Silver-mediated trifluoromethylation of arenes using TMSCF3

Article abstract of DOI:10.1021/ol202174a

The silver-mediated C-H trifluoromethylation of aromatic substrates using TMSCF₃ is described. The development, optimization, and scope of these transformations are reported. AgCF₃ intermediates are proposed.

Full text of DOI:10.1021/ol202174a

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5464–5467
Silver-Mediated Trifluoromethylation of
Arenes Using TMSCF3
Yingda Ye, Shin Hee Lee, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109, United States
mssanfor@umich.edu
Received August 10, 2011
ABSTRACT
The silver-mediated CÀH trifluoromethylation of aromatic substrates using TMSCF3 is described. The development, optimization, and scope of
these transformations are reported. AgCF3 intermediates are proposed.
Trifluoromethylated aromatic compounds are widely
prevalent in pharmaceuticals, agrochemicals, and organic
materials.1 As a result, the development of transition-
metal-mediated/catalyzed methods for introducing CF3
groups into organic molecules has been the subject of
intenseresearch. Overthe past5 yearsa varietyofPd2,3 and
Cu4,5-based protocols have been developed for the trifluoro-
methylation of aryl halides, aryl boronic acids, and aro-
matic carbonÀhydrogen bonds. In addition, several free
radical approaches are available for arene trifluoro-
methylation.6,7 Despite this extensive progress, current
trifluoromethylation methods have significant limitations.
Some systems utilize expensive trifluoromethylating re-
agents (e.g., S-(trifluoromethyl)thiophenium salts,3a,4f,5d
Togni’s reagent,5b,e or TESCF3).3b,5a Others involve
(1) (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (b)
€
Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Hagmann,
W. K. J. Med. Chem. 2008, 51, 4359. (d) Kirk, K. L. Org. Process Res.
Dev. 2008, 12, 305. (e) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Chem. Soc. Rev. 2008, 37, 320. (f) Grushin, V. V.; Tomashenko, O. A.
Chem. Rev. 2011, 111, 4475. (g) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le,
V.-D.; Roy, S. Tetrahedron 2011, 67, 2161.
(2) Recent examples of palladium-mediated arene trifluoromethyla-
tion reactions: (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc.
2006, 128, 4632. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc.
2006, 128, 12644. (c) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (d)
Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132,
2878. (e) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2010, 132, 14682. (f) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S.
J. Am. Chem. Soc. 2011, 133, 7577.
(3) Recent examples of Pd-catalyzed arene trifluoromethylation
reactions: (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 3648. (b) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.;
Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679. (c) Mu, X.;
Chen, S.; Zhen, X.; Liu, G. Chem.;Eur. J. 2011, 17, 6039. (d) Loy,
R. N.; Sanford, M. S. Org. Lett. 2011, 13, 2548.
(4) Recent examples of Cu-mediated trifluoromethylation reactions:
(a) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008,
130, 8600. (b) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organome-
tallics 2008, 27, 6233. (c) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060.
(d) McReynolds, K. A.; Lewis, R. S.; Ackerman, L. K. G.; Dubinina,
G. G.; Brennessel, W. W.; Vicic, D. A. J. Fluorine Chem. 2010, 131, 1108.
(e) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011,
76, 1174. (f) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu,
Y.-C.; Xiao, J.-C. Angew. Chem., Int. Ed. 2011, 50, 1896. (g) Morimoto,
H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 3793. (h) Tomashenko, O. A.; Escudero, E. C.; Belmonte,
M. M.; Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655.
(5) Recent examples of Cu-catalyzed trifluoromethylation reactions:
(a) Oishi, M.; Konda, H.; Amii, H. Chem. Commun. 2009, 1909. (b)
Shimizu, R.; Egami, H.; Nagi, T.; Chae, J.; Hamashima, Y.; Sodeoka,
M. Tetrahedron Lett. 2010, 51, 5947. (c) Knauber, T.; Arikan, F.;
€
Roschenthaler, G.-V.; Gooßen, L. J. Chem.;Eur. J. 2011, 17, 2689.
(d) Xu, J.; Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L.
Chem. Commun. 2011, 47, 4300. (e) Liu, T.; Shen, Q. Org. Lett. 2011, 13,
2342.
•
(6) Examples of arene/heteroarene trifluoromethylation with CF3 :
(a) Wakselman, C.; Tordeux, M. J. Chem. Soc., Chem. Commun. 1987,
1701. (b) Akiyama, T.; Kato, K.; Kajitani, M.; Sakaguchi, Y.;
Nakamura, J.; Hayashi, H.; Sugimori, A. Bull. Chem. Soc. Jpn. 1988,
61, 3531. (c) Sawada, H.; Nakayama, M. J. Fluorine Chem. 1990, 46, 423.
(d) Kirk, K. L.; Nishida, M.; Fujii, S.; Kimoto, H. J. Fluorine Chem.
1992, 59, 197. (e) McClinton, M. A.; McClington, D. A. Tetrahedron
1992, 48, 6555. (f) Kamigata, N.; Ohtsuka, T.; Fukushima, T.; Yoshida,
M.; Shimizu, T. J. Chem. Soc., Perkin Trans. 1 1994, 1339. (g) Kino, T.;
Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.;
Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (h) Ji, Y.; Brueckl, T.;
Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.;
Baran, P. S. Proc. Natl. Acad. Sci. USA 2011, 108, 14411.
(7) Examples of arene/heteroarene perfluoroalkylation with RF•: (a)
Cowell, A.; Tamborski, C. J. Fluorine Chem. 1981, 17, 345. (b) Dolbier,
W. R. Chem. Rev. 1996, 96, 1557. (b) Bravo, A.; Bjørsvik, H.-R.;
Fontana, F.; Liguori, L.; Mele, A.; Minisci, F. J. Org. Chem. 1997, 62,
7128. (c) Huang, X.-T.; Long, Z.-Y.; Chen, Q.-Y. J. Fluorine Chem.
2001, 111, 107. (d) Li, Y.; Li, C.; Yue, W.; Jiang, W.; Kopecek, R.; Qu, J.;
Wang, Z. Org. Lett. 2010, 12, 2374.
r
10.1021/ol202174a
Published on Web 09/20/2011
2011 American Chemical Society

