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 σ_p 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.

The regio- and stereochemical polar [3 + 2] cycloaddition of azomethine ylides with (E)-3-aryl-1-(pyren-1-yl)prop-2-en-1-ones as dipolarophiles, was studied using experimental and theoretical methods.     

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.

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.     

Activator free diastereoselective 1,3-dipolar cycloaddition: a quick access to coumarin based spiro multi heterocyclic adducts

A formal diastereoselective 1,3-dipolar cycloaddition of azomethine ylide and coumarin derivatives to construct coumarin based spiro multi heterocyclics has been described. The in situ generation of azo-ylide was achieved for various heterocyclic carbonyls (indenoquinoxaline and isatin). This transformation is also suitable for maleimide dipolarophiles for the synthesis of hydro-maleimide derivatives. These decarboxylative annulations neither required any catalyst nor any activator. Further the pure products were isolated by filtration from the reaction mixture after the reaction under ambient conditions.

A formal diastereoselective decarboxylative 1,3-dipolar cycloaddition of azomethine ylide and coumarins is achieved for the synthesis of spiro multi heterocyclic adducts without engaging any catalyst or activator in good yields.     

Regio- and stereoselective synthesis of spiropyrrolidine-oxindole and bis-spiropyrrolizidine-oxindole grafted macrocycles through [3 + 2] cycloaddition of azomethine ylides

A convenient and efficient method for the regioselective macrocyclization of triazole bridged spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a–i required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy chalcone 8a–i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6 and substituted methyl ketones 7a–i. The regio- and stereochemical outcome of the cycloadducts were assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the exemplary advantages of the employed macrocyclization procedure.

Spiropyrrolidine-oxindole grafted and bis-spiropyrrolizidine-oxindole grafted macrocyles with triazole as a spacer unit have been achieved via regioselective and stereoselective intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides (click reaction).     

Regio- and diastereoselective synthesis of spiropyrroloquinoxaline grafted indole heterocyclic hybrids and evaluation of their anti-Mycobacterium tuberculosis activity

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel hybrid heterocycles comprising spiropyrrolidine, indenoquinoxaline and indole structural units in excellent yields, has been achieved through a one-pot multicomponent process involving 1,3-dipolar cycloaddition as a key step. The 1,3-dipolar component is the azomethine ylide generated in situ from indenoquinoxaline and l-tryptophan and reacts with various substituted β-nitrostyrenes affording the spiroheterocyclic hybrids. The ring system thus created possesses two C–C and three C–N bonds and four adjacent stereogenic carbons, one of which is quaternary and the reaction proceeded with full diastereomeric control. All the synthesized compounds were assayed for their in vitro activity against Mycobacterium tuberculosis H37Rv using MABA assay. Interestingly, the compound bearing a 2-fluoro substituent on the aryl ring displayed an equipotent activity (MIC 1.56 μg mL⁻¹) to ethambutol against Mycobacterium tuberculosis H37Rv.

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel spiropyrrolidine tethered indole hybrids in excellent yields employing a one-pot multicomponent 1,3-dipolar cycloaddition strategy.     

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.

Curcumin has been transformed to several diversely substituted bis-pyrrolizidino/thiopyrrolizidino oxindolo/acenaphthyleno curcuminoids via a sequential azomethine ylide cycloaddition reaction.     

Nitrileimines as an alternative to azides in base-mediated click [3 + 2] cycloaddition with methylene active nitriles

Nitrileimines were implemented in practical click protocols with oxopropanenitriles for the straightforward 5-amino-1H-pyrazole synthesis via 1,3-dipolar cycloaddition. The reaction proceeds at room temperature in a short time with base catalysis and no chromatographic purification. High purity products were isolated by simple filtration. The selectivity of the reaction was observed.

Nitrileimines were implemented in practical click protocols with oxopropanenitriles for the straightforward 5-amino-1H-pyrazole synthesis via 1,3-dipolar cycloaddition.     

Highly functionalized pyrrolidine analogues: stereoselective synthesis and caspase-dependent apoptotic activity

Novel spiropyrrolidine heterocyclic hybrids were synthesized for the first time in a sustainable fashion employing a 1,3-dipolar cycloaddition strategy to form a new class of azomethine ylides generated from tyrosine and acenaphthenequinone. Following their synthesis and characterization, these heterocyclic hybrids were tested for their anticancer activities by incubation at different concentrations and durations with different cancer and non-cancer cell cultures, and the results indicated a potential therapeutic activity. Further analysis of cancer cell death revealed that it occurred through a caspase-related apoptotic pathway, specifically mediated by caspase-3. These results demonstrated that the obtained spiropyrrolidine heterocyclic hybrids may be good hit compounds for the development of potential therapeutic agents for the treatment of malignant tumors.

Spiropyrrolidines were synthesized employing a new class of azomethine ylide for the first time and were tested for their anticancer activity, where the cell death mechanism revealed that it is occurring through the caspase-3 dependent pathway.     

Synthesis and molecular modeling studies of cholinesterase inhibitor dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines]

A set of dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines] 8a–l was regioselectively synthesized utilizing multi-component azomethine cycloaddition reaction of 3-(arylmethylidene)pyrrolidine-2,5-diones 5a–e, isatins 6a–c and sarcosine 7. Single crystal X-ray studies of 8c add conclusive support for the structure. Compounds 8e and 8g reveal cholinesterase inhibitory properties with promising efficacy against both AChE and BChE and were found to be more selective towards AChE than BChE as indicted by the selectivity index like Donepezil (a clinically used cholinesterase inhibitory drug). Molecular modeling studies assist in understanding the bio-observations and identifying the responsible parameters behind biological properties.

Dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines] were regioselectively synthesized revealing cholinesterase (AChE, BChE) inhibitory properties.     

Introducing chirality in halogenated 3-arylsydnones and their corresponding 1-arylpyrazoles obtained by 1,3-dipolar cycloaddition

New 1-arylpyrazoles substituted with halogen atoms (Br, I) were synthesized from the corresponding sydnones by 1,3-dipolar cycloaddition. By introduction of a prochiral group such as isopropyl, in the ortho position of the benzene ring, in the starting phenylglycine 1 the rotamers caused by the hindered rotation between the phenyl and the heterocyclic ring were detected by NMR spectroscopy for 1-arylpyrazoles and for the first time for 3-arylsydnones. The N-nitrosophenylglycines present E–Z stereoisomerism due to the partial C–N double bond character. All the new compounds were structurally characterized by NMR spectroscopy and confirmed by X-ray crystallography. The crystal structures of N-nitrosophenylglycine 2c and of the sydnone 3c present similar Br⋯Br type II halogen contacts.

New 1-arylpyrazoles substituted with halogen atoms (Br, I) were synthesized from the corresponding sydnones by 1,3-dipolar cycloaddition.     

Monometallic and bimetallic Cu–Ag MOF/MCM-41 composites: structural characterization and catalytic activity

Monometallic and bimetallic MOF/MCM-41 composites (Cu, Ag and Cu–Ag) were synthesized via a solvothermal method. The synthesized composites were characterized by XRD, FTIR, SEM, EDX and BET surface area measurements. The acidity was determined through two techniques; potentiometric titration with n-butyl amine for determining the strength and the total number of acid sites and FTIR spectra of chemisorbed pyridine on the surface of MOFs for determining the type of acid sites (Brønsted and/or Lewis). All the prepared MOFs showed Lewis-acid sites and the higher acidity was observed for the bimetallic Cu–Ag MOF/MCM-41 composite. The catalytic activity was examined on the synthesis of 1-amidoalkyl-2-naphthol via the reaction of benzaldehyde, 2-naphthol and benzamide. The best yield (92.86%) was obtained in the least time (10 min) with a molar ratio 1.2 : 1.2 : 1.7 of benzaldehyde : β-naphthol : benzamide and 0.1 g bimetallic Cu–Ag MOF/MCM-41 composite under solvent-free conditions at 130 °C. Reuse of the catalysts showed that they could be used at least four times without any reduction in the catalytic activity.

Monometallic and bimetallic MOF/MCM-41 composites (Cu, Ag and Cu–Ag) were synthesized via a solvothermal method.     

Azide–alkyne cycloaddition reactions in water via recyclable heterogeneous Cu catalysts: reverse phase silica gel and thermoresponsive hydrogels

Functionalized reverse phase silica gel and thermoresponsive hydrogels were synthesized as heterogeneous catalysts supports. Cu(i) and Cu(ii) catalysts immobilized onto two types of supports were prepared and characterized. The copper catalyzed azide–alkyne cycloaddition was performed in water via a one-pot reaction and yielded good results. These catalysts are air stable and reusable over multiple uses.

Azide–alkyne cycloaddition reactions were performed via copper catalysts immobilized onto two types of supports in water.     

Highly diastereoselective construction of novel dispiropyrrolo[2,1-a]isoquinoline derivatives via multicomponent 1,3-dipolar cycloaddition of cyclic diketones-based tetrahydroisoquinolinium N-ylides

In the quest for new heterocyclic scaffolds exhibiting potentially biological activities for medicinal chemistry, a multicomponent 1,3-dipolar cycloaddition reaction of tetrahydroisoquinolinium N-ylides, generated in situ from cyclic diketones and isoquinoline, and (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones has been developed. This route provides workable access to dispiropyrrolo[2,1-a]isoquinoline-fused pyrrolidine-2,5-diones bearing two adjacent spiro-carbons. An unprecedented regioselectivity was observed in this 1,3-dipolar cycloaddition, leading to the construction of a novel dispirooxindole skeleton. The structure and relative stereochemistry of the spiranic adducts have been confirmed by three X-ray diffraction studies. To reinforce the observed regio- and stereoselectivity of the [3+2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction affords the kinetic products.

A new series of dispiropyrrolo[2,1-a]isoquinoline derivatives was synthesized by multicomponent 1,3-dipolar cycloaddition reaction of tetrahydroisoquinolinium N-ylides and (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones.     

Asymmetric 1,3-dipolar cycloaddition reaction of chiral 1-alkyl-1,2-diphospholes with diphenyldiazomethane

The 1,3-dipolar cycloaddition of chiral 1-alkyl-1,2-diphosphacyclopenta-2,4-dienes ((1-(−)-menthyl)oxymethyl-1,2-diphosphole and 1-(+)-neomenthyl-1,2-diphosphole) with diphenyldiazomethane leads to novel P-chiral bicyclic phosphiranes having six chiral centers. The degree of diastereoselectivity depends on the substituent at phosphorus, and dramatically increases in the case of (+)-neomenthyl group (de up to 71%). DFT calculations indicate that the cycloaddition is thermodynamically controlled.

The 1,3-dipolar cycloaddition of chiral 1-alkyl-1,2-diphosphacyclopenta-2,4-dienes with diphenyldiazomethane leads to novel P-chiral bicyclic phosphiranes having six chiral centers.     

Functionalized polyhedral oligosilsesquioxane (POSS) based composites for bone tissue engineering: synthesis,computational and biological studies

Functionalized polyhedral oligosilsesquioxanes (POSS) containing an isoxazolidine nucleus have been synthesized by microwave assisted 1,3-dipolar cycloaddition of N-methyl-C-alkoxycarbonyl nitrone 1 with POSS containing olefin moieties. The results of cycloaddition processes were rationalized by computational studies at the DFT level. The covalent conjugation of chitosan with the cycloadduct 3a leads to composite material CS-POSS 7 which was gelified using genipin as cross linking agent. The suitability of the system for bone tissue engineering purposes was evaluated by in vitro drug release studies using ketoprofen as a model drug and cytotoxicity assays performed on human fetal osteoblastic cells. The preliminary biological tests showed the lack of cytotoxicity of the hybrid material and suggest its potential role in bone tissue engineering applications.

Functionalized POSS containing an isoxazolidine nucleus have been synthesized by 1,3-dipolar cycloaddition and conjugated with chitosan for bone tissue engineering applications.     

Dearomative [3 + 2] cycloaddition reaction of nitrobenzothiophenes with nonstabilized azomethine ylides

A highly diastereoselective dearomative [3 + 2] 1,3-dipolar cycloaddition reaction of nitrobenzothiophenes with an in situ-generated nonstabilized azomethine ylides has been developed. The transformation provides a series of functionalized fused tricyclic benzo[4,5]thieno[2,3-c]pyrroles in good yields (up to 92%) under mild reaction conditions. In addition, a gram-scale experiment and the synthetic transformation of the cycloadduct further highlighted the synthetic utility. The relative configurations of the typical products were clearly confirmed by X-ray crystallography.

A simple and efficient method for the synthesis of benzo[4,5]thieno[2,3-c]pyrroles via dearomative [3 + 2] 1,3-dipolar cycloaddition reaction of nitrobenzothiophenes with an in situ-generated nonstabilized azomethine ylides have been developed.

The dearomative cycloaddition reactions are a powerful synthetic strategy to obtain valuable structural motifs which exist in numerous biologically active natural products, pharmaceutical agents, and also in synthetic and materials building blocks.¹ Among them, indole substrates gained more and more research interest to develop effective methods for the construction of indole-based skeletons and their functionalization via dearomative transformation.² Because the unique properties of indole ring systems are ubiquitous in biologically active alkaloids,³ the range of methodologies that have been explored to access dearomatized indole heterocycles is extremely extensive. In contrast to the dearomative reactions of indole substrates, the analogous benzothiophenes derivatives have been less explored.⁴ In addition, the benzo[b]thiophene derivatives that have found widespread application are frequently found in many bioactive compounds, pharmaceuticals, and as synthetic building blocks.⁵ Therefore, the development of efficient synthetic method to realize the dearomatization of benzo[b]thiophenes for the construction of diverse functionalized heteroarenes molecules continues to be an important and highly desirable in the organic synthetic community.On the other hand, 1,3-dipolar cycloaddition of azomethine ylides with electron deficient dipolarophiles that have a wide range of applications in organic synthesis, is a useful and facile synthetic process for five or six membered heterocyclic rings in one step.⁶ Especially, nonstabilized azomethine ylides generated in situ are highly active intermediates,⁷ with electron-deficient benzoheterocycles, including 2-nitroindoles or 3-nitroindoles (Scheme 1a)⁸ and benzo[b]thiophene 1,1-dioxides (Scheme 1b)⁹ as robust electrophiles to construct various polycyclic heterocyclic skeletons via the dearomative [3 + 2] 1,3-dipolar cycloaddition reaction in the simple way. However, 3- and 2-nitrobenzothiophenes have been uncovered as electrophiles for the dearomative 1,3-dipolar cycloaddition reactions with nonstabilized azomethine ylides to provide S-containing polyheterocyclic compounds. Enormous efforts have been devoted to the development of ever more efficient synthetic methods for the construction and direct functionalization of these heteroaromatic compounds. Herein, we describe a dearomative [3 + 2] cycloaddition reaction of 3-nitrobenzothiophenes with nonstabilized azomethine ylides without metal catalysts under mild reaction conditions, providing a convenient and efficient access to functionalized fused tricyclic benzo[4,5]thieno[2,3-c]pyrroles derivatives bearing two contiguous stereocenters. Additionally, we also successfully extended this new protocol to 2-nitrobenzothiophene and 2-nitrobenzofuran for the corresponding dearomatization products.Open in a separate windowScheme 1Dearomative cycloaddition reaction of electron-deficient heteroarenes with nonstabilized azomethine ylides.Initially, we chosed 3-nitrobenzothiophene 1a and N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a which generated in situ nonstabilized azomethine ylide in the presence of trifluoroacetic acid (TFA) as model substrates to optimize the reaction conditions. As the results are shown in

Rhodium(iii)-catalyzed C–H annulation of 2-acetyl-1-arylhydrazines with sulfoxonium ylides: synthesis of 2-arylindoles

An efficient Rh(iii)-catalyzed synthesis of 2-arylindole derivatives via intermolecular C–H annulation of arylhydrazines with sulfoxonium ylides was accomplished. A variety of 2-acetyl-1-arylhydrazines with sulfoxonium ylides were converted into 2-arylindoles in satisfactory yields. Excellent selectivity and good functional group tolerance of this transformation were also observed.

Rh(iii)-catalyzed intermolecular C–H annulation of arylhydrazines with sulfoxonium ylides for synthesis of 2-arylindole derivatives was well established.     

An intramolecular relay catalysis strategy for Knoevenagel condensation and 1,3-dipolar cycloaddition domino reactions

A relay catalysis strategy was established by using a bifunctional catalyst which was prepared by immobilization of organic chains containing secondary amine and Cu(ii) complex onto silica-coated nano-Fe₃O₄. The simply prepared nanoparticles acted as efficient, intramolecular relays and magnetically recyclable base-metal bifunctional catalysts for Knoevenagel condensation and 1,3-dipolar cycloaddition domino reactions to prepare 5-substituted 1H-tetrazoles with excellent yields.

A magnetically recoverable bifunctional catalyst was synthesized and effectively used in Knoevenagel condensation and 1,3-dipolar cycloaddition domino reactions.     

Fullerene C60 promoted photochemical hydroamination reactions of an electron deficient alkyne with trimethylsilyl group containing tertiary N-alkylbenzylamines

C₆₀-promoted photoaddition reactions of both trimethylsilyl- and a variety of alkyl group containing tertiary benzylamines (i.e., N-α-trimethylsilyl-N-alkylbenzylamines) with dimethyl acetylenedicarboxylate (DMAD) were carried out to explore the synthetic utility of trimethylsilyl group containing tertiary amines as a substrate in the photochemical hydroamination reactions with dimethyl acetylenedicarboxylate (DMAD). The results showed that photoreactions of all the trimethylsilyl containing N-alkylbenzylamines with DMAD, under an O₂-purged environment, produced non-silyl containing enamines efficiently through a pathway involving addition of secondary amines to DMAD, the former of which are produced by hydrolytic cleavage of in situ formed iminium ions. Exceptionally, five-membered N-heterocyclic rings, pyrroles, could be produced competitively in photoreaction of bulky alkyl (i.e., tert-butyl) group substituted benzylamines through a pathway involving 1,3-dipolar cycloaddition of azomethine ylides to DMAD. Furthermore, C₆₀-sensitized photochemical reactions of non-silyl containing benzylamines with DMAD under oxygenated conditions took place in a less efficient and non-regioselective manner to produce enamine photoadducts. The observations made in this study show that regioselectivity of C₆₀-promoted photochemical reactions of N-α-trimethylsilyl-N-alkylbenzylamines, leading to formation of secondary amines, can be controlled by the presence of the trimethylsilyl group, and that these trimethylsilyl containing tertiary amines can serve as a precursor of secondary amines for hydroamination reactions with a variety of electron deficient acetylenes.

C₆₀-promoted photoaddition reactions of N-α-trimethylsilyl-N-alkylbenzylamines with dimethyl acetylenedicarboxylate (DMAD) were carried out.     

Selective formation of dihydrofuran fused [60] fullerene derivatives by TEMPO mediated [3 + 2] cycloaddition of medium chain β-keto esters to C60

In this study, β-keto esters as readily available bio-based building blocks were used to decorate the C₆₀ sphere. Generally, cyclopropanated fullerene derivatives are obtained by the standard Bingel–Hirsch procedure. Herein, omitting the iodine from the reaction mixture and adding TEMPO afforded dihydrofuran fused C₆₀ fullerene derivatives. The mechanism of the reaction shifted from nucleophilic aliphatic substitution to oxidative [3 + 2] cycloaddition via fullerenyl cations as an intermediate. This mechanism is proposed based on a series of control experiments with radical scavengers. Therefore, dihydrofuran-fused C₆₀ derivatives were selectively obtained in good yields and their structures were established based on UV-Vis, IR, NMR spectroscopy and mass spectrometry. The electrochemical properties of the synthesized compounds were investigated by cyclic voltammetry. DFT calculations were performed in order to investigate the difference in stability, electronic properties and π-electron delocalization between methano and furano fullerenes.

In this study, β-keto esters as readily available bio-based building blocks were used to decorate the C₆₀ sphere.