Facile Synthesis of Nicotinic Acid Derivatives with Unsymmetrical Substitution Patterns

Article abstract of DOI:10.1081/SCC-120026851

Two novel methods for synthesis of nicotinic acid derivatives with unsymmetrical substitution patterns were presented via ketene dithioacetals. The ketene N,S-acetals 2 reacted with β-ketoesters or β-cyanoesters to give 4-amino-5-cyano-2-alkyl-6-methylthi

Full text of DOI:10.1081/SCC-120026851

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Facile Synthesis of Nicotinic Acid Derivatives with
Unsymmetrical Substitution Patterns
a
a
a
a
Wei-Guang Zhao , Zheng-Xiao Liu , Zheng-Ming Li & Bao-Lei Wang
a
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin, P.R. China
Published online: 21 Aug 2006.
To cite this article: Wei-Guang Zhao , Zheng-Xiao Liu , Zheng-Ming Li & Bao-Lei Wang (2003): Facile Synthesis of Nicotinic
Acid Derivatives with Unsymmetrical Substitution Patterns, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:24, 4229-4234
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 24, pp. 4229–4234, 2003
Facile Synthesis of Nicotinic Acid Derivatives
with Unsymmetrical Substitution Patterns
Wei-Guang Zhao, Zheng-Xiao Liu, Zheng-Ming Li,*
and Bao-Lei Wang
State Key Laboratory of Elemento-Organic Chemistry,
Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin, P.R. China
ABSTRACT
Two novel methods for synthesis of nicotinic acid derivatives with
unsymmetrical substitution patterns were presented via ketene
dithioacetals. The ketene N,S-acetals 2 reacted with b-ketoesters or
b-cyanoesters to give 4-amino-5-cyano-2-alkyl-6-methylthio-nicotinic
acid derivatives 3 or 2,4-diamino-5-cyano-6-methylthio-nicotinic acid
ethyl ester 4. However, 6-amino-5-cyano-2-alkyl-4-methylthio-
nicotinic acid esters 6 were obtained by the reaction of the ketene
dithioacetals 1 and b-amino-crotonates.
*Correspondence: Zheng-Ming Li, State Key Laboratory of Elemento-Organic
Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin,
3
00071, P.R. China; Fax: þ86-22-23505948; E-mail: nkzml@nk.sina.net.
229
4
DOI: 10.1081/SCC-120026851
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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230
Zhao et al.
Compounds containing a pyridine ring, such as vitamin B,
nicotinamide, and nicotinic acid, play important roles in metabolism
[
1]
and possess a wide spectrum of biological activity. Among the many
pyridines which have been developed as pharmaceuticals are piroxican,
an anti-inflammatory, nifedipine, and amlodipine, which are effective for
[
2]
the treatment of angina, and pinacidil, used to treat hypertension etc.
They are also involved in various agrochemical applications as herbicide,
[
2]
insecticide, and fungicide. An efficient and concise synthesis of poly
substituted pyridine compounds is demanded. The Hantzsch reactions
have been widely used to synthesize dihydropyridines and pyridines
[
3]
with symmetrical substitution patterns. But the synthesis of pyridines
with unsymmetrical substitution patterns often is difficult and involves
multi-step reactions.
Ketene dithioacetals and ketene N,S-acetals have been used as
versatile starting materials for the synthesis of a wide variety of new
[
4–6]
heterocycles and fused heterocycles,
but they are seldom reported to
[7]
form pyridine rings. Here we reported two novel synthetic methods to
the synthesis of pyridines unsymmetrical substitution patterns which
involves ketene dithioacetals and ketene N,S-acetals.
It has been reported that the metal ions may promote formation of
a carbon–carbon bond between the cyano group of nitriles and the
[
8,9]
intercarbonyl methylene group of b-dicarbonyl compounds.
previous article, we had reported
In the
the synthesis of pyrazolo[3,4-b]
[
10]
pyridines by the reactions of 5-aminopyrazole-4-acetonitrile and
b-dicarbonyl compounds in the presence of tin(IV) chloride.
Considering the above facts, we studied the condensation reaction of
ketene N,S-acetals 2 with b-ketoesters or b-diketone by using tin(IV)
chloride to synthesize polysubstituted pyridines.
The condensation of 2-cyano-3-amino-3-methylthio-acrylonitrile 2
with b-ketoesters was carried out in the presence of stoichiometric
amounts of tin (IV) chloride in medium yield, in 1:1:2 molar ratios
ꢀ
(
Sch. 1). The mixture was kept at 100 C without solvent or in refluxing
1
,4-dioxane for 5 h, and then was treated with a saturated aqueous
solution of sodium carbonate to give 4-amino-5-cyano-2-alkyl-
-methylthio-nicotinic acid derivatives 3 in medium yield. It is noted
6
that when ethyl cyanoacetate, instead of b-ketoesters, reacted with
compound 2, 2,4-diamino-5-cyano-6-methylthio-nicotinic acid ethyl
ester 4 could be obtained in low yield also. We investigated the
catalytic activity of different halides, e.g., BF and TiCl . Only SnCl
4
3
4
showed catalytic activity and resulted in complete conversion of the
starting 2.

