Regioselectivity azomethine ylide generation

A series of novel dispirooxindolecyclo[pyrrolo[l,2-c]thiazole-6,5 -thiazolidine] derivatives (172) were obtained regioselectively by the 1,3-dipolar cycloaddition reaction of 5-arylidene-2-thioxothiazolidin-4-ones (171) as dipolarophiles with nonstabilized azomethine ylides, generated in situ via decarboxylative condensation of isatin (155) and thiazolidine-4-carboxylic acid (170) in ethanol under both classical refluxing and ultrasound irradiation (Scheme 8.54). Because of the advantages of ultrasonic irradiation of mild reaction conditions, short reaction times, and high efficiency, it is quite profitable to develop the 1,3-dipolar cycloaddition of azomethine ylides under these conditions (Hua et al. 2012). 

Azomethine ylides 38 reacted with a variety of dipolarophiles to generate cycloadducts in a highly diastereo- and regioselective manner. The novel shapes, along with the rich array of functionalities displayed by these products, provide opportunities for the creation of chemical diversity (Scheme 12.28). 

These newly discovered methods have found wide synthetic application. Examples include the generation and cycloaddition of stabilized N-unsubstituted azomethine ylides, nonstabilized N-substituted azomethine ylides, and even the parent azomethine ylides bearing no carbon substituents (19). However, these modem procedures often require severe reaction conditions such as high reaction temperatures, the use of polar solvents, and the use of strong bases, among others. The poor stereo- and regioselectivities that are often observed in the cycloadditions of nonstabilized azomethine ylides have discouraged their use in the stereocontrolled synthesis of complex molecules. 

N-Metalated azomethine ylides (44) are probably the most synthetically useful of these dipoles, since they can be generated from readily available N-alkylide-neamino esters or nitriles through a simple activation method. The resulting 1,3-dipoles show high reactivity with a,p-unsaturated carbonyl acceptors to provide excellent stereo- and regioselectivities. A variety of asymmetric versions have been reported. 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Besides the 1,3-dipolar cycloaddition of azomethine ylides to C60, the Bingel cycloprop anation reaction is widely used for regioselective functionalization of fullerenes. In principle, this versatile modification involves the generation of carbon nucleophiles from a-halo esters and their subsequent addition to C60 [19]. The addition takes place exclusively on double bonds between two six-membered rings of the fullerene skeleton, yielding methanofullerenes. As shown in Scheme 2, addition of diethylbromomalonate to C60, in the presence of an auxiliary base... 

Deprotonation of N-methylpiperidine Al-oxide with LDA in THF at — 78°C takes place regioselectively on the least crowded methyl carbon to generate azomethine ylide 122 (8SJOC2910). Ylide 122 is again highly reactive toward nonactivated olefins such as ethene, cyclopentene, styrene, (E)- and (Z)-stilbene, and ( )-)S-methoxystyrene. 

When reacted with 1-aryl-3,3,3-trifluoropropynes, azomethine ylide 14, generated from the aziridine, provides pyrrolines in high yield, with no regioselectivity. These cycloadducts can be converted into the corresponding pyrroles or pyrrolidines.102... 

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