PhI(OAc)2-mediated oxidative trifluoromethylation of arenes with CF3SiMe3 under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.11.011

A PhI(OAc)₂-mediated oxidative trifluoromethylation of arenes with CF₃SiMe₃ under metal-free conditions has been described. This protocol precludes the need of substrate pre-functionalization and metal catalysts, enabling

Full text of DOI:10.1016/j.tetlet.2012.11.011

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PhI(OAc)2-Mediated Oxidative Trifluoromethylation of Arenes with
CF3SiMe3 under Metal-Free Conditions
Xinyue Wu, Lingling Chu, Feng-Ling Qing
PII:
S0040-4039(12)01932-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.011
TETL 42103
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Tetrahedron Letters
Please cite this article as: Wu, X., Chu, L., Qing, F-L., PhI(OAc)2-Mediated Oxidative Trifluoromethylation of
Arenes with CF3SiMe3 under Metal-Free Conditions, Tetrahedron Letters (2012), doi: http://dx.doi.org/10.1016/
j.tetlet.2012.11.011
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PhI(OAc)2-Mediated Oxidative
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Trifluoromethylation of Arenes with
CF3SiMe3 under Metal-Free Conditions
Xinyue Wu, Lingling Chu, and Feng-Ling Qing*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
PhI(OAc)2-Mediated Oxidative Trifluoromethylation of Arenes with CF3SiMe3 under
Metal-Free Conditions
Xinyue Wua, Lingling Chua, and Feng-Ling Qinga,b,*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A PhI(OAc)2-mediated oxidative trifluoromethylation of arenes with CF3SiMe3 under metal-free
conditions has been described. This protocol precludes the need of substrate pre-
functionalization and metal catalysts, enabling a direct access to a series of trifluoromethylated
arenes and heterocycles containing common functional groups in moderate and good yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylation
Metal-free
Hypervalent iodine
Trifluoromethylated arenes are widely prevalent in
pharmaceuticals and argochemicals because of the metabolic
stability, lipophilicity, and electron-withdrawing character of the
trifluoromethyl group (CF3-).1 As a result, it has been of great
synthetic interest to develop mild and efficient methods for the
incorporation of the CF3 moiety into aromatic compounds. Over
the past five years, significant advances have been made in
transition-metal-mediated or -catalyzed trifluoromethylation of
aryl halides,2 boronic acids,3 and even C-H bonds.4 Of
particularly importance is the direct trifluoromethylation of aryl
C-H bonds, which is more staightforward and more economical
trifluoromethylation protocols because it does not require the pre-
functionalized starting materials.4 In addition, this method
provides a more precise installation of the trifluoromethyl group
than the radical trifluoromethylation of simple arenes.5 Despite of
these tremendous progress, current direct trifluoromethylation
methods are limited by some combination of expensive reagents,
high temperatures, and limited substrate scope. Particularly,
transition metal catalysts are required for these reactions,
resulting in heavy-metal contamination of the products and
complicating the purification for pharmaceutical applications.
Thus, a more general direct trifluoromethylation of aryl C-H
bonds under metal-free and mild conditions is highly desirable.
transformation occurred via PhI(OAc)2-induced oxidation of
terminal alkene and then formation of the radical cation
intermediate A as a key intermediate. On the basis of this work
and previous reports on hypervalent iodine-induced
7
functionalization of arenes, we envisaged that PhI(OAc)2-
mediated oxidative trifluoromethylation of arenes under metal-
free conditions would be possible if an analogous aromatic
radical cation intermediate B was formed (Scheme 1b). Herein,
we report a facile method to access trifluoromethylated arenes
through PhI(OAc)2-mediated oxidative trifluoromethylation of
arenes with CF3SiMe3 under metal-free conditions.
