Synthesis of granulatimide bis-imide analogues

The synthesis of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to granulatimide is reported. These compounds can be considered as granulatimide analogues in which a maleimide heterocycle replaces the imidazole moiety. The synthesis of pyridino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraones is also reported. In these compounds, a 7-azaindole unit replaces the indole moiety present in the granulatimide and isogranulatimide structures.     

An expedient, regioselective synthesis of novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential

Several novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their 6-alkyl and 8-alkyl derivatives have been synthesised in high overall yields starting from 5-nitro and 6-nitroindazoles in a three-step route involving the regioselective cyclisation of thioureidoindazoles and indazolyl dithiocarbamates as the key steps. Some assorted thiazoloindazoles have been screened for anticancer properties, which demonstrated the anticancer potential of at least one product, justifying its further follow-up.     

One-pot two-step tandem reactions for selective synthesis of pyrrolo[2,1-a]isoquinolines and dihydro-, tetrahydro-derivatives

A sequential one-pot two-step tandem reaction for selective and efficient synthesis of pyrrolo[2,1-a]isoquinoline and its dihydro- and tetrahydro-derivatives has been developed. The tandem reactions of isoquinoline, α-halogenated methylene compounds, aromatic aldehydes, and cyanoacetamide firstly give tetrahydropyrrolo[2,1-a]isoquinolines as main products. The corresponding pyrrolo[2,1-a]isoquinolines and dihydropyrrolo[2,1-a]isoquinolines can be obtained directly by controlling oxidation with DDQ. The mechanism of this tandem reaction involved the 1,3-dipolar cycloaddition of isoquinolinium ylide as the key step. A unique elimination of the amido group preferring to the cyano group has been observed.     

A concise synthesis and electrochemical behavior of functionalized poly(thieno[3,4-b]thiophenes): New conjugated polymers with low bandgap

New thieno[3,4-b]thiophene derivatives were prepared via a short and versatile synthetic route. Electrochemical studies of 2-heptenylthieno[3,4-b]thiophene, 2-styrylthieno[3,4-b]thiophene, and 2-phenyl-3-(thieno[3,4-b]thiophene-2-yl)acrylonitrile and the corresponding polymers revealed that raising the HOMO and lowering the LUMO can be attained by functionalizing thieno[3,4-b]thiophene with aromatic resonance-enhancing and electron-withdrawing groups. The bandgap of resulting polymers varied from 0.78 to 1.0 eV, indicating that poly(2-phenyl-3-(thieno[3,4-b]thiophene-2-yl)acrylonitrile) is one of the lowest bandgap polymers ever reported.     

Investigation towards an efficient synthesis of benzo[g]isoquinoline-1,5,10(2H)-triones

As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv., the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones as the key intermediates is reported. The latter compounds have been prepared by treating 2-methoxycarbonyl-1,4-naphthoquinone with N-substituted enaminoesters under acidic conditions. These reagents are easily accessible from readily available 1,4-dihydroxy-2-naphthoic acid, β-ketoesters and primary amines. Finally, a short synthesis of substituted benzo[g]isoquinoline-1,5,10(2H)-triones is achieved by an oxidative addition of N-substituted enaminoesters onto methyl 1,4-dihydroxynaphthalene-2-carboxylate.     

Synthesis of novel dipyrazolo[3,4-b:3,4-d]pyridines and study of their fluorescence behavior

A convenient route was successfully developed for the synthesis of novel heterocycles such as pyrazolo[3,4-h][1,6]naphthyridine and dipyrazolo[3,4-b:3,4-d]pyridine (DPP) from pyrazolo[3,4-b]pyridine in good yield. The DPP derivatives synthesized were further studied for their fluorescence properties.     

Intramolecular Larock indole synthesis for the preparation of tricyclic indoles and its application in the synthesis of tetrahydropyrroloquinoline and fargesine

A general and efficient strategy for fused tricyclic indoles from substituted 2-halogenanilines via the palladium-catalyzed intramolecular Larock indolization process has been developed. Using this strategy, a number of 3,4- and 3,5-fused indoles with a variety of ring sizes can been prepared. The utility of this method is demonstrated through the synthesis of the known tetrahydropyrrolo[4,3,2-de]quinoline 10 and the first total synthesis of fargesine.     

Synthesis of 3,5-difunctionalized 1-methyl-1H-pyrazolo[3,4-b]pyridines involving palladium-mediated coupling reactions

Indirect iodination of 2-chloro-nicotinonitrile gave 2-chloro-5-iodonicotinonitrile, which was cyclized with methylhydrazine to lead to 3-amino-5-iodopyrazolo[3,4-b]pyridine. Position 3 was then protected by pivaloyl group and the resulting 5-iodo-3-pivaloylaminopyrazolo[3,4-b]pyridine was engaged in palladium-promoted coupling reactions with various reagents to give 3-pivaloylamino-5-substituted compounds. Deprotection and iododediazoniation followed by cross-coupling reactions in position 3 afforded novel unsymmetrical 3,5-disubstituted pyrazolo[3,4-b]pyridine species.     

