Retro Diels—Alder reaction reactions Lewis

Microwave heating has also been employed for performing retro-Diels-Alder cycloaddition reactions, as exemplified in Scheme 6.94. In the context of preparing optically pure cross-conjugated cydopentadienones as precursors to arachidonic acid derivatives, Evans, Eddolls, and coworkers performed microwave-mediated Lewis acid-catalyzed retro-Diels-Alder reactions of suitable exo-cyclic enone building blocks [193, 194], The microwave-mediated transformations were performed in dichloromethane at 60-100 °C with 0.5 equivalents of methylaluminum dichloride as catalyst and 5 equivalents of maleic anhydride as cyclopentadiene trap. In most cases, the reaction was stopped after 30 min since continued irradiation eroded the product yields. The use of short bursts of microwave irradiation minimized doublebond isomerization. 

In the presence of a more reactive dienophile, a retro Diels-Alder reaction can be carried out at or below room temperature when catalyzed by a Lewis acid.78 In fact, this process can be regarded as a trans-Diels-Alder reaction in which the C C bond is replaced by another more reactive functionality. Thus, when treated with fumaronitrile in the presence of EtAlCl2 at ambient temperature for 2 hours, compound 159 can easily be converted to compound 160 with the removal of cyclopentadiene (Scheme 5-48). 

The Lewis acid catalyzed reaction of furan (169) with ketovinylphosphonate 170 produced a mixture of adducts, both of which slowly underwent retro Diels-Alder reactions at room temperature121. When diethylaluminum chloride was used as the catalyst, the endo selectivity (with respect to the keto functionality) was enhanced from 171/172 = 58/42 to 78/22 by raising the reaction temperature from — 25 °C to 0°C (equation 47). This is in agreement with the FMO theory, since initial Lewis acid complexation is with the phosphonate group. 

Only in the retro Diels-Alder reaction of cyclohexene at 1000 °C do isotope effects provide some support for part of the reaction not being concerted, see D. K. Lewis, B. Brandt, L. Crockford, D. A. Glenar, G. Rauscher, J. Rodriguez and J. E. Baldwin, J. Am. Chem. Soc., 1993,115, 11728. 

Most of the synthetic applications of retro-Diels-Alder reactions involve cyclopentadiene or furan derivatives, but there are other dienes that have appropriate functionality for this process. One example is illustrated by heating pyrone 102 in a sealed tube at 200°C with bis(trimethylsilyl)acetylene to give 103, after initial formation of cycloadduct 104 and loss of carbon dioxide via a retro-Diels-Alder reaction.The retro-Diels-Alder usually requires higher temperatures than the Diels-AIder reaction, and the normal Diels-AIder product can be obtained without competition from the retro reaction. When the retro Diels-AIder reaction is desired, flash vacuum pyrolysis is a common technique used in synthesis. " Retro-Diels-Alder reactions can also be catalyzed by Lewis acids (sec. 11.6.A).An example that uses furan as a retro-Diels-Alder synthon is taken from work by Cannone et al., who used the retro-reaction as a synthetic route to 4-substituted... 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

The joining of a double or triple bond to an alkene reactant having a transferable allylic hydrogen is called an ene reaction ". The reverse process is called a retro-ene reaction. Like Diels-Alder reactions, Lewis acids such as AICI3 or BF3 can catalyze ene reactions. 

A classical example of a retro Diels-AIder reaction is the self condensation of cyclopentadiene (22) to give the cyclopentadienyl dimer 101. This reaction occurs quickly at temperatures > 25°C, but is slow at low temperatures such as -78°C. Many Diels-AIder reactions involving cyclopentadiene are done at low temperatures with Lewis acid catalysts (sec. 11.6.A) to suppress cyclopentadiene dimerization. When heated to 160-240°C, 101 undergoes a retro-Diels-Alder reaction to generate 2 equivalents of monomeric cyclopentadiene. 

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 reverse reactions of Diels-Alder reactions for thermal dissociations of cycloadducts in to dienes and dienophiles at higher temperatures or in the presence of Lewis acid or base are known as the retro-Diels-Alder (rDA) reactions. These reactions in most cases proceed in a concerted process. These reactions are often used for separation of diene or dienophile from their mixture with other compounds. Proper selection of conditions of these reactions provides new dienes and dienophiles, which are important synthons for synthesis of several bioactive natural products and organic molecules of complex structures. For example, the D-A adduct of 4-phenyl oxazole 110 with methyl acetylene dicarboxylate, on retro-D-A reaction gives new compounds, benzonitrile, and furan 3,4-dicarboxylic acid methyl ester 111 [65]. 

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