Dienophiles diethyl fumarate

More recently, Cheeseman and coworkers have investigated cycloaddition reactions of 2,6-dioxypyrazines (80jCS(Pl)1603). 2,6-Dihydroxy-3,5-diphenylpyrazine (77) reacts with electron deficient dienophiles such as iV-phenylmaleimide, diethyl maleate and diethyl fumarate (Scheme 26) to yield adducts of the 3,8-diazabicyclo[3.2.1]octane class such as (78). This reaction is believed to proceed by way of the betaine (79) and has precedent (69AG(E)604) in that photolysis of the bicyclic aziridine (80) generates analogous betaines which have been trapped in cycloaddition reactions. 

The Diels-Alder cycloaddition reaction (Section 14.4) is a pericvclic process that takes place between a diene (four tt electrons) and a dienophile (two tr electrons) to yield a cyclohexene product. Many thousands of examples of Diels-Alder reactions are known. They often take place easily at room temperature or slightly above, and they are stereospecific with respect to substituents. For example, room-temperature reaction between 1,3-butadiene and diethyl maleate (cis) yields exclusively the cis-disubstituted cyclohexene product. A similar reaction between 1,3-butadiene and diethyl fumarate (trans) yields exclusively the trans-disubstituted product. 

The importance of the relationship between the macrocycle cavity and the binding of two reagents is shown by the cycloadditions of cyclopentadiene with diethyl fumarate and ethyl acrylate in aqueous solution. The presence of jS-CD strongly accelerates the first cycloaddition, while it slows down the reaction rate of the second, probably because the cavity favors the binding of two molecules of either diene or dienophile [65c]. 

Experiments with 3-oxaquadricyclane 28 and diethyl fumarate or diethyl maleate indicate that the configuration of the dienophile is retained in the product. 

A similar reaction has been observed with l-methyl-3-(l-benzylthioethenyl)pyrrole. Adducts can also be obtained from dienophiles such as acrylonitrile, acrolein, methyl acrylate, and diethyl fumarate <91CPB489>. In this case the initial products are tetrahydroindoles which can be aromatized with ddq (Scheme 143). 

In 1965, Ishikawa and co-workers investigated the oxazole cycloaddition reactions of 4-methyloxazole, 5, with a variety of dienophiles (Fig. 3.3). The product distribution for these reactions was found to depend on the substituents on the dienophile as well as the reaction conditions. For example, the reaction of 4-methyloxazole with diethyl fumarate gave a mixture of pyridinols 6 and 7. 

Substituents such as carbonyl and cyano are electron-withdrawing and activate the dienophile toward cycloaddition. The electron-attracting properties of these groups arise from bond dipoles, which place a partial positive charge on the carbonyl or cyano carbon (see Section 1.5). Acrolein has one electron-withdrawing group attached to its dienophilic double bond. Diethyl fumarate and maleic anhydride, the most reactive and synthetically useful dienophiles you will encounter in this section, both have two. 

A variety of electron-deficient olefins were shown to be effective dienophiles, giving the expected cycloaddition products (Table 7.9). Reaction ofthe o-xylylene species 2 with maleic anhydride yielded only the cis product, while cis olefins (e.g., dimethyl or diethyl maleate) yielded a mixture of cis and tram cycloaddition products. Tram esters (diethyl fumarate and methyl crotonate) yielded tram adducts however, fumaronitrile gave a mixture of cis and tram adducts. In a separate experiment, it was discovered that upon exposure to the activated nickel, dimethyl maleate was isomerized to dimethyl fumarate. The exact mechanism of the isomerization is at this point unexplained. Noncyclic cis olefins appear to give mixtures of cis and tram cycloadducts, while tram olefins may yield tram products or mixtures of cis and tram products. In cases where mixtures are produced, the tram isomer is the major adduct isomer with the ratio of cis tram isomers apparently being affected by the nature of the olefin. Thus, although the cycloaddition reaction itself is still not proven to be a concerted rather than a stepwise process, the mixture of cis and tram cycloadducts could arise from isomerization of the olefin prior to the cycloaddition process. 

If we calculate the energy gap for the two possible HOMO-LUMO combinations between azadiene 1 and diethyl fumarate, the small difference in energy (10.93 eV) is found between the pair HOMO azadiene-LUMO fumarate (the difference between HOMO fumarate-LUMO azadiene is 12.09 eV). That is, despite that 2-azadiene 1 has a low energy HOMO it can react in a normal [4-1-2] cycloaddition process with a dienophile having a low energy LUMO. 

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