Palladium-catalyzed highly regioselective 2-arylation of 2,x-dibromopyridines and its application in the efficient synthesis of a 17β-HSD1 inhibitor

Article abstract of DOI:10.1016/j.tet.2013.10.065

2,3- and 2,5-Dibromopyridines reacted with arylboronic acids, catalyzed by Pd(OAc)₂/PPh₃ in the presence of K₂CO ₃ in CH₃CN/MeOH (2:1) at 50 C for 24 h, to afford 2-arylpyridines in good to high yield

Full text of DOI:10.1016/j.tet.2013.10.065

Tetrahedron 69 (2013) 10996e11003
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed highly regioselective 2-arylation of
2,x-dibromopyridines and its application in the efficient
synthesis of a 17
b-HSD1 inhibitor
,
b
,
a
a
c
a,
*
Qizhong Zhou a , Bin Zhang , Liangjun Su , Tiansheng Jiang , Rener Chen
,
*
Tieqi Du a, Yuyuan Ye a, Jianfen Shen a, Guoliang Dai a, Deman Han a, Huajiang Jiang a
,
*
a Department of Chemistry, Taizhou University, Taizhou 318000, China
b Department of Chemistry, Fudan University, Shanghai 200433, China
c College of Natural Sciences and Mathematics, University of Houston, Houston, TX 77204-5008, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 August 2013
Received in revised form 30 September 2013
Accepted 14 October 2013
Available online 26 October 2013
2,3- and 2,5-Dibromopyridines reacted with arylboronic acids, catalyzed by Pd(OAc)2/PPh3 in the pres-
ence of K2CO3 in CH3CN/MeOH (2:1) at 50 ꢀC for 24 h, to afford 2-arylpyridines in good to high yields,
while 2,4-dibromopyridine reacted with arylboronic acid pinacol esters, catalyzed by Pd(OAc)2/PPh3 in
the presence of KOH in CH3CN at 70 ꢀC for 24 h, to afford 2-arylpyridines in good to high yields. To
expand this methodology, a 17
b
-HSD1 inhibitor was synthesized in good yield.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Pyridines are significant components of many drugs and natural
products.1e3 2-Arylpyridines are widely used as substrates for CeH
activation.4 Substituted 2-arylpyridines are found in a wide range of
fluorescent probes,5 organic conjugated materials,6 metal com-
plexing ligands,7 pharmaceuticals,8 and natural products.9 (Fig. 1).
Substituted 2-arylpyridines can be prepared by selective Suzuki
coupling from 2,x-dihalopyridines, such as 2,5-,10 2,4-,11 or 2,3-
dibromopyridines,12 and arylboronic acids followed by other re-
actions, but the yields are usually low and high temperature may be
required.12b Previously, we have reported the copper-catalyzed
highly regioselective 2-aryloxylation of 2,x-dihalopyridines.13
fluorescent probe
Herein, we describe
a highly regioselective and efficient
palladium-catalyzed arylation of 2,x-dibromopyridines and its ap-
plication in the efficient synthesis of a 17b-HSD1 inhibitor.
2. Results and discussion
First,
a set of experiments was performed using 2,5-
dibromopyridine and phenylboronic acid as model substrates in
the presence of different ligands or bases in different temperatures
to explore the optimized reaction conditions (Table 1). In MeOH
with PPh3 as ligand and K2CO3 as base, the reaction afforded 3a, A,
and B in 73%, 4%, and 23% isolated yields, respectively (entry 3),
Fig. 1. The substituted 2-pyridyl motif is found in many important small molecules.
while in MeCN a better selectivity was achieved (entry 4). En-
couraged by these results, the reaction was investigated in a mix-
ture of acetonitrile and alcohol. In MeCN/EtOH (2:1) at 50 ꢀC, the
three products were obtained in 93%, 2%, and 0% yields, respectively
(entry 19), and in MeCN/MeOH (2:1), the yield of 3a could be fur-
ther improved to 97% (entry 22). We thus established the optimized
* Corresponding authors. Tel.: þ86 576 88660177; e-mail addresses: qizhong-
chou@yahoo.com (Q. Zhou), cre@tzc.edu.cn (R. Chen), jhj@tzc.edu.cn (H. Jiang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.065

Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
10997
(89%) and the best regioselectivity at 70 ꢀC. The yields for the side
products C and D were as low as 6% and 2%, respectively (entry 14).
After the optimized reaction condition was established, the re-
actions of 2,4-dibromopyridine with other phenylboronic acid
pinacol esters were investigated and the results are shown in
Table 4. Again, the pinacol esters bearing electron-donating groups
afforded good to high yields (81e95%, entries 1e8), while the nitro-
substituted substrate only gave the coupling product in 31% yield
(entry 9) and 2-cyano-5-pyridylboronic acid pinacol ester did not
give rise to the required product.
Why the regioselectivity is so high for the arylation of 2,3-, 2,5-,
and 2,4-dibromopyridines? We can explain that the 2-bromo of
2,x-dibromopyridines is more reactive than the 4-bromo, 5-bromo,
and 3-bromo of 2,x-dibromopyridines.11a,13,15
The high regioselectivity of the new method made it possible to
conveniently conduct the step-by-step coupling reactions for 2,x-
dibromopyridines. To demonstrate this, we studied the Suzuki,
Sonogashira, Ullmann, and Ullmann-typed coupling reactions of
3w with different substrates (Scheme 1), which all afforded the
coupling products 6e9 in excellent yields.
