Facile synthesis and herbicidal activity of novel multisubstituted pyridine derivatives

Article abstract of DOI:10.1002/jhet.296

(Chemical Equation Presented) Ketene N,S-acetals reacted with β-ketoesters in the presence of Zn(NO₃)₂ · 6H₂O as catalyst, in ethanol solvent, giving 6-alkylsulfanylpyridines 4 in good yields without complicated purificati

Full text of DOI:10.1002/jhet.296

January 2010
Facile Synthesis and Herbicidal Activity of Novel
Multisubstituted Pyridine Derivatives
171
Qingyun Ren,a Wenyan Mo,a Ling Gao,a Hongwu He,a* and Yucheng Gua,b
aThe Key Laboratory of Pesticide and Chemical Biology, Ministry of Education; College of
Chemistry, Central China Normal University, Wuhan 430079, People’s Republic of China
bSyngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY,
United Kingdom
*E-mail: he1208@mail.ccnu.edu.cn
Received June 17, 2009
DOI 10.1002/jhet.296
Published online 8 January 2010 in Wiley InterScience (www.interscience.wiley.com).
Ketene N,S-acetals reacted with b-ketoesters in the presence of Zn(NO3)2 ꢀ 6H2O as catalyst, in etha-
nol solvent, giving 6-alkylsulfanylpyridines 4 in good yields without complicated purification proce-
dures. Oxidization of compounds 4 with aqueous hydrogen peroxide in the presence of catalytic sodium
wolframate led to the formation of 6-alkylsulfonylpyridine derivatives 5, which could be further derivat-
ized in the 6-position by nucleophilic reactions with phenols or amines to give multisubstituted pyridine
compounds 8. Bioassays indicated that some of the compounds of the type 8 have good herbicidal activ-
ity at a dose of 100 mg/L on the roots of oil rape and barnyard grass.
J. Heterocyclic Chem., 47, 171 (2010).
INTRODUCTION
from a oxidization sequence and nucleophilic reactions.
A preliminary in vitro bioassay indicated that some of
the compounds of the type 8 have good herbicidal
activity.
Muti-substituted pyridine derivatives occupy a central
position in modern heterocyclic chemistry particularly in
the pharmaceutical and agrochemical fields [1–4].
Therefore, new and improved synthetic studies about the
preparation of this important heterocyclic ring system
are of contemporary interest. The Hantzsch reaction has
been proved to be a versatile method for the preparation
of a large range of pyridines and dihydropyridines with
symmetrical substitution patterns [5,6]. But the synthesis
of multi-substituted pyridines with unsymmetrical sub-
stitution patterns is often difficult and involves multi-
step sequences, so there is still a great need to develop
new approaches to pyridines of this type.
RESULTS AND DISCUSSION
The intermediates 1 and 2 can be prepared according
to a published method [7]. It was reported that 4-amino-
pyridine 4 (Scheme 1) was prepared in moderate yield
(48%) by using anhydrous stannic chloride as catalyst
[8,9]. However, we found that there were some draw-
backs with this method which need to be addressed.
First, this method requires anhydrous conditions because
tin (IV) chloride is readily hydrolyzed in water. Further-
more, the poor solubility of the reactants and the SnCl4
catalyst in toluene, used as the solvent for the reaction,
often leads to a low yield and prolonged reaction time.
And finally, the complex and cockamamie workup pro-
cedure involves a dilution of the reaction mixture with a
saturated aqueous solution of sodium carbonate and an
extraction of the reactant mixture with ethyl acetate
Our interests in the preparation of new heterocyclic
compounds prompted us to elaborate novel methods for
the synthesis of unsymmetrical multi-substituted pyri-
dines and the evaluation of their biological activities. In
this context, we report here an improved and convenient
synthesis of the unsymmetrical multisubstituted pyri-
dines 4 from easily accessible staring materials ketene
N,S-acetals 2 and b-ketoesters 3, as well as the prepara-
tion of various functional derivatives 5 and 8 resulting
C
V
2010 HeteroCorporation

172
Q. Ren, W. Mo, L. Gao, H. He, and Y. Gu
Vol 47
Scheme 1. Synthesis of 6-alkylsulfanyl substituted pyridines 4.
before the title compound can be isolated and purified
by a flash chromatography on silica gel.
whereas other variables were kept constant (entry 8 vs.
entry 9). However, when a catalytic amount of triethyl-
benzylammonium chloride (TEBA) was added to the
reaction, a maximum amount of the title compound 4b
was obtained (entry 10).
In this study, various catalysts, different solvents as
well as the reaction times and the molar ratios of reac-
tants were tested to optimize the reaction conditions.
The survey of reaction conditions and results are sum-
marized in Table 1. The initial study was performed on
the reaction of 2-(amino-methylthio-methylene)-malono-
nitrile with ethyl acetoacetate in the presence of anhy-
drous SnCl4 (2 equiv.) in refluxing toluene, which gave
a yield of 38% of 4b (entry 1). Corresponding reactions
carried out in polar solvents such as ethanol led to none
of the required product being observed (entry 2).
To investigate the scope of this reaction and to estab-
lish its tolerance of different substrates under the opti-
mized conditions, a range of different b-ketoesters 3 and
ketene N,S-acetals 2 were heated at reflux in ethanol in
the presence of stoichiometric amounts of zinc(II) nitrate
and a catalytic amount of TEBA. In all the cases inves-
tigated (Table 2), the expected pyridine 4 was isolated
in good to excellent yield (86–95%), and no regioiso-
meric products were detected.
It was found that catalysts and solvents have a
dramatic influence on the efficiency of the reaction. A
variety of catalysts, such as ZnCl2 (entries 3–4),
Zn(OAc)2 ꢀ 2H2O (entry 6), Zn(NO3)2 ꢀ 6H2O (entries
7–9), catalyze the reactions more efficiently than SnCl4
(entries 1–2). And when ethanol was used as the sol-
vent, Zn(NO3)2 ꢀ 6H2O provided the best catalytic effi-
ciency. We also found that the higher concentration of
b-ketoesters (2 equiv.) slightly increased the yield (entry
7 vs. entry 8).
Bearing in mind the fact that the alkylsulfanyl group
of compound 4 can be oxidized into alkylsulfonyl group,
we became interested in identifying new ways to synthe-
size pyridines in which the methylsulfonyl group could
serve as a leaving group to facilitate CAC bond-forming
in the reactions. 6-Alkylsulfanyl pyridine derivatives 4
was treated with aqueous hydrogen peroxide in the pres-
ence of sodium wolframate as catalyst to give 6-alkyl-
sulfonyl pyridine derivatives 5. Acetic acid was a sol-
vent of choice for the reaction stated in the literature
[10]. In our case, however, acetic acid was not the best
candidate as the reaction proceed in acetic acid at room
When using Zn(NO3)2 ꢀ 6H2O as catalyst, we found
that there was almost no change on the reaction yields
when the reaction time changed from 12 h to 6 h
Table 1
Optimization of the reaction conditions.
