Palladium-Catalyzed, Ligand-Controlled Chemoselective Oxidative Coupling Reactions of Benzene Derivatives with Acrylamides under an Oxygen Atmosphere

Full text of DOI:10.1002/cctc.201200649

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DOI: 10.1002/cctc.201200649
Palladium-Catalyzed, Ligand-Controlled Chemoselective
Oxidative Coupling Reactions of Benzene Derivatives with
Acrylamides under an Oxygen Atmosphere
Seiichiro Harada, Hiroki Yano, and Yasushi Obora*[a]
Amide groups, which contain nitrogen, are universally present
in nature and are found in many drugs such as penicillin, sali-
cylamide, and procainamide.[1] Amide groups can be trans-
formed into other functional groups and used as ligands.[2] For
example, Togo and co-workers reported the transformation of
tertiary amides into nitriles.[2a] Cinnamamides, one of the most
important classes of amides, are substances found in medici-
nally active compounds such as anticonvulsants, antidepres-
sants, central nervous system depression agents, and antimy-
cobacterials.[3] Although cinnamamides are highly sought,
atom-economic, efficient syntheses have not yet been estab-
lished. The conventional method for the synthesis of cinnama-
mides involves the reaction of the corresponding acrylic acid
with an amine. However, these reactions require high tempera-
tures and produce stoichiometric amounts of undesired by-
products. Recently, Tsuji and co-workers reported an improved
synthetic method for the preparation of cinnamamides, and it
involves the Pd-catalyzed addition of formamide to an alky-
ne.[4a] Saito and co-workers achieved the Rh-catalyzed hydra-
tion of cinnamonitrile to cinnamamide.[4b]
cient reoxidation system for the conversion of Pd0 into PdII. By
using this catalytic system, we achieved oxidative couplings of
benzene with olefins such as acrylates, acrolein, acrylonitrile,
and ethylene.[8] However, the reported Pd/HPMoV/O2 system is
not suitable for the reaction of benzene with acrylamide; a mix-
ture of di- and monoarylated products, obtained in 23 and
40% yield, respectively, was obtained. The development of an
alternative catalytic system for the synthesis of cinnamamides
from benzene derivatives and acrylamides that allows control
of the formation of mono- and diarylated acrylamide products
is therefore desirable.
In this communication, we report the oxidative coupling re-
actions of benzene derivatives with acrylamides by using cata-
lytic amounts of Pd(dba)2 combined with acetylacetone
(acacH) and molecular oxygen as the terminal oxidant
(Scheme S1, Supporting Information). Notably, this catalytic
system consists of readily available starting materials and does
not require external reoxidizing agents, that is, molecular
oxygen serves as the sole oxidant. By using this system, we
achieved chemoselective oxidative coupling by changing the
amount of ligand, that is, we developed an efficient synthetic
method that provides either monoarylation or diarylation
products simply by changing the molar ratio of Pd/acacH.
In our initial optimization study, benzene (1a) and N,N-dime-
thylacrylamide (2a) were selected as the model substrates. The
results obtained from screening of the Pd catalysts, ligands,
and solvents are summarized in Table 1. For example, the reac-
tion of 1a (60 mmol) with 2a (1.5 mmol) in the presence of
Pd(dba)2 (0.1 mmol, 6.7 mol%) and acacH (0.1 mmol,
6.7 mol%) in AcOH (10 mL) under an atmosphere of O2 (1 atm)
afforded the corresponding oxidative coupling product 3a in
75% isolated yield (Table 1, entry 1). A small amount of acety-
lated product 5a was formed alongside 3a. By changing the
Pd catalyst to Pd(PPh3)4, Pd(OCOCF3)2, and Pd(OAc)2, moderate
yields could be obtained (Table 1, entries 2–4). Among the li-
gands examined, acacH gave the highest yield, followed by
dbm (dbm = dibenzoylmethane), dba (dba = dibenzylidenea-
cetone), and F6-acacH (F6-acacH = 1,1,1,5,5,5-hexafluoropen-
tan-2,4-dione) (Table 1, entries 5–7). The reaction did not pro-
ceed well without a ligand (Table 1, entry 8).
