Synthesis of 4-methoxy and 5-methoxy substituted 7-aza-isoindolin-1-ones

Article abstract of DOI:10.3987/COM-13-12785

A simple and convenient route for the synthesis of a series of 4-methoxy or 5-methoxy substituted 7-aza-isoindolin-1-ones is described. Methoxyl substituted pyridine derivatives were cyclized with different amines under alkaline condition to give the desi

Full text of DOI:10.3987/COM-13-12785

HETEROCYCLES, Vol. 87, No. 10, 2013
2071
HETEROCYCLES, Vol. 87, No. 10, 2013, pp. 2071 - 2079. © The Japan Institute of Heterocyclic Chemistry
Received, 21st July, 2013, Accepted, 28th August, 2013, Published online, 12th September, 2013
DOI: 10.3987/COM-13-12785
SYNTHESIS OF 4-METHOXY AND 5-METHOXY SUBSTITUTED
7-AZA-ISOINDOLIN-1-ONES
Heng Zhou, Guanglong Sun, Zenglu Liu, Xiaoping Zhan, 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
4-methoxy or 5-methoxy substituted 7-aza-isoindolin-1-ones is described.
Methoxyl substituted pyridine derivatives were cyclized with different amines
under alkaline condition to give the desired products.
Isoindolinones have a common intermediate skeleton with numerous alkaloids and display various
biological properties of pharmaceutical interest.1-4 Introducing methoxyl group in the aromatic ring of
some isoindolinones could not only modulate the bioactivity of these compounds but also provide the
opportunity for further chemical modification.5-7 Although the methoxyl substituted isoindolinones are
widely used by biological and synthetic chemists, the synthesis of their aza-analogue derivatives were
rarely reported.8 We describe here a convenient synthetic route for 4-methoxy or 5-methoxy substituted
7-aza-isoindolin-1-ones.
4-Methoxy substituted analogs of 7-aza-isoindolin-1-one were synthesized according to Scheme 1.
Compound 2 was prepared by the oxidation of 1 with 30% hydrogen peroxide in HOAc. The following
nitration of 2 with a mixture of concentrated sulfuric acid and fuming nitric acid could afford 3.9
Compound 3 was then treated with K2CO3 in methanol to displace the nitro group with methoxy group
providing 4.10 Compound 5 was given by Pd/C catalyzed hydrogenation reduction. The free radical
reaction of N-bromosuccinimide (NBS)/azodiisobutyronitrile (AIBN) with 5 could generate 6 in CCl4 at
reflux. Different amines (a-e) were cyclized with 6 under alkaline condition to form the final
4-methoxy-7-aza-isoindolinones 7a-e.11,12

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HETEROCYCLES, Vol. 87, No. 10, 2013
OMe
N
NO2
OMe
iv
iii
i
ii
CO2Me
N
O
CO2Me
N
O
CO2Me
N
O
CO2Me
N
CO2Me
5 (90%)
3 (65%)
4 (91%)
2 (63%)
1
OMe
OMe
vi
v
Br
CO2Me
N R
H2N R
a-e
N
N
O
7a-e
6 (57%)
Scheme 1. Reagents and conditions: (i) 30% H2O2, HOAc, rt to 80 C. (ii) fuming HNO3, H2SO4,
95-100 C. (iii) K2CO3, MeOH, reflux. (iv) 10% Pd/C, H2, MeOH, rt. (v) NBS, AIBN, CCl4, reflux. (vi)
K2CO3, MeCN, rt to reflux.
5-Methoxy substituted analogs of 7-aza-isoindolin-1-one were synthesized in a similar thinking way
(Scheme 2). The nitration of 1 with tetrabutylammonium nitrate could involve nitro group on the
meta-position of pyridine ring.13,14 Compound 9 was obtained by the methoxylation of 8 in methanol with
a stronger base NaOMe. K2CO3 was also tried in this case, but no obvious product was generated.
MeO
MeO
O2N
iii
Br
ii
i
N
CO2Me
N
CO2Me
N
1
CO2Me
N
CO2Me
10 (45%)
9 (61%)
8 (60%)
MeO
iv
N R
H2N R
a-e
N
O
11a-e
+
－
Scheme 2. Reagents and conditions: (i) Bu4N NO3 , (CF3CO)2O, CH2Cl2, rt. (ii) NaH, MeOH, reflux.
(iii) NBS, AIBN, CCl4, reflux. (iv) K2CO3, MeCN, rt to reflux.
The bromomethyl product and the dibromomethyl product were obtained by a ratio of 3:1 when
compound 9 (1.0 equiv) was reacted with NBS (1.2 equiv) and AIBN (0.2 equiv) in CCl4 at reflux.
Meanwhile, the bromide 10 was not a stable compound and could slowly turn into black paste at room
temperature. Mass spectra of the paste suggested formation of polymeric species, presumably via
intermolecular reaction between the nucleophilic pyridine and the benzylic bromide.15 It was an
interesting contrast that the brominated product of compound 5 was mainly the bromide 6, which was
stable; presumably the bulk of the methoxyl group was key to avoiding dibromide and polymerization in

