Versatile palladium-catalyzed double carbonylation of aryl bromides

Article abstract of DOI:10.1039/c7cc07412c

A versatile palladium-catalyzed double carbonylation of aryl bromides has been developed. Using Pd(OAc)₂/BuPAd₂ as the catalyst system and DBU as the base, under relatively low CO pressure, various α-ketoamides were produced in good

Full text of DOI:10.1039/c7cc07412c

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Versatile Palladium-Catalyzed Double Carbonylation of Aryl
Bromides
Chaoren Shen,[a] Cornel Fink,[b] Gabor Laurenczy,[b] Paul J. Dyson,[b] and Xiao-Feng Wu*[a]
Abstract: A versatile palladium-catalyzed double carbonylation of
aryl bromides has been developed. With Pd(OAc)2/BuPAd2 as the
catalyst system and DBU as the base, under relatively low CO
pressure, various α-ketoamides were produced in good yields. In
order to get insight into the reaction pathway, real time NMR studies
were performed as well and a correlated reaction mechanism is
been given.
pressure, but the selectivity of the double carbonylation product
remained unchanged (Table 1, entries 2 and 3). Different
solvents were evaluated under 10 bar of CO at 90 C. Although
o
the conversion varies, but the selectivity does not improve
(Table 1, entries 4-8). Interestingly, the selectivity to the double
CO insertion product increases substantially in the presence of
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (Table 1, entry 9).
The desired 1-morpholino-2-(p-tolyl)ethane-1,2-dione product
was isolated in 57% yield with a conversion of 4-bromotoluene
of 73%. However, the other tested bases (K2CO3, Na2CO3,
Cs2CO3) provided similar results as DiPEA. The yield can be
further improved by increasing the temperature to 100 oC (Table
1, entry 10). Under these conditions, 71% of the double
carbonylation product was isolated with conversion of 95%.
α-Ketoamides and their derivatives are key constituents of
natural products, biologically active molecules, functional
materials, and various synthetic intermediates. Due to their
importance, numerous synthetic approaches have been
established for their synthesis.[1] Among the known procedures,
palladium-catalyzed double carbonylation of aryl halides with
carbon monoxide as the C1 building block is considered to be a
direct and efficient route.[1] Since the original report by
Yamamoto et al. in 1982,[2] various homogeneous and
heterogeneous palladium catalytic systems have been
developed for the double carbonylative synthesis of α-
ketoamides.[3] However, the CO pressure required is usually
high (>50 bar) and the substrates are confined to aryl iodides.
Compared to aryl iodides, the corresponding aryl bromides are
more readily-available, but less reactive and therefore their use
remains challenging. To the best of our knowledge, there is only
one example of palladium-catalyzed double carbonylation of aryl
bromides reported: Buchwald, Jensen and co-workers achieved
the double carbonylation of 4-bromobenzonitrile employing a
continuous-flow microreactor with palladium as the catalyst.[4]
However, the reaction efficiency and selectivity were not
optimum. Based on our on-going research on carbonylations,[5]
we set out to establish a versatile and efficient catalyst for the
double carbonylation of aryl bromides.
Table 1. Influence of solvent and base on the double carbonylation reaction.[a]
O
O
Br
O
N
N
H
N
Pd(OAc)2, Ligand
Base, solvent
O
+ CO
+
O
+
1
O
2
Me
Me
Me
CO
(bar)
Temp.
(°C)
Selec.
(1:2)[b]
Entry
Solvent
Base
Conv.[b]
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
DMSO
5
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
90
90
105
90
90
90
90
90
91:9
88:12
>99:1
91:9
53
94
>99
47
64
72
32
89
10
10
10
10
10
10
10
DMAc
85:15
85:15
1:1
Initially, we selected 4-bromotoluene and morpholine as
model substrates with Pd(OAc)2 (2 mol%) and BuPAd2 (6 mol%)
as the catalyst system, under 5 bar of CO in toluene at 90 oC for
24 hours with DiPEA (diisopropylethylamine) as the base. Here,
the BuPAd2 applied has properties including strong electron
donating, bulky and stable, and have been proven a powerful
Dioxane
DMF
p-Xylene
81:19
73
phosphine
Morpholino(p-tolyl)methanone
ligand
in
cross-coupling
and
transformations.
1-morpholino-2-(p-
9
Toluene
Toluene
10
10
DBU
DBU
90
6:94
8:92
(57)[c]
tolyl)ethane-1,2-dione were obtained from 4-bromotoluene
following single and double CO insertion reactions, with a
moderate conversion (Table 1, entry 1). The conversion was
improved by increasing the reaction temperature and CO
95
10
100
(71)[c]
[a] 4-Bromotoluene (0.5 mmol), morpholine (0.55 mmol, 1.1 equiv.), Pd(OAc)2
(2 mol%), BuPAd2 (6 mol%), base (1.5 equiv.), CO, solvent, 24 h. [b]
Conversion of 4-bromotoluene and the ratio of 1 and 2 were determined by
GC using hexadecane as the internal standard based on calibrations. [c]
Isolated yield.
[a]
[b]
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-
Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: xiao-feng.wu@catalysis.de
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique
Fédérale Lausanne (EPFL), CH-1015 Lausanne, Switzerland
Subsequent optimisation of the catalytic system was
carried out with DBU as the base. The ratio of
Pd(OAc)2:phosphine ligand was crucial, with lower amounts of
BuPAd2 resulting in much reduced conversions of 4-
bromotoluene (Table 2, entries 1-3). Evaluation of other
Supporting information for this article is given via a link at the end of
the document.

