1.3- Dipolar cycloadditions 1.3- dipoles

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

Frontier molecular orbital theory correctly rationalizes the regioselectivity of most 1,3-dipolar cycloadditions (73JA7287). When nitrile ylides are used as 1,3-dipoles, the dipole... 

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

The 1,3-dipolar cycloadditions offluonnatedallenes provide a rich and varied chemistry Allenes, such as 1,1-difluoroallene and fluoroallene, that have fluorine substitution on only one of their two cumulated double bonds are very reactive toward 1,3-dipoles Such activation derives from the electron attracting inductive and hyperconjugative effects of the allylic fluorine substituent(s) that give nse to a considerable lowering of the energy of the LUMO of the C(2)-C(3) n bond [27]... 

This type of reaction is represented by 1,3-dipolar cycloadditions, corresponding to one of the Huisgen categories (69MI1). The 1,3-dipolar cycloaddition corresponds to the interaction between a 1,3-dipole and a multiple system five-membered ring closure (Scheme 1). 

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

The 1,3-dipoles consist of elements from main groups IV, V, and VI. The parent 1,3-dipoles consist of elements from the second row and the central atom of the dipole is limited to N or O [10]. Thus, a limited number of structures can be formed by permutations of N, C, and O. If higher row elements are excluded twelve allyl anion type and six propargyl/allenyl anion type 1,3-dipoles can be obtained. However, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions have only been explored for the five types of dipole shown in Scheme 6.2. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

Basic Aspects of Metal-catalyzed 1,3-Dipolar Cycloaddition Reactions 212 The 1,3-Dipoles 212... 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

The class of 1,3-dipolar cycloadditions embraces a variety of reactions that can accomplish the synthesis of a diverse array of polyfunctional and stereochemically complex five-membered rings.3 The first report of a 1,3-dipolar cycloaddition of a nitrone (a 1,3-dipole) to phenyl isocyanate (a dipolarophile) came from Beckmann s laboratory in 1890,4 and a full 70 years elapsed before several investigators simultaneously reported examples of nitrone-olefin [3+2] cycloadditions.5 The pioneering and brilliant investigations of Huisgen and his coworkers6 have deepened our under-... 

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

In Chapter 10 of Part A, the mechanistic classification of 1,3-dipolar cycloadditions as concerted cycloadditions was developed. Dipolar cycloaddition reactions are useful both for syntheses of heterocyclic compounds and for carbon-carbon bond formation. Table 6.2 lists some of the types of molecules that are capable of dipolar cycloaddition. These molecules, which are called 1,3-dipoles, have it electron systems that are isoelectronic with allyl or propargyl anions, consisting of two filled and one empty orbital. Each molecule has at least one charge-separated resonance structure with opposite charges in a 1,3-relationship, and it is this structural feature that leads to the name 1,3-dipolar cycloadditions for this class of reactions.136... 

The other reactant in a dipolar cycloaddition, usually an alkene or alkyne, is referred to as the dipolarophile. Other multiply bonded functional groups such as imine, azo, and nitroso can also act as dipolarophiles. The 1,3-dipolar cycloadditions involve four it electrons from the 1,3-dipole and two from the dipolarophile. As in the D-A reaction, the reactants approach one another in parallel planes to permit interaction between the tt and tt orbitals. 

Another interesting variation of the 1,3-dipolar cycloaddition involves generation of 1,3-dipoles from three-membered rings. As an example, aziridines 7 and 8 give adducts derived from apparent formation of 1,3-dipoles 9 and 10, respectively.148... 

It is well known that azomethine ylides, which are usually formed in situ, are very good substrates for 1,3-dipolar cycloadditions. The group of Novikov and Khlebnikov [328] generated such a 1,3-dipol by reaction of difluorocarbene formed from CBr2F2 (2-626) with the imine 2-627. Cycloaddition of the obtained 2-629 with an ac-... 

Et2 group in 2-670. Since 2-670 contains both, a 1,3-dipole as well as a 1,3-dipolarophile moiety, it immediately undergoes a 1,3-dipolar cycloaddition to form the heterocyclic compound 2-671. 

Pagenkopf s group developed a novel domino process for the synthesis of pyrroles 4-183, which allows for the control over the installation of substituents at three positions and seems to be very suitable for combinatorial chemistry [62]. The process consists of a 1,3-dipolar cycloaddition of an intermediate 1,3-dipole formed from the cyclopropane derivative 4-181 with a nitrile to give 4-182 followed by dehydration and isomerization (Scheme 4.39). The yield ranges from 25 to 93 %, and the procedure also works well with condensed cyclopropanes. 

Within this chapter, two sections are devoted to rhodium and ruthenium. The two main procedures using rhodium are first, the formation of 1,3-dipoles from diazocompounds followed by a 1,3-dipolar cycloaddition [10] and second, hy-droformylation [11], The ruthenium-catalyzed domino reactions are mostly based on metathesis [12], with the overwhelming use of Grubbs I and Grubbs 11 catalysts. 

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

Besides isocyanides, Nair and coworkers also used carbenes to add to alkynes such as DMAD (9-90) leading to 1,3-dipoles, which can be trapped in a formal 1,3-dipolar cycloaddition (Scheme 9.21) [61]. Thus, the dimethoxycarbene 9-99, generated in situ through thermolysis of 9-98, reacts with DMAD (9-90) to give the dipole 9-100, which adds to an aldehyde 9-97 or a ketone. As the final product, dihydrofurans 9-101 are obtained in good yields. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

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