Synthesis of multi-substituted 4-aminopyridines via ring-opening and recyclization reactions of 2-iminopyridines

Article abstract of DOI:10.1039/c4ra02428a

A novel synthesis of multi-substituted 4-aminopyridines from 2-iminopyridines by a two-step procedure is described. During this transformation, 4-amino-2-iminopyridines undergo a regioselective ring-opening reaction in the presence of KOH in t-butanol to afford 5-oxo-pent-3- enimidamides, which are then converted into 4-aminopyridines in toluene under reflux following a 6π-azaelectrocyclization and N-to-N 1,3-sulfonyl group migration mechanism.

Full text of DOI:10.1039/c4ra02428a

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Synthesis of multi-substituted 4-aminopyridines via
ring-opening and recyclization reactions of
2-iminopyridines†
Cite this: RSC Adv., 2014, 4, 18198
a
a
a
Fenguo Zhou,ab Ning Zhang, Xiaoqing Xin, Xun Zhang, Yongjiu Liang, a Rui Zhanga
*
a
*
and Dewen Dong
A novel synthesis of multi-substituted 4-aminopyridines from 2-iminopyridines by a two-step procedure is
described. During this transformation, 4-amino-2-iminopyridines undergo a regioselective ring-opening
reaction in the presence of KOH in t-butanol to afford 5-oxo-pent-3-enimidamides, which are then
converted into 4-aminopyridines in toluene under reflux following a 6p-azaelectrocyclization and N-to-
N 1,3-sulfonyl group migration mechanism.
Received 20th March 2014
Accepted 1st April 2014
DOI: 10.1039/c4ra02428a
www.rsc.org/advances
2-[(amino)methylene]malononitriles, sulfonyl azides and
alkynes.14 To investigate the synthetic utilization of these aza-
Introduction
heterocycles, we examined the reaction behavior of 4-amino-2-
iminopyridines under different conditions. As results of these
studies, a novel and efficient protocol for the 4-aminopyridine
synthesis by a two-step procedure was developed. Herein, we
report the experimental results and the mechanism involved in
the cascade reactions.
The vast number of bioactive natural products and pharma-
ceutical drugs based on the pyridine ring system have become
very important areas of research in natural product and
medicinal chemistry.1 In addition, functionalized pyridines are
widely used as key intermediates in the preparation of natural
products and related structures.2 4-Aminopyridines, as an
important subset of pyridines, constitute the core structure of a
number of active pharmaceutical ingredients, such as torse-
mide,3 roumilast,4 pinacidil5 and piclamilast.6 The pharma-
ceutical and synthetic importance have directed great research
activities to synthesize 4-aminopyridines with diverse substitu-
tion patterns. Thus, a number of efficient approaches have been
developed based on either the modication of pyridines by
reduction reactions of p-nitropyridines,7 amination reactions of
p-halopyridines8 and denitrication reactions of p-azidopyr-
idines,9 or the construction of the skeleton from appropriately
open-chain precursors via tandem amination/annulation reac-
tion of ketoalkyne,10 cascade cyclization/oxidation of arylme-
thylidene derivatives of malononitrile dimer,11 three-
component reaction of malononitrile, cycloketones and
ammonium acetate,12 transition metal mediated cyclo-
trimerization of malononitrile.13
Results and discussion
In our previous work, we developed a facile and efficient solvent-
controlled regioselective synthesis of multi-substituted 4-
amino- and 6-amino-2-iminopyridines via the copper-catalyzed
three-component reaction of sulfonyl azides, alkynes, and 2-
[(amino)methylene]malononitriles based on the reaction
conditions selection (Scheme 1).14 Through the three compo-
nent reaction, 4-amino-2-iminopyridines 1 were synthesized in
moderate to good yield in THF at room temperature, whereas 6-
amꢀino-2-iminopyridines 10 were dominantly obtained in DMF at
50 C under N2.
Very recently, we achieved a facile synthesis of 2-imino-
pyridines via a copper-catalyzed three-component reaction of
aChangchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun
130022, China
bSchool of Chemistry and Environmental Engineering, Changchun University of Science
and Technology, Changchun 130022, China. E-mail: yjliang@ciac.ac.cn; dwdong@
ciac.ac.cn; Fax: +86 431 85262740; Tel: +86 431 85262190
† Electronic supplementary information (ESI) available: Copies of NMR spectra
for compounds 2–4, and crystallographic data for compounds 2a, 3a and 4a.
