Synthesis of 5-amino or 4-amino substituted 7-AZA-isoindolin-1-ones

Article abstract of DOI:10.3987/COM-13-12720

A simple and convenient route for the synthesis of a series of 5-amino or 4-amino substituted 7-aza-isoindolin-1-ones is described. Amino substituted pyridine derivatives were cyclized with different amines in alkaline condition to give the desired produc

Full text of DOI:10.3987/COM-13-12720

HETEROCYCLES, Vol. 87, No. 6, 2013, pp.. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 28th March, 2008, Accepted, 25th April, 2013, Published online, 10th May, 2013
DOI: 10.3987/COM-13-12720
SYNTHESIS
OF
5-AMINO
OR
4-AMINO
SUBSTITUTED
7-AZA-ISOINDOLIN-1-ONES
Heng Zhou, Qunfeng Shi, Xiangchao Liu, Xiaoping Zhan, Zenglu Liu, and
Zhenmin Mao*
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China
E-mail: mzmsjtu@gmail.com
Abstract – A simple and convenient route for the synthesis of a series of 5-amino
or 4-amino substituted 7-aza-isoindolin-1-ones is described. Amino substituted
pyridine derivatives were cyclized with different amines in alkaline condition to
give the desired products.
INTRODUCTION
Isoindolin-1-one and its aza-heterocyclic derivatives are well known by synthetic and biological chemists.
They are important structure units present in many bioactive molecules that possess a wide spectrum of
1
-4
biological activities and have been therefore the subject of continuing chemical study. With further
exploration, it is found that the substitution of amino group on the aromatic nuleus of some isoindolinones
5
-8
can increase the bioactivity or even lead to a new type of activity. A few methods for the synthesis of
9
10
11,12
amino substituted 4-aza, 5-aza and 6-aza
isoindolinones are reported. However, there are no data on
the 5-amino or 4-amino substituted analogs of 7-aza-isoindolin-1-one in the literature.
At the onset of the research, we examined the synthesis of amino substituted 7-aza-isoindolin-1-one
derivatives through the construction of 7-aza-isoindolinones followed by amino or nitro (which can be
reducted to amino easily) substitution on the pyridine ring. However, there are no obvious product
2 3 2 4
observed when using NaNH or HNO /H SO with 7-aza-isoindolinones. We decided to synthesize these
compounds with another strategy: amino substituted pyridine compounds will be established before
fusing of pyrrolidinones.
RESULTS AND DISCUSSION
5
-Amino substituted analogs of 7-aza-isoindolin-1-one were synthesized by the methodology as shown in
Scheme 1. The nitration of 1 with tetrabutylammonium nitrate method afforded 2 under mild

1
3,14
conditions.
given by the electrophilic substitution on 3 in the NBS/NH
N-bromosuccinimide (NBS) / azodiisobutyronitrile (AIBN) with 4 afforded 5 at reflux. Different amines
Compound 3 was obtained by Pd/C catalyzed hydrogenation reduction. Compound 4 was
1
5
4
OAc system. The free radical reaction of
(
a-d) were reacted with 5 in alkaline condition to form the final 5-amino-4,6-dibromo-7-aza-iso-
1
6,17
indolinones 6a-d.
Br
N
H N
H N
O N
2
iii
2
2
i
ii
N
CO Me
Br
CO Me
2
N
1
CO Me
N
CO Me
2
2
2
3 (92.2%)
4 (83.0%)
2 (50.0%)
Br
Br
H N
H N
v
2
2
iv
Br
N R
O
H N R
2
Br
N
Br
N
5
CO Me
a-d
2
6a-d
(50.0%)
+
－
Scheme 1. Reagents and conditions: (i) Bu
4
N NO
3
3
, (CF CO)
2
O, CH
2
Cl
2 2
, rt; (ii) 10% Pd/C, H , MeOH,
rt; (iii) NBS, NH OAc, MeCN; (iv) NBS, AIBN, CCl
4
4
, reflux; (v) K
2
CO
3
, MeCN, rt to reflux.
