Fourfold Diels–Alder Reaction of Tetraethynylsilane

A series of ethynylated silanes, including tetraethynylsilane, was treated with tetraphenylcyclopentadienone at 300 °C under microwave irradiation to give the aromatized Diels–Alder adducts as sterically encumbered mini‐dendrimers with up to 20 benzene rings. The sterically most congested adducts display red‐shifted emission through intramolecular π–π interactions in the excited state.     

The Diels–Alder Reaction in Total Synthesis

The Diels–Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels–Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.     

Industrial Applications of the Diels–Alder Reaction

The Diels–Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large‐scale applications (>1 kg) from a process research and development perspective.     

Enantioselective Organocatalytic Intramolecular Aza‐Diels–Alder Reaction

A highly efficient catalytic enantioselective intramolecular Povarov reaction was developed with primary anilines as 2‐azadiene precursors. A wide variety of angularly fused azacycles were obtained without column chromatography in high to excellent yields and with excellent diastereo‐ and enantioselectivity (d.r.>99:1 and up to e.r. 99:1). Furthermore, the catalyst loading could be lowered to 1 mol %, and the obtained azacycles could be used as key intermediates for further transformations to generate additional molecular diversity.     

Organic Chemistry of Graphene: The Diels–Alder Reaction

Herein, by using dispersion‐corrected density functional theory, we investigated the Diels–Alder chemistry of pristine and defective graphene. Three dienes were considered, namely 2,3‐dimethoxy‐1,3‐butadiene (DMBD), 9‐methylanthracene (9MA), and 9,10‐dimethylanthracene (910DMA). The dienophiles that were assayed were tetracyanoethylene (TCNE) and maleic anhydride (MA). When pristine graphene acted as the dienophile, we found that the cycloaddition products were 47–63 kcal mol^?1 less stable than the reactants, thus making the reaction very difficult. The presence of Stone–Wales translocations, 585 double vacancies, or 555‐777 reconstructed double vacancies did not significantly improve the reactivity because the cycloaddition products were still located at higher energy than the reactants. However, for the addition of 910DMA to single vacancies, the product showed comparable stability to the separated reactants, whereas for unsaturated armchair edges the reaction was extremely favorable. With regards the reactions with dienophiles, for TCNE, the cycloaddition product was metastable. In the case of MA, we observed a reaction product that was less stable than the reactants by 50 kcal mol^?1. For the reactions between graphene as a diene and the dienophiles, we found that the most‐promising defects were single vacancies and unsaturated armchair edges, because the other three defects were much‐less reactive. Thus, we conclude that the reactions with these above‐mentioned dienes may proceed on pristine or defective sheets with heating, despite being endergonic. The same statement also applies to the dienophile maleic anhydride. However, for TCNE, the reaction is only likely to occur onto single vacancies or unsaturated armchair edges. We conclude that the dienophile character of graphene is slightly stronger than its behavior as a diene.     

Recent Progress in Dehydro(genative) Diels–Alder Reaction

In recent years, remarkable progress has been made in dehydro or dehydrogenative Diels–Alder (D–A) reactions. This Minireview gives an overview of the major two strategies for dehydro(genative) Diels–Alder reactions, which differ in dehydrogenation and D–A cyclization sequence. Reactions in which D–A cycloaddition is followed by dehydrogenation are useful methods for the synthesis of various aromatic compounds, whereas advancements in dehydro genative procedures with oxidants or catalysts prior to D–A cycloaddition offer yet further new routes to functionalized cycloadducts. Recent leading findings are highlighted and the current state of the art, scope, and limitations of these processes are discussed in this Minireview.     

New Insights into the Diels–Alder Reaction of Graphene Oxide

Graphene oxide is regarded as a major precursor for graphene‐based materials. The development of graphene oxide based derivatives with new functionalities requires a thorough understanding of its chemical reactivity, especially for canonical synthetic methods such as the Diels–Alder cycloaddition. The Diels–Alder reaction has been successfully extended with graphene oxide as a source of diene by using maleic anhydride as a dienophile, thereby outlining the presence of the cis diene present in the graphene oxide framework. This reaction provides fundamental information for understanding the exact structure and chemical nature of graphene oxide. On the basis of high‐resolution ¹³C‐SS NMR spectra, we show evidence for the formation of new sp³ carbon centers covalently bonded to graphene oxide following hydrolysis of the reaction product. DFT calculations are also used to show that the presence of a cis dihydroxyl and C vacancy on the surface of graphene oxide are promoting the reaction with significant negative reaction enthalpies.     

An Enantioselective Inverse‐Electron‐Demand Imino Diels–Alder Reaction

The imino Diels–Alder reaction is an efficient method for the synthesis of aza‐heterocycles. While different stereo‐ and enantioselective inverse‐electron‐demand imino Diels–Alder (IEDIDA) reactions have been reported before, IEDIDA reactions including electron‐deficient dienes are unprecedented. The first enantioselective IEDIDA reaction between electron‐poor chromone dienes and cyclic imines, catalyzed by zinc/binol complexes is described. The novel reaction provides a facile entry to a natural product inspired collection of ring‐fused quinolizines including a potent modulator of mitosis.     

Liquid‐Crystalline Ionic Liquids as Ordered Reaction Media for the Diels–Alder Reaction

Liquid‐crystalline ionic liquids (LCILs) are ordered materials that have untapped potential to be used as reaction media for synthetic chemistry. This paper investigates the potential for the ordered structures of LCILs to influence the stereochemical outcome of the Diels–Alder reaction between cyclopentadiene and methyl acrylate. The ratio of endo‐ to exo‐product from this reaction was monitored for a range of ionic liquids (ILs) and LCILs. Comparison of the endo:exo ratios in these reactions as a function of cation, anion and liquid crystallinity of the reaction media, allowed for the effects of liquid crystallinity to be distinguished from anion effects or cation alkyl chain length effects. These data strongly suggest that the proportion of exo‐product increases as the reaction media is changed from an isotropic IL to a LCIL. A detailed molecular dynamics (MD) study suggests that this effect is related to different hydrogen bonding interactions between the reaction media and the exo‐ and endo‐transition states in solvents with layered, smectic ordering compared to those that are isotropic.     

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

A 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 (K_d=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 (k_cat=1.8 min^?1, K_NEM=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.     

Biomimetic Dopamine‐Diels–Alder Switches

Mussel adhesives function as tools for surface modifications of a wide variety of materials due to their remarkable adhesion properties. Herein, a combination of bioinspired mussel adhesives based on a dopamine derivative, polymer chemistry, and well‐established Diels–Alder (DA) chemistry leads to a bioinspired switchable surface system that possesses the capability of attaching and detaching specific polymers on demand. A dopaminemaleimide compound, which has been attached to a gold surface under maritime conditions undergoes DA‐ and retro‐DA‐click‐conjugations with cyclopentadiene‐carrying PEG chains. The surface attachment and the subsequent DA/rDA cycles are evidenced via XPS analysis.