CCDC 983980, 983981 and 983982. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ra02428a
Scheme 1
18198 | RSC Adv., 2014, 4, 18198–18204
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With these 4-amino-2-iminopyridines 1 in hand, we selected
RSC Advances
N-(4-amino-5-cyano-1,3-diphenylpyridin-2(1H)-ylidene)-4-methyl-
benzenesulfonamide 1a as a model compound to examine its
reaction behavior. Thus, the reaction of 1a and KOH (4.0 equiv.)
was rst attempted in DMSO at 80 ꢀC. As monitored by TLC, the
reaction proceeded, but the conversion was rather low. Aer
work-up and subsequent purication by column chromatog-
raphy of the resulting mixture, the reaction furnished two
products, which were characterized as 3-amino-4-cyano-5-oxo-
N,2-diphenyl-N0-tosylpent-3-enimid-amide 2a and 4-amino-1,5-
diphenyl-6-(tosylimino)-1,6-dihydro pyridine-3-carboxamide 3a
on the basis of their spectral and analytical data (Table 1, entry
1). The structures of 2a and 3a were further elucidated by X-ray
diffraction analysis (Fig. 1). Similar results were obtained when
the reaction was performed in DMF and absolute ethanol (Table
1, entries 2 and 3). Subjecting 1a and KOH (4.0 equiv.) to 95%
ethanol, 3a was exclusively obtained in 85% yield (Table 1, entry
4). The results revealed that 1a preferred the hydrolysis of the
nitrile to the ring-opening reaction of iminopyridine in the
presence of KOH, providing there was adequate water within
the reaction system.
To optimize the yield of 2a, the reaction conditions,
including solvents, bases, reaction temperature and time were
investigated. When the reaction of 1a with KOH (4.0 equiv.) in t-
BuOH was conducted at 80 ꢀC, 2a could be obtained in 71%
yield (Table 1, entry 5). With the increase of the amount of KOH
to 6 equiv., the reaction could be signicantly accelerated, as
could be veried by the shortened reaction time and high yield
of 2a (Table 1, entry 6). With the addition of 2.0 equiv. of water
to the reaction, the yield of 2a decreased due to the formation of
the hydrolyzed product 3a (Table 1, entry 7). However, no
Fig. 1 ORTEP drawings of 2a and 3a.
reaction was observed when 1a and KOH (6.0 equiv.) in t-BuOH
was conducted at 30 ꢀC (Table 1, entry 8). In the presence of
other inorganic and organic bases, such as K2CO3, dia-
zabicycloundecene (DBU) and triethylamine (TEA), the reaction
of 1a in t-BuOH could not take place (Table 1, entries 9–11).
Under the reaction conditions as for 2a in Table 1, entry 6, a
series of reactions of 1b–i were carried out in t-BuOH in the
presence of KOH at 80 ꢀC to determine the scope of the pyridine
synthesis, and some of the results are summarized in Table 2.
The ring-opening reaction proved to be suitable for 1a–i bearing
both electron-donating and electron-withdrawing substituents in
the aromatic ring in R1 and R2 to give the corresponding 2b–i in
moderate to good yields. It should be mentioned that a complex
mixture was formed when subjecting N-(6-amino-5-cyano-1,3-
diphenylpyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide 1a0
to the identical conditions. The results suggested that the
substituent pattern had signicantly affected the ring-opening
reaction of 2-iminopyridines.
It is well-known that pyridine derivatives tend to undergo
ring-opening reactions in the presence of base to form a mixture
of ring-opened isomers.15 Thus, there are two possible cleavage
modes for 2-iminopyridines 1, as an important class of pyridine
derivatives, mediated by base (Scheme 2).16 Actually, in the
Table 1 Reactions of 4-amino-2-iminopyridines 1a under different
conditionsa
Table 2 Ring-opening reaction of 2-iminopyridines 1a
Yieldd (%)
Entry
Base (equiv.)
Solvent
Time (h)
2a
3a
1
2
3
4
5
6
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (6)
KOH (6)
KOH (6)
K2CO3 (6)
DBU (6)
TEA (6)
DMSO
DMF
EtOH
12
12
12
4
12
1
13
14
17
0
71
83
65
0
8
11
23
85
0
0
16
0
Entry
1
R1
R2
2
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
Ph
Ph
p-MeC6H4
p-MeOC6H4
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
83
85
87
78
81
80
83
82
72
EtOH (95%)
t-BuOH
t-BuOH
t-BuOHb
t-BuOH
t-BuOH
t-BuOH
t-BuOH
o-MeC6H4
o-MeC6H4
p-MeC6H4
m-ClC6H4
p-ClC6H4
p-MeOC6H4
7
1
8c
9
12
12
12
12
p-MeC6H4
Ph
Ph
Ph
Ph
0
0
0
0
0
0
10
11
a
Reaction conditions: 1a (1.0 mmol), base, solvent (10 mL), 80 ꢀC.
a
b
H2O (2.0 equiv.) was added. c Reaction temperature: 30 ꢀC. d Isolated
Reaction conditions: 1 (1.0 mmol), KOH (6.0 mmol), t-BuOH (10 mL),
b
80 ꢀC, 1.0–2.0 h. Isolated yields.
yields.
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present work, 5-oxo-pent-3-enimidamide 2 was exclusively
obtained via path a, and no isomer A of 2 (via path b) or Dimroth
rearrangement product B was isolated from the reaction system.
These results demonstrated that the reaction of 2-iminopyr-
idines 1 with KOH in t-BuOH proceeded in a highly regiose-
lective manner.
It should be noted that 5-oxo-pent-3-enimidamides 2 showed
fascinating structural characteristics, especially their formyl,
cyano, amino and imino patterns, and could be exploited in
further organic transformations. In addition, its isomers 20 and
200 can be regarded as azatrienes that may undergo 6p-azae-
lectrocyclization under appropriate conditions to afford the
corresponding heterocycles.17 Thus, the azaelectrocyclization
reaction was attempted by subjecting 2a to toluene under reux.
