1,3-dipolar compounds

Two questions are of principal interest for predicting the structure of reaction products of 1,3-dipolar addition (1) Is the reaction stereospecific (2) Is the reaction regioselective The answer to the first question is yes with respect to the dipolarophile. Many specific recorded examples demonstrate that the cyclic product results from a stereospecific syn addition to olefins. The stereospecific addition that is observed is exactiy what would be expected on the basis of a concerted mechanism. 

With some 1,3-dipoles, two possible stereoisomers can be formed by syn additions differing in the relative orientation of the reacting molecules. In several cases where disubstituted diazomethanes have added to olefins, mixtures are obtained.This is comparable to the situation of endo versus exo stereochemistry in the Diels-Alder reaction. 

The question of regioselectivity is at this time a matter of some controversy, and there are no simple rules for predicting orientation in dipolar cycloadditions. In some cases, both possible cyclic adducts have been isolated from a cycloaddition reaction. There is no fundamental mechanistic requirement for regiospecificity. In particular, it is important to note that attempts to predict regioselectivity on the basis of the polarity of the 1,3-dipole and the dipolarophile are completely unreliable. 

The basis for the regioselectivity that is noted in most of the cycloadditions has 

There have been few studies comparing the reactivity of various 1,3-dipoles. Quite a lot of work has been done, however, on comparing the reactivity of various olefins as dipolarophiles. Several generalizations have come from such studies  

Mechanistic studies have shown that the transition state for cycloaddition of 1,3-dipoles to carbon-carbon multiple bonds is not very polar. The rate of reaction is not strongly sensitive to solvent polarity, and this is in agreement with viewing the addition as a concerted process. The formal destruction of charge that is indicated is more apparent than real, because most 1,3-dipoles are not highly polar 

A comprehensive review of 1,3-dipolar cycloaddition reactions is that of G. Bianchi, C. DeMicheli, and R. Gandolfi, in The Chemistry of Double Bonded Functional Groups Part i. Supplement A, S. Patai (ed.), John Wiley and Sons, New York (1977), pp. 369-532. For a review of intramolecular 1,3-dipolar cycloaddition reactions, see A. Padwa, Angew. Chem. Int, Ed. Engl. 15, 123 (1976). 

A complete analysis requires estimation or calculation of the energy of the orbitals which are involved. The orbital coefficients and energies for the most common systems have been summarized and further qualitative predictions can be made by considering the effect of additional substituents on the 1,3-dipole and dipolarophile (see Section 10.3 of Part A for a discussion.) 

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A completely different, important type of synthesis, which was developed more recently, takes advantage of the electrophilicity of nitrogen-containing 1,3-dipolar compounds rather than the nucleophilicity of amines or enamines. Such compounds add to multiple bonds, e.g. C—C, C C, C—O, in a [2 + 3 -cycioaddition to form five-membered heterocycles. 

A comprehensive review of reactions of isocyanates and 1,3-dipolar compounds has been previously pubhshed (51). The example shown illustrates the reaction of azides and isocyanates to yield tetrazoles (14,R = alkyl or aryl, R = aryl or sulfonyl) (52,53). 

The reactions of 1-azirines with ketenes and ketenimines represent non-concerted additions and are formally different from the additions to 47r-systems of dienes and 1,3-dipolar compounds (73JOC3466, 71CB2786). 

Mechanistically the 1,3-dipolar cycloaddition reaction very likely is a concerted one-step process via a cyclic transition state. The transition state is less symmetric and more polar as for a Diels-Alder reaction however the symmetry of the frontier orbitals is similar. In order to describe the bonding of the 1,3-dipolar compound, e.g. diazomethane 4, several Lewis structures can be drawn that are resonance structures ... 

A well-known example for a 1,3-dipolar compound is ozone. The reaction of ozone with an olefin is a 1,3-dipolar cycloaddition (see ozonolysis). 

Dipolar compounds often are highly reactive, and therefore have to be generated in situ. 

The ylides may be defined as dipolar compounds in which a carbanion is covalently bonded to a positively charged heteroatom. They are represented by the following general formula ... 

In the Wittig reaction, a phosphorus ylide, R2C—P(C6H03, also called a phosphoreme and sometimes written in the resonance form R2C=P(C6H5)3, adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine. (An ylide—pronounced ill-id—is a neutral, dipolar compound with adjacent plus and minus charges. A betaine—pronounced bay-ta-een—is a neutral, dipolar compound with nonadjacent charges.)... 

Ar-Arylbenzimidoyl)tetrazoles t, prepared from JV-arylbenzimidoyl chlorides and 5-(dimethylamino)- or 5-aryltetrazole, give 3//-l,3,4-benzotriazepines 4 on thermolysis. It has been proposed that the reaction proceeds by way of the dipolar compounds 2, which undergo [l,7]-antarafacial 871-electrocyclization to 3. The process is completed by a symmetry-allowed [1.5]-hydrogen shift. Selected examples are given.349-350... 

Azides add to double bonds to give triazolines. This is one example of a large group of reactions ([3-l-2]-cycloadditions) in which five-membered heterocyclic compounds are prepared by addition of 1,3-dipolar compounds to double bonds (see Table 15.3). These are compounds that have a sequence of three atoms A—B—C,... 

Since compounds with six electrons in the outer shell of an atom are usually not stable, the A—B—C system is actually one canonical form of a resonance hybrid, for which at least one other form can be drawn (see Table 15.3). 1,3-Dipolar compound can be divided into two main types ... 

The 1,3-dipolar eyeloaddition, also known as the Huisgen cycloaddition, is a elassie reaetion in organic chemistry consisting in the reaetion of a dipolar-ophile with a 1,3-dipolar compound that allows the produetion of various five-membered heteroeyeles. This reaction represents one of the most productive fields of modern synthetic organic chemistry. Most dipolarophiles are alkenes, alkynes, and molecules possessing related heteroatom functional... 

Lmines. Both (38) and (39) are mixtures of diastereoisomers. >J-Silylaminophosphines (40) with carbon disulphide gave dipolar compounds (41) which did not rearrange to insertion products like other... 

Pummerer-type dehydration of the sulfoxide 408 using acetic anhydride results in efficient formation of the 1,3-dipolar compound 409 which is able to undergo cycloaddition with dienophiles to generate tricyclic compounds such as 410 in good yield (Scheme 31) <2000T10011>. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Using curved-arrow notation, show how the following 1,3 dipolar compounds are formed from the indicated starting materials ... 

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