Letters in Organic Chemistry - Volume 16, Issue 3, 2019

The non-photolytic method for generation of arylnitroso oxides based on the reduction of nitrosobenzene by triphenylphosphine was used to study the products of the reaction of transphenylnitroso oxide with trans-stilbene. N,α-Diphenylnitrone and benzaldehyde were found to be the main stable products of the reaction, the first stage of which was [3+2]-cycloaddition to form the metastable 1,2,3-dioxazolidine intermediate. The obtained products were in agreement with our previous theoretical predictions.

The present study reported the preparation of a novel mutual prodrug containing meso-tetra (m-hydroxy phenyl) chlorin (m-THPC), PEG and folate. The folate receptor (FR) targeting compound is a water-soluble chemical incorporating a hydrophilic PEG spacer unit and a reducible selfimmolative disulfide-based linker system between the FR-targeting ligand and the chlorin. The m- THPC-s-s-PEG-Folate was proved to release the parent drug and exhibited significant targeting effects on HeLa cells. In addition, the redox-responsive folate targeting photosensitizer m-THPC-s-s-PEG-Folate showed slightly higher phototoxicity than m-THPC-PEG-Folate for HeLa cells.

Vilsmeier-Haack reaction is one of the most important chemical reactions used for formylation of electron-rich arens. Even though Vilsmeier-Haack reaction was studied on a wide variety of hydrazones of enolizable ketones, literature lacks the examples of the use of 4-substituted cyclohexanones as a substrate. The cyclization potential of hydrazones of cyclic keto compounds is still interested topic of investigation. In the present study, the reaction of various hydrazines with 4-substituted cyclohexanones was proceeded and the resulted hydrazones in crude form were treated with Vilsmeier- Haack reagent using both conventional as well as microwave methods. The reaction of phenyl hydrazine with 4-phenylcyclohexanone yielded the corresponding tetrahydro-1H-carbazole instead of hydrazone during solvent evaporation at 40ºC. By keeping the temperature of water bath to 0ºC, the corresponding hydrazone was isolated in crude form which was immediate treated with POCl3/DMF for 10 min at 90ºC using microwave irradiation method afforded novel 4,5,6,7-tetrahydroindazole derivative. Using this optimized condition, the substrate scope for the synthesis of tetrahydroindazole derivatives was explored and synthesized total 6 final compounds. The microwave assisted synthesis of tetrahydroindazoles from 4-substituted cyclohexanones has been reported for the first time under mild conditions in good yield. Easy work up procedure, high yielding, shortened reaction times, clean and ecofriendly are the main advantages of this protocol.

1H-Tetrazole 5-acetic acid (TAA) has been explored as a new organocatalyst for the synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-ones derivatives from 2’-aminoacetophenone under solventfree conditions. The method described herein is covenient and the catalyst could be reused. Mechanistic study of the reaction revealed that the reaction passing through initial activation of the aldehyde by the catalyst and the C-C bond formed through the intermolecular pathway. The synthesized compounds exhibit yellowish-white fluorescence when exposed to 350 nm UV light. Optical properties such as absorption and fluorescence emission spectra were monitored in methanol. Fluorescence emission properties in different solvents with different polarity indicate solvatochromic characteristics of the probes.

A new series of bis/mono ethyl-1-aryl-1H-tetrazole-5-carboxylate has been synthesized by treating respective tetrazole with ethyl chloroformate in THF and DIPEA as a catalyst. The structure of the novel molecule is characterized by FT-IR, 1H-NMR, 13C-NMR, and mass spectra. After conforming the structure, bis/mono ethyl-1-aryl-1H-tetrazole-5-carboxylate was subjected to hydrolysis under both acidic and basic conditions. The hydrolysis reaction did not occur; to know the relevant reason, we move to theoretical studies. DFT B3LYP method was used to determine the optimized structure and HOMO & LUMO energies of the title molecule. The energy was found to be from 4.23-5.31 eV. Energy gap was related to hardness and reactivity. Additionally, we provide the reason with respect to AIM analysis, which was performed for one molecule. The synthesized title molecules were characterized by IR, 1H & 13C NMR, mass and elemental analysis. Theoretical studies such as DFT and AIM analysis were also performed. All the synthesized compounds were verified by analytical data such as IR, NMR, elemental analysis, mass spectra and theoretical studies such as DFT and AIM analysis. The HOMO & LUMO energy was found to be from 4.5 eV to 5.2 eV. More energy gap results in enriched hardness in the molecule and decreased reactivity. From the AIM analysis result, we found that there is a formation of a weak bond between the oxygen of the carbonyl group and carbon of the phenyl group. Due to these reasons, the title molecule did not undergo hydrolysis reaction under both acidic and basic conditions. We report on the synthesis and characterization of bis/mono ethyl-1-aryl-1H-tetrazole-5- carboxylate. HOMO & LUMO energy were found to be 4.5 – 5.2 eV. High energy will increase the hardness of the molecule which will result in decreased reactivity of the molecule. Additionally, we provide AIM analysis done for the compound 6a and there is formation of a weak bond between the oxygen of the carbonyl group and carbon of the phenyl group. Oxygen used its lone pair of electron in the formation of a weak bond with carbon and hence oxygen become unreactive and so the hydrolysis reaction did not happen.

