Reaction Of Diethyl Research Articles

New cyano-acrylamide derivatives incorporating the thiophene moiety: Synthesis, anti-cancer, gene expression, DNA fragmentation, DNA damage, and in silico studies

New cyano-acrylamide derivatives bearing the thiophene moiety were prepared and rigorously characterized. Thus, the reaction of diethyl 5-(2-cyanoacetamido)-3-methylthiophene-2,4-dicarboxylate with aldehydes in the presence of piperidine afforded the title compounds in very good to excellent yields (range 81–96 %). All the newly synthesized compounds were evaluated as anti-cancer agents against five human cancer cell lines namely, MCF7 (human Caucasian breast adenocarcinoma), PC3 (human prostate cancer cell line), HepG2 (Human hepatocellular carcinoma), PACA2 (epithelial cell line derived from tumor tissue of pancreas), and BJ1 (normal skin fibroblast). While most of the compounds showed good activity against MCF-7, they showed limited activity against PC3, HepG2, and PACA2. Compound 9 showed potent anti-cancer activity against the PACA2 cell line with IC50 131.18 µM compared with the reference drug (doxorubicin, IC50 52.06 µM), while compound 10 exhibited potent anti-cancer activity against HePG2 cell lines with IC50 24.51 µM compared to the positive control (doxorubicin, IC50 39.73 µM). The gene expression, DNA fragmentation, and DNA damage of the most promising compounds were discussed. Additionally, compounds 9 and 10 showed favorable binding energies and strong interactions with CDK2, EGFR, ERα, VEGFFR, and Topoisomerase II receptors in the molecular docking simulation. These results suggest that these compounds have the potential to be effective candidates for anti-cancer therapy. Additionally, the in-silico ADMET profiles indicated that these compounds adhere to the Lipinski rules, indicating favorable physicochemical properties. These findings further support their potential for continued drug development efforts.

Synthesis of Substituted Aminopyrimidines as Novel Promising Tyrosine Kinase Inhibitors

A procedure has been proposed for the synthesis of a series of substituted N-(1,3-thiazol-2-yl)-pyrimidin-2-amines and N-(pyrimidin-2-yl)thioureas by reactions of diethyl 2-(ethoxymethylidene)malonate and ethyl 2-(ethyoxymethylidene)-3-oxobutanoate with 1,3-thiazol-2-ylguanidines and amidinothiourea, respectively. Preliminary screening has revealed high inhibitory activity of ethyl 2-(carbamothioylamino)-4-methylpyrimidine-5-carboxylate and ethyl 2-(carbamothioylamino)-6-oxo-1,6-dihydropyrimidine-5-carbox-ylate toward several protein kinases.

Synthesis of 6-Amino- and 6-Arylazoazulenes via Nucleophilic Aromatic Substitution and Their Reactivity and Properties.

The nucleophilic aromatic substitution (SNAr) reaction of diethyl 6-bromoazulene-1,3-dicarboxylate (1) with a variety of amines afforded the corresponding 6-aminoazulene derivatives 2a-2j in good-to-excellent yields. 6-Aminoazulene derivatives 3a-3f without the 1,3-diethoxycarbonyl functions were obtained by the deesterification of 2a-2f with 100% H3PO4. The reactivity of 6-aminoazulenes toward the bromination, SNAr, and palladium-catalyzed cross-coupling reactions was also clarified. 6-Arylazoazulenes 13a-13c were also prepared via the SNAr reaction of 1 with arylhydrazines, followed by oxidation with Pb(OAc)4 in the presence of N2H4. The structural, optical, and electrochemical properties of the 6-amino- and 6-arylazoazulenes were revealed by single-crystal X-ray structure analysis, UV/vis spectroscopy, voltammetry analysis, spectroelectrochemistry, and theoretical calculations.

