Diethyl(benzamido(diisopropoxyphosphoryl)methyl) phosphonate

Bisphosphonates are widely used in medicine and related areas, mainly for the treatment of bone diseases, such as osteoporosis. However, their synthesis is usually performed under harsh reaction conditions. In order to overcome this limitation, the present work illustrates a new synthetic route to access the title α-aminobisphosphonate in milder reaction conditions using α-phosphorylated imines as key intermediates.Financial support by Ministerio de Economía, Industria y Competividad (RTI2018-101818-B-I00) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. A.L.-F. thanks the Basque Country Government for a predoctoral grant

Stereoselective inverse conjugate addition of nitrogen and carbon nucleophiles to allenyl phosphine oxide. Synthesis of α,β-unsaturated phosphine oxides

Issue in Honor of Prof. Paweł Kafarski[EN] The reactivity of new three carbon synthon, generated in situ from the reaction of electrondeficient allenes with an appropriate phosphine as the catalyst, toward pronucleophilic reagents is described. Triphenylphosphine-catalyzed reaction of allenes derived from phosphine oxides with nitrogen- or carbonucleophiles gave the γ-addition product as a mixture of cis and trans isomers

Phosphorus substituted hydroxylamine and hydroxamic acid derivatives: synthesis and reactivity

Dedicated to Prof. Julio Alvarez-Builla on the occasion of his 65th anniversary.[EN] This review summarizes several reports concerning the synthesis and synthetic applications of hydroxylamines derived from phosphines, phosphine oxides and phosphonates, and phosphorus substituted hydroxamic acid derivatives. The first section outlines the synthesis and reactivity of phosphorus O-substituted and N-substituted hydroxylamines as well as several transformations of phosphorus substituted hydroxylamines including: rearrangement, hydrolysis, reduction and oxidation reactions. The second part of the review covers the synthesis and reactivity of phosphorus O-, N-, and C-substituted hydroxamic acid derivatives

A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives

Bronsted acids catalyze a multicomponent reaction of benzaldehyde with amines and diethyl acetylenedicarboxylate to afford highly functionalized gamma-lactam derivatives. The reaction consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.Financial support was provided by the Ministerio de Ciencia, Innovacion, y Universidades (RTI2018-101818-B-I00, MCIU/AEI/FEDER, UE), and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X. del Corte thanks Gobierno Vasco for a predoctoral grant

Sc(OTf)(3)-Mediated [4+2] Annulations of N-Carbonyl Aryldiazenes with Cyclopentadiene to Construct Cinnoline Derivatives: Azo-Povarov Reaction

We disclose the first accomplishment of the azo-Povarov reaction involving Sc(OTf)3-catalyzed [4 + 2] annulations of N-carbonyl aryldiazenes with cyclopentadiene in chloroform, in which N-carbonyl aryldiazenes act as 4π-electron donors. Hence, this protocol offers a rapid access to an array of cinnoline derivatives in moderate to good yields for substrates over a wide scope. The synthetic potential of the protocol was achieved by the gram-scale reaction and further derivatization of the obtained polycyclic product.Financial support by the Ministerio de Ciencia, Innovacion y Universidades (MCIU), Agencia Estatal de Investigacion (AEI) y Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-101818-B-I00, UE), and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.J.-A. thanks the Basque Country Government for the granted predoctoral fellowship. The authors thank technical and human support provided by SGIker (UPV/EHU/ERDF, EU)

Synthesis of Heterocyclic Fused [1,5]naphthyridines by Intramolecular HDA Reactions

Povarov reaction [1] can be considered as an example of HDA reactions and represents an excellent method for the preparation of nitrogen-containing heterocyclic compounds [2]. When aldimines, derived from aromatic amines and unsaturated functionalized aldehydes, are treated with a Lewis acid, the Povarov reaction takes place intramolecularly [3]. In this work, the synthesis of new families of heterocyclic fused [1,5]naphthyridines is reported. In this way, via an efficient and straightforward intramolecular Povarov reaction catalyzed by boron trifluoride etherate, tetrahydro-6H-chromeno[4,3-b][1,5]naphthyridines and tetrahydro-6Hquinolino[ 4,3-b][1,5]naphthyridines are obtained. Dehydrogenation of tetrahydroderivatives with DDQ gives compounds 6H-chromeno[4,3-b][1,5]naphthyridine and 6H-quinolino[4,3-b][1,5]naphthyridine. This methodology allows access to novel compounds with biological activity. Based on the success of camptothecin (CPT) and its derivatives as inhibitors of Topoisomerase I (TopI) [4], as well as our results obtained with naphthyridine derivatives [5], we report here that these novel heterocyclic compounds are possible candidates, some of them showing excellent activity as TopI inhibitors. The cytotoxic effect on several cancer and noncancer cell lines was also screened

Synthesis of Tetrasubstituted Phosphorus Analogs of Aspartic Acid as Antiproliferative Agents

An efficient general method for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid bearing tetrasubstituted carbons is reported through an aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates, in an umpolung process. In addition, the α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma). In view of the possibilities in the diversity of the substituents that offer the synthetic methodology, an extensive profile structure–activity is presented, measuring IC50 values up to 0.34 µM in the A549 and 9.8 µM in SKOV3 cell lines.Financial support by Ministerio de Economía, Industria y Competividad (PID2021-122558OB-I00) and Gobierno Vasco (GV-IT1701-22) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

5-Ethoxy-1-(4-methoxyphenyl)-5-methyl-3-phenylimidazolidine-2,4-dione

The title compound is a hydantoin derivative that has been synthesized through a three-component reaction of ethyl pyruvate, p-anisidine and phenyl isocyanate. This paper provides a comprehensive spectral dataset for the title compound, including 1H and 13C{1H} NMR, IR, HRMS, and X-ray crystallography analyses. A tentative mechanism comprising two complementary pathways is provided based on additional experiments with the preformed intermediates.Financial support by Ministerio de Economía, Industria y Competividad (MINECO, CTQ-2015-67871R) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

An Ugi three-component reaction using preformed α-phosphorated N-tosyl ketimines with different isocyanides in the presence of a carboxylic acid affords tetrasubstituted α-aminophosphonates. Due to the high steric hindrance, the expected acylated amines undergo a spontaneous elimination of the acyl group. The reaction is applicable to α-aryl ketimines bearing a number of substituents and several isocyanides. In addition, the densely substituted α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell line A549 (carcinomic human alveolar basal epithelial cell).Financial support by Ministerio de Economía, Industria y Competividad (MINECO, CTQ-2015-67871R) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

The Intramolecular Povarov Tool in the Construction of Fused Nitrogen-Containing Heterocycles

Nitrogen heterocycles are part of the structure of natural products and agents with important biological activity, such as antiviral, antibiotic, and antitumor drugs. For this reason, heterocyclic compounds are one of today’s most desirable synthetic targets and the Povarov reaction is a powerful synthetic tool for the construction of highly functionalized heterocyclic systems. This process involves an aromatic amine, a carbonyl compound, and an olefin or acetylene to give rise to the formation of a nitrogen-containing heterocycle. This review illustrates advances in the synthetic aspects of the intramolecular Povarov reaction for the construction of intricate nitrogen-containing polyheterocyclic compounds. This original review presents research done in this field, with references to important works by internationally relevant research groups on this current topic, covering the literature from 1992 to 2022. The intramolecular Povarov reactions are described here according to the key processes involved, using different combinations of aromatic or heteroaromatic amines, and aliphatic, aromatic, or heteroaromatic aldehydes. Some catalytic reactions promoted by transition metals are detailed, as well as the oxidative Povarov reaction and some asymmetric intramolecular Povarov processes.Financial support from the Ministerio de Ciencia, Innovación y Universidades (MCIU) (PID2021-122558OB-I00, UE), by Gobierno Vasco, Universidad del País Vasco (GV, IT1701- 22; UPV) and by Fundación Vital (VITAL21/01) is gratefully acknowledged. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Natur