Application of cyclic thiourea as an efficient ligand in palladium-catalyzed Hiyama cross-coupling reactions

Article abstract of DOI:10.1055/s-2008-1067018

Cyclic thiourea has been first utilized as an efficient ligand in palladium-catalyzed Hiyama cross-coupling reactions. In the presence of palladium(II) acetate, N,N′-bis(2,5-di-tert-butylphenyl)-N,N′- ethylenethiourea, tetrabutylammonium fluoride, and dioxane, aryl halides (X = I, Br, Cl) underwent smooth cross coupling with trimethoxy(phenyl)silane to afford the corresponding biaryl products in moderate to excellent yields. Furthermore, the thiourea can be recovered by column chromatography and reused with negligible loss in catalytic activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067018

PAPER
1415
Application of Cyclic Thiourea as an Efficient Ligand in Palladium-Catalyzed
Hiyama Cross-Coupling Reactions
P
alladium-Cata
h
lyze
d
H
iyam
i
a
Cross
-
-Coupli
s
ng Reactio
h
ns eng Wu,a,b Min Yang,*a Hong-ling Li,a,b Yan-xing Qi*a
a
National Engineering Research Center for Fine Petrochemical Intermediates, Lanzhou Institute of Chemical Physics, Lanzhou 730000,
P. R. of China
Fax +86(931)4968190; E-mail: minyang1@gmail.com; E-mail: qiyanxing@gmail.com
Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100039, P. R. of China
b
Received 25 October 2007
tylphenyl)imidazolidine-2-thione, L] was first utilized as
an efficient ligand in palladium-catalyzed Hiyama cross-
coupling reactions of aryl halides with trimethoxy(phe-
nyl)silane (Equation 1). Moreover, the thiourea ligand can
Abstract: Cyclic thiourea has been first utilized as an efficient
ligand in palladium-catalyzed Hiyama cross-coupling reactions. In
the presence of palladium(II) acetate, N,N¢-bis(2,5-di-tert-butylphe-
nyl)-N,N¢-ethylenethiourea, tetrabutylammonium fluoride, and di-
oxane, aryl halides (X = I, Br, Cl) underwent smooth cross coupling be recovered by column chromatography and reused with-
with trimethoxy(phenyl)silane to afford the corresponding biaryl
out obvious loss of catalytic activity.
products in moderate to excellent yields. Furthermore, the thiourea
can be recovered by column chromatography and reused with neg-
The catalytic efficiency of palladium–thiourea L in the
coupling reactions of 1-bromo-4-methoxybenzene (1a)
with trimethoxy(phenyl)silane (2) was initially evaluated
(Table 1). In the absence of the thiourea ligand, the cou-
pling reaction took place inefficiently to afford 3a with a
moderate 47% yield (entry 1). In contrast, the addition of
thiourea ligand L (ratio L/Pd 2:1) significantly increased
the yield of the reaction to 60% (entry 2) in the presence
of 3 mol% palladium(II) acetate and two equivalents of
tetrabutylammonium fluoride trihydrate. Furthermore, the
yield of 3a further improved to 68% as the ratio of thio-
urea to palladium increased to 4:1 (entry 3). Several
different palladium sources, including bis(dibenzylidene-
acetone)palladium(0), bis(acetonitrile)dichloropalladium,
and palladium(II) trifluoroacetate were also screened
(Table 1). The results show that bis(acetonitrile)dichloro-
palladium had the same efficient in the Hiyama reaction
as palladium(II) acetate, which gave the best results (entry
3 vs 4), while another palladium(II) source, palladium(II)
trifluoroacetate, containing the more dissociative trifluo-
roacetate ligand, resulted in a lower yield (entry 5). However,
the palladium(0) complex bis(dibenzylideneacetone)pal-
ladium(0) was less efficient (entry 6).
ligible loss in catalytic activity.
