Diastereoselective ZnCl2-Mediated Joullié-Ugi Three-Component Reaction for the Preparation of Phosphorylated N-Acylaziridines from 2H-Azirines.

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted N-acylaziridines based on a one-pot ZnCl2-catalyzed Joullié-Ugi three-component reaction of phosphorylated 2H-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of N-acylaziridines in moderate-to-good yields and up to 98:2 dr for substrates over a wide scope. The relevance of this synthetic methodology was achieved via a gram-scale reaction and the further derivatization of the nitrogen-containing three-membered heterocycle. The diastereo- and regioselective ring expansion of the obtained N-acylaziridines to oxazole derivatives was accomplished in the presence of BF3·OEt2 as an efficient Lewid acid catalyst.

Synthesis and Antiproliferative Activity of Phosphorus Substituted 4-Cyanooxazolines, 2-Aminocyanooxazolines, 2-Iminocyanooxazolidines and 2-Aminocyanothiazolines by Rearrangement of Cyanoaziridines.

Several phosphorus-substituted N-acylated cyanoaziridines 2 and N-carbamoylated cyanoziridines 5 were prepared in good to high yields. N-Acylated cyanoaziridines 2 were used, after ring expansion, in an efficient synthesis of oxazoline derivative 3a and in a completely regio-controlled reaction in the presence of NaI. Conversely, N-carbamoyl cyanoaziridines 5 reacted with NaI to obtain a regioisomeric mixture of 2-aminocyanooxazolines 7. Mild acidic conditions can be used for the isomerization of N-thiocarbamoyl cyanoaziridine 6a into a 2-aminocyanothiazoline derivative 8a by using BF3·OEt2 as a Lewis acid. Likewise, a one pot reaction of NH-cyanoaziridines 1 with isocyanates obtained 2-iminocyanooxazolidines 9 regioselectively. This synthetic methodology involves the addition of isocyanates to starting cyanoaziridines to obtain N-carbamoyl cyanoaziridines 5, which after the ring opening, reacts with a second equivalent of isocyanate to give the final 2-imino cyanooxazolidines 9. In addition, the cytotoxic effect on the cell lines derived from human lung adenocarcinoma (A549) was also screened. 2-Iminooxazolidines 9 exhibited moderate activity against the A549 cell line in vitro. Furthermore, a selectivity towards cancer cells (A549) over non-malignant cells (MCR-5) was detected.

Trabajando la relación Universidad-sociedad. Abordaje multidisciplinar y difusión social / Working the University-Society relationship. Multidisciplinary approach and social diffusion

INTRODUCCIÓN: La transferencia del conocimiento a la sociedad es una de las funciones importantes de la Universidad, lo que implica el uso de un lenguaje y unos medios adecuados hacia los diferentes colectivos de la sociedad, atendiendo a grupos de edad y situaciones socioeconómicas diversas. MATERIALES Y MÉTODOS: A través de las competencias transversales de cada grado, competencias genéricas que se relacionan con la puesta en práctica de una forma integrada de aptitudes, conocimientos y valores adquiridos, se ha realizado este proyecto de innovación docente con alumnado de la Universidad del País Vasco/Euskal Herriko Unibertsitatea. En él se han trabajado las habilidades del alumnado en el uso de diferentes registros de comunicación oral y escritura según la audiencia hacia la que se dirigen. Este trabajo se ha realizado dentro de un equipo multidisciplinar, de forma que el alumnado ha podido conocer y afrontar problemas de salud que requieren una actuación conjunta con otros profesionales del ámbito sanitario y científico. RESULTADOS Y CONCLUSIÓN: Esta interacción entre alumnado de diferentes grados ha permitido su enriquecimiento, proporcionándoles una visión más amplia de lo que pueden aportar los diferentes profesionales frente al mismo problema o reto. Desde este proyecto se ha planteado, a través de metodologías activas, favorecer la interacción entre los futuros profesionales de diferentes disciplinas y concienciar de la importancia de la transmisión de conocimiento a la sociedad, creando redes que contribuyan a la innovación y transferencia

INTRODUCTION: The transfer of knowledge to society is one of the important functions of the university, which implies the use of an appropriate language and means towards the different groups of society, attending to age groups and diverse socio-economic situations. MATERIALS AND METHODS: Through the transversal competences of each Degree, generic competences that are related to the implementation of an integrated form of acquired skills, knowledge and values, this teaching innovation project has been carried out with students from the University of The Basque Country (UPV / EHU). Thus, the student's abilities in the use of different oral and written communication registers according to the target audience have been studied. This work has been carried out within a multidisciplinary team, in such a way that the student has been able to know and face health problems that require joint action with other professionals in the health and scientific field. RESULTS AND CONCLUSION: This interaction among students of different degrees has allowed their enrichment, providing them with a broader vision of what different professionals can contribute to the same problem or challenge. From this project, it has been proposed, through active methodologies, to promote interaction between future professionals from different disciplines, and to raise awareness of the importance of the transmission of knowledge to society, creating networks that contribute to innovation and transfer

Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells.

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C-N double bond of 2H-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N-C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2H-azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of O- or S-nucleophiles to the starting 2H-azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested.

First synthesis of merged hybrids phosphorylated azirino[2,1-b]benzo[e][1,3]oxazine derivatives as anticancer agents.

This work describes a straightforward diastereoselective synthetic access to azirino[2,1-b]benzo[e][1,3]oxazines containing phosphorus substituents such as phosphonate or phosphine oxide, by means of nucleophilic addition of functionalized phenols to the C-N double bond of 2H-azirine derivatives. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. Some azirino[2,1-b]benzo[e][1,3]oxazines 4 and 6 exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been detected.

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams.

Benzo-fused γ-lactam rings such as isoindolin-2-ones and 2-oxindoles are part of the structure of many pharmaceutically active molecules. They can be often synthesized by means of multicomponent approaches and recent contributions in this field are summarized in this review. Clear advantages of these methods include the efficiency in saving raw materials and working time. However, there is still a need of new catalytic systems to allow the enantioselective preparation of these heterocycles by multicomponent reactions.

Synthesis and biological evaluation of cyanoaziridine phosphine oxides and phosphonates with antiproliferative activity.

This work reports an efficient diastereoselective synthetic methodology for the preparation of phosphorus substituted cyanoaziridines through the nucleophilic addition of TMSCN, as cyanide source, to the C-N double bond of 2H-azirine derivatives. The aziridine ring, in these novel cyanoaziridines, can be activated by simple N-tosylation or N-acylation. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. N-H and N-Substituted cyanoaziridines showed excellent activity against the A549 cell line in vitro. Moreover, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been observed.

Reaction of phosphinylated nitrosoalkenes with electron-rich heterocycles. Electrophilic aromatic substitution vs. cycloaddition.

The behavior of phosphinyl nitrosoalkenes with indole, pyrrole and 2,5-dimethylpyrrole is described. The reaction of nitrosoalkenes with indole leads to the formation of 3-substituted indoles. While a concerted asynchronous [4 + 2] cycloaddition process may explain the formation of 3-substituted indole when a methyl group is present at the 3-position of nitrosoalkene, the presence of a 3-methoxycarbonyl group at the same position of nitrosoalkene increases its electrophilic character, and both mechanisms, an electrophilic aromatic substitution and a [4 + 2] cycloaddition process, are predicted to be competitive, although thermodynamically the cycloaddition is favoured. Phosphinyl nitrosoalkenes react with pyrrole leading to the corresponding 2-substituted pyrroles, while the treatment of 2,5-dimethylpyrrole with these nitrosoalkenes gives rise to the formation of bicyclic 1,2-oxazines. The mechanism of the reaction of phosphinyl nitrosoalkenes with pyrrole and 2,5-dimethylppyrrole may be explained by an initial hetero-Diels-Alder cycloaddition in both cases, but only subsequent rearomatization in the case of pyrrole. Theoretical studies show very good agreement with the experimental findings and the proposed mechanisms.

Reaction of 2H-Azirine-Phosphine Oxides and -Phosphonates with Enolates Derived from ß-Keto Esters.

Cyclopenta[b]-pyrrole-2-phosphine oxides 4a and -phosphonates 4b,c are generated by the addition of cyclic enolates derived from ethyl 2-oxo-cyclopentanecarboxylate 2 to phosphorated 2H-azirines 1. However, the addition of enolate derived from acyclic 2-oxo-butanoate 10 to 2H-azirine phosphine oxide 1 led to vinylogous N-acyl-α-aminoalkyl phosphine oxides 12, involving the carbonyl group and the Cα of the keto ester 10. Ring closure of vinylogous derivative 12 in the presence of base afforded pyrrole-2-phosphine oxide 11. The addition of enolates derived from indenone-carboxylate 15 to 2H-azirines 1 led to the formation of functionalized N-substituted 1H-benzo[d]azepine derivatives 17.

Fluoroalkylated α,ß-unsaturated imines as synthons for the preparation of fluorinated triazinane-2,4-diones and dihydropyrimidin-2(1H)-ones.

A regioselective addition of isocyanates to fluoroalkylated α,ß-unsaturated imines 1 is described. Fluoroalkyl-substituted triazinane-2,4-diones 4 are obtained by the reaction of phenyl isocyanate with fluorinated imines 1, while fluorinated dihydropyridin-2(1H)-ones 7 are prepared when tosyl isocyanate is used. Tetrahydro-pyridin-2(1H)-one 10 is obtained by catalytic reduction of dihydropyridin-2(1H)-one 7. Computational studies are performed to explain the different behaviors of both isocyanates and the mechanisms of the processes.

Selective synthesis of substituted pyrrole-2-phosphine oxides and -phosphonates from 2H-azirines and enolates from acetyl acetates and malonates.

A simple and efficient selective synthesis of 1H-pyrrole-2-phosphine oxides 3 and -phosphonates 7 by addition of enolates derived from acetyl acetates to 2H-azirinylphosphine oxide 1 and -phosphonate 6 is reported. Nucleophilic addition of enolates derived from diethyl malonate to 2H-azirines 1 and 6 led to the formation of functionalized 2-hydroxy-1H-pyrrole-5-phosphine oxide 9 and -phosphonate 10, while vinylogous α-aminoalkylphosphine oxides 14 and -phosphonate 15 may be obtained from azirines and the enolate derived from diethyl 2-phenylmalonate. Ring closure of vinylogous derivatives 14 and 15 in the presence of base led to the formation of 1,5-dihydro-3-pyrrolin-2-ones containing a phosphine oxide 17 or a phosphonate group 18.

Synthesis of fluoroalkylated beta-aminophosphonates and pyridines from primary beta-enaminophosphonates.

A simple and efficient stereoselective synthesis of fluorine containing beta-aminophosphonates by reduction of beta-enaminophosphonates is described. Reduction with sodium cyanborohydride in the presence of zinc chloride and the catalytic hydrogenation of beta-enaminophosphonates gives beta-aminophosphonates. beta-Enaminophosphonates are also used as intermediates for the regioselective synthesis of fluoroalkyl-substituted pyridines.

Regioselective synthesis of fluoroalkylated beta-aminophosphorus derivatives and aziridines from phosphorylated oximes and nucleophilic reagents.

A simple and efficient stereoselective synthesis of fluoroalkyl substituted aziridine-2-phosphine oxides and -phosphonates by diastereoselective addition of methoxide, imidazole, benzenethiol, and Grignard reagents to functionalized ketoxime-phosphine oxides and -phosphonates is described. Aziridines are used as intermediates for the regioselective synthesis of fluorine containing beta-amino phosphine oxides and beta-amino phosphonates. Amino phosphorus derivatives can also be obtained from ketoximes derived from phosphine oxides and phosphonates with sodium borohydride.

Fluoroalkyl alpha,beta-unsaturated imines. Valuable synthetic intermediates from primary fluorinated enamine phosphonates.

[reaction: see text] A simple method for the preparation of fluoroalkyl allylamines or alpha,beta-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated beta-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.