Entry
Catalyst
Ratio 2a:3b:catalyst
Conditions
Time (h)
Yield (%)a
1
2
SnCl4
SnCl4
ZnCl2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:2:2
1:2:2
1:2:2
Toluene/reflux
Ethanol/reflux
Toluene/reflux
Ethanol/reflux
Ethanol/reflux
Ethanol/reflux
Ethanol/reflux
Ethanol/reflux
Ethanol/reflux
Ethanol/reflux
8
8
38
Failed
48
3
12
12
12
12
12
12
6
4
5
ZnCl2
60
31
ZnSO4ꢀ7H2O
Zn(OAc)2ꢀ2H2O
Zn(NO3)2ꢀ6H2O
Zn(NO3)2ꢀ6H2O
Zn(NO3)2ꢀ6H2O
Zn(NO3)2ꢀ6H2O þ TEBA
6
7
70
73
8
9
10
80
78
6
95
a Yield of pure isolated product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010 Facile Synthesis and Herbicidal Activity of Novel Multisubstituted Pyridine Derivatives
173
Table 2
Yields of compounds 4–7.
Compounds
R
Y
Yield (%)a,b
Compds
R
Y
Yield (%)a
4a
4b
4c
4d
4e
4f
Me
Me
MeO
EtO
90
95
86
91
87
89
5a
5b
5c
5d
6
Me
Me
Et
Et
\
MeO
EtO
MeO
EtO
EtO
EtO
85
91
78
83
50
67
Et
Et
MeO
EtO
PhCH2
PhCH2
MeO
EtO
7
\
a Yield of pure isolated product.
b Using Zn(NO2)2. ꢀ 6H2O and TEBA as catalyst.
temperature or refluxing temperature gave mainly the
byproduct of 4-amino-5-cyano-6-hydroxy-2-methyl-3-
ethyloxycarbonyl pyridine 6 (Scheme 2). It may be due
in part to the instability of 6-methylsulfonyl pyridine 5b
which could be hydrolyzed under the strong polar
conditions.
were performed to access other 6-substitued pyridine
derivatives. The direct reaction of compound 5 with
phenols failed to produce 6-aryloxy substituted pyridine
8a–j. However, when performed in the presence of cata-
lytic potassium carbonate in acetonitrile, the reaction
took place and offered 8a–j in good yield (Scheme 4).
Irrespective of the fact whether the substituents on the
phenols were electron-withdrawing or electron-releasing
groups, the reaction was completed smoothly at reflux-
ing temperature for 1–3 h. On the other hand, when the
reaction was performed with NaH as the catalyst, no
title product was separated out. This suggested that the
compound 5 was unstable and the SO2R group can be
replaced by hydride ion of NaH firstly, which led to the
next nucleophilic attack of phenoxides to methylsulfonyl
group not occurring.
On the other hand, when the reaction was performed
in a less polar solvent of dichloromethane with m-chlor-
operbenzoic acid (m-CPBA) as oxidizing reagent, a mix-
ture of 6-methylsulfonyl pyridine 5b and 6-methylsul-
finyl pyridine 7 were obtained (Scheme 2). In addition
to these observations, we also attempted to use other
solvents such as ethanol, methanol, acetonitrile, or even
mixtures of these solvents coupled with different oxidiz-
ing reagents. Finally, H2O2-DMF was identified as the
best oxidizing reagent-solvent combination in terms of
both operational simplicity and yield. Under the opti-
mized conditions, compound 4 was easily transformated
into compound 5 with a high yield after refluxing for 2
h in DMF with aqueous hydrogen peroxide in the pres-
ence of sodium wolframate as catalyst (Scheme 3). The
workup and purification of the reaction products were
easy and efficient.
Conversion of compound 5 into 6-alkylamino substi-
tuted pyridine 8k–p (Scheme 4) was effectively carried
out by treatment of acetonitrile solutions of the 6-meth-
ylsulfonyl substituted pyridine 5 with 2 equivalent of
amines at ambient temperature overnight followed by
straight-forward purification of recrystallization. It was
noteworthy that the isolated yield of 8k–p was good de-
spite that the amine is alkylamino or bulkyl heterocycle
amino group (Table 3).
With robust synthesis procedure of 6-methylsulfonyl
pyridine 5 in hand, a series of studies on compound 5
Scheme 2. Oxidization of 4b using HAc and CH2Cl2 as solvent.
Journal of Heterocyclic Chemistry
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174
Q. Ren, W. Mo, L. Gao, H. He, and Y. Gu
Vol 47
Scheme 3. Synthesis of 6-alkylsulfonyl pyridines 5.
and resonances were given in ppm (d) relative to TMS (d 0.00
ppm). 13C NMR spectra were recorded using CDCl3 as the sol-
vent on a Varian Mercury 600 spectrometer and resonances
are given in ppm (d) relative to CDCl3 (d 77.00 ppm). The el-
ementary analysis was performed on a Vario EL III elementary
analysis instrument. All of the solvents and materials were rea-
gent grade and purified as required.
General procedure for the preparation of compounds
(4a–f). A mixture of 2-(alkylsulfanyl-amino-methylene)-malo-
nonitrile 2 (10 mmol) and Zn(NO2)2 ꢀ 6H2O (20 mmol) and a
catalytic amount of TEBA (0.2 mmol) were added to a stirred
solution of b-ketoesters 3 (20 mmol) in ethanol (30 mL). The so-
lution was heated in an oil bath and refluxed for 6–8 h, and then
cooled to room temperature. The crude precipitated product was
collected by filtration. Further purification was accomplished by
recrystallization from ethanol to give pure products 4a–f.
4-Amino-5-cyano-2-methyl-6-methylsulfanyl-nicotinic acid
methyl ester (4a). This compound was obtained as white solid,
mp 141.2–143.2ꢂC, yield 90%; IR: 3418, 3315, 3197, 3002,
The compounds obtained were characterized fully by
1
using spectroscopic methods (IR, H NMR and EI-MS)
and elemental analysis. For example, the IR spectra of
8a revealed CN and C¼¼O absorption bands at 2225 and
1689 cmꢁ1 respectively, the signals attributable to the
1
NH2 are found at 3450 and 3346 cmꢁ1. The H NMR
spectrum of 8a also shows the signals of NH2 at 6.66
ppm as a broad absorption. The MS spectrum of 8a
shows strong molecular ion peak at m/z 331 with 100%
abundance. In the case of 8h [11], the structure was
additionally confirmed by single-crystal X-ray diffrac-
tion (Fig. 1).