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Nicotinic Acid Derivatives
4231
Scheme 1.
In an alternative approach, we planned to obtain nicotinic acid
derivatives 3 by the conjugate addition of b-amino crotonates to ketene
dithioacetals 1. The reaction was not carried out in presence of less than
two equivalent strong bases. However, not compound 3, but 6-amino-
5
-cyano-nicotinic acid ester 6 were obtained in presence of 2 molar
ratios NaH.
A solution of the compounds 5 in THF was added dropwise to a
solution of compounds 1 in THF in the presence of NAH (80%), in
:1:2 molar ratio. After removal of solvent, the residue was chromato-
1
1
graphed to yield the compounds 6. H NMR spectrograms of compounds
were similar to the compounds 3. However, they have completely
different value of R and melting points. MS spectrograms further
6
f
showed that two compounds had the same molecular ion peak and yet
had different fragment peaks. The base peak ion of compound 3b is mole-
cular ion peak, owing to stable intramolecular hydrogen bond. The mole-
.
cular ion of compound 3b lost MeOH and MeO to give ions with
approximately relative abundance of m/z 205 and 206 at a time.
However, the base peak ion of compound 6b at m/z 206 was formed by
.
losing a fragment of MeO .
And the IR spectra of 3b and 6b showed that 3b differed from 6b in
,
ꢁ
1
absorption peak of C¼O. The absorption peak of 3b, which is 1677 cm
ꢁ1
is 43 cm less than that of 6b, because the ester groups of 3b was located
at ortho position of the amino. These proved that compounds 3 and 6
were isomers. So we postulated the ketene dithioacetals 1 reacted with
b-amino crotonates to obtain compounds 6. (Sch. 2)
The two synthetic routes described can be considered as a facile
method to synthesize amino-nicotinic acid derivatives with unsymmet-
rical substitution patterns by utilizing the readily available dithioacetal
derivatives with different substituting group.

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232
Zhao et al.
Scheme 2.
EXPERIMENTAL
1
H NMR spectra were taken on a Bruker AC-P200 spectrometer.
Tetramethylsilane (TMS) was used as an internal standard. Elemental
analyses were carried out on a Yanaco MT-3 instrument. Melting
points were determined with a model Yanaco MP-500 apparatus and
uncorrected. Mass spectra were recorded on a HP 5989 instrument
(
EI). Infrared spectra were obtained on a Shimadzu-435 spectrometer.
General Procedure of 4-Amino-3-cyano-2-methylthio-
5-pyridinecarboxylic Acid Ester 3 and 4
2-Cyano-3-amino-3-methylthio-acrylonitrile 2 (0.14 g, 1 mmol) and
SnC1 (0.23 mL, 2 mmol) were added to a stirred esters (b-ketoesters or
4
cyanoacetate, 1 mmol) in 10 mL toluene. And then the reaction mixture
was refluxed for 5 h. A saturated aqueous solution of Na CO (50 mL)
2
3
was added to the reaction mixture. The suspension was extracted with
ethyl acetate (3 ꢂ 25 mL) and the combined extracts were dried (MgSO ).
4
After removal of solvent, the residue was purified by recrystallization
from ethanol. Spectral data and elemental analyses are given as follows:
ꢀ
a. Yield: 55%. White crystals. M.p.: 140–142 C. H NMR (CDCl ,
3
1
3
ppm): 2.58 (s, 3H, SCH ), 2.65 (s, 3H, CH ), 3.89 (s, 3H, OCH ), 6.80 (br,
3
3
3
þ
2
H, NH ). MS: m/z ¼ 237 (M , 100), 206 (15), 205 (29), 177 (59). Anal.
2
cald. for C H N O S: C, 50.62; H, 4.67; N, 17.71. Found: C, 50.50;
10 11 3 2
H, 4.93; N, 17.45.
b. Yield: 45%. White crystals. M.p.: 135.5–137 C. H NMR
CDCl , ppm): 1.39 (t, 3H, CH ), 2.59 (s, 3H, SCH ), 2.67 (s, 3H,
ꢀ
1
3
(
3
3
3
þ
CH ), 4.36 (q, 3H, OCH ), 6.70 (br, 2H, NH ). MS: m/z ¼ 251 (M ,
3
2
2
ꢁ
1
00), 223 (22), 206 (41), 205 (42), 179 (69). IR(cm ): 3387, 3286
1
(
NH ), 2207 (CN), 1677 (C¼O), 1661, 1542 (ring), 1231(C–O). Anal.
2

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Nicotinic Acid Derivatives
4233
calcd. for C H N O S: C, 52.57; H, 5.21; N, 16.72. Found: C, 52.33;
1
1
13
3
2
H, 5.45; N, 16.42.
c. Yield: 48%. White crystals. M.p.: 165–166 C. H NMR (CDCl ,
ppm): 2.55 (s, 3H, COCH ), 2.59 (s, 3H, SCH ), 2.65 (s, 3H, CH ), 6.50
ꢀ
1
3
3
3
3
3
(
br, 2H, NH ). Anal. calcd. for C H N OS: C, 54.28; H, 5.01; N, 18.99,
2 10 11 3
Found: C, 53.97; H, 5.07; N, 19.06.
d. Yield: 36%. White crystals. M.p.: 237–239 C. H NMR (DMSO,
ppm): 2.37 (s, 3H, SCH ), 2.54 (s, 3H, CH ), 6.84 (br, 2H, NH ),
ꢀ
1
3
3
3
2
7.01–7.72 (m, 5H, Ph), 10.45 (s, 1H, NH). Anal. calcd. for
C H N OS: C, 60.38; H, 4.73; N, 18.78. Found: C, 60.10; H, 4.69;
1
5
14
4
N, 18.48.
e. Yield: 57%. White crystals. M.p.: 121–122 C. H NMR (CDCl ,
ppm): 1.23 (t, 3H, CH ), 2.58 (s, 3H, SCH ), 2.95 (s, 2H, CH ), 3.89 (s,
ꢀ
1
3
3
3
3
2
3H, OCH ), 6.40 (br, 2H, NH ). Anal. calcd. for C H N O S: C, 52.57;
3 2 11 13 3 2
H, 5.21; N, 16.72. Found: C, 52.26; H, 5.89; N, 16.46.
ꢀ
. Yield: 17%. White crystals. M.p.: 169–170 C. H NMR (CDCl ,
3
1
4
ppm): 1.39 (t, 3H, CH ), 2.50 (s, 3H, SCH ), 4.38 (q, 2H, OCH ), 5.70
3
3
2
(br, 2H, NH ), 7.80 (br, 2H, NH ). Anal. calcd. for C H N O S:
2 2 10 12 4 2
C, 47.61; H, 4.79; N, 22.21. Found: C, 47.39; H, 4.80; N, 22.39.
General Procedure of 2-Amino-3-cyano-2-alkyl-
6-methylthio-5-pyridinecarboxylic Acid Ester 6
A solution of the b-amino crotonates (4a–b, 3 mmol) in THF was
added dropwise to a solution of 2-cyano-3,3-bis(methylthio)acrylonitrile
1
6
(0.61 g, 3.6 mmol) in THF in the presence of NaH (80%, 0.18 g,
mmol). After stirring 6 h, removal of solvent, the residue was
purified by chromatograph on silica gel column eluting with ethyl
acetate-petroleum ether. Spectral data and elemental analyses are given
as follows:
ꢀ
a. Yield: 24%. White crystals. M.p.: 158–160 C. H NMR (CDCl ,
3
1
6
ppm): 2.39 (s, 3H, SCH ), 2.60 (s, 3H, CH ), 3.90 (s, 3H, OCH ), 5.50 (br,
3
3
3
þ
2
H, NH ). MS: m/z ¼ 237 (M , 40), 206 (100), 205 (29). Anal. calcd. for
2
C H N O S: C, 50.62; H, 4.67; N, 17.71. Found: C, 50.36; H, 4.93;
10 11 3 2
N, 17.36.
b. Yield: 28%. White crystals. M.p.: 141–142 C. H NMR (CDCl ,
ppm): 1.37 (t, 3H, CH ), 2.38 (s, 3H, SCH ), 2.59 (s, 3H, CH ), 4.36 (q,
ꢀ
1
6
3
3
3
3
þ
2
(
H, OCH ), 5.44 (br, 2H, NH ). MS: m/z ¼ 251 (M , 28), 206 (100), 205
ꢁ
2
2
2
1
36), 177 (59). IR(cm ): 3382, 3231 (NH ), 2209 (CN), 1720 (C¼O),
11 13 3 2
1642, 1537 (ring), 1253 (C–O). Anal. calcd. for C H N O S: C, 52.57;
H, 5.21.; N, 16.72. Found: C, 52.34; H, 5.12; N, 16.59.

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234
Zhao et al.
ACKNOWLEDGMENT
The project was supported by ‘‘863’’ program (2001AA235011) and
the National Natural Foundation of China (No. 20202003).
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Received in the UK July 4, 2003