Palladium(II)-catalyzed direct carboxylation of alkenyl C-H bonds with CO2

Article abstract of DOI:10.1021/ja405503y

Pd-catalyzed direct carboxylation of alkenyl C-H bonds with carbon dioxide was realized for the first time. Treatment of 2-hydroxystyrenes and a catalytic amount of Pd(OAc)₂ with Cs₂CO₃ under atmospheric pressure of CO₂ afforded corresponding coumarins in good yield. Furthermore, isolation of the key alkenylpalladium intermediate via C-H bond cleavage was achieved. The reaction was proposed to undergo reversible nucleophilic addition of the alkenylpalladium intermediate to CO₂.

Full text of DOI:10.1021/ja405503y

Communication
Palladium(II)-Catalyzed Direct Carboxylation of Alkenyl C-H Bonds with CO2
Kota Sasano, Jun Takaya, and Nobuharu Iwasawa
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Jul 2013
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Palladium(II)-Catalyzed Direct Carboxylation of Alkenyl C-H Bonds
with CO2
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Kota Sasano, Jun Takaya, and Nobuharu Iwasawa*
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Supporting Information Placeholder
reaction. Examination of solvents revealed that various
ABSTRACT: Pd-catalyzed direct carboxylation of
kinds of solvents could be employed for this reaction.
alkenyl C-H bonds with carbon dioxide was realized for
While polar solvents such as DMF and DMSO gave the
the first time. Treatment of 2-hydroxystyrenes and a
desired product in slightly lower yield, diglyme gave the
catalytic amount of Pd(OAc)2 with Cs2CO3 under at-
best result for this reaction (entries 6-9). The reaction
mospheric pressure of CO2 afforded corresponding
without Pd(OAc)2 was carried out only to recover the
starting material quantitatively.10
coumarins in good yield. Furthermore, isolation of the
key alkenylpalladium intermediate via C-H bond cleav-
age was achieved. The reaction was proposed to undergo
reversible nucleophilic addition of the alkenylpalladium
intermediate to CO2.
Table 1. Screening of Reaction Conditions
1 atm CO2 (closed)
O
5 mol% Pd(OAc)2
3.0 equiv. base
HO
H3O+
O
solvent
100 ºC, 6 h
The catalytic, direct carboxylation of C-H bonds under
atmospheric pressure of carbon dioxide is highly attrac-
tive as a straightforward method for the synthesis of car-
boxylic acid derivatives.1 Recently, several groups in-
cluding ours reported transition metal catalyzed direct
carboxylation of sp2 C-H bonds of aromatic molecules,
however, catalytic carboxylation of alkenyl sp2 C-H
bonds has not yet been realized.2,3 Moreover, efficient
direct carboxylation of unactivated C-H bonds required
pyrophoric reducing reagent such as AlMe2(OMe) in
order to generate the highly nucleophilic species.2d,4 We
focused on Pd(II) catalysts, as the nucleophilic carboxy-
lation reaction of organopalladium(II) species has sever-
al precedents,5 and Pd(II) could undergo alkenyl C-H
bond cleavage without changing the valency of palladi-
um.6 We therefore expected that by utilizing these char-
acteristics, the catalytic direct carboxylation of alkenyl
C-H bonds could be achieved without using reducing
reagents. We have chosen 2-hydroxystyrenes as sub-
strate with the expectation that the hydroxy group would
behave as a directing group for C-H activation.7,8,9
We first examined the reaction employing α-phenyl-2-
hydroxystyrene 1a with 5 mol% of Pd(OAc)2 in diglyme
at 100 °C under CO2 atmosphere in a closed system in
the presence of various bases. And it was found that by
using KOt-Bu as base, the desired carboxylated product,
4-phenylcoumarin 2a, was obtained in 16% yield (Table
1, entry 3). The efficiency of the reaction was improved
dramatically by using Cs2CO3 as base to give 2a in high
yield (entry 6) but other bases were not effective for this
1a
2a
entry
solvent
base
none
2a (%)a
1a (%)a
1
2
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
cyclooctane
1,4-dioxane
DMF
0
2
quant.
96
LiOt-Bu
KOt-Bu
K2CO3
3
16
0
75
4
quant.
