الفهرس 
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Abstract
The chemistry of oxazolones and benzoxazinone had received great attention in last decades. The importance of these compounds is due to facile opening of the ring to give acyclic products which can recyclize again to afford a variety of heterocyclic system of synthetic and biological importance.
The original work of this thesis can be classified into two parts:
Part 1:
This part deals with the preparation of a series of new derivatives of anthracene via treatment of Anthracene with POCl3/DMF in o-dichlorobenzene under reflux yielded anthracene-9-carboxyaldehyde which was then heated with hippuric acid and acetic anhydride in presence of fused sodium acetate to afford 4-(anthracen-9-ylmethylene)-2-phenyloxazol-5(4H)-one (1a) (scheme1). When an alcoholic solution of compound 1a was stirred with hydrazine hydrate at room temperature, the hydrazide derivative 2a was obtained as a sole product in fairly good yield (scheme 1).
Scheme 1: Synthetic pathway for hydrazide derivative 2a
Ample chemical evidence for the suggested structure of compound 2a was deduced from its reaction with 3-chlorobenzaldehyde under reflux in ethanol, a Schiff base derivative 3a was obtained in a good yield (scheme 2). An attempt to construct an oxadiazole derivative 4a through refluxing of Schiff base 3a with dioxan and drops of acetic acid was achieved through cyclization of 3a (scheme 2). On the other hand, when hydrazide derivative 2a was refluxed with isatin in ethanol; the indole derivative 5a (scheme 2) was obtained as orange crystals in form of Syn. / Anti diastereomeric mixture
Scheme 2: Reactions of hydrazide derivative 2a with some carbonyl compounds
Acetylation of hydrazide derivative 2a with acetic anhydride afforded the acetyl derivative 6a (scheme 3). Refluxing of compound 2a with tetrachlorophthalic anhydride in acetic acid yielded dioxoindoline derivative 7a (scheme 3).
Scheme 3: Reactions of hydrazide derivative 2a with some acid anhydrides
When a mixture of hydrazide derivative 2a and chloroacetyl chloride was refluxed in dioxan, chloroacetyl derivative 8a was formed in fairly good yield (scheme 4). Similar treatment of compound 2a with benzoyl chloride in dioxan yielded the benzoyl derivative 9a (scheme 4). Cyclization of benzoyl hydrazide derivative 9a by fusion at 245-250C0 afforded the imidazole derivative 10a in a moderate yield (scheme 4)
Scheme 4: Reactions of hydrazide derivative 2a with some acid chlorides
Reflux of hydrazide 2a with phenyl isothiocyanate in dioxan afforded the benzamide derivative 11a (scheme 5). On the other hand, when an ethanolic solution of 2a was subjected to react with carbon disulfide in presence of sodium hydroxide as a catalyst. It afforded the oxadiazole derivative 12a.
Scheme 5: Reactions of hydrazide derivative 2a with phenyl isothiocyanate and carbon disulfide.
Insecticidal Screening
Compounds 2a, 3a, 5a, 6a, 7a, 8a, 9a, 11a and 12a were tested for insecticidal activity against Mythimna separata and Nilaparvata lugens using the standard test with a slight modification. The results shown in Table 1 showed that the majority of the tested compounds had effective insecticidal activity against the two pests. However, some of the compounds demonstrated moderate to weak insecticidal activity. Compounds 2a, 6a, 8a, 9a and 11a demonstrated strong insecticidal activities against both pests.
Table 1: Insecticidal activity of the evaluated compounds against M. separate and N. lugens.
Compd. Insecticidal activities at different concentrations (µg.mL-1)
(Mortality, %)
M. separate N. lugens
200 100 75 50 25 200 100 75 50 25
2a 100 100 100 94.9 90.3 100 100 98.4 90.2 84.8
3a 90.4 73.4 64.3 37.4 21.4 92.4 78.3 68.3 50.2 31.2
5a 75.8 61.3 48.2 19.3 17.1 76.2 61.3 42.4 28.3 25.4
6a 100 100 95.3 93.4 89.7 100 100 90 84.7 79.6
7a 83.2 67.3 54.2 24.8 22.2 85.1 69.2 51.3 30.1 26.5
8a 100 100 97.6 94.8 93.2 100 100 95 94.7 79.7
9a 100 100 95.2 90 89.6 100 100 72.3 59.3 34.6
11a 100 100 98.7 97.8 93.4 100 100 85 84.7 80.4
12a 52.3 34.2 18.7 15.6 13.3 53.5 30.6 16.9 14.2 11.8
Pyridalyl 100 100 100 98 93 - - - - -
Abamectin - - - - - 100 100 100 91 85
Part 2:
This part discusses the synthesis of a new benzoxazinone derivative 2b and utilize it in the preparation of some heterocyclic systems. The nucleophilic addition of anthranilic acid to furanone 1b produced the starting compound 2-(4 -oxo-1,4-diphenylbut-1-en-2-yl)- 4H-benzo[d][3,1]oxazin-4-one (2b) (scheme 6).
Scheme 6: synthesis of 2-(4-oxo-1,4-diphenylbut-1-en-2-yl)-4H-benzo[d][3,1]oxazin-4-one
The key starting compound 2b was used to prepare new quinazolinone and hydrazide derivatives via reaction of oxazinone derivative 2b with different nitrogen nucleophiles (scheme 7). Stirring of 2b at room temperature with an adequate amount of hydrazine hydrate in dioxan afforded the acid hydrazide derivative 3b in good yield, which cyclized under refluxing with n-butanal or fusion to give quinazolinone derivative 4b in 60% yield (scheme 7). On the other hand, refluxing of oxazinone derivative 2b with excess amount of hydrazine hydrate in dioxan yielded a mixture of 4b and amino quinazolinone derivative 5b in 40% yield (scheme 7). When the benzoxazinone derivative 2b was fused with ammonium acetate in thermal controlled oil bath , a brown solid product 6b has been separated (scheme 7).
Scheme 7: Reaction of 2b with nitrogen nucleophiles
When the hydrazide derivative 3b was refluxed with boiling acetic acid, the corresponding amino quinazolinone derivative 7b was formed, which easily acetylated to the corresponding acetylated derivative 8b (scheme 8). The hydrazide derivative 3b was fused with phthalic anhydride to give quinazolinone derivative 9b . Stirring of hydrazide derivative 3b with freshly distilled acetic anhydride at room temperature gave pyrolone derivative 10b (scheme 8).
Scheme 8: Reaction of 3b with acid and/or acid anhydride
Unfortunately, when the hydrazide derivative 3b was refluxed with phenyl isothiocyanate in dioxan, hydrolysis of 3b instead of nucleophilic attack of NH2 to phenyl isothiocyanate was performed to form acid derivative intermediate which was easily cyclized to the corresponding benzoxazinone derivative 2b (scheme 9). According to the less activity of hydrazide derivative towards reaction with phenyl isothiocyanate, the reaction was catalyzed via addition of ethanolic sodium hydroxide solution to refluxed mixture of 3b and phenyl isothiocyanate which afforded the quinazolinone derivative 11b. When acetic acid solution of 3b was stirring with potassium cyanate at room temperature, urea derivative 12b was formed in fairly good yield which easily cyclized to quinazoline derivative 13b (scheme 9) upon reflux with ethanolic sodium hydroxide solution.
Scheme 9: reaction of 3b with carbon electrophiles
Due to the less reactivity of acetylacetone, fusion of it with hydrazide derivative 3b gave the benzoxazinone derivative 2b (scheme 10). According to chemotherapeutic potential of pyrazole derivatives, authors would like to construct new pyrazole ring upon treatment of 3b with 1,3-diphenyl-1H-pyrazole-4-carboxyaldyhyde in refluxing ethanolic solution which afforded to pyrazolo quinazoline derivative 14b (scheme 10). As a chemical proof, the hydroxyl group in 14b was acetylated when 14b was allowed to be refluxed with acetic acid solution to give quinazoline derivative 15b in fairly good yield.
Scheme 10: reaction of 3b with carbonyl compounds
Cytotoxicity assay:
The activity of the prepared compounds was examined against Mammary gland Breast cancer (MCF-7) and Hepatocellular carcinoma (HEPG-2).Doxorubicin was used as a standard anticancer drug for comparison. The following table shows the toxic activity of the prepared compounds against human cancer cells.
Table 2: Toxic activity of the prepared compounds against cancer cells
o. Comp. In vitro Cytotoxicity IC50 (µM) •
HePG2 MCF7
•• Doxorubicin 4.50±0.2 4.17±0.2
1 2b 56.14±3.1 61.24±3.5
2 3b 8.96±0.6 3.84±0.2
3 4b 68.32±3.8 54.22±3.2
4 5b 6.90±0.4 5.58±0.3
5 6b 38.12±2.4 9.14±0.7
6 7b 63.57±3.6 39.27±2.4
7 8b 10.48±0.9 18.12±1.4
8 9b 52.18±2.9 29.28±2.1
9 10b 13.09±1.1 15.47±1.2
10 11b 83.60±4.1 78.69±4.0
11 12b 27.73±2.0 7.76±0.5
12 13b 19.38±1.4 23.68±1.8
13 14b 32.56±2.2 34.66±2.3
14 15b 75.51±3.9 44.40±2.6
15 16b 91.30±4.5 69.36±3.8
• IC50 (µM) : 1 – 10 (very strong). 11 – 20 (strong). 21 – 50 (moderate). 51 – 100 (weak) and above 100 (non-cytotoxic)