β-Oxo amides: Inexpensive and efficient ligands for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1055/s-2007-983891

β-Oxo amides were found to be inexpensive and efficient ligands for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. In the presence of palladium(II) acetate and N-(4-methoxyphenyl)-3-oxobutanamide (L7), a variety of aryl halides, including deactivated aryl chlorides and heteroaryl halides, were successfully coupled to arylboronic acids in moderate to excellent yields providing very high turnover numbers (maximum TON <950,000 and TOF <79,167). It is noteworthy that the reaction is conducted under mild and aerobic conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983891

PAPER
2957
b-Oxo Amides: Inexpensive and Efficient Ligands for the Palladium-Catalyzed
Suzuki–Miyaura Cross-Coupling Reaction
b
J
-Oxo
A
m
i
ides as
n
Ligands in
-
H
dium-CatalyzedSu
e
z
uki–Miya
n
ura Cross-C
g
ouplingReaction Li,* Yue-Hua Zhang, Ren-Jie Song, Ye-Xiang Xie, Chen-Liang Deng, Yun Liang
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education),
College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, P. R. of China
Fax +86(731)8872531; E-mail: jhli@hunnu.edu.cn
Received 11 May 2007; revised 22 June 2007
tanamide (L7), a variety of aryl halides were smoothly
Abstract: b-Oxo amides were found to be inexpensive and efficient
ligands for the palladium-catalyzed Suzuki–Miyaura cross-cou-
pling reaction. In the presence of palladium(II) acetate and N-(4-
methoxyphenyl)-3-oxobutanamide (L7), a variety of aryl halides,
coupled with arylboronic acids under mild conditions giv-
ing the products in moderate to excellent yields. More-
over, the catalytic system is highly efficient for the
including deactivated aryl chlorides and heteroaryl halides, were couplings of aryl iodides and bromides (the maximal TON
successfully coupled to arylboronic acids in moderate to excellent <950,000 and TOF <79,167).
yields providing very high turnover numbers (maximum TON
<
950,000 and TOF <79,167). It is noteworthy that the reaction is
Pd(OAc)2, L7
conducted under mild and aerobic conditions.
Ar1
Ar2 B(OH)2
Ar1 Ar2
X
+
Cs2CO3, DMF
r.t. or 80 °C
Key words: palladium(II) acetate, b-oxo amide, Suzuki–Miyaura
cross-coupling reaction, aryl halides, arylboronic acids
Ar , Ar2 = aryl, heteroaryl
1
maximum TON: 950000; TOF: 79167
X = I, Br, Cl
OMe
O
O
L7:
The palladium-catalyzed Suzuki–Miyaura coupling reac-
N
H
tion is one of the most widely used C–C bond-forming
1
reactions in organic synthesis. Generally, the Suzuki– Scheme 1
Miyaura coupling reaction is conducted using a palladi-
um–ligand (often a phosphine or a carbene ligand) com-
The palladium(II) acetate catalyzed cross-coupling of 4-
bromoanisole (1a) with phenylboronic acid (2a) was con-
ducted as a model reaction to optimize the reaction reac-
tions, and the results are summarized in Table 1. Initially,
a number of 1,3-dicarbonyls, including b-oxo esters, dike-
tones, b-oxo nitriles, and b-oxo amides, were tested as
ligands. It was found that most 1,3-dicarbonyls were high-
ly efficient in promoting the reaction, and b-oxo amides
were more effective than the other 1,3-dicarbonyls (en-
tries 1–17). Without any ligand, treatment of 4-bromoani-
sole (1a) with phenylboronic acid (2a), palladium(II)
acetate, and cesium carbonate in N,N-dimethylformamide
at room temperature after 12 hours afforded the corre-
sponding product 3 in a rather low yield (entry 1). Thus,
we attempted to perform the reaction using 1,3-dicarbon-
yls as ligands. The results indicated that the yield of the
target product 3 was increased slightly when either b-oxo
ester L1 or L2 or b-oxo nitrile L5 was added (entries 2, 3,
and 6), and the presence of diketones L3 and L4 even dis-
favored the reaction (entries 4 and 6). To our delight, the
yield of 3 was enhanced dramatically when using b-oxo
N-arylamides L6–L10 as the ligand (entries 7–11), and b-
oxo N-arylamides bearing a methyl or methoxy group on
the benzene ring L7–L9 gave the best results in terms of
the reaction rate. While 3-oxo-N-phenylbutanamide (L6)
enhanced the yield of the reaction of 4-bromoanisole (1a)
with phenylboronic acid (2a) to 93% after 12 hours, the
ligands L7–L9 provided ca. 96% yield of 3 in three hours.
2
,3
plex as the catalyst at high temperatures. However,
many of these phosphine and carbene ligands are expen-
sive or they are sensitive to air and/or moisture. Therefore4,
a wide range of alternative ligands, such as oxazolines,
5
6
7
8
amines, amino acids, heterocycles, diazabutadienes,
ureas, guanidine, hydrazones, surfactants, and oth-
9
10
11
12
1
3,14
ers,
have been developed to overcome these draw-
backs in recent years. Although most of these ligands are
inexpensive and stable, many are not commercially avail-
able and provide low turnover numbers (the loading of
palladium/ligand is often >1 mol%). In view of economic
and industrial interests, the development of a high turn-
over number catalytic system that includes an inexpensive
ligand as an alternative to these palladium/phosphine or
palladium/carbene catalytic systems is still significant.
