Manganese-catalyzed cross-coupling reactions of nitrogen nucleophiles with aryl halides in water

Article abstract of DOI:10.1039/b909803h

A facile and convenient strategy for the assembly of N-arylated heterocycles has been demonstrated using a MnCl₂·4H ₂O/trans-1,2-diaminocyclohexane catalyst and K₃PO ₄ as the base in water.

Full text of DOI:10.1039/b909803h

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Manganese-catalyzed cross-coupling reactions of nitrogen nucleophiles
with aryl halides in waterw
Yong-Chua Teo,*a Fui-Fong Yong,a Chai-Yun Poh,b Yaw-Kai Yana and Guan-Leong Chuab
Received (in Cambridge, UK) 18th May 2009, Accepted 10th August 2009
First published as an Advance Article on the web 28th August 2009
DOI: 10.1039/b909803h
A facile and convenient strategy for the assembly of N-arylated
heterocycles has been demonstrated using a MnCl2ꢀ4H2O/
trans-1,2-diaminocyclohexane catalyst and K3PO4 as the base
in water.
manganese-catalyzed homocoupling reaction of halides in the
presence of magnesium.10 Recently, Cahiez et al.. reported
efficient cross-coupling reactions between aryl Grignard reagents
and alkenyl halides,11 and the homocoupling of Grignard
reagents with atmospheric oxygen as oxidant.11 Zhou and
Xue also reported an oxidative homocoupling of Grignard
chlorides in the presence of a re-oxidant.12 Hererin, we report
the first solely manganese-catalyzed N-arylation of nitrogen
nucleophiles catalyzed by a combination of MnCl2ꢀ4H2O13
and trans-1,2-diaminocyclohexane in water. It is worth noting
that the reaction only proceeded efficiently when water was
used as the reaction medium. This has implications not only in
terms of green chemistry, but also in the mechanistic aspects of
the reaction.
Transition metal-catalyzed cross coupling reactions of nitrogen
nucleophiles with aryl halides has emerged as a powerful
synthetic strategy that finds widespread applications in the
synthesis of pharmaceuticals, natural products and conducting
materials.1 Typically, the classical methods for generating
C–N bonds have been fuelled by either the copper-mediated2
Ullmann reaction or the palladium-catayzed3 Buchwald–Hartwig
amination reaction. In the past decade, the use of iron salts as
alternatives to perform transition metal-mediated coupling
reactions has also shown to be a promising strategy for
sustainable development.4 Taillefer et al. described an efficient
Fe/Cu cooperative system that catalyzed the assembly of
N-arylated heterocycles,5 while Correa and Bolm reported
the first ligand-assisted direct Fe-catalyzed N-arylation of
nitrogen nucleophiles with aryl halides.6 Although significant
progress has been made in the aforementioned transformations,
there still remains a need to develop new, economical, and
environmentally-friendly protocols that utilize cheap and
sustainable metal catalysis. Previously, our group have
developed efficient protocols for C–N cross-coupling reactions
in water using either the Fe or Co catalytic systems.7 Encouraged
by these precedents and our interest in manganese catalysis, we
envisaged the application of manganese salts as cheap and
sustainable alternative catalysts for this reaction.
In our initial study, the reaction between iodobenzene (1)
and pyrazole (2) was chosen. Using the optimized conditions
from previous protocols,7 the reaction was carried out using a
combination of MnCl2ꢀ4H2O, N,N0-dimethylethylenediamine
(L1) and K3PO4ꢀH2O in water, affording the product in a
moderate yield (Table 1, entry 1). This promising result
prompted us to evaluate the merits of the assisting ligands
for the arylation process. To our delight, the reaction carried
out using trans-1,2-diaminocyclohexane (L3) as the assisting
ligand gave the N-arylated product with an excellent yield of
78% (Table 1, entry 3). The necessity of the manganese salt
and the ligand was confirmed when the absence of either one
of these reagents resulted in no products being formed
(Table 1, entries 7 and 8). Next, we probed the solvent effect
using a series of organic solvents. Interestingly, we found that
the reaction proceeded efficiently only when water was used as
the sole reaction medium. Low yields were obtained when
DMF, toluene or THF were employed as the solvent (Table 1,
entries 9–11), and no products were detected in the case of
DMSO or CH3CN as the reaction medium (Table 1, entries 12
and 13). These organic solvents were used directly without
undergoing rigorous drying processes. Further experiments
revealed that the nature of the bases had a pronounced impact
on the process. The choice of K3PO4ꢀH2O as the base was
critical for this coupling reaction, as Cs2CO3 and K2CO3 were
evaluated and shown to be ineffective. Finally, we proceed
to screen the efficiency of other manganese salts for the
N-arylation reaction. It is worth noting that good to excellent
yields ranging from 65–78% were obtained for the majority of
the manganese salts screened, including Mn(acac)2, Mn(ClO4)ꢀ
H2O, MnF2, Mn(OAc)2 and MnO2 (Table 1, entries 14–18).
As such, this protocol has the added advantage of versatility in
terms of the selection of the manganese salts for the reaction.
With these findings, MnCl2ꢀ4H2O was the manganese salt of
choice for the cross-coupling reactions, since it is the least
The use of manganese salts for cross-coupling reactions is
attractive from both economical and environmental points of
view as they are readily available, cheap and more environ-
mentally benign in comparison to other transition metals.
However, examples of manganese-mediated coupling reactions
are limited. Most of the manganese-catalyzed cross-coupling
reactions reported thus far required the use of organometallic
reagents or reactive halides such as activated aryl halides or
chloroenyes.8 Rueping and Ieawsuwan developed the cross-
coupling reaction of heterocyclic chlorides with aryl Grignard
reagents using Mn(II) catalysts.9 Yuan and Bian developed the
a Natural Sciences and Science Education, National Institute of
Education, Nanyang Technological University, 1 Nanyang Walk,
Singapore 637616. E-mail: yongchua.teo@nie.edu.sg;
Fax: (65) 6896 9414; Tel: (65) 6790 3846
b Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
w Electronic supplementary information (ESI) available: Experimental
procedure, and 1H and 13C NMR spectral data for the N-arylated
products. See DOI: 10.1039/b909803h
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Table 1 Optimization studies for the manganese-catalyzed cross-
coupling of iodobenzene (1) and pyrazole (2) in watera
Table 2 N-arylation of pyrazole 2 with aryl halides catalyzed by
MnCl2ꢀ4H2O/L3 in watera
Entry
1
ArX
Product
Yield (%)b
78
3a
3b
2
3
16
10
Entry
[Mn] source
Ligand
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
—
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
MnCl2ꢀ4H2O
Mn(acac)2
L1
L2
L3
L4
L5
L6
—
L6
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMF
Toluene
THF
DMSO
CH3CN
H2O
H2O
H2O
H2O
H2O
31
Trace
78
0
0
0
0
0
21
8
5
3c
4
5
6
7
3d
3e
3f
75
80
74
67
9
10
11
12
13
14
15
16
17
18
0
0
78
75
72
71
65
Mn(ClO4)2ꢀH2O
3g
MnF2
Mn(OAc)2
MnO2
8
9
3h
3i
73
86
a
Unless otherwise noted, the reaction was carried out with
1H-pyrazole (1.47 mmol), iodobenzene (2.21 mmol), K3PO4ꢀH2O
(2.94 mmol), Mn source (10 mol%) and ligand (20 mol%) in water
(0.75 mL) at 130 1C for 24 h. b Isolated yield after column chromatography.
10
3j
75
70
expensive. In summary, the optimal conditions for the
N-arylation of pyrazole were achieved using a combination
of MnCl2ꢀ4H2O (10 mol%), trans-1,2-diaminocyclohexane
(L3) (20 mol%) and K3PO4ꢀH2O (2 equiv.), stirred in water
at 130 1C for 24 h.
In order to rule out the possibility that the catalysis was
assisted by traces of Cu salts14 or other contaminants that
might be present in the Mn salts, we had carried out the
reaction of pyrazole and iodobenzene using high purity
99.99% MnCl2ꢀ4H2O (Sigma) under the optimized conditions.
This reaction afforded the product 3a in a good isolated yield
of 64%. As such, we can conclude that metal contaminants, if
present, do not play any significant role in this Mn-catalyzed
cross-coupling reaction.
