Simple synthesized Mannich bases as ligands in Cu-catalyzed N-arylation of imidazoles in water

Article abstract of DOI:10.1007/s00706-010-0363-8

1,4-Bis(2-hydroxy-5-methoxybenzyl)piperazine and its analogues were used as efficient ligands for CuI-catalyzed N-arylation of imidazoles with aryl halides in water under mild conditions (120 °C for 12 h) with 10 mol% of CuI, 20 mol% of the Mannich base, and two equivalents of KOH or K₂CO ₃ in the presence of 10 mol% phase transfer catalyst (n-Bu) ₄NBr. A variety of products were synthesized in moderate to excellent yields using this inexpensive catalytic system. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-010-0363-8

Monatsh Chem (2010) 141:1009–1013
DOI 10.1007/s00706-010-0363-8
ORIGINAL PAPER
Simple synthesized Mannich bases as ligands in Cu-catalyzed
N-arylation of imidazoles in water
•
Yefeng Zhu Yixing Shi Yunyang Wei
•
Received: 14 April 2010 / Accepted: 29 June 2010 / Published online: 5 August 2010
Ó Springer-Verlag 2010
Abstract 1,4-Bis(2-hydroxy-5-methoxybenzyl)piperazine
and its analogues were used as efficient ligands for
CuI-catalyzed N-arylation of imidazoles with aryl halides
in water under mild conditions (120 °C for 12 h) with
10 mol% of CuI, 20 mol% of the Mannich base, and two
equivalents of KOH or K2CO3 in the presence of 10 mol%
phase transfer catalyst (n-Bu)4NBr. A variety of products
were synthesized in moderate to excellent yields using this
inexpensive catalytic system.
to environmental problems. A breakthrough was made in
1999 by Buchwald et al. who performed such challenging
arylation reactions under mild conditions in good yields by
use of copper-chelating ligands such as 1,10-phenanthroline
[10, 11] and vicinal diamines [12]. In recent years, the
development of new ligands for copper-catalyzed cross-
coupling protocols has been an area of considerable interest.
As a result, a variety of ligands have been screened for the
N-arylation reaction between aryl halides and imidazoles
[13–21]. Despite these successes, efficient ligand-assisted
catalytic systems in the aqueous phase are rare [22–24].
Growing concern about pollution from organic solvents
has led to the development of more environmentally
friendly protocols in organic chemistry. In this context,
water has become the solvent of choice to perform many
organic transformations because of its properties such as
non-toxicity, low cost, and safety [25, 26]. However, the
synthesis of organic molecules in water faces challenges
such as water tolerance of the catalyst and the associated
problems of substrate solubility and reactivity [27]. In this
respect, the development of direct metal-catalyzed cou-
pling reactions that utilize less expensive and more
sustainable catalysts in water remains an elusive goal in
modern organic synthesis.
Keywords Catalysis Á Water Á Ligands Á Heterocycles Á
Arylation
Introduction
Nitrogen-containing heterocycles such as N-arylimidazoles
play an important role in the synthesis of a wide range of
medicinal [1–4], biological [5], and natural products [6] and
N-heterocyclic carbene chemistry [7, 8]. Traditionally, this
moiety has been prepared by nucleophilic aromatic substi-
tution of activated aryl halides with heterocycles by copper-
mediated coupling or via the classical Ullmann-type
coupling [6, 9]. In both cases the reactions require harsh
conditions (exposure of substrates to high temperature for
extended periods of time) and use of high boiling point polar
solvents and excess amounts of copper reagents, which lead
The Mannich reaction between phenols, formaldehyde,
and amines is often a simple, high-yielding reaction that
affords Mannich bases (Fig. 1) which are stable, polar
compounds and easily form water-soluble metal com-
plexes with copper and iron salts [28]. Recently, Sasmita
et al. [29] developed palladium-catalyzed Suzuki and
Heck coupling reactions using the Mannich base L3 as
ligand. However, according to our knowledge, application
of these inexpensive Mannich bases in copper-mediated
cross-coupling reactions in water has not yet been
reported.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-010-0363-8) contains supplementary
material, which is available to authorized users.
Y. Zhu Á Y. Shi Á Y. Wei (&)
School of Chemical Engineering, Nanjing University of Science
and Technology, Nanjing 210094, China
e-mail: ywei@mail.njust.edu.cn
123