Key words: palladium, ligands, cross-coupling reaction, aryl ha-
lides, trimethoxy(phenyl)silane
The palladium-catalyzed Hiyama coupling reaction of or-
ganosilicon compounds with aryl halides is an important
protocol for the synthesis of biaryls,1,2 which are impor-
tant core structural motifs in many biologically active
molecules and electronic organic materials.3 In addition,
organosilicon compounds are attractive due to their ease
of handling and low toxicity compared with other organo-
metallic reagents that are employed in cross-coupling pro-
cesses. Consequently, a few ligands including phosphine,4
imidazolium chloride,5 and nitrogen-based ligands6 have
been successfully applied in the palladium-catalyzed
Hiyama cross-coupling reaction. On the other hand, thio-
urea ligands, which are air- and moisture-stable and readi-
ly modified, have attracted considerable attention as a
new type of possible alternative to the widely used phos-
phine ligands in homogeneous palladium-catalyzed reac-
tions.7 Thus, investigation of thiourea ligands in
palladium-catalyzed reactions is of importance. Herein
we report that cyclic thiourea, N,N¢-bis(2,5-di-tert-bu-
tylphenyl)-N,N¢-ethylenethiourea [1,3-bis(2,5-di-tert-bu-
The Hiyama cross coupling was then tested at different
temperatures. At 60 °C, even with prolonged reaction
times, incomplete conversion was observed (Table 2, en-
try 1). The yield of the coupling product was enhanced
Pd(OAc)2, thiourea L
Ph
PhSi(OMe)3
X
+
TBAF·3H2O, dioxane, 80 °C
R
R
1
2
3
X = I, Br, Cl
N
N
thiourea L:
Ar
Ar
S
Ar = 2,5-(t-Bu)2C6H3
Equation 1
SYNTHESIS 2008, No. 9, pp 1415–1419
x
x
.
x
x
.2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1067018; Art ID: F19507SS
© Georg Thieme Verlag Stuttgart · New York

1416
Z.-s. Wu et al.
PAPER
Table 1 Effects of the Thiourea Ligand and Palladium Sourcea
Pd, L, dioxane
MeO
Br
PhSi(OMe)3
+
MeO
TBAF·3H2O, 80 °C
1a
2
3a
Entry
Palladium source
Ratio L/Pd
Yieldb (%)
1
2
3
4
5
6
Pd(OAc)2
–
47c
60
68
68
55
52
Pd(OAc)2
2:1
4:1
4:1
4:1
4:1
Pd(OAc)2
PdCl2(MeCN)2
d
Pd(tfa)2
Pd(dba)2
a Reaction conditions: 1a (0.167 mmol), 2 (0.33 mmol), Pd source (3 mol%), thiourea ligand L, TBAF·3 H2O (2 equiv), solvent (1 mL), argon,
80 °C, 12 h.
b Isolated yield.
c No thiourea was added.
d tfa = OCOCF3.
Table 2 Effects of Temperature, Solvent, and Additivea
Pd(OAc)2, L
MeO
MeO
Br
PhSi(OMe)3
+
TBAF·3H2O
1a
2
3a
Entry
1
Temp (°C)
Solvent
dioxane
dioxane
dioxane
dioxane
THF
Yieldb (%)
60
73
80
85
80
80
80
80
80
80
80
80
13
2
62
3
68
4
62
5
41
6
acetone
MeCN
DMF
68
7
58
8
4
9
DMSO
–
trace
tracec
58d
40e
10
11
12
dioxane
dioxane
a Reaction conditions: 1a (0.167 mmol), 2 (0.33 mmol), Pd(OAc)2 (3 mol%), thiourea ligand L (12 mol%), TBAF·3 H2O (2 equiv), solvent (1
mL), argon, indicated temperature, 12 h.
b Isolated yield.
c TBAF·3H2O (6 equiv).
d In air.
e 1 Equiv CuI was added.
with increased temperature (entries 1–3), and 80 °C was (entries 3 and 6). the use of more polar acetonitrile, N,N-
found to be optimal (entry 3) as a further increase in the dimethylformamide, and dimethyl sulfoxide resulted in
reaction temperature resulted in lower product yields (en- incomplete conversion (entries 7–9). We also examined
try 4). An extensive survey of solvents revealed that mod- the solvent-free Hiyama cross-coupling reaction in the
erate polar dioxane and acetone gave the best yields, presence of six equivalents of tetrabutylammonium fluo-
Synthesis 2008, No. 9, 1415–1419 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Hiyama Cross-Coupling Reactions
1417
ride,4h but poor yields were observed (entry 10). The at- The catalytic efficacy of palladium–thiourea in the Hiya-
tempt to use air instead of argon resulted in an ma reaction was then investigated further with a number
unsatisfactory yield of 3a (entry 11). Using copper(I) io- of aryl halides. As illustrated in Table 3, our catalyst sys-
dide, a promoter for Hiyama reaction in a previous re- tem is efficient for the Hiyama cross-coupling reactions of
port,2i was found to suppress the cross-coupling reaction various aryl halides 1a–m with trimethoxy(phenyl)silane
in this case (entry 12).
(2). Treatment of aryl iodides 1b–d with 2 afforded the
Table 3 Palladium(II) acetate–Thiourea Ligand L Catalyzed Cross Coupling of Aryl Halides with Trimethoxy(phenyl)silanea
Pd(OAc)2, thiourea L
PhSi(OMe)3
2
X +
Ph
TBAF, dioxane, 80 °C
R
R
3a–h
1
Entry
1
Aryl halide
Time (h)
2
Product
Yieldb (%)
95
1b
1c
1d
1e
1f
3b
I
I
I
Cl
Ph
Ph
Ph
Cl
2
1
3c
3a
3d
3b
3e
86
3
4
1
1
95
92c
OMe
OMe
O
O
5
6
7
5
4
86
86
81
Br
Br
Ph
Ph
Cl
Cl
1g
24
Br
Br
NO2
Ph
Ph
NO2
8
1h
24
3f
66
NO2
NO2
9
10
24
6
52
1i
3g
3c
3h
3e
3d
3c
3a
65d
Br
Br
Br
Cl
Br
Ph
Ph
Ph
Ph
Ph
11
12
13
14
15
16
1j
4
4
82d
39
1k
1l
24
24
24
48
78d,e
77f
NO2
O
NO2
O
1m
1n
1o
Cl
Cl
Cl
Ph
Ph
Ph
35g,h
11h
OMe
OMe
a Reaction conditions: 1 (0.167 mmol), 2 (0.33 mmol), Pd(OAc)2 (3 mol%), thiourea L (12 mol%), TBAF·3 H2O (2 equiv), dioxane (1 mL), at
80 °C.
b Isolated yield.
c Recycled thiourea ligand L was used.
d 2 (0.66 mmol), TBAF·3H2O (4 equiv).
e Dioxane (0.5 mL).
f 1m (0.33 mmol), 2 (1.32 mmol), Pd(OAc)2 (3 mol%), thiourea (12 mol%), TBAF·3H2O (4 equiv), dioxane (1 mL), 80 °C.
g Acetone (1 mL) as the solvent.
h No improvement of the coupling reaction yield was observed even at 100 °C.
Synthesis 2008, No. 9, 1415–1419 © Thieme Stuttgart · New York

1418
Z.-s. Wu et al.
PAPER
tube. The mixture was stirred at 80 °C for the indicated time
(Table 3) until complete consumption of starting material (TLC).
The mixture was cooled to r.t. 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–
h, which are all known compounds.
corresponding cross-coupled products in excellent yields
(entries 1–3). Importantly, thiourea ligand L can be recov-
ered after the cross-coupling reaction by column chroma-
tography and the recycled ligand had comparable catalytic
efficiency in the Hiyama coupling reaction (entry 4 vs. 3).
The efficiency of the catalyst system for the reactions of
aryl bromides decreased to some extent and prolonged re-
action times were required. For the coupling of the acti-
vated aryl bromides 1e–h with 2, moderate to good yields
of the corresponding cross-coupled products were ob-
tained (entries 5–8). For aryl halides, several functional
groups, including ether, acetyl, and nitro, are all compati-
ble with the cross-coupling conditions (entries 3, 5, 7, 8,
13, and 14). The dibromide 1i was successfully trans-
formed to its dicoupling product 3g in moderate yield. In-
creasing the amount of silane 2 and tetrabutylammonium
fluoride resulted in an improved yield of 65% (entry 10
vs. 9). This catalytic system also proved to be efficient for
the cross coupling of electron-neutral aryl bromide 1j, al-
though four equivalents of silane 2 and tetrabutylammoni-
um fluoride were required (entry 11), while a poor yield
was observed for the deactivated aryl bromide 1k (entry
12). It is noteworthy that this catalytic system is efficient
for electron-deficient aryl chlorides 1l and 1m (entries 13
and 14), the latter could not be activated in the Hiyama
coupling reaction by using simple a phosphine ligand such
as triphenylphosphine or tri-2-tolylphosphine and high
catalyst loading (10%) was required to obtain moderate
yields (47%) of the desired product even using the bulky
Buchwald’s ligand [2-(dicyclohexylphosphino)biphe-
nyl].4b,8 However, the reactions with aryl chlorides 1n,o
give poor yields of cross-coupled products even at 100 °C
(entries 15 and 16) with palladium black deposition ob-
served.
