Efficient synthesis of new pyrano[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidine-2,4-dione derivatives via a one-pot four-component reaction

This paper reports an efficient method for the synthesis of pyrano[2,3-d]pyrimidine derivatives via a one-pot four-component reaction between N,N-dimethyl barbituric acid, piperidine, aldehydes and 4-hydroxycoumarin. Mild reaction condition, easy purification and good yields are the main feature of this synthesis.     

Structure of Potassium and Cesium Barbiturates

The structures of catena-[K(μ₆-Hba?O,O,O,O′,O′,O″)] (I) and catena-[Cs(μ₆-Hba–O,O,O′,O′,O″,O″)] (II), where Н₂ba is barbituric acid C₄H₄N₂O₃, were characterized by powder X-ray diffraction. Crystallographic data: a = 14.1603 (4) Å, b = 3.68977 (9) Å, c = 10.9508 (3) Å, β = 82.226 (1)°, V = 566.90 (3) ų, space group P2₁/n, Z = 4 for I; a = 14.652 (1) Å, b = 11.7275 (7) Å, c = 3.8098 (3) Å, β = 79.140 (6)°, V = 642.90 (8) ų, space group C2/m, Z = 4 for II. The structural topologies of alkali metal complexes with barbituric acid and some its derivatives were compared. The thermal stability of complexes I and II in an air atmosphere was studied.     

Diastereoselective synthesis of spiro derivatives of 3-substituted 2,3,4,4a,5,6-hexahydro-1<Emphasis Type="Italic">H</Emphasis>-benzo[<Emphasis Type="Italic">c</Emphasis>]quinolizines

The cyclization via the mechanism of “tert-amino effect” of 2-(4-R-piperidino)benzaldehydes with cyclic active methylene components (Meldrum’s acid, 1,3-cyclohexanedione, and N,N-disubstituted barbituric acids) proceeded stereoselectively giving spiro-joined 2,3,4,4a,5,6-hexahydro-1H-benzo[c]quinolizines with axially oriented hydrogen atoms in the positions 3 and 4a of the benzo[c]quinolizine ring.     

“On-water” organic synthesis: <Emphasis Type="SmallCaps">l</Emphasis>-proline catalyzed synthesis of pyrimidine-2,4-dione-, benzo[<Emphasis Type="Italic">g</Emphasis>]- and dihydropyrano[2,3-<Emphasis Type="Italic">g</Emphasis>]chromene derivatives in aqueous media

In this work, functionalized pyrimidine-2,4-dione-, benzo[g]-, and dihydropyrano[2,3-g]chromene derivatives have been synthesized via a Michael addition of 2-hydroxy-1,4-naphthoquinone or 2,5-dihydroxy-1,4-benzoquinone to the Knoevenagel condensation product of an aldehyde with Meldrum’s acid, dimedone or barbituric acid in the presence of a catalytic amount of l-proline under refluxing conditions in water in good to excellent yields.     

Thebaine Adducts with Maleimides. Synthesis and Transformations

Diels-Alder reaction of thebaine with maleimides is structurally specific and yields [7,8,3′,4′ ]-succinimido-endo-ethenotetrahydrothebaines containing N′-alkyl, cycloalkyl, aralkyl or aryl substituents. N′-[1(S)-hydroxymethyl-2-methylpropyl]-succinimido-6,14-endo-ethenotetrahydrothebaine formed in reaction of S-valinol with (7α,8α)-anhydrido-6,14-endo-ethenotetrahydrothebaine. The reduction of the adducts by LiAlH₄ afforded N′-substituted 7,8-pyrrolidino-endo-ethenotetrahydrothebaines. The reduction of fused succinimides by NaBH₄ resulted in the corresponding 2′α-hydroxylactam derivatives. O-Demethylation of the tetrahydrothebaine pyrrolidine derivatives effected by BBr₃ afforded compounds of the tetrahydrooripavine series. The O-demethylation of tetrahydrothebaine succinimide derivatives gave rise to the corresponding 6-demethyl-endo-ethenotetrahydrooripavines. Alkylation conditions were found for N′-(4-hydroxyphenethyl)-substituted tetrahydrothebaine succinimide derivatives.     

Epoxidation and Heterocyclization of Arenesulfonamides of the Norbornene Series

Reactions of previously known and newly synthesized N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)arenesulfonamides with monoperoxyphthalic acid generated in situ from phthalic anhydride and 30% hydrogen peroxide lead mostly to the corresponding N-arylsulfonyl-exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonanes (azabrendanes). In some cases, N-(exo-5,6-epoxybicyclo[2.2.1]hept-5-en-exo-2-ylmethyl)arenesulfonamides were isolated as the only products or mixtures of alternative oxidation products were obtained. The presence of electron-acceptor nitro groups in the benzene ring and bulky substituents, primarily in the ortho position, is considered to be a structural factor preventing the primary oxidation products (epoxy derivatives) from undergoing heterocyclization.     

Arylation of adamantanamines: VIII. Optimization of the catalytic system for copper-catalyzed arylation of adamantane-containing amines

Arylation of adamantane-containing amines with iodobenzene in the presence of copper(I) and copper(II) compounds and various N,N-, N,O- and O,O-bidentate ligands was studied. The best results were obtained using the catalytic system CuI–rac-BINOL [1,1′-bi(naphthalen-2-ol)] (10/20 mol %). Reactions with iodobenzene derivatives containing electron-donor and electron-withdrawing substituents in the para position to the iodine atom were carried out under the optimal conditions.     

Thermodynamics of the dissociation of aminomethanesulfonic acid and its <Emphasis Type="Italic">N</Emphasis>-substituted derivatives in aqueous solutions at 293–313 K

ΔG, ΔH, and ΔS of the second dissociation step of aminomethanesulfonic acid and its N-methyl, N-hydroxyethyl, N-(tert-butyl), N-benzyl derivatives in aqueous solutions (at the isoelectric point where the ionic strength is 4.75 × 10^–4 М) are determined on basis of pH measurements at 293–313 K. It is found that an increase of the electron-acceptor properties of the substituents at nitrogen atom reduces the effect temperature has on the thermodynamic functions of dissociation. Enthalpy–enthropy compensation at an isothermodynamic temperature of 303 K is recorded.     

Use of dodecanoyl isothiocyanate as building block in synthesis of target benzothiazine,quinazoline, benzothiazole and thiourea derivatives

Dodecanoyl isothiocyanate (I) reacts additively with anthranilic acid to afford derivatives of thiourea II and benzothiazine IIIin a one-pot reaction. The cyclisation of thiourea II was achieved using acetic anhydride to form quinazoline derivative IV. The heating of quinazoline IV in acetic anhydride or butan-1-ol gave quinazoline derivatives V or VI, respectively. Benzothiazine III underwent trans-acylation to benzothiazine VII in boiling acetic anhydride. The treatment of IV with hydrazine hydrate, anthranilic acid or ethyl carbazate afforded derivatives of triazoloquinazoline VIII, quinazolinoquinazoline XI or thiosemicarbazide X, respectively. The reaction of I with 2-aminophenol or 2-aminothiophenol afforded thiourea derivative XIII or benzothiazole derivative XIV, respectively. Most of the synthesised compounds bear a lauroyl (dodecanoyl) group (a hydrocarbon moiety). The structures of the synthesised compounds were confirmed by microanalytical and spectral data.     

Extraction of Cesium-137 and Americium-241 by Calix[n]arenes from Carbonate-Alkaline Media

Trends of cesium-137 and americium-241 extraction from carbonate–alkaline media with p-tert-butylcalix[n]arenes with macrocycles of different size (n = 4, 6, 8), including monofunctional derivatives with lipophilic substituents for increasing their solubility in organic media, were studied. It was demonstrated that O-n-octyl ethers of p-tert-butylcalix[6]arene appeared to be the most efficient extractants for Cs(I) cations, while it was p-tert-butylthiacalix[4]arene for and americium(III) cations.     

Design,synthesis and anti-mycobacterial evaluation of some new <Emphasis Type="Italic">N</Emphasis>-phenylpyrazine-2-carboxamides

N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH₃-POA, 6-Cl-POA, 5-tert-butyl-POA and 5-tert-butyl-6-Cl-POA were designed and synthesised. The phenyl part was substituted with simple hydrophobic substituents chosen from methyl and halogens. 5-tert-Butyl-N-(5-fluoro-2-methylphenyl)pyrazine-2-carboxamide (9), N-(3-chloro-4-methylphenyl)-5-methylpyrazine-2-carboxamide (12), 6-chloro-N-(3-chloro-4-methylphenyl)pyrazine-2-carboxamide (13) and 6-chloro-N-(5-iodo-2-methylphenyl)pyrazine-2-carboxamide (18) possessed whole cell anti-mycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) of around 10 μM. Importantly, no cytotoxicity in the HepG2 model was detected in vitro at the concentrations tested and the estimated IC50 values were in hundreds of μM, indicating promising selectivity. N-(3-Chloro-4-methylphenyl)pyrazine-2-carboxamide (11) and N-(4-chloro-2-iodophenyl)pyrazine-2-carboxamide (21) exerted significant activity against Mycobacterium kansasii with MIC 12.6 μM and 8.7 μM, respectively. No activity was detected against Mycobacterium avium. SAR were in accordance with those observed for the derivatives previously published.     

Synthesis of new polydentate tweezers ligands of amido-amine type

A series of new tweezers amido-amine ligands containing pyrrole, bipyrrole, and dipyrrolylmethane fragments were synthesized by reaction of 2-thioxothiazolidin-3-yl derivatives of α-pyrrolecarboxylic acids {5-[1-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-1-methylethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-[(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)phenylmethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, and 3,4-dimethyl-pyrrole-2,5-dicarboxylic acid} with o-phenylenediamine. All compounds obtained were characterized by elemental analysis, NMR and mass spectra.     

Electrophilic heterocyclization of 6-alken(yn)ylsulfanyl-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(5<Emphasis Type="Italic">H</Emphasis>)-ones

6-Allylsulfanyl-1-arylpyrazolo[3,4-d]pyrimidin-4(5H)-ones react with iodine and sulfuric acid to give angular pyrazolothiazolopyrimidine derivatives. The reaction of 6-(prop-2-yn-1-ylsulfanyl)-1-(4-tolyl)-pyrazolo[3,4-d]pyrimidin-4(5H)-one with sulfuric acid gives angularly fused pyrazolo[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-4-one, whereas in the reaction with sodium methoxide linearly fused pyrazolo[3,4-d][1,3]-thiazolo[3,2-a]pyrimidin-4-one was formed. Linearly fused pyrazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazole derivatives were also obtained by reaction of 1-aryl-6-(3-phenylprop-2-en-1-ylsulfanyl)pyrazolo[3,4-d]pyrimidin-4(5H)-ones with sulfuric acid.     

Reaction of hexahydropyirimidine-2,4,6-trione with naphthalen-2-amine and benzaldehydes

Previously unknown 12-aryl-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-b]quinoline-9,11-diones were synthesized by three-component condensation of naphthalen-2-amine with substituted benzaldehydes and barbituric acid through intermediate 5-benzylidenebarbituric acids.     

Synthesis of Macrocyclic Stereoisomers Substituted with Oligolactide Fragments

Acylation of cone and 1,3-alternate stereoisomers of hydrazides of p-tert-butylthaicalix[4]arene tetrasubstituted at the lower rim with S,S-lactide in dimethylsulfoxide has afforded the macrocyclic oligolactide derivatives containing 16 (cone) to 24 (1,3-alternate) lactide fragments. It has been shown that nanosized aggregates (80 nm) are formed with silver nitrate in the case of the cone stereoisomer containing the oligolactide fragments at one side of the macrocyclic rim, whereas submicron particles (400 nm) are formed in the case of the 1,3-alternate conformation when the substituents are at different sides of the macrocycle.     

Regioselectivity in the reactions of <Emphasis Type="Italic">N</Emphasis>-(polychloroethylidene)-sulfonamides with 1<Emphasis Type="Italic">H</Emphasis>-pyrrole and 1-methyl-1<Emphasis Type="Italic">H</Emphasis>-pyrrole

N-(2,2,2-Trichloroethylidene)arenesulfonamides react with 1H-pyrrole and 1-methyl-1H-pyrrole to give the corresponding N-[2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethyl]arenesulfonamides. The reaction of N-(2,2,2-trichloroethylidene)trifluoromethanesulfonamide with pyrrole leads to a mixture of 2-mono-and 2,5-disubstituted pyrroles, whereas in the reaction with 1-methyl-1H-pyrrole only the 2-substituted compound is formed. N-(2,2-Dichloro-2-phenylethylidene)-4-methylbenzenesulfonamide reacts with 1H-pyrrole to form N-[2,2-dichloro-2-phenyl-1-(1H-pyrrol-2-yl)ethyl]-4-methylbenzenesulfonamide, and its reaction with 1-methyl-1H-pyrrole gives a mixture of 2-and 3-monosubstituted derivatives. The results of quantum-chemical calculations of the initial reactants and products indicate that the process is orbital-controlled. A good agreement is observed between the experimental data and theoretical conclusions concerning the dependence of the reaction regioselectivity on the nature of substituents in the electrophile molecule.     

