Friedel-Crafts aminoalkylation

In 2004 Terada and his group revealed that 2 methoxy furan (45) that can be considered as a vinylketene 0,0 acetal was sufficiently nucleophilic to engage Boc imines 44 in Bronsted acid catalyzed Friedel Crafts type reaction to furnish y aminoalkyl substituted furans 46 in excellent yields and up to 97% ee (Table 5.9) [ 16]. As already explained, phosphoric add 47 protonates the imine, thus generating a chiral contact ion pair the anionic counterion of which controls the enantioselectivity of the C C bond forming event. Although typically 2 mol% ofthe Bronsted acid were... 

Friedel-Crafts aminoalkylation l-(A-Butyl-A-methoxycarbonyl aminomethyl)-2,4,6-trimethoxybenzene 96% Improved selectivity with highly reactive substrates 2005/[44]... 

Nagaki, A., et al., Control of extremely fast competitive consecutive reactions using micromixing. Selective Friedel-Crafts aminoalkylation. Journal of the American Chemical Society, 2005, 127 11666-11675. 

Friedel-Crafts alkylations of arenes with mesylates, benzyl or allyl alcohols, aldehyde/diol combinations (reductive alkylation), 1,3-dienes, or alkenes in an ionic liquid are also effectively catalyzed by Sc(OTf)3. Sc(OTf)3 works as an efficient catalyst for the condensation reaction of trimethylhydroquinone with isophytol to afford a-tocopherol. 2-Aminoalkylation of phenols with a-iminoacetates (or glyoxylate/amine) is catalyzed by Sc(OTf)3 to produce amino acid derivatives. The Sc(OTf)3-catalyzed alkylations of indoles with a-hydroxy esters, aziri-dines, acetals, and aldehydes have been utilized as key steps of total syntheses as exemplified in eq 15. ... 

A highly enantioselective organocatalytic Friedel-Crafts aminoalkylation of indoles with in situ generated imines was reported by Zhang s group using a multicomponent approach. Chiral phosphoric acid 121 as an efficient catalyst... 

This approach provided a flexible strategy for identifying an optimal catalyst for a given transformation by taking advantage of the dynamic nature of the salt formation between 26 and easily tunable Bronsted bases. For example, a simple survey of various tertiary amines in combination with 26 in the Friedel-Crafts aminoalkylation between aromatic aldimines and N-benzylpyrrole made it feasible to rapidly single out the 26-N,N-dimethylbutylamine (1 1) salt as the most reactive and enantioselective catalyst (Scheme 7.46) [72]. 

An enantioselective, organocatalytic domino Friedel-Crafts aminoalkylation with imines generated in situ from trifluoroacetaldehyde hemiacetal (219) and aniline 220 for the synthesis of chiral trifluoromethyl-containing compounds was reported by Ma and coworkers (Scheme 42.51). Very high activity and selectivity was obtained using chiral phosphoric acid catalysts [109]. 

Scheme 42.51 Asymmetric domino Friedel-Crafts aminoalkylation of imines generated in situ from trifluoro-acetaldehyde hemiacetal and anilines catalyzed by a phosphoric acid.

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