Alkenes Diels-Alder reactions

Conjugated dienes have alternating single and double bonds. They may undergo 1,2- or 1,4-addition. Allylic carbocations, which are stabilized by resonance, are intermediates in both the 1,2- and 1,4-additions (Sec. 3.15a). Conjugated dienes also undergo cycloaddition reactions with alkenes (Diels-Alder reaction), a useful synthesis of six-membered rings (Sec. 3.15b). 

Alkenylmethyl) cyclic ethers are formed by the reaction of lactols and alkenes." Diels-Alder reactions. Diethylaluminum chloride deposited on silica seems to be a superior catalyst. Methylaluminum dichloride alone is effective in promoting intramolecular cycloadditions involving a furan ring as the diene. ... 

An oxazole-alkene Diels-Alder reaction has also been used to synthesize a tri-fluoromethylated pyridine related to pyridoxol. 5-Ethoxy-4-(trifluoromethyl)-2-oxazolecarboxylic acid 41 decarboxylated and then reacted with acrylic acid to give the expected 3-hydroxy-2-(trifluoromethyl)pyridine-4-carboxylic acid 42 in 63% yield (Fig. 3.13)." The electron-withdrawing trifluoromethyl group of 41 strongly modulates its reactivity, however, and it does not react with ethyl acrylate or A-phenyl maleimide. 

Since 1985, the major application of intramolecular oxazole-alkene Diels-Alder reactions has been in the held of natural product synthesis, in which readily available oxazole-olehns can provide access to highly substituted pyridines. All of the intramolecular reactions described here have four-atom linkers between the oxazole and olehn, found by Turchi to be optimal for these cycloadditions. 

The initially reported structure of the cyctotoxic ascidian alkaloid 2-bromolep-toclinidinone 105 was amenable to a synthesis approach using an intramolecular oxazole-alkene Diels-Alder reaction, as shown in the retro-synthetic analysis in Figure 3.29. In a model system, the A-benzyl-substituted amide 106 afforded a 50% yield of pyridine 107 after refluxing in benzene for 18 h with 0.75 equivalent of DMAP. The analogous NH-carboxamide faded to provide any of the desired tricyclic pyridine. This was attributed to a conformational preference that allows an internal hydrogen bond between the amide-NH and the oxazole, rather than the conformation that allows efficient overlap of the oxazole and olefin. The yield of 107 could be increased to 87% if the reaction was performed in the presence of the Lewis acid europium(hfc)3. This was not further elaborated since the structure of 2-bromoleptoclinidinone was subsequently revised in 1989. 

The bicyclic intermediate arising from Diels-Alder reaction of oxazoles with alkynes extrudes nitriles (comprised of the nitrogen atom and C4 of the oxazole) to form furans as the ultimate product of the cycloaddition. The same regioselectivity seen in alkene Diels-Alder reactions is noted here. 

Diels-Alder reaction is the 1,4-addition of an alkene or alkyne (dienophile) across a conjugated diene. An example is the addition of pro-penal to buta-l,3-diene to give A -tetrahy-... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

The reaction of o-iodophenol, norbornadiene and CO proceeds via alkene and CO insertions to afford the lactone 562, which is converted into coumarin (563) by the retro-Diels-Alder reaction. In this coumarin synthesis, norbona-diene behaves as a masked acetylene[4)3],... 

A particular kind of conjugate addition reaction earned the Nobel Prize in chemistry for Otto Diels and Kurt Alder of the University of Kiel (Germany) m 1950 The Diels-Alder reaction is the conjugate addition of an alkene to a diene Using 1 3 buta diene as a typical diene the Diels-Alder reaction may be represented by the general equation... 

The alkene that adds to the diene is called the dienophile Because the Diels-Alder reaction leads to the formation of a ring it is termed a cycloaddition reaction The prod uct contains a cyclohexene ring as a structural unit... 

The mechanism of the Diels-Alder reaction is best understood on the basis of a molecular orbital approach To understand this approach we need to take a more detailed look at the rr orbitals of alkenes and dienes... 

Section 10 12 Conjugate addition of an alkene (the dienophile) to a conjugated diene gives a cyclohexene derivative in a process called the Diels-Alder reaction It is concerted and stereospecific substituents that are cis to each other on the dienophile remain cis m the product... 

Diels-Alder reaction (Section 10 12) Conjugate addition of an alkene to a conjugated diene to give a cyclohexene denva tive Diels-Alder reactions are extremely useful in synthesis... 

Dienophile (Section 10 12) The alkene that adds to the diene in a Diels-Alder reaction... 

The primary and secondary products of photolysis of common diazirines are collected in Table 4. According to the table secondary reactions include not only isomerization of alkenes and hydrogen elimination to alkynes, but also a retro-Diels-Alder reaction of vibrationally excited cyclohexene, as well as obvious radical reactions in the case of excited propene. 

Commercial manufacture of this polymer was first announced by CdF Chimie in 1975 following about 10 years of study on the Diels-Alder reactions of alkenes with cyclopentadiene. In 1976 a plant with a capacity of 5000 tonnes per annum was put on stream and product marketed as Norsorex. Manufacturing under licence is now being extended to American Cyanamid whilst CdF Chimie has also signed a marketing agreement with Nippon Zeon. 

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 ... 

Another stereochemical feature of the Diels-Alder reaction is addressed by the Alder rule. The empirical observation is that if two isomeric adducts are possible, the one that has an unsaturated substituent(s) on the alkene oriented toward the newly formed cyclohexene double bond is the preferred product. The two alternative transition states are referred to as the endo and exo transition states ... 

Although hexafluoro-l,3-butadiene is better known for its [2+2] reactions, its Diels-Alder reactions, particularly with electron-deficient alkenes such as acrylonitrile and perfluoropropene, are not unknown [9] The first report of a Diels-Alder reaction is with an acetylenic dienophile Although the major product of Us reaction with phenylacetylene is its [2+2] adduct, a 3 5% yield of products of a Diels-Alder reaction is also observed [123] (equation 103)... 

Catalytic asymmetric Diels-Alder reactions are presented by Hayashi, who takes as the starting point the synthetically useful breakthrough in 1979 by Koga et al. The various chiral Lewis acids which can catalyze the reaction of different dieno-philes are presented. Closely related to the Diels-Alder reaction is the [3-1-2] carbo-cyclic cycloaddition of palladium trimethylenemethane with alkenes, discovered by Trost and Chan. In the second chapter Chan provides some brief background information about this class of cycloaddition reaction, but concentrates primarily on recent advances. The part of the book dealing with carbo-cycloaddition reactions is... 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

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