Synthesis, Antibacterial and Antifungal Properties of Cyclohexane Tosyloxyimine Derivative

Due to increasing antimicrobial resistance, functionally substituted cyclohexane derivatives are being explored as potential antimicrobial agents. Reaction of diethyl 4 - hydroxy - 6 - (hyd - roxyimino) - 4 - methyl - 2 - phenylcyclohexane - 1,3 - dicarboxylate with 4 - toluene sulfonyl chloride in boiling acetone in the presence of equimolar triethylamine resulted in formation of diethyl - 4 - hydroxy - 4 - methyl - 2 - phenyl - 6 - ((tosyloxy)imino) cyclohexane - 1,3 - dicarboxylate. The structure of novel compound was characterized by 1 H and 13 C NMR spectra and elemental analysis was performed. Agar well diffusion assay was used to screen novel compound against Gram - positive bacteria, Gram - negative bacteria and fungi. Test compound showed better antimicrobial properties against Gram - negative bac teria as compared to Gram - positive bacteria and fungi. Acinetobacter baumannii BDU - 32 was found to be most sensitive bacteria while Candida pseudotropicalis BDU MA88 was found to be most sensitive yeast.

Multicomponent synthesis of novel thiazolo[3,2-a]pyridin-8-yl-phosphonates as a model of plant growth regulator

A series of thiazolo[3,2-a]pyridin-8-yl-phosphonate derivatives have been obtained by the reaction of diethyl (E)-((4-oxothiazolidin-2-ylidene)methyl)phospohonate, malononitrile and two equivalent of various aromatic aldehydes in a multicomponent reaction with good yields. The structures of the new compounds are confirmed by spectroscopic methods (IR, 1H, 13C, 31P NMR and HRMS). Compound diethyl-(Z)-(5-amino-6-cyano-2-(4-nitrobenzylidene)-7-(4-nitrophenyl)-3-oxo-3,7-dihydro-2H-thiazolo[3,2-a]pyridin -8-yl)phosphonate (4k) at 1 mM concentration enhanced biomass plant height, number of branches and leaf area of tomato plants of at least two-fold compared to the control plants. In common bean plants, this compound enhanced the chlorophyl content and delayed senescence in comparison to the control plants. Therefore, in future studies, the compound(s) would be further tested to evaluate deeply their mode of action at physiological, biochemical and molecular level to finally enhance crop productivity of various plants.

Aminium salts obtained from diethyl [(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)methyl]phosphonate

In reaction of diethyl [(3,5-di-tert-butyl-4-oxocyclohexa-2,5-diеn-1-ylidene)methyl]phosphonate with N 1,N 1-dimethylethane-1,2-diamine aminophosphonate was obtained that was transformed into aminium salts by reactions with halogen derivatives of hydrocarbons.

Grubbs–Hoveyda Second-Generation Catalysts Activated by the Introduction of a Light Fluorous Tag onto the Bidentate Ligands

Various novel Grubbs–Hoveyda second-generation catalysts activated by a fluorous tag on the ligands were prepared. The catalyst bearing the 1-naphthyl group on the bidentate ligand exhibited the highest catalytic activity among the studied catalysts for the ring-closing­-metathesis reaction of diethyl 2-allyl-2-(2-methylallyl)malonate.

Synthesis and Crystal Structure of 10-(4-Nitrobenzyl)-3,7,9,11-Tetraoxo-2,4,6,8,10-Pentaaza[3.3.3]Propellane

N3a, N6a-Dibenzyl-2,5-dioxotetrahydroimidazo[4,5- d]imidazole-3a,6a(1 H,4 H)-dicarboxamide was obtained by the reaction of diethyl 2,5-dioxotetrahydroimidazo[4,5- d]imidazole-3a,6a(1 H,4 H)-dicarboxylate with benzylamine, and cyclised to give 10-benzyl-3,7,9,11-tetraoxo-2,4,6,8,10-pentaaza[3.3.3]propellane with p-TsOH as catalyst. 10-(4-nitrobenzyl)-3,7,9,11-tetraoxo-2,4,6,8,10-pentaaza[3.3.3] propellane was afforded by the nitration of the benzyl derivative in 65–68% nitric acid. The structure of 10-(4-nitrobenzyl)-3,7,9,11-tetraoxo-2,4,6,8,10-pentaaza[3.3.3]propellane was further confirmed by single-crystal X-ray diffraction. The syntheses of these propellane derivatives have several advantages such as mild reaction conditions, operational simplicity, and excellent yields.

