Copper-catalyzed highly regioselective 2-aryloxylation of 2,x-dihalopyridines

Article abstract of DOI:10.1016/j.tet.2012.10.025

2,x-Dihalopyridines reacted with phenols catalyzed by CuI/TMEDA in the presence of Cs₂CO₃ in DMSO at 110 °C under nitrogen atmosphere for 24 h to afford 2-aryloxypyridines in good to high yields except p-nitrophenol. To expand this methodology, a vanilloid receptor ligand used in treatments was prepared in good yield. This method has potential utility in the synthesis of pharmaceuticals, agrochemicals and even natural products.

Full text of DOI:10.1016/j.tet.2012.10.025

Tetrahedron 69 (2013) 327e333
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Copper-catalyzed highly regioselective 2-aryloxylation
of 2,x-dihalopyridines
,
a
,
,
*
Qizhong Zhou a , Bin Zhang b, Tieqi Du a, Haining Gu c, Yuyuan Ye a, Huajiang Jiang a, Rener Chen a
*
a Department of Chemistry, Taizhou University, Taizhou 318000, China
b College of Pharmacy, Zhejiang University of Technology, Hangzhou 310014, China
c Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2012
Received in revised form
23 September 2012
Accepted 9 October 2012
Available online 17 October 2012
2,x-Dihalopyridines reacted with phenols catalyzed by CuI/TMEDA in the presence of Cs2CO3 in DMSO at
110 ꢀC under nitrogen atmosphere for 24 h to afford 2-aryloxypyridines in good to high yields except
p-nitrophenol. To expand this methodology, a vanilloid receptor ligand used in treatments was prepared
in good yield. This method has potential utility in the synthesis of pharmaceuticals, agrochemicals and
even natural products.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
Br
R2
N
It is well known to all that pyridines are key backbones of
pharmaceuticals and natural products.1e3 Among pyridines,
substituted 2-aryloxypyridines are widely used as glucagon receptor
antagonists,4 endothelin antagonists,5,6 anti-hypercholesteremic,
anti-hyperlipoproteinemic and anti-hyperglycemic agents,7 herbi-
cides8,9 and vanilloid receptor ligands used in treatments10 (see
Fig. 1) etc.
Br
Br
Br
R1
N
N
NCONH2
N
Br
N
O
O
Sch 66336
Scheme 1. Retrosynthetic route for Sch 66336.
MeO
R1
N
Br
Br
R1
N
O
N
R1R2NH
R2
N
O
N
+
O
N
Pd cat/
Br
CO
N
R2
R1
N
N
O
O
R2
up to 82% yield, up to 98:2 (mono:bis)
F3C
F3C
Scheme 2.
Fig. 1. Structures of two vanilloid receptor ligands.10
Suzuki reaction but the yields and regioselectivities were not satis-
fied.13 The above methods inspired us to develop regioselective CeO
coupling of 2,x-dihalopyridines and phenols for the synthesis of
drugs, agrochemicals, and even natural products.
It had been postulated that the synthesis of Sch 66336 required
an efficient method for the preparation of 3-methyl-5-bromo-2-
pyridinecarboxyamides from 2,5-dibromo-3-methyl-pyridine
(see Scheme 1).11
Wu reported Pd-catalyzed regioselective carbonylation of 2,5-
dibromopyridine (see Scheme 2).11 Bach had reviewed regiose-
lective cross-coupling reactions of multiple halogenated pyridines.12
Cid reported Pd-catalyzed 2-arylation of 2,4-dibromopyridine via
Recently, Buchwald,14 Ma,15 Cristau,16 Kim,17 Bao,18 Xu,19 Sekar,20
Sreedhar,21 Punniyamurthy,22 Maiti23 and Hsieh24 et al. developed
efficient Ullman-type intermolecular CeO coupling from aryl
halides and phenols. Recently, copper catalyzed cross coupling of
aryl halides with phenols were reviewed.25 Ding reported that
2-bromopyridine reacted with phenol catalyzed by CuBr/(2-pyr-
idyl)acetone to afford 2-phenoxypyridine in 98% yield.26
To the best of our knowledge, copper-catalyzed regioselective
CeO coupling reaction has not been reported before. Herein, we
* Corresponding authors. Tel.: þ86 576 85137169; e-mailaddresses:qizhongchou@
yahoo.com (Q. Zhou), cre@tzc.edu.cn (R. Chen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.025

328
Q. Zhou et al. / Tetrahedron 69 (2013) 327e333
report Cu-catalyzed regioselective aryloxylation of 2,x-dihalopy-
dines (see Scheme 3) and expand its utility in organic synthesis.
The scope of the copper-catalyzed regioselective CeO bond
formation was explored by using a variety of 2,x-dihalopyridines
with substituted phenols under the optimized conditions. As shown
in Table 2, the listed 2,x-pyridines well underwent coupling
with all phenols bearing electron donating groups (see entries 1e3,
6e9, 12e15, and 18e19). 2,4-Dibromopyridine, 2,3-dibromopyr-
idine and 2,5-dibromopyridine reacted with p-chlorophenol to also
give high yields (see entries 4, 10 and 16, Table 2). Phenol bearing
nitro group, which is a strong electron withdrawing group gave very
low yields (see entries 5, 11 and 17, Table 2). 2,3,5-Trichloropyridine
reacted with 4-methylphenol to give product 3s in 93% yield. 2,3-
Dichloro-5-trifluoromethylpyridine (1e) bearing trifluoromethyl
group, which is a strong electron withdrawing group is unreactive
and showed worse selectivity, so the yield of 3t is very low. The
above results indicated that electronic variations on the phenol rings
have a significant impact on the yields. Why the regioselectivity is
Br
Br
R
R
[Cu]
O
HO
Br
N +
N
3
1
2
Scheme 3.
2. Results and discussion
As indicated in Table 1, the investigation was initiated by using
the coupling of 2,4-dibromopyridine and phenol as a model
reaction to explore the optimized reaction conditions.
Table 1
Copper-catalyzed phenoxylation of 2,4-dibromopyridine: optimization of the reaction conditionsa
[Cu] (10 mol%)
Br
OPh
OPh
Br
ligand (10 mol%)
base (2 eq)
+ HO
Br
+
+
Br
solvento(5 mL)
O
A
N
N
B
N
C
OPh
N2, 110 C, 24 h
N
0.5 mmol
0.6 mmol
Entry
Copper
Ligand
Base
Solvent
Temperature (ꢀC)
A: yielde (%)
B: yielde (%)
C: yielde (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
Cu2O
CuBr
L
L
L
L
L
-proline
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Na2CO3
KOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
Dioxane
Toluene
Dioxane
DMSO
DMSO
DME
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
110
110
110
110
110
110
Reflux
110
110
110
110
110
110
110
110
110
110
110
110
0
0
0
0
0
0
0
0
0
0
0
0
2.6
0
0
1.2
0
1.8
0
0
0
0
0
0
0
-proline
-proline
-proline
-proline
0
0
45
97
27
68
98
52
43
79
90
46
47
95
94
95
54
21
1.8
10
2
0
6
5
5.7
1
1.2
0
0
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
TMEDAb
9
10
11
12
13
14
15
16
17
18
19
PMDETAc
DMEDAd
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
0
0
0
Bold represents the best reaction condition.
a
Reaction conditions: CuI (0.05 mmol), ligand (0.05 mmol), 2,4-dibromopyridine (0.5 mmol), phenol (0.6 mmol), bases (1.0 mmol), solvents (5.0 mL), 110 ꢀC, N2, 24 h.
b
c
TMEDA (tetramethylethylenediamine).
PMDETA (1,1,4,7,7-pentamethyldiethylenetriamine).
DMEDA (N,N0-dimethylethylenediamine).
Isolated yield.
d
e
It was found that, under the catalysis of CuI and
L
-proline, 2,4-
so high for the aryloxylation of 2,4-dibromopyridine, 2,5-
dibromopyridine, and 2,3-dibromopyridine? We can explain that
the 2-bromo of 2,x-dibromopyridine is more reactive than the
4-bromo, 5-bromo, and 3-bromo of 2,x-dibromopyridine.13
After completion of the reaction, to demonstrate the applica-
bility of this method in the synthesis of drugs, agrochemicals and
even natural products, we functionalized 3a through Suzuki cou-
pling in 98% yield and through Sonogashira coupling in 93% yield
(Scheme 4).