Table 1
Palladium-catalyzed 2-arylation of 2,5-dibromopyridine with phenylboronic acid:
parametric studya,b
Entry
Ligand
Base
Solvent
T (ꢀC)
Yield (%)
(3a/A/B)
1c
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
ClCH2CH2Cl
THF
MeOH
CH3CN
Toluene
DME
Dioxane
DMAc
DMSO
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN/EtOH (1:1)
CH3CN/EtOH (2:1)
CH3CN/EtOHd
CH3CN/EtOHd
CH3CN/MeOHd
CH3CN/MeOHd
CH3CN/n-BuOHd
CH3CN/i-BuOHd
CH3CN/MeOHd
CH3CN/MeOHd
CH3CN/MeOHd
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
110
110
110
30
30
30
30
30
30
30
40
50
50
50
50
50
50
50
50
50
30:12:10
38:7:36
73:4:23
41:8:0
43:8:5
50:10:24
0:0:0
2c
3c
4c
5c
6c
7c
8c
40:9:18
26:7:8
9c
10c
11
12
13
14
15
16
17
18
19
20e
21
22f
23
24
25
26
27
41:13:12
54:22:12
67:8:18
15:5:50
24:13:10
53:9:3
0:0:0
75:8:3
80:0:0
93:2:0
PPh3
Sphos
Xphos
BINAP
Xantphos
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
The method can also be expanded to prepare compound 11,
a 17b-HSD1 inhibitor (Scheme 2). 2,4-Dibromopyridine reacted
with 2-chlorothiophene pinacoboronate under the standard con-
dition to give compound 10 in 82% yield and its coupling with 3-
hydroxyphenylboronic acid produced 11 in 90% yield. The total
yield (74%) is substantially higher than the route previously re-
ported (12%).8b
85:3:0
91:1:7
97:2:0
85:2:9
65:3:1
73:13:12
86:12:0
90:5:5
3. Conclusion
K3PO4
Cs2CO3
PPh3
In summary, we have described a highly regioselective approach
to bromo-2-arylpyridines, which involves palladium-catalyzed di-
rect 2-arylation of 2,5-, 2,3-, and 2,4-dibromopyridines in high
yields. The practicality of the new method has been demonstrated
by using it to synthesize a 17b-HSD1 inhibitor. Step-by-step cou-
pling reaction of other dihalopyridines is being investigated and the
results will be reported in due course.
The bold signifies the best reaction condition.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc)2 (5 mol %), ligand
(10 mol %), base (1 mmol), 24 h.
b
Isolated yield.
c
Compounds 1 (0.6 mmol), 2 (0.5 mmol), Pd(OAc)2 (5 mol %), ligand (10 mol %),
base (1 mmol), 24 h.
d
CH3CN/alcohol (2:1).
Compounds 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc)2 (2.5 mol %), ligand (5 mol %),
e
base (1 mmol), 24 h.
f
Compounds 1 (0.5 mmol), 2 (0.55 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
4. Experimental section
4.1. General
K2CO3 (1 mmol), 24 h.
conditions for this reaction: Pd(OAc)2/PPh3 as the catalysis system,
K2CO3 as the base, CH3CN/MeOH (2:1) as the solvent and at 50 ꢀC.
With the optimized reaction condition available, the scope of the
reaction was then investigated (Table 2). It can be found that phe-
nylboronic acids bearing electron-rich groups generally afforded
products (3ae3e, 3ie3m, 3re3t) in good to high yields (80e97%). 4-
Fluorophenylboronic acid also gave rise to good to high yields
(82e90%, 3f and 3n). Even 4-methoxyphenylboronic acid reacted
with 2,6-dibromopyridine to give a good yield (73%, 3x). Further-
more, substituted 2,3-dichloropyridines also reacted with phenyl-
boronic acid to give good yields (82e88%, 3u,3v). In contrast,
electron-withdrawing CF3- or NO2-substituted phenylboronic acid
gave low yields (21e50%, 3g, 3o,3p) and 4-pyridylboronic acid did
not afford any products (entries 8 and 17). Clearly, the new meth-
odology has the advantages of higher regioselectivity, higher yields,
more generality, simpler and cheaper catalyst system.10,12
The reaction of 2,4-dibromopyridine and phenylboronic acid
only gave a 68% yield of the product (3w). To further improve the
yield of the reaction, phenylboronic acid pinacol ester was used as
the coupling partner (Table 3).14 After an extensive investigation of
the reaction conditions, we found that with KOH as base, the re-
action could produce the required product selectively in 16% yield
in MeCN at 30 ꢀC (entry 3). Further screening of the ligands revealed
that PPh3 is still a suitable ligand leading to the highest yield of 3w
Typical procedure for the 2-arylation of 2,5- and 2,3-
dibromopyridines: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phe-
nylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol),
Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in
CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 ꢀC under
nitrogen atmosphere for 24 h and then cooled and the solid was
filtered off. The filtrate was then concentrated and the resulting
crude product was dissolved in CH2Cl2 (10 mL). The solution was
washed with water (10 mLꢁ3) and brine (10 mL), and dried over
sodium sulfate. Upon removal of the solvent with a rotavapor, the
resulting residue was subjected to column chromatography (pe-
troleum ether/AcOEt, 400:1) to give the desired product 3a
(114 mg, 97%) as a white solid.
Typical procedure for the 2-arylation of 2,4-dibromopyridine:
2,4-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid
pinacol ester (0.11 g, 0.55 mmol), KOH (56 mg, 1.0 mmol), Pd(OAc)2
(11 mg, 5 mol %), PPh3 (52 mg, 20 mol %) were dissolved in CH3CN
(6 mL). The reaction was stirred at 70 ꢀC under nitrogen atmo-
sphere for 24 h and then cooled. The solid was filtrated off and
the filtrate was concentrated. The crude product was then dissolved
in CH2Cl2 (10 mL) and the solution was washed with water
(10 mLꢁ3) and brine (10 mL), and dried over sodium sulfate.
Upon evaporation, the resulting residue was subjected to column

10998
Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
Table 2
Scope of Pd-catalyzed 2-arylation of 2,x-dibromopyridinesa,b
Entry
1
2
Products
Yield (%)
1
2
3
1a
1a
1a
2a
2b
2c
97
91
91
3a
3b
3c
4
1a
2d
94
3d
5
6
7
8
9
1a
1a
1a
1a
1b
2e
2f
85
90
50
0
3e
3f
2g
2h
2a
3g
3h
95
3i
3j
10
11
1b
1b
2b
2c
83
94
3k
12
13
1b
1b
2d
2e
93
80
3l
3m

Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
10999
Table 2 (continued )
Entry
1
2
Products
Yield (%)
14
15
16
17
1b
2f
82
46
21
0
3n
3o
3p
1b
1b
1b
2g
2i
2h
3q
3r
3s
18
19
20
1c
1d
1e
2a
2a
2a
82
88
90
3t
21
22
23
1f
2a
2a
2a
86
96
68
3u
1g
1h
3v
3w
24
1i
2e
73
3x
a
Reaction condition: 1 (0.5 mmol), 2 (0.55 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (1 mmol) in CH3CN/CH3OH (2:1, 6 mL) at 50 ꢀC under N2 for 24 h.
Isolated yield.
b
chromatography (petroleum ether/AcOEt, 400:1) to give 3w
(104 mg, 89%) as a colorless liquid.
129.2, 129.0, 128.3, 127.2, 127.1, 120.6; MS (EI): 231.0 (Mþ); HRMS
(EI) calcd for C17H13N: 231.1048, found: 231.1053.
