A highly efficient and reusable palladium(II)/cationic 2,2′-bipyridyl-catalyzed stille coupling in water

Article abstract of DOI:10.3390/molecules21091205

A water-soluble PdCl₂ (NH₃ )₂ /cationic 2,2′ -bipyridyl system was found to be a highly efficient catalyst for Stille coupling of aryl iodides and bromides with organostannanes. The coupling reaction was conducted at 110^°C in water, under aerobic conditions, in the presence of NaHCO₃ as a base to afford corresponding Stille coupling products in good to high yields. When aryltributylstannanes were employed, the reactions proceeded smoothly under a very low catalyst loading (as little as 0.0001 mol %). After simple extraction, the residual aqueous phase could be reused in subsequent runs, making this Stille coupling economical. In the case of tetramethylstannane, however, a greater catalyst loading (1 mol %) and the use of tetraethylammonium iodide as a phase-transfer agent were required in order to obtain satisfactory yields.

Full text of DOI:10.3390/molecules21091205

molecules
Article
A Highly Efficient and Reusable
Palladium(II)/Cationic 2,2’-Bipyridyl-Catalyzed
Stille Coupling in Water
†
Wei-Yi Wu , Ling-Jun Liu, Fen-Ping Chang, Yu-Lun Cheng and Fu-Yu Tsai *
Institute of Organic and Polymeric Materials, National Taipei University of Technology, 1, Sec. 3,
Chung-Hsiao E. Rd., Taipei 10608, Taiwan; willy.wu@lcygroup.com (W.-Y.W.); lingebubest@gmail.com (L.-J.L.);
a49001103@yahoo.com.tw (F.-P.C.); jacky0205333@yahoo.com.tw (Y.-L.C.)
*
Correspondence: fuyutsai@ntut.edu.tw; Fax: +886-2-2731-7174
†
Present address: R&D Department, LCY Chemical Corp., No. 68, Yan-Fa Rd., 2nd Dist.,
Nanzi Export Processing Zone, Kaohsiung City 811, Taiwan.
Academic Editors: Diego A. Alonso and Isidro M. Pastor
Received: 13 August 2016; Accepted: 6 September 2016; Published: 9 September 2016
0
Abstract: A water-soluble PdCl (NH ) /cationic 2,2 -bipyridyl system was found to be a highly
2
3 2
efficient catalyst for Stille coupling of aryl iodides and bromides with organostannanes. The coupling
◦
reaction was conducted at 110 C in water, under aerobic conditions, in the presence of NaHCO
3
as a base to afford corresponding Stille coupling products in good to high yields. When
aryltributylstannanes were employed, the reactions proceeded smoothly under a very low catalyst
loading (as little as 0.0001 mol %). After simple extraction, the residual aqueous phase could be
reused in subsequent runs, making this Stille coupling economical. In the case of tetramethylstannane,
however, a greater catalyst loading (1 mol %) and the use of tetraethylammonium iodide as a
phase-transfer agent were required in order to obtain satisfactory yields.
Keywords: stille coupling; water-soluble catalyst; reusable; aryl halides; organostannane
1
. Introduction
The palladium-catalyzed cross-coupling of aryl halides or pseudo-halides with organo-stannanes,
known as the Stille coupling, is one of the most powerful methods for the straightforward
construction of carbon–carbon bonds in synthetic chemistry [ ]. The main advantages of the
1–3
Stille coupling reaction include the stability and functional group tolerance of stannanes, the broad
reaction scope of aryl halides and pseudo-halides, and its chemoselectivity; therefore, this reaction
has been widely applied in natural product synthesis [4–10], biological research [11], and for
pharmaceutical purposes [12]. Stille coupling reactions are generally carried out in organic solvents
under homogeneous catalysis, and, hence, it is difficult to separate the catalyst from the reaction
mixture and then recycle it at the end of the reaction, leading to wastage of precious metals. Therefore,
the development of a recyclable and reusable catalytic system is highly attractive and valuable from
the viewpoints of green chemistry and practical application. To circumvent this problem, several new
strategies involving heterogenized homogeneous catalysts have been developed for recycling and
reusing catalysts, including the use of Pd complexes supported by silica gel [13,14], polymers [15,16],
nanoparticles [17
mesoporous silica [21
complexes with several green solvents, such as ionic liquids [43
,
18], porous metal
−
organic frameworks [19], bulky proazaphosphatrane ligands [20],
42]. Alternatively, combinations of palladium
45], polyethylene glycol [46 50],
–26], and metal nanoparticles [27
–
–
–
H O [51
–
54], or H O in the presence of surfactants [55
–
57], have also been applied as reusable
2
2
catalytic systems.