Penta‐2,4‐dien‐1‐ones by Formal [3+2] Cycloaddition–Rearrangement of Electron‐Deficient Diethyl 2‐(Dicyanomethylene)malonate with Alk­ynes

AbstractThe reactions of diethyl 2‐(dicyanomethylene)malonate, an electron‐deficient alkene, with donor‐activated and unactivated alkynes have been investigated. Moderately electron‐rich and unactivated alkynes undergo efficient formal [3+2] cycloaddition–rearrangement cascades to provide the corresponding penta‐2,4‐dien‐1‐one adducts in yields of up to 84 %. The structures of the solid dienone products were confirmed by X‐ray diffraction analysis. The buta‐1,3‐diene moieties in the dienones do not adopt planar s‐trans conformations but rather nonplanar geometries in which the two olefinic bonds are nearly orthogonal to each other. This transformation proceeds with excellent regioselectivity and with a wide range of alkynes without the need for a catalyst. Under the optimized reaction conditions, no competition with the [2+2] cycloaddition–retroelectrocyclization reaction (CA–RE) was observed.

Synthesis of chiral 3, 7-diazabicyclo[3.3.1]nonan-9-ones containing (R)-amino acid fragments

A reaction of diethyl 1, 3-acetonedicarboxylate with formaldehyde and (R)-alanine, (R)-valine, (R)-leucine, and (R)-phenylalanine ester hydrochlorides gave nonracemic 1, 5-bis(ethoxycarbonyl)-3, 7-diazabicyclo[3.3.1]nonan-9-one derivatives equipped with the corresponding amino acid moieties in 37—85% yield.

Reaction of diethyl vinylphosphonate with 1,3-benzothiazol-2-amine

Development of methods for the synthesis of new aminophosphoryl compounds is an important field of modern organoelement chemistry due to wide potential of using them as biologically active substances, extractants, and membrane carriers [1–3]. Of particular interest are phosphonates functionalized by pharmacophoric nitrogen-containing heterocyclic fragments. With the goal of obtaining such derivatives, we have studied the reaction of diethyl vinylphosphonate (1) with 1,3-benzothiazol-2-amine (2). An equimolar mixture of compounds 1 and 2 was heated for 25 h at 70°C. Repeated washing of the reaction mixture with hexane until constant refractive index gave a thick yellow transparent oil. The P NMR spectrum of the product contained only one signal at δP 28 ppm, indicating that the reaction was selective. The reaction of vinylphosphonate 1 with aminobenzothiazole 2 can take two paths involving attack on the β-carbon atom of the vinyl group by the endocyclic nitrogen atom of 2 with formation of adduct 3 (path a) or by the exocyclic amino nitrogen atom with formation of adduct 4 (path b). The H NMR spectrum of the product contained the following signals (CDCl3), δ, ppm: 1.36 t (6H, CH3CH2O, JHH = 7.06 Hz), 2.28 m (2H, PCH2, JPH = 18.6, JHH = 7.6 Hz), 3.82 m (2H, CH2N), 4.15 m (4H, CH3CH2O), 5.71 br.s (NH), 7.10–7.50 m (4H, Harom). We previously studied the reaction of diethyl 3-methylbuta-1,2-dien-1-ylphosphonate with 2-aminobenzothiazole [4], and the structure of the product was determined by X-ray analysis. It was found that the addition involved the endocyclic nitrogen atom. Taking these data into account, we presumed that the addition of phosphonate 1 to aminobenzothiazole 2 yields diethyl 2-[2-imino-1,3-benzothiazol-3(2H)-yl]ethylphosphonate (3). The above given H and P NMR spectral data are consistent with structure 3. Yield 64%, nD = 1.5553. Found, %: C 49.23; H 5.81. C13H19N2O3PS. Calculated, %: C 49.67; H 6.05. The H and P NMR spectra were recorded on a Varian Unity-300 spectrometer a t 300 and 121.4 MHz, respectively. The chemical shifts were measured relative to the residual proton signal of the solvent (H) or 85% H3PO4 (P, external standard). This study was funded by the subsidy allocated to Kazan Federal University for the project part of the state assignment in the sphere of scientific activities. ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 4, pp. 593–594. © Pleiades Publishing, Ltd., 2015. Original Russian Text © N.G. Khusainova, E.P. Pogodina, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 4, pp. 609–610.

The Mistake in Carl Bosch’s PhD Thesis: A Contribution to ‘Retro-Chemistry’

The reaction of diethyl 1,3-acetonedicarboxylate and 2-bromoacetophenone described in Carl Bosch’s PhD thesis revealed a mistake concerning the structure of the isolated compound. A rework of the original showed that not the described cyclohexenone derivative was isolated, but a highly functionalized α,β-unsaturated cyclopenten­one derivative was formed. The structure was determined by spectroscopic methods and X-ray crystal structure analysis. In analogy to Bosch’s reaction, some new derivatives were synthesized.

