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.     

Benzocyclobutadienes: An Unusual Mode of Access Reveals Unusual Modes of Reactivity

The reaction of an aryne with an alkyne to generate a benzocyclobutadiene (BCB) intermediate is rare. We report here examples of this reaction, revealed by Diels–Alder trapping of the BCB by either pendant or external electron‐deficient alkynes. Mechanistic delineation of the reaction course is supported by DFT calculations. A three‐component process joining the benzyne first with an electron‐rich and then with an electron‐poor alkyne was uncovered. Reactions in which the BCB functions in a rarely observed role as a 4π diene component in Diels–Alder reactions are reported. The results also shed new light on aspects of the hexadehydro‐Diels–Alder reaction used to generate the benzynes.     

Base‐Catalyzed Tandem Michael/Dehydro‐Diels–Alder Reaction of α,α‐Dicyanoolefins with Electron‐Deficient 1,3‐Conjugated Enynes: A Facile Entry to Angularly Fused Polycycles

Angularly fused carbocyclic frameworks and their heteroatom‐substituted analogues exist in many natural products that display a broad and interesting range of biological activities. Preparation of polycyclic products by cycloaddition reactions have been the long‐standing hot topic in the synthetic community. Dehydro‐Diels–Alder (DDA) reactions are one class of dehydropericyclic reactions that are derived conceptually by systematic removal of hydrogen atom pairs. A base‐promoted tandem Michael addition and DDA reaction of α,α‐dicyanoolefins with electron‐deficient 1,3‐conjugated enynes was realized in which a DDA reaction takes place between the arylalkynes and electron‐deficient tetrasubstituted olefin. The control experiments support the stepwise anionic reaction pathway rather than the concerted reaction pathway.     

Diversified Cycloisomerization/Diels–Alder Reactions of 1,6‐Enynes through Bimetallic Relay Asymmetric Catalysis

We report the combination of transition‐metal‐catalyzed diversified cycloisomerization of 1,6‐enynes with chiral Lewis acid promoted asymmetric Diels–Alder reaction to realize asymmetric cycloisomerization/Diels–Alder relay reactions of 1,6‐enynes with electron‐deficient alkenes. A broad spectrum of chiral [5,6]‐bicyclic products could be acquired in high yields (up to 99 %) with excellent diastereoselectivy (>19:1 dr) and enantioselectivity (up to 99 % ee).     

How Lewis Acids Catalyze Diels–Alder Reactions

The Lewis acid(LA)‐catalyzed Diels–Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled‐cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I₂<SnCl₄<TiCl₄<ZnCl₂<BF₃<AlCl₃. Emerging from our activation strain and Kohn–Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels–Alder reaction by a diminished Pauli repulsion between the π‐electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels–Alder reaction by enhancing the donor–acceptor [HOMO_diene–LUMO_dienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.     

Aromaticity and Stability of Azaborines

The influence of the relative boron and nitrogen positions on aromaticity of the three isomeric 1,2‐, 1,3‐, and 1,4‐azaborines has been investigated by computing the extra cyclic resonance energy, NICS(0)_πzz index and by visualizing the π‐electron (de)shielding pattern as a response of the π system to a perpendicular magnetic field. The origin of the known stability trend, in which the 1,2‐/1,3‐isomer is the most/least stable, was examined by using an isomerization energy decomposition analysis. The 1,3‐arrangement of B and N atoms creates a charge separation in the π‐electron system, which was found to be responsible for the lowest stability of 1,3‐azaborine. This charge separation can, in turn, be considered as a driving force for the strongest cyclic π‐electron delocalization, making this same isomer the most aromatic. Despite the well‐known fact that the B?N bond attenuates electron delocalization due to large electronegativity difference between the atoms, the 1,4‐B,N relationship reduces aromaticity to a greater extent by making the π‐electron delocalization more one‐directional (from N to B) than cyclic. Thus, 1,4‐azaborine was found to be the least aromatic. Its lower stability with respect to the 1,2‐isomer was explained by the larger exchange repulsion.     

Bioinspired Intramolecular Diels–Alder Reaction: A Rapid Access to the Highly‐Strained Cyclopropane‐Fused Polycyclic Skeleton

A bioinsipred gold‐catalyzed tandem Diels–Alder/Diels–Alder reaction of an enynal and a 1,3‐diene, forming the highly‐strained benzotricyclo[3.2.1.0^2,7]octane skeleton, was reported. In contrast, a Diels–Alder/Friedel–Crafts tandem reaction occurred instead when silver salts were used as the catalyst. Although both reactions experienced the similar Diels–Alder reaction of a pyrylium intermediate with a 1,3‐diene, they have different reaction mechanisms. The former proceeded with a stepwise Diels–Alder reaction, while the latter one with a concerted one.     

Manganese(I)‐Catalyzed C−H Activation/Diels–Alder/retro‐Diels–Alder Domino Alkyne Annulation featuring Transformable Pyridines

Complexity‐increasing Domino reactions comprising C?H allenylation, a Diels–Alder reaction, and a retro‐Diels–Alder reaction were realized by a versatile catalyst derived from earth‐abundant, non‐toxic manganese. The C?H activation/Diels–Alder/retro‐Diels–Alder alkyne annulation sequence provided step‐economical access to valuable indolone alkaloid derivatives through a facile organometallic C?H activation manifold with transformable pyridines.     

Controlling Covalent Connection and Disconnection with Light

The on‐going need for feature miniaturization and the growing complexity of structures for use in nanotechnology demand the precise and controlled formation of covalent bonds at the molecular level. Such control requires the use of external stimuli that offer outstanding spatial, temporal, as well as energetic resolution. Thus, photoaddressable switches are excellent candidates for creating a system that allows reversible photocontrol over covalent chemical connection and disconnection. Here we show that the formation of covalent bonds between two reagents and their scission in the resulting product can be controlled exclusively by illumination with differently colored light. A furyl‐substituted photoswitchable diarylethene was shown to undergo a reversible Diels–Alder reaction with maleimide to afford the corresponding Diels–Alder adduct. Our system is potentially applicable in any field already relying on the benefits of reversible Diels–Alder reactions.     

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

The first catalytic asymmetric inverse‐electron‐demand (IED) oxa‐Diels–Alder reaction of ortho‐quinone methides, generated in situ from ortho‐hydroxybenzyl alcohols, has been established. By selecting 3‐methyl‐2‐vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho‐hydroxybenzyl alcohols as precursors of dienes and 3‐methyl‐2‐vinylindoles as dienophiles, as well as the hydrogen‐bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa‐Diels–Alder reaction.     

Synthesis of a Phlorin from a Meso‐Fused Anthriporphyrin by a Diels–Alder Strategy

An anthracene‐containing meso‐fused carbaporphyrin, which has extended π‐conjugation pathways as compared to the corresponding naphthalene‐containing carbaporphyrin, has been synthesized. The weak global aromaticity of the anthriporphyrin also allowed its use as the diene for a Diels–Alder reaction with dimethyl acetylenedicarboxylate (DMAD). The resulting phlorin contains an interesting bicyclic structure. Moreover, to the best of our knowledge, this phlorin is the first Diels–Alder adduct of a diene forming part of the global π‐conjugation pathway of an aromatic porphyrinoid.     

Reaction energetics on long‐range corrected density functional theory: Diels–Alder reactions

The possibility of quantitative reaction analysis on the orbital energies of long‐range corrected density functional theory (LC‐DFT) is presented. First, we calculated the Diels–Alder reaction enthalpies that have been poorly given by conventional functionals including B3LYP functional. As a result, it is found that the long‐range correction drastically improves the reaction enthalpies. The barrier height energies were also computed for these reactions. Consequently, we found that dispersion correlation correction is also crucial to give accurate barrier height energies. It is, therefore, concluded that both long‐range exchange interactions and dispersion correlations are essentially required in conventional functionals to investigate Diels–Alder reactions quantitatively. After confirming that LC‐DFT accurately reproduces the orbital energies of the reactant and product molecules of the Diels–Alder reactions, the global hardness responses, the halves of highest occupied molecular orbital (HOMO)‐lowest unoccupied molecular orbital (LUMO) energy gaps, along the intrinsic reaction coordinates of two Diels–Alder reactions were computed. We noticed that LC‐DFT results satisfy the maximum hardness rule for overall reaction paths while conventional functionals violate this rule on the reaction pathways. Furthermore, our results also show that the HOMO‐LUMO gap variations are close to the reaction enthalpies for these Diels–Alder reactions. Based on these results, we foresee quantitative reaction analysis on the orbital energies. © 2012 Wiley Periodicals, Inc.     

Quadruple click reactions for the synthesis of cysteine‐terminated linear multiblock copolymers

Synthesis of cysteine‐terminated linear polystyrene (PS)‐b‐poly(ε‐caprolactone) (PCL)‐b‐poly(methyl methacrylate) (PMMA)/or poly(tert‐butyl acrylate)(PtBA)‐b‐poly(ethylene glycol) (PEG) copolymers was carried out using sequential quadruple click reactions including thiol‐ene, copper‐catalyzed azide–alkyne cycloaddition (CuAAC), Diels–Alder, and nitroxide radical coupling (NRC) reactions. N‐acetyl‐L ‐cysteine methyl ester was first clicked with α‐allyl‐ω‐azide‐terminated PS via thiol‐ene reaction to create α‐cysteine‐ω‐azide‐terminated PS. Subsequent CuAAC reaction with PCL, followed by the introduction of the PMMA/or PtBA and PEG blocks via Diels–Alder and NRC, respectively, yielded final cysteine‐terminated multiblock copolymers. By ¹H NMR spectroscopy, the DP_ns of the blocks in the final multiblock copolymers were found to be close to those of the related polymer precursors, indicating that highly efficient click reactions occurred for polymer–polymer coupling. Successful quadruple click reactions were also confirmed by gel permeation chromatography. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Why can the activation volume of the cycloadduct decomposition in isopolar retro‐Diels–Alder reactions be negative?

Rate constants of the Diels–Alder cycloaddition reaction of anthracene with tetracyanoethylene, enthalpy of solution of reactants and adduct, enthalpy of the reaction in solution, enthalpy and entropy of activation of the forward and retro‐Diels–Alder reactions were determined in 14 solvents. Temperature and pressure effects on the rate of the decomposition of the adduct formed from 9‐chloroanthracene and tetracyanoethylene were studied. Since the electrostriction effect can be excluded from the consideration of the isopolar Diels–Alder reaction, negative values of the activation volume in the retro‐Diels–Alder reactions can be caused by the different possibilities of penetration of the solvent molecules to large steric branched structures of the transition states and adducts. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 42: 117–125, 2010     

Access to 1‐Phospha‐2‐azanorbornenes by Phospha‐aza‐Diels–Alder Reactions

The unprecedented phospha‐aza‐Diels–Alder reaction between an activated electron‐poor imine and 2H‐phospholes yields 1‐phospha‐2‐azanorbornenes in a highly chemoselective and moderately diastereoselective reaction. The intermediate 2H‐phospholes, which act as dienes, are formed in situ from the corresponding 1H‐phospholes. Theoretical calculations confirm that the phospha‐aza‐Diels–Alder reaction is of normal electron demand. The reactive P?N bond in 1‐phospha‐2‐azanorbornenes can be cleaved by nucleophiles leading to the formation of 2,3‐dihydrophospholes.     

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

The first enantioselective total synthesis of (−)‐cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh₂(S‐TBPTTL)₄, and the enone 1,2‐addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain‐promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (−)‐ 1 was completed by a late‐stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.     

Preparation of 3‐arm star polymers (A3) via Diels–Alder click reaction

Diels–Alder click reaction was successfully applied for the preparation of 3‐arm star polymers (A₃) using furan protected maleimide end‐functionalized polymers and trianthracene functional linking agent (2) at reflux temperature of toluene for 48 h. Well‐defined furan protected maleimide end‐functionalized polymers, poly (ethylene glycol), poly(methyl methacrylate), and poly(tert‐butyl acrylate) were obtained by esterification or atom transfer radical polymerization. Obtained star polymers were characterized via NMR and GPC (refractive index and triple detector detection). Splitting of GPC traces of the resulting polymer mixture notably displayed that Diels–Alder click reaction was a versatile and a reliable route for the preparation of A₃ star polymer. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 302–313, 2008     

Stable Pyrrole‐Linked Bioconjugates through Tetrazine‐Triggered Azanorbornadiene Fragmentation

An azanorbornadiene bromovinyl sulfone reagent for cysteine‐selective bioconjugation has been developed. Subsequent reaction with dipyridyl tetrazine leads to bond cleavage and formation of a pyrrole‐linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene‐tagged protein through inverse electron demand Diels–Alder cycloaddition with subsequent double retro‐Diels–Alder reactions to form a stable pyrrole linkage. The sequence of site‐selective bioconjugation followed by bioorthogonal bond cleavage was efficiently employed for the labelling of three different proteins. This method benefits from easy preparation of these reagents, selectivity for cysteine, and stability after reaction with a commercial tetrazine, which has potential for the routine preparation of protein conjugates for chemical biology studies.     

Theoretical and Structural Analysis of Long CC Bonds in the Adducts of Polycyanoethylene and Anthracene Derivatives and Their Connection to the Reversibility of Diels–Alder Reactions

X‐ray structure determinations on four Diels–Alder adducts derived from the reactions of cyano‐ and ester‐substituted alkenes with anthracene and 9,10‐dimethylanthracene have shown the bonds formed in the adduction to be particularly long. Their lengths range from 1.58 to 1.62 Å, some of the longest known for Diels–Alder adducts. Formation of the four adducts is detectably reversible at ambient temperature and is associated with free energies of reaction ranging from ?2.5 to ?40.6 kJ mol^?1. The solution equilibria have been experimentally characterised by NMR spectroscopy. Density‐functional‐theory calculations at the MPW1K/6‐31+G(d,p) level with PCM solvation agree with experiment with average errors of 6 kJ mol^?1 in free energies of reaction and structural agreement in adduct bond lengths of 0.013 Å. To understand more fully the cause of the reversibility and its relationship to the long adduct bond lengths, natural‐bond‐orbital (NBO) analysis was applied to quantify donor–acceptor interactions within the molecules. Both electron donation into the σ*‐anti‐bonding orbital of the adduct bond and electron withdrawal from the σ‐bonding orbital are found to be responsible for this bond elongation.     

Beziehungen zwischen der stereoselektivität zweier diels—alder-reaktionen und den molekularrefraktionen zahlreicher lösungsmittel

The relationships between the steroselectivities and molecular refractions of various solvents for two Diels—Alder reactions of cyclopentadiene and acrylonitrile or methyl acrylate are studied. Good correlations between log (N/X)-values and molecular refractions of solvents are observed. Accordingly, it can be said that polarizabilities of solvents are important factors for the stereoselectivities of the Diels—Alder reactions studied.