, anhydrified over Na2SO4 and dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1) and gave 14 g of the title product (yield: 97%). was refluxed under nitrogen extracted with ethyl acetate the extract was washed with water dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1)

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

Procedure: To a solution of methyl magnesium iodide, which is prepared from magnesium (2.9 g) and methyl iodide (7.5 ml), in diethyl ether (150 ml) is added dropwise a solution of 4-cyclopentyloxy-3-methoxybenzaldehyde (17.6 g) in tetrahydrofuran (40 ml) at 0° C., and the mixture is stirred at room temperature for one hour. To the reaction mixture is added a saturated aqueous ammonium chloride solution (20 ml) at 0° C., and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure, and the residue is dissolved in acetonitrile (300 ml), and thereto is added manganese dioxide (55 g) at 0° C. The mixture is warmed to room temperature, and the mixture is stirred for three days. To the reaction mixture is added cerite (20 g), and the mixture is stirred for 30 minutes. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from chilled hexane to give 4-acetyl-1-cyclopentyloxy-2-methoxybenzene (13.8 g). the mixture is extracted with ethyl acetate The extract is concentrated under reduced pressure the residue is dissolved in acetonitrile (300 ml) is added manganese dioxide (55 g) at 0° C The mixture is warmed to room temperature the mixture is stirred for three days To the reaction mixture is added cerite (20 g) the mixture is stirred for 30 minutes The insoluble materials are removed by filtration the filtrate is concentrated under reduced pressure The residue is crystallized from chilled hexane

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

Procedure: To a solution of vanillin (50 g) in N,N-dimethylformamide (600 ml) are added 62.5% sodium hydride (13.9 g) and cyclopentyl bromide (38.8 ml) under ice-cooling, and the mixture is stirred at 90° C. overnight. The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide, and to the residue is added water. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 4-cyclopentyloxy-3-methoxybenzaldehyde (65 g). cooling The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide to the residue is added water The mixture is extracted with ethyl acetate the extract is washed dried concentrated under reduced pressure to remove the solvent The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1)

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

Procedure: To a solution of vanillin (50 g) in N,N-dimethylformamide (600 ml) are added 62.5% sodium hydride (13.9 g) and cyclopentyl bromide (38.8 ml) under ice-cooling, and the mixture is stirred at 90° C. overnight. The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide, and to the residue is added water. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 4-cyclopentyloxy-3-methoxybenzaldehyde (65 g). cooling The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide to the residue is added water The mixture is extracted with ethyl acetate the extract is washed dried concentrated under reduced pressure to remove the solvent The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1)

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

Procedure: A mixture of vanillin (10 g, 65.7 mmoles), cyclopentyl bromide (21.09 g, 196.7 mmoles), tetrabutylammonium bromide (211.8 mg, 0.675 mmoles) and K2CO3 (27.16 g, 199.48 mmoles) in tetrahydrofuran/water 8:2 (200 ml) was refluxed under nitrogen and vigorous stirring for 55 hours, then diluted with water, extracted with ethyl acetate, and the extract was washed with water, anhydrified over Na2SO4 and dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1) and gave 14 g of the title product (yield: 97%). was refluxed under nitrogen extracted with ethyl acetate the extract was washed with water dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1)

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

Procedure: Piperidine (0.45 mL, 4.5 mmol) was added to a suspension of 4-cyclopentyloxy-3-methoxybenzaldehyde (1.0 g, 4.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.92 g, 4.1 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-{[3-(4-cyclopentyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (1.06 g, 67%) as a pale yellow crystalline solid; mp 96-98° C.; δH (400 MHz, DMSO-d6) 1.46 (m, 2H, CH2), 1.67-1.71 (m, 4H, CH2), 1.90 (m, 2H, CH2), 3.81 (s, 3H, OCH3), 4.82 (t, J=5.6 Hz, 1H, OCH), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.94 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.19 (dd, J5′,6′=8.4, J5′,6′=1.6 Hz, 1H, H6′), 7.35 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 HZ, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.7, 32.3, 55.7, 79.5, 110.9, 114.0, 116.5, 119.7, 120.3, 122.5, 122.6, 127.0, 131.1, 134.0, 141.1, 141.7, 149.0, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C22H23NO5 [M+Na]+ 404.1468. found 404.1468; vmax 747, 1261, 1506, 1584, 1659, 2964, 3524 cm−1. treated The crude product was recrystallised from EtOH/water

