Cycloaddition Of Azomethine Ylides Research Articles

Catalyst-Controlled Chemodivergent [3+3] and [3+2] Formal Cycloadditions of Azomethine Ylides with Diphenylcyclopropenone

AbstractChemodivergent cycloadditions of azomethine ylides with diphenylcyclopropenone involving either Cu-catalyzed [3+3] or Ag-catalyzed [3+2] processes have been developed. These transformations provide a highly efficient method for the preparation of a variety of aromatic substituted dihydropyridinones and dihydropyrrolones with excellent regio and diasteroselectivities.

Zinc-Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides Using Planar Chiral [2.2]Paracyclophane-Imidazoline N,O-ligands.

We present a facile synthetic route toward a novel series of imidazolinyl‐[2.2]paracyclophanol (UCD‐Imphanol) ligands possessing central and planar chirality. Both sets of diastereomeric ligands were successfully purified by column chromatography. The preliminary application of this family of ligands showed excellent activities in the asymmetric Zn‐catalyzed azomethine ylide cycloaddition. Enantioenriched pyrrolidines, in a substrate scope of 20 examples, were accessed in high levels of endo/exo ratios (up to >99/1) and enantioselectivities (up to >99 % ee) with excellent yields (up to 99 %) by using (S,S,S P)‐UCD‐Imphanol/(S,S,R P)‐UCD‐Imphanol, respectively.

Zinc‐Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides Using Planar Chiral [2.2]Paracyclophane‐Imidazoline N,O‐ligands

AbstractWe present a facile synthetic route toward a novel series of imidazolinyl‐[2.2]paracyclophanol (UCD‐Imphanol) ligands possessing central and planar chirality. Both sets of diastereomeric ligands were successfully purified by column chromatography. The preliminary application of this family of ligands showed excellent activities in the asymmetric Zn‐catalyzed azomethine ylide cycloaddition. Enantioenriched pyrrolidines, in a substrate scope of 20 examples, were accessed in high levels of endo/exo ratios (up to >99/1) and enantioselectivities (up to >99 % ee) with excellent yields (up to 99 %) by using (S,S,SP)‐UCD‐Imphanol/(S,S,RP)‐UCD‐Imphanol, respectively.

Regio- and stereoselectivity of the 1,3-dipolar cycloaddition of azomethine ylides to (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones: A combined experimental and theoretical study

Functionalized oxindoles and pyrrolizidines form the central structural framework for numerous natural products with extensive biological and pharmacological applications. The requirement for high regio- and stereoselectivity is the main obstacle in the synthesis of such five-membered heterocycles. Multicomponent cycloaddition reactions often provide an efficient and straightforward approach for the preparation of specific regio- and stereoisomers. In this article, the regio- and stereochemistry of the polar [3 + 2]-cycloaddition (32CA) reaction of azomethine ylides prepared by the reaction of isatin derivatives and L-proline with a series of ( E )-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones was investigated by experimental and theoretical methods. Among the isatin and ( E )-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives, a remarkable inversion of regioselectivity was observed in the 32CA reaction of azomethine ylide generated by the reaction of L-proline and 5-chloroisatin or N -methyl-5-chloroisatin with ( E )-5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one. The regio- and stereochemical assignment of the structures of the cycloaddition products was determined by one- and two-dimensional (1D&2D) homonuclear and heteronuclear correlation nuclear magnetic resonance spectroscopy. The molecular mechanism as well as the regio- and stereoselectivity of the cycloaddition were investigated by means of global and local reactivity indices and a density functional theory (DFT) and explained in detail on the basis of the transition state stabilities of the reactants.

Synthesis of Bioactive Fluoropyrrolidines through 1,3-Dipolar Cycloadditions of Azomethine Ylides

Synthesis of Bioactive Fluoropyrrolidines through 1,3-Dipolar Cycloadditions of Azomethine Ylides

New Insights and Predictions into Complex Homogeneous Reactions Enabled by Computational Chemistry in Synergy with Experiments: Isotopes and Mechanisms

ConspectusHomogeneous catalysis and biocatalysis have been widely applied in synthetic, medicinal, and energy chemistry as well as synthetic biology. Driven by developments of new computational chemistry methods and better computer hardware, computational chemistry has become an essentially indispensable mechanistic "instrument" to help understand structures and decipher reaction mechanisms in catalysis. In addition, synergy between computational and experimental chemistry deepens our mechanistic understanding, which further promotes the rational design of new catalysts. In this Account, we summarize new or deeper mechanistic insights (including isotope, dispersion, and dynamical effects) into several complex homogeneous reactions from our systematic computational studies along with subsequent experimental studies by different groups. Apart from uncovering new mechanisms in some reactions, a few computational predictions (such as excited-state heavy-atom tunneling, steric-controlled enantioswitching, and a new geminal addition mechanism) based on our mechanistic insights were further verified by ensuing experiments.The Zimmerman group developed a photoinduced triplet di-π-methane rearrangement to form cyclopropane derivatives. Recently, our computational study predicted the first excited-state heavy-atom (carbon) quantum tunneling in one triplet di-π-methane rearrangement, in which the reaction rates and 12C/13C kinetic isotope effects (KIEs) can be enhanced by quantum tunneling at low temperatures. This unprecedented excited-state heavy-atom tunneling in a photoinduced reaction has recently been verified by an experimental 12C/13C KIE study by the Singleton group. Such combined computational and experimental studies should open up opportunities to discover more rare excited-state heavy-atom tunneling in other photoinduced reactions. In addition, we found unexpectedly large secondary KIE values in the five-coordinate Fe(III)-catalyzed hetero-Diels-Alder pathway, even with substantial C-C bond formation, due to the non-negligible equilibrium isotope effect (EIE) derived from altered metal coordination. Therefore, these KIE values cannot reliably reflect transition-state structures for the five-coordinate metal pathway. Furthermore, our density functional theory (DFT) quasi-classical molecular dynamics (MD) simulations demonstrated that the coordination mode and/or spin state of the iron metal as well as an electric field can affect the dynamics of this reaction (e.g., the dynamically stepwise process, the entrance/exit reaction channels).Moreover, we unveiled a new reaction mechanism to account for the uncommon Ru(II)-catalyzed geminal-addition semihydrogenation and hydroboration of silyl alkynes. Our proposed key gem-Ru(II)-carbene intermediates derived from double migrations on the same alkyne carbon were verified by crossover experiments. Additionally, our DFT MD simulations suggested that the first hydrogen migration transition-state structures may directly and quickly form the key gem-Ru-carbene structures, thereby "bypassing" the second migration step. Furthermore, our extensive study revealed the origin of the enantioselectivity of the Cu(I)-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with β-substituted alkenyl bicyclic heteroarenes enabled by dual coordination of both substrates. Such mechanistic insights promoted our computational predictions of the enantioselectivity reversal for the corresponding monocyclic heteroarene substrates and the regiospecific addition to the less reactive internal C═C bond of one diene substrate. These predictions were proven by our experimental collaborators. Finally, our mechanistic insights into a few other reactions are also presented. Overall, we hope that these interactive computational and experimental studies enrich our mechanistic understanding and aid in reaction development.

Diastereoselective cycloaddition of isatin azomethine ylides to 5-arylidene-2-thiohydantoins bearing 3-positioned chiral substituent

1,3-Dipolar cycloaddition of azomethine ylide, generated from isatin and sarcosine, with 5-arylidene-2-thiohydantoins equipped with various chiral substituents at the N3 atom occurs diastereoselectively. The highest selectivity with dr = 5 : 1 was observed for the 2-thiohydantoin bearing 1,2-diphenylethyl substituent.

Synthesis of a π-Extended Azacorannulenophane Enabled by Strain-Induced 1,3-Dipolar Cycloaddition.

The first example of a cyclophane bearing a nitrogen-containing buckybowl was synthesized via sequential 1,3-dipolar cycloaddition and palladium-catalyzed intramolecular cyclization. The key to the successful synthesis is the strain-induced 1,3-dipolar cycloaddition of a polycyclic aromatic azomethine ylide to the K-region of [7](2,7)pyrenophane. The resulting π-extended azacorannulenophane exhibits intriguing structural and physical properties, including unique variation of bowl depth, extraordinarily high-field chemical shifts in its 1 H NMR spectrum, a decreased HOMO-LUMO gap, and a red shift in the absorption/emission spectrum, when compared to those of the parent azacorannulene. These characteristics are derived from both the π-extension to the polycyclic aromatic system in the cyclophane structure and the increased curvature enforced by the seven-carbon aliphatic chain.

Synthesis of a π‐Extended Azacorannulenophane Enabled by Strain‐Induced 1,3‐Dipolar Cycloaddition

AbstractThe first example of a cyclophane bearing a nitrogen‐containing buckybowl was synthesized via sequential 1,3‐dipolar cycloaddition and palladium‐catalyzed intramolecular cyclization. The key to the successful synthesis is the strain‐induced 1,3‐dipolar cycloaddition of a polycyclic aromatic azomethine ylide to theK‐region of [7](2,7)pyrenophane. The resulting π‐extended azacorannulenophane exhibits intriguing structural and physical properties, including unique variation of bowl depth, extraordinarily high‐field chemical shifts in its1H NMR spectrum, a decreased HOMO–LUMO gap, and a red shift in the absorption/emission spectrum, when compared to those of the parent azacorannulene. These characteristics are derived from both the π‐extension to the polycyclic aromatic system in the cyclophane structure and the increased curvature enforced by the seven‐carbon aliphatic chain.

Isolation of phytochemicals from Dolichandrone atrovirens followed by semisynthetic modification of ixoside via azomethine ylide cycloaddition; computational approach towards chemo-selection

Aims of the study were the phytochemical investigation and chemical transformation of isolated compounds of medicinal plant listed in ‘Ayurveda’ like Dolichandrone atrovirens, endemic to Indian subcontinents. From chloroform extract of D. atrovirens four compounds; Ursolic acid (1), Maslinic acid (2), Lupeol (3), β-sitosterol (4) and from methanol extract five compounds; β-sitosterol-3-O-β-D-glucopyranoside (5), 10-O-trans-p-Methoxycinnamoylcatalpol (6), Kaempferol-3-O-β-D-glucopyranoside (7), 6-O-[6"(S)-hydroxy-2",6"dimethyl-2"(E)-7"-octadienoyl] catalpol (8) and Ixoside (9) were isolated. Ixoside was used for the semi-synthetic modification via azomethine ylide cycloaddition leading to novel spiro-oxindolo-pyrrolizidine adduct. The structures of novel adducts were elucidated by analysis of IR, MS and 1 D/2D NMR data. Furthermore, to confirm the chemo selection of only one double bond, we performed density functional theory (DFT) calculation, which confirms the chemo selectivity. In addition, in-silico ADME studies and atom-additive approach based on SASA was also examined for the molecules which suggest that they may be potential future candidates for drug discovery.

5‐Indolylidene‐2‐iminothiazolidin‐4‐ones – Convenient Starting Compounds for Stereoselective Synthesis of Novel Dispirooxindole Derivatives

AbstractA convenient method for the synthesis of novel dispirooxindoles containing 2‐iminothiazolidin‐4‐one moiety has been proposed. The method relies on a 1,3‐dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N‐alkyl amino acids including chiral ones to 5‐indolylidene‐2‐iminothiazolidin‐4‐ones. The method is suitable for preparing enantiomerically pure derivatives.

Catalytic enantioselective intramolecular 1,3-dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles.

An enantioselective synthesis of polycyclic fluorinated pyrrolidines has been achieved by Cu-catalyzed intramolecular 1,3-dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles. The method displays a wide scope and afforded the desired cycloadducts in high yields with up to 99% ee. These results demonstrate that fluoroalkyl substituents are excellent activating groups in this transformation.

Synthesis of bioactive fluoropyrrolidines via copper(i)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, and the development of efficient methods for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, incorporating fluorine containing groups into small molecules often changes their activities to a great extent due to the special physicochemical properties of fluorine atoms. Herein, we report an efficient route to obtain enantioenriched 3,3-difluoro- and 3,3,4-trifluoropyrrolidinyl derivatives by Cu(i)-catalysed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluorostyrenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and with excellent stereoselectivities (up to >20 : 1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant fungi showed that some products possess general and high biological activities; comparison with the low antifungal activities of corresponding nonfluorinated compounds revealed that the fluorine atoms at the pyrrolidinyl rings play a crucial role in the antifungal activity.

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.

1,3-Dipolar cycloaddition of azomethine ylides and imidoyl halides for synthesis of π-extended imidazolium salts

A new synthetic approach to π-extended imidazolium salts is developed based on 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with imidoyl chlorides in the presence of cesium fluoride as a key additive.

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.

Asymmetric 1,3-dipolar cycloaddition of 4-amino pyrazolone-based azomethine ylides: a straightforward approach to spiropyrazolones

An asymmetric [3 + 2] cycloaddition of 4-amino pyrazolone-derived azomethine ylides with α,β-enones has been established for the synthesis of 4-spiropyrazolone derivatives with four contiguous stereocenters.

Catalytic asymmetric construction of dispirotriheterocyclic structures through [3+2] cycloadditions of 4-amino pyrazolone-based azomethine ylides

An efficient and convenient catalytic asymmetric [3+2] cycloaddition of 4-amino pyrazolone-based azomethine ylides was developed, which delivers the multi-pharmacophore-containing dispirotriheterocyclic scaffolds with excellent stereoselectivities.

Azomethine ylide cycloaddition of 1,3-dienyl esters: highly regio- and diastereoselective synthesis of functionalized pyrrolidinochromenes.

An efficient protocol for the synthesis of tricyclic pyrrolidinochromenes has been developed via an intramolecular 1,3-dipolar cycloaddition of azomethine ylides generated in situ from 1,3-dienyl ester tethered O-hydroxyarylaldehyde and glycine esters. The reaction is highly regio- and diastereoselective in nature and provided the potentially bioactive pyrrolidine fused tricyclic cycloadducts in excellent yields with wide substrate scope. Interestingly this reaction constructs two rings and four contiguous stereogenic centers in which one of them is an all carbon quaternary center in a unique fashion.

An Experimental and Theoretical Study of the 1,3-Dipolar Cyclo­addition of Alloxan-Derived Azomethine Ylides to Cyclopropenes

AbstractA diastereoselective synthesis of biologically interesting spirobarbiturates has been achieved via [3+2] cycloaddition of alloxan-derived azomethine ylides to 3-R-1,2-diphenylcyclopropenes. With this approach, a range of spirobarbiturate-3-azabicyclo[3.1.0]hexanes and spirobarbiturate-cyclopropa[a]pyrrolizines were obtained in moderate to good yields with excellent diastereoselectivities. DFT calculations (M11 density functional theory) were carried out to shed light on the molecular mechanism of 1,3-dipolar cycloaddition of alloxan-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some obtained compounds against human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.