Alternatively, the transition-metal-catalyzed cross-coupling
reaction of haloarenes with olefins is a powerful tool for the
synthesis of a wide variety of organic compounds. The Mizoro-
ki–Heck reaction, a typical reaction of this type, is well-known
and useful for the construction of new CÀC bonds,[5] and Miz-
oroki–Heck reactions of iodo- or bromobenzene with acryla-
mides to produce cinnamamides have been developed.[6] How-
ever, the formation of stoichiometric amounts of salts resulting
from the haloarenes and bases is unavoidable if the existing
methods are used. Reactions for CÀC bond formation through
direct CÀH bond activation have therefore attracted increasing
attention. To this end, transition-metal-catalyzed cleavage of
aromatic CÀH bonds has been intensively investigated.[7] Al-
though various atom-economic reactions are known, a method
for the synthesis of cinnamamides starting from benzene and
acrylamide has, to the best of our knowledge, not yet been
reported.
Our research group found that a combination of molybdova-
nadophosphoric acid (HPMoV) and oxygen serves as an effi-
The solvent has a significant effect on this reaction, and an
acidic solvent is essential. The reaction was performed in
EtCOOH, and the yield of the product was similar to that ob-
tained when the reaction was performed in AcOH (Table 1,
entry 9). The use of other nonacidic solvents such as DMF and
benzene (solvent-free) did not result in the formation of the
oxidative coupling product (Table 1, entries 10 and 11).
[a] S. Harada, H. Yano, Dr. Y. Obora
Department of Chemistry and Material Engineering
Faculty of Chemistry, Materials and Bioengineering
Kansai University, Suita, Osaka 564-8680 (Japan)
Fax: (+81)6-6339-4026
E-mail: obora@kansai-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201200649.
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amides such as N-tert-butylacry-
lamide (2d) and N-isopropylacry-
lamide (2e) could also be used
in this transformation (Table 2,
entries 8 and 9).
Table 1. Pd-catalyzed oxidative reaction of benzene (1a) with acrylamide (2a) under various conditions.[a]
We accomplished the monoar-
ylation of acrylamide by chang-
ing the amount of ligand
(Table 1, entry 14), and we then
examined the substrate scope in
the monoarylation of acryla-
mides (Table 3). As is the case
with the diarylation reactions,
various monoarylated products
were formed selectively. Arenes
Entry
Pd catalyst
Ligand
[mol%]
Solvent
Yield [%][b]
4a
3a
82 (75)
61
58
49
35
30
53
53
80
n.d.[c]
n.d.[c]
1
n.d.[c]
6 (4)
5a
1
2
3
4
5
6
7
8
Pd(dba)2
Pd(PPh3)4
Pd(OCOCF3)2
Pd(OAc)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(OAc)2
acacH (0.1)
acacH (0.1)
acacH (0.1)
acacH (0.1)
F6-acacH (0.1)
dba (0.1)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
EtCOOH
DMF
n.d.[c]
n.d.[c]
n.d.[c]
11
9
16
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
33
n.d.[c]
71 (59)
32
8
28
21
25
16
19
14
10
–
dbm (0.1)
none
bearing
electron-donating
9
acacH (0.1)
acacH (0.1)
acacH (0.1)
acacH (0.1)
acacH (0.1)
acacH (0.4)
dbm (0.4)
acacH (0.1)
groups and electron-withdraw-
ing groups provided the corre-
sponding monoarylated prod-
ucts in moderate yields with the
formation of acetylated 5a as
a byproduct. In direct Heck-type
arylations, the production of
mixtures of mono- and diarylat-
ed adducts is often a problem.
This method provides a new
route for the selective synthesis
10
11
12[d]
13[e]
14[f]
15
16[g]
–
–
7
–
AcOH
AcOH
AcOH
AcOH
AcOH
25
28 (25)
31
20
14
23
40
[a] Conditions: 1a (60 mmol) was allowed to react in the presence of the Pd catalyst (0.1 mmol) and the ligand
(0.1–0.4 mmol) in AcOH (10 mL) at 908C for 16 h under an atmosphere of O2 (1 atm). [b] GC yields determined
by internal standard method. The isolated yield is given in parentheses. [c] Not detected by GC. [d] In air
(1 atm). [e] Under an atmosphere of Ar. [g] H7PMo8V4O40·22H2O (0.02 mmol) and NaOAc (0.06 mmol) were
added.
of
a variety of monoarylated
products.
