Transformations of enaminones. A simple one-pot synthesis of imidazolone derivatives

Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)carbamates 7 were prepared by the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) followed by substitution of the dimethylamino group with primary amines 5a–n to afford a mixture of (E) and (Z) diethyl 1-(1-(substituted)amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylates (6a–n), followed by cyclization to give final products 7a–n. The intermediate 6i was isolated and characterized and transformed into 7i. All imidazolones 7a–n were synthesized in one pot reaction sequences with individual reactions being very clean.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

Preparation of α- or β-trifluoromethylated vinylstannanes and their cross-coupling reactions

α- or β-Trifluoromethylated vinylstannanes 1, 2a, 3 and 4 were prepared form 1,1-bis(phenylthio)-2,2,3,3,3-pentafluoropropylbenzene (5) via several steps. The cross-coupling arylation reactions of 1–4 with aryl iodides bearing a bromo, methoxy, methyl, nitro or trifluoromethyl group on para- or meta-position of benzene ring afforded the corresponding coupling products in good yields. Compounds 1, 2a and 4 underwent the acylation reaction with various types of acyl chlorides to give the corresponding trifluoromethylated enone derivatives in good yields. Reduction of trifluoromethylated enone derivatives with LiAlH₄, followed by Fridel-Craft’s type of cyclization with AlCl₃ provided trifluoromethylated indene derivatives in good yields.     

Synthesis,structural studies and antituberculosis evaluation of new hydrazone derivatives of quinoline and their Zn(II) complexes

The quinoline hydrazone ligands were synthesized through multi-step reactions. The 2-hydroxy-3-formylquinoline derivatives (1a–1c) were prepared from acetanilide derivatives as starting materials using Vilsmeier–Haack reaction. Then the condensation of 2-hydroxy-3-formylquinoline derivatives with hydrazide derivatives (2a–2c) yielded quinoline hydrazone ligands (3a–3i). The synthesis of a new series of Zn(II) complexes carried out by refluxing with these quinoline hydrazone ligands (3a–3i) is reported. The molecular structures of the ligands (3a–3i) and the Zn complexes were characterized by elemental analysis and spectral studies like FT-IR, ¹H and ¹³C NMR, MS, UV–Visible and fluorescence. The preliminary results of antituberculosis study showed that most of the Zn(II) complexes 4a–4i demonstrated very good antituberculosis activity while the ligands 3a–3i showed moderate activity. Among the tested compounds 4e and 4g were found to be most active with minimum inhibitory concentration (MIC) of 8.00 μM and 7.42 μM respectively against Mycobacterium tuberculosis (H37 RV strain) ATCC No-27294 which is comparable to “first and second line” drugs used to treat tuberculosis.     

Highly diastereoselective alkylation,acylation and aldol condensation of cis- and trans-(N-acyloyl)hexahydrobenzoxazolidin-2-ones

The potential of hexahydrobenzoxazolidinones 1a–d as chiral auxiliaries was explored. N-Acylation of 1a–d, 2a–d and 3a–d was followed by methylation and benzylation via the corresponding sodium enolates generated by treatment with NaHMDS. Diastereoselectivities of 98% or higher were observed. The absolute configuration of the newly created stereogenic center was established by chemical correlation with 2-benzyl-1-propanol. The stereochemical results are congruent with addition to the electrophile from the less hindered face of a (Z)-configured enolate, the sodium cation being coordinated by both carbonyl oxygens of the substrate. cis- and trans-N-Propionyl derivatives 2a–d were treated with Bu₂BOTf/Et₃N to give dialkylboron enolates 6a–d, which were then reacted with acetaldehyde and benzaldehyde. ¹H and ¹³C NMR analyses showed the formation of a single diastereomeric aldol addition product, whose relative configuration was ascertained as syn from the measurement of the ³J_{H(2′)/H(3′)} coupling constants, and whose absolute configuration was determined by X-ray crystallographic analysis. The results are rationalized in terms of a Zimmerman–Traxler transition state, with a (Z)-configured enolate where boron is coordinated to the aldehyde carbonyl rather than the oxazolidinone carbonyl. Substrate 2a was also reacted with acyl chlorides via the sodium enolate (NaHMDS). The effect of reaction conditions on O- versus C-acylation, as well as the influence of solvent and additives on diastereoselectivity, are discussed.     