2214(CN), 1690(C¼¼O), 1610, 1550, 1238, 1096 cmꢁ1
;
1H
NMR (CDCl3): d 2.61 (s, 3H, SCH3), 2.68 (s, 3H, py-CH3),
3.92 (s, 3H, OCH3), 6.70 ppm (s, 2H, NH2); 13C NMR
(CDCl3): d 12.8, 27.6, 52.0, 89.1, 104.5, 114.5, 156.4, 163.7,
165.1, 168.2 ppm; ms: m/z 238 (Mþ þ1, 15), 237 (Mþ, 100),
236 (Mþ ꢁ1, 32), 205 (21), 177 (29); Anal. Calcd for
C10H11N3O2S: C, 50.62; H, 4.67; N, 17.71; S, 13.51. Found:
C, 50.90; H, 4.92; N, 17.78; S, 13.88.
4-Amino-5-cyano-2-methyl-6-methylsulfanyl-nicotinic acid
ethyl ester (4b). This compound was obtained as white solid,
mp 136.0–138.0ꢂC, yield 95%; IR: 3406, 3309, 3200, 2983,
The preliminary herbicidal activity of compounds 8
series was evaluated comparable to a commercial herbi-
cide 2,4-D, against two representative targets, oil rape
and barnyard grass, at concentrations of 100 mg/L and
10 mg/L, according to a literature method [12]. The
results are listed in Table 3 and show that these com-
pounds have moderate to good herbicidal activity
against the roots of these two species at the rate of 100
mg/L, especially against the root of oil rape. Compound
with substituted phenoxy moiety in position 6 of the
pyridine ring showed much better activity than 6-amino-
substituted compounds. Switching the substituent Y
from methoxy to ethoxy has no obvious effect on the in-
hibition rates.
2219(CN), 1682(C¼¼O), 1618, 1546, 1241, 1097 cmꢁ1
;
1H
NMR (CDCl3): d 1.41 (t, 3H, OCH2CH3, J ¼ 7.2 Hz), 2.62 (s,
3H, SCH3), 2.70 (s, 3H, py-CH3), 4.39 (q, 2H, OCH2, J ¼
7.2 Hz), 6.68 ppm (s, 2H, NH2); 13C NMR (CDCl3): d 12.8,
14.1, 27.6, 61.4, 89.1, 104.7, 114.5, 156.4, 163.6, 164.9, 167.8
ppm; ms: m/z 252 (Mþ þ1, 23), 251 (Mþ, 100), 250 (Mþ ꢁ1,
41), 223 (47), 205 (31), 177(30); Anal. Calcd for
C11H13N3O2S: C, 52.57; H, 5.21; N, 16.72; S, 12.76. Found:
C, 52.75; H, 4.80; N, 16.89; S, 12.72.
4-Amino-5-cyano-6-ethylsulfanyl-2-methyl-nicotinic
methyl ester (4c). This compound was obtained as white solid,
acid
In summary, we have developed an improved and
convenient synthetic method for the preparation of mul-
tisubstituted pyridine derivatives with unsymmetrical
substitution patterns. Some multisubstituted pyridines-
containing compounds could be synthesized from simple
precursors which are assembled in a modular fashion
from readily available and inexpensive starting materi-
als. The biological evaluation showed that some com-
pounds have good herbicidal activities and we feel that
this method will further facilitate exploration of this
increasingly important pharmacophore.
mp 137.2–139.2ꢂC, yield 86%; IR: 3406, 3310, 3276, 2951,
Scheme 4. Synthesis of 6-aroxy and 6-alkylamino substituted
pyridines 8.
EXPERIMENTAL
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. Mass spectra were meas-
ured on a Finnigan Trace MS 2000 spectrometer. IR spectra
were recorded on a PE-983 infrared spectrometer as KBr pel-
.
lets with absorption in cmꢁ1 1H NMR spectra were recorded
in CDCl3 or DMSO on a Varian Mercury 400 spectrometer
Journal of Heterocyclic Chemistry
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January 2010 Facile Synthesis and Herbicidal Activity of Novel Multisubstituted Pyridine Derivatives
175
Table 3
Yields and heribicidal activity (% inhibition) of compounds 8.
Oil rape (root/stalk)
Barnyard grass (root/stalk)
Compounds
R
Y
Yield (%)a
100 mg/L
10 mg/L
100 mg/L
10 mg/L
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
4-Br-C6H4O
4-Cl-2-F-C6H3O
3-MeO-C6H4O
3-NO2-C6H4O
C6H5O
MeO
MeO
MeO
MeO
MeO
EtO
77
75
83
75
79
88
93
87
90
89
90
89
87
73
78
82
85/69
60/27
52/27
74/62
90/65
79/42
68/27
90/65
59/50
77/52
38/31
16/12
28/8
45/19
54/27
16/19
45/0
79/52
72/13
69/44
83/39
73/48
79/39
79/39
72/48
90/44
84/28
59/35
48/13
62/44
59/22
52/35
52/30
59/28
52/35
72/44
33/14
C6H5O
4-Cl-C6H4O
2-NO2-C6H4O
2,3-diMe-C6H3O
4-Me-C6H4O
EtNH
EtO
EtO
EtO
EtO
EtO
EtO
MeO
MeO
EtO
54/27
35/19
67/44
b
b
b
b
/
/
/
/
b
b
b
b
n-PrNH
n-BuNH
PhCH2NH
Triazol-1-yl
Piperdin-1-yl
2,4-D
/
/
/
/
27/7
48/47
63/47
73/40
40/33
48/40
32/8
55/33
67/48
75/39
52/30
41/28
b
b
b
b
EtO
/
99/94
/
99/81
/
99/72
/
90/70
a Yield of pure isolated product.
b Not tested.
2213(CN), 1689(C¼¼O), 1612, 1546, 1240, 1093 cmꢁ1
;
1H
OCH3), 6.72 ppm (s, 2H, NH2); 13C NMR (CDCl3): d 14.6,
24.4, 27.6, 51.9, 89.2, 104.4, 114.5, 156.5, 163.7, 164.9, 168.2
ppm; ms: m/z 251 (Mþ, 66), 236 (26), 218 (81), 204 (15), 191
NMR (CDCl3): d 1.37 (t, 3H, SCH2CH3, J ¼ 7.2 Hz), 2.68 (s,
3H, Py-CH3), 3.25(q, 2H, SCH2CH3, J ¼ 7.2 Hz), 3.92(s, 3H,
Figure 1. The molecular structure of compound 8h.
