Normal Electron-demand Diels-Alder Reactions Research Articles

Click Chemistry with Cyclopentadiene.

Cyclopentadiene is one of the most reactive dienes in normal electron-demand Diels-Alder reactions. The high reactivities and yields of cyclopentadiene cycloadditions make them ideal as click reactions. In this review, we discuss the history of the cyclopentadiene cycloaddition as well as applications of cyclopentadiene click reactions. Our emphasis is on experimental and theoretical studies on the reactivity and stability of cyclopentadiene and cyclopentadiene derivatives.

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Role of Orbital Interactions and Activation Strain (Distortion Energies) on Reactivities in the Normal and Inverse Electron-Demand Cycloadditions of Strained and Unstrained Cycloalkenes

The Diels-Alder reactivities of a series of cycloalkenes, from the highly strained cyclopropene to the unstrained cyclohexene, have been studied with density functional theory using the M06-2X functional. The normal electron-demand Diels-Alder reactions with cyclopentadiene and the inverse electron-demand Diels-Alder reactions with 3,6-bis(trifluoromethyl)tetrazine were analyzed using the distortion/interaction-activation strain model. Previous studies showed that activation strain computed from the distorted reactants in the transition structures are larger for unstrained than strained cycloalkenes, and that most of the activation energy differences are accounted for by this difference. We have now analyzed the strain and interaction energy curves for the series of cycloalkenes along the reaction coordinate. Our analyses reveal that the strain curves associated with the distortion of the reactants in the Diels-Alder reactions are nearly identical and that the reactivity differences originate from differences in interaction energies. Analysis of the diene-dienophile interactions reveal that the reactivity trends result from differences in the strength of the primary and secondary orbital interactions.

Bidentate Lewis Acid Catalyzed Domino Diels-Alder Reaction of Phthalazine for the Synthesis of Bridged Oligocyclic Tetrahydronaphthalenes.

A domino process consisting of an inverse and a normal electron-demand Diels-Alder reaction is presented for the formation of bridged tri- and tetracyclic 1,2,3,4-tetrahydronaphthalenes catalyzed by a bidentate Lewis acid. The products were synthesized in a one-pot reaction from commercially available starting materials and contain up to six stereogenic centers. The tetrahydronaphthalenes were isolated as single diastereomers and are derivatives of phenylethylamine, which is well-known as a scaffold of amphetamine or dopamine.

Progress on the Asymmetric Diels-Alder Reaction ofα,β-Unsaturated Carbonyl Compounds

Diels-Alder reaction is a (4+2) concerted cycloaddition reaction, which has attracted considerable attention since its discovery. Asymmetric Diels-Alder reaction is an effective method for synthesis of chiral intermediates, so it was widely applied in the total synthesis of drugs and natural products. α,β-Unsaturated carbonyl compounds are a kind of highly reactive versatile intermediates in organic synthesis, according to its structural characteristics and catalytic types, recent advances in asymmetric normal electron-demand Diels-Alder reaction of α,β-unsaturated carbonyl compounds are reviewed in this paper. Keywords asymmetric Diels-Alder reaction; natural product; organic synthesis; α,β-unsaturated carbonyl compounds

ChemInform Abstract: Regiospecific Inverse Electron Demand Diels—Alder Reactions of 7‐Methylcoumarin‐4‐azadienes.

Condensation of 7-methylcoumarin-4-carbaldehyde with different anilines affords 7-methylcoumarin-4-azadienes. The 7-methylcoumarin-4-azadienes do not undergo normal electron demand Diels–Alder reaction with N-phenylmaleimide, but react with dihydropyran, dihydrofuran, and styrene via inverse electron demand Diels–Alder reaction in the presence of anhydrous ZnCl2. The diene involves the azomethine group and the aniline ring. The product is a mixture of two diastereomers in which the major diastereomer has all the hydrogens at the ring junction in cis configuration.

Facile, Diversity-Oriented, Normal-Electron-Demand Diels–Alder Reactions of 6-Amino-2H-pyran-2-ones with Diethyl Acetylene­dicarboxylate, 1,4-Naphthoquinone, and N-Phenylmaleimide

A series of 6-amino-4-methoxyphenyl-2 H -pyran-2-ones, having an electron-rich diene system, capable of undergoing normal-electron-demand (NED) Diels–Alder reaction, were synthesized. The Diels–Alder reaction of these pyrones with electron-deficient dienophiles – diethyl acetylene dicarboxylate, 1,4-naphthoquinone, and N -phenylmaleimide – followed three different pathways and gave structurally diverse products, aminobenzenes, aminoanthraquinones, and aminopolycyclic diimides, respectively. The amino group at the 6-position activated substantially the pyrone ring towards NED Diels–Alder reaction and the reaction has a potential to generate great structural diversity.

ChemInform Abstract: Clay Catalysis of the Non-Aqueous Diels-Alder Reaction and the Importance of Humidity Control.

Abstract Unmodified kaolin clays are a simple and viable alternative to ferric ion-exchanged montmorillonites as catalysts for the normal electron demand Diels-Alder reaction. Water is the enemy: at 1 – 2 % levels, the stereoselectivity drops by a factor two or three.

Behaviour of selenophenes substituted with electron-withdrawing groups in polar Diels–Alder reactions

The normal electron-demand Diels–Alder reactions between substituted selenophenes, nitro being one of these groups, and dienes of diverse reactivity give benzoselenophenes derivatives.

A novel application of the Diels–Alder reaction: nitronaphthalenes as normal electron demand dienophiles

Thermal reactions between nitronaphthalenes and butadienes were studied. It was demonstrated that these reactions are capable of undergoing the normal electron demand Diels–Alder reaction, with a variety of dienes affording the phenanthrene derivatives. The influence of the extension and type of substitution was also discussed. When the electron-withdrawing activation of the naphthalenic nucleus or the donor properties of the dienes were not enough, N-naphthylpyrroles were detected as main product, suggesting that a competitive reaction would probably take place. The results clearly confirmed the dienophilic nature of nitronaphthalenic double bonds and provided an alternative procedure for phenanthrene derivatives and N-naphthylpyrroles' synthesis. The relative reactivity of the reactants and the viability of the reactions were discussed from a theoretical point of view.

1‐Triflylpyrroles as Efficient Dienophiles in Normal Electron Demand [4 + 2] Cycloaddition Reactions under Pressure.

AbstractFor Abstract see ChemInform Abstract in Full Text.

1-Triflylpyrroles as efficient dienophiles in normal electron demand [4+2] cycloaddition reactions under pressure

1-Triflylpyrroles bearing acetyl group(s) on position 3, or 2 and 4, are efficient dienophiles in normal electron demand Diels-Alder reactions activated by high pressures and Lewis acids.

3‐Nitrocoumarins as Dienophiles in the Diels—Alder Reaction in Water. An Approach to the Synthesis of Nitrotetrahydrobenzo[c]chromenones and Dihydrodibenzo[b,d]furans.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Importance of charge-transfer effects in [4+2] cycloaddition reaction

The self-consistent charge and configuration method for subsystems is used to study the [4+2] cycloaddition of 1- and 2-monosubstituted butadienes (C 4H 5X, X=CN, Cl, F, CH 3, OH, NH 2) with monosubstituted ethylenes (C 2H 3Y, Y=Cl, F, CH 3, OH). All calculations are performed for reactive systems (diene/dienophile) in the transition-state geometries. The system ‘electronic’ activation energies are decomposed into deformation, Heitler-London (the sum of electrostatic and exchange-repulsion), charge-transfer (CT) and polarisation components. It is shown that the CT energy, which is often considered as the starting point for constructing reactivity indicators such as: the frontier orbitals, local softnesses, and Fukui functions, is not responsible for regioselectivity. Such behaviour of CT energy suggests that these criteria have not energetic origin. Nevertheless, the CT energy is the only term, which is very sensitive to the type of substituent in diene and dienophile and depends on donor/acceptor character of the attached substituents. The results obtained confirm the ortho rule of regioselectivity for the normal, inverse, and neutral electron demand Diels-Alder reactions (1-substituted butadienes/ethylenes). The para rule is valid only for normal electron demand Diels-Alder reactions (2-substituted butadienes/ethylenes).

Steric and Electronic Effects on an Antibody‐Catalyzed Diels–Alder Reaction

AbstractA series of substituted thiophene dioxides was tested as diene substrates for the antibody 1E9, which was elicited with a hexachloronorbornene derivative and normally catalyzes the inverse electron‐demand Diels–Alder reaction between 2,3,4,5‐tetrachlorothiophene dioxide (TCTD) and N‐ethylmaleimide (NEM). Previous structural and computational studies had suggested that the catalytic efficiency of this system derives in part from a very snug fit between the apolar active site and the transition state of this reaction. Nevertheless, replacing all the Cl‐atoms in the hapten with Br‐atoms leads to no loss in affinity (Kd=0.1 nM), indicating substantial conformational flexibility in the residues that line the binding pocket. Consistent with this observation, the 2,3,4,5‐tetrabromothiophene dioxide is a good substrate for the antibody (kcat=1.8 min−1, KNEM=14 μM), despite being considerably larger than TCTD. In contrast, normal electron‐demand Diels–Alder reactions between NEM and unsubstituted thiophene dioxide or 2,3,4,5‐tetramethylthiophene dioxide, which are much smaller or nearly isosteric with TCTD, respectively, are not detectably accelerated. These results show that the electronic properties of the 1E9 active site are optimized to a remarkable degree for the inverse electron‐demand Diels–Alder reaction for which it was designed. Indeed, they appear to play a more important role in catalysis than simple proximity effects.

One‐Step Synthesis of 2,9‐Disubstituted Phenanthrenes via Diels—Alder Reactions Using 1,4‐Disubstituted Naphthalenes as Dienophiles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

One-step synthesis of 2,9-disubstituted phenanthrenes via Diels–Alder reactions using 1,4-disubstituted naphthalenes as dienophiles

The normal electron-demand Diels–Alder reaction between 1,4-disubstituted naphthalenes, nitro being one of these two groups, and 1-methoxy-3-trimethylsililoxy-1,3-butadiene gives hydroxyphenanthrene derivatives, the yields being enhanced by placement of more electron-withdrawing groups on the dienophilic system. The nitro group as substituent directs the cycloaddition, and its cis-extrusion as nitrous acid along with the loss of methanol from primary adducts leads to the expected aromatized products.

Electron deficient dienes I. Normal and inverse electron demand Diels-Alder reaction of the same carbon skeleton

The synthesis of compound 11, which features a diene moiety bearing electron withdrawing groups at the 1 and 3 positions, and its completely regioselective inverse electron demand Diels-Alder reactions with 1,1-diethoxyethylene, ethyl vinyl ether and styrene are described. Endo addition is preferred. The direct synthetic precursor of 11, in which one of the electron withdrawing groups (a ketone) is protected, participates in normal electron demand Diels-Alder reactions with 1,4-naphthoquinone and N-phenylmaleimide, but is unreactive towards 1,1-diethoxyethylene.

Transition state stucture and frontier orbital influence on the cycloaddition reactions of 2,5-dimethyl-3,4-dimethylenethiophene with styrenes and benzaldehydes

The biradical 2,5-dimethyl-3,4-dimethylenethiophene reacts with styrenes and benzaldehydes to give fused cycloadducts. The effect of substituents on the efficiency of the benzaldehyde trapping reaction resembles that of normal electron-demand Diels-Alder reactions and is linear with the Hammett σ-constant. With the styrenes, the Hammett plot is non-linear. Frontier orbital theory provides a rationalization of these effects in terms of the uniquely HOMO-LUMO gap characteristic of biradicals.

Clay catalysis of the non-aqueous diels-alder reaction and the importance of humidity control

Unmodified kaolin clays are a simple and viable alternative to ferric ion-exchanged montmorillonites as catalysts for the normal electron demand Diels-Alder reaction. Water is the enemy: at 1 – 2 % levels, the stereoselectivity drops by a factor two or three.