Highly active and recyclable silica gel-supported palladium catalyst for mild cross-coupling reactions of unactivated heteroaryl chlorides

Article abstract of DOI:10.1039/c0gc00251h

Silica gel-supported β-ketoiminatophosphane-Pd complex (Pd@SiO ₂) was shown to be a highly active and long-lived catalyst for aqueous Suzuki, Stille and Sonogashira coupling reactions of heteroaryl chlorides. A wide range of heteroaryl chlorides could be efficiently coupled with different nucleophilic partners in the presence of only 0.5 mol% catalyst and under mild conditions. This is one of the most powerful heterogeneous catalysts for the couplings of diverse heteroaryl chlorides. Furthermore, the catalyst could be reused with almost consistent activity. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0gc00251h

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Highly active and recyclable silica gel-supported palladium catalyst for mild
cross-coupling reactions of unactivated heteroaryl chlorides†
Dong-Hwan Lee, Ji-Young Jung and Myung-Jong Jin*
Received 23rd June 2010, Accepted 3rd September 2010
DOI: 10.1039/c0gc00251h
Silica gel-supported b-ketoiminatophosphane-Pd complex (Pd@SiO2) was shown to be a highly
active and long-lived catalyst for aqueous Suzuki, Stille and Sonogashira coupling reactions of
heteroaryl chlorides. A wide range of heteroaryl chlorides could be efficiently coupled with
different nucleophilic partners in the presence of only 0.5 mol% catalyst and under mild
conditions. This is one of the most powerful heterogeneous catalysts for the couplings of diverse
heteroaryl chlorides. Furthermore, the catalyst could be reused with almost consistent activity.
Introduction
Results and discussion
Palladium-catalyzed coupling reactions are effective synthetic
methods for the construction of carbon–carbon bonds.1 Much
progress has been achieved with homogeneous Pd catalysts in
this area.2 One practical limit in performing homogeneously
catalyzed reactions is the difficulty of separating the catalysts
from the products and reusing the expensive catalysts con-
tinuously. These limits are of significant environmental and
economic concern in large-scale organic syntheses. The use of
heterogeneous catalysts would be an attractive solution to this
problem because of their easy separation and facile recycling.
Therefore, successful development of homogeneous catalysts has
been often followed by attempts to immobilize the catalysts on
a variety of polymeric organic or inorganic supports.3 Although
considerable efforts have been devoted to the development of
efficient heterogeneous catalysts, a long-standing limitation of
the coupling reaction arises from the inability to effectively
couple readily accessible and cheap deactivated aryl chlorides.
Successful examples of this are quite rare.4 Moreover, the cou-
plings of heteroaryl chlorides encounter more difficulty because
the competitive binding of such substrates to the metal center
results in the formation of catalytically inactive complexes.5
There is at present no general method for the heterogeneous
reactions of heteroaryl chlorides. Recently, magnetic particle-
supported b-ketoiminatophosphane-Pd complex was found to
be an efficient catalyst for the coupling reactions of aryl
chlorides.6 Our interest in this area led us to explore a reusable
palladium catalyst immobilized on commercial silica gel which
may have advantages over the homogeneous counterpart. Silica
gel is a well-established support for heterogeneous catalysts due
to its excellent thermal/chemical stability, cost-effectiveness, and
the fact that organic groups can be robustly anchored to the
surface.7 Herein, we describe the use of highly active silica gel-
supported Pd catalyst 3 for the Suzuki, Stille and Sonogashira
reactions of unreactive heteroaryl chlorides.
Silica gel-supported palladium catalyst (Pd@SiO2) 3 was pre-
pared from acetylacetone as shown in Scheme 1. Condensa-
tion of acetylacetone and 3-aminopropyltriethoxysilane under
microwave heating gave b-ketoiminopropyltriethoxysilane 1 in
high yields. Impressively, this reaction was complete within 3
mins in the absence of solvent. Deprotonation of 1 with EtOTl
or EtONa, followed by treatment with Pd2(m-Cl)2Me2(PPh3)2,
led to the formation of silylated Pd complex 2. Pd@SiO2
3 was obtained by heating 2 with silica gel in toluene at
100 ◦C. Loading amounts of Pd on the surface can be controlled
in this step. Pd@SiO2 3 of 0.19 mmol Pd/g was prepared for
this study and the value was confirmed by inductively coupled
plasma atomic emission spectrometry (ICP-AES).