HETEROCYCLES, Vol. 87, No. 10, 2013
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the case.
It was noticed that the yields of 7a-e and 11a-e were relevant to the amines used (Table 1). The cyclized
products of amine c were relatively of low yield as compared with other amines, since the nucleophilicity
of its amino group was weakened by the trifluoromethyl group on the benzene.
Table 1. Amines (a-e) and corresponding methoxyl substituted 7-aza-isoindolinones (7a-e and 11a-e)
Entry
Amines
7a-e
Yield (%)
11a-e
Yield (%)
OMe
N
MeO
N
a
72%
51%
N
O
H2N
N
O
OMe
N
MeO
N
b
c
65%
40%
53%
36%
H2N
N
O
N
O
CF3
OMe
CF3
MeO
CF3
N
N
O
H2N
N
N
O
OMe
OMe
N
OMe
OMe
OMe
OMe
MeO
N
d
67%
59%
59%
57%
H2N
N
O
N
OMe
O
OMe
N
MeO
N
H2N
N
e
N
O
O

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EXPERIMENTAL
1
Melting points were determined on a SGW X-4 melting point instrument and were uncorrected. HNMR
and 13C NMR spectra were carried out using Bruker Advance Ш 400 MHz spectrometer and
MERCURYplus 300 spectrometer. HRMS was measured on a Waters ACQUITYTM UPLC & Q-TOF
MS Premier system. Column chromatography was performed using Silica Gel (200-300 mesh) with the
eluents indicated.
General protocol 4-methoxy-2-(m-tolyl)-7-aza-isoindolin-1-one (7a)
m-Toluidine (140 mg, 1.31 mmol) and K2CO3 (90 mg, 0.65 mmol) were added to a solution of methyl
4-methoxy-3-(bromomethyl)picolinate 6 (170 mg, 0.65 mmol) in MeCN (15 mL) under the protection of
nitrogen. The resulting mixture was stirred at room temperature for 2 h and then heated to reflux for
another 4 h. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo.
The crude residue was purified by column chromatography (100:1 CH2Cl2/MeOH) to afford 7a as a white
1
solid (120 mg, yield 72%, mp 187~188 C). H NMR (400 MHz, DMSO-d6) δ: 8.64 (d, 1H, J = 6.0 Hz,
NCH), 7.75~7.77 (m, 2H, NCCH), 7.32 (tt, 1H, J = 8.0 Hz, 1.2 Hz, NCCHCH), 7.27 (d, 1H, J = 5.6 Hz,
NCHCH), 7.02 (d, 1H, J = 7.2 Hz, NCCHCHCH), 4.9 4(s, 2H, CH2N), 4.01 (s, 3H, CH3O), 2.36 (s, 3H,
13
CH3). C NMR (400 MHz, DMSO-d6) δ: 164.8, 161.1, 152.9, 151.1, 139.2, 138.2, 128.8, 125.1, 124.1,
119.8, 116.5, 109.1, 56.1, 45.9, 21.2. ESI-HRMS: calcd for C15H15N2O2 (MH+), 255.1134, found
255.1124.
4-Methoxy-2-[3,5--dimethylphenyl]-7-aza-isoindolin-1-one (7b)
7b was afforded by column chromatography (100:1 CH2Cl2/MeOH) as a white solid (yield 65%, mp
225~226 C). 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (d, 1H, J = 5.6 Hz, NCH), 7.58 (s, 2H, NCCH),
7.27 (d, 1H, J = 5.6 Hz, NCHCH), 6.85 (s, 1H, CCHC), 4.9 2(s, 2H, CH2N), 4.01 (s, 3H, CH3O), 2.31 (s,
6H, CH3). 13C NMR (400 MHz, DMSO-d6) δ: 164.8, 161.0, 152.8, 151.2, 139.2, 138.0, 125.9, 124.0,
116.9, 109.0, 56.1, 46.0, 21.1. ESI-HRMS: calcd for C16H17N2O2 (MH+), 269.1290, found 269.1294.
4-Methoxy-2-[3-(trifluoromethyl)phenyl]-7-aza-isoindolin-1-one (7c)
7c was afforded by column chromatography (200:1 CH2Cl2/MeOH) as a white solid (yield 40%, mp
1
215~216 C). H NMR (400 MHz, DMSO-d6) δ: 8.67 (d, 1H, J = 5.6 Hz, NCH), 8.46 (s, 1H, NCCHC),
8.16 (dd, 1H, J = 8.0 Hz, 1.6 Hz, NCCHCH), 7.70 (t, 1H, J = 8.0 Hz, NCCHCH), 7.56 (d, 1H, J = 8.0 Hz,
13
NCCHCHCH), 7.31 (d, 1H, J = 5.6 Hz, NCHCH), 5.06 (s, 2H, CH2N), 4.03 (s, 3H, CH3O). C NMR
(400MHz, DMSO-d6) δ: 165.3, 161.1, 153.0, 150.6, 139.9, 130.2, 129.5~129.8, 122.7~125.4, 124.3,
122.6, 120.6, 115.4, 109.3, 56.1, 46.0. ESI-HRMS: calcd for C15H12N2O2F3 (MH+), 309.0851, found
309.0867.
4-Methoxy-2-(3,5-dimethoxyphenyl)-7-aza-isoindolin-1-one (7d)

