Letter
Silver-Catalyzed C−H Trifluoromethylation of Arenes Using
Trifluoroacetic Acid as the Trifluoromethylating Reagent
Guangfa Shi, Changdong Shao, Shulei Pan, Jingxun Yu, and Yanghui Zhang*
Department of Chemistry, and Shanghai Key Lab of Chemical Assessment and Sustainability, Tongji University, 1239 Siping Road,
Shanghai 200092, P. R. China
S
* Supporting Information
ABSTRACT: Direct trifluoromethylation of arenes using TFA as the
trifluoromethylating reagent was achieved with Ag as the catalyst. This
reaction not only provides a new protocol for aryl C−H
trifluoromethylation, but the generation of CF3· from TFA may prove
useful in other contexts and could potentially be extended to other
trifluoromethylation reactions.
he incorporation of trifluoromethyl groups into organic
molecules can endow them with unique and useful
organic molecules, there remain drawbacks associated with their
use. Many of the reagents in Figure 1 are expensive, toxic, or
operationally inconvenient, and some are not commercially
available or generate large quantities of chemical waste.
Therefore, it is highly desirable to design new trifluoromethylat-
ing reagents without these drawbacks and develop reactions that
efficiently transform abundant but underutilized trifluoromethyl
sources.
In this respect, trifluoroacetic acid (TFA) has several attractive
features. It is cheap and readily available.15 CO2 is the sole
byproduct generated from TFA, which makes the reaction
environmentally benign.16 Notably, TFA has been successfully
applied to the trifluoromethylation of aryl iodides and aryl
bromides in the presence of catalytic or stoichiometric amounts
of copper.17
Attracted to these potential advantages, we sought to
investigate C−H trifluoromethylation of arenes using TFA.
Very few reactions of this type have previously been reported,
and they have required electrochemical18 or photochemical
conditions19 or relied on the use of a stoichiometric amount of
toxic XeF2.20 To the best of our knowledge, these reports are the
only earlier examples for direct C−H trifluoromethylation of
arenes with TFA as the CF3 sources. We aimed to develop more
generally useful trifluoromethylation methodology with TFA as
the CF3 source. To this end, herein we describe a silver-catalyzed
C−H trifluoromethylation reaction of arenes using TFA as the
trifluoromethylating reagent.
T
properties.1 As a result, the trifluoromethyl group is an essential
structural motif that is widely present in pharmaceuticals,
agrochemicals, and materials.2 Accordingly, the development of
efficient trifluoromethylation methods has been the subject of
extensive research.3 Trifluoromethylarenes are among the most
important and useful classes of trifluoromethylated organic
molecules. Therefore, their synthesis has attracted considerable
attention.4 Direct aryl C−H trifluoromethylation, in particular,
has been an active research topic in recent years,5 and various
catalytic reactions have been developed using transition metals,
including Pd,6 Cu,7 and others.8−11 Recently, radical trifluor-
omethylation has witnessed a resurgence of interest, and several
synthetically useful reactions have been disclosed for introducing
aryl trifluoromethyl groups.12,13
The rapid development of novel trifluoromethylation
reactions has largely been driven by the discovery of new
trifluoromethylating reagents.14 Generally speaking, trifluoro-
methylating reagents can be divided into three classes as shown
in Figure 1: (1) nucleophilic, (2) electrophilic, and (3) radical. It
should be noted, however, that depending on the reaction
conditions, these reagents can be converted in situ into different
reactive trifluoromethyl species. While the availability of these
reagents has enabled trifluoromethylation of a wide range of
We first examined trifluoromethylation of pyridine with TFA
under the standard Minisci reaction conditions.21 Unfortunately,
the reaction did not give any trifluoromethylated products.
Gratifyingly, after extensively surveying reaction conditions, we
found that terephthalonitrile could be trifluoromethylated with
TFA in 17% yield under the conditions as shown in Table 1, entry
3. Surprisingly, the yield increased to 55% when there was a small
opening in the flask and further improved to 81% including 21%
Received: November 3, 2014
Figure 1. Common trifluoromethylating reagents.
© XXXX American Chemical Society
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dx.doi.org/10.1021/ol503189j | Org. Lett. XXXX, XXX, XXX−XXX