Recently, 1,3-dicarbonyls including 1,3-diketones and b-
oxo esters were employed as highly active ligands for the
copper-catalyzed Ullmann-type coupling reaction,15
which raised the possibility of creating a more robust cat-
alytic system for palladium-catalyzed cross-coupling re-
actions. Indeed, b-oxo amides, in particular N-(4-
methoxyphenyl)-3-oxobutanamide (L7), were found to be
efficient ligands for the palladium-catalyzed Suzuki–
Miyaura coupling reaction (Scheme 1). In the presence of
palladium(II) acetate and N-(4-methoxyphenyl)-3-oxobu-
SYNTHESIS 2007, No. 19, pp 2957–2966
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-983891; Art ID: F08507SS
Georg Thieme Verlag Stuttgart · New York
©

2
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Table 1 Screening Conditionsa
Pd (OAc)2
MeO
Br
+
B(OH)2
MeO
1a
2a
3
b
Entry
1
Ligand
Base
Time (h)
12
Yield (%)
–
Cs CO
11
2
3
3
O
O
O
2
3
4
5
6
Cs CO
12
12
3
30
2
O
L1
O
OEt
Cs CO
22
6
2
3
3
3
L2
O
O
O
Cs CO
2
L3
O
Cs CO
3
<5
12
2
L4
O
CN
Cs CO
2
3
3
3
Ph
L5
O
O
7
8
Cs CO
12
3
93
96
2
N
H
L6
OMe
O
O
O
Cs CO
2
3
3
N
H
L7
O
9
Cs CO
3
3
96
2
N
H
OMe
L8
O
O
1
1
1
0
1
2
Cs CO
95
90
27
N
H
2
3
3
3
Me
L9
NO2
O
O
O
Cs CO
3
3
2
N
H
L10
OMe
O
Cs CO
2
N
H
L11
Synthesis 2007, No. 19, 2957–2966 © Thieme Stuttgart · New York

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b-Oxo Amides as Ligands in the Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reaction
2959
Table 1 Screening Conditionsa (continued)
Pd (OAc)2
MeO
Br
+
B(OH)2
MeO
1a
2a
3
b
Entry
Ligand
Base
Time (h)
3
Yield (%)
OMe
O
O
O
1
3
Cs CO
35
2
3
N
H
Cl
L12
OMe
O
1
1
4
5
Cs CO
3
trace
82
2
3
3
N
H
Cl
Cl
O
L13
O
Cs CO
12
2
N
H
L14
O
O
O
1
1
6
7
Cs CO
12
12
23
45
N
2
3
3
L15
O
Cs CO
2
NH2
L16
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
1
1
2
2
2
2
2
2
2
2
2
2
8c
9d
0
Cs CO
3
3
97
35
81
68
50
11
43
80
85
35
98
30
2
3
3
Cs CO
2
K CO
3
2
3
1
Na CO
3
2
3
2
K PO
3
3
4
3
Et N
3
3
4e
5f
6g
7h
8h,i
9i,j
Cs CO
3
2
3
Cs CO
3
2
3
3
3
3
3
Cs CO
3
2
Cs CO
12
12
12
2
Cs CO
2
Cs CO
2
a
b
c
d
e
f
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Pd(OAc) (1 mol%), ligand (2 mol%), base (1 mmol), DMF (1 mL), r.t.
Isolated yield.
L7 (3 mol%).
L7 (1 mol%).
EtOH (1 mL) instead of DMF.
Dioxane (1 mL) instead of DMF.
2
g
h
i
H O–DMF (1:10, 1 mL) instead of DMF.
2
Pd(OAc) (0.1 mol%) and ligand (0.2 mol%).
2
At 80 °C.
j
Pd(OAc) (0.01 mol%) and ligand (0.02 mol%).
2
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Ji.-H. Li et al.
PAPER
However, the catalytic activity was reduced sharply when loading of palladium to 0.01 mol% produced a low yield
there are substituents at the 2-position of the b-oxo of 3 even at 80 °C (TON = 3,000; entry 29).
N-arylamides L11–L13 (entries 12–14). For example, b-
As shown in Table 2, the palladium(II) acetate/L7 system
displayed highly catalytic activity for the Suzuki–
Miyaura coupling reaction, and the scope of the aryl ha-
oxo N-arylamide L11 bearing a methyl group at the 2-po-
sition gave the target product 3 in only 27% yield (entry
1
2). Satisfactory results were still achieved using b-oxo
lides was extended to some deactivated aryl chlorides and
heteroaryl halides. In the presence of palladium(II) acetate
and L7, substrate 1a with boronic acids 2b–d could also
be converted completely in three hours into the corre-
sponding cross-coupled products 4–6 in satisfactory
yields (entries 1–3). Subsequently, the reactions of three
aryl iodides 1b–d with 2a were examined under the stan-
dard conditions (entries 5–9). Treatment of 4-iodoanisole
N-alkylamide L14 as the ligand (entry 15). However, the
two other amide ligands L15 and L16, whether N-disub-
stituted or unsubstituted, both display less active for the
reaction based on the yield (entries 16 and 17). In addi-
tion, the screening results showed that the better palladi-
um/L7 ratio is 1:2 in view of yield and the reaction cost
(
entries 8, 18, and 19). Subsequently, a series of bases and
solvents were evaluated. The results showed that cesium
carbonate combined with N,N-dimethylformamide af-
forded the best results (entries 20–26), and the catalytic
efficiency was decreased to some extent by adding water
(
1b) (0.5 mmol) with phenylboronic acid (2a) (0.6 mmol),
palladium(II) acetate (1 mol%), and L7 (2 mol%) for one
hour afforded the target product 3 in quantitative yield
(
entry 4). However, only 43% yield of 3 was observed af-
(
entries 8 and 26). Finally, the catalytic activity of the pal-
ter 12 hours at a loading of 0.1 mol% palladium (entry 5),
fortunately 3 could also be obtained in quantitative yield
under these conditions when the reaction was performed
at 80 °C (entry 6). Noteworthy is that the successfully re-
action of 1b with 2a for 12 hours to give 3 in good yield
in the presence of 0.0001 mol% of palladium and 0.0002
mol% of L7 (TON = 900,000, TOF = 75,000; entry 7).
