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.

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.

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.

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.

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.

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.

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.

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.

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.