Diels-Alder, synthetic applications

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 illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

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 ... 

Given structure 1 as a target and the recognition that it contains the retron for the Diels-Alder transform, the application of that transform to 1 to generate synthetic precursor 2 is straightforward. The problem of synthesis of 1 is then reduced retrosynthetically to the simpler... 

Synthesis of multisubstituted furan rings using silyl protection 99CSR209. Synthetic applications of furan Diels-Alder chemistry 97T14179. Transformation of furans to N-heterocycles by aza-Achmatovicz reaction 98SL105. 

A versatile synthetic route to enantiomeric ally pure Diels-Alder adducts was deduced and found dependent on the application of enantiomerically pure 5-methoxy-174a (R=Me) and 5-(l-menthyloxy)-2(5//)-furanones 174b (R = menthyl), which were expected to undergo tt-face-selective cycloaddition with dienes. The reaction was effected by heating no Lewis acid catalysts were required (Scheme 55) (88JOC1127). 

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). 

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. 

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. 

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. 

Kappe C. O., Murphree S. S., Padwa A. Synthetic Applications of Fnran Diels-Alder Chemistry Tetrahedron 1997 53 14179-14233... 

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... 

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. 

Though the Diels-Alder addition of reactive TADs is a well-known reaction used for a range of both synthetic and analytical applications, some new modifications have appeared during the covered period (Equation 60). Selected examples are given in Table 1. 

Synthetic applications of other decarbonylation reactions are found in the conversion of cyclooctatetraene to barrelene 250), with the photodecarbonyla-tion of a Diels-Alder adduct as key step (2.31) and the preparation of tetrathioesters from 1,3-dithioles (2.32) 251). The most remarcable application of such a reaction up to date is the synthesis of tetra t.butyltetrahedrane from a tricyclic ketone precursor (2.33) 252). 

Nitrile oxides are oxidized by tertiary amine N-oxides, for example, N-methylmorpholine N-oxide, in various solvents at room temperature to unstable nitrosocarbonyl compounds. In the presence of dienes, such as 1,3-cyclo-hexadiene, they afford Diels-Alder adducts, e.g., 372 fromPhCNO, in fair yields. The mild conditions used in oxidizing a variety of nitrile oxides promise a wide application of this method in synthetic processes (420). 

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. 

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