الفهرس 
BenzochromenesOnly 14 pages are availabe for public view
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Abstract
Heterocyclic compounds, in particular oxygen-containing molecules, represent an indispensable class due to their physicochemical properties. The literature reveals that chromene and benzochromene derivatives are important pharmacophores associated with a broad range of pharmacological activities.
Benzochromene nucleus has been emerged as a promising and attractive scaffold in the development of potent antitumor agents. Based on these considerations, the interest of the author was focused on synthesizing new heterocycles including benzochromene moieties with suitable substituents. In summary, this thesis comprises the following:
Introduction:
It covers a brief survey on the benzochromene derivatives including structure, nomenclature, methods of preparation, chemical reactions, and their biological activities.
Results and Discussion:
In this section, the reactions utilized for synthesis of novel 1H-benzo[f]chromene, benzo[f]chromeno[2,3-d]pyrimidine and 14H-benzo[f]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives are discussed with references to the knowledge available in the literature.
Mechanistic pathways are proposed to the synthesis of some compounds.
Thus, treatment of naphthalene-2,7-diol (24) with a mixture of 4-chlorobenzaldehde (10) and malononitrile (11a) or with α-cyano-4-chlorocinnamonitrile (36) in ethanolic piperidine solution under reflux for 1 h afforded 1:1 adduct, 3-amino-1-(4-chlorophenyl)-9-hydroxy-1H-benzo[f]chromene-2-carbo-nitrile (25).
In a similar manner, the reaction of naphthalene-2,7-diol (24) with a mixture of 4-chlorobenzaldehyde (10) and ethyl
cyanoacetate (11b) in ethanolic piperidine solution under reflux for 2 h afforded 1:1 adduct, ethyl 3-amino-1-(4-chlorophenyl)-9-hydroxy-1H-benzo[f]chromene-2-carboxylate (91), while reaction of (24) with ethyl α-cyano-4-chlorocinnamate (37) in ethanolic piperidine solution under reflux for 2 h afforded the ethyl 3-amino-1-(4-chlorophenyl)-9-hydroxy-1H-benzo[f]chromene-2-carboxylate-ethyl α-cyano-4-chlorocinnamate complex (92) instead of the β-enaminoester (91). The structure of (92) was confirmed by spectral data and X-ray single crystal data.
Interaction of 3-amino-1-(4-chlorophenyl)-9-hydroxy-1H-benzo[f]chromene-2-carbonitrile (25) with acetic anhydride for 0.5 h afforded the open chain product 9-acetoxy-3-acetylamino-1-(4-chlorophenyl)-1H-benzo[f]chromene-2-carbonitrile (93), while heating of the compound (25) with acetic anhydride for
3 h afforded the cycloaddition product 2-acetoxy-12-(4-chloro-phenyl)-10,11-dihydro-9-methyl-12H-benzo[f]chromeno[2,3-d]-pyrimidin-11-one (94) with acylation of the hydroxyl group at 9-position into the acetoxy group. Besides, condensation of compound (25) with formamide under reflux for 6 h afforded the cycloaddition product 11-amino-12-(4-chlorophenyl)-2-hydroxy-12H-benzo[f]chromeno[2,3-d]pyrimidine (95), while benzoylation of the compound (25) with benzoyl chloride under reflux gave the cycloaddition product 2-benzoxy-12-(4-chloro-phenyl)-10,11-dihydro-9-phenyl-12H-benzo[f]chromeno[2,3-d]-pyrimidin-11-one (96) with benzoylation of the hydroxyl group at 9-position into the benzoxy group.
Reaction of the compound (25) with triethyl orthoformate in acetic anhydride under reflux gave 9-acetoxy-1-(4-chloro-phenyl)-3-ethoxymethyleneamino-1H-benzo[f]chromene-2-carbonitrile (97) with acylation of the hydroxyl group at 9-position and reaction of compound (25) with the neat triethyl orthoformate gave the corresponding 1-(4-chlorophenyl)-3-ethoxymethyleneamino-9-hydroxy-1H-benzo[f]chromene-2-carbonitrile (98), while condensation of (25) with dimethylform-amide-dipentylacetal (DMF-DPA) in benzene under reflux gave 1-(4-chlorophenyl)-3-dimethylaminomethyleneamino-9-hydroxy-1H-benzo[f]chromene-2-carbonitrile (99). In addition, the structure of compound (97) was confirmed by X-ray single crystal data.
Ammonolysis of the imidate (97 and 98) with NH3 gas bubbled in absolute methanol at room temperature under stirring for 1 h gave the cycloaddition product 11-amino-12-(4-chloro-phenyl)-2-hydroxy-12H-benzo[f]chromeno[2,3-d]pyrimidine (95) (m.p., mixed m.p., identical IR and MS spectrum) with deacylation of the acetoxy group at 2-position into hydroxyl group in the case of imidate (97). The aminopyrimidine derivative (95) can be obtained as described before from the reaction of the compound (25) with formamide (m.p., mixed m.p., identical IR and MS spectrum). Treatment of (97 and 98) with dimethylamine or diethylamine in absolute methanol at room temperature under stirring for 1h gave the open chain products 1-(4-chlorophenyl)-3-dimethylaminomethyleneamino-9-hydroxy-1H-benzo[f]chromene-2-carbonitrile (99) and 1-(4-chlorophenyl)-3-diethylaminomethyleneamino-9-hydroxy-1H-benzo[f]-chromene-2-carbonitrile (100) (m.p., mixed m.p., identical IR and MS spectrum) respectively, with deacylation of the acetoxy group at 2-position into hydroxyl group in the case of imidate (97). The imidine (99) can be obtained as described before from the reaction of compound (25) and DMF-DPA (m.p., mixed m.p., identical IR and MS spectrum). Besides, reaction of imidates (97 and 98) with methylamine or hydrazine hydrate under the same conditions afforded the cycloaddition products 12-(4-chlorophenyl)-10,11-dihydro-2-hydroxy-11-imino-10-methyl-12H-benzo[f]chromeno[2,3-d]pyrimidine (101) and 10-amino-12-(4-chlorophenyl)-10,11-dihydro-2-hydroxy-11-imino-12H-benzo[f]chromeno[2,3-d]pyrimidine (102) (m.p., mixed m.p., identical IR and MS spectrum) with deacylation of the acetoxy group at 2-position into hydroxyl group in the case of imidate (97). Also, reaction of the aminoimino compound (102) with benzaldehyde afforded the open chain Schiff base product 10-benzylideneamino-12-(4-chlorophenyl)-10,11-dihydro-2-hydroxy-11-imino-12H-benzo[f]chromeno[2,3-d]pyrimidine (103).
The aminoimino compound (102) proved to be the key precursor for the synthesis of a variety of 2-substituted 14H-benzo[f]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives. Thus, treatment of the aminoimino compound (102) with triethyl orthoformate in dry benzene at reflux temperature gave 14-(4-chlorophenyl)-12-hydroxy-14H-benzo[f]chromeno[3,2-e]-[1,2,4]triazolo[1,5-c]pyrimidine (104a), while acylation of the aminoimino compound (102) with acetyl chloride afforded 14-(4-chlorophenyl)-12-hydroxy-2-methyl-14H-benzo[f]chromeno-[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (104b).
The structures assigned to the new compounds were supported by infrared, mass spectrum, nuclear magnetic resonance data and elemental analyses.
Also, some of the synthesized compounds were tested for their in-vitro antimicrobial activity against different microorganisms representing Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis and Staphylococcus epidermtitis), Gram-negative bacteria (Enterococcus cloaca, Escherichia coli and Salmonella typhimurium) using the standard antibiotic Gentamycin (5 mg/mL) as reference drugs and fungi (Aspergillus fumigates, Aspergillus flavus and Candida Albicans) using the standard antibiotic Ketoconazol. Some compounds showed congruent results against the most tested microorganisms compared to the standard drugs.
Experimental:
In this section, the methods utilized for the synthesis of the target compounds are discussed.
References:
The thesis is terminated with 100 references relevant to the work discussed.