1010
Y. Zhu et al.
OH
OH
OH
OH
Table 1 Results of N-arylation of imidazole with bromobenzene
N
N
N
N
N
N
Br
H
N
CuI, ligand, PTC
Base, H2O
N
OCH3
OH
OCH3
Me
OH
Me
OH
+
L1
L3
L2
L4
N
OH
3a
1
2
Me3C
CMe3
N
N
N
Entry
Cu source
Ligand
Base
Yielda (%)
CMe3
CMe3
Cl
Cl
1
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L1
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
Et3N
90
85
2
3
92
Fig. 1 Structures of Mannich bases L1–L4
4
83
81b
5
Results and discussion
6
28
7
L1
L1
L1
L1
L1
L1
L1
0
In this paper, we present an environmentally friendly
protocol for N-arylation of imidazoles with aryl halides
catalyzed by CuI with Mannich bases as ligands in water.
In our initial study, bromobenzene and imidazole were
chosen as model substrates for the coupling reaction
in water. The standardized protocol was carried out by
using imidazole (1.2 equiv), bromobenzene (1 equiv),
base (2 equiv), CuI (10 mol%), ligand (20 mol%), and
(n-Bu)4NBr as the phase transfer catalyst (PTC, 10 mol%)
in water at 120 °C for 12 h.
8
CuI
CuI
CuI
CuI
CuI
CuI
68
9
\5
\5
78c
69d
72e
10
11
12
13
Pyridine
KOH
KOH
KOH
Unless otherwise noted, the reaction was carried out with imidazole
(2.40 mmol), bromobenzene (2.00 mmol), KOH (4.00 mmol), CuI
(10 mol%), L1 (20 mol%), and PTC (10 mol%) in 2 cm3 water at
120 °C for 12 h
It can be seen from Table 1 that the CuI–L1 combina-
tion successfully promoted the coupling reaction in a yield
around 90% in water. The catalytic efficiency of the other
Mannich ligands was also evaluated in the same reaction
system (Table 1, entries 2–4). The more beneficial and
inexpensive ligand L1 was chosen for further reactions.
Table 1 also shows that more than one equivalent of base is
needed for the reaction to take place. In the presence of two
equivalents of an inorganic base, KOH or K2CO3, 90 or
68% yield of the N-arylation product was obtained. Only a
trace amount of product was found when organic bases
such as triethylamine and pyridine were used (Table 1,
entries 9 and 10). The more effective and inexpensive KOH
was chosen for further reactions. Meanwhile, the control
experiments showed that the presence of CuI was indis-
pensable and Mannich base ligand and PTC were beneficial
for the coupling. No product was detected in the absence of
CuI; only 28% yield was obtained by using CuI as catalyst
in the absence of any ligand; in the absence of the PTC
only 81% yield was obtained (Table 1, entries 5–7). Fur-
thermore, temperatures lower than 120 °C decrease the
reaction rate and conversion (Table 1, entry 11). In sum-
mary, the optimal conditions for the N-arylation process
consist of the combination of CuI (10 mol%), Mannich
base L1 (20 mol%), PTC (10 mol%), and KOH (2 equiv)
at 120 °C for 12 h in water.
a
Yield calculated by GC
b
Without PTC
c
The reaction temperature was 100 °C
The reaction was performed with CuI (5 mol%) and L1 (10 mol%)
d
e
The reaction was performed with KOH (3.00 mmol)
bromides were tested under the optimized reaction condi-
tions using imidazole as model substrate. The results are
shown in Table 2.
The results indicate clearly that the reaction of imid-
azole with aryl iodides provided slightly superior yields
than those with aryl bromides employed as arylating
agents. Most of the substituted aryl iodides and electron-
deficient aryl bromides afford N-arylimidazole products in
water with excellent yields ranging from 78 to 93%
(Table 2, entries 1–7). However, the arylation of electron-
rich aryl bromides resulted in lower yields (47–64%) even
with prolonged reaction time (24 h, Table 2, entries
8–11). It is noteworthy that the present protocol could
tolerate many functional groups. Imidazole could be
selectively arylated in the presence of a free amino or
hydroxyl group (Table 2, entries 9 and 10). However,
when p-nitroiodobenzene was used as arylating agent,
hydrolysis took place in the presence of KOH. Use of
K2CO3 instead of KOH as base led to the formation of
the desired N-arylation product in 93% yield (Table 2,
entry 3). When 4-chlorobromobenzene was used as the
In order to evaluate the scope of the process with respect
to the aryl halides, a variety of substituted aryl iodides and
123

Mannich bases as ligands in Cu-catalyzed N-arylation of imidazoles in water
Table 2 N-Arylation of
imidazole with aryl halides
1011
N
H
X
catalyzed by CuI/L1/PTC
in water
L1
N
N
CuI, , (n-Bu)4NBr
+
Y
KOH, H2O, 120 oC
N
Y
R
R
X = I, Br
Y = CH, N
3a 3h
-
Entry
1
ArX
Product
Yielda (%)
N
N
N
I
N
90
78
3a
3b
3c
3a
3c
3d
3e
3b
3f
N
N
H3C
O2N
I
I
H3C
O2N
N
N
2
3
93c
85
Br
Br
N
N
4
N
O2N
Cl
Br
O2N
Cl
N
5
87
N
Br
N
6
83
7
85
N
N
N
N
H3C
H2N
Br
Br
Br
H3C
H2N
N
N
8
47
9
62b
60b
64b
N
HO
HO
N
10
11
a
Isolated yield after column
chromatography
3g
3h
N
b
H3CO
Br
H3CO
N
Reaction time was 24 h
c
K2CO3 as the base
electrophilic counterpart, the reaction showed high che-
moselectivity, and only the bromo functionality reacted
(Table 2, entry 6).
in water. This method avoids the use of toxic organic
solvents and precludes the need for stringent inert condi-
tions. The ligand L1 could easily be synthesized via
Mannich reaction from inexpensive starting materials.
To expand the scope of this protocol further, this new
catalytic system was applied to a variety of nitrogen het-
erocycles. In order to get better yields, the reaction time
was extended to 24 h and the results are shown in Table 3.
To our delight, most of the nitrogen nucleophiles such as
pyrrole, indole, and benzimidazole were found to be
effective nucleophilic counterparts for the coupling pro-
cess, affording the corresponding coupling products in
excellent yields (82–92%). Notably, the sterically hindered
2-methylimidazole could undergo selective N-arylation
with 2-bromopyridine to afford the corresponding coupling
product in 81% yield (Table 3, entry 6).
Experimental
All reagents unless otherwise stated were purchased from
commercial suppliers and used without further purification.
Column chromatography was carried out with silica gel
(200–300 mesh). Thin-layer chromatography was carried
1
out using silica gel GF254 plates. H NMR spectra were
recorded on Bruker DPX (300 or 400 MHz) with CDCl3 as
solvent. Chemical shifts are reported in ppm using TMS as
internal standard. Gas chromatography mass spectra (GC/
MS) were recorded on an Agilent Technologies 6890 N
instrument with an Agilent 5973 N mass detector (EI) and
In summary, we have developed a simple, practical, and
efficient protocol for the N-arylation of imidazoles with
aryl halides promoted by a ligand-assisted copper catalyst
123

1012
Y. Zhu et al.
Table 3 N-Arylation of
nitrogen heterocycles with
aryl halides catalyzed by
CuI/L1/PTC in water
L1
CuI, , (n-Bu)4NBr
+
N-Het
4-7
X
Het-NH
KOH, H2O, 120 oC
Y
Y
X = I, Br
Y = CH, N
Entry
1
Het-NH
ArX
Product
Yielda (%)
H
N
N
I
4
5
92
85
Br
I
2
3
H
N
N
90
82
Br
Br
4
5
H
N
N
N
6
7
90
81
N
N
N
N
H
N
H3C
N
Br
N
6
CH3
a
N
Isolated yield after column
chromatography
N
an HP5-MS 30 m 9 0.25 mm capillary apolar column
(Stationary phase: 5% diphenyldimethylpolysiloxane film,
0.25 lm). GC/MS method: initial temperature 100 °C,
initial time 2 min, ramp 10 °C/min until 250 °C then held
for 20 min.
chromatography on silica gel. All products were known
and characterized by 1H NMR spectroscopy, the data were
found to be identical with those reported in the literature
[13–24, 30–34].
Acknowledgments We are grateful to Nanjing University of Sci-
ence and Technology for financial support.
Synthesis of Mannich bases L1–L4
The Mannich bases were synthesized according to Refs.
[28, 29].
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