Pyrrolidines => azomethine ylids

Polymer-supported azomethine ylids generated from a-silylimines through a 1,2-silatropic shift, are shown to be versatile reagents suitable for the synthesis of libraries of pyrrolidine derivatives after 1,3-dipolar cycloaddition with a series of dipolarophiles. Effectively substituents R1, R2 and dipolarophiles A=B and A=B can be chosen to get the desired adduct.146... 

The first study consisted of labelling one of the reactive carbon centers with deuterium. Thus, cycloaddition with a dissymmetric dipolarophile led to a 1 1 mixture of two deuterated pyrrolidines, indicative of the ambivalence.411 412 In the second study, 13C was used to label one of the carbons a- to nitrogen, and once again a 1 1 mixture of labeled pyrrolidines was obtained.413 These results demonstrate that free resonance of an unstabilized azomethine ylid occurs during the reaction. 

The benzotriazolyl group is a good leaving group. This feature was exploited in the use of benzotriazolylmethyl-aminomethyltrimethylsilane as a precursor of an azomethine ylid. At reflux in toluene, benzotriazolyltrimethylsilane was eliminated and formation of the ylid underwent quantitative [l,3]dipolar cycloaddition with diethyl fumarate, for example, giving a frans-3,4-dicarboethoxy pyrrolidine derivative exclusively. Other examples were reported as well.442... 

This technique has been applied to the synthesis of epibatidine, an alkaloid which exhibits nonopiod analgesic activity 200-500 times greater than that of morphine. Boc-protected 2,5-bis(trimethylsilyl)pyrrolidine has been chosen as the precursor of the azomethine ylid and cis- and rra .v-ethyl-(6-chloro-3-piperidyl )-2-propenoates as the dipolarophiles.448,449... 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

Cycloaddition to pyrrolidines. The reaction of diethyl aminomalonate with formaldehyde can generate an azomethine ylid (a - b) which cycloadds to 1,2-dipolarophiles to form pyrrolidines. 

Aziridines are a convenient source of 5-membered heterocyclics such as pyrrolidines, imidazolidones, or oxazolidones, formed by addition of the intermediate azomethine ylids to double bonds . The conversion of 1-iminopyridinium ylids to l(lH),2-diazepines by photoisomerization has been reported by 3 different groups... 

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