Fumaronitrile reaction with

Enders et al. (53) reported the use of chiral l,3-dioxan-5-ylamines in condensation reactions with aromatic aldehydes to form ylides in situ, which underwent thermal cycloaddition reactions with excellent yields. Treatment of 193 with benzaldehyde or p-fluorobenzaldehyde in the presence of excess dimethyl fumarate or fumaronitrile gave rise to the expected adducts in 85% yield with a >96% diastereomeric excess. For nitriles (R = CN), the endo/exo selectivity was higher at 70 30 than for the esters (R = C02Me) at 55 45 (Scheme 3.56). 

Numerous examples involving the preparation of tetrahydrothiophenes via [3 + 2] cycloaddition of thiocarbonyl ylides with electron-poor alkenes have been reported. Thiobenzophenone (5)-methylide (16), generated from 2,5-dihydro-1,3,4-thiadiazole (15) and analogous compounds, react with maleic anhydride, N-substituted maleic imide, maleates, fumarates, and fumaronitrile at —45°C (28,91,93,98,128,129). Similar reactions with adamantanethione (5)-methylide (52) and 2,2,4,4-tetramethyl-3-thioxocyclobutanone (5)-methylide (69) occur at ca. +45°C and, generally, the products of type 70 were obtained in high yield (36,94,97,130) (Scheme 5.25). Reaction with ( )- and (Z)-configured dipolaro-philes stereospecifically afford trans and cis configured adducts. 

Cycloaddition reactions were also carried out using l,2-bis(trifluoromethyl)-fumaronitrile (137,138,191,192). Seven-membered cychc ketene imines (186-188) could actually be isolated in good yields from the reactions with 69,... 

Nan ya et al. (97) also reported the synthesis of isoindolediones by the reaction of miinchnones with 1,4-benzoquinones. Reactions with an unsymmetrical mtinchnone were not regioselective. Several groups have examined the reactions of miinchnones with unsaturated nitriles, including 2-chloroacrylonitrile (98), cinna-monitrile (78,99) and fumaronitrile (78) to give unexpected products in several cases. Eguchi and co-workers (100) smdied the cycloaddition of several mtinch-nones with electron-deficient trifluoromethylated olehns. Thus, miinchnones 176... 

Conversely, furans with electron-withdrawing groups e.g. CHO, CN, C02Me) in the 2-position show reduced Diels-Alder reactivity. Although furan-2-carboxaldehyde is a poor diene the related N,N-dimethylhydrazones do take part in reactions with a range of dienophiles including maleic anhydride, maleimides, and fumaronitrile (88JOC1199). 

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). 

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... 

Mesoionic compounds may undergo 1,3-dipolar cycloaddition reactions. Thus anhydro-1 -hydroxythiazolo[3,2-a]guinolinium hydroxide (396) is a substrate for the reaction with DMAD. The formation of the pyrrolo[l,2-a]quinoline (397) from this reaction involves COS elimination from the initial adduct. Ethyl propiolate also reacts in the same fashion. The orientation in the cycloadduct can be arrived at from the ylide form (396a). With fumaronitrile, however, the fused pyridinone (398) is formed by loss of sulfur from the primary cycloadduct (78JOC2700). 

Lithium perchlorate in diethyl ether has also been reported to accelerate Diels-Alder reactions significantly and this system has been applied to obtain Diels-Alder adducts that were inaccessible via conventional means [213-219]. A linear dependence of kobs on [Li+] is observed for the Diels-Alder reaction of DMA with acrylonitrile in LiC104-Et20 solution, while a second-order dependence of koba on [Li+] is involved for the reactions with fumaronitrile and dimethyl acetylenedi-carboxylate [216]. This suggests the possible contribution of Li -catalyzed electron transfer step in the Diels-Alder reaction as the case of Mg +-catalyzed Diels-Alder reaction in Scheme 12. However, such an electron transfer mechanism has not been confirmed in the Li -catalyzed Diels Alder reactions. 

Cyanopyrazole heterocycles were easily prepared via thermolysis of tetrazolo[l,5-3]pyridazines, tetrazolo[l,5- ]pyr-imidines, or tetrazolo[l,5- ]pyridines <2000TL2699>. Tetrazolylacroleins 809 underwent ring transformation on reaction with fumaronitrile 810 to afford pyrazolyl derivatives 811 (Equation 181) <2003T7485>. Mechanistically, the tetrazolylacrolein is believed to react with the dipolarophile via a 1,3-dipolar cyclization route to give a... 

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]. 

The second method was based on a cycloaddition reaction of olefinic and acetylenic dipolarophiles to xanthinium-(N7) ylides. Xanthinium-(N7) ylides 22 were generated from 7-substituted 1,3,9-trimethylxanthinium tosylates 21 by deprotonation with triethylamine in dry acetonitrile followed by reaction with dipolarophiles 23 and 25 (dimethyl fumarate, fumaronitrile, methyl acrylate, acrylonitrile and the like). Reaction with dimethyl fumarate afforded the endo-(24a) and exo-(24b) adducts in a 3 2 ratio. The stereochemistry of these compounds was established by H-NMR and X-ray analysis (84H2199). With derivatives of acrylic acid 25, only endo adducts (26)... 

This reaction appears to be generally applicable to dienophiles. Acrylonitrile or fumaronitrile react with triethyl phosphite in ethanol to provide the corresponding j -cyanophosphonate esters (44% and 55%, respectively). Ethyl propiolate, triethyl phosphite, and ethanol furnish diethyl 2-carbethoxy-l-ethoxyethylphosphonate, which most probably arises by addition of ethanol to an intermediate species rather than to reactant or product. Reaction of crotonaldehyde with triethyl phosphite in phenol provides the diphenyl acetal of jS-(diethoxyphosphinyl) butyraldehyde (36) (82%). Substitution of ethanol for phenol in this reaction results in a somewhat lower yield (59%) of the corresponding diethyl acetal as well as a 19% yield of the ethyl enol ether of this same aldehyde. 

An important new development is the demonstration that Diels-Alder reactions with phospholes and fumaronitriles are greatly accelerated under pressure, and this has led to the synthesis of a number of new 7-phosphanorbornene derivatives. Thus, 3,4-dimethyl-1-phenylphosphole reacted with fumaronitrile at 30 C under 9 kbar for 24 h to give an adduct in 67% yield (Equation (8)) <89T7083>. The stereochemistry at phosphorus was confirmed by x-ray analysis. 

In a three-component reaction with 1 and fumaronitrile dissolved in phenyl azide, the 7V-phenyl substituted thiocarbonyl 5-imide (28, Ar = Ph) cycloadds to fumaronitrile to give the corresponding 1,2-thiazolidine derivative. ... 

Dipolarophiles which contain an electron-deficient substituent undergo smooth cycloaddition reactions with nitrile ylides. The relative reactivity of the nitrile ylide toward a series of dipolarophiles is determined primarily by the extent of stabilization afforded the transition state by interaction of the dipole highest-occupied (HO) and dipolarophile lowest-unoccupied (LU) orbitals. Substituents which lower the dipolarophile LU energy accelerate the 1,3-dipolar cycloaddition reaction. For example, fumaronitrile undergoes cycloaddition at a rate which is 189,000 times faster than methyl crotonate. Ordinary olefins react so sluggishly that their bimolecular rate constants cannot be measured. 

These yfides where shown to dissociate to carbene and pyridine with low activation barrier. The equilibrium constant of the reaction increases with increasing electron-withdrawing ability of substituents in the pyridine ring. There was no reaction with unsubstimted pyridine or picolinic acid nitrile, hi the reaction of nicotinic acid nitrile with the fumaronitrile a mixture of the regioisomeric products was formed ... 

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