Pd-catalyzed C-H oxygenation with TFA/TFAA: Expedient access to oxygen-containing heterocycles and late-stage drug modification

Article abstract of DOI:10.1002/anie.201207458

Functionalized phenols are valuable industrial chemicals related to pharmaceuticals, agrochemicals, and polymers. Therefore, the direct catalytic hydroxylation of arenes to produce phenols has attracted much attention. Although tremendous progress has been made in this field, there are still difficult substrates which remain unmet challenges for direct hydroxylation in terms of regio- and chemoselectivity, as well as the practicality of current methods (Scheme 1). For example, 2-hydroxy aromatic ketones are useful synthetic intermediates for the preparation of various oxygen-containing heterocycles such as benzofuranone, chromanone, benzoxazole, and dibenzooxazepine; they also serve as key building blocks for drugs such as celiprolol, acebutolol, and propafenone. Traditional strategies for accessing 2-hydroxy aromatic ketones have mainly involved the oxidation of benzylic alcohols, the hydrolysis of aromatic halides, Fries rearrangement of esters or the demethylation of methyl phenyl ether. These methods generally suffer from one limitation or another, such as tedious reaction procedures, harsh reaction conditions, low yields, or the formation of side products. Hence, direct transformation of readily available aromatic ketones into valuable 2-hydroxylated products by transition metal-catalyzed C-H functionalization is arguably a highly efficient and atom-economic method to access these compounds. Moreover, developing a more general strategy for the regio- and chemoselective C-H oxygenation of a variety of challenging arenes would be especially desirable for phenol synthesis (Scheme 1).

Full text of DOI:10.1002/anie.201207458

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Communications
DOI: 10.1002/anie.201207458
Catalytic Hydroxylation
À
Pd-Catalyzed C H Oxygenation with TFA/TFAA: Expedient Access
to Oxygen-Containing Heterocycles and Late-Stage Drug Modifica-
tion**
Gang Shan, Xinglin Yang, Linlin Ma, and Yu Rao*
Dedicated to Professor Geert-Jan Boons on the occasion of his 50th birthday
Functionalized phenols are valuable industrial chemicals
related to pharmaceuticals, agrochemicals, and polymers.[1]
Therefore, the direct catalytic hydroxylation of arenes to
produce phenols has attracted much attention. Although
tremendous progress has been made in this field, there are
still difficult substrates which remain unmet challenges for
direct hydroxylation in terms of regio- and chemoselectivity,
as well as the practicality of current methods (Scheme 1). For
products. Hence, direct transformation of readily available
aromatic ketones into valuable 2-hydroxylated products by
À
transition metal-catalyzed C H functionalization is arguably
a highly efficient and atom-economic method to access these
compounds. Moreover, developing a more general strategy
À
for the regio- and chemoselective C H oxygenation of
a variety of challenging arenes would be especially desirable
for phenol synthesis (Scheme 1).
À
In the last decade, C H bond activation catalyzed by the
weak coordination of transition metals,[6,7] especially palla-
dium,[8] for the synthesis of aromatic and heteroaromatic
compounds has proven to be highly selective and atom
economical. In our continuous studies of preparing function-
alized phenols, we envisioned that palladium(II) catalysts,
À
under the proper acidic conditions, could allow C H bond
cleavage by an ortho-metalation process through weak
coordination with the carbonyl oxygen of aryl ketones,
benzoates, benzamides, or even the sulfonyl oxygen of
sulfonamides.[9,10] Consequently, in theory, a C O bond
À
formation is possible by reductive elimination to afford the
corresponding phenols with suitable acids[11] (Scheme 1). To
the best of our knowledge, the direct catalytic ortho-
hydroxylation of aryl ketones, benzoates, benzamides, aceta-
nilides, and sulfamides with a mixture of trifluoroacetic acid
and trifluoroacetic anhydride (TFA/TFAA) and palla-
Scheme 1. A new general approach to functionalized phenols.
example, 2-hydroxy aromatic ketones are useful synthetic
intermediates for the preparation of various oxygen-contain-
ing heterocycles such as benzofuranone, chromanone, ben-
zoxazole, and dibenzooxazepine; they also serve as key
building blocks for drugs such as celiprolol, acebutolol, and
propafenone. Traditional strategies for accessing 2-hydroxy
aromatic ketones have mainly involved the oxidation of
benzylic alcohols,[2] the hydrolysis of aromatic halides,[3] Fries
rearrangement of esters[4] or the demethylation of methyl
phenyl ether.[5] These methods generally suffer from one
limitation or another, such as tedious reaction procedures,
harsh reaction conditions, low yields, or the formation of side
dium(II) has not yet been achieved. Herein, we report the
II
À
first example of Pd -catalyzed regioselective C H oxygen-
ation of these substrates and its convenient application to the
synthesis of oxygen-containing heterocycles and late-stage
drug modification. Of particular note, it was found that the
reaction can actually be effectively performed at room
temperature. Our preliminary mechanistic study discovered
the dual role of TFA/TFAA as both the oxygen source and the
À
essential factor for C H activation.
To test our hypothesis, we initiated a model study with
aromatic ketone 1 in the presence of Pd(OAc)2 in AcOH/
Ac2O solvent system with PhI(OAc)2 as the terminal oxidant
(Ac = acetyl; Table 1). However, neither acetoxylated nor
hydroxylated products were formed. After many unsuccessful
attempts, we turned our attention to more acidic systems, such
as TCA/TCAA (TCA = trichloroacetic acid) and TFA/
TFAA. To our delight, the phenol product 2 was observed
in less than 10% yield with TCA/TCAA (entry 2) and 32%
yield with TFA/TFAA after stirring for 10 h at 1008C
[*] G. Shan, X. Yang, L. Ma, Prof. Dr. Y. Rao
Department of Pharmacology and Pharmaceutical Sciences
School of Medicine and School of Life Sciences
Tsinghua University, Beijing, 100084 (China)
E-mail: yrao@mail.tsinghua.edu.cn
[**] This work was supported by a national “973” grant
(2011CB965300), an NSFC grant (21142008), Tsinghua University
985 Phase II funds, and the Tsinghua University Initiative Scientific
Research Program. TFA=trifluoroacetic acid, TFAA=trifluoroace-
tic anhydride.
(entry 3). This initial result suggests that PdII catalyzed C H
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207458.
activation, with the carbonyl oxygen of aryl ketones as an
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Table 1: Optimization of the reaction conditions.
Entry Oxidant[a]
Conditions[b]
Yield[c]
[%]
1
2
3
4
5
6
7
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
Cu(OAc)2
BQ
pyridine, AcOH/Ac2O, 1008C, 10 h
TCA/TCAA, 1008C, 10 h
TFA/TFAA, 1008C, 10 h
TFA/TFAA, 1008C, 10 h
TFA/TFAA, 1008C, 10 h
TFA/TFAA, 1008C, 10 h
TFA/TFAA, 1008C, 10 h
NR
<10
32
NR
NR
trace
9
oxone
benzoyl
peroxide
tert-butyl
peroxide
NFSI
selectfluor
selectfluor
selectfluor
PhI(OAc)2
8
TFA/TFAA, 1008C, 10 h
NR
9
TFA/TFAA, 1008C, 10 h
TFA/TFAA, 1008C, 3 h
TFA/TFAA, 1008C, 3.5 h
pyridine, TFA/TFAA, 1008C, 4 h
TFA/TFAA, 1008C, 4 h
56
10
11
12
13
14
15
16
17
18
61 (77)[d]
80
77
60
32
76
75
76
46
PhI(CF3CO2)2 TFA/TFAA, 1008C, 4 h
K2S2O8
K2S2O8
K2S2O8
K2S2O8
pyridine, TFA/TFAA, 1008C, 4 h
TFA/TFAA, 1008C, 4 h
TFA/TFAA, 1008C, 3 h
[PdCl2(MeCN)2], TFA/TFAA, 1008C,
2 h
Scheme 2. Regio- and chemoselective hydroxylation of aryl ketones.
Reactions conducted at room temperature. Yields shown are of
isolated products. Data in parentheses are yields from reactions
conducted at room temperature.
19
20
21
K2S2O8
K2S2O8
K2S2O8
[PdCl2(PPh3)2], TFA/TFAA, 1008C, 2 h 40
Pd(CO2CF3)2, TFA/TFAA, 1008C, 2 h 61
[Pd(acac)2], TFA/TFAA, 1008C, 2 h
46
[a] 1.1 equiv of oxidant were used. [b] In all cases a 9:1 ratio of acid to
anhydride was used. [c] Yield of isolated product. [d] Conversion is
shown in parentheses. Ac=acetyl, acac=acetylacetonate, BQ=1,4-
benzoquinone, NSFI=N-fluorobenzenesulfonimide, NR=no reaction,
TCA=trichloroacetic acid, TFA=trifluoroacetic acid, TFAA=trifluoro-
acetic anhydride.
para substituents, as well as electron withdrawing and
electron donating functional groups (such as halides, esters,
amides, aldehydes, alkyl, nitro, and methoxy groups) were
well tolerated. For unsymmetrical diaryl ketone substrates,
the more electron-rich parts were preferentially hydroxylated
(5, 9, 10). In some cases, dihydroxylated products (4b, 6c)
were also obtained in minor amounts. To our delight, when
ketones containing easily oxidizable a-protons were tested, it
was found that these ketones can also be transformed into
hydroxylated products (22–34) with remarkable chemoselec-
tivity. These phenols are either difficult to prepare or require
tedious additional steps with traditional methods. During our
investigation, it was noticed that many substrates can be
facilely transformed into products at 50–608C in a short
period of time (3–4 h), which caused us to wonder if the
reactions could be run at room temperature. Surprisingly, our
test results showed that aryl ketone substrates can be
converted into the desired phenol products at ambient
temperature (Scheme 2), albeit over a longer reaction time
(typically 24–48 hrs). To the best of our knowledge, this is the
effective coordinating group, could happen under certain
acidic conditions. Apparently, the strong acidity of TFA
played a key role in this reaction. Encouraged by these
preliminary results, we began to optimize the reaction
conditions. After extensive testing, we found that select-
fluor[12] and K2S2O8[13] were superior to other oxidants. It was
found that a high ratio of TFAA will significantly slow down
the speed of the reaction and that a ratio of TFA/TFAA of
around 9:1 is most suitable for the reaction. There are only
slight differences with the addition of ligands such as pyridine
in terms of reaction rates and conversion ratios. Some other
PdII catalysts were tested in the reaction as well, such as
[PdCl2(MeCN)2], [PdCl2(PPh3)2], Pd(CF3CO2)2, and [Pd-
(acac)2] (acac = acetylacetonate), but were not as efficient
as Pd(OAc)2. Generally, 0.05 equiv of Pd(OAc)2 was enough
to effectively promote the reaction. It was also noted that the
reaction time can actually be shortened, the reaction typically
proceeds to completion within 3–4 h at 908C.
À
only example of a phenol synthesis by Pd-catalyzed C H
activation that has been accomplished at room temperature.
Some substrates, such as ketones containing reactive
a-protons (24–27), produced better yields at room temper-
ature than at higher temperature. More intriguingly, dioxy-
benzone (36), an organic compound widely used in sunscreen
to block UVB and short-wave UVA rays,[14] was readily
prepared by our new method at room temperature without
the need to protect the free hydroxy group of 35, which
supports both the practicality and effectiveness of this novel
With these optimized conditions in hand, we next set out
to explore the scope of this new reaction. As displayed in
Scheme 2, a variety of aromatic ketones were smoothly
transformed into the corresponding phenol products in
moderate to excellent yields. The scope of the substituents
was found to be very broad. Aryl groups with ortho, meta, and
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approach. Moreover, this reaction was conducted without the
need for air-and water-free conditions [Eq. (1)].
Subsequently, the reaction conditions were applied to
other substrates, including benzoates, benzamides, acetani-
lides, and sulfonamides. As displayed in Scheme 3, we were
Scheme 4. Transformations of 2-hydroxy aromatic ketones into various
oxygen-containing heterocycles. Conditions: a) benzaldehyde, NaOH,
EtOH, RT, 12 h, 72%; I2, DMSO, reflux, 1 h, 85%. b) Benzaldehyde,
NaOH, EtOH, RT, 12 h, 72%; AcOH, reflux, 144 h, 80%. c) Tf2O,
pyridine, CH2Cl2, À788C–RT, 2 h, 83%; DBU, DMF, 0.2 h, 81%;
d) KOH, H2O, 1008C, 15 h, 95%; e) CuOAc, K2CO3, 8-hydroxyquinoline,
O2, DMA, 1408C, 24 h, 60%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DMA=dimethylacetamide, DMF=dimethylformamide, DMSO=dime-
thylsulfoxide, Tf=trifluoromethanesulfonyl.
Scheme 5. Regio- and chemoselective modification of ibuprofen.
[a] %conversion.