dibromopyridine in DMSO was not consumed completely after
24 h at 110 ꢀC, delivering A in 45% yield and B in 21% yield (entry 5,
Table 1). Replacement of
improved regioselectivity (entries 10 and 11). Replacement of
-proline with 1,10-phenanthroline or TMEDA gave high regiose-
L-proline with PMEDTA or DMEDA, gave
L
lectivity and high yield (entries 6 and 9). Changing bases from
CS2CO3 to K3PO4, K2CO3, Na2CO3, or KOAc also decreased the re-
action yields (entries 12e15). When CuCl, Cu2O or CuBr were used
instead of CuI, the reaction yields only decreased slightly (entries
16e18). In absence of copper and ligand, 2,4-dibromopyridine
reacted with phenol to afford the product in only 54% yield
(entry 19). Based on these results, we concluded that, with CuI/
TMEDA as the catalyst, Cs2CO3 as the base, and DMSO as the
solvent, this was the optimized set of conditions for this
transformation (see entry 9, Table 1).
To expand this methodology, a vanilloid receptor ligand10 used
in treatments (compound 7) was prepared (see Scheme 5).
2,4-Dibromopyridine reacted with 8-hydroxyquinoline with the
standard method to give compound 6 in 71% yield. Compound
6
reacted with 4-trifluoromethylphenyl boronic acid in the
presence of Pd(OAc)2/PPh3 with KOH in MeOH to afford compound
7 in 74% yield. Trifluoromethyl in 4-trifluoromethylphenyl boronic

Q. Zhou et al. / Tetrahedron 69 (2013) 327e333
329
Table 2
Synthesis of various 2-aryloxypyridines from 2,x-dihalopyridines and substituted phenols
Entry
1
2,x-Dibromopyridines
Phenols
Product
Yield (%)
91
89
91
86
7
2a
2b
2c
2d
2e
1a
3a
3b
3c
3d
3e
2
3
4
5
1a
1a
1a
1a
6
1a
83
2f
3f
7
8
2a
2b
91
98
1b
3g
1b
3h
9
1b
1b
2c
75
90
3i
10
2d
3j
(continued on next page)

330
Q. Zhou et al. / Tetrahedron 69 (2013) 327e333
Table 2 (continued )
Entry
2,x-Dibromopyridines
Phenols
Product
Yield (%)
18
11
12
13
1b
2e
2f
3k
1b
77
96
3l
2a
1c
3m
14
15
16
17
1c
1c
1c
1c
2b
2c
2d
2e
91
95
92
7
3n
3o
3p
3q
18
19
20
1c
2f
85
3r
3s
2b
2b
93
24
1d
3t
10
1e
3u
acid is a strong electron withdrawing group, so the yield of com-
pound 7 is lower than that of compound 4. Therefore, a Cu-
catalyzed regioselective aryloxylation of 2,x-dihalopyridines
would be an interesting approach to some drugs and even natural
products.
3. Conclusions
In conclusion, we have developed a facile and efficient approach
for highly regioselective aryloxylation of 2,x-dihalopyridines with
up to 96% yield. The CuI/TMEDA catalytic system displays excellent

Q. Zhou et al. / Tetrahedron 69 (2013) 327e333
331
B(OH)2
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
K2CO3 (2 eq)
Pd(Ph3P)2Cl2 (5 mol%)
Br
N
O
N
CuI (5 mol%)
Cs2CO3 (2 eq)
CH3CN, reflux, 24 h
N2
MeOH, reflux, 24 h
N2
O
3a
N
O
4
5
93%
98%
Scheme 4.
CF3
F3C
B(OH)
2 1.5eq
CuI (5 mol%)
Br
N
OH
1eq
TMEDA (5 mol%)
Cs2CO3 (2eq)
Br
N
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
N
N
+
N
DMSO,110 0C
KOH (2eq)
Br
N2, 24h
CH3OH, reflux, N2, 24h
74%
O
6
1eq
N
71%
O
7
Scheme 5.
functional group compatibility and high regioselectivity in the
presence of a broad range of functional groups though p-nitro-
phenol gave low yields. High regioselectivity and high yield is
owing to the different electro property of 2- and other halogen in
the 2,x-dihalopyridines. To expand this methodology, 4-bromo-2-
phenoxypyridine was functionalized with Suzuki and Sonogashira
reaction in high yield. We also prepared a vanilloid receptor ligand
in good yield with Suzuki reaction. This method has utility in the
synthesis of pharmaceuticals, agrochemicals, and even natural
products. High regioselective fuctionalization of 2,x-dibromopyr-
idines is currently underway.
