Synthesis, characterisation and antimicrobial activity of new benzo[a]phenoxazine based fluorophores

N-[5-(3-Aminopropylamino)-10-methyl-9H-benzo[a]phenoxazin-9-ylidene]ethanaminium chloride (Bze-NH₂) was prepared and used as a precursor in the synthesis of new polycyclic cationic dyes. In addition to the potentiality of Bze-NH₂ as a non-covalent fluorescent probe, the presence of a free amino group in its structure prompted us to study the application of this functionalised heterocycle in the covalent labelling of glycine and valine amino acids, as models of biomolecules. All compounds obtained showed strong absorbance and high emission at long-wavelengths (λ_em >640 nm). Furthermore, all benzo[a]phenoxazine derivatives synthesised were evaluated as antifungal agents against Saccharomyces cerevisiae, considering the commercial Nile Blue A (NB) as a lead compound. The results revealed that they exhibited good activity, which was usually superior to NB, the most effective compound displaying a minimum inhibitory concentration (MIC) value of 15 μM.     

Synthesis and fluorescence properties of novel benzo[a]phenoxazin-5-one derivatives

Thirteen, benzo[a]phenoxazin-5-one derivatives 3a-m were synthesized from 4-nitrosoaniline hydrochlorides 1a-m and ethyl 1,3-dihydroxynaphthoate 2 and their fluorescence properties were discussed in terms of the electronic effect of substituents. A coupling reaction was carried out with 6-carbethoxy-9-N-(2-hydroxyethyl)-N-methylamino-5H-benzo[a]phenoxazin-5-one (3k) and acetyl-DL-alanine to afford N-[(6-carbethoxy-5-oxo-5H-benzo[a]phenoxazin)-9-yl]-N-methylaminoethylene acetyl-DL-alanine ester (4).     

The photochemical reactions of 5H-benzo[a]phenoxazin-5-one with alkylthiols and thiophenol

6-Alkylthio- and 6-phenylthio-5H-benzo[a]phenoxazin-5-ones have been synthesized by the photochemical reaction of 5H-benzo[a]phenoxazin-5-one with alkylthiols and thiophenol.     

Synthesis of some 5H-benzo[a]phenoxazin-5-one derivatives

The substituted 6-bromo and 6-chloro-5H-benzo[a]phenoxazin-5-ones, prepared by condensation of substituted 2-aminophenols with 2,3-dibromo or 2,3-dichloro-1,4-naphthoquinone in methanolic potassium hydroxide solution, have been dehalogenated to substituted 5H-benzo[a]phenoxazin-5-ones in the presence of sodium hydrosulfite dissolved in aqueous pyridine under nitrogen atmosphere.     

Synthesis of annelated [a]aza-anthracenones and thieno[3,2-g]aza-naphthalenones through ring transformation of 2H-pyran-2-one followed by photocyclization

A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-6-carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles) has been developed by the ring transformation of suitably functionalized 2H-pyran-2-one with α-oxoketene cyclic aminals to intermediates (8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyridine-7-ylidene)-acetonitriles and (9-aroyl-6-aryl-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-8-ylidene)-acetonitriles) followed by their photocyclization either in CHCl₃ or acetonitrile. This reaction was further explored for the synthesis of methyl 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carboxylate, 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carbonitriles, 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a,10-triazabenzo[a]anthracene-7-carbonitriles, 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diazacyclopenta[b]phenanthrene-7-carbonitriles from the similar reactions.     

Near-infrared solid-state fluorescent naphthooxazine dyes attached with bulky dibutylamino and perfluoroalkenyloxy groups at 6- and 9-positions

No solid-state fluorescence is observed for 9-(diethylamino)benzo[a]phenoxazin-5-one (Nile Red). However, 9-dibutylamino-6-{perfluoro[4-methyl-3-(1-methylethyl)-2-penten]-2-oxy}benzo[a]phenoxazin-5-one showed fluorescence maximum at 717 nm in solid state with fluorescence quantum yield 0.024. X-ray crystallographic analysis suggests that prevention of network π−π interactions by the bulky fluorine-containing and dibutylamino groups is essential to show solid-state fluorescence.     

Oxidation of 3-hydroxykynurenine. A reexamination

The oxidation mixture of 3-hydroxykynurenine ( 1 ), treated with aqueous acetic anhydride and, subsequently, with acidic methanol, yields the 1-hydroxy-3-carbomethoxy-5-methoxy-11-(β-aspartoyl-N-acetyl-methyl ester)pyrido[3,2-a]phenoxazine ( 5 ), the 1-hydroxy-11-(β-aspartoyl-N-acetyl-methyl ester)-5.H-pyrido[3,2-a]-phenoxazin-5-one ( 6 ), the 1-methoxy-11-(β-aspartoyl-N-acetyl-methyl ester)-5H-pyrido[3,2-a]phenoxazin-5-one ( 6a ), the l,5-dimethoxy-11-(β-aspartoyl-N-acetyl-methyl ester)pyrido[3,2-a]phenoxazine ( 7 ) and the 1-methyl-1(1′-[11-(β-aspartoyl-methyl esterimino)]ethenyl)ketal-1H,5H-pyrido[3,2-a]phenoxazin-5-one ( 8 ). A probable scheme, for the compound formation, is reported.     

Synthesis of aza-aromatic hydroxylamine-O-sulfonates and their application to tandem nucleophilic addition-electrophilic 5-endo-trig cyclization

Hydroxylamine-O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine-O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition-electrophilic 5-endo-trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G^∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine-O-sulfonates and N-(5-methoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2H-[1,2,4]thiadiazolo[3,2-a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC₅₀ in the range 1.47-2.97 μM).     

3-methylthio-1,2-dithiolylium salts : Reaction with 4-hydroxy-6-methyl-2H-pyran-2-one and 4-hydroxycoumarin

The reaction of 4- and 5-aryl-3-methylthio-1,2-dithiolylium iodides with 4-hydroxy-6-methyl-2$\text{H}$-pyran-2-one and 4-hydroxycoumarin has been studied. 4-Substituted salts yielded 3-aryl-7-methyl-2-thioxo-2$\text{H}$,5$\text{H}$-pyrano [3,2-c]pyran-5-ones and 3-aryl-2-thioxo-2H,5H-pyrano[3,2-c]benzo[e]pyran-5-ones, respectively, whereas 5-substituted salts gave rise to 3-(5′-aryl-1′,2′-dithiol-3′-ylidene)-6-methyl-2$\text{H}$-pyran-2,4-diones and 3-(5′-aryl-1′,2′-dithiol-3′-ylidene)-2$\text{H}$-benzo [b]-pyran-2,4-diones.     

Reaction of 3-oxo-N-phenylbutanethioamide with 5-amino-1H-1,2,4-triazoles

Reactions of 3-oxo-N-phenylbutanethioamide with 3-substituted 5-amino-1H-1,2,4-triazoles in acetic acid led to the formation of 5-methyl-7,8-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thiones, 7-methyl-5,8-dihydrol[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones and 7-methyl-5-phenylamino[1,2,4]triazolo[1,5-a]pyrimidines. The structure of the products was proved by the ¹H and ¹³C NMR spectra, X-ray diffraction data, and chemical transformations.     

Synthesis of 11-aza-5H-benzophenoxazin-5-one and 11-Aza-5H-pyridophenoxazin-5-one derivatives

The 1,6-disubstituted- and 4,6-disubstituted-11-aza-5H-benzo[a]phenoxazin-5-one as well as 6-substituted-11-aza-5H-pyrido[a]phenoxazin-5-one derivatives were prepared by the condensation of 2-amino-3-hydroxypyridine with 5-substituted-2,3-dihalogeno-1,4-naphthoquinones and 6,7-dibromo-5,8-quinolinequinone respectively. The resulting compounds were subjected to reduction, acetylation, dehalogenation and reaction with aniline.     

The synthesis of indolo- and pyrrolo[2,1-a]isoquinolines

The synthesis of fused isoquinolines from N-benzyl protected indoles and pyrroles is described. For example, treatment of t-butyl-2-(2-formyl-3,4-dihydro-1-naphthalenyl)-3-methyl-1H-indole-1-carboxylate with KOBu^t in DMF provided 14-methyl-8-phenylbenzo[h]indolo[2,1-a]isoquinoline in good yield. Analogous N-benzylpyrrole precursors could similarly be cyclized to give pyrrolo[2,1-a]isoquinolines.     

Synthesis and ring transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-ones

Heating 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolinium chloride in the presence of hydrazine bishydrate produces regioselectively the five-membered heterocycle 1-amino-1,2,3,9a-tetrahydro-9,9,9a-trimethylimidazo[1,2-a]indol-2(9H)-one. The assignment of the structure is based on extensive ¹H, ¹³C and ¹⁵N NMR spectroscopic studies. No ring-chain tautomerism of the 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one was observed to open-chain hydrazides or the corresponding six-membered 1,2,10,10a-tetrahydro[1,2,4]triazino[4,3-a]indol-3(4H)-one. Further transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one were performed by treatment with aromatic aldehydes, acid chlorides and isocyanates giving access to 40 novel hydrazones, N,N′-diacylhydrazines, N-acyl-N′-carbamoylhydrazines and 1,3,4-oxadiazoles.     

Simple synthesis of 6-alkyl-5H-benzo[a]phenoxazin-5-ones

6-Alkyl-5H-benzo[a]phenoxazin-5-ones were prepared by the reaction of 5H-benzo[a]phenoxazin-5-one with carboxylic acid in the presence of silver ion and peroxydisulfate.

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Eine einfache Synthese von 6-Alkyl-5H-benzo[a]phenoxazin-5-onen (Kurze Mitteilung)

Zusammenfassung 6-Alkyl-5H-benzo[a]phenoxazin-5-one wurden mittels Reaktion von 5H-Benzo[a]phenoxazin-5-onen mit Carbonsäuren in Gegenwart von Silberionen und Peroxydisulfat dargestellt.

     

Synthesis and properties of pyrimido[4,5-<Emphasis Type="Italic">a</Emphasis>]- and pyrido[4,3-<Emphasis Type="Italic">a</Emphasis>]carbazole derivatives

Methods for the synthesis of substituted pyrimido [4,5-a]- and pyrido[4,3-a]carbazoles were proposed. Condensation of 2-(dimethylaminomethylene)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one with guanidine and thiourea afforded 2-amino-8-methyl-6,11-dihydro-5H-pyrimido[4,5-a]carbazole and 8-methyl-3,5,6,11-tetrahydro-2H-pyrimido[4,5-a]carbazole-2-thione, respectively. The reaction of cyano(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-ylidene)acetamide with dimethylformamide dimethyl acetal gave N-(dimethylamino-methylene)cyano(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-ylidene)acetamide. Cyclization of the latter yielded 1-cyano-8-methyl-3,5,6,11-tetrahydro-2H-pyrido[4,3-a]carbazol-2-one.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2740–2744, December, 2004.     

A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

NMR study on the tautomeric equilibria between the hydrazone imine and diazenyl enamine forms in side chained quinoxalines: Solvent effects and temperature dependence

The reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoxaline 6 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazonium chloride gave 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)-ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8b , respectively, while the reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydrotetrazolo[1,5-a]quinoxaline 7 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazomum chloride provided 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9b , respectively. Compounds 8a,b and 9a,b showed the tautomeric equilibria between the hydrazone imine C and diazenyl enamine D forms in dimethyl sulfoxide and/or trifluoroacetic acid, and the effects of solvent and temperature on the tautomer ratios of C to D were studied by the nmr measurements in a series of mixed trifluoroacetic acid/dimethyl sulfoxide media (compounds 8a,b and 9a,b ) and at various temperatures (compounds 8a,b ).     

Photochemistry of ommochromes and related compounds

The photochemistry of some synthetic ommochromes, the 1-methoxy-11-(β-aspartoyl-acetyl-methyl ester)-5H-pyrido[3,2-a]phenoxazin-5-one ( 2 ), the 1-methyl-1-(1′-[1′[11-(β-aspartoyl-methyl ester-imino)]ethenyl)-ketal-1 H,5H-pyrido[3,2-a]phenoxazin-5-one ( 3 ) and the 1,5-dimethoxy-11-(β-aspartoyl-N-acetyl-methyl ester)-pyrido[3,2-a]phenoxazine ( 4 ), obtained from the oxidation of the 3-hydroxykynurenine ( 1 ), has been examined. In an acidic methanol solution of 2 , a reversible solvent photoaddition was observed, associated with a yellow-red bathochromic shift. The mixture, stored in the dark, quantitatively records the starting absorption spectrum. In an acidic enviroment, 3 and 4 , affording 2 , show the same photochemical behaviour. A plausible mechanism, for explanation of the process is suggested.     

Cyclization of 2-chloro-3-(1,4-oxocyclohexa-2,5-dienylideneamino)-1,4-dihydronaphthalene-1,4-diones into 6-chloro-10,12a-dihydroxy-7H,12aH-benzo[c]phenoxazin-5-ones

2-Chloro-3-(4-oxocyclohexa-2,5-dienylideneamino)-1,4-dihydronaphthalene-1,4-diones maintained in the conc. sulfuric acid undergo cyclization affording in a high yield 6-chloro-10,12a-dihydroqи-7H,12aH-benzo[c]phenoxazin-5-ones whose structure is proved by XRD analysis.