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176
Q. Ren, W. Mo, L. Gao, H. He, and Y. Gu
Vol 47
(100), 186 (41), 159 (47), 130 (29); Anal. Calcd for
C11H13N3O2S: C, 52.57; H, 5.21; N, 16.72; S, 12.76. Found:
C, 52.90; H, 4.97; N, 16.60; S, 12.36.
4-Amino-5-cyano-6-methylsulfonyl-2-methyl-nicotinic acid
methyl ester (5a). This compound was obtained as white solid,
mp 172.0–174.0ꢂC, yield 85%; IR: 3409, 3298, 2928,
2223(CN), 1697(C¼¼O), 1613, 1554, 1307, 1255, 1138 cmꢁ1
;
4-Amino-5-cyano-6-ethylsulfanyl-2-methyl-nicotinic
ethyl ester (4d). This compound was obtained as white solid,
acid
1H NMR (CDCl3): d2.76 (s, 3H, Py-CH3), 3.32 (s, 3H,
SO2CH3), 3.99 (s, 3H, OCH3), 7.05 ppm (s, 2H, NH2); ms:
m/z 269 (Mþ, 7), 237 (5), 218 (9), 205 (51), 190 (14), 175
(52), 158 (21), 129 (28); Anal. Calcd for C10H11N3O4S: C,
44.60; H, 4.12; N, 15.60; S, 11.91. Found: C, 44.73; H, 4.00;
N, 15.42; S, 12.27.
mp 145.0–146.9ꢂC, yield 91%; IR: 3411, 3305, 3268, 2978,
2213(CN), 1680(C¼¼O), 1609, 1544, 1240, 1092 cmꢁ1
;
1H
NMR (CDCl3): d (ppm): 1.37 (t, 3H, CH3, J ¼ 7.2 Hz), 1.41
(t, 3H, CH3, J ¼ 7.2 Hz), 2.68 (s, 3H, Py-CH3), 3.25 (q, 2H,
SCH2CH3, J ¼ 7.6 Hz), 4.38 (q 2H, OCH2CH3, J ¼ 7.2 Hz,),
6.69 ppm (s, 2H, NH2); 13C NMR (CDCl3): d 14.6, 24.4, 27.6,
51.9, 61.3, 89.2, 104.4, 114.5, 156.5, 163.7, 164.9, 168.2 ppm;
ms: m/z 265 (Mþ, 36), 250 (7), 232 (30), 204 (62), 191 (99),
186 (57), 159 (100), 131 (50); Anal. Calcd for C12H15N3O2S:
C, 54.32; H, 5.70; N, 15.84; S, 12.08. Found: C, 54.53; H,
5.41; N, 16.04; S, 12.35.
4-Amino-5-cyano-6-methylsulfonyl-2-methyl-nicotinic acid
ethyl ester (5b). This compound was obtained as white solid,
mp 154.3–156.0ꢂC, yield 91%; IR: 3415, 3287, 2924,
2224(CN), 1690(C¼¼O), 1606, 1550, 1274, 1139 cmꢁ1
;
1H
NMR (CDCl3): d 1.45 (t, 3H, OCH2CH3, J ¼ 7.2 Hz), 2.76 (s,
3H, Py-CH3), 3.32 (s, 3H, SO2CH3), 4.46 (q, 2H, OCH2CH3,
J ¼ 7.2 Hz), 7.05 ppm (s, 2H, NH2); 13C NMR (CDCl3): d
14.0, 27.0, 39.3, 62.4, 89.3, 110.3, 111.8, 157.5, 159.6, 163.8,
166.5 ppm; ms: m/z 284 (Mþ þ1, 4), 283 (Mþ, 25), 237 (14),
219 (100), 191 (19), 175 (63), 131 (36); Anal. Calcd for
C11H13N3O4S: C, 46.63; H, 4.63; N, 14.83; S, 11.32. Found:
C, 46.87; H, 4.54; N, 15.04; S, 11.25.
4-Amino-6-benzylsulfanyl-5-cyano-2-methyl-nicotinic acid
methyl ester (4e). This compound was obtained as yellow solid,
mp 139.4–141.7ꢂC, yield 87%; IR: 3426, 3307, 3004, 2211(CN),
1677(C¼¼O), 1603, 1547, 1250 cmꢁ1; 1H NMR (CDCl3): d 2.71
(s, 3H, Py-CH3), 3.92 (s, 3H, OCH3), 4.51 (s, 2H, PhCH2), 6.69
(s, 2H, NH2), 7.24–7.41 ppm (m, 5H, Ph-H); 13C NMR (CDCl3):
d 27.6, 33.9, 52.1, 89.1, 104.8, 114.4, 127.3, 128.4, 129.1, 137.4,
156.6, 163.7, 164.2, 168.2 ppm; ms: m/z 314 (Mþ þ1, 17), 313
(Mþ, 100), 312 (Mþ ꢁ1, 27), 280 (18), 255 (4); Anal. Calcd for
C16H15N3O2S: C, 61.32; H, 4.82; N, 13.41; S, 10.23. Found: C,
61.41; H, 4.39; N, 13.33; S, 10.53.
4-Amino-5-cyano-6-ethylsulfonyl-2-methyl-nicotinic
acid
methyl ester (5c). This compound was obtained as white solid,
mp 128.0–129.3ꢂC, yield 78%; IR: 3427, 3342, 2926,
2226(CN), 1731(C¼¼O), 1640, 1529, 1570, 1324, 1252, 1137
1
cmꢁ1; H NMR (CDCl3): d 1.41(t, 3H, SO2CH2CH3, J ¼ 7.2
4-Amino-6-benzylsulfanyl-5-cyano-2-methyl-nicotinic acid
ethyl ester (4f). This compound was obtained as yellow solid,
mp 109.7–112.0ꢂC, yield 89%; IR: 3419, 3312, 2986,
Hz), 2.76 (s, 3H, Py-CH3), 3.53(q, 2H, SO2CH2CH3, J ¼ 7.2
Hz), 3.99(s, 3H, OCH3), 7.10 ppm (s, 2H,NH2); ms: m/z 283
(Mþ, 2), 252 (8), 218 (36), 205 (52), 192 (100), 191 (87), 176
(24), 160 (25), 131 (49); Anal. Calcd for C11H13N3O4S:
C11H13N3O4S: C, 46.63; H, 4.63; N, 14.83; S, 11.32. Found:
C, 46.73; H, 4.34; N, 14.83; S, 11.51.
