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.     

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4‐oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α‐silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels–Alder cycloaddition through a point‐chirality, axial‐chirality, point‐chirality transfer process.     

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.     

Mn‐Catalyzed Dehydrocyanative Transannulation of Heteroarenes and Propargyl Carbonates through C−H Activation: Beyond the Permanent Directing Effects of Pyridines/Pyrimidines

Pyridines/pyrimidines are common and effective directing groups in C?H activation. However, they are poorly functionalizable heteroarenes. Reported in this work is Mn‐catalyzed dehydrocyanative transannulation between three classes of heteroarenes and propargyl carbonates. The pyridyl/pyrimidyl groups in the heteroarenes initially function as directing groups to enable C?H allenylation; they then undergo intramolecular Diels–Alder/retro‐Diels–Alder reactions with the allene moiety to afford fused carbo/heterocycles. Three key intermediates at different stages of the reaction were isolated.     

Chiral Dawson‐Type Hybrid Polyoxometalate Catalyzes Enantioselective Diels–Alder Reactions

Can achiral organocatalysts linked to chiral polyanionic metal oxide clusters provide good selectivity in enantioselective C?C bond formations? The answer to this question is investigated by developing a new active hybrid polyoxometalate‐based catalyst for asymmetric Diels–Alder reaction. Chirality transfer from the chiral anionic polyoxometalate to the covalently linked achiral imidazolidinone allows Diels–Alder cycloaddition products to be obtained with good yields and high enantioselectivities when using cyclopentadiene and acrylaldehydes as partners.     

From Enantiopure Hydroxyaldehydes to Complex Heterocyclic Scaffolds: Development of Domino Petasis/Diels–Alder and Cross‐Metathesis/Michael Addition Reactions

One‐step assembly of hexahydroisoindole scaffolds by a sequence that combines the Petasis (borono‐Mannich) and Diels–Alder reactions is described. The unique selectivity observed experimentally was confirmed by quantum calculations. The current method is applicable to a broad range of substrates, including free sugars, and holds significant potential to efficiently and stereoselectively build new heterocyclic structures. This easy and fast entry to functionalized polycyclic compounds can be pursued by further transformations, for example, additional ring closure by a cross‐metathesis/Michael addition domino sequence.     

Rolf Huisgen's Classic Studies of Cyclic Triene Diels–Alder Reactions Elaborated by Modern Computational Analysis

Rolf Huisgen explored the Diels–Alder reactions of 1,3,5‐cycloheptatriene (CHT) and cyclooctatetraene (COT) with the dienophiles maleic anhydride and 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione (PTAD) to determine the kinetics and mechanisms of various electrocyclizations and Diels–Alder reactions. These reactions have been examined with density functional theory. Modern computational chemistry has provided information not previously available by experiment. Transition states for all the reactions have been identified, and their Gibbs energies are used to explain the experimental reactivities. Zwitterionic intermediates were not found in the [4+2] cycloadditions of both CHT or COT with PTAD and are thus not involved in these reactions. [2+2+2] cycloadditions, as an alternative path to the Diels–Alder products, are highly disfavored. Rapid double nitrogen inversion was found for the cycloaddition products with PTAD.     

Synthesis of C1-Substituted 7-Oxanorbornadienes

7-Oxanorbornadienes are valuable synthetic intermediates as they can serve as general templates to create highly substituted ring systems. However, to date, only very few C1-substituted 7-oxanorbornadienes have been synthesized and can be found in the literature. In this article, synthesis of some C1-substituted 7-oxanorbornadienes was achieved by the Diels–Alder reaction between 2-substituted furans and dimethylacetylene dicarboxylate. Moderate to good yields (13–85%) of the Diels–Alder reactions were observed. These C1-substituted 7-oxanorbornadienes will find applications as valuable synthetic intermediates and are useful in the studies of transition-metal-catalyzed reactions.     

“Self‐Lockable” Liquid Crystalline Diels–Alder Dynamic Network Actuators with Room Temperature Programmability and Solution Reprocessability

Novel main‐chain liquid crystalline Diels—Alder dynamic networks (LCDANs) were prepared that exhibit unprecedented ease for actuator programming and reprocessing compared to existing liquid crystalline network (LCN) systems. Following cooling from 125 °C, LCDANs are deformed with aligned mesogens self‐locked at room temperature by slowly formed Diels–Alder (DA) bonds, which allows for the formation of solid 3D actuators capable of reversible shape change, and strip walker and wheel‐capable light‐driven locomotion upon either thermally or optically induced order–disorder phase transition. Any actuator can readily be erased at 125 °C and reprogrammed into a new one under ambient conditions. Moreover, LCDANs can be processed directly from melt (for example, fiber drawing) and from solution (for example, casting tubular actuators), which cannot be achieved with LCNs using exchangeable covalent bonds. The combined attributes of LCDANs offer significant progress toward developing easily programmable/processable LCN actuators.     

