Synthesis of optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one

Bicyclo[2.2.2]octanone is an important building block for the synthesis of bioactive compounds and natural products. Herein, we present a new synthetic route for the formation of (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one derivatives via a catalytic asymmetric Michael reaction in high stereoselectivity and yields.     

l-proline as an efficient asymmetric induction catalyst in the synthesis of chromeno[2,3-d]pyrimidine-triones,xanthenes in water

The multi-component reactions involving aromatic aldehydes, dimethylcyclohexane-1, 3-dione/cyclohexane-1, 3-dione and barbituric acids were carried out in presence of the organo catalyst l-proline in aqueous medium at ambient temperature. The reactions afforded chromeno[2,3-d]pyrimidinones in excellent yields and with high enantioselectivities. The above reactions exhibited the efficient asymmetric induction property of the organo catalyst l-proline as reported earlier. In the absence of barbituric acid the method proved equally efficient when aromatic aldehydes readily condensed with 2 mol of cyclohexane-1, 3-dione in presence of l-proline to give Xanthenes derivatives in good yields. The protocol reported here is benign to the environment as water is used as the solvent and purification does not involve any chromatographic procedures. Selected compounds were further studied using DFT calculations in order to establish a clear picture about the geometric parameters and the electronic absorption spectra of the compounds.     

Mass spectrometry of pyrrolo [2, 3- b] pyrazines and pyrazino [2, 3- b]indole

The first mass spectra of pyrrolo [2, 3-b] pyrazine and some of its derivatives and of pyrazino [2, 3-b] indole are reported and compared with those of related compounds. Differences between the spectra of some aryl substituted derivatives are described and discussed.     

Catalyst-free synthesis of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-carboxylic acids via a three-component condensation

The synthesis of a number of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-carboxylic acids via a facile route involving the reaction between 2-amino-3-pyridinecarboxylic acid, benzaldehyde derivatives, and isonitriles is reported. The structures of the synthesized compounds are proved by X-ray crystallography.     

Synthesis,Antibacterial, and Antioxidant Evaluation of Novel Series of Condensed Thiazoloquinazoline with Pyrido,Pyrano, and Benzol Moieties as Five- and Six-Membered Heterocycle Derivatives

A novel synthesis of thiazolo[2,3-b]quinazolines 4(a–e), pyrido[2′,3′:4,5]thiazolo[2,3-b]quinazolines {5(a–e), 6(a–e), and 7(a–e)}, pyrano[2′,3′:4,5]thiazolo[2,3-b]quinazolines 8(a–e), and benzo[4,5]thiazolo[2,3-b]quinazoloine9(a–e) derivatives starting from 2-(Bis-methylsulfanyl-methylene)-5,5-dimethyl-cyclohexane-1,3-dione 2 as efficient α,α dioxoketen dithioacetal is reported and the synthetic approaches of these types of compounds will provide an innovative molecular framework to the designing of new active heterocyclic compounds. In our study, we also present optimization of the synthetic method along with a biological evaluation of these newly synthesized compounds as antioxidants and antibacterial agents against the bacterial strains, like S. aureus, E. coli, and P. aeruginosa. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 μg/mL while the others exhibited better antibacterial activity at 100 μg/mL. The results of this study showed that compound 6(c) possessed remarkable antibacterial activity, whereas compound 9(c) exhibited the highest efficacy as an antioxidant. The structures of the new synthetic compounds were elucidated by elemental analysis, IR, ¹H-NMR, and ¹³C-NMR.     

Synthesis Chiral Dihydropyridine Derivatives from Geniposide and Primary Amine

Since Ohno and co-workers[1] reported the first example of asymmetric reduction using a model of coenzyme NADH in 1975, numerous efforts have been made to construct model compounds mimicking the activity of NADH and many publications have appeared. [2] Here we reported the design and synthesis of novel chiral dihydropyridine derivatives which can be used as NADH model from geniposide and primary amine.     

Synthesis, computational modelling and liquid crystalline properties of some [3]ferrocenophane-containing Schiff’s bases and β-aminovinylketone: Molecular geometry-phase behaviour relationship

Rotationally fixed [3]ferrocenophane extends the variety of possible molecular geometries in its derivatives in comparison with unbridged ferrocenes. In this respect molecular geometry-liquid crystalline properties relationship studies in [3]ferrocenophane mesogens are of considerable interest. Different positional isomers of mono- and di-substituted [3]ferrocenophanes which are obtained by incorporating one or two promesogenic building blocks into the cyclopentadienyl rings are reported in this article. A series of mono-substituted [3]ferrocenophane-containing Schiff’s bases was synthesized by condensing isomeric p-aminophenyl [3]ferrocenophanes with appropriate aldehydes. Isomers of di-substituted [3]ferrocenophane amines gave rise to a series of azomethines with two promesogenic substituents in the cyclopentadienyl rings. Besides, a β-enaminoketone was prepared from 3-(p-aminophenyl)[3]ferrocenophane. Nematic and smectic mesophases were observed in the synthesized compounds under a polarizing optical microscope. The [3]ferrocenophane-containing β-enaminoketone showed complex mesomorphic behaviour connected with occurrence of the keto-enamine and imino-enol tautomeric equilibrium in this compound. On the base of computational models obtained by semi-empirical quantum chemistry calculations the molecular geometry-phase behaviour relationships were examined. It was demonstrated that mesomorphism of [3]ferocenophane azomethines depends on the spatial orientation of the substituents with respect to the propanediyl bridge in a case of mono-, and as well as to each other in a case of di-substituted derivatives.     

Cyclization reactions of 3-hydrazino[1, 2, 4]triazino[5, 6-b]indole

The reaction of 3-hydrazino[1, 2, 4]triazino[5, 6-b]indole I with nitrous acid affords the azide III which could be cyclized with acetic anhydride to 10-acetyl-10H-tetrazolo[5′,1′:3, 4][1, 2, 4]triazino[5, 6-b]indole IIb . Cyclization reactions of I with acetic anhydride, ethyl chloroformate, carbon disulphide and aromatic aldehydes to the corresponding fused triazolo derivatives V–VIII are reported. On the other hand cyclization reactions of I with malononitrile, ethyl cyanoacetate, ethyl acetoacetate and acetylacetone to the corresponding condensed pyrazolino derivatives IX–XI are also reported. The reaction of I with α-dicarbonyl compounds to form mono and dihydrazones are reported. The structure of the compounds prepared and their cyclization mechanisms are reported.     

Synthesis of derivatives of pyrrolo[1, 2-α]pyrmidine

Continuing investigations in the field of the synthesis of condensed heterocyclic systems containing pyrrole and indole fragments ¦1–3¦, we have condensed of 2-aminopyrrole derivatives with various 1, 3-dicarbonyl compounds. The reaction took place at the boil in solutions in pyridine or acetic acid, and also without a solvent at 150–160° C, forming in a single stage derivatives of pyrrolo[1, 2-a]pyrimidine (I–III) and pyrrolo[2, 1-b]-tetrahydroquinazoline (IV–VI). The condensation of 2-aminopyrrole with acetoacetic and substituted acetoacetic esters led to 4-oxo derivatives of pyrrolo[1, 2-β]pyrimidine (VII and VIII).     

Synthesis and conformational analysis of naphth[1′,2′:5,6][1,3]oxazino[3,2-c][1,3]benzoxazine and naphth[1′,2′:5,6][1,3]oxazino[3,4-c][1,3]benzoxazine derivatives

A new functional group, the hydroxy group, was inserted into a Betti base by reaction with salicylaldehyde, and the naphthoxazine derivatives thus obtained were converted by ring-closure reactions with formaldehyde, acetaldehyde, propionaldehyde or phosgene to the corresponding naphth[1′2′:5,6][1,3]oxazino[3,2-c][1,3]benzoxazine derivatives. Further, the conformational analysis of these polycyclic compounds by NMR spectroscopy and an accompanying molecular modelling are reported; especially, both quantitative anisotropic ring current effects of the aromatic moieties in these compounds and steric substituent effects were employed to determine the stereochemistry of the naphthoxazinobenzoxazine derivatives.     

手性二环[3.3.0]辛-3-烯类化合物的合成

研究了5-(1-孟氧基)-3-溴-2(5H)-呋喃酮新手性源(1)与某些碳亲核试剂发生的串联不对称Michael加成/分子内亲核取代反应,反应中生成2个新的手性中心得到一般方法难以合成的光学纳二环[3.3.0]辛-3-烯类化合物.通过[α]、IR、UV、¹HNMR、¹³CNMR、MS、元素分析以及X射线四圆衍射等方法确定了手性二环[3.3.0]辛-3-稀类化合物化学结构和绝对构型.     

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high yields (up to 99 %) and good to excellent enantiomeric excesses (up to 99% ee). The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are important skeletons in biological and pharmaceutical compounds.     

Synthesis and Analgesic Activities of Some 2-(Benzazolylacetyl)amino-3-ethoxycarbonylthiophene Derivatives

In this study, some 2-[2-(benzazole-2-thioxy)acetylamino]-3-ethoxycarbonylthiophene and 2-[2-(benzazole-1-yl)acetylamino]-3-ethoxycarbonylthiophene compounds were obtained by the reaction of 2-chloroacetylamino-3-ethoxycarbonylthiophene derivatives and a suitable benzazole-2-thione or benzimidazole derivatives. Analgesic activities of the compounds were tested by using tail-flick and tail-immersion methods. It is reported that some of the compounds showed remarkable analgesic activities.     

Synthesis,characterization and antimicrobial evaluation of 2,5-disubstituted-4-thiazolidinone derivatives

In the present study novel derivatives of 4-thiazolidinone were prepared from biphenyl-4-carboxylic acid and evaluated for their in vitro antimicrobial activity against two Gram negative strains (Escherichia coli and Pseudomonas aeruginosa) and two Gram positive strains (Bacillus subtilis and Staphylococcus aureus) and fungal strain Candida albicans and Aspergillus niger. The newly synthesized compounds were characterized by IR, ¹H NMR and C, H, N analyses. The results revealed that all synthesized compounds have a significant biological activity against the tested microorganisms. Among the synthesized derivatives 4g (biphenyl-4-carboxylic acid [2-(3-bromophenyl)-5-(3-nitrobenzylidene)-4-oxo-thiazolidin-3-yl]-amide) and 4i (biphenyl-4-carboxylic acid [5-(3-bromobenzylidene)-2-(3-bromophenyl)-4-oxo-thiazolidin-3-yl]-amide) were found to be most effective antimicrobial compounds.     

Azocalixarenes.8: synthesis and investigation of the absorption spectra of di-substituted azocalix[4]arenes containing chromogenic groups

The synthesis of series of chromogenic di-substituted azocalix[4]arene derivatives is described. A ketone moiety as a different chelating agent is grafted on the lower rim of p-tert-butylcalix[4]arenes. Eight novel azocalix[4]arenes (1–8) are prepared by linking 2-, 3- and 4-nitroaniline, 4-phenylazoaniline, 3- and 4-chloroaniline or 2- and 4-methylaniline to 25,27-diacetonyloxy-26,28-dihydroxy-11,23-di-(tert-butyl)calix[4]arene through a diazo-coupling reaction, and characterized by UV–Vis, FT-IR and ¹H-NMR spectroscopic techniques and elemental analysis, consecutively. The absorption spectra of the di-substituted azocalix[4]arenes are discussed, according to effect of varying pH and solvent upon the absorption ability of azocalix[4]arenes. The colors of these azocalix[4]arenes are compared with respect to nature of their aromatic rings and substituents there in. Concentration effects on the visible absorption maxima of these compounds are also reported.     

Discovery of New Pyrazolopyridine,Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design,Synthesis, Docking Studies,and Anti-Proliferative Activity

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-⁻C² functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C²-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC₅₀ values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC₅₀ 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC₅₀ ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC₅₀ 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.     

Synthesis and Antioxidant,Anti-Inflammatory,and Analgesic Activity of Novel Polycyclic Pyrimido[4,5-b]quinolines

The behavior of the 2-methylthio-pyrimido[4,5-b]quinolin-4-one towards differently substituted amines is reported. Also, the reactivity of 3-aminothiazolo[3′,2′ :1,2]-pyrimido[4,5-b]quinoline-2-carbonitrile towards formic acid, urea, thiourea, formamide, and carbon disulfide is discussed. Some of the synthesized derivatives possess biological activities as anti-inflammatory and analgesic agents. Some of these selective biologically active compounds were screened for antioxidant properties.     

Synthesis,including asymmetric synthesis,of 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium carbenoids as the key reaction

The addition reactions of α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the sulfoxide-magnesium exchange reaction. 1,5-Carbon–hydrogen insertion (1,5-CH insertion) reaction of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantiopure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes from α,β-unsaturated carbonyl compounds and dichloromethyl p-tolyl sulfoxide in short steps.     

Conventional vs. Microwave- or Mechanically-Assisted Synthesis of Dihomooxacalix[4]arene Phthalimides: NMR,X-ray and Photophysical Analysis §

Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K₂CO₃ in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (¹H, ¹³C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.     

Facile synthesis of spiro[benzo[e]indole-2,2′-piperidine] derivatives and their transformation to novel fluorescent scaffolds

The reaction of azaheterocyclic enamines with acrylamide was employed for the preparation of novel fluorescent scaffolds possessing a benzo[e]indoline moiety. Reaction of 3-substituted 2-methylidene-1H-benzo[e]indole with acrylamide gave rise to spiro[benzo[e]indole-2,2′-piperidin]-6′-ones. Ring opening reactions of the latter spiro compounds were investigated. Benzo[e]indoline derivatives possessing 2-(3-carbamoylpropyl), 2-[3-(ethoxycarbonyl)propyl] and 2-(4-aminobutyl) side chains were synthesised. The optical properties of the benzo[e]indoline derivatives were studied by UV-vis and fluorescence spectroscopy.