98
5
CsOH•H2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
6
86b
80
72
73
69
8
7
14
8
24
9
16
10
DMSO
25
a Based on 1H NMR. b Isolated yield.
This reaction was applied to various functionalized 2-
hydroxystyrenes. A wide range of substrates bearing an
electron-donating or an electron-withdrawing group on
the phenyl ring at α-position of 2-hydroxystyrene gave
the corresponding coumarins in good yield (Table 2,
entries 2-5). Furthermore the substrates bearing a func-
tional
group
such
as
4-cyanophenyl,
3,4-
methylenedioxyphenyl, pyrrole, and thiophene group
also provided the desired carboxylation products without
affecting these groups (entries 6-9). It should be noted
that bromophenyl moiety was not affected under the
reaction conditions, implying no formation of Pd(0) spe-
cies (entry 10). α-Methyl and non-substituted 2-
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hydroxystyrenes also gave the corresponding coumarins
Page 2 of 5
ly, the carboxylation reactions of the complexes 3a and
4a themselves with CO2 did not proceed at all,13 howev-
er, they showed a similar catalytic activity just like
Pd(OAc)2 when they were employed as a catalyst under
the conditions shown in Table 2.
1
2
3
4
5
6
7
8
(entries 11 and 12). Substitution of methyl or methoxy
group on the phenol ring caused no problem with in-
creased catalyst loadings and 3-hydroxypyridine deriva-
tive 1p afforded corresponding carboxylation product 2p
in moderate yield (entries 13-16). Unfortunately, β-
substituted 2-hydroxystyrenes did not give the desired
products.
Scheme 1. Formation of Alkenylpalladium Complex-
es
DMSO
O
DMSO
Table 2. Generality
HO
9
Pd
1.0 equiv. Pd(OAc)2
10
11
12
13
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16
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O
Ph
H
1 atm CO2 (closed)
5 mol% Pd(OAc)2
3.0 equiv. Cs2CO3
DMSO-d6, rt, 30 min
HO
Ph
O
H3O+
R3
1a
R3
3a(DMSO)2 92%
(NMR yield)
diglyme
0.5 equiv. Pd(OAc)2
3.0 equiv. Cs2CO3
DMSO-d6, rt, 100 min
R1
100 ºC, time
R1
R2
1a-p
R2
2a-p
a
Entry
R1
H
R2
H
R3
time
Yield
Ph
1
2
3
4
5
6
86%
Ph
1a
8 h
7 h
2a
2b
O
Cs Pd
p-MeOC6H4
p-MeC6H4
o-MeC6H4
p-CF3C6H4
p-NCC6H4
1b
1c
1d
1e
1f
83%
O
12 h
18 h
6 h
2c 82%
2c 78%
Ph
2e
2f
81%
90%
4a 74%
(NMR yield)
6 h
O
a
7
8
1g
1h
88%
7 h
6 h
2g
ORTEP diagram of alkenylpalladium complex 4a•diglyme at the
50 % probability level (H atoms have been omitted for clarity). The
diagram shows a half of dimerized symmetric structure.
O
2h 74%
NMe
S
As these intriguing results concerning stoichiometry
were thought to be due to the reversible nucleophilic
addition of the alkenylpalladium intermediate to CO2
and its unfavorable equilibrium for carboxylation prod-
uct, the following experiment was carried out to confirm
this point. Thus, in-situ formation of cesium carboxylate
2a-Cs by treatment of CsOH•H2O and coumarin 2a,
followed by addition of Pd(OAc)2 (1 equiv.) was moni-
9
81%
1i
10 h
2i
10
11a
p-BrC6H4
82%
83%
73%
1j
4 h
10 h
8 h
2j
Me
H
1k
1l
2k
2l
12
13
1m
1n
1o
2m 84%
2n 80%
H
Ph
Ph
Ph
6 h
12 h
12 h
MeO
H
1
14b
15b
MeO
Me
tored by H NMR in DMSO-d6 (Scheme 2). As a result,
H
2o
75%
the complex 3a’ similar to 3a(DMSO)2 was generated
by rapid decarboxylation at room temperature.14 This
result confirmed the reversibility of the carboxylation
reaction with CO2 with the equilibrium in favor of the
decarboxylation side.15 Under the catalytic conditions,
the equilibrium would become in favor of the carboxyla-
tion side due to the participation of the third molecule of
substrate to regenerate complex 4a.16
H
HO
16c
1p
15 h
2p 50%
Ph
N
a
b
Cyclooctane was used as solvent. 7.5 mol% of Pd(OAc)2 was em-
ployed. c 10 mol% of Pd(OAc)2 was employed.