As indicated by TLC results, the reaction proceeded smoothly.
Aer work-up and subsequent purication by column chro-
matography of the resulting mixture, the reaction furnished a
product, which was characterized as N-(4-amino-5-cyano-3-
phenylpyridin-2-yl)-4-methyl-N-phenyl benzene sulfonamide 4a
on the basis of its spectral and analytical data (Table 3, entry 1).
Scheme
pyridines 4.
3
Proposed mechanism for the synthesis of 4-amino-
In the same fashion, a range of reactions of 5-oxo-pent-3-
enimidamides 2b–i bearing different aromatic substituents
were carried out, and some of the results are summarized in
Table 3. It was found that all the reactions could proceed effi-
ciently to afford the corresponding 4-aminopyridines 4b–i in
good to excellent yields. The structure of 4a was further eluci-
dated by the X-ray single crystal analysis (ESI). Therefore, we
provide a novel and alternative synthetic protocol for multi-
substituted 4-aminopyridines.
On the basis of all the results obtained and the literature, a
plausible mechanism for the synthesis of 4-aminopyridines 4
from 5-oxo-pent-3-enimidamides 2 is proposed as depicted in
Scheme 3. As a tautomer of 5-oxo-pent-3-enimidamides 2, N-
tosylpenta-2,4-dienimid amide 20 is a multi-substituted aza-
triene, which undergoes a 6p-azaelectrocyclization at high
temperature to give a 1,2-dihydropyridine intermediate C.17
Upon a [1,3]sigmatropic sulfonyl group migration of C,18 4-
aminopyridine 4 is nally formed with the elimination of water.
Conclusions
Scheme 2 Possible ring-opening reactions of 2-imino-pyridines 1.
Table 3 Reactions of 5-oxo-pent-3-enimidamides 2a
In summary, a novel synthesis of multi-substituted 4-amino-
pyridines from 2-iminopyridines has been developed by a two-
step procedure. This protocol is associated with readily avail-
able starting materials, mild conditions, simple execution, high
regioselectivity and a wide range of synthetic potential of
products. Expanding the scope of the methodology and further
exploration of the utility of the as-synthesized functionalized 4-
aminopyridines in pharmacology are currently underway in our
laboratory.
Entry
2
R1
R2
4
Yieldb (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
p-MeC6H4
p-MeOC6H4
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
89
87
88
91
84
81
83
92
86
Experimental section
General
o-MeC6H4
o-MeC6H4
p-MeC6H4
m-ClC6H4
p-ClC6H4
p-MeOC6H4
All reagents were purchased from commercial sources and used
p-MeC6H4
without treatment, unless otherwise indicated. 1H NMR and 13
C
Ph
Ph
Ph
Ph
ꢀ
NMR spectra were recorded at 25 C at 400 MHz (or 300 MHz)
and 100 MHz, respectively, with TMS as internal standard. IR
spectra (KBr) were recorded on FTIR spectrophotometer in the
range of 400–4000 cmꢁ1. Starting materials 1a–i are known
compounds and prepared according to the literature.14
a
Reaction conditions: 2 (1.0 mmol), toluene (10 mL), reux, 5.0–12.0 h.
Isolated yields.
b
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1604, 1585, 1450, 1409, 1384, 1261, 1178, 1128, 1078, 1037, 979,
869, 811, 802, 725; anal. calcd (%) for C26H24N4O4S: C, 63.92; H,
4.95; N, 11.47; S, 6.56; found: C, 63.78; H, 4.91; N, 11.41; S, 6.59.
3-Amino-4-cyano-5-oxo-2-phenyl-N-(o-tolyl)-N0-tosylpent-3-
Typical procedure for the synthesis of substituted 3-amino-4-
cyano-5-oxo-N0-tosylpent-3-enimidamide 2 (2a as an example)
To a stirred mixture of N-(4-amino-5-cyano-1,3-diphenyl pyr-
idin-2(1H)-ylidene)-4-methyl benzenesulfonamide 1a (441 mg,
1.0 mmol) and tert-butanol (10 mL) was added KOH (336 mg,
6.0 mmol) at room temperature. The reaction mixture was
1
ꢀ
enimidamide (2d). Colourless solid, mp: 141–143 C; H NMR
(300 MHz, CDCl3) d ¼ 10.74 (1H, s, NH2), 9.88 (1H, s, NH2), 9.14
(1H, s, CHO), 8.01 (1H, s, Ar-NH), 7.78 (2H, d, J ¼ 8.1 Hz, Ar-H),
7.37–7.17 (8H, m, Ar-H), 7.14 (1H, d, J ¼ 7.2 Hz, Ar-H), 7.02 (2H,
d, J ¼ 7.5 Hz, Ar-H), 4.92 (1H, s, CH), 2.43 (3H, s, CH3), 1.83 (3H,
s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 187.2, 168.4, 162.6,
143.9, 137.8, 135.4, 133.5, 131.8, 131.4, 129.7, 129.5, 129.4,
128.5, 127.7, 127.4, 126.3, 118.5, 84.3, 49.6, 21.5, 17.1; IR (KBr,
cmꢁ1): 3421, 3247, 3232, 2962, 2925, 2852, 2202, 1645, 1610,
1591, 1579, 1467, 1400, 1272, 1135, 1085, 754; anal. calcd (%) for
stirred at 80 ꢀC for
1 h. When the starting material
was consumed completely (monitored by TLC), the mixture
was cooled to room temperature and diethyl ether (30 mL) was
added. The precipitates were ltered, washed with diethyl
ether (10 mL), and was added into the mixture of saturated
aqueous NH4Cl solution (10 mL) and CH2Cl2 (20 mL) and
stirred for a few minutes. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (2 ꢂ 20 mL). The
combined organic layer was washed with water (2 ꢂ 10 mL),
dried over Na2SO4 and ltered. The ltrate was concentrated
under vacuum and the resulting residue was puried by ash
column chromatography to give 2a (380 mg, 83%) as a col-
ourless solid.
