General and highly efficient fluorinated-N-heterocyclic carbene-based catalysts for the palladium-catalyzed Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tet.2012.05.068

A general and highly efficient trifluoromethylated-N-heterocyclic carbene (NHC)-based catalyst for the palladium-catalyzed Suzuki-Miyaura reaction was reported. In the presence of the catalyst, reactions of non-activated aryl chlorides and triflates with aryl boronic acids occurred at room temperature with good to excellent yields (63-98%). In addition, catalysts generated from a combination of Pd(OAc)₂/imidazolium salt 6a is not only effective for the coupling of heteroaryl boronic acid with aryl halides and heteroaryl halides, but also efficient for coupling of other heteroaryl halides and heteroaryl boronic acids. Finally, the catalyst is highly effective for Suzuki-Miyaura reaction of aryl bromides and chlorides with 0.01-0.1 mol % loading if the temperature was raised at refluxed THF/H₂O.

Full text of DOI:10.1016/j.tet.2012.05.068

Tetrahedron 68 (2012) 6535e6547
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
General and highly efficient fluorinated-N-heterocyclic carbeneebased catalysts
for the palladium-catalyzed SuzukieMiyaura reaction
*
Taoping Liu, Xiaoming Zhao, Qilong Shen, Long Lu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and highly efficient trifluoromethylated-N-heterocyclic carbene (NHC)-based catalyst for the
palladium-catalyzed SuzukieMiyaura reaction was reported. In the presence of the catalyst, reactions of
non-activated aryl chlorides and triflates with aryl boronic acids occurred at room temperature with
good to excellent yields (63e98%). In addition, catalysts generated from a combination of Pd(OAc)2/
imidazolium salt 6a is not only effective for the coupling of heteroaryl boronic acid with aryl halides and
heteroaryl halides, but also efficient for coupling of other heteroaryl halides and heteroaryl boronic acids.
Finally, the catalyst is highly effective for SuzukieMiyaura reaction of aryl bromides and chlorides with
0.01e0.1 mol % loading if the temperature was raised at refluxed THF/H2O.
Received 13 March 2012
Received in revised form 14 May 2012
Accepted 18 May 2012
Available online 26 May 2012
Keywords:
SuzukieMiyaura reaction
Fluoride
N-Heterocyclic carbene
Aryl halides
Ó 2012 Elsevier Ltd. All rights reserved.
Heteroaryl halides
1. Introduction
palladium complex (carbene)Pd(cinnamyl)Cl or (carbene)Pd(3-
bromopyridine)Cl2 displays much higher reactivity in the Suzu-
The SuzukieMiyaura reaction, coupling of an aryl halide with an
organoboron reagent, has become arguably one of the most effi-
cient methods for the construction of carbonecarbon bond in or-
ganic synthesis both in a laboratory and industrial scale.1 Early
works in the SuzukieMiyaura reaction were conducted using tri-
arylphosphines as the ancillary ligand. In the last 10 years, exten-
sive efforts from the groups of Buchwald,2 Fu,3 Herrmann,4 Nolan,5
Beller,6 and others7,8 have led to the discovery of much more effi-
cient catalysts by employing electron-rich, sterically bulky dia-
lkylbiarylphines, trialkyl-phosphines, or N-heterocyclic carbenes.
The enhanced reactivity of the catalysts has dramatically expanded
the scope of the SuzukieMiyaura reaction to include unactivated
aryl chlorides, aryl tosylates, heteroaryl halides or boronic acids,
and hindered substrates.
kieMiyaura cross-coupling of aryl chlorides with low catalyst load-
ing.5,8 We recently initiated a project to study if fluoroalkylated NHCs
will enhance the catalytic activity of the catalyst since it is well
known that the fluoroalkyl group is electron withdrawing and can
adjust the electronic effect of the ligand. Herein, we report that cat-
alysts generated from a combination of Pd(OAc)2 and fluorinated
NHCs are much more reactive for the SuzukieMiyaura reaction than
those catalysts from non-fluorinated counterparts. The scope of the
reaction was studied to include room temperature coupling of
unactivated aryl chlorides, coupling of heteroaryl halides or hetero-
aryl boronic acids, and coupling of aryl bromides and chlorides with
low catalyst loadings.
2. Results and discussion
Among these catalysts, highly reactive palladium complexes
containing N-heterocyclic carbenes (NHCs)9 are especially attractive
because they are: (1) sterically demanding ligands with better
2.1. Preparation of trifluoromethylated NHCs
Trifluoromethylated NHCs9 were prepared from readily avail-
able 2,4,6-tribromoaniline acetate in six steps, as illustrated
in Scheme 1. Treatment of 2,4,6-tribromoaniline acetate 1 with
3,3,3-trifluoro-1-propene under the Heck conditions, followed by
hydrogenation and deprotection under acidic conditions gave
2,4,6-tri(trifluoromethylpropanyl)-aniline 4 in 57% yield over three
steps. Condensation of compound 4 with glyoxal, subsequent re-
duction by NaBH4, and cyclization with HC(OEt)3 afforded the
desired imidazolium salt 6a in 62% yield of three steps (Scheme 1).
s
-donor ability than tertiary phosphines; (2) low toxicity; (3) high
dissociation energies of the PdeNHC bond; and (4) convenient
preparation. Herrmann initially reported Pd(NHC)2 (NHC¼1,3-bisa-
damantlyimidazolin-2-ylidene) catalyzed the coupling of aryl chlo-
rides with arylboronic acids at room temperature.4 More recently,
Nolan and Organ disclosed independently that monocarbene-
* Corresponding author. E-mail address: lulong@sioc.ac.cn (L. Lu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.068

6536
T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
NHCOCH3
NHCOCH3
Br
15 mol% Pd(OAc)2
F3C
3.0 equiv. Bu4NBr
DMF, 90 oC, 24 h
78%
CF3
5.0 equiv. NaOAc
Br
CF3
+
Br
CF3
3
1
NH2
H
O
H
i) H2 (1atm), Pd/C, EtOAc, RT
ii) Me3OBF4, CH2Cl2, RT
iii) CF3COOH, MeOH, RT
F3C
CF3
O
57%
MeOH, HCO2H, RT, 24 h
86%
CF3
4
R
R
R
R
R
R
i) NaBH4, THF/MeOH, 95%
ii) HC(OEt)3, NH4Cl, 76%
R
N
N
R
R
N
N
R
Cl
R
R
R = CH2CH2CF3, 5
R = CH2CH2CF3, 6a
Scheme 1. Preparation of imidazolium salt 6a.
Table 1
Initially, the SuzukieMiyaura reaction of p-chloroanisole and
phenylboronic acid was investigated in the presence of in situ
generated palladium catalysts from 3 mol % of Pd(OAc)2 and 6 mol
% of 6a with different bases in different solvents at room temper-
ature. Less than 5% of the coupled product was observed when the
reaction was conducted in THF using K2CO3 or K3PO4 as the base
(Table 1, entries 1 and 2). We reasoned that the low solubility of the
base in THF is likely the cause of low conversion. When the reaction
was conducted in THF/H2O (5:1, v/v) mixed solvent with K2CO3
as the base, the yield of the product was significantly improved to
62% (Table 1, entry 3). Switching the base to K3PO4 led to even
higher yield (91%, Table 1, entry 5). The amount of water influences
the reaction slightly. Reactions in the presence of different amount
of added water occurred to high yields if the ratio of THF/H2O is
higher than 2:1 (Table 1, entries 9e11). Effects of palladium pre-
cursors were further studied and it was found that using other
palladium precursors such as Pd(PPh3)4, Pd2(dba)3, or PdCl2 resul-
ted in much lower yields or no product (Table 1, entries 6e8). In
contrast with Nolan’s conclusion that the ligand/palladium ratio
close to 1 generally enhances the catalytic activity,5a the reaction
catalyzed by Pd(OAc)2/6a was insensitive to the ligand precursor/
palladium ratio when the catalyst loading is higher than 0.5 mol %.
Reactions in the presence of both 1:1 or 2:1 ratio of ligand pre-
cursor/palladium occurred to full conversion and gave the desired
products in 90% and 91% yields, respectively (Table 1, entries 5 and
12). However, when the catalyst loading was lowered to 0.1 mol %,
reactions in the presence of catalyst with 2:1 ratio of ligand pre-
cursor 6a/palladium occurred to 56% yield, while the same reaction
in the presence of catalyst with 1:1 ratio of ligand 6a/palladium
gave the desired product in 16% yield.
Effect of different catalysts, solvents, and bases on the SuzukieMiyaura reaction of p-
chloroanisole with phenylboronic acid at room temperaturea
Catalyst
Base
Cl
Ph
+
PhB(OH)
2
Solvent, RT
MeO
MeO
Entry
Catalyst/ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K3PO4
K2CO3
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
THF
THF/H2O (5:1)
<5
<5
62
21
91
THF/H2O (5:1)
THF/H2O (5:1)
THF/H2O (5:1)
THF/H2O (5:1)
THF/H2O (5:1)
THF/H2O (10:1)
THF/H2O (2:1)
THF/H2O (1:5)
THF/H2O (5:1)
THF/H2O (5:1)
THF/H2O (5:1)
<5
d
d
9
92
95
10
11
12
13
14
78
90c
16d
56e
a
Standard conditions: Pd(OAc)2 (3 mol %), 6a (6 mol %), p-chloroanisole
(0.8 mmol), phenyl boronic acid (1.2 mmol), K3PO4 (2.8 mmol), THF/H2O (5:1), room
temperature, 3 h.
b
Isolated yield.
c
Pd(OAc)2 (0.5 mol %) and 6a (1.0 mol %) were used, room temperature, 12 h.
Pd(OAc)2 (0.1 mol %) and 6a (0.1 mol %) were used.
Pd(OAc)2 (0.1 mol %) and 6a (0.2 mol %) were used.
d
e
6bee and 8aec of imidazolium salt 6a and evaluated the catalytic
reactivity of complexes containing non-fluorinated NHCs derived
from 6bee and 8aec. Imidazolium salts 6bee with saturated
backbone and 8aed with unsaturated backbone were prepared
according to the procedure reported in the literature. A comparison
of the performance of the catalysts generated from these imidazo-
lium salts in the SuzukieMiyaura reaction of p-chloroanisole and
phenylboronic acid at room temperature is shown in Table 2.
Interestingly, catalysts generated from non-fluorinated imida-
zolium salts 6bee gave the coupling product in much lower yields
after 3 h at room temperature. For example, imidazolium salt 6d
2.2. Study of the activity of palladium complexes generated
from trifluorinated imidazolim salt 6a and non-perfluorinated
imidazolium salts 6be6e and 7ae7c in the SuzukieMiyaura
reaction
To probe the fluorine-effect of imidazolium salt 6a that gave rise
to high reactivity, we prepared a number of non-fluorinated analogs

T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
6537
Table 2
give the desired products after 12 h at room temperature in
excellent yield (Table 3, entries 1e6). Reactionsof stericallyhindered
aryl chlorides at mild conditions are challenging. With the
catalyst generated from trifluoromethylated imidazolium salt 6a,
2-chloroanisole and 2-chlorotoluene coupled with arylboronic
acids in excellent yields (Table 3, entries 7e9). Even hindered 2,6-
dimethylphenyl chloride gave the coupled product in good to ex-
cellent yields (Table 3, entries 11 and 12). Electron-poor arylchloride
such as 4-acetylphenyl chloride also was equally effective in the
presence of catalyst generated from trifluoromethylated imidazo-
lium salt 6a and excellent yields were obtained when coupled with
arylboronic acid (Table 3, entry 13).
SuzukieMiyaura reaction in the presence of the catalyst generated from different
imidazolium saltsa
Cl
Pd(OAc)2/NHC
Ph
+
PhB(OH)2
R
K3PO4
MeO
MeO
THF/H2O (5:1)
RT
R
R
R
R
R
R
N
N
R
R
N
N
R
Cl
Cl
R
R
2.4. SuzukieMiyaura reaction of aryl triflates at room
temperature
R = CH2CH2CH3, 6b
CH2CH2CH2CH3, 6c
CH2CH2CH(CH3)2, 6d
CH3, 6e
R = CH2CH2CH3, 8a
CH2CH2CH2CH3, 8b
CH3, 8c
Aryl triflates are very useful coupling partners in the cross-
coupling reaction and considered as attractive alternatives to aryl
halides since they can be easily prepared from readily available
phenols. The catalyst generated from trifluoromethylated imida-
zolium salt 6a was effective for the coupling of aryl triflates at
room temperature. Reactions of o, m, p-tolyl triflates occurred to
give the desired products in good to excellent yields (Table 4,
entries 1e5).
Entry
Catalyst
Conversionb (%)
100c (91)
1
Pd(OAc)2/6a
Pd(OAc)2/6b
Pd(OAc)2/6c
Pd(OAc)2/6d
Pd(OAc)2/6e
Pd(OAc)2/8a
Pd(OAc)2/8b
Pd(OAc)2/8c
2
3
4
5
6
7
8
28
38
56
18
39
51
28
2.5. SuzukieMiyaura reaction of heteroaryl halides or
heteroaryl boronic acids
a
Standard condition: Pd(OAc)2 (3 mol %), 6a (6 mol %), p-chloroanisole
(0.8 mmol), phenyl boronic acid (1.2 mmol), K3PO4 (2.8 mmol), THF/H2O (5:1), room
temperature, 3 h.
Hetero-biaryls are important structure motifs in many bi-
ologically active molecules, pharmaceuticals, and therapeutic
drugs.10 In recent years, tremendous efforts have been focused on
the discovery of active catalyst for coupling of heteroaryl halides or
heteroaryl boronic acids including substrates containing nitrogen
heterocycles.11 The presence of such groups often causes the de-
activation of the catalysts and requires high catalyst loading. For
example, thiophenes are found in numerous natural products as
well as molecules for highly conducting oligomers and polymers.
However, the SuzukieMiyaura reaction of thiophene boronic acid
was problematic. It was found that catalysts generated from imi-
dazolium salt 6a were highly effective for SuzukieMiyaura reaction
of 3-thiophene boronic acid. 3-Thiophene boronic acid coupled
with a variety of aryl chlorides to give the desired coupled products
in 85e95% yields (Table 5, entries 1e5). More interesting, reactions
of 3-thiophene boronic acid with unactivated heteroaryl chlorides
such as 3-chloropyridine and 5-methyl-2-chlorothiophene oc-
curred to full conversion after 12 h at reflux to give the desired
coupled products in 87% and 90% yield, respectively (Table 5,
entries 6 and 7). Catalysts generated from imidazolium salt 6a are
not only effective for the coupling of 3-thiophene boronic acid with
aryl halides and heteroaryl halides, but also efficient for coupling of
other heteroaryl halides and heteroaryl boronic acids. Unactivated
heteroaryl halides are challenging substrates in SuzukieMiyaura
reactions. However, by using 3 mol % Pd(OAc)2/6 mol % imidazo-
lium salt 6a, reactions of a variety of unactivated aryl or heteroaryl
chlorides proceeded smoothly in good to excellent yields (Table 5,
entries 12e17). Other heteroaryl boronic acids such as 3-pyridyl
boronic acid or 2-benzofuryl boronic acid also coupled with unac-
tivated aryl or heteroaryl chlorides under the Pd(OAc)2/imidazo-
lium salt 6a in excellent yields (Table 5, entries 8e10).
b
Determined by GC.
Isolated yield.
c
with an iso-pentyl group, which is sterically similar to a 3,3,3-tri-
fluoro-propyl group formed much less reactive catalysts than did
imidazolium salt 6a (Table 2, entry 4). Imidazolium salts 6be6c and
6e with smaller steric hindrance formed much lesser active catalyst
than did imidazolium salt 6a. The catalysts from these imidazolium
salts formed the coupled product in 18e38% yields (Table 2, entries
2, 3, and 5).
Likewise, catalysts generated from imidazolium salts 8aec with
unsaturated backbone were much less reactive than those from
imidazolium salt 6a. Reactions of 4-chloroanisole with phenyl-
boronic acid in the presence of 3 mol % these catalysts gave the
desired products in 28e51% yields.
From these studies, we conclude that the steric hindrance of the
trifluoromethyl group in the imidazolium salt 6a does notcontribute
significantly to the high reactivity of the catalyst but is very impor-
tant for reactivity of the catalyst. We attribute the high reactivity of
the catalyst from imidazolium salt 6a to the strong electron with-
drawing trifluoromethyl group that (1) decreases the electron
density of the corresponding carbene, which facilitate the dissoci-
ation of NHC from Pd(NHC)2 to generate active monocarbene-
palladium species; (2) makes the monocarbene-palladium species
less electron-rich, which promotes the reductive-elimination in the
catalytic cycle to form the product.
2.3. Scope of the SuzukieMiyaura reaction of electron-rich
aryl chlorides at room temperature
Under the optimized reaction conditions as shown in Table 1,
entry 12, we next explored the scope of the SuzukieMiyaura re-
action of a variety of aryl chlorides with arylboronic acids, and the
results were summarized in Table 2. Reactions of electron-rich aryl
chlorides such as 4-methoxyphenylchloride and 4-chlorotoluene
with a number of arylboronic acids occurred to full conversion to
2.6. SuzukieMiyaura reaction of aryl halides with low
catalyst loading
Lowering the loading of the homogeneous catalyst is highly
desirable due to not only the decreased cost of the catalyst and
more importantly the ease for its removal, particularly on industrial

6538
T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
Table 3
Room-temperature SuzukieMiyaura coupling of aryl chlorides with arylboronic acidsa
Entry
1
Aryl chloride
Arylboronic acid
Product
Yieldc (%)
91
9a
9b
9c
MeO
Cl
Cl
Cl
B(OH)
MeO
MeO
2
Me
Me
2
3
97b
95b
MeO
MeO
B(OH)
2
F C
CF
3
3
B(OH)
MeO
2
OMe
B(OH)
MeO
4
9d
95b
MeO
Cl
Cl
MeO
2
5
6
9e
9f
91b
89
MeO
Me
t-Bu
B(OH)2
MeO
Bu-t
Cl
B(OH)
Me
2
OMe
Cl
OMe
7
8
9g
9h
98
87
B(OH)
2
Me
OMe
Cl
Me
B(OH)
2
MeO
Me
Me
OMe
B(OH)
9
9i
87b,d
Cl
2
MeO
MeO
MeO
Cl
10
11
9j
96
B(OH)
2
Me
Me
9k
84b
Cl
Cl
OMe
MeO
B(OH)
2
Me
Me
Me
OMe
Me
Me
OMe
B(OH)
12
9l
63b
98
2
Me
O
O
13
9m
B(OH)
Cl
2
a
Standard condition: Pd(OAc)2 (0.5 mol %), 6a (1.0 mol %), aryl chloride (0.8 mmol), aryl boronic acid (1.2 mmol), K3PO4 (2.8 mmol), THF/H2O (5:1), room temperature, 12 h.
Pd(OAc)2 (3 mol %) and 6a (6 mol %)were used.
Isolated yield.
b
c
d
Along with 3e5% of biphenyl, respectively.

