A simple, diversity oriented synthesis of highly substituted pyridines

Article abstract of DOI:10.1002/jhet.614

Figure represented. A particularly straightforward and efficient protocol for the synthesis of highly substituted pyridines, based on a condensation reaction of β-aminocrotonitrile and easily accessible (E)-2-oxo-4-aryl-but- 3-enoic acids and (E)-4-oxo-4-

Full text of DOI:10.1002/jhet.614

792
A Simple, Diversity Oriented Synthesis of Highly Substituted
Pyridines
Vol 48
Katarzyna Kaczanowska,a,b Holger Eickhoff,a Klaus Albert,b Karl-Heinz
Wiesmu¨ller,a,b and Arnaud-Pierre Schaffnera*
aEMC microcollections GmbH, Sindelfinger St. 3, Tu¨bingen D-72070, Germany
b
¨
_
Institut fu_r Organische Chemie, Fakultat fur Chemie und Pharmazie, Eberhard Karls
¨
¨
Universitat Tubingen
*E-mail: schaffner@microcollections.de
Received May 28, 2010
DOI 10.1002/jhet.614
Published online 7 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
A particularly straightforward and efficient protocol for the synthesis of highly substituted pyridines,
based on a condensation reaction of b-aminocrotonitrile and easily accessible (E)-2-oxo-4-aryl-but-3-enoic
acids and (E)-4-oxo-4-aryl-but-2-enoic acids is described.
J. Heterocyclic Chem., 48, 792 (2011).
INTRODUCTION
We report a particularly straightforward protocol for
the synthesis of pyridine regioisomers based on condensa-
tion reactions of b-aminocrotonitrile 2 and commercially
available or easily accessible (E)-2-oxo-4-aryl-but-3-enoic
acids 1a–h [7] and (E)-4-oxo-4-aryl-but-2-enoic acids
4a–h [8]. Although the addition of b-aminocrotonitrile 2
to chalcones is well documented [1,9], the synthesis of
pyridines using dicarbonyl systems described herein has
not yet been studied.
The pyridine motif is among the most common hetero-
cyclic compounds found in various pharmaceuticals,
agrochemicals, and natural products [1]. Pyridines exhibit
antifungal activity against Candida albicans [2,3], a
major fungal pathogen, anti-HIV [4] as well as antibacte-
rial activity [3] and target a wide variety of biological
receptors [1,5].
In the search for novel bioactive compounds exists a
continued strong demand for versatile syntheses of pyri-
dine derivatives. Although numerous approaches leading
to the pyridine moiety have been reported over the last
decades, the preparation of non-symmetrical, substituted
pyridine rings remains a significant challenge [1,6].
A few elegant methods for the synthesis of highly
substituted pyridines appeared in the recent literature
[6]. Some of these approaches involve multicomponent
reactions [6a–c], rhodium-catalyzed activation of alkenyl
CAH bond [6f–g], isoxazole ring expansion [6h], or
routes based on aza-Diels-Alder reaction [6i]. The
described methods are often low-yielding and limited in
applicability due to restricted functionalities at certain
positions. In this context, our aim was to develop an
efficient method that gives a high flexibility considering
substituent pattern in the pyridine ring.
RESULTS AND DISCUSSION
Treatment of (E)-2-oxo-4-aryl-but-3-enoic acids 1a–h
with potassium t-butoxide in acetonitrile at ambient
temperature afforded pyridines 3a–h in good yields
(Scheme 1, Table 1). The formation of the product
proceeds by condensation of 1 with b-aminocrotonitrile
2 generated in situ. When the reaction was performed in
dichloromethane or in tetrahydrofuran with commercially
available b-aminocrotonitrile, no improvement of the
yield or the reaction time was observed. Depending on the
substitution pattern of the aromatic ring, full conversion
required 3–16 h. The increase of the amount of t-butoxide
did not significantly influence the reaction time.
The use of (E)-4-oxo-4-aryl-but-2-enoic acids 4a–h
under the same reaction conditions makes possible the
C
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July 2011
A Simple, Diversity Oriented Synthesis of Highly Substituted Pyridines
793
Scheme 1
Table 2
Synthesis of pyridines 5a-h via scheme 2a.
Compound number
Ar
Yield (%)
5a
5b
5c
5d
5e
5f
4-Fluoro-phenyl
3-Chloro-phenyl
4-Chloro-phenyl
2,4-Dichloro-phenyl
3,4-Dichloro-phenyl
4-Methoxy-phenyl
Furan-2-yl
74
67
86
81/65b
54
86/55b
63
61
Table 1
Synthesis of pyridines 3a–h via scheme 1a.
5g
5h
Thiophen-2-yl
a Unless otherwise mentioned, all reactions were carried out using (E)-
4-oxo-4-aryl-but-2-enoic acid 1 (1.0 mmol), t-BuOK (2.0 mmol), and
acetonitrile (5 mL) at room temperature for 16 h.
Compound number
3a
Ar
Yield (%)
2-Fluoro-phenyl
4-Fluoro-phenyl
61/51b
66
60
b Product (starting from 20 mmol of substrate) isolated by crystalli-
zation from acetonitrile.
3b
3c
3d
3e
3f
3-Chloro-phenyl
4-Chloro-phenyl
2,6-Dichloro-phenyl
4-Methoxy-phenyl
Benzo[1,3]dioxol-5-yl
Thiophen-2-yl
73
81
71/50b
62
62
The formation of products 3 and 5 can be described
as cyclocondensation reaction of the corresponding sub-
strates 1 and 4 with b-aminocrotonitrile 2. The enamine
2 is formed in situ by dimerization of acetonitrile
catalyzed by potassium t-butoxide. Within the first
hour 4d gave the intermediate/dihydropyridine 6, which
slowly aromatized to the pyridine 5d (Scheme 3).
Several modifications of the functional groups of pyri-
dines 3 and 5 were performed to generate compound
diversity.
3g
3h
a Unless otherwise mentioned, all reactions were carried out using
(E)-2-oxo-4-aryl-but-3-enoic acid 1 (1.0 mmol), t-BuOK (3.0 mmol),
and acetonitrile (5 mL) at room temperature for 16 h.
b Product (starting from 20 mmol of substrate) isolated by crystalliza-
tion from acetonitrile.
substituent flexibility at the 2- and 4-positions of the
target molecules (Schemes 1 and 2). Compounds 4a–h
reacted with b-aminocrotonitrile to give the regioisomers
5a–h in good to excellent yields (Table 2). Similarly as
for 3, some differences in the reactivity depending on the
substitution of the aromatic ring were observed. Neverthe-
less 16 h were sufficient for the full conversion of the
substrate to the desired product. Two equivalents of
potassium t-butoxide were used, because an increase of
the amount of base lead to the formation of byproducts.