2211(CN), 1673(C¼¼O), 1606, 1546, 1237 cmꢁ1
;
1H NMR
(CDCl3): d 1.41 (t, 3H, OCH2CH3, J ¼ 7.2 Hz), 2.72 (s, 3H,
Py-CH3), 4.38 (q, 2H, OCH2CH3, J ¼ 7.2 Hz), 4.51 (s, 2H,
PhCH2), 6.70 (s, 2 H, NH2), 7.24–7.41 ppm (m, 5 H, Ph-H);
13C NMR (CDCl3): d 14.1, 27.5, 33.9, 61.2, 88.9, 104.9,
114.3, 127.2, 128.4, 129.1, 137.4, 156.6, 163.5, 163.9, 167.7
ppm; ms: m/z 328 (Mþ þ1, 18), 327 (Mþ, 100), 326 (Mþ ꢁ1,
74), 299 (11), 255 (28), 212 (38); Anal. Calcd for
C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83; S, 9.79. Found: C,
62.14; H, 4.97; N, 12.76; S, 9.63.
4-Amino-5-cyano-6-ethylsulfonyl-2-methyl-nicotinic
acid
ethyl ester (5d). This compound was obtained as white solid,
mp 102.5–103.7ꢂC, yield 83%, IR: 3421, 3327, 2921, 2226(CN),
1694(C¼¼O), 1611, 1526, 1553, 1316, 1140 cmꢁ1
;
1H NMR
(CDCl3): d 1.39–1.59 (m, 6H, 2* CH3), 2.76 (s, 3H, Py-CH3),
3.52(q, 2H, SO2CH2CH3, J ¼ 7.2 Hz), 4.47(q, 2H, OCH2CH3,
J ¼ 6.8 Hz), 7.12 ppm (s, 2H, NH2); ms: m/z 298 (Mþ þ1, 2),
297 (Mþ, 3), 233 (9), 205 (25), 187 (5), 161 (12), 132 (20); Anal.
Calcd for C11H13N3O4S: C12H15N3O4S: C, 48.47; H, 5.08; N,
14.13; S, 10.78. Found: C, 48.73; H, 4.78; N, 14.12; S, 11.06.
4-Amino-5-cyano-6-hydroxy-2-methyl-nicotinic acid ethyl
ester (6). This compound was obtained as white solid, mp
>270ꢂC, yield 50%; 1H NMR (DMSO): d 1.28 (t, 3H,
OCH2CH3, J ¼ 7.2 Hz), 2.42 (s, 3H, Py-CH3), 4.26 (q, 2H,
OCH2CH3, J ¼ 7.2 Hz), 7.58 (s, 2H, NH2), 11.68 ppm (s, 1H,
OH); Anal. Calcd for C10H11N3O3: C, 54.29; H, 5.01; N,
19.00. Found: C, 54.43; H, 4.97; N, 18.83.
General procedure for the preparation of compounds
(5a–d, 6,7). A mixture of 4-amino-5-cyano-2-methyl-6-alkyl-
sulfanyl-nicotinic acid alkyl esters 4a–d (10 mmol) and the ca-
talysis sodium wolframate (0.1 mmol) were added to DMF (30
mL) and heated to 40ꢂC. A solution of aqueous hydrogen per-
oxide (12 mmol) in ethanol (5 mL) was added at a rate of 1d/s
to keep the internal temperature below 50ꢂC. The mixture
stirred at 60ꢂC for 3 h and then cooled. The reaction mixture
poured into 300 mL of water and the solution was stirred for
4–6 h at room temperature and the precipitate was collected
by filtration. The products were air dried and recrystallized
from ethanol to give pure product 4-amino-5-cyano-6-alkylsul-
fonyl- 2-methyl-nicotinic acid alkyl esters 5a–d.
When this reaction was performed in a solvent of acetic
acid, the product 6 was obtained in 50% yield. And when the
same reaction was carried out in presence of m-chloroperben-
zoic acid (m-CPBA), as oxidizing reagent in CH2Cl2, a mix-
ture of 6-methylsulfonyl pyridine 5b and 6-methylsulfinyl pyri-
dine 7 were obtained. The purification procedure was carried
out by flash silica gel chromatography using petroleum ether/
ethyl acetate (3:1, v/v) as eluent to give product 7 in 67%
yield and 5b in 25% yield.
4-Amino-5-cyano-6- methylsulfinyl-2-methyl-nicotinic acid
ethyl ester (7). This compound was obtained as white solid, mp
132.2–134.4ꢂC, yield 67%; 1H NMR (CDCl3): d 1.44 (t 3H,
OCH2CH3, J ¼ 7.2 Hz,), 2.76 (s, 3H, Py-CH3), 2.94 (s, 3H,
SOCH3), 4.46 (q, 2H, OCH2CH3, J ¼ 7.2 Hz), 7.04 ppm (s, 2H,
NH2); ms: m/z 267 (Mþ, 12), 250 (10), 219 (72), 175 (100), 131
(11); Anal. Calcd. for C11H13N3O3S: C, 49.43; H, 4.90; N,
15.72; S, 12.00. Found: C, 49.51; H, 4.44; N, 15.62; S, 12.26.
General procedure for the preparation of compounds
(8a–j). A mixture of 4-amino-5-cyano-6-methylsulfonyl-2-
methyl-nicotinic acid alkyl ester 5a or 5b (5mmol) and
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DOI 10.1002/jhet

January 2010 Facile Synthesis and Herbicidal Activity of Novel Multisubstituted Pyridine Derivatives
177
catalytic amount of K2CO3 (0.1 mmol) were added to a solu-
tion of substituted phenol (5 mmol) in anhydrous acetonitrile
(20 mL). The solution was heated to 80ꢂC in an oil bath to
bring the mixture to reflux for 1–2 h and then cooled to room
temperature. The precipitated crude product was collected by
filtration. The filtrate was recrystallized from dichloromethane/
petroleum ether to give pure 4-amino-5-cyano-2-methyl-6-sub-
stitutedphenoxy- nicotinic acid alkyl ester 8a–j.
4-Amino-5-cyano-2-methyl-6-phenoxy-nicotinic acid ethyl
ester (8f). This compound was obtained as white solid, mp
126.9–128.5ꢂC, yield 88%; IR: 3402, 3308, 2984, 2230(CN),
1680(C¼¼O), 1625, 1491, 1566, 1265, 1096 cmꢁ1
;
1H NMR
(CDCl3): d 1.40 (t, 3H, OCH2CH3, J ¼ 7.2 Hz), 2.52 (s, 3H,
Py-CH3),4.38(q 2H, OCH2CH3, J ¼ 7.2 Hz,), 6.88 (s, 2H,
NH2), 7.15–7.41 ppm (m, 5 H, Ar-H); ms: m/z 298 (Mþ þ1,
15), 297 (Mþ, 47), 250 (35), 226 (41), 225 (54), 224 (100),
194 (27), 176 (24), 183 (55), 118 (61), 77 (46); Anal. Calcd.
for C16H15N3O3: C, 64.64; H, 5.09; N, 14.13. Found: C,
64.54; H, 4.79; N, 14.11.