4.1.1. 5-Bromo-2-phenylpyridine (3a). Compound 3a: white solid,
mp 74e75 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.74 (d, J¼1.6 Hz, 1H),
7.95e7.97 (m, 2H), 7.87(dd,J1¼2.4 Hz, J2¼2.8Hz,1H), 7.62(d, J¼8.4 Hz,
1H), 7.43e7.49 (m, 3H); 13C NMR (CDCl3,100 MHz): 156.1,150.9,139.7,
138.3,129.7, 129.2, 127.1, 122.0,119.6; MS (ESI): 234.1 [MþH]þ; HRMS
(ESI) [MþH]þ calcd for C11H9BrN: 233.99129, found: 233.99171.
4.1.4. 5-Bromo-2-(4-methylphenyl)pyridine (3b). Compound 3b:
white solid, mp 109e110 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.70 (d,
J¼1.6 Hz, 1H), 7.90e7.86 (m, 3H), 7.57 (d, J¼8.4 Hz, 1H), 7.26 (d,
J¼8.0 Hz, 2H), 2.39 (s, 3H); 13C NMR (CDCl3, 100 MHz): 156.1, 150.8,
139.7, 139.4, 135.7, 129.8, 126.9, 121.5, 119.1, 21.5; MS (ESI): 248.0
[MþH]þ; HRMS (ESI) [MþH]þ calcd for C12H11BrN: 248.0069,
found: 248.0067.
4.1.2. 2-Bromo-5-phenylpyridine (A). Compound A: white solid, mp
76e77 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.57 (d, J¼2.4 Hz, 1H), 7.71
(dd, J1¼2.4 Hz, J2¼2.4 Hz, 1H), 7.39e7.54 (m, 6H); 13C NMR (CDCl3,
100 MHz): 148.7, 141.1, 137.2, 136.7, 136.2, 129.5, 128.7, 128.2, 127.2;
MS (EI): 233.0 (Mþ); HRMS (EI) calcd for C11H8BrN: 232.9840,
found: 232.9846.
4.1.5. 5-Bromo-2-(3-methylphenyl)pyridine (3c). Compound 3c:
white solid, mp 40e41 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.72 (d,
J¼2.4 Hz, 1H), 7.70e7.84 (m, 3H), 7.58 (dd, J1¼2.4 Hz, J2¼2.4 Hz, 1H),
7.34 (t, J¼7.6 Hz, 1H), 7.23 (d, J¼7.6 Hz, 1H), 2.42 (s, 3H); 13C NMR
(CDCl3, 100 MHz): 156.3, 150.7, 139.6, 138.4, 138.3, 130.4, 129.0,
127.7, 124.2, 122.0, 119.5, 21.8; MS (ESI): 248.1 [MþH]þ; HRMS (ESI)
[MþH]þ calcd for C12H11BrN: 248.0069, found: 248.0058.
4.1.3. 2,5-Diphenylpyridine (B). Compound B: white solid, mp
173e174 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.93 (d, J¼2.0 Hz, 1H), 8.04
(d, J¼7.2 Hz, 2H), 7.91 (dd, J1¼2.0 Hz, J2¼2.0 Hz, 1H), 7.77 (d,
J¼8.0 Hz, 1H), 7.61 (d, J¼7.2 Hz, 2H), 7.37e7.49 (m, 6H); 13C NMR
(CDCl3, 100 MHz): 156.4, 148.3, 139.2, 137.9, 135.3, 135.1, 129.3,
4.1.6. 5-Bromo-2-(2-methylphenyl)pyridine (3d). Compound 3d:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.75 (d, J¼2.4 Hz,1H), 7.85
(dd, J1¼2.8 Hz, J2¼2.4 Hz, 1H), 7.24e7.37 (m, 5H), 2.35 (s, 3H); 13C

11000
Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
Table 3
Table 4
Pd-catalyzed 2-arylation of 2,4-dibromopyridine: parametric studya,b
Scope of Pd-catalyzed 2-arylation of 2,4-dibromopyridinea,b
Entry
Catalyst
Ligand
T/ꢀC
Yield (%)
(3w/C/D)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(dba)3
Pd(OAc)2
Pd(dppe)2Cl2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
30
30
30
30
14:0:0
25:4:0
16:0:0
28:14:7
37:13:9
27:18:0
44:20:0
65:2:9
56:7:10
40:5:0
56:4:8
0:0:0
PPh3
PPh3
PPh3
PPh3
1038-95-5
855-38-9
37943-90-1
5518-53-5
18437-78-0
13406-29-6
1259-35-4
PPh3
30
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
70
9
10
11
12
13
14
15
16
Entry
1
4
Products
Yield (%)
89
88:6:2
89:6:2
77:13:0
38:7:0
PPh3
PPh3
PPh3
65
60
4a
3w
5a
5b
5c
The bold signifies the best reaction condition.
a
Compounds 1h (0.5 mmol), 4a (0.55 mmol), [Pd] (5 mol %), ligand (20 mol %),
KOH(1 mmol), CH3CN, 24 h.
2
3
4
5
6
7
8
9
4b
4c
4d
4e
4f
91
86
95
84
93
89
81
31
b
Isolated yield. 1038-95-5: Tri-p-tolyphosphine; 855-38-9: Tris(4-methox-
yphenyl)phosphine; 37943-90-1: diphenyl-2-pyridylphosphine; 5518-53-5: Tri(2-
furyl) phosphine; 18437-78-0: Tris(p-fluorophenyl) phosphine; 13406-29-6:
Tris(p-trifluoromethylphenyl) phosphine; 1259-35-4: Tris(pentafluorophenyl)
phosphine.
NMR (CDCl3, 100 MHz): 158.6, 150.3, 139.2, 139.1, 136.0, 131.1, 129.7,
128.9, 126.2, 125.6, 119.2, 20.5; MS (ESI): 248.0 [MþH]þ; HRMS (ESI)
[MþH]þ calcd for C12H11BrN: 248.0069, found: 248.0058.
4.1.7. 5-Bromo-2-(4-methyloxyphenyl)pyridine (3e). Compound 3e:
white solid, mp 136e137 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.69 (d,
J¼2.0 Hz, 1H), 7.92 (d, J¼8.4 Hz, 2H), 7.82 (dd, J1¼2.4 Hz, J2¼2.0 Hz,
1H), 7.55 (d, J¼8.4 Hz, 1H), 6.98 (d, J¼8.8 Hz, 2H), 3.86 (s, 3H); 13C
NMR (CDCl3, 100 MHz): 161.1, 155.7, 150.5, 139.7, 130.8, 128.4, 121.2,
118.7, 114.5, 55.7; MS (ESI): 264.0 [MþH]þ; HRMS (ESI) [MþH]þ
calcd for C12H11BrNO: 264.0019, found: 264.0012.
5d
5e
4g
4h
4i
5f
4.1.8. 5-Bromo-2-(4-fluorophenyl)pyridine (3f). Compound 3f:
white solid, mp 73e74 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.71 (d,
J¼2.4 Hz, 1H), 7.92e7.96 (m, 2H), 7.84 (dd, J1¼2.4 Hz, J2¼2.0 Hz, 1H),
7.55 (d, J¼8.4 Hz, 1H), 7.14 (t, J¼8.8 Hz, 2H); 13C NMR (CDCl3,
100 MHz): 164.0 (d, J¼247.6 Hz), 155.1, 150.9, 139.6, 134.6 (d,
J¼3.2 Hz), 128.9 (d, J¼9.2 Hz), 121.5, 119.5, 116.1 (d, J¼20.9 Hz); MS
(ESI): 252.0 [MþH]þ; HRMS (ESI) [MþH]þ calcd for C11H8BrFN:
251.9819, found: 251.9817.
5g
5h
4 .1. 9 . 5 - B ro m o - 2 - ( 4 - t r i fl u o ro m e t hyl p h e n yl ) p y r i d i n e
(3g). Compound 3g: white solid, mp 109e110 ꢀC; 1H NMR (CDCl3,
400 MHz): 8.76 (d, J¼1.6 Hz, 1H), 8.07 (d, J¼8.0 Hz, 2H), 7.90 (dd,
J1¼2.0 Hz, J2¼2.4 Hz, 1H), 7.68 (dd, J1¼8.4 Hz, J2¼8.4 Hz, 3H); 13C
NMR (CDCl3, 100 MHz): 154.5, 151.3, 141.8, 139.8, 131.5 (q,
J¼33.2 Hz), 127.3, 126.1 (q, J¼3.6 Hz), 124.4 (d, J¼270.4 Hz), 122.1,
120.6; MS (EI): 303.0 (Mþ); HRMS (EI) calcd for C12H7BrF3N:
300.9714, found: 300.9711.
10
4j
0
5i
a
Compound 1h (0.5 mmol), compound 4 (0.55 mmol), Pd(OAc)2 (5 mol %), PPh3
(20 mol %), KOH(1 mmol), CH3CN, 24 h.
b
Isolated yield.
123.5, 122.1; MS (EI): 233.0 (Mþ); HRMS (EI) calcd for C11H8BrN:
232.9840, found: 232.9844.
4.1.10. 3-Bromo-2-phenylpyridine (3i). Compound 3i: yellow liq-
uid; 1H NMR (CDCl3, 400 MHz): 8.62 (dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H),
7.98 (dd, J1¼1.6 Hz, J2¼1.6 Hz,1H), 7.68 (dd, J1¼1.6 Hz, J2¼1.2 Hz, 2H),
7.40e7.48 (m, 3H), 7.12 (dd, J1¼4.8 Hz, J2¼4.8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): 158.3, 148.2, 141.6, 139.6, 129.5, 129.0, 128.2,
4.1.11. 3-Bromo-2-(4-methylphenyl)pyridine (3j). Compound 3j:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.60 (dd, J1¼1.2 Hz,
J2¼1.6 Hz, 1H), 7.96 (dd, J1¼1.6 Hz, J2¼1.6 Hz, 1H), 7.59 (d, J¼8.0 Hz,

Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
11001
J¼4.4 Hz, 1H), 8.32 (d, J¼6.8 Hz, 2H), 8.04 (d, J¼8.4 Hz, 1H), 7.88 (d,
J¼7.6 Hz, 2H), 7.23e7.27 (m, 1H); 13C NMR (CDCl3, 100 MHz): 156.1,
148.7, 148.1, 145.8, 141.9, 130.8, 124.6, 123.5, 120.0, MS (EI): 278
(Mþ); HRMS (EI) calcd for C11H7BrN2O2: 277.9691, found:
277.9690.
4.1.18. 5-Bromo-4-methyl-2-phenylpyridine (3r). Compound 3r:
colorless liquid; 1H NMR (CDCl3, 400 MHz): 8.68 (s, 1H), 7.93e7.95
(s, 2H), 7.57 (s, 1H), 7.38e7.47 (m, 3H), 2.43 (s, 3H); 13C NMR (CDCl3,
100 MHz): 156.3, 151.2, 147.7, 138.4, 129.4, 129.0, 127.0, 122.9, 122.3,
22.7; MS (EI): 249.1 (Mþ); HRMS (EI) calcd for C12H10BrN: 246.9997,
found: 246.9999.
Scheme 1. Application of the 4-bromo-2-phenyl-pyridine to the other reactions.
4.1.19. 5-Bromo-3-methyl-2-phenylpyridine (3s). Compound 3s:
colorless liquid; 1H NMR (CDCl3, 400 MHz): 8.58 (d, J¼2.0 Hz, 1H),
7.73 (d, J¼2.4 Hz, 1H), 7.39e7.50 (m, 5H), 2.34 (s, 3H); 13C NMR
(CDCl3, 100 MHz): 157.4, 148.1, 140.9, 139.7, 132.9, 129.0, 128.5, 119.1,
20.1; MS (EI): 248.1 (Mþ); HRMS (EI) calcd for C12H9BrN: 245.9918,
found: 245.9921.
4.1.20. 5-Chloro-3-bromo-2-phenylpyridine (3t). Compound 3t:
white solid, mp 60e61 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.58 (d,
J¼1.6 Hz, 1H), 8.00 (d, J¼2.0 Hz, 1H), 7.64e7.67 (m, 2H), 7.42e7.48
(m, 3H); 13C NMR (CDCl3, 100 MHz): 156.6, 147.1, 140.7, 138.7, 130.7,
129.5, 129.3, 128.3, 119.6; MS (EI): 268.9 (Mþ); HRMS (EI) calcd for
Scheme 2. Application of the 2,4-dibromopyridine to the inhibitor of 17b-HSD1 (11).
