Dipolar Reagents

Above we saw a criss-cross addition of benzalazine with MA involving two 1,3-dipoles. A number of other reagents which fall in the class of 1,3-dipoles, e.g., diazoalkanes, nitrile oxides, and azides, also react with MA to yield intermediates with unique structural features. Many of these products are formed in good yields, thus increasing their importance as intermediates for the synthesis of other compounds, such as pharmaceuticals and monomers. 

The reaction of diazomethane with dimethyl fumarate was reported by Von Pechmann to give the diester of 2-pyrazoline-4,5-dicarboxylic acid 25 (21,26) product was isolated as the acid after hydrolysis. 

Hampel has examined the reaction of MA with diazomethane. The reaction in ether at 5°C gave an 85% yield of the product expected by the 1,3-dipolar cycloaddition to MA and was assigned structure 26. No comment 

Substituted diazoalkanes could react similarly. Gruning and Lorberth have studied the addition reaction of trimethyllead diazoacetic ester 28 with MA to obtain an 85% yield of the pyrazoline derivative 29. Maleic acid and 

A variety of substituted diazoalkanes have been examined. Rodina et reported formation of a spiro pyrazoline 31 from the cyclic diazoketone 30. The product on further heating to 141°C loses 1 mole of N2 to yield a spiro cyclopropane derivative 32. 

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Generation and reactions of carbonyl ylides, nonstabilized 1,3-dipolar reagents 98YGK681. 

The use of chiral dipolarophiles, such as the nitrile oxide additions to chiral furanones, have received much interest. The cycloaddition of various 1,3-dipolar reagents to the enantiomeric ally pure furanones 170 and 227 showed excellent diastereofacial control by the menthyloxy substituent, especially in nitrone and nitrile oxide additions (cf. Table II) (88TL5317). 

The 1,3-dipolar reagent diazomethane reacts with oxepin and substituted derivatives to afford 1 1 or 2 1 adducts 13 or 14 across the C-C double bonds of the isomeric benzene oxides.238 239 In the 1 1 addition product 13, the two heterocycles adopt a cis orientation.238 The nitrogen can be extruded by irradiation of the dihydropyrazole. 

The mechanism of attack of 1,3-dipolar reagents on fluoroalkenes can be considered to be either stepwise or concerted. Heteroaromatic N-imines react by a stepwise 1,3 addition to perfluoroalkenes and -alkynes to give fluorinated pyrazolo[l,5-a]pyridines [82JCS(P1)1593]. Pyridinium /-butoxycarbonylmethylide with fluoroalkenes gave pyrrolo[l,2-a]pyri-dines [86JCS(P 1) 1769] and indolizines (22) are obtained with pyridinium phenacylide [91JFC(51)407]. 

Tetrafluoroallene reacted with the 1,3-dipolar reagent, N-phenylsyd-none, to give a 4-trifluoromethylpyrazole, whereas tetrafluoropropyne gave a mixture of isomers. The difference in behavior was explained on the basis of frontier orbitals [82JCS(P 1)2207]. 

In general, metalated 2-azaallyl anions derived from imines of a-amino esters serve both as Michael donors and as 1,3-dipolar reagents the course of the reaction, as well as the stereochemical outcome depends upon the base and the reaction conditions82,83. 

The 1,3-dipolar reagent can in some cases be generated by the in situ opening of a suitable three-membered ring system. For example, aziridines can add to activated double bonds to give pyrrolidines, for example," ... 

Nitro compounds are versatile precursors for diverse functionalities. Their conversion into carbonyl compounds by the Nef reaction and into amines by reduction are the most widely used processes in organic synthesis using nitro compounds. In addition, dehydration of primary nitro compounds leads to nitrile oxides, a class of reactive 1,3-dipolar reagents. Nitro compounds are also good precursors for various nitrogen derivatives such as nitriles, oximes, hydroxylamines, and imines. These transformations of nitro compounds are well established and are used routinely in organic synthesis. 

Dipolar cycloadditions are the most general method for the synthesis of five-membered heterocycles [51]. Various easily available and efficient 1,3-dipolar reagents are able to react with double or triple bonds to afford many different classes of structurally differentiated, selectively substituted heterocycles... 

Other 1,3-dipolar reagents show the same mode of reactivity towards cyclopropenones. Thus, the Munchnones 412 serving as potential azomethine ylides259-261 or the nitrile ylids 41 3262 effect expansion of the three-membered ring to the 4-pyridone systems 411/414 as a result of (2 + 3) cycloaddition to the C /C2 bond. 