Molecules 2016, 21, 1205; doi:10.3390/molecules21091205
www.mdpi.com/journal/molecules

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0
We recently reported that cationic 2,2 -bipyridyl is an excellent ligand to bring PdCl (NH ) into
2
3 2
the aqueous phase, in order to efficiently perform several carbon–carbon bond-formation reactions,
and the residual aqueous solution can be reused for the next run [58 63]. As part of our continuing
–
efforts in the development of water-soluble and reusable catalytic systems for carbon–carbon
0
bond-forming reactions, we report, herein, on a reusable PdCl (NH ) /cationic 2,2 -bipyridyl catalytic
2
3 2
system, which can be applied for Stille coupling of aryl halides with organostannanes in water under
aerobic conditions, in the presence of NaHCO as a base. The loading amount of the catalyst in a single
3
batch reaction could be reduced to as little as 0.0001 mol % (1 ppm), still affording products in high
yields (Scheme 1).
Scheme 1. Palladium-catalyzed Stille coupling in water.
2
. Results and Discussion
2
.1. Optimization of Stille Coupling Conditions
0
Water-soluble cationic 2,2 -bipyridyl ligand
L was synthesized according to our previously-
published method [58
,59]. The catalytic system was prepared by mixing equimolar amounts of
PdCl (NH ) and in water, and then it was stored under air. Stock solutions of this catalytic system
L
2
3 2
were prepared at different concentrations to obtain various catalyst loadings. In order to discover the
0
optimal conditions, the coupling of 4 -iodoacetophenone (1a, 1 mmol) and PhSnBu (2a, 1.2 mmol) in
3
◦
the presence of PdCl (NH ) /
L
(1 mol %) in water (3 mL), at 110 C for 0.5 h, was first investigated,
2
3 2
and the results are summarized in Table 1.
0
Table 1. Optimization studies for the Pd(NH ) Cl /
L
-catalyzed Stille coupling of 4 -iodoacetophenone
3
2
2
a
(
1a) and PhSnBu (2a) in water .
3
Yield (%) b
Entry
Base
KOH
K PO
1
2
3
4
5
6
70
75
85
60
74
95
32
35
0
3
4
K CO
2
3
KF
KOAc
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
c
7
8
9
d
e
1
0 f
90
95
g
11
a
2 3 2 2
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), base (2 mmol), PdCl (NH ) /L (1 mol %), H O (3 mL)
◦
b
c
d
0
at 110 C for 0.5 h;
Isolated yields; In the absence of
,2 -Bipyridine-4,4 -dicarboxylic acid was used as the ligand; PhSnCl
L
;
2,2 -Bipyridyl was used as the ligand;
e
0
0
f
g
2
3
(1.2 mmol) was used; PhSnMe
3
(
1.2 mmol) was used.
Initially, several commonly-used bases were screened, and it was found that the use of NaHCO3
provided the Stille coupling product in a 95% yield, which was higher than the yields obtained using
other inorganic bases (Entries 1–6). Then, two additional experiments were performed to demonstrate

Molecules 2016, 21, 1205
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the necessity of water-soluble ligand
L
. Under the same conditions as Entry 6, only a 32% yield of
the cross-coupling product was obtained in the absence of the ligand (Entry 7), and a 35% yield was
0
obtained when
L
was replaced with neutral 2,2 -bipydryl (Entry 8). These results clearly revealed
that use of the water-soluble ligand was crucial in this Stille coupling reaction. When basic aqueous
0
0
soluble 2,2 -bipyridine-4,4 -dicarboxylic acid was employed as ligand, however, Stille coupling did not
occur, hence, 1a and 2a remained intact (Entry 9). Other phenylstannane sources, such as PhSnCl and
3
PhSnMe , were also examined. Although these two reagents furnished 3aa in 90% and 95% yields,
3
respectively (Entries 10 and 11), PhSnBu can be synthesized from the much cheaper ClSnBu ; hence,
3
3
aryltributylstannanes were applied for the reactions.