2H), 7.26 (d, J¼7.6 Hz, 2H), 7.08e7.11 (m, 1H); 2.41 (s, 3H); 13C NMR
(CDCl3, 100 MHz): 158.4, 148.2, 141.6, 139.0, 136.8, 129.5, 128.9,
123.3, 120.1, 21.6; MS (EI): 247.0 (Mþ); HRMS (EI) calcd for
C11H7BrClN: 266.9450, found: 266.9453.
C
12H10BrN: 246.9997, found: 246.9998.
4.1.12. 3-Bromo-2-(3-methylphenyl)pyridine (3k). Compound 3k:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.61 (dd, J1¼1.2 Hz,
J2¼1.2 Hz, 1H), 7.96 (dd, J1¼1.2 Hz, J2¼1.2Hz,1H), 7.48 (d, J¼6.8 Hz, 2H),
7.34 (t, J¼7.6 Hz, 1H), 7.24 (d, J¼8.0 Hz, 1H), 7.11 (dd, J1¼4.8 Hz,
J2¼4.8 Hz, 1H), 2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz): 158.5, 148.1,
141.5, 139.6, 137.9,130.1, 129.7, 128.0, 126.6, 123.4, 120.1, 21.7; MS (EI):
247.0 (Mþ);HRMS(EI)calcd forC12H10BrN: 246.9997, found: 247.0001.
4.1.21. 3,5-Dichloro-2-phenylpyridine (3u). Compound 3u: white
solid, mp 50e51 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.55 (d, J¼2.4 Hz,
1H), 7.80 (d, J¼2.0 Hz, 1H), 7.68e7.71 (m, 2H), 7.42e7.48 (m, 3H);
13C NMR (CDCl3, 100 MHz): 154.9, 146.7, 137.7, 137.3, 130.7, 130.4,
129.5, 129.4, 128.4; MS (EI): 223.0 (Mþ); HRMS (EI) calcd for
C11H7Cl2N: 222.9956, found: 222.9954.
4.1. 2 2. 3 - Ch lo ro- 5 - t r iflu o r o m e t hyl - 2 - p h e nyl p y r i d i n e
(3v). Compound 3v: colorless liquid; 1H NMR (CDCl3, 400 MHz):
8.85 (s, 1H), 8.04 (d, J¼1.6 Hz, 1H), 7.74e7.77 (m, 2H), 7.48e7.52 (m,
3H); 13C NMR (CDCl3, 100 MHz): 160.2, 144.5 (m), 137.2 (d,
J¼2.2 Hz),135.6,130.5,130.0,129.7,128.5,126.4 (q, J¼13.2 Hz),123.0
(d, J¼261.9 Hz); MS (EI): 257.1 (Mþ); HRMS (EI) calcd for
4.1.13. 3-Bromo-2-(2-methylphenyl)pyridine (3l). Compound 3l:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.62 (dd, J1¼1.2 Hz,
J2¼1.2 Hz, 1H), 7.98 (dd, J1¼0.8 Hz, J2¼1.2 Hz, 1H), 7.15e7.35 (m, 5H),
2.14 (s, 3H); 13C NMR (CDCl3, 100 MHz): 159.8, 148.0, 140.7, 139.9,
135.9, 130.4, 128.9, 128.8, 125.8, 123.7, 121.6, 19.6; MS (EI): 247.0
(Mþ); HRMS (EI) calcd for C12H10BrN: 246.9997, found: 246.9996.
C12H7ClF3N: 257.0219, found: 257.0214.
4.1.14. 3-Bromo-2-(4-methoxyphenyl)pyridine
(3m). Compound
3m: yellow solid, mp 61e62 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.59
(dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H), 7.96 (dd, J1¼1.2 Hz, J2¼1.6 Hz, 1H),
7.66e7.69 (m, 2H), 7.08 (dd, J1¼4.8 Hz, J2¼4.8 Hz, 1H), 6.98 (d,
J¼8.4 Hz, 2H), 3.85 (s, 3H); 13C NMR (CDCl3, 100 MHz): 160.3, 157.9,
148.1, 141.7, 132.1, 131.0, 123.0, 119.9, 113.6, 55.5; MS (EI): 263.0
(Mþ); HRMS (EI) calcd for C12H10BrNO: 262.9946, found: 262.9950.
4.1.23. 4-Bromo-2-phenylpyridine (3w). Compound 3w: colorless
liquid; 1H NMR (CDCl3, 400 MHz): 8.48 (d, J¼5.2 Hz, 1H), 7.87e7.96
(m, 3H), 7.36e7.48 (m, 4H); 13C NMR (CDCl3,100 MHz): 159.0,150.5,
138.1, 133.8, 129.9, 129.1, 127.2, 125.5, 124.1; MS (EI): 233.1 (Mþ);
HRMS (EI) calcd for C11H8BrN: 232.9840, found: 232.9843.
4.1.24. 6-Bromo-2-(4-methoxyphenyl)pyridine (3x). Compound 3x:
white solid, mp 113e114 ꢀC; 1H NMR (CDCl3, 400 MHz): 7.91e7.94
(m, 2H), 7.50e7.59 (m, 2H), 7.31e7.33 (m, 1H), 6.94e6.97 (m, 2H),
3.84 (s, 3H); 13C NMR (CDCl3, 100 MHz): 161.2, 158.5, 142.3, 139.1,
130.5,128.6,125.7,118.4,114.4, 55.6; MS (EI): 263.0 (Mþ); HRMS (EI)
calcd for C12H10BrNO: 262.9946, found: 262.9951.
4.1.15. 3-Bromo-2-(4-fluorophenyl)pyridine (3n). Compound 3n:
white solid, mp 90e91 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.61 (dd,
J1¼1.2 Hz, J2¼1.2 Hz, 1H), 7.98 (dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H),
7.67e7.71 (m, 2H), 7.11e7.17 (m, 3H); 13C NMR (CDCl3, 100 MHz):
163.2 (d, J¼247.3 Hz), 157.3, 148.3, 141.7, 135.7 (d, J¼3.2 Hz), 131.6 (d,
J¼8.2 Hz), 123.6, 120.0, 115.2 (d, J¼22.0 Hz); MS (EI): 251.0 (Mþ);
HRMS (EI) calcd for C11H7BrNF: 250.9746, found: 250.9744.
4.1.25. 2-Bromo-4-phenylpyridine (C). Compound C: white solid,
mp 62e63 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.40 (d, J¼5.2 Hz, 1H),
7.69 (d, J¼0.8 Hz, 1H), 7.59 (dd, J1¼2.0 Hz, J2¼1.6 Hz, 2H), 7.44e7.51
(m, 4H); 13C NMR (CDCl3, 100 MHz): 151.5, 150.6, 143.2, 137.0, 129.9,
129.5, 127.3, 126.1, 121.1; MS (EI): 233.0 (Mþ); HRMS (EI) calcd for
4.1.16. 3 -Bromo-2-(4-tr ifluoromethylphenyl)pyridine
(3o). Compound 3o: white solid, mp 51e52 ꢀC; 1H NMR (CDCl3,
400 MHz): 8.64 (dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H), 8.02 (dd, J1¼1.2 Hz,
J2¼1.2 Hz, 1H), 7.68 (dd, J1¼8.0 Hz, J2¼8.4 Hz, 4H), 7.19 (dd,
J1¼4.4 Hz, J2¼4.4 Hz, 1H), 13C NMR (CDCl3, 100 MHz): 157.0, 148.4,
143.1, 141.9, 131.0 (q, J¼32.4 Hz), 130.1, 125.3 (q, J¼3.6 Hz), 124.4 (d,
J¼270.4 Hz), 124.2, 120.0; MS (EI): 301.0 (Mþ); HRMS (EI) calcd for
C11H8BrN: 232.9840, found: 232.9842.
4.1.26. 2,4-Diphenylpyridine (D). Compound D: yellow liquid; 1H
NMR (CDCl3, 400 MHz): 8.71 (d, J¼5.6 Hz, 1H), 8.04 (d, J¼7.2 Hz,
2H), 7.90 (s, 1H), 7.65e7.90 (m, 2H), 7.39e7.49 (m, 7H); 13C NMR
(CDCl3, 100 MHz): 158.3, 150.3, 149.5, 139.7, 138.8, 129.3 (d,
C
12H7BrF3N: 300.9714, found: 300.9716.
4.1.17. 3-Bromo-2-(4-nitrophenyl)pyridine (3p). Compound 3p:
white solid, mp 148e149 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.67 (d,

11002
Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
J¼9.0 Hz), 129.0, 127.3 (d, J¼3.1 Hz), 120.5, 119.0; MS (EI): 230.0
100 MHz): 158.2, 150.1, 149.6, 139.6, 139.5, 135.7, 130.1, 129.3, 129.0,
127.3, 127.2, 120.3, 118.8, 21.5; MS (EI): 245.2 (Mþ); HRMS (EI) calcd
for C18H15N: 245.1204, found: 245.1209.
(Mþ); HRMS (EI) calcd for C17H13N: 231.1048, found: 231.1045.
4.1.27. 4-Bromo-2-(4-methylphenyl)pyridine (5a). Compound 5a:
white solid, mp 60e61 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.46 (d,
4.1.36. 2-Phenyl-4-(4-methylphenylethynyl)pyridine (7). Compound
7: white solid, mp 121e122 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.66 (d,
J¼5.2 Hz, 1H), 8.01 (d, J¼7.2 Hz, 2H), 7.82 (s, 1H), 7.42e7.50 (m, 5H),
7.31 (d, J¼4.8 Hz, 1H), 7.18 (d, J¼8.4 Hz, 2H), 2.38 (s, 3H); 13C NMR
(CDCl3, 100 MHz): 157.6, 149.6, 139.9, 138.8, 133.0, 132.1, 129.6 (d),
129.1, 127.2, 124.1, 122.8, 119.3, 94.7, 86.7, 21.9; MS (EI): 269.2 (Mþ);
HRMS (EI) calcd for C20H15N: 269.1204, found: 269.1205.
J¼5.2 Hz,1H), 7.84e7.86 (m, 3H), 7.25e7.34 (m, 3H), 2.40 (s, 3H); 13
C
NMR (CDCl3, 100 MHz): 159.0, 150.4, 140.0, 135.3, 133.7, 129.8, 127.1,
125.2, 123.8, 21.5; MS (EI): 249.1 (Mþ); HRMS (EI) calcd for
C
12H10BrN: 246.9997, found: 246.9999.
4.1.28. 4-Bromo-2-(3-methylphenyl)pyridine (5b). Compound 5b:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.48 (d, J¼5.2 Hz, 1H),
7.87 (d, J¼1.6 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J¼7.6 Hz, 1H), 7.33e7.37
(m, 2H), 7.24 (d, J¼7.6 Hz, 1H), 2.42 (s, 3H); 13C NMR (CDCl3,
100 MHz): 159.2, 150.4, 138.8, 138.1, 133.8, 130.7, 129.0, 127.9, 125.4,
124.4, 124.2, 21.7; MS (EI): 247.1 (Mþ); HRMS (EI) calcd for
4.1.37. 2-Phenyl-4-(4-methylphenoxy)pyridine (8). Compound 8:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.51 (d, J¼6.0 Hz,1H), 7.91
(d, J¼7.2 Hz, 2H), 7.36e7.45 (m, 3H), 7.20e7.26 (m, 3H), 7.01 (d,
J¼8.4 Hz, 2H), 6.74 (dd, J1¼2.4 Hz, J2¼2.8 Hz), 2.37 (s, 3H); 13C NMR
(CDCl3,100 MHz): 166.1,159.8,152.1,151.3,139.4,135.2,130.9,129.3,
128.9, 127.2, 120.8, 110.7, 109.1, 21.1; MS (EI): 260.2 (Mþ); HRMS (EI)
calcd for C18H15NO: 261.1154, found: 261.1156.
C
12H10BrN: 246.9997, found: 246.9995.
4.1.29. 4-Bromo-2-(2-methylphenyl)pyridine (5c). Compound 5c:
colorless liquid; 1H NMR (CDCl3, 400 MHz): 8.50 (d, J¼5.2 Hz, 1H),
7.59 (d, J¼1.6 Hz, 1H), 7.25e7.43 (m, 5H), 2.36 (s, 3H); 13C NMR
(CDCl3, 100 MHz): 161.5, 150.0, 139.2, 136.1, 133.2, 131.1, 129.8, 129.1,
127.7, 126.2, 125.2, 20.5; MS (EI): 248.1 (Mþ); HRMS (EI) calcd for
4.1.38. 2-Phenyl-4-(p-tolylthio)pyridine (9).1 Compound 9: white
solid, mp 84e85 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.40 (d, J¼5.6 Hz,
1H), 7.86 (d, J¼7.2 Hz, 2H), 7.36e7.47 (m, 6H), 7.26 (d, J¼8.0 Hz, 2H),
6.83 (dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H), 2.41 (s, 3H); 13C NMR (CDCl3,
100 MHz): 157.5, 151.9, 149.4, 140.3, 139.2, 135.5, 131.0, 129.3, 128.9,
127.2, 126.1, 119.3, 117.8, 21.6; MS (EI): 276.1 (Mþ); HRMS (EI) calcd
for C18H15NS: 277.0925, found: 277.0930.
C
12H9BrN: 245.9918, found: 245.9920.
4.1.30. 4-Bromo-2-(4-ethylphenyl)pyridine (5d). Compound 5d:
colorless liquid; 1H NMR (CDCl3, 400 MHz): 8.47 (d, J¼5.6 Hz, 1H),
7.86e7.89 (m, 3H), 7.25e7.35 (m, 3H), 2.70 (q, J¼8.0 Hz, 2H), 1.26 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 159.2, 150.5, 146.3, 135.7,
133.6, 128.7, 127.2, 125.2, 123.8, 28.9, 15.7; MS (EI): 261 (Mþ); HRMS
(EI) calcd for C13H12BrN: 261.0153, found: 261.0155.
4 .1. 3 9 . 4 - B r o m o - 2 - ( 5 - c h l o r o t h i o p h e n - 2 - yl ) p y r i d i n e
(10).1 Compound 10: yellow solid, mp 69e70 ꢀC; 1H NMR (CDCl3,
400 MHz): 8.32 (d, J¼5.2 Hz, 1H), 7.70 (d, J¼1.6 Hz, 1H), 7.28e7.31
(m, 2H), 6.91 (d, J¼4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 153.2,
150.5, 142.1, 133.8, 133.6, 127.6, 125.5, 124.6, 121.5; MS (EI): 274.9
(Mþ); HRMS (EI) calcd for C9H5BrClNS: 272.9015, found: 272.9014.
4.1.31. 4-Bromo-2-(4-methoxyphenyl)pyridine (5e). Compound 5e:
yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.44 (d, J¼5.2 Hz, 1H),
7.91 (d, J¼8.4 Hz, 2H), 7.82 (s, 1H), 7.30e7.32 (m, 1H), 6.98 (d,
J¼8.4 Hz, 2H), 3.84 (s, 3H); 13C NMR (CDCl3, 100 MHz): 161.2, 158.7,
150.4, 133.6, 130.8, 128.6, 124.7, 123.3, 114.5, 55.6; MS (EI): 263.1
(Mþ); HRMS (EI) calcd for C12H10BrNO: 262.9946, found: 262.9950.
4.1.40. 4-(3-Hydroxyphenyl)-2-(5-chlorothiophen-2-yl)pyridine
(11).8b Compound 11: yellow solid, mp 190e191 ꢀC; 1H NMR
(CDCl3, 400 MHz): 9.70 (s, 1H), 8.54 (d, J¼5.2 Hz, 1H), 8.18 (s, 1H), 1H
NMR 7.91 (d, J¼4.4 Hz, 1H), 7.54 (dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H),
7.20e7.37 (m, 4H), 6.91e6.93 (m, 1H); 13C NMR (CDCl3, 100 MHz):
158.9, 152.4, 150.7, 149.4, 144.6, 139.2, 131.4, 131.0, 129.1, 126.2, 121.1,
118.6, 117.3, 116.3, 114.7; MS (EI): 287.0 (Mþ); HRMS (EI) calcd for
4.1.32. 4-Bromo-2-(4-phenylphenyl)pyridine (5f). Compound 5f:
white solid, mp 105e106 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.52 (d,
J¼4.8 Hz, 1H), 8.04e8.06 (m, 2H), 7.94 (d, J¼1.6 Hz, 1H), 7.64e7.73
(m, 4H), 7.38e7.49 (m, 4H); 13C NMR (CDCl3, 100 MHz): 158.7, 150.7,
142.7, 140.6,137.1, 133.8, 129.1, 128.0, 127.8, 127.7, 127.4, 125.5, 124.0;
MS (EI): 309.0 (Mþ); HRMS (EI) calcd for C17H12BrN: 309.0153,
found: 309.0151.
C15H10ClNOS: 287.0172, found: 287.0171.
Acknowledgements
This work was supported by the Natural Science Foundation of
China (21172166, 21203135, and 21375092), China Postdoctor
Foundation (2013M541456), The Science and Technology Plan
Project of Zhejiang Province (2011C37055), and Taizhou Science
Project (121ZD04).
4.1.33. 4-Bromo-2-(3-phenylphenyl)pyridine (5g). Compound 5g:
colorless liquid; 1H NMR (CDCl3, 400 MHz): 8.52 (d, J¼5.2 Hz, 1H),
8.19 (t, J¼1.6 Hz, 1H), 7.92e7.95 (m, 2H), 7.66 (d, J¼7.2 Hz, 3H),
7.24e7.56 (m, 5H); 13C NMR (CDCl3, 100 MHz): 159.1, 150.7, 142.2,
141.1, 138.8, 133.8, 129.6, 129.1, 128.7, 127.8, 127.5, 126.2, 126.1, 125.7,
124.3; MS (EI): 309 (Mþ); HRMS (EI) calcd for C17H12BrN: 309.0148,
found: 309.0150.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.10.065.
4.1.34. 4-Bromo-2-(4-nitrophenyl)pyridine (5h). Compound 5h:
yellow solid, mp 168e169 ꢀC; 1H NMR (DMSO-d6, 400 MHz): 8.63
(d, J¼5.2 Hz, 1H), 8.32e8.44 (m, 5H), 7.76 (d, J¼3.6 Hz,1H); 13C NMR
(DMSO-d6, 100 MHz): 155.2, 151.0, 148.0, 143.2, 133.6, 128.1, 126.9,
124.5,123.9; MS (EI): 278.0 (Mþ); HRMS (EI) calcd for C11H7BrN2O2:
277.9691, found: 277.9690.
References and notes
1. Dong, H.; Latka, R. T.; Driver, T. G. Org. Lett. 2011, 13, 2726e2729.
2. Mousseau, J. J.; Bull, J. A.; Charette, A. B. Angew. Chem., Int. Ed. 2010, 49,
1115e1118.
