Pd-catalyzed dearboxylative heck coupling with dioxygen as the terminal oxidant

Article abstract of DOI:10.1021/ol102158n

Pd-catalyzed decarboxylative Heck coupling of aromatic carboxylic acids with various olefins is developed using O₂ as the terminal oxidant. Enhancement of O₂ pressure leads to improving reaction turnover in this transformation and allows significantly reducing catalyst loading for efficient conversion of electron-rich benzoic acids. A Pd catalyst supported by a carbene ligand enables using electron-deficient benzoic acids as coupling partners.

Full text of DOI:10.1021/ol102158n

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4992-4995
Pd-Catalyzed Dearboxylative Heck
Coupling with Dioxygen as the Terminal
Oxidant
Zhengjiang Fu, Shijun Huang, Weiping Su,* and Maochun Hong
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure
of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
wpsu@fjirsm.ac.cn
Received September 9, 2010
ABSTRACT
Pd-catalyzed decarboxylative Heck coupling of aromatic carboxylic acids with various olefins is developed using O2 as the terminal oxidant.
Enhancement of O2 pressure leads to improving reaction turnover in this transformation and allows significantly reducing catalyst loading for
efficient conversion of electron-rich benzoic acids. A Pd catalyst supported by a carbene ligand enables using electron-deficient benzoic
acids as coupling partners.
Of contemporary interest is the transition-metal-catalyzed
decarboxylative cross-coupling for C-C bond formation.
Work along this line has been motivated by the concept that
decarboxylative cross-coupling reactions open up new op-
portunities to employ a large pool of readily available
aromatic carboxylic acids as arylating reagents.1-5 In 2002,
Myers and co-workers reported the first example of Pd-
catalyzed decarboxylative Heck coupling of benzoic acids
with styrene or R,ꢀ-unsaturated carbonyls, providing an
attractive alternative to traditional Heck coupling.2a In view
of the requirement for high loadings of palladium catalyst
and silver salt in Myers’ protocol, there is still significant
room for improvement for the decarboxylative Heck reaction.
To address the issue associated with the use of excessively
expensive silver salt, we have established a Pd-catalyzed
method for decarboxylative Heck coupling in which 1.2
equiv of BQ (BQ ) p-benzoquinone) was used as a
replacement for a silver salt.2f Unfortunately, this method is
(1) Gooꢀen, L. J.; Rodr´ıguez, N.; Gooꢀen, K. Angew. Chem., Int. Ed.
2008, 47, 3100
.
(2) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am.
Chem. Soc. 2005, 127, 10323. (c) Forgione, P.; Brochu, M.-C.; St-Onge,
M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006,
128, 11350. (d) Wang, Z.; Ding, Q.; He, X.; Wu, J. Org. Biomol. Chem.
2009, 7, 863. (e) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009,
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Huang, S.; Wang, M.; Su, W. Chem.sEur. J. 2010, 16, 5876. (k) Zhang,
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(3) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Rudolphi, F.; Oppel, C.; Rodr´ıguez, N. Angew. Chem.,
Int. Ed. 2008, 47, 3043. (c) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J.
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Liu, X. Chem.sEur. J. 2009, 15, 3666. (e) Shang, R.; Fu, Y.; Wang, Y.;
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A. Chem. Commun. 2009, 7173. (b) Cornella, J.; Sanchez, C.; Banawa, D.;
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10.1021/ol102158n  2010 American Chemical Society
Published on Web 10/01/2010

limited to electron-rich aromatic carboxylic acids. Goossen
and Larrosa have independently disclosed that Ag salts were
effective catalysts for protodecarboxylation of a wide range
of benzoic acids,4 pointing out the possibility that a silver
salt is responsible for the decarboxylative process in the Pd/
Ag-promoted decarboxylative Heck reaction. In our inves-
tigation on decarboxylative coupling of benzoic acids with
indoles, we observed that Pd-catalyzed decarboxylation
occurred for electron-rich aromatic carboxylic acids including
heteroaromatic ones, whereas decarboxylation of electron-
deficient aromatic carboxylic acids resulted from the con-
tribution of the silver salt.2j Herein, we demonstrate that the
Pd catalyst itself can effect decarboxylative Heck coupling
of both electron-rich and electron-deficient aromatic car-
boxylic acids without the need for any Ag salt when
dioxygen is used as the terminal oxidant and show that due
to the difference in reactivity between electron-rich aromatic
carboxylic acids and electron-deficient ones different Pd
catalysts are required for decarboxylative Heck coupling to
occur: Pd(OAc)2 efficiently works for electron-rich aromatic
carboxylic acids, while the Pd(OAc)2/SIPr system (SIPr )
1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-
ylidene) enables the use of electron-deficient aromatic
carboxylic acids as coupling partners.
°C in the presence of 10 mol % of Pd(TFA)2 (TFA )
trifluoroacetate) under 1 atm of dioxygen provided the
desired product 3aa in 85% yield (Table 1, entry 1). Using
Table 1. Decarboxylative Heck Coupling of
2,4-Dimethoxybenzoic Acid 1a with Methyl Acrylate 2a under
Different Conditionsa
,
entry
Pd (mol %)
oxidant (1 atm) isolated yield (%)b c
1
2
Pd(TFA)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
O2
O2
O2
O2
air
air
85
90
73
89
34
36
3
4d
5
6e
a Conditions: 1a (0.2 mmol), 2a (0.4 mmol), 5% DMSO-DMF (2 mL),
120 °C, 10 h. b Average of two runs. c The E/Z ratio of product is >20:1,
as determined by H NMR. d The reaction was carried out under 1.8 atm
1
of O2. e The reaction was carried out under 1.8 atm of air.
For economical and environmental reasons, there is an
increasing demand for the use of dioxygen as an oxidant for
metal-catalyzed selective oxidation reactions. In this field,
remarkable progress has been made,6 including oxidation of
alcohols to carbonyl compounds,7 oxygenation of olefins,8
and oxidative cross-coupling reactions.9 To the best of our
knowledge, however, the catalytic decarboxylative coupling
of aromatic carboxylic acids with dioxygen as an oxidant
has not been reported previously. Since Pd-catalyzed aerobic
oxidative reactions generally involve direct aerobic oxidation
of Pd(0) species that compete with aggregation of the catalyst
into inactive palladium black, the rapid oxidation of the Pd(0)
intermediate is a key to achieving efficient conversion for
these reactions.9c In this report, we observed that in many
cases a slight increase in dioxygen pressure significantly
improved the yields due to acceleration of oxidation of the
Pd(0) intermediate.
Pd(OAc)2 in place of Pd(TFA)2 furnished 90% isolated yield
under otherwise identical conditions (entry 2). An amount
of 5 mol % of Pd(OAc)2 furnished a decreased yield under
1 atm of dioxygen (entry 3); however, a slight increase in
dioxygen pressure (1.8 atm) allowed reducing palladium
loading to 5 mol % without compromising the yield (entry
4). However, the reaction gave poor yields under both 1 and
1.8 atm of air (Table 1, entries 5 and 6).
We next evaluated the substrate scope of this protocol with
respect to aromatic carboxylic acids. As shown in Table 2, this
protocol was applicable to the coupling of a broad array of
aromatic carboxylic acids with methyl acrylate 2a. An amount
of 5 mol % of Pd(OAc)2 with 1.8 atm of O2 furnished good to
excellent yields with many electron-rich aromatic carboxylic
acids. Compared with 2,4-dimethoxybenzoic acid, 2-methoxy-
4-methylbenzoic acid is less electron-rich and thereby less
reactive, providing the corresponding product in 75% yield with
10 mol % of Pd(OAc)2 under 1 atm of dioxygen and 34% yield
with 5 mol % of Pd(OAc)2 under 1.8 atm of dioxygen (Table
2, entry 3). Compared with its isomer 2,4,5-trimethoxybenzoic
acid, 2,4,6-trimethoxybenzoic acid was a less effective substrate
to afford 70% yield in the presence of 10 mol % of Pd(OAc)2
under 1 atm of dioxygen, which reflected the effect of
substitution pattern on the reactivity of benzoic acids toward
decarboxylative coupling (Table 2, entries 4 and 5). In the
reaction of benzoic acid bearing an amino group, 2 mol % of
Pd(OAc)2 gave rise to a yield comparable to that obtained with
5 mol % of Pd(OAc)2 under 1.8 atm of dioxygen, presumably
because coordination of the amino-containing substrate to the
Pd center stabilized the Pd catalyst (Table 2, entry 6). An
elevated dioxygen pressure (3.2 atm) was required to deliver
an excellent yield for benzoic acid bearing a bromo substituent,
which could be explained by rapid aerobic oxidation of a Pd(0)
intermediate under a higher dioxygen pressure that should
We initiated our investigation by examining the decar-
boxylative coupling of 2,4-dimethoxybenzoic acid 1a with
2 equiv of methyl acrylate 2a. Gratifyingly, the reaction
conducted in 5% DMSO/DMF (v/v) mixed solvents at 120
(6) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b)
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Int. Ed. 2003, 42, 3512. (b) Andappan, M. M. S.; Nilsson, P.; von Schenck,
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V.; Chatwichien, J.; Stahl, S. S. Org. Lett. 2007, 9, 4331. (d) Li, B.-J.;
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Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733. (f) Shi,
Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7895. (g)
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Org. Lett., Vol. 12, No. 21, 2010
4993

