Diels-Alder reaction synthetic application

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). 

Transannular Diels-Alder reaction is also one of the most prominent synthetic methods of intramolecular Diels-Alder reaction. The applications of transannular Diels-Alder reaction are mostly found in biomimetic synthesis. The reasonable use of transannular Diels-Alder strategy can significantly simplify the synthesis route and improve the artistic quality of synthesis, and at the same time, it can also provide a meaningful reference for the speculation of the routes of biosynthetic... 

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". ... 

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. 

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 ... 

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. 

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. 

The first chapter presents the general aspects of the reaction Chapters 2-6 illustrate the various methods and their applications in organic synthesis. At the end of each chapter a list of graphically abstracted Diels-Alder reactions is presented to show selected synthetic applications of the specific methodology. The discussion of the various topics is not exhaustive because our aim has been to emphasize the synthetic potential of each method. Chapter 7 reports a list of books, reviews, monographs and symposia proceedings which have appeared since 1990 and an index of keywords to help the reader find a particular paper of interest. 

The Scope and Synthetic Applications of the Diels-Alder Reaction... 

Synthetic Applications of the Diels-Alder Reaction. Diels-Alder reactions have long played an important role in synthetic organic chemistry.74 The reaction of a substituted benzoquinone and 1,3-butadiene, for example, was the first step in one of the early syntheses of steroids. The angular methyl group was introduced by the methyl group on the quinone and the other functional groups were used for further elaboration. 

Diels-Alder reactions are attractive for synthetic application because of the predictable regio- and stereochemistry. There are, however, limitations on the types of compounds that can serve as dienophiles or dienes. As a result, the idea of synthetic equivalence has been exploited by development of dienophiles and dienes that meet the reactivity requirements of the Diels-Alder reaction and can then be converted to the desired structure. For each of the dienophiles and dienes given below, suggest a Diels-Alder reaction and subsequent transformation(s) that would give a product not directly attainable by a Diels-Alder reaction. Give the structure of the diene or dienophile synthetic equivalent and indicate why the direct Diels-Alder reaction is not possible. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

Cycloadditions and cyclization reactions are among the most important synthetic applications of donor-substituted allenes, since they result in the formation of a variety of carbocyclic and heterocyclic compounds. Early investigations of Diels-Alder reactions with alkoxyallenes demonstrated that harsh reaction conditions, e.g. high pressure, high temperature or Lewis acid promotion, are often required to afford the corresponding heterocycles in only poor to moderate yield [12b, 92-94]. Although a,/3-unsaturated carbonyl compounds have not been used extensively as heterodienes, considerable success has been achieved with activated enone 146 (Eq. 8.27) or with the electron-deficient tosylimine 148 (Eq. 8.28). Both dienes reacted under... 

In this section, the literature about Diels-Alder reactions will be presented in a conceptual and illustrative way. After a profound introduction dealing with the development of mechanistic understanding of the Diels-Alder reaction, some interesting recent synthetic developments and applications will be presented. The reaction types and fields of interest are structured in such a way that they can be easily linked to ongoing research from the past ten years. Special attention will be paid to the application of chiral auxiliaries and chiral Lewis acids in asymmetric Diels-Alder reactions. 

The activation of various reactions by Lewis acids is now an everyday practice in synthetic organic chemistry. In contrast, solvent effects on Lewis acid catalysed Diels-Alder reactions have received much less attention. A change in the solvent can affect the association step leading to the transition structure. Ab initio calculations on the Diels-Alder reaction of cyclopentadiene and methyl vinyl ketone in aqueous media showed that there is a complex of the reactants which also involves one water molecule119. In an extreme case solvents can even impede catalysis120. The use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis acid catalysed Diels-Alder reactions is thus well justified. General solvent effects, in particular those of water, will be discussed in the following section. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

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