As for the synthesis of the regioisomer 3, reaction in
dichloromethane or tetrahydrofuran with commercially
available b-aminocrotonitrile did not improve reaction
times and yields of the pyridine 5. It was observed that
the cyano group of the regioisomer 5 is particularly sensi-
tive and undergoes hydrolysis during aqueous acidic
workup. Therefore, water free 4M HCl/dioxane was used.
The procedure was easily scaled up to 20 mmol, and
the products were isolated in good yields by crystallization
from acetonitrile (Table 1, 3a and 3f; Table 2, 5d and 5f).
The pyridines were readily converted to the corre-
sponding N-oxides 7 and 12 as outlined on Schemes 4
and 5 [10]. 2-Aryl pyridine 5d reacted only at higher
temperature. At 100ꢀC, N-oxide formation of 5d was
observed as well as hydrolysis of the cyano group to
the corresponding pyridine dicarboxylic acid 12. Both
derivatives, 7 and 12, were isolated in very good yields.
To form N-hydroxyamidines, pyridine carboxylic
acids 3 and 5 were first amidated using (benzotriazol-1-
yloxy) tripyrrolidinophosphonium hexafluorophosphate
(PyBOP) as coupling reagent to give amides 8 and 13
Scheme 3
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

794
K. Kaczanowska, H. Eickhoff, K. Albert, K.-H. Wiesmu¨ller, and A.-P. Schaffner
Vol 48
Scheme 5
(Schemes 4 and 5). Both regioisomers were isolated in
excellent yields. Amides 8a and 13a were treated with
hydroxylamine and potassium t-butoxide in dimethyl
sulfoxide at 100ꢀC [5a]. 2-Aryl pyridine 13a formed
the expected product 14 within 2 h. The regioisomer
8a appeared to be more sensitive and at the same condi-
tions hydrolyzed to give the diamide 9. Any other
combination of bases and solvents did not lead to the
formation of the hydroxyamidine from 8a. Additionally,
we observed that 4-aryl pyridines 3 with free carboxy
group stayed unaffected under the described conditions,
but its regioisomer 2-aryl pyridine 5 with carboxy group
in position 4 decomposed.
The dicyano-pyridines 10 and 15 were synthesized in
high yields by dehydration of the primary amides 8b
and 13b, respectively, with phosphorus oxychloride
(Schemes 4 and 5) [11].
Attempts to transform 3d into its hydrazide failed.
The acid was unreactive in aqueous hydrazine (50%) at
100ꢀC and was unstable at higher temperatures. How-
ever, the acid 5c reacted with hydrazine to give the
hydrazide 11 in an excellent yield (Scheme 5) [12].
CONCLUSIONS
In conclusion, we have developed a facile and efficient
synthesis of highly substituted pyridines based on the
reaction of easily accessible (E)-2-oxo-4-aryl-but-3-enoic
acids and (E)-4-oxo-4-aryl-but-2-enoic acids with b-ami-
nocrotonitrile. The method provides an opportunity for
the introduction of a variety of functional groups. Further
extension of the reactions and the application of the
protocols in the synthesis of biologically active com-
pounds are in progress.
EXPERIMENTAL
Starting materials (E)-2-oxo-4-aryl-but-3-enoic acids 1 and
(E)-4-oxo-4-aryl-but-2-enoic acids 4 were synthesized according
to the literature procedures [7,8] or were obtained commercially
and used as received. All chemicals were used as purchased
from commercial suppliers. Analytical TLC were performed
with ALUGRAM silica gel 60 F254 plate. Flash chromato-
graphy was done on Combi Flash 5q 16x. Visualization was
accomplished using UV light. Column chromatography was
carried out using MN silica gel 60 (70–230 mesh ASTM).
The mass spectra were measured on a Waters LC/MS system
(Alliance 2795 HPLC, SQD mass detector, PDA 996 detector;
Grom-Sil 80 ODS-7 PH 4 lm, 2.0 ꢁ 40 mm; ionizing voltage
10 eV). For FT-ICR-MS measurements, the APEX II Bruker
Daltonics (4.7 Tesla) spectrometer was used. NMR analyses
were performed on a Bruker 400 Ultra Shield instrument.
Melting points were measured on Bu¨chi Melting Point B-540.
IR spectra were obtained on Bruker-Vector 22.
Scheme 4
General procedure for the synthesis of (E)-2-oxo-4-aryl-
but-3-enoic acids (1). A solution of potassium hydroxide
(2.52 g, 45 mmol) in methanol (7.5 mL) was added dropwise
to a solution of pyruvic acid (2.11 mL, 30 mmol) and benzal-
dehyde (30 mmol) in methanol (15 mL) at 0ꢀC. The reaction
temperature was kept at 25ꢀC for 1 h and at 0ꢀC for 16 h. The
yellow solid was filtered off and washed twice with cold meth-
anol and once with diethyl ether. The crude residue was taken
up in water, acidified with 1M HCl and extracted with
dichloromethane. The combined organic phases were dried
over anhydrous sodium sulphate and concentrated to afford the
product as a solid that was used without further purification.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
A Simple, Diversity Oriented Synthesis of Highly Substituted Pyridines
795
150.2 (C), 152.4 (C), 162.2 (C), 165.1 (C); FT-ICR-MS:
calculated for C14H9ClN2O2Hþ: 273.0425, found: 273.0425.
5-Cyano-4-(2,4-dichloro-phenyl)-6-methyl-pyridine-2-carbox-
ylic acid (3e). 71% yield, colorless solid, mp 226–227ꢀC
(dec.); IR (neat, cmꢂ1) kmax: 3144, 2974, 2937, 2878, 2827,
2229, 1683, 1587, 1558, 1477, 1432, 1388, 1226, 1181, 1056,
1004; 1H NMR (400 MHz, DMSO-d6) d ppm 2.78 (s, 3 H),
7.59 (m, 1 H), 7.70 (m, 2 H), 7.81 (s, 1 H); 13C NMR (100
MHz, DMSO-d6) d ppm 23.5 (CH3), 109.1 (C), 115.4 (C),
121.8 (CH), 128.7 (CH), 132.3 (C), 132.9 (CH), 133.6 (C),
149.0 (C), 156.4 (C), 161.5 (C), 166.0 (C); FT-ICR-MS:
calculated for C14H8Cl2N2O2Hþ: 307.0036, found: 307.0036.
General procedure for the synthesis of (E)-4-oxo-4-aryl-
but-2-enoic acids (4). Glyoxylic acid monohydrate (3.68 g, 40
mmol) was added to a solution of acetophenone (40 mmol) in
acetic acid (50 mL) and concentrated hydrochloric acid (5 mL).
The mixture was refluxed for 16 h. After evaporation of the sol-
vent, the yellow residue was taken up in ethyl acetate, filtered
and air dried to afford the desired product as a yellow solid
that was used in the next step without further purification.
