Aminoalkylation of Indoles with α-Polyfluoroalkylated Cyclic Imines

• Published in: European journal of organic chemistry 2013-04, Vol.2013 (11), p.2237-2245
• Main Authors: Shevchenko, Nikolay E., Shmatova, Olga I., Balenkova, Elisabeth S., Röschenthaler, Gerd-Volker, Nenajdenko, Valentine G.
• Format: Article
• Language: English
• Subjects: Alkylation; Amines; Fluorine; Iminium salts; Lewis acids; Medicinal chemistry; Nitrogen heterocycles
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201201661

The reaction of cyclic ketimines with indoles was studied. A dramatic difference between the electrophilicity of perfluoroalkyl‐substituted and non‐fluorinated imines was demonstrated. In good agreement with our calculations, the Friedel–Crafts‐type alkylation of indoles only takes place with α‐polyfluoroalkylated cyclic imines that are activated by boron trifluoride–diethyl ether. The reaction proceeds under mild conditions and provides the opportunity to obtain promising alkaloid‐like structures that contain a fluoroalkyl group. As a result, α‐CF3‐ and α‐C2F5‐substituted pyrrolidines, piperidines, and azepanes that contain an indole moiety can be prepared efficiently. Polyfluoroalkylated cyclic imines form reactive electrophilic species by activation with Lewis acids. The reaction of such iminium salts with various indole derivatives proceeds under mild conditions as a chemoselective Friedel–Crafts‐type aminoalkylation and gives α‐CF3‐ and α‐C2F5‐substituted pyrrolidines, piperidines, and azepanes that contain an indole moiety.