N-methyliminodiacetic acid as a simple and highly efficient ligand for palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides

Article abstract of DOI:10.1002/aoc.3279

A simple, air-stable, inexpensive and easily prepared molecule, N-methyliminodiacetic acid (MIDA), is reported as a ligand for palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of phenylboronic acid with aryl chlorides. The yield of the corresponding Suzuki coupling reaction is up to around 90% at both high temperature of 80°C and room temperature under ambient atmosphere.

Full text of DOI:10.1002/aoc.3279

Full Paper
Received: 12 October 2014
Revised: 13 December 2014
Accepted: 26 December 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3279
N-methyliminodiacetic acid as a simple and
highly efficient ligand for palladium-catalyzed
Suzuki–Miyaura cross-coupling of aryl chlorides
a,b
a
a,b
a
a
Liang Qi , Xiuling Zhou , Xiaogang Li , Wei Li , Meiyun Lv
a,b
and Mengping Guo *
A simple, air-stable, inexpensive and easily prepared molecule, N-methyliminodiacetic acid (MIDA), is reported as a ligand for
palladium-catalyzed Suzuki–Miyaura cross-coupling reaction of phenylboronic acid with aryl chlorides. The yield of the corre-
sponding Suzuki coupling reaction is up to around 90% at both high temperature of 80°C and room temperature under ambient
atmosphere. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: MIDA; cross-coupling; aryl chlorides; ambient atmosphere
reactions in aqueous media under ambient atmosphere. Therefore,
such catalysts show potential applications in industry.
Introduction
[
31]
Nowadays the Suzuki cross-coupling reaction is used as a usual
[
1]
method to construct C–C bonds, particularly for the formation
of unsymmetric biaryl compounds. This reaction has been much
[
2–7]
Results and Discussion
studied since its discovery in 1979.
Many improvements on
the original protocol have been reported in terms of
catalyst/ligand systems, solvents, additives and experimental con-
ditions.
Optimization of Reaction Conditions
[1, 8-15]
Initially, the cross-coupling of 4-bromobenzene with phenylboronic
acid in 6 ml of solvent (ethanol–H O, 1:1) under to air was carried
It is well known that the activation of inert aryl chlorides is a
breakthrough in the laboratory. However, the cost of aryl bromides
is much higher than that of aryl chlorides, and so it is very imprac-
ticable to use aryl bromides in industry. Recently, large numbers of
groups have been working on the synthesis of catalysts in the acti-
vation of aryl chlorides. And highly active catalyst systems of palla-
2
out using various bases, such as NaOH and KOH. This gives different
yields, so this reaction was chosen as a model one for screening ba-
ses. The results are summarized in Table 1. Organic bases such as
Et N, dipropylamine and morpholine, which are colorless oily liq-
3
uids and insoluble in water, demonstrate low activity in the present
protocol (Table 1, entries 9–11). Subsequently, a series of inorganic
bases were examined (Table 1, entries 1–8). KOH, a typical inorganic
base in the palladium-catalyzed Suzuki reaction, was the first
inorganic base tested in the system, providing a positive result of
a 76% yield of the cross-coupling product in 30 min (Table 1,
[
16–21]
dium supported by bulky electron-rich phosphines
or
sterically demanding ligands are attracting much attention. But
only well-engineered electron-rich phosphine ligands are stable
[
22]
upon exposure to air, even at higher temperatures. What is more,
phosphine is environmentally unfriendly. N-heterocyclic carbenes
[23–29]
(NHCs)
and metallocycle scaffolds have been used as alterna-
entry 1). NaOH and Na
(Table 1, entries 2 and 3). K
different results (Table 1, entries 5–8). It is clear from the results that
the most efficient base in the present catalytic system is K CO
2
CO
3
provide results similar to that of KOH
tives to tertiary phosphines in cross-coupling reactions. Further-
more, NHC ligands have also been used to activate aryl chlorides
in the Suzuki reaction. Transition metal complexes of NHCs are nor-
mally stable towards air, moisture and high temperature; and they
are also suitable to be catalyst precursors. NHCs always have bulky
structures; even the ones with simple structures could make the re-
action proceed smoothly.
3
PO
4
Á3H O, KH PO , NaF and Cs CO give
2
2
4
2
3
,
3
2
which provides an isolated yield of 82% in 30 min, resulting in a
good turnover number.
In our group, we have been looking for a simple, air-stable, low-
cost and highly active ligand, and N-methyliminodiacetic acid
*
Correspondence to: Mengping Guo, Engineering Center of Jiangxi University for
Lithium Energy, Yichun University, Yichun 336000, PR China. Email:
604032318@qq.com
[30]
(MIDA) has been found to be a candidate. To the best of our
knowledge, MIDA has not been used as a ligand in transition-
metal-catalyzed Suzuki cross-coupling reactions. It not only can
be dissolved in water but also can be obtained easily and cheaply.
Meanwhile, this ligand is stable towards air, moisture and heat
treatment, and it can be used to activate Suzuki cross-coupling
a Institute of Coordination Catalysis, College of Chemistry and Bio-engineering,
Yichun University, Yichun 336000, People’s Republic of China
b Engineering Center of Jiangxi University for Lithium Energy, Yichun University,
Yichun 336000, People’s Republic of China
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.

L. Qi et al.
a
Table 1. Effect of base on cross-coupling reaction
2–5). However, ethanol shows lower activity (Table 2, entry 1). Then,
some other common solvents were tested in the model reaction
(Table 2, entries 6–10). The results indicate that n-butyl alcohol ex-
hibits high catalytic activity (Table 2, entry 4). The ratio of water
and n-butyl alcohol was also optimized, and the results show that
H O–n-butyl alcohol at a ratio of 1:1 is the best one. What is more,
2
in order to confirm that MIDA serves as a ligand in the reaction,
two reactions of the optimized system were carried out (Table 2, en-
tries 17 and 18). It is obvious that the palladium-catalyzed ligand-
free Suzuki reaction can occur, but the yield is poor. So it is inferred
that MIDA serves as a ligand and improves the yield of the reaction.
b
Entry
Base
Yield (%)
1
2
3
4
5
6
7
8
9
KOH
NaOH
Na CO
CO
PO
KH PO
NaF
Cs CO
Et
76
78
72
82
73
50
31
65
45
26
31
2
3
K
2
3
Scope and Limitations of Substrates
K
3
4
Á3H
4
2
O
With the optimized conditions in hand, we further studied the gen-
erality of the cross-coupling reactions of aryl halides and
2
phenylboronic acid in the presence of 2 mol% PdCl /MIDA ligand
2
2
3
and 3 mmol K CO at 80°C and room temperature, in a solvent of
3
N
2
3
water and n-butyl alcohol (1:1). The results are summarized in
Table 3. Various 4-substituted aryl chlorides, bearing either
electron-donating or electron-withdrawing groups, such as –OCH3,
1
0
1
Dipropylamine
Morpholine
1
a
Reaction conditions: 1 mmol bromobenzene, 1.2 mmol phenylboronic
acid, 3 mmol base, 0.02 mmol PdCl , 0.02 mmol ligand (MIDA), room
2
temperature, 30 min, 6 ml H
2
O–ethanol (1:1). In situ reaction.
a
Table 3. Suzuki reaction of aryl halides with phenylboronic acid
b
Isolated yield.
a
Table 2. Effect of solvent on cross-coupling reaction
b
c
Entry
R
R′
H
H
H
H
H
H
H
H
H
Time (h)
Temp. (°C)
Yield (%)
b
Entry
2
Solvent:H O (6 ml) = 1:1
Yield (%)
d
1
4-Me
4-NO
4-COCH
2-CN
8
8
RT
100
RT
45
62
86
94
74
76
71
73
47
65
39
58
90
99
42
71
55
70
64
96
31
46
73
42
51
1
2
3
4
5
6
7
8
9
Ethanol
82
93
90
98
96
74
32
26
40
47
38
76
88
84
78
59
10
7
2
3
4
2
4
Methanol
Isopropanol
4
80
3
4
RT
n-Butyl alcohol
n-Propyl alcohol
Acetone
4
80
4
RT
4
80
DMSO
d
5
4-OCH
3
8
RT
THF
8
100
RT
Acetonitrile
1,4-Dioxane
6
7
8
4-H
4
10
11
12
13
14
15
16
17
18
4
80
n-Butyl alcohol–H
n-Butyl alcohol–H
n-Butyl alcohol–H
n-Butyl alcohol–H
n-Butyl alcohol–H
n-Butyl alcohol–H
n-Butyl alcohol–H
n-Butyl alcohol–H
2
O (6:0)
O (5:1)
O (4:2)
O (2:4)
O (1:5)
O (0:6)
O (3:3)
O (3:3)
4-CF
3
4
RT
2
4
80
2
4-CN
4
RT
2
4
80
2
9
4-COOCH
3
4
RT
2
4
80
c
2
d
1
0
1
4-Me
Me
Me
Me
F
12
8
100
80
d
2
1
4-CF
3
a
d
Reaction conditions: 1 mmol aryl halide, 1.2 mmol phenylboronic acid,
mmol K CO , 0.02 mmol PdCl , 0.02 mmol ligand (MIDA), 6 ml
12
13
2-Me-6-Me
4-Me
12
12
8
100
100
80
d
3
2
3
2
solvent, room temperature, 30 min. In situ reaction.
14
15
16
4-CF
3
F
b
c
Isolated yield.
4-F
F
8
80
PdCl
2
without ligand.
4-H
F
8
80
d
Pd(OAc) without ligand.
2
a
Reaction conditions: 1 mmol aryl halide, 1.2 mmol phenylboronic acid,
mmol K CO , 0.02 mmol PdCl , 0.02 mmol ligand (MIDA), 6 ml
O–n-butyl alcohol (1:1). In situ reaction.
RT, room temperature.
3
H
2
2
3
2
To search for efficient solvents (Table 2) in the model coupling re-
action, some green alcohols were examined firstly. Methanol,
isopropanol, n-propyl alcohol and n-butyl alcohol provide positive
results for the cross-coupling products in 30 min (Table 2, entries
b
c
Isolated yield.
d
2
0.03 mmol PdCl , 0.03 mmol ligand (MIDA).
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2015)

MIDA as a ligand for Suzuki–Miyaura reaction
a
Table 4. Suzuki reaction of aryl halides with phenylboronic acid
improvement to the crossing-coupling reaction and the possibility
of industrialization.
Experimental
Aryl chlorides, MIDA and phenylboronic acid were purchased from
Alfa Aesar. Other chemicals were obtained commercially and used
without prior purification. All products were isolated using thin-layer
chromatography with a silica gel using n-hexane and ethyl acetate
unless otherwise noted. Compounds described in the literature were
b
c
Entry
R
Time (h)
Temp. (°C)
Yield (%)
1
2
3
4
CH
3
4
4
4
4
4
4
4
4
RT
80
RT
80
RT
80
RT
80
26
29
44
66
52
75
67
87
1
13
characterized using H NMR and C NMR spectra and compared with
1
reported data. H NMR spectra were recorded with a Bruker Avance II
CN
400 spectrometer using tetramethylsilane as the internal standard.
All Suzuki reactions were carried out under air. A mixture of aryl
halide (1.0 mmol), phenylboronic acid (1.2 mmol), base (3.0 mmol),
NO
2
PdCl (0.02 mol%, 0.0036 g), ligand MIDA (0.02 mol%, 0.0029 g), wa-
2
H
ter (3.0 ml) and n-butyl alcohol (3.0 ml) was stirred at 80°C for the
indicated time. The reaction mixtures were extracted with ethyl ac-
etate (3 × 10 ml). The solvent was concentrated under vacuum.
a
Reaction conditions: 1 mmol aryl halide, 1.2 mmol phenylboronic acid,
mmol K CO , 0.02 mmol PdCl , 0.02 mmol ligand (MIDA), 6 ml
O–n-butyl alcohol (1:1). In situ reaction.
RT, room temperature.
3
2
3
2
H
2
Acknowledgements
b
c
We are grateful to the National Natural Science Foundation of China
Isolated yield.
(no. 21063015), the Jiangxi Provincial Natural Science Foundation of
China (no. 20114BAB203012) and the Key Science and Technology
plan of Yichun City (no. [2010] 24) for their financial support.
–
CN, –COCH , –CH , –CF , –COOCH and –NO , provide the corre-
3 3 3 3 2
sponding products in moderate to good yields. No matter
electron-donating or electron-withdrawing groups, the reaction at
high temperature gives a better yield than that at room tempera- References
ture. Also, aryl chlorides with electron-withdrawing groups
[
[
[
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and 7). 4-Acetylchlorobenzene, 4-cyanochlorobenzene and
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[
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lower yields. When we delayed the reaction time, increased the tem-
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[
[
[
[
(
Table 3, entries 1 and 5). The cross-coupling reactions proceed very
smoothly, even when increasing the steric effect of the aryl chloride
Table 3, entry 4).
(
[
[
[
[
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cyanopyridine have an electron-withdrawing group, and they also
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in place of phenylboronic acid. The results are summarized in Table 3
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(
Summary
Supporting Information
MIDA, a simple, easily obtained and air-stable ligand, can
activate aryl chlorides in the palladium-catalyzed Suzuki–Miyaura
reaction in water and n-butyl alcohol (1:1). This will bring an
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web-site.
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc