Pd-catalyzed aerobic oxidative coupling of anilides with olefins through regioselective C-H bond activation

Article abstract of DOI:10.1016/j.tetlet.2007.06.001

Pd-catalyzed aerobic oxidative coupling of anilides with olefins was achieved through selective C-H bond activation. Compared to the previous studies, not only did we successfully use molecular oxygen to replace the chemical oxidant, but we also obtained

Full text of DOI:10.1016/j.tetlet.2007.06.001

Tetrahedron Letters 48 (2007) 5449–5453
Pd-catalyzed aerobic oxidative coupling of anilides with
olefins through regioselective C–H bond activation
Jia-Rui Wang, Chu-Ting Yang, Lei Liu* and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 9 January 2007; revised 28 May 2007; accepted 1 June 2007
Available online 5 June 2007
Abstract—Pd-catalyzed aerobic oxidative coupling of anilides with olefins was achieved through selective C–H bond activation.
Compared to the previous studies, not only did we successfully use molecular oxygen to replace the chemical oxidant, but we also
obtained improved yields for a number of substrates. The reaction tended to give high yields for electron-rich anilides and electron-
deficient olefins, with a best yield up to 91%.
Ó 2007 Elsevier Ltd. All rights reserved.
Pd-catalyzed selective activation of C–H bonds can lead
to useful organic reactions to assemble value-added mole-
cules through C–C bond formation.1 This synthetic
strategy is attractive for the chemical and pharmaceuti-
cal industries, not only because it may greatly simplify
and shorten the synthetic sequence for various types of
organic compounds, but also because it may allow the
utilization of cheap and environmentally benign reac-
tants (e.g., hydrocarbons instead of organic halides).2
Currently, catalytic C–H bond activation has become
an area of rapid growth where many interesting chal-
lenges still remain to be overcome.3 One such example
is the direct, oxidative coupling of olefins with aromatic
hydrocarbons (Scheme 1). Compared to the standard
Heck reaction4 and the more recent ‘reverse’ Heck reac-
tion,5 direct olefin arylation reaction is obviously advan-
tageous in terms of starting material price and
byproduct (i.e., halogenated salt) disposal.
Evidently a certain oxidant is required to achieve the
above direct coupling between an olefin and an arene.
Pd(II) could be one of the choices. For instance, in early
1981 Horino and Inoue reported that the reaction of
acetanilides with Pd(OAc)2 gave an ortho-palladated
complex, which could further react with an olefin to pro-
duce the corresponding 2-[(acetylamino)phenyl] olefin
(Scheme 2).6 An obvious disadvantage of this reaction
was that a stoichiometric amount of expensive Pd was
required to complete the transformation. To overcome
this limitation, de Vries and van Leeuwen reported in
2002 the interesting finding that combination of a cata-
lytic amount (2 mol %) of Pd and a stoichiometric
amount of a chemical oxidant (i.e., benzoquinone) could
also be used to achieve the same olefin arylation reaction
as shown in Scheme 2.7
X
halogenation
R
Heck
R
direct coupling
+
H
N
R
O
O
H
H
N
Pd
Pd
N
reverse
Heck
O
R
Pd(OAc)2
O
R
halogenation
X
O
O
O
O
R
Scheme 1.
N
H
*
Scheme 2.
Corresponding authors. E-mail: leiliu@ustc.edu.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.001