The other two iodides 1c and 1d could also smoothly un-
dergo coupling with 2a at a loading of 0.0001 mol% pal-
ladium in satisfactory yields (entries 8 and 9).
ladium(II) acetate/L7 system was further examined (en-
tries 27–29). In the presence of 0.1 mol% of palladium(II)
acetate and 0.2 mol% of L7, substrate 1a (0.5 mmol) was
reacted with boronic acid 2a (0.6 mmol) in N,N-dimethyl-
formamide at room temperature for 12 hours to give the
corresponding product 3 in 35% yield (TON = 350; entry
2
7), whereas the yield of 3 was enhanced to 98% at 80 °C
(
TON = 980; entry 28). However, further decreasing the
Table 2 Palladium(II) Acetate/L7 Catalyzed Suzuki–Miyaura Cross-Couplings of Aryl Halides 1 with Arylboronic Acids 2a
Pd(OAc)2, L7
1
2
Ar1 Ar2
Ar X
+
Ar B(OH)2
Cs2CO3, DMF
1
2
b
Entry
1
Ar X
Ar B(OH)
Time (h)
3
Product
Yield (%)
2
MeO
Br
MeO
2b
F
B(OH)2
4
95
98
1
a
2
3
4
1a
B(OH)2
3
3
1
5
6
3
2
c
B(OH)2
B(OH)2
1a
70
Me
2
d
MeO
I
100
1
b
2a
2a
2a
2a
5c
6c,d
7d,e
1b
1b
1b
12
12
12
3
3
3
43
98
90
I
8d,e
2a
2a
12
12
7
8
78
95
Me
1
c
9d,e
O2N
I
1
d
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PAPER
b-Oxo Amides as Ligands in the Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reaction
2961
a
Table 2 Palladium(II) Acetate/L7 Catalyzed Suzuki–Miyaura Cross-Couplings of Aryl Halides 1 with Arylboronic Acids 2 (continued)
Pd(OAc)2, L7
1
2
Ar1 Ar2
Ar X
+
Ar B(OH)2
Cs2CO3, DMF
1
2
b
Entry
Ar X
Ar B(OH)
Time (h)
4
Product
Yield (%)
2
1
1
1
0
2
O N
Br
2a
8
99
99
93
1
e
1d,f
1e
2a
2a
12
4
8
9
O
2
Br
1
1
f
1
1
3
4
Br
2a
2a
1
1
10
11
100
98
g
Me
Br
1
h
Br
1
1
5d
2a
2a
12
1
7
71
83
Me
1
Me
i
Br
6
12
Me
1
j
1
1
7
8
2a
2a
3
13
14
80
33
Br
Br
1
k
Br
16
N
1
1l
1l
l
1
2
9d
0c,d
2a
2a
16
20
14
14
85
80
N
1d
2d
Br
2a
6
15
100
2
N
1
1
m
2
2a
3
16
89
Br
S
n
N
2
2
3d,g
2a
2a
3
17
11
72
21
Br
Br
1
o
4d
Me
Cl
16
1
1p
p
2
2
5d,h
6d,h
2a
2a
16
16
11
10
57
65
Cl
1
q
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Ji.-H. Li et al.
PAPER
a
Table 2 Palladium(II) Acetate/L7 Catalyzed Suzuki–Miyaura Cross-Couplings of Aryl Halides 1 with Arylboronic Acids 2 (continued)
Pd(OAc)2, L7
1
2
Ar1 Ar2
Ar X
+
Ar B(OH)2
Cs2CO3, DMF
1
2
b
Entry
Ar X
Ar B(OH)
Time (h)
16
Product
Yield (%)
2
2
7d,h
MeO
Cl
2a
3
46
1
r
N
8d,h
Cl
2a
16
15
85
2
N
1
s
a
b
c
d
e
f
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc) (1 mol%), L7 (2 mol%), Cs CO (1 mmol), DMF (1 mL), r.t.
Isolated yield.
2
2
3
Pd(OAc) (0.1 mol%) and L7 (0.2 mol%).
2
At 80 °C.
Pd(OAc) (0.0001 mol%) and L7 (0.0002 mol%).
2
Pd(OAc) (0.01 mol%) and L7 (0.02 mol%).
2
g
h
2
(1.2 mmol).
Pd(OAc) (3 mol%), L7 (6 mol%) and TBAB (20 mol%).