4-Amino-6-(4-chloro-phenoxy)-5-cyano-2-methyl-nicotinic
acid ethyl ester (8g). This compound was obtained as white
solid, mp 184.0–184.7ꢂC, yield 93%; IR: 3450, 3346, 2982,
4-Amino-5-cyano-6-(4-bromophenoxy)-2-methyl-nicotinic acid
methyl ester (8a). This compound was obtained as white solid,
mp 161.0–163.0ꢂC, yield 77%; IR: 3400, 3308, 2955,
2225(CN), 1689(C¼¼O), 1616, 1546, 1567, 1270, 1160 cmꢁ1
;
1H NMR (CDCl3): d 2.07 (s, 3H, Ar-CH3), 2.32 (s, 3H, Ar-
CH3), 2.48 (s, 3H, Py-CH3), 3.90 (s, 3H, OCH3), 6.80 (s, 2H,
NH2 ), 6.92–7.11 ppm (m, 3H, Ar-H); ms: m/z 311 (Mþ, 29),
310 (10), 296 (49), 264 (28), 236 (19), 103 (41), 91 (44), 77
(100), 66(19); Anal. Calcd. for C17H17N3O3: C, 65.58; H,
5.50; N, 13.50. Found: C, 65.35; H, 5.11; N, 13.41.
2222(CN), 1708(C¼¼O), 1570, 1490, 1230 cmꢁ1
;
1H NMR
(CDCl3): d 1.40 (t, 3H, OCH2CH3, J ¼ 7.2 Hz), 2.51 (s, 3H,
Py-CH3), 4.38 (q, 2H, OCH2CH3, J ¼ 7.2 Hz), 6.66 (s, 2H,
NH2), 7.10–7.36 ppm (m, 4H, Ar-H); 13C NMR (CDCl3): d
14.1, 27.4, 61.5, 78.8, 105.0, 113.7, 123.1, 129.2, 130.5, 150.8,
159.2, 163.3, 165.1, 167.4; ms: m/z 332 (Mþ þ1, 9), 331 (Mþ,
100), 302 (15), 284 (33), 258 (91), 222 (19), 194 (21), 152
(64); Anal. Calcd for C16H14ClN3O3: C, 57.93; H, 4.25; N,
12.67. Found: C, 57.88; H, 4.03; N, 12.62.
4-Amino-5-cyano-6-(4-chloro-2-fluorophenoxy)-2-methyl-nico-
tinic acid methyl ester (8b). This compound was obtained as
white solid, mp 184.0–184.7ꢂC, yield 75%; IR: 3409, 3318,
2959, 2223(CN), 1692(C¼¼O), 1627, 1551, 1497, 1574, 1269,
1094 cmꢁ1 1H NMR (CDCl3): d 2.49 (s, 3H, Py-CH3), 3.90
;
(s, 3H, OCH3), 6.90 (s, 2H, NH2), 7.15–7.18 ppm (m, 3H, Ar-
H). ms: m/z 335 (Mþ, 49), 303 (29), 275 (82), 236 (24) 213
(22), 170 (100), 169 (83), 129 (43), 77 (31), 66 (75); Anal.
Calcd. for C15H11ClFN3O3: C, 53.66; H, 3.30; N, 12.52.
Found: C, 53.99; H, 3.30; N, 12.41.
4-Amino-5-cyano-6-(3-methoxyphenoxy)-2-methyl-nicotinic
acid methyl ester (8c). This compound was obtained as white
solid, mp 188.0–190.0ꢂC, yield 83%; IR: 3412, 3313, 2964,
4-Amino-5-cyano-2-methyl-6-(2-nitrophenoxy)-nicotinic acid
ethyl ester (8h). This compound was obtained as yellow solid,
mp 141.0–143.0ꢂC, yield 87%; IR: 3386, 3298, 2979,
2229(CN), 1684(C¼¼O), 1618, 1569, 1272 cmꢁ1
;
1H NMR
(CDCl3): d 1.38 (t, 3H, OCH2CH3, J ¼ 7.2 Hz), 2.42 (s, 3H,
Py-CH3), 4.37 (q, 2H, OCH2CH3, J ¼ 7.2 Hz), 6.90 (s, 2H,
NH2), 7.34–8.12 ppm (m, 4H, Ar-H); 13C NMR (CDCl3): d
14.1, 27.4, 61.5, 78.7, 105.4, 113.4, 125.2, 125.5, 126.2, 134.6,
142.2, 145.2, 159.2, 162.3, 164.9, 167.3 ppm; ms: m/z 342
(Mþ, 10), 331 (21), 296 (50), 268 (100), 250 (22), 224 (26),
194 (12), 176 (15), 152 (16); Anal. Calcd for C16H14N4O5: C,
56.14; H, 4.12; N, 16.37. Found: C, 56.29; H, 3.81; N, 16.51.
4-Amino-5-cyano-2-methyl-6-(2,3-dimethylphenoxy)-nicotinic
acid ethyl ester (8i). This compound was obtained as yellow
solid, mp 159.8–161.8ꢂC, yield 90%; IR: 3391, 3297, 2980,
2221(CN), 1688(C¼¼O), 1613, 1568, 1501, 1263, 1090 cmꢁ1
;
1H NMR (CDCl3): d 2.46 (s, 3H, CH3), 3.75 (s, 3H, Ar-
OCH3), 3.89 (s, 3H, OCH3), 6.80 (s, 2H, NH2), 6.96–7.22 ppm
(m, 4H, Ar-H). 13C NMR (CDCl3): d 27.4, 51.9, 55.9, 78.3,
104.4, 112.8, 114.1, 120.7, 122.9, 126.4, 141.5, 151.6, 159.1,
164.0, 165.3, 168.1 ppm; ms: m/z 313 (Mþ, 11), 298 (26), 250
(62), 222 (34), 210 (18), 194 (15), 173 (19), 147 (24), 91 (46),
77 (100); Anal. Calcd for C16H15N3O3: C, 61.34; H, 4.83; N,
13.41. Found: C, 61.56; H, 4.51; N, 13.23.
2229(CN), 1679(C¼¼O), 1617, 1543, 1565, 1271, 1100 cmꢁ1
;
1H NMR (CDCl3): d 1.39 (t, 3H, OCH2CH3, J ¼ 7.2 Hz),
2.07 (s, 3H, Ar-CH3), 2.32 (s, 3H, Ar-CH3); 2.48(s, 3H, Py-
CH3), 4.37 (q, 2H, OCH2CH3, J ¼ 7.2 Hz), 6.90 (s, 2H, NH2),
6.92–7.10 ppm (m, 3H, Ar-H); ms: m/z 325 (Mþ, 100), 310
(92), 296 (23), 282 (45), 264 (69), 253 (36), 236 (48), 218
(12), 208 (15), 146 (15), 102 (53), 91 (44); Anal. Calcd. for
C18H19 N3O3: C, 66.45; H, 5.89; N, 12.91. Found: C, 66.47;
H, 5.52; N, 13.06.