Molecular oxygen at atmospheric pressure is a prerequisite
for the catalytic system. In contrast, the reaction did not pro-
ceed at all when it was performed under an atmosphere of Ar
(Table 1, entry 13).
We next examined two different types of acrylates to
expand the scope of this catalytic system, and the reactions
were successful. Similarly, if the amount of acacH changed,
monoarylated or diarylated products (i.e., 7 or 8) could be ob-
tained in good to high yields (Table 4).
Interestingly, monoarylation product 4a was selectively ob-
tained with the use of 0.4 mmol of acacH (Table 1, entry 14). In
a previous report on the Pd-catalyzed Mizoroki–Heck reaction
of bromobenzene and acrylaminde, Nꢁjera demonstrated that
the mono-/diarylation chemoselectivity was controlled by
changing the amount of the haloarene.[6] In contrast, the
amount of benzene did not affect the chemoselectivity in our
system. Thus, the use of 10 mmol of 1a resulted in a considera-
ble decrease in the yield of 3a, and a negligible amount of 4a
was formed (<2%). Thus, by adjusting the amount of ligand,
the monoarylation product was preferentially formed.
The course of the reaction of 1a with 2a was studied over
24 h (Figure 1). The amount of 4a produced increased until
6 h. At that point, the amount of 3a produced increased grad-
ually, as the amount of 4a produced decreased. This result
suggests that 3a was produced through the formation from
4a. However, it seems to be difficult to control the formation
of mono- and diarylation products by adjusting the reaction
time. Our method therefore provides an efficient route for the
selective synthesis of mono- and diarylation products simply
by changing the ratio of Pd/acacH.
The scope of the reaction was examined by using various
arenes 1 with acrylamides 2 under diarylation reaction condi-
tions (Table 2). First, various arenes were tested. Good yields
were obtained in the reaction between acrylamide (2a) and
electron-rich arenes such as p-xylene, and 1,4-dimethoxyben-
zene (Table 2, entries 1 and 2). Conversely, the reaction of 1,4-
difluorobenzene afforded product 3d in moderate yield
(Table 2, entry 3). The reactions of o-xylene and toluene result-
ed in mixtures of regioisomers (Table 2, entries 4 and 5). The
reactions of a variety of acrylamides were successful. Thus,
N,N-diethylacrylamide (2b) and N-acryloylmorpholine (2c) pro-
vided 3-phenylcinnamamides 3g and 3h, respectively, in excel-
lent yields (Table 2, entries 6 and 7). Intriguingly, secondary
By using this protocol, we could easily access b-arylcinnama-
mides by introducing two different arene groups from simple
arenes and acrylamides. Thus, the reaction of p-xylene (1b)
with 4a (which was prepared by reaction of benzene with ac-
rylamide, as shown in Table 1, entry 14) under the conditions
of Table 1, entry 1 afforded b-(2,5-dimethylphenyl)cinnama-
mide (9) in 73% isolated yield with high selectivity (Scheme 1).
A plausible reaction pathway for the direct oxidative cou-
pling of benzene with acrylamide is shown in Scheme S1 (Sup-
porting Information).[5,7,8,10] The coupling reaction is considered
to proceed by a reaction pathway similar to that proposed by
Fujiwara et al.[10] First, electrophilic attack by Pd on the aromat-
ic CÀH bond produces aryl–Pd species A. Then, coordination
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Table 2. Transformation of arenes 1 into b-arylcinnamamides 3.
Table 3. Transformation of arenes 1 into cinnamamides 4.
Entry Arene
Acrylamide
Product, yield [%][b]
Entry
Arene
Acrylamide
Product, Yield [%][b]
1[c]
2a
1
2a
1b
55 (4b)
[29 (5a)]
1b
79 (3b)
2[c]
2a
2
3
2a
1c
1d
1e
45 (4c)
[20 (5a)]
1c
79 (3c)
3
4
5
2a
2a
2a
49 (4d)
[0 (5a)]
2a
1d
1e
55 (3d)
68 (3e)[c]
31 (3 f)[d]
63 (4e)[e,f]
[15 (5a)]
4
5
2a
2a
1 f
1a
32 (4 f)[c,g,h]
[0 (5a)]
1 f
1a
6
6
7
2b
2c
2d
2e
81 (4g)[i]
[15 (5b)]
2b
80 (3g)
7[d]
1a
1a
1a
52 (4h)
[22 (5c)]
1a
2c
2d
2e
75 (3h)
77 (3i)
83 (3j)
8
61 (4i)
[0 (5d)]
8[e]
1a
1a
9
58 (4j)
[0 (5e)]
9[e]
[a] The reaction was performed under conditions of Table 1, entry 14.
[b] Isolated yield. The isolated yield of 5 is given in square brackets.
[c] 0.6 mmol of acacH was used. [d] 0.5 mmol of acacH was used. [e] Iso-
lated as a 92:8 mixture of 4e/3e. [f] The regiochemistry was confirmed
by comparison of the spectra of the authentic sample prepared by the re-
ported Mizoroki–Heck reaction of acrylamide with 2,3- and 3,4-dimethy-
liodobenzene.[9] [g] Isolated as a 91:9 mixture of 4 f/3 f and a 14:37:49
mixture of o-/m-/p- regioisomers of 4 f. The major regioisomer is shown
in the table. [h] The regiochemistry was confirmed by comparison of the
spectra of the authentic sample prepared by the reported Mizoroki–Heck
reaction of acrylamide with o-, m-, and p-iodotoluenes.[9] [i] Isolated as
a 93:7 mixture of 4 f/3 f.
[a] The reaction was performed under the conditions of Table 1, entry 1.
[b] Isolated yield. The isolated yield of byproduct 5 under all conditions
was less than 5%. [c] Reaction gives a mixture of regioisomers in a ratio
of 76:15:9, the structures of which were not determined. [d] Reaction
gives an intractable mixture of six regioisomers. The structure of the
regioisomers were not determined because of the intricacy of spectral
comparison between the regioisomers. [e] Reaction time was 30 h.
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the scope of this reaction and the elucidation of the active
species to control the chemoselectivity are currently underway.
In conclusion, we developed a facile synthetic approach to
cinnamamide catalyzed by a Pd/acacH/O2 system. This is the
first example of the synthesis of cinnamamide from benzene
and acrylamide. This reaction proceeds smoothly under an at-
mosphere of molecular oxygen at atmospheric pressure and
does not require external reoxidizing agents. In addition, we
have accomplished the selective synthesis of monoarylated ac-
rylamide products by adjusting the Pd/acacH ratio.
Table 4. Reaction of 1a with acrylates by using the Pd/acacH/O2
system.[a]
Entry
1[a]
Acrylate
Product
Yield [%][c]
83 (7a)
2[a]
3[b]
4[b]
82 (8a)
50 (7b)
53 (8b)
Experimental Section
[a] The reaction was performed under conditions of Table 1, entry 1.
[b] The reaction was performed under conditions of Table 1, entry 14.
[c] Isolated yield.
General Procedure: In a 50-mL round-bottomed flask, a mixture of
1a (4.7 g, 60 mmol) and 2a (0.26 g, 1.5 mmol) was treated with
Pd(dba)2 (58 mg, 0.1 mmol) and acetylacetone (10 mg, 0.1 mmol)
in AcOH (10 mL) under an atmosphere of O2 (1 atm). The reaction
mixture was stirred at 908C for 16 h. The crude reaction mixture
was cooled to room temperature, and the solvent was evaporated
under reduced pressure. After removal of the solvent, the residue
was purified by column chromatography on Florisil (n-hexane/ethyl
acetate=4:1). Desired product 3a was isolated in 75% yield.
Acknowledgements
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) [Grant-in-Aid for Scientific
Research, MEXT-Supported Program for the Strategic Research
Foundation at Private Universities (2010–2014)],the Japan Sci-
ence and Technology Agency (JST) (ALCA), and the Kansai Univer-
sity Research Grants (Grant-in-Aid for Encouragement of Scien-
tists, 2012).
Figure 1. Reaction time course curves for the yields of 3a and 4a in the dia-
rylation of 2a (same conditions as those for Table 1, entry 1).
of A with acrylamide 2 followed by syn insertion leads to com-
plex B. Resulting product 4 is then obtained by b-hydride elim-
ination from complex B along with a Pd–H intermediate. The
Pd–H intermediate is reduced to Pd0, and the resulting Pd0
species is reoxidized to generate the PdII species with the pro-
duction of molecular oxygen.
Keywords: CÀH bond activation · chemoselectivity · amides ·
cross-coupling · palladium
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Received: September 14, 2012
Published online on October 30, 2012
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