2
.2. Reuse Studies of the Residual Aqueous Solution
We then studied the reusability of the aqueous catalytic system for Stille coupling, which is
important from the viewpoints of practical utilization and economics. Coupling of 1a and 2a under
the conditions of Entry 6, in Table 1, was performed in order to test the feasibility of this approach
(
Scheme 2). After completion of the first run, the organic portion was easily separated from the
aqueous phase by simple extraction with hexane (3 mL 3), and 3aa was isolated in a 95% yield
using a typical work-up procedure. The residual aqueous solution was then subjected to the next
×
reaction run, charged with the same reactants, 1a and 2a, and NaHCO . It was found that this residual
3
aqueous solution could be reused at least four times, and a 78% isolated yield was reached in the
fourth reuse run. In order to know the partitioning of the catalyst in the organic phase, the first run
was performed again. After extracting the reaction mixture with hexane, the organic phase was then
used for ICP-MASS analysis. It was found that there was no leaching of Pd into the organic phase.
Thus, the slight decrease in activity was presumably due to a gradual decay of the catalytic activity.
O
O
PdCl (NH ) /L (1 mol%)
2
3 2
+
SnBu3
o
NaHCO , H O, 110 C, 0.5 h
3
2
I
1a
2a
3aa
First run: 95%
First reuse run: 90%
Second reuse run: 85%
Third reuse run: 83%
Fourth reuse run: 78%
Scheme 2. Catalyst reuse studies in Stille coupling of 1a and 2a.
2
.3. Scope of Substrates and Loading Amounts of Catalyst
Encouraged by the excellent results of the reuse studies of the residual aqueous solution, we then
examined the scope of substrates, and attempted to reduce the catalyst loading required (Table 2).
Aryl iodides 1a and 1b with electron-withdrawing groups at the para-position coupled with various
aryltributylstannanes 2a–2c under 0.01 mol % catalyst loading, giving the corresponding Stille coupling
products at yields between 90% and 98%, in 3 h (Entries 1, 3 and 4, 6, and 8 and 9). Further reduction
of the catalyst loading to 0.0001 mol % (1 ppm), and increase of the reaction scale to 10 mmol, resulted
in the corresponding Stille coupling products being obtained at yields between 72% and 82%, in 48 h
(Entries 2, 5, and 7), and the highest turnover number (TON) achieved was up to 820,000 (Entry 2).
Iodobenzene (1c) showed only a slightly lower rate compared with electron-withdrawing 1a and 1b
,
but still resulted in excellent yields by prolonging the reaction time to 6 h (Entries 10–12). For aryl
iodides bearing an electron-donating group at the para-position, 1d and 1e, high yields were isolated
in 6 h, with a catalyst loading of 0.01 mol % (Entries 13, 15–17, and 19 and 20). Similarly, in the cases
of entries 14 and 18, 59% and 66% yields were obtained, respectively, in 48 h, under 1 ppm catalyst
loading, using a reaction scale of 10 mmol (Entries 14 and 18).

Molecules 2016, 21, 1205
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Table 2. Pd-catalyzed Stille coupling of aryl iodides (1) and aryltributylstannane (2) in water a.
Yield (%) b
Entry
Aryl Iodide
4-IC H COMe 1a
ArSnBu3
C H SnBu 2a
[Pd] (mol %)
Duration (h)
1
0.01
0.0001
0.01
0.01
0.0001
0.01
0.0001
0.01
0.01
0.01
0.01
0.01
0.01
0.0001
0.01
0.01
0.01
0.0001
0.01
3
48
3
3
48
3
48
3
3
6
6
6
6
48
6
6
6
48
6
3aa (98)
3aa (82)
3ab (97)
3ac (93)
3ac (72)
3ba (91)
3ba (75)
3bb (93)
3bc (90)
3ca (95)
3cb (95)
3cc (90)
3da (89)
3da (59)
3db (82)
3dc (88)
3cc (94)
3cc (66)
3eb (84)
3ec (80)
6
4
6
5
3
c
2
1a
2a
4-FC H SnBu 2b
3
4
1a
1a
1a
6
5
3
4-MeOC H SnBu 2c
6
5
3
c
5
2c
6
4-IC H CN 1b
2a
2a
2b
2c
2a
2b
2c
2a
2a
2b
2c
2a
2a
2b
2c
6
4
c
7
1b
1b
1b
8
9
1
1
1
1
0
1
2
3
C H I 1c
6
5
1c
1c
4-IC H Me 1d
6
4
c
1
4
1d
1d
1d
1
1
1
5
6
7
4-IC H OMe 1e
6
4
c
1
8
1e
1e
1e
1
2
9
0
0.01
6
a
c
O (3 mL) at 110 C; b Isolated yields;
◦
Reaction conditions:
1
(1 mmol),
2
(1.2 mmol), NaHCO
3
(2 mmol), H
2
◦
1
(10 mmol), 2 (12 mmol), NaHCO3 (20 mmol), H2O (30 mL) at 110 C.
Analogous reactions of cheaper aryl bromides were also investigated (Table 3). Activated aryl
bromides 4a and 4b, were efficiently coupled with 2a under conditions identical to those used for
–
c
aryl iodides; however, a longer reaction time was required (Entries 1–9).
Table 3. Pd-catalyzed Stille coupling of aryl bromides (4) and aryltributylstannane (2) in water a.
Yield (%) b
Entry
Aryl Bromide
ArSnBu3
C H SnBu 2a
[Pd] (mol %)
Duration (h)
1
4-BrC H COMe 4a
0.01
0.0001
0.01
0.001
0.01
0.001
0.01
0.01
0.01
1
6
48
6
12
6
12
6
3aa (96)
3aa (70)
3ab (96)
3ab (91)
3ac (92)
3ac (95)
3ba (93)
3bb (90)
3bc (88)
3ca (92)
3cb (96)
3cc (94)
3cc (84)
3eb (83)
3ec (97)
3fa (90)
3fa (96)
3fa (56)
3fb (94)
3fc (88)
6
4
6
5
3
c
2
4a
2a
3
4
5
6
7
8
9
4a
4a
4a
4a
4-FC H SnBu 2b
6
5
3
2b
4-MeOC H SnBu 2c
6
5
3
2c
4-BrC H CN 4b
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2a
2a
2b
2c
6
4
4b
4b
8
8
1
1
1
1
1
1
0
1
2
3
4
5
C H Br 4c
24
36
36
24
24
36
3
12
48
12
12
6
5
4c
4c
1
1
1
1
1
1
4-BrC H OMe 4e
6
4
4e
4e
d
d
1
1
6
7
4-BrC6H4OH 4f
4f
4f
4f
4f
0.01
0.0001
0.01
0.01
c,d
1
8
1
2
9 d
0
d
a
O (3 mL) at 110 C; b Isolated yields;
◦
Reaction conditions:
4
4
(1 mmol),
2
(1.2 mmol), NaHCO
3
(2 mmol), H
2
c
◦
d
(10 mmol), 2 (12 mmol), NaHCO3 (20 mmol), H2O (30 mL) at 110 C; 3 equiv. of NaHCO3 was applied.
A very low catalyst loading could also be applied when employing electron-withdrawing aryl
bromides. For example, the coupling of 4a and 2a furnished 3aa in a 70% yield with a 1 ppm catalyst

Molecules 2016, 21, 1205
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loading in 48 h (Entry 2). In the cases of 4c and electron-donating 4e, the reactions were much slower
than those of the iodide analogs. Hence, conduction of the reaction using a 1 mol % catalyst loading and
prolongation of the reaction time were necessary in order to obtain satisfactory yields (Entries 10–15).
These results indicated that the oxidative addition of a carbon–bromine bond to palladium may be the
rate-determining-step in this catalytic cycle. Surprisingly, the reaction rate was dramatically enhanced
when deactivated 4-bromophenol (4f) was employed (Entries 16–20). Compound 4f was soluble in
basic aqueous solution, producing 4-bromophenoxide. This aryl bromide then underwent oxidative
addition to palladium under homogeneous conditions, making this step much faster than for other
water-insoluble aryl bromides. Taking advantage of this water-soluble property, 4f coupled with 2a
very smoothly, providing a 56% yield (TON = 560,000) of 3fa under a catalyst loading of only 1 ppm at
◦
1
10 C for 48 h (Entry 18).
2
3
The utility of this reaction protocol for the formation of Csp –Csp carbon–carbon bonds was
also evaluated. As illustrated in Table 4, the coupling of 1a and SnMe4,
5
, using 1 mol % catalyst
◦
loading at 110 C for 24 h, gave 6a in only a 51% yield (Entry 1). The use of two equivalents of
5 in
◦
the reaction was owing to its low boiling point (74–75 C). In order to improve upon this outcome,
a phase-transfer agent was added into the reaction [55
–57]. The use of tetrabutylammonium bromide
(TBAB) and tetrabutylammonium hydroxide (TBAOH) led to the formation of 6a in yields of 63%
and 70%, respectively (Entries 2 and 3). It is worth noting that a 91% isolated yield of 6a could be
achieved when tetraethylammonium iodide (TEAI) was applied in the reaction system (Entry 4). Thus,
1b coupled with 5 under such conditions afforded 6b in a 78% yield (Entry 5). However, a low product
yield was obtained when electron-rich 1e was utilized (Entry 6). Activated aryl bromides 4a and 4b
were also coupled with 5, furnishing 6a and 6b in 40% and 31% yields, respectively (Entries 7 and 8).
Table 4. Pd-catalyzed Stille coupling of aryl halides (1 or 4) and tetramethylstannane (5) in water a.
Yield (%) b
Entry
Aryl Halide
Duration (h)
1 c
4-IC H COMe 1a
24
24
24
24
24
36
48
48
6a (51)
6a (63)
6a (70)
6a (91)
6b (78)
6e (42)
6a (40)
6b (31)
6
4
d
2
1a
1a
1a
3 e
4
5
6
7
8
4-IC H CN 1b
6 4
4-IC H OMe 1e
6 4
4-BrC H COMe 4a
6 4
4-BrC H CN 4b
6
4
a
Reaction conditions:
1
or
4
(1 mmol),
5
(2 mmol), PdCl
2
(NH
3
)
2
/
L
(1 mol %), tetraethylammonium iodide
◦
b
c
(
TEAI, 1 mmol), NaHCO
3
(2 mmol), H
2
O (3 mL) at 110 C; Isolated yields; In the absence of TEAI;
d
e
Tetrabutylammonium bromide (TBAB, 1 mmol) was used. Tetrabutylammonium hydroxyl (TBAOH,
mmol) was used.
1
3
. Experimental Section
3
.1. General Information
Chemicals were purchased from commercial suppliers and were used without further
0
purification. Cationic 2,2 -bipyridyl ligand was prepared according to published procedures [58
,59].
1
13
Aryltributylstannanes were prepared according to known procedures [64]. All H- and C-NMR
spectra were recorded in CDCl or DMSO-d at 25 C on a Bruker Biospin AG 300 NMR spectrometer
◦
3
6
(
Bruker Co., Faellanden, Switzerland), in which chemical shifts (
δ
in ppm) were determined with
1
respect to the non-deuterated solvent as a reference ( H-NMR: CHCl at 7.24, non-deuterated DMSO
at 2.49 ppm; 13C-NMR: CDCl at 77.0, DMSO-d at 39.5 ppm). Melting points were recorded using a
3
3
6
melting point apparatus, and were uncorrected.

Molecules 2016, 21, 1205
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3
.2. Typical Stille Coupling Procedure
A sealable tube, equipped with a magnetic stirring bar, was charged with aryl halide (1 mmol),
organotin (1.2 mmol), NaHCO (2 mmol), and H O (2 mL). In the case of tetramethyltin, the addition
3
2
of tetraethylammonium iodide (TEAI, 1 mmol) was required. After the addition of PdCl (NH ) /
L
2
3 2
aqueous solution (1 mL H O; different concentrations were required for various substrate/catalyst
2
ratios), the tube was sealed under air using a Teflon-coated screw cap. The reaction vessel was then
◦
placed in an oil bath at 110 C for the indicated reaction duration (see Tables 2–4). After cooling of
the reaction mixture to room temperature, the aqueous solution was extracted with hexane or ethyl
acetate; the organic phase was dried over MgSO , and the solvent was then removed under vacuum.
4
Column chromatography on silica gel afforded the desired product (see Supplementary Materials for
the copies of NMR spectra).
4
-Phenylacetophenone (3aa, Table 2, Entries 1 and 2, and Table 3, Entries 1 and 2). CAS: 92-91-1; white
◦
◦
1
solid (m.p. = 119–121 C, lit. [59] 119–121 C). H-NMR (CDCl ):
7
δ 2.62 (s, 3H), 7.39–7.41 (m, 1H),
3
13
.44–7.48 (m, 2H), 7.60–7.63 (m, 2H), 7.66–7.68 (m, 2H), 8.01–8.03 (m, 2H); C-NMR (CDCl3): δ 26.6,
1
27.1(2C), 127.2 (2C), 128.2, 128.8 (2C), 128.9 (2C), 135.7, 139.8, 145.7, 197.7.
0
4
-Acetyl-4 -fluorobiphenyl (3ab, Table 2, Entry 3, and Table 3, Entries 3 and 4). CAS: 720-74-1; white
◦
◦
1
solid (m.p. = 103–104 C, lit. [59] 103–104 C). H-NMR (CDCl ):
H), 7.55–7.63 (m, 4H), 7.99–8.02 (m, 2H); 13C-NMR (CDCl3):
C), 127.0 (2C), 128.8 (d, JC-F = 7.5 Hz, 2C), 128.9 (2C), 135.8, 136.0 (d, JC-F = 3.0 Hz), 144.7, 163.0
δ
2.62 (s, 3H), 7.14 (t, J = 9.0 Hz,
3
2
2
δ 26.6, 115.9 (d, JC-F = 22.5 Hz,
(d, JC-F = 247.5 Hz), 197.7.
0
4
-Acetyl-4 -methoxybiphenyl (3ac, Table 2, Entries 4 and 5, and Table 3, Entries 5 and 6). CAS: 13021-18-6;
◦
◦
1
pale yellow solid (m.p. = 153–155 C, lit. [59] 153–155 C). H-NMR (CDCl ):
.98 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H); C-NMR
δ 2.60 (s, 3H), 3.84 (s, 3H),
3
13
6
(
CDCl ): δ 26.6, 55.3, 114.3 (2C), 126.5 (2C), 128.3 (2C), 128.9 (2C), 132.1, 135.2, 145.3, 159.8, 197.7.
3
4
-Phenylbenzonitrile (3ba, Table 2, Entries 6 and 7, and Table 3, Entry 7). CAS: 2920-38-9; white
◦
◦
1
solid (m.p. = 89–91 C, lit. [65] 89–90 C). H-NMR (CDCl ):
7
δ
7.38–7.50 (m, 3H), 7.55–7.59 (m, 2H),
3
.65–7.73 (m, 4H); 13C-NMR (CDCl3):
δ 110.8, 118.9, 127.2 (2C), 127.7 (2C), 128.6, 129.1 (2C), 132.6 (2C),
1
39.1, 145.6.
4
-(4-Fluorophenyl)benzonitrile (3bb, Table 2, Entry 8 and Table 3, Entry 8). CAS: 10540-31-5; white solid
◦
◦
1
(m.p. = 115–117 C, lit. [66] 116–118 C). H-NMR (CDCl ):
δ
7.15 (t, J = 9.0 Hz, 2H), 7.52–7.56 (m, 2H),
3
7
.60–7.63 (m, 2H), 7.68–7.61 (m, 2H); 13C-NMR (CDCl3):
δ 110.9, 115.9 (d, JC-F = 21.8 Hz, 2C), 118.8,
1
27.5 (2C), 128.9 (d, JC-F = 8.3 Hz, 2C), 132.6 (2C), 135.2 (d, JC-F =3.0 Hz), 144.6, 163.1 (d, JC-F = 246.8 Hz).
0
4
-Methoxybiphenyl-4-carbonitrile (3bc, Table 2, Entry 9 and Table 3, Entry 9). CAS: 58743-77-4; pale
◦
◦
1
yellow solid (m.p. = 104–106 C, lit. [67] 104–105 C). H-NMR (CDCl ):
d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.60–7.69 (m, 4H); 13C-NMR (CDCl3):
2C), 119.1, 127.1 (2C), 128.3 (2C), 131.4, 132.5 (2C), 145.2, 160.2.
δ 3.84 (s, 3H), 6.99
3
(
(
δ
55.4, 100.4 114.5
◦
Biphenyl (3ca, Table 2, Entry 10 and Table 3, Entry 10). CAS: 92-52-4; white solid (m.p. = 71–72 C,
◦
1
13
lit [68] 71–72 C). H-NMR (CDCl ):
δ 7.34–7.40 (m, 2H), 7.44–7.49 (m, 4H), 7.61–7.64 (m, 4H); C-NMR
3
(
CDCl ): δ 127.1 (4C), 127.2(2C), 128.7 (4C), 141.2 (2C).
3
4
-Fluorobiphenyl (3cb, Table 2, Entry 11 and Table 3, Entry 11). CAS: 324-74-3; white solid
◦
◦
1
(
(
(
m.p. = 72–73 C, lit. [69] 72–73 C). H-NMR (CDCl ):
m, 2H), 7.52–7.61 (m, 4H); C-NMR (CDCl3):
δ
7.10–7.15 (m, 2H), 7.34–7.37 (m,1H), 7.41–7.46
115.6 (d, JC-F = 21.0 Hz, 2C), 127.0 (2C), 127.2, 128.7
d, JC-F = 8.3 Hz, 2C), 128.8 (2C), 137.3 (d, JC-F = 3.0 Hz), 140.2, 162.4 (d, JC-F = 245.3 Hz).
3
13
δ

Molecules 2016, 21, 1205
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4
-Methoxybiphenyl (3cc, Table 2, Entries 12, 17 and 18, and Table 3, Entries 12 and 13). CAS: 613-37-6;
◦
◦
1
white solid (m.p. = 85–87 C, lit. [59] 85–87 C). H-NMR (CDCl ):
2
δ
3.85 (s, 3H), 6.99 (d, J = 9.0 Hz,
3
H), 7.31–7.34 (m, 1H), 7.40–7.45 (m, 2H), 7.52–7.58 (m, 4H); 13C-NMR (CDCl3):
δ
55.3, 114.2 (2C), 126.6,
1
26.7 (2C), 128.1 (2C), 128.7 (2C), 133.7, 140.8, 159.1.
◦
4
4
7
-Methylbiphenyl (3da, Table 2, Entries 13 and 14). CAS: 644-08-6; white solid (m.p. = 43–45 C, lit. [59
]
◦
1
3–45 C). H-NMR (CDCl ):
.50–7.53 (m, 2H), 7.58–7.61 (m, 2H); C-NMR (CDCl3):
δ
2.41 (s, 3H), 7.24–7.28 (m, 2H), 7.34–7.36 (m, 1H), 7.42–7.47 (m, 2H),
3
13
δ
21.1, 126.8, 126.9 (4C), 128.7 (2C), 129.5 (2C),
1
37.0, 138.3, 141.1.
0
◦
4
-Fluoro-4 -methylbiphenyl (3db, Table 2, Entry 15). CAS: 72093-43-7; white solid (m.p. = 79–81 C,
◦
1
lit. [70] 78–79 C). H-NMR (CDCl ):
m, 2H), 7.50–7.54 (m, 2H); C-NMR (CDCl3): 21.1, 115.6 (d, JC-F = 21.8 Hz, 2C), 126.8 (2C), 128.5
d, JC-F = 8.3 Hz, 2C), 129.5 (2C), 137.0, 137.2 (d, JC-F = 3.0 Hz), 137.4, 162.3 (d, JC-F = 247.5 Hz).
δ
2.39 (s, 3H), 7.11 (t, J = 9.0 Hz, 2H), 7.23–7.25 (m, 2H), 7.42–7.45
3
13
(
(
δ
0
4
-Methoxy-4 -methylbiphenyl (3dc, Table 2, Entry 16). CAS: 53040-92-9; white solid (m.p. = 113–114
◦
◦
1
C, lit. [59] 113–114 C). H-NMR (CDCl ):
d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H); 13C-NMR (CDCl3):
δ 21.0, 55.2, 114.1
2C), 126.5 (2C), 127.9 (2C), 129.4 (2C), 133.6, 136.3, 137.9, 158.9.
δ 2.42 (s, 3H), 3.87 (s, 3H), 7.01 (d, J = 9.0 Hz, 2H), 7.27
3
(
(
0
4
-Fluoro-4 -methoxybiphenyl (3eb, Table 2, Entry 19 and Table 3, Entry 14). CAS: 450-39-5; white solid
◦
◦
1
(
(
(
m.p. = 88–90 C, lit. [59] 88–90 C). H-NMR (CDCl ):
m, 2H), 7.44–7.51 (m, 4H); C-NMR (CDCl3):
2C), 128.2 (d, JC-F = 7.5 Hz, 2C), 132.8, 136.9 (d, JC-F = 3.0 Hz), 159.1, 162.0 (d, JC-F = 243.8 Hz).
δ
3.84 (s, 3H), 6.94–6.99 (m, 2H), 7.07–7.13
3
13
δ 55.3, 114.2 (2C), 115.5 (d, JC-F = 21.8 Hz, 2C), 128.0
0
4
(
(
,4 -Dimethoxybiphenyl (3ec, Table 2, Entry 20 and Table 3, Entry 15). CAS: 2132-80-1; pale yellow solid
◦
◦
1
m.p. = 178–180 C, lit. [68] 178–180 C). H-NMR (CDCl ):
m, 4H); 13C-NMR (CDCl ): δ 55.3 (2C), 114.1 (4C), 127.7 (4C), 133.4 (2C), 158.6 (2C).
δ
3.84 (s, 6H), 6.93–6.97 (m, 4H), 7.45–7.49
3
3
◦
-Phenylphenol (3fa, Table 3, Entries 16–18). CAS: 92-69-3; white solid (m.p. = 148–150 C, lit. [59]
4
1
(
◦
48–150 C). H-NMR (DMSO–d ): δ 6.86 (d, J = 9.0 Hz, 2H), 7.25–7.28 (m, 1H), 7.36–7.57 (m, 6H), 9.57
6
1
br, 1H); 13C-NMR (DMSO–d6):
δ
115.7 (2C), 126.0 (2C), 126.4, 127.8 (2C), 128.8 (2C), 130.9, 140.2, 157.2.
◦
4
-Hydroxy-4-fluorobiphenyl (3fb, Table 3, Entry 19). CAS: 324-94-7; white solid (m.p. = 168–170 C,
◦
1
lit. [71] 167–170 C). H-NMR (DMSO–d ):
δ 6.84 (d, J = 9.0 Hz, 2H), 7.21 (t, J = 9.0 Hz, 2H), 7.44
6
13
(d, J = 9.0 Hz, 2H), 7.55–7.60 (m, 2H), 9.56 (br, 1H); C-NMR (DMSO–d6):
δ
115.5 (d, JC-F = 21.0 Hz,
2C), 115.7 (2C), 127.7 (2C), 127.8 (d, JC-F = 9.0 Hz, 2C), 130.0, 136.7 (d, JC-F = 3.0 Hz), 157.1, 161.2
(d, JC-F = 240.8 Hz).
◦
4
-Hydroxy-4-methoxybiphenyl (3fc, Table 3, Entry 20). CAS: 16881-71-3; white solid (m.p. = 173–175 C,
◦
1
lit. [72] 171–173 C). H-NMR (DMSO–d ):
2
δ
3.75 (s, 3H), 6.82 (d, J = 9.0 Hz, 2H), 6.95 (d, J =9.0 Hz,
6
13
H), 7.40 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 9.46 (br, 1H); C-NMR (DMSO–d6):
δ
55.1, 114.2
(2C), 115.7 (2C), 127.0 (2C), 127.2 (2C), 130.7, 132.8, 156.5, 158.1.
0
1
4
(
-Methylacetophenone (6a
[
73], Table 4, Entries 1–4 and 7). CAS: 122-00-9; colorless liquid. H-NMR
13
CDCl3):
δ 2.38 (s, 3H), 2.55 (s, 3H), 7.23 (d, J = 9.0 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H); C-NMR (CDCl3):
δ 21.6, 26.5, 128.4 (2C), 129.2 (2C), 134.6, 143.8, 197.8.
1
p-Tolunitrile (6b
[
74], Table 4, Entries 5 and 8). CAS: 104-85-8; colorless liquid. H-NMR (CDCl ):
δ
2.39
3
13
(s, 3H), 7.24 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H); C-NMR (CDCl3):
2C), 131.9 (2C), 143.6.
δ 21.8, 109.2, 119.1, 129.8
(

Molecules 2016, 21, 1205
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1
4
(
1
-Methylanisole (6e
s, 3H), 3.79 (s, 3H), 6.82 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H); C-NMR (CDCl3):
13.6 (2C), 129.7, 129.8 (2C), 157.4.
[
26], Table 4, Entry 6). CAS: 104-93-8; colorless liquid. H-NMR (CDCl ):
δ
2.30
3
13
δ
20.4, 55.2,
3
.3. Procedure for Reuse of the Catalytic Aqueous Solution
The reaction was conducted following the procedure described in Section 3.2., and under the
reaction conditions shown in Table 1, Entry 6. After the initial reaction, the aqueous reaction mixture
was extracted with hexane (3 mL 3) under vigorous stirring. The organic layer was separated from
×
the aqueous phase by syringe, and the organic product was isolated from the combined organic phase
according to a previously-described in Section 3.2. The residual aqueous solution was then charged
with 1a, 2a, and NaHCO for the next reaction.
3
4
. Conclusions
In conclusion, we have proved that the PdCl (NH ) /cationic 2,2 -bipyridyl system is highly
0
2
3 2
efficient and provides a reusable catalyst for Stille couplings. This catalytic system exhibits
a high efficiency for the coupling of aryl iodides and activated aryl bromides with various
aryltributylstannanes under a very low catalyst loading (1 ppm). This water-compatible catalytic
system enables the reaction to be conducted by a very simple procedure, allowing easy separation
of the catalytic aqueous solution from the organic products, rendering it very suitable for
practical applications.
Supplementary Materials: The following are available online at: http://www.mdpi.com/1420-3049/21/9/1025/
1
13
s1: copies of H- and C-NMR spectra of all Stille coupling products.
Acknowledgments: This research was financially supported by the Ministry of Science and Technology of
Taiwan (MOST 104-2113-M-027-003). We thank Yi-Tsu Chan (National Taiwan University) for performing
ICP-MASS analysis.
Author Contributions: Wei-Yi Wu and Fu-Yu Tsai conceived and designed the research; Ling-Jun Liu,
Fen-Ping Chang, and Yu-Lun Cheng performed the experiments; Fu-Yu Tsai wrote the paper.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of compounds 3 and 6 are available from the authors.
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