Friedel-Crafts reaction iminium catalysis

Iminium ion catalysis was demonstrated by Deng and coworkers for the conjugate addition of a,a-dicyanoalkenes to benzylideneacetone with the use of a TFA salt of 36 [100] and by Chen and coworkers for the Friedel-Crafts reaction of indoles with a, 3-unsaturated ketones [101] as catalyzed by the C9 amino derivative of cinchonine 42 (Scheme 6.47). 

Iminium catalysis is another key catalytic concept in aminocatalysis. Initialworkwas disclosed by MacMillan for the Diels-Alder reaction of cyclopentadiene and a,P-unsaturated aldehydes [12], but it was rapidly extended to Michael additions (including Friedel-Crafts reactions). Now iminium catalysis has been established as a general mode for nucleophilic addition to a,]3-unsaturated carbonyl compounds. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

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