Pd(II)-Catalyzed ortho-trifluoromethylation of arenes using TFA as a promoter

Article abstract of DOI:10.1021/ja909522s

"Chemical equation presented" A Pd(II)-catalyzed C-H activation/trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent using diverse heterocycle directing groups is reported. The presence of trifluoroacetic acid is crucial for this catalytic reaction.

Full text of DOI:10.1021/ja909522s

Published on Web 02/25/2010
Pd(II)-Catalyzed ortho-Trifluoromethylation of Arenes Using TFA as a
Promoter
Xisheng Wang,† Larry Truesdale,‡ and Jin-Quan Yu*,†
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
and Department of External R&D InnoVation, La Jolla Laboratories, Pfizer Inc., 10777 Science Center DriVe,
San Diego, California 92121
Received November 9, 2009; E-mail: yu200@scripps.edu
Scheme 1. Plausible Reaction Pathways for Trifluoromethylation
Fluorinated compounds possess unique physical properties that make
them indispensible for application as pharmaceuticals, agrochemicals,
and organic materials.1 In medicinal chemistry, for example, the
incorporation of CF3 groups into drug candidates often improves their
binding selectivity, lipophilicity, and metabolic stability.1b,2 Notably,
many biologically active aromatics, including the commercially
successful antidepressant Prozac and the herbicide Fusilade, contain
CF3 groups as the essential motif.3 As a consequence, the development
of new methods for the introduction of trifluoromethyl groups onto
aromatic rings has received intensive attention.4 Recent findings
concerning the stoichiometric and catalytic coupling of ArI with in
situ-generated CuCF35 provides an alternative to the century-old Swarts
reaction.6 Moreover, a single example of Pd(0)-catalyzed coupling of
ArI with CF3I using Zn power and a Pd(0) catalyst under ultrasonic
irradiation has also been reported.7 Generally speaking, the challenge
of developing cross-coupling reactions to forge carbon-CF3 bonds is
largely rooted in the inert nature of the metal-CF3 species.8 Herein
we report a Pd(II)-catalyzed arene trifluoromethylation reaction via
C-H activation.
Table 1. Pd(II)-Catalyzed C-H Trifluoromethylationa
entry
catalyst
additive (equiv)
oxidant (equiv)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
16d
17e
Pd(OAc)2
Pd(OAc)2
Pd(OTFA)2
Pd(OTFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
50
0
52
5
TFA (10)
On the basis of the three distinct modes of reactivity of ArPd(II)
species with nucleophiles,7 electrophiles9 and highly oxidizing re-
agents,10 we envisioned three possible reaction pathways (A, B, and
C, respectively) that could follow a C-H activation event to give the
trifluoromethylated products, as outlined in Scheme 1.
TFA (10)
AcOH (10)
TsOH (10)
TfOH (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
0
0
Although oxidation of Pd(II) to higher oxidation states by CF3+
has not been observed to date, the electrophilic trifluoromethylating
reagent 1a is known to react with carbon nucleophiles.11-13 Therefore,
it is also possible that ArPd(II) species generated from C-H activation
could react with 1a as an electrophile to give ArCF3 via path B. To
minimize possible complications in our exploratory studies, we selected
2-phenylpyridine (2a), for which cyclopalladation is known to be
robust, as the platform for screening the reaction conditions. Initially,
we found that the reaction of 2a with 10-20 mol % Pd(OAc)2 and 1
equiv of 1a under various conditions did not give observable amounts
of desired product (Table 1, entry 1). However, we were pleased to
find that the presence of 10 equiv of trifluoroacetic acid (TFA) in
dichloroethane (DCE) promoted the trifluoromethylation reaction,
giving the desired product 3a in 50% yield (entry 2). Notably, the
lack of reactivity with Pd(OTFA)2 alone suggests that the presence of
TFA is essential for the observed trifluoromethylation reaction (entries
3 and 4). Other acids such as AcOH, TsOH, and TfOH, on the other
hand, were not effective (entries 5-7).
Cu(OAc)2 (1)
Cu(OTFA)2 (1)
Cu(OTf)2 (1)
AgOAc (2)
Ag2CO3 (1)
Ag2O (1)
70
71
47
43
45
44
30
0
BQ (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
86
11
a Unless otherwise noted, the reaction conditions were as follows: 2a
(0.2 mmol), Pd(II) catalyst (0.02 mmol, 10 mol %), 1a (0.3 mmol, 1.5
