Double carbonylation of aryl iodides with amines under an atmospheric pressure of carbon monoxide using sulfur-modified Au-supported palladium

Article abstract of DOI:10.1039/c4gc02469a

A double carbonylation of aryl iodides with amines proceeded smoothly under an atmospheric pressure of carbon monoxide by using palladium nanoparticles (Pd NPs) leached from a sulfur-modified Au-supported palladium material (SAPd), producing α-ketoamides in good to excellent yields. This journal is

Full text of DOI:10.1039/c4gc02469a

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Double carbonylation of aryl iodides with amines
under an atmospheric pressure of carbon
monoxide using sulfur-modified Au-supported
palladium†
Cite this: DOI: 10.1039/c4gc02469a
Received 18th December 2014,
Accepted 17th February 2015
Nozomi Saito,*a,c Takahisa Taniguchi,a Naoyuki Hoshiya,‡a Satoshi Shuto,b
DOI: 10.1039/c4gc02469a
www.rsc.org/greenchem
Mitsuhiro Arisawa*§b,c and Yoshihiro Sato*a,c
A double carbonylation of aryl iodides with amines proceeded
smoothly under an atmospheric pressure of carbon monoxide by
using palladium nanoparticles (Pd NPs) leached from a sulfur-
modified Au-supported palladium material (SAPd), producing
α-ketoamides in good to excellent yields.
ð1Þ
We developed a sulfur-modified Au-supported Pd (SAPd)
material, which immobilized 300–400 μg of palladium on the
piranha-treated Au mesh (100 mesh, 12 mm × 14 mm), and it
showed remarkable reactivity for Suzuki–Miyaura coupling,8a,b,d,e
and Buchwald–Hartwig amination,8c,e as well as C–H bond
activation,8f,g with low leaching and highly recyclable charac-
teristics. Furthermore, recent studies in which the structure of
the SAPd material was analyzed revealed that palladium nano-
particles (Pd NPs) of approximately 5 nm in size were immobi-
lized on its surface.8i
During the course of further investigation of synthetic
applications of the SAPd material, we found that double
carbonylation of aryl iodides with amine proceeded under an
atmospheric pressure of CO to afford an α-ketoamide with
good chemoselectivity. Thus, a solution of p-iodoanisole (1a)
and morpholine (2a) in DMF was heated at 80 °C for 24 hours
in the presence of a sheet of SAPd, which was prepared by a
2nd-generation method,8e under an atmospheric pressure of
CO without stirring,9 giving α-ketoamide 3aa in 40% yield
accompanied by the formation of amide 4aa in 9% yield and
recovery of 1a (Scheme 1). As mentioned above, there have
been no reports on efficient double carbonylation under an
atmospheric pressure of CO in the absence of any ligands or
specific additives. We therefore decided to conduct further
investigation of ligand-free double carbonylation of aryl
iodides under an atmospheric pressure of CO by utilizing
SAPd.
In 1982, Yamamoto1a and Tanaka1b independently reported
the first palladium-catalyzed double carbonylation of aryl
halides with amines giving α-ketoamides, which are important
fragments found in some biologically active molecules2 as well
as valuable synthons for the preparation of nitrogen-contain-
ing compounds3 (eqn (1)). Since then, various synthetic appli-
cations of double carbonylation have been demonstrated, and
it is now widely utilized as a promising and indispensable
methodology for the synthesis of α-ketoamides.4,5
It is well known that Pd-catalyzed double carbonylation
proceeds efficiently under a high pressure of carbon monoxide
(CO). Recently, several examples of double carbonylation
under an atmospheric pressure of CO have been reported.6 In
these cases, however, the reaction proceeded only in the pres-
ence of some specific additives, such as a copper co-catalyst,
nucleophilic amine base6b–e or a bulky trialkylphosphine.6c
Ligand- and additive-free double carbonylations under such
mild conditions have not been reported.7
aLaboratory of Fine Synthetic Chemistry, Faculty of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, Japan. E-mail: biyo@pharm.hokudai.ac.jp
bLaboratory of Organic Chemistry for Drug Development, Faculty of Pharmaceutical
Sciences, Hokkaido University, Sapporo 060-0812, Japan
cACT-C, Japan Science and Technology Agency (JST), Sapporo, 060-0812, Japan
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
When the reaction in Scheme 1 was carried out, precipi-
tation of Pd-black was observed in the reaction vessel, indicat-
ing that aggregation of Pd NPs occurs via exfoliation of Pd NPs
from the surface of SAPd under the reaction conditions.10 This
result also means that SAPd cannot be reused for further
double carbonylations by this procedure. Therefore, we
c4gc02469a
‡Current address: Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto
607-8412, Japan.
