Room temperature aryl trifluoromethylation via copper-mediated oxidative cross-coupling

Article abstract of DOI:10.1021/jo1023377

A method for the room temperature copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids has been developed. This protocol is amenable to normal benchtop setup and reactions typically require only 1-4 h. Proceeding under mild conditions, the method tolerates a range of functional groups, allowing access to a variety of trifluoromethylarenes.

Full text of DOI:10.1021/jo1023377

pubs.acs.org/joc
of the metal center to undergo reductive elimination to afford
Room Temperature Aryl Trifluoromethylation
via Copper-Mediated Oxidative Cross-Coupling
trifluoromethylarenes.5 Despite these challenges, recent reports
from Grushin,6a Sanford,6b,c Yu,7 and our own group8 have
demonstrated the use of Pd catalysts for the trifluoromethyla-
tion of aromatic substrates. While these represent important
achievements in trifluoromethylarene synthesis, significant
limitations of these Pd-based methods remain (e.g., generality,
user friendliness, cost). Thus we decided to also investigate
copper-mediated processes.
Todd D. Senecal, Andrew T. Parsons, and
Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Room 18-490, Cambridge, Massachusetts 02139,
United States
While there are few reports of palladium-mediated trifluoro-
methylation protocols, copper-mediated processes have been
studied extensively. Pioneering investigations by Burton shed
light on the instability and complexity of [Cu-CF3].9 Matsui’s
use of trifluoroacetate salts10 and Chen’s methyl fluorosul-
fonyldifluoroacetate11 have been shown to be attractive sources
of trifluoromethyl anion for copper-mediated couplings with
aryl iodides. Schlosser’s trifluoromethylation of pyridine io-
dides proceeds at room temperature, but to date its substrate
scope is narrow.12 Vicic illustrated the ability of ligands to
stabilize [Cu-CF3].13 This concept was further expanded upon
in an important paper by Amii that disclosed the first copper-
catalyzed trifluoromethylation process of aryl iodides.14 As is
the case with many copper-based cross-coupling reactions,
these techniques are applicable to aryl iodides or activated aryl
bromides, providing complementary reactivity to palladium-
based systems. While substantial progress has been made, the
development of alternate copper-mediated trifluoromethyla-
tions remains an attractive goal.
sbuchwal@mit.edu
Received November 29, 2010
A method for the room temperature copper-mediated
trifluoromethylation of aryl and heteroaryl boronic acids
has been developed. This protocol is amenable to normal
benchtop setup and reactions typically require only 1-4 h.
Proceeding under mild conditions, the method tolerates a
range of functional groups, allowing access to a variety of
trifluoromethylarenes.
Recently, Qing reported a method for the copper-mediated
oxidative trifluoromethylation of alkynes.15 Analogous to this
transformation, we postulated that a copper-mediated oxida-
tive coupling could be used to access benzotrifluorides. One of
the most notable copper-promoted oxidative couplings is the
Chan-Lam reaction,16 where an aryl boronic acid is coupled
with an amine or alcohol, typically at room temperature. The
mild conditions of a Chan-Lam-type coupling would be an
advantage relative to those employed in the methods currently
available for benzotrifluoride synthesis. Due to its potential
utility, we began investigating the development of a system for
the room temperature oxidative trifluoromethylation of aryl
boronic acids (Figure 1).
The development of methods for the construction of
organofluorine compounds is of great importance due to
the presence of fluorine in 20% of pharmaceuticals and 30%
of agrochemicals that are currently on the market.1 In
particular, the benzotrifluoride group is present in several
top-selling pharmaceuticals, including Januvia (Sitagliptin),
Celebrex (Celecoxib), Prozac (Fluoxetine), and Avodart
(Dutasteride). While trifluoromethyl groups possess many
desirable characteristics such as electron-withdrawing char-
acter, high lipophilicity, and excellent metabolic stability,2
their installation is often far from routine.
Traditionally, benzotrifluorides are formed through treat-
ment of benzotrichlorides with HF and/or metal fluorides
such as SbF5 (Swarts reaction),3 conditions that are typically
unsuitable for functionalized late-stage intermediates. Transi-
tion metal-mediated cross-coupling offers the potential for mild
conditions. Nevertheless, progress has been hampered by the
inherent instability of the trifluoromethyl anion4 and reluctance
During the preparation of this manuscript, Qing described
the first oxidative trifluoromethylation of aryl and vinyl boro-
nic acids to afford the Csp2-CF3 products in high yields.17
(7) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.
(8) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679.
(9) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832.
(10) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981, 1719.
(11) Chen, Q. Y.; Wu, S. W. J. Chem. Soc., Chem. Commun. 1989, 705.
(12) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 327.
(13) (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.
(14) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
(15) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(16) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetra-
hedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron
Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
(17) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060.
€
(1) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(2) Yamazaki, T.; Tagauchi, T.; Ojima, I. In Fluorine in Medicinal Chemistry
and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell: Chichester, Great
Britain, 2009; pp 3-46.
(3) Swarts, F. Bull. Acad. R. Belg. 1892, 24, 309.
(4) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(5) Hughes, R. P. Adv. Organomet. Chem. 1990, 31, 183.
(6) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
12644. (b) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010,
132, 2878. (c) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2010, 132, 14682.
1174 J. Org. Chem. 2011, 76, 1174–1176
Published on Web 01/14/2011
DOI: 10.1021/jo1023377
r
2011 American Chemical Society

Senecal et al.
JOCNote
TABLE 2. Oxidative Trifluoromethylation of Aryl and Heteroaryl
Boronic Acidsa,b
FIGURE 1. Chan-Lam coupling (top) and proposed oxidative
aryl trifluoromethylation (bottom).
TABLE 1. Optimization of the Copper-Mediated Oxidative
Trifluoromethylation of Aryl Boronic Acidsa,b
yield (%)
entry
Cu source
ligand
c
atmosphere
1
2a
3
1
2
3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
Cu(OAc)2
Cu(OAc)2
none
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
NEt3
air
air
O2
O2
O2
N2
O2
O2
O2
O2
42
24
1
5
0
0
5
32
0
0
0
4
2
0
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
45
71
24
21
20
0
60
11
67h
4
1
5d
6
58
30
5
7
34
0
7
8e
9f
10g
aReaction conditions: ArB(OH)2 (1 mmol), Cu(OAc)2 (1 mmol),
˚
ligand (1.1 mmol), TMSCF3 (2 mmol), CsF (2 mmol), 4 A mol sieves
(250 mg), 5 mL of 1,2-dichloroethane (DCE), 1 atm of air, O2, or N2.
bYields determined by gas chromatography with dodecane as an internal
c
d
e
f
˚
˚
standard. 2.2 equiv. T = 60 °C. No 4 A mol sieves. No 4 A mol sieves,
5 equiv of H2O. gSolvent = i-PrCN. hBenchtop setup, isolated yield,
average of 2 runs.
While a notable achievement, this method requires use of a
nitrogen-filled glovebox, highly air-sensitive [Cu(OTf)]2 C6H6,
3
5 equiv of trifluoromethyltrimethylsilane (TMSCF3), the slow
addition of the boronic acid substrate, and use of superstoichio-
metric quantities of Ag2CO3 as the reoxidant. Herein, we report
a complementary method for the oxidative trifluoromethyla-
tion of aryl and heteroaryl boronic acids that ameliorates many
of these limitations and provides a useful means to prepare
benzotrifluorides.
We commenced our studies by examining the trifluoro-
methylation of 4-phenoxyphenylboronic acid under typical
Chan-Lam-type conditions. Using 1 equiv of Cu(OAc)2, 2.2
equiv of NEt3, and TMSCF3 as the trifluoromethylating reagent
in an atmosphere of air, 5% of benzotrifluoride product was
observed (Table 1, entry 1). In accord with a bevy of literature
precedent for copper-mediated aryl trifluoromethylation reac-
tions,14,15,17 addition of 1,10-phenanthroline as a ligand sub-
stantially increased the yield of 2a to 45% (Table 1, entry 2). In
addition to the desired product, a significant amount of arene 1
(24%), via protodeboronation, was formed. Switching to an
atmosphere of dry oxygen resulted in substantially less arene
formation (1%) and increased the yield of the desired product to
71% (Table 1, entry 3). The use of oxygen as the stoichiometric
reoxidant has obvious advantges in terms of efficiency and cost
relative to the use of Ag2CO3. An examination of different
aReaction conditions: ArB(OH)2 (1 mmol), Cu(OAc)2 (1 mmol),
1,10-phenanthroline (1.1 mmol), TMSCF3 (2 mmol), CsF (2 mmol),
˚
4 A mol sieves (250 mg/mmol ArB(OH)2), solvent (5 mL/mmol ArB-
(OH)2). bIsolated yields; average of 2 runs. c19F NMR yield, average of 2
runs with DCE as the solvent; chromatographically inseperable from
5% to 10% aryl chloride byproduct.
copper sources revealed that the use of Cu halides resulted in
the formation of significant quantities of aryl halide byproduct 3
(Table 1, entry 4). Even when using a copper source without a
halide counterion [e.g., Cu(OAc)2], a 5% yield of aryl chloride
was still observed, presumably due to halide transfer from the
dichloroethane solvent. As the separation of aryl chloride byprod-
uct from the desired trifluoromethylarenes was problematic, we
explored the use of a variety of nonchlorinated solvents. Of these,
isobutyronitrile (i-PrCN) proved best, providing a 67% yield of
benzotrifluoride product with no observed products of proto-
deboronation or chlorination (Table 1, entry 10).18
With optimal conditions in hand, we investigated the scope
of this transformation (Table 2). Electron-rich and -deficient
aryl boronic acids can be trifluoromethylated in moderate to
(18) Under all conditions examined, no ArCF2CF3 products were ob-
served.
J. Org. Chem. Vol. 76, No. 4, 2011 1175

Senecal et al.
JOCNote
good yields on both 1 mmol (Table 2) and 10 mmol scales
(eq 1). Arenes bearing substitution in the ortho position (2d, 2e,
2l, 2n, 2o) are typically difficult substrates for copper-mediated
cross-coupling processes.19 Thus, we were pleased that these
substrates provided the corresponding trifluoromethyl arenes
in good yield. We note that in some cases (2e), biaryl formation
via oxidative homocoupling of the aryl boronic acids is seen as a
byproduct.
Five- and six-membered heteroaryl boronic acids can also
be trifluoromethylated. Whereas unprotected indoles gave
poor results,20 both N-methyl (2j) and N-Boc (2n) indoles
were competent substrates. It should be noted that since five-
membered heteroaryl boronic acids substituted at the 2-
position are more prone to protodeboronation,21 ∼10-
20% heteroarene is also observed.
In contrast to other methods for benzotrifluoride synth-
esis, the mild conditions of this method provide a high level
of functional group tolerance. While aromatic iodides are
not compatible with the method, boronic acids bearing
chloro (2c) or bromo (2d) groups are acceptable substrates,
providing convenient handles for subsequent functionaliza-
tion processes. Substrates containing aldehydes or ketones
are problematic for many trifluoromethylation methods.
This is due to their tendency to undergo competitive 1,2-
addition of the trifluoromethyl anion to yield R-trifluoro-
methyl alcohols.22 While substrates bearing aldehyde moi-
eties were not viable for our method, a boronic acid bearing a
methyl ketone chemoselectively provided the trifluoro-
methylarene (2f). Although silyl protecting groups are ubi-
quitous in organic synthesis, high reaction temperatures in
conjunction with fluoride activators have prevented their use
in trifluoromethylation chemistry. The mild conditions of
our method allow for the efficient trifluoromethylation of
boronic acids containing a tert-butyldimethylsilyl-protected
phenol (2g) and an N-triisopropylsilyl-protected pyrrole
(2k).
Experimental Section
General Procedure for the Oxidative Trifluoromethylation of
Aryl Boronic Acids. To a test tube equipped with a magnetic stir
˚
bar was added 250 mg of 4 A powdered molecular sieves and
cesium fluoride (304 mg, 2.0 mmol, 2.0 equiv). The vessel was
sealed with a Teflon-lined septum, evacuated, and flame-dried
under vacuum until the sieves were fully activated. The test tube
was allowed to cool to room temperature, after which it was
backfilled with argon. To a separate vial was added 1,10-phenan-
throline (198 mg, 1.1 mmol, 1.1 equiv), copper(II) acetate (181 mg,
1.0 mmol, 1.0 equiv), and aryl boronic acid (1.0 mmol, 1.0 equiv).
The vessel was fitted with a Teflon-lined septum and subsequently
purged with argon. The contents of the vial containing the
copper(II) acetate, 1,10-phenanthroline, and aryl boronic
were quickly added to the test tube containing the sieves and
cesium fluoride. The test tube containing all solid reagents was
then evacuated and backfilled with oxygen gas (via balloon
fitted with a syringe and needle);this sequence was repeated a
total of three times. Solvent (5 mL) and TMSCF3 (0.3 mL,
2.0 mmol, 2.0 equiv) were then added to the reaction tube via
syringe, which was then placed under a balloon of O2 and was
stirred vigorously for the specified time. After the reaction was
complete, the reaction was filtered through a plug of Celite on
silica and eluted with diethyl ether (50 mL). 4-Fluorotoluene
(330 μL, 3 mmol) was added as an internal standard, and the
yield of the crude reaction was measured via 19F NMR. The
solution was then preadsorbed onto silica, dried in vacuo,
and purified via silica gel column chromatography to yield
the benzotrifluoride product. A representative example is as
follows.
1-Phenoxy-4-(trifluoromethyl)benzene (2a). 2a was obtanied
by following the general procedure with 214 mg of 4-phenoxyphe-
nylboronic acid and isobutyronitrile as the solvent. The reaction
was complete after 1 h of stirring and the product was purified by
column chromatography (silica gel, hexanes, visualized with UV
and KMnO4) to yield 1-phenoxy-4-(trifluoromethyl)benzene as a
1
colorless oil. (161 mg, 68%). H NMR (300 MHz, CDCl3) δ
7.66-7.55 (m, 2H), 7.48-7.36 (m, 2H), 7.25-7.17 (m, 1H),
7.12-7.02 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 160.7 (q, J =
1.4 Hz), 155.9, 130.3, 127.3 (q, J = 3.7 Hz), 125.0 (q, J = 32.7 Hz),
124.7 (s), 124.4 (q, J = 269.8 Hz), 120.2, 118.1. The complexity of
1H and 13C NMR spectra is due to 19F coupling. 19F NMR (282
MHz, CDCl3) δ -62.22. IR (neat, cm-1) 3066, 3043, 1618, 1591,
1514, 1491, 1247, 1168, 1123, 1066.
Acknowledgment. We thank the National Institutes of
Health for financial support of this project (Grant GM-
46059). T.S. thanks EMD Serono and the Martin Family
Society of Fellows for Sustainability for graduate fellow-
ships. A.P. is a Ruth L. Kirschstein Postdoctoral Fellow of
the National Institutes of Health (Grant 1F32GM093532)
for which he is grateful. The 300 MHz NMR instrument used
was supported by the National Science Foundation (NSF,
Grants CHE-9808061 and DBI-9729592).
In summary, we have developed a room temperature
method for the oxidative trifluoromethylation of aryl and
heteroaryl boronic acids. The mild reaction conditions allow
for high functional group compatibility previously unseen in
trifluoromethylation chemistry. Moreover, the ability to
conduct the reaction under typical benchtop conditions
and the use of oxygen as the stoichiometric reoxidant will
make this method of use to medicinal and academic chemists.
ꢀ
(19) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
Supporting Information Available: Detailed reaction pro-
tocols as well as spectral data of all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) No CF3H was observed upon oxidative trifluoromethylation of
unprotected indole boronic acids, suggesting that protonation of trifluoro-
methyl anion by the unprotected indole is not responsible for the low yield of
product.
(21) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132,
14073.
(22) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
Note Added after ASAP Publication. Reference 6 was
incomplete in the version published on 1/14/2011. This was
fixed in the version published on 1/28/2011.
1176 J. Org. Chem. Vol. 76, No. 4, 2011