N-Phenylsydnone 116 reacts readily with perfluoropropadiene to form pyrazoles 118 in 63% yield [59, 60], Actually, perfluoropropadiene reacts with a whole series of 1,3-dipolar reagents providing an efficient entry to hetero- and carbocycles 119, 121, 123 and 125. 

Reactions of 1,1-difluoropropadiene or monofluoropropadiene and a 1,3-dipolar reagent such as diazo compounds, nitrones, nitrile oxides and carbonyl ylides are an excellent route to five-membered heterocycles, such as 126 and 127 [61-63]. 

The reactivity of peroxo metal complexes as nucleophilic oxidants is a known process ". To visualize this type of reactivity one has to refer to peroxo metal complexes as a 1,3-dipolar reagent M+-0-0 interacting in a bimolecular fashion with electrophilic dipo-larophiles such as electron-poor olefins " (equation 15), to form peroxymetallacycle intermediates. 

Vinylpyrroles can also react as 2ir-electron systems to yield the expected heterocyclic derivatives through the cyclization of the vinyl group with 1,3-dipolar reagents (80H(14)185). 

Frequently, [3+2] cycloadditions of 1,3-dipolar reagents such as PhN3, diazoalkanes, or nitrile oxides to acyclic phosphaalkenes provides access... 

Exclusion of carbon dioxide from A-triphenylmethyl-5-oxazolidinone (2) under heating generates the corresponding 1,3-dipolar reagent, which adds readily to La2 / -C8o yielding both [5,6]-adducts and [6,6]-adducts [136], The [6,6]-adduct can be crystallized from the mixture, although exhaustive HPLC separations were ineffective. X-ray data present a [6,61-close structure and the motion of the two La atoms was found to be stopped by the cycloaddition of the adduct (Figure 7.8). 

Reaction of the amino-substituted phosphaalkyne Pr 2N-C=P with diazoalkanes 23a-23c as 1,3-dipolar reagents took place in toluene solution at ambient temperature with evolution of N2 and elimination of diisopropyl cyanamide. After 3-5 h bicyclic diphosphiranes 24a-24c were isolated. While solutions of 24a and 24c were stable, the mixture of diastereoisomers 24b decomposed in toluene (Scheme 8). 

Cycloadditions between substituted fulvenes and 1,3-dipolar reagents have been the subject of considerably less study than the corresponding diene-mediated chemistry, paralleling the situation seen in the tropone series. For the most part, however, the reactivity patterns formulated in the fulvene-diene studies are repeated in the analogous 1,3-dipole reactions. 

A number of cyclopropyl-substituted five-membered heterocycles have been synthesized by addition of various 1,3-dipolar reagents to (alk-l-enyl)cyclopropanes. Most reactions were performed using tricyclo[3.1.0.0 ]hex-3-ene and tricyclo[3.1.0.0 ]hex-3-en-3-yl phenyl sul-fone, giving the corresponding cycloadducts in very good yields on treatment with azides, a carbonyldicobalt complex, nitrile oxides, diphenylni-trilimine, (4-nitrophenyl)benzenecarbonitrile ylide, and diazoalkanes. For example, addition of tricyclo[3.1.0.0 ]hex-3-ene (1) to 4-nitrophenyl azide gave dihydro-1,2,3-triazole 2 in 94 /o yield. ... 

Acceptable yields of [3-1-2] cycloadducts were also obtained when l-methyl-6-methylene-tricyclo[3.2.1.0 ]oct-3-en-8-one was reacted with phenyl azide and 2,4,6-trimethylbenzenecar-bonitrile oxide.Interestingly, the two 1,3-dipolar reagents exhibited different regiochem-istry the azide reacted with the endocyclic double bond whereas the A-oxide attacked the exocyclic C-C double bond. ... 

Imides of this type behave as 1,3-dipolar reagents in cycloaddition reactions. For example, imide 69 reacts readily with dimethyl acetylene-dicarboxylate to form the cycloadduct 73, but this undergoes spontaneous... 

The exo double bond of 4-alkylidene and 4-arylidene-5(4//)-oxazolones undergoes cycloaddition reactions with 1,3-dipolar reagents. For example, nitrile oxides add to 2-phenyl-4-ethoxymethylene-5(4//)-oxazolone (88) to give spirocyclic products that may be hydrolyzed to 4-aminoisooxazoles... 

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