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

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted -acylaziridines based on a one-pot ZnCl-catalyzed Joullié-Ugi three-component reaction of phosphorylated 2-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of -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.

3D Bioprinted Hydroxyapatite or Graphene Oxide Containing Nanocellulose-Based Scaffolds for Bone Regeneration.

Bone tissue is usually damaged after big traumas, tumors, and increasing aging-related diseases such as osteoporosis and osteoarthritis. Current treatments are based on implanting grafts, which are shown to have several inconveniences. In this regard, tissue engineering through the 3D bioprinting technique has arisen to manufacture structures that would be a feasible therapeutic option for bone regenerative medicine.

Modulation of Conductivity of Alginate Hydrogels Containing Reduced Graphene Oxide through the Addition of Proteins.

Modifying hydrogels in order to enhance their conductivity is an exciting field with applications in cardio and neuro-regenerative medicine. Therefore, we have designed hybrid alginate hydrogels containing uncoated and protein-coated reduced graphene oxide (rGO). We specifically studied the adsorption of three different proteins, BSA, elastin, and collagen, and the outcomes when these protein-coated rGO nanocomposites are embedded within the hydrogels.

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

Several phosphorus-substituted -acylated cyanoaziridines and -carbamoylated cyanoziridines were prepared in good to high yields. -Acylated cyanoaziridines were used, after ring expansion, in an efficient synthesis of oxazoline derivative and in a completely regio-controlled reaction in the presence of NaI. Conversely, -carbamoyl cyanoaziridines reacted with NaI to obtain a regioisomeric mixture of 2-aminocyanooxazolines .

Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of - and -Nucleophiles to 2-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 2-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.

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.

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.

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.

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.

Reaction of 2H-Azirine-Phosphine Oxides and -Phosphonates with Enolates Derived from β-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.

Fluoroalkylated α,β-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,β-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.

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.

Reaction of 2H-azirine phosphine oxide and -phosphonates with nucleophiles. Stereoselective Synthesis of functionalized aziridines and alpha- and beta-aminophosphorus derivatives.

[reaction: see text] A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 3, and -phosphine oxide 5 by diastereoselective addition of Grignard reagents to 2H-azirine phosphonate 1 and -phosphine oxide 4 is reported. Similarly, the addition of heterocyclic amines and benzenethiol to aziridines 1 and 4 yielded functionalized aziridines 10, 11, and 18. These aziridines are used as intermediates for the regioselective synthesis of beta-aminophosphine oxides 6 and beta-aminophosphonates 7, as well as alpha- aminophosphonates 8.

Preparation of fluoroalkyl imines, amines, enamines, ketones, alpha-amino carbonyls, and alpha-amino acids from primary enamine phosphonates.

A simple method for preparation of fluoroalkyl beta-enaminophosphonates 1 from alkylphosphonates 2 and perfluoroalkyl nitriles 3 is reported. Olefination reaction of functionalized phosphates 1 with aldehydes gives alpha,beta-unsaturated imines 5. Acid hydrolysis of these fluoroalkyl derivatives 5 affords alpha,beta-unsaturated ketones 6, while their selective reduction with hydrides leads to the formation of allylamines 7, enamines 8, and saturated ketones 9 or amines 10.

Reaction of acetylenic esters and N-functionalized phosphazenes. 1,2-versus 1,4-addition of N-vinylic phosphazenes.

Reaction of phosphazenes derived from aminophosphonates with acetylenic esters leads to conjugated phosphorus ylides. The formation of these stabilized ylides is explained through a [2 + 2] cycloaddition reaction of the P = N linkage of the phosphazene (1,2-addition) and the triple bond of the acetylenic ester followed by ring opening of the azaphosphete intermediate. However, in the case of N-vinylic phosphazenes, the phosphazenes derived from triphenyl- and trimethyl-phosphine react as enamines (1,4-addition) with diacetylenic esters, whereas in phosphazenes derived from trimethylphosphine a 1,2-addition of ethyl propiolate to the P = N linkage of the phosphazene is produced.

Asymmetric synthesis of 2H-azirines derived from phosphine oxides using solid-supported amines. Ring opening of azirines with carboxylic acids.

A simple and efficient asymmetric synthesis of 2H-azirine-2-phosphine oxides 3 is described. The key step is a solid-phase bound achiral or chiral amine-mediated Neber reaction of beta-ketoxime tosylates derived from phosphine oxides 1. Reaction of 2H-azirines 3 and 11 with carboxylic acids 4 gives phosphorylated ketamides 5 and 12.

Synthesis of pyrazine-phosphonates and -phosphine oxides from 2H-azirines or oximes.

[reaction: see text] Tetrasubstituted pyrazines containing two phosphonate groups 2 in positions 2 and 5 and trisubstituted pyrazines containing a phosphonate 5 or a phosphine oxide group 7 in position 2 are obtained by thermal treatment of 2H-azirine-2-phosphonates 1 and -phosphine oxides 6. These pyrazines can also be prepared from beta-ketoxime tosylates 9 and 10 or from oxime derived from phosphine oxide 11.

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.