boxylative Heck reaction,2a was observed for the first time to
undergo decarboxylative coupling with methyl acrylate 2a,
albeit in a low yield (Table 2, entry 10). Heteroaromatic
carboxylic acids proved to be suitable substrates, regardless of
the presence or absence of a substituent on the position ortho
to the carboxyl (Table 2, entries 11-15). This reaction can be
scaled up. For example, the reaction of 1a with 2a on a 1 mmol
scale gave a yield (85%) comparable to that on a 0.2 mmol scale.
When this reaction was expanded to electron-deficient
benzoic acids, very low yields of the desired products were
obtained due to the poor reactivity of the Pd(II) catalyst
toward decarboxylation of electron-deficient benzoic acids.
The previous studies by Goossen, Larrosa, and us have
established that silver salts efficiently promote decarboxy-
lation of electron-deficient benzoic acids.2j,k,4 The difference
in the ability to promote decarboxylation between Ag(I) and
Pd(II) likely results from the fact that Ag(I) is more electron
rich than Pd(II). Thus, we speculated that a combination of
Pd(II) with a strong electron-donating ligand such as an
N-heterocyclic carbene would improve the activity of the
Pd catalyst in decarboxylative coupling of electron-deficient
benzoic acids by enhancing the electron density at the Pd(II)
center. We were pleased to find that the Pd(OAc)2/SIPr system
effected decarboxylative Heck coupling of electron-deficient
benzoic acids in moderate to good yields (Table 3).
Table 2. Decarboxylative Heck Coupling of Aromatic
Carboxylic Acids with Methyl Acrylate 2aa
Table 3. Decarboxylative Heck Coupling of Electron-Deficient
Benzoic Acids with SIPr as Liganda
a Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (10 mol %), O2 (1
atm), 5% DMSO-DMF (2 mL), 120 °C, 10 h. b The ratio of E/Z > 20:1, as
determined by 1H NMR. c Isolated yield by an average of two runs. d Yield in
parentheses based on Pd(OAc)2 (5 mol %) with O2 (1.8 atm). e Yield in
parentheses based on Pd(OAc)2 (2 mol %) with O2 (1.8 atm). f Yield
in parentheses based on Pd(OAc)2 (10 mol %) with O2 (3.2 atm). g Yield in
parentheses based on Pd(OAc)2 (10 mol %) with O2 (1.8 atm).
a Conditions: 1 (0.2 mmol), 2 (0.6 mmol), Pd(OAc)2 (10 mol %),
SIPr-HCl (10 mol %), base (10 mol %), O2 (1 atm), DMF (2 mL), 10 h.
b The ratio of E/Z > 20:1, as determined by 1H NMR. c Isolated yield by an
average of two runs.
reduce the concentration of Pd(0) species and therefore ef-
ficiently inhibit oxidative addition of the C-Br bond by the
Pd(0) complex (Table 2, entry 7). As exemplified by 3-chloro-
2,6-dimethoxy-5-nitrobenzoic acid, the addition of an electron-
withdrawing group to the aromatic ring of benzoic acid led to
a decrease in yield due to concomitant formation of a proto-
decarboxylation product (Table 2, entry 8). However, electron-
deficient trifluorobenzoic acid formed the hoped-for product in
a good yield (Table 2, entry 9). Ortho-substituted acetobenzoic
acid, a substrate that is unreactive in Pd/Ag-catalyzed decar-
Using 10 mol % of Pd(OAc)2 as catalyst, the decarboxy-
lative Heck coupling of a variety of olefins with 2,4-
dimethoxybenzoic acid 1a was also investigated under 1 atm
of dioxygen; it is also revealed that an increase in dioxygen
pressure efficiently improved the reaction turnover between
the yields obtained with 5 mol % of Pd(OAc)2 under 1.8
atm of dioxygen and the yields obtained with 10 mol % of
Pd(OAc)2 under 1 atm of dioxygen (Table 4). A sterically
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Org. Lett., Vol. 12, No. 21, 2010

sively in good yields with an E/Z ratio >20 (Table 4, entries
2-7). N-Vinyl phthalimide, a heteroatom-substituted olefin,
participated in this reaction to provide the corresponding
product in 57% yield with 10 mol % of Pd(OAc)2 under 1.8
atm of dioxygen (Table 4, entry 8). 1,2-Disubstituted olefins
can also be arylated with a high level of stereoselectivity in
good yields to furnish trisubstituted olefins of which struc-
tures were unequivocally confirmed by NOESY experiments
(Table 4, entries 9-11). For example, (E)-methyl crotonate
produced trisubstituted E isomer in 67% yield with an E/Z
ratio >20 (Table 4, entry 9), and both (E)-1,2-dibenzoyleth-
ylene and dimethyl fumarate stereoselectively generated the
Z isomer in 81% and 58% yields, respectively (Table 4,
entries 10 and 11). It is noteworthy that the Heck coupling
of 1,2-disubstituted olefins for synthesis of trisubstituted
olefins is not common because of the lower reactivity of this
kind of olefin.9g,10 The reaction of unactivated alkyl-
substituted olefins preferentially formed trans-styrenyl olefins
with terminal olefins and allylic olefins as minor products
(Table 4, entries 12 and 13). Thus, a broad range of both
mono- and disubstituted olefins can be used as coupling
partners in this decarboxylative Heck reaction.
Table 4. Decarboxylative Heck Coupling of
2,4-Dimethoxybenzoic Acid 1a with Various Olefinsa
In summary, we have developed a new Pd-catalyzed
method for decarboxylative Heck coupling of various
aromatic carboxylic acids with a wide range of olefins by
using dioxygen as the terminal oxidant. Increasing dioxygen
pressure resulted in a raised reaction turnover for this
transformation, and as for electron-rich benzoic acid, increas-
ing dioxygen pressure enabled a lowering of the catalyst
loading. Furthermore, enhancing electron density of Pd(II)
via coordination of the electron-donating N-heterocyclic
carbene ligand to the Pd(II) center efficiently improved the
yield for electron-deficient benzoic acids. Efforts are currently
underway to improve the efficiency of this reaction further
and use dioxygen as a terminal oxidant for other decarboxy-
lative coupling reactions.
Acknowledgment. Financial support from the 973 Pro-
gram (2006CB932903, 2009CB939803), NSFC (20821061,
20925102), “The Distinguished Oversea Scholar Project”,
“One Hundred Talent Project”, and Key Project from CAS
is greatly appreciated.
a Conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10 mol %), O2
(1 atm), 5% DMSO-DMF (2 mL), 120 °C, 10 h. b The ratio of E/Z > 20:1
unless otherwise noted, as determined by 1H NMR. c Isolated yield by
average of two runs. d The ratio of Z/E > 20:1, as determined by NOESY
experiment and 1H NMR. e Yield in parentheses based on Pd(OAc)2 (5 mol
%) with O2 (1.8 atm). f Yield in parentheses based on Pd(OAc)2 (10 mol
%) with O2 (1.8 atm). g The ratio of desired product to minor product.
Supporting Information Available: Detailed experimen-
tal procedures and characterization for products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102158N
(10) (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b)
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and electronically diverse array of styrene derivatives
smoothly underwent reactions to form (E)-stilbenes exclu-
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