Nonstabilized Azomethine Ylides Research Articles

Visible‐Light‐Mediated Cycloaddition of Azobenzenes and Nonstabilized Azomethine Ylides to Access 1,2,4‐Triazolidines

AbstractA visible‐light‐mediated cycloaddition of azobenzenes and nonstabilized azomethine ylides has been developed to access 1,2,4‐triazolidines. With readily available organic dye rose bengal as a photocatalyst and alkyl tertiary amines as precursors for azomethine ylides, the reaction proceeded smoothly under visible light irradiation at room temperature, affording various 4‐alkyl‐1,2‐diaryl‐1,2,4‐triazolidines with yields of up to 96%. Preliminarily mechanistic studies suggest that the nonstabilized azomethine ylides are formed in situ through photoredox catalysis.

Dichotomic Dearomatizations of Benzene vs Pyridine Rings of Sulfonyloxypyridine via (3 + 2) Cycloaddition.

Electron-poor arenesulfonyloxypyridines are selectively dearomatized whether on the pyridine or on the phenyl group through 1,3-dipolar cycloaddition (1,3-DC) involving non-stabilized azomethine ylides (AMY). Electronic effects of substituents on the aromatic rings allow to induce the regioselectivity of the transformation. Novel pyrrolidinic polycyclic heterocycles are thereby produced under mild acidic conditions at room temperature.

Photocatalyzed (3+2) Cycloaddition for the Dearomatization of Electron-Poor Arenes under Flow Conditions.

The photocatalyzed dearomative reaction between various electron-deficient aromatic compounds and a non-stabilized azomethine ylide is successfully performed in a flow system. Whereas the use of supported eosin as organic photocatalyst exhibits limited efficiency, turning to the soluble Rose Bengal allows to transform a broad range of substrates from hetarenes (indole, benzofuran, quinoline, pyridine) to naphthalenes and benzenes. This photocatalyzed (3+2) dearomative cycloaddition under green light irradiation provides a simple and efficient access to tridimensional pyrrolidino scaffolds with a tetrasubstituted carbon center at ring junction and can be performed in the friendly ethyl acetate. Computational studies support the mechanism involving azomethine ylide as reactive species toward the electron-poor arene.

A step-economical and diastereoselective synthesis of dispirooxindole-pyrrolizines bearing seven stereocenters

A thermodynamic-promoting diastereoselective synthesis of dispirooxindole-pyrrolizines was developed by a five-component reaction with a dual 1,3-dipolar cycloadditions process of non-stabilized azomethine ylides that includes the decarboxylation of glycine and αCH functionalization of generated pyrrolidines in situ. This process is a solid and versatile strategy for rapidly assembling fused pyrrolizines with two spirooxindoles bearing seven stereocenters. Homogeneous Brønsted acid catalysis and benign solvent in one-step reaction can be used to promote the green process, with by-products of CO2 and H2O, and potentiating environmental tolerance.

Selective [3 + 2] cycloaddition reaction of isothiazol‐3(2h)‐ones with in situ formed azomethine ylide to thiazolidines and oxazolidines

AbstractNovel selective [3 + 2] cycloaddition reactions between in situ formed nonstabilized azomethine ylide generated from N‐benzyl‐1‐methoxy‐N‐((trimethylsilyl)methyl)methanamine enabled by Lewis acids and bioactive molecules isothiazol‐3(2H)‐ones have been developed. The reaction selectively afforded novel thiazolidines or cyclo‐fused oxazolidinones depending on Lewis acid catalyst system of reaction used.

Highly functionalized dispiropyrrolidine embedded indandione hybrids as potent cholinesterase inhibitors

New class of highly functionalized dispiropyrrolidine tethered indandione heterocycles in good yield were obtained through stereo- and regioselective single-pot three component cycloaddition methodology between benzylidene-indandione and non-stabilized azomethine ylide. The ylide generated from active diketone and aminophenylpropanoic acid via dehydration/decarboxylative pathway. The synthesized dispiropyrroldine comprising indandiones were elucidated through 1H and 13C NMR spectroscopic analysis, the stereo and regioselective formation of the dispiropyrrolidine were unequivocally assigned by X-ray diffraction analysis. Compound thus synthesized were assayed as potential inhibitor for the treatment of AD. Spiropyrrolidine 4h that bearing methoxy group on the phenyl ring showed significant activity, IC50 of 3.24 ± 0.25 and 10.25 ± 0.16 μM against acetyl and butyryl cholinesterase enzyme, respectively. The lead compound 4h executed to investigate for their docking simulation that showed strong binding affinity with binding site of the cholinesterase protein.

