Diels-Alder cycloaddition applications

A convenient synthetic route to obtain these compounds is the thermal Diels Alder cycloaddition of 1 -methoxybutadiene (18b) with carbonyl compounds, but this route is limited to aldehydes activated by an electron-withdrawing substituent. Non-activated carbonyl compounds require drastic conditions or fail to react. Application of high pressure overcomes this limitation. 

Dias L. C. Chiral Lewis Acid Catalysts in Diels-Alder Cycloadditions Mechanistic Aspects and Synthetic Applications of Recent Systems J. Braz. Chem. Soc. 1997 8 289-332... 

Padwa A. Application of Diels-Alder Cycloaddition Chemistry for Heterocyclic Synthesis Prog. Heterocycl. Chem. 1995 7 21-42... 

Posner G. H. Stereocontrolled Synthesis of Functionalized Cyclohexenes Via Diels-Alder Cycloadditions of 2-Pyrones and 2-Pyridones-Applications to Synthesis of Physiologically Active Compounds in Stereocontrolled Org. Synth. 1994 177, Ed. Trost B. M., Pb. Blackwell Oxford... 

Cycloaddition reactions often require the use of harsh conditions such as high temperatures and long reaction times. These conditions are not compatible with sensitive reagents or products such as natural products. The applicability of Diels-Alder cycloadditions is, moreover, limited by the reversibility of the reaction when a long reaction time is required. The short reaction times associated with microwave activation avoid the decomposition of reagents and products and this prevents polymerization of the diene or dienophile. All these problems have been conveniently solved by the rapid heating induced by microwave irradiation, a situation not accessible in most classical methods. With the aid of microwave irradiation, cydoaddition reactions have been performed with great success [9, 10]. 

Diels-Alder cycloaddition reactions of electron-poor dienophiles to electron-rich dienes, which are generally carried out thermally, afford widespread applications for C—C bond formation. On the basis of their electronic properties, numerous dienes can be characterized as electron donors and dienophiles as electron acceptors. Despite the early suggestions by Woodward,206 the donor/ acceptor association and electron-transfer paradigm are usually not considered as the simplest mechanistic formulation for the Diels-Alder reaction. However, the examples of cycloaddition reactions described below will show that photoirradiation of various D/A pairs leads to efficient cycloaddition reactions via electron-transfer activation. 

In the late 1970s, Kirchhoff at Dow Chemical Company developed the use of benzocyclobutenes in polymer synthesis and modification. These efforts culminated in 1985 with the issuance of the first patent describing the use of benzocyclobutene in the synthesis of high-molecular-weight polymer.27 Similar work that involved a thermosetting system based on Diels-Alder cycloaddition between terminal benzocyclobutene and alkyne groups,28,29 was reported separately and independently by Tan and Arnold.28 Since these initial discoveries, the field of benzocyclobutene polymers has expanded rapidly and benzocyclobutene chemistry constitutes the basis of a new and versatile approach to the synthesis of high-performance polymers for applications in the electronics and aerospace industries.30... 

Another application of this strategy is the construction of cyclic systems bearing 1,4-dissonant relationships. For example, the synthesis of the hasubanan alkaloid ring system 35. reported in 1972 by Evans [24], involves the Diels-Alder cycloaddition of a dienyl sulphoxide 32 with an endocyclic enamine 33, followed by a [2,3]-sigmatropic rearrangement of the resulting cycloadduct 34 (Scheme 5.21). 

An example of the second type of modification is the application of the Diels-Alder cycloaddition reaction to polders and copol ers containing pendant or backbone furan moieties. The use of bis-dienophiles such as propiolic acid and its esters or bis-maleimides provides a means of crosslinking based on multiple bridging by the double interchain lycloadditions. The thermal reversibility of these reactions allows the return to the original linear structure (thermoplastic material) by simply heating the gel. 

Chinese chemists have reported the synthesis of pentacyclo[4.3.0.0 , 0 ]nonane-2,4-bis(trinitroethyl ester) (88). This compound may find potential use as an energetic plastisizer in futuristic explosive and propellant formulations. The synthesis of (88) uses widely available hydroquinone (81) as a starting material. Thus, bromination of (81), followed by oxidation, Diels-Alder cycloaddition with cyclopentadiene, and photochemical [2 - - 2] cycloaddition, yields the dione (85) as a mixture of diastereoisomers, (85a) and (85b). Favorskii rearrangement of this mixture yields the dicarboxylic acid as a mixture of isomers, (86a) and (86b), which on further reaction with thionyl chloride, followed by treating the resulting acid chlorides with 2,2,2-trinitroethanol, gives the energetic plastisizer (88) as a mixture of isomers, (88a) and (88b). Improvements in the synthesis of nitroform, and hence 2,2,2-trinitroethanol, makes the future application of this product attractive. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

Methylene-6-phenyl-2-trichloromethyl-5,6-dihydro-4i/-l,3-oxazine 137 proved applicable as a precursor for a 2-acylamino-l,3-diene as a Diels-Alder cycloaddition partner. Treatment of 137 with DMAD in the presence of Zn(OTf)2 (0.2 equiv) in toluene at 100 °C provided cycloadduct 138 in 57% yield after 2 days (Equation 13) <2006OL3537>. 

The very reactive arynes have also been used as dienophiles in Diels-Alder cycloadditions with vinyl heterocycles and are included here, after the acetylenic esters, because of the similarity of their reactive functions. This reaction is of considerable importance because of its application in the synthesis of polycyclic compounds. 

A further means of access to unsaturated carbohydrates from nonsugars is by application of the hetero-Diels Alder cycloaddition reaction between substituted-1,3-dienes (167) and aldehydes to give dihydropyrans (168). This... 

K. Mikami, Y. Motoyama, and M. Terada, Asymmetric catalysis of Diels-Alder cycloadditions by an MS-free binaphthol-titanium complex dramatic effect of MS, linear vs positive nonlinear relationship and synthetic applications, J. Am. Chem. Soc., 116 (1994) 2812-2820. 

Some novel C60-based assemblies were recently synthesized by [4+2] Diels-Alder cycloaddition reactions. Thus, fused tetrathiafulvalene-C60 dyads and C60-tetra-thiafulvalene-C60 dumbbell triads, in which the fullerene acceptor is doubly tethered to the donor tetrathiafulvalene through a rigidified cyclohexene ring [108], were prepared. With this novel approach, control of the relative orientation as well as the distance between the donor and acceptor units was achieved. Thereby, through-space interactions were expected to dominate because of the special topology of the constructed molecules. More examples of such donor-acceptor hybrid systems are discussed in the appropriate following sections, with their potential use in innovative technological applications. 

Another application of camphor-based chiral auxiliaries is the use in stereoselective Diels-Alder cycloadditions (Chapter 26), especially for the construction of quaternary carbon centers. One example, shown in Scheme 5.12, uses a camphor-derived lactam 30 as the auxiliary.54... 

CONTENTS The Synthesis of Seven-Membered-Rings General Strategies and the Design and Development of a New Class of Cycloaddition Reactions, Paul A. Wender and Jennifer A. Love. Recent Advances in Diels -Alder Cycloadditions of 2-Pyrones, Benjamin T. Woodard and Gary H. Posner. The Inter- and Intramolecular [4 + 4] Photocycloaddition of 2-Pyridones and Its Application to Natural Product Synthesis, Scott McN. Sieburth. 3 + 4 Annulations Between Rhodi- J s... 

The inter- and intramolecular Diels-Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCU promoted the endo-seXccuve. inter-molecular Diels-Alder cycloadditions of furans with a,/3-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the o-isomer as the major cycloadduct. A catalytic enantioselective Diels-Alder reaction between furan and acryloyl oxazolidinone to provide the < 46i-adduct in 97% ee was achieved by using the cationic bis(4-fer7-butyloxazoline)copper(ll) complex 55, as shown in Equation (41) <1997TL57>. 

Many of the reactions observed in molecular s)mthetic cages are reactions that enzymes are not known to catalyze examples are Diels-Alder cycloaddition and 1,3-dipolar cycloaddition. This behavior constitutes a reason to explore further the range of applications of these supramolecular assemblies. The fact that cycloaddition reactions are t) ically catalyzed is probably a result of the similarity of the transition state and the reactants and products. This characteristic of the cycloadditions makes product inhibition inevitable, unless additional reactions are operative that alter the shape and functionality of the adduct that is formed and thus reduce its association constant with the cage. 

Ionic liquids can be used as replacements for many volatile conventional solvents in chemical processes see Table A-14 in the Appendix. Because of their extraordinary properties, room temperature ionic liquids have already found application as solvents for many synthetic and catalytic reactions, for example nucleophilic substitution reactions [899], Diels-Alder cycloaddition reactions [900, 901], Friedel-Crafts alkylation and acylation reactions [902, 903], as well as palladium-catalyzed Heck vinylations of haloarenes [904]. They are also solvents of choice for homogeneous transition metal complex catalyzed hydrogenation, isomerization, and hydroformylation [905], as well as dimerization and oligomerization reactions of alkenes [906, 907]. The ions of liquid salts are often poorly coordinating, which prevents deactivation of the catalysts. 

Nucleic acid selection methods have also been exploited for the development of novel RNA enzymes or ribozymes (58). An m-vitro-selected RNA that contains the modified nucleotide 5-(4-pyridylmethyl)-uridine (Table 1) can catalyze carbon-carbon bond formation in a Diels-Alder cycloaddition, with an 800-fold rate acceleration compared with a random RNA (49). Modified RNAs that contain the same uridine modification have also been selected to mediate metal-metal bond formation in the synthesis of palladium nanoparticles (59). Modified RNAs are likely to have many other applications as novel ribozymes that catalyze important biological reactions or can be used to create novel materials. 

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