Azomethine ylids 1,3-dipolar cycloadditions

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 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... 

The covalent assembly of functional Jt-systems is a general synthetic principle and in some cases they can even be achieved in a multi-component fashion. One of the most impressive examples is the very elegant access to covalently linked donor-fullerene arrangements by 1,3-dipolar cycloadditions with in situ-generated azomethine ylids [59]. However, here only the multi-component de novo synthesis of the chromophore structures will be considered. The major developments have been achieved in condensation-based and cross-coupling strategies. 

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. 

Finally, enantiomerically pure sulfinimines have also been used as precursors of chiral imidazolidines by 1,3-dipolar cycloaddition with azomethine ylids [181]. Reactions of different arylsulfinimines 245 with dipoles 246 are highly stereoselective, mainly affording diastereoisomer 247 (absolute configuration unequivocally established by X-ray studies), which was readily transformed into vicinal diamine 248 (Scheme 111). 

The cyclodehydration of 2-substituted-A/-acylthiazolidine-4-carboxylic acids yields bicyclic munchnones. This mesoionic ring system acts as a cyclic azomethine ylid and can undergo 1,3-dipolar cycloaddition reactions with dipolarophiles. A range of chiral pyrrolo[l,2-c]thiazoles have been prepared by this method both intermolecularly and intramolecularly. 

An interesting spirocyclic thiazolidine ring system has been reported. Starting from the thiazolethione 67 and the aziridine 68, which when heated to 100 °C forms the azomethine ylid 69, undergoes a 1,3-dipolar cycloaddition reaction to afford the cycloadduct 70 as the sole regioisomer <02H393>. 

The Stereoselectivity of 1,3-Dipolar Cycloadditions. There is no endo mle for 1,3-dipolar cycloadditions like that for Diels-Alder reactions. Stereoselectivity, more often than not, is low, as shown by the reactions of C,/V-diphenylnitrone—both regioisomers 6.238 and 6.239 (R=C02Et) from the reaction with ethyl acrylate are mixtures of exo and endo isomers, only a little in favour of the exo product. Similarly, the reactions of methyl crotonate with nitrones favour the exo product 6.242 over the endo 6.243. In contrast, other reactions are endo selective, as in the cycloaddition 6.244 of an azomethine ylid to dimethyl maleate giving largely the endo adduct 6.245. 

In contrast, other reactions are endo selective, as in the cycloaddition 6.354 of an azomethine ylid to dimethyl maleate giving largely (80 20) the endo adduct endo-6.355.869,870 Thus the stereoselectivity depends in a not always predictable way upon the dipole, the dipolarophile and their substituents, in contrast to Diels-Alder reactions, which more often than not obey the endo rule. It is advisable, when planning a synthesis, to look up close analogies before relying upon the exo or endo stereoselectivity of a 1,3-dipolar cycloaddition. 

The mesomeric betaine (100) underwent 1,3-dipolar cycloaddition, with DMAD in toluene at 100°C, to give a mixture of two products (101) and (102). Compound (101) was formed by initial 1,3-dipolar cycloaddition of DMAD to the azomethine ylid fragment of (100) to yield a tricyclic intermediate which fragmented to (101). Compound (102) was formed via ring opening of (100) to a ketene intermediate which underwent a hetero Diels-Alder reaction with DMAD to give (102) <92JCS(P1)2789>. 

Mesoionic thiazoles such as (69) can be considered to be potential precursors in basic media of cyclic azomethine ylids. These mesoionic thiazoles can be generated from 5-(tert-butylamino)thiazolium chlorides (68). They can undergo 1,3-dipolar cycloaddition reactions with carbon disulphide. The initial cycloadducts (70) and (71) rapidly eliminate tert-butyl isothiocyanate at room temperature to give the thiazolium-... 

The final pyrrolizidine synthesis we will consider is Vedejs approach to retronecine. This synthesis relies on a dipolar cycloaddition reaction for direct construction of the pyrrolizidine nucleus. The key reaction was to be a 1,3-dipolar cycloaddition between an azomethine ylid of type 57 and an acrylate of type 58. It was projected that this would provide 56 (or 57 after loss of methanol), which would then be converted to retronecine (21) via a sequence involving late-stage introduction of the C1-C2 double bond. 

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. 

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