T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
6539
Table 4
Room-temperature SuzukieMiyaura coupling of aryl triflates with arylboronic acidsa
Entry
Aryl triflate
Arylboronic acid
Product
Yieldb (%)
Me
Me
1
9n
9o
96
92
B(OH)
2
2
2
OTf
Me
Me
2
B(OH)
B(OH)
OTf
3
4
9p
9q
92
83
Me
OTf
Me
Me
Me
Me
MeO
B(OH)
2
OTf
OMe
Me
OMe
B(OH)
5
9r
95
OTf
2
MeO
a
Standard condition: Pd(OAc)2 (0.5 mol %), 6a (1.0 mol %), aryl chloride (0.8 mmol), aryl boronic acid (1.2 mmol), K3PO4 (2.8 mmol) 10a, THF/H2O (5:1), room temperature,
12 h.
b
Isolated yield.
scale for questions of toxicity of the impurity in the final product.12
It was found that catalysts generated from imidazolium salt 6a
is highly effective for SuzukieMiyaura reaction with 0.01e0.1 mol %
loading if the temperature was raised at refluxed THF/H2O (5:1),
as shown in Table 6. For example, reactions of hindered 2-
bromoanisole with electronic neutral or rich aryl boronic acids
occurred with 0.01 mol % Pd(OAc)2 to give the desired products in
good to excellent yields (75e95%) (Table 6, entries 1e4). Reactions
with electron-poor aryl boronic acids required 0.1 mol % catalyst to
full conversion (Table 6, entries 5 and 6).
Reactions of activated aryl chlorides and bromides with aryl
boronic acids occurred with 0.01e0.05 mol % loading to afford the
desired products in good to excellent yields (Table 6, entries 8e12).
Nolan has shown that monocarbene-palladium complex (carbene)
Pd(cinnamyl)Cl displays much higher reactivity than Pd(NHC)2 in
the SuzukieMiyaura cross-coupling.5a However, in our cases, the
high reactive catalyst required 2 equiv of trifluoromethylated
NHC for one palladium to give high efficiency. When the ratio of
NHC/Pd dropped to 1, reaction of p-chloroanisole with phenyl
boronic acid occurred with 17% yield in the presence of 0.1 mol %
catalyst.
products in good to excellent yields. The mechanism of the reaction
is under investigation currently in our lab.
4. Experimental section
4.1. General
Unless otherwise noted, all reactions were performed in an oven-
dried glasswares under an Ar atmosphere. Commercially obtained
reagents were used without further purification. All solvents were
purified by standard methods. 1H, 13C, and 19F NMR spectra were
recorded on 300 MHz (or 400 MHz), 100.5 MHz, and 282 MHz
spectrometer. 1H NMR and 13C NMR chemical shifts were de-
termined relative to internal standard TMS at
d
0.0 and 19F NMR
chemical shifts were determined relative to CFCl3 as internal stan-
dard. All reactions were monitored by TLC or 19F NMR spectroscopy.
Flash column chromatography was performed on silica gel
(300e400 mesh) unless otherwise stated.
4.2. Preparation of 2,4,6-tribromo-N-acetylaniline 1
2,4,6-Tribromoaninile (60 g, 180 mmol) was added to acetic
anhydride (400 mL) in a three-neck round-bottom flask equipped
with a mechanic stirrer, a thermometer, and a reflux condenser.
The mixture was stirred and the temperature increased quickly. A
few drops of sulfuric acid was added when the temperature was
dropped to 60 ꢀC. The mixture was allowed to stir for 6 h and was
cooled to room temperature. The solid was filtered and recrys-
tallized from ethanol to give 2,4,6-tribromo-N-acetylaniline 1
3. Conclusions
In summary, we have demonstrated that catalyst generated
from trifluoromethylated imidazolium salt 6a is a highly reactive
and practical catalyst for SuzukieMiyaura coupling of aryl and
heteroaryl chlorides, bromides and triflates. Reactions of non-
activated aryl chlorides and triflates occurred smoothly in good to
excellent yields in the presence of 0.5 mol % Pd(OAc)2 and 1.0 mol %
6a. Reactions of heteroaryl halides or heteroaryl boronic acids
however, required higher catalyst loading (3 mol % Pd(OAc)2 and
6 mol % 6a). At high temperature, the catalyst loading can be low-
ered to 0.01e0.1 mol % for reactions of aryl bromides and chlorides
with a variety of arylboronic acids to generate the corresponding
(58 g, 87%). 1H NMR (300 M, DMSO-d6)
d 2.03 (s, 3H), 8.01 (s, 2H),
9.91 (s, 1H).
4.2.1. N-[2,4,6-Tri-(3,3,3-trifluoro-1-propenyl)-phenyl]-act-amide
3. Into three-neck round-bottom flask were added 2,4,6-
tribromo-N-acetylaniline (30.0 g, 80.6 mmol), Pd(OAc)2 (2.70 g,
a

6540
T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
Table 5
SuzukieMiyaura coupling of heteroaryl substratesa
Entry
Aryl chloride
Arylboronic acid
Product
Yieldb (%)
92
B(OH)
2
1
10a
MeO
MeO
Cl
S
S
B(OH)
B(OH)
B(OH)
B(OH)
B(OH)
B(OH)
OMe
Me
OMe
Cl
2
2
2
2
2
2
2
3
4
5
6
7
8
10b
10c
10d
10e
10f
95
85
94
95
87
90
89
S
S
S
S
S
S
S
S
Me
Cl
O
O
Cl
S
Me
Me
Cl
S
Cl
S
N
N
Me
10g
10h
Me
Cl
S
S
S
OMe
OMe
Cl
B(OH)
2
N
N
B(OH)
B(OH)
2
N
9
10i
10j
82
85
Cl
S
S
N
N
Cl
2
10
N
N
N
11
12
B(OH)
OMe
10k
10l
85
92
MeO
Cl
2
O
O
MeO
OMe
Cl
Cl
B(OH)
2
N
N
Me
Me
13
14
10m
10n
82
97
B(OH)
2
2
N
N
N
F
F
B(OH)
Cl
N

T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
6541
Table 5 (continued )
Entry
Aryl chloride
Arylboronic acid
Product
Yieldb (%)
15
16
10o
10p
88
86
B(OH)
2
Cl
S
S
S
MeO
OMe
B(OH)
Cl
S
2
B(OH)
N
N
N
2
17
18
10q
10r
92
43
Et
Cl
Ph
Ph
Et
N
Ph
B(OH)
Me
Me
Me
2
Cl
Cl
Ph
S
S
S
S
Me
a
Standard conditions: Pd(OAc)2 (3 mol %), 6a (6 mol %), aryl chloride (0.8 mmol), aryl boronic acid (1.2 mmol), K3PO4 (2.8 mmol), THF/H2O (5:1), reflux, 12 h.
Isolated yield.
b
12.1 mmol), NaOAc (33.0 g, 403 mmol), n-Bu4NBr (55.0 g,
242 mmol), and DMF (200 mL) under argon atmosphere. The at-
mosphere was exchanged three times with 3,3,3-trifluoropropene.
The mixture was vigorously stirred for 24 h at 120 ꢀC and then
allowed to cool to room temperature. The solvent was removed
under vacuum. The residue was dissolved in ethyl acetate (100 mL)
and washed with water (200 mL). The organic layer was separated
and dried over Na2SO4. The solvent was removed under vacuum
and the residue was purified by flash chromatography (Et2O as the
eluent) to give the desired product as a white solid. Mp 239e240 ꢀC.
chromatography (petroleum ether/ethyl acetate¼50:1 as the elu-
ent) to give the desired product 4 as a white solid (4.5 g, 58%). Mp
145e146 ꢀC. 1H NMR (300 MHz, CDCl3)
d 2.28e2.44 (m, 6H),
2.72e2.77 (m, 6H), 3.57 (s, 2H), 6.81 (s, 2H); 19F NMR (CDCl3)
d
ꢁ67.23 (t, J¼11.0 Hz, 6F), ꢁ67.04 (t, J¼11.0 Hz, 3F); 13C NMR
(CDCl3)
d
24.2, 27.3, 33.0 (q, J¼28.4 Hz), 36.0 (q, J¼28.4 Hz), 121.2,
126.6 (q, J¼276.7 Hz), 126.7 (q, J¼276.7 Hz), 128.5, 129.4, 140.1. MS
(ESI) m/z 382.1 (MþHþ). IR (film, cmꢁ1
) n 3425, 2989, 1635, 1613,
1489, 1463, 1383, 1313, 1254, 1134, 1091, 989. HRMS for C15H17F9N
(MþHþ): calcd 382.1211, found 382.1211. Anal. Calcd for
C15H16F9N: C, 47.25; H, 4.23; N, 3.67. Found: C, 47.39; H, 4.00;
N, 3.42.
1H NMR (300 MHz, CD3OD)
d 2.24 (s, 3H), 6.57e6.80 (m, 3H),
7.26e7.36 (m, 3H), 8.03 (s, 2H). 19F NMR (CD3OD)
d
ꢁ65.42 (dd,
J¼2.0 Hz, 7.3 Hz, 6F), ꢁ65.15 (dd, J¼2.0 Hz, 7.3 Hz, 3F); 13C NMR
(CD3OD)
d
20.5, 117.2 (q, J¼28.4 Hz), 118.5 (q, J¼28.4 Hz), 123.0 (q,
4.2.3. N,N0-Bis-[2,4,6-tri(3,3,3-trifluoro-propyl)phenyl]-1,4-
diazadiene 5. To a mixture of aniline (2.3 g, 6.0 mmol) and glyoxal
(3 mol, 40% aqueous solution) in methanol was added a few drops
of formic acid. The mixture was stirred at room temperature for
24 h, and the yellow precipitations appeared. After the reaction was
completed, the solid was filtered, washed with methanol, and dried
under vacuum to give N,N0-bis-[2,4,6-tri(3,3,3-trifluoro-propyl)
J¼268 Hz), 123.1 (q, J¼268 Hz), 126.5, 123.1, 123.2, 133.1, 135.0,
135.5, 170.8. MS (EI) m/z 417 (14), 375 (100), 356 (4), 334 (5), 316
(23), 266 (24), 43(41). IR (film, cmꢁ1
) n 3246, 1669, 1585, 1515, 1465,
1437, 1378, 1303, 1281, 1116, 973. HRMS for C17H13F9NO (MþHþ):
calcd 418.0848, found 418.0855.
4.2.2. 2,4,6-Tri(3,3,3-trifluoro-1-propyl)aniline 4. Into
a
round-
phenyl]-1,4-diazadiene
126e128 ꢀC. 1H NMR (300 MHz, CDCl3)
2.71e276 (m, 6H), 2.82e2.87 (m, 3H), 7.00 (s, 4H), 8.13 (s, 2H). 19F
NMR (CDCl3)
ꢁ67.49 (t, J¼11.0 Hz, 12 F), ꢁ66.98 (t, J¼11.0 Hz, 6F).
13C NMR (CDCl3)
22.8, 27.6, 33.7 (q, J¼28.8 Hz), 35.6 (q, J¼28.8 Hz),
5
(2.0 g, 85%) as yellow solid. Mp
bottom flask were added 2,4,6-tri-(3,3,3-trifluoro-1-propenyl)-
acetylaniline (8.0 g, 19.2 mmol), Pd/C (10%, 400 mg), and EtOAc
(100 mL). Hydrogen was bubbled into the mixture for 30 min and
a balloon containing hydrogen gas was connected to the reaction
system. The mixture was stirred at room temperature for 24 h. The
mixture was filtered and washed with ethyl acetate (10 mLꢂ3). The
solvent was removed under vacuum and the residue was used di-
rectly without further purification.
The solid obtained from the previous step was dissolved in
methylene chloride (200 mL). MeO3$BF4 (3.6 g, 24 mmol) was
added dropwise. The mixture was stirred at room temperature for
12 h until the disappearance of the starting material as de-
termined by TLC. To the mixture was added CF3CO2H (20 mL) and
methanol (10 mL). The resulted mixture was allowed to stir for 2 h.
The pH of the mixed solution was adjusted to 8e9 with saturated
aqueous NaHCO3. The organic layer was separated and the water
phase was washed with ethyl acetate (10 mLꢂ3). The organic
phase was combined and dried over Na2SO4. The solvent was re-
moved under vacuum and the residue was purified by flash
d
2.26e2.44 (m, 12H),
d
d
126.5 (q, J¼276.7 Hz), 126.6 (q, J¼276.7 Hz), 128.3, 128.4, 136.5,
147.8, 163.5. MS (ESI) m/z 785.2 (MþHþ). IR (film, cmꢁ1):
n 2983,
2934, 1639, 1456, 1385, 1311, 1251, 1223, 1151, 1132, 1097, 993. Anal.
Calcd for C32H30F18N2: C, 48.99; H, 3.85; N, 3.57. Found: C, 49.13; H,
4.09; N, 3.34.
4.2.4. N,N0-Bis-[2,4,6-tri(3,3,3-trifluoro-propyl)phenyl]-ethylene-di-
amine 5a. To a solution of N,N0-bis-[2,4,6-tri(3,3,3-trifluoro-pro-
pyl)-phenyl]-1,4-diazadiene (552 mg, 0.7 mmol) in 20 mL of
MeOH/THF (2:3) was added NaBH4 (267 mg, 7 mmol). The yellow
color of the reaction mixture turned into white after 1.5 h. The re-
action was quenched by a saturated aqueous NH4Cl. The resulting
mixture was extracted with ether, and washed with deionized
water. The organic layer was separated and dried over Na2SO4. The
solvent was removed under reduced pressure to afford the diamine

6542
T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
Table 6
.SuzukieMiyaura coupling at low catalyst loadinga
Entry
Aryl halide
Arylboronic acid
Product
Loading (mol %)
0.01
Yieldb (%)
75
OMe
OMe
1
11a
B(OH)
2
Br
OMe
Br
OMe
Br
OMe
2
3
11b
11c
0.01
0.01
95
95
t-Bu
B(OH)2
t
Bu
OMe
Me
B(OH)
2
Me
OMe
OMe
Br
Me
CF
4
11d
0.01
91
B(OH)
2
2
Me
OMe
OMe
Br
3
5
6
11e
11f
0.1
0.1
69
99
B(OH)
F C
3
OMe
OMe
Br
F C
3
B(OH)
2
CF
3
Br
7
8
11g
11h
0.1
76
98
B(OH)
2
N
N
O
F C
3
O
O
0.01
Br
Br
B(OH)
2
CF
3
O
9
11i
11j
0.01
97
B(OH)
2
10
11
11
0.01
0.003
0.05
84
64
98
Cl
Br
B(OH)
Cl
2
O
O
11k
11l
B(OH)
B(OH)
Cl
2
CN
Cl
CN
12
0.05
0.05
63
45
2
13
11m
Me
Cl
MeO
B(OH)
Me
OMe
2
a
Standard conditions: Pd(OAc)2/6a as indicated in the table, aryl chloride (0.8 mmol), aryl boronic acid (1.2 mmol), K3PO4 (2.8 mmol), THF/H2O (5:1), reflux, 12 h.
Isolated yield.
b

T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
6543
derivative 5a (525 mg, 95%) as a white solid. Mp 102e103 ꢀC. 1H
NMR (300 MHz, CDCl3) 2.32e2.44 (m, 12H), 2.77e2.83 (m, 3H),
the residue was purified by flash chromatography to give 2,4,6-
tripropyl-1-nitrobenzene (8.7 g, 74%) as a colorless oil.
d
2.89e2.93 (m, 6H), 3.14 (s, 4H), 6.92 (s, 4H); 19F NMR (CDCl3)
d
ꢁ66.9 (t, J¼11.0 Hz, 6F), ꢁ66.6 (t, J¼11.0 Hz,12 F); 13C NMR (CDCl3)
23.5, 27.0, 34.3 (q, J¼28.3 Hz), 35.1 (q, J¼28.3 Hz), 50.34, 126.0 (q,
4.4.1. 2,4,6-Tripropyl-1-nitrobenzene. Colorless oil. Yield 74%. IR
d
(film, cmꢁ1): 2964, 2935, 2875,1600,1568,1527,1467,1371, 833.1H
n
J¼276.6 Hz),126.1 (q, J¼276.6 Hz),127.7,133.5,134.8,142.2. MS (ESI)
NMR (300 MHz, CDCl3)
d
0.87 (t, J¼6.9 Hz, 9H), 1.48e1.62 (m, 6H),
m/z 789.2 (MþHþ). IR (film, cmꢁ1
)
n
2955, 1479, 1468, 1380, 1306,
2.41e2.52 (m, 6H), 6.87 (s, 2H). 13C NMR (CDCl3)
d
13.6, 13.8,
1253, 1225, 1144, 1095, 1033, 990. Anal. Calcd for C32H34F18N2: C,
48.74; H, 4.35; N, 3.55. Found: C, 48.95; H, 4.42; N, 3.36.
23.9, 24.2, 33.3, 37.5, 127.8, 133.3, 144.5, 149.6. MS (EI) m/z 249
(4.7), 232 (35), 204 (13), 176 (77), 91 (40), 43 (50). HRMS: exact
mass calcd C15H23NO2 (Mþ): 249.1729, found 249.1732. Anal. Calcd
for C15H23NO2: C, 72.25; H, 9.03; N, 5.62. Found: C, 72.24; H, 9.31;
N, 5.89.
4.2.5. N,N0-Bis-[2,4,6-tri(3,3,3-trifluoro-propyl)phenyl]-4,5-
dihydroimidazolium chloride 6a. A mixture of diamine (8.5 g,
22 mmol), NH4Cl (1.33 g, 25 mmol), and triethyl orthoformate
(8.35 g, 56.0 mmol) was stirred at 110 ꢀC for 1.5 h under argon flow
(to drive out EtOH from the reaction system). After the reaction was
completed, the solid was filtered and recrystallized from CHCl3/
ether to give N,N0-bis-[2,4,6-tri(3,3,3-trifluoro-propyl)phenyl]-4,5-
dihydroimidazolium chloride 5.53 g (57%) as a white solid. Mp
4.4.2. 2,4,6-Tributyl-1-nitrobenzene. Colorless oil. Yield 69%. IR
(film, cmꢁ1):
n
2960, 2933, 2874, 1600, 1527, 1466, 1371, 1106, 838.
1H NMR (300 MHz, CDCl3)
0.88e0.96 (m, 9H), 1.28e1.40 (m, 6H),
1.52e1.63 (m, 6H), 2.49e2.60 (m, 6H), 6.93 (s, 2H). 13C NMR (CDCl3)
13.7, 13.8, 22.2, 22.5, 31.1, 32.9, 33.3, 35.3, 127.7, 133.7, 144.8, 149.5.
d
d
217e221 ꢀC. 1H NMR (300 MHz, CDCl3)
2.68e2.92 (m, 12H), 3.02e3.21 (m, 4H), 4.38 (s, 4H), 7.11 (s, 4H),
d
2.39e2.66 (m, 8H),
MS (EI) m/z 291 (13), 274 (100), 204 (64), 162 (29), 71 (23), 43 (13).
Anal. Calcd for C18H29NO2: C, 74.18; H, 10.03; N, 4.81. Found: C,
74.26; H, 10.03; N, 4.81.
11.76 (s, 1H); 19F NMR (CDCl3)
d
ꢁ66.4 (t, J¼10.8 Hz, 6F), ꢁ66.2
(dd, J¼10.8 Hz, 12F); 13C NMR (CDCl3)
d 23.0, 27.5, 33.6 (q,
J¼28.8 Hz), 34.5 (q, J¼28.8 Hz), 51.9, 125.8 (q, J¼276.2 Hz), 126.0 (q,
4.4.3. 2,4,6-Tri-iso-pentyl-1-nitrobenzene. Colorless oil. Yield 59%.
J¼276.2 Hz), 127.7, 136.8, 142.2, 162.8. IR (film, cmꢁ1
)
n
2952, 1625,
IR (film, cmꢁ1):
n
2958, 2872, 1600, 1527, 1468, 1386, 1369, 1170,
875, 840. 1H NMR (300 MHz, CDCl3)
0.90e0.98 (m, 18H),
1.43e1.62 (m, 9H), 2.47e2.60 (m, 6H), 6.91 (s, 2H). 13C NMR (CDCl3)
22.3, 22.4, 27.7, 28.0, 29.4, 33.5, 40.1, 40.5, 127.6, 134.1, 145.2, 149.4.
1604, 1446, 1390, 1311, 1256, 1134, 1103, 980. MS (ESI) m/z 799.3
(MꢁClꢁ). HRMS for C33H33F18N2 (MꢁClꢁ): calcd 799.2350, found
799.2322.
d
d
MS (EI) m/z 333 (15), 316 (63), 288 (13), 277 (18), 206 (100), 43 (31).
Anal. Calcd for C21H35NO2: C, 75.63; H, 10.58; N, 4.20. Found: C,
75.43; H, 10.45; N, 4.24.
4.3. Preparation of 1,3,5-trialkylbenzene
1-Bromopropane (25 g, 0.20 mol) was added dropwise to
a mixture of Mg (5.0 g, 0.21 mol) in diethyl ether (100 mL) at room
temperature. The mixture was refluxed for 2 h and then cooled to
room temperature. The new prepared Grignard reagent was then
added to a mixture of 1,3,5-trichlorobenzene (10.4 g, 570 mmol)
and Ni(dppe)Cl2 (75 mg, 0.14 mmol) in 100 mL of diethyl ether at
room temperature. The mixture was stirred overnight and
quenched by adding a saturated aqueous NH4Cl. The resulting
mixture was extracted with ether, and washed with deionized
water. The organic layer was separated and dried over Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by flash chromatography to give 1,3,5-trialkylbenzene
(9.75 g, 84%) as a colorless oil.
4.5. Preparation of 2,4,6-trialkylaniline 4
A mixture of 2,4,6-tripropyl-1-nitrobenzene (4.72 g 19.0 mmol),
ammonia chloride (2.0 g, 37.9 mmol), zinc (8.94 g, 137 mmol) and
water (150 mL) was stirred at 100 ꢀC for 4 h. The mixture was
cooled to room temperature. The solid was filtered and the aqueous
solution was extracted by diethyl ether. The organic layer was
combined and washed with deionized water, and dried over
Na2SO4. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography to give 2,4,6-
tripropylaniline (2.9 g, 69%) as a colorless oil.
4.5.1. 2,4,6-Tripropylaniline 4b. Colorless oil. IR (film, cmꢁ1):
3387, 3003, 2985, 2931, 2871, 1625, 1604, 1479, 1378, 853. 1H NMR
(300 MHz, CDCl3) 1.00e1.13 (m, 9H), 1.63e1.81 (m, 6H), 2.54e2.59
n 3475,
4.3.1. 1,3,5-Tripropylbenzene. Colorless oil. Yield 84%. 1H NMR
d
(300 MHz, CDCl3)
(t, J¼7.5 Hz, 6H), 6.59 (s, 3H).
d
0.68 (t, J¼8.5 Hz, 9H), 1.37 (m, 6H), 2.29
(m, 6H), 3.57 (br, 2H), 6.87 (s, 2H). 13C NMR (CDCl3)
d 14.0, 14.4, 22.1,
25.1, 34.0, 37.6, 126.6, 127.3, 132.2, 139.5. MS (ESI) m/z 220 (MþHþ).
Anal. Calcd for C15H25N: C, 82.13; H, 11.49; N, 6.39. Found: C, 82.44;
H, 11.75; N, 6.53.
4.3.2. 1,3,5-Tributylbenzene. Colorless oil. Yield 79%. 1H NMR
(300 MHz, CDCl3)
1.56e1.61 (m, 6H), 2.54 (t, J¼7.5 Hz, 6H), 6.81 (s, 3H).
d
0.92 (t, J¼6.9 Hz, 9H), 1.32e1.39 (m, 6H),
4.5.2. 2,4,6-Tributylaniline 4c. Colorless oil. 82% yield. IR (film,
cmꢁ1):
n
3477, 3388, 3003, 2958, 2929, 2872, 2860, 1625, 1604,
1479, 1378, 863. 1H NMR (300 MHz, CDCl3)
0.81e0.90 (m, 9H),
1.20e1.39 (m, 12H), 2.37e2.42 (m, 6H), 3.40 (br, 2H), 6.67 (s, 2H).
13C NMR (CDCl3)
13.9, 22.4, 22.8, 31.1, 31.4, 34.1, 34.9, 126.7, 127.0,
4.3.3. 1,3,5-Tri-iso-pentylbenzene. Colorless oil. Yield 92%. 1H NMR
d
(300 MHz, CDCl3)
(t, J¼8.4 Hz, 6H), 6.81 (s, 3H).
d
0.92 (d, J¼6.3 Hz, 18H), 1.41e1.53 (m, 9H), 2.54
d
132.4, 139.2. MS (EI) m/z 261 (31), 218 (100). Anal. Calcd for
C18H31N: C, 82.69; H, 11.95; N, 5.36. Found: C, 82.66; H, 11.95;
N, 5.13.
4.4. Preparation of 2,4,6-trialkyl-1-nitrobenzene
A mixture of HNO3 (5.0 mL) and HOAc (5.0 mL) was added
dropwise to a solution of 1,3,5-tripropylbenzene (9.7 g, 0.047 mol)
in acetic anhydride (15.0 mL) at 0 ꢀC. The mixture was stirred for 3 h
at room temperature before being dumped into ice/water (200 mL).
The mixture was then extracted with ether, and washed with
deionized water. The organic layer was separated and dried over
Na2SO4. The solvent was removed under reduced pressure and
4.5.3. 2,4,6-Tri-iso-pentylaniline 4d. Colorless oil. 73% yield. IR
(film, cmꢁ1):
n
3477, 3381, 3003, 2955, 2930, 2870, 1624,1603, 1479,
1468, 1384, 1367, 872. 1H NMR (300 MHz, CDCl3)
0.89e1.02 (m,
18H), 1.40e1.69 (m, 9H), 2.41e2.52 (m, 6H), 3.38 (br, 2H), 6.75 (s,
2H). 13C NMR (CDCl3)
22.5, 27.8, 28.2, 29.6, 33.1, 38.1, 41.3, 126.8,
127.0, 132.8, 139.1. MS (EI) m/z 303 (54), 246 (100). Anal. Calcd for
d
d

