Activation of aryl chlorides in water for Suzuki coupling with a hydrophilic salen-Pd(II) catalyst

Article abstract of DOI:10.1016/j.catcom.2016.08.010

For exploiting aqueous condition, we have designed a simple water-soluble palladium Schiff-base catalyst for Suzuki-Miyaura reactions of aryl halides with arylboronic acids. The reactions could be performed in neat water with aryl bromides and iodides at room temperature and with aryl chlorides at 100 °C. Good-to-excellent yields of cross-coupling products were obtained with a diverse range of aryl halides including heteroaryl halides. Interestingly, the homogeneous catalyst could be conveniently recycled with aryl bromides or chlorides for at least four times, although a progressive decrease in the product yields were noticed.

Full text of DOI:10.1016/j.catcom.2016.08.010

Activation of aryl chlorides in water for Suzuki coupling with a hydrophilic
salen-Pd(II) catalyst
Nasifa Shahnaz, Amlan Puzari, Bidisha Paul, Pankaj Das
PII:
DOI:
Reference:
S1566-7367(16)30268-0
doi: 10.1016/j.catcom.2016.08.010
CATCOM 4740
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
20 April 2016
15 June 2016
5 August 2016
Please cite this article as: Nasifa Shahnaz, Amlan Puzari, Bidisha Paul, Pankaj Das,
Activation of aryl chlorides in water for Suzuki coupling with a hydrophilic salen-Pd(II)
catalyst, Catalysis Communications (2016), doi: 10.1016/j.catcom.2016.08.010
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ACCEPTED MANUSCRIPT
Activation of aryl chlorides in water for Suzuki coupling with a
hydrophilic salen-Pd(II) catalyst
Nasifa Shahnaz, Amlan Puzari, Bidisha Paul, Pankaj Das*
Department of Chemistry, Dibrugarh University, Dibrugarh 786004, Assam, India
ABSTRACT
For exploiting aqueous condition, we have designed a simple water-soluble palladium Schiff-
base catalyst for Suzuki-Miyaura reactions of aryl halides with arylboronic acids. The reactions
could be performed in neat water with aryl bromides and iodides at room temperature and with
o
aryl chlorides at 100 C. Good-to-excellent yields of cross-coupling products were obtained with
a diverse range of aryl halides including heteroaryl halides. Interestingly, the homogeneous
catalyst could be conveniently recycled with aryl bromides or chlorides for at least four times,
although a progressive decrease in the product yields were noticed.
Keywords: Water-soluble catalyst, Suzuki–Miyaura reaction, Schiff-base, Aryl chloride, Aqueous
media
1
. Introduction
The palladium-catalyzed Suzuki-Miyaura reaction has become one of the most powerful
methods for generating diversified biaryls which are used as building blocks for the synthesis of
fine chemicals, functional materials and industrial starting materials [1]. During the past two
decades an exponential rise in the number of publications has been seen in the Suzuki-Miyaura
reactions [2-4]. Incidentally, majority of the reported works dealt with catalytic systems that are
usually successful for aryl bromides or iodides [5,6]. On the contrary, highly active catalysts for
efficient activations of aryl chlorides are still limited. Since the first report of activations of aryl
chloride in Suzuki reaction in 1998 [7], many research groups viz. Fu [8], Kwong [9,10],
Buchwald [11,12] Sarkar [13], Hong [14], Lee [15], Rajabi [16], and others [17,18] are
constantly involved in developing novel catalysts for aryl chloride activations.
_
_____________________________________________________________________________
Corresponding author: Tel.: +91-373-2370210; fax: +91-373-2370323.
*
E-mail: pankajd29@yahoo.com (P.Das).

