Rapid and efficient trifluoromethylation of aromatic and heteroaromatic compounds using potassium trifluoroacetate enabled by a flow system

Article abstract of DOI:10.1002/anie.201306094

Going to the source: The trifluoromethylation of aryl/heteroaryl iodides has been demonstrated using a flow system, thus enabling a rapid rate of reaction. A broad spectrum of trifluoromethylated compounds was prepared in good to excellent yields using CF₃CO₂K as the trifluoromethyl source. The process has the advantage of short reaction times and uses convenient [CF₃] sources. Copyright

Full text of DOI:10.1002/anie.201306094

Angewandte
Chemie
DOI: 10.1002/anie.201306094
Cross-Coupling
Rapid and Efficient Trifluoromethylation of Aromatic and
Heteroaromatic Compounds Using Potassium Trifluoroacetate
Enabled by a Flow System**
Mao Chen and Stephen L. Buchwald*
The development of synthetic methods to introduce trifluoro-
methyl groups into aromatic and heteroaromatic compounds
is of considerable interest as CF3-substituted molecules often
possess improved physical and chemical properties.[1] As
a result, a variety of synthetic methods have been developed
to accomplish this task.[2,3] Nagib and MacMillan[4] and Baran
and co-workers[5] reported elegant examples of (hetero)-
aromatic trifluoromethylation reactions by CF3 radical pro-
cesses. These have the advantage of being simple and high
yielding, though a lack of regiocontrol is observed with
certain classes of substrates. Although palladium and copper
systems have been developed for the trifluoromethylation of
(hetero)aromatic precursors, the scope of heterocyclic sub-
strates handled by these methods is limited (Scheme 1).[3] In
Since the pioneering work by Wiemers and Burton,[6]
a great deal of effort has been expended to devise convenient
means of generating a [CuCF3] species, which is the presumed
key intermediate in many copper-mediated trifluoromethy-
lation processes.[3,7–10] In 2008, Vivic and co-workers disclosed
that [CuCF3] could be stabilized with NHC ligands,[11] and the
resulting complexes were applied to the room temperature
transformation of aryl iodides into aryl trifluoromethyl
compounds. Amii and co-workers then reported the first
copper-catalyzed aromatic trifluoromethylation process uti-
lizing Et3SiCF3.[3b] The subsequent use of the isolated
[(phen)CuCF3] reagent by Hartwig and co-workers allowed
the successful transformation of a variety of aryl halides and
several heteroaryl iodides into trifluoromethyl (hetero)ar-
enes.[3g]
Among the various trifluoromethylating reagents, fluoro-
form and trifluoroacetate salts are stable and low priced, and
thus represent attractive CF3 sources for many applications.
Seminal work by Grushin and co-workers demonstrated the
viability of fluoroform in trifluoromethylation processes.[3h,12]
While a major step forward, the need to manipulate gaseous
CF3H is inconvenient for some applications. Because of the
ease of handling and low cost, trifluoroacetate salts have been
used by Matsui and co-workers and others in the trifluoro-
methylation of aryl halides.[8–10] Only a limited number of
heterocycles have been successfully furnished under batch
conditions. In those processes, up to 10 equivalents of sodium
Scheme 1. Aromatic trifluoromethylation under batch and flow condi-
tions.
À
À
trifluoroacetate were used, and mixtures of Ar CF3, Ar
À
addition, they usually necessitate the use of an excess of
expensive or gaseous CF3 reagents (the latter which are more
difficult to handle in normal laboratory settings) and have
reaction times ranging from hours to days. Thus, it would be
desirable to devise a rapid and efficient method which can be
applied to a broad range of substrates and employs a low-cost
CF3 source.
C2F5, and Ar H were usually obtained during reaction times
À
of several hours. The separation of Ar CF3 from these side
products is usually difficult because of their similar physical
properties. Given our experience in both flow and trifluoro-
methylation chemistry,[3a,13] we wondered if a method com-
bining the two would be advantageous. Herein, we report an
efficient aromatic trifluoromethylation process conducted
under flow conditions. With this operationally simple method,
a broad spectrum of trifluoromethylated aromatic and
heteroaromatic compounds can be prepared from the corre-
sponding aryl iodides in a protocol requiring only minutes of
residence time, and using CF3CO2K as the CF3 source.