General procedure for the synthesis of 4-aryl pyridines
(3). Potassium t-butoxide (0.337 g,
3 mmol) was added
portionwise to a solution of (E)-2-oxo-4-(aryl)-but-3-enoic acid 1
(1 mmol) in acetonitrile (5 mL) at room temperature. After 16 h
(the reaction monitored by LC/MS), the solvent was removed
under reduced pressure. The crude product was taken up in
water, acidified with 1M HCl and extracted with dichlorome-
thane. The combined organic phases were dried over anhydrous
sodium sulphate and concentrated. The solid product 3 was iso-
lated by column chromatography with silica gel using a gradient
of petroleum ether-ethyl acetate (from 4:1 to 1:1).
5-Cyano-4-(4-methoxy-phenyl)-6-methyl-pyridine-2-carboxylic
acid (3f). 71% yield, colorless solid, mp 196ꢀC; IR (neat,
cmꢂ1) kmax: 3284, 3174, 2974, 2937, 2871, 2229, 1727, 1602,
1536, 1499, 1425, 1388, 1336, 1233, 1174, 1130, 1063, 1026,
916, 835; 1H NMR (400 MHz, DMSO-d6) d ppm 2.77 (s, 3
H), 3.84 (s, 3 H), 7.13 (m, 2 H), 7.67 (m, 2 H), 7.92 (s, 1 H);
13C NMR (100 MHz, DMSO-d6) d ppm 23.8 (CH3), 55.5
(CH3), 109.2 (C), 114.6 (CH), 116.8 (C), 121.6 (CH), 127.4
(C), 130.2 (CH), 150.0 (C), 153.3 (C), 161.0 (C), 162.3 (C),
165.3 (C); FT-ICR-MS: calculated for C15H12N2O3Hþ:
269.0921, found: 269.0919.
5-Cyano-4-(2-fluoro-phenyl)-6-methyl-pyridine-2-carboxyꢂli1c
acid (3a). 61% yield, brown solid, mp 188ꢀC; IR (neat, cm
)
k
max: 3085, 2882, 2792, 2230, 1945, 1705, 1614, 1581, 1546,
1493, 1452, 1386, 1255, 1220, 919, 869, 796, 756; 1H NMR
(400 MHz, DMSO-d6) d ppm 2.81 (s, 3 H), 7.43 (m, 2 H), 7.63
(m, 2 H), 7.98 (s, 1 H); 13C NMR (100 MHz, DMSO-d6) d ppm
4-Benzo[1,3]dioxol-5-yl-5-cyano-6-methyl-pyridine-2-carbox-
ylic acid (3g). 62% yield, colorless solid, mp 211ꢀC; IR (neat,
cmꢂ1) kmax: 3306, 3174, 3078, 2974, 2945, 2871, 2229, 1764,
1727, 1587, 1536, 1499, 1447, 1388, 1336, 1233, 1196, 1152,
1034, 916; 1H NMR (400 MHz, DMSO-d6) d ppm 2.77 (s, 3 H),
6.14 (s, 2 H), 7.11 (m, 1 H), 7.19 (m, 1 H), 7.29 (m, 1 H), 7.91
(m, 1 H); 13C NMR (100 MHz, DMSO-d6) d ppm 23.8 (CH3),
101.9 (CH2), 108.7 (CH), 108.8 (CH), 109.4 (C), 116.6 (C),
121.7 (CH), 123.2 (CH), 129.0 (C), 147.9 (C), 149.1 (C), 150.0
(C), 153.2 (C), 162.2 (C), 165.2 (C); FT-ICR-MS: calculated for
C15H10N2O4Hþ: 283.0713, found: 283.0712.
2
23.7 (CH3), 111.0 (C), 115.8 (C), 116.2 (d, JCAF ¼ 21.22 Hz,
2
CH), 122.7 (CH), 123.1 (d, JCAF ¼ 14.63 Hz, C), 125.2
3
4
(d, JCAF ¼ 3.66 Hz, CH), 131.2 (d, JCAF ¼ 2.19 Hz, CH),
3
132.7 (d, JCAF ¼ 8.05 Hz, CH), 148.4 (C), 150.4 (C), 158.5
1
(d, JCAF ¼ 248.10, C), 161.9 (C), 165.1 (C); FT-ICR-MS:
calculated for C14H9FN2O2Hþ: 257.0721, found: 257.0721.
5-Cyano-4-(4-fluoro-phenyl)-6-methyl-pyridine-2-carboxylic
acid (3b). 66% yield, colorless solid, mp 201ꢀC; IR (neat,
cmꢂ1) kmax: 3292, 3115, 3078, 2229, 1757, 1602, 1550, 1506,
5-Cyano-6-methyl-4-thiophen-2-yl-pyridine-2-carboxylic aꢂci1d
1
1417, 1388, 1344, 1314, 1226, 1159, 1108, 849, 717; H NMR
(400 MHz, DMSO-d6) d ppm 2.79 (s, 3 H), 7.43 (m, 2 H),
(3h). 62% yield, yellow solid, mp 200ꢀC; IR (neat, cm
)
max: 3336, 3100, 2893, 2849, 2222, 1919, 1764, 1713, 1580,
k
7.77 (m, 2 H), 7.96 (s, 1 H); 13C NMR (100 MHz, DMSO-d6)
1
1536, 1417, 1388, 1299, 1218, 1144, 849, 798, 702; H NMR
(400 MHz, DMSO-d6) d ppm 2.77 (s, 3 H), 7.33 (m, 1 H),
7.97 (m, 2 H), 8.04 (s, 1 H); 13C NMR (100 MHz, DMSO-d6)
d ppm 23.9 (CH3), 106.8 (C), 116.9 (C), 120.3 (CH), 129.1
(CH), 130.5 (CH), 131.5 (CH), 136.2 (C), 145.3 (C), 150.3
(C), 163.1 (C), 165.1 (C); FT-ICR-MS: calculated for
C12H8N2O2SHþ: 245.0379, found: 245.0378.
2
d ppm 23.8 (CH3), 109.7 (C), 116.0 (C), 116.3 (d, JCAF
¼
3
21.96, CH), 121.9 (CH), 131.1 (d, JCAF ¼ 8.78, CH), 131.8
4
(d, JCAF ¼ 2.93, C), 150.1 (C), 152.6 (C), 162.2 (C), 163.3
1
(d, JCAF ¼ 248.83, C), 165.2 (C); FT-ICR-MS: calculated for
C14H9FN2O2Hþ: 257.0721, found: 257.0719.
