Chiral Brønsted Acid‐Mediated Enantioselective Organocatalytic Three‐Component Reaction for the Construction of Trifluoromethyl‐Containing Molecules

Abstract

In combination with the advantages of organocatalysis, we have developed a highly enantioselective Friedel-Crafts aminoalkylation of indoles with imines generated in situ from trifluoroacetaldehyde methyl hemiacetal and aniline. Novel chiral trifluoromethyl-containing compounds were obtained in high yields with excellent enantioselectivities. This methodology was further extended to difluoroacetaldehyde methyl hemiacetal to demonstrate the broad scope of substrates.

Asymmetric Organocatalysis

“…Ma and co-workers reported an enantioselective Friedel-Crafts reaction of indoles with imines generated in situ from trifluoroacetaldehyde or difluoroacetaldehyde methyl hemiacetal and aniline by utilizing chiral catalyst 116e. High yields (80-99%) and excellent enantioselectivities (79-98% ee) have been obtained for a wide scope of indoles [105].…”

Chiral Brønsted‐Acid‐Catalyzed Enantioselective Arylation of Ethyl Trifluoroacetoacetate and Ethyl Trifluoropyruvate

“…[10] Recently, we have demonstrated that chiral phosphoric acids can catalyze some arylation reactions of trifluoroacetaldimines (generated in situ) and simple trifluoromethyl ketones with good to excellent enantioselectivities. [11] As a part of our ongoing studies, we would like to report our preliminary results on chiral Brønsted-acid-catalyzed enantioselective direct arylation of ethyl 4,4,4-trifluoroacetoacetate (ETFAA) and ethyl trifluoropyruvate.…”

Chiral Phosphoric Acid‐Catalyzed Asymmetric Aza‐Friedel–Crafts Reaction of Indoles with Cyclic N‐Acylketimines: Enantioselective Synthesis of Trifluoromethyldihydroquinazolines

“…[3] In this regard, our group has developed a highly enantioselective F-C aminoalkylation of indoles with aldimines generated in situ from trifluoro-A C H T U N G T R E N N U N G acetaldehyde methyl hemiacetal and aniline (Scheme 1a). [4] Bolm and co-workers described an organocatalyzed F-C reaction of indoles with trifluoropyruvate-derived imines to afford trifluoromethylamines with a tetrasubstituted carbon stereocenter (Scheme 1b). [5] However, the electrophilic partners were limited to acyclic imines.…”

“…The TLC detection showed that the reaction was complete after 12 h. The desired product 4a was achieved in 96% yield, but only a moderate ee value (36%) was observed ( Table 1, entry 1). To improve the enantioselectivity, chiral phosphoric acids with various substitutents at the 3,3'-positions of the BINOL scaffold were evaluated, and the 2,4,6-triisopropylphenyl-substituted catalyst 1f was found to be the best (97% yield, 78% ee) ( Table 1, entries [1][2][3][4][5][6]. A survey of solvents indicated that CH 2 ClCH 2 Cl (DCE) was optimal in terms of yield and enantioselectivity (Table 1, entries 7-11).…”