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

Procedure: Bromocyclopentane (7.0 mL, 66 mmol) was added to a suspension of vanillin (5.0 g, 33 mmol) and potassium carbonate (13.6 g, 99 mmol) in EtOH (75 mL) and treated according to Procedure 3. 4-Cyclopentyloxy-3-methoxybenzaldehyde (7.1 g, 98%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.62 (m, 2H, CH2), 1.78-2.04 (m, 6H, CH2), 3.89 (s, 3H, OCH3), 4.86 (tt, J=6.0, 3.2 Hz, 1H, OCH), 6.94 (d, J5,6=8.0 Hz, 1H, H5), 7.38 (d, J2,6=2.0 Hz, 1H, H2), 7.41 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.82 (s, 1H, CHO); δC (100 MHz, CDCl3) 24.1, 32.8, 56.0, 80.6, 109.4, 112.8, 126.6, 129.5, 150.2, 153.4, 190.9; vmax 977, 1260, 1504, 1580, 1680, 2869, 2956 cm−1. treated

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

Procedure: To a solution of methyl magnesium iodide, which is prepared from magnesium (2.9 g) and methyl iodide (7.5 ml), in diethyl ether (150 ml) is added dropwise a solution of 4-cyclopentyloxy-3-methoxybenzaldehyde (17.6 g) in tetrahydrofuran (40 ml) at 0° C., and the mixture is stirred at room temperature for one hour. To the reaction mixture is added a saturated aqueous ammonium chloride solution (20 ml) at 0° C., and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure, and the residue is dissolved in acetonitrile (300 ml), and thereto is added manganese dioxide (55 g) at 0° C. The mixture is warmed to room temperature, and the mixture is stirred for three days. To the reaction mixture is added cerite (20 g), and the mixture is stirred for 30 minutes. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from chilled hexane to give 4-acetyl-1-cyclopentyloxy-2-methoxybenzene (13.8 g). the mixture is extracted with ethyl acetate The extract is concentrated under reduced pressure the residue is dissolved in acetonitrile (300 ml) is added manganese dioxide (55 g) at 0° C The mixture is warmed to room temperature the mixture is stirred for three days To the reaction mixture is added cerite (20 g) the mixture is stirred for 30 minutes The insoluble materials are removed by filtration the filtrate is concentrated under reduced pressure The residue is crystallized from chilled hexane

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

Procedure: To a solution of vanillin (50 g) in N,N-dimethylformamide (600 ml) are added 62.5% sodium hydride (13.9 g) and cyclopentyl bromide (38.8 ml) under ice-cooling, and the mixture is stirred at 90° C. overnight. The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide, and to the residue is added water. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 4-cyclopentyloxy-3-methoxybenzaldehyde (65 g). cooling The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide to the residue is added water The mixture is extracted with ethyl acetate the extract is washed dried concentrated under reduced pressure to remove the solvent The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1)

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

Procedure: A mixture of vanillin (10 g, 65.7 mmoles), cyclopentyl bromide (21.09 g, 196.7 mmoles), tetrabutylammonium bromide (211.8 mg, 0.675 mmoles) and K2CO3 (27.16 g, 199.48 mmoles) in tetrahydrofuran/water 8:2 (200 ml) was refluxed under nitrogen and vigorous stirring for 55 hours, then diluted with water, extracted with ethyl acetate, and the extract was washed with water, anhydrified over Na2SO4 and dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1) and gave 14 g of the title product (yield: 97%). was refluxed under nitrogen extracted with ethyl acetate the extract was washed with water dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1)