5-Cyano-4-(3-chloro-phenyl)-6-methyl-pyridine-2-carbox-
ylic acid (3c). 60% yield, colorless solid, mp 206ꢀC; IR (neat,
cmꢂ1) kmax: 3078, 3048, 2886, 2775, 2672, 2605, 2222, 1705,
1565, 1543, 1447, 1381, 1329, 1270, 1233, 1144, 1108, 908, 879,
General procedure for the synthesis of 2-aryl pyridines
(5). Potassium t-butoxide (0.224 g,
2 mmol) was added
portionwise to a solution of (E)-4-oxo-4-(aryl)-but-2-enoic acid 4
(1 mmol) in acetonitrile (5 mL) at room temperature. After 16 h
(reaction monitored by LC/MS), the solvent was removed under
reduced pressure. The mixture was suspended in dioxane and
acidified with water free 4M HCl in dioxane. After evaporation
of the solvent, the residue was taken up in water and extracted
with dichloromethane. The combined organic phases were dried
over anhydrous sodium sulphate and concentrated. The solid
product 5 was isolated by flash chromatography using dichloro-
methane-methanol gradient (from 99:1 to 95:5).
1
798; H NMR (400 MHz, DMSO-d6) d ppm 2.80 (s, 3 H), 7.64
(m, 3 H), 7.79 (m, 1 H), 7.98 (s, 1 H); 13C NMR (100 MHz,
DMSO-d6) d ppm 23.8 (CH3), 109.8 (C), 116.3 (C), 121.9 (CH),
127.4 (CH), 128.4 (CH), 130.1 (CH), 130.9 (CH), 133.7 (C), 137.4
(C), 150.3 (C), 152.1 (C), 162.2 (C), 165.1 (C); FT-ICR-MS:
calculated for C14H9ClN2O2Hþ: 273.0425, found: 273.0426.
5-Cyano-4-(4-chloro-phenyl)-6-methyl-pyridine-2-carboxylic
acid (3d). 73% yield, colorless solid, mp 208ꢀC; IR (neat,
cmꢂ1) kmax: 3085, 2982, 2937, 2864, 2229, 1742, 1713, 1602,
1580, 1543, 1506, 1417, 1226, 1181, 1144, 1085, 1049, 967,
857; 1H NMR (400 MHz, DMSO-d6) d ppm 2.79 (s, 3 H),
7.66 (m, 2 H), 7.73 (m, 2 H), 7.97 (s, 1 H); 13C NMR (100
MHz, DMSO-d6) d ppm 23.8 (CH3), 109.7 (C), 116.3 (C),
121.8 (CH), 129.1 (CH), 130.5 (CH), 134.2 (C), 135.3 (C),
3-Cyano-6-(4-fluoro-phenyl)-2-methyl-isonicotinic
acid
(5a). 74% yield, colorless solid, mp 286–287ꢀC (dec.); IR
(neat, cmꢂ1) kmax: 3240, 3085, 2229, 1794, 1727, 1602, 1580,
1558, 1513, 1454, 1403, 1358, 1307, 1226, 1159, 1137, 842,
657; 1H NMR (400 MHz, DMSO-d6) d ppm 2.78 (s, 3 H),
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Vol 48
7.33 (m, 2 H), 8.22 (m, 3 H); 13C NMR (100 MHz, DMSO-
3-Cyano-6-furan-2-yl-2-methyl-isonicotinic acid (5g). 63%
yield, yellow solid, mp 170ꢀC (dec.); IR (neat, cmꢂ1) kmax
2
d6) d ppm 23.9 (CH3), 104.9 (C), 116.0 (d, JCAF ¼ 21.23 Hz,
:
3
CH), 116.0 (C), 117.1 (CH), 129.8 (d, JCAF ¼ 9.52 Hz,
3182, 3092, 2897, 2222, 1720, 1577, 1532, 1442, 1352, 1322,
1269, 1239, 1202, 1089, 1037, 917, 707, 662; 1H NMR
(400 MHz, DMSO-d6) d ppm 2.74 (s, 3 H), 6.74 (m, 1 H),
7.39 (m, 1 H), 7.99 (m, 1 H), 8.00 (s, 1H); 13C NMR (100
MHz, DMSO-d6) d ppm 23.7 (CH3), 104.1 (C), 115.8 (CH),
116.1 (C), 129.0 (CH), 129.2 (CH), 131.8 (CH), 142.2 (C),
142.6 (C), 154.3 (C), 163.0 (C), 164.5 (C); FT-ICR-MS: calcu-
lated for C12H8N2O3Hþ: 229.0608, found: 229.0610.
4
CH),132.8 (d, JCAF ¼ 2.93 Hz, C), 142.8 (C), 157.4 (C),
1
162.8 (C), 163.8 (d, JCAF ¼ 248.83 Hz, C), 164.5 (C);
FT-ICR-MS: calculated for C14H9FN2O2Naþ: 279.0540, found:
279.0541.
3-Cyano-6-(3-chloro-phenyl)-2-methyl-isonicotinic acid (5b).
:
67% yield, colorless solid, mp 194ꢀC; IR (neat, cmꢂ1) kmax
3011, 2819, 2635, 2524, 2214, 1713, 1624, 1572, 1513, 1425,
1
1381, 1373, 1322, 1263, 1233, 1144, 1093, 938, 879; H NMR
3-Cyano-6-thiophen-2-yl-2-methyl-isonicotinic acid (5h). 61%
yield, yellow solid, mp 207–208ꢀC (dec.); IR (neat, cmꢂ1) kmax
:
(400 MHz, DMSO-d6) d ppm 2.80 (s, 3 H), 7.57 (m, 2 H),
8.13 (m, 1 H), 8.21 (m, 1 H), 8.30 (s, 1 H); 13C NMR (100
MHz, DMSO-d6) d ppm 23.9 (CH3), 105.7 (C), 115.9 (C),
117.6 (CH), 126.0 (CH), 127.0 (CH), 130.5 (CH), 131.0 (CH),
134.0 (C), 138.4 (C), 143.2 (C), 156.9 (C), 162.9 (C), 164.5
(C); FT-ICR-MS: calculated for C14H9ClN2O2Hþ: 273.0425,
found: 273.0425.
3152, 3130, 2920, 2852, 2215, 1692, 1592, 1547, 1479, 1404,
1232, 1172, 1074, 1037, 954, 887, 767, 714; 1H NMR (400
MHz, DMSO-d6) d ppm 2.72 (s, 3 H), 7.22 (dd, J ¼ 4.83, 3.81
Hz, 1 H), 7.83 (m, 1 H), 8.08 (m, 1 H), 8.21 (s, 1 H); 13C NMR
(100 MHz, DMSO-d6) d ppm 23.8 (CH3), 104.2 (C), 113.2 (CH),
113.2 (CH), 115.3 (CH), 116.1 (C), 142.6 (C), 146.5 (CH), 150.3
(C), 151.3 (C), 163.3 (C), 164.3 (C); FT-ICR-MS: calculated for
C12H8N2O2SHþ: 245.0379, found: 245.0380.