2
Encouraged by these results, a variety of aryl bromides A working mechanism was proposed as outlined in
and heteroaryl bromides were employed as the substrates Scheme 2 on the basis of the previously proposed mecha-
1
for the palladium(II) acetate/L7 catalyzed Suzuki– nism. To elucidate the present results, a Pd(0)L interme-
4
Miyaura coupling reaction (entries 10–23). It was ob- diate A was proposed.1 The screening results of the
served that the palladium(II) acetate/L7 system is still ef- ligands indicated that b-oxo amides were more efficient
ficient for the reaction of aryl bromides, which underwent that b-oxo esters, 1,3-diketone, and b-oxo nitrile, which
coupling with 2a smoothly in good to excellent yield at 1 suggested that the coordination of nitrogen atom with pal-
mol% to 0.01 mol% loadings of palladium (entries 10– ladium occurred. On the other hand, a control reaction dis-
,17
1
7). However, the catalytic activity of the palladium(II) closed that palladium(II) acetylacetonate provided a 28%
acetate /L7 system decreased to some extent for the cou- yield of the desired product 3 after three hours
plings of heteroaryl bromides, and higher reaction temper- (Scheme 3), whereas palladium(II) acetate combined with
atures were required (entries 18–23). The reaction of 2- acetylacetonate (L3) gave only 6% yield of 3 (Table 1, en-
bromopyridine (1l) with 2a, for example, afforded a low try 4). These results demonstrated that the coordination of
yield of the target product 14 at room temperature, where- the oxygen atom with palladium to form the enolate plays
as the yield of 14 increased sharply to 85% at 80 °C (en- an important role in the reaction. The results in Table 1
tries 18 and 19). The results also showed that the reaction further support this (Table 1, entries 7–15). Satisfactory
of substrate 1l with 2a could be conducted smoothly in results were obtained using b-oxo amides L6–L10 and
good yield under 0.1 mol% of palladium (TON = 800; en- L14 ligand, whereas the yield was reduced sharply using
try 20). It is worth noting that substrates 1k and 1o can b-oxo amides L11 and L12 having a substituent at the 2-
performed the Suzuki–Miyaura coupling reaction with
boronic acid 2a to synthesize the corresponding polyaryls
O
O
1
3 and 17 in good yields (entries 17 and 23).
R
1
R X
2L
N
L
X
To our delight, aryl chlorides, including deactivated chlo-
rides, were also suitable substrates under the palladium(II)
acetate/L7 catalyzed Suzuki–Miyaura coupling condi-
tions in the presence of tetrabutylammonium bromide.16
Although the reaction of 4-chlorotoluene (1p) with 2a, 1
mol% of palladium(II) acetate and 2 mol% of L7 provided
a low yield of 11 even at 80 °C (entry 24), substrate 1p
could work well with 2a to provide a moderate yield of 11
when 3 mol% of palladium and 20 mol% of tetrabutylam-
monium bromide were added (entry 25). Moderate to
good yields were still achieved from the couplings of the
other aryl chlorides 1q,r and heteroaryl chloride 1s with
H
Pd(OAc)2
Pd(0)L4
A
Pd
R1
L
B
2
R B(OH)2
R1 R2
2
+
base
2L
L
R2
Pd
R1
baseX, B
O
L
HO
NH
NH
C
R
Pd(0)L4 =
Pd
R
OH
2
a under the same conditions (entries 26–28).
O
Scheme 2 A possible mechanism
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b-Oxo Amides as Ligands in the Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reaction
2963
Pd (1 mol%)
MeO
a (0.5 mmol)
Br
+
B(OH)2
2a (0.6 mmol)
MeO
Cs2CO3 (1 mmol)
DMF, r.t., 3 h
1
3
(28%)
Pd = Pd(MeCOCH2COMe)2 (from Acros)
Scheme 3 A control reaction
position. Furthermore, no reaction was observed using of aryl halides including aryl chlorides and heteroaryl ha-
ligand L13, which does not have an enol form (Table 1, lides were smoothly coupled with arylboronic acids in
entry 14). Thus, we deduced that the Pd(0)L intermediate moderate to excellent yields. Based on the results, several
4
1
may be presented as intermediate A. The H NMR data of features were established: (1) The reaction was carried out
palladium(II) acetate/L7 (1:2) in situ also support the gen- under mild conditions. Many coupling reactions proceed-
eration of intermediate A (Figure 1).
ed at room temperature. (2) The palladium(II) acetate/L7
system is highly efficient (the maximal turnover numbers
are <950,000 and turnover frequencies are <79,167). The
coupling of aryl iodides could be conducted smoothly at a
loading of 0.001 mol% palladium, and the reaction of aryl
bromides were also worked well in the presence of 1
mol% to 0.01 mol% of palladium. (3) The reaction is gen-
eral because its scope was extended to deactivated aryl
chlorides and heteroaryl halides. Further efforts to extend
the application of these ligands in other cross-coupling re-
actions and organic synthesis are underway in our labora-
tory.
In summary, an inexpensive and efficient ligand for the
palladium-catalyzed Suzuki–Miyaura coupling reaction
of aryl halides with arylboronic acids has been developed.
In the presence of palladium(II) acetate and L7, a variety
NMR spectroscopy was performed on an Inova-400 (Varian), an
Inova-500 (Varian) or a Bruck-300 (Bruck) spectrometer operating
1
13
1
at 400 MHz ( H NMR) and 100 MHz ( C NMR), 500 MHz ( H
1
3
1
NMR) and 125 MHz ( C NMR) or 300 MHz ( H NMR) and 75
MHz ( C NMR) with CDCl as the solvent and TMS as internal
1
3
3
standard. MS analysis was performed on GC-MS analysis (Shimad-
zu GCMS-QP2010).
Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reac-
tions; General Procedure
A mixture of aryl halide 1 (0.5 mmol), arylboronic acid 2 (0.6
mmol), Pd(OAc) (the indicated amount in Table 1 and Table 2), L7
2
(
the indicated amount in Table 1 and Table 2), Cs CO (1 mol), and
2 3
DMF (1 mL) was stirred at r.t. or 80 °C for the indicated time until
complete consumption of starting material as monitored by TLC.
After the mixture was filtered and evaporated, the residue was then
purified by flash column chromatography (hexane or hexane–
EtOAc) to afford the corresponding coupled product.
4
-Methoxybiphenyl (3)2a
1
H NMR (400 MHz, CDCl ): d = 7.57–7.53 (m, 4 H), 7.42 (t, J = 7.6
Hz, 2 H), 7.33 (t, J = 7.25, 1 H), 6.98 (d, J = 8.8, 2 H), 3.86 (s, 3 H).
3
1
3
C NMR (100 MHz, CDCl ): d = 159.1, 140.8, 133.7, 128.7, 128.1,
3
1
26.7, 126.6, 114.2, 55.3.
+
LRMS (EI, 70 eV): m/z (%) = 184 (M , 100).
4
,4¢-Dimethoxybiphenyl (4)17
1
H NMR (300 MHz, CDCl ): d = 7.48 (d, J = 8.4 Hz, 4 H), 6.95 (d,
J = 8.87 Hz, 4 H), 3.84 (s, 6 H).
3
1
3
C NMR (100 MHz, CDCl ): d = 158.7, 133.5, 127.7, 114.1, 59.3.
3
+
LRMS (EI, 70 eV): m/z (%) = 214 (M , 100).
4
-Fluoro-4¢-methoxybiphenyl (5)2d
1
H NMR (300 MHz, CDCl ): d = 7.50–7.45 (m, 4 H), 7.09 (t, J = 8.4
Hz, 2 H), 6.96 (d, J = 8.7 Hz, 2 H), 3.83 (s, 3 H).
3
Figure 1 1H NMR of palladium(II) acetate/L7 (1:2) in situ
Synthesis 2007, No. 19, 2957–2966 © Thieme Stuttgart · New York

2
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Ji.-H. Li et al.
PAPER
1
3
13
C NMR (100 MHz, CDCl ): d = 163.7, 160.4, 159.0, 132.7, 128.2
C NMR (125 MHz, CDCl ): d = 140.8, 140.2, 128.8, 127.5, 127.3,
3
3
(
d, J = 9.3 Hz, 1 C), 128.0, 115.5 (d, J = 28.2 Hz, 1 C), 114.2, 55.3.
127.0.
+
+
LRMS (EI, 70 eV): m/z (%) = 202 (M , 100).
LRMS (EI, 70 eV): m/z (%) = 230 (M , 100).
18
4
¢-Methoxy-2-methylbiphenyl (6)2d
2-Phenylpyridine (14)
1
1
H NMR (400 MHz, CDCl ): d = 7.26–7.22 (m, 6 H), 6.95 (d,
J = 8.4 Hz, 2 H), 3.85 (s, 3 H), 2.28 (s, 3 H).
H NMR (400 MHz, CDCl ): d = 8.59 (d, J = 4.8 Hz, 1 H), 7.99 (d,
J = 6.8 Hz, 2 H), 7.78–7.71 (m, 2 H), 7.48 (t, J = 8.8 Hz, 2 H), 7.42
(t, J = 7.2 Hz, 1 H), 7.26–7.21 (m, 1 H).
3
3
1
3
C NMR (100 MHz, CDCl ): d = 158.5, 141.5, 135.5, 134.3, 130.3,
3
1
3
1
30.2, 129.9, 127.0, 125.8, 113.5, 55.3, 20.6.
C NMR (100 MHz, CDCl ): d = 157.4, 149.6, 139.3, 136.7, 128.9,
128.7, 126.9, 122.1, 120.5.
3
+
LRMS (EI, 70 eV): m/z (%) = 198 (M , 100).
+
LRMS (EI, 70 eV): m/z (%) = 155 (M , 100).
2
-Methylbiphenyl (7)2d
1
19
H NMR (400 MHz, CDCl ): d = 7.40 (t, J = 7.2 Hz, 2 H), 7.32 (t,
J = 6.8 Hz, 3 H), 7.25–7.23 (m, 4 H), 2.27 (s, 3 H).
5-Phenylpyrimidine (15)
H NMR (400 MHz, CDCl ): d = 9.21 (s, 1 H), 8.97 (s, 2 H), 7.59
(d, J = 8.8 Hz, 2 H), 7.53 (t, J = 8.8 Hz, 2 H), 7.47 (t, J = 7.2 Hz, 1
3
1
3
1
3
C NMR (100 MHz, CDCl ): d = 141.9, 135.3, 130.3, 129.8, 129.2,
3
H).
1
28.0, 127.2, 126.7, 125.7, 125.6, 20.4.
13C NMR (100 MHz, CDCl
28.9, 126.7.
): d = 157.3, 154.8, 134.2, 134.1, 129.3,
+
3
LRMS (EI, 70 eV): m/z (%) = 168 (M , 100).
1
+
4
-Nitrobiphenyl (8)2c
LRMS (EI, 70 eV): m/z (%) = 156 (M , 100).
1
H NMR (400 MHz, CDCl ): d = 8.30 (d, J = 8.8 Hz, 2 H), 7.74 (d,
J = 8.8 Hz, 2 H), 7.64 (d, J = 6.9 Hz, 2 H), 7.52–7.44 (m, 3 H).
3
2
0
2-Phenylthiophene (16)
1
1
3
H NMR (400 MHz, CDCl
): d = 7.61–7.57 (m, 2 H), 7.35 (t, J = 7.6
3
Hz, 2 H), 7.29–7.23 (m, 3 H), 7.05 (t, J = 4.0 Hz, 1 H).
C NMR (100 MHz, CDCl ): d = 147.6, 147.1, 138.8, 129.2,
28.91, 127.8, 127.4, 124.1.
3
1
13C NMR (100 MHz, CDCl
25.9, 124.7, 123.0.
): d = 144.4, 134.3, 128.8, 127.9, 127.4,
+
3
LRMS (EI, 70 eV): m/z (%) = 199 (M , 100).
1
+
1
-Biphenyl-4-ylethanone (9)2c
LRMS (EI, 70 eV): m/z (%) = 160 (M , 100).
1
H NMR (400 MHz, CDCl ): d = 8.04 (d, J = 8.4 Hz, 2 H), 7.69 (d,
J = 8.4 Hz, 2 H), 7.64 (d, J = 7.6 Hz, 2 H), 7.48 (t, J = 7.2 Hz, 2 H),
7
3
2
1
3,5-Diphenylpyridine (17)
1
.41 (t, J = 7.2 Hz, 1 H), 2.65 (s, 3 H).
H NMR (400 MHz, CDCl ): d = 8.83 (s, 2 H), 8.10 (s, 1 H), 7.66
(d, J = 8.4 Hz, 4 H), 7.52 (t, J = 8.0 Hz, 4 H), 7.45 (t, J = 7.2 Hz, 2
3
1
3
C NMR (75 MHz, CDCl ): d = 198.1, 146.1, 140.2, 136.2, 130.1,
3
H).
1
29.2, 128.6, 127.6, 118.5, 27.0.
13C NMR (100 MHz, CDCl
28.3, 127.3.
): d = 147.0, 137.8, 136.7, 133.0, 129.2,
+
3
LRMS (EI, 70 eV): m/z (%) = 196 (M , 100).
1
Biphenyl (10)2
c
LRMS (EI, 70 eV): m/z (%) = 231 (M , 100.
+
1
H NMR (400 MHz, CDCl ): d = 7.60 (d, J = 8.4 Hz, 4 H), 7.45 (t,
J = 7.4 Hz, 4 H), 7.35 (t, J = 7.8 Hz, 2 H).
3
Acknowledgment
1
3
C NMR (75 MHz, CDCl ): d = 141.6, 129.1, 127.6, 127.5.
3
+
The authors thank the Key Project of Chinese Ministry of Education
LRMS (EI, 70 eV): m/z (%) = 154 (M , 100).
(No. 206102), Fok Ying Tung Education Foundation (No. 101012),
-Methylbiphenyl (11)2a
H NMR (400 MHz, CDCl ): d = 7.59 (t, J = 7.6 Hz, 2 H), 7.49 (d,
J = 8.0 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.6 Hz, 1 H),
the National Natural Science Foundation of China (No. 20572020),
Program for New Century Excellent Talents in University (No.
NCET-06-0711) and Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20060542007) for financial sup-
port.
4
1
3
7
1
.24 (d, J = 8.0 Hz, 2 H), 2.40 (s, 3 H).
3
C NMR (100 MHz, CDCl ): d = 141.1, 138.3, 137.0, 129.5, 128.7,
3
1
27.3, 127.2, 127.0, 21.1.
+
References
LRMS (EI, 70 eV): m/z (%) = 168 (M , 100).
(
1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev.
3
,5-Dimethylbiphenyl (12)2a
1
995, 95, 2457. (b) Metal-Catalyzed Cross-Coupling
1
H NMR (400 MHz, CDCl ): d = 7.59 (d, J = 8.4 Hz, 2 H), 7.44 (t,
J = 8.0 Hz, 2 H), 7.34 (d, J = 7.2 Hz, 1 H), 7.23 (s, 2 H), 7.02 (s, 1
H) 2.40 (s, 6 H).
3
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998. (c) Cross-Coupling Reactions, In Topics
in Current Chemistry, Vol. 219; Miyaura, N., Ed.; Springer:
Berlin, 2002. (d) Herrmann, W. A. Angew. Chem. Int. Ed.
2002, 41, 1290. (e) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.;
Lee, H. M.; Yang, C.; Nolan, S. P. J. Organomet. Chem.
1
3
C NMR (100 MHz, CDCl ): d = 141.5, 138.1, 128.9, 128.7, 127.9,
3
1
27.2, 127.1, 125.1, 21.4.
+
LRMS (EI, 70 eV): m/z (%) = 182 (M , 100).
2002, 653, 69. (f) Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004. (g) Bellina, F.; Carpita, A.;
Rossi, R. Synthesis 2004, 2419. (h) Baudoin, O. Eur. J. Org.
Chem. 2005, 4223. (i) Phan, N. T. S.; Van Der Sluys, M.;
Jones, C. W. Adv. Synth. Catal. 2006, 348, 609.
1
,4-Diphenylbenzene (13)12c
1
H NMR (500 MHz, CDCl ): d = 7.72–7.68 (m, 8 H), 7.50 (t, J = 7.2
Hz, 4 H), 7.40 (t, J = 7.2 Hz, 2 H).
3
Synthesis 2007, No. 19, 2957–2966 © Thieme Stuttgart · New York

PAPER
(
b-Oxo Amides as Ligands in the Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reaction
2965
2) For selected representative papers on palladium/phosphine-
Huang, J.; Zhang, C.; Trudell, M. L.; Nolan, S. P.
catalyzed Suzuki–Miyaura cross-couplings, see: (a) Old, D.
W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
Organometallics 2002, 21, 2866. (g) Xiao, J.-C.; Shreeve, J.
M. J. Org. Chem. 2005, 70, 3072. (h) Hahn, F. E.; Jahnke,
M. C.; Pape, T. Organometallics 2007, 26, 150.
120, 9722. (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem.
Int. Ed. 1999, 38, 2413. (c) Wolfe, J. P.; Singer, R. A.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
Pyrimidines: (i) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Synlett
2005, 1897.
9550. (d) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
(8) For a representative paper on palladium/diazabutadiene-
catalyzed Suzuki–Miyaura cross-couplings, see: Grasa, G.
A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001, 3, 1077.
(9) For representative papers on palladium/urea-catalyzed
Suzuki–Miyaura cross-couplings, see: (a) Dai, M. J.; Liang,
B.; Wang, C. H.; You, Z. J.; Xiang, J.; Dong, G. B.; Chen, J.
H.; Yang, Z. Adv. Synth. Catal. 2004, 346, 1669. (b) Chen,
W.; Li, R.; Han, B.; Li, B.; Chen, Y.; Wu, Y.; Ding, L.;
Yang, D. Eur. J. Org. Chem. 2006, 1177. (c) Cui, X.; Zhou,
Y.; Wang, N.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2007,
48, 163.
(10) For representative papers on palladium/guanidine-catalyzed
Suzuki–Miyaura cross-couplings, see: Li, S.; Lin, Y.; Cao,
J.; Zhang, S. J. Org. Chem. 2007, 72, 4067.
(11) For representative papers on palladium/hydrazone-catalyzed
Suzuki–Miyaura cross-couplings, see: (a) Mino, T.; Shirae,
Y.; Sakamoto, M.; Fujita, T. Synlett 2003, 882. (b) Mino,
T.; Shirae, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2005,
70, 2191.
2
000, 122, 4020. (e) Netherton, M. R.; Dai, C.; Neuschütz,
K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. (f) Liu,
S.-Y.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 2408.
(g) Revell, J. D.; Ganesan, A. Org. Lett. 2002, 4, 3071.
(
h) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 13662. (i) Tang, Z.-Y.; Lu,
Y.; Hu, Q.-S. Org. Lett. 2003, 5, 297. (j) Hu, Q.-S.; Lu, Y.;
Tang, Z.-Y.; Yu, H.-B. J. Am. Chem. Soc. 2003, 125, 2856.
(
k) Adjabeng, G.; Brenstrum, T.; Wilson, J.; Frampton, C.;
Robertson, A.; Hillhouse, J.; McNulty, J.; Capretta, A. Org.
Lett. 2003, 5, 953. (l) Jensen, J. F.; Johannsen, M. Org. Lett.
2
003, 5, 3025. (m) Walker, S. D.; Barder, T. E.; Martinelli,
J. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43,
871. (n) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
o) Guo, M.; Jian, F.; He, R. Tetrahedron Lett. 2006, 47,
033.
1
(
2
(
3) For representative papers on palladium/carbene-catalyzed
Suzuki–Miyaura cross-couplings, see: (a) Gstottmayr, C.
W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M.;
Herrmann, W. Angew. Chem. Int. Ed. 2002, 41, 1363.
(12) For representative papers on palladium/surfactant-catalyzed
Suzuki–Miyaura cross-couplings, see: (a) Bhattacharya, S.;
Srivastava, A.; Sengupta, S. Tetrahedron Lett. 2005, 46,
3557. (b) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005,
70, 6122. (c) Xin, B.; Zhang, Y.; Cheng, K. J. Org. Chem.
2006, 71, 5725.
(
b) Navarro, O.; Kelly, R. A. III; Nolan, S. P. J. Am. Chem.
Soc. 2003, 125, 16194. (c) Navarro, O.; Marion, N.;
Oonishi, Y.; Kelly, R. A. III; Nolan, S. P. J. Org. Chem.
2
006, 71, 685; and references cited therein. (d) Marion, N.;
(13) For selected representative papers on palladium/the other
ligand-catalyzed Suzuki–Miyaura cross-couplings, see:
(a) Chen, M.-T.; Huang, C.-A.; Chen, C.-T. Eur. J. Inorg.
Chem. 2006, 4642. (b) Gupta, A. K.; Song, C. H.; Oh, C. H.
Tetrahedron Lett. 2004, 45, 4113. (c) Liu, Q.-P.; Chen, Y.-
C.; Wu, Y.; Zhu, J.; Deng, J.-G. Synlett 2006, 1503.
(d) Alonso, D. A.; Botella, L.; Najéra, C.; Pacheco, M. C.
Synthesis 2004, 1713. (e) Alonso, D. A.; Najéra Carmen;
Pacheco, M. C. J. Org. Chem. 2002, 67, 5588.
Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S.