4
-Amino substituted analogs of 7-aza-isoindolin-1-one were synthesized according to Scheme 2, with
similar thinking way. The difference is that the oxidation of pyridine N atom is necessary for involving
1
8
nitro group on the para-position. Moreover, the amount of NBS used to synthesis 10 was 1.1 equivalents
of 9, while 4 was synthesized by 2.0 equivalents NBS with 1.0 equivalent 3. This is due to the strong
electron-donating effect of amino group which can improve the nucleophilic capability of its
ortho-position.
NO2
NH2
NH
2
Br
iv
iii
i
ii
N
CO Me
N
CO Me
N
CO
Me
2
N
O
CO Me
2
2
N
CO Me
2
2
O
8
1
0 (88.0%)
9
(91.2%)
(62.1%)
1
7 (65.3%)
NH2
NH2
Br
Br
vi
v
Br
N R
H N R
2
N
N
CO Me
2
a-d
O
1
2a-d
1
1 (60.5%)
Scheme 2. Reagents and conditions: (i) 30% H
5-100 C; (iii) 10% Pd/C, H , MeOH, rt; (iv) NBS, NH
CO , MeCN, rt to reflux.
2
O
2
, HOAc, rt to 80 C; (ii) fuming HNO
3 2 4
, H SO ,
9
K
2
4
OAc, MeCN; (v) NBS, AIBN, CCl , reflux; (vi)
4
2
3

Methyl bromination of 2 or 8 was hard to proceed, because the polarization of nitro group weakened the
conjugated system which can stabilize the generated free radical. In addition, though reaction (iii) and (iv)
in Scheme 1 are both bromination reaction, the mechanism between them is different. Reaction (iii) is
electrophilic substitution on pyridine ring. But (iv) is free radical reaction on methyl group. A strange
4
phenomenon was that, if 3 was reacted with NBS/AIBN at reflux in CCl directly (free radical conditions),
the mixture would generated including 4, 5, 13 and other by-products, which were hard to be separated. It
may be attributed to the strong electron-donating effect of amino group. Similar results occurred on 9.
H N
2
H N
2
NBS, AIBN
CCl , reflux
4
+ 5 +
4
Br
N
2
CO Me
N
3
2
CO Me
13
It was noticed that the yields of 6a-d and 12a-d were relevant to the amines used (Table1). The products
of amines a and b were relatively of high yield. It may be due to the nucleophilicity of amino group
elevated by the electron-donating group on the benzene. The products of amine c were lower than d. It
might be that the exsitence of two trifluoromethyl group leads to generate nitrogen anion in alkaline
condition, which is beneficial for the nucleophilic attack to bromomethyl group. This assumption needs to
be proved by further studies.
Table 1. Amines (a-d) and corresponding amino substituted 7-aza-isoindolinones (6a-d and 12a-d)
Entry
Amines
6a-d
Yield(%)
12a-d
Yield(%)
Br
N
NH2
H N
Br
2
a
N
65.6%
66.7%
N
H N
2
Br
N
O
O
NH2
OMe
OMe
CF3
Br
OMe
OMe
H N
Br
2
b
c
H N
70.3%
30.2%
60.1%
43.5%
N
N
2
Br
N
N
O
OMe
CF3
O
OMe
CF3
Br
NH2
H N
Br
2
N
N
H N
2
Br
N
N
O
O

CF3
Br
N
NH2
CF3
CF3
CF3
H N
Br
2
d
H N
N
59.8%
55.3%
2
N
Br
N
CF3
O
CF
3
O
EXPERIMENTAL
Melting points were determined on a SGW X-4 melting point instrument and were uncorrected. HNMR
1
1
3
and CNMR spectra were carried out using Bruker Advance Ⅲ 400 MHz spectrometer and
TM
MERCURYplus 300 spectrometer. HRMS was measured on a Waters ACQUITY UPLC & Q-TOF MS
Premier system. Column chromatography was performed using Silica Gel (200-300 mesh) with the
eluents indicated.
General protocol for the synthesis of compounds 6a-d and 12a-d
2 3
Amines a-d (1.1 equiv) and K CO (1.5 equiv) were added to a solution of methyl 5-amino-4,6-
dibromo-3-(bromomethyl)picolinate 5 or methyl 4-amino-5-bromo-3-(bromomethyl)picolinate 11 (1.0
equiv) in MeCN under the protection of nitrogen. The resulting mixture was stirred at room temperature
for 2 h and then heated to reflux for another 5 h. The reaction mixture was cooled to room temperature,
filtered and concentrated in vacuo. The crude residue was purified by column chromatography
(
conditions specified). And the resulting product was obtained by concentrating appropriate fractions. The
yields were specified for each individual case.