Phosphonium ylides in the multicomponent synthesis of pyrrolidines

A multicomponent synthesis of pyrrolidines starting from phosphonium ylides, N-alkylglycines and carbonyl compounds was performed in 37–87% yields. This approach is based on a Wittig/Huisgen tandem reaction and simultaneous generation of the two reactive intermediates: alkene and azomethine ylide from the same carbonyl compound. Both stabilized and nonstabilized azomethine ylides were employed in this process allowing the construction of highly substituted dispiropyrrolidines as well as simple 3-substituted pyrrolidines.

Highly efficient and diastereoselective construction of substituted pyrrolidines bearing a quaternary carbon center via 1,3‐dipolar cycloaddition

AbstractA general approach to substituted pyrrolidines via [3 + 2] cycloaddition between nonstabilized azomethine ylides and cyanosulfones was developed. The efficient method provides a series of substituted pyrrolidines bearing a quaternary carbon center in high yields (up to 98%) excellent diastereoselectivities (up to >25:1 dr) under ambient reaction conditions.

Spectroscopic, computational and mechanistic studies on regio- and stereoselectivity of the 1,3-dipolar cycloaddition reaction in the synthesis of dispiro[indoline-3,2′-pyrrolidine-3′,3"-indolines] festooned with pyrene moiety

• Novel polyheterocyclic pyrene-grafted dispiro-pyrrolidine oxindolines have synthesized. • 1D and 2D-NMR spectroscopy found to be excellent tool for confirmation of the regio- and stereochemistry of the cycloadducts. • The regioselectivity were studied by evaluating global and local electrophilicity and nucleophilicity descriptors. • local descriptors Parr functions proposed by Domingo is promising indices to explain the regioselectivity of cycloaddition processes. An efficient and catalyst-free multicomponent sequence for synthesizing fused new polyheterocyclic pyrene-grafted dispiro-pyrrolidine oxindolines through 1,3-dipolar cycloaddition reaction mediated by non-stabilized azomethine ylides is reported herein. The regio- and stereochemistry of the cycloadducts were determined on the basis of one-dimensional (1D) and two-dimensional (2D) homonuclear and heteronuclear correlation NMR spectroscopy. The mechanism of the cycloaddition reaction, as well as regioselectivity were discussed by evaluating global and local electrophilicity and nucleophilicity descriptors at B3LYP/6-31G level of theory. The findings suggested that the polarity and charge transfer flow between azomethine ylides (dipole) and 5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones (dipolarophiles) was consistent with the global reactivity descriptors and substitutional pattern. These outcomes based on local descriptors Parr functions proposed by Domingo were found to be quite promising indices for the study of organic reactivity and to explain the regioselectivity of cycloaddition processes.

3 + 2] cycloaddition of nonstabilized azomethine ylides and 2-benzothiazolamines to access imidazolidine derivatives

A simple and practical method for the construction of 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition reaction has been developed. This reaction could smoothly proceed between nonstabilized azomethine ylides generated in situ and 2-benzothiazolamines to deliver a wide scope of differently substituted imidazolidines in high yields (up to 98%). The structure of one example was confirmed by X-ray single-crystal structure analysis.

Microwave Assisted a Highly Atom Economic, Chemo-, Regio- and Stereoselective Synthesis and Evaluation of Dispiro[1H-indene-2,3′-pyrrolidine- 2′,3′′-[3H]indole]-1,2′′(1′′H)diones as Antibacterial and Antifungal Agents

1,3-Dipolar cycloaddition of in situ generated non-stabilized azomethine ylides through the decarboxylative condensation of sarcosine and substituted isatins with 2-(arylmethylene)-2,3-dihydro-1H-inden-1-ones in microwave produced dispiro[1H-indene-2,3Œ-pyrrolidine-2Œ,3ŒŒ-[3H]indole]-1,2ŒŒ(1ŒŒH)diones in a highly stereo- and regio-selective fashion. The synthesized compounds were subjected to antibacterial and antifungal studies. It was found that many compounds possess a considerable antibacterial and antifungal activity against all the tested organisms.

Three-Component [3+2] Cycloaddition for Regio- and Diastereoselective Synthesis of Spirooxindole-Pyrrolidines.

1,3-Dipolar cycloaddition of nonstabilized azomethine ylides derived from α-C-H functionalization of tetrahydroisoquinoline for regio- and diastereoselective synthesis of spirooxindole-pyrrolidines is developed. A three-component reaction of readily available cyclic amine, aryl aldehydes, and olefinic oxindoles provides a pot, atom and step economy (PASE) approach for making spiro-heterocyclic compounds with biological interest.

