Palladium-catalyzed oxidative double C-H functionalization/carbonylation for the synthesis of xanthones

Article abstract of DOI:10.1002/anie.201201050

Two at once: Xanthones with different functional groups were obtained with CO (balloon) in the presence of a simple catalytic system that consists of Pd(OAc)₂, K₂S₂O₈, and trifluoroacetic acid (see scheme). Preliminary mechanism studies reveal that the second C-H functionalization might be the rate-determining step. Copyright

Full text of DOI:10.1002/anie.201201050

Angewandte
Chemie
DOI: 10.1002/anie.201201050
À
C H Activation
À
Palladium-Catalyzed Oxidative Double C H Functionalization/
Carbonylation for the Synthesis of Xanthones**
Hua Zhang, Renyi Shi, Pei Gan, Chao Liu, Anxing Ding, Qiuyi Wang, and Aiwen Lei*
À
The chemical structure of xanthone constitutes the central
core of a wide variety of naturally occurring and manmade
compounds, which exhibit extraordinary biological and phar-
maceutical properties (e.g. antibacterial, anti-inflammatory,
anticancer, and antiviral).[1] The xanthone scaffold has even
been described as “privileged structure”, since members of
this structural class are able to interact with different types of
drug targets and attracted interests across a broad spectrum of
sciences from chemistry and biology to medicine
(Scheme 1).[2] Among the known synthetic routes to obtain
The double C H functionalization/carbonylation of
simple diaryl ethers with CO would represent a very attractive
and sustainable approach towards the syntheses of xanthone,
À
because neither of the two C H bonds need to be prefunc-
tionalized, and diaryl ethers can be easily synthesized from
basic chemicals (Scheme 1). Transition-metal-catalyzed car-
bonylation of aromatic halides with CO in the presence of
various nucleophiles has undergone rapid development,[5]
since the pioneering work of Heck and co-workers in
1974.[6] During the past decade, increased attention has
À
been focused on Pd-catalyzed aromatic C H functionaliza-
tion/carbonylation.[7] Very recently, Pd-catalyzed direct trans-
À
formation of two C H bonds simultaneously has attracted
more and more interest.[8] However, double C H function-
À
alization/carbonylation remains an outstanding challenge.
Owing to the synthetic importance of the xanthone
structure and our continuous interests in the Pd-catalyzed
oxidative coupling[8c] and carbonylation reactions,[7b] herein,
À
we describe the first Pd-catalyzed double C H functionaliza-
tion/carbonylation of diaryl ethers to form biologically active
xanthone derivatives.
The combination of Pd(OAc)2 and K2S2O8 in trifluoro-
acetic acid (TFA) at 508C gave the best result for the
oxidative carbonylation of 4-tolyl ether (1a) under 1 atm CO
(Table 1, entry 1). With these conditions, a 93% yield of 2,7-
Scheme 1. Strategies towards syntheses of xanthones. X=OH, OMe.
the xanthone skeleton, the cyclodehydration of 2,2’-dihy-
droxybenzophenones and electrophilic cycloacylation of 2-
aryloxybenzoic acids are the most popular methods
(Scheme 1).[3] However, both methods involve multistep
procedures under harsh reaction conditions, in which strong
acids or toxic metals are often used.[4] Because of the
important biological applications of xanthones, the develop-
ment of an efficient and general synthetic route with reduced
waste and in fewer steps is highly desirable.
À
Table 1: Pd-catalyzed oxidative double C H carbonylation of 1a: effects
of reaction parameters.[a]
Entry
Variation from “standard conditions”
Yield[%][b]
1
2
3
4
5
6
7
8
none
93
0
PdCl2, instead of Pd(OAc)2
[Pd(dba)2], instead of Pd(OAc)2
MnO2, instead of K2S2O8
BQ, instead of K2S2O8
Na2S2O8, instead of K2S2O8
Cu(OAc)2, instead of K2S2O8
O2, instead of K2S2O8
[*] H. Zhang, R. Shi, P. Gan, C. Liu, A. Ding, Q. Wang, Prof. A. Lei
The College of Chemistry and Molecular Sciences
Wuhan University
17
87
90
47
34
0
Wuhan, Hubei (P.R. China)
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
9
TFA/TFAA (9:1), instead of TFA
TFA/HOAc (1:9), instead of TFA
258C, instead of 508C
56
0
32
27
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
10
11
12
diphenyl ether, instead of 1a
730000 Lanzhou (China)
[**] This work was supported by the National Natural Science
Foundation of China (21025206, 20832003, and 20972118) and the
973 Program (2012CB725302).
[a] Standard reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (2.5 mol%),
K2S2O8 (2 equiv), 1 atm CO, TFA (1.0 mL), 508C, 2 h. [b] The yield was
determined by GC, calibrated using biphenyl as internal standard.
