Regioselective trifluoromethylation of N-heteroaromatic compounds using trifluoromethyldifluoroborane activator

Tomoaki Nishida, Haruka Ida, Yoichiro Kuninobu () and Motomu Kanai ()
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Tomoaki Nishida: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Haruka Ida: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Yoichiro Kuninobu: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Motomu Kanai: Graduate School of Pharmaceutical Sciences, The University of Tokyo

Nature Communications, 2014, vol. 5, issue 1, 1-6

Abstract: Abstract Many important drugs, agrochemicals and their lead compounds contain trifluoromethyl group(s). Most processes currently used to access trifluoromethyl group-containing molecules are performed by substitution of the carboxy or trichloromethyl groups using hazardous fluorinating reagents under harsh reaction conditions. Cross-coupling reactions between organohalides or boronic acids/esters and trifluoromethylating reagents are also used. Direct C-H trifluoromethylation of organic molecules, however, is the ideal method of introducing trifluoromethyl group(s). Despite the recent advances in C-H trifluoromethylation of N-heteroaromatic compounds, regioselective C-H trifluoromethylation of six-membered heteroaromatic compounds has yet to be achieved. Herein we present a general and reliable method for the synthesis of trifluoromethyl group-containing N-heteroaromatics through highly regioselective addition of a trifluoromethyl nucleophile to pyridine, quinoline, isoquinoline and two or three heteroatom-containing N-heteroaromatic N-oxides activated by trifluoromethyldifluoroborane. The C-H trifluoromethylation proceeds under mild conditions in gram scale with high functional group tolerance. This method will be useful in both laboratory and industrial processes.

Date: 2014
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DOI: 10.1038/ncomms4387

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