Ethyl 7-hydroxycoumarin-3-carboxylate

Brown solid

To a solution of 2, 4-dihydroxybenzaldehyde (3.70 mmol) in diethyl malonate (7.90 mmol) piperidine (10 drops) was added, and the resulting solution was stirred for 2 hours at r.t. The resulting solution was then acidified with an aqueous solution of HCl10percent (5 mL). The precipitate was filtrated and washed with cold water (10 mL). The desired product was purified by flash chromatography using dichloromethane : ethyl acetate (70: 30) as eluent furnishing 3 (0.735g) in 97percent yield. Diethyl malonate (6.6 mL, 43.3 mmol) and 2, 4-dihydroxybenzaldehyde (6.0 g, 43.3 mmol) were added to the flask and piperidine (4.4 mL, 44.3 mmol) was slowly added at room temperature.When the reaction mixture turns pale yellow, it is further stirred for 1 hour, HCl 10percent (50 mL) was added. After grinding the green suspension, Filtration and washing with water gave the desired compound as a pink solid (9.32 g, 92percent).A solution of 2, 4-dihydroxybenzaldehyde (0.500 g, 3.60 mmol) and diethyl malonate (0.70 ml, 4.00 mmol) were placed in 100 ml of a vial and dissolved in 95percent Ethanol (20ml), the solution color is reddish brown transparent liquid; then add piperidine (0.40ml, 4.00mmol), the solution surface pan-green light, began to reflux, the reaction after about 6h, the solution becomes dark brown.Cooled to room temperature, concentrated under reduced pressure to a red viscous, ethanol recrystallized, and filtered to give compound 3 (0.758 g, 3.24 mmol) as a pale yellow solid in 90percent yield.ESI-MS m / z 233 (M-1).General procedure: A mixture of o-hydroxy benzaldehyde (2 mmol), 1, 3-dicarbonyl compound (2 mmol) and Fe3O4-DA-Phe (30mg)was mixed in a 50 mL flask and irradiated under microwavefor the time indicated in (Table 6.1). The reaction progresswas monitored by TLC. After completion of the reaction, thereaction mixture was cooled to room temperature which thensolidified within an hour. The resulting solidified mixturewas diluted with ethyl acetate (5 mL) and the catalyst wasseparated by using external magnet and dried for reuse. Thereaction mixture was washed twice with water and solventwas evaporated under reduced pressure which yielded thecrude product, which was further purified by recrystallization.The same procedure was used for synthesis of derivatives.All synthesized coumarin derivatives were characterizedusing analytical techniques such as IR and 1H NMR.The identity of these compounds was established by comparisonof IR, 1H NMR spectral data and their melting pointswith those of reported samples (Table 4) [23-33]. Spectraldata for all compounds are listed.General procedure: α-substituted ethyl acetate (1.0 mmol)and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant stirring. After 10 minutes benzaldehyde/salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated under reduce pressure. The product was extracted with ethyl acetate, dried over Na2, 4-dihydroxybenzaldehyde (6.9 g, 0.05 mol), diethyl malonate (9.6 g, 0.06 mol) and piperidine(0.2 g, 2.5 mmol) were refluxing in 150 mL ethanol for 10 h. After cooled to room temperature, thecrude products were filtrated and recrystallized from methanol [19].Ethyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate (1e): Light yellow solid; yield 81percent. ESI-HRMS [M +Na]+: (m/z) Calcd. for C12H10O5Na: 257.0420. Found: 257.0434.General procedure: Diethyl malonate (7.5 mL, 49 mmol), 2, 4-dihydroxybenzaldehyde (5.1 g, 37 mmol) or 2, 4-dihydroxy-5-halogenbenzaldehyde, piperidine (0.5 mL, 6 mmol) and 3 drops of acetic acid were dissolved in a 50 mL flask of ethanol (10 mL) to form a mixture. The reaction mixture was heated with stirring for 4.5 h. After cooling, the solid was collected using a vacuum filer. The solid product was filtered and washed with cold ethanol, then dried. The crude product was recrystallized with ethanol to obtain the purified product 1a (6.06g, 25.9 mmol) or 1b-1d. The complex was characterized byCompound 1 was synthesized according to the reported papers.To a 250 mL round bottom flask was added 2, 4-dihydroxybenzaldehyde(10 g, 72.5 mmol) and 30 mL of absolute ethanol, Stir to make it fully dissolved. diethyl malonate (17.2 mL, 101.9 mmol), hexahydropyridine (0.57 mL, 5.76 mmol)Glacial acetic acid (0.16 mL, 2.88 mmol), heated at 90 °C with stirring, TLC tracks the progress of the reaction. After about 15 h, TLC (EA: PE = 1: 2) was significantThe reaction is basically complete. The reaction solution was allowed to cool to room temperature, 200 mL of ice water was added and allowed to stand overnight at -20 ° C. The filtrate was filtered to give 12.4 g of a yellow solid in 73percent yield. The crude product was recrystallized from 95percent ethanol to give 10.8 g of a pale yellow needle-like solid in a yield of 64percentSynthesis of a compound of Formula (I) where RGeneral procedure: The substituted coumarin-3-carboxylic acid ethyl esters (Scheme 2) were prepared by Knoevenagel reaction. To a mixture of diethyl malonate (1 mmol) and the appropriate salicylaldehyde (1 mmol) in ethanol (10 ml) was added piperidine (5 mol percent) and the reaction mixture was stirred at the room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under vacuum and the residue was purified by chromatography. The obtained substituted coumarin-3-carboxylic acid ethyl ester (2 mmol) was dissolved in 10percent NaOH (50 ml), then 3 N HCl (50 ml) was added the mixture. The suspension was filtered and dried under vacuum to provide substituted coumarin-3-carboxylic acid. The coumarin-3-carboxylic acid (2 mmol) was added to thionyl chloride (30 ml), the reaction mixture was refluxed for about 2 h, the thionyl chloride was removed under vacuum. The desired substituted coumarin-3-carbonyl chloride was obtained. To a mixture of substituted coumarin-3-carbonyl chloride (2 mmol) and toluene (20 ml) or ethyl ether (20 ml) was added dropwise appropriate alcohol (2 mmol) and then the reaction mixture was refluxed for about 12 h. The solvent was removed under vacuum and the residue was purified by chromatography.General procedure: Piperidine (21 mg, 30 molpercent) was added slowly to a stirred solution of salicylaldehyde (1a, 100 mg, 1 equiv) and ethyl 4, 4, 4-trichloro-3-oxobutanoate(2, 192 mg, 1 equiv) in toluene (2mL) at room temperature. The reaction mixture was refluxed for 4 h. After completion of the reaction (TLC), the crude product was subjected to column chromatography purification using silica gel(60:120) provided coumarin 3a as colorless solid.