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7d was afforded by column chromatography (100:1 CH2Cl2/MeOH) as a white solid (yield 67%, mp
216~217 C). 1H NMR (400 MHz, DMSO-d6) δ: 8.65 (d, 1H, J = 5.6 Hz, NCH), 7.28 (d, 1H, J = 5.6 Hz,
NCHCH), 7.17 (d, 2H, J = 2.4 Hz, NCCH), 6.37 (t, 1H, J =2 .4 Hz, CCHC), 4.95 (s, 2H, CH2N), 4.01 (s,
13
3H, CH3O), 3.79 (s, 6H, CH3O). C NMR (400 MHz, DMSO-d6) δ: 165.0, 161.0, 160.6, 152.9, 151.0,
140.8, 124.0, 109.1, 97.7, 96.4, 56.1, 55.3, 46.1. ESI-HRMS: calcd for C16H17N2O4 (MH+), 301.1188,
found 301.1201.
4-Methoxy-2-hexyl-7-aza-isoindolin-1-one (7e)
7e was afforded by column chromatography (200:1 CH2Cl2/MeOH) as a white solid (yield 59%, mp
1
96~97 C). H NMR (400 MHz, CDCl3) δ: 8.65 (d, 1H, J = 5.6 Hz, NCH), 6.89 (d, 1H, J = 5.6 Hz,
NCHCH), 4.33 (s, 2H, CH2N), 3.97 (s, 3H, CH3O), 3.66 (t, 2H, J = 7.2 Hz, NCH2), 1.65~1.70 (m, 2H,
NCH2CH2), 1.25~1.38 (m, 6H), 0.88 (t, 3H, J = 6.8 Hz, CH3). 13C NMR (400 MHz, DMSO-d6) δ: 165.6,
161.0, 152.4, 151.7, 124.3, 108.4, 55.9, 44.8, 41.9, 30.9, 27.5, 25.9, 22.0, 13.9. ESI-HRMS: calcd for
C14H21N2O2 (MH+), 249.1603, found 249.1598.
General protocol 5-methoxy-2-(m-tolyl)-7-aza-isoindolin-1-one (11a)
m-Toluidine (165 mg, 1.54 mmol) and K2CO3 (106 mg, 0.77 mmol) were added to a solution of methyl
5-methoxy-3-(bromomethyl)picolinate 10 (200 mg, 0.77 mmol) in MeCN (15 mL) under the protection of
nitrogen. The resulting mixture was stirred at room temperature for 1 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 (100:1 CH2Cl2/MeOH) and recrystallized
1
from MeOH to afford 11a as a yellow solid (100 mg, yield 51%, mp 229~230 C). H NMR (400 Hz,
DMSO-d6) δ: 8.45 (d, 1H, J = 2.4 Hz, NCH), 7.69 (d, 1H, J = 2.8 Hz, CH3OCCH), 7.72~7.74 (m, 2H,
NCCH), 7.32~7.36 (t, 1H, J = 7.6 Hz, NCCHCH), 7.02 (d, 1H, J = 7.6 Hz, CH3CCH), 4.97 (s, 2H, NCH2),
3.95 (s, 3H, OCH3), 2.37 (s, 3H, CCH3). 13C NMR (400 MHz, CDCl3) δ: 165.0, 157.9, 142.8, 140.6,
139.2, 139.1, 136.0, 129.0, 125.6, 119.9, 116.4, 113.9, 56.1, 48.2, 21.7. ESI-HRMS: calcd for
C15H15N2O2 (MH+), 255.1134, found 255.1134.
5-Methoxy-2-[3,5-dimethylphenyl]-7-aza-isoindolin-1-one (11b)
11b was afforded by column chromatography (100:1 CH2Cl2/MeOH) as a faint yellow solid (yield 53%,
mp 271~272 C). 1H NMR (400 Hz, CDCl3) δ: 8.49 (d, 1H, J = 2.0 Hz, NCH), 7.47 (s, 2H, NCCH), 7.29
(d, 1H, J = 2.0 Hz, CH3OCCH), 6.84 (s, 1H, NCCCH), 4.78 (s, 2H, NCH2), 3.96 (s, 3H, OCH3), 2.36 (s,
6H, CH3). 13C NMR (400 MHz, CDCl3) δ: 165.0, 157.8, 143.1, 140.6, 139.2, 138.9, 135.8, 126.6, 117.2,
113.9, 56.1, 48.4, 21.6. ESI-HRMS: calcd for C16H17N2O2 (MH+), 269.1280, found 269.1290.
5-Methoxy-2-[3-(trifluoromethyl)phenyl]-7-aza-isoindolin-1-one (11c)
11c was afforded by column chromatography (150:1 CH2Cl2/MeOH) as a white solid (yield 36%, mp