134.9, 130.0, 125.4, 122.1, 121.5, 114.9; MS (EI): 248.0 (Mþ); HRMS
(EI) calcd for C11H8BrNO: 248.9789, found: 248.9793.
4.1.3. Compound C. White solid, mp 87e88 ꢀC; 1H NMR (CDCl3,
400 MHz): 8.04 (d, J¼5.6 Hz, 1H), 7.36e7.43 (m, 4H), 7.10e7.26
(m, 6H), 6.58 (dd, J1¼2.0 Hz, J2¼2.4 Hz, 1H), 6.39 (t, J¼2.4 Hz, 1H);
13C NMR (CDCl3, 100 MHz): 167.9, 165.8, 154.3, 149.1, 130.5, 129.9,
125.8, 125.0, 121.5, 121.2, 108.4, 99.0; MS (EI): 262.0 (Mþ); HRMS
(EI) calcd for C17H13NO2: 263.0946, found: 263.0944.
4.1.4. Compound 3b. Yellow solid, mp 63.1e64.7 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.17 (d, J¼5.6 Hz, 1H), 7.24 (d, J¼8.4 Hz, 2H), 6.96
(d, J¼8.4 Hz, 3H), 6.80 (dd, J1¼2.4 Hz, J2¼2.0 Hz, 1H), 2.38 (s, 3H);
13C NMR (CDCl3, 100 MHz): 166.5, 151.3, 151.2, 143.2, 136.0, 131.1,
120.8, 115.7, 111.9, 21.1; MS (ESI): 263.9 [MþH]þ; HRMS (ESI)
[MþH]þ calcd for C12H11BrNO: 264.0019, found: 264.0016.
4. Experimental
4.1. General procedure for the copper-catalyzed coupling
reaction of 2,x-dihalopyridines and phenols
4.1.5. Compound 3c. Yellow solid, mp 64.7e66.1 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.18 (d, J¼6.0 Hz, 1H), 6.94e7.03 (m, 5H), 6.79
(dd, J1¼2.8 Hz, J2¼2.0 Hz, 1H), 3.83 (s, 3H); 13C NMR (CDCl3,
100 MHz): 166.9, 157.7, 151.1, 146.8, 143.1, 122.1, 115.6, 115.4, 111.7,
55.9; MS (ESI): 280.0 [MþH]þ; HRMS (ESI) [MþH]þ calcd for
C12H11BrNO2: 279.9968, found: 279.9955.
2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g,
1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol),
and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL).
The reaction was stirred at 110 ꢀC under nitrogen atmosphere for
24 h. When the reaction mixture was cooled, the reaction mixture
was filtered. The mixture was dissolved with dichloromethane
(25 mL). Then the mixture was washed with brine (3ꢁ30 mL). The
organic phase was dried over sodium sulfate. After evaporation of
the solvent, the mixture was subjected to column chromatography
with petroleum ether/ethyl acetate (20:1) as eluent to give pure
product.
4.1.6. Compound 3d. Pale yellow solid, mp 67.4e68.8 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.22 (d, J¼6.0 Hz, 1H), 7.39e7.43 (m, 2H),
6.98e7.06 (m, 3H), 6.82 (dd, J1¼2.4 Hz, J2¼2.0 Hz); 13C NMR (CDCl3,
100 MHz): 165.9, 152.2, 151.4, 143.2, 131.6, 130.7, 122.4, 115.9, 112.0;
MS (ESI): 283.9 [MþH]þ; HRMS (ESI) [MþH]þ calcd for
C11H8BrClNO: 283.9472, found: 283.9460.
4.1.1. Compound 3a. Pale yellow liquid; 1H NMR (CDCl3, 400 MHz):
8.20 (d, J¼7.6 Hz, 1H), 7.45 (t, J¼7.6 Hz, 2H), 7.29 (t, J¼7.2 Hz, 1H),
7.09 (d, J¼7.6 Hz, 2H), 6.98 (d, J¼2.0 Hz, 1H), 6.82 (dd, J1¼2.4 Hz,
J2¼2.8 Hz); 13C NMR (CDCl3, 100 MHz): 166.3, 153.7, 151.2, 143.1,
130.7, 126.3, 121.1, 115.9, 112.1; MS (ESI): 249.9 [MþH]þ; HRMS (ESI)
[MþH]þ calcd for C11H9BrNO: 249.9852, found: 249.9862.
4.1.7. Compound 3e. Yellow solid, mp 121.9e123.0 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.27e8.29 (m, 2H), 8.03 (d, J¼5.6 Hz, 1H),
7.24e7.29 (m, 4H); 13C NMR (CDCl3, 100 MHz): 163.0, 159.1, 148.3,
144.7, 135.5, 125.8, 123.6, 121.5, 116.1; MS (EI): 295.0 (Mþ); HRMS
(EI) calcd for C11H7BrN2O3: 293.9640, found: 293.9637.
4.1.2. Compound B. Yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.00
(d, J¼5.2 Hz, 1H), 7.40 (t, J¼8.0 Hz, 2H), 7.21 (t, J¼7.6 Hz, 1H),
7.08e7.13 (m, 4H); 13C NMR (CDCl3, 100 MHz): 164.6, 153.8, 148.5,
4.1.8. Compound 3f. Yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.17
(d, J¼6.0 Hz, 1H), 7.77e7.91 (m, 3H), 7.45e7.55 (m, 3H), 8.17

332
Q. Zhou et al. / Tetrahedron 69 (2013) 327e333
(d, J¼7.6 Hz, 1H), 6.99 (d, J¼2.0 Hz, 1H), 6.80 (dd, J1¼2.0 Hz,
J2¼2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 166.7, 151.3, 149.3, 143.3,
135.3, 128.4, 127.2, 127.1, 126.8, 126.5, 126.0, 121.5, 117.2, 115.7, 111.7;
MS (ESI): 302.0 [MþH]þ; HRMS (ESI) [MþH]þ calcd for C15H11BrNO:
300.0019, found: 300.0022.
7.02e7.06 (m, 2H), 6.89e6.93 (m, 2H), 6.78 (d, J¼8.8 Hz,1H), 3.80 (s,
3H); 13C NMR (CDCl3, 100 MHz): 163.2, 157.0, 148.5, 147.2, 142.1,
122.5, 115.0, 113.3, 112.9, 55.8; MS (EI): 279.0 (Mþ); HRMS (EI) calcd
for C12H9BrNO2: 277.9817, found: 277.9820.
4.1.18. Compound 3p. Pale yellow solid, mp 40.3e41.3 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.20 (d, J¼2.4 Hz, 1H), 7.77 (dd, J1¼2.4 Hz,
J2¼2.8 Hz, 1H), 7.31 (d, J¼8.8 Hz, 2H), 7.06 (d, J¼8.8 Hz, 2H), 6.85 (d,
J¼7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 162.4, 152.5, 148.6, 142.4,
130.5, 130.0, 122.8, 114.1, 113.5; MS (ESI): 283.8 [MþH]þ; HRMS
(ESI) [MþH]þ calcd for C11H8BrClNO: 283.9468, found: 283.9472.
4.1.9. Compound 3g. Yellow liquid; 1H NMR (CDCl3, 400 MHz): 8.05
(dd, J1¼2.0 Hz, J2¼2.0 Hz,1H), 7.90 (dd, J1¼1.6 Hz, J2¼2.0 Hz,1H), 7.40
(t, J¼8.0 Hz, 2H), 7.22 (t, J¼7.2 Hz, 1H), 7.15 (d, J¼8.0 Hz 2H), 6.86 (q,
J¼4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 160.1, 153.9, 146.2, 142.8,
129.8,125.3,121.6,119.8,108.0; MS (ESI): 249.9 [MþH]þ; HRMS (ESI)
[MþH]þ calcd for C11H9BrNO: 249.9862, found: 249.9861.
4.1.19. Compound 3q. Yellow solid, mp 87.6e89.3 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.24e8.29 (m, 3H), 7.87 (dd, J1¼2.4 Hz,
J2¼2.4 Hz, 1H), 7.27 (d, J¼8.8 Hz, 2H), 6.97 (d, J¼8.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz): 161.2, 159.3, 148.7, 144.5, 142.9, 125.8, 121.2,
115.4, 114.4; MS (EI): 294.0 (Mþ); HRMS (EI) calcd for C11H7BrN2O3:
293.9640, found: 293.9643.
4.1.10. Compound 3h. Paleyellowliquid; 1H NMR (CDCl3, 400 MHz):
8.04 (dd, J1¼1.6 Hz, J2¼1.6 Hz,1H), 7.89 (dd, J1¼1.2 Hz, J2¼1.6 Hz,1H),
7.19 (d, J¼5.2 Hz, 2H), 7.03 (d, J¼8.4 Hz, 2H), 6.84 (dd, J1¼4.4 Hz,
J2¼4.8 Hz 1H), 2.35 (s, 3H); 13C NMR (CDCl3, 100 MHz): 160.3, 151.6,
146.2, 142.7, 134.9, 130.4, 121.5, 119.5, 107.8, 21.2; MS (EI): 264.0
(Mþ); HRMS (EI) calcd for C12H10BrNO: 262.9946, found: 262.9950.
4.1.20. Compound 3r. Pale yellow solid, mp 83.3e84.3 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.18 (d, J¼2.4 Hz, 1H), 7.90 (dd, J1¼8.4 Hz,
J2¼8.0 Hz, 2H), 7.72e7.75 (m, 2H), 7.42e7.51 (m, 3H), 7.21 (d,
J¼8.0 Hz, 1H), 6.85 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
163.4, 149.9, 148.9, 142.3, 135.2, 128.3, 127.6, 126.8, 126.6, 126.0,
125.7, 122.1, 117.5, 113.8, 112.7; MS (EI): 298.1 (Mþ); HRMS (EI) calcd
for C15H9BrNO: 297.9868, found: 297.9867.
4.1.11. Compound 3i. White solid, mp 86.6e87.3 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.05 (dd, J1¼0.8 Hz, J2¼0.8 Hz, 1H), 7.90
(d, J¼7.6 Hz, 1H); 7.09 (d, J¼8.8 Hz, 2H), 6.93 (d, J¼8.8 Hz, 2H), 6.85
(dd, J1¼5.2 Hz, J2¼4.8 Hz, 1H), 3.81 (s, 3H); 13C NMR (CDCl3,
100 MHz): 160.5, 157.1, 147.3, 146.2, 142.8, 122.8, 119.5, 114.9, 107.7,
55.9; MS (ESI): 280.0 [MþH]þ; HRMS (ESI) [MþH]þ calcd for
C12H11BrNO2: 279.9968, found: 279.9967.
4.1.21. Compound 3s. Colorlessliquid;1HNMR(CDCl3,400MHz):7.95
(d, J¼2.0 Hz, 1H), 7.72 (d, J¼2.0 Hz, 1H), 7.20 (d, J¼8.4 Hz, 2H), 7.02 (dt,
J1¼2.4 Hz, J2¼2.0 Hz, 2H), 2.35 (s, 3H); 13CNMR(CDCl3,100MHz):158.1,
151.2, 143.7, 138.9, 135.2, 130.4, 125.5, 121.4, 119.6, 21.1; MS (EI): 252.1
(Mþ); HRMS (EI) calcd for C12H9Cl2NO: 253.0061, found: 253.0060.
4.1.12. Compound 3j. Pale yellow solid, mp 58.6e60.3 ꢀC; 1H NMR
(CDCl3, 400 MHz): 8.05 (dd, J1¼1.2 Hz, J2¼1.2 Hz, 1H), 7.92
(dd, J1¼1.6 Hz, J2¼1.6 Hz,1H), 7.36 (d, J¼10.0 Hz, 2H), 7.10 (d, J¼8.8 Hz,
2H), 6.89 (dd, J1¼4.8 Hz, J2¼4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
159.8,152.4,146.1,143.0,130.6,129.8,123.1,120.1,107.9;MS(EI):285.0
(Mþ); HRMS (EI) calcd for C11H6BrClNO: 281.9321, found: 281.9325.
4.1.22. Compound 3t. Colorless liquid; 1H NMR (CDCl3, 400 MHz):
8.26 (s, 1H), 7.96 (d, J¼2.0 Hz, 1H), 7.24 (d, J¼8.4 Hz, 2H), 7.05 (d,
J¼8.4 Hz, 2H), 2.38 (s, 3H); 13C NMR (CDCl3, 100 MHz): 161.8, 150.8,
142.9 (q, J¼4.3 Hz),136.5 (d, J¼2.7 Hz),135.8,130.6, 124.5,122.2 (m),
121.6, 119.5, 21.2; MS (EI): 287.1 (Mþ); HRMS (EI) calcd for
C13H9ClF3NO: 287.0325, found: 287.0324.
4.1.13. Compound 3k. Pale yellow solid, mp 100.4e101.7 ꢀC; 1H
NMR (CDCl3, 400 MHz): 8.29 (d, J¼8.8 Hz, 2H), 8.12 (dd, J1¼1.6 Hz,
J2¼1.6 Hz,1H), 8.00 (dd, J1¼1.2 Hz, J2¼1.2 Hz,1H), 7.29e7.31 (m, 2H),
7.02 (q, J¼4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 159.2, 158.9,
146.3, 144.8, 143.5, 125.8, 121.6, 121.3, 108.6; MS (EI): 294.0 (Mþ);
HRMS (EI) calcd for C11H7BrN2O3: 293.9640, found: 293.9638.
4.1.23. Compound 3u. Colorless liquid; 1H NMR (CDCl3, 400 MHz):
8.10 (s, 1H), 7.35 (d, J¼1.6 Hz, 1H), 7.20 (d, J¼6.4 Hz, 4H), 7.02 (dd,
J1¼8.4 Hz, J2¼8.0 Hz, 4H), 2.36 (s, 6H); 13C NMR (CDCl3, 100 MHz):
157.9, 153.5, 151.0, 139.0 (d, J¼724.2 Hz), 138.0 (q, J¼5.0 Hz), 134.7,
130.9, 130.4, 124.9, 122.8, 122.2 (d, J¼8.0 Hz), 121.9, 121.7, 119.2, 21.1,
21.0; MS (EI): 359.0 (Mþ); HRMS (EI) calcd for C20H16F3NO2:
359.1133, found: 359.1129.
4.1.14. Compound 3l. Yellow solid, mp 86.6e87.3 ꢀC; 1H NMR
(CDCl3, 400 MHz): 7.92e7.96 (m, 3H), 7.86 (d, J¼7.6 Hz, 1H), 7.72
(d, J¼8.4 Hz, 1H), 7.42e7.49 (m, 3H), 7.28 (d, J¼7.6 Hz, 1H), 6.83
(q, J¼4.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 160.4, 149.9, 146.4,
142.9, 135.2, 128.2, 127.6, 126.6, 126.5, 125.8, 125.6, 122.1, 119.9,
117.8, 107.7; MS (ESI): 324.0 (MþHþNa)þ; HRMS (ESI) [MþH]þ
calcd for C15H11BrNO: 300.0019, found: 300.0021.
4.1.24. Compound 4. Brown liquid; 1H NMR (CDCl3, 400 MHz): 8.50
(d, J¼5.2 Hz, 1H), 7.81 (d, J¼8.4 Hz, 2H), 7.40 (t, J¼8.0 Hz, 2H),
7.21e7.26 (m, 4H), 7.11 (d, J¼8.0 Hz, 2H), 6.73 (dd, J1¼2.4 Hz,
J2¼2.4 Hz,1H), 2.37 (s, 3H); 13C NMR (CDCl3, 100 MHz): 165.8, 159.8,
154.5, 151.2, 139.4, 136.4, 130.4, 129.6, 127.0, 125.5, 120.9, 110.6,
109.0, 21.5; MS (ESI): 262.1 [MþH]þ; HRMS (ESI) [MþH]þ calcd for
C18H16NO: 262.1226, found: 262.1223.
4.1.15. Compound 3m. Pale yellow liquid; 1H NMR (CDCl3,
400 MHz): 8.21 (d, J¼2.4 Hz, 1H), 7.74 (dd, J1¼2.4 Hz, J2¼3.2 Hz, 1H),
7.39 (t, J¼8.0 Hz, 2H), 7.22 (t, J¼5.6 Hz, 1H), 7.11 (d, J¼8.0 Hz, 2H),
6.81 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 162.8, 154.0,
148.6, 142.2, 130.0, 125.3, 121.4, 113.7, 113.3; MS (EI): 250.0 (Mþ);
HRMS (EI) calcd for C11H8BrNO: 248.9789, found: 248.9785.
4.1.25. Compound 5. Pale yellow liquid; 1H NMR (CDCl3, 400 MHz):
8.43 (d, J¼5.6 Hz, 1H), 7.44 (dd, J1¼8.0 Hz, J2¼7.6 Hz, 4H), 7.24e7.28
(m,1H), 7.11 (dd, J1¼8.0 Hz, J2¼7.6 Hz, 4H), 7.02 (d, J¼2.4 Hz,1H), 6.79
(dd, J1¼2.0 Hz, J2¼2.4 Hz, 1H), 2.34 (s, 3H); 13C NMR (CDCl3,
100 MHz): 165.1, 154.0, 151.5, 145.2, 139.5, 132.2, 130.5, 129.3, 125.8,
121.0, 119.1, 115.2, 111.7, 90.1, 88.0, 21.7; MS (ESI): 286.0 [MþH]þ;
HRMS (ESI) [MþH]þ calcd for C20H16NO: 286.1226, found: 286.1222.
4.1.16. Compound 3n. Pale yellow liquid; 1H NMR (CDCl3,
400 MHz): 8.20 (d, J¼1.6 Hz,1H), 7.72 (dd, J1¼2.8 Hz, J2¼2.0 Hz,1H);
7.19 (d, J¼8.0 Hz, 2H), 6.99e7.01 (m, 2H), 6.79 (d, J¼8.8 Hz, 1H), 2.35
(s, 3H); 13C NMR (CDCl3, 100 MHz): 163.1, 151.6, 148.5, 142.1, 134.9,
130.5, 121.3, 113.4, 113.1, 21.1; MS (ESI): 264.1 [MþH]þ; HRMS (ESI)
[MþH]þ calcd for C12H11BrNO: 264.0013, found: 264.0019.
4.1.17. Compound 3o. Pale yellow liquid; 1H NMR (CDCl3,
400 MHz): 8.20 (d, J¼2.4 Hz,1H), 7.72 (dd, J1¼2.4 Hz, J2¼2.8 Hz, 1H),
4.1.26. Compound 6. Yellow solid, mp 91e92 ꢀC; 1H NMR (CDCl3,
400 MHz): 8.99e8.89 (m, 1H), 8.17e8.25 (m, 2H), 7.79 (dd,

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333
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416e417.
J1¼2.4 Hz, J2¼2.4 Hz,1H), 7.56e7.51 (m, 1H), 7.45e7.48 (m, 2H), 6.96
(s, 1H), 6.81e6.84 (m, 1H); 13C NMR (CDCl3, 100 MHz): 166.8, 151.1
(d, J¼4.2 Hz), 149.5, 143.1, 141.4, 136.5, 130.3, 126.9, 126.4, 122.4,
121.1, 115.9, 112.0; MS (EI): 301.0 (Mþ); HRMS (EI) calcd for
C14H9BrN2O: 299.9898, found: 299.9893.
6. Sakurai, K.; Niwa, S.; Oono, S.; Uchita, H. Jpn. Kokai Tokkyo Koho, 1998,
JP 10029979 A 19980203.
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4.1.27. Compound 7. White solid, mp 129e130 ꢀC; 1H NMR (CDCl3,
400 MHz): 8.91 (dd, J1¼1.6 Hz, J2¼1.6 Hz, 1H), 8.53 (d, J¼5.2 Hz, 1H),
8.24 (dd, J1¼1.6 Hz, J2¼1.6 Hz, 1H), 8.02 (d, J¼8.4 Hz, 2H), 7.78 (d,
J¼8.4 Hz,1H), 7.67 (d, J¼8.0 Hz, 2H), 7.58 (t, J¼8.0 Hz,1H), 7.42e7.50
(m, 3H), 6.77 (dd, J1¼2.4 Hz, J2¼2.4 Hz, 1H); 13C NMR (CDCl3,
100 MHz): 166.6, 158.1, 151.6, 151.0, 150.3, 142.8, 141.7, 136.5, 131.1
(q, J¼32.7 Hz), 130.3, 127.5, 126.9, 125.8 (t, J¼5.1 Hz), 124.4 (d,
J¼811.8 Hz), 123.1, 122.4, 120.7, 111.4, 110.0; MS (EI): 365.0 (Mþ);
HRMS (EI) calcd for C21H13F3N2O: 366.0980, found: 366.0981.
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Acknowledgements
This work was supported by the Natural Science Foundation of
China (21172166) and Zhejiang Province (Y4100783) for support of
grant.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.10.025.
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