Continuous flow synthesis of 6-monoamino-6-monodeoxy-ß-cyclodextrin.

The first continuous flow method was developed for the synthesis of 6-monoamino-6-monodeoxy-ß-cyclodextrin starting from native ß-cyclodextrin through three reaction steps, such as monotosylation, azidation and reduction. All reaction steps were studied separately and optimized under continuous flow conditions. After the optimization, the reaction steps were coupled in a semi-continuous flow system, since a solvent exchange had to be performed after the tosylation. However, the azidation and the reduction steps were compatible to be coupled in one flow system obtaining 6-monoamino-6-monodeoxy-ß-cyclodextrin in a high yield. Our flow method developed is safer and faster than the batch approaches.

Three-Component Reaction of 3-Formyl-6-Methylchromone, Primary Amines, and Secondary Phosphine Oxides: A Synthetic and Mechanistic Study.

A fast, mild, and efficient catalyst-free approach has been developed for the synthesis of chromonyl-substituted α-aminophosphine oxides by the three-component reaction of 3-formyl-6-methylchromone, primary amines, and secondary phosphine oxides at ambient temperature. Carrying out the reaction with aliphatic amines or aminoalcohols at a higher temperature (80 °C), phosphinoyl-functionalized 3-aminomethylene chromanones were formed instead of the corresponding chromonyl-substituted α-aminophosphine oxides. No reaction occurred when 3-formyl-6-methylchromone and secondary phosphine oxides were reacted with aromatic amines in the absence of any catalyst. Applying a basic catalyst, the formation of the phosphinoyl-functionalized 3-aminomethylene chromanones was observed; however, the reaction was not complete. Detailed experimental and quantum chemical studies were performed to study the transformation. Moreover, the in vitro cytotoxicity of phosphinoyl-functionalized 3-aminomethylene chromanones was also investigated in three different cell lines, such as human lung adenocarcinoma (A549), mouse fibroblast (NIH/3T3), and human promyelocytic leukemia (HL60) cells. Several derivatives showed modest activity against the human promyelocytic leukemia (HL60) cell line.

Multicomponent Synthesis of Potentially Biologically Active Heterocycles Containing a Phosphonate or a Phosphine Oxide Moiety.

Several multicomponent synthetic approaches were elaborated for plenty of novel nitrogen or oxygen heterocycles containing a phosphonate or a phosphine oxide moiety. All multicomponent reactions were optimized through a model reaction in respect of the heating mode, molar ratio of the starting materials, atmosphere, catalyst, temperature, reaction time and solvent applied, and then, the extended preparation of small libraries of structurally-related compounds was performed. Most of the reactions could be considered as "green syntheses", as they were carried out in the absence of any catalyst and/or solvent using microwave (MW) irradiation or even at ambient temperature. The scaling-up of a MW-assisted synthesis was also elaborated in a continuous flow MW system. Altogether more than 150 heterocyclic organophosphorus compounds were synthesized, among them several derivatives showed moderate or promising activity against the HL-60 cell line and Bacillus subtilis bacteria.

Study of the Three-Component Reactions of 2-Alkynylbenzaldehydes, Aniline, and Dialkyl Phosphites-The Significance of the Catalyst System.

New, practical approaches for the synthesis of α-amino (2-alkynylphenyl)-methylphosphonates and 1,2-dihydroisoquinolin-1-ylphosphonates were developed. By the propylphosphonic anhydride (T3P®)-mediated Kabachnik-Fields reaction of 2-alkynylbenzaldehydes, aniline, and dialkyl phosphites, α-amino (2-alkynylphenyl)-methylphosphonates were obtained selectively in high yields. The method developed is a simple operation and did not require a chromatographic separation since the products could be isolated from the reaction mixture by a simple extraction. At the same time, 2,3-disubstituted-1,2-dihydroisoquinolin-1-ylphosphonates could be prepared effectively from the same kinds of starting materials (2-alkynylbenzaldehydes, aniline, and dialkyl phosphites) at 60 °C in a short reaction time by changing the catalyst for CuCl. Therefore, it was proved that the catalyst system applied played a crucial role with respect to the reaction outcome.

Three-component synthesis, utilization and biological activity of phosphinoyl-functionalized isoindolinones.

A new method for the synthesis of 3-oxoisoindolin-1-ylphosphine oxides bearing same or different substituents on the phosphorus atom is described. The one-pot three-component reaction of 2-formylbenzoic acid, primary amines and achiral or P-stereogenic secondary phosphine oxides provided the target compounds under catalyst-free, mild conditions and for short reaction times. The deoxygenation of a 3-oxoisoindolin-1-ylphosphine oxide was also studied, and the phosphine obtained could be converted to a sulphide and to a platinum complex. The crystal structures of a selected phosphine oxide and the corresponding platinum species were investigated by X-ray diffraction analysis. The biological activity, such as in vitro cytotoxicity on different cell lines and antibacterial activity of the 3-oxoisoindolin-1-ylphosphine oxides was also investigated. Based on the IC50 values obtained, several derivatives showed moderate activity against the HL-60 cell line and two compounds containing 3,5-dimethylphenyl groups on the phosphorus atom showed promising activity against Bacillus subtilis bacteria.

PMDTA-catalyzed multicomponent synthesis and biological activity of 2-amino-4H-chromenes containing a phosphonate or phosphine oxide moiety.

A new approach for the preparation of (2-amino-3-cyano-4H-chromen-4-yl)phosphonate derivatives is described. The multicomponent reaction of salicylaldehydes, malononitrile and dialkyl phosphites catalyzed by pentamethyldiethylenetriamine (PMDTA) provided the bicyclic derivatives in high yields. The method developed did not require chromatographic separation, since the products could be recovered from the reaction mixture by simple filtration. Our approach made also possible condensation with secondary phosphine oxides, and this reaction has not been previously reported in the literature. The crystal structures of five derivatives were studied by single-crystal XRD analysis. The in vitro cytotoxicity on different cell lines and the antibacterial activity of the (2-amino-4H-chromen-4-yl)phosphonates synthesized were also explored. According to the IC50 values determined, several derivatives showed moderate or promising activity against mouse fibroblast (NIH/3T3) and human promyelocytic leukemia (HL-60) cells. Furthermore, three (2-amino-3-cyano-4H-chromen-4-yl)phosphine oxides were active against selected Gram-positive bacteria.

Study on the Microwave-Assisted Batch and Continuous Flow Synthesis of N-Alkyl-Isoindolin-1-One-3-Phosphonates by a Special Kabachnik-Fields Condensation.

A simple and efficient microwave (MW)-assisted method was elaborated for the catalyst-free synthesis of isoindolin-1-one-3-phosphonates by the three-component condensation of 2-formylbenzoic acid, aliphatic primary amines and various dialkyl phosphites. The batch and the continuous flow reactions were optimized in respect of the temperature, the reaction time and the molar ratio of the starting materials. To evaluate the potential of MW irradiation, comparative thermal experiments were also carried out. In order to obtain "real time" information about the condensation, the special Kabachnik-Fields reaction of 2-formylbenzoic acid, butylamine and diethyl phosphite was monitored by in situ FT-IR spectroscopy. The novel title compounds could be prepared in high yields at low temperature under a short reaction time. A suitable method could also be developed for the preparation of the isoindolin-1-one-3-phosphonates at a "few g" scale by using a continuous flow MW reactor.

Synthesis and In Vitro Cytotoxicity and Antibacterial Activity of Novel 1,2,3-Triazol-5-yl-phosphonates.

Novel 1,2,3-triazol-5-yl-phosphonates were prepared by the copper(I)-catalyzed domino reaction of phenylacetylene, organic azides and dialkyl phosphites. The process was optimized on the synthesis of the dibutyl (1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)phosphonate in respect of the catalyst, the base and the solvent, as well as of the reaction parameters (molar ratio of the starting materials, atmosphere, temperature and reaction time). The method elaborated could be applied to a range of organic azides and dialkyl phosphites, which confirmed the large scope and the functional group tolerance. The in vitro cytotoxicity on different cell lines and the antibacterial activity of the synthesized 1,2,3-triazol-5-yl-phosphonates was explored. According to the IC50 values determined, only modest antibacterial effect was detected, while some derivatives showed moderate activity against human promyelocytic leukemia HL-60 cells.

Synthesis of (1,2,3-triazol-4-yl)methyl Phosphinates and (1,2,3-Triazol-4-yl)methyl Phosphates by Copper-Catalyzed Azide-Alkyne Cycloaddition.

An efficient and practical method was developed for the synthesis of new (1,2,3triazol4yl)methyl phosphinates and (1,2,3-triazol-4-yl)methyl phosphates by the copper(I)catalyzed azide-alkyne cycloaddition (CuAAC) of organic azides and prop-2-ynyl phosphinate or prop-2-ynyl phosphate. The synthesis of (1benzyl-1H-1,2,3-triazol-4-yl)methyl diphenylphosphinate was optimized with respect to the reaction parameters, such as the temperature, reaction time, and catalyst loading. The approach was applied to a range of organic azides, which confirmed the wide scope and the substituent tolerance of the process. The method elaborated represents a novel approach for the synthesis of the target compounds.

Microwave-Assisted Kabachnik⁻Fields Reaction with Amino Alcohols as the Amine Component.

In this paper, the microwave (MW)-assisted catalyst-free and mostly solvent-free Kabachnik-Fields reaction of amino alcohols, paraformaldehyde, and various >P(O)H reagents (dialkyl phosphites, ethyl phenyl-H-phosphinate, and secondary phosphine oxides) is reported. The synthesis of N-2-hydroxyethyl-α-aminophosphonate derivatives was optimized in respect of the temperature, the reaction time, and the molar ratio of the starting materials. A few by-products were also identified. N,N-Bis(phosphinoylmethyl)amines containing a hydroxyethyl group were also prepared by the double Kabachnik-Fields reaction of ethanolamine with an excess of paraformaldehyde and secondary phosphine oxides. The crystal structure of a 2-hydroxyethyl-α-aminophosphine oxide and a bis(phosphinoylmethyl)ethanolamine was studied by X-ray analysis.

Microwave-assisted synthesis of N,N-bis(phosphinoylmethyl)amines and N,N,N-tris(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms.

A family of N,N-bis(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms was synthesized by the microwave-assisted and catalyst-free Kabachnik-Fields reaction of (aminomethyl)phosphine oxides with paraformaldehyde and diphenylphosphine oxide. The three-component condensation of N,N-bis(phosphinoylmethyl)amine, paraformaldehyde and a secondary phosphine oxide affording N,N,N-tris(phosphinoylmethyl)amine derivatives was also elaborated. This method is a novel approach for the synthesis of the target products.

Application of the Microwave Technique in Continuous Flow Processing of Organophosphorus Chemical Reactions.

The microwave (MW) technique is an efficient tool in the realization of organic reactions, as well as in the analytical field and in the food industry. The continuous flow approach is of special interest as a promising way to scale-up MW-assisted syntheses. Besides summarizing the batch precedents, this review focuses on the utilization of the MW technique in the continuous-flow realization of organophosphorus transformations. The advantages of the continuous flow technique against the batch accomplishment are also shown. A few materials chemistry-related applications are also mentioned.

Continuous Flow Alcoholysis of Dialkyl H-Phosphonates with Aliphatic Alcohols.

The continuous flow alcoholysis of dialkyl H-phosphonates by aliphatic alcohols in the absence of a catalyst was elaborated using a microwave (MW) reactor equipped with a flow cell. By the precise control of the reaction conditions, the synthesis could be fine-tuned towards dialkyl H-phosphonates with two different and with two identical alkyl groups. In contrast to the "traditional" batch alcoholysis, flow approaches required shorter reaction times, and the products became available at a larger scale.

Synthesis of platinum, palladium and rhodium complexes of α-aminophosphine ligands.

α-Aminophosphine-type ligands are of interest as building blocks of transition metal complexes. This review focuses on the utilization of α-aminophosphines as monodentate and bidentate ligands in platinum, palladium and rhodium complexes. Besides the linear derivatives, the applications of cyclic α-aminophosphines as ligands are also summarized. Various aspects, such as synthesis, structure and applications, as well as the catalytic activity of these complexes are discussed.

Access to Fluorazones by Intramolecular Dehydrative Cyclization of Aromatic Tertiary Amides: A Synthetic and Mechanistic Study.

An efficient synthesis has been developed for the preparation of 9H-pyrrolo[1,2-a]indol-9-ones (fluorazones) from readily available anthranilic acid derivatives via a one-pot amide- and pyrrole-formation step, followed by an intramolecular cyclodehydration. The cyclodehydration process is mediated by the activation of aromatic tertiary amides by triflic anhydride (Tf2O). Comparison of various benzo-substituents is shown to demonstrate the high functional group tolerance of this transformation. In addition, study of the reaction mechanism is also presented to unfold the exact role of the applied base additive. Herein, as a first example, we report our findings that Tf2O-mediated amide activation is obstructed by the easy protonation of amides by the formed triflic acid during the activation step. Additionally, it has been also proven that the base additive is not involved in the transformation of O-triflyliminium triflates into reactive species (e.g., nitrilium triflates) and is only responsible to neutralize the superacid to avoid the protonation of both the secondary or tertiary amides.

The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction.

A family of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides was synthesized by the microwave-assisted solvent-free addition of dialkyl phosphites and diphenylphosphine oxide, respectively, to imines formed from benzaldehyde derivatives and primary amines. After optimization, the reactivity was mapped, and the fine mechanism was evaluated by DFT calculations. Two α-aminophosphonates were subjected to an X-ray study revealing a racemic dimer formation made through a N-H···O=P intermolecular hydrogen bridges pair.

Microwave-assisted synthesis of (aminomethylene)bisphosphine oxides and (aminomethylene)bisphosphonates by a three-component condensation.

A practical method was elaborated for the synthesis of (aminomethylene)bisphosphine oxides comprising the catalyst- and solvent-free microwave-assisted three-component condensation of primary amines, triethyl orthoformate and two equivalents of diphenylphosphine oxide. The method is also suitable for the preparation of (aminomethylene)bisphosphonates using (MeO)2P(O)H/(MeO)3CH or (EtO)2P(O)H/(EtO)3CH reactant pairs and even secondary amines. Several intermediates referring to the reaction mechanism together with a few by-products could also be identified.

[Khat (Catha edulis): is it "coffee" or "cocaine"?]. / Khat (Catha edulis): "kávé" vagy "kokain"?

Regular consumption of khat's (Catha edulis) fresh leaves seriously affects the health, the social and economic life of the subject. Therefore, it is hazardous both to the individual and to the community. According to the latest reports, consumption of chat may exert some unknown and unreported gastrointestinal and hepatic effects. On the basis of studies performed by the authors, it seems that khat (cathinone) has no gastric or duodenal ulcerogenic effect. However, it does cause a significant enlargement of the hepatic mitochondria. In addition, a concern arose recently that the profit of illegal traffic of the plant may reach some illegal (terrorist) organisations. Therefore it seems that the so-called "khat-problem" needs further and more effective control.

The Kabachnik-Fields reaction: mechanism and synthetic use.

The Kabachnik-Fields (phospha-Mannich) reaction involving the condensation of primary or secondary amines, oxo compounds (aldehydes and ketones) and >P(O)H species, especially dialkyl phosphites, represents a good choice for the synthesis of α-aminophosphonates that are of significant importance due to their biological activity. In general, these three-component reactions may take place via an imine or an α-hydroxy-phosphonate intermediate. The monitoring of a few Kabachnik-Fields reactions by in situ Fourier transform IR spectroscopy has indicated the involvement of the imine intermediate that was also justified by theoretical calculations. The Kabachnik-Fields reaction was extended to >P(O)H species, comprising cyclic phosphites, acyclic and cyclic H-phosphinates, as well as secondary phosphine oxides. On the other hand, heterocyclic amines were also used to prepare new α-amino phosphonic, phosphinic and phosphine oxide derivatives. In most cases, the synthesis under solvent-free microwave (MW) conditions is the method of choice. It was proved that, in the cases studied by us, there was no need for the use of any catalyst. Moreover, it can be said that sophisticated and environmentally unfriendly catalysts suggested are completely unnecessary under MW conditions. Finally, the double Kabachnik-Fields reaction has made available bis(phosphonomethyl)amines, bis(phosphinoxidomethyl)amines and related species. The bis(phosphinoxidomethyl)amines serve as precursors for bisphosphines that furnish ring platinum complexes on reaction with dichlorodibenzonitriloplatinum.