Recently,
we
reported
copper-catalyzed
oxidative
trifluoromethylation of terminal alkenes with CF3SiMe3 in the
presence of PhI(OAc)2, allowing efficient access to a wide range
of trifluoromethylated allylic compounds.6 It was significant to
observe that the oxidative trifluoromethylation of 1 proceeded
smoothly under metal-free conditions by the action of PhI(OAc)2
to afford the side product 3 in 51% yield along with the desired
product 2 in 12% yield (Scheme 1a). We surmised that this
Scheme 1. PhI(OAc)2-Mediated Oxidative
Trifluoromethylation under Metal-Free Conditions

2
Tetrahedron
2c
K3PO4 (4.0)
NaOAc (4.0) NMP [0.3M]
CsF (4.0) NMP [0.3M]
t-BuOK (4.0) NMP [0.3M]
NMP [0.3M]
/
43
29
29
trace
28
29
26
41
70
45
70
46
To test our hypothesis on the metal-free oxidative
3c
/
trifluoromethylation of arenes, mesitylene 4a was initially
employed to react with CF3SiMe3 using PhI(OAc)2 as an oxidant
and K2CO3 as a base under the same conditions of metal-free
oxidative trifluoromethylation of alkenes (Table 1).6
Gratifyingly, the desired product 5a was obtained in 29% yield
(Table 1, entry 1). Exploration of bases revealed that K3PO4 was
more effective than other bases, such as NaOAc and CsF, while
t-BuOK was completely ineffective with almost no formation of
the desired product (entries 1-5). We also screened the solvent
and found that besides NMP, CH3CN also provided an acceptable
yield of product 5a, while reactions conducted in DMF, DMSO,
or 1,2-dichloroethane (DCE) gave low yields (entries 6-9).
Considering the convenience of reaction workup, we continued
our studies by using CH3CN as the optimal solvent. Substrate
concentration was found to be important in facilitating this
transformation. As the concentration of substrate 4a was
increased from 0.3 M to 1 M, the yield of the trifluoromethylated
product was increased to 70%, however, further increase in
concentration was not beneficial for the reaction (entries 9-11).
Reducing the amount of CF3SiMe3 and K3PO4 from 4.0 equiv to
2.4 euqiv and PhI(OAc)2 from 2.0 equiv to 1.2 equiv has no
significant impact on the reaction efficiency, and the desired
product was obtained without any loss in yield (entry 12). To
further increase the reaction efficiency, a series of Lewis acids,
which are known to be able to activate the hypervalent iodine(III)
reagents,7d,8 were screened (entries 13-17). However, most of
Lewis acids we tested, including BF3·Et2O, Cu(OAc)2, FeCl3, and
In(OTf)3, were ineffective in the current reaction (entries 13-16).
Recently, Sanford and Brase independently reported Ag-
mediated trifluoromethylation of aromatic substrates using
nucleophilic CF3SiMe3 as a trifluoromethylating reagent, abeit
4.0 equiv Ag salts are required to facilitate these
transformations.4d,4g Inspired by these results, we surmised that
the addition of AgOTf might be helpful in enhancing the reaction
efficiency. Experimentally, the desired product 5a was obtained
in 85% yield in the presence of catalytic AgOTf (entry 17). We
also examined the reactivity of AgOTf under these conditions. As
shown in entry 18, stoichiometric AgOTf provided only 14%
yield of product 5a, precluding the possibility of AgOTf-
mediated oxidative trifluoromethylation in the current reaction.
This result further indicates that this pathway might not involve a
trifluoromethyl radical intermediate, which has been proposed by
Sanford and Brase in Ag-mediated trifluoromethylation.4d,4g
Interestingly, the highest yield of 5a was achieved in the
presence of catalytic amount of benzoquinonine (BQ) (entry 19).
However, no product was observed when stoichiometric amount
of BQ instead of PhI(OAc)2 was employed as an oxidant under
otherwise identical conditions (entry 20). At this stage, the role of
BQ remains to be elucidated.
4c
/
5c
/
6c
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
K3PO4 (2.4)
DMF [0.3M]
DMSO [0.3M]
DCE [0.3M]
/
7c
/
8c
/
9c
MeCN [0.3M]
MeCN [1.0M]
MeCN [2.0M]
MeCN [1.0M]
MeCN [1.0M]
MeCN [1.0M]
MeCN [1.0M]
MeCN [1.0M]
MeCN [1.0M]
MeCN [1.0M]
/
10c
11c
12
13
14
15
16
17
18d
19
20d
/
/
/
BF3·Et2O (1.0)
Cu(OAc)2 (0.1) 63
FeCl3 (0.1)
46
In(OTf)3 (0.1)
AgOTf (0.1)
AgOTf (1.2)
62
85
14
MeCN [1.0M] BQ (0.2)
MeCN [1.0M] BQ (1.2)
95
none
a Reaction conditions: 4a (0.3 mmol), CF3SiMe3 (0.72 mmol, 2.4 equiv),
PhI(OAc)2 (0.36 mmol, 1.2 equiv), base (0.72 mmol, 2.4 equiv), 4Å MS (50
mg), addictive, solvent, 85 oC, 6h.
b Yields of 5a were determined by 19F NMR with fluorobenzene as an internal
standard.
c CF3SiMe3 (1.2 mmol, 4.0 equiv), PhI(OAc)2 (0.6 mmol, 2.0 equiv), base
(1.2 mmol, 4.0 equiv).
d In the absence of PhI(OAc)2.
With the optimized reaction conditions in hand (Table 1, entry
19), the substrate scope of the PhI(OAc)2-mediated oxidative
trifluoromethylation of arenes under metal-free conditions was
then investigated. As shown in Table 2, a series of electron-rich
arenes bearing electron-donating alkyl and alkoxy groups (4a-4h)
were good for this transformation, affording the corresponding
products in moderate to excellent yields (Table 2, entries 1-8).
This oxidative trifluoromethylation reaction also proceeded
successfully with aromatic substrates containing an electron-
withdrawing group such as Cl (4i), Br (4j), or keto groups (4k) to
give the trifluoromethylated products in moderate to good yields
(entries 9-11). Several common functional groups, including
ester, keto, Cl and Br, are tolerated under the reaction conditions,
providing opportunities for further transformations (entries 7-11).
Importantly, the heterocycles such as indoles (4l-4m) and N-
methyl pyrrole (4n) were also amenable to this oxidative
trifluoromethylation protocol and useful yields were obtained
under the standard reaction conditions (entries 12-14). In most
cases, mixtures of regioisomers were produced in these
transformations, albeit with a moderate regioselectivity (Table 2).
Some regioisomers can be separated by chromatography to
provide the single trifluoromethylated products (entries 5, 9-10).
Notably, the current oxidative protocol can be easily extended to
the direct perfluoroalkylation of arenes to give the
perfluoroalkylated product 5o in good yield (entry 15).
Table 1. Optimization of Oxidative Trifluoromethylation of
Mesitylenea
Base
Additive
(equiv)
/
Yield of 5a
(%)b
Entry
1c
Solvent
(equiv)
K2CO3 (4.0)
NMP [0.3M]
29

3
12
13
72%
62%
4l
Table 2. PhI(OAc)2-Mediated Oxidative Trifluoromethylation
of Arenesa
4m
14
15
94% (a : b = 6.4 : 1)b
4n
4o
Entry Substrate 4
Product 5
Isolated yield
95%b
86%
1
4a
a Reaction conditions: 4 (0.5 mmol), CF3SiMe3 (1.2 mmol, 2.4 equiv),
PhI(OAc)2 (0.6 mmol, 1.2 equiv), K3PO4 (1.2 mmol, 2.4 equiv), BQ (0.1
mmol, 0.2 equiv), 4Å MS (80 mg), CH3CN [1.0 M], 85 oC, 6h. Isolated yields.
Isomer ratios were determined by 19F NMR spectroscopy.
2
72% (a : b= 1.5 : 1)
4b
b Yields were determined by 19F NMR spectroscopy with fluorobenzene as
an internal standard.
3
4
59% (a : b= 1.4 : 1)
4c
In
summary,
a
PhI(OAc)2-mediated
oxidative
trifluoromethylation of arenes with CF3SiMe3 under metal-free
conditions has been developed, providing a direct method for
synthesizing trifluoromethylated arenes without the need of pre-
functionalization. A variety of trifluoromethylated arenes and
heterocycles were obtained under mild conditions in moderate to
good yields. This method is amenable to normal benchtop setup
and tolerates a range of functional groups. The optimized
conditions for the oxidative trifluoromethylation of arenes were
also effective for the oxidative perfluoroalkylation.
78%
4d
5
73% (a : b = 11 : 1)
4e
6
7
43% (a : b = 8 : 1)
4f
Acknowledgments
National Natural Science Foundation of China (21072028,
20832008) and National Basic Research Program of China
(2012CB21600) are greatly acknowledged for funding this work.
55% (a : b = 1.3 : 1)
4g
Supplementary Material
8
56% (a : b = 1.5 : 1)
4h
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.....
References and notes
1. (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, 2004. (b) Hird, M. Chem. Soc. Rev. 2007, 36, 2070. (c)
Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305. (d) Furuya, T.;
Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (e) Tomashenko,
O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475. (f) Besset, T.;
Schneider, C.; Cahard, D. Angew. Chem. Int. Ed. 2012, 51, 5048.
Angew. Chem. Int. Ed. 2012, 51, 5048. (g) Pan, F.; Shi, Z. Acta
Chim. Sinica 2012, 70, 1679. (h) Qing, F.-L. Chin. J. Org. Chem.
2012, 32, 815. (i) Lü, C.; Shen, Q.; Liu, D. Chin. J. Org. Chem.
2012, 32, 1380. (j) Wu, X. F.; Neumann, H.; Beller, M. Chem.
Asian. J. 2012, 7, 1744. (k) Studer, A. Angew. Chem. Int. Ed. 2012,
51, 8950. (l) Ye, Y.; Sanford, S. Synlett 2012, 23, 2005.
2. For recent examples of transition metal-mediated or -catalyzed
trifluoromethylation of aryl halides, see: (a) Dubinina, G. G.;
Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600. (b)
Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909. (c)
Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. (d) Kondo, H.;
Oishi,M.; Fujikawa, K.; Amii, H. Adv. Synth. Catal. 2011, 353,
1247. (e) Knauber, T.; Arikan, F.; Roschenthaler, G. V.; Goossen,
9
79% (a : b = 3.2 : 1)
50% (a : b = 1 : 1)
56% (a : b = 3.3 : 1)
4i
10
11
4j
4k

4
Tetrahedron
L. J. Chem. Eur. J. 2011, 17, 2689. (f) Zhang, C.-P.; Wang, Z.-
Chu, L.; Qing, F.- L. J. Am. Chem. Soc. 2012, 134, 1298. (c) Mu,
X.; Chen, S.; Zhen, X.; Liu, G. Chem. Eur. J. 2011, 17, 6039. (d)
Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464. (e)
Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224. (f)
Iqbal, N.; Choi, S.; Ko, E.; Cho, E. J. Tetrahedron Lett. 2012, 53,
2005. (g) Hafner, A.; Bräse, S., Angew. Chem., Int. Ed. 2012, 51,
3713. (h) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2012, 134, 11948.
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-Ad_an, E. C.; Belmonte,
M. M.; Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655. (i)
Kremlev, M. M.; Mushta, A. I.; Tyrra, W.; Yagupolskii, Y. L.;
Naumann, D.; Möller, A. J. Fluorine Chem. 2012, 133, 67.
3. For recent examples of transition metal-mediated or -catalyzed
trifluoromethylation of boronic acids, see: (a) Chu, L.; Qing, F.-L.
Org. Lett. 2010, 12, 5060. (b) Senecal, T. D.; Parsons, A. T.;
Buchwald, S. L. J. Org. Chem. 2011, 76, 1174. (c) Xu, J.; Luo, D.-
F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem.
Commun. 2011, 47, 4300. (d) Liu, T.; Shen, Q. Org. Lett. 2011,
13, 2342. (e) Zhang, C. -P.; Cai, J.; Zhou, C. -B.; Wang, X. -P.;
Zheng, X.; Gu, Y. -C.; Xiao, J. -C. Chem. Commun. 2011, 47,
9516. (f) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2012, 51, 536. (g) Liu, T.; Shao, X.; Wu, Y.; Shen, Q.
Angew. Chem., Int. Ed. 2012, 51, 540. (h) Jiang, X. L.; Chu, L. L.;
Qing, F.-L. J. Org. Chem. 2012, 77, 1251. (i) Khan, B. A.; Buba,
A. E.; Gooßen, L. J. Chem. Eur. J. 2012, 18, 1577 (j) Ye, Y.;
Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034. (k) Novák, P.;
Lishchynskyi, A.; Grushin, V. V. Angew. Chem., Int. Ed. 2012, 51,
7767.
5. For recent examples of radical trifluoromethylation, see: (a) Kino,
T.; Nagase, Y.; Ohtsuka, Y.; Yamampto, K.; Uraguchi, D.;
Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (b)
Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su,
S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. 2011,
108, 14411.
6. Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106.
7. (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
(b) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita, Y. Angew.
Chem., Int. Ed. 2008, 47, 1301. (c) Dohi, T.; Ito, M.; Yamaoka,
N.;Morimoto, K.; Fujioka, H.; Kita, Y. Angew. Chem., Int. Ed.
2010, 49, 3334. (d) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem.
Soc. 2011, 133, 5996. (e) Kantak, A. A.; Potavathri, S.; Barham,
R. A.; Romano, K. M.; DeBoef, B. J. Am. Chem. Soc. 2011, 133,
19960.
4. For recent examples of transition metal-mediated or -catalyzed
trifluoromethylation of aryl C-H bonds, see: (a) Wang, X.;
Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648. (b)
8. (a) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett.
2006, 8, 2007. (b) Lee, J. M.; Park, E. J.; Cho, S. H.; Chang, S. J.
Am. Chem. Soc. 2008, 130, 7824.