Azomethine Ylide Formation Research Articles

Theoretical Study of the Mechanism of the Formation of Azomethine Ylide from Isatine and Sarcosine and Its Reactivity in 1,3-Dipolar Cycloaddition Reaction with 7-Oxabenzonorbornadiene.

The reaction mechanism of tthe formation of azomethine ylides from isatins and sarcosine is addressed in the literature in a general manner. This computational study aims to explore the mechanistic steps for this reaction in detail and to assess the reactivity of formed ylide in a 1,3-dipolar cycloaddition reaction with 7-oxabenzonorbornadiene. For this purpose, density functional theory (DFT) calculations at the M06-2X(SMD,EtOH)/6-31G(d,p) level were employed. The results indicate that CO2 elimination is the rate-determining step, the activation barrier for 1,3-dipolar cycloaddition is lower, and the formed ylide will readily react with dipolarophiles. The substitution of isatine with electron-withdrawal groups slightly decreases the activation barrier for ylide formation.

Синтез спиропирролизидинов, содержащих хиноксалиновый и пиррольный фрагменты

The reaction of 1,3-dipolar cycloaddition azomethine ylides obtained by the in situ interaction of 11H-indeno[1,2-b]quinoxalin-11-one and proline, and 3-phenyl-1-pyrrolyl-2-en-1-ones has been used for the synthesis of substituted spiropyrrolizidines in continuation of the study the use of new enones as dipolarophiles. The conditions for the implementation of a three-component synthesis (temperature regime, solvent, activation method) are selected. The best performance has been obtained by refluxing the reaction mixture in ethanol. Ultrasonic activation did not reduce the reaction time or increase the yields significantly. The reaction proceeds regio- and diastereoselectively with the formation of a single type of products in 72–76% yields. It has been found that carrying out the process in the mode of a four-component reaction using ninhydrin and 1,2-phenylphamine, the reaction product of which is 11H-indeno[1,2-b]quinoxalin-11-one, with the selected dipolarophile is impossible due to the formation of ninhydrin azomethine ylide and proline and its interaction with a dipolarophile to give substituted spiro[indene-2,3’- pyrrolysine]-1,3-diones, which has been proven by a counter synthesis using enone, ninhydrin and proline, which also results in the same type products with yields of 89–92%. A probable scheme of the studied transformations is proposed. Regio- and diastereoselectivity testifies in favor of concerted cycloaddition, passing in both cases through a transition state in which a bond is formed between the most electrophilic β-carbon atom of the enone system and the nucleophilic carbon atom of the dipole. The reasons for the observed features are discussed. The composition and structure of the final products have been confirmed by elemental analysis, 1Н, 13С NMR, HMBC, NOESY spectroscopy. The resulting compounds contain pharmacophoric quinoxaline and pyrrole fragments and can be used to study various types of biological activity characteristic of structures with similar fragments.

Fullerene C70 as Photoredox Catalyst for the Synthesis of Pyrrolo[2,1-a]isoquinolines by 1,3-Dipolar Cycloaddition-Aromatization Sequence.

Herein, fullerene (C70 ) is introduced as an effective photoredox catalyst for the construction of a highly functionalised pyrrolo[2,1-a]isoquinoline framework by 1,3-dipolar cycloaddition-aromatisation reaction sequence. The ability of C70 to efficiently harvest visible light, its long-triplet state lifetime, good photostability, and strong singlet oxygen generation potential (Φ▵ ≈1), make it an efficient photoredox catalyst. Upon photoirradiation, C70 promotes the formation of singlet oxygen and superoxide radical by energy transfer (EnT) and single electron transfer (SET) mechanism. The superoxide radical acts as a potential oxidant in the formation of azomethine ylide through the oxidation-deprotonation tandem process. Azomethine ylide further participates in [3+2]-cycloaddition reaction protocol with alkene/alkyne to give the corresponding pyrrolo[2,1-a]isoquinolines. Interestingly, this protocol allows the activation of a wide range of substrates giving access to a diverse library of 48 well-decorated pyrrolo[2,1-a]isoquinolines with good functional group tolerance.

Catalyst‐/Additive‐Free One‐Pot Synthesis of Oxazolidines in Water via Regioselective and Stereoselective C−H Functionalization Approach

AbstractA catalyst‐free approach for the synthesis of oxazolidine derivatives is developed here. Though the synthesized oxazolidines contain three stereogenic centers, single diastereomer of the product is obtained. Single crystal X‐ray analysis of the product confirmed the stereochemistry. The reaction is performed by taking tetrahydroisoquinoline/cyclic benzylic amine (1 equivalent) and aromatic aldehyde (2 equivalent) in water under refluxing condition which produces excellent yield (87–96 %). With pyrrolidine as amine substrate, the reaction gives α,β‐unsaturated cyclic imines which is an example of β‐C−H functionalization of secondary amine. The proposed mechanism shows that the reaction proceeds through the formation of azomethine ylide which undergoes [3+2]‐cycloaddition reaction providing the oxazolidine product.

Synthesis of 2-trifluoromethylated 3-pyrrolines/pyrrolidines via [3+2] cycloaddition of azomethine ylides with the participation of 3,3,3-trifluoroalanine

2-Trifluoromethylated 3-pyrrolines and pyrrolidines were synthesized via condensation of 3,3,3-trifluoroalanine with carbonyl compounds, decarboxylative formation of azomethine ylides, and the subsequent [3+2] cycloaddition with electron deficient alkynes and alkenes. The reaction proceeded under mild conditions to give the adducts in moderate to good yields. The product 3-pyrroline was successfully converted to the corresponding pyrrole upon treatment with o-iodoxybenzoic acid.

Decarboxylative Cyclization of Proline with o-Alkynylbenzaldehyde through an Unexploited 8π-Electrocyclization: A DFT Study.

We employed density functional theory (DFT) methods to investigate the most plausible mechanism of cyclization/ring expansion of proline with o-alkynylbenzaldehyde. This one-pot reaction starts with the in situ formation of azomethine ylide, which can undergo three different reaction pathways to form the final product. Two mechanisms are based on nucleophilic addition and 4π-electrocyclization of the azomethine ylide, and our results indicate that the rate-determining step (RDS) of these two cyclizations are 40.1 and 40.2 kcal/mol, respectively. The third novel pathway relies upon 8π-electrocyclization as the key step of this reaction; interestingly, the RDS of this cyclization is ∼20.6 kcal/mol, which shows this route to be most feasible. Thus, we introduce a novel mechanism for the electrocyclization reaction of conjugated azomethine ylides that can help chemists to design and access a new series of compounds.

Synthesis, NMR, anti-oxidant, anti-cancer activity, Molecular docking, DFT Calculations and in silico ADME analysis of 3′-benzoyl-4′-phenyl-5′-(piperazin-1-ylmethyl)spiro[indoline-3,2′-pyrrolidin]-2-one derivatives

A series of seven novel spirooxindoles derivatives were synthesized by a three-component 1,3-dipolar cycloaddition method. The reaction proceeds through the formation of azomethine ylides generated in situ by the decarboxylative condensation of isatin and amine with dipolarophile chalcones. The antioxidant results revealed that the IC50 value of compounds 4a,4b,4d and 4f are very excellent against hydroxyl radical (IC50 = 15.9 to 30.3 µg/ml) and superoxide radical scavenging activity (IC50 = 14.7 to 22.2 µg/ml) whereas standard antioxidant Vitamin C showed their IC50 value only in the range of 25.0 and 20.0 µg/ml. Cytotoxic activity by MTT assay revealed that the compounds 4a,4b,4d and 4f exhibited broad inhibition on the KB cell lines with IC50 values of 6.5, 9.5, 32.5 and 55 µM, respectively. The observed IC50 values revealed that compound 4b possessed more inhibitory effect against the cancer cells. The anticancer activities of these derivatives were studied using molecular docking studies and it is compared with their experimental results. In addition, good oral bioavailability was predicted for all compounds by in silico calculations of ADME (absorption, distribution, metabolism, and elimination) and pharmacokinetic parameters. Finally the geometrical structure was optimized by density functional theory (DFT) method at B3LYP/6–31 G (d, p) as the basic set. The HOMO-LUMO energies describe the charge transfer takes place within the molecule. Molecular electrostatic potential has been analyzed.

Rhodium-Catalyzed C-H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles.

Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C-H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxy-substituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C-H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric syntheses of morphinan drugs, including the opioid antagonist (-)-naltrexone, which is extensively used for the treatment of drug abuse.

Construction of Spiro[3-azabicyclo[3.1.0]hexanes] via 1,3-Dipolar Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived Azomethine Ylides

AbstractThe multi-component 1,3-dipolar cycloaddition of ninhydrin, α-amino acids (or peptides), and cyclopropenes for the synthesis of spirocyclic heterocycles containing both 3-azabicyclo[3.1.0]hexane and 2H-indene-1,3-dione motifs has been developed. This method provides easy access to 3-azabicyclo[3.1.0]hexane-2,2′-indenes with complete stereoselectivity and a high degree of atom economy under mild reaction conditions. A broad range of cyclopropenes and α-amino acids have been found to be compatible with the present protocol, which offers an opportunity to create a new library of biologically significant scaffold (3-azabicyclo[3.1.0]hexane). In addition, the сomprehensive study of mechanism of azomethine ylide formation from ninhydrin and sarcosine was performed by means of M11 density functional theory (DFT) calculations. It has been revealed that experimentally observed 1-methylspiro[aziridine-2,2′-indene]-1′,3′-dione is a kinetically controlled product of this reaction and appears to act as a 1,3-dipole precursor. This theoretical study also shed light on the main transformations of the azomethine ylide derived from ninhydrin and sarcosine such as a 1,3-dipolar cycloaddition to cyclopropene dipolarophiles, a dimerization reaction and a (1+5) electrocyclization reaction. The antitumor activity of some synthesized compounds against cervical carcinoma (HeLa­) cell line was evaluated in vitro by MTS-assay.

One-pot synthesis of spirooxindole-pyrrolizidine compounds using magnetically separable Fe3O4-graphene oxide (Fe3O4-GO) catalyst

A couple of novel Spirooxindole-pyrrolizidine compounds have been synthesized from chalcone derivatives as α, β-unsaturated carbonyl compounds by the help of heterogeneous magnetically separable Fe3O4-GO catalyst. Four steps involved in this research are synthesis of Fe3O4-GO catalyst, synthesis of chalcone derivatives from 4-hydroxybenzaldehyde and cinnamaldehyde, synthesis of spirooxindole-pyrrolizidine derivatives by 1,3-dipolar-cycloaddition reaction through the formation of azomethine ylide, and the last is antioxidant activity assay using DPPH method. The result showed that the use of Fe3O4-GO catalyst as much as 5 wt% can increase the reaction yield to 86.27 %. From the DPPH assay, it is known that spirooxindole-pyrrolizidine derivatives have an antioxidant activity but spirooxindole-pyrrolizidine derived from 4-hydroxybenzaldehyde is the better one.

Catalytic Asymmetric Tandem Cycloisomerization/[5+2] Cycloaddition Reaction of N-Aryl Nitrone Alkynes with Methyleneindolinones.

An asymmetric tandem cycloisomerization and intermolecular [5+2] cycloaddition reaction of 2-ethynylphenyl-substituted nitrones with methyleneindolinones was realized. The process includes the palladium(II)-promoted in situ formation of azomethine ylide and the following chiral N,N'-dioxide-Co(II) complex-catalyzed regio-, diastereo-, and enantioselective [5+2] cycloaddition reaction. The desired spiro-tropanyl oxindoles were obtained in good yields with excellent dr and ee values. On the basis of the determination of the catalyst structure, a possible transition state model was proposed.

Photoinduced Nonstabilized Azomethine Ylide Formation for the Preparation of Fluorine Containing Pyrrolidines.

A mild and reproducible method for the formation of a nonstabilized azomethine ylide was developed by photoinduced reaction catalyzed with eosin Y under green light irradiation. Resulting 1,3-dipole was trapped with fluoroalkenes, fluoroalkylated alkenes, and representative dipolarophiles to access pyrrolidine scaffolds, including spirocyclic compounds. The mechanism involved in this transformation was investigated, showing clearly a catalytic redox cycle with eosin Y.

Photoaddition reactions of N-benzylglycinates containing α-trimethylsilyl group with dimethyl acetylenedicarboxylate: competitive formation of pyrroles vs. β-enamino esters.

A study was conducted to gain insight into the preparative potential of photosensitized reactions of acyclic N-benzylglycinates containing an α-trimethylsilyl group with dimethyl acetylenedicarboxylate (DMAD). The photosensitizers employed in the reactions include 9,10-dicyanoanthracene (DCA), 1,4-dicyanonaphthalene (DCN), rose bengal (RB) and fullerene C60. The results show that photoirradiation of oxygenated solutions containing the photosensitizers, glycinates and dimethyl acetylenedicarboxylate leads to competitive formation of pyrroles and β-enamino-esters. The distributions of pyrrole and β-enamino-ester products formed in these reactions are highly influenced by the electronic nature of the phenyl ring substituent on the benzylglycinates and the photosensitizer used. These photoaddition reactions take place via mechanistic pathways involving competitive formation of azomethine ylides and secondary amines, generated by a mechanistic routes involving initial SET from the benzylglycinates to photosensitizers.

Pd/C‐Catalyzed Dehydrogenative [3+2] Cycloaddition for the Synthesis of Functionalized Tropanes

A Pd/C‐catalyzed cascade approach for the synthesis of attractive benzo‐fused tropanes was developed. The reaction proceeds through a sequential Pd/C‐catalyzed dehydrogenative formation of azomethine ylides from amines and 1,3‐dipolar cycloaddition. It allows the generation of structurally complex benzo‐fused tropanes in good yields with excellent diastereoselectivities under mild reaction conditions. Preliminary results of asymmetric version of the reaction reveal that the copper catalyst and chiral monophosphoramidite ligand can furnish optically active products with moderate ee.

Addition of tryptophan methyl-ester on [60]fullerene: theoretical investigation of the mechanisms of azomethine ylides and fulleropyrrolidine formation.

In this paper, we perform the synthesization of carbon nanoparticles for active principle vectorization, with the suggestion of a reaction mechanism of tryptophan methyl ester addition on [60]fullerene. Firstly, we studied the effect of tryptophan form on its addition reaction on [60]fullerene. So, in order to determine the preferred environment that makes this reaction the most favorable, we considered all tryptophan possible forms in our investigation: the molecular, the zwitterionic, and the dibasic forms. Secondly, we investigate the proposed reaction mechanism of tryptophan methyl ester addition on [60]fullerene using theoretical thermodynamic calculation. Our hypothesis suggests the formation of azomethine ylide molecule in a first step followed by its addition on [60]fullerene in the second step by the photo-addition reaction involving the oxygen in its singlet state. The stability of each reactive intermediate involved in this mechanism is verified thermodynamically. The 12 most stable conformations of azomethine ylide were observed through potential energy surface analysis. They were obtained by a relaxed scan of the four dihedral angles. The calculations were conducted on the optimized geometry of fulleropyrrolidine mono-adduct and the bulk values of its thermodynamic constants were also determined. Infrared spectra observed in 100-4000cm-1 region confirmed our hypothesis suggesting the first step of azomethine ylide formation followed by the second step of azomethine ylide addition on [60]fullerene by ν(Caliphatic-C-N), ν(Caromatic-C-N) and δ(N-H) coupled with ν(C-N) absorption bond. Graphical abstract Optimized geometry of the Fulleropyrrolidine monoaduct molecule.

Development of Novel Preparations for Nitrogen Heterocycles Based on Cascade Reactions

Nitrogen heterocycles are important skeletons in biologically active compounds such as medicines and natural alkaloids. However, in terms of the efficiency of the synthetic process, the many synthetic steps required to achieve the target compounds with complex architectures pose a significant problem. To overcome this challenge, novel approaches were developed to afford biologically active heterocycles, 1,2-diazepines, pyrroloisoquinolines, and pyrrolizidines utilizing cascade reactions that enable multiple bond formation in a one-pot process. This review discusses three one-pot reactions: 1) 1,2-diazepine synthesis from cyclobutenones and lithiodiazoesters via cascade 4π-8π electrocyclization; 2) synthesis of pyrroloisoquinolines from alkynylimino esters triggered by gold-catalyzed azomethine ylide formation; and 3) pyrrolizidine synthesis via three-component coupling reactions of iminoesters, acetylenes, and maleimides through the gold-catalyzed azomethine ylide generation/[3+2]-cycloaddition/enamine cyclization reaction.

Metal-free approach for the ʟ-proline mediated synthesis of nitrones from nitrosobenzene

An efficient, and metal-free approach for the ʟ-proline mediated synthesis of nitrones from nitrosobenzene and benzaldehydes has been established. The reaction undergoes very efficiently at room temperature in methanol as a solvent. The reaction is assumed to involve that the initial formation of azomethine ylide and [2 + 3] cycloaddition of nitrosobenzene, followed by the subsequent retro [2 + 3] cycloaddition could offer the desired nitrone.

Multicomponent synthesis, biological evaluation and molecular docking of new spiro-oxindole derivatives

A new series of spiro-oxindoles that were identified based upon their ability to inhibit methionine tRNA synthase (PDB ID: 1PFV) and glucosamine-6-phosphate synthase (PDB ID: 1JXA) enzymes in virtual screening was synthesized by a three-component 1,3-dipolar cycloaddition method. The reaction proceeds through the formation of azomethine ylides generated in situ by the decarboxylative condensation of isatin and amino acids with dipolarophile chalcones. These compounds are active against Staphylococcus aureus, Escherichia coli, Aspergillus niger and Aspergillus flavus, supporting the in silico screening. In addition, their antitubercular activity was assessed using the MABA method. The compounds 3′-[(4-fluorophenyl)carbonyl]-4′-phenylspiro[indole-3,2′-pyrrolidin]-2(1H)-one 3a, 4′-(4-bromophenyl)-3′-[(4-fluorophenyl)carbonyl]-5′-(hydroxymethyl) spiro[indole-3,2′-pyrrolidin]-2(1H)-one 3e and 4′-(4-chlorophenyl)-3′-[(4-fluorophenyl)carbonyl]-5′-(2-methylpropyl)spiro[indole-3,2′-pyrrolidin]-2(1H)-one 3g are potent molecules with MIC of 0.8μg/mL. In the DPPH radical scavenging assay, compounds 4′-(4-chlorophenyl)-3′-[(4-fluorophenyl)carbonyl]spiro[indole-3,2′-pyrrolidin]-2(1H)-one 3b, 4′-(4-chlorophenyl)-3′-[(4-fluorophenyl)carbonyl]-5′-(hydroxymethyl)spiro[indole-3,2′-pyrrolidin]-2(1H)-one 3d and 4′-(4-bromophenyl)-3′-[(4-fluorophenyl)carbonyl]-5′-(hydroxymethyl)spiro[indole-3,2′-pyrrolidin]-2(1H)-one 3e exhibited significant radical scavenging capacity.

Highly selective intermolecular one-pot three component 1,3-dipolar cycloaddition reaction of aldehydes, with phosphonates and proline

The use of l-proline to act as an organocatalyst in the aldol reaction of acylphosphonates and non enolizable aldehydes failed; however, it reacted with the aldehydes to afford azomethine ylides after decarboxylation that in turn underwent 1,3-dipolar cycloaddition with the acylphosphonates to form a bicyclic hexahydropyrrolo[1,2-c]oxazol-1-ylphosphonates in good yield. No azomethine ylide formation was observed on the reaction of acylphosphonates with proline.

Theoretical investigation on two different mechanisms of fulleropyrrolidine formation

Fulleropyrrolidine synthesis by photo-addition of glycine methyl ester (GME) to [60] fullerene has been recently realized and experimentally studied. Two possible hypotheses were suggested for its formation pathway, but there was no consensus about the most favorable one. Thus, in order to find the most probable mechanism, we performed a detailed theoretical investigation of the reaction between GME and [60] fullerene studying both mechanisms suggested experimentally. The first hypothesis involves two additions of two GME radicals in two steps to C60 followed by a NH3 departure, whereas the second one involves azomethine ylide formation in a first step and followed by a cycloaddition to [60] fullerene. All the transition states and the intermediates in the reaction steps for both mechanisms were determined. The energetic profiles of both mechanisms were drawn and compared. Several levels of theory were used for the purpose, with the aim to investigate which low-cost level is sufficient to settle and which mechanism is probably involved. For the purpose, semiempirical (AM1), DFT on geometries optimized at AM1 level, and finally DFT on geometries optimized at DFT level were considered. At DFT level, GGA (PBE), hybrid (PBE0) and meta-GGA (M06-2X) were used, with a 6-31+G(d) basis set. We proved that the release of NH3 and the ring formation step in the first mechanism require a higher energy barrier compared to the second mechanism reaction steps like tautomerization and H2O departure. Thus, we can conclude that the second mechanism involving in a first step the azomethine ylide formation is more favorable than the first mechanism. The interest in using in a first step a semiempirical determination of reaction paths is highlighted, and the choice of the exchange–correlation functional is discussed.