temperatures greater than 100 °C2b,3a,b,4d and/or exhibit
modest substrate scope/generality.3c,5a,b,6 Free radical
based methods often require inconvenient electrochemical
or photochemical activation procedures6b,d,e or utilize
potentially explosive reagents like peroxides at elevated
temperatures.6c,g Additionally, CÀH bond trifluoro-
methylation methods (which are particularly attractive
because they do not require prefunctionalized starting
materials) remain especially limitedin substrate scope.3a,d,6
We were interested in the possibility of addressing some
of these limitations by identifying metals other than Cu or
Pd that could promote the formation of benzotrifluorides.
We were attracted to Ag based on the fact that it is readily
available, is directly below Cu on the periodic table
(suggesting the potential for similar reactivity), and has
recently proven a useful promotor for other organometal-
lic reactions.8 There are also a number of reports describ-
ing the synthesis of AgCF3 complexes.9,10 However, the
reactivity of these species has not been explored exten-
sively,9,10 thereby suggesting opportunities for new reac-
tion discovery. We report herein that the combination of
AgOTf, KF, and TMSCF3 can be used for the CÀH
trifluoromethylation of aromatic substrates under mild
conditions. The development, scope, and mechanism
of this transformation are discussed herein.
TMSCF3 (o: m: p ratio =1.5: 1: 1.2). This result clearly
demonstrates the orthogonal reactivity of AgCF3 and
CuCF3 reagents with arylÀH versus arylÀI bonds. Con-
ducting this same procedure with benzene in place of PhI
afforded the CÀH trifluoromethylation product PhCF3
in 28% yield (Scheme 1b).
This Ag-mediated CÀH trifluoromethylation reaction
was optimized using benzene (20 equiv) as the substrate
and DCE as the solvent (see Supporting Information for
evaluation of other solvents). Since this is a net 2eÀ
oxidation reaction (where AgI is presumably acting as
the terminal oxidant), our optimization studies began with
2 equiv of various AgI salts. As shown in Table 1, the use of
2 equiv of AgF, AgNO3, or AgOTf in the presence of
2 equiv of KF afforded trifluorotoluene in modest yield,
with AgOTf providing the best result (entries 3À5). In
contrast, AgOAc and Ag2O generated <10% product
under analogous conditions (entries 1 and 2). Moving
from 2 to 4 equiv of AgOTf/KF improved the yield from
68 to 87% (entries 5 and 6). Importantly, KF is required
for the AgOTf reaction (entry 7), presumably to activate
the TMSCF3. For comparison, we also examined the
reactivity of CuI salts like [CuOTf]2 C6H6 and CuI under
3
these conditions. As shown in entries 9 and 10, they
provided none of the CÀH trifluoromethylation product,
again highlighting the complementarity of this Ag-based
method versus more traditional Cu-mediated trifluoro-
methylation protocols.
Scheme 1. Reaction of AgCF3 with PhI and Benzene
Table 1. Optimization of Trifluoromethylation Reactiona,b
metal salt/
entry
metal salt
AgOAc
KF equiv
yield (%)
1
2/2
2/2
2/2
2/2
2/2
4/4
4/0
4/4
2/2
4/4
6
6
2
Ag2O
CuCF3 complexes are well-known to react with aryl
iodides to afford benzotrifluoride products.4 Thus, we first
sought to examine the reactivity of AgCF3 with PhI
(Scheme 1a). AgCF3 was generated in situ from the reac-
tion of AgF with TMSCF3 in MeCN for 15 min at 25 °C
using the procedure of Tyrra and Naumann.9 PhI (20
equiv) was then added, and the reaction was heated at
85 °C for 24 h. 19F NMR spectroscopic analysis of the
crude reaction mixture did not show the presence of
PhCF3. Instead, three isomeric CÀH trifluoromethylation
products were observed in 15% total yield based on
3
AgNO3
AgF
40
45
68
87
0
4
5
AgOTf
AgOTf
AgOTf
AgOTf
6
7c
8d
9
53
0
[CuOTf]2 C6H6
3
10
CuI
0
a General conditions: C6H6 (20 equiv), TMSCF3 (1 equiv) in DCE at
85 °C for 24 h. b Yields determined by 19F NMR analysis. c No KF.
d Conditions: C6H6 (1 equiv), TMSCF3 (5 equiv), AgOTf (4 equiv), KF
(4 equiv) in DCE at 85 °C for 24 h.
(8) (a) Teverovskiy, G.; Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2011, 50, 7312. (b) Huang, C.; Liang, T.; Harada, S.; Lee, E.;
Ritter, T. J. Am. Chem. Soc. 2011, 133, 13308.
(9) For a review on silver perfluoroalkyl complexes: Tyrra, W. E.;
Naumann, D. J. Fluorine Chem. 2004, 125, 823.
The final optimized conditions (20 equiv of benzene, 4
equiv of AgOTf and KF, 1 equiv of TMSCF3 at 85 °C for
24 h) were readily scalable, affording trifluorotoluene in
87%, 84%, and 87% yield on 0.08, 0.5, and 1 mmol scales,
respectively. Notably, the use of benzene as the limiting
(10) Wang, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang, W.; Feng, X.;
Huang, K. W. Organometallics 2011, 30, 3229.
Org. Lett., Vol. 13, No. 20, 2011
5465