Synthesis and properties of 1-aroyl-5,5-dialkyl-2,3,5,6-tetrahydropyrrolo[ 2,1-<Emphasis Type="Italic">a</Emphasis>]isoquinoline-2,3-diones

Acylation of 1-methyl-3,3-dialkyl-3,4-dihydroisoquinolines with acid chlorides afforded enaminoketones. Enaminophenylketones from the obtained series were reacted with oxalyl chloride to provide 1-benzoyl-5,5-dialkyl-2,3,5,6- tetrahydropyrrolo[2,1-a]isoquinoline- 2,3-diones. The reaction of the latter with binucleophiles leads to the opening of the pyrrole ring and to the heterocyclization: Under the effect of o-phenyldiamine qinoxaline is formed, 1,2-cyclohexanediamine provides the hexahydro-benzimidazole system, о-aminophenol gives benzoxazole, 3-hydroxy-2-amino-pyridine furnishes oxazolo[4,5-b]pyridine. In the reaction with hydrazine hydrate the acylation occurs with hydrazide formation.     

Thermal,acid-catalyzed,and photolytic transformations of spirocyclic 3H-pyrazoles formed by reactions of methyl,phenyl, and p-tolyl phenylethynyl sulfones with 9-diazofluorene

Methyl, phenyl, and p-tolyl phenylethynyl sulfones react with 9-diazofluorene in diethyl ether at 20°C to give 1,3-dipolar cycloaddition products according to von Auwers’ rule, the corresponding spirocyclic 3H-pyrazoles. The spiro adducts undergo isomerization into 5-R-sulfonyl-3-phenylpyrazolo[1,5-f]phenanthridines on heating in boiling toluene for 2 h; heating of the same pyrazoles in boiling benzene, acetonitrile, or ethanol leads to mixtures of 5-R-sulfonyl-3-phenylpyrazolo[1,5-f]phenanthridines and 3-R-sulfonyl-3a-phenyl-3aH-dibenzo[e,g]indazoles, the latter prevailing. The indazoles are kinetically controlled thermolysis products which are quantitatively converted into phenanthridines on heating in toluene. Sulfonyl-substituted spirocyclic 3H-pyrazoles and indazoles in glacial acetic acid at 20°C in the presence of a catalytic amount of sulfuric acid are transformed into 3a-phenyl-2H-dibenzo[e,g]indazol-3(3aH)-one. Under analogous conditions, sulfonyl-substituted phenanhtridines give rise to 3-phenyl-1H-dibenzo[e,g]indazole. Photolysis of spirocyclic 3H-pyrazoles yields mixtures of sulfonylcyclopropenes and 2H-cyclopenta[j,k]fluorenes.     

Synthesis of new donor-acceptor polymers containing thiadiazoloquinoxaline and pyrazinoquinoxaline moieties: low-band gap, high optical contrast, and almost black colored materials

Two low band gap conjugated polymers, poly[4,9-bis(4-hexylthien-2-yl)-6,7-di(thien-2-yl)-[1,2,5]thiadiazolo[3,4-g]quinoxaline] (PHTTQ) and poly[5,10-bis(4-hexylthien-2-yl)-2,3,7,8-tetra(thien-2-yl)pyrazino[2,3-g]quinoxaline] (PHTPQ), consisting of alternating electron-rich 3-hexylthiophene and electron-deficient 6,7-di(thien-2-yl)-[1,2,5]thiadiazolo[3,4-g]quinoxaline (TTQ) and 2,3,7,8-tetra(thien-2-yl)-2,3-dihydropyrazino[2,3-g]quinoxaline (TPQ) units were synthesized electrochemically. The structures of the π-conjugated monomers were tailored using thiophene as the pendant group on the acceptor units (TTQ and TPQ). The electrochemical and optical properties of the polymers were investigated by cyclic voltammetry and UV-vis-NIR spectroscopy. The absorption spectra of PHTPQ, revealing a 1.0 eV band gap, exhibited three maxima at 352 nm, 535 nm, and 750 nm. Consequently, its absorption spectra cover the region between 400 and 800 nm, which make the polymer almost black in appearance. PHTTQ shows a λ_max value of 820 nm and a band gap of 0.8 eV which is very low among other [1,2,5]thiadiazolo[3,4-g]quinoxaline-containing donor-acceptor type polymers.     

Stereoselective synthesis of dihydrothiadiazinoazines and dihydrothiadiazinoazoles and their pyrolytic desulfurization ring contraction

Intramolecular base catalyzed C-C bond formation led to exclusive stereoselective syntheses of trans-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, trans-7,8-dihydro-6H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, and trans-3,4-dihydro-2H-[1,3,4]thiadiazino[2,3-b]quinazolin-10-one. trans-6,7-Dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines isomerize slowly in CDCl₃ and more rapidly in DMSO-d₆ into the corresponding cis-stereoisomers. The other trans-6,7-dihydro-[1,3,4]thiadiazines isomerize also in DMSO-d₆ into the corresponding cis-stereoisomers. Pyrolytic conversion of these heterocyclic condensed dihydrothiadiazines into their corresponding pyrazolo[5,1-b][1,2,4]triazoles, pyrazolo[5,1-c][1,2,4]triazin-4-ones and pyrazolo[4,3-b]quinazolin-9-ones via desulfurization ring contraction is described.     

Nucleophilic cyclization of 3-alkynylquinoxaline-2-carbonitriles into pyrido[3,4-b]quinoxalines

3-Alkynylquinoxaline-2-carbonitriles have been synthesized from 3-chloroquinoxaline-2-carbonitrile via the Sonogashira reaction. Treatment of 3-alkynylquinoxaline-2-carbonitriles with an alkylamine or ammonia has been shown to produce stable enamines, e.g., (Z)-3-(2-aryl-2-aminovinyl)quinoxaline-2-carbonitriles. Their base-induced cyclization gave the previously unknown pyrido[3,4-b]quinoxalin-1(2H)-imines or pyrido[3,4-b]quinoxalin-1-amines. 3-Alkynylquinoxaline-2-carbonitriles were directly transformed into pyrido[3,4-b]quinoxalin-1(2H)-imines by heating with an alkylamine and K₂CO₃ in DMF. The ionization constants, and absorption and fluorescent properties of the resulted pyrido[3,4-b]quinoxalin-1(2H)-imines were measured.     

Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.     

Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives.     

Synthesis of 1H-benzo[g]indazole derivatives: propargyl–allenyl isomerization and 6π-electrocyclization involving two aromatic π-bonds

An efficient synthesis of 1H-benzo[g]indazoles starting from Morita–Baylis–Hillman (MBH) adducts is disclosed. The synthesis was carried out from MBH bromide via a sequential copper-catalyzed alkynylation, one-pot synthesis of pyrazole, propargyl–allenyl isomerization, and a 6π-electrocyclization involving two aromatic π-bonds and an allenyl π-bond.     

Synthesis and biological activity of fluorinated 2-amino-4-aryl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles

The heterocyclic nucleus s-triazino[1,2-a]benzimidazole has been reported to exhibit antibacterial activity. In this study, seven new 3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazole derivatives were prepared via cyclocondensation between 2-guanidinobenzimidazole and fluorine substituted (including trifluoromethyl) benzaldehydes. The structures of all the compounds were confirmed by ¹H, ¹³C NMR and IR spectral data. Spectral data also suggested the existence of various tautomeric forms of the fluorine-containing s-triazino[1,2-a]benzimidazole compounds. The synthesized compounds were also screened for antibacterial and bovine dihydrofolate reductase (DHFR) inhibitory activities. The compound 3g substituted with a 3′,5′-bis(trifluoromethyl)phenyl moiety demonstrated the best antibacterial activity in the series. None of the tested compounds significantly inhibited bovine DHFR.     

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of dipyrrolo[3,4-a:3,4-c]carbazole-triones

The syntheses of dipyrrolo[3,4-a:3,4-c]carbazole-1,4,6-triones and dipyrrolo[3,4-a:3,4-c]carbazole-3,4,6-triones are reported. These compounds can be considered as granulatimide analogues in which a maleimide replaces the imidazole moiety and a five-membered lactam ring replaces the upper maleimide. The Chk1 inhibitory properties of the more soluble compounds have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, and human colon carcinoma HT29 and HCT116. Due to their insolubility, the biological activities of the other compounds in this series could not be evaluated. All the tested compounds proved to be potent Chk1 inhibitors.     

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3-b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1-b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1H)-one and 4-amino-3(2H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).     

Synthesis and functionalisation of 1H-pyrazolo[3,4-b]pyridines involving copper and palladium-promoted coupling reactions

A convenient route to novel 3-iodo-1H-pyrazolo[3,4-b]pyridines via iododediazonation of 3-amino-1H-pyrazolo[3,4-b]pyridines, which are obtained by copper-catalysed cyclisation of 2-chloro-3-cyanopyridine with hydrazines. We describe also efficient coupling reactions from 3-iodo derivatives with various reagents according to Suzuki, Heck, Stille, and Sonogashira conditions.