Two efficient methods for the synthesis of novel indole-based chalcone derivatives

Two powerful methods for the synthesis of indole-based chalcone derivatives, namely (E)-1-(2-chloro-1-(4-chlorobenzyl)-1H-indol-3-yl)-3-aryl(hetaryl)prop-2-en-1-ones (3a–l), are described, involving the ultrasound-assisted or solvent-free Claisen–Schmidt condensation reaction of 3-acetyl-2-chloro-1-(4-chlorobenzyl)indole (1) and various aromatic aldehydes (2a–l). The ultrasound-assisted Claisen–Schmidt condensation reaction was carried out using 1,4-dioxane as solvent and KOH as base at room temperature to give the corresponding products (3a–l) in yields ranging from 75 to 88 %. Alternatively, the Claisen–Schmidt condensation reaction could also be conducted under solvent-free conditions to obtain the products (3a–l) in comparable yields. The two procedures offer easy access to indole-based chalcone derivatives in short reaction times and good yields under mild conditions. Particularly, the advantageous aspect of the solvent-free method could avoid the use of environmentally hazardous and toxic solvents, and also reduced costs. The structures of all the newly synthesized indole-based chalcones 3a–l were confirmed by spectral data and elemental analyses.     

Characterization and pharmacological evaluation of new pyridine analogs

Reaction of 5-ethyl pyridine-2-ethanol 1 and methane sulphonyl chloride gives corresponding sulphonate 2; which on condensation with p-hydroxy benzaldehyde will give 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde 3. A series of chalcones 4a–o were prepared from 3 and substituted aromatic acetophenone. Chalcones 4a–o further react with guanidine nitrate to give a series of pyrimidines 5a–o which condense with 3,4-dichlorobenzylchloride to give amide derivatives 6a–o. Newly synthesized compounds have been examined on the basis of spectral analysis. All the compounds were screened against different gram-positive and gram-negative bacteria. Most of these compounds showed better inhibitory activity in comparison with the standard drugs.     

Stereospecific conversion of cyclic phosphorothioates into chlorophosphates

The reaction of the individual diastereoisomeric cyclic phosphorothioates 2a, 2b in the trans-2,4,7-trioxa-3-phosphabicyclo (4.4.0) decane and 4a, 4b in the trans-2,4,7-trioxa-3-phosphabicyclo (4.3.0) nonane series with sulphuryl chloride affords the corresponding sulphenyl chlorides 5a, 5b, 6a, 6b with retention of the configuration of the phosphorus atom. The reaction of the latter with phosphorus trichloride leads stereospecifically to the chlorophosphates 7a, 7b, 8a and 8b with full retention of configuration at phosphorus.     

Synthesis and in vitro cytotoxic evaluation of some novel hexahydroquinoline derivatives containing benzofuran moiety