In order to obtain information on the reaction mecha-
nism, observation of the reaction intermediates was ex-
amined under stoichiometric conditions (Scheme 1).
Treatment of α-phenyl-2-hydroxystyrene 1a with
Pd(OAc)2 (1 equiv.) in DMSO-d6 at room temperature
smoothly afforded the cyclometalated complex
3a(DMSO)2, which was generated via alkenyl C-H bond
cleavage.11,12 In contrast, the mixture of 1a and 0.5
equivalent of Pd(OAc)2 with Cs2CO3 was found to give
an alkenyl palladium intermediate 4a, which was coor-
dinated by a cesium salt of 1a. Complex 4a was also
observed under the catalytic reaction conditions using
DMSO-d6 as a solvent and the structure was confirmed
by X-ray analysis of a single crystal.13 Quite interesting-
Scheme 2. Decarboxylation of Palladium Carboxylate
Complexes
O
CsO
L
L
Pd
2.2 equiv.
CsOH•H2O
1.1 equiv.
Pd(OAc)2
O
CsO
2a
DMSO-d6
80 ºC, 4.5 h
rt, 1 h
Ph
Ph
3a'
2a-Cs
Although further studies are required to clarify the
precise mechanism of the reaction, our proposed mecha-
nism is shown in Scheme 3. First the six-membered
alkenyl palladium intermediate 4 is produced by chela-
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tion-assisted alkenyl C-H bond cleavage of 2-
1
2
3
4
5
6
7
8
REFERENCES
hydroxystyrene with Pd(OAc)2 along with coordination
of the second molecule of 2-hydroxystyrene 1 as its ce-
sium salt. Subsequently, alkenyl palladium(II) 4 under-
goes reversible nucleophilic carboxylation to afford pal-
ladium carboxylate intermediate A, which reacts with
another molecule of 2-hydroxystyrene 1 and base to give
coumarin with regeneration of the cyclometalated inter-
mediate 4.17 The shift of the carboxylation-
decarboxylation equilibrium to the carboxylation side
could be attributed to the lactonization process.18
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(2) (a) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int.
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Scheme 3. Proposed Mechanism
R
R
Pd(OAc)2
CO2
O
O
O
Pd
Cs2CO3
O
Cs Pd
O
1
Cs
O
– CO2
R
R
(4) Direct carboxylation reactions of C-H bonds without reducing
reagents were reported but they were limited to substrates that have
rather acidic protons (pKa of about 30), see ref 2a, 2b, 2c, and 2e.
(5) For recent selected examples of Pd-catalyzed carboxylation re-
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Organometallics 2005, 24, 4500. (b) Yeung, C. S.; Dong, V. M. J. Am.
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Y.-Y.; Bi, L.; Georg, G. I. J. Org. Chem. 2013, 78, 6163. See also ref
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4
A
O
OH
O
R
+ CsHCO3
CsOH
1
R
+ Cs2CO3
2
In conclusion, we have developed a catalytic direct
carboxylation of unactivated alkenyl C-H bond of 2-
hydroxystyrenes. This is the first example of Pd(II)-
catalyzed alkenyl C-H bond functionalization with nu-
cleophilic carboxylation. Furthermore, isolation of the
alkenyl palladium intermediate suggested the im-
portance of the regeneration step of intermediate 4 in
this reaction. Further studies to reveal the detailed
mechanism are in progress.
ASSOCIATED CONTENT
Supporting Information. Preparative methods, spectral
and analytical data for compound 1, 2, 3a, 4a, and crystal-
lographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
niwasawa@chem.titech.ac.jp
ACKNOWLEDGMENT
This research was supported by Grant-in-Aids for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan and ACT-C program
from the Japan Science and Technology Agency. K.S. has
been granted a Research Fellowship of the Japan Society
for the Promotion of Science for Young Scientists.