3-Cyano-6-(4-chloro-phenyl)-2-methyl-isonicotinic acid (5c).
86% yield, brown solid, mp 295–297ꢀC (dec.); IR (neat,
cmꢂ1) kmax: 3454, 2805, 2635, 2236, 1720, 1601, 1575, 1551,
1494, 1431, 1386, 1337, 1248, 1091, 1015, 903, 829, 746,
667; 1H NMR (400 MHz, DMSO-d6) d ppm 2.80 (s, 3 H),
7.58 (m, 2 H), 8.20 (m, 2 H), 8.27 (s, 1 H); 13C NMR (100
MHz, DMSO-d6) d ppm 23.9 (CH3), 105.3 (C), 116.0 (C),
117.3 (CH), 129.1 (CH), 129.2 (CH), 135.1 (C), 135.7 (C),
143.0 (C), 157.2 (C), 162.9 (C), 164.5 (C); FT-ICR-MS: calcu-
lated for C14H9ClN2O2Hþ: 273.0425, found: 273.0426.
3-Cyano-6-(2,4-dichloro-phenyl)-2-methyl-1,4-dihydro-
pyridine-4-carboxylic acid (6). Brown crystals, mp 179–
181ꢀC (dec.); IR (neat, cmꢂ1) kmax: 3262, 3233, 3115, 3004,
2849, 2620, 2207, 1698, 1668, 1624, 1580, 1513, 1469, 1417,
1381, 1307, 1248, 1122, 1085, 916; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.01 (s, 3 H), 4.02 (d, J ¼ 4.83 Hz, 1 H),
4.71 (m, 1 H), 7.37 (d, J ¼ 8.14 Hz, 1 H), 7.46 (dd, J ¼ 8.19,
2.03 Hz, 1 H), 7.69 (d, J ¼ 2.03 Hz, 1 H), 8.84 (s, 1 H),
12.61 (s, 1 H); 13C NMR (100 MHz, DMSO-d6) d ppm 17.9
(CH3), 41.0 (CH), 73.1 (C), 99.2 (CH), 120.9 (C), 127.5 (CH),
129.2 (CH), 132.3 (CH), 133.4 (C), 133.6 (C), 134.1 (C),
134.2 (C), 149.7 (C), 173.0 (C); FT-ICR-MS: calculated for
C14H10Cl2N2O2Hþ: 309.0192, found: 309.0192.
3-Cyano-6-(2,4-dichloro-phenyl)-2-methyl-isonicotinic aꢂci1d
(5d). 65% yield, red solid, mp 180ꢀC (dec.); IR (neat, cm
)
k
max: 3100, 3070, 2882, 2852, 2230, 1750, 1584, 1554, 1404,
1329, 1224, 1142, 1097, 1037, 872, 819, 789, 722, 609; 1H
NMR (400 MHz, DMSO-d6) d ppm 2.80 (s, 3 H), 7.58 (dd, J
¼ 8.34, 2.02 Hz, 1 H), 7.67 (d, J ¼ 8.33 Hz, 1 H), 7.79 (d, J
¼ 2.02 Hz, 1 H), 8.05 (s, 1 H); 13C NMR (100 MHz, DMSO-
d6) d ppm 23.7 (CH3), 105.9 (C), 115.8 (C), 121.8 (CH), 127.9
(CH), 129.7 (CH), 132.2 (C) , 133.1 (CH), 135.1 (C), 135.8
(C), 142.6 (C), 157.6 (C), 162.9 (C), 164.3 (C); FT-ICR-MS:
calculated for C14H8Cl2N2O2Hþ: 307.0036, found: 307.0037.
3-Cyano-6-(3,4-dichloro-phenyl)-2-methyl-isonicotinic aꢂci1d
5-Cyano-4-(4-fluoro-phenyl)-6-methyl-1-oxy-pyridine-2-
carboxylic acid (7). 5-Cyano-6-methyl-4-(4-fluoro-phenyl)-
pyridine-2-carboxylic acid 3b (0.064 g, 0.25 mmol) was
dissolved in acetic acid (2 mL) and 30% hydrogen peroxide
was added (2 mL). The mixture was stirred for 2 h at 80ꢀC
and then kept at room temperature for 16 h. The resulting yel-
low crystals were filtered, washed with acetic acid and water,
and air dried to give 0.041 g (60%) of the product 7. Mp 160–
162ꢀC; IR (neat, cmꢂ1) kmax: 3347, 3071, 2991, 2926, 2867,
2809, 2221, 1735, 1655, 1510, 1401, 1365, 1292, 1241, 1161,
1060, 1002, 907, 828, 777; 1H NMR (400 MHz, CDCl3) d
ppm 2.95 (s, 3 H), 7.29 (m, 2 H), 7.66 (m, 2 H), 8.45 (s, 1 H);
13C NMR (100 MHz, CDCl3) d ppm 17.2 (CH3), 113.6 (C),
(5e). 54% yield, colorless solid, mp 165ꢀC; IR (neat, cm
)
k
max: 3100, 2897, 2860, 2230, 1705, 1569, 1427, 1329, 1269,
1247, 1149, 1029, 887, 834, 677; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.79 (s, 3 H), 7.75 (d, J ¼ 8.65 Hz, 1 H),
8.14 (dd, J ¼ 8.39, 2.03 Hz, 1 H), 8.31 (s, 1 H), 8.37 (d, J ¼
2.03 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) d ppm 23.8
(CH3), 105.8 (C), 115.8(C), 117.6 (CH), 127.4 (CH), 129.0
(CH), 131.2 (CH), 132.0 (C), 133.5 (C), 136.7 (C), 143.1 (C),
155.8 (C), 162.9 (C), 164.4 (C); FT-ICR-MS: calculated for
C14H8Cl2N2O2Hþ: 307.0036, found: 307.0038.
2
113.6 (C), 116.9 (d, JCAF ¼ 21.95 Hz, CH), 127.3 (CH),
4
3
129.6 (d, JCAF ¼ 3.66 Hz, C), 130.7 (d, JCAF ¼ 8.78, CH),
1
138.6 (C), 144.7 (C), 153.8 (C), 160.1 (C), 164.5 (d, JCAF
¼
253.95, C); FT-ICR-MS: calculated for C14H9FN2O3Naþ:
295.0489, found: 295.0490.
3-Cyano-6-(4-methoxy-phenyl)-2-methyl-isonicotinic acid (5f).
:
86% yield, yellow solid, mp 186ꢀC; IR (neat, cmꢂ1) kmax
3011, 2974, 2871, 2842, 2237, 1742, 1602, 1565, 1513, 1454,
5-Cyano-4-(4-methoxy-phenyl)-6-methyl-pyridine-2-car-
boxylic acid 3,4-dichloro-benzylamide (8a). 5-Cyano-6-
methyl-4-(4-methoxy-phenyl)-pyridine-2-carboxylic acid 3f
(0.040 g, 0.15 mmol) was dissolved in 5 mL dichloromethane.