equiv), DCE (1 mL), 110 °C, 48 h. b Isolated yield. c No Pd(OAc)2 was
added. d 1b was used instead of 1a. e 1c was used instead of 1a.
the vacant sites of Pd(II) or reduce Pd(II) to Pd(0). With these
considerations in mind, we began to test additives that we hypothesized
could act as both Lewis acids for sulfur and oxidants for Pd(0). We
found that the presence of copper(II) acetate significantly improved
the yield, while other oxidants proved ineffective (entries 11-14). A
control experiment showed that no trifluoromethylation product was
observed using Cu(OAc)2 in the absence of Pd(OAc)2 (entry 15). At
this stage, the role of Cu(OAc)2 remains to be elucidated.
To investigate effects of the counteranion in 1a, we performed the
trifluoromethylation of 2a with 5-(trifluoromethyl)dibenzothiophenium
tetrafluoroborate (1b) and found that the yield could be increased to
86% (entry 16). While the origin of this improvement remains to be
Although either pathway B or C would theoretically regenerate the
catalytically active Pd(II) species, the concomitant release of a sulfur-
containing compound (the sulfoxide formed from 1a was detected by
GC-MS) could be problematic in that this compound could occupy
† The Scripps Research Institute.
‡ Pfizer Inc.
9
3648 J. AM. CHEM. SOC. 2010, 132, 3648–3649
10.1021/ja909522s  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. C-H Trifluoromethylation of Pyridine Derivativesa b
Table 3. C-H Trifluoromethylation Using Diverse Heterocyclic
,
Directing Groupsa b
,
a Unless otherwise noted, the reaction conditions were as follows:
substrate (0.2 mmol), Pd(OAc)2 (0.04 mmol, 20 mol %), Cu(OAc)2 (0.2
mmol, 1.0 equiv), 1b (0.3 mmol, 1.5 equiv), TFA (2.0 mmol, 10 equiv),
DCE (1 mL), 110 °C, 48 h. b Isolated yield. c Pd(OAc)2 (10 mol %) was
used.
The use of TFA was found to be crucial for the success of this
Ar-CF3 bond-forming protocol, and Cu(OAc)2 was found to be
effective for enhancing the catalytic turnover. Subsequent studies
to apply this catalytic transformation to other broadly useful classes
of substrates are currently underway in our laboratory.
Acknowledgment. We gratefully acknowledge the National
Science Foundation (NSF CHE-0910014), The Scripps Research
Institute, and Pfizer for financial support and the Alfred P. Sloan
Foundation for a fellowship (J.-Q.Y.). We thank Dr. Abid Masood
for helpful discussions.
a Unless otherwise noted, the reaction conditions were as follows:
substrate (0.2 mmol), Pd(OAc)2 (0.02 mmol, 10 mol %), Cu(OAc)2 (0.2
mmol, 1.0 equiv), 1b (0.3 mmol, 1.5 equiv), TFA (2.0 mmol, 10 equiv),
DCE (1 mL), 110 °C, 48 h. b Isolated yield. c Pd(OAc)2 (15 mol %) was
used. d Pd(OAc)2 (20 mol %) was used.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
investigated, it appears that 1b exhibits stronger electrophilicity and
is thus more reactive with the ArPd(II) species. Trifluoromethylation
with Togni’s reagent (1c) under these optimized reaction conditions
gave only 11% yield (entry 17).
References
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With this newly established C-H trifluoromethylation protocol in
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presence of Cl in the products is very useful for further synthetic
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to give the desired products in less than 20% yield. The exclusive
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protocol (Table 3). The lack of reactivity when unsubstituted 2-phe-
nylpyrimidine was used as a substrate (to form the presumed product
4a) is likely due to the electron-withdrawing nature of the pyrimidine
group. Indeed, introduction of an electron-donating methyl or methoxy
group onto the biphenyl system allowed trifluoromethylation to proceed
effectively, giving the desired products in 58-88% yield (4b-e).
Furthermore, we were pleased to find that both imidazole (5) and
thiazole (6), two commonly encountered motifs in medicinal chemistry,
could also be used as directing groups for this C-H activation/
trifluoromethylation reaction.
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In summary, we have developed a new Pd(II)-catalyzed trifluo-
romethylation reaction of arenes through C-H functionalization.
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