Efficient palladium-catalyzed suzuki-miyaura reactions using phenolic schiff base ligands under ambient conditions in aqueous media

Article abstract of DOI:10.1007/s11243-013-9704-x

The palladium complexes of a series of simple Schiff base ligands with or without phenolic hydroxyl groups have been found to be the excellent catalysts for the Suzuki-Miyaura reactions of aryl iodides, aryl bromides and activated aryl chlorides under ambient conditions in aqueous ethanol media. The introduction of phenolic hydroxyl and/or pyridine groups to the ligands increased the catalytic activity. Under optimal reaction conditions, satisfactory to excellent yields of biaryls were obtained with a wide range of substrates for relatively low loadings of catalyst. Graphical Abstract: Phenolic hydroxyl group and N₄-type Schiff base ligands (L1-2) have been proven to be the excellent catalysts for the Suzuki-Miyaura reactions of aryl iodides, aryl bromides and activated aryl chlorides in aqueous ethanol under ambient. Furthermore, a diverse choice of functionalized arylboronic acids bearing difluoro, trifluoro and trifluoromethyl substituents were successfully coupled (>97 %)[Figure not available: see fulltext.].

Full text of DOI:10.1007/s11243-013-9704-x

Transition Met Chem (2013) 38:401–405
DOI 10.1007/s11243-013-9704-x
Efficient Palladium-catalyzed Suzuki–Miyaura reactions using
phenolic Schiff base ligands under ambient conditions
in aqueous media
Zhonggao Zhou
Xiuhua Zhou Qi Qi
•
•
Zhenyun Zhou
•
•
Aichen Chen
•
Yongrong Xie
Received: 5 January 2013 / Accepted: 4 February 2013 / Published online: 19 February 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract The palladium complexes of a series of simple
Schiff base ligands with or without phenolic hydroxyl
groups have been found to be the excellent catalysts for the
Suzuki–Miyaura reactions of aryl iodides, aryl bromides and
activated aryl chlorides under ambient conditions in aque-
ous ethanol media. The introduction of phenolic hydroxyl
and/or pyridine groups to the ligands increased the catalytic
activity. Under optimal reaction conditions, satisfactory to
excellent yields of biaryls were obtained with a wide range
of substrates for relatively low loadings of catalyst.
Suzuki–Miyaura cross-coupling is undoubtedly the most
powerful tool to selectively generate biaryls [5]. Indeed, there
have been a few reports about the employment of Schiff base
ligands in Pd-catalyzed Suzuki reactions [6–15]. Singh and
co-workers reported that the catalytic activity increases with
the length of alkyl chain of the Schiff base ligand [14].
Recently, Das and co-workers reported two N -Schiff base
4
ligands whose palladium complexes were used as efficient
catalysts for Suzuki reactions in aqueous media [12]. On the
other hand, sterically hindered and phenolic substituted
ligands also display good activity in Pd-catalyzed Suzuki
reactions [16–19]. However, Suzuki reactions with deacti-
vated aryl bromides did not occur for Pd(II) complexes
of Schiff base ligands with phenolic groups only [6]. The
development of simple, low-cost and efficient catalysts for
the Suzuki reaction is a topic of great interest. However, to the
best ofour knowledge, therehas been noreport ofthe catalytic
activity of Pd(II) complexes with phenolic hydroxyl substi-
tuted Schiff base ligands for Suzuki reactions. Thus, in order
to extend the scope of Schiff base ligands further in Suzuki
reactions, we have investigated the palladium complexes
of two phenolic Schiff base ligands L1 [3-methoxy-
Introduction
Schiff bases are considered to be ‘‘privileged ligands’’
because they are easily synthesized and form complexes with
almost all transition metals [1]. Many Schiff base complexes
show excellent catalytic activity in various reactions under
reflux conditions, even in the presence of air [2, 3]. An
industrially useful cross-coupling to synthesize fine chemi-
cals and pharmaceuticals, namely the Heck reaction, was
successfully catalyzed using Schiff base complexes [4].
6
-(((methyl-2-pyridinylmethyl)imino)methyl)-phenol) andL2
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-013-9704-x) contains supplementary
material, which is available to authorized users.
(
1-((1-(pyridin-2-yl)ethylimino)methyl)naphthalen-2-ol]
[20], plus another two racemic Schiff base ligands L3 [21],
L4 [22] in Pd-catalyzed Suzuki reactions (Scheme 1). We
herein present our results for the use of these new catalysts in
Suzuki reactions under air in aqueous media.
Z. Zhou (&) ꢀ Z. Zhou ꢀ A. Chen ꢀ Q. Qi ꢀ Y. Xie
College of Chemistry and Chemical Engineering,
Gannan Normal University, Ganzhou 341000,
People’s Republic of China
e-mail: zhgzhou@foxmail.com
Y. Xie
e-mail: yongrongxie@foxmail.com
Experimental
All chemicals employed in the synthesis were analyti-
cal grade, obtained commercially and used as received
without further purification. The solvents dioxane and
X. Zhou
Fujian Inspection and Research Institute for Product Quality,
Fuzhou 35002, People’s Republic of China
123

4
02
Transition Met Chem (2013) 38:401–405
0
0
0
0
[
24], 4-Acetyl-3 ,4 ,5 -trifluoro-1,1 -biphenyl (Table 4, entry
0 0 0
1
1) [15], 4-Acetyl-3 ,5 -difluoro-1,1 -biphenyl (Table 4,
0
0
0
entry 12) [25], 4-Acetyl-3 ,5 -ditrifluoromethyl-1,1 -biphenyl
Table 4, entry 13) [26].
(
Results and discussion
To evaluate the efficiencies of the new catalysts for the
Suzuki reaction, initially we screened the reaction of a
relatively deactivated substrate, namely 4-bromotoluene,
with phenylboronic acid. We have investigated the proce-
dure with respect to five key variables in our catalyst
system: (1) solvent composition, (2) reaction temperature,
(3) effect of the base, (4) ligand composition and (5) cat-
alyst loading and ratio. During the course of these studies,
we discovered that the reaction can be run smoothly under
air when KOH or NaOH is used as base in ethanol (95 %),
thus improving its operational simplicity.
Scheme 1 The selected Schiff base ligands
tetrahydrofuran were dried by standard methods, and other
solvents were used directly. The Schiff bases L1 [20], L2
[
20], L3 [21] and L4 [22] were prepared as reported. NMR
spectra were recorded on a Bruker Avance III 400 MHz
spectrometer, and coupling constants (J values) are given
in Hertz.
GC–MS analyses for all of the experiments were car-
ried out on an Agilent 6890 GC with 5973 mass detector,
using an AT.SE-30 column of 50 m length, 0.32 mm
diameter and 0.5-lm-film thicknesses. GC parameters for
Suzuki reactions were as follows: injector temperature
Our first step was to identify the best solvent system,
since solvents have a key influence on the reaction envi-
ronment and affect the catalyst activity, especially in
transition metal catalyzed chemistry [27]. Casalnuovo and
Calabrese transferred this reaction to aqueous conditions as
early as 1990 [28]. Further, phase transfer catalysts and the
addition of water-soluble organic co-solvents have been
employed with great success in recent years [12, 15, 29].
The reactions were conducted in various solvents, with the
results given in Table 1. The ligands L1–4 were combined
2
80 °C; detector temperature 280 °C; initial temperature
00 °C; initial time 5 min; temperature ramp 1, 30 °C
1
-
1
-1
;
min ; final temperature 200 °C; ramp 2, 20 °C min
final temperature 250 °C; run time 30 min; inject 1.0 lL;
helium as the GC carrier gas; pressure of the system was
3
.5 bar.
General procedure for the Suzuki reaction
with Pd(OAc) in situ and used as catalysts for the Suzuki
2
reaction (Table 1). When the reaction was conducted in
ethanol with K CO as base and 0.5 mol % of catalyst, we
The appropriate amounts of ligand, base and metal pre-
cursor were added to the required solvent (3.0 mL). The
mixture was stirred for 30 min, and then, the aryl halide
2
3
were delighted to observe that the desired products were
isolated in nearly quantitative yields within 2 h with
(
0.5 mmol) and aryl boronic acid (0.75 mmol) were added,
Pd(OAc) /L1 as catalyst (Table 1, Entry 5). It is obvious
2
and the mixture was stirred under reflux in air. The course
of the reaction was monitored by GC–MS analysis, and
yields were calculated against the aryl halides. On com-
pletion of the reaction, the solvent was removed under
that temperature also constitutes a critical parameter for the
Suzuki reaction; L1 and L2 gave only poor yields at room
temperature (Table 1, Entries 1–4).
Among the various solvents explored, the best results
were obtained with EtOH (95 %), plus a small amount of
water to facilitate the reaction. Longer reaction times were
required with higher water contents, and trace biphenyl was
observed (Table 1, Entries 5–8). When neat water was used
as solvent, tri(p-tolyl)boroxine [30], phenol [31] and
biphenyl were observed as side products (Table 1, Entry
14). It was also observed that the phenolic and pyridine
groups of the ligand were crucial for achieving high cata-
lytic activities, and the use of supporting ligands with
relatively bulky substituents also increases the catalytic
activity.
reduced pressure. The residue was diluted with H O
2
(
3.0 mL) and Et O (3.0 mL), followed by extraction with
2
Et O (2 9 3.0 mL). The organic fraction was dried over
2
anhydrous MgSO4 then filtered, and the solvent was
evaporated under reduced pressure. The crude product was
purified by column chromatography using 200–300 mesh
silica gel, and the purified products were characterized by
0
NMR spectra as 4-Methyl-1,1 -biphenyl (Table 4, entries
0
1
, 2 and 8) [16], 4-Cyano-1,1 -biphenyl (Table 4, entry 3)
0
[
23], 4-Methoxy-1,1 -biphenyl (Table 4, entry 4) [24],
0
4
-Acetyl-1,1 -biphenyl (Table 4, entry 5) [16], 2-Methyl-
0
1
,1 -biphenyl (Table 4, entry 6) [24], Biphenyl (Table 4,
0
However, under similar experimental conditions, L3 and
L4 were found to be less effective, producing only poor to
moderate yields (Table 1, Entries 5–14). Therefore, in the
entry 7) [15], 4-Trifluoromethyl-1,1 -biphenyl (Table 4,
0
entry 9) [17], 2-Methoxy-1,1 -biphenyl (Table 4, entry 10)
1
23

Transition Met Chem (2013) 38:401–405
403
Table 1 Effect of various parameters on the Suzuki reactions
Table 2 Effects of base on the Suzuki reactions
a
a
Entry Solvent
Temperature Time Conversion (%)
(h)
L1 L2 L3 L4
Entry
Base
Time (h)
Conversion (%)
(°C)
L1
L2
1
2
3
4
Ethanol
r.t.
r.t.
r.t.
r.t.
24
24
3
24 36
15 25
26 23
43 45
–
–
–
–
–
–
–
–
1
2
3
4
5
6
7
8
9
Cs
KOH
PO
KH PO
2
CO
3
3
1
1
3
1
1
3
3
3
3
3
3
1
21
97
92
42
85
96
79
72
0
34
99
95
47
90
99
88
75
0
Methanol
Acetone
K
3
4
Acetone/Water
3
2
4
(3/1)
t
NaOBu
NaOH
5
6
Ethanol
85
85
2
3
98 99 86 65
90 95 82 44
Ethanol/Water
2 3
Na CO
(
3/1)
Ethanol/Water
1/1)
Ethanol (95 %) 85
NaHCO
NaOAc
LiCl
3
7
85
4
98 96 83 46
(
10
11
12
13
2
4
8
9
1
1
1
1
1
1
3
3
1
3
3
1
99 99 85 50
98 99 80 62
59 65 41 30
94 96 55 51
65 70 35 31
60 65 30 22
92 99 87 46
Et
Blank
CO
3
N
42
4
49
5
Methanol
Dioxane
Toluene
85
0
1
2
3
4
110
110
K
2
3
99
99
Tetrahydrofuran 80
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
0.75 mmol), catalyst (0.5 mol %, Pd(OAc) :L = 1:1), Base (2.0
equiv), Ethanol (95 %) (3.0 mL), reflux, under air
(
2
Acetonitrile
Water
85
100
a
Average of two runs, measured by GC–MS
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
0.75 mmol), catalyst (0.5 mol %, Pd(OAc) :L = 1:1), K CO (2.0
equiv), solvent (3.0 mL), reflux, under air
(
2
2
3
a
Table 3 Effect of palladium source and ligand ratio on the Suzuki
reactions
Average of two runs, measured by GC–MS
a
following experiments, we used only L1 and L2 as sup-
porting ligands (Scheme 2).
Entry
Pd source
Ratio
Conv. (%)
L1
L2
The presence and the nature of the base, additional
functional groups and additives (such as tetraalkylammo-
nium salts) can also play an important role in the outcome
of the Suzuki reaction [32]. In general, the base generates
an intermediate compound with Pd(II) that undergoes
transmetallation with boronic acid derivatives [23]. In the
present system, KOH (without any biphenyl) was found to
1
PdCl
Pd(CF
Pd(COD)Cl
Pd (dba)
2
1:1
86
94
95
93
97
67
65
82
48
92
95
97
94
99
79
72
86
48
2
3
COO)
2
1:1
3
2
1:1
4
2
3
1:1
5
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
1:1
6
1:1.5
1:2
7
be the most appropriate base, as with the alternatives
t
Cs CO , NaOBu , K PO , Et N, Na CO , etc.), longer
(
8
1:0.9
1:0
2
3
3
4
3
2
3
reaction times were necessary for reasonable conversions
9
b
b
(
Table 2).
10
11
1:1
95
97
80
c
c
The source of palladium and the palladium-ligand molar
1:1
76
ratio also play key roles in Pd-catalyzed Suzuki reactions
33]. We therefore investigated the model reaction using
Reaction conditions: 4-bromotoluene (0.5 mmol), phenylboronic acid
(0.75 mmol), palladium source catalyst (0.5 mol %, Pd:L = 1:1),
KOH (2.0 equiv), ethanol (95 %) (3.0 mL), reflux, 1 h
[
different palladium sources and palladium-ligand molar
a
ratios (Table 3). We observed that Pd(OAc) and a 1:1
2
Average of two runs, measured by GC–MS
b
palladium-ligand ratio gave the optimum reaction rate
Catalyst 0.2 mol %
c
(
Table 3, entry 5). Increasing the amount of ligand had a
Catalyst 0.1 mol %
Scheme 2 Suzuki reactions of 4-bromotoluene with phenylboronic acid
123

4
04
Transition Met Chem (2013) 38:401–405
Table 4 Suzuki reactions of
various aryl halides with aryl
boronic acids
Reaction conditions: aryl halide
(
(
0.5 mmol), arylboronic acid
0.75 mmol), KOH (1.0 mmol),
EtOH (95 %) (3.0 mL),
2
Pd(OAc) /L (0.2 mol %), reflux,
in air
a
Average of two runs, isolated
yields
b
1
.0 mmol TBAB
significant negative influence on the yields (Table 3, entries
and 7), which might be due to coordinative saturation of
(C95 %) when phenyl boronic acid is a coupling partner. We
expanded the set to include electron rich and electron defi-
cient aryl halides and boronic acids in order to gauge the
compatibility of these species with our reaction conditions.
A variety of functionalities are tolerated for the aryl bromide
including ketone, nitrile and methoxy groups (Table 4,
entries 3–5). Furthermore, a diverse choice of functionalized
arylboronic acids bearing difluoro, trifluoro and trifluoro-
methyl substituents were successfully coupled (Table 4,
entries 11–13). The generally good yields observed for both
6
the metal center [34]. The optimum concentration of L1 and
L2 with Pd(OAc) for catalysis was found to be 0.2 mol %,
2
while the reaction time was optimized as 1 h.
Having demonstrated that ligand L1 can participate in
efficient catalytic reactions, it was of interest to compare the
relative efficiency of the more sterically demanding ligand
L2 under identical reaction conditions. Thus, L2 exhibits
slightly higher yields in all cases except for aryl chlorides
1
23

Transition Met Chem (2013) 38:401–405
405
ligands L1 and L2 for the coupling of aryl boronic acids with
aryl bromides, iodides and activated aryl chlorides are also
noteworthy. However, this system gave poorer yields
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1
1
1
1
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Conclusions
The catalytic activities of palladium(II) complexes of four
Schiff base ligands with or without phenolic substituents
were explored in the Suzuki–Miyaura reaction. We have
developed a simple, low-cost and high-yielding method-
ology for the reaction in aqueous ethanol as solvent. High
yields were obtained in coupling reactions utilizing
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Appl Organomet Chem 25:616–619
1
8. Zhou ZG, Du ZY, Hu QS, Shi JC, Xie YR, Liu YL (2012)
Transition Met Chem 37:149–153
9. Xue J, Zhou ZG, Liu YL, Huang L, Yu HW, Xie YR, Lai C
(2012) Transition Met Chem 37:331–335
1
Pd(OAc) /L1-2 as the catalyst, and the results were com-
2
parable for ligands L3 and L4. Moderate to high yields and
distinct differences in catalytic activities highlight the
influence of the phenolic group and pyridine N atom in the
catalytic process.
20. Wen HR, Wang Y, Chen JL, Tang YZ, Liao JS, Liu CM (2012)
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Acknowledgments This work was financially supported by the
National Natural Science Foundation of China (No. 21241005 and
21061001), the Key Laboratory of Jiangxi University for Functional
Materials Chemistry and Gannan Normal University.
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