5450
J.-R. Wang et al. / Tetrahedron Letters 48 (2007) 5449–5453
In the present study we report a further, significant
improvement for the above C–H activation reaction,
where the chemical oxidant has been successfully chan-
ged to molecular oxygen. We consider this improvement
to be important not only from the viewpoint of econom-
ical efficiency (O2 is available at virtually no cost), but
also from the perspective of environmental friendliness
(aerobic oxidation produces water instead of any other
environmentally hazardous byproduct). As for the sub-
ject of oxidative olefin–arene coupling via C–H bond
activation, Milstein and co-workers once reported the
use of Ru catalysts and O2 as oxidant.8 However, fairly
high temperatures (e.g., 180 °C) and high pressures (e.g.,
2 atm O2 and 6.1 atm CO) were required in this Ru sys-
tem. Here, we accomplish a Pd-catalyzed, O2-mediated
regioselective olefin–anilide coupling catalytically under
much milder conditions (namely, only at 60 °C and
under 1 atm O2).
bond at the ortho position in the acetanilide to form
an ortho-palladated complex; (2) cross-coupling between
the ortho-palladated complex and n-butylacrylate to
produce the desired product and Pd(0); and (3) re-oxida-
tion of Pd(0) to Pd(II) to repeat the catalytic cycle.
Because the first two steps were demonstrated to be fine
in the original study by Horino and Inoue,6 we hypoth-
esized that the recycling of Pd(II) from the reduced
Pd(0) should constitute the limiting factor for the cata-
lytic turnovers.
On the basis of various recent reports about Pd-cata-
lyzed aerobic oxidative transformations including
alcohol oxidation,9 amine oxidation,10 and oxidative C–
C
11 and C–N couplings,12 we found that two approaches
were often used to accelerate the re-oxidation of Pd(0).
The first approach was the use of a ligand including pyr-
idine and Et3N to facilitate the direct oxidation of Pd(0)
to Pd(II) by O2. The second was the addition of a co-cat-
alyst such as Cu(II) salts that could mediate the redox
between Pd(0) and O2. It was found that the addition of
Et3N or pyridine did not improve the yield (entries 3
and 4). On the other hand, the addition of a catalytic
amount of Cu(OAc)2 (5 mol %) was found to increase
the yield dramatically to about 80% (entry 5).
We began the study by focusing on the reaction between
acetanilide and n-butylacrylate under 1 atm of O2. It was
found that at room temperature the oxidative coupling
did not take place with 2 mol % of Pd(OAc)2 (Table 1,
entry 1). However, when the temperature was raised to
80 °C we were pleased to find that the desired reaction
occurred, albeit with a low yield (49%, entry 2). This
observation demonstrated that the idea of using O2 as
the oxidant was valid for the direct arylation of olefin.
The mechanism of this reaction was presumably com-
posed of three steps: (1) insertion of Pd(II) to the C–H
To further increase the yield, we next studied the
byproducts in the reaction. It was soon realized that n-
butyl acrylate could easily polymerize at high tempera-
tures. To diminish this side reaction, we tried to lower
the reaction temperature. It was found that at 60 °C
the yield was slightly higher (84%, entry 6) whereas at
room temperature no reaction could take place (entry
7). Subsequent studies at 60 °C showed that a higher
loading of Cu would reduce the yield, probably because
Cu could compete with Pd for the amide nitrogen bind-
ing (entries 8 and 9). Meanwhile, a lower loading of Pd
would also reduce the yield (entries 10 and 11) for an
obvious reasons. Eventually the optimal loadings of
Cu(OAc)2 and Pd(OAc)2 were both found to be
3 mol % (entries 12 and 13), under which conditions
the yield reached 90%. We also found that TsOH had
some important influence on the reaction (entries 13–
15) allowing for a loading of 1.0 mmol. The reason for
the beneficial effect of TsOH was that TsOÀ could
increase the electrophilicity of Pd(II) center by replacing
AcOÀ and therefore, cause a faster activation of the
C–H bond. Furthermore, it was found that the optimal
solvent system was AcOH/toluene (2:1) where the yield
reached 92% (entry 14). In comparison, the yield in pure
AcOH was only 76% (entry 16) and the yield in AcOH/
toluene (1:1) was 89% (entry 17). Noteworthily de Vries
and van Leeuwen reported an optimal yield of 72% in
their Pd/benzoquinone procedure,7 as compared to
92% in our case. Thus we not only successfully used
molecular oxygen to replace benzoquinone as oxidant,
but also achieved a higher yield in the reaction.
Table 1. Pd-catalyzed aerobic oxidative coupling of acetanilide with
n-butyl acrylatea
H
N
H
Pd(OAc)2
N
+
O
CO2Bu
O2 (1atm),16 h
O
CO2Bu
Entry
Pd(OAc)2
(mol %)
Cu(OAc)2
(mol %)
TsOH
(mmol)
T (°C)
Yield
(%)
1
2
3b
4c
5
6
7
8
9
10
11
12
13
2
2
2
2
2
2
2
2
2
1
1
3
3
3
3
3
3
0
0
0
0
5
5
5
10
2
5
1
5
3
3
3
3
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
0.5
1.0
1.0
25
80
80
80
80
60
25
60
60
60
60
60
60
60
60
60
60
0
49
44
51
81
84
0
80
87
53
52
90
90
92
69
76
89
14
15
16d
17e
a Reaction conditions: acetanilide (3 mmol), n-butyl acrylate (3 mmol),
HOAc (5 mL), toluene (2.5 mL) O2 (1 atm), 16 h, GC yield.
b 20 mol % NEt3 was added.
Having successfully optimized the conditions,13 we next
examined the scope of this newly developed reaction for
the aerobic oxidative coupling of various anilines and
olefins. Here we determined the isolated yields instead
of the GC yields in order to ensure the practical effi-
c 20 mol % of pyridine was added.
d Only 6 mL of HOAc as solvent.
e HOAc (3 mL), toluene (3 mL).

J.-R. Wang et al. / Tetrahedron Letters 48 (2007) 5449–5453
Table 2. Aerobic oxidative coupling of anilides with olefinsa
5451
R3
N
R3
N
3 mol% Pd(OAc)2,
3 mol% Cu(OAc)2
R2
R2
+
R4
O
TsOH, AcOH/toluene,
O2 (1 atm), 60oC, 16 h
O
R1
R1
R4
Entry
1
Anilide
Olefin
Product
Yield (%)
82
Ref. yieldc (%)
H
N
H
N
COOBu
(72)
O
O
CO2Bu
H
N
H
N
2
3
4
57
—
—
—
O
COOMe
O
O
O
CO2Me
H
N
H
N
26
O
Ph
Ph
H
N
H
N
71b
O
COOBu
CO2Bu
H
N
Ph
O
H
N
Ph
5
6
79
(55)
COOBu
COOBu
O
CO2Bu
N
N
0
—
O
O
CO2Bu
H
N
H
N
7
8
89
91
(62)
(85)
O
COOBu
COOBu
MeO
O
MeO
CO2Bu
H
N
H
N
O
O
CO2Bu
H
N
H
N
9
11b
—
O
COOBu
Cl
O
Cl
CO2Bu
(continued on next page)

5452
J.-R. Wang et al. / Tetrahedron Letters 48 (2007) 5449–5453
Table 2 (continued)
Entry
Anilide
Olefin
Product
Yield (%)
14
Ref. yieldc (%)
—
H
N
H
N
10
COOBu
O
O
Br
Br
CO2Bu
H
N
H
N
11
0
—
O
COOBu
O2N
O
O2N
CO2Bu
a Anilide (3 mmol), olefin (3 mmol), Pd(OAc)2 (3 mol %), Cu(OAc)2 (3 mol %), TsOH (1 mmol), HOAc (5 mL), toluene (2.5 mL), O2 (1 atm), 60 °C,
16 h. Isolated yields.
b Yield determined by 1H NMR.
c Yields reported in Ref. 7.
ciency of our procedure (Table 2). It was found that
besides n-butyl acrylate, methyl acrylate and styrene
could also be applied to the reaction (entries 1–3). None-
theless, the yield for styrene was relatively low (26%). A
similar observation was reported by de Vries and van
Leeuwen with their Pd/benzoquinone procedure,7 where
the coupling yield for 4-chlorostyrene was only 58%.
Thus, it appeared that the Pd-catalyzed oxidative olefin
arylation was more suitable for electron-deficient
alkenes.
tron deficient substrates (i.e., 4-chloro-phenylacetamide
and 4-bromophenyl-acetamide) displayed a much lower
reactivity (entries 9 and 10). Interestingly, for the halo-
genated substrates we only observe the oxidative cou-
pling products at the anilide ortho position, but not
any Heck-type products at the halogenated positions.
Furthermore, for the most electron deficient substrate
(i.e., 4-nitrophenyl-acetamide) we could not isolate any
desirable product (entry 11). It should be pointed out
that some similar substituent effects were reported by
de Vries and van Leeuwen.7 In their work, 4-methoxy-
phenyl-acetamide gave a yield of 62%, as compared to
89% in our case. Although they only tested one elec-
tron-deficient substrate (i.e., 4-trifluoromethyl-phenyl-
acetamide), they reported an NMR yield of 29% for this
particular case.
As to the acyl groups, we examined acetyl, propionyl,
and benzoyl (entries 1, 4, 5). The isolated yields were
found to be 82%, 71%, and 79%, respectively. These
results showed that both the aliphatic and aromatic acyl
groups could be well tolerated in the reaction. It is worth
noting that de Vries and van Leeuwen reported an iso-
lated yield of 55% for their N-phenylbenzamide case,7
which should be compared to 79% in our reaction.
To summarize, in the present study we reported Pd-cat-
alyzed aerobic oxidative coupling of anilides with olefins
via regioselective C–H bond activation.14,15 Compared
to the previous work by de Vries and van Leeuwen,7
we not only successfully used molecular oxygen to re-
place the chemical oxidant, but also obtained improved
yields for a number of substrates. The reaction tended to
give higher yields for the electron-rich anilides and elec-
tron-deficient olefins. Our current research is focused on
extending the aerobic method to other Pd-catalyzed
selective C–H bond activation processes, where the oxi-
dants are often reported to be expensive or dangerous
Next we examined N-methyl-N-phenylacetamide (entry
6). This substrate was found to provide no desired prod-
uct even after an elongated reaction time. Compared to
N-phenylacetamide in entry 1, it was evident that the
presence of an N-methyl group completely blocked
the C–H activation. This observation indicated that
the nitrogen atom (or the amidyl oxygen in a deproto-
nated amide, but not in an N-methylated amide) should
be deeply involved in the Pd-mediated C–H process, pre-
sumably by coordinating to the metal in the same man-
ner as originally proposed by Horino and Inoue.6 Thus,
the oxidative coupling reaction developed in this study
was dependent on the amide directing group. The
requirement for an amide directing group also promised
a high regioselectivity in the C–H bond activation, as
manifested by the fact that only one coupling product
could be observed in the reactions.
t
materials such as PhI(OAc)2, Ag2O, and BuOOtBz.
Acknowledgment
We thank NSFC (No. 20472079) for the financial
support.
Substituents on the aromatic ring of the acetanilide were
also found to influence the efficiency of the coupling
significantly. Electron rich substrates (i.e., 4-methoxy-
phenyl-acetamide and p-tolylacetamide) tended to give
relatively higher yields (entries 7 and 8), whereas elec-
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