1.3- dipolar cycloaddition reactions with azomethine yhdes

Upon heating, aziridine 191 opened in the conrotatory manner to give azomethine yhdes 192 and/or 193, which underwent 1,3-dipolar cycloaddition reactions with alkenes and acetylenes. With styrene, for example, pyrrolidine 194 was formed exclusively in 81 % yield, and the regiochemistry of the cycloaddition was ascribed to control by the LUMO of the electron-deficient azomethine ylide. The cis relationship of the phenyl and benzoyl groups was attributed to secondary orbital interactions between them in the transition state. 

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. 

Grigg and co-workers (383) found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloadditions of azomethine ylides derived from arylidene imines of glycine (Scheme 12.91). This work was published in 1991 and is the first example of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition. The reaction of the azomethine yhde 284a with methyl acrylate 285 required a stoichiometric amount of cobalt and 2 equiv of the chiral ephedrine ligand. Up to 96% ee was obtained for the 1,3-dipolar cycloaddition product 286a. 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

The Williams group published a three-component condensation reaction starting from oxindolidene acetate 158 which reacted with the azomethine yhde 161 formed in situ from the diphenylmorpholinone 160 and the isoprenoid aldehyde 159 (Scheme 32) [138-140]. The spiro compound 162 was obtained by 1,3-dipolar cycloaddition and converted further to the pentacyclic diketopiperazine 164. 

In an approach to the stemofoUne class of alkaloids, the Martin group discovered an unusual set of conditions for generating azomethine yHdes. Oxidation of compound 186 under Swem conditions afforded a 5 1 mixture of 189 and 190 in 69% yield (Scheme 38) (2011TL2048). The formation of these two molecules can be easily rationalized via an intramolecular 1,3-dipolar cycloaddition of dipole 188, but the mechanism through which the azomethine ylide is formed under Swem conditions is not well understood. The authors proposed that the oxidized product 187a derived from 186 reacted with one of the electrophifrc species formed under the reaction... 

Subsequently, the one-pot organocatalytic [C+NC+CC] coupling reaction between aldehydes 204, dialkyl-2-aminomalonate 205 and a,p-unsaturated aldehydes 28 was achieved with highly chemo-and enantioselectivity by Cordova, et al Scheme 3.66 [83]. The mechanism involved the 1,3-dipolar cycloaddition of azomethine yhde and chiral iminium intermediate, via re-facial and endo-addition to give the pyrroUdine derivatives. Later, the authors reported a similar approach to 5-hydroxypyrrolidme 208 from acylaminomalonates 207 and a,P-unsaturated aldehydes 28, Scheme 3.67 [84]. 

The spirocyclic oxindole core structure was constructed by an asymmetric 1,3-dipolar cycloaddition in the total synthesis of (—)-spirotryprostatin B. A reaction of oxazi-none 137 with aldehyde 138 and oxindole 139 resulted in spirooxindole 141 via the chiral azomethine yhde 140, simultaneously creating three bonds and four stereogenic centers in one step (Scheme 16.20). ... 

---