Diels-Alder Type Reaction Research Articles

Phukettosides A–E, mono- and bis-iridoid glycosides, from the leaves of Morinda umbellata L

Four undescribed bis-iridoid glycosides, named phukettosides A–D, and one iridoid glycoside, referred to as phukettoside E, were isolated and fully characterized from the leaves of Morinda umbellata L. Phytochemical analysis also revealed the presence of eight known compounds. The structures were determined through extensive analysis of 1D and 2D-NMR spectroscopic and HRMS spectral data, and the absolute configurations of the isolates were deduced through ECD calculations. Biogenetic pathways for the bis-iridoid glycosides, phukettosides A–C, through intermolecular Diels-Alder type reactions, were proposed. The isolated compounds, with the exception of phukettosides B and D, were evaluated against a panel of cancer cell lines (MOLT-3, HuCCA-1, A549, HeLa, HepG2, and MDA-MB-231) and a non-cancerous cell line (MRC-5) for their cytotoxicity. None of the isolates had significant cytotoxic effects on the tested cell lines.

Synthesis of New 1Н-Pyrrolo[3,4-с]pyridine-1,3(2Н)-diones

A method for the synthesis of a series of new substituted 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones was proposed based on the Diels–Alder type reaction of 4-methoxy-1,3-oxazoles with maleimide derivatives.

The Role of Iodine Catalyst in the Synthesis of 22-Carbon Tricarboxylic Acid and Its Ester: A Case Study

Here, 22-carbon tricarboxylic acid (C22TA) and its ester (C22TAE) were prepared via the Diels–Alder reaction of polyunsaturated fatty acids (PUFAs) and their esters (PUFAEs) as dienes with fumaric acid (FA) and dimethyl fumarate (DF) as dienophiles, respectively. The role of an iodine catalyst for the synthesis of C22TA and C22TAE in the Diels–Alder type reaction was investigated using a spectroscopic approach. The chemical structures of the products were characterized using proton nuclear magnetic resonance (1H-NMR) and electrospray ionization mass spectrometry (ESI-MS) analysis. Results showed that nonconjugated dienes can react with dienophiles through a Diels–Alder reaction with an iodine catalyst, and that iodine transformed the nonconjugated double bonds of dienes into conjugated double bonds via a radical process. DF was more favorable for the Diels–Alder reaction than FA. This was mainly because the dienophile DF contained an electron-withdrawing substituent, which reduced the highest and lowest occupied molecular orbital (HOMO–LUMO) energy gap and accelerated the Diels–Alder reaction. By transforming nonconjugated double bonds into conjugated double bonds, iodine as a Lewis acid increased the electron-withdrawing effect of the carbonyl group on the carbon–carbon double bond and reduced the energy difference between the HOMO of diene and the LUMO of dienophile, thus facilitating the Diels–Alder reaction.

Osmanicin, a Polyketide Alkaloid Isolated from Streptomyces osmaniensis CA-244599 Inhibits Elastase in Human Fibroblasts.

The strain Streptomyces osmaniensis CA-244599 isolated from the Comoros islands was submitted to liquid-state fermentation coupled to in situ solid-phase extraction with amberlite XAD-16 resin. Elution of the trapped compounds on the resin beads by ethyl acetate afforded seven metabolites, osmanicin (1), streptazolin (2), streptazone C (3), streptazone B1 (4), streptenol C (5), nocardamine (6) and desmethylenylnocardamine (7). Osmanicin (1) is a newly reported unusual scaffold combining streptazolin (2) and streptazone C (3) through a Diels-Alder type reaction. Experimental evidence excluded the spontaneous formation of 1 from 2 and 3. The isolated compounds were evaluated for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 1 exhibited the most potent activity with an IC50 of 3.7 μM.

Bis-Annulation By Electrocatalysis

We recently reported the application of electrocatalysis to promote Diels-Alder type reactions between electronically mismatched substrates. In this talk, we will describe our new results which showcase bis-annulations. A catalytic amount of electricity was used in these reactions to make two six-rings on bis-anethole derivatives. Currently, more diene partners are under investigation to see the scope of the reaction.

Dimerization of quercetin, Diels-Alder vs. radical-coupling approach: a joint thermodynamics, kinetics, and topological study.

Quercetin is a prototypical antioxidant and prominent member of flavonoids, a large group of natural polyphenols. The oxidation of quercetin may lead to its dimerization, which is a paradigm of the more general polyphenol oligomerization. There exist two opposing mechanisms to describe the dimerization process, namely radical-coupling or Diels-Alder reactions. This work presents a comprehensive rationalization of this dimerization process, acquired from density functional theory (DFT) calculations. It is found that the two-step radical-coupling pathway is thermodynamically and kinetically preferred over the Diels-Alder reaction. This is in agreement with the experimental results showing the formation of only one isomer, whereas the Diels-Alder mechanism would yield two isomers. The evolution in bonding, occurring during these two processes, is investigated using the atoms in molecules (AIM) and electron localization function (ELF) topological approaches. It is shown that some electron density is accumulated between the fragments in the transition state of the radical-coupling reaction, but not in the transition state of the Diels-Alder process. Graphical Abstract Quantum chemistry calculations of the dimerization process of quercetin show that a radical coupling approach is preferred to a Diels-Alder type reaction, in agreement with experimental results. Analysis of the bonding evolution highlights the reaction mechanism.

Reprint of: Synthesis, characterization and radiolabeling of carborane-functionalized tetrazines for use in inverse electron demand Diels–Alder ligation reactions

Carborane-tetrazine derivatives were developed that can be used to enable boron clusters to bind specific targets in vivo using pretargeting strategies and bioorthogonal inverse electron demand Diels–Alder chemistry. Specifically, 1,12-dicarba-closo-dodecaborate-1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)methanamide and 1,2-dicarba-closo-dodecaborate-1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)methanamide were synthesized in 49% and 78% yield respectively, and X-ray structures of both compounds determined. The ortho-carborane derivative was converted to the corresponding nido-cluster under mild conditions, and the product successfully radiolabelled with 125I and 123I. The carborane-tetrazines react rapidly and in quantitative yields with (E)-cyclooct-4-enol (TCO) via a [4 + 2] inverse-electron demand Diels–Alder type reaction, where the second order rate constant in acetonitrile for the iodinated cluster was 199 ± 26 M−1s−1. The labelled tetrazines were stable in solution for extended periods and they were shown to bind in vitro to H520 cells, labelled with a TCO-modified antibody. Imaging studies on the 123I-labeled carborane-tetrazine were performed in healthy mice, and demonstrated minimal loss of iodine in vivo and high uptake in the liver and gall bladder. The reported compounds offer an alternative means of developing targeted boron neutron capture therapy (BNCT) and boron-based molecular imaging agents.

Synthesis, characterization and radiolabeling of carborane-functionalized tetrazines for use in inverse electron demand Diels–Alder ligation reactions

Carborane-tetrazine derivatives were developed that can be used to enable boron clusters to bind specific targets in vivo using pretargeting strategies and bioorthogonal inverse electron demand Diels–Alder chemistry. Specifically, 1,12-dicarba-closo-dodecaborate-1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)methanamide and 1,2-dicarba-closo-dodecaborate-1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)methanamide were synthesized in 49% and 78% yield respectively, and X-ray structures of both compounds determined. The ortho-carborane derivative was converted to the corresponding nido-cluster under mild conditions, and the product successfully radiolabelled with 125I and 123I. The carborane-tetrazines react rapidly and in quantitative yields with (E)-cyclooct-4-enol (TCO) via a [4 + 2] inverse-electron demand Diels–Alder type reaction, where the second order rate constant in acetonitrile for the iodinated cluster was 199 ± 26 M−1s−1. The labelled tetrazines were stable in solution for extended periods and they were shown to bind in vitro to H520 cells, labelled with a TCO-modified antibody. Imaging studies on the 123I-labeled carborane-tetrazine were performed in healthy mice, and demonstrated minimal loss of iodine in vivo and high uptake in the liver and gall bladder. The reported compounds offer an alternative means of developing targeted boron neutron capture therapy (BNCT) and boron-based molecular imaging agents.

Investigation of thermochemistry associated with the carbon-carbon coupling reactions of furan and furfural using ab initio methods.

Upgrading furan and small oxygenates obtained from the decomposition of cellulosic materials via formation of carbon-carbon bonds is critical to effective conversion of biomass to liquid transportation fuels. Simulation-driven molecular level understanding of carbon-carbon bond formation is required to design efficient catalysts and processes. Accurate quantum chemical methods are utilized here to predict the reaction energetics for conversion of furan (C4H4O) to C5-C8 ethers and the transformation of furfural (C5H6O2) to C13-C26 alkanes. Furan can be coupled with various C1 to C4 low molecular weight carbohydrates obtained from the pyrolysis via Diels-Alder type reactions in the gas phase to produce C5-C8 cyclic ethers. The computed reaction barriers for these reactions (∼25 kcal/mol) are lower than the cellulose activation or decomposition reactions (∼50 kcal/mol). Cycloaddition of C5-C8 cyclo ethers with furans can also occur in the gas phase, and the computed activation energy is similar to that of the first Diels-Alder reaction. Furfural, obtained from biomass, can be coupled with aldehydes or ketones with α-hydrogen atoms to form longer chain aldol products, and these aldol products can undergo vapor phase hydrocycloaddition (activation barrier of ∼20 kcal/mol) to form the precursors of C26 cyclic hydrocarbons. These thermochemical studies provide the basis for further vapor phase catalytic studies required for upgrading of furans/furfurals to longer chain hydrocarbons.

Reactivity for the Diels–Alder Reaction of Cumulenes: A Distortion-Interaction Analysis along the Reaction Pathway

Cumulenes, including allene, ketenimine, and ketene, can be employed as dienophiles in Diels-Alder type reactions. The activation energies of a Diels-Alder reaction between cyclopentadiene and either the C ═ C bond or the other C ═ X (X = C, N, or O) bond in cumulenes have been calculated by G3B3, CBS-QB3, M06-2X, and B3LYP methods. The reactivity trend for the C ═ C bond in cumulenes is allene > ketenimine > ketene and that of the C ═ X bond in cumulenes is ketene > allene > ketenimine. Application of distortion-interaction analysis only at transition states does not give a satisfactory explanation for these reactivities. By employing distortion-interaction analysis along reaction pathways, we found that the reactivity of the C ═ C and C ═ X bond in cumulenes is controlled by both of its distortion and interaction energies. The lowest distortion energy of allene leads to its highest reactivity; the higher interaction energy results in higher activation energy of ketene than that of ketenimine. Compared with the reactivity of the C ═ X bond in cumulenes, the C ═ O bond in ketene has the lowest activation energy to react with cyclopentadiene, due to its lowest interaction energy, whereas the lower distortion energy of ketenimine than that of allene leads to a higher reactivity. The distortion energy of the reactants can be attributed to folding ability and molecule strain. The corresponding interaction energy of the reactants is controlled by orbital interaction, closed-shell repulsion, and static repulsion.

Covalent Functionalization of Graphene with Reactive Intermediates

Graphene, a material made exclusively of sp(2) carbon atoms with its π electrons delocalized over the entire 2D network, is somewhat chemically inert. Covalent functionalization can enhance graphene's properties including opening its band gap, tuning conductivity, and improving solubility and stability. Covalent functionalization of pristine graphene typically requires reactive species that can form covalent adducts with the sp(2) carbon structures in graphene. In this Account, we describe graphene functionalization reactions using reactive intermediates of radicals, nitrenes, carbenes, and arynes. These reactive species covalently modify graphene through free radical addition, CH insertion, or cycloaddition reactions. Free radical additions are among the most common reaction, and these radicals can be generated from diazonium salts and benzoyl peroxide. Electron transfer from graphene to aryl diazonium ion or photoactivation of benzoyl peroxide yields aryl radicals that subsequently add to graphene to form covalent adducts. Nitrenes, electron-deficient species generated by thermal or photochemical activation of organic azides, can functionalize graphene very efficiently. Because perfluorophenyl nitrenes show enhanced bimolecular reactions compared with alkyl or phenyl nitrenes, perfluorophenyl azides are especially effective. Carbenes are used less frequently than nitrenes, but they undergo CH insertion and C═C cycloaddition reactions with graphene. In addition, arynes can serve as a dienophile in a Diels-Alder type reaction with graphene. Further study is needed to understand and exploit the chemistry of graphene. The generation of highly reactive intermediates in these reactions leads to side products that complicate the product composition and analysis. Fundamental questions remain about the reactivity and regioselectivity of graphene. The differences in the basal plane and the undercoordinated edges of graphene and the zigzag versus arm-chair configurations warrant comprehensive studies. The availability of well-defined pristine graphene starting materials in large quantities remains a key obstacle to the advancement of synthetic graphene chemistry.

ChemInform Abstract: Microwave‐Assisted Synthesis of Medicinally Relevant Indoles

AbstractReview: 138 refs.

Net reactivity index (Δω)

AbstractA Hammett‐type relationship has been obtained for a set of substituted benzoic acids, in terms of the net electrophilicity index. A new multiphilic descriptor, the net reactivity index (NRI) has been proposed. It can properly describe whether a Diels–Alder type reaction would follow a polar‐stepwise pathway or a non‐polar‐concerted mechanism. It can also clearly delineate whether a reaction is of normal or inverse electron demand type, in case the minimum ionization potential and the maximum electron affinity values do not belong to the same molecule in a diene–dienophile pair. Copyright © 2011 John Wiley & Sons, Ltd.

Chemistry and biosynthesis of isoprenylated flavonoids from Japanese mulberry tree

Many isoprenylated flavonoids have been isolated from Japanese mulberry tree (Moraceae). Among them, kuwanons G (1) and H (2) were the first isolated active substances exhibiting a hypotensive effect. These compounds are considered to be formed through an enzymatic Diels-Alder type reaction between an isoprenyl portion of an isoprenylphenol as the diene and an α, β-double bond of chalcone as the dienophile. The absolute configurations of these Diels-Alder type adducts were confirmed by three different methods. The stereochemistries of the adducts were consistent with those of ones in the Diels-Alder reaction involving exo- and endo-addition. Some strains of Morus alba callus tissues have a high productivity of mulberry Diels-Alder type adducts, such as chalcomoracin (3) and kuwanon J (4). The biosynthetic studies of the mulberry Diels-Alder type adducts have been carried out with the aid of the cell strain. Chalcomoracin (3) and kuwanon J (4) were proved to be enzymatic Diels-Alder type reaction products by the administration experiments with O-methylchalcone derivatives. Furthermore, for the isoprenoid biosynthesis of prenylflavonoids in Morus alba callus tissues by administration of [1,3-13C2]- and [2-13C]-glycerol, a novel way through the junction of glycolysis and pentose-phosphate cycle was proved. Two independent isoprenoid biosynthetic pathways, that for sterols and that for isoprenoidphenols, operate in the Morus alba cell cultures. The former is susceptible to compactin (ML-236) and the latter resists to compactin in the cell cultures, respectively.

Microbial transformation of benzothiophenes, with carbazole as the auxiliary substrate, by Sphingomonas sp. strain XLDN2-5

Benzothiophenes are a toxic and relatively recalcitrant fraction of coal-tar creosote. We investigated the co-metabolic transformation of benzothiophene (BT) and its derivatives by the carbazole (CA) degrader Sphingomonas sp. XLDN2-5, which is not able to grow on benzothiophenes as the sole carbon source. Among the benzothiophenes tested, BT, 2-methylbenzothiophene (2-MBT) and 5-methylbenzothiophene (5-MBT) were co-metabolically converted. For 3-methylbenzothiophene, there was complete inhibition of growth on CA. The common transformation products for BT, 2-MBT and 5-MBT are the corresponding sulfoxides and sulfones. For BT, several high-molecular-mass sulfur-containing aromatic compounds, including benzo[b]naphtho[1,2-d]thiophene, benzo[b]naphtho[1,2-d]thiophene-7-oxide, 6a,11b-dihydrobenzo[b]naphtho[1,2-d]thiophene, 6a,11b-dihydrobenzo[b]naphtho[1,2-d]thiophene-7-oxide, and a new product, 6,12-epithiobenzo[b]naphtho[1,2-d]thiophene, were detected by GC-MS. These high-molecular-mass products are thought to be generated from a Diels-Alder-type reaction. Investigations with a combination of GC and flame ionization detection showed that about 17 % of BT was transformed to benzo[b]naphtho[1,2-d]thiophene. Aerobic transformation of benzothiophenes to sulfoxides and sulfones can reduce their toxicity, and facilitate their biodegradation. However, the formation of the high-molecular-mass products, such as benzo[b]naphtho[1,2-d]thiophene, should be considered in the biodegradation of benzothiophenes.

Hetero Diels—Alder Type Reactions Between Danishefsky′s Dienes in the Presence of Lewis Base Catalysts. An Efficient Method for the Synthesis of Substituted 2,3‐Dihydropyran‐4‐ones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

THE PRESENCE OF POLYCYCLIC AROMATIC HYDROCARBONS (PAH) IN OIL OBTAINED AT PYROLYSIS OF JORDAN OIL SHALE

The presence of polycyclic aromatic hydrocarbons (PAH) in the oil obtained at pyrolysis of Jordan oil shale in a fluidised-bed reactor in the atmosphere of nitrogen and nitrogen/steam has been investigated. The final pyrolysis temperature was 520 °C, at which the maximum oil yield was established. The derived oils were fractionated into chemical classes using mini-column liquid chromatography followed by analysis using capillary column gas chromatography with mass spectrometry (GC/MS) for identification and quantification of PAH. The derived oils were found to contain significant amounts of PAH, mainly naphthalene, fluorene and phenanthrene and their alkylated derivatives, and lower amounts of fluoranthrene, pyrene and chrysene. Some of the PAH found in the derived oils are known to be carcinogenic and/or mutagenic, and consequently the oils may represent a significant environmental and health hazard. The PAH have probably formed via Diels-Alder type reactions or via gas-phase cracking of aliphatic compounds.

Green chemical approaches and tools in the development of environmentally friendly synthetic methods

Addressing the recommendations of the 12 basic lows of green chemistry, the microwave technique was utilized in phospha-Mannich, Diels-Alder and inverse Wittig type reactions, moreover under solventless conditions. In the phase transfer catalysed alkylation of CH-acidic compounds, the quaternary onium salts could be substituted by MW irradiation. The effect of chiral phase transfer catalysts was compared on suitable, potentially enantioselective model reactions. Mono- and bidental P-ligands were developed to make available novel platinum complexes that can be useful as catalysts. Finally, esterifications including diesterifications were studied by in situ Fourier Transform IR spectroscopy.

New Findings on the Diels−Alder Reactions. An Analysis Based on the Bonding Evolution Theory

Two Diels-Alder type reactions, i.e., normal electron demand (NED) between 1,3-butadiene (BD) and acrolein (Acr) and inverse electron demand (IED) between 2,4-pentadienal (PDA) and methyl vinyl ether (MVE), have been investigated using the bonding evolution theory (BET). BET combines topological analysis of the electron localization function (ELF) and catastrophe theory. Catalyst effect has been incorporated through Lewis acid BH3. The B3LYP hybrid HF/DFT method along with 6-31G(d), 6-311++G(d,p) basis sets have been used. All reactions yield two-stage mechanism and there is no topological evidence that they might be concerted with two bonds partially formed during transition structure. A formation of six-membered ring requires 10 (or 11) steps separated by two types of catastrophes: fold and cusp. The first "intermolecular" bond (C1-C6) is formed at 1.93, 1.92 A (NED) and 1.92, 1.97 A (IED). The six-membered ring is "closed" at 2.11, 2.13 A (NED) and 2.5, 2.6 A (IED) via formation of the second bond C4-C5. All reactions begin with "reduction" of C=C bonds to single C-C (cusp catastrophes). Subsequently, the nonbonding electron density is concentrated (fold catastrophes) on terminal C atoms. Finally the new bonds, C1-C6 and C4-C5, are established (cusp catastrophes). Both magnitude and regularity of the electron redistribution, happening during reactions enable us to distinguish two effects: (1) the "ring effect", where a large amount of electron density is regularly transferred from double C=C bonds to intermolecular regions and single C-C bonds, (2) the "side chain effect"--usually weaker and irregular--involving substituents' bonds. In the transition structure, well formed bonding basin V(C1,C6), is observed only for the PDA...BH3/MVE reaction. For other reactions only the nonbonding basins: V(C1) and V(C6), are found in the interaction region C1...C6.

A study on pyrolysis and cross-link formation of poly( p-phenylene butadiyne) by thermoanalysis and spectroscopy

In this study, we prepared a type of arylacetylene, poly( p-phenylene butadiynylene), PPPB, and studied its pyrolysis behavior. A pellet of PPPB maintained its shape and provided a carbonization yield of 94% by heat-treatment at 1000 °C, although it experienced exothermal reaction and partial fusion at approximately 200 °C. It was also found that PPPB did not show graphitization even when it was heat-treated at 3000 °C. X-ray diffraction (XRD) study revealed the breakdown of the initial crystal structure of PPPB at 200 °C and a formation of the carbon structure at above 650 °C. By combining the results of TG–MS, FT-IR, and 13C NMR, a mechanism for pyrolysis of PPPB including the cross-link formation was proposed, which included a Diels–Alder type reaction between the terminal acetylene and the diene structure comprising of diacetylene and phenyl groups, which is facilitated by increased mobility due to the partial fusion and the presence of the terminal acetylene groups.