Remarkable ligand effect on the palladium-catalyzed double carbonylation of aryl iodides

Article abstract of DOI:10.1039/b600632a

The use of t-Bu₃P as a ligand dramatically improved the generality of the double carbonylation of aryl iodides, and Mo(CO)₆ was also found to be effective as a CO source in the system. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600632a

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Remarkable ligand effect on the palladium-catalyzed double
carbonylation of aryl iodides{
Muneaki Iizuka and Yoshinori Kondo*
Received (in Cambridge, UK) 16th January 2006, Accepted 20th February 2006
First published as an Advance Article on the web 8th March 2006
DOI: 10.1039/b600632a
carbonylation reactions in some recent papers, no significant
The use of t-Bu3P as a ligand dramatically improved the
generality of the double carbonylation of aryl iodides, and
Mo(CO)6 was also found to be effective as a CO source in the
system.
ligand effect has been demonstrated for the carbonylation of aryl
iodides.6
For double carbonylation, it was recently reported that the Pd/
PPh3/DABCO/THF system7 is effective for aryl iodides without
electron withdrawing groups and the reaction was conducted at
room temperature under an atmospheric pressure of carbon
monoxide. However, the protocol is only applicable to those aryl
iodides without electron withdrawing groups.
The palladium-catalyzed carbonylation of aryl halides in the
presence of carbon monoxide is an important methodology for the
preparation of carbonyl containing derivatives.1 The procedure
usually tolerates a wide range of functionalities and has been
employed for the synthesis of many biologically active molecules.
The palladium-catalyzed double carbonylation of aryl halides has
also been extensively studied. After the early reports on double
carbonylation,2 extensive mechanistic investigations were carried
out.3 It has been reported that the smooth formation of an
aroylpalladium intermediate 3 is the key to the successful double
carbonylation of an aryl halide.3g The migration step, forming 3
from the intermediate 2, is critically influenced by the electron
density of the aryl moiety. Therefore, aryl halides with electron
withdrawing groups have been regarded as unfavorable substrates
for double carbonylation.3g In order to overcome this limitation,
double carbonylation was investigated using various ligands and
bases, and the remarkable facilitating effect of t-Bu3P was
demonstrated.
In our initial investigation of double carbonylation, we chose
4-iodonitrobenzene (4) as a substrate for carbonylation. Intro-
duction of an electron withdrawing substituent, such as a nitro
group at the para position, increases the reactivity of palladation
but decreases the selectivity of a-ketoamide formation. Namely,
4-iodonitrobenzene can be regarded as the most unfavorable sub-
strate for double carbonylation and the most suitable, challenging
substrate for the optimization experiment of selective double
carbonylation. The choice of an amine as a nucleophile is impor-
tant, and the steric bulkiness of amines has a great influence on the
formation of a-ketoamides.3g Pyrrolidine was chosen as a nucleo-
phile because of its tendency in a previous report to give the amide
rather than the a-ketoamide, taking the most unfavorable case into
consideration.3g The choice of base is also considered to be
important for the selectivity, and DBU is known to be favorable
for single carbonylation from the results of a previous report.7
When the reaction of 4 and pyrrolidine in the presence of
Pd2(dba)3, PPh3 and DBU was carried out at room temperature,
single carbonylation proceeded smoothly to give amide 6, as
expected from the previous reports (Table 1, entry 1). No
formation of the double carbonylated a-ketoamide was observed.
Other ligands such as DPPF and DPPP were examined, and they
also showed similar single carbonylation selectivity (Table 1,
entries 2 and 3). To our surprise however, when t-Bu3P was used
as a ligand, the selectivity dramatically changed, and the double
carbonylation product 5 was predominantly formed (Table 1,
entry 4). On the other hand, the similar, basic, bulky ligand Cy3P
showed a different selectivity from t-Bu3P, and the formation of
amide 6 was found to be favorable (Table 1, entry 5).
Commercially available Pd(t-Bu3P)2 showed almost the same
selectivity as Pd2(dba)3/2t-Bu3P (Table 1, entry 6). When the base
was switched to Et3N from DBU, the selectivity changed towards
the formation of amide 6, and the reaction became slow (Table 1,
entry 7). DABCO was found to be suitable for single carbonyla-
tion when combined with t-Bu3P, in contrast to the previous
report,7 and inorganic bases such as Cs2CO3 and K3PO4 were also
favorable for single carbonylation (Table 1, entries 8, 9 and 10).
Other amine nucleophiles were examined for carbonylation, and
Fig. 1
In recent years, t-Bu3P has been shown to exhibit a unique
reactivity in a variety of palladium-catalyzed coupling reactions.4
The use of t-Bu3P has mainly focused on the coupling reaction
of aryl chlorides and aryl bromides, and the lower reactivity
against bromides has been commented-on in some palladium-
catalyzed coupling reactions.5 Although t-Bu3P was employed in
Graduate School of Pharmaceutical Sciences, Tohoku University,
Aramaki Aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan.
E-mail: ykondo@mail.pharm.tohoku.ac.jp; Fax: (+81) 22-795-6804;
Tel: (+81) 22-795-6804
{ Electronic Supplementary Information (ESI) available: Experimental
procedures and spectral data for synthesized compounds. See DOI:
10.1039/b600632a
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Chem. Commun., 2006, 1739–1741 | 1739

