Dienophiles dimethyl fumarate

Donor substituents on the vinyl group further enhance reactivity towards electrophilic dienophiles. Equations 8.6 and 8.7 illustrate the use of such functionalized vinylpyrroles in indole synthesis[2,3]. In both of these examples, the use of acetyleneic dienophiles leads to fully aromatic products. Evidently this must occur as the result of oxidation by atmospheric oxygen. With vinylpyrrole 8.6A, adducts were also isolated from dienophiles such as methyl acrylate, dimethyl maleate, dimethyl fumarate, acrolein, acrylonitrile, maleic anhydride, W-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest[3]. 

The discovery that Lewis acids can promote Diels-Alder reactions has become a powerful tool in synthetic organic chemistry. Yates and Eaton [4] first reported the remarkable acceleration of the reactions of anthracene with maleic anhydride, 1,4-benzoquinone and dimethyl fumarate catalyzed by aluminum chloride. The presence of the Lewis-acid catalyst allows the cycloadditions to be carried out under mild conditions, reactions with low reactive dienes and dienophiles are made possible, and the stereoselectivity, regioselectivity and site selectivity of the cycloaddition reaction can be modified [5]. Consequently, increasing attention has been given to these catalysts in order to develop new regio- and stereoselective synthetic routes based on the Diels-Alder reaction. 

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 pioneer work on this subject using simple 1-azadienes is due to Ghosez et al. (82TL3261 85JHC69) they succeeded in reacting 1-azadienes as 47r-electron components in Diels-Alder cycloadditions. Thus, l-dimethylamino-3-methyl-l-azabuta-l,3-diene (a,/3-unsaturated hydrazone) 54 did undergo [4 + 2] cycloaddition to typical electron-poor dienophiles, e.g., methyl acrylate, dimethyl fumarate, acrylonitrile, maleic anhydride, and naphthoquinone, producing pyridine derivatives 55-57 (Scheme 14). 

In the fused compounds (241) and (242) the furan ring fails to react as a diene and Diels-Alder reaction with dienophiles occurs on the terminal carbocyclic rings. However, (243) and (244) afford monoadducts with dimethyl fumarate by addition to the furan rings (70JA972). The rates of reaction (Table 2) of a number of dehydroannuleno[c]furans with maleic anhydride, which yield fully conjugated dehydroannulenes of the exo type (247), have been correlated with the aromaticity or antiaromaticity of the products (76JA6052). It was assumed that the transition state for the reactions resembled products to some extent, and the relative rates therefore are a measure of the resonance energy of the products. The reaction of the open-chain compound (250), which yields the adduct (251), was taken as a model. Hence the dehydro[4 + 2]annulenes from (246) and (249) are stabilized compared to (251), and the dehydro[4 ]annulenes from (245) and (248) are destabilized (Scheme 84). 

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... 

The reaction with dienophiles of the sulfur-substituted 3-vinylpyrrole, generated in situ by the alkylation of the 3-thioacetylpyrrole, has also been utilized to obtain indoles. Reactions with dimethyl maleate, dimethyl fumarate, methyl acrylate, acrylonitrile, and acrolein gave the corresponding cycloadducts which were directly transformed to the corresponding indoles by treatment with DDQ (91CPB489). 

When (67) was treated with a wide variety of cycloaddition reagents under various conditions, it behaved as a diene or a dienophile but not as a 1,3-dipole. As a dienophile it reacted with 2,3-dimethyl-1,3-butadiene to give (70) and with cyclopentadiene to give an analogous product. As a diene it reacted with [2.2.1] bicycloheptene to give (72), presummably via (71), by loss of carbon monoxide and hydrogen. No products were isolated when (67) was treated with maleic anhydride, dimethyl acetylene-dicarboxylate, diphenylacetylene, dimethyl fumarate, carbon disulfide, isobutyl vinyl ether, cyclohexene, and cyclopentene. 

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... 

A triplex has been proposed as an intermediate in some photoreactions. Yang and co-workers [54] found that addition of 1,3-dienes to anthracene excimers leads to different products than does its adition to monomeric excited arenes. Lewis and co-workers [55, 56] found that stilbene excimers can be intercepted by dimethyl fumarate to give an oxetane through a presumed triplex. More recently, Schuster and co-workers [57,58] studied the Triplex Diels-Alder reaction of 1,3-dienes with enol, alkene, and acetylenic dienophiles. Take 9,10-dicyanonaphthalene (DCN)/indene (IN)/l,3-cyclohexadiene (CHD) system as an example ... 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

Acyclic dienamines are relatively unstable, but very reactive towards electron-poor dienophiles as describe in a review article (1984). A more recent example shows the preparation of sterically encumbered 1-amino-1,3-diene (125) and its, nevertheless, efficient and highly stereoselective [4 + 2] cycloaddition to dimethyl fumarate (Scheme 32). Elimination of pyrrolidine, by heating the non-iso-lated cycloadduct with acetic anhydride, afforded hexahydronaphth ene (126), a key intermediate for a synthesis of drimane-type sesquiterpenes. 