Early in our work, in studies carried out under batch
conditions, we found that the rate of the decarboxylation of
CF3CO2K could be substantially accelerated by increasing the
reaction temperature from 1608C to 2008C in the presence of
copper iodide.[14] In principle, this rapid decarboxylation
process could facilitate the generation of the desired [CuCF3]
intermediate. While the high temperature and the increased
pressure which occurs during decarboxylation[15] can present
[*] Dr. M. Chen, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We thank Novartis International AG and the National Institutes of
Health for financial support (GM46059). The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health. We thank Dr.
John R. DeBergh and Dr. Christine Nguyen for assistance with the
preparation of this manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306094.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Substrate scope of the trifluoromethylation of aromatic com-
problems under batch conditions, especially on a larger scale,
flow processes are able to readily manage reaction parame-
ters such as temperature, pressure, and residence times.[16–18]
The handling of solids under flow conditions can be
problematic. Considering the low solubility of CuI in NMP,
we first examined a number of ligands, such as 1,10-
phenanthroline, 2,2’-bipyridine, TMEDA, DMEDA, and
pyridine, to establish suitable reaction conditions. Pyridine
proved to be the optimal ligand, thus furnishing a homogenous
solution in combination with CuI. The CuI (2.0 equiv)/
pyridine (2.4 equiv) combination was applied to a mixture
of CF3CO2K (2.0 equiv) and 4-iodobipenyl (1.0 equiv) at
2008C for 15 minutes to provide an excellent yield of 4-
trifluoromethylbiphenyl (95% as determined by 19F NMR
spectroscopy). Only trace amounts of the reduced product
(biphenyl) or double insertion product (4-pentafluoroethyl
biphenyl), were detected (< 2% as judged by GC analysis).
Interestingly, when CF3CO2K was replaced with CF3CO2Na
under otherwise identical reaction conditions, only a 40%
yield of the desired product was realized.[19]
pounds under flow conditions.[a]
We next adapted our process to flow conditions. A
solution of CF3CO2K, CuI, and pyridine in NMP was mixed
with a solution of 4-trifluoromethylbiphenyl in NMP and
introduced into a stainless steel tube reactor submerged in
a preheated 2008C bath using an optimized 16 minute
residence time (Figure 1). At this point the mixture was
[a] Yields of isolated products (average of two runs) based on 1 mmol
scale are shown. See the Supporting Information for details.
sulfonamide- (2e), and chloro-substituted (2 f) aryl com-
pounds as well.
In light of the above results, we next focused on expanding
the scope of this method to heteroaryl substrates (Table 2).[8b]
Nitrogen-containing heterocycles are known to coordinate
with copper species, and thus represent a challenging class of
substrates for copper-catalyzed processes. As shown in
Table 2, a variety of heterocyclic compounds including
pyridines (2m, 2n, and 2o), indole (2p), pyrimidine (2q),
pyrazine (2r), quinoline (2s), isoquinoline (2t), imidazopyr-
idine (2u), and pyrrolopyridine (2v) substrates could be
efficiently coupled with the trifluoromethyl group under the
flow conditions. Trifluoromethylpyrazole is the core unit of
many pharmaceuticals, agrochemicals, and potential drug
candidates (e.g., Celecoxib, Mavacoxib, Razaxaban, SC-
560),[20] but these five-membered heterocycles are poor
substrates for palladium-catalyzed processes.[21] However, by
using this flow method, both 2- and 3-trifluoromethyl-
substituted pyrazoles (2w and 2x) could be prepared in
good yields.
Figure 1. Flow setup for the aromatic trifluoromethylation. See the
Supporting Information for details. NMP=N-methylpyrrolidone.
diluted with a stream of ethyl acetate (controlled with back-
pressure regulators). Finally, the resulting mixture was
collected and subsequently purified in a standard fashion by
column chromatography to afford 2a in 87% yield upon
isolation (Table 1).
Having established efficient flow conditions, the substrate
scope was investigated (Table 1) using the flow setup shown in
Figure 1. All of the substrates underwent complete conver-
sion using a 16 minute residence time, thus affording products
in good to excellent yields and in over 95% purity. The high
selectivity for trifluoromethylation further enhances the
À
efficiency of this method, since the separation of Ar H,
a typical side product of trifluoromethylation processes, from
One of the major advantages of flow chemistry involves
the ease-to-scale-up reactions. To further demonstrate the
robustness of our flow system, we successfully performed the
trifluoromethylation of ethyl 4-iodobenzoate under flow
conditions on a 10 mmol scale (Scheme 2). In a period of
208 minutes, we were able to generate two grams (10 mmol)
of product.
À
Ar CF3 can often be difficult. The aromatic trifluoromethy-
lation reaction could be successfully carried out with para-,
meta-, and ortho-substituted aryl substrates. In addition,
electron-deficient, electron-neutral, and electron-rich iodo-
arenes are all suitable substrates. As illustrated in Table 1, the
flow conditions tolerate ester- (2b), nitro- (2c), amide- (2d),
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Table 2: Substrate scope of the trifluoromethylation of heteroaromatic
compounds under flow conditions.[a]
Figure 2. Hammett plots of competition experiments. See the Support-
ing Information for details.
a nucleophilic [CuCF3] species which undergoes oxidative
addition with aryl iodides, and slightly favors substrates with
electron-withdrawing groups. The 1 value observed here was
similar to that obtained from other copper-catalyzed or
copper-mediated processes in our group.[22]
In conclusion, we have developed a simple, scalable, and
efficient technique to introduce a trifluoromethyl group into
aromatic and heteroaromatic compounds by copper-mediated
cross-coupling reactions. This method represents the first
example of aromatic trifluoromethylation conducted in flow,
using stable, cost-effective, and easy-to-handle CF3CO2K as
the CF3 source. Of importance, very short reaction times
(minutes) are required to achieve full conversion of (hetero)-
aryl starting materials in this process. To increase the
practicality of the protocol, all components used to assemble
our reactors are available from commercial sources. More-
over, we have also successfully performed a Hammett study
using a 1 minute residence time at 2008C by employing flow
techniques, thus providing a reliable method of studying the
reaction under “hot and fast”, and synthetically relevant
reaction conditions.
[a] Yields of isolated products (average of two runs) based on 1 mmol
scale are shown. See the Supporting Information for details.
Experimental Section
General procedure: A solution of aryl iodide (0.6m) in NMP was
loaded into a stainless steel syringe and a solution of CuI (0.8m),
CF3CO2K (0.8m) and pyridine (0.96m) in NMP was loaded into
a second stainless steel syringe. The flow rates of two solutions were
40 mL/min and 60 mL/min separately delivering with two Harvard
Apparatus syringe pumps. After mixing with a T-mixer, the resulting
mixture was delivered into the stainless steel reactor (1/16 inch OD,
0.046 inch ID, 1.6 mL volume) at 200–2108C (Caution: Hot! A
suitable bath oil should be used[23]). Upon exiting the reactor, the
reaction was quenched with EtOAc (100 mL/min). Next, after
reaching steady state, the sample was collected in order to obtain
exactly 1 mmol of product. Further safety information as well as
details of the flow setup and workup procedures can be found in the
Supporting Information.
Scheme 2. Trifluoromethylation of ethyl 4-iodobenzoate on 10 mmol
scale. See the Supporting Information for details.
To probe the mechanism of this reaction, we performed
a Hammett study. Because of the small size of microflow
reactors, an advantage of their use is their efficient mass and
heat transfer with short reaction times which are difficult to
control in a batch reactor.[16] Accordingly, a flow system with
the same setup as shown in Figure 1 was used to conduct the
kinetic study. All experiments were performed under reaction
conditions under a 1 minute residence time at 2008C. In
competition experiments, an excess of the equimolar mixture
of 3- or 4-substituted aryl iodides and iodobenzene relative to
CF3CO2K was used. The relative rates of different reactions
were extracted from the product distributions after reaching
a steady state. As shown in Figure 2, a linear correlation (R2 =
0.98) with a slope of 0.52 was observed using this flow method.
The positive 1 value is consistent with the presence of
Sample analysis: NMR and IR spectroscopies were used to
identify the products.
Received: July 12, 2013
Published online: && &&, &&&&
Keywords: copper · cross-coupling · fluorine · flow chemistry ·
.
synthetic methods
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
X. F. Wu, A. Zapf, A. Cotte, M. Gotta, M. Beller, Top. Catal.
2012, 55, 426.
[10] For examples of using CF3CO2K as CF3 sources, see R. W. Lin,
R. I. Davidson, U.S. Patent 4808748, 1989.
[11] G. G. Dubinina, H. Furutachi, D. A. Vicic, J. Am. Chem. Soc.
2008, 130, 8600.
[12] A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz, V. V.
Grushin, J. Am. Chem. Soc. 2011, 133, 20901.
[13] For selected recent examples, see: a) A. DeAngelis, D.-H. Wang,
S. L. Buchwald, Angew. Chem. 2013, 125, 3518; Angew. Chem.
Int. Ed. 2013, 52, 3434; b) M. Chen, S. L. Buchwald, Angew.
Chem. 2013, 125, 4341; Angew. Chem. Int. Ed. 2013, 52, 4247;
c) N. Chernyak, S. L. Buchwald, J. Am. Chem. Soc. 2012, 134,
12466.
[1] a) K. Mꢀller, C. Faeh, F. Diederich, Science 2007, 317, 1881;
b) M. Schlosser, Angew. Chem. 2006, 118, 5558; Angew. Chem.
Int. Ed. 2006, 45, 5432; c) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320; d) C. Isanbor, D.
OꢁHagan, J. Fluorine Chem. 2006, 127, 303; e) P. Kirsch, Modern
Fluoroorganic Chemistry: Synthesis Reactivty, Applications,
Wiley-VCH, Weinheim, 2004; f) T. Umemoto, Chem. Rev.
1996, 96, 1757; g) S. G. K. Prakash, A. K. Yudin, Chem. Rev.
1997, 97, 757; h) B. R. Langlois, T. Billard, Synthesis 2003, 185;
i) M. A. McClinton, D. A. McClinton, Tetrahedron 1992, 48,
6555; j) R. P. Singh, J. M. Shreeve, Tetrahedron 2000, 56, 7613;
k) I. Kieltsch, P. Eisenberger, K. Stanek, A. Togni, Chima 2008,
62, 260.
[2] For recent reviews of trifluoromethylation, see: a) O. A. Toma-
shenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475; b) J.-A. Ma,
D. Cahard, J. Fluorine Chem. 2007, 128, 975; c) R. J. Lundgren,
M. Stradiotto, Angew. Chem. 2010, 122, 9510; Angew. Chem. Int.
Ed. 2010, 49, 9322; d) S. Roy, B. T. Gregg, G. W. Gribble, V.-D.
Le, S. Roy, Tetrahedron 2011, 67, 2161; e) X.-F. Wu, H.
Neumann, M. Beller, Chem. Asian J. 2012, 7, 1744; f) T.
Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470.
[14] See Figure S-1 in the Supporting Information for details.
[15] When 10 mmol CF3CO2K is decarboxylated in a 20 mL sealed
flask at 2008C, the pressure increases to about 15 atm according
to the ideal gas law.
[16] For selected reviews in flow chemistry, see: a) S. V. Ley, Chem.
Rec. 2012, 12, 378; b) J. Wegner, S. Ceylan, A. Kirschning, Chem.
Commun. 2011, 47, 4583; c) B. P. Mason, K. E. Price, J. L.
Steinbacher, A. R. Bogdan, D. T. McQuade, Chem. Rev. 2007,
107, 2300; d) J.-i. Yoshida, A. Nagaki, T. Yamada, Chem. Eur. J.
2008, 14, 7450; e) C. Wiles, P. Watts, Chem. Commun. 2011, 47,
6512; f) A. Cukalovic, J. C. M. R. Monbaliu, C. V. Stevens, Top.
Heterocycl. Chem. 2010, 23, 161; g) T. Fukuyama, M. T. Rahman,
M. Sata, I. Ryu, Synlett 2008, 151.
[17] a) W. Ehrfeld, V. Hessel, H. Lçwe, Microreactors: New Tech-
nology for Modern Chemistry, Wiley-VCH, Weinheim, 2000;
b) P. H. Seeberger, T. Blume, New Avenues to Efficient Chemical
Synthesis-Emerging Technologies, Springer, Berlin, 2007; c) T.
Wirth, Microreactors in Organic Synthesis and Catalysis, Wiley-
VCH, Weinheim, 2008.
[18] For examples of handling high-temperature conditions in flow,
see: a) J. Sedelmeier, I. R. Baxendale, S. V. Ley, Green Chem.
2009, 11, 683; b) I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley,
G. K. Tranmer, Chem. Eur. J. 2006, 12, 4407; c) N. Zaborenko,
M. W. Bedore, T. F. Jamison, K. F. Jensen, Org. Process Res. Dev.
2011, 15, 131; d) A. G. OꢁBrien, Z. Horvꢂth, F. Lꢄvesque, J. W.
Lee, A. Seidel-Morgenstern, P. H. Seeberger, Angew. Chem.
2012, 124, 7134; Angew. Chem. Int. Ed. 2012, 51, 7028; e) M. G.
Organ, P. R. Hanson, A. Rolfe, T. B. Samarakoon, U. Farman, J.
Flow Chem. 2011, 1, 32; f) Y. Zhang, T. F. Jamison, S. Patel, N.
Mainolfi, Org. Lett. 2011, 13, 280; g) D. Cantillo, H. Sheibani,
C. O. Kappe, J. Org. Chem. 2012, 77, 2463; h) H. Kawanami, K.
Matsushima, M. Sato, Y. Ikushima, Angew. Chem. 2007, 119,
5221; Angew. Chem. Int. Ed. 2007, 46, 5129; i) J. G. Stevens,
R. A. Bourne, M. V. Twigg, M. Poliakoff, Angew. Chem. 2010,
122, 9040; Angew. Chem. Int. Ed. 2010, 49, 8856; j) B. Gutmann,
J.-P. Roduit, D. Roberge, C. O. Kappe, Angew. Chem. 2010, 122,
7255; Angew. Chem. Int. Ed. 2010, 49, 7101; k) J. Baek, P. M.
Allen, M. G. Bawendi, K. F. Jensen, Angew. Chem. 2011, 123,
653; Angew. Chem. Int. Ed. 2011, 50, 627.
[3] For selected recent examples, see: a) E. J. Cho, T. D. Senecal, T.
Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science 2010,
328, 1679; b) M. Oishi, H. Kondo, H. Amii, Chem. Commun.
2009, 1909; c) N. D. Ball, J. B. Gary, Y. Ye, M. S. Sanford, J. Am.
Chem. Soc. 2011, 133, 7577; d) X.-G. Zhang, H.-X. Dai, M. Wasa,
J.-Q. Yu, J. Am. Chem. Soc. 2012, 134, 11948; e) Y. Ye, M. S.
Sanford, J. Am. Chem. Soc. 2012, 134, 9034; f) T. Knauber, F.
Arikan, G.-V. Rçschenthaler, L. J. Gooßen, Chem. Eur. J. 2011,
17, 2689; g) H. Morimoto, T. Tsubogo, N. D. Litvinas, J. F.
Hartwig, Angew. Chem. 2011, 123, 3877; Angew. Chem. Int. Ed.
2011, 50, 3793; h) P. Novꢂk, A. Lishchynskyi, V. V. Grushin,
Angew. Chem. 2012, 124, 7887; Angew. Chem. Int. Ed. 2012, 51,
7767; i) M. M. Kremlev, W. Tyrra, A. I. Mushta, D. Naumann,
Y. L. Yagupolskii, J. Fluorine Chem. 2010, 131, 212; j) C. P.
Zhang, Z. L. Wang, Q. Y. Chen, C. T. Zhang, Y. C. Gu, J. C.