Background: Tetrahydroindazole, a member of the fused-pyrazole system, is a least studied class of heterocyclic compounds owing to its scarcity in nature. However, a large number of synthetically prepared tetrahydroindazoles are known to show a variety of biological activities such as interleukin- 2 inducible T-Cell kinase inhibitors, AMPA receptor positive allosteric modulators, antitumor, antituberculosis, anti-inflammatory and antimicrobial activities. Vilsmeier-Haack reaction is one of the most important chemical reactions used for formylation of electron rich arenes. Even though Vilsmeier- Haack reaction was studied on a wide variety of hydrazones derived from active methylene compounds, literature lacks the examples of the use of 4-substituted cyclohexanones as a substrate for the synthesis of 4,5,6,7-tetrahydroindazoles. The study of the reaction of Vilsmeier-Haack reagent with hydrazones derived from cyclic keto compounds having active methylene has been considered the interested topic of investigation. In the present study, ethyl cyclohexanone-4-carboxylate was treated with one equivalent of various hydrazines for two hours and the resulted hydrazones were further treated with an OPC-VH reagent (Vilsmeier-Haack reagent isolated from phthaloyl dichloride and N,Ndimethylformamide) afforded 4,5,6,7-tetrahydroindazoles in excellent yields. The synthesized compounds 4a-f and 5a-f were screened for their antioxidant activities using the DPPH radical scavenging assay. The target compounds were synthesized regioselectively using 4+1 approach in excellent yields. A number of experiments using both conventional heating as well as microwave irradiation methods were tried and on comparison, microwave irradiation method was found excellent in terms of easy work up, high chemical yields, shortened reaction times, clean and, no by-products formation. Some of the synthesized compounds showed significant antioxidant activity. The microwave assisted synthesis of 4,5,6,7-tetrahydroindazoles from ethyl cyclohexanone-4-carboxylate has been reported under mild conditions in excellent yield. Easy work up, high chemical yield, shortened reaction times, clean and no by-products formation are the major advantages of this protocol. These advantages may make this method useful for chemists who are interested in developing novel 4,5,6,7-tetrahydroindazole based drugs.

The chemical mechanisms of protonated diamines-catalyzed decarboxylation of oxaloacetic acid anions in water solutions have been studied by using density functional theory. The calculated results show that the activated Gibbs free energy of the decarboxylation step is the highest in the whole diamine-catalytic processes for OA2-, and protonated ethylenediamine (ENH+) is the best catalyst of the five diamines, which is consistent with the study of Thalji et al. However, for OA-, different with OA2-, the dehydration step is the rate-determining one except 1,3-diaminopropane, and protonated 1,4- diaminobutane is the best catalyst of the five catalysts. The results also indicate that the second amino group participates in the reaction as the proton acceptor or proton donor, and it assists in decarboxylation by hydrogen bonds, decreasing the active Gibbs free energy barrier of the whole catalytic process. These results provide insight into the precise catalytic mechanism of several enzymes whose reactions are known to proceed via an imine intermediate.

2-Amino-4,5-dihydro-3-furancarbonitriles (ADFCs) have attracted much attention due to their utility as valuable synthetic intermediates for the preparation of a series of acyclic and cyclic organic compounds. On the other hand, indoles substituted with furans are highly interesting compounds displaying a wide range of biological and pharmaceutical activities. However, to the best of our knowledge, indole substituted 2-amino-4,5-dihydro-3-furancarbonitriles have not been previously reported. A new and efficient synthesis of indole substituted 2-amino-4,5-dihydro-3-furancarbonitriles has been developed in two steps using water as a solvent. The first step of the sequence involves threecomponent reaction of phenylglyoxals, indoles and malononitrile under aqueous and catalyst-free conditions for the synthesis of indole substituted β,β-dicyanoketones. Reduction of the obtained β,β- dicyanoketones with sodium borohydride in water at room temperature afforded the indole substituted 2-amino-4,5-dihydro-3-furancarbonitriles in good yields. Several substituted phenylglyooxals were reacted smoothly with indole or 2-methylindole and malononitrile to give the corresponding indole substituted β,β-dicyanoketones in good yields. Treatment of the obtained β,β-dicyanoketones with sodium borohydride in water furnished exclusively the indole substituted 2-amino-4,5-dihydro-3- furancarbonitriles in good yields. We have developed an efficient straightforward access to indole substituted β,β-dicyanoketones by one-pot three-component reaction of phenylglyoxals, indoles and malononitrile. The synthetic utility of obtained indole substituted β,β-dicyanoketones has been outlined by the preparation of indole substituted 2-amino-4,5-dihydro-3-furancarbonitriles. The advantage of catalyst-free, atom-economical and environmental benignity render it promising methods for preparation of indole substituted 2-amino-4,5-dihydro-3-furancarbonitriles.