4-Amino-5-cyano-6-(3-nitrophenoxy)-2-methyl-nicotinic acid
methyl ester (8d). This compound was obtained as yellow solid,
mp 141.0–143.0ꢂC, yield 75%; IR: 3387, 3281, 2954,
2232(CN), 1695(C¼¼O), 1630, 1598, 1531, 1575, 1269, 1097
1
cmꢁ1; H NMR (CDCl3): d 2.42 (s, 3H, Py-CH3), 3.90 (s, 3H,
OCH3), 6.90 (s, 2H, NH2), 7.34–8.12 ppm (m, 4H, Ar-H); ms:
m/z 296 (Mþ ꢁ O2, 11), 283 (Mþ ꢁ NO2, 44), 282 (100), 250
(43), 222 (9), 206 (10), 91 (7), 77 (6); Anal. Calcd. for
C15H12N4O5: C, 54.88; H, 3.68; N, 17.07. Found: C, 55.16; H,
3.64; N, 16.89.
4-Amino-5-cyano-2-methyl-6-phenoxy-nicotinic acid methyl
ester (8e). This compound was obtained as white solid, mp
171.0–173.0ꢂC, yield 79%; IR: 3393, 3286, 2957, 2229(CN),
4-Amino-5-cyano-2-methyl-6-(4-methylphenoxy)-nicotinic acid
ethyl ester (8j). This compound was obtained as white solid,
mp 106.9–108.3ꢂC, yield 89%; IR: 3397, 3279, 2942,
2224(CN), 1689(C¼¼O), 1626, 1505, 1566, 1266, 1097 cmꢁ1
;
1H NMR (CDCl3): d 1.39 (t, 3H, OCH2CH3, J ¼ 7.2 Hz),
2.37 (s, 3H, Ar-CH3), 2.52(s, 3H, Py-CH3), 4.37 (q, 2H,
OCH2CH3, J ¼ 7.2 Hz), 6.92 (s, 2H, NH2), 7.03–7.19 ppm
(m, 3H, Ar-H); ms: m/z 311 (Mþ, 100), 296 (6), 282 (14), 265
(52), 239 (82), 237 (46), 222 (7), 132 (30), 91 (16), 77 (8);
Anal. Calcd. for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50.
Found: C, 65.86; H, 5.97; N, 13.57.
1692(C¼¼O), 1630, 1594, 1492, 1267, 1096 cmꢁ1
;
1H NMR
(CDCl3): d 2.41 (s, 3H. Py-CH3), 3.90 (s, 3H, OCH3), 6.90 (s,
2H, NH2) 7.34–8.12 ppm (m, 5H, Ar-H); 13C NMR (CDCl3): d
27.4, 52.0, 78.8, 104.6, 113.9, 121.6, 125.3, 129.2, 152.3, 159.1,
163.8, 165.4, 167.9 ppm; ms: m/z 284 (Mþ þ1, 7), 283 (Mþ,
55), 282 (Mþ ꢁ1, 23), 251(17), 225 (63), 222 (44), 194 (28),
130 (22), 118 (75), 77 (100); Anal. Calcd for C15H13N3O3: C,
63.60; H, 4.63; N, 14.83. Found: C, 63.89; H, 4.57; N, 14.70.
General procedure for the preparation of compounds
(8k–p). A mixture of 4-amino-5-cyano-6-methylsulfonyl-2-
methyl-nicotinic acid alkyl ester 5a or 5b (5 mmol),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

178
Q. Ren, W. Mo, L. Gao, H. He, and Y. Gu
Vol 47
alkylamines or heterocycleamines (10 mmol), and 20 mL of
acetonitrile was stirred for 4–5 h at room temperature. The
color of the reaction mixture was changed into yellow. The
reaction mixture was poured into 100 mL of water and this so-
lution was stirred for 2 h. The crude product that precipitated
was collected by filtration. The filtrate was recrystallized from
dichloromethane/petroleum ether to give pure 4-amino-5-
cyano-2-methyl-6-alkylamino-nicotinic acid alkyl esters 8 k–p.
4-Amino-5-cyano-2-methyl-6-triazolyl-nicotinic acid ethyl
ester (8o). This compound was obtained as yellow solid, m.p.
196.0–198.0ꢂC, yield 78%; 1H NMR (CDCl3): d 1.45(t, J ¼
7.2 Hz, 3H, OCH2CH3), 2.75 (s, 3H, Py-CH3), 4.45(q, J ¼ 7.2
Hz, 2H, OCH2CH3), 7.08 (s, 2H, NH2), 8.19(s, 1H, triazole-
H), 9.18 ppm (s, 1H, triazole-H); ms: m/z 272 (Mþ, 44.9), 227
(91.4), 225(100), 199 (26), 173 (10), 144 (6); Anal. Calcd. for
C12H12N6O2: C, 52.94; H, 4.44; N, 30.87. Found: C, 53.22; H,
4.64; N, 31.12.
4-Amino-5-cyano-2-methyl-6-ethylamino-nicotinic
acid
ethyl ester (8k). This compound was obtained as white solid,
mp 151.0–154.0ꢂC, yield 90%; 1H NMR (CDCl3): d 1.24(t,
3H, NHCH2CH3, J ¼ 7.2 Hz), 1.38(t, 3H, OCH2CH3, J ¼ 7.2
Hz), 2.60 (s, 3H, Py-CH3), 3.55–3.61(m, 2H, NHCH2CH3),
4.33(q, 2H, OCH2CH3, J ¼ 6.8 Hz), 5.08(s, 1H, NH), 6.68
ppm (s, 2H, NH2); ms: m/z 248 (Mþ, 100), 233(88.0), 219
(84.8), 205(64.9), 187 (46.8), 174 (98.7), 159 (38.0), 117 (6.0),
44 (7.9); Anal. Calcd. for C12H16N4O2: C, 58.05; H, 6.50; N,
22.57. Found: C, 57.75; H, 6.02; N, 22.77.
4-Amino-5-cyano-2-methyl-6-piperdinyl-nicotinic acid ethyl
ester (8p). This compound was obtained as yellow solid, m.p.