ChemInform Abstract: Rhodium‐Catalyzed Cross‐Coupling of Vinylarenes with Arylaluminum Reagents in the Presence of Ketones.

Rhodium-catalyzed addition/elimination of arylaluminum reagents with vinylarenes was achieved to obtain stilbene derivatives. The reaction of diethyl(phenyl)aluminum with styrene in the presence of the chloro(1,5-cyclooctadiene)rhodium(I) dimer, [RhCl(cod)]2, and diisopropyl ketone (2,4-dimethyl-3-pentanone) as an additive occurred to give (E)-stilbene in quantitative yield. The use of other arylaluminum reagents afforded β-arylated products in good to excellent yields. This reaction was found to be promoted by ketones as additives, which are reduced to the corresponding alcohols, as confirmed by analysis of the crude reaction mixture by 1H NMR spectroscopy.

A convenient synthesis of cyclopropane malonyl peroxide

Cyclopropane-1,1-dicarbonyl peroxide was prepared in 85% yield by the reaction of diethyl cyclopropane-1,1-dicarboxylate with the urea hydrogen peroxide clathrate in the presence of methanesulfonic acid.

Stereoselective Synthesis of α-fluoro-β-trifluoromethyl-α,β-unsaturated Esters by Horner-Wadsworth-Emmons Coupling

α-Fluoro-β-trifluoromethyl-α,β-unsaturated esters were synthesized via the reaction of diethyl (1-fluoro-1- carbethoxymethyl) phosphonate with a variety of aromatic/heterocyclic trifluoromethyl ketones and trifluoroacetaldehyde ethyl hemiacetal by the Horner-Wadsworth-Emmons (HWE) coupling. The effect of base, solvent, as well as reactant ratio has been investigated. The present method is highly stereoselective, attractive and convenient for the synthesis of the target compounds due to the availability of the reagents, simplicity of the approach and good yields of the products. Keywords: α-fluoro-β-trifluoromethyl-α-β-unsaturated esters, Horner-Wadsworth-Emmons coupling, trifluoromethyl ketones.

ChemInform Abstract: Reaction of Propa‐1,2‐dienylphosphonates with Ethylenediamine.

Alkenylphosphonates containing aminoorganyl groups in the β-position with respect to the phosphoryl fragment are promising from the practical viewpoint as biologically active compounds. With a view to obtain new derivatives of this series, we examined reactions of allenylphosphonates with ethylenediamine. The reaction of diethyl propa-1,2-dienylphosphonate (Ia) with ethane-1,2-diamine was accompanied by strong heat evolution, and it led to the formation of a thick oily product. The IR spectrum of this product lacked absorption band at 1960 cm typical of the C=C=C triad, but bands corresponding to stretching vibrations of C=C bond (1635 cm) and NH and NH2 groups (3200–3360 cm) appeared. In the H NMR spectrum of the product (DMSO-d6) we observed a doublet signal at δ 1.95 ppm (3H, CH3C=, JPH = 1.9 Hz), which indicated the absence of terminal H2C= group. Also, a doublet signal was present at δ 3.41 ppm (JPH = 12.5 Hz) due to CH= proton in the α-position with respect to phosphorus, whereas there was no signal assignable to protons in PCH2 methylene group with a characteristic coupling constant JPH of 18– 22 Hz. These findings allowed us to exclude theoretically possible imine structure [1, 2]. Signals from the ethoxy groups in the phosphoryl fragment were located in the expected regions, at δ , ppm: 1.03 t (6H, CH3CH2, JHH = 7.1 Hz) and 4.01 m (4H, CH2O). Only one phosphorus signal was present at δP 27.5 ppm in the P NMR spectrum (DMSO-d6) The above data led us to conclude that phosphonate Ia reacts with ethane-1,2-amine via attack by the amino nitrogen atom in the latter on the central sp-hybridized carbon atom of the cumulene fragment to produce enamine structure, diethyl 2-(2-aminoethylamino)prop-1-en-1-ylphosphonate (II) (Scheme 1). It should be noted that compound II is capable of undergoing enamine–imine tautomerism, depending on the solvent. In CDCl3, the adduct exists as mixtures of several tautomers, as follows from the presence of additional signals in the P NMR spectrum, δP 22.44, 22.62, 26.07, 26.58, and 26.67 ppm. In the H NMR spectrum of a solution in CDCl3 we observed a doublet from methylene protons at δ 2.54 ppm (2H, PCH2C, JPH = 22.4 Hz), while no signal assignable to terminal methylene group H2C was present. These data indicated formation of imino tautomer III. The presence of numerous signals in the P NMR spectrum (CDCl3) may also be attributed to Z/E isomerism of different tautomers. The H NMR spectrum was also strongly complicated. On the other hand, we cannot rule out initial isomerization of allenylphosphonate Ia into propynylphosphonate, followed by addition of ethylenediamine to the triple bond. Enamine II was also synthesized by reaction of diethyl prop-2-yn-1-ylphosphonate with ethylenediamine. By reaction of ethylenediamine with 2.5 equiv of diethyl, diisopropyl, and dibutyl propa-1,2-dienylphosphonates Ia–Ic we obtained bis-phosphonates IV–VI (Scheme 2). The P NMR spectra of IV–VI contained only one signal. Compounds IV–VI displayed in the ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 9, pp. 1399–1400. © Pleiades Publishing, Ltd., 2013. Original Russian Text © N.G. Khusainova, E.P. Pogodina, A.V. Gerasimov, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 9, pp. 1415–1416.

