Applications of Diels-Alder Reactions

In Part B, the cycloaddition of 1,3-cyclopentadiene with maleic anhydride is examined (Eq. 12.5). This experiment provides an opportunity to investigate the stereoselectivity of the Diels-Alder reaction. Monomeric 1,3-cyclopentadiene cannot be purchased because it readily dimerizes at room temperature by a Diels-Alder reaction to give dicyclopentadiene (Eq. 12.8), which is commercially available. Fortunately, the equilibrium between the monomer and the dimer can be established at the boiling point of the dimer (170 °C, 760 torr) by a process commonly called cracking, and the lower-boiling 1,3-cyclopentadiene may then be isolated by fractional distillation. The diene must be kept cold in order to prevent its redimerization via a Diels-Alder reaction prior to use in the desired Diels-Alder reaction. 

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Side Note 15.2. Synthetic Applications of Diels-Alder Reactions... 

Beyond the hitherto discussed syntheses, there exist numerous further current and impressive applications of Diels-Alder reactions involving 1-oxa-1,3-butadienes which can only briefly be mentioned here due to the limits of space. Burke s group has developed an elegant retro-oxa Diels-Alder/all-carbon-Diels-Alder protocol which was employed as key step in the total syntheses of ( )-... 

The most fully explored synthetic applications of Diels-Alder reaction in annotation of pyrroles and indoles involves use of vinyl derivatives. Because of the donor character of the heteroaromatic ring, vinylpyrroles and vinylindoles react as electron-rich dienes. Various aspects of both the synthesis and cycloaddition reactions of vinylindoles have been reviewed. <85JHC585, 86CZ95, 88H(27)1253>. 

Application of Diels-Alder Reactions with 3-Vinylindoles... 

Application of Diels-Alder Reactions with 3-Vinytindoles in the Synthesis of P and y-Carboline Alkaloids... 

Another useful application of Diels-Alder reactions of hexafluorobutyne is to provide adducts, whose thermal decomposition generates transient species R2M=CHa (e.g. M = Si see Vol. 2, p. 115), and this technique has now been extended to a germylene synthesis (see Scheme The butsme also enters into... 

The Development and Synthetic Application of Diels-Alder Reaction... 

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". ... 

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 ... 

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... 

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. 

According to the frontier orbital theory, a bond preferentially forms between the atoms with the largest frontier orbital amplitudes (Sect. 3.4 in the Chapter Elements of a Chemical Orbital Theory by Inagaki in this volume). This is applicable for the regioselectivities of Diels-Alder reactions [15]. The orbital mixing rules are shown here to be useful to understand and design the regioselectivities. 

The orbital mixing theory was developed by Inagaki and Fukui [1] to predict the direction of nonequivalent orbital extension of plane-asymmetric olefins and to understand the n facial selectivity. The orbital mixing rules were successfully apphed to understand diverse chemical phenomena [2] and to design n facial selective Diels-Alder reactions [28-34], The applications to the n facial selectivities of Diels-Alder reactions are reviewed by Ishida and Inagaki elesewhere in this volume. Ohwada [26, 27, 35, 36] proposed that the orbital phase relation between the reaction sites and the groups in their environment could control the n facial selectivities and review the orbital phase environments and the selectivities elsewhere in this volume. Here, we review applications of the orbital mixing rules to the n facial selectivities of reactions other than the Diels-Alder reactions. 

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]. 

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... 

Besides metal containing Lewis acids, non-metal additives have also found application in catalysis. These studies are quite pertinent to the development of artificial enzymelike catalysts. As there is a large number of Lewis basic sites in living systems able to be involved in hydrogen bonds, the analysis of the catalytic activity of hydrogen bonding additives would give some indication as to the existence of Diels-Alder reactions... 

C. MacMillan, /. Am. Chem. Soc. 2000, 122, 4243-4244. For the synthesis of polymer-bound derivatives of the MacMillan catalyst and applications in Diels-Alder reactions, see M. Benaglia, G. Celentano,... 

The application of Diels-Alder methodology to pyridine formation can take different approaches. The heteroatom can be sourced from the diene or the dienophile and by varying its position in the starting materials can lead to strategies for different substitution patterns in the pyridine product. While such approaches are well documented, recent reports have both extended the range of derivatives available and incorporated new technology to assist in the optimization of reactions. 

Furan is an excellent diene in a wide variety of Diels-Alder reactions, providing oxabicyclic compounds with useful synthetic applications. However, Diels-Alder reactions with furans are often reversible and require a highly reactive dienophile in order to provide useful yields of the cycloadduct. As shown in Scheme 17, furans have now been shown to undergo synthetically useful Diels-Alder reactions with azirines. The reaction of furan with azirine 91 provides cycloadduct 92 in 100% yield <1998J(P1)299>. Aziridine 92, while crystalline, is moisture sensitive, decomposing to aziridine 93. An X-ray structure of 92 was obtained which confirmed the exo-natute of the cycloaddition reaction in contrast to the r/o-cycloadditions seen in the formation of 88 <2001J(P1)2969>. 

No doubt the Diels-Alder reaction will lend itself to further extensions of scope and selectivity. Nevertheless, the current state of the art and the pivotal applications of Diels-Alder adducts (XXX) for the efficient chemo-, regio- and stereo-selective syntheses of complex structures, e.g. via annulation processes (a, b) and/or cleavage reactions (c, d, e) speak for themselves (Scheme 6). An adequate treatise would vastly exceed the limits of this chapter. 

A wide range of hetero 2-aza-1,3-butadienes have been shown to participate as 4rr components of Diels-Alder reactions (Figure 4). Perhaps the most widely recognized class of hetero 2-aza-1,3-butadienes is the A -acylimines (l-oxa-3-aza-l,3-butadiene) ° and comprehensive reviews of their 4tt participation in LUMOdiene-controlled Diels-Alder reactions are available. The recent disclosure of the 4ir participation of A -acylimines in intramolecular [4 + 2] cycloaddition reactions (equation 11), and the use of optically active A -acylimines in productive LUMOdiene-controlled [4 + 2] cycloaddition reactions, illustrate applications of the systems that have not been explored fully (equation 12). ... 

Although this chapter is limited to intermolecular all-carbon reactions, the literature connected to this type of Diels-Alder reactions is still immense. The last general reviews about intermolecular Diels-Alder reactions date from nearly ten years ago - v During the past decade, several reviews were published dealing with specialized topics such as mechanistic aspects , specific dienes 2-35 dienophiles , applications in synthesis " ° and introduction of chirality by using chiral auxiliaries qj- chiral Lewis acids . ... 

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