108.0–110.0ꢂC, yield 82%; 1H NMR (CDCl3): d 1.38(t, J ¼
7.2 Hz, 3H, OCH2CH3), 1.67(d, J ¼ 7.2 Hz, 6H, 3*CH2), 2.56
(s, 3H, Py-CH3), 3.82(d, J ¼ 7.2 Hz, 4H, 2*CH2), 4.32(q, J ¼
7.2 Hz, 2H, OCH2CH3), 6.88 ppm (s, 2H, NH2); 13C NMR
(CDCl3): d 14.2, 24.6, 26.0, 28.1, 48.3, 60.5, 73.3, 98.9, 117.7,
158.9, 160.3, 164.4, 168.2 ppm; ms: m/z 288 (Mþ, 100), 259
(46), 245 (33), 231 (26), 205(64), 187 (37), 173 (52), 158
(35), 84 (75); Anal. Calcd. for C15H20N4O2: C, 62.48; H, 6.99;
N, 19.43. Found: C, 62.18; H, 7.26; N, 19.21.
4-Amino-5-cyano-2-methyl-6-propylamino-nicotinic
acid
ethyl ester (8l). This compound was obtained as white solid,
mp 141.0–142.0ꢂC, yield 89%; 1H NMR (CDCl3): d 0.97(t,
J ¼ 7.2 Hz, 3H, NHCH2CH3), 1.38(t, J ¼ 7.2 Hz, 3H,
OCH2CH3), 1.63(m, 2H, CH2CH2CH3), 2.60 (s, 3H, Py-CH3),
3.50(q, J ¼ 6.8 Hz, 2H, NHCH2CH2), 4.33(q, J ¼ 7.2 Hz, 2H,
OCH2CH3), 5.12(s, 1H, NH), 6.68 ppm (s, 2H, NH2); 13C
NMR (CDCl3): d 11.3, 14.3, 22.9, 28.3, 42.8, 60.6, 72.5, 99.5,
116.3, 158.4, 158.5, 166.3, 168.2 ppm; Anal. Calcd. for
C13H18N4O2: C, 59.53; H, 6.92; N, 21.36. Found: C, 59.46; H,
6.74; N, 21.50.
Acknowledgments. The project is supported by National Key
Project for Basic Research Development Program of China (No.
2003CB114406), the National Natural Science Foundation of
China (No. 20772042 ), the National Key Technologies R & D
Program of China (No. 2006BAE01A01-10) and Syngenta.
REFERENCES AND NOTES
4-Amino-5-cyano-2-methyl-6-butylamino-nicotinic
methyl ester (8m). This compound was obtained as white
acid
[1] Yildiz, D. Toxicon 2004, 43, 619.
[2] Cutshall, N. S.; Kucera, K. A.; Ursion, R.; Latham, J.; Ihle,
N. C. Bioorg Med Chem Lett 2002, 12, 1517.
[3] Roth, H. J.; Kleemann, A. In Pharmaceutical Chemistry.
Drug Synthesis; Wiley: New York, 1988; Vol.1.
[4] Gilchrist, T. L. In Heterocyclic Chemistry, 3rd ed.; Addison
Wesley Longman: Harlow, 1997; p 127.
solid, m.p. 139.9–141.3ꢂC, yield 87%; IR: 3424, 3349, 2959,
2201(CN), 1669(C¼¼O), 1611, 1507, 1565, 1274, 1092 cmꢁ1
;
1H NMR (CDCl3): d 0.95(t, J ¼ 7.2 Hz, 3H, CH2CH3), 1.37–
1.42(m, 2H, CH2CH2CH3), 1.55–1.62 (m, 2H, CH2CH2CH3),
2.60 (s, 3H, Py-CH3), 3.54(q, J ¼ 6.4 Hz, 2H, NHCH2CH2),
3.87(s, 3H, OCH3), 5.12(s, 1H, NH), 6.68 ppm (s, 2H, NH2);
ms: m/z 262 (Mþ, 38), 247 (7), 233 (55), 219 (100), 206 (46),
187 (78), 174 (49), 159 (19); Anal. Calcd. for C13H18N4O2: C,
59.53; H, 6.92; N, 21.36. Found: C, 59.30; H, 7.12; N, 21.05.
[5] Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna,
P. R. Synthesis 2006, 55.
[6] Rabin, J. C.; Kirsch, G.; Beley, M. J Heterocycl Chem
2000, 37, 1077.
[7] Zhao, W. G.; Wang, S. H.; Wang, W. Y.; Li, Z. M. Huaxue
Shiji 2000, 22, 376.
4-Amino-5-cyano-2-methyl-6-benzylamino-nicotinic
methyl ester (8n). This compound was obtained as white solid,
acid
[8] Veronese, A. C.; Callegari, R.; Morellic, C. F. Tetrahedron
1995, 51, 12277.
m.p. 138.8–140.8ꢂC, yield 73%; IR: 3423, 3345, 2949,
2202(CN), 1673(C¼¼O), 1602, 1503, 1562, 1284, 1091 cmꢁ1
;
[9] Zhao, W. G.; Liu, Z. X.; Li, Z. M.; Wang, B. L. Synth
Commun 2003, 33, 4229.
1H NMR (CDCl3): d 2.62 (s, 3H, Py-CH3), 3.88(s, 3H, OCH3),
4.75(d, J ¼ 5.6 Hz, 2H, NHCH2), 5.44(s, 1H, NH), 6.74 (s,
2H, NH2), 7.28–7.37 ppm (m, 5H, Ph-H); 13C NMR (CDCl3):
d 28.2, 44.8, 51.5, 72.8, 99.8, 116.0, 127.5, 127.8, 128.6,
138.5, 158.1, 158.4, 166.4, 168.5 ppm; ms: m/z 296 (Mþ,
100), 263 (11), 236 (6), 218 (8), 191 (16), 159 (10), 106 (66),
91 (27); Anal. Calcd. for C16H16N4O2: C, 64.85; H, 5.44; N,
18.91. Found: C, 65.28; H, 5.39; N, 18.74.
[10] Liu, H.; Wang, H. Q.; Ding, M. W.; Liu, Z. J.; Xiao, W. J.
J Fluorine Chem 2006, 127, 1584.
[11] Crystal structure of compound 8h has been deposited at the
Cambridge Crystallographic Data Center and allocated the reference
no. CCDC 662948.
[12] Yang, F. L.; Liu, Z. J.; Huang, X. B.; Ding, M. W. J Heter-
ocycl Chem 2004, 41, 77.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet