Synthesis and Antimicrobial Activity of Some Derivatives of (7- Hydroxy-2-oxo-2h-chromen-4-yl)-acetic Acid Hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l,


Introduction
A number of natural and synthetic coumarin (2-oxo-2H-chromene) derivatives have been reported to exert notably antimicrobial [1,2] as well as antifungal [3,4] and tuberculostatic [5] activity.Moreover, the antibiotic novobiocin belongs to the hydroxy coumarin series.On the other hand, a large number of hydrazides have been reported to be of biological interest [6,7], while oxadiazole derivatives and thiosemicarbazides have been reported to possess antibacterial [8,9], antifungal [10,11] and other biological activities.Furthermore, a number of substituted thiazolines and thiazolidinones were found to exhibit appreciable antimicrobial and antifungal activities [12][13][14][15][16].It was therefore thought worthwhile to incorporate the hydrazide, thiosemicarbazide and oxadiazole moieties into the coumarin nucleus.
Hydrazinolysis of esters is the conventional method for preparing acyl hydrazides [17,18].However, when this method was applied to an α, β-unsaturated ester, the predominant product was the corresponding pyrazolidinone, the result of hydrazinolysis and an undesired subsequent intramolecular Michael-type addition [19].Alternatively, acyl hydrazides may be prepared by condensing carboxylic acids with hydrazine in the presence of coupling agents.Unfortunately, most of these methods afford low yields and involve complicated product isolations [20][21][22], although Zhang et al. have reported good yields using carbodiimide-based coupling reagents such as 1hydroxybenzotriazole (HOBt) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) [23].In connection with our previous work [24][25][26] on the synthesis of coumarins, in the present paper we describe the preparation of the new hydrazide derivatives, heterocycles and Schiff ' s bases from (7-hydroxy-2-oxo-2H-chromen-4-yl )-acetic acid methyl ester.
The high frequency region of the IR spectra of these compounds contains (N-H, O-H) stretching vibration bands at 3398 and 3245 cm -1 .The absorption in the 1623-1598 cm -1 region corresponds to that of the amide group (-NHCO-).The presence of lactone carbonyl group (›C=O) is indicated by absorption bands at 1702 and 1700 cm -1 .The 1 H-NMR spectra of compounds 4-8 exhibited singlets in the 8.03-10.58ppm region corresponding to the NH, -HC=N-and OH protons.
Upon condensation of 2 with acetylacetone in ethanol containing a catalytic amount of acetic acid, the corresponding derivative 11 was obtained in 54% yield.Compound 12 was prepared accordingly, by heating the carbohydrazide 2 with CS 2 in the presence of ethanolic potassium hydroxide.On the other hand, reaction of 2 with KSCN in refluxing ethanol containing catalytic amounts of HCl gave, after treating the salt 13, which was converted directly to 14 by heating it in aqueous KOH followed by acidification with HCl in good yield.
Cyclization of thiosemicarbazide 7 with chloroacetylchloride in chloroform afforded thiazolidinone derivative 15 (Scheme 4).The structures of compounds 11-15 were confirmed by their analytical data and their IR and 1 H-NMR spectra.The IR absorptions due to the (OH) and C=O functions appeared at 3224 and 1712 cm -1 .The absorption bands associated with other functional groups present all appeared in the expected regions.The 1 H-NMR spectra of compounds 11-15 exhibited singlets at δ 4.06 ppm for the methylenic group (CH 2 ) and at δ 10.65 ppm corresponding to the OH protons.

General
The melting points were taken on an Electrothermal capillary melting point apparatus and are uncorrected.Thin-layer chromatography was performed with fluorescent silica gel plates HF 254 (Merck), and plates were viewed under UV 254 and 265 light.Silica gel (230-400 mesh) was used for flash chromatography separations.The elemental analyses for C, H and N were done on a Perkin-Elmer Analyzer 2440.Infrared spectra (ν-cm -1 ) were recorded on a Beckmann FT-IR 3303, using KBr disks. 1 H-NMR spectra were recorded on JEOL EX-270 MHz NMR Spectrometer at 293 °K in DMSO-d 6 .Spectra were internally referenced to TMS.Peaks are reported in ppm downfield of TMS.
Compound 1 (12.40 g, 50 mmol) was dissolved in a solution containing methanol (120 mL) and 100 % hydrazine hydrate (12 mL) the and the mixture was left standing overnight at 25ºC.The product was separated, collected by suction filtration, washed with methanol and light petroleum, and recrystallized from diluted acetic acid or water to give compound (2)

General procedure for the preparation of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid arylidenhydrazides 3a-l.
A mixture of compound 2 (1.17 g, 5.0 mmol) and the appropriate aromatic aldehyde a-l (5.0 mmol) was refluxed in ethanol/acetic acid (24:1, 25 mL) for 3 hours.The excess of solvent was then removed under reduced pressure, the precipitate formed after cooling was collected by filtration and recrystalized from ethanol to give compounds 3a-l.