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HETEROCYCLES, Vol. 87, No. 10, 2013
260~262 C). 1H NMR (400Hz, DMSO-d6) δ: 8.48 (d, 1H, J = 2.4 Hz, NCH), 8.43 (s, 1H, NCCHCCF3),
8.10 (d, 1H, J = 8.4 Hz, NCCH), 7.69~7.73 (m, 2H, CF3CCHCH), 7.54 (d, 1H, J = 2.4 Hz, CH3OCCH),
13
5.08 (s, 2H, NCH2), 3.97 (s, 3H, OCH3). C NMR (400MHz, DMSO-d6) δ: 165.0, 162.3, 157.9, 146.0,
141.4, 140.2~140.6, 138.2, 137.7, 130.2, 120.3~122.3, 120.4, 114.3, 108.2, 56.2, 47.8. ESI-HRMS: calcd
for C15H12N2O2F3 (MH+), 309.0851, found 309.0851.
5-Methoxy-2-(3,5-dimethoxyphenyl)-7-aza-isoindolin-1-one (11d)
11d was afforded by column chromatography (50:1 CH2Cl2/MeOH) as a yellow solid (yield 59%, mp
218~221 C). 1H NMR (400Hz, DMSO-d6) δ: 8.45 (d, 1H, J = 2.4 Hz, NCH), 7.69 (d, 1H, J = 2.4 Hz,
CH3OCCH), 7.14 (d, 2H, J = 2.0 Hz, NCCH), 6.37 (t, 1H, J = 2.4 Hz, NCCHCCH), 4.96 (s, 2H, NCH2),
13
3.95 (s, 3H, OCH3), 3.79 (s, 6H, OCH3). C NMR (400 MHz, DMSO-d6) δ: 164.7, 160.7, 157.7, 141.8,
141.1, 140.3, 137.3, 114.2, 97.6, 95.9, 56.2, 55.2, 48.0. ESI-HRMS: calcd for C16H17N2O4 (MH+),
301.1187, found 301.1188.
5-Methoxy-2-hexyl-7-aza-isoindolin-1-one (11e)
1
11e was afforded by column chromatography (200:1 CH2Cl2/MeOH) as a white solid (yield 57%). H
NMR (400MHz, DMSO-d6) δ: 8.36 (d, 1H, J = 2.8 Hz, NCH), 7.24 (d, 1H, J = 2.4 Hz, CH3OCCH), 4.31
(s, 2H, NCH2), 3.89 (s, 3H, CH3O), 3.58 (t, 2H, J = 7.2 Hz, NCH2), 1.60~1.64 (m, 2H, NCH2CH2),
1.24~1.37 (m, 6H), 0.82~0.86 (t, 3H, J = 6.8 Hz, CH3). 13C NMR (400 MHz, DMSO-d6) δ: 166.2, 157.3,
143.3, 139.8, 136.5, 114.2, 56.0, 47.3, 42.8, 31.5, 28.3, 26.5, 22.5, 14.0. ESI-HRMS: calcd for
C14H21N2O2 (MH+), 249.1603, found 249.1612.
2-(Methyoxycarbonyl)-3-methylpyridine 1-oxide (2)
Cold (5 C) 30% hydrogen peroxide (7 mL, 66 mmol) was added to a solution of methyl
3-methylpicolinate 1 (5 g, 33 mmol) in glacial AcOH (15 mL) at room temperature. The mixture was
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 aqueous Na2CO3 solution, extracted with CH2Cl2 and the organic layer was dried (anhydrous
Na2SO4), concentrated, and purified by chromatography (50:1 CH2Cl2/MeOH) to give 2 as paint yellow
liquid (3.5 g, yield 63%). 1H NMR (300 MHz, CDCl3): δ 8.05 (d, 1H, J = 3.2 Hz, NCH), 7.20 (d, 1H, J =
3.3 Hz, NCHCHCH), 7.10~7.16 (m, 1H, NCHCH), 3.99 (s, 3H, CH3O), 2.26 (s, 3H, CH3). MS: m/z 168.1
(MH+).
2-(Methyoxycarbonyl)-3-methyl-4-nitropyridine 1-oxide (3)
2-(Methyoxycarbonyl)-3-methylpyridine 1-oxide 2 (2.3 g, 13.8 mmol) was added to cold conc.sulfuric
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,

HETEROCYCLES, Vol. 87, No. 10, 2013
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the mixture was neutralized with saturated aqueous Na2CO3 solution at 0 C, extracted with CH2Cl2 and
the organic layer was dried (anhydrous Na2SO4), concentrated, and purified by chromatography (75:1
1
CH2Cl2/MeOH) to afford 3 as a faint yellow solid (1.9 g, yield 65%, mp 166~168 C). H NMR (300
MHz, CDCl3): δ 8.15 (d, 1H, J = 3.3 Hz, NCH), 8.02 (d, 1H, J = 3.4 Hz, NCHCH), 4.06 (s, 3H, CH3O),
2.55 (s, 3H, CH3). MS: m/z 213.0 (MH+).
2-(Methyoxycarbonyl)-3-methyl-4-methoxypyridine 1-oxide (4)
2-(Methyoxycarbonyl)-3-methyl-4-nitropyridine 1-oxide 3 (0.5 g, 2.35 mmol) was dissolved in anhydrous
MeOH (20 mL). And potassium carbonate (356 mg, 2.57 mmol) was added to the solution. Then the
mixture was heated slowly to reflux and reacted for 2.5 h. When the temperature was cooled down, most
of the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and
washed with water (15 mL). The organic layer was dried (anhydrous Na2SO4), concentrated, and purified
by chromatography (25:1 CH2Cl2/MeOH) to afford 4 as a white solid (423 mg, yield 91%, mp 57~58 C).
1H NMR (400 MHz, CDCl3): δ 8.09 (d, 1H, J = 7.2 Hz, NCH), 6.75 (d, 1H, J = 7.2 Hz, NCHCH), 4.03 (s,
3H, CH3O), 3.91 (s, 3H, CH3O) , 2.13 (s, 3H, CH3). MS: m/z 198.1 (MH+).
Methyl 4-methoxy-3-methylpicolinate (5)
10% Pd/C (50 mg) was added to a solution of 2-(methyoxycarbonyl)-3-methyl-4-methoxypyridine
1-oxide 4 (423 mg, 2.14 mmol) in MeOH (15 mL) at room temperature. The resulting mixture was stirred
under H2 (1 atm) for 3 h and then filtered. The filtrate was concentrated in vacuo and the residue was
purified by chromatography (50:1 CH2Cl2/MeOH) to afford 5 as a colorless solid (350 mg, yield 90%, mp
1
52~54 C). H NMR (400 MHz, CDCl3): δ 8.43 (d, 1H, J = 5.2 Hz, NCH), 6.87 (d, 1H, J = 5.2 Hz,
NCHCH), 3.97 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 2.40 (s, 3H, CH3). MS: m/z 182.1 (MH+).
Methyl 4-methoxy-3-(bromomethyl)picolinate (6)
A mixture of methyl 4-methoxy-3-methylpicolinate 5 (265 mg, 1.46 mmol) in CCl4 (25 mL) with
N-bromosuccinimide (287 mg, 1.61 mmol) and azodiisobutyronitrile (30 mg, 0.18 mmol) was refluxed
for 1 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under
reduced pressure. The residue was purified by chromatography (pure CH2Cl2) to afford 6 as a yellow
1
solid (218 mg, 57%, mp 162~165 C). H NMR (300 MHz, CDCl3): δ 8.53 (d, 1H, J = 5.7 Hz, NCH),
6.96 (d, 1H, J = 5.4 Hz, NCHCH), 4.96 (s, 2H, CH2Br), 4.01 (s, 3H, CH3O), 4.00 (s, 3H, CH3O). MS: m/z
261.1 (MH+).
Methyl 3-methyl-5-nitropicolinate (8)
Trifluoroacetic anhydride (61.2 mL, 0.44 mol) was added dropwise at 0 C to a solution of methyl
3-methylpicolinate 1 (30.4 g, 0.20 mol) and tetrabutylammonium nitrate (67.0 g, 0.22 mol) in CH2Cl2
(500 mL). The mixture was stirred at room temperature for 18 h after which it was neutralized with

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HETEROCYCLES, Vol. 87, No. 10, 2013
saturated aqueous Na2CO3 solution, extracted with CH2Cl2 and the organic layer was dried (anhydrous
Na2SO4), concentrated, and purified by chromatography (6:1 cyclohexane/EtOAc) to afford 8 as a white
solid (23.4 g, yield 60%, mp 80~82 C). 1H NMR (300 MHz, CDCl3): δ 9.30 (s, 1H, NCH), 8.41 (s, 1H,
NCHCCH, 4.02 (s, 3H, CH3O), 2.70(s, 3H, CH3). MS: m/z 197.1 (MH+).
Methyl 5-methoxy-3-methylpicolinate (9)
60% Sodium hydride (6.2 g, 0.15 mol) was dissolved in anhydrous MeOH (500 mL). And methyl
3-methyl-5-nitropicolinate (19.6 g, 0.10 mol) was added to the solution. Then the mixture was heated
slowly to reflux and reacted for 2.5 h. When the temperature was cooled down, most of the solvent was
removed under reduced pressure. The residue was neutralized with diluted hydrochloric acid to pH=7 and
extracted with CH2Cl2 (200 mL) for three times. The organic layer was dried (anhydrous Na2SO4) and
concentrated. The residue was purified by chromatorgraphy (50:1 CH2Cl2/MeOH) to afford 9 as a red
1
brown solid (11.0 g, yield 61%, mp 67~69 C). H NMR (400 MHz, CDCl3): δ 8.24 (d, 1H, J = 2.8 Hz,
NCH), 7.06 (d, 1H, J = 2.4 Hz, CH3OCCH), 3.96 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 2.64 (s, 3H, CH3).
MS: m/z 182.1 (MH+).
Methyl 5-methoxy-3-(bromomethyl)picolinate (10)
A mixture of methyl 5-methoxy-3-methylpicolinate 9 (362 mg, 2.0 mmol) in CCl4 (20 mL) with
N-bromosuccinimide (427 mg, 2.4 mmol) and azodiisobutyronitrile (66 mg, 0.4 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 (pure CH2Cl2) to afford 10 as a yellow solid (235
mg, yield 45%). 1H NMR (400 MHz, CDCl3): δ 8.33 (d, 1H, J = 2.4 Hz, NCH), 7.34 (d, 1H, J = 2.4 Hz,
CH3OCCH), 4.98 (s, 2H, CH2Br), 4.00 (s, 3H, CH3O), 3.95 (s, 3H, CH3O). MS: m/z 261.1 (MH+).
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.
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