Trifluoromethylation of Aryl and Heteroaryl Halides
with Fluoroform-Derived CuCF<sub>3</sub>: Scope, Limitations, and
Mechanistic Features
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Abstract
Fluoroform-derived
CuCF<sub>3</sub> recently discovered in our
group exhibits remarkably high reactivity toward aryl and heteroaryl
halides, performing best in the absence of extra ligands. A broad
variety of iodoarenes undergo smooth trifluoromethylation with
the “ligandless” CuCF<sub>3</sub> at 23–50 °C
to give the corresponding benzotrifluorides in nearly quantitative
yield. A number of much less reactive aromatic bromides also have
been trifluoromethylated, including pyridine, pyrimidine, pyrazine,
and thiazole derivatives as well as aryl bromides bearing electron-withdrawing
groups and/or ortho substituents. Only the most electrophilic chloroarenes
can be trifluoromethylated, e.g., 2-chloronicotinic acid. Exceptionally
high chemoselectivity of the reactions (no side-formation of arenes,
biaryls, and C<sub>2</sub>F<sub>5</sub> derivatives) has allowed for
the isolation of a large number of trifluoromethylated products in
high yield on a gram scale (up to 20 mmol). The CuCF<sub>3</sub> reagent
is destabilized by CuX coproduced in the reaction, the magnitude of
the effect paralleling the Lewis acidity of CuX: CuCl > CuBr >
CuI.
While S<sub>N</sub>Ar and S<sub>RN</sub>1 mechanisms are not operational,
there is a well-pronounced ortho effect, i.e., the enhanced reactivity
of ortho-substituted aryl halides 2-RC<sub>6</sub>H<sub>4</sub>X toward
CuCF<sub>3</sub>. Intriguingly, this ortho-effect is observed for
R = NO<sub>2</sub>, COOH, CHO, COOEt, COCH<sub>3</sub>, OCH<sub>3</sub>, and even CH<sub>3</sub>, but not for R = CN. The fluoroform-derived
CuCF<sub>3</sub> reagent and its reactions with haloarenes provide
an unmatched combination of reactivity, selectivity, and low cost