§Current address: Graduate School of Pharmaceutical Sciences, Osaka Univer-
sity, 1-6 Yamada-oka, Suita, Osaka 565-0862, Japan.
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Table 1 Reactions of p-iodoanisole (1a) and various amines
Run
Amine 2
α-Ketoamide 3
Amide 4
1
2
3
2b (n = 0, X = CH2)
2c (n = 1, X = CH2)
2d (n = 1, X = NMe)
3ab: 82%
3ac: 94%
3ad: 86%
4ab: 10%
4ac: 6%
4ad: 11%
Scheme 1 Reaction of p-iodoanisole (1a) and morpholine (2a) under a
CO atmosphere (1 atm) in the presence of SAPd.
4
3ae: 87%
4ae: 9%
5
3af: quant
4af:—
6
7
8
9
2g:nBuNH2
3ag: 74%
3ah: 75%
3ai: 87%
3aj: 70%
3ak:—
4ag: 22%
4ah: 20%
4ai:—
2h:nPr2NH
Scheme 2 Optimization of the reaction procedure.
2i: Bn(Me)NH
2j: TBSOCH2CH2(Me)NH
2k: C6H5NH2
4aj:—
10
4ak: 55%a
decided to adopt a two-step protocol that was previously
reported for C–H alkynylation using SAPd;8f the first step is the
leaching of a sufficient amount of Pd from SAPd by contact
with p-iodoanisole and the second step is the carbonylation
process. Thus, a solution of 1a in the presence of K2CO3 and a
sheet of SAPd in DMF were heated at 80 °C for 2 hours under
an Ar atmosphere without stirring (1 atm). After removal of
SAPd from the reaction vessel, 2a was added to the reaction
mixture and then the resulting mixture was stirred at 80 °C for
24 h under a CO atmosphere (1 atm). As a result, p-iodoanisole
(1a) was completely consumed, and double carbonylation
product 3aa was produced in 85% yield along with amide
derivative 4aa in 11% yield (Scheme 2).
With the optimal procedure, studies on the scope and limit-
ation of double carbonylation using SAPd were conducted.
First, reactions of p-iodoanisole (1a) with various aliphatic
amines were investigated (Table 1). Reactions of 1a and sec-
ondary cyclic amines 2b–2f gave the corresponding α-keto-
amides 3ab–3af in high yields (runs 1–5). Acyclic primary and
secondary amines 2g–2j were also applicable for double
carbonylation, and the desired coupling products 3ag–3aj were
obtained in good yields (runs 6–9). On the other hand, the
reaction using aniline (2j) gave only amide 4ak in 55% yield,
and α-ketoamide 3ak was not obtained (run 10).
a NMR yield.
Table 2 Reactions of various aryl iodides and morpholine (2a)
Run
Aryl iodide 1
α-Ketoamide 3
Amide 4
1
2
3
4
5
6
7
lb 3-MeOC6H4I
lc 2-MeOC6H4I
ld 3,5-Me2C6H3I
le 3,4,5-(MeO)3C6H2I
1f C6H5I
lg 4-ClC6H4I
lh 4-MeO2CC6H4I
3ba: 84%
3ca: 29%a
3da: 76%
3ea: 84%
3fa: 69%
3ga: 65%
3ha: 46%
4ba: 14%
4ca: 55%a
4da: 7%
4ea: 4%
4fa: 21%
4ga: 27%
4ha: 42%
8
3ia: 44%
4ia: 52%
9
3ja: 84%
3ka: 94%
4ja: 16%
4ka: 6%
Next, the reactions of various aryl iodides and morpholine
(2a) were investigated, and the results are summarized in
Table 2. When m-iodoanisole (1b) was used, α-ketoamide 3ba
was obtained with good chemoselectivity (run 1). On the other
hand, the reaction using o-iodoanisole (1c) as a substrate gave
mono carbonylation product 4ca as the major product (run 2).
Reactions of 2a with 3,5-dimethyliodobenzene (1d) and 3,4,5-
trimethoxyiodobenzene (1e) afforded the corresponding
10
11
3la: 80%
4la: 17%
double carbonylation products 3da and 3ea, respectively, in a NMR yield.
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Table 3 Reusability of SAPd and catalyst loadinga
Yields SDb,c (%)
Amount of leached
Cycle
3aa
4aa
Pd SDd (μg)
1st
87
88
91
91
90
3
3
1
2
1
7
8
7
8
7
1
1
1
1
1
56 43
50 35
2nd
3rd
4th
5th
28
7
Scheme 3 One-step synthesis of anti-HIV agent 3ml.
30 16
23 16
Average of 89
5 cycles
7
38
a Conditions: la (0.5 mmol), 2a (1.5 mmol) , K2CO3(1.0 mmol) , DMF
(3 mL). b Yield was determined by GC analysis using bibenzyl as an
internal standard. c Yields are average values of 3 reactions. d Amounts of
leached Pd were measured by ICP-MS analysis and are average values of
three experiments.
Scheme 4 Large-scale reactions.
of the amounts of leached palladium in the reaction mixtures
were also conducted by inductively coupled plasma mass
spectroscopy (ICP-MS) analysis, and the catalyst loading in
each reaction was estimated to be 0.009–0.18 mol%.10
In summary, we demonstrated double carbonylation of aryl
iodides and amines catalyzed by Pd nanoparticles leached
from the SAPd material giving α-ketoamides with good chemo-
selectivities.12 It is noteworthy that the reaction proceeded
even under an atmospheric pressure of carbon monoxide
without any specific additives or ligands. Further studies along
this line are in progress.
high yields (runs 3 and 4). When iodobenzene (1f) was sub-
jected to double carbonylation conditions, α-ketoamide 3fa
was obtained in 69% yield accompanied by the formation of
benzamide derivative 4fa in 21% yield (run 5). On the other
hand, the reactions of aryl iodides 1g–1i bearing an electron-
withdrawing group on the aromatic ring resulted in increases
in the formation of mono carbonylation products 4ga–4ia com-
pared to the amounts of products obtained from the reactions
of aryl iodides having an electron-donating group (runs 6–8).
Double carbonylation of heteroaromatic compounds 1j–1l pro-
ceeded in a chemoselective manner, giving the corresponding
α-ketoamides 3ja–3la in high yields (runs 9–11).
Acknowledgements
It is noteworthy that the potent anti-HIV agent 3ml11 could
be synthesized in one step via double carbonylation of 2-iodo-
naphthalene (1m) with N-benzoylpiperazine (2l) (Scheme 3).
Next, a large-scale reaction by using SAPd was investigated
(Scheme 4). As a result, the reaction of 10 mmol of 1a with 2a
gave 3aa in 85% yield (2.1 g) with good chemoselectivity
(eqn (2)). Furthermore, multi-gram synthesis of anti-HIV agent
3ml was also achieved by using 10 mmol of 1m (eqn (3)).
It was expected that a sufficient amount of Pd NPs
remained on SAPd even after a sufficient amount of Pd NPs for
the progress of double carbonylation had leached into the
reaction mixture. Thus, we investigated the reusability of SAPd
and also measured amounts of the leached palladium in the
reaction mixtures (Table 3). After the solution of 1a in DMF in
the presence of K2CO3 and SAPd had been heated at 80 °C for
2 hours, SAPd was removed and reused in the next reaction. It
was found that SAPd could be used for at least five reaction
cycles without a significant loss of catalytic activity, and
double carbonylated products were obtained in good yields
and with good chemoselectivities in all cycles. Measurements
This work was partly supported by a Grant-in-Aid for Scientific
Research (C) (no. 26460002) and a Grant-in-Aid for Scientific
Research (B) (no. 26293001) from JSPS and by a Grant-in-Aid
for Scientific Research on Innovative Areas “Molecular
Activation Directed toward Straightforward Synthesis” (nos.
23105501 and 25105701) from MEXT, Japan.
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9 The SAPd material easily breaks up by physical impact of
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without stirring.
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the surface of Pd nanoparticles. Therefore, insertion of CO
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the nucleophilic attack of amines on the carboyl moiety on
Pd would proceed efficiently to give α-ketoamides with
good chemoselectivities.
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