3. Yuan, C.; Chang, C.; Siegel, D. J. Org. Chem. 2013, 78, 5647e5668.
4. See some recent examples of CeH activation of 2-arylpyridines: (a) Zhou, B.;
Chen, H.; Wang, C. J. Am. Chem. Soc. 2013, 135, 1264e1267; (b) Hofmann, N.;
Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877e5884; (c) Brasse, M.; Campora,
J.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2013, 135, 6427e6430; (d) Pan,
F.; Lei, Z.; Wang, H.; Li, H.; Sun, J.; Shi, Z. Angew. Chem., Int. Ed. 2013, 52,
4.1.35. 2-Phenyl-4-(4-methylphenyl)pyridine (6). Compound 6:
white solid, mp 95e96 ꢀC; 1H NMR (CDCl3, 400 MHz): 8.71 (d,
J¼5.6 Hz,1H), 8.04 (d, J¼7.6 Hz, 2H), 7.91 (d, J¼0.8 Hz,1H), 7.31e7.59
(m, 6H), 7.26 (d, J¼20 Hz, 2H), 2.41 (s, 3H); 13C NMR (CDCl3,

Q. Zhou et al. / Tetrahedron 69 (2013) 10996e11003
11003
2063e2067; (e) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew. Chem.
, Int. Ed. 2013, 52, 2207e2211; (f) Li, X.; Yu, S.; Wang, F.; Wan, B.; Yu, X. Angew.
Chem., Int. Ed. 2013, 52, 2577e2580; (g) Aiso, H.; Kochi, T.; Mutsutani, H.; Ta-
nabe, T.; Nishiyama, S.; Kakiuchi, F. J. Org. Chem. 2012, 77, 7718e7724.
5. Tang, B.; Yu, F.; Li, P.; Tong, L.; Duan, X.; Xie, T.; Wang, X. J. Am. Chem. Soc. 2009,
131, 3016e3023.
Kan, I.; Thangaraju, K.; Park, Y. S.; Kim, J. J.; Kwon, S.; Kim, Y. Dyes Pigm.
2011, 92, 603e609; (c) Rao, Y.; Amarne, H.; Zhao, S.; McCormick, T. M.;
Martic, S.; Sun, Y.; Wang, R.; Wang, S. J. Am. Chem. Soc. 2008, 130,
ꢀ
12898e12900; (d) Ismail, M. A.; Arafa, R. K.; Brun, R.; Wenzler, T.; Miao,
Y.; Wilson, W. D.; Generaux, C.; Bridges, A.; Hall, J. E.; Boykin, D. W. J.
Med. Chem. 2006, 49, 5324e5332; (e) Handy, S. T.; Wilson, T.; Muth, A. J.
Org. Chem. 2007, 72, 8496e8500; (f) Wong, K.; Hwu, T.; Balaiah, A.; Chao,
T.; Fang, F.; Lee, C.; Peng, Y. Org. Lett. 2006, 8, 1415e1418; (g) Burzicki, G.;
6. Durben, S.; Baumgartner, T. Inorg. Chem. 2011, 50, 6823e6836.
7. (a) Chi, C.; Chiang, C.; Liu, S.; Yueh, H.; Chen, C.; Chen, C. J. Mater. Chem. 2009, 19,
5561e5571; (b) Whittell, G. R.; Manners, I. Adv. Mater. 2007, 19, 3439e3468; (c)
Yamaguchi, Y.; Kobayashi, S.; Miyamura, S.; Okamoto, Y.; Wakamiya, T.; Mat-
subara, Y.; Yoshida, Z. Angew. Chem. 2004, 116, 370e373; Angew. Chem., Int. Ed.
2004, 43, 366e369.
8. (a) Sha, F.; Wu, L.; Huang, X. J. Org. Chem. 2012, 77, 3754e3765; (b) Oster, A.;
Klein, T.; Werth, R.; Kruchten, P.; Bey, E.; Negri, M.; Marchais-Oberwinkler, S.;
Frotscher, M.; Hartmann, R. W. Bioorg. Med. Chem. 2010, 18, 3494e3505; (c)
Heim-Riether, A.; Taylor, S. J.; Liang, S.; Donghong, A. G.; Xiong, Z.; Michael, A.
E.; Collins, B. K.; Farmer, B. T.; Haverty, K.; Hill-Drzewi, M.; Junker, H.-D.;
Margarit, S. M.; Moss, N.; Neumann, T.; Proudfoot, J. R.; Keenan, L. S.; Sekul, R.;
Zhang, Q.; Li, J.; Farrow, N. A. Bioorg. Med. Chem. Lett. 2009, 19, 5321e5324; (d)
Sun, L.; Yang, Z.; Guo, H.; Pei, W. Chin. J. Org. Chem. 2012, 32, 624e626.
9. (a) Aida, W.; Ohtsuki, T.; Li, X.; Ishibashi, M. Tetrahedron 2009, 65, 369e373; (b)
Kitamura, A.; Tanaka, J.; Ohtani, I. I.; Higa, T. Tetrahedron 1999, 55, 2487e2492.
10. (a) Hudson, Z. M.; Sun, C.; Helander, M. G.; Amarne, H.; Lu, Z.; Wang, S.
Adv. Funct. Mater. 2010, 20, 3426e3439; (b) So, K. H.; Kim, R.; Park, H.;
ꢀ
Voisin-Chiret, A. S.; Sopkova-de Oliveira Santos, J.; Rault, S. Tetrahedron
2009, 65, 5413e5417.
11. (a) Sicre, C.; Alonso-Gomez, J.; Cid, M. M. Tetrahedron 2006, 62,
ꢀ
11063e11072; (b) Blackaby, W. P.; Atack, J. R.; Bromidge, F.; Castro, J. L.;
Goodacre, S. C.; Hallett, D. J.; Lewis, R. T.; Marshall, G. R.; Pike, A.; Smith,
A. J.; Street, L. J.; Tattersall, D. F. D.; Wafford, K. A. Bioorg. Med. Chem. Lett.
2006, 16, 1175e1179.
12. (a) Ding, M.; He, F.; Poss, M. A.; Rigat, K. L.; Wang, Y.; Roberts, S. B.; Qiu, D.;
Fridell, R. A.; Gao, M.; Gentlesa, R. G. Org. Biomol. Chem. 2011, 9, 6654e6662; (b)
Dong, C.; Liu, T.; Hu, Q. Synlett 2009, 1081e1086.
13. Zhou, Q.; Zhang, B.; Du, T.; Gu, H.; Ye, Y.; Jiang, H.; Chen, R. Tetrahedron 2013, 69,
327e333.
14. Furuya, T.; Benitez, D.; Tkatchouk, E.; Strom, A. E.; Tang, P.; Goddard, W. A., III;
Ritter, T. J. Am. Chem. Soc. 2010, 132, 3793e3807.
15. Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem.
Soc. 2009, 131, 6632e6639.