3-Amino-4-cyano-5-oxo-N,2-diphenyl-N0-tosylpent-3-enimid-
amide (2a). Colourless solid, mp: 135–137 ꢀC; 1H NMR (300
MHz, CDCl3) d ¼ 10.69 (1H, s, NH2), 10.07 (1H, s, NH2), 9.07
(1H, s, CHO), 7.75 (2H, d, J ¼ 8.1 Hz, Ar-H), 7.37–7.13 (9H, m, Ar-
H, Ph-NH), 7.07 (2H, d, J ¼ 7.2 Hz, Ar-H), 6.96 (2H, d, J ¼ 6.0 Hz,
Ar-H), 4.89 (1H, s, CH), 2.39 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3) d ¼ 187.1, 168.8, 162.3, 143.8, 137.9, 134.7, 131.8, 130.1,
129.8, 129.6, 129.6, 129.3, 128.7, 128.2, 127.4, 126.4, 118.6,
117.6, 84.5, 50.9, 21.6; IR (KBr, cmꢁ1): 3353, 3240, 3168, 3064,
2921, 2833, 2759, 2202, 1645, 1608, 1581, 1496, 1460, 1394,
1271, 1251, 1184, 1134, 1085, 987, 811, 746; anal. calcd (%) for
C
26H24N4O3S: C, 66.08; H, 5.12; N, 11.86; S, 6.79; found: C,
66.31; H, 5.07; N, 11.78; S, 6.74.
3-Amino-4-cyano-5-oxo-N-(o-tolyl)-2-(p-tolyl)-N0-tosylpent-3-
1
ꢀ
enimidamide (2e). Colourless solid, mp: 145–147 C; H NMR
(300 MHz, CDCl3) d ¼ 10.74 (1H, s, NH2), 9.89 (1H, s, NH2), 9.13
(1H, s, CHO), 7.94 (1H, s, Ar-NH), 7.80 (2H, d, J ¼ 8.1 Hz, Ar-H),
7.38–7.18 (5H, m, Ar-H), 7.15 (1H, d, J ¼ 7.5 Hz, Ar-H), 7.04 (2H,
d, J ¼ 8.1 Hz, Ar-H), 6.92 (2H, d, J ¼ 8.1 Hz, Ar-H), 4.88 (1H, s,
CH), 2.44 (3H, s, CH3), 2.30 (3H, s, CH3), 1.85 (3H, s, CH3); 13
C
NMR (100 MHz, CDCl3) d ¼ 187.1, 168.7, 162.8, 143.8, 139.6,
137.9, 135.4, 133.5, 131.4, 130.0, 129.5, 128.6, 128.4, 127.7,
127.4, 126.3, 118.5, 84.2, 49.3, 21.5, 21.0, 17.2; IR (KBr, cmꢁ1):
3359, 3261, 3188, 3035, 2921, 2860, 2831, 2754, 2206, 1645,
1612, 1587, 1465, 1396, 1278, 1137, 1081, 981, 754, 663; anal.
calcd (%) for C27H26N4O3S: C, 66.65; H, 5.39; N, 11.51; S, 6.59;
found: C, 66.48; H, 5.43; N, 11.48; S, 6.55.
3-Amino-4-cyano-5-oxo-2-phenyl-N-(p-tolyl)-N0-tosylpent-3-
C
25H22N4O3S: C, 65.48; H, 4.84; N, 12.22; S, 6.99; found: C,
1
ꢀ
enimidamide (2f). Colourless solid, mp: 163–165 C; H NMR
(300 MHz, CDCl3) d ¼ 10.75 (1H, s, NH2), 10.04 (1H, s, NH2), 9.13
(1H, s, CHO), 7.79 (2H, d, J ¼ 8.2 Hz, Ar-H), 7.46–7.26 (5H, m, Ar-
H, Ar-NH), 7.24 (1H, s, Ar-H), 7.19–7.08 (4H, m, Ar-H), 6.88 (2H,
d, J ¼ 8.1 Hz, Ar-H), 4.95 (1H, s, CH), 2.44 (3H, s, CH3), 2.36 (3H,
s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 187.09, 168.86, 162.42,
143.71, 139.47, 132.00, 130.35, 129.50, 128.67, 127.06, 126.31,
118.53, 84.45, 50.62, 21.52, 21.08; IR (KBr, cmꢁ1): 3336, 3249,
3037, 3006, 2921, 2833, 2758, 2206, 1647, 1616, 1596, 1508,
1479, 1423, 1400, 1346, 1272, 1137, 1087, 987, 815; anal. calcd
(%) for C26H24N4O3S: C, 66.08; H, 5.12; N, 11.86; S, 6.79; found:
C, 66.35; H, 5.16; N, 11.88; S, 6.75.
65.26; H, 4.81; N, 12.17; S, 6.92.
3-Amino-4-cyano-5-oxo-N-phenyl-2-(p-tolyl)-N0-tosylpent-3-
1
ꢀ
enimidamide (2b). Colourless solid, mp: 129–131 C; H NMR
(300 MHz, CDCl3) d ¼ 10.71 (1H, s, NH2), 10.09 (1H, s, NH2), 9.09
(1H, s, CHO), 7.79 (2H, d, J ¼ 8.1 Hz, Ar-H), 7.32 (5H, m, Ar-H,
Ph-NH), 7.23 (1H, s, Ar-H), 7.08 (2H, d, J ¼ 8.1 Hz, Ar-H), 6.98
(4H, d, J ¼ 7.8 Hz, Ar-H), 4.87 (1H, s, CH), 2.43 (3H, s, CH3), 2.31
(3H, s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 187.0, 169.1, 162.4,
143.7, 140.6, 139.7, 137.9, 134.7, 131.1, 130.2, 129.7, 129.4,
129.2, 128.5, 127.4, 126.3, 123.7, 118.6, 84.3, 50.6, 21.5, 21.0; IR
(KBr, cmꢁ1): 3396, 3369, 3251, 3184, 3068, 3029, 2960, 2921,
2835, 2759, 2198, 1643, 1604, 1583, 1461, 1392, 1284, 1257,
1143, 1085, 987, 813, 750; anal. calcd (%) for C26H24N4O3S: C,
66.08; H, 5.12; N, 11.86; S, 6.79; found: C, 66.31; H, 5.06; N,
11.78; S, 6.71.
3-Amino-N-(3-chlorophenyl)-4-cyano-5-oxo-2-phenyl-N0-tosyl-
pent-3-enimidamide (2g). Colourless solid, mp: 160–162 ꢀC; 1H
NMR (300 MHz, CDCl3) d ¼ 10.76 (1H, s, NH2), 10.11 (1H, s,
NH2), 9.14 (1H, s, CHO), 7.83 (2H, d, J ¼ 8.1 Hz, Ar-H), 7.48–7.29
(7H, m, Ar-H, Ar-NH), 7.17 (2H, d, J ¼ 7.2 Hz, Ar-H), 7.04 (1H, d, J
¼ 7.5 Hz, Ar-H), 6.98 (1H, s, Ar-H), 6.90 (1H, s, Ar-H), 4.88 (1H, s,
CH), 2.47 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 187.0,
168.8, 161.9, 143.9, 135.9, 135.3, 131.4, 130.7, 129.9, 129.6,
128.7, 128.0, 126.5, 125.8, 118.6, 84.6, 51.5, 21.6; IR (KBr, cmꢁ1):
3361, 3251, 3164, 3062, 2929, 2840, 2765, 2200, 1643, 1604,
1583, 1573, 1390, 1271, 1130, 1080; anal. calcd (%) for
3-Amino-4-cyano-2-(4-methoxyphenyl)-5-oxo-N-phenyl-N0-
tosylpent-3-enimidamide (2c). Colourless solid, mp: 137–139
ꢀC; 1H NMR (300 MHz, CDCl3) d ¼ 10.72 (1H, s, NH2), 10.07 (1H,
s, NH2), 9.09 (1H, s, CHO), 7.79 (2H, d, J ¼ 8.1 Hz, Ar-H), 7.42–
7.25 (5H, m, Ar-H, Ar-NH), 7.22 (1H, s, Ar-H), 7.02 (4H, d, J ¼ 8.7
Hz, Ar-H), 6.79 (2H, d, J ¼ 8.7 Hz, Ar-H), 4.84 (1H, s, CH), 3.77
(3H, s, CH3O), 2.42 (3H, s, CH3); 13C NMR (1001 MHz, CDCl3) d
¼ 187.0, 169.3, 162.5, 160.3, 143.7, 137.9, 134.7, 123.0, 129.7,
129.4, 129.2, 127.4, 126.3, 123.1, 118.6, 114.9, 84.2, 55.2, 50.2,
21.5; IR (KBr, cmꢁ1): 3340, 3244, 3151, 2962, 2840, 2198, 1639,
C
25H21ClN4O3S: C, 60.91; H, 4.29; N, 11.36; S, 6.50; found: C,
61.25; H, 4.24; N, 11.29; S, 6.44.
