Diels-Alder reaction with dimethyl maleate

Earle and coworkers [54] have performed Diels-Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except [BMIMJPF4, and gave almost quantitative yields after 18-24h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. 

Table 6.10 Diels-Alder reactions of cyclopentadiene with dimethyl maleate, ethylacrylate and acrylonitrile in neutral ionic liquids...

Diels-Alder reactions are stereospecific with respect to the E- and Z-relationships in both the dienophile and the diene. For example, addition of dimethyl fumarate and dimethyl maleate with cyclopentadiene is completely stereospecific with respect to the cis or trans orientation of the ester substituents. 

The first report suggesting specific activation of an organic reaction by MW was that of Berlan et al. [28] who observed that some Diels-Alder reactions occurred more rapidly on MW heating than under conventional heating at the same temperature (95 °C). The reactions were performed in two different solvents, xylene and dibutyl ether and the rate enhancements were slightly higher in xylene, the less polar solvent. For example the rate enhancement of the reaction of 2,3-dimethyl-l,3-butadiene 21 with methyl vinyl ketone 22 was 8 times in xylene and 2.3 times in dibutyl ether, based on the half lives of the reactions. Reaction of anthracene 3 with diethyl maleate 23 in xylene (Scheme 4.12) resulted in an approximately fourfold rate in-... 

The generation of benzo[c]furan as a transient species by retro Diels-Alder reactions has been used for synthetic purposes. When the adduct (414) was decomposed in the presence of dimethyl fumarate the product (415) was obtained decomposition of (414) with dimethyl maleate yielded the adducts (416) and (417) in the ratio 2 1 (Scheme 110) (69TL5231). 

Olah et al.902 demonstrated in 1979 that Nafion-H is able to catalyze Diels-Alder reaction of anthracene with a number of dienophile (maleic anhydride [Eq. (5.329)], para-benzoquinone, dimethyl maleate, dimethyl fumarate) in chloroform or benzene... 

Complete stereoselectivity occurs in the Diels-Alder reaction through syn addition of the dienophile to the diene. Hence, the reaction of dimethyl fumarate and dimethyl maleate with cyclopentadiene yields the trans and cis adducts, respectively (Scheme 26.1).29... 

The Stereoselectivity of 1,3-Dipolar Cycloadditions. There is no endo mle for 1,3-dipolar cycloadditions like that for Diels-Alder reactions. Stereoselectivity, more often than not, is low, as shown by the reactions of C,/V-diphenylnitrone—both regioisomers 6.238 and 6.239 (R=C02Et) from the reaction with ethyl acrylate are mixtures of exo and endo isomers, only a little in favour of the exo product. Similarly, the reactions of methyl crotonate with nitrones favour the exo product 6.242 over the endo 6.243. In contrast, other reactions are endo selective, as in the cycloaddition 6.244 of an azomethine ylid to dimethyl maleate giving largely the endo adduct 6.245. 

Tetrasubstituted-l,2,3,4,5,6,7,8-octahydrocarbazoles 1137 were synthesized in 46-90% yields by a novel tandem Diels-Alder reaction in one step from A -benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole 1136 and dienophiles such as maleic anhydride, maleimide, ethyl maleate, fumaronitrile, and ethyl acrylate (Scheme 222) <20000L73>. The 2,3,6,7-tetrasubstituted carbazoles 1138 were then synthesized in 29-87% yields from compound 1137 by oxidation with DDQ. 

In the Diels-Alder reaction of cyclopentadiene with dimethyl maleate, both exo and endo products are theoretically possible. Only the endo product 6-6 is found. 

The three-step procedure above illustrates the usefulness of a 1-amino-3-siloxy diene for the synthesis of functionalized cyclohexenones and is representative of the general usefulness of the dienes. The first step in the sequence, the Diels-Alder reaction between the parent aminosiloxy diene nd methyl acrylate, cleanly produces the cycloadduct as a mixture of endo and exo diastereomers. This diene also reacts with many other dienophiles and the results are summarized in Table I.3 The cycloadducts are generally obtained as mixtures of endo-exo diastereomers, except for the reactions with N-phenylmaleimide and methacrolein, which proceed with high endo selectivity, and with dimethyl maleate, which gives predominantly the exo adduct. 

Extrusion of sulfur dioxide from oxidized thiophene derivatives is an exceptional method to prepare cis-dienes as components for Diels-Alder reactions. An example of this approach utilizes the Diels-Alder reactivity of the furan ring in substituted 4//,6ff-thieno[3,4-c]furan-3,S-dioxides to react with a variety of dienophiles such as DMAD, dimethyl maleate and dimethyl fumarate which then lose SO2 to form another reactive diene (Eq. 17) <94H961>. A review of the preparation and use of 4i/,6f/-thieno[3,4-c]furan-S,5-dioxides as well as other heteroaromatic-fused 3-suIfolenes is report <94H1417>. The preparation of dihydrothienooxazole 80 requires the careful control of the reaction time and temperature as well as the reactants molar ratio <94JOC2241>. Specific control of the alkylation conditions for 81 (X = COCH3) allows for the preparation of either 1,4-disubstituted or 1,6-disubstituted 4, 6//-thieno[3,4-c]furan-S,S-dioxides. These molecules could be used as intermediates for the preparation of novel pentacyclic compounds <94JCS(P1)1371>. 

