Passerini Lewis acid-mediated

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

In many instances, ketals can serve as masked carbonyls in the Passerini reaction. The product a-alkoxyamides, exemplified here by 21 and 22, can be obtained in high yield from the appropriate ethyl or methyl ketals mediated by either Bronsted or Lewis acids. Both cyclic and acyclic acetals can function as suitable substrates. 

There are many examples of Passerini-tj e reactions mediated by Lewis acids with TiCU having the most widespread use. Passerini-type reactions using TiCU are compatible with a variety of functional groups as can be seen in the nearly quantitative reaction of a-isocyano phosphonate ester 25 with benzaldehyde. An examination of TiCU-mediated diastereoselective Passerini reaction failed to show any clear stereoselection with chiral isocyanide 26 among many other cases. Weaker Lewis acids such as SiCL can also mediate Passerini-twe reactions, but effectively do so only in the presence of a Lewis base. Demnark demonstrated that a-hydroxyamides, such as 27, could be formed in good yields, by using Lewis bases such as pyridine-7V-oxide to activate the SiCU-... 

Denmark has described several chiral bis-phosphoramides as Lewis base activators of weak Lewis acid SiCL and demonstrated their ability to mediate an enantioselective Passerini-type reaction. Catalytic bis-phosphoramide 36 and stoichiometric SiCU, in the presence of a proton scavenger (Htinig s base), promoted the formation of a-hydroxyamides with remarkably good enantioselectivity and yield. A variety of aromatic and unsaturated aldehydes and aryl, alkyl, and functionalized alkyl isocyanides proved to be useful and effective starting materials. High yields of Passerini products were attributed to the production of imidoyl chloride 37, which reduced the prevalence of the nitrilium intermediate and prevented the addition of a second equivalent of isonitrile. 

---