Electrochemical Generation of a Nonstabilized Azomethine Ylide: Access to Substituted N-Heterocycles.

Azomethine ylides are fascinating 1,3-dipoles for [3 + 2] cycloaddition reactions toward the construction of N-heterocycles. Herein, an efficient and environmentally benign electrochemical approach for the generation of a nonstabilized azomethine ylide has been established under metal-free and external oxidant-free conditions. The resulting 1,3-dipole undergoes a [3 + 2] cycloaddition reaction with olefins. This electrosynthetic methodology indulges a straightforward and facile approach for the construction of substituted pyrrolidines.

Reactions of 4-Pyrones with Azomethine Ylides as a Chemo­selective Method for the Construction of Multisubstituted Pyrano[2,3-c]pyrrolidines

Abstract4-Pyrones bearing electron-donating and electron-withdrawing groups react with nonstabilized azomethine ylides to form pyrano[2,3-c]pyrrolidines in moderate to good yields. The reaction proceeds chemoselectively as a 1,3-dipolar cycloaddition of the azomethine ylide at the carbon–carbon double bond of the pyrone activated by the electron-withdrawing substituent. The reactivity of 4-pyrones toward azomethine ylides was rationalized by computational studies with the use of reactivity indexes. The pyrano[2,3-c]pyrrolidine moiety could be modified, for example by a ring-opening transformation under the action of hydrazine to provide pyrazolyl-substituted pyrrolidines.

Stereoselective synthesis and discovery of novel spirooxindolopyrrolidine engrafted indandione heterocyclic hybrids as antimycobacterial agents

Novel spirooxindolopyrrolidine embedded indandione heterocyclic hybrids were obtained in excellent yields via a regio- and stereoselective one-pot three component reaction between Baylis-Hillman adduct and non-stabilized azomethine ylides. The structure of newly synthesized compounds was elucidated through 1D and 2D spectroscopic data and the stereochemistry was determined by single crystal X-ray diffraction analysis. In vitro tubercular activity against Mycobacterium tuberculosis H37Rv using MABA assay reveals that the compound bearing chlorine substituted on the oxindole ring displayed the most potent activity with MIC 0.78 μg/mL and is two-fold active than the standard drug, ethambutol (MIC 1.56 μg/mL).

Reaction of N-benzyl azomethine ylide with aryl isothiocyanates: synthesis of (Z)-N-aryl-3-benzylthiazolidine-5-imines

The reaction of aryl isothiocyanates with nonstabilized azomethine ylides generated in situ by various methods was studied. It was established that the use of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in the presence of trifluoroacetic acid in the role of a catalyst led to the formation of (Z)-N-aryl-3-benzylthiazolidin-5-imines in 22–47% yields.

Three Ways Aliphatic Aldehydes React with Nonstabilized Azomethine Ylides

Aliphatic aldehydes readily react with nonstabilized azomethine ylides in one of the three ways to give oxazolidines, pyrrolidines, or Mannich bases, depending on the structure of the starting compound and the reaction conditions. The use of N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzylamine in DMF provided 5-alkyloxazolidines in 40–97% yields. On the other hand, three-component reactions of aliphatic aldehydes bearing one α-hydrogen with N-methyl(benzyl)glycine and formaldehyde gives Mannich bases in yields of 47–98%. A similar reaction of aldehydes bearing branched alkyl groups and two hydrogen atoms at the α-position proceeds as a domino process that gives 3-alkyl-3-formylpyrrolidines in yields of 34–93%.

Dearomatization of 3-cyanoindoles by (3 + 2) cycloaddition: from batch to flow chemistry

1,3-Dipolar dearomatizing cycloadditions between a non-stabilized azomethine ylide and 3-cyanoindoles or benzofuran afford the corresponding 3D-heterocycles bearing a quaternary carbon centre at the ring junction. While 6 equivalents of ylide precursor 1 are required for full conversion in a classical flask, working under flow conditions limits the excess (3 equiv., tR = 1 min) and leads to a cleaner process, affording cycloadducts that are easier to isolate.

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.

Formal [3 + 2] cycloaddition of azomethine ylides generated in situ with unactivated cyclic imines: A facile approach to tricyclic imidazolines derivatives

AbstractA simple and efficient method for the synthesis of tricyclic imidazolines derivatives via [3 + 2] 1,3‐dipolar cycloaddition between nonstabilized azomethine ylide generated in situ with unactivated cyclic imines is reported here. The method provided easy and mild access to various fused tricyclic hexahydroimidazo[5,1‐a]isoquinolines in excellent yields (up to 96%). This protocol is simple and easy to handle.