A series of new ethyl 4-(2-(benzofuran-2-yl)-4-substituted-1,4,5,6,7,8-hexahydroquinolin-1-yl)-benzoate 3a–c was synthesized by Michael condensation of benzofuran chalcones 1a–c and cyclohexanone to give 2-(2-benzofuranyl)-4-substituted-5,6,7,8-tetrahydro-4-H -chromene 2a–c, followed by reaction of the latter with ethyl 4-aminobenzoate. Condensation of 3a–c with different amines afforded the corresponding amides 4a–e. On the other hand, upon treatment compounds 3a–c with hydrazine hydrate gave the benzohydrazide derivatives 5a–c. The reaction of compounds 5a–c with different thio/isocyanate gave the corresponding thiosemicarbazide and semicarbazide derivatives 6a–c. Meanwhile compounds 5a–c were reacted with ethyl cyanoacetate and different β-dicarbonyl compounds such as acetyl acetone, ethyl acetoacetate, and diethyl malonate to afford pyrazolyl derivatives 7a, b; 8a, b; 9a, b; and 10a–c, respectively. Moreover, 5a–c were reacted with carbon disulfide to synthesize the corresponding oxadiazolyl derivatives 11a–c, while their condensation with different aromatic aldehydes gave the corresponding Schiff bases 12a–d. Cytotoxic evaluation of some of the newly synthesized compounds against human hepatocellular carcinoma cell lines (HepG-2) revealed that the tested compounds produce promising inhibitory effect against the growth of HepG-2 cells with IC₅₀ values ranged from 11.9 to 19.3 µg/mL.     

Novel benzyl-substituted vanadocene anticancer drugs

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(3,4-dimethoxyphenyl) fulvene (1b) and 6-(3,4,5-trimethoxyphenyl) fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to vanadium with VCl₄ to yield the benzyl-substituted vanadocenes bis-[(p-methoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3c). The two vanadocenes 3a and 3c were characterised by single crystal X-ray diffraction. All three vanadocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC50 values and compare them with the corresponding titanocene dichloride derivatives. Vanadocenes 3b–c were found to have IC50 values of 9.1 and 8.3 μM, while 3a showed a superior value of 3.0 μM, respectively.     

Synthesis of new chiral calix[4]arene diamide derivatives for liquid phase extraction of α-amino acid methylesters

The synthesis of chiral diamide derivatives of calix[4]arene from the reaction of p-tert-butylcalix[4]arene diester 1a and calix[4]arene diester 1b with various amino alcohols were reported. The ¹H and ¹³C NMR, data showed that the compounds synthesized exist in the cone conformation. The extraction study properties of these new compounds 3a,b–4a,b towards some selected α-amino acid methylesters are also reported.     

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives: a new facile synthesis of substituted 2,3-dihydrobenzoxepine-4-carboxylates

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives 2a–t with (ethoxycarbonylmethylene)triphenylphosphorane provided the 2-oxoethylidene-2,3-dihydrobenzoxepine-4-carboxy-lates 3a–t with Z (cis) selectivity. Various basic catalysts were studied for the reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with the combination of Wittig reagent to provide compound 3b. The reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with other Wittig reagents, such as methylene(triphenylene)phosphorane and (1-ethoxycarbonylethylidene)triphenylphosphorane provided ketone derivative 4a rather 2-oxoethylidene derivative 3b. The ketone derivative 4a was reacted with Wittig reagent (ethoxycarbonylmethylene)triphenylphosphorane to give 2,3-dihydrobenzoxepine-4-carboxylate 3b. The present approach is novel, straight forward and being reported for the first time.     

Synthesis of indenes by ytterbium-catalyzed carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes with acetals

Ytterbium-catalyzed tandem carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes 1 with acetals 2 afforded the corresponding indene derivatives 3 in good to high yields. For example, in the presence of 10 mol % of Yb(OTf)₃ the reaction of 1-phenylbenzylidenecyclopropane 1a with the dimethyl acetals of benzaldehyde 2a, p-tolualdehyde 2b, and p-anisaldehyde 2c gave 1,3-diphenyl-2-(2-methoxyethyl)indene 3a, 2-(2-methoxyethyl)-3-phenyl-1-(p-tolyl)indene 3b, and 1-(p-anisyl)-2-(2-methoxyethyl)-3-phenylindene 3c in 82%, 80%, and 80% yields, respectively.     

Flash vacuum pyrolysis of azolylacroleins and azolylbutadienes

2-Aryl-5-acroleinyl-1,2,3,4-tetrazoles (1a–d) and 2-aryl-5-butadienyl-1,2,3,4-tetrazoles (1e–g) were subjected to flash vacuum pyrolysis. Acroleinyl derivatives resulted in nitrogen extrusion to give nitrilimines followed by ring closure to give the corresponding indazoles 3a–d in good yields. On the other hand, butadiene derivatives underwent ring fragmentation to give p-substituted anilines without formation of the expected indazoles. Differences between thermal behaviour of 2-(4-chlorophenyl)-5-acroleinyl-1,2,3,4-tetrazole (1c) and 1-(4-chlorophenyl)-4-acroleinyl-1,2,3-triazole (2) were studied in details. DFT calculations have been used to examine the nitrilimine and carbene nature of the intermediates involved in the thermal reactions of azolyl derivatives.     

Utilization of 2-ylidene-4-thiazolidinones in the synthesis of heterocyclic compounds. Part I: Synthesis of pyrazoles

2-Ylidene and 2,5-diylidene-4-thiazolidinones 2a–d were synthesized and converted into pyrazole derivatives 4a–d by reaction with hydrazine hydrate. A mechanism of this novel conversion is suggested.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Synthesis of spiroindene-1,3-dione isothiazolines via a cascade michael/1,3-dipolar cycloaddition reaction of 1,3,4-oxathiazol-2-one and 2-arylidene-1,3-indandiones

The reaction of 1,3,4-oxathiazol-2-one derivative with 2-arylidene-1,3-indandione to furnish novel spiroindene-1,3-dione isothiazoline derivatives by Michael/1,3-dipolar [3+2]-cycloaddition reaction was investigated. The key 1,3-dipolar cycloaddition reaction step was examined in toluene solvent at reflux temperature to obtain mixture of two regioisomers (6a and 6b – 14a and 14b) and single isomers (15–20). The scope of this new reaction was demonstrated with many examples with high reactivity and yields.     

Synthesis and biological activity of some fluorinated arylhydrazotriazoles

Potential biologically active derivatives of arylhydrazotriazole (3a–l) were prepared by the condensation reaction of diazonium salts using various aromatic amines (1a–l) and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanones (2). The synthesized products were obtained in 75–85% yield. All the synthesized products were having good-excellent antifungal activity as compared with standard (Fluconazole and Ketoconazole) drugs.     

Synthesis of α1-oxindole-α-hydroxyphosphonates under catalyst-free conditions using polyethylene glycol (PEG-400) as an efficient and recyclable reaction medium

A simple, efficient, eco-friendly, and cost-effective method has been developed for the synthesis of α¹-oxindole-α-hydroxyphosphonate derivatives (3a–o) by a one-pot reaction of isatins (1a–o) with trialkyl phosphites (2a–o) under catalyst-free-conditions using inexpensive, non-toxic polyethylene glycol (PEG-400) in excellent yields (82–92%). The present methodology offers an environmental acceptability; low cost, high yields, and recyclability of the PEG-400 are the important features of this protocol.     

Photochemical transformation of β,β′-dithienyl substituted o-divinylbenzenes leading to 1,2-dihydronaphthalenes or fused pentacyclic compounds: first evidence of electrocyclization process via 2,3-dihydronaphthalene intermediates

The photochemical behaviour of 2,2′-(o-phenylenedivinylene)dithiophenes (7a–c), 3,3′-(o-phenylenedivinylene)dithiophene (8a) and 3,3′-(o-phenylenedivinylene)dibenzothiophene (8b) was studied under the low concentrations. An intramolecular reaction via the 2,3-dihydronaphthalene intermediate has been observed in all studied examples accompanied by dimerization and polymerization. The 1,2-dihydro-2,3-dithienylnaphthalenes (9a–c) were isolated (7–9%) from the 2-thiophene derivatives while the 3-thiophene derivatives gave polycyclic structures (13–44% yield).