Cycloaddition Of Azomethine Ylides Research Articles

Synthesis and cytotoxicity of novel dispiro derivatives of 5-arylidenoxazolones, potential inhibitors of p53—MDM2 protein-protein interaction

Regioselective synthesis of new dispiro indolinones combining both an indolinone and an oxazolone fragment in their structure comprised the 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from isatin and sarcosine, at 2-aryl-5-arylmethylidene-substituted 1,3-oxazol-5(4H)-ones. When ortho and para halogen atoms were present in the aromatic substituents of the starting oxazolones, complex mixtures containing large amounts of oxazoline ring opening products and their dispiro derivatives were formed. The cytotoxicity of compounds was tested by MTT on LNCaP, PC3, HCT116, MCF7, A549, HEK, and VA13 cell lines. The compound possessing the best cytotoxicity revealed the IC50 = 1.08±0.96 μM towards the p53- expressing LNCaP cells and lower activity (IC50 = 3.21±1.45 μM) towards the non-expressing p53 protein PC3 cells, however, it has proved inactive towards the HCT cells, both expressing (HCТ+/+) and non-expressing (HCT–/–) p53.

Azomethine Ylide Cycloaddition Approach toward Dendrobine: Synthesis of 5-Deoxymubironine C.

A concise route to the azatricyclo[6.2.1.04,11]undecane core of (-)-dendrobine and (-)-mubironine C is described wherein an unstabilized azomethine ylide cycloaddition provides the complete carbon framework of the natural products. The cyclization precursor is made in short order from ( R)-carvone through an unconventional high-pressure Ireland-Claisen reaction. Attempts to install a final hydroxyl group through an intramolecular lactonization strategy and the observation of an unexpected and highly complex enal-ene product are also reported.

Metal Complex-Controlled Regio-, Diastero- and Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides with Benzo[b]thiophene Sulfones.

The Cu(MeCN)4 PF6 /DTBM-Segphos complex catalyzed the highly diastereo- and enantioselective 1,3-dipolar cycloaddition of azomethine ylides with benzo[b]thiophene sulfones with the usual regiochemistry to give single isomers of the exo-cycloadducts in good yields. In contrast, the AgOAc/ThioClickFerrophos complex catalyzed the reaction with atypical regiochemistry to give the endo-cycloadducts as major products with excellent enantioselectivities. Thus, the choice of chiral metal complex enabled the regio- and stereoselective synthesis of chiral fused sulfolanes.

A Highly Enantioselective Copper/Phosphoramidite-Thioether-Catalyzed Diastereodivergent 1,3-Dipolar Cycloaddition of Azomethine Ylides and Nitroalkenes.

In contrast to the plethora of catalytic systems that enable access to any enantiomers of the chiral products by simply choosing between a pair of enantiomeric or pseudoenantiomeric chiral catalysts, few analogously effective protocols exist for the synthesis of compounds bearing multiple stereogenic centers with full control of the absolute and relative stereochemical configurations. Here, we report the application of our previously developed modular phosphoramidite-thioether ligands for the copper-catalyzed diastereodivergent asymmetric 1,3-dipolar cycloaddition of azomethine ylides and nitroalkenes. Our catalytic system enables wide substrate scope, great stereochemical control, and high reaction efficiency.

Catalytic asymmetric construction of spiropyrrolidines via 1,3-dipolar cycloaddition of azomethine ylides.

Spirocyclic pyrrolidines are structural motifs frequently found in a wide variety of natural products, pharmaceuticals and biologically significant compounds. In the past few years, catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides have shown to be one of the most straightforward methods for the stereoselective preparation of diverse biologically important spiropyrrolidine heterocycles in high yields with excellent enantioselectivities under mild reaction conditions. In this review, we will discuss the recent major developments in the catalytic enantioselective synthesis of chiral spiropyrrolidine derivatives since 2009.

The chemical functionalization of graphene nanoplatelets through solvent-free reaction.

Graphene nanoplatelets (GNPs) were functionalized through 1,3-dipolar cycloaddition of azomethine ylide using a solvent-free approach and under different reaction conditions. The yield and the functionality of the carboxyl-terminated pyrrolidine ring attached on the surface of GNPs could be affected by varying the reaction temperature as well as the reactant to GNP weight ratio. The functionalized GNPs were characterized extensively using a range of spectroscopic and microscopy techniques.

Facile access to regio- and stereoselective synthesis of highly functionalized spiro[indoline-3,2'-pyrrolidines] incorporating a pyrene moiety: experimental, photophysical and theoretical approach.

The regio- and stereochemical polar [3 + 2] cycloaddition of azomethine ylides, which were generated in situ by the reaction of isatin and sarcosine or benzylamine, with (E)-3-aryl-1-(pyren-1-yl)prop-2-en-1-ones as dipolarophiles, was studied using experimental and theoretical methods. The chemical structures and relative configurations of all products have been fully established by 1D and 2D homonuclear and heteronuclear correlation NMR spectrometry. The effects of the electronic and steric factors of the reactions were discussed. The photophysical properties of the synthesized spiro[indoline-3,2′-pyrrolidin]-2-ones and 5′-phenyl-spiro[indoline-3,2′-pyrrolidin]-2-ones were studied. The mechanism of the reactions was investigated using global and local reactivity indices and frontier molecular orbital (FMO) analysis at the B3LYP/6-31G level of theory. The relationship between the electrophilicity index ω of the dipolarophiles and the Hammett constant σp has been studied. The theoretical scale of reactivity correctly explains the electrophilic activation/deactivation effects promoted by electron-withdrawing and electron-releasing substituents in the para-position of the dipolarophiles.

Sequential (3 + 2) cycloaddition and (5 + n) annulation for modular synthesis of dihydrobenzoxazines, tetrahydrobenzoxazepines and tetrahydrobenzoxazocines

A method for the (3 + 2) cycloaddition of azomethine ylides followed by a (5 + n) double SN2 substitution is introduced for the modular synthesis of dihydrobenzoxazines, tetrahydrobenzoxazepines and tetrahydrobenzoxazocines.

Organocatalytic [3 + 2] cycloaddition of oxindole-based azomethine ylides with 3-nitrochromenes: a facile approach to enantioenriched polycyclic spirooxindole-chromane adducts.

An organocatalytic asymmetric [3 + 2] cycloaddition of oxindole-based azomethine ylides with 3-nitro-2H-chromenes has been developed. This reaction provides a facile approach to densely functionalized polycyclic spirooxindole-chromane adducts featuring four contiguous stereogenic centers, including two tetrasubstituted carbon centers. The products were obtained in high yields with good to excellent stereoselectivities (up to 99% yields, 96% ee and >20 : 1 dr). In addition, the spiro[pyrrolidine-2,3'-oxindole]-chromane adducts could be readily derivatized via simple oxidation and reduction treatment. A dual activation working model to illuminate the stereochemical course of the [3 + 2] cycloaddition event is proposed.

Facile one-pot synthesis of spirooxindole-pyrrolidine derivatives and their antimicrobial and acetylcholinesterase inhibitory activities

A library of novel spirooxindole-pyrrolidine derivatives were facilely synthesized via 1,3-dipolar cycloaddition of azomethine ylide generated from sarcosine and paraformaldehyde with various 3-methyleneoxindolines.

Unexpected regiochemistry in [3+2] cycloaddition reaction of azomethine ylides of indenoquinoxalinone series to arylidene malononitriles

1,3-Dipolar cycloaddition of azomethine ylides generated in situ from proline and indenoquinoxalinones occurred at the double bond of arylidene malononitriles upon heating in isopropanol, leading to the respective spirocyclic adducts with cis orientation of the aryl substituent and the quinoxaline moiety. The regioselectivity of this process depended on the electron donor-acceptor properties of substituents in the aromatic ring of the dipolarophile molecule. Analogous reaction involving azomethine ylide derived from sarcosine produced adducts with a trans relationship of the most sterically demanding substituents.

Diastereoselective synthesis of dispirooxindoles via [3+2] cycloaddition of azomethine ylides to 3-phenacylideneoxindoles and evaluation of their cytotoxicity.

The three-component reaction of 1,2,3,4-tetrahydroisoquinoline, isatins and 3-phenacylideneoxindoles in refluxing ethanol afforded dispiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline-3′,3′-indolines] (4a–4x) in good yields via 1,3-dipolar cycloaddition of in situ generated azomethine ylide with the exocyclic double bond of 3-phenacylideneoxindoles. 1H NMR spectra and single crystal structures indicated the reaction has high regioselectivity and diastereoselectivity. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation against mouse breast cancer cells 4T1 and human liver cancer cells HepG2 by MTT assay. The results demonstrated that some of the compounds showed cytotoxicities to cell lines of 4T1 and HepG2, and indicated that novel spirooxindoles may become potential lead compounds for further biological screenings of their medicinal applications.

Synthesis of diversely substituted bis-pyrrolizidino/ thiopyrrolizidino oxindolo/acenaphthyleno curcuminoids via sequential azomethine ylide cycloaddition.

Curcumin has been transformed to several diversely substituted bis-pyrrolizidino/thiopyrrolizidino oxindolo/acenaphthyleno curcuminoids via a sequential azomethine ylide cycloaddition reaction using isatins/acenaphthoquinone and proline/thioproline as the reagents. The products were separated via extensive chromatography and characterized by 1D/2D NMR and HRMS analysis.

Lewis Acid-Catalyzed Intramolecular [3+2] Cross-Cycloaddition of Aziridine 2,2-Diesters with Conjugated Dienes for Construction of Aza-[n.2.1] Skeletons.

A novel Lewis acid-catalyzed [3+2] intramolecular cross-cycloaddition (IMCC) between aziridine 2,2-diesters and conjugated dienes has been developed. This is the first regiospecific IMCC of intramolecular 1,3-dipolar cycloadditions of azomethine ylides with carbon=carbon double bonds, and supplies a general and efficient strategy for construction of structurally complex and diverse aza-[n.2.1] skeletons. The [3+2]IMCC could be carried out under mild conditions and in gram scale. More importantly, 3-alkyl-substituted aziridines were also successful. The excellent structural diversity, the facile operation and the versatile post-modifications will support the applications of the [3+2]IMCC in natural products synthesis and drugs discovery.

Synthesis of Pyrrole‐Fused Corannulenes: 1,3‐Dipolar Cycloaddition of Azomethine Ylides to Corannulene

AbstractIn the long history of corannulene chemistry, the 1,3‐dipolar cycloaddition to corannulene is unprecedented. Reported herein is the 1,3‐dipolar cycloaddition of a polycyclic aromatic azomethine ylide to corannulene, a reaction which occurs exclusively at the rim bond of corannulene, from the convex side in an exo fashion. The cycloadducts were successfully converted, by successive oxidative dehydrogenation, into pyrrole‐fused corannulenes, which exhibited pronounced solvatofluorochromism.

Generation of New 1,3‐Dipolar Azomethine Ylide via Reaction of Ethyl Glycinate with Dialkyl But‐2‐ynedioate and Tandem 1,3‐Dipolar Cycloaddition Reaction

AbstractThe triethylamine promoted reaction of ethyl glycinate hydrochloride with but‐2‐ynedioate in ethanol at room temperature afforded a new kind of 1,3‐dipolar azomethine ylide. The sequential [3+2] cycloaddition of the new azomethine ylide with 2‐arylidene‐1,3‐indanediones or 2‐arylideneoxindoline‐2‐ones successfully resulted in functionalized spiro[indene‐2, 3′‐pyrrolidines] or spiro[indoline‐3, 3′‐pyrrolidine] derivatives in moderate to good yields and with high diastereoselectivity. The relative configuration of the spiro compounds were clearly elucidated by analysis of NMR spectra and determination of single crystal structures.

Synthesis of Pyrrole-Fused Corannulenes: 1,3-Dipolar Cycloaddition of Azomethine Ylides to Corannulene.

In the long history of corannulene chemistry, the 1,3-dipolar cycloaddition to corannulene is unprecedented. Reported herein is the 1,3-dipolar cycloaddition of a polycyclic aromatic azomethine ylide to corannulene, a reaction which occurs exclusively at the rim bond of corannulene, from the convex side in an exo fashion. The cycloadducts were successfully converted, by successive oxidative dehydrogenation, into pyrrole-fused corannulenes, which exhibited pronounced solvatofluorochromism.

Cycloaddition reactions in the synthesis of isoindolines (microreview)

A summary of the most recent approaches toward isoindoline derivatives via cycloaddition reaction is discussed. The microreview covers the latest selected examples (2010–2017) on the synthesis of isoindolines that are divided into several distinct categories depending on the structure of the starting compound – intramolecular [3+2] cycloaddition of azides, [3+2] cycloaddition of azomethine ylides, [2+2+2] cycloadditions, and others.

Novel asymmetric synthesis of spiroindene-1,3dione-pyrrolidines via CoII/amino acids complex catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides and 2-arylidenindane-1,3-diones

Cobalt II(l-phenylalanine)2 was used effectively for the first time in a catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with 2-arylidenindane-1,3-diones, affording a series of novel spiropyrrolidine derivatives with good to high yields (up to 90%), excellent diastereoselectivities (only exo’-3 were detected), and good enantioselectivities (up to 87% ee).

Covalent Functionalization of FeCo/Graphitic Shell Nanocrystals via 1,3‐Dipolar Cycloaddition

AbstractCovalently functionalized water‐soluble FeCo/graphitic shell nanocrystals (f−FeCo/GC NCs) were synthesized via 1,3‐dipolar cycloaddition of azomethine ylides generated in situ from sarcosine and glucose. The FeCo core has superparamagnetic properties at room temperature, and the graphitic shell exhibits near‐infrared optical absorbance. Acetylation of the hydroxyl groups on the f−FeCo/GC NCs gives doubly functionalized FeCo/GC (ff−FeCo/GC) NCs that are soluble only in organic solvents such as ethyl acetate. The f−FeCo/GC NCs were shown to be excellent T1 or T2 MRI contrast agents. Especially, due to the hydrophilic and compact surface functionalization, f−FeCo/GC NCs exhibit a doubled r1 relaxivity and half r2/r1 ratio compared to those of the non‐covalently PL‐PEG‐functionalized FeCo/GC NCs. This work shows not only the first synthesis of covalently functionalized highly water‐soluble metal NCs coated with a single‐layered graphitic shell, but also for the first time the MR enhancing properties of the covalently functionalized magnetic NCs.