Cycloaddition Reaction Of Azomethine Ylides Research Articles

Unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with benzylidene thiazolidinediones: synthesis of pharmacologically active spiroindoline oxazepine derivatives and theoretical study.

An unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with 5-benzylidenethiazolidine-2,4-diones has been successfully developed for the synthesis of the novel pharmacologically active 4',5'-dihydro-3'H-spiro[indoline-3,2'-[1, 3] oxazepin]-2-one derivatives in basic condition. Easy purification, high yield, short experimental time and operational simplicity are specific advantages of this protocol. Furthermore, all the synthesized compounds have been evaluated for antioxidant and antibacterial activities. According to the results, most of the synthesized compounds exhibited DPPH radical scavenging activity and nine of them showed antibacterial properties. The reaction mechanism and 1H NMR spectrum have been evaluated by B3LYP/6311G method.

A Regioselective Synthesis of Carbazole‐Appended Dispiropyrrolothiazoles/Pyrrolidines: Synthesis, Computational Studies and In Vitro Anticancer Activity

AbstractAnti‐oncological active carbazole appended dispiroindenoquinoxalinepyrrolothiazoles and dispiroacenaphthylenepyrrolidines were synthesized regioselectively via 1,3‐dipolar cycloaddition reaction of azomethine ylide to exocyclic linkage of dipolarophile. The synthesized spiranic compounds are fully characterized by means of spectral, X‐ray crystallography and elemental analysis. Computational details of theoretical calculations have been discussed for compound 4 g (p‐Cl‐phenyl substituted pyrrolothiazole‐carbazole system) using DFT (Density Functional Theory) approach at the M06‐2X/LANL2DZ level of theory. The cytotoxic effects of the dispiro compounds were examined on cancerous cell lines such as lung cancer (A549) and breast cancer (MCF‐7) cell lines. Compound 4 g was found to be the most promising derivative against A549 (20±1.0 μg/ml) and MCF‐7 (21±1.5 μg/ml) cells. Furthermore, the morphological changes and apoptotic induction of the promising candidates have been studied by AO/EB (Acridine Orange/Ethidium Bromide) and DAPI (4′,6‐diamidino‐2‐phenylindole) staining methods.

Azomethine ylide cycloaddition: a versatile tool for preparing novel pyrrolizidino-spiro-oxindolo hybrids of the doubly conjugated alkamide piperine.

A facile, multicomponent (MCR) atom-economic synthesis of novel spiro-oxindolo pyrrolizidine adducts of piperine has been achieved via an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction. Either of the two conjugated double bonds in piperine takes part in the reaction to produce two regioisomeric adducts in racemic form. Acenaphthoquinone, ninhydrin and different isatin derivatives were reacted with proline and piperine to afford a never before reported library of 22 compounds. The structures of the products were determined by 1D/2D NMR, mass spectral analysis and confirmed by X-ray crystallography of selected products. Chiral HPLC separation was performed to measure the specific rotation and CD spectra of the enantiomers for two racemic compounds.

A Photocatalyst-Free, SET-Mediated Photochemical Approach for the Synthesis of Dumbbell-Like Amine-Functionalized Bis-C60 Fullerene through C–C Bond Formation

A novel method for the synthesis of dumbbell-like amine-functionalized bis-C60 fullerene from simple bis-α-silyl tertiary benzyl amines and C60 fullerene is described. The photoreactions between bis-α-silyl tertiary benzyl amines and C60 furnished single-bonded bis-aminomethyl-1,2-dihyrofullerenes and double-bonded 1,2,5-trisubstituted bis-fulleropyrrolidines through 1,3-dipolar cycloaddition reactions of azomethine ylides under mild conditions.

Synthesis of heterocycle appended spiro(oxindole-3,2’-pyrrolidine) derivatives from heterocyclic ylidenes and azomethine ylide through 1,3-dipolar cycloaddition reactions

Spiro(oxindole-3,2’-pyrrolidine) is a privileged scaffold displaying a wide spectrum of biological activities. A series of these molecules containing heterocyclic rings attached to the pyrrolidine unit has been synthesized utilizing the classical 1,3-dipolar cycloaddition reaction of azomethine ylide with heterocyclic ylidenes. The method portrays a two-step functionalization of thiophene/furan with spiropyrrolidine oxindoles in the second/third positions. Biological activity evaluation for antibacterial, cell toxicity, and anticancer potential were done. Compounds exhibited no antibacterial activity. However, they were found to be non-cytotoxic upto 100 µg/ml and to exhibit potent anticancer activity by activating pro-apoptotic genes p53 and caspase 7.

All-Fullerene Electron Donor-Acceptor Conjugates.

The synthesis and characterization of a covalent all-fullerene C60 -Lu3 N@Ih -C80 electron donor-acceptor conjugate has been realized by sequential 1,3-dipolar cycloaddition reactions of azomethine ylides on Lu3 N@Ih -C80 and C60 . To the best of our knowledge, this is the first time that two fullerenes behaving as both electron donor (Lu3 N@Ih -C80 ) and acceptor (C60 ) are forming an electroactive dumbbell. DFT calculations reveal up to 16 diastereomeric pairs, that is, 8 with syn and 8 with anti orientation, with the anti-RSSS isomer being the most stable. Spectroelectrochemical absorption and femtosecond transient absorption experiments support the notion that a C60 ⋅- -Lu3 N@Ih -C80 ⋅+ charge-separated state is formed. Spin conversion from the charge-separated singlet state C60 ⋅- -Lu3 N@Ih -C80 ⋅+ into the corresponding triplet state is facilitated by the heavy-atom effect stemming from the Lu3 N-cluster, which, in turn, slows down the charge recombination by one order of magnitude.

All‐Fullerene Electron Donor–Acceptor Conjugates

AbstractThe synthesis and characterization of a covalent all‐fullerene C60‐Lu3N@Ih‐C80 electron donor–acceptor conjugate has been realized by sequential 1,3‐dipolar cycloaddition reactions of azomethine ylides on Lu3N@Ih‐C80 and C60. To the best of our knowledge, this is the first time that two fullerenes behaving as both electron donor (Lu3N@Ih‐C80) and acceptor (C60) are forming an electroactive dumbbell. DFT calculations reveal up to 16 diastereomeric pairs, that is, 8 with syn and 8 with anti orientation, with the anti‐RSSS isomer being the most stable. Spectroelectrochemical absorption and femtosecond transient absorption experiments support the notion that a C60⋅−‐Lu3N@Ih‐C80⋅+ charge‐separated state is formed. Spin conversion from the charge‐separated singlet state C60⋅−‐Lu3N@Ih‐C80⋅+ into the corresponding triplet state is facilitated by the heavy‐atom effect stemming from the Lu3N‐cluster, which, in turn, slows down the charge recombination by one order of magnitude.

Diastereoselective synthesis of diverse 3,2′-pyrrolidinyl bispirooxindoles via 1,3-dipolar cycloaddition reactions of azomethine ylides with exocyclic α,β-unsaturated ketones and in silico studies for prediction of bioactivity

A three-component highly regio- and diastereoselective 1,3-dipolar cycloaddition reaction between isatin, a series of primary amino acids (10 nos), and exocyclic α,β-unsaturated ketones was developed towards the synthesis of a small library of bispirooxindole (20 nos) at ambient temperature. The developed reaction afforded highly substituted 3,2′-pyrrolidine-bispirooxindole with two vicinal spiro-quaternary and four contiguous stereocenters from the cheap and abundant starting materials. The products were obtained with good to excellent yields (50-95%) and as a single diastereoisomer in the majority of the cases. Primary amino acids were served as amine component for the in-situ generation of azomethine ylides from isatin. Molecular docking studies were carried out to explore the synthesized bispirooxindoles as inhibitors of the epidermal growth factor receptor (EGFR). Two compounds exhibited excellent binding affinity towards EGFR receptor.

Synthesis of new polyhedral oligomeric silsesquioxane derivatives as some possible antimicrobial agents

1,3-Dipolar cycloaddition reactions were studied to synthesize Polyhedral oligomeric silsesquioxane (POSS)-based norbornyl imide derivatives containing izoxazoline groups in good yields. And also 1,3-dipolar cycloaddition reactions of azomethine ylides with POSS-based norbornene dipolarophiles for a synthesis of the novel POSS-based norbornane-fused spiro-1,3-indandionolylpyrrolidines are reported. All newly synthesized POSS compounds were structurally characterized by FTIR, 1H, 13C NMR, HRMS and GC/MS analyses.

A new trifluoromethylated sulfonamide phosphine ligand for Ag(i)-catalyzed enantioselective [3 + 2] cycloaddition of azomethine ylides.

A newly developed Ming-Phos ligand with a 3,5-bis(trifluoromethyl)phenyl substituent was demonstrated to be highly efficient for Ag-catalyzed asymmetric [3 + 2] cycloaddition reactions of azomethine ylides with maleimides, cyclopentene-1,3-diones, and N-(2-t-butylphenyl)maleimide. Being easily prepared on the gram scale in one step, the ligand in combination with a Ag catalyst enables the synthesis of a variety of highly functionalized bicyclic pyrrolidine derivatives in good yields and excellent enantioselectivities under mild conditions.

A one-pot three-component synthesis of fused Spiro-Indoline/Indene derivatives derived from ethynyl azaindole by 1,3-dipolar cycloaddition reaction

A one-pot method for the simple, efficient, and environmentally benign protocol for the synthesis of Spiro-Indoline/Indene derivatives containing Aza indole moiety as a side chain is outlined. The 1,3-dipolar cycloaddition reaction of azomethine ylides derived from ethynyl Azaindole under mild conditions is accomplished. The low cost, easy availability of the starting material, and simple reaction conditions suggest the possible use of the present method for large-scale preparations.

Silica‐Supported Silver as a Green and Sustainable Catalyst for the [3+2]‐Cycloaddition Reaction of Azomethine Ylides with 2′‐Hydroxychalcone Derivatives

AbstractA reusable heterogeneous silver nanoparticle catalyst supported on silica was used for the [3+2]‐cycloaddition reaction of azomethine ylides with 2′‐hydroxychalcone derivatives. The green and sustainable catalytic protocol afforded highly functionalized pyrrolidines, indolizidines, and pyrrolizidines in good yields with high regio‐ and diastereoselectivities.

Efficient synthesis of spirooxindole-pyrrolizidines and dispirooxindole-piperazines

ABSTRACTA simple and efficient approach for the construction of spirooxindole-pyrrolizidines and dispirooxindole-piperazines by cycloaddition reaction of azomethine ylide generated by isatin and proline has been demonstrated successfully. The formation of two different types of frameworks by two different modes of cycloaddition is explored. The developed protocol highlights simple reaction conditions, easy workup processes, and very good yields of products.

A Facile One-Pot Construction of Succinimide-Fused Spiro[Pyrrolidine-2,3'-Oxindoles] via 1,3-Dipolar Cycloaddition Involving 3-Amino Oxindoles and Maleimides.

Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3′-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from 3-amino oxindoles and aldehydes with maleimides has been described. The protocol provides a facile and efficient access to structurally diverse succinimide-fused spiro[pyrrolidine-2,3′-oxindole] compounds in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of cycloaddition products has been assigned by X-ray diffraction analysis.

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.

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.

A Convenient Synthesis of Fused Tetrahydroazocines from Acenaphthylene-1,2-dione, Proline, and Acetylenic Esters

A synthesis of dialkyl (12E,14E)-7-oxo-10,11-dihydro-7H,9H-azocino[2,1-a]benzo[de]isoquinoline-13,14-dicarboxylates through a 1,3-dipolar cycloaddition reaction of azomethine ylides, generated in situ from proline and acenaphthylene-1,2-dione, with dialkyl acetylenedicarboxylates is described. According to the X-ray diffraction data, the tetrahydroazocine ring has a rigid twist-boat form with approximate local C2 symmetry.

A molecular electron density theory study of [3 + 2] cycloaddition reactions of chiral azomethine ylides with β-nitrostyrene

The molecular mechanism and selectivity of the [3 + 2] cycloaddition (32CA) reaction of a chiral azomethine ylide (AY) with β-nitrostyrene (NS) have been studied within the Molecular Electron Density Theory (MEDT) using DFT methods at the MPWB1K/6-31G(d) computational level. Analysis of the electronic structure of AY indicates that this species has a pseudodiradical structure that enables its participation in pdr-type 32CA reactions. Analysis of the conceptual DFT reactivity indices allows classifying the AY as a strong nucleophile and NS as a strong electrophile, suggesting a polar process, while Parr functions permit to predict a high regioselectivity. The 32CA reaction presents a relatively low activation enthalpy, 4.1 kcal·mol−1, and is completely regio- and stereoselective. ELF topological analysis allows characterising the molecular mechanism of these pdr-type 32CA reactions as a non-concerted two-stage one-step mechanism, the reaction being classified as a [2n + 2τ] process.

A one-pot synthesis of functionalized indenopyrrolizines from ninhydrin, α-amino acids, and acetylenic esters

An efficient synthesis of tetraalkyl 6a-hydroxy-3-alkyl-11-oxo-6a,11-dihydro-3H-indeno[1,2-g]pyrrolizine-1,2,5,6-tetracarboxylates via 1,3-dipolar cycloaddition reaction of azomethine ylides (generated in situ from α-amino acids and ninhydrin) with dialkyl acetylenedicarboxylates is described. The stereochemistry of these N-heterocycles has been confirmed by X-ray diffraction study.

Access to Imidazolidine-Fused Sulfamidates and Sulfamides Bearing a Quaternary Center via 1,3-Dipolar Cycloaddition of Nonstabilized Azomethine Ylides.

A 1,3-dipolar cycloaddition reaction of nonstabilized azomethine ylides and cyclic N-sulfonyl imines has been developed providing a workable access to imidazolidine-fused sulfamidates, sulfamides, and benzosultams bearing a quaternary center. Distinct from the available literature, this current work enables to make entry, for the first time, into the novel imidazolidine-fused sulfamidates and sulfamides. Furthermore, the selective imidazolidine ring opening accompanied by CH2 extrusion yielded tetra-substituted sulfamidates with an aminomethyl group. In addition, imidazolidine ring opening coupled with SO2 extrusion provided synthetically useful 1,2-diamines.