(7) Recently, Alper’s group reported Pd-catalyzed oxidative cy-
clocarbonylation of 2-hydroxystyrenes with carbon monoxide for the
synthesis of coumarins, see; Ferguson, J.; Zeng, F.; Alper, H. Org.
Lett. 2012, 14, 5602.
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(8) For Pd-catalyzed C-H bond functionalization reactions with
phenolic hydroxyl group as directing group, see; (a) Satoh, T.; Ka-
wamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997, 36,
1740. (b) Miura, M.; Tsuda, T.; Satoh, T.; Nomura, M. Chem. Lett.
1997, 1103. (c) Satoh, T.; Inoh, J.-I.; Kawamura, Y.; Kawamura, Y.;
Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 2239. (d)
Kawamura, Y.; Satoh, T.; Miura, M.; Nomura, M. Chem. Lett. 1999,
961. (e) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu,
J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250. (f) Wei, Y.; Yoshikai,
N. Org. Lett. 2011, 13, 5504.
(9) Hoberg and co-workers reported nickel-mediated reaction of
styrene with CO2 to give cinnamic acid, which is an early example of
a formal direct carboxylation of styrene using a stoichiometric amount
of nickel although this reaction proceeded through oxidative cycliza-
tion followed by β-hydride elimination. See; Hoberg, H.; Peres, Y.;
Milchereit, A. J. Organomet. Chem. 1986, 307, C38.
1
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(10) Under harsher conditions with KOt-Bu as base, a mixture of
some carboxylated products was obtained. See Supporting Infor-
mation.
1
(11) Alkenylpalladium complex 3a(DMSO)n (n<2; H NMR spec-
trum and elemental analysis indicated n≈1.7) was isolated in 41%
yield, which gave a single crystal suitable for X-ray analysis by ligand
exchange of DMSO with 1,10-phenanthoroline. See Supporting In-
formation.
(12) Newkome, G. R.; Theriot, K. J.; Cheskin, B. K.; Evans, D.
W.; Gregory, R. B. Organometallics 1990, 9, 1375. See also ref 3g.
(13) For full experimental details, see Supporting Information.
1
(14) H NMR spectrum of 3a’, whose “L” might be acetate anion,
was in good agreement with a mixture of 3a(DMSO)n and CsOAc (2
equiv.) in DMSO-d6.
(15) For recent reviews on decarboxylative cross-coupling reac-
tions, see; (a) Baudoin, O. Angew. Chem., Int. Ed. 2007, 46, 1373. (b)
Goossen, L. J.; Rodríguez, N.; Goossen, K. Angew. Chem., Int. Ed.
2008, 47, 3100. (c) Satoh, T.; Miura, M. Synthesis 2010, 3395. (d)
Rodríguez, N. Goossen, L. J. Chem Soc. Rev. 2011, 40, 5030. (e)
Shang, R.; Liu, L. Sci. China Chem. 2011, 54, 1670. (f) Cornella, J.;
Larrosa, I. Synthesis 2012, 653.
(16) Although none of the product was obtained at all when 50
mol% of Pd(OAc)2 was employed, coumarin 2a was obtained in 32%
yield when 33 mol% of Pd(OAc)2 was employed in cyclooctane.
These results indicated that the third molecule of substrate was re-
quired for the formation of the coumarin by the reaction with complex
4a.
(17) Direct observation of the reaction of 1a in DMSO-d6 revealed
1
that coumarin 2a was formed in 63% yield (determined by H NMR)
under the catalytic conditions without quenching by 1 N HCl.
(18) Exchange of palladium carboxylates with cesium carboxylates
could also be an important step for the shift of the equilibrium, alt-
hough direct observation of the reaction mixture did not show the
presence of 2a-Cs during the reaction.
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1
2
3
4
5
6
7
8
9
1 atm CO2 (closed)
5 mol% Pd(OAc)2
3.0 equiv. Cs2CO3
O
H
R
R
HO
O
O
Cs Pd
O
R
diglyme, 100 ºC
R
Direct Alkenyl C-H Carboxylation with CO2
Key intermediate
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment