Novel zinc ion-catalyzed synthesis of unsymmetric multisubstituted pyridines

Article abstract of DOI:10.1080/00397910902978015

A facile and convenient synthesis of unsymmetric multisubstituted pyridines from β-ketoesters and ketene N,S-acetals or ketene N,N-acetals has been achieved in good yields catalyzed by Zn(NO₃)₂6H ₂O in the presence of triethylbenzylammonium (TEBA) chloride in ethanol. This reaction was carried out under economical, one-pot reaction conditions (using easily obtained starting materials, and inexpensive catalyst and solvent) and offers considerable improvements over traditional methodology.

Full text of DOI:10.1080/00397910902978015

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Novel Zinc Ion–Catalyzed Synthesis of
Unsymmetric Multisubstituted Pyridines
Qingyun Ren a , Wenyan Mo a , Yongyan Yao a , Hongwu He a &
Yucheng Gu a b
a Key Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
Wuhan, Hubei, P. R. China
b Syngenta, Jealott's Hill International Research Centre, Bracknell,
Berkshire, United Kingdom
Published online: 29 Dec 2009.
To cite this article: Qingyun Ren , Wenyan Mo , Yongyan Yao , Hongwu He & Yucheng Gu (2009): Novel
Zinc Ion–Catalyzed Synthesis of Unsymmetric Multisubstituted Pyridines, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:2, 303-312
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Synthetic Communications1, 40: 303–312, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902978015
NOVEL ZINC ION–CATALYZED SYNTHESIS OF
UNSYMMETRIC MULTISUBSTITUTED PYRIDINES
Qingyun Ren,1 Wenyan Mo,1 Yongyan Yao,1 Hongwu He,1
and Yucheng Gu1,2
1Key Laboratory of Pesticide and Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Wuhan,
Hubei, P. R. China
2Syngenta, Jealott’s Hill International Research Centre, Bracknell,
Berkshire, United Kingdom
A
facile and convenient synthesis of unsymmetric multisubstituted pyridines from
b-ketoesters and ketene N,S-acetals or ketene N,N-acetals has been achieved in good yields
catalyzed by Zn(NO3)2 ꢀ 6H2O in the presence of triethylbenzylammonium (TEBA) chlor-
ide in ethanol. This reaction was carried out under economical, one-pot reaction conditions
(using easily obtained starting materials, and inexpensive catalyst and solvent) and offers
considerable improvements over traditional methodology.
INTRODUCTION
The development of new ways to make pyridines is of considerable interest.
One reason for this interest is the fact that many natural products, such as vitamin
B, nicotinamide, and nicotinic acid, which play important roles in metabolism and
possess a wide spectrum of biological activities, contain a pyridine ring.[1,2] The main
synthetic methods used for the preparation of pyridines with symmetrical sub-
stitution patterns include the Hantzsch reaction,[3,4] but the synthesis of multisubsti-
tuted pyridines with unsymmetric substitution patterns is often difficult and involves
multistep sequences, so there is still a great need to develop new approaches to
pyridines of this type.
It has been reported[5] that metal ions may promote the formation of a carbon–
carbon bond between nitriles and the intercarbonyl methylene group in b-dicarbonyl
compounds. Veronese et al.[6] first reported the synthesis of 4-aminopyridines via the
reactions of b-enaminonitriles with b-ketoesters in the presence of stoichiometric
amounts of tin(IV) chloride, and Zhao and coworkers[7] used similar chemistry for
the synthesis of nicotinic acid derivatives. However, the scope of the reaction has
not been properly investigated, and the literature does not describe optimized
reaction conditions.
Received December 20, 2008.
Address correspondence to Hongwu He, Key Laboratory of Pesticide and Chemical Biology,
Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road,
Wuhan, Hubei 430079, China. E-mail: he1208@mail.ccnu.edu.cn
303

304
Q. REN ET AL.
As a result of our interest in the synthesis of biologically active compounds,
recently we have successfully applied this tin(IV) chloride–promoted reaction to
the synthesis of multisubstituted pyridines 3B (Eq. 1). However, we found that some
issues associated with this method needed to be addressed. First, this method
requires anhydrous conditions because tin(IV) chloride is readily hydrolyzed
in water. Furthermore, the poor solubility of the reactants and the SnCl4 catalyst
in toluene, used as the solvent for the reaction, often leads to a poor yield and
prolonged reaction time. And finally, the complex workup procedure involves the
dilution of the reaction mixture with a saturated aqueous solution of sodium carbon-
ate and extraction of the reactant mixture with ethyl acetate before the title
compound can be isolated and purified by flash chromatography on silica gel.
To overcome these limitations, a new and facile approach for the synthesis of
multisubstituted pyridine derivatives using the reaction of ketene N,S-acetals or
ketene N,N-acetals with b-ketoesters in the presence of zinc(II) nitrate as a catalyst
has been developed and is reported here.
RESULTS AND DISCUSSION
In this study, various catalysts, different solvents, reaction times, and the molar
ratios of reactants were tested to optimize the reaction conditions. The survey of
reaction conditions and results are summarized in Table 1. The initial study was
performed on the reaction of 2-(amino-methylthio-methylene)-malononitrile with
acetylacetone in the presence of SnCl4 (2 equiv.) in refluxing toluene, which gave a
yield of 38% of 3C (entry 1). Corresponding reactions carried out in polar solvents
such as ethanol and dimethylformamide (DMF) led to none of the required product
(entries 2 and 3). Using these experiments as starting points, the effect of altering
other components of the reaction was studied.
Catalysts and solvents have a dramatic influence on the efficiency of the reac-
tion, as summarized in Table 1. A variety of catalysts, such as FeCl3 ꢀ 6H2O (entry 4),
ZnCl2(entries 5–10), Zn(OAc)2 ꢀ 2H2O (entry 14), and Zn(NO3)2(entries 15–22),
catalyze the reactions more efficiently than SnCl4 (entries 1–3). A survey of solvents
showed that ethanol was more efficient than toluene, benzene, acetonitrile, or DMF
(entries 5–10, Table 1). When ethanol was used as the solvent, the sequence of the
yields with different catalysts is Zn(NO3)2(entry 15) ꢁ Zn(NO3)2 ꢀ 6H2O (entry
23) ꢁ Zn(OAc)2 ꢀ 2H2O (entry 14) ꢁ ZnCl2(entry 9) ꢁ ZnSO4 ꢀ 7H2O (entry 11).
Although Zn(NO3)2 provided better catalytic efficiency than Zn(NO3)2 ꢀ 6H2O (entry
17 vs. entry 23, entry 22 vs. entry 25), the latter was chosen for further experiments
because it is more easily obtained and handled.
We found that the molar ratio of the reactants has a modest effect on the
efficiency of the reaction. Thus a ratio of N,S-acetal–b-ketoester–catalyst of 1:1:2

ZINC ION–CATALYZED SYNTHESIS OF PYRIDINES
305
Table 1. Optimization of the reaction conditions
Entry
Catalyst
N,S-Acetal–ketoester–catalyst
Conditions
Time (h) Yield (%)a
1
2
SnCl4
SnCl4
SnCl4
1:1:2
1:1:2
1:1:2
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:1
1:1:0.5
1:1:0.25
1:2:2
1:1:2
1:1:2
1:2:2
1:2:2
1:2:2
1:2:2
Toluene=reflux
Ethanol=reflux
DMF=110
8
8
38
Failed
Failed
58
3
8
4
FeCl3 ꢀ 6H2O
ZnCl2
ZnCl2
Toluene=reflux
Toluene=reflux
Benzene=reflux
CH3CN=reflux
Ethanol=reflux
Ethanol=reflux
DMF=110
8
5
12
12
12
12
12
12
12
12
12
12
8
48
45
6
7
ZnCl2
ZnCl2
49
54
8
9
ZnCl2
ZnCl2
60
53
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
ZnSO4 ꢀ 7H2O
CuCI2
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
Ethanol=reflux
31
Failed
Failed
70
Mg(CIO4)2
Zn(OAc)2 ꢀ 2H2O
Zn(NO3)2
72
81
Zn(NO3)2
Zn(NO3)2
10
12
14
12
12
12
12
12
20
12
6
83
80
Zn(NO3)2
Zn(NO3)2
79
75
Zn(NO3)2
Zn(NO3)2
Zn(NO3)2
63
87
Zn(NO3)2 ꢀ 6H2O
Zn(NO3)2 ꢀ 6H2O
Zn(NO3)2 ꢀ 6H2O
Zn(NO3)2 ꢀ 6H2O
Zn(NO3)2 ꢀ 6H2O þTBAB
Zn(NO3)2 ꢀ 6H2O þTEBA
73
54
80
78
6
86
93
6
aYield of pure isolated product.
gave a slightly better yield than a ratio of 1:1:1 (compare entries 17 and 19, respect-
ively), and yields dropped when a lower proportion of the catalyst was used (entries
20 and 21). The greater concentration of b-ketoesters (2 equivalents) reduced
the reaction time and slightly increased the yield (entry 18 vs. entry 22, entry 23
vs. entry 25).
The reaction time has not a remarkable effect on the efficiency of the reaction
when using Zn(NO3)2 as catalyst. When the reaction time changed from 8 to 14 h
(entries 15–18) and other variables were kept constant, the results revealed that
12 h was probably the most effective time for the cyclization reaction (entry 17,
Table 1). However, when using Zn(NO3)2 ꢀ 6H2O as catalyst, we found that a further
increase in the reaction time led to lower yield (entry 23 vs. entry 24), and there was

306
Q. REN ET AL.
almost no change on the reaction yields when the reaction time was reduced to 6 h
within the conditions established (entry 25 vs. entry 26).
Reasoning that a phase-transfer catalyst may assist the solubility of the
reactants, a catalytic amount of TBAB (tetrabutylammonium bromide) (entry 27)
or TEBA (triethylbenzylammonium chloride) (entry 28) was added to some reac-
tions. When the molar ratio of reactants was 1:2:2, using Zn(NO3)2 ꢀ 6H2O and
TEBA as the catalyst, at refluxing temperature for 6 h, a maximum amount of the
title compound was obtained in pure ethanol (entry 28).
To investigate the scope of this reaction and establish its tolerance for different
substrates under the optimized conditions, a range of different b-ketoesters 2 and
ketene N,S-acetals 1 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 3 was isolated in good to excellent yield (85–
95%), and no regioisomeric products were detected. However, when the b-ketoester
was replaced by ethyl cyanoacetate, no corresponding pyridine was obtained under
these reaction conditions.
To illustrate the practicality of our protocol, different b-ketoesters 2 were
allowed to react with a variety of ketene N,N-acetals 4 under the optimal reaction
conditions. The expected novel multisubstituted pyridines 5 were isolated following
simple workup and purification by recrystallization (Table 3). It is worth noting that
the yields of the pyridines 5 were great when the amino group in the precursor
carried a bulky benzyl substituent.
Although the detailed mechanism of this reaction is not clear at this stage, it
is likely that the reaction proceeds through the Michael addition of b-ketoesters to
the ketene N,S-acetal followed by subsequent ring closure. The zinc ion stabilized
the enol carbanion for facilitating the reaction. Further investigations of the scope
Table 2. Yields of compounds 3
Entry
R
Y
Compounds
Yield (%)a
1
2
3
4
5
6
7
8
9
Me
Me
MeO
EtO
Me
3A
3B
3C
3D
3E
3F
3G
3H
31
90
95
93
86
91
89
87
89
85
Me
Et
MeO
EtO
Me
Et
Et
PhCH2
PhCH2
PhCH2
MeO
EtO
Me
aYield of pure isolated product.

ZINC ION–CATALYZED SYNTHESIS OF PYRIDINES
307
Table 3. Yields of compounds 5
Entry
R
Y
Compounds
Yield (%)a
1
2
3
4
5
6
(CH2)2CH3
(CH2)3CH3
PhCH2
EtO
EtO
EtO
MeO
Me
5A
5B
5C
5D
5E
5F
41
45
81
83
75
90
PhCH2
2-CIPhCH2
4-MeOPhCH2
EtO
aYield of pure isolated product.
and mechanism of the reaction are under way. A tentative mechanism for the forma-
tion of the multisubstituted pyridine derivative is shown in Scheme 1.
All the compounds obtained were fully characterized by spectroscopic analysis
[infrared (IR), 1H NMR 13C NMR, and electron-impact mass spectrometry
(EI-MS)] and elemental analysis. In the case of 3I, the structure was additionally
confirmed by single-crystal x-ray diffraction (Fig. 1). (Crystal structure of compound
3I has been deposited at the Cambridge Crystallographic Data Center and allocated
the reference no. CCDC 653953.)
In summary, we have developed a new and straightforward procedure for the
preparation of multisubstituted pyridines with unsymmetrically positioned substitu-
ents. This procedure should be applicable to the synthesis of a variety of potentially
bioactive pyridines, starting with readily available precursors such as ketene N,S- or
N,N-acetals and b-ketoesters, Zn(NO3)2 ꢀ 6H2O, and TEBA as catalyst. The appli-
cation of this strategy toward the synthesis of other multisubstituted pyridines is
currently being explored.
Scheme 1. Possible mechanism of the synthesis of pyridines.

308
Q. REN ET AL.
Figure 1. Perspective view of the x-ray crystal structure of 3I.
EXPERIMENTAL
General
Melting points were measured on an electrothermal melting-point apparatus
and are uncorrected. Mass spectra were measured on a Finnigan Trace MS 2000
spectrometer. IR spectra were recorded on a PE-983 IR spectrometer as KBr pellets
.
with absorption in centimetersꢂ1 1H NMR spectra were recorded on a Varian
Mercury 400 spectrometer using CDCl3 as the solvent. Chemical shifts are given in
parts per million (ppm) (d) relative to tetramethylsilane (TMS) (d 0.00 ppm). 13C
NMR spectra were recorded on a Varian Mercury 600 spectrometer using CDCl3 as
the solvent. Chemical shifts are given in ppm (d) relative to CDCl3 (d 77.00 ppm).
Elemental analyses were performed on a Vario EL III elemental analysis instrument.
All of the solvents and materials were reagent grade and purified as required.
Synthesis of 4-Amino-5-cyano-2-methyl-6-alkylsulfanyl-nicotinic
Acid Derivatives 3A–I
A mixture of 2-(amino-alkylthio-methylene)-malononitrile 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 1 (20 mmol) or acetylacetone 1 (20 mmol) in
anhydrous ethanol (30 ml). The mixture was heated under reflux under nitrogen
for 6 h and then cooled. The precipitate was recrystallized from ethanol–water to
give 4-amino-5-cyano-2-methyl-6-alkylsulfanyl-nicotinic acid derivatives 3A–I in
good yields.
Selected Data
4-Amino-5-cyano-2-methyl-6-methylsulfanyl-nicotinic acid methyl
ester 3A. White crystal; yield 90%; mp 141.2–143.2ꢃC; 1H NMR (400 MHz CDCl3)
d (ppm): 2.61 (s, 3H, SCH3), 2.68 (s, 3H, py-CH3), 3.92 (s, 3H, OCH3), 6.70 (s, 2H,
NH2); 13C NMR (150 MHz CDCl3) d (ppm): 12.8, 27.6, 52.0, 89.1, 104.5, 114.5,

ZINC ION–CATALYZED SYNTHESIS OF PYRIDINES
309
156.4, 163.7, 165.1, 168.2; MS (EI) m=z: 238 (Mþ þ 1, 15), 237 (Mþ, 100), 236
(Mþ ꢂ1, 32), 205 (21), 177 (28); IR (KBr) t (cmꢂ1): 3418, 3315, 3197, 3002, 2214
=
(CN), 1690 (C O), 1610, 1550, 1238, 1096. 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
1
3B. White crystal; yield 95%; mp 136.0–138.0ꢃC; H NMR (400 MHz CDCl3) d
(ppm): 1.41 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 2.62 (s, 3H, SCH3), 2.70 (s, 3H,
py-CH3), 4.39 (q, J ¼ 7.2 Hz, 2H, OCH2), 6.68 (s, 2H, NH2); 13C NMR (150 MHz
CDCl3) d (ppm): 12.8, 14.1, 27.6, 61.4, 89.1, 104.7, 114.5, 156.4, 163.6, 164.9,
167.8; MS (EI) m=z: 252 (Mþ þ 1, 23), 251 (Mþ, 100), 250 (Mþ ꢂ1, 41), 223 (47),
205 (31), 177(30); IR (KBr) t (cmꢂ1): 3406, 3309, 3200, 2983, 2219 (CN), 1682
=
(C O), 1618, 1546, 1241, 1097. 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.
5-Acetyl-4-amino-6-methyl-2-methylsulfanyl-nicotinonitrile 3C. White
1
crystal; yield 93%; mp 164.8–165.1ꢃC; H NMR (400 MHz CDCl3) d (ppm): 2.58
(s, 3H, COCH3), 2.62 (s, 3H, SCH3), 2.68 (s, 3H, py-CH3), 6.62 (s, 2H, NH2); 13C
NMR (150 MHz CDCl3) d (ppm): 12.8, 27.2, 33.0, 89.3, 114.5, 114.6, 155.0, 161.0,
164.7, 202.3; MS (EI) m=z: 221 (Mþ, 100), 206 (44), 204 (43), 177 (36), 160 (40);
IR (KBr) t (cmꢂ1): 3416, 3334, 3233, 3006, 2210 (CN), 1668 (C O), 1619, 1542,
=
1235. Anal. calcd. for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99; S, 14.49. Found:
C, 54.47; H, 4.70; N, 19.28; S, 14.22.
4-Amino-5-cyano-6-ethylsulfanyl-2-methyl-nicotinic acid methyl ester
3D. White crystal; yield 86%; mp 137.2–139.2ꢃC; 1H NMR(400 MHz CDCl3) d
(ppm): 1.37 (t, J ¼ 7.2 Hz, 3H, SCH2CH3), 2.68 (s, 3H, Py-CH3), 3.25 (q, J ¼ 7.2 Hz,
2H, SCH2CH3), 3.92 (s, 3H, OCH3), 6.72(s, 2H, NH2); 13C NMR (150 MHz CDCl3)
d (ppm): 14.6, 24.4, 27.6, 51.9, 89.2, 104.4, 114.5, 156.5, 163.7, 164.9, 168.2; MS (EI)
m=z: 251 (Mþ, 66), 236 (26), 218 (81), 204 (15), 191 (100), 186 (41), 159 (47), 130 (29);
IR (KBr) t (cmꢂ1): 3406, 3310, 3276, 2951, 2871, 2213 (CN), 1689 (C O), 1612,
=
1546, 1240, 1093. 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-ethylsulfanyl-2-methyl-nicotinic acid ethyl ester
3E. White crystal; yield 91%; mp 145.0–146.9ꢃC; 1H NMR(400 MHz CDCl3) d
(ppm): 1.37 (t, J ¼ 7.2 Hz, 3H, CH3), 1.41 (t, J ¼ 7.2 Hz, 3H, CH3), 2.68 (s, 3H,
Py-CH3), 3.25 (q, J ¼ 7.6 Hz, 2H, SCH2CH3), 4.38 (q, J ¼ 7.2 Hz, 2H, OCH2CH3),
6.69 (s, 2H, NH2); 13C NMR (150 MHz CDCl3) d (ppm): 14.6, 24.4, 27.6, 51.9,
61.3, 89.2, 104.4, 114.5, 156.5, 163.7, 164.9, 168.2; MS (EI) m=z: 265 (Mþ, 36),
250 (7), 232 (30), 204 (62), 191 (99), 186 (57), 159 (100), 131 (50); IR (KBr) t
(cmꢂ1): 3411, 3305, 3268, 2978, 2874, 2213 (CN), 1680 (C O), 1609, 1544, 1240,
=
1092. 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.
5-Acetyl-4-amino-2-ethylsulfanyl-6-methyl-nicotinonitrile 3F. Yellow
1
crystal; yield 89%; mp 133.2–135.2ꢃC; H NMR (400 MHz CDCl3) d (ppm): 1.38
(t, J ¼ 7.2 Hz, 3H, SCH2CH3), 2.59 (s, 3H, COCH3), 2.70 (s, 3H, py-CH3), 3.28
(q, J ¼ 5.6 Hz, 2H, SCH2CH3), 6.68 (s, 2H, NH2); 13C NMR (150 MHz CDCl3) d

310
Q. REN ET AL.
(ppm): 14.6, 24.4, 27.2, 32.9, 89.4, 114.4, 114.5, 155.1, 161.0, 164.5, 202.3; MS (EI)
m=z: 236 (Mþ þ 1, 37), 235 (Mþ, 100), 234 (Mþꢂ1, 52), 220 (54), 202 (53), 192
(16), 160 (18); IR (KBr) t (cmꢂ1): 3398, 3300, 3191, 2971, 2214 (CN), 1658
=
(C O), 1606, 1532, 1228. Anal. calcd. for C11H13N3OS: C, 56.15; H, 5.57; N,
17.86; S, 13.63. Found: C, 56.24; H, 5.88; N, 18.05; S, 13.60.
4-Amino-6-benzylsulfanyl-5-cyano-2-methyl-nicotinic acid methyl ester
1
3G. Yellow crystal; yield 87%; mp 139.4–141.7ꢃC; H NMR (400 MHz CDCl3) d
(ppm): 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(m, 5H, Ph-H); 13C NMR (150 MHz CDCl3) d (ppm): 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;
MS (EI) m=z: 314 (Mþ þ 1, 17), 313 (Mþ, 100), 312 (Mþꢂ1, 27), 280 (18), 255 (4);
IR (KBr) t (cmꢂ1): 3426, 3307, 3004, 2211 (CN), 1677 (C O), 1603, 1547, 1250.
=
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-6-benzylsulfanyl-5-cyano-2-methyl-nicotinic acid ethyl ester
1
3H. Yellow crystal; yield 89%; mp 109.7–112.0ꢃC; H NMR (400 MHz CDCl3) d
(ppm): 1.41 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 2.72 (s, 3H, Py-CH3), 4.38 (q, J ¼ 7.2 Hz,
2H, OCH2CH3), 4.51 (s, 2H, PhCH2), 6.70 (s, 2 H, NH2), 7.24–7.41(m, 5 H,
Ph-H); 13C NMR (150 MHz CDCl3) d (ppm): 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; MS (EI) m=z: 328
(Mþ þ 1, 18), 327 (Mþ, 100), 326 (Mþꢂ1, 74), 299 (11), 255 (28), 212 (38); IR
(KBr) t (cmꢂ1): 3419, 3312, 2986, 2211 (CN), 1673 (C O), 1606, 1546, 1237. 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.
5-Acetyl-4-amino-2-benzylsulfanyl-6-methyl-nicotinonitrile 3I. Yellow
1
crystal; yield 85%; mp 154.2–155.2ꢃC; H NMR (400 MHz CDCl3) d (ppm): 2.58
(s, 3H, COCH3), 2.70 (s, 3H, py-CH3), 4.50 (s, 2H, SCH2Ph), 6.62 (s, 2H, NH2),
7.23–7.41 (m, 5H, Ph); 13C NMR (150 MHz CDCl3) d (ppm): 27.1, 32.9, 33.9,
89.1, 114.3, 114.8, 127.2, 128.4, 129.1, 137.3, 155.1, 160.9, 163.7, 202.3; MS (EI)
m=z: 298 (Mþ þ 1, 22), 297 (Mþ, 100), 296 (Mþꢂ1, 48), 265 (18), 220 (11); IR
(KBr) t (cmꢂ1): 3447, 3341, 2975, 2207 (CN), 1663 (C O), 1615, 1534, 1233. Anal.
=
calcd. for C16H15N3OS: C, 64.62; H, 5.08; N, 14.13; S, 10.78. Found: C, 64.97; H,
5.39; N, 14.21; S, 10.90.
Synthesis of 4-Amino-5-cyano-2-methyl-6-alkylamino-Nicotinic
Acid Derivatives 5A–F
A mixture of N-substituted diaminomethylene-malononitrile 4 (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 2 (20 mmol) or acetylacetone 2 (20 mmol) in
anhydrous ethanol (30 ml). The mixture was heated under reflux for 6 h and then
cooled. The precipitate was recrystallized from ethanol–water to give 4-amino-5-
cyano-2-methyl-6-alkylamino-nicotinic acid derivatives 5A–F in good yield.

ZINC ION–CATALYZED SYNTHESIS OF PYRIDINES
311
Selected Data
4-Amino-6-propylamino-5-cyano-2-methyl-nicotinic acid ethyl ester
5A. White solid; yield 41%; Mp 141.0–142.0ꢃC; 1H NMR (400 MHz CDCl3) d
(ppm): 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 (s, 2H,
NH2); 13C NMR (150 MHz CDCl3) d (ppm): 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. Anal. calcd. for C13H18N4O2: C,
59.53; H, 6.92; N, 21.36. Found: C, 59.46; H, 6.74; N, 21.50.
4-Amino-6-butylamino-5-cyano-2-methyl-nicotinic acid ethyl ester
5B. White solid; yield 50%; Mp 129.8–131.2ꢃC; 1H NMR (400 MHz CDCl3) d
(ppm): 0.96 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 1.36–1.43 (m, 5H, OCH2CH3
þCH2CH2CH3), 1.58 (t, J ¼ 4.0 Hz, 2H, CH2CH2CH3), 2.60 (s, 3H, Py-CH3), 3.54
(q, J ¼ 6.4 Hz, 2H, NHCH2CH2), 4.32 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 5.14 (s, 1H,
NH), 6.68 (s, 2H, NH2); 13C NMR (150 MHz CDCl3) d (ppm): 13.8, 14.3, 19.9,
28.3, 31.8, 40.8, 60.6, 72.5, 99.5, 116.3, 158.3, 158.4, 166.3, 168.2; MS (EI) m=z:
276 (Mþ, 39), 261 (5), 247 (48), 234 (84), 219 (36), 205 (43), 187 (56), 174 (100),
162 (26); IR (KBr) t (cmꢂ1): 3421, 3353, 2958, 2198 (CN), 1669 (C O), 1612,
=
1505, 1563, 1273, 1094. Anal. calcd. for C14H20N4O2: C, 60.85; H, 7.30; N, 20.28.
Found: C, 60.85; H, 6.99; N, 20.14.
4-Amino-6-benzylamino-5-cyano-2-methyl-nicotinic acid ethyl ester
5C. White solid; yield 61%; Mp 156.5–158.0ꢃC; 1H NMR (400 MHz CDCl3) d
(ppm): 1.39 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 2.62 (s, 3H, Py-CH3), 4.34 (q, J ¼ 7.2 Hz,
2H, OCH2CH3), 4.75 (d, J ¼ 5.6 Hz, 2H, NHCH2), 5.42 (s, 1H, NH), 6.74 (s, 2H,
NH2), 7.24–7.37 (m, 5H, Ph-H); 13C NMR (150 MHz CDCl3) d (ppm): 14.2, 28.2,
44.8, 60.7, 72.8, 100.0, 116.1, 127.5, 127.8, 128.6, 138.6, 158.0, 158.5, 166.3, 168.1;
MS (EI) m=z: 310 (Mþ, 100), 281 (8), 263 (8), 236 (5), 205 (11), 159 (9), 106 (78),
91 (31); IR (KBr) t (cmꢂ1): 3433, 3361, 2980, 2200 (CN), 1673 (C O), 1602, 1504,
=
1564, 1241, 1025. Anal. calcd. for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found:
C, 65.75; H, 5.61; N, 17.82.
4-Amino-6-benzylamino-5-cyano-2-methyl-nicotinic acid methyl ester
5D. White solid; yield 73%; Mp 138.8–140.8ꢃC; 1H NMR (400 MHz CDCl3) d
(ppm): 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 (m, 5H, Ph-H); 13C NMR (150 MHz
CDCl3) d (ppm): 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; MS (EI) m=z: 296 (Mþ, 100), 263 (11), 236 (6), 218 (8), 191 (16),
159 (10), 106 (66), 91 (27); IR (KBr) t (cmꢂ1): 3423, 3345, 2949, 2202 (CN), 1673
=
(C O), 1602, 1503, 1562, 1284, 1091. Anal. calcd. for C16H16N4O2: C, 64.85; H,
5.44; N, 18.91. Found: C, 65.28; H, 5.39; N, 18.74.
5-Acetyl-4-amino-2-(2-chlorobenzyl)amino-6-methyl-nicotinonitrile 5E.
1
Yellow solid; yield 45%; Mp 191.2–192.5ꢃC; H NMR (400 MHz CDCl3) d (ppm):
2.54 (s, 3H, COCH3), 2.60 (s, 3H, Py-CH3), 4.84 (d, J ¼ 5.6 Hz, 2H, NHCH2),
5.63 (s, 1H, NH), 6.88 (s, 2H, NH2), 7.23–7.43(m, 4H, Ph-H); 13C NMR
(150 MHz CDCl3) d (ppm): 28.1, 33.3, 42.7, 79.1, 110.5, 115.8, 126.9, 128.9, 129.6,

312
Q. REN ET AL.
130.0, 133.7, 135.9, 157.7, 157.8, 164.5, 201.1; MS (EI) m=z: 316 (Mþ þ 2, 10), 315
(Mþ þ 1, 15), 314 (Mþ, 42), 299 (6), 279 (92), 203 (5), 175 (14), 160 (11), 140
(100), 125 (72); IR (KBr) t (cmꢀ1): 3406, 3338, 2916, 2203 (CN), 1722 (C O),
1583, 1503, 1554, 1280, 1038. Anal. calcd. for C16H15ClN4O: C, 61.05; H, 4.80; N,
17.80. Found: C, 61.46; H, 4.54; N, 17.81.
=
4-Amino-5-cyano-6-(4-methoxybenzyl)amino-2-methyl-nicotinic acid
ethyl ester 5F. White solid 0.82 g; yield 80%; Mp 133.7–135.8ꢁC; 1H NMR
(400 MHz CDCl3) d (ppm): 1.39 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 2.62 (s, 3H,
Py-CH3), 3.81 (s, 3H, OCH3), 4.33 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 4.67 (d,
J ¼ 2.8 Hz, 2H, NHCH2), 5.36 (s, 1H, NH), 6.68 (s, 2H, NH2), 6.86–7.27 (m, 4H,
Ph-H); 13C NMR (150 MHz CDCl3) d (ppm): 14.2, 28.2, 44.4, 55.2, 60.7, 72.7,
99.9, 113.9, 116.1, 129.2, 130.6, 157.9, 158.5, 158.9, 166.3, 168.1; MS (EI) m=z:
340 (Mþ, 100), 325 (10), 293 (5), 205 (7), 136 (59), 121 (89), 77 (11); IR (KBr) t
(cmꢀ1): 3485, 3360, 2938, 2202 (CN), 1670 (C O), 1594, 1510, 1561, 1246, 1024.
=
Anal. calcd. for C18H20N4O3: C, 63.52; H, 5.92; N, 16.46. Found: C, 63.46; H,
5.64; N, 16.45.
ACKNOWLEDGMENTS
This project was supported by the National Key Project for Basic Research
Development Program of China (No. 2003CB114400), the National Natural Science
Foundation of China (No. 20772042), the National Science and Technique
Foundation of China (No. 2006BAE01A01-10), and Syngenta Ltd.
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