The investigation of the Diels-Alder reaction of 2-substituted-a,/5-unsaturated hydrazones in a concentrated solution of LiNTf2 in MeCN revealed a spectacular rate increase when the reaction of 80 with A-phenylmaleimide (81) was run in this media (2.5 M LiNTf2-MeCN) (Sch. 40). These conditions also enable cycloadditions to be performed with less reactive dienophiles such as dimethyl fumarate or malate such cycloadditions result in stereospecific cyclizations [90]. 

The cycloaddition is ascribable to the oxyanion of hydrogen-bonded enolate (ArO —HNEt3 ) rather than to the hydrogen-bonded enol (ArOH—NEtj). An enantioselective version of the reaction was achieved by using a homochiral amine [27]. Similarly the reactions with less reactive dienophiles such as dimethyl fumarate, fumaronitrile, maleonitrile and methyl acrylate give the Diels-Alder adducts quantitatively when the cycloadditions are carried out in THF or CHCI3 in the presence of EtjN, while in MeOH Michael adducts were isolated. Experimental evidence supports the hypothesis that the base-catalyzed cycloadditions of anthrone with dienophiles are concerted Diels-Alder processes [25b]. 

Dienes derived from pyranosidic hexoses react with activated dienophiles to afford adducts with good to excellent diastereoselectivities. Cycloaddition of methyl-2,3-didcoxy-2,3-cnc-3-vinyl-4,6-0-benzylidene-a-D-glucopyranoside (15) to maleic anhydride (9), 4-quinone (22) and dimethyl acetylenedicarboxylate (17) furnishes single adducts 16,18 and 23, respectively, while the reaction with dimethyl fumarate produced two diastereomers 20 and 21 in a 1 1 ratio. Naphthoquinone (24) produces endo- and exo-isomers 25 and 26 in a d.r. 90 10. In each case all products arise from attack on the same face of diene 151S. 

The 1-azadiene and the dienophilic character of 2-alkenyl-5,6-dihydro-4//-l,3,4-oxadiazines (150 Section 6.17.6.2) have been explored (Scheme 21) <93TL457>. Attempts to effect cycloaddition with DMAD, dimethyl fumarate, and acrylonitrile failed, whereas with maleic anhydride and A-methylmaleimide unexpected noncyclic adducts (e.g. 151) are obtained. The alkenyl oxadiazines also fail to give cycloadducts with l-methoxy-3-trimethylsilyloxy-l,3-butadiene with or without the presence of a Lewis acid catalyst. However, with methyl penta-2,4-dienoate mixtures of diastereo-isomeric products (e.g. 152) are formed, albeit slowly, by [4 + 2] cycloaddition at the alkenyl side chain, rather than at the C2—N3 imine bond. 

Solid state excitation of electron donor-acceptor complexes of various diaryl-acetylenes and dichlorobenzoquinone in either the acceptor or the 1 2 complex absorption bands induces [2+2] cycloaddition and produces identical mixtures of the quinone methides. Evidence is presented for the participation of an ion-radical pair as the reactive intermediate in both cases. Irradiation of an appropriately substituted o-hydroxybenzyl alcohol precursor generates the corresponding o-quinone methide which is reported to undergo an efficient [4+2] cycloaddition to form the hexahydrocannabinol system. Time-resolved studies confirm the intermediacy of the o-quinone methide and show its lifetime to be > 2 ms. Laser photolysis of 1,2-bis(phenoxymethyl)benzene, l,2-bis[(phenylthio)-methyl]benzene, and l,2-bis[(phenylseleno)methyl]benzene occurs by a two-photon process to produce o-quinodimethane which will cycloadd to various dienophiles including maleic anhydride, dimethyl maleate, dimethyl fumarate, fumaronitrile and dimethyl acetylenedicarboxylate. ... 

From Table 7 (column ii) a notable difference of reactivity between dimethyl fumarate and dimethyl maleate is seen. This is not fortuitous, since, in most cases, tra/is-l, 2-disubstituted ethylenes were found to be better or much better dienophiles than their cis isomers, in classical Diels-Alder reactions ktrawlkos ratios up to 740 are reported . Steric compression in adducts obtained from... 

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