Xiao, Angew. Chem. 2011, 123, 1936; Angew. Chem. Int. Ed.
2011, 50, 1896; k) M. Dçbele, M. S. Wiehn, S. Brꢃse, Angew.
Chem. 2011, 123, 11737; Angew. Chem. Int. Ed. 2011, 50, 11533;
l) T. Liu, X. Shao, Y. Wu, Q. Shen, Angew. Chem. 2012, 124, 555;
Angew. Chem. Int. Ed. 2012, 51, 540; m) L. Chu, F.-L. Qing, J.
Am. Chem. Soc. 2012, 134, 1298; n) Z. Weng, R. Lee, W. Jia, Y.
Yuan, W. Wang, X. Feng, K. W. Huang, Organometallics 2011,
30, 3229; o) J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X.
Lu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 8436; p) G.
Danoun, B. Bayarmagnai, M. F. Grꢀnberg, L. J. Gooßen, Angew.
Chem. 2013, 125, 7972; Angew. Chem. Int. Ed. 2013, 52, 7972.
[4] D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480, 224.
[5] Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su,
D. G. Blackmond, P. S. Baran, Proc. Natl. Acad. Sci. USA 2011,
108, 14411.
[6] D. M. Wiemers, D. J. Burton, J. Am. Chem. Soc. 1986, 108, 832.
[7] a) G. K. S. Prakash, R. Krishnamurti, G. A. Olah, J. Am. Chem.
Soc. 1989, 111, 393; b) G. P. Stahly, D. R. Bell, J. Org. Chem.
1989, 54, 2873; c) A. Kruse, G. Siegemund, D. C. A. Schumann, I.
Ruppert, Ger. Offen. DE3805534, 1988.
[8] For examples of using CF3CO2Na as CF3 sources, see: a) K.
Matsui, E. Tobita, M. Ando, K. Kondo, Chem. Lett. 1981, 1719.
b) This paper investigated the reactions of heteroaryl substrates:
G. E. Carr, R. D. Chambers, T. F. Holmes, J. Chem. Soc. Perkin
Trans. 1 1988, 921; c) Y. Li, T. Chen, H. Wang, R. Zhang, K. Jin,
X. Wang, C. Duan, Synlett 2011, 1713.
[19] See Table S-1 in the Supporting Information for details.
[20] a) C. Lamberth, Heterocycles 2007, 71, 1467; b) J. Elguero,
A. M. S. Silva, A. C. Tomꢄ in Modern Heterocyclic Chemistry
(Eds.: J. Alvarez-Builla, J. J. Vaquero, J. Barluenga), Wiley-
VCH, Weinheim, 2011, pp. 635 – 725.
[21] Y. Ye, M. S. Sanford, Synlett 2012, 2005.
[22] E. R. Strieter, B. Bhayana, S. L. Buchwald, J. Am. Chem. Soc.
2009, 131, 78.
[23] For example, the silicone oil from Alfa Aesar, catalogue number
45896, with a temperature range of 25–2508C.
[9] For examples using CF3CO2Me, see: a) B. R. Langlois, N.
Roques, J. Fluorine Chem. 2007, 128, 1318; b) T. Schareina,
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Cross-Coupling
M. Chen, S. L. Buchwald*
&&&& — &&&&
Rapid and Efficient Trifluoromethylation
of Aromatic and Heteroaromatic
Compounds Using Potassium
Trifluoroacetate Enabled by a Flow System
Going to the source: The trifluoromethy-
lation of aryl/heteroaryl iodides has been
demonstrated using a flow system, thus
enabling a rapid rate of reaction. A broad
spectrum of trifluoromethylated com-
pounds was prepared in good to excellent
yields using CF3CO2K as the trifluoro-
methyl source. The process has the
advantage of short reaction times and
requires convenient [CF3] sources.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!