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DOI: 10.1039/C7CC07412C
Table 3. Synthesis of α-ketoamides.[a]
palladium precursors, ligands and bases did not improve the
catalytic system (Table 2, entries 4-6). Notably, with PPh3 and
P(2,4,6-(MeO)3C6H3)3 no product was detected and with P(tBu)3
the conversion was significantly reduced (Table 2, entries 7-9).
Notably, improved yields can be achieved with lower amounts of
DBU with 75% of desired α-ketoamide obtained (Table 2, entry
10). Decreased the loading of the catalyst dramatically
decreased the conversion of substrates (Table 2, entry 11).
α-Ketoamides
Entry
1
Yield
75%
Table 2. Optimization of the reaction conditions.[a]
2
3
72%
68%
Entry
[Pd]
Ligand
Selec.(1:2)[b]
Conv.[b]
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
BuPAd2 (4 mol%)
BuPAd2 (2 mol%)
BuPAd2 (8 mol%)
BuPAd2 (6 mol%)
BuPAd2 (6 mol%)
14:86
1:99
5:95
8:92
8:92
76
4
5
6
71%
66%
70%
9
97/(74)[c]
94/(72)[c]
97/(75)[c]
Pd2(dba)3
6
7
Pd(OAc)2
Pd(OAc)2
BuPAd2 (6 mol%)
PPh3 (6 mol%)
6:94
/
75[d]/(59)[c]
<5
P(2,4,6-(MeO)3C6H3)3
(6 mol%)
O
O
8
Pd(OAc)2
/
<5
N
7
8
61%
64%
O
9
Pd(OAc)2
Pd(OAc)2
tBu3P·HBF4 (6 mol%)
10:90
7:93
85
O
10
BuPAd2 (6 mol%)
100[e]/(75)[c]
Pd(OAc)2
(1 mol%)
11
BuPAd2 (3 mol%)
5:95
12
[a] 4-Bromotoluene (0.5 mmol), morpholine (0.55 mmol, 1.1 equiv.), palladium
(2 mol%), ligand, DBU (1.5 equiv.), CO (10 bar), toluene, 100 oC, 24 h. [b]
Conversion of 4-bromotoluene and the ratio of 1 and 2 were determined by
GC using hexadecane as the internal standard based on calibrations. [c]
Isolated yield. [d] DBN (1.5 equiv.). [e] DBU (1.1 equiv).
9
62%
Using the optimized reaction conditions, we evaluated
various aryl bromides and amines to verify the scope of our
procedure (Table 3). In general, good yields of the desired α-
ketoamides were obtained. A double, double carbonylation can
be obtained when piperazine was used as the coupling partner
with the product isolated in 53% yield. It is important to note that
only the mono-carbonylation product was formed when aniline,
N-methylaniline or n-butylamine was used as the reaction
partners. In the case of aryl bromides with electron-withdrawing
substituents or heterocyclic aryl bromides as the substrates, a
mixture of mono- and double-carbonylation products was formed
(1:1-2:1). Chlorobenzene was tested as the substrate under
standard conditions as well, but not reaction could be detected.
10
11
12
62%
76%
67%

Page 3 of 5
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DOI: 10.1039/C7CC07412C
inserted into the Pd-N bond (Scheme 1, eq.1). However,
complex 1a is prone to reductive elimination, which will lead to
formation of the amide as the main product. Hence, pathway 1 is
more likely predominant under high CO pressure (>50 bar).
Another possibility is via 2b as the intermediate, then
transmetalation with acylpalladium complex to give the key
complex (Scheme 1, eq.2). Real-NMR studies were performed
for this pathway. In tolueneD8 under 13CO pressure, started with
morpholine and Pd(OAc)2, no 2b could be detected with or
without DBU, or DBU + BuPAd2 in 13C NMR. Hence, pathway 2
can be excluded as well. The third possibility is through 3a as
the intermediate (Scheme 1, eq.3). This pathway can explain the
relative low CO pressure of this system and also the role of base.
13
71%
14
15
16
17
18
69%
70%
66%
68%
63%
19
20
78%
61%
21
22
74%
61%
23
24
54%
Scheme 1. Proposed reaction mechanism.
53%[b]
Additionally, our model system was performed under 13CO
pressure as well (Scheme 2). The reaction proceeds smoothly at
80 oC and gave the same range of yield.
[a] Reaction conditions: 0.5 mmol of aryl bromides, 0.55 mmol of amines, 2
mol % of Pd(OAc)2, 6 mol% of BuPAd2 and 0.55 mmol of DBU in toluene (2.0
mL), CO (10 bar), 100 °C, 24 h. [b] 0.5 mmol of 4-bromotoluene, 0.25 mmol of
piperazine.
Concerning the reaction pathway, based on literature and
our understandings, three possibilities have been proposed and
all through amido acylpalladium complex as the key intermediate
(Scheme 1). One pathway is through amino acylpalladium
intermediate 1a, reductive elimination occurred after another CO
Scheme 2. 13CO experiment.

ChemComm
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DOI: 10.1039/C7CC07412C
133, 18114-18117; (c) V. de la Fuente, C. Godard, E. Zangrando, C.
Claver, S. Castillón Chem. Commun. 2012, 48, 1695-1697; (d) S.
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Godard, S. Castillón, C. Claver, F. Maseras, J. J. Carbó, Chem. Eur. J.
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Wang, C. Liu, Y. Huang, Y. Hu, B. Zhang, Chem. Commun. 2016, 52,
2960-2963.
In conclusion,
a
versatile palladium-catalyzed double
carbonylation of aryl bromides has been developed. With
Pd(OAc)2/BuPAd2 as the catalyst system and DBU as the base,
under relatively low CO pressure, various α-ketoamides were
produced in good yields.
Acknowledgement
C.S. thanks the China Scholarship Council for financial support.
We also thank the analytical department of the Leibniz Institute
for Catalysis at the University of Rostock for their excellent
technical support as well as Prof. Matthias Beller and Prof.
Armin Börner for their generous support.
[4]
[5]
E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L. Buchwald, K. F.
Jensen, Angew. Chem. Int. Ed. 2007, 46, 1734-1737.
(a) Y. Li, K. Dong, F. Zhu, Z. Wang, X.-F. Wu, Angew. Chem. Int. Ed.
2016, 55, 7227-7230; (b) F. Zhu, Y. Li, Z. Wang, X.-F. Wu, Angew.
Chem. Int. Ed. 2016, 55, 14151-14154; (c) Y. Li, F. Zhu, Z. Wang, X.-F.
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[1]
C. De Risi, G. P. Pollini, V. Zanirato, Chem. Rev. 2016, 116, 3241-3305
and references therein.
[2]
[3]
F. Ozawa, A. Yamamoto, Chem. Lett. 1982, 6, 865-868.
Selected recent examples of homogeneous and heterogeneous
palladium-catalyzed double carbonylation of aryl iodides, see: (a) P.
Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D. Lupp, T.
Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061-6071.; (b) S. D. Friis, R.
H. Taaning, A. T. Lindhardt, T. Skrydstrup, J. Am. Chem. Soc. 2011,

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DOI: 10.1039/C7CC07412C
TOC
R1
N
R1
HN
O
Pd(OAc)2, BuPAd2
ArBr
+
+
CO
Ar
R2
DBU, Toluene, 100 °C
R2
O
24 examples
up to 78% yield