reagent (1 equiv) along with 5 equiv of TMSCF3 also led to
an acceptable 53% yield (entry 8).
Table 2. Substrate Scope of Silver-Mediated Trifluoromethyla-
tiona,b
This Ag-mediated CÀH trifluoromethylation reaction
was applicable to a variety of different arene substrates. As
shown in Table 2, arenes bearing electron-donating alkyl
or alkoxy substituents reacted in good to excellent yield
(entries 1À10). In general, these transformations pro-
ceeded with a modest preference for trifluoromethylation
at CÀH sites ortho and para to the electron-donating alkyl
or alkoxy groups. Heteroaromatics like N-methyl pyr-
role, thiophene, and caffeine were also good substrates
for CÀH trifluoromethylation and reacted with moderate
to excellent site selectivity (entries 12, 13, and 15).11 Under
our optimal conditions PhI reacted to form a mixture of the
o-, m-, and p-trifluoromethylated isomers in 46% total
yield (entry 11). The trifluoromethylation of naphthalene
proceeded in good yield with modest selectivity for the
R-position (entry 14).
The optimal reaction conditions were also effective for
transfer of other perfluoroalkyl groups. For example, the
AgOTf/KF-mediated reaction of benzene with TMSC3F7
afforded (heptafluoropropyl)benzene in 60% yield
(Scheme 2).
Scheme 2. Ag-Mediated Perfluoroalkylation of Benzene
We initially hypothesized that this transformation pro-
ceeded via a pathway involving Ag-promoted generation
•
of a trifluoromethyl radical (CF3 ) (Scheme 3, step a),
which then participates in a radical aromatic substitution
•
reaction. Addition of CF3 to the aromatic ring to generate
intermediate A (step b) followed by SET from A to a
second equivalent of AgI (step c) would release the product
along with HOTf and Ag0. Importantly, free radical arene
trifluoromethylation6 and perfluoroalkylation7 have signif-
icant precedent in the literature. Most commonly, CF3• is
generated from CF3Br or CF3I either photochemically or
electrochemically.6b,d,e A morerecent report by Yamakawa
and co-workers demonstrated radical trifluoromethyla-
tion of aromatic compounds using CF3I, FeII, and
H2O2.6g However, to our knowledge, the use of TMSCF3
as a precursor to radical arene trifluoromethylation has
not been reported.
•
To test for the possibility of CF3 intermediates, we
examined the AgOTf/KF-promoted reaction of benzene
with TMSCF3 in the presence of a variety of radical
initiators/inhibitors. In the presence of light (which is
frequently used to promote radical reactions), the reaction
a General conditions: substrate (10 equiv), TMSCF3 (1 equiv) in
DCE at 85 °C for 24 h. b Yield and selectivity determined by 19F NMR
analysis of the crude reaction mixtures. c 20 equiv of substrate used.
d 5 equiv of substrate used.
(11) Several other heteroaromatics, including furan (16% yield),
2-methylfuran (7% yield), pyridine (2% yield, 2 isomers), and 1-methy-
limidazole (3% yield, 3 isomers), afforded low yields of monotrifluo-
romethylated products under our standard conditions.
5466
Org. Lett., Vol. 13, No. 20, 2011

The involvement of caged and/or Ag-associated radicals is
a likely possibility. Notably, Kamigata has proposed a
mechanism involving “radical intermediates confined in the
coordination sphere of Ru” for related transformations.6f
Scheme 3. Possible Free Radical Pathway for Ag-Mediated
Trifluoromethylation
Scheme 4. Comparison of Reactivity and Selectivity of Radical
Trifluoromethylation
proceeded in a slightly lower yield (75% versus 87%). This
may be due to the light sensitivity of Ag salts.12 The
addition of azobisisobutyronitrile (AIBN), a radical in-
itiator, led to a moderate decrease in the overall yield of the
reaction. The use of 20 mol % of AIBN resulted in a 77%
yield of PhCF3, while a 57% yield was obtained upon
addition of 1 equiv of this additive.12 Nitrobenzene has
been employed previously as an inhibitor of SET steps
(like step c in Scheme 3) during free radical trifluoro-
methylation.6a Interestingly, the addition of 1 equiv
of NO2Ph had little effect on the Ag-mediated reaction of
benzene with TMSCF3 (85% versus 87% yield in the
absence of this additive). TEMPO has been utilized in
• 3c
theliteratureasa trapforCF3 . The additionof 1 equiv of
TEMPO led to a dramatic reduction in yield (to 7%) under
otherwise analogous conditions.
Because the results with the radical inhibitors/initiators
were somewhat ambiguous, we next sought to compare the
site selectivity of TMSCF3/AgOTf/KF-mediated trifluo-
In conclusion, this report describes the silver-mediated
trifluoromethylation of aromatic substrates with TMSCF3.
These reactions are proposed to proceed via a AgCF3
intermediate, and preliminary studies suggest against free
•
romethylation to that of a known CF3 reaction. Under the
reaction conditions described by Yamakawa and co-
workers,6g anisole reacted with in situ generated CF3 to
•
form a 7.5:1:5 ratio of o/m/p trifluoromethylated products
(Scheme 4). This reaction shows significantly higher o/p
selectivity compared to our Ag-mediated transformation
(where o/m/p = 2.7:1:1.2). Veratrole also reacted with
different site selectivity for trifluoromethylation with
•
CF3 as an intermediate. Importantly, these Ag-mediated
reactions proceed with complementary reactivity to analo-
gous transformations of CuCF3 reagents. Ongoing studies
are focused on probing the mechanism and developing
related Ag-catalyzed trifluoromethylation reactions.
CF3 versus TMSCF3/AgOTf/KF (Scheme 4).13 While
•
further studies are needed to gain a complete mechanistic
picture of the TMSCF3/AgOTf/KF-mediated reaction,
these results suggest against a purely free radical pathway.
Acknowledgment. We thank the NIH NIGMS
(GM073836) for financial support. We also thank
Dr. Rebecca Loy (postdoc in MSS group), Brannon Gary
(graduatestudent inMSSgroup), and Dr. Marion Emmert
(postdoc in MSS group) for helpful discussions.
(12) It is possible that light/AIBN do not have an effect on this system
because they are not capable of promoting the AgÀCF3 bond homolysis
(step a in Scheme 3).
•
(13) The different selectivity with CF3 does not appear to be a
Supporting Information Available. Experimental pro-
cedures along with experimental and spectroscopic data
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
temperature or•solvent effect. For example, when the Fe-catalyzed
reaction of CF3 with veratrole (Scheme 4) was conducted at 85 °C, it
afforded 10.2:1 selectivity (67% yield). Similarly, when DCE was used as
the solvent in place of DMSO, the product was obtained with 7.7:1
selectivity (4% yield).
Org. Lett., Vol. 13, No. 20, 2011
5467