Highly β-Regioselective Friedel-Crafts Aminoalkylation of Pyrroles with Cyclic Perfluoroalkylated Imines

• Published in: European journal of organic chemistry 2013-05, Vol.2013 (15), p.3049-3058
• Main Authors: Shmatova, Olga I., Shevchenko, Nikolay E., Balenkova, Elisabeth S., Röschenthaler, Gerd-Volker, Nenajdenko, Valentine G.
• Format: Article
• Language: English
• Subjects: Amines; Electrophilic substitution; Fluorine; Lewis acids; Nitrogen heterocycles; Regioselectivity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201201725

A Friedel–Crafts‐type alkylation reaction was studied between various pyrroles and α‐polyfluoroalkylated cyclic imines that were activated by Lewis acids. The reaction proceeded under mild conditions and provided a high yielding synthesis of α‐CF3‐substituted pyrrolidines and piperidines as well as seven‐membered analogues that contained a pyrrole ring. The unpredictably high β‐selectivity for the aminoalkylation of both 1H‐pyrrole and N‐substituted pyrrole was observed as a result of a thermodynamically‐controlled electrophilic substitution reaction. The computational data are in full agreement with the experimental results, which confirmed the observed regioselectivity as a result of the lower energy of the β‐substituted pyrroles that contain α‐trifluoromethyl‐substituted pyrrolidine, piperidine, and azepane rings. Trifluoromethyl‐substituted cyclic imines were activated by various Lewis acids and underwent a reaction with pyrrole derivatives. An unpredictable β‐selectivity was observed. The regioselectivity of the aminoalkylation was explained by computation data, which also confirmed the isomerization of the α isomer into the β isomer.