Pd(II)-catalyzed ortho trifluoromethylation of arenes and insights into the coordination mode of acidic amide directing groups

Article abstract of DOI:10.1021/ja305259n

A Pd(II)-catalyzed trifluoromethylation of ortho C-H bonds with an array of N-arylbenzamides derived from benzoic acids is reported. N-Methylformamide has been identified as a crucial promoter of C-CF₃ bond formation from the Pd center. X-ray characterization of the C-H insertion intermediate has revealed a rare coordination mode of acidic amides as directing groups and the origin of their capacity in directing C-H activation.

Full text of DOI:10.1021/ja305259n

Communication
pubs.acs.org/JACS
Pd(II)-Catalyzed Ortho Trifluoromethylation of Arenes and Insights
into the Coordination Mode of Acidic Amide Directing Groups
Xing-Guo Zhang, Hui-Xiong Dai, Masayuki Wasa, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
coordination mode of acidic amides as effective directing
groups (eq 2).
ABSTRACT: A Pd(II)-catalyzed trifluoromethylation of
ortho C−H bonds with an array of N-arylbenzamides
derived from benzoic acids is reported. N-Methylforma-
mide has been identified as a crucial promoter of C−CF3
bond formation from the Pd center. X-ray characterization
of the C−H insertion intermediate has revealed a rare
coordination mode of acidic amides as directing groups
and the origin of their capacity in directing C−H
activation.
In the ortho trifluoromethylation of 2-phenylpyridine
substrates (eq 1),11 the strongly coordinating pyridyl group is
able to direct cyclopalladation in the presence of the
trifluoromethylating reagent 2a. However, dibenzo[b,d]-
thiophene released from reagent 2a can coordinate to the Pd
catalyst and prevent C−H activation when weakly binding
carboxyl and hydroxyl groups are used as directing groups. To
overcome this problem, we turned to a recently developed
acidic amide auxiliary with higher binding affinity than carboxyl,
which has been highly versatile in directing a diverse range of
sp2 and sp3 C−H activation reactions.13,14 We therefore began
to test whether N-arylbenzamide 1a could perform as a viable
substrate for the Pd-catalyzed ortho trifluoromethylation with
2a under suitable conditions. Following the previous conditions
for the trifluoromethylation of 2-phenylpyridines,11 1a was
treated with 2a in the presence of 1 equiv of Cu(OAc)2 and 10
equiv of TFA in 1,2-dichloroethane (DCE) at various
temperatures. Unfortunately, the trifluoromethylation of 1a
did not proceed under these conditions, presumably because of
the absence of a weak base, which was found to be essential for
the C−H activation of acidic N-arylbenzamides13,14 and
carboxylic acids.15 Noting that both inorganic and organic
bases, including N,N-dimethylformamide (DMF), were pre-
viously found to be effective in promoting Pd-catalyzed C−H
activation of benzoic acids,15b we tested various bases [see the
Supporting Information (SI)] and found that the trifluor-
omethylation proceeded in the presence of 15 equiv of DMF,
giving the desired product 3a in 23% yield (Scheme 1).
rifluoromethylated arenes are essential structural motifs in
T
a great number of pharmaceuticals, agrochemicals, and
organic materials.1,2 As a consequence, extensive efforts have
been recently directed toward the development of methods for
introducing trifluoromethyl groups onto arenes.3 To date, Pd-
or Cu-catalyzed/mediated cross-coupling reactions of aryl
halides4,5 or boronic acids6 with trifluoromethylating reagents
have been a major focus of study in this area. While direct
trifluoromethylation of heteroarenes via electrophilic substitu-
tion, the Minisci reaction, and deprotonation reactions have
been successfully developed,7,8 transition-metal-catalyzed tri-
fluoromethylation of aryl C−H bonds remains a largely
unsolved problem, presumably because of the slowness of
aryl/CF3 reductive elimination and a lack of ligands that are
mutually compatible for both the reductive elimination and C−
H activation steps.9,10
We recently reported the first example of Pd(II)-catalyzed
ortho trifluoromethylation of 2-phenylpyridines (eq 1) using
Scheme 1. DMF-Promoted Trifluoromethylation of 1a
Initial screening of the reaction parameters failed to improve
the yield. We surmised that the dibenzo[b,d]thiophene released
from 2a during the reaction could inhibit the C−H activation
and result in poor turnovers, and we therefore decided to
increase the amount of Cu(OAc)2 to scavenge the free
thiophene. We found that the reaction yield improved to
trifluoroacetic acid (TFA) and Cu(OAc)2 as crucial pro-
moters.11 In contrast to the broad substrate scope of other C−
H activation transformations using weakly coordinating
directing groups,12 the trifluoromethylation of synthetically
versatile arenes remains to be demonstrated. Herein we report
the Pd(II)-catalyzed trifluoromethylation of benzamides using
an N-alkylformamide as a crucial promoter. Moreover, the C−
H insertion intermediate of the benzamide was characterized by
X-ray crystallographic analysis, providing insights into the
Received: May 31, 2012
Published: July 11, 2012
© 2012 American Chemical Society
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Communication
57% with 2.0 equiv of Cu(OAc)2 (Table 1, entry 3). The
coordination of Cu(OAc)2 with 2a could also generate more
Cu(OAc)2 may play other roles in addition to being a
scavenger for the thiophene (Table 1, entries 14−18; also see
the SI). Although TFA was found to be essential for the
trifluoromethylation of 2-phenylpyridines,11 the absence of
TFA did not have a deleterious effect on the yield of 3a (entry
19). We also found that the counteranions in reagents 2b or 2a
do not have a significant impact on this reaction (entry 20). It is
worth noting that Togni’s reagent and TMSCF3 were
ineffective.
a
Table 1. Reaction Optimizations with Other Ligands
With these optimized conditions in hand, we surveyed the
substrate scope of the benzamides (Table 2). Arenes with o-
ab
,
Table 2. Pd-Catalyzed Ortho Trifluoromethylation
b
entry
additive (equiv)
Lewis acid (equiv)
yield (%)
1
2
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2)2 (2)
Cu(OAc)2 (2)
Cu(OTf)2 (2)
Cu(TFA)2 (2)
CuF2 (2)
NR
23
−
L1 (15)
3
L1 (15)
L2 (15)
L3 (15)
L4 (15)
L5 (15)
L6 (15)
L7 (15)
L8 (15)
L4 (10)
L4 (2)
57
4
61
5
75
6
79
7
72
8
21
9
trace
NR
64
10
11
12
13
14
15
16
17
18
22
L4 (0.2)
L4(15)
24
28
L4 (15)
L4 (15)
L4 (15)
L4 (15)
L4 (15)
L4 (15)
34
64
Yb(OTf)3 (2)
−
Cu(OAc)2 (2)
NR
trace
57
c
19
d
20
Cu(OAc)2 (2)
65
a
Conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd(OAc)2 (10 mol %),
b
c
TFA (1 mmol), DCE (3 mL), 130 °C, 24 h. Isolated yields. Without
TFA. 2b was used.
d
+
reactive CF3 species and promote trifluoromethylation. To
improve the yield further, various amide additives L1−L8 were
tested. The N-monoalkylated amides significantly improved the
yield of the trifluoromethylation reaction (entries 5−7). When
15 equiv of N-methylformamide (L4) was used, the product 3a
was isolated in 79% yield (entry 6). Subsequent investigation of
the formamides showed that the yield decreased when bulkier
amides were used (entries 7 and 8). Additionally, trifluor-
oacetamide L7 and carbamate L8 were ineffective and did not
provide the desired product (entries 9 and 10). The sensitive
dependence of the reaction on the structure of the formamide
additives is suggestive of their role as a ligand in addition to
their action as a base. Consistent with this hypothesis, a
catalytic amount of L4 (0.2 equiv) was sufficient to promote
the trifluoromethylation, albeit giving lower yields (entries 11−
13).
a
Conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)2 (10 mol %),
Cu(OAc)2 (0.2 mmol), TFA (1 mmol), L4 (1.5 mmol), DCE (3 mL),
b
c
130 °C, 24 h. Isolated yields are shown. 2a (0.2 mmol) for 48 h.
and m-methyl substitution gave yields of 84 and 94%,
respectively (3b and 3c), whereas the p-methyl-substituted
arene afforded a lower yield of 53% (3d). Similar results were
obtained for MeO-substituted arenes (3e and 3f). The
reactions of tert-butyl- and phenyl-substituted arenes afforded
the desired products in 77 and 67% yield, respectively (3g and
3h). Trifluoromethylation of fluoro-, chloro- and bromoarenes
proceeded smoothly to give their corresponding products in
Removing Cu(OAc)2 or replacing it with the Lewis acid
Yb(OTf)3 resulted in loss of reactivity, indicating that
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40−82% yields (3i−n). The presence of strongly electron-
withdrawing CO2Me and CF3 groups at the para position
reduced the yield to 55% (3o) and 32% (3p), respectively.
Trifluoromethylation of trisubstituted arenes gave tetrasub-
stituted arenes in good yields (3q and 3r). Highly selective β-
trifluoromethylation of a naphthalene-based substrate gave the
product in 75% yield (3s).
To elucidate the origin of the reactivity of the amide auxiliary
for C−H activation under the trifluoromethylation conditions,
we decided to investigate how the amide substrate coordinates
to the Pd(II) center. Following our previous study of the
coordination mode of sodium carboxylate 4,15 we anticipated
that we would be able to identify an analogous C−H insertion
intermediate 5 that could be formed directly from precursor 6.
It is reasonable to postulate that precursor 6 is more reactive
than 7, as the former could achieve a minimum dihedral angle
between the C−H and Pd−OAc bonds with less entropic cost
because of the geometry of the imine moiety. Although we
could not observe the formation of 5, we were able to obtain
the analogous alkali amidate 8 in the presence of counter-
cations. Thus, treatment of benzamide 1a with 1.5 equiv of
Pd(OAc)2 and 2 equiv of CsF in DCE at 130 °C with or
without L4 afforded arylpalladium complex 8 as a yellow
powder in 99% yield (Scheme 2). The X-ray structure of
nitrogen atom in 7 is involved in directing C−H activation,
which could account for the superior reactivity of acidic amide
substrates compared to simple amides.
To test the viability of complex 8 to undergo trifluor-
omethylation, we conducted a series of experiments that shed
light to the importance of Cu(OAc)2 and L4 in this reaction.
The reaction of 8 with 2a in the absence of L4 or Cu(OAc)2
was sluggish and gave less than 5% yield of the desired product
3a. In contrast, trifluoromethylation of 8 with 2a in the
presence of L4 and Cu(OAc)2 gave the desired product in 45%
yield (Scheme 2), suggesting that both L4 and Cu(OAc)2 are
crucial for the C−CF3 bond-forming step. The moderate yield
is not surprising considering that the preformed dimer is
perhaps not as reactive as the monomer generated in situ in the
presence of L4.
The detailed redox chemistry involved in the C−CF3 bond-
forming step remains to be investigated. On the basis of the
observed stoichiometric oxidation of [(bzq)Pd(OAc)]2 (bzq =
benzo[h]quinoline) to the corresponding Pd(IV) species by
16
+
+
CF3 , the reaction of 8 with CF3 could proceed through a
Pd(II)/Pd(IV) pathway with L4 as the enabling ligand
(Scheme 3). However, an electrophilic cleavage pathway that
Scheme 3. Redox Chemistry for C−CF3 Bond Formation
Scheme 2. Coordination Mode of Acidic Amides
proceeds on a Pd(II) center cannot be ruled out, in view of the
fact that the oxidation of Pd(II) to Pd(IV) is less facile with
weakly coordinating substrates.
In summary, we have developed a Pd(II)-catalyzed
trifluoromethylation of N-arylbenzamides derived from readily
available benzoic acids. N-Methylformamide has been identified
as a crucial promoter of C−CF3 bond formation from the Pd
center. A rare X-ray structure of the C−H insertion
intermediate has provided valuable insight into the coordina-
tion mode of acidic amides and the possible origin of their
power in directing C−H activation.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
complex 8 showed that the acidic amide forms a cesium
amidate that coordinates to the Pd(II) center via the imine
moiety (Figure 1). The structure of 8 is consistent with our
hypothesis that the sp2-nitrogen atom in 6 instead of sp3
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute, the
U.S. NSF (CHE-1011898), and Novartis for financial support.
X.-G.Z. is a visiting scholar from Wenzhou University and was
sponsored by the China Scholarship Council and the National
Natural Science Foundation of China (21002070).
Figure 1. ORTEP diagram of Pd(II) complex 8. Thermal ellipsoids are
drawn at 50% probability, and H atoms have been omitted for clarity.
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