BQ=1,4-benzoquinone, dba=dibenzylideneacetone, TFAA=trifluoro-
acetic anhydride.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201050.
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[a]
À
Table 2: Pd-catalyzed oxidative double C H carbonylation of different diaryl ethers.
dimethyl xanthone (2a) was
obtained within two hours. The
choice of palladium catalyst was
crucial for the reaction. When Pd-
(OAc)2 was replaced by PdCl2,
essentially no reaction occurred
(Table 1, entry 2). The use of [Pd-
(dba)2] as catalyst decreased the
Entry
2
Product
Yield
[%][b]
Entry
2
Product
Yield
[%][b]
yield
dramatically
(Table 1,
1
2
3
4
2a
2b
2c
2d
96
92
50
65
11
12
13
14
2k
2l
76
63
70
70
entry 3). As to oxidant, K2S2O8
gave the highest yield for this oxi-
dative reaction. MnO2 and BQ were
also effective and afforded 2a in 87
and 90% yield, respectively
(Table 1, entries 4 and 5). Other
oxidants such as Na2S2O8, Cu-
(OAc)2, and O2 showed less or no
efficiency in terms of chemical
yields (Table 1, entries 6–8). Addi-
tion of TFAA as co-solvent led to
a decreased yield while a mixed
solvent of HOAc and TFA led to no
reaction (Table 1, entries 9 and 10).
2m
2n
5
6
2e
2 f
41
82
15
16
2o
2p
89
71
A
lower reaction temperature
resulted in a slower reaction, afford-
ing 32% yield of 2a (Table 1,
entry 11). Notably, when diphenyl
ether was employed as the sub-
strate, relatively low yield of the
corresponding carbonylated prod-
7
2g
2h
2i
71
56
51
58
17
18
19
20
2q
2r
2s
2t
52
46
34
27
uct
entry 12).
was
obtained
(Table 1,
8
With the above optimized con-
ditions, the oxidative carbonylation
of a range of symmetrical diaryl
ethers was tested (Table 2). Diaryl
ethers substituted with alkyl groups,
such as methyl and tert-butyl,
afforded the corresponding xan-
thones in excellent yields (Table 2,
entries 1 and 2). The carbonylation
of the aryl ether bearing methoxy
groups produced the xanthone in
9
10
2j
[a] Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (2.5 mol%), K2S2O8 (2 equiv), 1 atm CO, TFA (1.0 mL),
508C, 2–6 h. [b] Yield of isolated product.
50% yield (Table 2, entry 3). To our delight, a Br substituent
could be well tolerated in this oxidative reaction (Table 2,
entry 4). Moreover, dinaphthyl ether could also be carbony-
lated to form the corresponding naphthyl xanthone (Table 2,
entry 5).
Furthermore, we investigated the oxidative carbonylation
of unsymmetrical diaryl ethers with CO (Table 2). In general,
substrates bearing both electron-donating and -withdrawing
substituents worked well under the optimized reaction
conditions. The reaction of diaryl ethers containing tert-
butyl and methoxy groups produced the xanthones 2 f and 2g
in 82% and 71% yield, respectively (Table 2, entries 6 and 7).
Treatment of an ether bearing the strong electron-withdraw-
ing group CF3 with CO afforded 2h in moderate yields
(Table 2, entry 8). Surprisingly, ester and ketone groups were
tolerated under these acidic conditions (Table 2, entries 9 and
10). Halo substituents, such as F, Cl, and Br, were all well-
tolerated, which provided the possibility for further function-
alization (Table 2, entries 11–13). In a similar manner,
naphthyl xanthone 2n was obtained in 70% yield (Table 2,
entry 14). Multi-substituted ethers also reacted well in this
carbonylation (Table 2, entries 15 and 16).
To further explore the scope of the reaction, various
mono-substituted diaryl ethers were tested. Substrates with
either electron-donating substituents such as Me, OMe, or
electron-withdrawing substituent F reacted smoothly to give
the desired products (Table 2, entries 17–19). Nonsubstituted
diphenyl ether afforded xanthone in 27% yield (Table 2,
entry 20).
To gain some preliminary insights into the reaction
mechanism, we monitored the oxidative carbonylation of
different substrates using React IR spectroscopy (Figure 1).
2
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As shown in Figure 1, zero-order kinetics for the carbon-
ylation of different substrates were observed, thus indicating
II
À
that the first C H functionalization of diaryl ether with Pd
Scheme 2. Proposed reaction mechanism.
À
Figure 1. Kinetic plots of oxidative double C H carbonylation of differ-
ent substrates.
consisting of Pd(OAc)2, K2S2O8, and TFA, a variety of
diaryl ethers could be directly carbonylated to xanthones in
moderate to good yields. Moreover, various functional groups
were tolerated under the optimized conditions. Notably, this
transformation provides an effective and practical protocol
towards the syntheses of bioactive xanthones. Preliminary
was not the rate-determining step. Furthermore, the carbon-
ylation of 1a was conducted under different pressures of CO
(Figure 2). The kinetic profiles were overlaid, indicating that
the insertion of CO was not rate-determining under the
À
mechanism studies revealed that the second C H function-
alization might be the rate-determining step. Further studies
on substrate scope and mechanism are currently underway
and will be reported in due course.
Experimental Section
General procedure: In an oven-dried Schlenk tube equipped with
a stir bar, Pd(OAc)2 (2.5 mol%), K2S2O8 (2 equiv), and diaryl ether
(0.2 mmol) were combined. A balloon filled with CO was connected
to the Schlenk tube by the side tube and purged three times. Then,
TFA (1.0 mL) was added to the tube through a syringe. The Schlenk
tube was heated at 508C for 2–6 h (as indicated by TLC) and then
cooled to room temperature. After the gas from the balloon was
released carefully, the reaction was quenched by water and extracted
with CH2Cl2 three times. The combined organic layers were dried
over anhydrous Na2SO4, and the solvent was evaporated in vacuum.
The desired products were obtained in the corresponding yields after
purification by flash chromatography on silica gel with petroleum
ether and ethyl acetate.
À
Figure 2. Kinetic profiles of oxidative double C H carbonylation of 1a
with different CO pressures.
conditions. The reductive elimination of ArCOPdAr species
has been reported to be a facile process;[9] therefore, we
À
concluded that the second C H fuctionalization might be the
rate-determining step of this catalytic cycle.
Received: February 8, 2012
Published online: && &&, &&&&
On the basis of above results and previous studies,[10] we
À
À
propose a mechanism for this double C H functionalization/
Keywords: C H activation · oxidative carbonylation ·
palladium · synthetic methods · xanthones
.
carbonylation reaction (Scheme 2). Pd(OTFA)2 is formed
in situ by the reaction of Pd(OAc)2 with TFA. Then, the fast
electrophilic palladation of 1a with Pd(OTFA)2 affords the
arylpalladium species I, which further reacts with CO to
produce the intermediate II. The subsequent intramolecular
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À
C H functionalization and reductive elimination of III gives
the xanthone 2a and generates the Pd0 species. Pd(OTFA)2 is
then regenerated by oxidation with K2S2O8 in the presence of
TFA.
In conclusion, we have developed the first Pd-catalyzed
double C H functionalization/carbonylation of diaryl ethers
to form xanthones. By using a simple catalytic system
À
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
À
C H Activation
H. Zhang, R. Shi, P. Gan, C. Liu, A. Ding,
Q. Wang, A. Lei*
&&&& — &&&&
Palladium-Catalyzed Oxidative Double
À
C H Functionalization/Carbonylation for
the Synthesis of Xanthones
Two at once: Xanthones with different
functional groups were obtained with CO
(balloon) in the presence of a simple
catalytic system that consists of Pd-
(OAc)2, K2S2O8, and trifluoroacetic acid
(see scheme). Preliminary mechanism
À
studies reveal that the second C H
functionalization might be the rate-
determining step.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!