ChemInform Abstract: An Improved Synthesis and Some Reactions of Diethyl 4‐Oxo‐4H‐pyran‐2,5‐dicarboxylate.

AbstractCondensation of 2‐(dimethylamino)methylene‐3‐oxobutanoate with diethyl oxalate in the presence of NaH and following HCl‐promoted cyclization offers an improved synthesis of 4‐oxo‐4H‐pyran‐2,5‐dicarboxylate (IV).

Experimental and Theoretical Studies of Bromination of Diethyl 2,4,6‐Trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate

ABSTRACTA reaction of diethyl 2,4,6‐trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate with 1, 2, and more equivalents of N‐bromosuccinimide (NBS) in methanol was investigated by NMR spectroscopy at a temperature interval ranging from 25 to 40°C. The reaction was found to proceed through several steps. The structures of the intermediates diethyl 3‐bromo‐2,4,6‐trimethyl‐3,4‐dihydropyridine‐3,5‐dicarboxylate, diethyl 3‐bromo‐2‐methoxy‐2,4,6‐trimethyl‐1,2,3,4‐tetrahydropyridine‐3,5‐dicarboxylate, and diethyl 3,5‐dibromo‐2‐methoxy‐2,4,6‐trimethyl‐2,3,4,5‐tetrahydropyridine‐3,5‐dicarboxylate were identified by multinuclear (1H, 13C, and 15N) NMR spectral data. The optimal structures of all species participating in the reaction as well as changes in their relative energies along with the proposed pathway of the reaction were analyzed by quantum‐chemical calculations. The mechanism of bromination of diethyl 2,4,6‐trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate with NBS in methanol was found to favor the bromination in the 2,6‐methyl side chains as the only products in full agreement with experimental observations.

Rhodium‐Catalyzed Cross‐Coupling of Vinylarenes with Arylaluminum Reagents in the Presence of Ketones

AbstractRhodium‐catalyzed addition/elimination of arylaluminum reagents with vinylarenes was achieved to obtain stilbene derivatives. The reaction of diethyl(phenyl)aluminum with styrene in the presence of the chloro(1,5‐cyclooctadiene)rhodium(I) dimer, [RhCl(cod)]2, and diisopropyl ketone (2,4‐dimethyl‐3‐pentanone) as an additive occurred to give (E)‐stilbene in quantitative yield. The use of other arylaluminum reagents afforded β‐arylated products in good to excellent yields. This reaction was found to be promoted by ketones as additives, which are reduced to the corresponding alcohols, as confirmed by analysis of the crude reaction mixture by 1H NMR spectroscopy.

A Mild Synthesis of New Aryl Vinyl Ethers and Diethyl 1-[(Alkyl)(cyano)methyl]vinylphosphonates via the Substitution of a 2,3-Difunctional Allyl Bromide

A novel class of aryl vinyl ethers 3 and diethyl 3-cyano-3-alkylprop-1-en-2-ylphosphonates 4 has been prepared, respectively, from coupling reaction of diethyl 1-(bromomethyl)-2-cyanovinylphosphonate 2 with phenols and Gilman reagents.