Sulfur-ligand/Pd-catalyzed cross-coupling reactions of aryl halides with arylboronic acids under aerobic conditions

Article abstract of DOI:10.1007/s10562-010-0342-z

An air-and moisture-stable monodentate sulfur-ligand was synthesized. The ligand was found to be effective in Pd-catalyzed cross-coupling reactions of various aryl halides with arylboronic acids under aerobic conditions. This catalytic system is tolerant of a wide range of functional groups. The new complex structure of the sulfur-ligand/Pd^II has been determined by single-crystal X-ray diffraction.

Full text of DOI:10.1007/s10562-010-0342-z

Catal Lett (2010) 137:69–73
DOI 10.1007/s10562-010-0342-z
Sulfur-Ligand/Pd-Catalyzed Cross-Coupling Reactions of Aryl
Halides with Arylboronic Acids Under Aerobic Conditions
•
•
•
Hong-ling Li Zhi-sheng Wu Min Yang
Yan-xing Qi
Received: 4 January 2010 / Accepted: 6 April 2010 / Published online: 20 April 2010
Ó Springer Science+Business Media, LLC 2010
Abstract An air-and moisture-stable monodentate sulfur-
ligand was synthesized. The ligand was found to be
effective in Pd-catalyzed cross-coupling reactions of vari-
ous aryl halides with arylboronic acids under aerobic
conditions. This catalytic system is tolerant of a wide range
of functional groups. The new complex structure of the
sulfur-ligand/PdII has been determined by single-crystal
X-ray diffraction.
ligands are generally required to stabilize the reactive
palladium intermediates, and excellent results have been
reported for Pd-catalyzed Suzuki reactions [9–11]. How-
ever, many phosphines are sensitive to air and moisture
resulting in limitations on their applications [12]. There-
fore, the application of alternative ligands in metal-cata-
lyzed synthetic transformations opens up new opportunities
in catalysis [13–18]. Sulfur-containing compounds were
traditionally categorized as catalyst poisons due to their
strong coordinative and adsorptive properties, which ren-
dered them totally ineffective as catalysts [19, 20].
Recently, efforts have been focused on the development of
sulfur-ligands/metal catalyzed reactions [21–25], among
which thioureas emerged as one of the most efficient
ligands owing to their stability to air and moisture, desir-
able coordinating ability with metal, as well as their greater
stability at elevated temperatures relative to phosphine
ligands, which may enable their use over a broader range of
reaction conditions [26–37]. However, Suzuki coupling
reactions catalyzed by simple non-chiral monodentate
thiourea has not been attempted so far [7, 8].
Keywords Cross-coupling reaction ꢀ Palladium ꢀ
Sulfur-ligand ꢀ Catalysis
1 Introduction
Suzuki cross-coupling reaction represents one of the most
widely used processes for the synthesis of biaryls, impor-
tant building blocks of pharmaceuticals [1], polymers [2]
and ligands for catalysis [3]. As a result, considerable
efforts have been directed toward the development of
efficient Suzuki cross-coupling reactions [4–8]. Phosphine
Herein we report the synthesis of bulky sulfur-ligand 4
and its application in Pd-catalyzed cross-coupling reactions
of various aryl halides with arylboronic acids under aerobic
conditions.
Li and Wu contributed equally to this work.
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-010-0342-z) contains supplementary
material, which is available to authorized users.
2 Experimental
H. Li ꢀ Z. Wu ꢀ M. Yang (&) ꢀ Y. Qi (&)
State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000,
People’s Republic of China
Chemicals and solvents were all purchased from com-
1
mercial supplies and were used directly. H NMR and 13C
NMR spectra were recorded at 400 MHz and 100.6 MHz
with a Varian Mercury 400 spectrometer. Mass spectro-
metric data were obtained using a Hewlett Packard 5988
GC/MS.
e-mail: minyang1@gmail.com
Y. Qi
e-mail: qiyanxing@gmail.com
123

70
H. Li et al.
C6H4But-
p
C6H4But-
p
C6H4But-
N
p
C6H4But-
p
C6H4But-
NH2
p
NH HN
glyoxal, C2H5OH
H2O, rt
N
NaBH4, EtOH
reflux
But
But
But
But
But
7
8
6
Aryl
-ButC6H4
C6H4But-
p
N
p
Aryl
Cl
S
N
N
thiophosgene, THF
Na2CO3, rt
PdCl2(CH3CN)2
CH2Cl2
N
Pd
Cl
N
S
Aryl
S
N
But
But
Aryl
5 Aryl = 2-(4'-tBuC6H4), 5-tBuC6H3
4
Scheme 1 Synthesis of sulfur ligand 4 and its Pd complex 5
2.1 Synthesis of 4
The method for preparation of a novel sulfur-containing
ligand 4 is shown in Scheme 1. A solution of thiophosgene
(1.2 mmol) in dry THF at room temperature was added
dropwise to a stirred mixture of N,N0-disubstituted diamine
8 (588 mg, 1.0 mmol) and Na2CO3 (1.5 mmol) in dry
THF. After stirred at room temperature for 24 h, water and
ethyl acetate were added. The organic layer was washed
with dilute HCl and brine, dried and concentrated. The pure
sulfur-ligand 4 was obtained through flash chromatography
as white solid (371.5 mg, 59% yield). m.p. 258–259 °C; 1H
NMR (300 MHz, CDCl3) d 7.57–7.52 (m, 6H), 7.44–7.39
(m, 6H), 7.36–7.33 (m, 2H), 3.25 (s, 4H), 1.42 (s, 18H),
1.35 (s, 18H); 13C NMR (100 MHz, CDCl3) d 184.2, 151.1,
150.2, 138.1, 136.7, 136.0, 130.3, 128.4, 127.5, 125.1,
49.4, 34.7, 34.5, 31.4, 31.3; IR (CH2Cl2) 1468, 1410, 1340,
1244, 1131 cm-1; LRMS (EI, 20 eV): m/z 630 (M?, 100),
631 (49); HRMS (EI) calcd for C27H17N2S (M?):
630.4008, found 630.3968.
Fig. 1 Structure of complex 5. Hydrogen atoms have been omitted
for clarity
2.3 General Procedure for the Suzuki Coupling
Reaction
All reactions were conducted under aerobic conditions. A
mixture of aryl halide 1a (0.2 mmol), arylboronic acid 2a
(0.24 mmol), Pd(OAc)2 (1.5 mol%), sulfur-ligand
2.2 Synthesis of Complex 5
i
(3 mol%), K2CO3 (3 equivalents), and PrOH/H2O (2 mL)
were taken in a sealed tube. Then the mixture was stirred at
100 °C for the desired time (Table 1) until complete con-
sumption of starting material as monitored by TLC. After
the reaction mixture was cooled down to room temperature
and filtered through a pad of silica gel, the filtrate was
concentrated and the residue was purified by column
chromatography (hexane or hexane/EtOAc) to afford 3a.
0.20 mmol of PdCl2(CH3CN)2 and 0.20 mmol of ligand
4 were dissolved in 4 mL of dichloromethane. The
solution was stirred at room temperature for 24 h
affording a green solid precipitate which was collected
by filtration and washed with cold ether. Suitable crystal
for X-ray analysis was obtained by slow diffusion of
diethyl ether into saturated dichloromethane solution of
the complex.
X-ray diffraction data collection was performed on a
Bruker Smart APEX CCD diffractometer using graphite
3 Results and Discussion
˚
monochromated Mo Ka radiation (k = 0.71073 A) at
As shown in Table 1, the reaction of iodobenzene (1a) with
4-methoxy-phenylboronic acid (2a) was chosen as a model
reaction to test the catalytic activity of palladium/ligand 4
catalyst system. A series of solvent systems including
296 K. The diffraction frames were integrated using the
SAINT package. The structure was solved by direct
methods using the program SHELXS97. The crystal
structure plot is shown in Fig. 1.
123

Sulfur-Ligand/Pd-Catalyzed Cross-Coupling Reactions of Aryl Halides
71
Table 1 Effects of catalysts, solvents and bases on the Suzuki reaction of iodobenzene (1a) and 4-methoxy-phenylboronic acid (2a)
catalyst/4
+
MeO
B(OH)2
I
MeO
solvent, base
100°C
1a
2a
-ButC6H4
3a
p
C6H4But-
p
N
N
4:
S
But
But
Entry
Catalyst
Solvent (v/v)
iPrOH
Base (equiv.)
Isolated yield (%)
1
Pd(OAc)2
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (2)
K3PO4 (3)
Cs2CO3 (3)
K2CO3 (3)
K2CO3 (3)
75
90
72
68
16
77
87
87
66
85
77
86
84
2
Pd(OAc)2
iPrOH/H2O (10/1.5)
iPrOH/H2O (8.5/1.5)
NMP/H2O (3/1)
3
Pd(OAc)2
4
Pd(OAc)2
5
Pd(OAc)2
Dioxane/H2O (10/1.5)
Toluene/H2O (10/1.5)
iPrOH/H2O (10/1.5)
iPrOH/H2O (10/1.5)
iPrOH/H2O (10/1.5)
iPrOH/H2O (10/1.5)
iPrOH/H2O (10/1.5)
iPrOH/H2O (10/1.5)
iPrOH/H2O (10/1.5)
6
Pd(OAc)2
7
PdI2
8
Pd2(dba)3
9
Pd(OAc)2
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2 (1.0 mol%)
Pd(OAc)2 (0.5 mol%)
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (1.5 mol%), 4 (3 mol%), base, and solvent (2 mL) at 100 °C under air for 7 h
iPrOH, iPrOH/H2O, NMP/H2O, dioxane/H2O, toluene/H2O
Miyaura coupling reaction of aryl iodides (1a–e) with
various arylboronic acids (2a–g) were then investigated in
iPrOH/H2O at 100 °C and representative results are sum-
marized in Table 2. These results indicated that: (a) Good
functional group compatibility was observed. For example,
substituents such as chloro, nitro, methyl and methoxy
groups on the aryl halide and methoxy, alkyl, hydroxyl and
formyl (either ortho- or para-position) groups on arylbo-
ronic acids were all tolerated (entries 7–8, 10–15). (b)
Notably, this catalytic system was also effective for steri-
cally hindered substrates. Hindered 1-iodo-2-nitrobenzene
(1c) was successfully coupled with ortho-substituted aryl-
boronic acids (2c–e) to give 2, 2’-disubstituted biphenyl in
moderate to excellent yields (entries 11–13).
The scope of the PdII/4 catalytic system was further
extended to the reactions of the less reactive aryl bromides
1f–j and the challenging aryl chlorides 1k–o with arylbo-
ronic acids 2a (Table 3). The coupling reactions worked
well for aryl bromides of different electronic effects 1f–j,
affording moderate to excellent yields of the corresponding
products (entries 1, 2, and 5–7). Remarkably, excellent
yield (94%) of the coupling product 3q could also be
achieved at 0.5 mol% catalyst loading (entry 3). Further-
more, in contrast to many phosphine ligands and carbene
ligands, good catalytic activity of the recycled sulfur-
ligand 4 by column chromatography was observed (entry
4), which gave an opportunity to develop a new kind of
i
were first evaluated (entries 1–6). The mixture of PrOH
and H2O with a 10/1.5 (v/v) ratio was found to be the
optimal solvent system for this reaction, indicating that
appropriate amount of water improved the cross-coupling
reaction yield (entries 1–3) [5]. It is well-known that
Suzuki reaction is catalyzed by Pd(0), and Pd(OAc)2 is
readily reduced to the catalytically active Pd(0) state by
phosphines and many other reagents [38, 39]. We specu-
lated that iPrOH not only acted as a solvent but also played
a role of reductive reagent which reduced Pd(II) to Pd(0)
and, thus, facilitated the catalytic reaction [40]. To gain
evidence the formation of Pd(0), an ESI–MS study of a
iPrOH solution of thiourea 4/Pd(OAc)2 (2/1 ratio) was
performed and a peak at m/z = 1367.6 was identified to be
[Pd(0)ꢀ(4)2 ? H]? ion. Two other palladium reagents
including PdI2 and Pd2(dba)3 were then examined, both of
which were less effective than Pd(OAc)2 (entry 2 vs.
entries 7 and 8). The use of K2CO3 as a base led to a higher
yield than other commonly used bases such as K3PO4 and
Cs2CO3 (entry 2 vs. entries 10 and 11). Finally, the effects
of the amounts of base and Pd(OAc)2 on the reaction were
also tested (entries 9, 12 and 13). Lower yields were
obtained when the amounts of either base or palladium
were reduced.
The catalytic activities of the new palladium catalyst
system of PdII combined with a new ligand 4 for Suzuki–
123

72
H. Li et al.
Table 2 Cross-coupling reactions of aryl iodides with arylboronic
acids
Table 3 Cross-coupling of aryl bromides/chlorides 1 with 4-meth-
oxy-phenylboronic acid 2a
I
+
R'
B(OH)2
+
(HO)2
B
OMe
R
X
OMe
R'
R
R
R
2
3
1
X=Br, Cl
1
2a
3
Aryl halide
(R)
T (h)
Isolated
yield (%)
Entry
Arylboronic acid
Products
Entry
Aryl halide
Product
Isolated
yield (%)
(HO)2
B
B
OMe 2a
OMe 3a
1
2
3
R=H 1a
1a
7
7
7
90
75
74
Br
COCH3
MeO
COCH3
NO2
1
2
3
4
99
99
1f
3p
Br
NO2
MeO
(HO)2
1g
3q
2b
3b
3c
3d
1g
1g
3q
3q
94a
90b
1a
(HO)2
B
2c
C2H5
C2H5
4
5
1a
1a
7
3
90
93
(HO)2
B
NO2
NO2
2d
5
93
Br
MeO
1h
OMe 1i
1j
3r
OHC
B
OHC
(HO)2
2e
3e
Br
MeO
6
7
8
89
66
2
3o
3a
CHO 2f
CHO 3f
(HO)2
B
6
7
1a
1a
3
24
4
85
70
98
93
94
96
Br
MeO
1j
3a
73c
(HO)2
B
OH 2g
OMe 2a
2b
OH 3g
Cl
O2
NO2
MeO
NO2
9
70c,d
65c,d
55c,d
(HO)2
(HO)2
(HO)2
B
Cl
OMe 3h
8
4-Cl 1b
1b
N
O2
N
1k
3s
Cl
NO2
10
11
3q
B
Cl
9
3
1l
3i
Cl
O2
MeO
OMe
B
OMe 2a
10
11
2-NO2 1c
1c
6
N
O2
3p
3a
N
1m
3j
NO2
3j
12
13
40c,d
11c,d
Cl
COCH3
1n
11
(HO)2
B
2c
NO2
3k
3l
Cl
1o
C2H5
C
2H5
12
13
1c
1c
11
8
92
57
(HO)2
B
Reaction conditions:
1
(0.2 mmol), 2a (0.24 mmol), catalyst
2d
NO2
(1.5 mol%, Pd/4 = 1/2), K2CO3 (3 equivalents), and solvent (iPrOH/
H2O = 10/1.5, 2 mL) at 100 °C under air for 24 h
OHC
OHC
B
a
(HO)2
Catalyst (0.5 mol%)
i
Recycled 4 (1 mol%), PrOH/H2O = 10/1.5, 1 mL
2e
NO2
3m
b
c
d
(HO)2
B
B
OMe 2a
OMe 3n
20 mol% TBAB was added
14
15
4-CH3 1d
8
78
77
2a (0.30 mmol), catalyst (3 mol%), 130 °C
(HO)2
OMe 2a
MeO
4-OCH3 1e
22
2
3o
coupling reactions (entries 9–12). For example, in the
presence of 3 mol% of catalyst and 20 mol% TBAB,
coupling of 1k, 1l with 2a afforded 70 and 65% yield of 3s
and 3q, respectively (entries 9 and 10). To our knowledge,
these are the best results of thiourea/Pd catalyzed Suzuki
coupling for electron-deficient aryl chlorides. The only
reported example necessitated high ratio of arylboronic
acid to aryl chloride (2/1) to obtain moderate yield (30%)
of the desired product 3q using the bidentate sulfur-ligand
[33]. These results demonstrated the potential of such
monodentate sulfur-ligands for the use in Pd-catalyzed
reactions. Acceptable yields were achieved even for less
reactive aryl chloride 1m and 1n (entries 11 and 12).
However, very low yield (11%) was obtained for electron-
neutral chlorobenzene 1o and homocoupling product of 2a
was observed (entry 13).
Reaction conditions:
1 (0.2 mmol), 2 (0.24 mmol), catalyst
(1.5 mol%, Pd/4 = 1/2), K2CO3 (3 equivalents), and solvent (iPrOH/
H2O = 10/1.5, 2 mL) at 100 °C under air
immobilized catalyst. For the electronically neutral phenyl
bromide 1j, catalytic amount of TBAB (Tetrabutylammo-
nium bromide) was required to enhance the yield (entry 8).
It is believed that three roles of TBAB may play in the
reaction: (a) stabilization of the low coordinate Pd(0)
species; (b) activation of Pd0 species with the formation of
anionic species; (c) phase transfer catalyst for the inorganic
base/solvent/substrate/product phases [18, 41, 42]. It is
noteworthy that this catalytic system is effective for elec-
tron-deficient aryl chlorides 1k–n in the presence of
20 mol% TBAB, although the catalyst loading and the
reaction temperature were increased to facilitate the cross-
123

Sulfur-Ligand/Pd-Catalyzed Cross-Coupling Reactions of Aryl Halides
73
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In summary, an efficient non-chiral monodentate sulfur-
ligand 4/palladium catalytic system for the Suzuki coupling
reaction has been investigated. Under aerobic condition, in
the presence of this catalytic system, the cross-coupling
reactions of various aryl halides with arylboronic acid
proceeded smoothly in moderate to excellent yields. The
sulfur-ligand can be recovered by column chromatography,
and good catalytic activity of the recycled sulfur-ligand
was observed. In addition, the cross-coupling reaction by
this catalyst is tolerant of a wide range of functional
groups. The complex structure of the sulfur-ligand/PdII has
been determined by single-crystal X-ray diffraction. Cur-
rently, further efforts to immobilize this new catalyst on
mesoporous materials and apply them on C–C bond for-
mation reactions are underway in our laboratory.
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