Scheme 1 Synthesis of silica gel-supported b-ketoiminatophosphanyl
palladium complex 3.
Today, the Suzuki reaction is probably one of the most popular
Pd-catalyzed coupling reactions.8 This reaction involving hete-
rocycles is of interest to the pharmaceutical industry because
of the special biological activities displayed by the heterobiaryl
compounds.9 We first tested catalyst 3 in the Suzuki reaction of
heteroaryl chlorides with arylboronic acids in water (Table 1).
We used water as reaction media for environmental benefit,
even though the activity was accelerated in organic solvents.
Tetrabutylammonium bromide (TBAB) as a phase transfer
agent was added to enhance the reactivity in water. Various
Department of Chemical Science and Engineering, Inha University,
Incheon, 402-751, South Korea. E-mail: mjjin@inha.ac.kr;
Fax: +82 32-872-0959; Tel: +82 32-860-7469
† Electronic supplementary information (ESI) available: Compound
characterizations and NMR data. See DOI: 10.1039/c0gc00251h
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Table 1 Suzuki coupling of heteroaryl chlorides with arylboronic
Table 1 (Contd.)
acidsa
Entry Heteroaryl chloride Arylboronic aicd
18
Time/h Yield (%)b
Entry Heteroaryl chloride Arylboronic aicd
1
Time/h Yield (%)b
5
93 (94)
4
5
94 (96)
88 (90)
19
20
21
22
6
6
6
8
90 (92)
92 (95)
88 (91)
87 (89)
2
3
4
5
5
5
5
91 (95)
93 (95)
90 (94)
23
24
8
86 (90)
84 (88)
6
7
8
6
6
6
92 (96)
86 (89)
87 (92)
10
25
26
8
8
91 (93)
85 (87)
a Reaction conditions: heteroaryl chloride (1.0 mmol), arylboronic acid
(1.2 mmol), 3 (0.5 mol%), TBAB (0.5 mmol), H2O (2 mL) and 60 ◦C.
b Isolated yields (GC yields in parenthesis). c Reaction temperature:
80 ◦C.
9
8
86 (90)
10
11
5
6
94 (96)
91 (93)
chloro-pyridines were coupled with arylboronic acids in the
presence of 0.5 mol% of 3 at 60 ◦C to afford the corresponding
products in excellent yields (entries 1–9). The catalyst also
displayed high rate in the coupling of heteroaryl chlorides such
as 2-chloropyrimidine, 2-chloroquinoline, 1-chloroisoquinoline,
and chloroimidazoles (entries 10–14). Importantly, unprotected
aminochloropyridines were also deemed to be suitable coupling
substrates (entries 15–17). It is known that the coupling of basic
heteroaryl chlorides bearing an unprotected amino group is
affected by a competitive binding affinity of the amino group to
the Pd center of the catalyst.10 The reaction is quite impressive
when the scope of this catalytic system was further extended to
the coupling of chlorothiophenes. 2- and 3-chlorothiophenes
underwent coupling with arylboronic acids to provide the
desired products in high yields (entries 18–22). These results
came as a surprise since chlorothiophenes in the coupling
reaction are challenging substrates due to the strong affinity
of the sulfur to the Pd.5c Furthermore, this catalytic system
allowed for the coupling with 2- and 3-pyridineboronic acid,
known as a less efficient reagent, although somewhat longer
time was required (entries 23–26). Regardless of the substituent,
our catalyst showed unprecedented activity for the mild Suzuki
coupling reaction of heteroaryl chlorides in water.
12
8
92 (94)
13
14
6
8
90 (92)
84 (87)
15c
16c
17c
10
10
8
86 (88)
80 (84)
92 (95)
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Table 2 Stille coupling of heteroaryl chlorides with organostannanesa
Table 3 Sonogashira coupling of heteroaryl chlorides with alkynesa
Entry Heteroaryl chloride Organostannane Time/h Yield (%)b
Entry Heteroaryl chloride Alkyne
1
Time/h Yield (%)b
1
4
90 (94)
5
6
96 (98)
87 (88)
2
3
3
5
94 (96)
84 (86)
2
3
4
5
8
90 (92)
91 (93)
4
5
6
8
86 (88)
83 (87)
5
6
7
6
85 (88)
82 (85)
90 (93)
10
6
6
7
6
6
91 (93)
89 (92)
8
8
86 (89)
8
9
5
5
92 (96)
91 (92)
a Reaction conditions: heteroaryl chloride (1.0 mmol), alkyne
(1.2 mmol), 3 (0.5 mol%), piperidine (2.0 mmol), TBAB (0.5 mmol),
H2O and 60 ◦C (2 mL). b Isolated yields (GC yields in parenthesis).
10
11
5
4
85 (87)
93 (95)
1–5). High reactivity was also observed for the coupling of 4-
chloropyrimidine, 2-chloroquinoline, and 2-chloroquinoline-4-
carboxylic acid (entries 6–8). Moreover, the catalyst was found
to be active for the coupling of 2- and 3-chlorothiophene. (entries
9–13). The important aldehyde functional group was tolerated
under the present conditions (entry 11). One of the most useful
applications of the Stille reaction is the coupling with vinyl- and
allystannanes. Satisfactory results were obtained in the reaction
of 2-chloropyridine or 3-chlorothiophene with tributylvinys-
tanne and allytributylstanne under mild heating (entries 14–16).
Theheterogeneous Stille coupling of heteroarylchlorides has not
been reported to date. Interestingly, these results are comparable
to those of the homogeneous counterpart.12 It is apparent that
this catalyst has the specific advantages of homogeneous and
heterogeneous catalysts.
12
13
8
81 (84)
83 (85)
10
14
15
16
5
5
6
82 (86)
87 (91)
81 (84)
The application range of catalyst 3 was extended to the
Sonogashira reaction of heteroaryl chlorides with terminal
alkynes in water (Table 3). The Sonogashira reaction is one of
the most powerful methods for the construction of C(sp2)–C(sp)
bonds. In most cases, the reactions with aryl chlorides require
high catalyst loadings, elevated reaction temperatures, and CuI
as the co-catalyst.13 Efficient copper-free Sonogashira coupling
of heteroaryl chlorides was achieved in the presence of only
0.5 mol% catalyst. Excellent catalytic activity was observed in
the coupling of 2- and 3-chloropyridine with phenylacetylene
or 4-ethynyltoluene at 60 ◦C (entries 1–4). The catalyst was
capable of performing this coupling with other alkynes such as
propargyl alcohol and 1-octyne (entries 5 and 6). Besides, 2- and
a Reaction conditions: heteroaryl chloride (1.0 mmol), organostannane
(1.2 mmol), 3 (0.5 mol%), CsF (2.0 mmol), EtOH–H2O (2 mL, 1 : 1) and
50 ◦C. b Isolated yields (GC yields in parenthesis).
We next investigated the Stille coupling of heteroaryl chlo-
rides with arylstannanes in aqueous ethanol (Table 2). The
Stille coupling of aryl and heteroaryl chlorides remains a
challenge especially under mild conditions.11 Chloropyridines
were coupled well with only 0.5 mol% of 3 at 50 ◦C (entries
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Table 4 Recycling of catalyst 3 in Suzuki coupling of heteroaryl
Experimental
chlorides with phenylboronic acida
All reagents were used as received from commercial source.
All manipulations were conducted under an atmosphere of
dry nitrogen. Microwave irradiation was performed with a
Discover microwave synthesis system (CEM Co.). 1H, 13C,
and 31P NMR spectra were recorded on a Bruker AM 400
(400 MHz). Chemical shifts were quoted in parts per million
(ppm) referenced to the appropriate solvent peak or 0.0 ppm for
tetramethylsilane. 31P NMR spectra were referenced to external
PPh3 (0 ppm relative to free PPh3). Elemental analyses (EA)
were carried out using EA-110 (Thermo Finnigan). GC/GC-
MS analyses were performed on an Agilent 6890 N GC coupled
to an Agilent 5975 Network Mass Selective Detector. Analysis
of Pd content was measured by inductively coupled plasma–
atomic emission spectroscopy (ICP-AES) using OPTIMA 4300
DV (Perkin–Elmer).
Entry Heteroaryl chloride Cycle Yield (%)b Pd leaching (ppm)
1
2
3
1
2
3
4
5
6
90
92
91
92
91
90
0.151
0.008
0.006
0.01
0.007
0.003
1
2
3
4
5
6
95
92
91
93
91
89
0.127
0.034
0.011
0.006
0.014
0.012
1
2
3
4
5
6
94
95
94
91
93
92
0.108
0.023
0.009
0.013
0.008
0.011
Synthesis of b-ketoiminopropyltriethoxysilane 1
Acetylacetone (1.1 g, 11.0 mmol) and 3-aminopropyltriethoxy-
silane (2.21 g, 10.0 mmol) were placed in a 10 mL glass tube.
The vessel was sealed with a septum and placed into the
microwave cavity. The reaction temperature was raised from rt
to 130 ◦C under microwave irradiation of 150 W. The power was
maintained for 3 min. After allowing the mixture to cool to rt,
the reaction mixture was vacuumed under reduced pressure to
give b-ketoiminopropyltriethoxysilane 1 as a light yellow liquid
(2.94 g, 97%). 1H NMR (400 MHz, CDCl3) d 10.82 (br s, 1H),
4.99 (s, 1H), 3.82 (q, J = 6.8 Hz, 6H), 3.24 (q, J = 12 Hz, 2H), 2.00
(s, 3H), 1.92 (s, 3H), 1.75 (t, J = 7.2 Hz, 2H), 1.22 (t, J = 6.8 Hz,
9H), 0.68 (t, J = 7.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 194.29, 162.80, 94.91, 58.34, 45.41, 28.68, 23.82, 18.75, 18.25,
7.60 ppm; Anal. Calcd. for C14H29NO4Si (303.19): C, 55.41; H,
9.63; N, 4.62. Found: C, 55.62; H, 9.54; N, 4.58.
a Recycling tests were carried out under the same reaction conditions
in Table 1. The reaction times were the same as those in Table 1. b GC
yields.
3-chlorothiophene underwent the coupling very well under the
same conditions (entries 7 and 8). All of the reactions afforded
the corresponding products in excellent yields. To the best of
our knowledge, this represents the first successful example of a
heterogeneous Sonogashira reaction of heteroaryl chlorides in
water.
The recycling of the catalyst is an important issue in the
heterogeneous reaction. We turn our attention to reusability
of our Pd catalyst. As shown in Table 4, catalyst 3 was recycled
in the Suzuki couplings of 2-chloro-3-methylpyridine, 3-amino-
6-chloropyridine and 2-chlorothiophene with phenylboronic
acid, respectively. We have observed that the catalyst could be
reused at least six times without significant loss of activity.
After the reaction, Pd metal in the solution was analyzed by
ICP-AES method. Less than 0.06% Pd of the initially added
catalyst was leached out from the catalyst surface. The isolated
solution did not exhibit any further reactivity. In addition,
the recovered Pd catalyst was very similar to the original in
the XANES and EXAFS patterns. It indicates that the Pd(II)
catalyst on the support surface might be still maintained after the
reaction.
Synthesis of b-ketoiminatopropyltriethoxysilanephosphane-Pd
complex 2
A solution of Tl(OC2H5) (300 mg, 1.2 mmol) in THF (10 mL)
was added dropwise at room temperature to a solution of
b-ketoiminopropyltriethoxysilane (0.30 g, 1.0 mmol) in THF
(10 mL). After stirring for 2 h at room temperature, a solution
of Pd2(m-Cl)2Me2(PPh3)214 (0.51 g, 0.6 mmol) in THF (5 mL) was
dropwise added to the mixture. After 2 h, the mixture was filtered
through celite on a frit. The solvent was removed under reduced
pressure and the residue was washed with hexane (30 mL) and
extracted with methylene chloride (10 mL). Removal of the
solvent gave Pd complex 2 as a light brown oil (0.56 g, 82%). 1H
NMR (400 MHz, CDCl3) d 7.79–7.52 (m, 5H), 7.49–7.27 (m,
10H), 4.70 (s, 1H), 3.83 (q, J = 6.8 Hz, 6H), 3.45 (m, 2H), 2.00 (s,
3H), 1.75 (m, 2H), 1.52 (s, 3H), 1.22 (m, 9H), 0.63(t, J = 7.2 Hz,
2H), 0.097 (d, J = 2.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 176.86, 163.95, 134.74, 134,63, 132.00, 131.91, 131.78, 131.37,
130.90, 129.83, 128.43, 128.30, 128.05, 127.76, 127.66, 97.94,
67.93, 58.43, 58.33, 58.16, 26.14, 25.64, 18.59, 18.39, 18.34, 7.69,
-2.21 ppm; 31P NMR (162 MHz, CDCl3) d 43.88 ppm; Anal.
Calcd. For C33H46NO4PPdSi (686.20): C, 57.76; H, 6.76; N, 2.04.
Found: C, 57.74; H, 6.53; N, 2.10.
Conclusions
We have demonstrated that silica gel-supported Pd complex
3 exhibits high catalytic activity for the Suzuki, Stille, and
Sonogashira coupling reactions. A wide range of structurally
and electronically diverse unreactive heteroaryl chlorides were
coupled very well in aqueous solution. In particular, the
performance of the catalyst was fully retained during the
reuse process. These represent very successful heterogeneous
coupling reactions of unreactive heteroaryl chlorides under mild
conditions.
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Synthesis of silica gel–supported b-ketoiminatophosphane-Pd
General procedure for the Sonogashira coupling reaction
complex 3
Heteroaryl chloride (1.0 mmol), alkyne (1.2 mmol), piperidine
(170 mg, 2.0 mmol), TBAB (161 mg, 0.5 mmol) and catalyst 3
(26 mg, 0.5 mol%) were mixed in H2O (2.0 mL). The mixture
was stirred at 60 ◦C in an air atmosphere. The reaction was
monitored periodically by GC. After completion of the reaction,
the mixture was cooled to room temperature, filtered, and
extracted with diethyl ether three times. The combined organic
layers were concentrated under reduced pressure. The crude was
analysed by GC/GC-MS and then purified by short-column
chromatography on silica gel. The product was confirmed by 1H
NMR.
R
Silica gel (1.0 g, Merckꢀ 9385, particle size 230–400 mesh,
surface area 550 m2 g-1) was added to a solution of 2 (136 mg,
0.21 mmol) in toluene (10 mL) and the mixture was refluxed
for 12 h. After cooling, the reaction mixture was filtered and
washed with CH2Cl2 (10 mL ¥ 3), and dried at 60 ◦C under
vacuum to yield silica-supported Pd complex Pd@SiO2 3 (1.10 g)
as a brown powder (Fig. 1). The Pd content of 0.19 mmol g-1
was measured by inductively coupled plasma (ICP)
analysis.
Acknowledgements
This work was supported by National Research Foundation of
Korea Grant funded by Korean Government (2009-0072013)
and the Carbon Dioxide Reduction & Sequestration R&D
Center of the 21st Century Frontier R&D Programs.
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Fig. 1 Optical microscope image of Pd@SiO2 3.
General procedure for the Suzuki coupling reaction
Heteroaryl chloride (1.0 mmol), arylboronic acid (1.2 mmol),
K2CO3 (276 mg, 2.0 mmol), TBAB (161 mg, 0.5 mmol) and
catalyst 3 (26 mg, 0.19 mmol g-1, 0.5 mol%) were mixed
in H2O (2.0 mL). The mixture was stirred at 60 ◦C in an
air atmosphere. The reaction was monitored periodically by
GC. After completion of the reaction, the mixture was cooled
to room temperature, filtered, and extracted with diethyl ether
three times. The filtered catalyst was washed with diethyl ether
and the combined organic layers were concentrated under
reduced pressure. The crude product was analysed by GC/GC-
MS and then purified by short-column chromatography on silica
1
gel. The product was confirmed by H NMR. The separated
catalyst was successively reused for the next reaction without
any pre-treatment.
General procedure for the Stille coupling reaction
Heteroaryl chloride (1.0 mmol), organostannane (1.2 mmol),
CsF (302 mg, 2.0 mmol) and catalyst 3 (26 mg, 0.5 mol%)
were mixed in EtOH–H2O (2.0 mL, 1 : 1). The reaction mixture
◦
was stirred at 50 C and monitored periodically by GC. After
completion of the reaction, the mixture was cooled to room
temperature and filtered. After removal of EtOH, diethyl ether
(5 mL) and water (2 mL) was added. The layers were separated
and the aqueous layer was extracted with diethyl ether two times.
The combined organic layers were concentrated under reduced
pressure. The crude product was analysed by GC/GC-MS and
then purified by short column chromatography on silica gel to
1
afford the desired product. The product was confirmed by H
11 For heterogeneous Stille reaction, see (a) J. C. Garcia-Martinez, R.
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