Synthesis of Some Potentially Bioactive Compounds From Visnaginone

The reaction of 5-acetyl-6-hydroxy-4-methoxybenzo[b]furan (visnaginone Ia) with 2-diethylaminoethylchloride led to the formation of 5-acetyl-6-diethylamino-ethoxy-4-methoxybenzo[b]furan (II), whereas condensation of compound II with some aromatic aldehydes afforded the corresponding chalcones IIIa-c. Methylation of visnaginone (Ia) gave 5-acetyl-4,6-dimethoxybenzo[b]furan (Ib), which in turn reacted with some aromatic aldehydes to give the corresponding chalcones IIId,e. The reaction of chalcones IIId,e with hydrazine hydrate in alcohol gave the pyrazoline derivatives IVa,b, whereas when the same reaction was carried out in acetic acid it afforded the N-acetylpyrazoline derivatives Va,b. Similarly, the reaction of IIId,e with phenyl hydrazine in acetic acid led to the formation of phenylpyrazoline derivatives VIa,b, whereas condensation of chalcones IIId,e with hydroxyl amine hydrochloride gave the isoxazoline derivatives VIIa,b. The reaction of compound II with phenylhydrazine and 2,4,6-trichlorophenylhydrazine afforded the corresponding phenyl hydrazone derivatives VIIIa,b. Mannich bases IXa,b were synthesized by the reaction of visnaginone (Ia) with piperidine and benzylamine in the presence of formaline.


Results and Discussion
As shown in Scheme 1, visnaginone (Ia) was reacted with diethylaminoethyl chloride in acetone to afford 4-methoxy-5-acetyl-6-diethylamino-ethoxybenzofuran (II). The reaction of II with some aromatic aldehydes, namely, benzaldehyde, anisaldehyde and 4-chlorobenzaldehyde in dry methanol in the presence of sodium methoxide afforded the cinnamoyl derivatives IIIa-c. Methylation of visnaginone (Ia) with methyl iodide in dry acetone led to the formation of 6-methoxy visnaginone (Ib). The reaction of (Ib) with benzaldehyde and anisaldehyde afforded the corresponding chalcones IIId,e. The action of hydrazines on chalcones IIId,e was studied and it was found that when compounds IIId,e were reacted with one equivalent hydrazine hydrate in alcohol, they afforded the pyrazoline derivatives Iva,b, and when the same reaction was carried out in acetic acid the Nacetylpyrazolinyl derivatives Va,b were obtained. The reaction of IIId,e with phenyl hydrazine was carried out in boiling acetic acid to afford the phenyl pyrazolinyl derivatives VIa,b. On the other hand, the isoxazolinyl derivatives VIIa,b were obtained when chalcones IIId,e were reacted with hydroxylamine hydrochloride. Visnaginone Ia reacted with phenyl hydrazine and 2,4,6trichlorophenyl hydrazine to yield the corresponding hydrazones VIIIa,b. Also, visnaginone was reacted with piperidine and benzylamine under Mannich conditions to afford the corresponding Mannich bases IXa,b.

General
Melting points are uncorrected. 1 H-NMR spectra were run using TMS as internal reference on a Jeol EX-270 NMR spectrometer. IR spectra were recorded on a FT/IR Jasco 300 E instrument. The prepared compounds were analyzed for C, H and N and the microanalytical data is in full agreement with the suggested structures (Table 1). Compound Ia was prepared according to Musante [13].
Compound Ib was prepared according to Schonberg [14] and compound IXa was prepared according to Ragab [7]. The biological activity of the prepared compounds is under investigation and will be published separately in near future.

General procedure for the preparation of 5-substituted cinnamoyl-6-(2-diethylaminoethoxy)-4methoxy benzo[b]furans (IIIa-c).
Compound II (0.3 mole) was reacted with a mixture of the appropriate aromatic aldehyde (0.3 mole), dry methanol (30 mL) and sodium methoxide (from 3g Na and 30 mL methanol) with stirring at room temperature for 4 hrs., then water (750 mL) was added and the mixture extracted with ethyl acetate. The organic layer washed with water, dried over anhydrous sodium sulphate, concentrated and crystallized from methanol.

General procedure for the preparation of 5-substituted cinnamoyl-4,6-dimethoxybenzo[b]furans (IIId,e).
6-Methoxy visnaginone Ib (0.1 mole) was dissolved in ethyl alcohol (15 mL). The appropriate aromatic aldehyde (0.1 mole) was added, followed by the addition of a solution of sodium hydroxide (30%, 12 mL). The mixture was stirred and allowed to stand at room temperature for 24 hrs., then diluted with water (270 mL) and acidified with dilute solution HCl. The precipitate formed was filtered off and crystallized from ethyl alcohol.

General procedure for the preparation of 5-(1-arylhydrazono-ethyl)-6-(2-diethylaminoethoxy)-4methyl benzo[b]furans (VIIIa,b).
Compound II (0.01 mole) was dissolved in ethyl alcohol (10 mL), 0.1 mole of a hydrazine was added (phenyl hydrazine in case of VIIIa and 2,4,6-trichlorophenyl hydrazine in case of VIIIb), followed by the addition of few drops of acetic acid and the reaction mixture was refluxed for 5 hrs. and then cooled. The solid material was filtered off and crystallized from ethyl alcohol.