Palladium(II)-catalyzed selective monofluorination of benzoic acids using a practical auxiliary: A weak-coordination approach

Article abstract of DOI:10.1002/anie.201102985

Finally, a choice! A highly selective palladium(II)-catalyzed ortho-monofluorination reaction has been achieved for the first time through a weak coordination (see scheme; Ar=2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl) . Simple modification of this protocol allows for a choice between mono- and difluorination. The mono- and difluorinated benzoic acid derivatives are valuable in the pharmaceutical and agrochemical industries. Copyright

Full text of DOI:10.1002/anie.201102985

DOI: 10.1002/anie.201102985
À
C H Fluorination
Palladium(II)-Catalyzed Selective Monofluorination of Benzoic Acids
Using a Practical Auxiliary: A Weak-Coordination Approach**
Kelvin S. L. Chan, Masayuki Wasa, Xisheng Wang, and Jin-Quan Yu*
Transition-metal-catalyzed carbon–fluorine bond-forming
reactions have been extensively studied because of the
significant demand for versatile, mild, and regioselective
methods to prepare fluorinated organic compounds, espe-
cially fluorinated arenes, which are valuable in pharmaceut-
ical and agrochemical industries.[1,2] In addition to conven-
tional electrophilic aromatic substitution reactions, fluorina-
tion reactions of aryl silicon, aryl boron, and aryl tin reagents
using electrophilic fluorine sources mediated or catalyzed by
transition metals have emerged as useful methods to prepare
fluorinated arenes.[3–10] Notably, the Pd0-catalyzed displace-
ment of the leaving groups in aryl bromides and aryl triflates
by the nucleophilic fluoride anion has also been demonstrated
recently.[11] However, the development of methods to directly
There are two major obstacles for developing reactions of this
À
type. First, directed palladation of C H bonds is significantly
inhibited by the fluorinating reagents. It has been proposed
that the supporting pyridine ligand of the fluorinating
reagents either competes with the directing group for the
binding site at the PdII center, or the electrophilic fluorine
atom could complex with the Lewis basic directing group and
weaken its ability to bind to the PdII center. Second, the use of
À
Pd(OAc)2, which is a broadly useful catalyst for C H
functionalization, would lead to the formation of a PdIV
+
À
À
species following C H activation and oxidation with F ; C
OAc reductive elimination of this {PdIV(OAc)(F)} species
À
outcompetes the relatively slow C F reductive elimina-
tion.[15–18] To address the first problem, Sanford and co-
workers employed a strongly coordinating pyridine directing
group to ensure cyclometalation with 2-phenylpyridines.[12]
We had previously devised an X-type (Scheme 1) anionic
À
fluorinate unactivated aryl C H bonds has met with limited
À
success; only two examples of directed ortho C H fluorina-
tion have been reported to date.[12,13] In both of these cases,
the formation of a mixture of inseparable mono- and
difluorinated arenes is often problematic for practical appli-
cations. Herein, we report the ortho fluorination of an
important class of broadly useful benzoic acid substrates
using a readily removable acidic amide as the auxiliary
[Eq. (1); OTf = trifluoromethanesulfonyl]. Either mono- or
Scheme 1. Proposed mechanism for difluorination using an X-type
directing group.
difluorinated arenes can be obtained in a highly selective
manner by tuning the reaction conditions.
À
While a number of Pd-catalyzed electrophilic C H
halogenation reactions of synthetically useful substrates
triflamide directing group to avoid direct competition with
the pyridine moieties of the fluorinating reagents.[13] In
addition, we used Pd(OTf)2 as the catalyst to ensure selective
have been developed,[14] a practical protocol for catalytic C
H fluorination using electrophilic fluorine remains elusive.
À
À
À
C F reductive elimination instead of C OAc reductive
elimination. It should also be noted that a redox-neutral
PdII/PdII electrophilic cleavage pathway instead of a PdII/PdIV
catalytic pathway could be operating with these weakly
coordinating substrates.
[*] K. S. L. Chan, M. Wasa, Dr. X. Wang, Prof. Dr. J.-Q. Yu
Department of Chemistry
The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Homepage: http://www.scripps.edu/chem/yu
Although triflamides can be converted into other func-
tional groups to meet synthetic needs, the necessity for the
presence of ortho or meta substitution to prevent difluorina-
tion is a significant limitation of the approach. The formation
of the difluorination product is probably due to the slow
displacement of the X-type monofluorinated product at-
tached to the PdII center by the substrate. The use of a
strongly coordinating L-type directing group such as pyridine
caused similar problems.[12] We envisioned that the use of our
recently developed weakly coordinating L-type acidic
[**] We gratefully acknowledge TSRI and the US NSF (NSF CHE-
1011898), Amgen, and Eli Lilly for financial support. We thank the
A. P. Sloan Foundation for a fellowship (J.-Q.Y.), the Agency for
Science, Technology and Research (A*STAR) Singapore for a
predoctoral fellowship (K.C.), and Bristol Myers Squibb for a
predoctoral fellowship (M.W.). TSRI Manuscript no. 21264.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102985.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9081

