SYNTHESIS REACTIONS AND ANTIOXIDANT ACTIVITY OF SOME NEW HETEROCYCLES DERIVED FROM 2-ACETYLNAPHTHALENE

2-Methyl-4-(1-(naphthalen-2-yl)ethylidene)oxazol-5(4H)-one 2 was used as precursor for the preparation of some novel (1-(4-substituted)-2-methyl-4-(1-naphthalen-2yl)ethylidene)-1H-imidazol-5(4H)-one derivatives 4a, b and other derivatives 3a,b, 5-12. Furthermore, the preparation of thieno[2,3-d]pyrimidin-4(3H)-one derivative 16,17 and 4iminothieno[2,3-d] pyrimidin-3-ylamine derivative 18, 19 is described starting from 2aminothiophen-3-carbonitrile derivative 15a. Some of the prepared products revealed a promising antioxidant activity by using 1,1-diphenyl-2,2-picryl hydrazyl free radical (DPPH) method.


RESULTS AND DISCUSSION
The interaction of 2-acetylnaphthalene 1 with acetyl glycine in acetic anhydride and in the presence of fused sodium acetate effected cyclization and afforded the corresponding 2-methyl-4-(1-(naphthalen-2-yl)ethylidene)oxazol-5(4H)-one 2 (scheme 1).The structure of the oxazolinone derivative 2 was confirmed by elemental analysis and spectral data.The IR spectrum showed absorption band at 1668.9 cm -1 (C=O); moreover, 1 H-NMR spectrum exhibited signals at δ2.05, 2.70 ppm for two methyl groups and 7.60-8.15for six aromatic protons, 8.47 (s, 1H, C -1 naphthyl) and its mass spectrum afforded a molecular ion peak M + at m/z 251 (3.82%).The behaviour of oxazolinone derivative 2 towards some nucleophilic reagents was discussed under different conditions, as well as its transformation into the corresponding imidazolinone derivatives.Thus, interaction of 2 with p-nitroaniline or pchloroaniline in ethanol with boiling led to ring opening and gave the corresponding 2acetamido-N-substituted-3-(naphthalen-2-yl)but-2-enamides 3a,b which underwent heterocyclization by heating with acetic acid in the presence fused sodium acetate and produced imidazolinone derivatives 4a,b in 70% yield (scheme 1).On the other hand, compound 4a,b could be obtained in one step and better yield by direct reaction of 2 with pnitroaniline or p-chloroaniline under reflux in acetic acid and fused sodium acetate (89% yield) (scheme 1).
The structures of compounds 3 and 4 were deduced from elemental analysis and spectral data.IR spectra of 3 which showed absorption bands characteristic for 2NH groups while IR spectrum of 4 showed the absence of this absorption bands (c.f.exp.)Similarly, the reaction of oxazolinone 2 with secondary amines in ethanol or acetic acid led to ring opening to produce the corresponding acetamido compounds without transmitting into imidazolinone as in the case of primary amines.When compound 2 was treated with N,Ndiethylamine or morpholine in ethanol under reflux, the corresponding 2-acetamido-N,Ndiethyl-3-(naphthalen-2-yl)but-2-enamide 5 and N-1-morphoilino-3-naphthalen-2-yl)-1oxobut-2-en-2-yl)acetamide 6, were produced, respectively (scheme 1).The IR spectra of 5 and 6 showed characteristic absorption bands for (2C=O) and (NH) groups.Also 1 HNMR spectra (δ, ppm) revealed signals at 1.01 (t, J=7.5Hz, 6H, 2CH 3 ), 3.51 (q, J=7.5H, 4H, 2CH 2 ) for compound 5 and for compound 6 revealed signals at 3.24-3.70(m, 8H, 4CH 2 , morphilino) (c.f.exp.)Also, the behaviour of oxazolinone ring towards binucleophile reagent such hydrazine hydrate and phenylenediamine was studied hoping to prepare different heterocyclic of five and six membered ring hoping to have good pharmacological activity.Thus, interaction of oxazolinone 2 with hydrazine hydrate in ethanol under stirring at room temperature caused ring opening to give the corresponding hydrazide derivative 7, while the product that isolated from the reaction of 2 with hydrazine hydrate in ethanol with boiling for 2h was formulated as the triazine derivative 8 (scheme 2).The structures of compounds 7 and 8 were deduced from elemental analysis and spectral data.The 1 H-NMR spectrum of compound 7 (δ, ppm) reaveled signals at 3.72 (br, 2H, NH 2 ), 9.25, 9.51 (2s, 2H, 2NH) exchangeable with D 2 O, while mass spectrum of compound 8 exhibited a molecular ion peak at m/z = 265 (18.67%) (c.f.exp.).
Moreover, interaction of oxazolinone 2 with p-phenylenediamine in ethanol consumed one mole of oxazolinone and produce 2-acetamido-N-(4-aminophenyl)-3-(naphthalen-2-yl)but-2-enamide 9 which under-went heteocyclization by heating with acetic acid in the presence fused sodium acetate and produced imidazolinone derivative 10 (scheme 2).The proposed structures of compounds 9 and 10 was confirmed by elemental analysis and spectral data (c.f.exp.).Treatment of the later compound with p-toluene sulphonyl chloride or p-chlorobenzaldehyde afforded the corresponding sulfonamide derivative 11 and the Schiff base 12, respectively.Inspection of the IR spectrum of the reaction product 11 revealed absorption bands characteristic for (NH), (C=O) groups at 3432,, 1671 and (SO 2 ) group at 1187, 1361cm -1 ; 1 H-NMR spectrum showed signals (δ, ppm) at 1.22, 1.52, 2.57(3s, 9H, 3CH 3 ), and 7.25 (s, 1H, NH, exchangeable with D 2 O), while for compound 12 the 1 H-NMR spectrum revealed a signal at 9.83ppm characteristic for (-CH=N-) (c.f.exp.).It was reported (Hessien, et al., 2009;Hafez, et al., 2010) that various activated nitriles and enaminonitriles were used as intermediates for the syntheses of thieno derivatives and thienopyrimidine derivatives.Thus, condensation of 2-acetyl naphthalene 1 with malononitrile in ethanolic-piperidine solution under reflux gave the corresponding ethylidinemalononitrile derivative 13.IR spectrum showed sharp absorption bands at 2210 and 1589 characteristic for (2C≡N) group and (C=C), respectively and the MS spectrum showed a molecular ion peak at m/z = 218 (M + , 100%).Treatment of 13 with elemental sulfur under Gewald reaction conditions (Gewald, 1965) furnished 2-aminothiophene-3carbonitrile derivatives 15a.The formation of compound 15a occurred via thiation of methyl group in compound 13 to give 14 as an intermediate followed by intramolecualr cyclization (scheme 3).Compound 15a was also obtained directly by interaction of ketone 1 with a mixture of malononitrile and elemental sulfur in the presence of few drops of triethylamine.The obtained product 15a through out the two pathways was checked by TLC and mixed m.p which showed no depression.
Similarly, when compound 1 was treated ethyl cyanoacetate and elemental sulfur under Gewald reaction conditions (Gewald, 1965) gave the corresponding ethyl-2aminothiophen-3-carboxylate derivative 15b (scheme 3).The IR spectra showed absorption bands (, cm -1 ) at 2206 (CN) and 3202 & 3322 (NH 2 ) groups for 15a while for 15b showed (C=O) at 1721 and NH 2 at 3200, 3321 (c.f.exp.) The 4-pyrmidinone derivative was prepared by reacting compound 15a with formic acid under reflux to give derivative 16 (scheme 3).Product 16 was formed presumably via intermediacy of the corresponding oxazinimine derivative (Abdelrazek, et al., 1996;Hegab, et al., 2007) which then rearranged under the conditions of the reaction.On the other hand, when compound 15a was refluxed with triethyl orthoformate, it afforded derivative 17.When the ethanolic solution of the later compound was stirred at room temperature with hydrazine hydrate, it afforded 4-iminopyrimidin-3-ylamine derivative 18. the structures of compounds 16-18 were deduced from elemental analysis and spectral data.IR spectra showed the absence of cyano group for 16 and 18, while 1 H-NMR spectrum revealed signals characteristic for ethyl group for 17 (c.f.exp.).However, the pyrmidin-4-ylhydrazine derivative 19 was obtained by treatment of compound 17 with hydrazine hydrate under reflux (scheme 3).Also, compound 18 was isomerized to corresponding more stable 4hydrazino derivative 19 upon reflux in ethanol in the presence of hydrazine hydrate.Actually, hydrazine hydrate acts as a base in this Dimroth type of rearrangement, which involves a sequence of ring opening and ring closure reaction (Mohamed, et al., 2005;Rashad, et al., 2005;Hegab et al., 2007).Antioxidant activity.

RESULTS:
The provided compounds showed different antioxidant activity using 1,1-diphenyl-2,2-picryl hydrazyl free radical (DPPH) radical scavenging method compared to ascorbic acid standard as shown by the following table :

Experimental
Melting points were recorded on an electrothermal IA 9100 digital melting point apparatus and were uncorrected.IR spectra (V max in cm -1 ) were recorded on a Shimadzu FT-IR 8300 spectrophotometer using KBr pellets technique. 1H-NMR and 13 C-NMR spectra were recorded using Bruker WM-400 spectrophotometer using DMSO-d 6 as the solvent and TMS as the internal reference (chemist shifts in ppm).The mass spectra were run at 70 eV with a finnigan SSQ7000 spectrophotometer (thermo-instrument system incorporation, USA) Elemental analysis were operated using Mario El Mentar apparatus, Organic microanalysis unit.Elemental analysis and the above spectra were measured the at National Research Center.Pharmacology was carried out in the Regional Center for Mycology & Biotechnology, Al-Azhar University.

Procedure 1:
A solution of compound 2 (0.01 mol) in acetic acid (20 mL) was treated with 1gm of fused sodium acetate and (0.01 mol) of (p-nitroaniliine, p-chloroaniline,or p-aminoaniline).The mixture was heated for 3h, the solid obtained was collected and recrystallized to give 4a,b and 10.

Procedure 2:
A mixture of (compound 3a,3b, or 9)(0.01 mol) and 1gm of fused sodium acetate in acetic acid (20 mL) was refluxed for 2h.After cooling, the product formed was filtered off, air dried and recrystallized to give 4a,b and 10.

Procedure A:
A solution of ethylidenemalononitrite 13 (0.01 mol) and sulfur powder (0.01 mol) in ethanol (30 mL) containing few drops of piperidine, was refluxed for 3h.The solid product was filtered and recrystallized to give 15a.

Procedure B: For preparation of 15a and 15b:
A mixture of compound 1 (0.01 moL), malononitrile or ethyl cyanoacetate (0.01 moL) and sulfur powder (0.01 moL) was refluxed in ethanol containing few drops of triethylamine for 2h. the solid formed after filtration and cooling was crystallized to give 15a and 15b respectively.
Compound 18 (0.01 mol) was dissolved in 20 mL ethanol and then drops of hydrazine hydrate were added, then the reaction mixture was heated under reflux temperature for 2h and evaporated under reduced pressure to give compound 19.Product 19 which was obtained from this isomarization is identical in all respects (physical and spectral data) to those prepared by method A.

Antioxidant Assay:
The antioxidant activity of extract was determined by the DPPH free radical scavenging assay method (Sonia, et al., 2008) in triplicate and average values were considered.

DPPH antioxidant assay
Freshly prepared (0.004%w/v) methanol solution of 2,2-diphenyl-l-picrylhydrazyl (DPPH) radical was prepared and stored at 10°C in the dark.A methanol solution of the test compound was prepared.A 40ul aliquot of the methanol solution was added to 3ml of DPPH solution.Absorbance measurements were recorded immediately with a Milton Roy Spectronic 201 UV-visible spectrophotometer.The decrease in absorbance at 515 nm was determined continuously, with data being recorded at 1 min intervals until the absorbance stabilized (16 min).Tocopherol was used as a reference standard and dissolved in distilled water to make the stock solution with the same concentration.The absorbance of the DPPH radical without antioxidant was also measured as control and 95% methanol was used as blank.All the determinations were performed in three replicates and averaged.% Scavenging of the DPPH free radical was measured using the following equation: % DPPH radical-scavenging = [(Absorbance of control -Absorbance of test Sample)/ (Absorbance of control)] x 100 .

Table I .
Antioxidant activity of some synthesized compounds