P. J. Am. Chem. Soc. 2006, 128, 4101.
(
4) For representative papers on palladium/oxazoline-catalyzed
Suzuki–Miyaura cross-couplings, see: (a) Tao, B.; Boykin,
D. W. Tetrahedron Lett. 2002, 43, 4955. (b) Gossage, P. A.;
Jenkins, H. A.; Yadav, P. N. Tetrahedron Lett. 2004, 45,
7689. (c) Wang, L. Chin. J. Chem. 2006, 24, 770.
(
d) Alcalde, E.; Dinares, I.; Mesquida, N.; Rodriguez, S.
Synthesis 2007, 865. (e) Takemoto, T.; Iwasa, S.; Hamada,
H.; Shibatomi, K.; Kameyama, M.; Motoyama, Y.;
Nishiyama, H. Tetrahedron Lett. 2007, 48, 3397.
(14) For selected representative papers on ligand-free palladium-
catalyzed Suzuki–Miyaura cross-couplings see: (a) Deng,
Y.; Gong, L.; Mi, A.; Liu, H.; Jiang, Y. Synthesis 2003, 337.
(b) Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Tetrahedron
Lett. 2004, 45, 6959. (c) Kantam, M. L.; Roy, S.; Roy, M.;
Sreedhar, B.; Choudary, B. M. Adv. Synth. Catal. 2005, 347,
2002. (d) Liu, W.-J.; Xie, Y.-X.; Liang, Y.; Li, J.-H.
Synthesis 2006, 860. (e) Deng, C.-L.; Guo, S.-M.; Xie, Y.-
X.; Li, J.-H. Eur. J. Org. Chem. 2007, 1457; and references
cited therein.
(
5) For representative papers on palladium/amine-catalyzed
Suzuki–Miyaura cross-couplings, see: (a) Tao, B.; Boykin,
D. W. Tetrahedron Lett. 2003, 44, 7993. (b) Tao, B.;
Boykin, D. W. J. Org. Chem. 2004, 69, 4330. (c) Li, J.-H.;
Liu, W.-J. Org. Lett. 2004, 6, 2809. (d) Li, J.-H.; Liu, W.-J.;
Xie, Y.-X. J. Org. Chem. 2005, 70, 5409. (e) Li, J.-H.; Hu,
X.-C.; Liang, Y.; Xie, Y.-X. Tetrahedron 2006, 62, 31.
(
1
f) Li, J.-H.; Zhu, Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62,
0888. (g) Xie, Y.-X.; Li, J.-H.; Yin, D.-L. Chin. J. Org.
(15) (a) Buck, E.; Song, Z. J.; Tschan, D.; Dormer, P. G.;
Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.
(b) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742. (c) Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9,
643. (d) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 3490. (e) Lv, X.; Bao, W. J. Org.
Chem. 2007, 72, 3863.
Chem. 2006, 26, 1155.
(
(
6) For representative papers on palladium/amino acid-
catalyzed Suzuki–Miyaura cross-couplings, see: Cui, X.;
Tian, Q.; Wang, J.-R.; Liu, L.; Guo, Q.-X. Synthesis 2007,
3
93.
7) For representative papers on palladium/heterocycle-
catalyzed Suzuki–Miyaura cross-couplings, see:
(16) According to the previous and present results, three roles of
TBAB may play in the reaction: (i) activation of the active
Pd(0) species with the formation of anionic species, (ii)
stabilization of the low coordinate Pd(0) species, (iii) phase-
transfer catalyst for the inorganic base/solvent/substrate/
product phases. For representative papers on TBAB-
improved Suzuki reactions, see: (a) Badone, D.; Baroni, M.;
Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org. Chem. 1997,
62, 7170. (b) Bedford, R. B.; Blake, M. E.; Butts, C. P.;
(
a) Mathews, C. J.; Smith, P. J.; Welton, T. J. Mol. Catal. A:
Chem. 2004, 214, 27. Pyridines: (b) Wu, W.-Y.; Chen, S.-
N.; Tsai, F.-Y. Tetrahedron Lett. 2006, 47, 9267. (c) Mai,
W.; Gao, L. Synlett 2006, 2553. (d) Jimenez-Sanchidrian,
C.; Mora, M.; Ruiz, J. R. Catal. Commun. 2006, 7, 1025.
Pyrazoles: (e) Mukherjee, A.; Sarkar, A. Tetrahedron Lett.
2005, 46, 15. Imidazoles: (f) Grasa, G. A.; Viciu, M. S.;
Synthesis 2007, No. 19, 2957–2966 © Thieme Stuttgart · New York

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PAPER
(18) Venkatraman, S.; Li, C.-J. Org. Lett. 1999, 1, 1133.
(19) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(20) Wynberg, H.; van Driel, H. J. Am. Chem. Soc. 1965, 87,
3998.
Holder, D. Chem. Commun. 2003, 466. (c) Lysén, M.;
Köhler, K. Synlett 2005, 1671; and references cited therein.
(
2
d) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7,
101. (e) Liu, W.-J.; Xie, Y.-X.; Liang, Y.; Li, J.-H.
Synthesis 2006, 860.
17) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am.
Chem. Soc. 1985, 107, 972.
(21) Komatsu, M.; Ohgishi, H.; Ohshiro, Y.; Agawa, T.
Tetrahedron Lett. 1976, 17, 4589.
(
Synthesis 2007, No. 19, 2957–2966 © Thieme Stuttgart · New York