Dipolarophiles dimethyl acetylenedicarboxylate

The exploration of novel preparative routes commands much attention in isothiazole chemistry. Especially interesting are the reactions of 3-phenyl-l,2,4-oxathiazol-5-one with acetylenic esters which afford isothiazoles in high yield (72, 7). The reaction is envisaged as a 1,3-dipolar addition of benzonitrile 7V-sulphide, produced as a transient intermediate, to the dipolarophilic dimethyl acetylenedicarboxylate or propiolic ester. Isothiazoles are also produced by photoisomerization of thiazoles (72, 19). Nitrenes may be implicated in the thermal decomposition of 2-azidoaryl thioketones into benzoisothiazoles (72, 51). 

However, at least one example is known of acetylated nitronic acids 9 (Scheme 8.3) supposed to react directly with a dipolarophile (dimethyl acetylenedicarboxylate) to give the expected isoxazole derivatives 11 via the unstable intermediate adducts 10 (R = Ph) rather than via nitrile oxides. In fact, isolated 9 (R = Ph), in standard reaction conditions but in the absence of dipolarophile, decomposed to benzoic acid, with no diphenylfuroxan being detected [30]. Notice that this result refers only to the mentioned dipolarophile, whereas attempted reaction with other dipolarophiles (maleic anhydride or diphenylacetylene) failed. 

Intermolecular Reactions Dimethyl acetylenedicarboxylate (DMAD) is frequently used as an alkyne dipolarophile (23, 24, 126b, 152, 241, 333). 

Quaternarization of 43 with phenacyl bromide produced the corresponding salt 51 that was reacted with several triple-bond-containing dipolarophiles (Scheme 4), such as dimethyl acetylenedicarboxylate (DMAD) or alkyl propiolates to give tricyclic compounds 52, 53 and 54, 55. Compound 51 reacted also with acrylonitrile as dipolaro-phile in MeCN/K2C03 to give the cycloadduct 56 as a mixture of diasteroisomers. 

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. - ... 

The meso-ionic l,3>2-oxathiazol-5-ones (169) show an interesting range of reactions with nucleophiles including ammonia, primary amines, and aqueous alkali. They also react with l,3-dipolarophiles, including dimethyl acetylenedicarboxylate and methyl propiolate, yielding isothiazoles (171) and carbon dioxide. 1,3-Dipolar cycloaddition reactions with alkenes such as styrene, dimethyl maleate, and methyl cinnamate also lead to isothiazoles (171) directly. BicycUc intermediates (cf. 136) were not isolable these cycloaddition reactions with alkenes giving isothiazoles involve an additional dehydrogenation step. 

The formation of various 1 1 adducts from dehydrodithizone 413, R = R = Ph, and various 1,3-dipolarophiles has been reported. Thus, dimethyl acetylenedicarboxylate yields 419, X = COOMe, tetra-cyanoethylene yields 420, and e oxycarbonylmethylenetriphenylphos-phorane yields the betaine 421. These transformations have been considered as 1,3-dipolar cycloaddition reactions of a novel type. It seems to us rather unlikely that these transformations are concerted 1,3-dipolar cycloadditions the alternative that they are reactions involving dipolar intermediates (e.g., 422, 423, and 424) should also be considered. The... 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

Several 1,3-dipolar cycloaddition reactions of cinnolinium-4-olates have been reported. The methyl derivative (243) with dimethyl acetylenedicarboxylate gives adduct 247. Previously, the formation of a 1 1 adduct between compound 243 and phenylacetylene had been reported by Lunt and Threlfall. The 6-chloro derivative (233 R = Me, R = R = R = R = H, R = Cl) forms similar adducts with dimethyl acetylenedicarboxylate and diphenylacetylene and a single regioisomer with phenylacetylene. No reaction with olefinic dipolarophiles was observed. 

The formation and intramolecular dipolar cycloaddition of azomethine ylides formed by carbenoid reaction with C=N bonds has recently been studied by the authors group.84 Treatment of 2-(diazoace-tyl)benzaldehyde O-methyl oxime (176) with rhodium(II) octanoate in the presence of dimethyl acetylenedicarboxylate or N-phenylmaleimide produced cycloadducts 178 and 179, respectively. The cycloaddition was also carried out using p-quinone as the dipolarophile. The major product isolated corresponded to cycloadduct 180. The subsequent reaction of this material with excess acetic anhydride in pyridine afforded diacetate 181 in 67% overall yield from 176. The latter compound incorporates the basic dibenzofa, d -cyclohepten-5,10-imine skeleton found in MK-801,85 which is a selective ligand for brain cyclidine (PCP) receptors that has attracted considerable attention as a potent anticonvulsive and neuro-protective agent.86,87... 

Both of the known oxathiolium systems have been trapped in situ by dipolarophiles. Compound (88) reacts with dimethyl acetylenedicarboxylate (DMAD), but not phenyl isocyanate or isothiocyanate, to yield thiophene (89), following loss of carbon dioxide as shown in Scheme 10 (77CPB1471). Similarly, oxathioliums (90) may be trapped by a variety of alkynic dipolarophiles to give furans (91) as shown in Scheme 11. The reaction, which appears to be regiospecific when unsymmetrical alkynes are used, is a useful way of preparing furans containing amine or thioether functionality (75AG(E)422). 

Several 3-hydroxy-2//-pyrazolo[4,3-c]isoquinolinium inner salts undergo reaction with dipolarophiles in 1,3-cycloaddition reactions <03JOC8700>. The best yields with the cleanest mixture of compounds is when R = PMB and dimethyl acetylenedicarboxylate (DMAD) is the dipolarophile. 

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