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Although some success has been achieved by the groups, unfortunately, majority of such systems
either uses expensive phosphines [7-15,17] or toxic organic solvents like dioxane [7,9,10], DMF
[
13,18], toluene [8,12] or THF [12,14]. In recent years, considerable stress has been given in
developing environmentally benign processes and hence most of the aforesaid systems are not
sustainable both from the economical and ecological contexts. In fact, there has been a long
standing interest of activations of aryl chlorides in aqueous media under phosphine-free systems.
Recent examples suggest that one of the best ways to increase aqueous-phase reactivity, is to
design water-soluble ligands/catalysts by introducing hydrophilic functionalities like –SO , -
3
COO [19,20]. The most striking feature of such water-soluble catalysts is that despite being
homogeneous in nature; the catalyst can be easily separable from the product by simple biphasic
extractions strategy and can be reused. The strategy was first reported in the cross-coupling
reactions by Casalnuovo and Calabrese in 1990 using a sulfonated-phosphine ligand [21]. Since
then, several such hydrophilic phosphine-based systems have been explored by Shaughnessy
[
22,23], Buchwald [24], Turkmen [19]. Later, the methodology has also been extended to
phosphine-free analogues such as pyridyl-triazole [25], NHC [26,27], Schiff-base [28,29],
diimine [30], thiosemicarbazone [31] palladacycle [32] etc.
Since the past few years, we are also involved in developing efficient catalytic systems
for Suzuki-Miyaura reactions in aqueous media [33-35]. Although we remained successful in
developing efficient catalytic systems that worked with aryl bromides in water, until now our
attempts remained unproductive with aryl chlorides in water. Herein, we report synthesis of a
new water-soluble salen-Pd(II) complex and explored its catalytic potential for the Suzuki-
Miyaura reactions of aryl halides including aryl chlorides in neat water.
2
. Experimental
2
.1 Preparation of Complex 1
A solution of the ligand, L-1 (0.598 g, 2 mmol) in 15 mL methanol was added drop wise to a
o
solution of Pd(OAc) (0.224 g, 1 mmol) in 10 mL methanol. The mixture was stirred at 60 C for
2
3
h and then the solution was cooled and filtered. After evaporating the solvent from the filtrate a
brown solid mass was obtained which was washed with cold methanol and dried under vacuum
to obtain the complex 1.

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2
.2 General Procedure for the Suzuki–Miyaura reaction
The Suzuki reaction was performed in a 50 mL round-bottomed flask, aryl halide (0.5
mmol), arylboronic acid (0.65 mmol), K CO (1 mmol), Complex 1 (0.2-1 mol %) and water (4
2
3
mL) were charged and stirred for the required time at room temperature for aryl bromides or at
o
1
00 C for aryl chlorides. After completion, the mixture was cooled down to room temperature,
diluted with water (10 mL) and extracted with diethylether (3 x 15 mL). The organic layer was
washed with brine (3 x 15 mL), dried over anhydrous Na SO . The crude products were
2
4
chromatographed on silica gel (ethyl acetate/hexane).
3
. Results and discussion
3
.1 Catalyst preparation
The Pd complex 1 was prepared by reacting the ligand L-1 with Pd(OAc) in methanol
2
-1
for 3 h (Scheme 1). In the FTIR spectrum of complex 1, the νC=N stretching appears at 1645 cm
1
13
which is significantly higher than the νC=N stretching band of the ligand. The H and C NMR
1
spectra of 1 are consistent with the structure of the complex. In the H NMR spectrum, an upfield
13
shift of the peak for imine proton to δ 8.04, whereas, in the C NMR spectrum, a downfield shift
of δ 3 ppm in the imine-carbon has been observed. The ESI-mass spectrum of 1 shows a peak at
+
m/z 702.86 that corresponds to the M ion.
3
.2 Catalysis
To evaluate the catalytic efficiency of our complex, a series of experiments were
performed taking 4-bromobenzaldehyde and phenylboronic acid as representative substrates with
various inorganic bases in water at room temperature. As shown in Table S1, at a catalyst
loading of 0.5 mol%, complex 1 gave excellent yields (84-100%) with almost all bases; however,
K CO displayed the best result and was chosen for further reactions (entry 7). Taking K CO as
2
3
2
3
the base, 0.2 mol% catalyst was found to be optimum for our system (entry 8). Under optimized
condition, the performance of the catalyst was tested in water using various aryl/heteroaryl
bromides and iodides (Table 1). Aryl halides containing para-substituted electron withdrawing

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groups (-CHO, -COCH , -NO , -COPh) and donating groups (-CH , -OCH reacted elegantly
3
2
3
3)
with phenylboronic acid producing 92-98% yields (entries 1-8) Interestingly, sterically
demanding substrates viz. 2-bromobenzaldehyde, 2-bromo-1,3-dimethylbenzene, 2-bromo-1,3,5-
triisopropylbenzene and 1-bromo-2,5-dimethoxybenzene also underwent smooth coupling with
phenylboronic acid with 0.4 mol% palladium loading (entries 16-19). These high yields were
also maintained with para-chloro and para-tolyl substituted phenylboronic acids (entries 9&10).
Heteroaryl halides viz. 5-bromopyrimidine, 2-bromo-3-methylthiophene, 2-iodothiophene and 3-
iodopyridine underwent smooth coupling to give corresponding products in 87-97% (entries 22-
2
5). Substitution of phenylboronic acid with different thienylboronic acids in the coupling
reaction of aryl bromides (entries 11, 12&15) also resulted in impressive yields (62-91%).
However our protocol was not active with alkylboronic acid (entry 13). Although a catalyst
loading of 0.2 mol% proved to be essential for quantitative conversions, however the turnover
numbers (TON) obtained were rather low ( less than 500). This TON could be increased
significantly by performing the reactions with reduced catalyst loading. The best TON (14400)
was obtained with a catalyst loading of 0.005 mol% (Table S1, entry 12).
Encouraged by the excellent results obtained for the reactions with aryl bromides in
water, we tried to perform the coupling reaction of 4-chloroanisole with phenylboronic acid
under similar experimental conditions. Unfortunately, the catalytic system was found to be
inactive at room temperature (Table S2, entry 1). However, on increasing the reaction
o
temperature to 100 C and catalyst quantity to 1 mol % almost quantitative conversion of
biphenyl was achieved (entry 6). The scope of our catalytic system in aqueous medium was
o
further investigated by employing various aryl chlorides and arylboronic acids at 100 C in water
(Table 2). It has been observed that the product yields of some substrates could be considerably
enhanced by employing Jeffery conditions i.e. using Cetrimonium bromide (CTAB) as phase-
transfer agent in 1:1 proportions w.r.t aryl halide. Chlorobenzenes comprising para-substituted
groups viz.-OCH and -CH (Table 2, entries 1,3-5) underwent efficient coupling with
3
3
arylboronic acids to give the corresponding coupling products in excellent yields (89-95%). On
the other hand, the coupling reaction between para-NO chlorobenzene with phenyl- or tolyl
2
boronic acid gave relatively poor yields. However, the yields could be significantly improved by
using CTAB as the phase-transfer agent with water (entries 2,6). Similar trend was also observed
in case of 4-chloroacetophenone and 4-chlorobenzylalcohol, where the addition of CTAB

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resulted in increase in yields of the desired products (entries 9,11). The Suzuki coupling of 4-
chloroanisole with heteroarylboronic acids also proceeded with moderate conversions (entries
7
,8). It may be noted that under slightly extended reaction time, our catalyst can also tolerate
meta-substituted aryl chlorides viz. 3-chlorobenzyl alcohol (entry 12) and 3-chloronitrobenzene
entry 13) and gave the desired products in reasonably good yields. Unfortunately, our protocol
was not very effective with ortho-substituted aryl chloride viz. 2-chloronitrobenzene, as only
2% product was isolated (entry 14). To our delight, heteroaryl chlorides viz. 2-chlorothiophene
(
1
and 3-chloropyridine, which are considered to be difficult substrates, could also be activated with
our catalyst in water (entries 15,16).
3
.3 Catalyst recycling
Usually, one of the major disadvantages of traditional homogeneous catalysts is their
difficulty in recycling. However, in the present case, the catalyst is water-soluble, and after
performing the initial reaction the catalyst was separated by biphasic solvent extraction strategy
using diethyl ether. The organic layer containing the product was separated with a separating
funnel and the remaining aqueous phase was used as catalyst for the next cycle. The recyclability
of complex 1 was investigated both for aryl bromide and aryl chloride using 4-bromoanisole and
4
-chloronitrobenzene respectively (Tables S3 and S4). The complex 1 could be recycled up to
four times, however a progressive decrease in yields was observed. For instance, in the reaction
between 4-bromoanisole with phenylboronic acid, 92% yields were obtained in first recycle
while, it drops to 69% in the fourth recycle. A possible reason for this decrease in activity could
be due to the handling loss of catalyst during biphasic separation. It may be mentioned that,
similar type of decrease in activity of a water-soluble homogeneous Pd-catalyst on subsequent
reusing was also reported earlier [29-31].
4
. Conclusion
In summary, we have developed a water-soluble Pd-salen catalyst that demonstrated
excellent Suzuki-Miyaura activity in water. Most notably, aryl/heteroaryl chlorides including
deactivated and sterically hindered substrates were coupled successfully in pure water. As the

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catalyst is water-soluble, it can be easily recycled, although a progressive decrease in activity
was noticed on subsequent recycling.
Acknowledgements
The DST, New Delhi, is gratefully acknowledged for financial support (Project no:
2
015/000021). The UGC, New Delhi is also acknowledged for SAP-DRS and BSR-RFSMS
fellowship.
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Legends.
Scheme 1 Synthesis of ligand and complex.
Table 1: Room temperature Suzuki-Miyaura reaction of aryl/heteroaryl bromides and iodides
a
with arylboronic acids in water.
a
Table 2: Suzuki-Miyaura reaction of aryl/heteroaryl chlorides with arylboronic acids in water.

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Scheme 1

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Table 1
b
c
Entry R-X
R'
Time (h) Yield (%) TON
1
2
3
4
5
6
7
8
9
1
1
1
4-CHO-C H Br
C H
8
96
92
98
97
95
93
96
94
93
94
74
91
480
460
490
485
475
465
480
470
465
470
370
455
6
4
6
5
5
5
5
5
5
4-COCH -C H Br
C H
6
8
3
6
4
4-NO -C H Br
C H
6
8
2
6
4
4-OCH -C H Br
C H
6
8
3
6
4
4-CH -C H Br
C H
6
8
3
6
4
4-COPh-C H Br
C H
6
10
6
6
4
4-CH -C H I
C H
3
6
4
6
5
4-COCH -C H I
C H
6
3
6
4
6
5
4-OCH -C H Br
4-Cl-C H4
10
10
10
3
6
4
6
0
1
2
4-OCH -C H Br
4-CH -C H
4
3
6
4
3
6
4-OCH -C H Br
3-Thienylboronic acid
3
6
4
4-OCH -C H Br
5-Acetyl-2-thienylboronic 10
acid
3
6
4
1
3
4-OCH -C H Br
(2-methylpropyl)boronic
8
trace
-
3
6
4
acid
C H
1
1
1
1
1
1
2
2
2
2
4
5
6
7
8
9
0
1
2
3
C H Br
8
90
62
450
310
210
225
6
5
6
5
C H Br
2-Thienylboronic acid
C H
10
10
8
6
5
d
2-CHO-C H Br
84
6
4
6
5
5
5
5
5
5
5
5
d
2,6-CH -C H Br
C H
6
90
3
6
3
i
d
2,4,6- Pr- C
H
Br
C
H
10
10
10
6
81
202.5
220
6
2
6
d
2,5-OCH -C H Br
C H
6
88
3
6
3
d
3-OCH -C H Br
C H
6
91
227.5
232.5
470
3
6
4
d
3-NO -C H I
C H
6
93
2
6
4
5-Bromopyrimidine
C H
6
8
94
97
2-Bromo-3-
C H
6
8
485
methylthiophene
2-Iodothiophene
2
4
C H
8
87
435
6
5

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2
5
3-Iodopyridine
C H
8
89
445
6
5
a
Reaction condition: aryl halide (0.5 mmol), arylboronic acid (0.65 mmol), K CO (1 mmol),
2
3
H O (4 mL), Complex 1 (0.2 mol%), RT.
2
b
Isolated yields.
Turnover number (TON).
c
d
0
.4 mol% Complex 1 was used.

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Table 2
b
c
Entry R-Cl
R'
Time (h) Yield (%) / TON
1
2
3
4
5
6
7
8
4-OCH -C H Cl
C H
5
5
5
6
6
6
8
8
93
45 (96)
95
3
6
4
6
5
5
5
d
d
d
4-NO -C H Cl
C H
2
6
4
6
4-CH -C H Cl
C H
6
3
6
4
4-OCH -C H Cl
4-Cl-C H4
4-CH -C H
4-CH -C H
3-Thienylboronic acid
5-Acetyl-2-
89
94
41 (93)
51
84
3
6
4
6
4-OCH -C H Cl
3
6
4
3
6
4
4-NO -C H Cl
2
6
4
3
6
4
4-OCH -C H Cl
3
6
4
4-OCH -C H Cl
3
6
4
thienylboronic acid
C H
9
1
4-COCH -C H Cl
6
6
61 (87)
57
3
6
4
6
5
0
C H Cl
3-NO -C H
2 6 4
6
5
d
1
1
1
1
1
1
1
2
3
4
5
6
4-CH OH-C H Cl
C H
C H
6
6
8
8
8
6
6
55 (76)
38 (60)
27 (64)
2
6
4
6
5
5
d
3-CH OH-C H Cl
2
6
4
d
3-NO -C H Cl
C H
2
6
4
6
5
5
5
5
d
2-NO -C H Cl
C H
trace (12)
2
6
4
6
d
3-Chloropyridine
2-Chlorothiophene
C H
64 (91)
6
d
C H
6
70 (95)
a
Reaction condition: aryl chloride (0.5 mmol), arylboronic acid (0.65 mmol), K CO (1 mmol),
2
2
3
o
H O (4 mL) Complex 1 (1 mol%), 100 C.
b
Isolated yields.
Turnover number (TON).
CTAB (0.5 mmol) was added.
c
d

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Graphical abstract

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Highlights



A water soluble palladium catalyst has been synthesized and characterized.
The Suzuki reactions of aryl chlorides could be performed in water.
The homogeneous catalyst could be recycled at least for four cycles.