4-Methoxybiphenyl (3a)6a
1H NMR (400 MHz, CDCl3): d = 7.56 (t, J = 8 Hz, 4 H), 7.44 (t,
J = 7.6 Hz, 2 H), 7.32 (t, J = 6.8 Hz, 1 H), 6.99 (d, J = 8 Hz, 2 H),
3.87 (s, 3 H).
4-Chlorobiphenyl (3b)2a
1H NMR (400 MHz, CDCl3): d = 7.53–7.58 (m, 4 H), 7.36–7.48 (m,
5 H).
Biphenyl (3c)6a
1H NMR (400 MHz, CDCl3): d = 7.59 (d, J = 8.4 Hz, 4 H), 7.43 (t,
J = 7.2 Hz, 4 H), 7.36 (t, J = 7.8 Hz, 2 H).
1-Biphenyl-4-ylethanone (3d)6a
1H NMR (400 MHz, CDCl3): d = 8.04 (d, J = 8 Hz, 2 H), 7.69 (d,
J = 8.4 Hz, 2 H), 7.64 (d, J = 7.2 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H),
7.41 (t, J = 6.8 Hz, 1 H), 2.66 (s, 3 H).
4-Nitrobiphenyl (3e)6a
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.8 Hz, 2 H), 7.74 (d,
J = 8.8 Hz, 2 H), 7.63 (d, J = 7.2 Hz, 2 H), 7.53–7.46 (m, 3 H).
3-Nitrobiphenyl (3f)7e
1H NMR (400 MHz, CDCl3): d = 8.47 (s, 1 H), 8.20 (d, J = 8.4 Hz,
1 H), 7.92 (d, J = 8 Hz, 1 H), 7.65–7.60 (m, 3 H), 7.51 (t, J = 6.8 Hz,
2 H), 7.45 (t, J = 7.6 Hz, 1 H).
p-Terphenyl (3g)9
1H NMR (400 MHz, CDCl3): d = 7.68 (t, J = 8.4 Hz, 8 H), 7.49 (t,
J = 7.2 Hz, 4 H), 7.39 (t, J = 7.2 Hz, 2 H).
4-Methylbiphenyl (3h)6a
1H NMR (400 MHz, CDCl3): d = 7.56 (d, J = 7.2 Hz, 2 H), 7.47 (d,
J = 7.6 Hz, 2 H), 7.41 (t, J = 7.8 Hz, 2 H), 7.31 (t, J = 6.8 Hz, 1 H),
2.38 (s, 3 H), 7.24 (t, J = 7.6 Hz, 2 H).
In summary, we have first reported an efficient palladi-
um(II) acetate–thiourea catalytic system for the Hiyama
cross-coupling reactions of aryl halides with tri-
methoxy(phenyl)silane for the construction of biaryl
units. It is noteworthy that thiourea can be recovered by
column chromatography and reused without significant
loss in catalytic activity, which is contrast to the tradition-
al phosphine and nitrogen-base ligands. A variety of aryl
halides, including iodides, bromides, and chlorides, were
coupled with trimethoxy(phenyl)silane to give biaryls
with moderate to excellent yields. Further investigation to
extend the application of this catalyst system in other cou-
pling transformations is currently under way in our labo-
ratory.
Acknowledgment
This work was supported by the Natural Science Foundation of
Gansu Province (3ZS061-A25-007) and the Foundation of Lanzhou
Institute of Chemical Physics.
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A mixture of aryl halide 1 (0.167 mmol), PhSi(OMe)3 (2, 0.33
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Synthesis 2008, No. 9, 1415–1419 © Thieme Stuttgart · New York

PAPER
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Synthesis 2008, No. 9, 1415–1419 © Thieme Stuttgart · New York