Cobalt-catalyzed N-arylation of nitrogen nucleophiles in water

Article abstract of DOI:10.1002/chem.200802483

The first cobalt-catalyzed N-arylation of nitrogen heterocycles with electrophilic aryl halides in water mediated by a combination of readily available and cheap CoCl₂·6H₂O with the chelating diamine was reported. Investigation of the ligand system show that the reaction proceeds through a biphasic system with the best yield achieved when the reaction is carried out using a combination of CoCl₂·6H ₂O and N,N'-dimethylethylenediamine (dmeda). Aryl iodides are found to be more reactive than aryl bromides as electophilic counterpart in the coupling reactions, producing the products in much higher yields. Heterocycles, such as indole and 7-azaindole are found to be effective nucleophilic counterparts for the coupling process and produce N-phenyl derivatives.

Full text of DOI:10.1002/chem.200802483

DOI: 10.1002/chem.200802483
Cobalt-Catalyzed N-Arylation of Nitrogen Nucleophiles in Water
Yong-Chua Teo*[a] and Guan-Leong Chua[b]
Transition-metal-catalyzed cross-coupling reactions for
cross-coupling of nitrogen nucleophiles with aryl halides
without the need for reducing agents or electrochemical pro-
cedures.
the generation of carbon–heteroatom bonds has emerged as
a versatile strategy for chemical synthesis.[1] In particular,
the intense demand for the N-arylation of nitrogen hetero-
cycles with aryl halides has been fuelled by their application
in the production of key synthons that are prevalent build-
ing blocks for the construction of many natural products
and biologically active pharmaceutical agents. The vast ma-
jority of the existing protocols for performing this type of
transformation have been mediated by palladium-, copper-
and, more recently, iron-metal catalysts.[2] Although signifi-
cant progress have been made in the aforementioned trans-
formations, there is still a need to develop new environmen-
tally friendly strategies that utilize inexpensive and more
substainable metal catalysts for this class of reaction.
The use of cobalt salts as an alternative metal catalyst to
perform established transition-metal-catalyzed cross-cou-
pling reactions has recently emerged as a new and promising
strategy.[3,4] These methods are characterized by the low
cost, ready availability, and environmentally friendly nature
of the cobalt salts used, in addition to the mild reaction con-
ditions. However, the majority of cobalt-catalyzed cross-cou-
pling procedures either require the presence of excess re-
ducing agents[5] or involve electrochemical techniques.[6] En-
couraged by our interest in cobalt catalysis and the need for
a more direct, versatile, and simple-to-operate catalytic
system, we envisaged the application of cobalt salts for the
Organic reactions in water have recently attracted much
attention because water is an inexpensive, safe, and environ-
mentally benign medium.[7] The majority of recent strategies
for transition-metal coupling reactions in water have been
promoted either by palladium- or copper-metal catalysts.[8]
Henceforth, as part of our endeavors towards the develop-
ment of environmentally friendly protocols, efforts were di-
rected towards performing the cobalt-catalyzed coupling re-
action using water as the sole reaction media. Herein, we
have disclosed the first cobalt-catalyzed N-arylation of nitro-
gen heterocycles with electrophilic aryl halides in water
mediated by a combination of readily available and cheap
CoCl2·6H2O with the chelating diamine N,N’-dimethyleth-
AHCTUNGTREGyNNNU lenediamine (dmeda). It is worth noting that the coupling
reaction proceeded in water in the presence of the cobalt
catalyst without the need for other reducing agents or elec-
trochemical methods.
The reaction between iodobenzene 1 and 1H-pyrazole 2
was chosen as the model process for the cobalt-catalyzed
coupling reaction in water. To evaluate the merits of various
ligands and cobalt sources for the N-arylation process, a
series of experiments was carried out by using a standard-
AHCTUNGTREGiNNNU zed protocol. The reaction was carried out by using 1H-pyr-
azole (1 equiv), iodobenzene (1.5 equiv), cobalt source
(10 mol%), ligand (20 mol%), and tri-potassium phosphate-
1-hydrate (K3PO4·H2O; 2 equiv) in water at 1208C for 24 h.
The optimization studies are shown in Table 1.
[a] Dr. Y.-C. Teo
Natural Sciences and Science Education
National Institute of Education
Nanyang Technological University
1 Nanyang Walk, 637616 (Singapore)
Fax : (+65)6896-9414
Investigation into the ligand system revealed that the re-
action proceeded via a biphasic system with the best yield
achieved when the reaction was carried out using a combi-
nation of CoCl2·6H2O and N,N’-dimethylethylenediamine
(dmeda; L4; Table 1, entry 4). A moderate yield was also
achieved when trans-1,2-diaminocyclohexane L3 (Table 1,
entry 3) was employed as the assisting ligand. Control ex-
periments were also carried out to confirm that no product
was obtained in the absence of either the ligand or the
cobalt source (Table 1, entries 6 and 7). With these encour-
aging results, we proceeded to screen the efficiency of the
E-mail: yongchua.teo@nie.edu.sg
[b] Dr. G.-L. Chua
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, 637371 (Singapore)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802483.
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Chem. Eur. J. 2009, 15, 3072 – 3075

COMMUNICATION
Table 1. Screening of various ligands and cobalt sources for the N-aryla-
Table 2. N-arylation of pyrazole 2 with aryl halides catalyzed by
tion of pyrazole 2 in water.[a]
CoCl2·6H2O/dmeda in water.[a]
Entry
1
ArX
Product
Yield [%][b]
81
2
3
32
16
Entry
Co source
Ligand
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
none
L1
L2
L3
L4
L5
none
L4
L4
L4
L4
L4
L4
L4
0
0
52
68
trace
0
4
5
6
75
80
82
0
CoCl2
67
12
0
61
60
81[c]
[Co
[Co
Co(ClO4)2·6H2O
Co(oxalate)2·2H2O
CoCl2·6H2O
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
[a] Unless otherwise noted, the reaction was carried out with 1H-pyrazole
(2.16 mmol), iodobenzene (3.24 mmol), K3PO4·H2O (4.32 mmol), Co
source (10 mol%), and ligand (20 mol%) in water (1.5 mL) at 1208C for
20 h. [b] Isolated yield after column chromatography. [c] Reaction was
stirred at 1208C for 36 h.
7
80
various cobalt sources for the N-arylation process by using a
catalyst loading of 10 mol% and 20 mol% of L4 in water.
Among the cobalt sources screened, the best reactions were
catalyzed by CoCl2·6H2O or CoCl2 in combination with L4
to give the N-arylated products in yields of 68 and 67%, re-
spectively, (Table 1, entries 4 and 8). With these findings,
CoCl2·6H2O was chosen as the cobalt source for the cross-
coupling reactions because it is less expensive than CoCl2.
8
9
85
21
24
16
10
11
Moreover, the reactions employing Co
ACHTUGNTNERN(UNG ClO4)2·6H2O and
Co(oxalate)2·2H2O as cobalt sources also afforded the ary-
ACHTUNGTRENNUNG
lated products in good yields of 61 and 60%, respectively
(Table 1, entries 11 and 12). In summary, the optimal condi-
tions for the N-arylation process in water was achieved by
[a] Unless otherwise noted, the reaction was carried out with 1H-pyrazole
(2.16 mmol), aryl halide (3.24 mmol), K3PO4·H2O (4.32 mmol),
CoCl2·6H2O (10 mol%), and dmeda (20 mol%) in water (1.5 mL) at
1208C for 36 h. [b] Isolated yield after column chromatography.
using
a combination of CoCl2·6H2O (10 mol%), L4
(20 mol%) and K3PO4·H2O (2 equiv) at 1208C for 36 h,
which afforded the product in a good yield of 81% (Table 1,
entry 13).
With a set of optimized conditions in hand, a study was
initiated to explore the generality of the aryl halides in the
N-arylation process. We carried out the reactions with a va-
riety of substituted aryl iodides and bromides as the electro-
phile and 1H-pyrazole as the nitrogen nucleophile under the
optimized reaction conditions. The results obtained are
shown in Table 2.
affording the products in much higher yields (up to 85%).
However, ortho substituents on the aryl iodides hampered
the reaction and led to lower yields (Table 2, entries 2 and
3). The reaction was highly chemoselective, reacting only
with the carbon atom with the iodine substituent even in the
presence of chloro or fluoro substituents (Table 2, entries 3,
5, 7, and 8). The reaction was simple and convenient to per-
form in a screw-capped reaction vial, thereby precluding the
need for stringent inert conditions. Moreover, the applica-
In general, aryl iodides were more reactive than aryl bro-
mides as electrophilic counterpart in the coupling reactions,
Chem. Eur. J. 2009, 15, 3072 – 3075
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www.chemeurj.org
3073

Y.-C. Teo and G.-L. Chua
tion of water as the reaction media and the use of
CoCl2·6H2O, an inexpensive and environmentally benign
source of cobalt, greatly enhances the economic and envi-
ronmentally friendly aspects of this catalytic system.
The scope of the arylation reaction was tested with other
heterocycles and acyclic and cyclic amides. The results are
shown in Table 3. Heterocycles, such as indole and 7-azain-
dole, were found to be effective nucleophilic counterparts
for the coupling process and afforded the respective N-
phenyl derivatives (Table 3, entries 1–4) in good yields (up
to 86%). However, less satisfactory results were obtained in
the case of both acyclic and cyclic amide derivatives
(Table 3, entries 5–6 and 7–8, respectively) and only trace
amounts of the desired products were detected when aro-
matic (Table 3, entry 9) and alkyl amines (Table 3, entry 10)
were employed.
In summary, we have developed a very practical and effi-
cient protocol for the N-arylation of nitrogen nucleophiles
with substituted aryl iodides and bromides promoted by a
ligand-assisted cobalt catalyst in water. Features worth
noting include 1) the N-arylation of various nitrogen nucleo-
philes with substituted aryl halides, which proceeded effi-
ciently in water to afford a broad spectrum of valuable com-
pounds from commercially available substrates; 2) the pro-
cedure is simple to perform and only mild conditions were
required; 3) the catalytic system can be easily generated by
using a mixture of the simple, inexpensive, and environmen-
tally friendly CoCl2·6H2O and L4; 4) the coupling reaction
takes place efficiently without the need for other cometal
catalysts. Further studies to elucidate the mechanism of this
catalytic system and to extend this process to other coupling
reactions is ongoing in our laboratory.
Table 3. N-arylation of indole, 7-azaindole, benzamide, and pyrrolidin-2-
one with aryl halides catalyzed by CoCl2·6H2O/dmeda in water.[a]
Entry
1
NuH
ArI
Product
Yield [%][b]
62
2
3
43
86
Experimental Section
The N-nucleophile (2.16 mmol), CoCl2·6H2O (98% purity; 0.216 mmol),
K3PO4·H2O (4.32 mmol), the aryl halide (3.24 mmol), L4 (0.432 mmol),
and water (1.5 mL) were added to a reaction vial and a screw cap was
fitted to it. The reaction mixture was stirred under air in a closed system
at 1208C for 36 h, then the heterogeneous mixture was cooled to RT and
diluted with dichloromethane. The resulting solution was directly filtered
through a pad of Celite. The organic extracts were decanted to remove
residual water and further dried with anhydrous MgSO4. The solvent was
then removed under reduced pressure and the crude product purified by
column chromatography on silica gel to afford the N-arylated product.
The identity and purity of known products were confirmed by 1H and
13C NMR spectroscopic analysis. See the Supporting Information for full
details.
4
77
5
6
7
28
24
27
Acknowledgements
We would like to thank the National Institute of Education (Grant No.
RP5/06 TYC) and Nanyang Technological University for their generous
support.
8
25
Keywords: cobalt · cross-coupling · heterogeneous catalysis ·
N-arylation · water chemistry
9
trace
trace
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Cobalt-Catalyzed N-Arylation
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Received: November 27, 2008
Published online: February 13, 2009
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3075