Fatima Al-Omran

New synthetic approaches to condensed pyridazinones: alkylpyridazinyl carbonitriles as building blocks for the synthesis of condensed pyridazinones

Abstract The pyridazinyl-5-carbonitriles (3a-d) were prepared via condensing the aryl hydrazones 2a-d with ethyl cyanoacetate. Similar condensation of 2a with malononitrile gives the pyrido[2,3-c]pyridazine derivative (8). Compounds 3a-d reacted with elemental sulphur in refluxing ethanolic solutions in the presence of triethylamine to yield the thieno[3,4-d]pyridazinones 9a-d. The 1,3,4-thiadiazaacenaphthene 12 was prepared via reacting 9e with diethyl fumarate. In contrast, only the phthalazines 14a-c were produced from the reaction of 13a-c with 9e. Compounds 9a-c reacted with acrylonitrile to yield the 1,3,4-thiadiazaacenaphthenes 18a, b. Compound 3a condensed with benzaldehyde to yield 19a. Condensation of 3a, c, d with dimethylformamide dimethylacetal afforded 19b-d. Compound 19b cyclized into 20b when refluxed in acetic acid in the presence of ammonium acetate. This same product was obtained from the reaction of the amide 3g with formaldehyde in refluxing pyridine. The reaction of 3a, c with arylidenemalononitrile (23a, b) gives the tetrahydrophthalazines 25a-c. The pyridazin-4-ones 26a-d were prepared from the reaction of 2a-d with dimethylformamide dimethylacetal in refluxing dioxane. The crystal and molecular structure of compound 18a was solved by X-ray analysis.

Reactivity of condensed thiophenes in the Diels-Alder reaction: The reactivity of 3-aminothieno [3,4:3`,4`] benzo [b] pyranone; 3-aminothieno [3,4-c] quinoline and of 5-amino-7-substituted thieno [3,4-d] pyridazinone toward electron-poor olefins and acetylenes

Abstract The thieno [3,4:3`,4`] benzo [b] pyranone (3b) and the thieno [3,4-c] quinoline (3c) are prepared via reacting 4-methylcoumarin-3-carbonitrile (9a) and 4-methyl-2-oxo-1,2-dihydroquinolin-3-carbonitrile (9b) with elemental sulphur. Similarly the thieno [3,4:3`,4`] naphtho [1,2-b] pyran (11) is prepared from reaction of (10) and elemental sulphur. The condensed thiophenes (3b,c) and (11) react with a variety of electron-poor olefins to yield products of addition followed by hydrogen sulphide elimination. The reaction of (3b,c) and (11) with ethyl propiolate in refluxing dioxane/acetic acid mixture affords the condensed thiepins (24a,c). The nature of product of reaction of (3b,c) and (11) with dimethyl acetylenedicarboxylate is dependent on applied reaction conditions. Thus the reaction of (3b,c) and (11) with dimethyl acetylenedicarboxylate in refluxing dioxane afforded condensed thiepins while at 250°C products of addition and desulfurization are obtained. Whereas thienopyridazinones (1a,b) react with ethyl acrylate and diethyl fumarate to yield thiadiazaacenaphthenones (31a-c) respectively, compounds (1a,b) react with N-phenylmaleimide to yield phthalazine (32). The thienopyridazinone (1c) failed to react with the same reagents under similar conditions.

Reaction of pregnenolone with cyanoacetylhydrazine: Novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1 through its reaction with cyanoacetylhydrazine (2) gave the hydrazide-hydrazone derivative 3. The latter compound underwent heterocyclization reactions to give the pyrazole, pyridine, thiazole and thiophene derivatives of pregnenolone. The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were studied. Some of tested compounds were found to exhibit much higher inhibitory effects towards the three tumor cell lines than the reference drug, doxorubicin.

Synthesis of condensed heteroaromatics: novel synthesis of aminoquinolizinone derivatives as anti-HIV agents

Abstract New routes for the synthesis of aminoquinolizinone derivatives with interesting biological activities are reported. Reactions enaminones 2 and 9 with malononitrile affords aminoquinolizinone derivatives 7a and 7b. Fusion of acetylcyclohexanone (1) with DMF DMA and ethyl cyanoacetate affords only product 11. Treatment of the latter product with malononitrile affords the aminoquinolizinone derivative 15. Reaction of chalcone 17 with malononitrile furnished the product 22. Condensation of (1) with arylidenemalononitrile 23a,b affords compounds 28a,b, respectively. The structure of the newly synthesized compounds was elucidated by elemental analyses and 1H NMR spectra and in some cases by 13C NMR investigation.

Heterocyclic ring extension of estrone: Synthesis and cytotoxicity of fused pyran, pyrimidine and thiazole derivatives

The one pot reaction of estrone with the aromatic aldehydes 2a-c and either of malononitrile or ethyl cyanoacetate afforded the fused pyran derivatives 4a-f. On the other hand, carrying the same reaction using thiourea instead of the cyanomethylene reagent gave the fused pyrimidine derivatives 6a-c. The latter compounds reacted with phenacyl bromide to give the thiazolo[3,2-a]pyrimidine derivatives 8a-c. The reaction of the title compound with bromine gave the monobromo derivative 13 which in turn reacted with either thiourea or cyanothioacetamide to give the thiazole derivatives 14 and 16, respectively. The cytotoxicity of the newly synthesized products was evaluated against six human cancer and normal cell lines where the results showed that compounds 4c, 4f, 6b, 8b, 8c, 10, 13, 16, 18c and 19c exhibited optimal cytotoxic effect against the cancer cell lines, with IC50s in the nM range.

New route for synthesis, spectroscopy, and X-ray studies of 2-[aryl-(6′-hydroxy-4′,4′-dimethyl-2′-oxocyclohex-6′-enyl)methyl]-3-hydroxy-5,5-dimethylcyclohex-2-enone and 1,8-dioxo-octahydroxanthenes and antitumor evaluation

Treatment of 1-(benzothiazol-2-yl-thio)-acetonitrile 1 with 5,5-dimethyl-1,3-cyclohexanedione-(dimedone) 2 and aromatic aldehyde 3a, b in refluxing ethanol containing a catalytic amount of piperidine lead to bisdimedone derivatives 5a and b in short periods of times with excellent yields and not 4H-chromen-5(6H)-one derivatives 8. The compound 5a was then cyclized to 1,8-dioxo-octahydroxanthene derivative 6. The structures of the synthesized compounds were elucidated by elemental analysis 1H NMR and 13C NMR spectra, COSY, HSQC, HMBC, MS, and X-ray crystallographic investigations. The cytotoxicity of the synthesized compounds 5a, b, and 6 were studied and evaluated. Three human tumor and three normal cell lines, namely as breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268), human fibroblast (WI-38), normal prostate epithelial cells, and normal colon mucosal, NCM 460 cells, respectively. The tested compounds were found to exhibit higher inhibitory effects toward the tumor and normal cell lines than the reference drug, doxorubicin.

Diels-Alder in heterocyclic synthesis : a novel synthesis of cycloalkanopyridazinimine, 1,7-alkanothienopyridazines and 1,8-alkanophthalazines: new ring system

Transformation of the newly synthesized alkano[c]pyridazines and 1,7 propanothienopyridazines into 1,8-propanophthalazinones and 1,9-propanothiepinopyridazinones using [4+2] cycloaddition reaction with electron poor olefins and acetylenedicarboxylate derivatives, respectively is described.

Studies with 2-(acetonylthio)benzothiazole. New routes to isoxazoles, isoxazolo[3,4-b]pyridines, pyrazolo[1,5-a]pyrimidines, pyridines and quinolizines

Derivatives of isoxazole, isoxazolo[3,4-b]pyridine, pyrazolo-[1,5-a]pyrimidine and pyridin-2(1H)-one incorporating a benzothiazole-2-thio residue have been synthesised. The structures of these newly synthesised compounds are characterised by elemental analysis, IR, 1H and 13C NMR, NOE and MS.

2-(3-Arylhydrazono-3-formyl-2-oxopropyl)-1H-isoindole-1,3(2H)-dione in heterocyclic synthesis. Novel derivatives of pyridazin-6(1H)-one, pyridazin-6(1H)-imine, and pyrazolo[5,1-c][1,2,4]triazine incorporating an N-(2-oxoethyl)phthalimide moiety

A novel series of 2-(3-arylhydrazono-3-formyl-2-oxopropyl)-1H-isoindole-1,3-(2H)-diones has been prepared and their utility as building blocks in the synthesis of novel derivatives of pyridazin-6(1H)-ones, pyridazin-6(1H)-imines, and pyrazolo[5,1-c][1,2,4]triazines incorporating a N-(2-oxoethyl)phthalimide moiety is investigated.

Studies with Polyfunctionally Substituted Heteroaromatics: A Novel Synthesis of Substituted 4,8-Diaminoisoquinolines as Potential Antiparasitic Agents

New routes for the synthesis of 4,8-diaminoisoquinolines and pyridine utilizing a 3,4-diaminobut-3-en-2-one (2) as starting material are reported.