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Table 1
Product distributiona
Entry
‘‘Pd’’
R1
R2
Base
Time/h
4
5
6
7
Yield of 5 (%)b
1
2
3
4
5
6
7
8
9
Pd2(dba)3/2PPh3
Pd2(dba)3/DPPF
Pd2(dba)3/DPPP
Pd2(dba)3/2t-Bu3Pc
Pd2(dba)3/2Cy3P
Pd(t-Bu3P)2
–(CH2)4–
DBU
DBU
DBU
DBU
DBU
DBU
Et3N
DABCO
Cs2CO3
K3PO4
DBU
DBU
DBU
d
3
14
14
3
24
2
24
24
1.5
1.5
12
7
0
0
0
0
0
0
0
0
80
0
80
13
15
25
56
—
—
—
100
100
100
10
100
12
72
68
75
44
0
0
0
10
0
8
0
0
0
0
—
—
—
73 (5a)
—
77 (5a)
—
—
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
0
Pd(t-Bu3P)2
22
17
0
Pd2(dba)3/2t-Bu3Pc
Pd(t-Bu3P)2
Pd(t-Bu3P)2
—
—
10
11
12
13
a
0
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
b
H
H
n-Bu
t-Bu
Et
—
—
—
—
—
—
—
—
—
45 (72)d (5b)
55 (65)d (5c)
85 (5d)
Et
9
Estimated by 1H-NMR. Isolated yields. HBF4 salt was used. Cs2CO3 was used in the case of values in parentheses.
c
the a-ketoamides were obtained in good selectivities (Table 1,
entries 11, 12 and 13). The exact role of t-Bu3P in the double
carbonylation is still under investigation to determine the under-
lying rationale of the selectivity, but the assistance of a migration
from the intermediate 2 to 3 is considered to be one of the factors,
as suggested in Fig 1.
conventionally, a high temperature was required to release CO
molecules using microwave irradiation. We recently reported that
CH3CN is effective for releasing CO from Mo(CO)6, but that the
generation of CO from Mo(CO)6 at room temperature has yet to
be accomplished.9
When the conventional catalyst system using PPh3 was
employed, the carbonylation was quite slow due to the reluctant
release of CO from Mo(CO)6 (Table 3, entries 1 and 2). When our
new protocol using t-Bu3P was employed, the double carbonyla-
tion proceeded smoothly at room temperature to give 10 in good
yield (Table 3, entry 3). When the base was switched to DABCO
from DBU, the amide 11 was obtained as a main product (Table 3,
entry 4).
The double carbonylation of other aryl halides with other
functional groups (FGs) was also examined using pyrrolidine or
n-butylamine as the nucleophile. Aryl halides with electron
withdrawing groups such as ethoxycarbonyl or cyano underwent
double carbonylation in high yields in the presence of Pd(t-Bu3P)2
and DBU (Table 2, entries 1, 2, 3 and 4). Iodobenzene and
4-iodoanisole were also converted into the a-ketoamide selectively
by this new catalyst system (Table 2, entries 5, 6, 7 and 8). Ortho
substituents did not affect the double carbonylation, and the
reaction of methyl 2-iodobenzoate proceeded smoothly to give the
a-ketoamide (Table 2, entry 9).
In summary, the use of t-Bu3P as a ligand has dramatically
improved the generality of the double carbonylation of aryl
iodides. The facilitated formation of aroylpalladium species, at
present, are presumed to be responsible for the observed selectivity,
but further careful investigations are necessary for a more
fundamental understanding of the real effect that t-Bu3P has on
these carbonylation reactions. Further investigations on the scope
and limitations of t-Bu3P-assisted double carbonylation,{ and
mechanistic studies are now under way.
Recently, in situ generation of CO has been investigated, with
Mo(CO)6 being regarded as an excellent CO generator.8 However,
Table 2
Table 3
Entry
FG
8
R1
R2
Time/h
9
Yield (%)a
1
2
3
4
5
6
7
8
9
4-CN
4-CN
4-COOEt
4-COOEt
H
H
4-OMe
4-OMe
8a
8a
8b
8b
8c
8c
8d
8d
–(CH2)4–
1.5
12
2
12
24
12
24
12
3.5
9a
9b
9c
9d
9e
9f
9g
9h
9i
92
60
99
76
92
64
93
93
68
Product distributiona Yield (%)b
H
n-Bu
–(CH2)4–
H
n-Bu
–(CH2)4–
Entry
‘‘Pd’’
Base
7d
10
11
10 11
H
n-Bu
–(CH2)4–
1
2
3
PdCl2(C3H5)2, 2PPh3 DBU 84
PdCl2(C3H5)2, 2PPh3 DABCO 95
6
0
93
11
10
0
7
89
—
—
70
—
—
—
—
67
H n-Bu
–(CH2)4–
Pd(t-Bu3P)2
Pd(t-Bu3P)2
DBU
DABCO
0
0
2-COOMe 8e
4
a
a
b
Isolated yield
Estimated by 1H-NMR. Isolated yields
1740 | Chem. Commun., 2006, 1739–1741
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This work was partly supported by Grants-in-Aid for Scientific
Research (nos. 16659002, 16033208 and 16390002) from the
Ministry of Education, Science, Sports and Culture, Japan, and a
grant from the Sumitomo Foundation.
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