Reactions of vinyl 2,3-epoxypropyl ethers with 4,5-dihydro-1H-pyrazoles

Reactions of vinyl 2,3-epoxypropyl ether and 2-(vinyloxy)ethyl 2,3-epoxypropyl ether with 4,5-dihydro-1H-pyrazoles give, respectively, 3-vinyloxy-1-(4,5-dihydro-1H-pyrazol-1-yl)propan-2-ols and 3-(2-vinyloxyethoxy)-1-(4,5-dihydro-1H-pyrazol-1-yl)propan-2-ols in 70–91% yield.     

Synthesis of novel 1-(2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)-uracil and -thymine, and their corresponding S-oxidized derivatives

On the basis of molecular variations on isosteric replacements from the prototype 1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil a series of 3-(2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)-uracil or -thymine O,N-acetals was prepared. The nature of the cis- and trans-sulfoxide isomers was established by means of their conformational analyses carried out with Sybyl and after comparing the theoretical results with the ¹H NMR responses of the target molecules. (RS)-3-(1,1-Dioxo-2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)thymine and (1S*,3S*)-1-(1-oxo-3,5-dihydro-2H-4,1-benzoxathiepin-3-yl)thymine were found to be inhibitors of the MCF-7 cell growth.     

Chemoenzymatic synthesis of both enantiomers of 3-hydroxy-2,3-dihydro-4H-chromen-4-one

4-Oxo-3,4-dihydro-2-chromen-3-yl acetate is synthesized using manganese(III)acetate starting from 2,3-dihydro-4H-chromen-4-one. K₂CO₃ mediated hydrolysis of 4-oxo-3,4-dihdro-2-chromen-3-yl acetate furnished 3-hydroxy-2,3-dihydro-4H-chromen-4-one in high yield.The enantioselective hydrolysis of (±)-4-oxo-3,4-dihydro-2-chromen-3-yl acetate in various organic solvent-phosphate buffer (pH7) systems and enantioselective transesterification of (±)-3-hydroxy-2,3-dihydro-4H-chromen-4-one in organic solvents was investigated by screening a range of lipases. The lipase Amano PS, PPL, PLE and CCL-catalyzed asymmetric ester hydrolysis and transesterification afforded the enantiomers of 3-hydroxy-2,3-dihydro-4H-chromen-4-one and 4-oxo-3,4-dihydro-2-chromen-3-yl acetate with high enantiomeric excess (up to 97% ee) and in good yields.     

Meso-trans-diaryldihexadecyltetrabenzoporphyrins and their zinc complexes: Synthesis and spectra

3-[(1-Oxo-1H-isoindol-3-yl)(phenyl)methylidene]-2,3-dihydro-1H-isoindol-1-one, 3-[(1-oxo-1H-isoindol-3-yl)(1-naphthyl)methylidene]-2,3-dihydro-1H-isoindol-1-one, and 3-[(1-oxo-1H-isoindol-3-yl)(9-anthryl)methylidene]-2,3-dihydro-1H-isoindol-1-one were prepared by the reactions of phthalimide with phenylacetic, 1-naphthylacetic, and 9-anthrylacetic acids, respectively. Heating of these precursors with stearic acid in the presence of zinc oxide yielded zinc complexes of meso-trans-diphenyldihexadecyltetrabenzoporphyrin, meso-trans-di(1-naphthyl)dihexadecyltetrabenzoporphyrin, and meso-trans-di(9-anthryl)dihexadecyltetrabenzoporphyrin, respectively. Treatment of the metal complexes with HCl yielded the porphyrin bases. The spectral properties of the compounds were studied.     

Synthesis of 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-imidazo-[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids

Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride. The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-dibenzyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones were reduced to the corresponding 1,3-dialkyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, and the latter reacted with itaconic acid to produce 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids. 1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acid was obtained by analogous reaction with 5-amino-2,3-dihydro-1H-imidazo[4,5-b]-pyridin-2-one.     

Medium benzene-fused oxacycles with the 5-fluorouracil moiety: synthesis, antiproliferative activities and apoptosis induction in breast cancer cells

On the basis of the increase in lipophilicity, novel benzannelated six- and seven-membered derivatives have been synthesized, starting from 2-hydroxybenzyl alcohols, 2-hydroxybenzaldehydes, and catechol. The X-ray structure of (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil (5) is presented and compared with its conformational analysis at the semiempirical (AM1) and ab initio (6-31G^∗) levels and NOE effects. A good agreement between both experimental and theoretical data was found showing a chair conformation for the 2,3-dihydro-5H-1,4-dioxepin ring and an axial orientation of the 5-FU moiety on the C3 position. Compounds 5 and (RS)-1-(7-methoxy-2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil (6) were found to be the most potent inhibitor of MCF-7 cells growth. (RS)-1-(2,3-Dihydrobenzoxepin-2-yl)-5-fluorouracil (8) induced apoptosis up to 57.33% of cell population after 24 h.     

Five-membered dioxoheterocycles: XCIX. Reaction of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones with indoles. Crystal and molecular structure of substituted 2-(indol-3-yl)pyrrole

1-Aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones react with indole and 2-methylindole with the formation of methyl 1-aryl-3-aroyl-4-hydroxy-2-(1H-indol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates. Crystal and molecular structure of methyl 3-benzoyl-4-hydroxy-2-(2-methyl-1H-indol-3-yl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylate was examined.     

Synthesis of phosphorylated isoindolinone derivatives

The synthesis of diethyl [2-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)ethyl]phosphonates and diethyl [3-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propyl]phosphonates, via metallation (sec-BuLi) of N-substituted isoindolin-1-ones and then the reaction of the generated lithiated species 4 with diethyl vinylphosphonate or diethyl 3-bromopropylphosphonate, respectively, is described.     

Synthesis of 2-thioxoimidazolines via reaction of 1-unsubstituted 3-aminoquinoline-2,4-diones with isothiocyanates

3-Alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with alkyl/aryl isothiocyanates to give 3a-alkyl/aryl-1,2,3,3a-tetrahydro-9b-hydroxy-2-thioxo-5H-imidazo[4,5-c]quinolin-4(9bH)-ones in high yields. These compounds rearrange in boiling acetic acid or concd hydrochloric acid to give novel 4-(2-aminophenyl)-1H-imidazole-2(3H)-thiones, 1,3-bis(2-(2,3-dihydro-2-thioxo-1H-imidazol-5-yl)phenyl)ureas and minor N-(2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenyl)acetamides. In the presence of ethanol, the starting compounds rearrange in boiling acetic acid to give ethyl 2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenylcarbamates. All compounds were characterized by their ¹H, ¹³C, IR and MS spectra and some of them also by ¹⁵N NMR data. The structures of two compounds were supported by single-crystal X-ray diffraction.     

Synthesis of 7-iodo(arylsulfanyl)methyl-7,8-dihydro-[1,3]thiazolo[2,3-i]purinium pentaiodide (perchlorates) and their transformation into 4-amino-5-(1,3-thiazol-2-yl)imidazole derivatives

Intramolecular electrophilic cyclization of 6-allylsulfanylpurine by the action of iodine and arenesulfenyl chlorides gave 7-iodomethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium pentaiodide and 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates, respectively. 7-Iodomethyl-7,8-dihydro-[1,3]thiazolo[2,3-i]purin-6-ium iodide reacted with sodium and potassium alkoxides to produce alkyl N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-4-yl]formimidates, and its reaction with secondary cyclic amines afforded 5-(4-methyl-1,3-thiazol-2-yl)-N-[morpholin-4-yl(or piperidin-1-yl)methylidene]-1H-imidazol-4-amines. Successive treatment of 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates with sodium acetate and morpholine led to the formation of 5-(4-arylsulfanylmethyl-4,5-dihydro-1,3-thiazol-2-yl)-N-(morpholin-4-ylmethylidene)-1H-imidazol-4-amines.     

Regioselective addition of aromatic amines at the exocyclic C=C bond of 2-(2-Oxo-2,3-dihydro-1H-indol-3-ylidene)acetic acid esters

Methyl and ethyl 2-(2-oxo-2,3-dihydro-3H-indol-3-ylidene)acetates react with aromatic amines to give products of regioselective addition at the α-position of the activated exocyclic C=C bond, methyl and ethyl 2-arylamino-2-(2-oxo-2,3-dihydro-1H-indol-3-yl)acetates.     

Synthesis,anticancer, and computational studies of 1, 3, 4-oxadiazole-purine derivatives

Theophylline-7-acetic acid (acefylline) ( 3 ) and its derivatives are pharmacologically active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of 2-((5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)-N-arylacetamides ( 10a-j ) has been reported. All the synthesized derivatives ( 10a-j) were structurally verified by FT-IR, ¹H NMR, ¹³C NMR and evaluated for their anti-cancer (using MTT assay), hemolytic and thrombolytic potential. N-(4-Chlorophenyl)-2-(5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)acetamide ( 10g ) was found to be the most active against human liver cancer cell lines (Huh7) having cell viability 53.58 ± 1.28 using 100 μg/mL concentration of compound which was further in-silico modelled to describe the possible mechanistic insights for its anti-proliferative activity. The results of hemolytic and thrombolytic activities indicated that these derivatives were less toxic and hold considerable potential as a drug candidate. 2-(5-((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(2-fluorophenyl)acetamide ( 10c ) of the series was found to be least toxic with 0.1% hemolysis relative to ABTS (95.5%) as positive control. 2-(5-((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(tetrahydro-2H-pyran-4-yl)acetamide ( 10j ) exhibited potent clot lysis activity (90%) as compared to negative control DMSO (0.57%).     

Reaction of 2-(2-oxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-indol-3-ylidene)acetic acid esters with benzene-1,2-diamine and 2-aminobenzenethiol

2-(2-Oxo-2,3-dihydro-1H-indol-3-ylidene)acetic acid esters reacted with benzene-1,2-diamine or 2-aminobenzenethiol to give (2-oxo-2,3-dihydro-1H-indol-3-yl)-substituted 3,4-dihydroquinoxalin-2(1H)-ones or 2H-1,4-benzothiazin-3(4H)-ones.     

Synthesis and anticancer activity studies of novel 1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)uracil and (6′-substituted)-7- or 9-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-7H- or 9H-purines

On the basis of a molecular variation on an isosteric replacement (F→H) from the prototype (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil, the derivative (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)uracil 4 was prepared. Later on, the pyrimidine base was substituted by the purine moiety with the objective of increasing both the lipophilicity and the structural diversity of the target molecules. The 6′-halogen substituent of the (RS)-9- or 7-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-9H- or 7H-purines shows an interesting reactivity, which is presented and discussed. The anticarcinogenic potential of the target molecules is reported against the MCF-7 cancer cell line.     

Molecular rearrangement of 1-substituted 9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones—an unexpected pathway to new indole and imidazolinone derivatives

1-Substituted 3a-alkyl/aryl-9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones and 3′-substituted 3-alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones react in boiling acetic acid to give 2-alkyl/aryl-1H-indol-3-yl-ureas and/or 1,3-bis[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)-phenyl]-ureas. By the action of hydrochloric acid, the first of them rearrange to give 4-(2-aminophenyl)-1,3-dihydroimidazol-2-ones. The structure of 1,3-bis[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)-phenyl]-ureas was confirmed by their synthesis. All compounds were characteried by their ¹H NMR, ¹³C NMR, IR spectra, atmospheric pressure chemical ioniation mass spectra, and some of them also by ¹⁵N NMR spectroscopic data.     

5,15-dialkyl-substituted tetrabenzoporphyrins and their zinc complexes. Synthesis and spectral properties

Reactions of phthalimide with capric and stearic acids gave 1-[1-(1-oxo-1H-isoindol-3-yl)nonylidene]-2,3-dihydro-1H-isoindol-3-one and 1-[1-oxo-1H-isoindol-3-yl)heptadecylidene]-2,3-dihydro-1H-isoindol-3-one, respectively. The latter were heated with zinc(II) acetate to obtain zinc complexes of 5,15-dioctyl-and 5,15-dihexadecyltetrabenzoporphyrins. The same complexes were synthesized by reaction of 1-(1-oxo-1H-isoindol-3-ylmethylidene)-2,3-dihydro-1H-isoindol-3-one with capric or stearic acid in the presence of zinc(II) oxide. The corresponding free porphyrin ligands were obtained by treatment of the metal complexes with sulfuric acid.     

Five-membered 2,3-dioxo heterocycles: LXIII. Cascade recyclization of isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates with cyclic enamines. Crystalline and molecular structure of 1′-benzyl-6′,6′-dimethyl-3-[(Z)-phenyl(phenylamino)methylidene]-6′,7′-dihydro-3H-spiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraone

Isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates reacted with N-substituted 3-amino-5,5-dimethylcyclohex-2-en-1-ones to give the corresponding 1′-substituted (Z)-6′,6′-dimethyl-3-[phenyl(arylamino)methylidene]-6′,7′-dihydro-3H-spiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraones. The structure of 1′-benzyl-6′,6′-dimethyl-3-[(Z)-phenyl(phenylamino)methylidene]-6′,7′-dihydro-3Hspiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraone was proved by X-ray analysis.     

Intramolecular cyclization of 4-amino-3-alkylsulfanyl-1,2,4-triazoles as a method for annelation of thiadiazine and thiadiazole rings

4-Amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiols reacted with N-substituted isatins to give 2-oxo-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4-triazole-4-ylimino]-2,3-dihydro-1H-indoles which were treated with phenacyl bromides to obtain the corresponding S-phenacyl derivatives. The latter underwent base-catalyzed intramolecular cyclization with formation of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines spiro-fused to 2-oxo-2,3-dihydro-1H-indole fragment at C³. Analogous cyclization of 2,6-di-tert-butyl-4-[5-hetaryl-3-(2-aryl-2-oxoethylsulfanyl)-4H-1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienones involved the imino nitrogen atom to produce the corresponding 6-aroyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hetaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles.     

Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3-trifluoropropionate with 1,3-binucleophiles

Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3-trifluoropropionate with 1,3-binucleophiles such as benzamidines, aminothiazoline, and 2-aminocrotonic acid nitrile results in trifluoromethyl-containing 3,5-dihydro-4-ones, 2,3-dihydro-6H-imidazo[2,1-b]thiazol-5-one, and 4,5-dihydro-1H-pyrrole-3-carbonitrile.     

Reaction of Diethyl Vinylphosphonate with Benzimidazole and 2-Aminobenzimidazole

Benzimidazole reacted with diethyl vinylphosphonate to give diethyl 2-(1H-benzimidazol-1-yl)- ethylphosphonate. The addition of 2-aminobenzimidazole to vinylphosphonate involved the endocyclic nitrogen atom with formation of diethyl 2-(2-imino-2,3-dihydro-1H-benzimidazol-1-yl)ethylphosphonate.