PyBOP (0.088 g, 0.17 mmol) and triethylamine (0.042 mL,
0.30 mmol) were successively added followed by addition of
3,4-dichloro-benzylamine (0.031 mL, 0.23 mmol). After 3-h
stirring at room temperature (the reaction monitored by TLC),
the solvent was removed, and the product as a colorless solid
(0.063 g, 99%) was isolated by filtration on silica gel using
1
1388, 1322, 1292, 1263, 1226, 1174, 1144, 1026, 820, 672; H
NMR (400 MHz, DMSO-d6) d ppm 2.76 (s, 3 H), 3.83 (s, 3
H), 7.06 (m, 2 H), 8.14 (m, 2 H), 8.17 (s, 1 H); 13C NMR
(100 MHz, DMSO-d6) d ppm 23.9 (CH3), 55.4 (CH3), 103.8
(C), 114.4 (CH), 116.2 (C), 116.3 (CH), 128.7 (C), 129.0
(CH), 142.5 (C), 158.2 (C), 161.6 (C), 162.7 (C), 164.7 (C);
FT-ICR-MS: calculated for C15H12N2O3Hþ: 269.0921, found:
269.0921.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
A Simple, Diversity Oriented Synthesis of Highly Substituted Pyridines
797
petroleum ether–ethyl acetate (2:1) as eluent. Mp 152ꢀC; IR
(neat, cmꢂ1) kmax: 3415, 3385, 2927, 2357, 2222, 1735, 1682,
1517, 1457, 1352, 1269, 1232, 1179, 1142, 1059, 999, 887,
797; 1H NMR (400 MHz, CDCl3) d ppm 2.83 (s, 3 H), 3.87
(s, 3 H), 4.63 (d, J ¼ 6.36 Hz, 2 H), 7.04 (m, 2 H), 7.20 (m, 1
H), 7.40 (m, 1 H), 7.44 (m, 1 H), 7.62 (m, 2 H), 8.17 (s, 1 H),
8.44 (t, J ¼ 5.98 Hz, 1 H); 13C NMR (100 MHz, CDCl3) d ppm
24.0 (CH3), 42.5 (CH2), 55.4 (CH3), 109.5 (C), 114.6 (CH),
116.8 (C), 119.6 (CH), 127.1 (CH), 127.6 (C), 129.7 (CH),
130.1 (CH), 130.7 (CH), 131.7 (C), 132.8 (C), 138.2 (C), 150.3
(C), 154.6 (C), 161.5 (C), 161.9 (C), 163.2 (C); FT-ICR-MS:
calculated for C22H17Cl2N3O2Naþ: 448.0590, found: 448.0591.
for 2 h. The excess of the reagent was removed in vacuo, and the
product as a colorless solid (0.044 g, 86%) was isolated by
column chromatography (petroleum ether–ethyl acetate, 10:1).
Mp 174–176ꢀC; IR (neat, cmꢂ1) kmax: 3449, 3363, 3267, 3155,
3089, 2948, 2229, 1807, 1703, 1637, 1585, 1533, 1481, 1422,
1362, 1318, 1229, 1088, 1007, 822; 1H NMR (400 MHz, CDCl3)
d ppm 2.91 (s, 3 H), 7.55 (m, 4 H), 7.66 (s, 1 H); 13C NMR (100
MHz, CDCl3) d ppm 24.2 (CH3), 110.8 (C), 115.2 (C), 116.0
(C), 125.5 (CH), 129.7 (CH), 129.8 (CH), 132.5 (C), 135.4 (C),
137.6 (C), 153.4 (C), 164.6 (C); FT-ICR-MS: calculated for
C14H8ClN3Hþ: 254.0480, found: 254.0478.
6-(4-Chloro-phenyl)-3-cyano-2-methyl-isonicotinic
acid
4-(4-Chloro-phenyl)-5-cyano-6-methyl-pyridine-2-carbox-
ylic acid amide (8b). 5-Cyano-6-methyl-4-(4-chloro-phenyl)-
pyridine-2-carboxylic acid 3d (0.041 g, 0.15 mmol) was
dissolved in 5 mL dichloromethane. PyBOP (0.088 g, 0.17
mmol) and triethylamine (0.042 mL, 0.30 mmol) were succes-
sively added followed by addition of 1-hydroxybenzotriazol am-
monium salt (0.035 mg, 0.23 mmol). After 3 h stirring at room
temperature (the reaction monitored by TLC), the solvent was
removed and the product 8b as a colorless solid (0.030 g, 73%)
was isolated by filtration on silica gel using petroleum ether–
ethyl acetate (2:1) as eluent. Mp 214–216ꢀC (dec.); IR (neat,
cmꢂ1) kmax: 3449, 3360, 3277, 3155, 3041, 2218, 1707, 1643,
1580, 1535, 1490, 1420, 1382, 1356, 1318, 1241, 1152, 1095,
1018, 910, 852, 827, 699; 1H NMR (400 MHz, DMSO-d6) d
ppm 2.81 (s, 3 H), 7.69 (m, 4 H), 7.96 (s, 2 H), 8.28 (s, 1 H); 13C
NMR (100 MHz, DMSO-d6) d ppm 23.7 (CH3), 109.2 (C), 116.5
(C), 119.2 (CH), 129.1 (CH), 130.5 (CH), 134.4 (C), 135.2 (C),
151.8 (C), 152.6 (C), 161.6 (C), 164.6 (C); FT-ICR-MS:
calculated for C14H10ClN3ONaþ: 294.0405, found: 294.0404.
hydrazide (11). A suspension of 5c (0.082 g, 0.3 mmol) in
50% hydrazine/water (2mL) in a sealed tube was heated at
150ꢀC for 24 h. The precipitate was filtered, washed with
water, and air-dried to afford the product 11 (0.080 g, 94%) as
a yellow solid. Mp 336–339ꢀC (dec.); IR (neat, cmꢂ1) kmax
:
3295, 3202, 2992, 2906, 2826, 1659, 1609, 1541, 1474, 1412,
1381, 1350, 1165, 1103, 1035, 998, 825, 782, 733; 1H NMR
(400 MHz, DMSO-d6) d ppm 3.08 (s, 3 H), 5.56 (s, 2 H), 7.57
(d, J ¼ 8.39 Hz, 2 H), 8.22 (d, J ¼ 8.65 Hz, 2 H), 8.37
(s, 1 H), 12.00 (s, 1 H); 13C NMR (100 MHz, DMSO-d6) d
ppm 26.7 (CH3), 112.4 (CH), 118.6 (C), 128.7 (CH), 129.1
(CH), 134.9 (C), 136.0 (C), 136.5 (C), 146.1 (C), 154.0 (C),
157.3 (C), 157.7 (C); FT-ICR-MS: calculated for
C14H11ClN4OHþ: 287.0694, found: 287.0694.
6-(2,4-Dichloro-phenyl)-2-methyl-1-oxy-pyridine-3,4-di-
carboxylic
acid
(12). 3-Cyano-2-methyl-6-(2,4-dichloro-
phenyl)-isonicotinic acid 5d (0.077 g, 0.25 mmol) was dissolved
in acetic acid (2 mL), and then 30% hydrogen peroxide was added
(2 mL). After stirring for 5 h at 100ꢀC, the mixture was poured on
ice/water and extracted with chloroform (3 ꢁ 10 mL). The aque-
ous phase was then concentrated in vacuo and dried by lyoph-
ilization to afford the product 12 (0.075 g, 87%) as a brown
solid. Mp 172–173ꢀC (dec.); IR (neat, cmꢂ1) kmax: 3520,
3415, 3175, 3032, 2882, 2785, 1705, 1577, 1412, 1374, 1322,
1262, 1202, 1142, 1092, 1052, 977, 902, 857, 812, 774, 677;
1H NMR (400 MHz, D2O) d ppm 2.49 (s, 3 H), 7.36 (d, J
¼ 8.39 Hz, 1 H), 7.47 (d, J ¼ 8.14 Hz, 1 H), 7.64 (s, 1 H),
7.85 (s, 1 H); 13C NMR (100 MHz, D2O/DMSO-d6) d ppm
16.7 (CH3), 128.0 (CH), 129.2 (C), 129.4 (CH), 131.0 (CH),
131.7 (C), 133.3 (CH), 135.7 (C), 137.8 (C), 140.2 (C), 147.8
(C), 148.4 (C), 168.7 (C), 173.8 (C); FT-ICR-MS: calculated
for C14H9Cl2NO5Hþ: 341.9931, found: 341.9929.
4-(4-Methoxy-phenyl)-6-methyl-pyridine-2,5-dicarboxylic
acid 5-amide 2-(3,4-dichlorobenzylamide) (9). Hydroxyl-
amine hydrochloride (0.021 g, 0.30 mmol) and potassium
t-butoxide (0.045 g, 0.40 mmol) were successively added to
the suspension of 5-cyano-4-(4-methoxy-phenyl)-6-methyl-pyr-
idine-2-carboxylic acid 3,4-dichloro-benzylamide 8a (0.043 g,
0.10 mmol) in dimethyl sulfoxide (1 mL). The mixture was
stirred for 16 h at 100ꢀC, cooled to room temperature and
diluted with water. After acidification with 1M HCl, the
mixture was extracted with dichloromethane. The combined
organic phases were dried over anhydrous sodium sulphate,
concentrated, and the residue was purified by column chroma-
tography with on silica gel using dichloromethane-methanol
(40:1) as eluent to afford product 9 as a colorless solid
(0.037 g, 84%). Mp 151ꢀC; IR (neat, cmꢂ1) kmax: 3705, 3668,
3351, 3107, 2974, 2864, 1735, 1661, 1506, 1358, 1285, 1240,
1137, 1056, 1026, 820, 650; 1H NMR (400 MHz, CDCl3) d ppm
2.62 (s, 3 H), 3.82 (s, 3 H), 4.58 (d, J ¼ 6.36 Hz, 1 H), 5.74 (s, 1
H), 5.81 (s, 1 H), 6.92 (m, 2 H), 7.18 (dd, J ¼ 8.39, 2.03 Hz, 1
H), 7.39 (d, J ¼ 8.39 Hz, 2 H), 7.45 (m, 3 H), 7.97 (s, 1 H), 8.48
(t, J ¼ 6.36 Hz, 1 H); 13C NMR (100 MHz, CDCl3) d ppm 22.5
(CH3), 42.3 (CH2), 55.3 (CH3), 114.3 (CH), 120.3 (CH), 127.1
(CH), 129.2 (C), 129.6 (CH), 129.7 (CH), 130.6 (CH), 131.5
(C), 132.7 (C), 132.7 (C), 138.5 (C), 147.8 (C), 148.4 (C), 154.9
(C), 160.5 (C), 164.0 (C), 170.3 (C); FT-ICR-MS: calculated for
C22H19Cl2N3O3Naþ: 466.0696, found: 466.0696.
3-Cyano-N-(3,4-dichloro-benzyl)-6-(4-methoxy-phenyl)-2-
methyl-isonicotinamide (13a). This compound was obtained
according to the procedure for 8a, using compound 5f as a
starting material. Eluent dichloromethane–methanol (40:1),
yield: 0.063 g (99%), colorless solid, mp 242ꢀC; IR (neat,
cmꢂ1) kmax: 3454, 3100, 2893, 2834, 2347, 1764, 1698, 1595,
1513, 1425, 1381, 1336, 1248, 1167, 1130, 1093, 1019.019.8,
1
835, 753; H NMR (400 MHz, DMSO-d6) d ppm 2.76 (s, 3 H),
3.83 (s, 3 H), 4.52 (d, J ¼ 5.85 Hz, 2 H), 7.10 (m, 2 H), 7.39
(dd, J ¼ 8.39, 2.03 Hz, 1 H), 7.62 (d, J ¼ 8.39 Hz, 1 H), 7.66
(d, J ¼ 2.03 Hz, 1 H), 8.11 (s, 1 H), 8.20 (m, 2 H), 9.50
(t, J ¼ 5.85 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) d ppm
23.9 (CH3), 41.8 (CH2), 55.4 (CH3), 103.5 (C), 114.4 (CH),
114.7 (CH), 116.8 (C), 127.8 (CH), 129.0 (C), 129.1 (CH),
129.5 (CH), 129.6 (C), 130.6 (CH), 131.0 (C), 139.8 (C), 146.8
(C), 158.1 (C), 161.6 (C), 162.2 (C), 164.2 (C); FT-ICR-MS:
calculated for C22H17Cl2N3O2Hþ: 426.0771, found: 426.0772.
4-(4-Chloro-phenyl)-6-methyl-pyridine-2,5-dicarbonitrile
(10). 5-Cyano-6-methyl-4-(4-chloro-phenyl)-pyridine-2-carbox-
ylic acid amide 8b (0.054 g, 0.20 mmol) was dissolved in phos-
phorus oxychloride (2 mL), and the mixture was heated at 100ꢀC
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

798
K. Kaczanowska, H. Eickhoff, K. Albert, K.-H. Wiesmu¨ller, and A.-P. Schaffner
Vol 48
REFERENCES AND NOTES
6-(4-Chloro-phenyl)-3-cyano-2-methyl-isonicotinamide
(13b). This compound was obtained according to the proce-
dure for 8b, using compound 5c as a starting material. Eluent
dichloromethane–methanol (40:1), yield: 0.040 g (99%), color-
less solid, mp 203–205ꢀC (dec.); IR (neat, cmꢂ1) kmax: 3467,
3348, 3178, 2948, 2859, 2222, 1666, 1570, 1540, 1414, 1311,
1244, 1199, 1073, 1007, 836, 733, 651; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.77 (s, 3 H), 7.60 (m, 2 H), 8.04 (s, 1 H),
8.17 (s, 1 H), 8.21 (m, 2 H), 8.41 (s, 1 H); 13C NMR
(100 MHz, DMSO-d6) d ppm 23.8 (CH3), 104.6 (C), 115.7
(CH), 116.1 (C), 129.1 (CH), 129.2 (CH), 135.4 (C), 135.7
(C), 147.5 (C), 156.9 (C), 162.4 (C), 165.5 (C); FT-ICR-MS:
calculated for C14H10ClN3ONaþ: 294.0405, found: 294.0404.
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Dash, J.; Reissig, H.-U. Chem Eur J 2009, 15, 6811; (c) Jiang, B.;
Hao, W.-J.; Wang, X.; Shi, F.; Tu, S.-J. J Comb Chem 2009, 11, 846;
(d) Eidamshaus, C.; Reissig, U. Adv Synth Catal 2009, 351, 1162; (e)
Subudhi, B. B.; Panda, P. K.; Swain, S. P.; Sarangi, P. Acta Pol Pharm
Drug Res 2009, 66, 147; (f) Colby, D. A.; Bergman, R. G.; Ellman, J.
A. J Am Chem Soc 2008, 130, 3645; (g) Parthasarathy, K.; Jeganmo-
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5-(N-Hydroxycarbamimidoyl)-4-(4-methoxy-phenyl)-6-
methyl-pyridine-2-carboxylic acid 3,4-dichlorobenzylamide
(14). Hydroxylamine hydrochloride (0.021 g, 0.30 mmol) and
potassium t-butoxide (0.034 g, 0.30 mmol) were successively
added to the suspension of 3-cyano-N-(3,4-dichloro-benzyl)-6-
(4-methoxy-phenyl)-2-methyl isonicotinamide 13a (0.043 g,
0.10 mmol) in dimethyl sulfoxide (1 mL). The mixture was
stirred for 2 h at 100ꢀC, cooled to room temperature, and
diluted with water. The yellow precipitate was filtered, washed
with water, and air dried to give the product 14 as a yellow
solid (0.043 g, 94%). Mp 270ꢀC (dec.); IR (neat, cmꢂ1) kmax
:
3484, 3329, 3210, 2886, 2834, 2783, 1735, 1639, 1558, 1513,
1462, 1417, 1358, 1285, 1255, 1181, 1122, 1026, 938, 827,
606; 1H NMR (400 MHz, DMSO-d6) d ppm 2.57 (s, 3 H),
3.81 (s, 3 H), 4.44 (d, J ¼ 5.85 Hz, 2 H), 5.88 (s, 2 H), 7.05
(m, 1 H), 7.40 (m, 1 H), 7.61 (m, 1 H), 7.73 (s, 1 H), 8.08
(m, 2 H), 8.75 (t, J ¼ 5.85 Hz, 1 H), 9.45 (s, 1 H); 13C NMR
(100 MHz, DMSO-d6) d ppm 22.6 (CH3), 41.5 (CH2), 55.3
(CH3), 114.2 (CH), 114.5 (CH), 124.2 (C), 127.5 (CH), 128.1
(CH), 129.0 (CH), 129.2 (C), 130.3 (C), 130.6 (CH), 130.7
(C), 140.2 (C), 145.5 (C), 149.8 (C), 155.1 (C), 157.7 (C),
160.5 (C), 166.9 (C); FT-ICR-MS: calculated for
C22H20Cl2N4O3Hþ: 459.0985, found: 459.0986.
6-(4-Chloro-phenyl)-2-methyl-pyridine-3,4-dicarbonitrile
(15). This compound was obtained according to the procedure
for 10, using compound 13b as a starting material. Yield:
0.043 g (84%), colorless solid, mp 193ꢀC; IR (neat, cmꢂ1
)
max: 3378, 3252, 3155, 3096, 2963, 2926, 2229, 1644, 1577,
k
¨
[8] Messer, R.; Schmitz, A.; Moesch, L.; Haner, R. J Org
1540, 1451, 1407, 1370, 1325, 1236, 1088, 999, 881, 844,
747, 644; 1H NMR (400 MHz, CDCl3) d ppm 2.90 (s, 3 H),
7.50 (m, 2 H), 7.89 (s, 1 H), 8.01 (m, 2 H); 13C NMR (100
MHz, DMSO-d6) d ppm 24.3 (CH3), 108.0 (C), 114.0 (C),
114.1 (C), 119.5 (CH), 124.8 (C), 128.8 (CH), 129.6 (CH),
134.1 (C), 138.2 (C), 159.2 (C), 163.4 (C); FT-ICR-MS:
calculated for C14H8ClN3Naþ: 276.0299, found: 276.0299.
Chem 2004, 69, 8558.
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Troth, J. R.; Coffen, D. L. Tetrahedron 1998, 54, 4085; (b) Marzinzik,
A. L.; Felder, E. R. J Org Chem 1998, 63, 723; (c) Bowman, M. D.;
Jacobson, M. M.; Blackwell, H. E. Org Lett 2006, 8, 1645.
[10] (a) Yamamoto, J.; Iyagawa, M.; Yamauchi, S.; Nakazawa,
O.; Umezu, M. Tetrahedron 1981, 37, 1871; (b) Ochiai, J. J Org
Chem 1953, 18, 534; (c) Youssif, S. ARKIVOC 2001, 242.
[11] Piwinski, J. J.; Wong, J. K.; Chan, T.-M.; Green, M. J.;
Ganguly, A. K. J Org Chem 1990, 55, 3341.
Acknowledgments. The authors are grateful for financial sup-
port of the EC Marie Curie RTN ‘‘CanTrain’’ (CT-2004-
[12] Borzilleri, R. M.; Zheng, X.; Qian, L.; Ellis, C.; Cai, Z.-W.;
Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R.; Kukral, D. W.; Fura, A.;
Kamath, A.; Vyas, V.; Tokarski, J. S.; Barrish, J. C.; Hunt, J. T.;
Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. J Med Chem 2005, 48, 3991;
(b) Dydio, P.; Zielinski, T.; Jurczak, J. J Org Chem 2009, 74, 1525.
¨
512481). Colleagues from the Eberhard Karls Universitat
Tu¨bingen are acknowledged for technical support in the
NMR and FT-ICR-MS measurements. They also thank Prof.
Dr. Gu¨nther Jung for proof-reading this manuscript.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet