Acid Catalyzed Diels-Alder Reactions Research Articles

MEDT analysis of mechanism and selectivities in non-catalyzed and lewis acid-catalyzed diels–alder reactions between R-carvone and isoprene

Within the context of Molecular Electronic Density Theory (MEDT), this study investigates the Diels–Alder reaction among isoprene (2) and R-carvone (1R) applying DFT simulations, with and without Lewis acid (LA) catalysis. The results show that carvone (1R) acts as an electrophile and isoprene (2) as a nucleophile in a polar process. LA catalysis increases the electrophilicity of carvone, thereby improving the reactivity and selectivity of the reaction by reducing the activation Gibbs free energy. Parr functions reveal that the C5=C6 double bond is more reactive than the C9=C10 double bond, indicating chemoselectivity. The examination of the Electron Localization Function (ELF) reveals high regio- and stereoselectivity, indicating an asynchronous mechanism for the LA-catalyzed DA reaction. Furthermore, it is suggested that cycloadduct 3 has great anti-HIV potential because it exhibits lower binding energies than azidothymidine (AZT) in the docking studies of cycloadducts 3 and 4 amongst a primary HIV-1protein (1A8O plus 5W4Q).

The Origin of Catalysis and Regioselectivity of Lewis Acid-Catalyzed Diels-Alder Reactions with Tropone.

We have studied the uncatalyzed and Lewis acid (LA)-catalyzed cycloaddition reaction between tropone and 1,1-dimethoxyethene using dispersion-corrected relativistic density functional theory (DFT). The LA catalysts BF3, B(C6H5)3, and B(C6F5)3 efficiently accelerate both the competing [4+2] and [8+2] cycloaddition reactions by lowering the activation barrier up to 12 kcal mol-1 compared to the uncatalyzed reaction. Our study reveals that the LA catalyst promotes both cycloaddition reaction pathways by LUMO-lowering catalysis and demonstrates that Pauli-lowering catalysis is not always the operative catalytic mechanism in cycloaddition reactions. Judicious choice of the LA catalyst can effectively impart regiocontrol of the cycloaddition: B(C6H5)3 furnishes the [8+2] adduct while B(C6F5)3 yields the [4+2] adduct. We discovered that the regioselectivity shift finds its origin in the ability of the LA to absorb distortion by adopting a trigonal pyramidal geometry around the boron atom.

Computational molecular refinement to enhance enantioselectivity by reinforcing hydrogen bonding interactions in major reaction pathway.

Computational analyses have revealed that the distortion of a catalyst and the substrates and their interactions are key to determining the stability of the transition state. Hence, two strategies "distortion strategy" and "interaction strategy" can be proposed for improving enantiomeric excess in enantioselective reactions. The "distortion strategy" is used as a conventional approach that destabilizes the TS (transition state) of the minor pathway. On the other hand, the "interaction strategy" focuses on the stabilization of the TS of the major pathway in which an enhancement of the reaction rate is expected. To realize this strategy, we envisioned the TS stabilization of the major reaction pathway by reinforcing hydrogen bonding and adopted the chiral phosphoric acid-catalysed enantioselective Diels-Alder reaction of 2-vinylquinolines with dienylcarbamates. The intended "interaction strategy" led to remarkable improvements in the enantioselectivity and reaction rate.

Front Cover: How Ionization Catalyzes Diels‐Alder Reactions (Chem. Eur. J. 40/2022)

Ionization of the dienophile is an effective method to enhance the Diels–Alder reaction between buta-1,3-diene and acrylaldehyde. The origin of this ionization catalysis is both a reduction in steric Pauli repulsion and simultaneous enhancement of the orbital interactions between the reactants. Our work demonstrates the similarities and differences between radical–cation and Lewis acid-catalyzed Diels–Alder reactions. More information can be found in the Research Article by T. A. Hamlin, F. M. Bickelhaupt, and co-workers (DOI: 10.1002/chem.202200987).

How Ionization Catalyzes Diels-Alder Reactions.

The catalytic effect of ionization on the Diels‐Alder reaction between 1,3‐butadiene and acrylaldehyde has been studied using relativistic density functional theory (DFT). Removal of an electron from the dienophile, acrylaldehyde, significantly accelerates the Diels‐Alder reaction and shifts the reaction mechanism from concerted asynchronous for the neutral Diels‐Alder reaction to stepwise for the radical‐cation Diels‐Alder reaction. Our detailed activation strain and Kohn‐Sham molecular orbital analyses reveal how ionization of the dienophile enhances the Diels‐Alder reactivity via two mechanisms: (i) by amplifying the asymmetry in the dienophile's occupied π‐orbitals to such an extent that the reaction goes from concerted asynchronous to stepwise and thus with substantially less steric (Pauli) repulsion per reaction step; (ii) by enhancing the stabilizing orbital interactions that result from the ability of the singly occupied molecular orbital of the radical‐cation dienophile to engage in an additional three‐electron bonding interaction with the highest occupied molecular orbital of the diene.

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels-Alder reaction.

The p-TsOH-catalyzed Diels–Alder reaction of 3-(indol-3-yl)maleimides with chalcone in toluene at 60 °C afforded two diastereoisomers of tetrahydropyrrolo[3,4-c]carbazoles, which can be dehydrogenated by DDQ oxidation in acetonitrile at room temperature to give the aromatized pyrrolo[3,4-c]carbazoles in high yields. On the other hand, the one-pot reaction of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones with chalcones or benzylideneacetone in acetonitrile in the presence of p-TsOH and DDQ resulted in polyfunctionalized carbazoles in satisfactory yields. The reaction mechanism included the DDQ oxidative dehydrogenation of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones to the corresponding 3-vinylindoles, their acid-catalyzed Diels–Alder reaction and sequential aromatization process.

Rapid construction of the tricyclic core of annotinine hydrate

A rapid construction of the tricyclic scaffold of annotinine hydrate has been accomplished in only four steps from conveniently available starting materials. This short synthesis featured an efficient Lewis acid-catalyzed Diels–Alder reaction to construct the 4a, 8a- cis -hydroquinoline skeleton and a 5- exo -trig radical cyclization reaction to assemble the γ-butylrolactone motif.

Catalytic hydrotreatment of humins into cyclic hydrocarbons over solid acid supported metal catalysts in cyclohexane

Humins are common undesirable sideproducts during many acid-catalyzed reactions in renewable biomass platform conversion. However, few studies have been reported to the efficient utilization of humins. For the first time, the selective catalytic conversion of biomass-derived humins into cyclic hydrocarbons with high conversion rate and selectivity is presented using a home-made Ru/W-P-Si-O bifunctional catalyst. The multistage polymerization structure of humins was studied through controlled experiments. Results show that the CC bond network can be efficiently depolymerized at a mild reaction temperature of 340–380 °C, catalyzed by the cooperative catalysis of nano-Ru particles and porous strong Lewis solid acid. Particularly, 95.4% conversion of humins was achieved under the optimal condition with up to 88.3% yield of cyclic hydrocarbons. The detailed composition after liquefaction was also analyzed. This study paves the way for the efficient production of cyclic and aromatic hydrocarbons from furan-derived humin polymer through Lewis acid-catalyzed Diels–Alder reactions between furan rings.

3,20-Dihydroxy-13α-19-norpregna-1,3,5(10)-trienes. Synthesis, structures, and cytotoxic, estrogenic, and antiestrogenic effects

New 3,20-dihydroxy-13α-19-norpregna-1,3,5(10)-trienes were synthesized. The effects of these compounds on breast cancer cells and ERα activation were investigated. The scaffold of compounds containing the six-membered ring D′ annulated at 16α,17α-positions was constructed via the Lewis acid catalyzed Diels-Alder reaction of butadiene with 3-methoxy-13α-19-norpregna-1,3,5(10),16-tetraen-20-one 5 under a pressure of 600 MPa. The hydrogenation of primary cyclohexene adduct 6 followed by the one-pot reduction–demethylation (DIBAH) gave target epimeric 3,20-dihydroxy steroids 8a and 8b. The Corey-Chaykovsky reaction of the same conjugated ketone 5 gave a 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH yielded 3,20(R,S)-dihydroxy-16α,17α-methyleno-13α-19-norpregna-1,3,5(10)-triene 10. The hydrogenation of the 16,17-double bond of compound 5 produced a mixture of 17α- and 17β-epimeric ketones, reduction–demethylation of which gave 3,20(S)-dihydroxy-13α,17α-19-norpregna-1,3,5(10)-triene 12a and 3,20(R)-dihydroxy-13α,17β-19-norpregna-1,3,5(10)-triene 12b. All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. All target compounds showed pronounced cytotoxic effect against MCF-7 breast cancer cells and NCI/ADR-RES doxorubicin-resistant cells at micromolar concentrations. The ERα-mediated luciferase reporter gene assay demonstrated that all compounds, except for compound 10, are ERα inhibitors, while cyclopropane compound 10 proved to be an ERα activator. Docking experiments showed that all compounds are well accommodated to LBD ERα but have some differences in the binding mode.

Carbocation Lewis Acid Catalyzed Diels-Alder Reactions of Anthracene Derivatives.

The carbocation salt [Ph3C][BArF] has been identified as a viable Lewis acid catalyst for the Diels-Alder reactions between anthracene derivatives and unsaturated carbonyl compounds with good selectivity and high efficiency.

Mechanisms and Origins of Selectivities of the Lewis Acid-Catalyzed Diels-Alder Reactions between Arylallenes and Acrylates.

The mechanisms of recently reported Lewis acid-catalyzed Diels-Alder reactions of arylallenes and acrylates were studied using density functional theory calculations. A stepwise mechanism involving short-lived zwitterion intermediates is established. The reaction is endo-selective in the presence of Lewis acid catalyst. The [2 + 2] cycloaddition is not observed because of the greater charge separation in the first step of the [2 + 2] cycloaddition. The origins of chirality transfer in the Diels-Alder reaction using chiral arylallenes are uncovered, and the absolute stereochemistry of the product is predicted.

ZrCl4 Catalysed Diastereoselective Synthesis of Spirocarbocyclic Oxindoles via [4+2] Cycloaddition

AbstractSpirocarbocyclic‐oxindole is priviledged scaffold in heterocyclic chemistry, which paved the attention of synthetic chemist due to generation of a new stereocenter. Numerous methodologies have been developed for spirooxindoles but very few methods are available for carbocyclic oxindoles. Most of the reported cycloaddition reactions are five membered rings instead of six membered rings, tethered with oxindole scaffold. Lewis acid catalysed Diels Alder reaction is a comparatively better approach to functionalize this unique scaffold. An efficient diastereoselective synthesis of spirocarbocyclic‐oxindoles with six membered cabocyclic backbone was achieved via ZrCl4 catalyzed [4+2] cycloaddition of α‐ylideneoxindoles with dienes in good to excellent yields within a short span of time.

First catalytic hetero-Diels–Alder reaction of imidazole-2-thiones and in silico biological evaluation of the cycloadducts

The Lewis acid-catalyzed Diels–Alder reactions of suitably substituted imidazole-2-thiones with dienes were studied. It was found that the electron density of the imidazole core influenced the reaction, since electron withdrawing groups led to the novel spiro-derivatives 2 whereas electron donating groups gave rise to the sulfur substituted imidazole derivatives 6. The reaction conditions were optimized and full assignment of all 1H and 13C NMR chemical shifts has been unambiguously achieved. In silico evaluation of the cycloadducts by means of molecular modeling in three different proteins and calculation of ADME-Tox properties was performed.

Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis.

Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels–Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid–Cu2+ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities.

Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis.

Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels–Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid–Cu2+ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities.

Rosin based epoxy coating: Synthesis, identification and characterization

Ketone type derivative of rosin was prepared by dehydrocarboxylation of isomerized abietic acid. Coupling of dipimaryl ketone with maleic anhydride was performed by acetic acid catalyzed Diels–Alder reaction. Afterwards, the dipimaryl ketone was epoxidized to get the corresponding tetra glycidyl ester. The chemical structure of the synthesized products was confirmed by UV, FTIR and 1H NMR spectroscopic analyses. Cured resins using a rosin-based crosslinker and p-phenylene diamine (a commercial crosslinker) were evaluated using dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA) and some preliminary universal coating tests. Results showed that the fully rosin-based epoxy system gave better performance than commercially bisphenol-A based one. This finding was attributed to a liquid crystal behavior of the rosin-based crosslinker. Mesomorphic transition temperature and liquid crystalline texture of the rosin-based crosslinker were investigated by polarized optical microscopy (POM) and differential scanning calorimetry (DSC).

Indium-catalyzed microwave-accelerated pot economic C–C bond formation process towards the ‘dry-media’ synthesis of pyrimidine derivatives

Substituted pyrimidines can be constructed in good yields via a microwave-accelerated C–C bond formation process through Lewis acid catalysed Diels–Alder reaction from easily available uracil diene and electron deficient acetylene carboxylate.

Ultrafast Two-Dimensional Infrared Spectroscopy Resolves the Conformational Change of an Evans Auxiliary Induced by Mg(ClO4)2

Structure determination of reactive species is a key step in understanding reaction mechanisms. We demonstrate the application of polarization-dependent two-dimensional infrared spectroscopy (P2D-IR) as a powerful tool combining structure resolution with ultrafast time resolution. We apply this technique to investigate the substrate-catalyst complexes in a Lewis acid catalyzed Diels-Alder reaction. Using Mg(ClO(4))(2) as a Lewis acid, we found that an additional complex besides the chelate typically postulated as reactive species forms. Experimental access to this new species leads to a deeper understanding of the observed selectivities for the Diels-Alder reaction catalyzed by Lewis acids. Our findings are supported by density functional computations at the M06/6-31+G(d,p) level, including solvent corrections.

ジエンの活性化を基盤とする触媒的Ｄｉｅｌｓ‐Ａｌｄｅｒ反応の開発と生理活性シクロヘキセンオキシド類およびカルバ糖類合成への応用

The base-catalyzed Diels-Alder (DA) reaction is a unique cycloaddition, which comprises the combination of electron deficient dienophiles and dienes having acidic functional groups that are activated by bases. It is quite opposite to the well-known Lewis acid-catalyzed DA reactions that include electron rich dienes and dienophiles that are activated by Lewis acids or Bronsted acids. In our continuous effort to develop the base-catalyzed DA, we have found that three different classes of compounds, 3-hydroxy-2-pyrone, 3-hydroxy-2-pyridone, and α-tropolone can be used as dienes suitable for the DA reaction. All the base-catalyzed DA reactions we have developed are accelerated by mild amine bases and give the corresponding products in quantitative to moderate yields. As well as acid-catalyzed DA reactions, chiral base catalysts and/or chiral dienophiles provide the enantioselective DA reactions. Because the resulting DA adducts that have various functional groups and rigid bicyclic ring systems, are attractive building blocks for natural products, particularly for cyclohexene oxides and carbasugars, some synthetic applications to give biologically active compounds using the DA adducts are described.

Lewis acid-catalyzed Diels-Alder reaction of 2-cyclopentenones with Danishefsky’s diene: double bond isomerization of tetrahydro-1H-indene-1,5(7aH)-diones, and attempts on an asymmetric catalysis

This work describes the investigation of the Diels-Alder reaction of the electron-rich diene trans- 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefskys diene) and the non-activated dienophiles 2-cyclopentenone and 2-methyl-2-cyclopentenone with respect to reactivity, regioselectivity and stereoselectivity. An observed double bond isomerization limits the practicability of 2-cyclopentenone as a dienophile in Diels-Alder reactions. 2-Methyl-2- cylopentenone could be converted quantitatively into one regioisomeric Diels-Alder adduct, however the stereochemical control turned out to be very demanding.