Communications
amide[19] could allow for the rapid displacement of the
Having optimized the directing group, we subsequently
carried out an extensive survey of reaction conditions using
substrate 2 (Table 1). Among the solvents examined, only
monofluorinated product by the substrate, thereby affording
monoselectivity (Scheme 2). At this stage, the X-type coor-
dination mode of these acidic amides cannot be ruled out and
extensive investigations are being carried out in our labo-
ratory.
Table 1: Optimization of the reaction conditions.[a]
Entry
Solvent
T [8C]
t [h]
F+
Yield [%][b]
2 [%][c]
2a
2b
1
2
3
PhCF3
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
120
120
120
120
120
80
100
120
120
120
120
120
120
120
2
2
2
2
2
2
2
0.5
1
2
2
2
2
F1
F1
F1
F1
F1
F1
F1
F1
F1
F1
F2
F3
F4
F5
16
15
82
50
76
60
73
50
66
79
63
34
70
60
53
42
5
0
8
0
1
1
1
13
2
0
0
0
18
8
11
16
9
39
25
49
33
8
27
66
30
40
Scheme 2. Three possible coordination modes.
4[d]
5[e]
6
With these considerations in mind, we initiated our study
on the ortho fluorination of benzoic acid derivatives by
carrying out a systematic tuning of the directing group
(Scheme 3). Starting materials were fully recovered when
7
8
9
10[f]
11
12
13
14
2
[a] Reaction conditions: 0.1 mmol of substrate, 10 mol% of [Pd(OTf)2-
(MeCN)4], 20 mol% of NMP, 1.5 equiv of F+ reagent, 2 mL of solvent,
1
N2. [b] Yield was determined by H NMR analysis of the crude reaction
mixture in CDCl3 using CH2Br2 as the internal standard. [c] Recovered
starting material 2. [d] Pd(OAc)2 was used. [e] No NMP was added.
[f] 3.0 equiv of F1 was used. Ar=2,3,5,6-tetrafluoro-4-(trifluoromethyl)-
phenyl.
PhCF3, EtOAc, and MeCN gave the fluorinated products 2a
and 2b in respectable yields (entries 1–3). We found that the
use of MeCN as the solvent was essential for obtaining high
monoselectivity (entry 3). This observation is consistent with
the hypothesis that the acidic amide acts as an L-type
directing group, and MeCN serves as a spectator ligand that
can displace the relatively weakly coordinated L-type product
from the PdII center to avoid a second fluorination (Schemes 1
and 2). When Pd(OAc)2 was used as the catalyst, undesired
ortho-acetoxylated products were consistently observed in
10–15% yields by 1H NMR spectroscopy (entry 4), however,
this could be prevented by using [Pd(OTf)2(MeCN)4]
(entry 3). The presence of a catalytic amount of N-methyl-2-
pyrrolidinone (NMP) slightly improved the yield from 76 to
82% of the monofluorinated product 2a (entries 5 and 3).
The reaction temperature could be lowered from 1208C
(entry 3) to 80 and 1008C (entries 6 and 7) to afford 2a
exclusively, albeit in lower yields. A gradual increase in the
conversion was observed with an increase in reaction time
(entries 8 and 9). Attempts to further improve the conversion
by prolonging the reaction time resulted in the formation of
Scheme 3. Systematic tuning of the directing group. The reaction
conditions used were: 0.1 mmol of substrate, 10 mol% of [Pd(OTf)2-
(MeCN)4], 20 mol% of NMP, 1.5 equiv of N-fluoro-2,4,6-trimethylpyr-
idinium triflate (F1), 2 mL of MeCN, 1208C, N2, 8 h. The yield was
determined by H NMR analysis of the crude reaction mixture in CDCl3
using CH2Br2 as the internal standard. NMP=N-methyl-2-pyrrolidi-
none, SM=starting material.
1
simple benzoic acid or N-phenylbenzamide were used as
substrates. However, it was found that when the acidic amide
N-2,6-difluorophenylbenzamide was treated with N-fluoro-
2,4,6-trimethylpyridinium triflate (F1) and [Pd(OTf)2-
(MeCN)4] (10 mol%) in MeCN at 1208C the desired mono-
fluorinated product was obtained in 50% yield. No fluorina-
tion took place in the absence of the Pd catalyst. The yields
were further improved to 84% when the acidity of the amides
was increased (Scheme 3). Most importantly, only less than
5% of the difluorinated product was formed, thus providing a
useful method for selectively introducing the fluorine atom at
the ortho position.
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more difluorinated product 2b and poorer mass balance (see
the Supporting Information). Increasing the amount of the F+
source (F1) from 1.5 to 3 equivalents resulted in higher
conversion but inferior monoselectivity (entry 10). We also
screened for other F+ sources (entries 11–14), and found that
