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.

 References

[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.

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.

References:

• J. Egan, R. Hunter, C. H. Kaschula, H. M. Marques, A. Misplon, J. C. Walden, J. Med. Chem. 2000, 43, 283
• H. Kaschula, T. J. Egan, R. Hunter, N. Basilico, S. Parapini, D. Tarameli, E. Pasini, D. Monti, J. Med. Chem. 2002, 45, 3531.
• J. Egan, K. R. Koch, P. L. Swan, C. Clarkson, D. A. V. Schalkwyk, P. J. Smith, J. Med. Chem. 2004, 47, 2926. 
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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.

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.

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.

References

[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.