Scheme 3. Benzoate, benzamide, acetanilide, and sulfonamide as sub-
strates. Yields shown are of isolated products. Pr=propyl.
very pleased to find that these three types of compounds were
successfully transformed into the corresponding phenol
products in modest to good yields. For sulfonamides in
particular, this is the first time that these compounds have
been directly converted into ortho-hydroxylated sulfona-
mides, which can serve as valuable synthetic intermediates
for quick access to analogues of the billion-dollar drug
tamsulosin.[15]
Further investigations were performed to gain some
insight into the reaction mechanism, which is shown in
Scheme 6. The result of parallel competition experiments
À
To demonstrate the synthetic utility of this C H oxygen-
ation reaction, a variety of biologically important oxygen-
containing heterocyclic compounds were prepared from
2-hydroxylated aryl ketone products. As shown in Scheme 4,
chromanone 48, benzofuran-3(2H)-one 50, and benzoxazole
derivatives, as well as more challenging heterocycles such as
xanthone 49 and dibenzooxazepine can be readily accessed
from the corresponding 2-hydroxylated ketones using known
transformations.[16]
Scheme 6. Separate rate constants and KIE studies. Conditions for all
À
reactions shown: PdII, TFA/TFAA, K2S2O8.
Late-stage modification of drug candidates by C H
activation is a particularly attractive approach for modern
drug discovery, which greatly depends on the practicality of
such chemical processes. Therefore, in Scheme 5 we show the
feasibility of our new reaction by performing direct regio- and
surely shows that the electron-rich aromatic ring reacts much
faster than its electron-poor counterpart (14/17 6:1). Further-
more, consistent and significant KIE values were observed
from both intra- (kH/kD = 5.6) and intermolecular (kH/kD = 5.0
À
chemoselective C H oxygenation of ibuprofen ethyl ester 52
(a representative nonsteroidal anti-inflammatory drug),
which can provide a new approach to prepare novel ibuprofen
analogues. As aromatic ketones, esters, amides, and sulfona-
mides are common scaffolds in drugs and natural products,
this method can potentially open a facile route to rapid access
of hydroxylated analogues of a broad range of substrates.
À
and 6.2) isotope effect studies, which indicated that the C H
bond cleavage step might be involved in the rate-limiting step
of this transformation.
To elucidate the effect of TFA/TFAA in this oxygenation
reaction and to clarify the oxygen source, we conducted
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a series of experiments designed to investigate the mecha-
nistic pathway (Scheme 7). This included the preparation of
a crystal of reaction intermediate 55 (Figure 1) with a stoi-
chiometric amount of Pd(OAc)2, which underwent a subse-
Scheme 8. Proposed mechanism.
palladium(II) dimeric intermediate. In step b, PdII is oxidized
into a possible PdIV intermediate.[18] The final step, step c,
involves carbon–oxygen bond-forming reductive elimination
to afford the trifluoroacetated product and to turn PdIV back
into PdII. The trifluoroacetated product is then converted into
a hydroxylated ketone after aqueous workup.
Scheme 7. Investigation of the mechanistic pathway. Conditions:
a) 100% Pd(OAc)2, TFA, RT. b) K2S2O8, RT, TFA/TFAA. c) 5% Pd(OAc)2,
K2S2O8, TFA/TFAA, RT. Ada=adamantyl.
In summary, a novel PdII catalyzed regioselective phenol
synthesis has been developed for the production of a broad
range of functionalized phenols from easily accessible mate-
rials, such as aryl ketones, benzoates, benzamides, acetani-
À
lides, and sulfonamides. It was found that C H oxygenation
can even be carried out at room temperature. Preliminary
mechanistic studies reveal that the TFA/TFAA solvent
À
system serves as both the critical C H functionalization
factor and as the oxygen source. The reaction demonstrates
excellent reactivity, ortho-selectivity, good functional group
tolerance, and high yields. Its utility has been well exemplified
in further synthetic applications and the late-stage modifica-
tion of drugs. By employing a combination of PdII catalysts,
oxidants, and TFA/TFAA, we have discovered a highly
effective catalyst system for this unique regioselective oxy-
genation reaction. Further studies into the scope and the
mechanism of this reaction are in progress in our laboratory.
Received: September 15, 2012
Published online: November 19, 2012
Figure 1. Crystal structure of 55. Ellipsoids set at 35% probability.
À
Keywords: C H activation · drug modification · hydroxylation ·
palladium · phenol synthesis
.
quent oxidation with K2S2O8 to afford the desired product 18.
The trifluoroacetate-substituted product 57 (confirmed by
NMR analysis) was also obtained from the reaction, which,
upon aqueous workup and purification by silica gel column
chromatography was completely converted into the phenol
product 17. These results clearly supported the double effects
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À
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