The optimized structural parameters and electronic properties including frontier molecular orbital (FMO) analysis, molecular electrostatic potential and NBO charge analysis of (E,Z)-2-(4- amino-5-oxo-3-(thiophene-2-ylmethyl)-4,5-dihydro-1,2,4-triazole-1-yl)-N'-(thiophene-2-ylmethylene) acetohydrazide were investigated by using density functional theory (DFT) at B3LYP/6-311++G(d,p) level. The global reactivity parameters were evaluated in accordance with the energy values of HOMO and LUMO of each determined conformer. The molecule was experimentally characterized by means of FT-IR and NMR spectroscopic methods and also theoretically by B3LYP/6-311++G(d,p) and B3LYP/cc-pVTZ method (FT-IR and NMR, respectively). The theoretical results of spectroscopic analysis show good agreement with experimental outcomes. The natural bond orbital (NBO) analyses for studied conformers were performed at B3LYP/6-311++G(d,p) level to find hyperconjugative interactions as well as intramolecular hydrogen bond interaction. Besides, theoretical results indicate that the optimized structure of conformer E and Z possesses N128;’H···N and N128;’H···S weak hydrogen bonding, respectively.

N-Myristoylation, an irreversible protein modification, occurs by the covalent attachment of myristate with the N-terminal glycine of the eukaryotic and viral proteins, and is associated with a variety of pathogens and disease-related proteins. Identification of myristoylation sites through experimental mechanisms can be costly, labour associated and time-consuming. Due to the association of N-myristoylation with various diseases, its timely prediction can help in diagnosing and controlling the associated fatal diseases. Herein, we present a method named N-MyristoylG-PseAAC in which we have incorporated PseAAC with statistical moments for the prediction of N-Myristoyl Glycine (NMG) sites. A benchmark dataset of 893 positive and 1093 negative samples was collected and used in this study. For feature vector, various position and composition relative features along with the statistical moments were calculated. Later on, a back propagation neural network was trained using feature vectors and scaled conjugate gradient descent with adaptive learning was used as an optimizer. Selfconsistency testing and 10-fold cross-validation were performed to evaluate the performance of N-MyristoylG-PseAAC, by using accuracy metrics. For self-consistency testing, 99.80% Acc, 99.78% Sp, 99.81% Sn and 0.99 MCC were observed, whereas, for 10-fold cross validation, 97.18% Acc, 98.54% Sp, 96.07% Sn and 0.94 MCC were observed. Thus, it was found that the proposed predictor can help in predicting the myristoylation sites in an efficient and accurate way.

A part of a running research project directed to building coordinated polymers based on the rigid aromatic s-triazine, the researchers reported the synthesis, characterization, antimicrobial, antioxidant and anti-inflammatory activities of four new transition metal complexes derived from the nanosized diol monomer (H2L ligand) as early representatives of its nanosized o-naphthol-based polyester. The reaction of the new nanosized N2O2 donor diimine containing sulfone with zinc (II), copper (II), nickel (II) and cobalt (II) ions offered nonconducting metal complexes. The SEM image showed the diol monomer was organized as well-defined nanosized rod-like morphology. Spectroscopic and magnetic susceptibility studies displayed the tetrahedral geometries for Zn (II), Co (II) and Ni (II) complexes while the Cu (II) complex had square planar geometry. The antioxidant and antiinflammatory activities were in the order [Cu2L2].4H2O > [Zn2L2] > [Ni (HL)2] > [Co2L2] > H2L. Despite the ligand, [Cu2L2].4H2O, [Zn2L2] and [Co2L2] complexes displayed no efficacy against the screened microbes, only the tetrahedral Ni (II) complex exhibited moderate activity. The reporting complexes possessed several notable advantages that render them as promising alternatives for the development of therapeutic agents. Selection of the rigid O-substituted naphthol ring as a source of Odonor ligands is expected to construct high dimensional frameworks and more easily contributing and controlling metallic topology.