6544
T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
C21H37N: C, 83.10; H, 12.29; N, 4.61. Found: C, 83.09; H, 12.07;
N, 4.48.
1.21e1.39 (m, 12H), 1.41e1.59 (m, 12H), 2.43 (t, J¼7.8 Hz, 6H),
2.55 (t, J¼7.8 Hz, 6H), 3.04 (s, 4H), 6.76 (s, 4H). 13C NMR
(CDCl3)
d 14.0, 14.1, 22.5, 22.9, 31.4, 33.2, 33.8, 35.2, 51.0, 127.4,
4.6. Preparation of N,N0-bis-[2,4,6-trialkylphenyl]-1,4-
diazadiene 5
135.5, 137.0, 142.6. MS (ESI) m/z 549 (MþHþ). Anal. Calcd for
C38H64N2: C, 83.15; H, 11.75; N, 5.10. Found: C, 82.96; H, 11.57;
N, 4.94.
Two drops of formic acid were added to a mixture of 2,4,6-
tripropylaniline (2.4 g, 11 mmol) and glyoxal (1.1 g, 5.5 mmol, 40%
aqueous solution) in methanol (20 mL). The mixture was stirred at
room temperature overnight. The products were precipitated from
the reaction mixture as a yellow solid or oil and were used without
further purification.
4.7.3. N,N0-Bis-(2,4,6-tri-iso-pentylphenyl)-ethylenediamine
7d. Colorless oil. Without further purification and used directly in
the next step. IR (film, cmꢁ1):
n
3365, 2955, 2931, 2870, 1625, 1468,
1384, 1367, 1224, 872. 1H NMR (300 MHz, CDCl3)
0.82e0.96
(m, 36H), 1.36e1.60 (m, 18H), 2.38e2.43 (m, 6H), 2.44e2.60 (m,
6H), 3.04 (s, 4H), 6.76 (s, 4H). 13C NMR (CDCl3)
22.6, 22.7, 27.9,
d
d
4.6.1. N,N0-Bis-[2,4,6-tripropylphenyl]-1,4-diazadiene
solid. Mp 69e70 ꢀC. IR (film, cmꢁ1):
2959, 2931, 2871, 1630, 1464,
1377, 1226, 1198, 850. 1H NMR (300 MHz, CDCl3)
0.82e0.98
5b. Yellow
28.3, 29.5, 33.3, 40.4, 41.0, 51.1, 127.3, 136.0, 137.3, 142.5. MS (EI) m/z
303 (53), 246 (100). Anal. Calcd for C44H76N2: C, 83.48; H, 12.10; N,
4.42. Found: C, 83.74; H, 12.33; N, 4.31.
n
d
(m, 18H), 1.42e1.70 (m, 12H), 2.44 (t, J¼7.6 Hz, 6H), 2.53 (t,
J¼7.6 Hz, 6H), 7.08 (s, 4H), 8.09 (s, 2H). 13C NMR (CDCl3)
d
13.9,
4.7.4. N,N0-Bis-((2,4,6-trialkyl)phenyl)-4,5-dihydroimidazolium
chloride 8. A mixture of diamine (1.53 g, 3.3 mmol), NH4Cl (185 mg,
3.46 mmol), and triethyl orthoformate (1.22 g, 8.25 mmol) was
stirred at 110 ꢀC for 1.5 h under argon flow (to drive out EtOH from
the reaction system). After the reaction was completed, the solid
was filtered and recrystallized from CHCl3/ether to give N,N0-bis-
((2,4,6-tripropyl)phenyl)-4,5-dihydroimidazolium chloride 0.93 g
(69%) as a white solid.
14.1, 23.7, 24.6, 33.8, 37.6, 127.4, 130.7, 138.7, 147.3, 163.3. Anal.
Calcd for C32H48N2: C, 83.42; H, 10.50; N, 6.08. Found: C, 83.30; H,
10.75; N, 5.95.
4.6.2. N,N0-Bis-[2,4,6-tributylphenyl]-1,4-diazadiene 5c. Yellow oil.
83% yield. IR (film, cmꢁ1):
n
2958, 2931, 2872, 2860, 1629, 1463,
1378, 1207, 1140, 862. 1H NMR (300 MHz, CDCl3)
d
0.72e0.99
(m, 18H), 1.28e1.41 (m, 12H), 1.44e1.65 (m, 12H), 2.45 (t, J¼7.8 Hz,
6H), 2.56 (t, J¼7.8 Hz, 6H), 6.89 (s, 4H), 8.10 (s, 2H). 13C NMR (CDCl3)
4.7.5. N,N0-Bis-((2,4,6-tripropyl)phenyl)-4,5-dihydroimidazolium
d
13.9, 14.0, 22.4, 22.7, 31.3, 32.8, 33.7, 35.2, 127.2, 130.9, 139.0, 147.2,
chloride 8a. White solid. Mp 271e273 ꢀC, 69% yield. IR (film, cmꢁ1):
163.3. Anal. Calcd for C38H60N2: C, 83.76; H, 11.10; N, 5.14. Found: C,
83.80; H, 11.07; N, 4.99.
n
2960, 2932, 2870, 2758, 1619, 1597, 1465, 1252, 1093, 860. 1H
NMR (CDCl3, 300 MHz, TMS)
J¼7.2 Hz, 12H), 1.52e1.61 (m, 12H), 2.51e2.62 (m, 12H), 4.77 (s, 4H),
7.00 (s, 4H), 8.19 (s, 1H). 13C NMR (CDCl3)
13.7, 14.2, 24.0, 24.3,
d
0.94 (t, J¼7.2 Hz, 6H), 1.03 (t,
4.6.3. N,N0-Bis-[2,4,6-tri-iso-pentylphenyl]-1,4-diazadiene
d
5d. Yellow solid. Mp 41e42 ꢀC, 64% yield. IR (film, cmꢁ1):
n
2955,
2929, 2869, 1631, 1577, 1467, 1383, 1366, 1207, 871. 1H NMR (CDCl3,
300 MHz)
0.89 (d, J¼6.4 Hz, 24H), 0.95 (d, J¼6.4 Hz, 12H),
1.37e1.64 (m, 18H), 2.44 (t, J¼8.2 Hz, 6H), 2.55 (t, J¼8.2 Hz, 6H),
6.89 (s, 4H), 8.10 (s, 2H). 13C NMR (CDCl3)
22.5, 27.9, 28.1, 29.4,
30.9, 33.2, 37.7, 54.3, 128.1, 129.2, 139.2, 145.5, 158.3. MS (ESI) m/z
475 (MꢁClꢁ). HRMS: exact mass calcd C33H51N2: 475.4046, found
475.4060.
d
d
4.7.6. N,N0-Bis-((2,4,6-tributyl)phenyl)-4,5-dihydroimidazolium
33.4, 39.9, 40.9, 127.0, 131.3, 139.4, 147.0, 163.2. MS (ESI) m/z 629
(MþHþ). Anal. Calcd for C44H72N2: C, 84.01; H,11.54; N, 4.45. Found:
C, 84.31; H, 11.41; N, 4.18.
chloride 8b. White solid. Mp 142e144 ꢀC, 41% yield. IR (film, cmꢁ1):
n
2957, 2931, 2750, 1605, 1529, 1466, 1376, 1222, 1047, 766. 1H NMR
(300 MHz, CDCl3)
1.51e1.69 (m, 12H), 2.56e2.65 (m, 12H), 4.74 (s, 4H), 7.00 (s, 4H),
8.17 (s, 1H). 13C NMR (CDCl3)
13.7, 13.9, 22.2, 2.7, 30.8, 32.9, 33.2,
d 0.91e1.01 (m, 18H), 1.28e1.48 (m, 12H),
4.7. Preparation of N,N0-bis-(2,4,6-trialkylphenyl)-
d
ethylenediamine
35.3, 54.1, 127.8, 128.9, 139.3, 145.7, 158.2. MS (ESI) m/z 559
(MꢁClꢁ). HRMS: exact mass calcd C39H64N2: 560.5064, found
560.5065.
To a solution of N,N0-bis-(2,4,6-tripropylphenyl)-1,4-diazadiene
obtained from the previous step in 50 mL of MeOH/THF (2:3) was
added NaBH4 (4 g). The yellow color of the reaction mixture turned
into white after 1.5 h. The reaction was quenched by a saturated
aqueous NH4Cl. The resulting mixture was extracted with ether,
and washed with deionized water. The organic layer was separated
and dried over Na2SO4. The solvent was removed under reduced
pressure to afford the diamine derivative.
4 . 7 . 7 . N , N 0- B i s - ( ( 2 , 4 , 6 - t r i - i s o - p r o p y l ) p h e n y l ) - 4 , 5 -
dihydroimidazolium chloride 8d. White solid. Mp 163e167 ꢀC, 45%
yield. IR (film, cmꢁ1):
n
2954, 2868, 2794, 1620, 1598, 1468, 1384,
1366, 1266, 875. 1H NMR (300 MHz, CDCl3)
0.90e1.00 (m, 36H),
1.44e1.71 (m, 18H), 2.56e2.66 (m, 12H), 4.69 (s, 4H), 6.99 (s, 4H),
8.52 (s, 1H). 13C NMR (CDCl3)
22.4, 22.6, 27.7, 28.1, 28.9, 33.6, 39.9,
d
d
40.4, 53.9, 127.7, 128.9, 139.6, 145.9, 158.9. MS (ESI) m/z 643.8
(MꢁClꢁ). HRMS: exact mass calcd C45H76N2: 644.6003, found
644.5984.
4.7.1. N,N0-Bis-(2,4,6-tripropylphenyl)-ethylenediamine
7b. Colorless oil. 69% yield. IR (film, cmꢁ1):
n
2959, 2930, 2871,
1466, 1416, 1378, 1234, 1091. 1H NMR (300 MHz, CDCl3)
0.81e0.97
(m, 18H), 1.41e1.62 (m, 12H), 2.41 (t, J¼7.6 Hz, 6H), 2.54 (t, J¼7.6 Hz,
6H), 3.05 (s, 4H), 6.74 (s, 4H). 13C NMR (CDCl3)
13.9, 14.3, 24.0,
d
4.7.8. N,N0-Bis-((2,4,6-tripropyl)phenyl)-4,5-imidazolium chloride
d
6b. White solid. Mp 142e144 ꢀC, 32% yield. 1H NMR (300 MHz,
24.6, 33.8, 37.6, 51.0, 127.6, 135.2, 136.7, 142.7. MS (ESI) m/z 465
(MþHþ). HRMS: exact mass calcd C32H53N2: 465.4203, found
465.4214.
CDCl3)
d 0.90e1.00 (m, 18H), 1.52e1.72 (m, 12H), 2.27e2.59
(m, 8H), 2.62 (t, J¼7.6 Hz, 4H), 7.07 (s, 4H), 7.98 (s, 2H), 9.96 (s, 1H).
13C NMR (CDCl3)
d 13.8, 14.1, 23.8, 24.3, 33.3, 37.8, 126.2, 128.1,
129.7, 138.4, 138.6, 146.2. MS (ESI) m/z 473 (MꢁClꢁ).
4.7.2. N,N0-Bis-(2,4,6-tributylphenyl)-ethylenediamine 7c. Colorless
oil. Without further purification and used directly in the next
4.7.9. N,N0-Bis-((2,4,6-tributyl)phenyl)-4,5-imidazolium chloride
step. IR (film, cmꢁ1):
n
3366, 2957, 2929, 2860, 1467, 1415, 1224,
6c. White solid. Mp 201e203 ꢀC, 39% yield. IR (film, cmꢁ1):
862. 1H NMR (300 MHz, CDCl3)
d
0.85 (t, J¼7.2 Hz, 18H),
n
2958, 2931, 2781, 1617, 1595, 1466, 1377, 1257, 1169, 866. 1H NMR

T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
6545
(CDCl3, 300 MHz)
2.27e2.47 (m, 8H), 2.64 (t, J¼7.8 Hz, 4H), 7.06 (s, 4H), 7.95 (s, 2H),
9.84 (s, 1H). 13C NMR (CDCl3)
13.8, 22.4, 22.6, 30.9, 32.7, 33.2,
35.5, 126.0, 127.9, 129.5, 138.5, 138.6, 146.4. MS (ESI) m/z 557.6
(MꢁClꢁ). HRMS: exact mass calcd C39H62N2: 558.4907, found
558.4885.
d
0.88e1.01 (m, 18H), 1.25e1.65 (m, 24H),
300 MHz, TMS)
7.78 (d, J¼7.5 Hz, 2H).
d
3.97 (s, 3H), 7.16e7.25 (m, 2H), 7.54e7.66 (m, 5H),
d
4.8.8. 2-Methoxyl-20-methylbiphenyl5a 9h (Table 3, entry 8). The
general procedure afforded 96% of the title compound. 1H NMR
(CDCl3, 300 MHz, TMS) d 2.34 (s, 3H), 3.91 (s, 3H), 7.11e7.20 (m, 2H),
7.32e7.52 (m, 6H).
4.7.10. N,N0-Bis-((2,4,6-tri-iso-pentyl)phenyl)-4,5-imidazolium chlo-
ride 6d. White solid. Mp 168e173 ꢀC, 37% yield. IR (film, cmꢁ1):
4.8.9. 2-Methoxyl-20-methylbiphenyl5a 9i (Table 3, entry 9). The
n
2956, 2870, 1650, 1533, 1468, 1385, 1367, 1227, 874. 1H NMR
general procedure afforded 96% of the title compound. 1H NMR
(300 MHz, CDCl3)
1.28e1.58 (m, 18H), 2.20e2.65 (m, 12H), 7.05 (s, 4H), 7.79 (s, 2H),
10.3 (s, 1H). 13C NMR (CDCl3)
22.4, 22.5, 27.8, 27.9, 29.0, 33.7, 39.7,
40.4, 125.3, 127.6, 129.5, 138.9, 139.7, 146.6. MS (ESI) m/z 641.9
(MꢁClꢁ). HRMS: exact mass calcd C45H76N2: 642.5846, found
642.5929.
d
0.89 (d, J¼6.8 Hz, 24H), 0.96 (d, J¼6.8 Hz, 12H),
(CDCl3, 300 MHz, TMS) d 2.34 (s, 3H), 3.91 (s, 3H), 7.11e7.20 (m, 2H),
7.32e7.52 (m, 6H).
d
4.8.10. 3-Methoxylbiphenyl5a 9j (Table 3, entry 10). The general
procedure afforded 96% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS) d 3.97 (s, 3H), 7.04e7.07 (m, 1H), 7.32e7.36 (m, 2H),
7.50e7.58 (m, 4H), 7.74e7.76 (m, 2H).
4.7.11. N,N0-Bis-((2,4,6-trimethyl)phenyl)-4,5-imidazolium chloride
6e. White solid. 53% yield. 1H NMR (300 MHz, CDCl3)
d
2.18 (s, 12H),
4.8.11. 4-Methoxy-20,20-dimethylbiphenyl16 9k (Table3, entry 11). The
2.35 (s, 6H), 7.02 (s, 4H), 7.66 (s, 2H), 10.66 (s, 1H). MS (ESI) m/z
general procedure afforded 84% of the title compound. 1H
305.3 (MꢁClꢁ).
NMR (CDCl3, 300 MHz, TMS)
(m, 7H).
d 2.04 (s, 6H), 3.85 (s, 3H), 6.95e7.10
4.8. General method for the SuzukieMiyaura reaction of aryl
chlorides or aryl triflates at room temperature
4.8.12. 2-Methoxy-20,20-dimethylbiphenyl5a 9l (Table 3, entry 12). The
general procedure afforded 63% of the title compound. 1H
In a schlenk tube with a magnetic bar, 6a (40 mg, 6 mol %),
Pd(OAc)2 (5.4 mg, 3 mol %), and K3PO4 (594 mg, 2.8 mmol) in
5 mL of THF/H2O (5:1) were placed under argon. Aryl chloride
(0.8 mmol) was added via syringe and followed by adding
phenylboronic acid (1.2 mmol). The resulting mixture was stir-
red at room temperature for 12 h. The solvent was evaporated
in vacuo and the residue was purified by flash column chro-
matography (petroleum ether/EtOAc¼100:1) to give the desired
product.
NMR (CDCl3, 300 MHz, TMS)
(m, 7H).
d 2.00 (s, 6H), 3.68 (s, 3H), 6.93e7.39
4.8.13. 4-Acetylbiphenyl5a 9m (Table 3, entry 13). The general pro-
cedure afforded 98% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
2H), 7.69 (d, J¼7.8 Hz, 2H), 8.04 (d, J¼7.8 Hz, 2H).
d
2.65 (s, 3H), 7.40e7.50 (m, 3H), 7.62 (d, J¼7.5 Hz,
4.8.14. 2-Methylbiphenyl13 9n (Table 4, entry 1). The general pro-
cedure afforded 95% of the title compound. 1H NMR (CDCl3,
4.8.1. 4-Methoxybiphenyl14 9a (Table 3, entry 1). The general pro-
300 MHz, TMS) d 2.47 (s, 3H), 7.42e7.46 (m, 4H), 7.51e7.59 (m, 5H).
cedure afforded 92% of the title compound. 1H NMR (CDCl3,
4.8.15. 3-Methylbiphenyl13 9o (Table 4, entry 2). The general pro-
300 MHz, TMS)
(m, 1H), 7.39e7.44 (m, 2H), 7.52e7.57 (m, 4H).
d
3.85 (s, 3H), 6.98 (d, J¼8.1 Hz, 2H), 7.26e7.30
cedure afforded 99% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
6H), 7.75 (d, J¼7.5 Hz, 2H).
d
2.58 (s, 3H), 7.33 (d, J¼7.2 Hz, 1H), 7.46e7.61 (m,
4.8.2. 4-Methoxy-20-methylbiphenyl5a 9b (Table 3, entry 2). The
general procedure afforded 98% of the title compound. 1H NMR
4.8.16. 4-Methylbiphenyl13 9p (Table 4, entry 3). The general pro-
(CDCl3, 300 MHz, TMS) d 2.43 (s, 3H), 3.96 (s, 3H), 7.08e7.11 (m, 2H),
7.38e7.42 (m, 6H).
cedure afforded 94% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
2H), 7.73 (d, J¼7.5 Hz, 2H).
d
2.53 (s, 3H), 7.37e7.58 (m, 5H), 7.64 (d, J¼8.1 Hz,
4.8.3. 4-Methoxy-30-trifluoromethylbiphenyl14 9c (Table 3, entry
3). The general procedure afforded 95% of the title compound. 1H
NMR (CDCl3, 300 MHz, TMS)
7.54e7.66 (m, 4H), 7.76e7.79 (m, 1H), 7.90e7.92 (m, 1H).
d
3.91 (s, 3H), 7.08 (d, J¼9.0 Hz, 2H),
4.8.17. 4-Methoxy-20-methylbiphenyl14 9q (Table 4, entry 4). The
general procedure afforded 98% of the title compound. 1H NMR
(CDCl3, 300 MHz, TMS) d 2.43 (s, 3H), 3.96 (s, 3H), 7.08e7.11 (m, 2H),
7.38e7.42 (m, 6H).
4.8.4. 2,40-Dimethoxybiphenyl13 9d (Table 3, entry 4). The general
procedure afforded 95% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
7.16e7.24 (m, 2H), 7.39 (d, J¼9.0 Hz, 2H).
d 3.73 (s, 3H), 3.76 (s, 3H), 6.86e6.93 (m, 4H),
4.8.18. 2-Methoxyl-20-methylbiphenyl5a 9r (Table 4, entry 5). The
general procedure afforded 96% of the title compound. The 1H NMR
is same as those of compound 9h.
4.8.5. 4-tert-Butyl-40-methoxybiphenyl19 9e (Table 3, entry 5). The
general procedure afforded 91% of the title compound. 1H NMR
4.9. General method for the SuzukieMiyaura reaction of
heteroaryl halides or heteroaryl boronic acids
(CDCl3, 300 MHz, TMS)
2H), 7.41e7.53 (m, 6H).
d
1.36 (s, 9H), 3.84 (s, 3H), 6.96 (d, J¼8.9 Hz,
4.8.6. 4-Methylbiphenyl5a 9f (Table 3, entry 6). The general pro-
In a dry schlenk tube with a magnetic bar, 6a (40 mg, 6 mol
%), Pd(OAc)2 (5.4 mg, 3 mol %), and K3PO4 (594 mg, 2.8 mmol) in
5 mL of THF/H2O (5:1) were placed under argon. Heteroaryl
halide (0.8 mmol) was added via syringe and followed by
adding phenylboronic acid (1.2 mmol). The resulting mixture
was stirred at reflux for 12 h. The solvent was evaporated in
vacuo and the residue was purified by flash column
cedure afforded 94% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
2H), 7.73 (d, J¼7.5 Hz, 2H).
d
2.53 (s, 3H), 7.37e7.58 (m, 5H), 7.64 (d, J¼8.1 Hz,
4.8.7. 2-Methoxylbiphenyl14 9g (Table 3, entry 7). The general pro-
cedure afforded 93% of the title compound. 1H NMR (CDCl3,

6546
T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
chromatography (petroleum ether/EtOAc¼100:1) to give the
300 MHz, TMS)
1H), 8.57e8.58 (m, 2H).
d
2.25 (s, 3H), 7.18e7.33 (m, 5H), 7.62 (d, J¼7.8 Hz,
desired product.
4.9.1. 3-(4-Methoxylphenyl)thiophene15 10a (Table 5, entry 1). The
4.9.14. 3-Fluoro-2-phenylpyridine 10n (Table 5, entry 14). The gen-
eral procedure afforded 97% of the title compound. 1H NMR (CDCl3,
general procedure afforded 92% of the title compound. 1H NMR
300 MHz, TMS)
d 7.23e7.29 (m, 1H), 7.43e7.51 (m, 4H), 7.95e7.97
(CDCl3, 300 MHz, TMS)
d
3.82 (s, 3H), 6.92 (d, J¼8.7 Hz, 2H),
(m, 2H), 8.51e8.53 (m, 1H).
7.33e7.35 (m, 3H), 7.52 (d, J¼8.7 Hz, 2H).
4.9.15. 2-Phenylthiophene13 10o (Table 5, entry 15). The general
4.9.2. 3-(2-Methoxylphenyl)thiophene16 10b (Table 5, entry 2). The
procedure afforded 88% of the title compound. 1H NMR (CDCl3,
general procedure afforded 95% of the title compound. 1H NMR
300 MHz, TMS)
d 7.06e7.62 (m, 8H).
(CDCl3, 300 MHz, TMS)
d 3.76 (s, 3H), 6.88e6.92 (m, 2H), 7.18e7.27
(m, 2H), 7.39e7.45 (m, 2H), 7.55 (s, 1H).
4.9.16. 2-(2-Methoxyphenyl)thiophene21 10p (Table 5, entry 16). The
general procedure afforded 86% of the title compound. 1H
4.9.3. 3-(2-Methylphenyl)thiophene15 10c (Table 5, entry 3). The
general procedure afforded 85% of the title compound. 1H NMR
NMR (CDCl3, 300 MHz, TMS)
d 3.75 (s, 3H), 6.80e6.91 (m, 2H),
6.94e6.99 (m, 1H), 7.18e7.21 (m, 2H), 7.36e7.40 (m, 1H), 7.48e7.53
(m, 1H).
(CDCl3, 300 MHz, TMS)
d 2.33 (s, 3H), 7.13e7.34 (m, 7H).
4.9.4. 1-(4-(Thiophen-3-yl)phenyl)ethanone15 10d (Table 5, entry
4). The general procedure afforded 94% of the title compound. 1H
NMR (CDCl3, 300 MHz, TMS) d 2.62 (s, 3H), 7.43 (m, 2H), 7.57 (s, 1H),
4.9.17. 2-(Biphenyl-4-yl)-5-ethylpyrimidine22 10q (Table 5, entry
17). The general procedure afforded 92% of the title compound. 1H
7.69 (d, J¼8.4 Hz, 2H), 7.99 (d, J¼8.4 Hz, 2H).
NMR (CDCl3, 300 MHz, TMS)
d
1.31 (t, J¼7.5 Hz, 3H), 2.68 (q,
J¼7.5 Hz, 2H), 7.36e7.48 (m, 3H), 7.67 (d, J¼6.9 Hz, 2H), 7.72 (d,
4.9.5. 3-p-Tolylthiophene18 10e (Table 5, entry 5). The general pro-
J¼8.4 Hz, 2H), 8.50 (d, J¼8.4 Hz, 2H), 8.65 (s, 2H).
cedure afforded 95% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
(m, 3H), 7.48 (d, J¼7.8 Hz, 2H).
d
2.36 (s, 3H), 7.20 (d, J¼7.8 Hz, 2H), 7.36e7.39
4.9.18. 1,2-Bis(2-methyl-5-phenylthiophen-3-yl)cyclopent-1-ene 10r
(Table 5, entry 18). The general procedure afforded 43% of the title
compound. 1H NMR (CDCl3, 300 MHz, TMS)
d 1.94 (s, 6H), 2.08 (m,
4.9.6. 3-(Thiophen-3-yl)pyridine19 10f (Table 5, entry 6). The gen-
2H), 2.84 (d, J¼7.6 Hz, 4H), 7.03 (s, 2H), 7.19e7.25 (m, 2H), 7.30e7.35
eral procedure afforded 87% of the title compound. 1H NMR (CDCl3,
(m, 4H), 7.50 (d, J¼7.8 Hz, 2H).
300 MHz, TMS)
d 7.11e7.14 (m, 1H), 7.29e7.38 (m, 3H), 7.87
(d, J¼7.5 Hz, 1H), 8.52 (m, 1H), 8.89 (m, 1H).
4.10. General method for the SuzukieMiyaura reaction with
low catalyst loading
4.9.7. 5-Methyl-2,30-bithiophene20 10g (Table 5, entry 7). The gen-
eral procedure afforded 90% of the title compound. 1H NMR (CDCl3,
In a schlenk tube with a magnetic bar, aryl chloride (0.8 mmol),
arylboronic acid (1.2 mmol), K3PO4 (594 mg, 2.8 mmol), and 5 mL
of THF/H2O (5:1) were placed under argon. The amount of the
palladium catalyst was added as indicated in Table 6. The resulting
mixture was stirred at reflux for 12 h. The solvent was evaporated
in vacuo and the residue was purified by flash column chroma-
tography (petroleum ether/EtOAc¼100:1) to give the desired
product.
300 MHz, TMS)
(m, 3H).
d 2.53 (s, 3H), 6.72 (s, 1H), 7.02 (m, 1H), 7.30e7.42
4.9.8. 3-(2-Methoxyphenyl)pyridine15 10h (Table 5, entry 8). The
general procedure afforded 89% of the title compound. 1H
NMR (CDCl3, 300 MHz, TMS)
d 3.75 (s, 3H), 6.94e7.02 (m, 2H),
7.24e7.35 (m, 3H), 7.81 (d, J¼7.5 Hz, 1H), 8.51 (d, J¼3.3 Hz, 1H), 8.77
(s, 1H).
4.10.1. 2-Methoxyl-40-tert-butyl-biphenyl18 11b (Table 6, entry
2). The general procedure afforded 94% of the title compound. 1H
4.9.9. 3-(Thiophen-2-yl)pyridine17 10i (Table 5, entry 9). The gen-
eral procedure afforded 82% of the title compound. 1H NMR (CDCl3,
NMR (CDCl3, 300 MHz, TMS)
d 1.35 (s, 9H), 3.80 (s, 3H), 6.96e7.03
300 MHz, TMS)
d
7.30e7.53 (m, 4H), 7.86 (d, J¼7.5 Hz, 2H), 8.54
(m, 2H), 7.26e7.33 (m, 2H), 7.41e7.49 (m, 4H).
(m, 1H), 8.88 (m, 1H).
4.10.2. 2-Methoxyl-40-methylbiphenyl23 11c (Table 6, entry 3). The
4.9.10. 3,30-Bipyridine17 10j (Table 5, entry 10). The general pro-
general procedure afforded 98% of the title compound. 1H NMR
cedure afforded 85% of the title compound. 1H NMR (CDCl3,
(CDCl3, 300 MHz, TMS)
d 2.44 (s, 3H), 3.85 (s, 3H), 7.01e7.08 (m,
300 MHz, TMS)
d
7.40e7.44 (dd, J¼6.4 Hz, 5.1 Hz, 1H), 7.89
2H), 7.27e7.39 (m, 4H), 7.47e7.50 (m, 2H).
(d, J¼6.4 Hz, 1H), 7.66 (d, J¼5.1 Hz, 1H), 8.85 (s, 1H).
4.10.3. 2-Methoxyl-20-methylbiphenyl5a 11d (Table 6, entry 4). The
4.9.11. 2-(4-Methoxyphenyl)benzofuran15 10k (Table 5, entry
11). The general procedure afforded 85% of the title compound. 1H
general procedure afforded 96% of the title compound. 1H NMR
(CDCl3, 300 MHz, TMS) d 2.34 (s, 3H), 3.91 (s, 3H), 7.11e7.20 (m, 2H),
7.32e7.52 (m, 6H).
NMR (CDCl3, 300 MHz, TMS)
d 3.86 (s, 3H), 6.88 (s, 1H), 6.97
(d, J¼8.1 Hz, 2H), 7.23e7.29 (m, 2H), 7.8e7.54 9 (m, 2H), 7.80
(d, J¼8.1 Hz, 2H).
4.10.4. 2-Methoxyl-20-trifluoromethylbiphenyl24 11e (Table 6, entry
5). The general procedure afforded 69% of the title compound. 1H
NMR (CDCl3, 300 MHz, TMS) d 3.75 (s, 3H), 6.80e6.87 (m, 3H),
4.9.12. 3-(2-Methoxylphenyl)thiophene15 10l (Table 5, entry 12). The
general procedure afforded 95% of the title compound. 1H NMR
(CDCl3, 300 MHz, TMS)
(m, 2H), 7.39e7.45 (m, 2H), 7.55 (s, 1H).
d
3.76 (s, 3H), 6.88e6.92 (m, 2H), 7.18e7.27
7.17e7.28 (m, 2H), 7.36e7.50 (m, 2H), 7.66 (d, J¼7.8 Hz, 1H).
4.10.5. 2-Methoxyl-30-trifluoromethylbiphenyl15 11f (Table 6, entry
6). The general procedure afforded 99% of the title compound. 1H
4.9.13. 3-o-Tolylpyridine14 10m (Table 5, entry 13). The general
procedure afforded 82% of the title compound. 1H NMR (CDCl3,
NMR (CDCl3, 300 MHz, TMS)
d
3.86 (s, 3H), 6.93 (d, J¼8.1 Hz, 1H),

T. Liu et al. / Tetrahedron 68 (2012) 6535e6547
6547
2 In Metal-catalyzed Cross-coupling Reaction; Diederich, F., de Meijere, A., Eds.;
Wiley-VCH: New York, NY, 2004; (d) Miyaura, N. Top. Curr. Chem. 2002, 219, 11;
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Buchwald, S. L. Nature Protocols 2007, 2, 3115.
3. (a) Netherton, M. R.; Dai, C.; Neuschuta, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
10099; (b) Kirchoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 13662.
4. (a) Herrmann, W. A.; Reisinger, C. P.; Spiegler, M. J. Organomet. Chem. 1998, 557,
93; (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
7.10 (s, 1H), 7.16 (d, J¼7.5 Hz, 1H), 7.37 (t, J¼7.8 Hz, 1H), 7.50e7.60
(m, 2H), 7.73 (d, J¼7.8 Hz, 1H), 7.82 (m, 1H).
4.10.6. 3-Phenylpyridine15 11g (Table 6, entry 7). The general pro-
cedure afforded 76% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
J¼3.6 Hz, 1H), 8.85 (s, 1H).
d
7.33e7.59 (m, 6H), 7.86 (d, J¼7.8 Hz, 1H), 6.58 (d,
5. (a) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J.
Am. Chem. Soc. 2006, 128, 4101; (b) Navarro, O.; Marion, N.; Mei, J.; Nolan, S.
P. Chem.dEur. J. 2006, 12, 5142; (c) Organ, M. G.; Alimsiz, S. C.; Sayah, M.;
Hoi, K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48, 2383; (d) Altenhoff,
G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126,
15195.
6. (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153; (b)
Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann, C.;
Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun. 2004, 38.
4.10.7. 4-Acetyl-30-trifluoromethylbiphenyl25 11h (Table 6, entry
8). The general procedure afforded 98% of the title compound. 1H
NMR (CDCl3, 300 MHz, TMS)
d 2.51 (s, 3H), 7.45e7.56 (m, 4H), 7.65
(d, J¼7.2 Hz, 1H), 7.73 (s, 1H), 7.92 (d, J¼8.4 Hz, 2H).
4.10.8. 4-Acetylbiphenyl5a 11i (Table 6, entry 9). The general pro-
cedure afforded 98% of the title compound. 1H NMR (CDCl3,
7. (a) Fihri, A.; Luart, D.; Len, C.; Solhy, A.; Chevrinb, C. P. V. Dalton Trans. 2011, 40,
3116; (b) Hierso, J.-C.; Fihri, A.; Amardeil, R.; Meunier, P.; Doucet, H.; Santelli,
M. Tetrahedron 2005, 61, 9759; (c) Scivanti, A.; Beghetto, V.; Matteoli, U.;
Antonaroli, S.; Marini, A.; Crociani, B. Tetrahedron 2005, 61, 9752; (d) Dai, W.-
M.; Li, Y.; Zhang, Y.; Lai, K. W.; Wu, J. Tetrahedron Lett. 2004, 45, 1999; (e)
Joshaghani, M.; Daryanavard, M.; Rafiee, E.; Xiao, J.; Collin Baillie, C. Tetrahe-
dron Lett. 2007, 48, 2025; (f) Arvela, R.; Leadbeater, N. E.; Mack, T. L.; Kormos,
C. M. Tetrahedron Lett. 2006, 47, 217; (g) Jiang, N.; Ragauskas, A. J. Tetrahedron
Lett. 2006, 47, 197; (h) Lee, D.-H.; Jin, M.-J. Org. Lett. 2011, 13, 252; (i) Hierso, J.-
300 MHz, TMS)
2H), 7.69 (d, J¼7.8 Hz, 2H), 8.04 (d, J¼7.8 Hz, 2H).
d
2.65 (s, 3H), 7.40e7.50 (m, 3H), 7.62 (d, J¼7.5 Hz,
4.10.9. 4-Chlorobiphenyl26 11j (Table 6, entry 10). The general pro-
cedure afforded 84% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
d 7.24e7.55 (m, 9H).
ꢀ
C.; Beauperin, M.; Meunier, P. Eur. J. Inorg. Chem. 2007, 3767; (j) Diebolt, O.;
4.10.10. 4-Chlorobiphenyl5a 11k (Table 6, entry 11). The general
Braunstein, P.; Nolan, S. P.; Cazin, C. S. J. Chem. Commun. 2008, 3190; (k) Baillie,
C.; Zhang, L.; Xiao, J. J. Org. Chem. 2004, 69, 7779; (l) Kwong, F. Y.; Lam, W. H.;
Yeung, C. H.; Chan, K. S.; Chan, A. S. C. Chem. Commun. 2004, 1922; (m)
Sprengers, J. W.; Wassenaar, J.; Clement, N. D.; Cavell, K. G.; Elsevier, C. J.
procedure afforded 84% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
d 7.24e7.55 (m, 9H).
ꢀ
Angew. Chem., Int. Ed. 2005, 44, 2026; (n) Jackstell, R.; Gomez Andreu, M.;
4.10.11. Biphenyl-2-carbonitrile25 11l (Table 6, entry 12). The general
€
Frisch, A.; Selvakumar, K.; Zapf, A.; Klein, H.; Spannenberg, A.; Rottger, D.;
Briel, O.; Karch, R.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 986.
8. (a) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46,
2768; (b) Valente, C.; C¸ alimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G.
Angew. Chem., Int. Ed. 2012, 51, 3314.
9. (a) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361; (b)
Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913; (c) Bourissou, D.; Guerret, O.;
Gabba, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39; (d) Herrmann, W. A.; Kacher,
C. Angew. Chem., Int. Ed. 1997, 36, 2162.
procedure afforded 63% of the title compound. 1H NMR (CDCl3,
300 MHz, TMS)
(m, 2H).
d 7.21e7.32 (m, 2H), 7.35e7.50 (m, 5H), 7.56e7.59
4.10.12. 4-Methoxy-40-methylbiphenyl14 11m (Table 6, entry 13). The
general procedure afforded 98% of the title compound. 1H
10. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell Science: Malden, MA,
NMR (CDCl3, 300 MHz, TMS)
d 2.38 (s, 3H), 3.84 (s, 3H), 6.95 (d,
2000; (b) Tyrell, E.; Brookes, P. Synthesis 2004, 4, 469.
J¼8.2 Hz, 2H), 7.22 (d, J¼7.8 Hz, 2H), 7.44 (d, J¼7.8 Hz, 2H), 7.50 (d,
11. (a) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 3484; (b) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3358; (c) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649; (d) Kondolff, I.;
Doucet, H.; Santelli, M. Synlett 2005, 2057; (e) Thompson, A. E.; Hughes, G.;
Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. J. Org. Chem. 2005, 70, 388;
(f) Kudo, N.; Pereghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282; (g)
Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel,
E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8,
1787.
J¼8.2 Hz, 2H).
Acknowledgements
The authors gratefully acknowledge the financial support from
National Basic Research Program of China (2010CB126103), Special
Fund for Agro-scientific Research in the Public Interest (201103007),
the National Key Technologies R&D Program (2011BAE06B05),
Shanghai Scientific Research Program (10XD1405200), the Key
Program of National Natural Science Foundation of China
(21032006), National Natural Science Foundation of China
(21172245/B020304/21172248), for financial support.
12. Garret, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889.
13. Yamada, Y. M. A.; Watanabe, T.; Beppu, T.; Fukuyama, N. ,; Torri, K.; Uozumi, Y.
Chem.dEur. J. 2010, 16, 11311.
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17. Fleckenstein, C. A.; Plenio, H. Chem.dEur. J. 2008, 14, 4267.
18. Andrus, M. B.; Song, C. Org. Lett. 2001, 3, 3761.
Supplementary data
19. Lee, D.-H.; Choi, M.; Yu, B.-W.; Ryoo, R.; Taher, A.; Hossain, S.; Jin, M.-J. Adv.
Synth. Catal. 2009, 351, 2912.
20. Saini, G.; Lucas, N. T.; Jacob, J. Tetrahedron Lett. 2010, 51, 2956.
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.05.068.
References and notes
1. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437; (b)
Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419; (c) Miyaura, N., Chapter