Synthesis and in vitro antibacterial evaluation of 6-substituted 4-amino-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidines

Pyrazolo[3,4-d]pyrimidines are one of the most important classes of fused heterocyclic compounds which exhibit a broad range of biological and medicinal properties. They are known as anticancer, antifungal, antibacterial, antiviral and anti-inflammatory agents. In this study, some new 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidine derivatives were prepared via reaction of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile with various nitriles in the presence of sodium ethoxide as catalyst. The inhibitory properties of synthesized compounds were studied according to CLSI guidelines against some pathogenic bacteria including four gram-positive strains (Streptococcus pyogenes, Staphylococcus aureus, Bacillus cereus and Bacillus subtilis subsp. spizizenii) and three gram-negative strains (Pseudomonas aeruginosa, Shigella flexneri and Salmonella enterica subsp. enterica). The antibacterial effects of all derivatives were compared with those of antibiotics belonging to different classes. The values were reported as inhibition zone diameter (IZD), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The effect of substituents on the biological activity of derivatives was discussed as well. The inhibitory effect of compound 6a, was shown to be the most, with MIC values in the range of 32–4096 μg/mL. Since most of the synthesized compounds were effective against Streptococcus pyogenes and Pseudomonas aeruginosa, they can be considered as inhibitors of these two bacteria.     

Synthesis and membrane-protective activity of 2,6-diisobornylphenol derivatives with <Emphasis Type="Italic">N</Emphasis>- and <Emphasis Type="Italic">O</Emphasis>-containing fragments at position 4

Two series of new amide derivatives containing 2,6-diisobornylphenol moiety were synthesized based on 3,5-diisobornyl-4-hydroxybenzoic acid and 4-butylaminomethyl-2,6-diisobornylphenol. Toxicity, membrane-protective (MP) and antioxidant (AO) activity of the obtained compounds were evaluated using red blood cells of laboratory mice as the test object. The tests demonstrated the absence of hemolytic activity for all the synthesized derivatives and the presence of high MP and AO activity under conditions of acute H₂O₂-induced oxidative stress for (3,5-diisobornyl-4-hydroxyphenyl)(morpholino)methanone and N-n-butyl-N-(3,5-diisobornyl-4-hydroxybenzyl)acetamide. A comparison of the data of the newly obtained compounds and those of described earlier 2,6-diisobornylphenol derivatives with N- and O-containing fragments at position 4 (alkoxymethyl, carboxy, and aminomethyl derivatives) led to a conclusion that the most promising for further studies of pharmacological activity are compounds containing methoxycarbonyl, methoxymethyl, ethoxymethyl, morpholinomethyl, di-n-butylaminomethyl, (azepan-1-yl)methyl, or N-acetyl-N-alkylaminomethyl function, which provide low toxicity and high MP and AO activity.     

Diels-alder reactions with cyclic sulfones: VIII. Organic catalysis in the synthesis of spiro[1-benzothiophene-4,5′-pyrimidine]-2′,4′,6′-trione 1,1-dioxides and 2′-thioxospiro[1-benzothiophene-4,5′-pyrimidine]-4′,6′-dione 1,1-dioxides

5-Isopropenyl-2,3-dihydrothiophene 1,1-dioxide reacted with 5-methylidenepyrimidine-2,4,6-triones and 5-methylidene-2-thioxopyrimidine-4,6-diones in the presence of chiral amines or amino acids with high regio- and stereoselectivity to give optically active derivatives of barbituric and thiobarbituric acids spirofused at the 5-position to 1-benzothiophene 1,1-dioxide fragment. The reaction of 5-isopropenyl-2,3-dihydrothiophene 1,1-dioxide with 5-(2-methoxybenzylidene)-2-thioxopyrimidine-4,6-dione (generated in situ from 2-methoxybenzaldehyde and thiobarbituric acid) in the presence of (?)-ephedrine or L-4-(tert-butyldimethylsiloxy) proline gave the corresponding 2-thioxospiro[1-benzothiophene-4,5′-pyrimidine]-4′,6′-dione 1,1-dioxide with an enantiomeric excess of 80%.