Strain‐Promoted Reaction of 1,2,4‐Triazines with Bicyclononynes

Strain‐promoted inverse electron‐demand Diels–Alder cycloaddition (SPIEDAC) reactions between 1,2,4,5‐tetrazines and strained dienophiles, such as bicyclononynes, are among the fastest bioorthogonal reactions. However, the synthesis of 1,2,4,5‐tetrazines is complex and can involve volatile reagents. 1,2,4‐Triazines also undergo cycloaddition reactions with acyclic and unstrained dienophiles at elevated temperatures, but their reaction with strained alkynes has not been described. We postulated that 1,2,4‐triazines would react with strained alkynes at low temperatures and therefore provide an alternative to the tetrazine cycloaddition reaction for use in in vitro or in vivo labelling experiments. We describe the synthesis of a 1,2,4‐triazin‐3‐ylalanine derivative fully compatible with the fluorenylmethyloxycarbonyl (Fmoc) strategy for peptide synthesis and demonstrate its reaction with strained bicyclononynes at 37 °C with rates comparable to the reaction of azides with the same substrates. The synthetic route to triazinylalanine is readily adaptable to late‐stage functionalization of other probe molecules, and the 1,2,4‐triazine‐SPIEDAC therefore has potential as an alternative to tetrazine cycloaddition for applications in cellular and biochemical studies.     

Identification of new flavan‐3‐ol monoglycosides by UHPLC‐ESI‐Q‐TOF in grapes and wine

Flavan‐3‐ol monoglycosides, having four aglycons (+)‐catechin, (?)‐epicatechin, (?)‐epigallocatechin and epicatechin gallate monomeric units, are detected for the first time in Vitis vinifera L. cv. Merlot grape seeds and wine. These compounds were analyzed in red wine, seed and skin extracts by electrospray ionization quadrupole time of flight mass spectrometry (MS) in negative mode. Fragment ions derived from retro‐Diels Alder, heterocyclic ring fragmentation, benzofuran forming fragmentation and glycoside fragmentations were detected in targeted MS/MS mode. These compounds were not detected in skins; the comparative study showed evidence that these glycosylated compounds originate only from grape seeds. Our method allows for the identification of these glycosylated compounds based on their exact mass and their specific fragmentation pattern. However, exact glucose position on the monomeric units can not be determined. This work allowed us to partially identify 14 new flavan‐3‐ol monoglycosides, based on the exact mass of the molecular ions and their specific retro‐Diels Alder, heterocyclic ring fragmentation, benzofuran forming fragmentation and glycoside fragmentations. Copyright © 2012 John Wiley & Sons, Ltd.     

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     

Catalytic Asymmetric Diels–Alder Reaction of Quinone Imine Ketals: A Site‐Divergent Approach

The catalytic asymmetric Diels–Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl‐substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels–Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3‐alkyl quinone imine ketals from the inherently favored unsubstituted C?C bond to the disfavored alkyl‐substituted C?C bond.     

Regioselective Synthesis of Polycyclic and Heptagon‐embedded Aromatic Compounds through a Versatile π‐Extension of Aryl Halides

A versatile π‐extension reaction was developed based on the three‐component cross‐coupling of aryl halides, 2‐haloarylcarboxylic acids, and norbornadiene. The transformation is driven by the direction and subsequent decarboxylation of the carboxyl group, while norbornadiene serves as an ortho ‐C−H activator and ethylene synthon via a retro‐Diels–Alder reaction. Comprehensive DFT calculations were performed to account for the catalytic intermediates.     

Synthesis of dimethyl heterocyclic‐o‐dicarboxylates using dimethyl acetylenedicarboxylate

Dimethyl acetylenedicarboxylate (DMAD) is a very important and useful reagent for the preparation of dimethyl heterocyclic‐o‐dicarboxylates, which are key intermediates in the synthesis of fused pyridazine derivatives. The synthesis of thiopyranes by the Diels‐Alder reaction of dithiocarboxylate derivatives, synthesis of various cyclazines by [2 + 8] cycloaddition reactions, and synthesis of dimethyl pyrazolo[3,4‐b]pyridine‐5,6‐dicarboxylates and polycyclic heterocycles containing the 1,6‐naphthyridine ring system by the reaction of o‐aminonitrile compounds with DMAD are described here.     

Ynamide Carbopalladation: A Flexible Route to Mono‐, Bi‐ and Tricyclic Azacycles

Bromoenynamides represent precursors to a diversity of azacycles by a cascade sequence of carbopalladation followed by cross‐coupling/electrocyclization, or reduction processes. Full details of our investigations into intramolecular ynamide carbopalladation are disclosed, which include the first examples of carbopalladation/cross‐coupling reactions using potassium organotrifluoroborate salts; and an understanding of factors influencing the success of these processes, including ring size, and the nature of the coupling partner. Additional mechanistic observations are reported, such as the isolation of triene intermediates for electrocyclization. A variety of hetero‐Diels–Alder reactions using the product heterocycles are also described, which provide insight into Diels–Alder regioselectivity.     

A Well‐Defined Aluminum‐Based Lewis Acid as an Effective Catalyst for Diels–Alder Transformations

A catalytically active aluminum‐based system for Diels–Alder transformations is reported. The system was generated by mixing a β‐diketiminate‐stabilized aluminum bistriflate compound with Na[BAr^Cl₄] (Ar^Cl=3,5‐Cl₂C₆H₃). Solid‐state analysis of the catalytic system reveals a unique structure incorporating a two‐dimensional coordination polymer. According to the experimental results obtained from several Diels–Alder transformations, the aluminum‐based system appears to be a more practical and more robust alternative to the recently reported compounds based on carbon and silicon cations.     

Reactivity of Single‐Walled Carbon Nanotubes in the Diels–Alder Cycloaddition Reaction: Distortion–Interaction Analysis along the Reaction Pathway

Diels–Alder cycloaddition is one of the most powerful tools for the functionalization of single‐walled carbon nanotubes (SWCNTs). Density functional theory at the B3‐LYP level of theory has been used to investigate the reactivity of different‐diameter SWCNTs (4–9,5) in Diels–Alder reactions with 1,3‐butadiene; the reactivity was found to decrease with increasing SWCNT diameter. Distortion/interaction analysis along the whole reaction pathway was found to be a better way to explore the reactivity of this type of reaction. The difference in interaction energy along the reaction pathway is larger than that of the corresponding distortion energy. However, the distortion energy plots for these reactions show the same trend. Therefore, the formation of the transition state can be determined from the interaction energy. A lower interaction energy leads to an earlier transition state, which indicates a lower activation energy. The computational results also indicate that the original distortion of the SWCNTs leads to an increase in the reactivity of the SWCNTs.     

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.     

Influence of substituent groups at the 3‐position on the mass spectral fragmentation pathways of cephalosporins

The structural fragment ions of nine cephalosporins were studied by electrospray ionization quadrapole trap mass spectrometry (Q‐Trap MSⁿ) in positive mode. The influence of substituent groups in the 3‐position on fragmentation pathway B, an α‐cleavage between the C7? C8 single bond, coupled with a [2,4]‐trans‐Diels‐Alder cleavage simultaneously within the six‐membered heterocyclic ring, was also investigated. It was found that when the substituent groups were methyl, chloride, vinyl, or propenyl, fragmentations belonging to pathway B were detected; however, when the substituents were heteroatoms such as O, N, or S, pathway B fragmentation was not detected. This suggested that the [M–R₃]⁺ ion, which was produced by the bond cleavage within the substituent group at the 3‐position, had a key influence on fragmentation pathway B. This could be attributed to the strong electronegativity of the heteroatoms (O, N, S) that favors the production of the [M–R₃]⁺ ion. Moreover, having the positive charge of the [M–R₃]⁺ ion localized on the nitrogen atom in the 1‐position changed the electron density distribution of the heterocyclic structure, which prohibits a [2,4]‐reverse‐Diels‐Alder fragmentation and as a result fragmentation pathway B could not occur. The influence of the substituent group in the 3‐position was determined by the intensity ratio (e/d) of ions produced by fragmentation pathway A, a [2,2]‐trans‐Diels‐Alder cleavage within the quaternary lactam ring, including the breaking of the amide bond and the C6? C7 single bond (ion d), and fragmentation pathway B (ion e). The results indicate that the electronegativity of the substituent group was a key influencing factor of pathway B fragmentation intensity, because the intensity ratio (e/d) is higher for a chlorine atom, a vinyl, or a propenyl group than that of a methyl group. This study provided some theoretical basis for the identification of cephalosporin antibiotics and structural analysis of related substances in drugs. Copyright © 2010 John Wiley & Sons, Ltd.