Efficient cobalt-catalyzed C-N cross-coupling reaction between benzamide and aryl iodide in water

Article abstract of DOI:10.1039/c4ob01483a

A practical and efficient strategy for the N-arylation of benzamide catalysed by a Co(C₂O₄)·2H₂O/dmeda system in water is reported. Under the optimized conditions, a wide variety of N-arylated products were obtained in good yields (up to 92%) using substituted aryl iodides.

Full text of DOI:10.1039/c4ob01483a

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Biomolecular Chemistry
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Efficient cobalt-catalyzed C–N cross-coupling
reaction between benzamide and aryl iodide
in water†
Cite this: Org. Biomol. Chem., 2014,
2, 7478
1
Received 15th July 2014,
Accepted 11th August 2014
Bryan Yong-Hao Tan and Yong-Chua Teo*
DOI: 10.1039/c4ob01483a
www.rsc.org/obc
A practical and efficient strategy for the N-arylation of benzamide required the use of expensive phosphine as the ligand for the
2
1
2 4 2
catalysed by a Co(C O )·2H O/dmeda system in water is reported. cross-coupling reaction. Punniyamurthy et al. demonstrated
Under the optimized conditions, a wide variety of N-arylated pro- the synthesis of benzimidazoles and benzoxazoles using a
ducts were obtained in good yields (up to 92%) using substituted combination of Co(acac) ·2H O and 1,10-phenanthroline.
2
2
aryl iodides.
However, this reaction is limited to only intramolecular C–N
2
2
and C–O cross-coupling reactions.
Our research group reported the first successful application
of CoCl in combination with N,N′-dimethylethylenediamine
dmeda) as a chelating ligand for the N-arylation of nitrogen
N-Arylbenzamides constitute a valuable class of organic com-
pounds that are of great importance in pharmaceutical and
biological sciences. In particular, the allosteric modulator
2
(
1
2
CPPHA, the anticancer drug imatinib, and the anti-
23
heterocycles with aryl iodides. This protocol excluded the
need for reducing agents or electrochemical techniques to
regenerate the active catalytic species while displaying comp-
lementary advantages of reported protocols. Based on this pre-
cedent where we observed that although the N-arylation can be
efficiently carried out on several nitrogen heterocycles to afford
the intended products in good yields, an attempt on the cross-
coupling of benzamide with iodobenzene only afforded a low
yield of 28%. Moreover, we have recently reported a bimetallic
CuI/MnF2 catalytic system for the cross-coupling of benz-
amides with aryl iodides. However, the protocol exhibited
limited substrate scope for substituted benzamides and the
use of KOH as a strong base restricted the synthetic utility of
3
arrhythmic agent encainide have demonstrated important
biological activities associated with them. As such, there has
been much interest in the development of new catalytic
methods to prepare N-arylbenzamides.
Among the strategies developed to date, the transition-
metal-catalyzed C–N cross coupling reaction between aromatic
amides and aryl halides has emerged as a straightforward and
inexpensive approach to N-arylated amides. The majority of
4
–7
the established protocols involved the use of palladium,
8
,9
10–12
13–16
nickel, copper,
and more recently, iron catalysts
to
catalyse the cross-coupling reactions. Despite the significant
progress made in the aforementioned metal catalysts, the
development of any new and sustainable protocols for the syn-
thesis of these target compounds can be of great synthetic
importance.
Cobalt salts have emerged as a viable alternative in the field
of catalysis, with rapid progress being made in the area of C–C
cross-coupling reactions due to its low cost, ready availability
24
the protocol. Henceforth, as part of our ongoing interest in
cobalt catalysis as well as development of practical and sus-
tainable strategies, herein, we wish to report an efficient and
straightforward cross coupling of benzamides with aryl iodides
to assemble N-arylbenzamides. In this instance, the use of
Cs CO as the base with Co(C O )·2H O as the catalyst was
2
3
2
4
2
1
7–20
and environmentally benign nature.
However, reports on
critical for the success of this new protocol. The reaction pro-
ceeds efficiently in air excluding the need for stringent inert
conditions. It is worth noting that the reaction only proceeds
efficiently when water is used as the solvent. This use of water
the application of cobalt as an efficient catalyst for the for-
mation of C–N bonds have been limited. Toma et al. reported
the N-arylation of secondary amines using CoCl2 which
2
5,26
not only adheres to the principle of green chemistry
but
also has implications in the mechanistic aspects of the
reaction.
We initiated our investigation to identify the optimal con-
ditions using benzamide and iodobenzene as the model sub-
strates. Firstly, the effect of different bases on the arylation
Natural Sciences and Science Education, National Institute of Education,
Nanyang Technological University, Nanyang Walk, Singapore 637616, Singapore.
E-mail: yongchua.teo@nie.edu.sg; Fax: (+65) 6896 9414
†
Electronic supplementary information (ESI) available: Detailed experimental
procedures, NMR data and NMR spectra for all new compounds. See DOI:
0.1039/c4ob01483a
1
2 3
reaction was investigated. To our delight, a switch to Cs CO
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Table 1 Optimization studies on the Co-catalyzed cross-coupling of and ligand loadings were reduced. We were pleased to report
a
benzamide and iodobenzene
that an excellent product yield of 90% was obtained (entry 20).
However, further reduction of the catalyst and ligand loadings
led to a drastic drop in yield (entry 21). Control reactions were
carried out in the absence of either cobalt salt or L1 (entries
22 and 23). As expected, a trace amount or no reaction was
observed for these reactions. Lastly, a control reaction was
carried out through the application of the protocol by Bolm
2
and Buchwald, whereby ppm amounts of CuCl afforded a
2
7
yield of 97%. Only a trace amount of product was obtained
when Co(C O )·2H O was applied to the same protocol. Hence,
b
Entry Catalyst
Base
Ligand Solvent
Yield (%)
2
4
2
the presence of ppm amounts of copper contaminants that
will catalyze the reaction can be effectively ruled out. In
summary, the optimal conditions for the cobalt-catalyzed
N-arylation of benzamide involved a combination of Co
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
CoCl
CoCl
CoCl
CoCl
CoBr
Co(OAc)
Co(ClO
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
Co(C
—
2
2
2
2
K
3
PO
Cs CO
CO
CsOAc
4
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
L1
L1
—
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
DMF
28
63
18
Trace
48
40
48
82
30
24
0
62
59
Trace
Trace
Trace
Trace
2
3
K
2
3
2
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
(C
2 4 2 2 3
O )·2H O (10 mol%), Cs CO (2 equiv.), and L1 (20 mol%)
2
4
O
H
)
2
·6H
2
O
O
in water at 120 °C for 24 h in air.
2
5
2
2
2
2
2
2
2
2
2
2
2
2
4
)·2H
2
With the optimized conditions obtained, we proceeded to
evaluate the scope of this reaction with various substituted
aryl halides. In general, with the exception of sterically-
hindered ortho substituents, good to excellent yields were
obtained. An excellent yield of 92% was afforded with 2-fluoro-
iodobenzene, perhaps due to its less bulky nature and induc-
tive effect as compared with the other ortho substituents
7
O
2
)
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
O
O
O
O
O
O
O
O
O
O
O
O
4
4
4
4
4
4
4
4
4
4
4
4
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
)·2H
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
DMSO
THF
Toluene
Methanol Trace
3
(Table 2, entry 2). Bulkier ortho substituents (Cl, OMe, CH )
Ethanol
Water
Water
Water
Water
Trace
required higher catalyst and ligand loadings for the reaction to
afford moderate amounts of the corresponding N-arylated pro-
ducts (entries 3–5). Both the electron-donating and electron-
withdrawing substituents at the meta and para positions were
c
90
d
15
0
Co(C
2
O
4
)·2H
2
O
Trace
a
Reaction conditions: Co catalyst (20 mol%), base (2.94 mmol),
benzamide (1.47 mmol), ligand (40 mol%), water (0.3 cml),
b
iodobenzene (2.21 mmol), 120 °C for 24 h in air. Isolated yield. The
a
Table 2 N-arylation of benzamide with various substituted aryl halides
reaction was carried out using 10 mol% Co(C
2
O
4
)·2H
2
O and 20 mol%
2
)·2H O
d
dmeda. The reaction was carried out using 5 mol% Co(C
and 10 mol% dmeda.
2
O
4
2
3
from K PO used in our previously reported conditions led to
3
4
b
a marked increase in yield from 28% to 63% (Table 1, entries 1 Entry
and 2). The choice of Cs CO as the base was further proved to
have a pronounced effect on the reaction when K CO and
CsOAc only afforded a poor yield of 18% and a trace amount of
the arylated products, respectively (entries 3 and 4). Next, the
efficiency of various cobalt(II) salts for this transformation was
evaluated (entries 5–9). We found that the best cobalt(II)
ArX
Product
Yield (%)
2
3
1
2
3
4
5
6
7
8
9
1
PhI
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2a
90
92
20
2
3
2-F-PhI
2-Cl-PhI
2-OMe-PhI
2-Me-PhI
3-F-PhI
3-Cl-PhI
3-Br-PhI
c
60
c
35
75
80
c
89
76
2 4 2
source was Co(C O )·2H O, which gave a good yield of 82%
c
3-CF
3
-PhI
(
entry 8). Further screening to determine the merits of ligands
0
3-OMe-PhI
3-Me-PhI
4-F-PhI
4-Cl-PhI
4-CF
4-OMe-PhI
4-Me-PhI
PhBr
72
75
c
on the arylation reaction revealed that L1 (dmeda) was the 11
1
1
1
2
3
4
90
most suitable ligand (entries 10–13), while cyclic diamine
ligands also afforded the product in good yields of 62 and 59%
respectively (entries 12 and 13). Different organic solvents were 15
then screened to investigate the solvent effect on the coupling
reaction (entries 14–19). With only trace products formed for
all the organic solvents tested, including protic solvents like
methanol and ethanol, we concluded that water plays an
essential role in facilitating the cross coupling reaction. To
c
82
c
3
-PhI
65
60
75
24
1
1
6
7
c
a
Unless otherwise stated, the reaction was carried out with Co-
)·2H O (10 mol%), Cs CO (2.94 mmol), benzamide (1.47 mmol),
dmeda (20 mol%), water (0.3 ml), substituted iodobenzene
2.21 mmol), 120 °C for 24 h in air. Isolated yield. The reaction was
)·2H O and 40 mol% dmeda.
(
C
2
O
4
2
2
3
b
c
(
increase the atom economy of the reaction, both the catalyst carried out using 20 mol% Co(C
O
2 4
2
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a
Table 3 N-arylation of various substituted benzamide with iodobenzene
b
Entry
R
Product
Yield
1
2
3
4
5
6
7
8
9
2-F
2-Cl
2-CF
2-Me
2-NH
3-F
3a
3b
3c
3d
3e
3f
3g
3h
3i
65
54
80
87
18
84
3
Fig. 1 Yield of 2a (%) versus concentration of benzamide used (M).
2
c
3-CF
3
65
3-OMe
3-Me
4-Cl
4-Br
4-OMe
4-Me
80
73
87
82
70
77
concentration of the substrates to maximize the yield of
product 2a. Fig. 1 shows the dependence of the yield of 2a on
the concentration of benzamide used. Indeed, we found that
the use of 0.3 ml water in the reaction mixture gave the
highest yield of the product in 90%, while significant
reductions in yields were observed before or beyond this point.
1
1
1
1
0
1
2
3
3j
3k
3l
3m
a
Unless otherwise stated, the reaction was carried out with Co-
)·2H O (10 mol%), Cs CO (2.94 mmol), benzamide (1.47 mmol),
(C
O
2 4
2
2
3
dmeda (20 mol%), water (0.3 ml), substituted iodobenzene This also implied that an optimum concentration of 4.9 M of
b
c
(
2.21 mmol), 120 °C for 24 h in air. Isolated yield. The reaction was
benzamide, the limiting reagent, was important to ensure the
effective mixing between the substrates in the biphasic
mixture under the catalytic conditions.
carried out using 20 mol% Co(C )·2H O and 40 mol% dmeda.
2
O
4
2
Based on the reported literature, we proposed that the C–N
cross-coupling reaction comprises of three steps, namely the
coordination of benzamide to the active catalytic species with
a Co(II) core, followed by the oxidation addition of the aryl
iodide to form the Co(IV) intermediate, and concluded through
the reductive elimination of the product to regenerate the
active catalytic species as shown in Scheme 1. We postulated
that water might also play a vital role in the activation of the
Co/dmeda pre-catalyst to generate the active Co(II) species that
facilitated the oxidative addition step and subsequent cross-
coupling reaction. Nevertheless, more mechanistic studies are
required to elucidate the active catalytic species and under-
stand the role of water in the catalytic cycle.
tolerated, as the reactions using the corresponding substituted
aryl iodides gave good to excellent yields of up to 90% (entries
6
–16). It was observed that only mono-arylated products were
obtained in all instances, suggesting that coupling of iodo-
benzene to secondary amides was not viable under the cata-
lytic conditions. However, this protocol is limited to only aryl
iodides, an attempt to use bromobenzene as the electrophilic
partner gave a low yield of 24% even at a higher catalyst
loading (entry 17).
Next, the scope of our methodology was investigated
through the cross-coupling of a variety of differently substi-
tuted benzamides with iodobenzene. We were delighted to
report that a wide variety of the functional groups can be toler-
ated by the protocol to afford good to excellent yields of the
N-arylated derivatives (Table 3, entries 1–13), with the exception
of 2-amino group (entry 5). This could be due to the additional
basic property conferred by the amino substituent which ham-
pered the reaction, a trend that was commonly observed in
similar cross-coupling reactions using copper or palladium cat-
alysts. The electronic nature and the position of the substitu-
ents did not appear to have any significant effect on the yield.
This protocol is only limited to benzamides, as the cross-coup-
ling of primary alkyl amides such as acetamide and propion-
amide cannot be achieved.
Given that other organic solvents did not appear to
promote the reaction, further probing into the effect of water
on the reacting substrates was carried out. While the issue of
substrate solubility can be overcome partly by increasing the
volume of water used, a lower concentration will inevitably
have an adverse effect on the rate of the reaction. Therefore, by
manipulating the volume of water used in the model reaction,
Scheme 1 Proposed mechanism for cobalt-catalyzed N-arylation of
we aim to find the intricate balance between the solubility and benzamide.
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3
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In summary, we have developed a convenient and efficient
strategy for the N-arylation of benzamide using a mixture
of environmentally benign and commercially available
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2 4 2
Co(C O )·2H O/dmeda catalytic system. The protocol can be
applied to differently substituted iodobenzene to afford the
N-arylated derivatives in good to excellent yields of up to 92%.
These findings clearly demonstrated the application of cobalt
salts as a sustainable alternative in transition-metal catalyzed
carbon–heteroatom bond formation reactions. Further investi-
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0
2 3
.147 mmol), Cs CO (2.94 mmol), benzamide (1.47 mmol), N,
N′-dimethylethylenediamine (dmeda) (0.294 mmol), distilled
water (0.3 ml) and aryl halide (2.21 mmol) was added to a reac-
tion vial and a screw cap was fitted to it. The reaction mixture
was stirred under air in a closed system at 120 °C for 24 h, fol-
lowing which the heterogeneous mixture was cooled to room
temperature and diluted with dichloromethane. The diluted
2
8
3
2 4
reaction mixture was dried with anhydrous Na SO and the
1
solvent was removed under reduced pressure. The crude
product was loaded into the column using minimal amounts
of dichloromethane and methanol and was purified by silica-
gel column chromatography to afford the N-arylated product.
3
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The identity and purity of products were confirmed by H and
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C NMR spectroscopic analysis.
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2
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