F1 provided the best result; notably the less-expensive
fluorinating reagent Selectfluor F4 gave a respectable 70%
yield of 2a (entry 13).
With the optimized reaction conditions established, we
converted a wide variety of commercially available benzoic
acids into the corresponding N-arylbenzamides to examine
the scope of the fluorination protocol (Scheme 4). A range of
different functional groups on the aromatic ring were
tolerated, albeit in various product yields. Generally, a shorter
reaction time was required in the presence of electron-
donating alkyl and alkoxy substituents (2a, 3a, 4a, and 6a)
and resulted in improved yields. The presence of a methoxy
group led to substantial loss of material; gratifyingly, the
monofluorinated product 5a was obtained in 54% yield by
carrying out the reaction at 1008C for 24 h. Substrates
containing electron-withdrawing substituents and/or strongly
coordinating heteroatoms, such as acetoxy, acetyl, cyano,
halo, and trifluoromethyl substituents (1b, 7a–16a), required
longer reaction times and gave compromised yields. Only a
trace amount of the difluorinated products was obtained, if
any (see the Supporting Information). The difficulty in the
chromatographic separation of the starting material, mono-
fluorinated product, and the trace amount of difluorinated
product resulted in reduced yields upon isolation. Chloro and
bromo substitution at the ortho, meta, and para positions were
tolerated (8a–12a), and these products could serve as
valuable synthons for further elaboration.
To obtain the difluorinated products, we screened reaction
conditions to minimize the presence of monofluorinated
products, and thus facilitate the purification process. We
found that fluorination in PhCF3 with 3 equivalents of F1 at
1208C for 2 h afforded the desired difluorinated products in
good yields, accompanied by less than 5% of the correspond-
ing monofluorinated products, as observed by 1H NMR
spectroscopy (Scheme 5).
Scheme 5. Difluorination of benzamides. The reaction conditions used
were: 0.1 mmol of substrate, 10 mol% of [Pd(OTf)2(MeCN)4],
50 mol% of NMP, 3.0 equiv of N-fluoro-2,4,6-trimethylpyridinium tri-
flate (F1), 1 mL of PhCF3, 1208C, N2, 2 h. The yield is of the isolated
products. Ar=2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl.
It merits mentioning that 4-aminoheptafluorotoluene,
which is used for the preparation of the N-arylbenzamide
substrates, can be readily prepared by treating inexpensive
octafluorotoluene with ammonium hydroxide in 1,4-dioxane,
or purchased from commercial sources [Eq. (2)]. After the
PdII-catalyzed selective monofluorination of the N-arylbenz-
amides, base-catalyzed hydrolysis of the amides readily
Scheme 4. Monofluorination of benzamides. Unless otherwise speci-
fied the reaction conditions used were: 0.1 mmol of substrate,
10 mol% of [Pd(OTf)2(MeCN)4], 20 mol% of NMP, 1.5 equiv of N-
fluoro-2,4,6-trimethylpyridinium triflate (F1), 2 mL of MeCN, 1208C,
N2, 24 h. The yield is of the isolated products. [a] The reaction was
carried out for 8–12 h. [b] The reaction was carried out for 2–3 h.
[c] The reaction was carried out at 1008C for 2 h. [d] The reaction
carried out at 1008C. [e] 1 mL of PhCF3 was used as the solvent,
50 mol% of NMP was used and the reaction was carried out for 2 h.
Ar=2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl.
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Communications
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In summary, we have developed a highly selective PdII-
catalyzed ortho-monofluorination protocol for benzoic acids
using a practical N-arylamide auxiliary. This reaction protocol
has allowed us to prepare both mono- and difluorinated
benzoic acid derivatives, which are of tremendous importance
in the pharmaceutical and agrochemical industries. Studies to
expand the scope of this reaction to simple carboxylic acid
substrates without using auxiliaries are currently ongoing in
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Received: April 30, 2011
Published online: July 11, 2011
À
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Keywords: auxiliaries · benzoic acids · C H activation ·
fluorination · weak coordination
.
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