Diels-Alder reaction, application

Dihydropyrones as dienophiles in the Diels-Alder reaction application to the synthesis of 1-oxadecalones [158]... 

There was no reaction between 199a and dienes 197 under atmospheric pressure, at low temperature (55 °C) and for long period of time (72h). A moderate conversion was obtained by heating for 48h 199a with dienes 197 in toluene at 110 °C (Table 3). These results clearly demonstrate the advantage of HP conditions to accelerate the Diels-Alder reaction. Application of best reaction conditions to the series of coumarins 199b-g afforded a series of substituted 6a-cyano-tetrahydro-6H-benzo[c]chromen-6-ones (Table 4). 

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

Unfortunately, the number of mechanistic studies in this field stands in no proportion to its versatility" . Thermodynamic analysis revealed that the beneficial effect of Lewis-acids on the rate of the Diels-Alder reaction can be primarily ascribed to a reduction of the enthalpy of activation ( AAH = 30-50 kJ/mole) leaving the activation entropy essentially unchanged (TAAS = 0-10 kJ/mol)" . Solvent effects on Lewis-acid catalysed Diels-Alder reactions have received very little attention. A change in solvent affects mainly the coordination step rather than the actual Diels-Alder reaction. Donating solvents severely impede catalysis . This observation justifies the widespread use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis-acid catalysed Diels-Alder reactions. 

The Diels-Alder reaction is often quoted as an example of a reaction that is little influenced by the solvent. However, this is not fully justified, since particularly water can have a pronounced effect on the rate of this reaction. This was first noticed by E elte et al." in 1973 and rediscovered in 1980 by Breslow In the years that followed this intriguing discovery, it turned out that acceleration of Diels-Alder reactions by water is a general phenomenon that can ultimately result in up to 12,800 fold accelerations". Synthetic applications followed rapidly". ... 

As final examples, the intramolecular cyclopropane formation from cycloolefins with diazo groups (S.D. Burke, 1979), intramolecular cyclobutane formation by photochemical cycloaddition (p. 78, 297f., section 4.9), and intramolecular Diels-Alder reactions (p. 153f, 335ff.) are mentioned. The application of these three cycloaddition reactions has led to an enormous variety of exotic polycycles (E.J. Corey, 1967A). 

Two types of cycloaddition reactions have found application for the Synthetic elaboration of indoles. One is Diels-Alder reactions of 2- and 3-vinylindoles which yield partially hydrogenated carbazoles. The second is cycloaddition reactions of 2,3-indolequinodimethane intermediates which also construct the carbazole framework. These reactions arc discussed in the following sections. 

Frontier orbital analysis is a powerful theory that aids our understanding of a great number of organic reactions Its early development is attributed to Professor Kenichi Fukui of Kyoto University Japan The application of frontier orbital methods to Diels-Alder reactions represents one part of what organic chemists refer to as the Woodward-Hoffmann rules a beautifully simple analysis of organic reactions by Professor R B Woodward of Harvard University and Professor Roald Hoffmann of Cornell University Professors Fukui and Hoffmann were corecipients of the 1981 Nobel Prize m chemistry for their work... 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

Development of base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone and its application to synthesis of bioactive compounds 99YGK84. 

Development and application of hetero Diels-Alder reactions with participation of amino acid-derived chiral acylnitroso compounds 98T1317. 

The basis of the Diels-Alder reaction developed in the twenties, and the contribution by Woodward and Hoffmann in the sixties, are two very important milestones in chemistry. Both discoveries were met with widespread interest the applications made are fundamental to modern society the tests which it has survived and the corollary predictions which have been verified are impressive. 

Application of this catalytic process was extended to asymmetric intramolecular Diels-Alder reactions. Synthetically useful intermediates with octalin and decalin skeletons were obtained in high optical purity by use of a catalytic amount of the chiral titanium reagent [45] (Scheme 1.57, Table 1.25). The core part of the mevi-nic acids was enantioselectively synthesized by use of this asymmetric intramolecular reaction [46] (Scheme 1.58). 

The inverse electron-demand Diels-Alder reaction is also accelerated by Lewis acids, but the successful application of chiral Lewis acids to this kind of Diels-Alder reaction is very rare. Marko and coworkers applied Kobayashi s catalyst system (Yb(OTf)3-BINOL-amine) to the Diels-Alder reaction of 3-methoxycarbonyl-2-py-rone with vinyl ether or sulfide [58] (Scheme 1.72, Table 1.29). A bulky ether or... 

Numerous examples of intramolecular Diels-Alder reactions have been repor-ted especially from application in the synthesis of natural products, where stereoselectivity is of particular importance e.g. syntheses of steroids. " ... 

The photophysical properties of porphycenes make these structures potential sensitizers for an application in Photodynamic Tumor Therapy (PDT). To improve the photophysical properties and to modify possible biological activity it is necessary to have porphycenes with an extended chromophore and/or with additional functional groups for further modifications. The Diels-Alder reaction of a vinyl porphycene allows for the preparation of benzoporphycenes with an extended chromophore9 and additional functional groups (cf. Section 1.1.2.4.). 

In another synthetic application, first reported by Smith and Stirling142, the bis-2,3-(phenylsulfinyl)-l, 3-butadiene 94 has been prepared in low yield by two spontaneous sequential [2,3]-sigmatropic rearrangements of the Ws-sulfenate ester (93). More recently, the yield of this reaction (equation 42) has been improved159, and a related dienyl sulfoxide 95 has been reported (equation 43)160. This type of sulfoxide is of considerable interest in view of recent studies on Diels-Alder reactions of polysubstituted butadienes161-164. 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

There are many types of Diels-Alder reactions that are carried out under thermal conditions. This chapter will deal with the most significant developments, the potential and range of applications of this methodology of both the intermolecular and intramolecular cycloadditions in organic synthesis. 

The Diels Alder reaction provides a valuable tool for functionalizing buck-minsterfullerene (Ceo)- Functionalized Ceo derivatives may have important applications as conductive materials [45] and in biological chemistry [46]. 

Sauer and Heldmann [97] recently reported an interesting application of ethynyltributyltin as an electron-rich dienophile in an inverse electron-demand Diels-Alder reaction with the electron-deficient triazine derivative 94. This method is interesting because the reaction is highly regioselective and the trialkylstannyl group is easily replaced by several groups under mild conditions, leading to substituted pyridines 95 (Scheme 2.41). 

This chapter will mostly deal with the applications of the Lewis-acid-catalyzed Diels Alder reaction to organic synthesis and the influence of Lewis acids on reactivity, stereoselectivity and regioselectivity of the cycloadditions. 

The /lomo-Diels-Alder reaction is a [2 + 2 + 2] cycloaddition of a 1,4-diene with a dienophile which produces two new bonds and a cyclopropane ring. This reaction is an example of a multi-ring-forming reaction that to date has found few applications in synthesis, since the use of 1,4-dienes has been limited mainly to bridged cyclohexa-1,4-dienes and almost exclusively to norbornadiene. Lewis-acid catalysts accelerate /lowo-Diels-Alder reactions and increase the selectivity for the [2 + 2 + 2] vs. [2 + 2] cycloaddition. 

The low solubility of fullerene (Ceo) in common organic solvents such as THE, MeCN and DCM interferes with its functionalization, which is a key step for its synthetic applications. Solid state photochemistry is a powerful strategy for overcoming this difficulty. Thus a 1 1 mixture of Cgo and 9-methylanthra-cene (Equation 4.10, R = Me) exposed to a high-pressure mercury lamp gives the adduct 72 (R = Me) with 68% conversion [51]. No 9-methylanthracene dimers were detected. Anthracene does not react with Ceo under these conditions this has been correlated to its ionization potential which is lower than that of the 9-methyl derivative. This suggests that the Diels-Alder reaction proceeds via photo-induced electron transfer from 9-methylanthracene to the triplet excited state of Ceo-... 

Until the 1980s this technique was used mostly in mechanistic investigations to obtain information about the structure and properties of the transition state of the Diels-Alder reaction. Now, the technique is mainly used in applications of synthetic organic chemistry. 

Tfctcro-Diels Alder reaction is a powerful methodology in the synthesis of heterocyclic compounds. Using the high pressure technique has greatly extended the synthetic applications of this methodology. 

Tropones are non-benzenoid compounds that behave like 47r-components in a Diels Alder reaction. These compounds are of interest because of their synthetic applications based on the Diels Alder reaction, since the cycloadducts can be easily converted into a large variety of compounds. 

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