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The potential and scope of the microwave tool; A case study on the synthesis of phosphinates 

The microwave (MW) technique became an important tool in organophosphorus chemistry [1]. On the one hand, otherwise reluctant reactions, such as the esterification of P-acids may be enhanced [2], on the other hand, catalyst systems may be simplified on MW irradiation.

Our model reaction was the esterification of phosphinic derivatives. The classical method is the reaction of phosphinic chlorides with alcohols (A) that is, however, not green. Alternative possibilities are the cyclic propylphosphonic acid (T3P®)-promoted esterifications (B), the alkylating esterifications (C), and the direct esterifications (D) that take place only on MW irradiation [3].

                                               >P(O)Cl             +            ROH               -------------->              >P(O)OR            +                  HCl             (A)

                                               >P(O)OH  +   ROH    +    T3P®              -------------->              >P(O)OR            +                 T3P-H2O      (B)

                                               >P(O)OH  +    RX      +   K2CO3             -------------->              >P(O)OR   +    KX   +   CO2    +   H2O      (C)

                                               >P(O)OH             +           ROH               -------------->              >P(O)OR            +                  H2O             (D)

                                               R = alkyl or aryl              X = Br or I

The last MW-assited method that is the "greenest" protocol due to the atom-efficiency is discussed in detail together with extensions.

It is also the purpose of this presentation to elucidate the scope and limitations of the MW tool in synthetic organic chemistry in general, and to interpret the special MW effects [4]. The usefulness of MW irradiation for a specific reaction may be predicted on the basis of its energetics. We were the first who modelled the distribution and effect of the local overheatings, and compared the theory with the practice [4]. All these considerations were possible on the basis of the results (eg. enthalpy of activation values) of our quantum chemical calculations, and utilizing the pseudo first order kinetic equation and the Arrhenius equation.


[1] Keglevich, G.; Bálint, E.; Kiss, N. Z. in: Milestones in Microwave Chemistry – SpringerBriefs in Molecular Science, Ed.: Keglevich, G.; Springer, Switzerland, 2016, Ch. 3, pp. 47-76.

[2] Keglevich, G.; Kiss, N. Z.; Grün, A.; Bálint, E.; Kovács, T. Synthesis 2017, 49, 3069-3083.

[3] Keglevich, G.; Rádai, Z.; Kiss N. Z. Green Proc. Synth. 2017, 6, 197-201.

[4] Keglevich, G.; Kiss, N. Z.; Mucsi Z. Pure Appl. Chem. 2016, 88, 931-939.

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  • 186 Reads
In vitro Antimalarial activity against P. falciparum (CQS-10 and CQR-K1 strain) and β-Haematin inhibition of novel synthesized Quinoline-Triazole analogues

Chloroquine (CQ) analogues are the most important scaffolds used as an anti-malarial drug, and helping human world to control and eradicate malaria for decades. Biologically, it is expected that CQ is selectively deposited in the food vacuole of the parasite, and exerting its antimalarial effect by preventing the polymerization of the toxic heme. Researchers are involved in synthesizing a number of CQ analogues to overcome its drug-resistance properties but still the toxicity has been a major problem with many of them. Nevertheless, the question of whether this problem can be overcome remains of great interest. Our vision is thus to continue with this approach, we have synthesized more hydrophilic derivatives which are likely to be less toxic 4-aminosubstituted-7-chloroquinolines analogous. Our previous experience says that the production of this class of compounds is not a problem, but purification of these quinoline analogues are very challenging.

            After synthesizing a series of more hydrophilic derivatives which were biologically potent, we have synthesized a series of Chloro- and Cyano- substituted quinoline-triazole conjugates and other lipophilic antimalarial scafolds in competitive yield. These quinoline-triazole analogues were showing good to moderate In vitro antimalarial activity against P. falciparum (CQS-10 & CQR-K1 strain) and also showing β-haematin inhibition activity. For synthesizing quinoline-triazole conjugates, we have synthesized amine-triazole counterpart first and then coupled with the 4,7-Dichloro or 4-Chloro-7-Cyano-quinoline. These compounds are well characterized by NMR, mass, IR and other analytical tools. These compounds will be submitted for testing against CYP3A4, an enzyme important in drug metabolism inhibition which is often related to adverse drug effects and for hERG liability. In vitro antimalarial activity will be measured in chloroquine sensitive and resistant P. falciparum and drug metabolism tested in mice. At the same time association with Fe(III)PPIX and β-haematin inhibition and then that you will be testing various biological properties in the future.


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  • 226 Reads
Synthesis of New Derivatives of Monoazaphenothiazine via Tandem Catalysis

Abstract                                                                                                                                                                                                                                                                                                            The synthesis of new linear monoazaphenothiazine and its substituted derivatives via nickel catalyzed amidation reaction is reported. This was achieved by the condensation of 2-aminothiophenol and 2,3,5-trichloropyridine in aqueous basic medium to produce a new heterocyclic ring, 3-chloro-1-azaphenothiazine. Upon applying, Buchwald–Hartwig Cross coupling reaction, it leads to the syntheses of an array of new 3-amido derivatives which were obtained in good yields. The structures of the synthesized compounds were established based on their analytical and spectra data.

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In vitro Antimicrobial activity of Newly Synthesized Monoazaphenothiazine Derivatives.

Abstract                                                                                                                                                                                                                                                                                                 The antimicrobial activity of newly synthesized linear monoazaphenothiazine derivatives; 3-benzamido-1-azaphenothiazine, 3-trifluoromethamido-1-azaphenothiazine, 3-trichloromethanamido-1-azaphenothiazine and 3-(4-nitrobenzamido)-1- azaphenothiazine have been evaluated against bacteria and fungal strains.  Results showed that most of the synthesized linear monoazaphenothiazine derivatives were significantly active against the tested microorganisms. The correlation between antimicrobial activity and the chemical structure of phenothiazines was discussed.

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  • 295 Reads
Synthesis of α-aminophosphonates and related derivatives under microwave conditions

α-Aminophosphonates and related derivatives form one of the most important class of organophosphorus compounds due to their broad spectrum of biological activity. The most widely applied synthetic routes toward α‑aminophosphonates and α‑aminophosphine oxides is the Kabachnik-Fields (phospha-Mannich) reaction involving the condensation of an amine, an oxo compound and a >P(O)H species, such as dialkyl phosphite or secondary phosphine oxide. Etyl octyl phosphite and alkyl phenyl-H-phosphinates were also applied as the P‑reagent [1]. The other route is the Pudovik reaction of imines with >P(O)H species. An eco-friendly, solvent- and catalyst-free accomplishment for the synthesis of various α‑aminophosphonates was developed under microwave (MW) conditions starting from different primary or secondary amines. The phospha-Mannich reaction was also investigated in aqueous solution using triethyl phosphite as the P-reagent. Optically active derivatives were also obtained starting from (S)-α-phenylethylamine [2]. Bis(aminophosphonates) were synthesized by the double Kabachnik–Fields reaction. Furthermore, the synthesis of bis(aminophosphine oxides) was also studied starting from various secondary phosphine oxides [3]. After double deoxygenation, the bis-phosphines were utilized as bidentate P-ligands in the synthesis of cyclic platinum and palladium complexes. A facile catalyst- and solvent-free method was elaborated for the synthesis of amino-methylenebisphosphonates and amino-methylenebis(phosphine oxides) by the three-component MW-assisted condensation of an amine, an orthoformate and dialkyl phosphites or diphenyl phosphine oxides. Finally, a „green” accomplishment of the Pudovik reaction giving α‑aryl-α-aminophosphonate derivatives was performed.


[1]       Keglevich, G.; Szekrényi, A. Lett. Org. Chem. 2008, 5, 616.

[2]       Bálint, E.; Tajti, Á.; Kalocsai, D.; Mátravölgyi, B.; Karaghiosoff, K.; Czugler, M.; Keglevich, G. Tetrahedron, 2017, 73, 5659.

[3]       Bálint, E.; Tripolszky, A.; Jablonkai, E.; Karaghiosoff, K.; Czugler, M.; Mucsi, Z.; Kollár, L.; Pongrácz, P.; Keglevich G. J. Organomet. Chem. 2016, 801, 111.

[4]       Bálint, E.; Tajti, Á.; Ádám, A.; Csontos, I.; Karaghiosoff, K.; Czugler, M.; Ábrányi-Balogh, P.; Keglevich, G. Beilstein J. Org. Chem. 2017, 13, 76.

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  • 152 Reads
Imidazole dicarboxylic acid as a new catalyst for the synthesis of 1,4-dihydropyridines in ball-mill

One useful technique which used to combine economic and ecofriendly benefits is the multicomponent reaction (MCR), which contains some synthesis phases to enhance cost-effectiveness and energy savings and are carried out without separation of intermediates. MCRs have shown to be leading techniques in heterocyclic chemistry in the context of green methods [1,2]. These procedures are atom economic in nature, and forming directed products in high yields.

To access green chemistry in synthesis, one promising approach is to replace new green methods with classical methods by means of non-toxic reagents [3]. In order to use green and non-toxic reagent and catalyst, 1-H-imidazole-4,5-dicarboxylic acid was synthesized using previous reported method [4].  By means of this method, 1-H-imidazole-4,5-dicarboxylic acid was synthesized with more acidic properties than normal imidazole. After synthesizing this homogeneous catalyst, an efficient three component procedure was advanced for synthesis of 1,4- dihydropyridines (1,4-DHP) at room temperature in ball-mill and using imidazole dicarboxylic acid as catalyst. The structures of the new compounds were completely confirmed by useful spectral analyses. Imidazole dicarboxylic acid was synthesized and characterized by FT-IR and its melting point. The key advantages of this process are good to high yields, short reaction times, easy work-up and eco-friendly and non-toxic reagents.

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  • 87 Reads
Organocatalyzed synthesis of optically active cyanohydrins starting from alpha-ketoesters

Optically active cyanohydrins are valuable building blocks in organic synthesis, as they can be converted in several interesting compounds as β-aminoalcohols, α-hydroxyacids or α-hydroxyketones. Different methodologies have been developed in order to obtain these compounds with high yields and optical purities, including organocatalysed reactions. The use of small organic molecules as catalysts has emerged as an useful tool for the preparation of chiral compounds, being employed different organocatalysts in the asymmetric synthesis of cyanohydrins.
The enantioselective cyanosilylation of a set of prochiral α-ketoesters with trimethylsilyl cyanide employing different chiral hydrogen bond catalysts has been performed. We have mainly focused in the use of  bifunctional thioureas containing a tertiary amine or a quaternary ammonium moiety in their structure. The parameters that can affect to the reaction activity and selectivty (solvent, cyanide source and its concentration, temperature and additives), have been studied and optimised in order to obtain the final products with the highest yields and selectivities. Thus, it is possible to obtain the highly functionalized chiral cyanohydrins in good yields and moderate enantiomeric excesses by working in toluene at -45ºC and employing cinchona based (thio)ureas.

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  • 125 Reads
Chromatographic and Computational Study of Hydro-lipophilic Properties of N-Alkoxyphenylhydroxy-naphthalenecarboxamides

N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently reported as series of compounds with antimycobacterial, antibacterial and herbicidal activity. As it was found that the lipophilicity of these significantly biologically effective agents determined their activity, in this study hydro-lipophilic properties of all three series are investigated. All fifty-seven anilides were analysed using the reversed-phase high performance liquid chromatography method for lipophilicity measurement. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, the correlation between the logarithm of capacity factor k and log P/Clog P values calculated in various ways is discussed as well as the relationships between the lipophilicity and the chemical structure of the studied compounds.

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L-Proline-functionalized magnetic nanocomposite: a green magnetic nanocatalyst for efficient synthesis of imidazo[1,2-a]pyridines

Nowadays, magnetic nanocatalysts have attracted much attention as beneficial strategy in green chemistry. Organocatalysis has received considerable attention in organic synthesis. Among all organocatalysts, proline has shown considerable catalytic efficiency in different organic synthesis due to easily accessible and available in both enantiomeric forms. Recently, much interest has been paid to the immobilization of organocatalyst onto magnetic nanoparticles for catalytic application in organic reactions. Imidazo[1,2-a]pyridines are an important class of nitrogen based heterocyclic compounds, which have been widely used in pharmaceutical industry due to their interesting biological activities. So far, several methods have been reported for the synthesis of these important frameworks. In continuation of our research, herein, an efficient and selective synthesis of imidazo[1,2-a]pyridine derivatives were carried out using aromatic aldehydes, 2-aminopyridines and trimethylsilyl cyanide (TMSCN) in the presence of a catalytic amount of L-proline-functionalized magnetic nanocatalyst (Fe3O4@L-proline) in ethanol at room temperature in high yields. The solid nanocatalyst can be recovered easily and reused without any significant loss of the catalytic activity.  

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Synthesis and Characterization of Melamine-modified Hydrogels: The Study of Dye Removal from Aqueous Solutions

In the present study, a class of melamine-modified hydrogels were prepared for use as dye removal adsorbents from aqueous solutions. In the first step, poly(itaconic acid-co-maleic anhydride) and poly(vinyl acetate-co-maleic anhydride) were synthesized. Then the copolymers were modified by melamine to prepare the final adsorbents. The adsorbents were characterized by Fourier-transform infrared spectroscopy (FT-IR). The dye removal studies were then carried out for the adsorbents and different parameters were investigated in order to reach an optimized condition for each of the adsorbents.