Dipolarophiles fumarates

Mathias and Moore (30-33) described a new synthesis of isomiinchnones 55 via the thermal cyclization of A-(chloroacetyl)lactams (54) (Scheme 10.7). These isomiinchnones can be captured by NPM to give fused 2-pyridones in moderate yields. Cycloadducts from the reaction with DMAD are produced in much lower yields (<17%), and other olefinic dipolarophiles (fumarate, maleate, acrylate, and dicyanocyclobutene) are unreactive. Reaction of 7/-(chloroacetyl)benzamide (57) in the presence of NPM gave 58 in low yield. 

Dipolarophiles D14. The 1,3-dipolar cycloaddition of nitrones to dimethyl maleate and dimethyl fumarate is widely used in the synthesis of polyhydroxy alkaloid derivatives of dihydroindolizidinone (81), pyrrolizidine (119), (—)-codonopsinine, and (+ )-hyacinthacines Ai and A2 (312). In cases of unstable nitrones, syntheses of cycloadducts are performed in situ (81). 

The 3 + 2-cycloaddition of 1,2-dithiophthalides with nitrilimines yields benzo[c]thio-phenespirothiadiazoles regioselectively. The azomethineimines isoquinolinium-iV-aryllimide and A-(2-pyridyl)imide readily undergo 1,3-dipolar cycloaddition with electron-deficient dipolarophiles, dimethyl fumarate and dimethyl maleate, to yield tetrahydropyrazolo[5,l-a]isoquinolines in high yield. ° The 1,3-dipolar cycloadditions of electron-poor 1,3-dipoles, bicyclic azomethine ylides (27), with ( )-l-A,A-dimethylaminopropene to yield cycloadducts (28) and (29) are examples of non-stereospecific cycloadductions (Scheme 9). The synthesis of protected... 

The [3 -f 2] cycloaddition of aziridines and dipolarophiles, like dimethyl acetylenedicarboxylate or dimethyl fumarate and maleate, was investigated by Gaebert and Mattay. Via C—C and C—bond cleavage five-membered heterocycles are formed in moderate yields. The different product ratios dependent on the reaction conditions (PET/direct excitation/thermal reaction) gave insights to the reaction details and are summarized in the proposed mechanism (Scheme 52) [84],... 

The meso-ionic l,3-dithiol-4-ones (134) participate - in 1,3-dipolar cycloaddition reactions giving adducts of the general type 136. They show a remarkable degree of reactivity toward simple alkenes including tetramethylethylene, cyclopentene, norbomene, and norbor-nadiene as well as toward the more reactive 1,3-dipolarophilic olefins dimethyl maleate, dimethyl fumarate, methyl cinnamate, diben-zoylethylene, A -phenylmaleimide, and acenaphthylene. Alkynes such as dimethyl acetylenedicarboxylate also add to meso-ionic 1,3-dithiol-4-ones (134), but the intermediate cycloadducts are not isolable they eliminate carbonyl sulfide and yield thiophenes (137) directly. - ... 

Photochemical cycloaddition reactions between sydnones (1) and 1,3-dipolarophiles take place to give products which are different from, but isomeric with, the thermal 1,3-dipolar cycloaddition products. These results are directly interpreted in terms of reactions between the 1,3-dipolarophiles and Ae nit mine (316). The photochemical reactions between sydnones and the following 1,3-dipolarophiles have been reported dicyclopentadiene, dimethyl acetylene dicarboxylate, dimethyl maleate, dimethyl fumarate, indene, carbon dioxide, and carbon disulfide. ... 

The cycloaddition of substituted acrylates has been investigated with cyclic nitronate 24 (Table 2.49) (14). The cycloaddition of a 1,1-disubstituted dipolar-ophile (entry 2), proceeds in good yield, but both 1,2-disubstituted alkenes fail to react. The effect of substitution pattern on the dipolarophile was investigated with a slightly more reactive nitronate (Table 2.50) (228). Less sterically demanding alkenes such as cyclohexene, cyclopentene, and methyl substituted styrenes react, albeit at elevated temperature. The only exception is the 1,1-disubstituted alkene (entry 4), which reacts at room temperature. Both stilbene and dimethyl fumarate fail to provide the desired cycloadduct. In a rare example of the dipolar cycloaddition of tetra-substituted alkenes, tetramethylethylene reacts at 50 °C over 3 days to give a small amount of the cycloadduct (entry 7). 

Addition of freshly prepared MgBr2.0Et2 to the reaction gave universal improvements in yield of the products (59). Previously poor dipolarophiles now gave good to excellent yields, especially in the case of dimethyl fumarate which. 

Alkene dipolarophiles such as diethyl fumarate were shown to be somewhat less reactive than electron poor acetylenes (9), but were effective for the formation of dihydrofuran derivatives (Scheme 4.7). 

This French group (145) has also been able to divert the usual Diels-Alder cycloaddition pathway of Reissert salts with oleftnic esters to a 1,3-dipolar cycloaddition pathway by the addition of triethylamine. In addition, mtinchnone imine 243 can be trapped with dipolarophiles to furnish 244 (146). No Diels-Alder cycloadducts derived from the oxazolium salt were detected. In contrast, fumarate... 

When the a-substituent is methyl (R = Me), deprotonation occurs readily with NEt3 at room temperature. Although the cycloaddition step of the resultant ylide with sterically less hindered or reactive dipolarophiles (A-methylmaleimide, methyl acrylate, methyl methacrylate, and dimethyl fumarate) proceeds faster than the ylide generation step, the cycloaddition step becomes rate determining if sterically... 

Olefinic dipolarophiles, such as dimethyl fumarate, fumaronitrile, ethyl vinyl ether, A-phenylmaleimide, norbornene, and norbornadiene, react with... 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

Scheme 1.36). The heteroatomic diethyl fumarate analogue 122 can also act as a dipolarophile, with its reaction leading to imidazotriazole 123. 

Other dipolarophiles (yield, ratio 2-Ph 3-COOMe cis trans) methyl maleate (91%, 5 4) methyl fumarate (83%, 2 3) AMnethyl maleimide (85%, 1 2) methyl acrylate (83%, 5 4). 

However, an unprecedented result is obtained when maleimide, fumarates, maleate and dibenzoylethylene are used as dipolarophiles, as hydromethylenation of olefins results.405,406... 

This result has been confirmed with other dipolarophiles. Conservation of the original geometry is observed as exemplified by reactions with methyl dimaleate and fumarate. In the presence of a base such as the methoxide anion, the ri.v-isomer issued from fumarate was transformed into the more stable traw.v-cycloadduct form from maleate. Cycloaddition of benzaldehyde leads to TV-benzyl-5-phenyloxazolidine.65 443... 

This above result was only obtained with maleimide as the dipolarophile. With dimethyl fumarate and fumaronitrile, A2-pyrrolines are obtained, probably because of the acidity of the hydrogen atoms a- to ester and nitrile functionalities. Reaction with alkynes produces pyrrole derivatives in good to excellent yields and with aromatic aldehydes leads regioselectively to oxazolidines in moderate yields.263... 

Work from the Grigg group since the late 1990s has focused on extensions of the chemistry detailed above. In one effort, it was shown how the unique reactivity of isocyanides allows them to function as azomethine ylide precursors. The reaction of isocyanide 120 with dipolarophiles 121 proceeds in the presence of silver acetate to afford dehydropyrroles 122 in good yield (Scheme 2.32, Table 2.10). Reaction with dimethyl maleate (76) afforded the corresponding product in excellent yield and diastereoselectivity. In contrast, its stereoisomer, dimethyl fumarate (26), furnished a 6 4 mixture of isomers under identical conditions.59 The authors proposed a stepwise mechanism for this reaction (Scheme 2.33). 

The benzo derivative (128) reacts as a thiocarbonyl ylide. Addition of N-(p-tolyl)maleimide gives a mixture of the exo (71%) and endo (16%) adducts (129 Ar=p-tolyl), which in hot acetic acid eliminate hydrogen sulfide giving the pyrido[l,2-a]benzimidazole (130 Ar=p-tolyl). Analogous 1 1 cycloadducts (131) are formed with dimethyl maleate, dimethyl fumarate, methyl crotonate and methyl acrylate. In contrast to the transformation (129) —> (130), treatment of the adducts (131 R = H, Me) with hot acetic acid gives the tetracyclic compounds (133) via the benzimidazole derivatives (132 R = H, Me). Reaction with alkynic 1,3-dipolarophiles gives pyrido[l,2-a]benzimidazole (134) by desulfurization of the primary adducts (80CL1369). 

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