11
3k
a
Unless otherwise noted, the reaction was carried out with
1H-pyrazole (1.47 mmol), aryl halide (2.21 mmol), K3PO4ꢀH2O
(2.94 mmol), MnCl2ꢀ4H2O (10 mol%) and L3 (20 mol%) in water
b
(0.75 mL) at 130 1C for 24 h. Isolated yield after column
chromatography.
aryl iodine moiety was confirmed by the chemoselective results
from arenes with mixed halides, whereby the coupling only
takes place on the carbon atom with the iodo substituent in the
presence of other halides (Table 2, entries 8–10). These results
were similar to previous reports on catalytic systems based on
Fe and Co.
Having optimized the reaction conditions for the manganese
catalyzed arylation process, a study was initiated to explore
the generality of various aryl halides with pyrazole. The results
are shown in Table 2.
Finally, the scope of the manganese-catalyzed cross-
coupling reaction was tested with other nitrogen heterocycles,
and cyclic and acyclic amide derivatives. As shown in Table 3,
7-azaindole and indazole were effective nucleophilic partners
for the coupling reaction, which afforded the corresponding
products with good to excellent yields (Table 3, entries 1–5).
The N-arylation of a representative substituted pyrazole,
3-methylpyrazole, also gave the N-phenyl derivatives with
good yields (Table 3, entries 6–8). Poor yields were observed
In general, good to excellent yields were obtained for
sterically unhindered aryl halides. Ortho-substituted aryl halides
gave poor yields regardless of the electronic nature of the
substituent (Table 2, entries 2 and 3). Also, this protocol was
limited only to aryl iodides, since the employment of bromo-
benzene and 4-bromoanisole as electrophilic partners gave
only trace amounts of the products. The reactivity of the
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This journal is The Royal Society of Chemistry 2009
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Table 3 N-arylation of 7-azaindole, indazole, 3-methylpyrazole and
indole with aryl halides catalyzed by MnCl2ꢀ4H2O/L3 in watera
to various arylated N-heterocycles. Further investigation to
broaden Mn catalysis as a sustainable strategy for other
cross-coupling reactions is ongoing.
Notes and references
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p. 699; (c) I. P. Belatskaya and A. V. Cheprakov, Coord. Chem.
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ArX
Product
Yield (%)b
1
87
2
3
4
91
77
90
5301; (g) R. Martın, C. H. Larsen, A. Cuenca and S. L. Buchwald,
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Org. Lett., 2007, 9, 3379.
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Chem., 2002, 219, 131 and ref. cited therein.
5
6
82
78
7
8
9
75
72
25
20
4 For general reviews, see: (a) C. Bolm, J. Legros, J. Le Paih and
L. Zani, Chem. Rev., 2004, 104, 6217; (b) A. Furstner and
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R. Martin, Chem. Lett., 2005, 34, 624; E. B. Bauer, Curr. Org.
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10
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a
Unless otherwise noted, the reaction was carried out with nitrogen
nucleophile (1.47 mmol), aryl halide (2.21 mmol), K3PO4ꢀH2O
(2.94 mmol), MnCl2ꢀ4H2O (20 mol%) and L3 (40 mol%) in
8 (a) G. Cahiez, D. Bernard and J. F. Normant, J. Organomet.
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b
water (0.75 mL) at 130 1C for 48 h. Isolated yield after column
chromatography.
in the coupling of indole with aryl iodides (Table 3, entries 9
and 10). Currently, this catalytic system is not effective
when heterocycles such as pyrrole, imidazole or triazole are
employed in the process, as only trace amount of the products
are observed. Moreover, reactions carried out using benzyl-
amine, pyrrolidin-2-one, benzamide and aniline were also
unsuccessful.
In summary, a convenient route to N-arylated products
promoted by a ligand-assisted Mn catalysis in water has been
developed. The low cost and readily available Mn salts, the
mild reaction conditions, and the operational simplicity and
practicality render this transformation an attractive alternative
12 Z. Zhou and W. Xue, J. Organomet. Chem., 2009, 694, 599.
13 MnCl2ꢀ4H2O with Z 99% purity purchased from Sigma Aldrich
was used in all experiments reported here.
14 S. L. Buchwald and C. Bolm, Angew. Chem., Int. Ed., 2009, 48,
5586.
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This journal is The Royal Society of Chemistry 2009
6260 | Chem. Commun., 2009, 6258–6260