The effect of pressure on the rate and product distribution of oxazole Diels-Alder reactions has been studied for 5-methoxy-2-methyl-4-(4-nitrophenyl)oxazole 61, a 5-alkoxyoxazole (Fig. 3.18). " " At atmospheric pressure, 61 gave low yields of cycloaddition products with A -phenyl maleimide and did not react at all with dimethyl maleate or dimethyl fumarate, even when heated at 110°C for 100 h. However, after 10 min at 10 kbar, a benzene solution of 61 and iV-phenyl maleimide provided a 4 1 mixture of endo (62) and exo (63) adducts in quantitative yield. Longer reaction times result in equilibration of 62 and 63, which is postulated to occur via a retro-Diels-Alder reaction, producing a 65 35 ratio after 25 h at 10 kbar. If the reaction is carried out at 10 kbar for 25 h using methanol as the solvent, hydroxypyridine 64 is isolated in quantitative yield. Dimethyl maleate could be induced to react with 61 only at elevated temperature and pressure (10 kbar, 60°C, lOOh, CgHg) to give a 71% yield of hydroxypyridine 65. However, even these... 

The stereochemistry of the adduct obtained in many Diels-Alder reactions can be selected on the basis of two empirical rules formulated by Alder and Stein in 1937. According to the cis principle , the relative stereochentistry of substituents in both the dienophile and the diene is retained in the adduct. That is, a dienophile with trans substituents will give an adduct in which the trans configuration of the substituents is retained, while a cis disubstituted dienophile will form an adduct in which the substituents are cis to each other. This aspect is often referred to as the stereospecific nature of the Diels-Alder reaction. For example, in the reaction of cyclopentadiene with dimethyl maleate, the cis adducts 74 and 75 are formed, while in the reaction with dimethyl fumarate, the trans configuration of the ester groups is retained in the adduct 76 (3.64). 

Diek-Alder reactions. Cycloaddition reactions of furanes are usually only useful in the case of very reactive dienophiles, such as maleic anhydride and dimethyl acetylenedicarboxylate, since the adducts readily undergo a retro Diels-Alder reaction because of the aromatic character of furane. Dauben and Krabbenhoft find, however, that cycloadducts can be formed in fair to high yields by carrying out the reaction at room temperature at 15,000 atm. pressure (15 kbar)° for 4-14 hours. The yields in the case of acrylic dienophiles are 557o> but they are relatively low (0 25%) with crotonic dienophiles. The adduct of furane with dimethyl maleate is obtained in 947 yield as the endo-cis isomer. 

Diels-Alder transition states for the reaction of 1,3-cyclopentadiene with dimethyl maleate. 

Another pioneer in the Diels-Alder reactions of vinylpyrroles was Noland, who also developed the reactions of vinylindoles to yield carbazoles. Some examples of the former are shown in Scheme 2 (equations 1 and 2) [4-7], Jones and his colleagues were equally active in this cycloaddition chemistry of vinylpyrroles (equations 3 and 4) [8-12], These workers measured the rates of the reaction between 1-methyl-2-vinylpyrrole and seven dienophiles, with maleic anhydride being 4800 to 50,000 times more reactive than the other dienophiles (DMAD, maleonitrile, fumaronitrile, dimethyl maleate, methyl acrylate, and acrylonitrile) [8], In a clever tactic to thwart the formation of dihydroindoles, Jones used an excess of methyl propio-late to convert the initial adduct to a second Diels-Alder cycloadduct that subsequently loses ethene by a retro-Diels-Alder reaction to afford the dimethyl 1-methyl (phenyl)-4,7-dicarboxylates (equation 4). The reactions are concerted and were consistent with FMO calculations (HOMO[vinylpyrrole]-LUMO[alkene]). The yields are 54% to 81%, but attempts to dehydrogenate the tetrahydroindole products to indoles were unsuccessful. 2-Vinylpyrrole itself undergoes Michael additions and polymerization with these dienophiles. Domingo, Jones, and coworkers subsequently... 

SCHEME 4.10 Diels—Alder reactions of isomeric dimethyl maleate and dimethyl fumarate with buta-1,3-diene. 

The Pummerer rearrangement can also be carried in tandem with a Diels-Alder reaction. This sequence has been utilized in the syntheses of the arylnaphthalene lignan natural products. Sulphoxide 64 in acetic anhydride was slowly added to a solution of dimethyl maleate in acetic anhydride under reflux, resulting in cycloadduct 65 in 85% yield. 

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