5
6
-Amino-4,6-dibromo-2-(m-tolyl)-7-aza-isoindolin-1-one (6a)
2 2
a was afforded by column chromatography (100:1 CH Cl /MeOH) as a white solid (yield 65.6%, mp
1
>
300 C). HNMR (300MHz, DMSO-d
6
) δ: 7.67~7.72 (m, 2H, NCCH), 7.29 (t, 1H, J = 7.5 Hz,
CCHCH), 6.43 (s, 2H, NH ), 4.81 (s, 2H, CH N), 2.33 (s, 3H,
CH
3
3
CCHCH), 6.98 (d, 1H, J = 6.6 Hz, CH
3
2
2
1
3
CH
). CNMR (400MHz, DMSO-d
6
) δ: 163.4, 143.1, 139.2, 138.2, 138.1, 137.5, 128.7, 128.6, 124.9,
+
1
5
6
>
19.5, 116.3, 109.2, 48.3, 21.2. ESI-HRMS: calcd for C14
H
12
N
3
OBr
2
(MH ), 395.9347, found 395.9330.
-Amino-4,6-dibromo-2-(3,5-dimethoxyphenyl)-7-aza-isoindolin-1-one (6b)
b was afforded by column chromatography (100:1 CH Cl /MeOH) as a grey solid (yield 70.3%, mp
2
2
1
300 C). HNMR (400MHz, DMSO-d
6
) δ: 7.11 (d, 2H, J = 2.0 Hz, NCCH), 6.42 (s, 2H, NH
2
), 6.35 (t,
1
3
1
H, J = 2.0 Hz, CCHC), 4.82 (s, 2H, CH
2
N ), 3.78 (s, 6H, CH
3
O). CNMR (400MHz, DMSO-d ) δ:
6
1
63.5, 160.6, 143.1, 140.8, 138.0, 137.3, 128.7, 109.1, 97.6, 96.0, 55.3, 48.4. ESI-HRMS: calcd for
+
C
15
H
14
N
3
O
3
Br
2
(MH ), 441.9402, found 441.9395.
5
6
-Amino-4,6-dibromo-2-[3-(trifluoromethyl)phenyl]-7-aza-isoindolin-1-one (6c)
c was afforded by column chromatography (200:1 CH Cl /MeOH) as a white solid (yield 30.2%, mp
2
2

1
2
93~295 C). HNMR (400MHz, DMSO-d
6
) δ: 8.39 (s, 1H, NCCHC), 8.13 (dd, 1H, J = 8.0 Hz, 2.0 Hz,
CCHCH), 6.50 (s, 2H, NH ),
) δ: 163.8, 143.4, 140.0, 138.4, 136.8, 130.1,
NCCHCH), 7.68 (t, 1H, J = 8.0 Hz, NCCHCH), 7.54 (d, 1H, J = 8.0 Hz, CF
3
2
1
3
4
.95 (s, 2H, CH
2
N). CNMR (400MHz, DMSO-d
6
129.1~130.1, 128.8, 122.7~125.4, 122.4, 120.4, 115.1~115.2, 108.9, 48.3. ESI-HRMS: calcd for
+
C
14
H
9
N
3
OF
3
Br
2
(MH ), 449.9064, found 449.9078.
5
6
-Amino-4,6-dibromo-2-[3,5-bis(trifluoromethyl)phenyl]-7-aza-isoindolin-1-one (6d)
2 2
d was afforded by column chromatography (200:1 CH Cl /MeOH) as a white solid (yield 59.8%, mp
1
>
300 C). HNMR (400MHz, DMSO-d ) δ: 8.60 (s, 2H, NCCH), 7.87 (s, 1H, CCHC), 6.57 (s, 2H, NH ),
6
2
1
3
5
.04 (s, 2H, CH
2
N). CNMR (400MHz, DMSO-d
6
) δ: 164.2, 143.7, 141.1, 138.6, 136.2, 130.7~131.1,
+
128.9, 121.8~124.5, 118.6, 116.7, 108.7, 48.5. ESI-HRMS: calcd for C15
H
8
N
3
OF
6
Br
2
(MH ), 517.8938,
found 517.8929.
4
1
2
1
2
1
-Amino-5-bromo-2-(m-tolyl)-7-aza-isoindolin-1-one (12a)
2 2
2a was afforded by column chromatography (100:1 CH Cl /MeOH) as a white solid (yield 66.7%, mp
1
74~276 C). HNMR (300MHz, DMSO-d
6
) δ: 8.39 (s, 1H, NCH), 7.64~7.69 (m, 2H, NCCH), 7.32 (t,
CCHCH), 6.85 (s, 2H, NH ), 4.76 (s, 2H, NCH ),
H, J = 7.8 Hz, NCCHCH), 7.01 (d, 1H, J = 7.8 Hz, CH
3
2
2
13
.34 (s, 3H, CH
3
). CNMR (400MHz, DMSO-d
6
) δ: 164.9, 151.6, 148.5, 147.0, 139.4, 138.3, 128.9,
+
25.0, 121.1, 119.5, 116.2, 106.6, 46.9, 21.3. ESI-HRMS: calcd for C14
H
13
N
3
OBr (MH ), 318.0242,
found 318.0239.
4
1
2
-Amino-5-bromo-2-(3,5-dimethoxyphenyl)-7-aza-isoindolin-1-one (12b)
2b was afforded by column chromatography (100:1 CH
2
Cl
2
/MeOH) as a white solid (yield 60.1%, mp
), 7.08 (s, 2H,
1
84~287 C). HNMR (300MHz, DMSO-d
6
) δ: 8.56 (s, 1H, NCH), 7.53 (s, 2H, NH
2
1
3
NCCH), 6.41 (s, 1H, CCHC), 3.71 (s, 6H, CH O). CNMR (400MHz, DMSO-d ) δ: 162.7, 160.7, 149.5,
3
6
+
1
3
4
1
>
47.5, 144.6, 140.3, 121.1, 105.8, 97.6, 96.4, 55.3, 47.8. ESI-HRMS: calcd for C15
15 3 3
H N O Br (MH ),
64.0297, found 364.0281.
-Amino-5-bromo-2-[3-(trifluoromethyl)phenyl]-7-aza-isoindolin-1-one (12c)
2c was afforded by column chromatography (150:1 CH Cl /MeOH) as a white solid (yield 43.5%, mp
2
2
1
300 C). HNMR (400MHz, DMSO-d
6
) δ: 8.44 (s, 1H, NCH), 8.24 (s, 1H, NCCHC), 8.14 (d, 1H, J =
8
2
1
.0 Hz, NCCHCH), 7.72 (t, 1H, J = 8.4 Hz, NCCHCH), 7.55 (d, 1H, J = 8.0 Hz, NCCHCHCH), 6.84 (s,
1
3
2 2 6
H, NH ), 4.87 (s, 2H, NCH ). CNMR (400MHz, DMSO-d ) δ: 165.6, 152.0, 148.2, 147.0, 140.1, 130.3,
10 3 3
29.3~130.1, 122.7~125.4, 122.2, 121.3, 120.4, 114.8, 106.8, 46.8. ESI-HRMS: calcd for C14H N OF Br
+
(
MH ),371.9959, found 371.9952.
4
1
-Amino-5-bromo-2-[3,5-bis(trifluoromethyl)phenyl]-7-aza-isoindolin-1-one (12d)
2d was afforded by column chromatography (150:1 CH Cl /MeOH) as a white solid (yield 55.3%, mp
2
2

1
>
300 C). HNMR (400MHz, DMSO-d
6
) δ: 8.54 (s, 1H, NCH), 8.50 (s, 2H, NCCH), 7.98 (s, 1H, CCHC),
1
3
7
2 2 6
.32 (s, 2H, NH ), 5.00 (s, 2H, NCH ). CNMR (400MHz, DMSO-d ) δ: 164.0, 149.1, 148.8, 144.6,
9 3 6
140.6, 130.5~131.5, 121.7~124.4, 121.5, 118.6, 117.4, 106.3, 47.5. ESI-HRMS: calcd for C15H N OF Br
+
(
MH ), 439.9833, found 439.9807.
Methyl 3-methyl-5-nitropicolinate (2)
Trifluoroacetic anhydride (3.06 mL, 0.022 mol) was added dropwise at 0 C to a solution of methyl
-methylpicolinate 1 (1.52 g, 0.010 mol) and tetrabutylammonium nitrate (3.35 g, 0.011 mol) in CH Cl2
3
2
(
50 mL). The mixture was stirred at room temperature for 18 h after which it was neutralized with
saturated aqueous Na CO solution, extracted with CH Cl and the organic layer was dried (anhydrous
2
3
2
2
Na
2
SO
4
), concentrated, and purified by chromatography (6:1 cyclohexane/EtOAc) to afford 2 as white
1
solid (0.98 g, yield 50.0%, mp 80~82 C). HNMR (300MHz, CDCl ): δ 9.30 (s, 1H, NCH), 8.41 (s, 1H,
3
NCHCCH, 4.02 (s, 3H, CH
Methyl 5-amino-3-methylpicolinate (3)
0% Pd/C (50 mg) was added to a solution of methyl 3-methyl-5-nitropicolinate 2 (0.96 g, 4.9 mmol) in
MeOH (15 mL) at room temperature. The resulting mixture was stirred under H (1 atm) for 2 h and then
3 3
O), 2.70 (s, 3H, CH ).
1
2
filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography (50:1
1
CH
2
Cl
2
/MeOH) to afford 3 as offwhite solid (0.75 g, yield 92.2%, mp 145~146 C). HNMR (300MHz,
CDCl ): δ 8.00 (d, 1H, J = 2.4 Hz, NCH), 6.79 (d, 1H, J = 2.4 Hz, NCHCCH), 3.92 (s, 3H, CH O), 2.56
3
3
3
(s, 3H, CH ).
Methyl 5-amino-4,6-dibromo-3-methylpicolinate (4)
N-Bromosuccinimide (2.14 g, 12 mmol) was added to a solution of methyl 5-amino-3-methylpicolinate 3
0.98 g, 6 mmol) and NH OAc (31 mg, 0.4 mmol) in MeCN (20 mL). The mixture was stirred at room
(
4
temperature for 5 h and then concentrated in vacuo. The residue was purified by chromatography (6:1
1
cyclohexane/EtOAc) to afford 4 as faint yellow solid (1.07 g, yield 83.0%, mp 146~148 C). HNMR
(300MHz, CDCl
3 2 3 3
) δ: 5.01 (s, 2H, NH ), 3.93 (s, 3H, OCH ), 2.67 (s, 3H, CH ).
Methyl 5-amino-4,6-dibromo-3-(bromomethyl)picolinate (5)
A mixture of methyl 5-amino-4,6-dibromo-3-methylpicolinate 4 (400 mg, 1.24 mmol) in CCl (20 mL)
4
with N-bromosuccinimide (264 mg, 14.8 mmol) and azodiisobutyronitrile (90 mg, 0.54 mmol) was
refluxed for 5 h. The reaction mixture was then cooled to room temperature, filtered and concentrated
under reduced pressure. The residue was purified by chromatography (10:1 cyclohexane/acetone) to
1
afford 5 as yellow solid (250 mg, yield 50.0%, mp 84~86 C). HNMR (300MHz, CDCl
3
) δ: 5.14 (s, 2H,
2 2 3
NH ), 5.11 (s, 2H, BrCH ), 3.97 (s, 3H, CH O)
2
-(Methyoxycarbonyl)-3-methylpyridine 1-oxide (7)

Cold (5 C) 30% hydrogen peroxide (7 mL, 66 mmol) was added to a solution of methyl
-methylpicolinate 1 (5 g, 33 mmol) in glacial AcOH (15 mL) at room temperature. The mixture was
3
heated in an oil bath for 24 h, with the internal temperature adjusted to 80±5 C. The excess AcOH and
water are removed under reduced pressure. The residue was cooled to 0-5 C and neutralized with
saturated Na
2
CO
3
solution, extracted with CH
2
Cl
2
and the organic layer was dried (anhydrous Na
2
4
SO ),
concentrated, and purified by chromatography (50:1 CH Cl /MeOH) to give 7 as paint yellow liquid (3.6
2 2
1
g, yield 65.3%). HNMR (300MHz, CDCl ): δ 8.05 (d, 1H, J = 3.2 Hz, NCH), 7.20 (d, 1H, J = 3.3 Hz,
3
NCHCHCH), 7.10~7.16 (m, 1H, NCHCH), 3.99 (s, 3H, CH
3
O), 2.26 (s, 3H, CH
-(Methyoxycarbonyl)-3-methyl-4-nitropyridine 1-oxide (8)
-(Methyoxycarbonyl)-3-methylpyridine 1-oxide 7 (2.3 g, 13.8 mmol) was added to cold conc.sulfuric
3
).
2
2
acid (15 mL). And fuming yellow nitric acid (4 mL) was added dropwise to the solution for 20 min. Then
the mixture was heated slowly to 95-100 C and reacted for 5 h. When the temperature was cooled down,
the mixture was neutralized with saturated aqueous Na CO solution at 0 C, extracted with CH Cl and
2
3
2
2
the organic layer was dried (anhydrous Na
CH Cl
300MHz, CDCl
2
SO
4
), concentrated, and purified by chromatography (75:1
1
2
2
/MeOH) to afford 8 as faint yellow solid (1.8 g, yield 62.1%, mp 166~168 C). HNMR
(
3
): δ 8.15 (d, 1H, J = 3.3 Hz, NCH), 8.02 (d, 1H, J = 3.4 Hz, NCHCH), 4.06 (s, 3H,
CH
3
O), 2.55 (s, 3H, CH ).
3
Methyl 4-amino-3-methylpicolinate (9)
0% Pd/C (50 mg) was added to a solution of 2-(methyoxycarbonyl)-3-methyl-4- nitropyridine 1-oxide 8
0.7 g, 3.3 mmol) in MeOH (15 mL) at room temperature. The resulting mixture was stirred under H (1
atm) for 4 h and then filtered. The filtrate was concentrated in vacuo and the residue was purified by
1
(
2
chromatography (50:1 CH
2
Cl
): δ 8.18 (d, 1H, J = 2.8 Hz, NCH), 6.65 (d, 1H, J = 2.7 Hz, NCHCH), 4.28 (s,
O), 2.55 (s, 3H, CH ).
2
/MeOH) to afford 9 as white solid (0.5 g, yield 91.2%, mp 65~67 C).
1
HNMR (300MHz, CDCl
3
2
H, NH ), 3.97 (s, 3H, CH
2
3
3
Methyl 4-amino-5-bromo-3-methylpicolinate (10)
N-Bromosuccinimide (1.22 g, 6.8 mmol) was added to a solution of methyl 4-amino-3-methylpicolinate 9
(
1.03 g, 6.2 mmol) and NH OAc (53 mg, 0.7 mmol) in MeCN (20 mL). The mixture was stirred at room
4
temperature for 1 h and then concentrated in vacuo. The residue was purified by chromatography (100:1
1
CH
300MHz, CDCl
Methyl 4-amino-5-bromo-3-(bromomethyl)picolinate (11)
A mixture of methyl 4-amino-5-bromo-3-methylpicolinate 10 (500 mg, 2.0 mmol) in CCl
N-bromosuccinimide (427 mg, 2.4 mmol) and azodiisobutyronitrile (164 mg, 1.0 mmol) was refluxed for
2
Cl
2
/MeOH) to afford 10 as faint yellow solid (1.33 g, yield 88.0%, mp 135~137 C). HNMR
(
3 2 3 3
) δ: 8.47(s, 1H, NCH), 4.89 (s, 2H, NH ), 4.01 (s, 3H, OCH ), 2.50 (s, 3H, CH ).
4
(25 mL) with

1
h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced
pressure. The residue was purified by chromatography (200:1 CH
2
Cl
2
/MeOH) to afford 11 as yellow solid
),
1
(
392 mg, 60.5%, mp 228~231 C). HNMR (300MHz, CDCl
3
) δ: 8.34 (s, 1H, NCH), 5.10 (s, 2H, NH
2
2 3
4.77 (s, 2H, BrCH ), 3.88 (s, 3H, CH O).
ACKNOWLEDGEMENTS
The authors are grateful for the financial support by the National Significant and Special Project of New
Created Drugs. The Instrumental Analysis Center of Shanghai Jiaotong University and Shanghai
Zhongke Qiaochang Crop Protection Inc. are acknowledged for providing all the spectra data.
REFERENCES
1
.
M. R. Lunn, D. E. Root, A. M. Martino, S. P. Flaherty, B. P. Kelley, D. D. Coovert, A. H. Burghes,
N. T. Man, G. E. Morris, J. Zhou, E. J. Androphy, C. J. Sumner, and B. R. Stockwell, Chem. Biol.,
2
004, 11, 1489.
2
.
.
U. Galli, O. Mesenzani, C. Coppo, G. Sorba, P. L. Canonico, G. C. Tron, and A. A. Genazzani, Eur.
J. Med. Chem., 2012, 55, 58.
3
Z. Shen, P. S. Ramamoorthy, N. T. Hatzenbuhler, D. A. Evrard, W. Childers, B. L. Harrison, M.
Chlenov, G. Hornby, D. L. Smith, K. M. Sullivan, L. E. Schechter, and T. H. Andree, Bioorg. Med.
Chem. Lett., 2010, 20, 222.
4
.
C. Alhambra, C. Becker, T. Blake, A. Chang, J. R. Damewood, T. Daniels, B. T. Dembofsky, D. A.
Gurley, J. E. Hall, K. J. Herzog, C. L. Horchler, C. J. Ohnmacht, R. J. Schmiesing, A. Dudley, M. D.
Ribadeneira, K. S. Knappenberger, C. Maciag, M. M. Stein, M. Chopra, X. F. Liu, E. P. Christian, J.
L. Arriza, and M. J. Chapdelaine, Bioorg. Med. Chem., 2011, 19, 2927.
5
6
7
8
.
.
.
.
.
L. Fu, X. Liu, C. Ling, J. Cheng, X. Guo, H. He, S. Ding, and Y. Yang, Bioorg. Med. Chem. Lett.,
2
012, 22, 814.
H. Fujimoto, T. Noguchi, H. Kobayashi, H. Miyachi, and Y. Hashimoto, Chem. Pharm. Bull., 2006,
4, 855.
5
G. W. Muller, R. Chen, S.-Y. Huang, L. G. Corral, L. M. Wong, R. T. Patterson, Y. Chen, G. Kaplan,
and D. I. Stirling, Bioorg. Med. Chem. Lett., 1999, 9, 1625.
M. Suizu, Y. Muroya, H. Kakuta, H. Kagechika, A. Tanatani, K. Nagasawa, and Y. Hashimoto,
Chem. Pharm. Bull., 2003, 51, 1098.
9
1
1
J. B. Campbell and J. W. Firor, J. Org. Chem., 1995, 60, 5243.
0. D. Taniyama, Y. Mitsuoka, and K. Hata, PCT Int. Appl., 2010, WO2010125799, A120101104.
1. V. S. Berseneva, V.A. Bakulev, W. Dehaen, S. Toppet, and M. Borovkova, Tetrahedron, 2007, 63,

4
491.
2. A. N. Vasiliev, A. N. Lyshchikov, O. E. Nasakin, and Ya.S. Kayukov, Chem. Heterocycl. Compd.,
004, 40, 460.
1
1
2
3. F. George Njoroge, B. Vibulbhan, P. Pinto, T.-M. Chan, R. Osterman, S. Remiszewski, J. Del
Rosario, R. Doll, V. Girijavallabhan, and A. K. Ganguly, J. Org. Chem., 1998, 63, 445.
4. J. V. Crivello, J. Org. Chem., 1981, 46, 3056.
1
1
5. B. Das, K. Venkateswarlu, A. Majhi, V. Siddaiah, and K. R. Reddy, J. Mol. Catal. A: Chem., 2007,
2
67, 30.
1
6. B. Fan, Z. Liu, M. Tang, Y. Xu, X. Tang, and Z. Mao, Synth. Commun., 2008, 38, 3231.
1
7. E. A. Wydysh, S. M. Medghalchi, A. Vadlamudi, and C. A. Townsend, J. Med. Chem., 2009, 52,
3
317.
1
8. E. C. Taylor and A. J. Crovetti, Org. Synth., 1963, 4, 654.