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3-Amino-N-(4-chlorophenyl)-4-cyano-5-oxo-2-phenyl-N0-tosyl- Typical procedure for the synthesis of substituted N-(4-amino-
pent-3-enimidamide (2h). Colourless solid, mp: 142–145 ꢀC; 1H 5-cyanopyridin-2-yl)-4-methyl benzenesulfonamide 4 (4a as an
NMR (300 MHz, CDCl3) d ¼ 10.77 (1H, s, NH2), 10.06 (1H, s, example)
NH2), 9.13 (1H, s, CHO), 7.83 (2H, d, J ¼ 8.1 Hz, Ar-H), 7.49–7.27
(7H, m, Ar-H), 7.17 (2H, d, J ¼ 7.21 Hz, Ar-H), 6.95 (2H, d, J ¼ 8.4
Hz, Ar-H), 6.82 (1H, s, Ar-H), 4.88 (1H, s, CH), 2.46 (3H, s, CH3);
13C NMR (100 MHz, CDCl3) d ¼ 186.8, 168.9, 161.9, 143.8, 137.6,
135.3, 133.2, 132.0, 129.8, 129.5, 128.9, 128.7, 126.3, 118.7, 84.4,
51.6, 21.5; IR (KBr, cmꢁ1): 3423, 3315, 3271, 3244, 3166, 2210,
1639, 1610, 1583, 1400, 1085, 985; anal. calcd (%) for
3-Amino-4-cyano-5-oxo-N,2-diphenyl-N0-tosylpent-3-enimidamide
2a (450 mg, 1.0 mmol) was added into toluene (10 mL). The
mixture was heated to reux for 5 h. Aer the 2a was consumed
completely (monitored by TLC), the mixture was concentrated
under vacuum. The residue was puried by ash column
chromatography to give 4a (392 mg, 89%) as a colourless solid.
N-(4-Amino-5-cyano-3-phenylpyridin-2-yl)-4-methyl-N-phenyl-
benzenesulfonamide (4a). Colourless solid, mp: 176–178 ꢀC; 1H
NMR (300 MHz, CDCl3) d ¼ 8.39 (1H, s, Py-H), 7.61 (2H, d, J ¼
8.2 Hz, Ar-H), 7.47–7.38 (3H, m, Ar-H), 7.19 (2H, d, J ¼ 8.1 Hz, Ar-
H), 7.10 (3H, d, J ¼ 6.0 Hz, Ar-H), 7.01 (2H, t, J ¼ 7.5 Hz, Ar-H),
6.65 (2H, d, J ¼ 7.5 Hz, Ar-H), 4.81 (2H, s, NH2), 2.40 (3H, s,
CH3); 13C NMR (100 MHz, CDCl3) d ¼ 155.4, 154.7, 150.8, 143.3,
138.9, 136.4, 130.8, 129.7, 129.3, 128.9, 128.6, 128.3, 128.2,
127.3, 120.2, 115.3, 93.4, 21.5; IR (KBr, cmꢁ1): 3465, 3338, 3238,
3205, 3064, 3029, 2921, 2228, 1637, 1571, 1560, 1488, 1469,
1413, 1350, 1292, 1255, 1164, 1110, 1089, 1037; anal. calcd (%)
for C25H20N4O2S: C, 68.16; H, 4.58; N, 12.72; S, 7.28; found: C,
68.28; H, 4.56; N, 12.68; S, 7.24.
N-(4-Amino-5-cyano-3-(p-tolyl)pyridin-2-yl)-4-methyl-N-phenyl-
benzenesulfonamide (4b). Colourless solid, mp: 224–226 ꢀC; 1H
NMR (300 MHz, CDCl3) d ¼ 8.37 (1H, s, Py-H), 7.60 (2H, d, J ¼
8.1 Hz, Ar-H), 7.32–7.15 (4H, m, Ar-H), 7.14–7.06 (1H, m, Ar-H),
7.06–6.92 (4H, m, Ar-H), 6.67 (2H, d, J ¼ 7.8 Hz, Ar-H), 4.81 (2H,
s, NH2), 2.43 (3H, s, CH3), 2.41 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3) d ¼ 155.4, 154.9, 150.7, 143.2, 139.0, 138.6, 136.4, 129.9,
129.5, 128.9, 128.6, 128.4, 128.2, 127.7, 127.3, 126.3, 120.4,
115.4, 93.2, 21.5, 21.2; IR (KBr, cmꢁ1): 3487, 3384, 3228, 3068,
2921, 2202, 1598, 1577, 1558, 1488, 1465, 1419, 1352, 1245,
1159, 1091, 1029, 1010; anal. calcd (%) for C26H22N4O2S: C,
68.70; H, 4.88; N, 12.33; S, 7.05; found: C, 68.65; H, 4.89; N,
12.30; S, 7.01.
N-(4-Amino-5-cyano-3-(4-methoxyphenyl)pyridin-2-yl)-4-
methyl-N-phenylbenzenesulfonamide (4c). Colourless solid,
mp: 234–235 ꢀC; 1H NMR (300 MHz, CDCl3) d ¼ 8.37 (1H, s, Py-
H), 7.61 (2H, d, J ¼ 8.2 Hz, Ar-H), 7.19 (2H, d, J ¼ 8.1 Hz, Ar-H),
7.10 (1H, d, J ¼ 7.1 Hz, Ar-H), 7.08–6.99 (4H, m, Ar-H), 6.95 (2H,
d, J ¼ 8.7 Hz, Ar-H), 6.69 (2H, d, J ¼ 7.5 Hz, Ar-H), 4.82 (2H, s,
NH2), 3.88 (3H, s, CH3O), 2.40 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3) d ¼ 159.8, 155.6, 155.1, 150.6, 143.2, 139.0, 136.4, 131.0,
128.9, 128.6, 128.3, 128.2, 127.3, 122.7, 120.1, 115.4, 114.7, 93.3,
55.3, 21.5; IR (KBr, cmꢁ1): 3483, 3386, 3234, 3064, 2964, 2939,
2898, 2837, 2216, 1610, 1596, 1569, 1560, 1512, 1463, 1423,
1406, 1350, 1247, 1178, 1161, 1020, 1002, 962, 696, 676, 567,
522; anal. calcd (%) for C26H22N4O3S: C, 66.37; H, 4.71; N, 11.91;
S, 6.81; found: C, 66.11; H, 4.68; N, 11.85; S, 6.78.
N-(4-Amino-5-cyano-3-phenylpyridin-2-yl)-4-methyl-N-(o-tolyl)-
benzenesulfonamide (4d). Colourless solid, mp: 215–217 ꢀC; 1H
NMR (300 MHz, CDCl3) d ¼ 8.35 (1H, s, Py-H), 7.63 (2H, d, J ¼
8.1 Hz, Ar-H), 7.38 (3H, d, J ¼ 3.3 Hz, Ar-H), 7.22 (2H, d, J ¼ 8.1
Hz, Ar-H), 7.09–6.86 (4H, m, Ar-H), 6.75 (1H, t, J ¼ 7.2 Hz, Ar-H),
6.62 (1H, d, J ¼ 7.8 Hz, Ar-H), 4.66 (2H, s, Py-NH2), 2.43 (3H, s,
CH3), 1.45 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 155.8,
C
25H21ClN4O3S: C, 60.91; H, 4.29; N, 11.36; S, 6.50; found: C,
60.66; H, 4.27; N, 11.29; S, 6.46.
3-Amino-4-cyano-N-(4-methoxyphenyl)-5-oxo-2-phenyl-N0-
tosylpent-3-enimidamide (2i). Colourless solid, mp: 159–161 ꢀC;
1H NMR (300 MHz, CDCl3) d ¼ 10.74 (1H, s, NH2), 9.94 (1H, s,
NH2), 9.11 (1H, s, CHO), 7.78 (2H, d, J ¼ 8.1 Hz, Ar-H), 7.41–7.25
(5H, m, Ar-H, Ar-NH), 7.23 (1H, s, Ar-H), 7.12 (2H, d, J ¼ 7.2 Hz,
Ar-H), 6.89 (2H, d, J ¼ 9.0 Hz, Ar-H), 6.81 (2H, d, J ¼ 9.0 Hz, Ar-
H), 4.92 (1H, s, CH), 3.78 (3H, s, CH3), 2.43 (3H, s, CH3); 13C
NMR (100 MHz, CDCl3) d ¼ 187.0, 169.0, 162.7, 159.9, 143.6,
137.9, 131.7, 129.5, 129.4, 128.7, 127.1, 126.3, 118.6, 114.7, 84.4,
55.4, 50.9, 21.5; IR (KBr, cmꢁ1): 3380, 3253, 3157, 2966, 2840,
2779, 2198, 1641, 1612, 1581, 1512, 1467, 1407, 1274, 1135,
1085, 985; anal. calcd (%) for C26H24N4O4S: C, 63.92; H, 4.95; N,
11.47; S, 6.56; found: C, 64.18; H, 4.91; N, 11.49; S, 6.60.
Typical procedure for the synthesis of substituted 4-amino-6-
(tosylimino)-1,6-dihydro pyridine-3-carboxamide 3 (3a as an
example)
To a stirred mixture of N-(4-amino-5-cyano-1,3-diphenylpyr-
idin-2(1H)-ylidene)-4-methylbenzenesulfonamide 1a (441 mg,
1.0 mmol), ethanol (10 mL 95%) was added KOH (224 mg, 6.0
mmol) at room temperature. The reaction mixture was stirred
at 80 ꢀC for 4 h. When the starting material was consumed
completely (monitored by TLC), the mixture was concentrated
under vacuum. The residue was poured into the mixture of
saturated aqueous NH4Cl solution (10 mL) and CH2Cl2 (20 mL)
and stirred for a few minutes. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2 ꢂ 10 mL).
The combined organic layer was washed with water (2 ꢂ 10
mL), dried over Na2SO4 and ltered. The ltrate was concen-
trated in vacuum and the resulting residue was puried by
ash column chromatography to give 3a (389 mg, 85%) as a
colourless solid.
4-Amino-1,5-diphenyl-6-(tosylimino)-1,6-dihydropyridine-3-
1
carboxamide (3a). Colourless solid, mp: 238–240 ꢀC; H NMR
(300 MHz, DMSO-d6) d ¼ 8.46 (1H, s, Py-NH2), 8.32 (1H, s, Py-H),
8.12 (1H, s, CONH2), 7.57 (1H, s, CONH2), 7.49–7.28 (7H, m, Ar-
H), 7.20 (3H, d, J ¼ 7.5 Hz, Ar-H), 6.82 (4H, s, Ar-H), 5.89 (1H, s,
Py-NH2), 2.23 (3H, s, CH3); 13C NMR (100 MHz, DMSO-d6) d ¼
168.2, 156.6, 152.5, 145.3, 143.2, 142.6, 138.8, 133.5, 132.0,
129.0, 128.9, 128.7, 128.3, 127.9, 124.9, 113.5, 105.2, 21.1; IR
(KBr, cmꢁ1): 3460, 3400, 3346, 3255, 3224, 3195, 3056, 3002,
2921, 2223, 1672, 1635, 1595, 1494, 1477, 1411, 1355, 1124,
1083, 750, 698; anal. calcd (%) for C25H22N4O3S: C, 65.48; H,
4.84; N, 12.22; S, 6.99; found: C, 65.11; H, 4.78; N, 12.18; S, 6.93.
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154.8, 150.1, 143.3, 138.4, 137.5, 137.0, 131.5, 131.1, 130.9, 63.22; H, 4.03; N, 11.80; S, 6.75; found: C, 63.48; H, 4.06; N,
129.6, 129.5, 129.3, 128.6, 128.5, 127.8, 125.4, 118.2, 115.4, 92.3, 11.85; S, 6.72.
21.5, 17.8; IR (KBr, cmꢁ1): 3458, 3359, 3224, 3028, 2921, 2223,
N-(4-Amino-5-cyano-3-phenylpyridin-2-yl)-N-(4-methoxy-phenyl)-
1622, 1573, 1488, 1463, 1417, 1402, 1348, 1161, 1085, 676, 572; 4-methylbenzenesulfonamide (4i). Colourless solid, mp: 227–
1
ꢀ
anal. calcd (%) for C26H22N4O2S: C, 68.70; H, 4.88; N, 12.33; S, 229 C; H NMR (300 MHz, CDCl3) d ¼ 8.37 (1H, s, Py-H), 7.60
7.05; found: C, 68.55; H, 4.81; N, 12.28; S, 7.01.
(2H, d, J ¼ 8.1 Hz, Ar-H), 7.50–7.41 (3H, m, Ar-H), 7.23–7.07 (4H,
N-(4-Amino-5-cyano-3-(p-tolyl)pyridin-2-yl)-4-methyl-N-(o-tolyl)- m, Ar-H), 6.51 (4H, s, Ar-H), 4.80 (2H, s, NH2), 3.71 (3H, s,
benzenesulfonamide (4e). Colourless solid, mp: 213–214 ꢀC; 1H CH3O), 2.41 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 158.7,
NMR (300 MHz, CDCl3) d ¼ 8.32 (1H, s, Py-H), 7.61 (2H, d, J ¼ 155.5, 154.7, 150.8, 143.2, 136.3, 131.5, 131.0, 130.0, 129.8,
8.1 Hz, Ar-H), 7.24–7.09 (4H, m, Ar-H), 7.03 (1H, t, J ¼ 7.2 Hz, Ar- 129.3, 129.0, 128.7, 128.6, 120.0, 115.4, 113.4, 93.3, 55.2, 21.5; IR
H), 6.91 (1H, d, J ¼ 7.2 Hz, Ar-H), 6.84 (2H, d, J ¼ 7.8 Hz, Ar-H), (KBr, cmꢁ1): 3481, 3458, 3382, 3353, 3236, 3053, 2912, 2839,
6.74 (1H, t, J ¼ 7.2 Hz, Ar-H), 6.62 (1H, d, J ¼ 7.8 Hz, Ar-H), 4.67 2748, 2225, 1620, 1573, 1560, 1508, 1463, 1413, 1340, 1245,
(2H, s, NH2), 2.42 (3H, s, CH3), 2.40 (3H, s, CH3) 1.45 (3H, s, 1163, 1089, 1033, 678, 561; anal. calcd (%) for C26H22N4O3S C,
CH3); 13C NMR (100 MHz, CDCl3) d ¼ 155.9, 155.0, 150.0, 143.2, 66.37; H, 4.71; N, 11.91; S, 6.81; found: C, 66.21; H, 4.66; N,
138.6, 138.4, 137.5, 137.1, 131.5, 130.8, 130.1, 129.5, 129.3, 11.88; S, 6.77.
128.4, 128.0, 127.8, 125.3, 118.4, 115.5, 92.2, 21.5, 21.1, 17.8; IR
(KBr, cmꢁ1): 3458, 3359, 3226, 3028, 2921, 2223, 1622, 1573,
1417, 1402, 1350, 1161, 676, 572; anal. calcd (%) for
Acknowledgements
C
27H24N4O2S: C, 69.21; H, 5.16; N, 11.96; S, 6.84; found: C,
Financial support of this research by the National Natural
Science Foundation of China (51073150 and 21172211) and Jilin
Provincial Science and Technology Development (20111802 and
201105030) is greatly acknowledged.
69.59; H, 5.11; N, 11.91; S, 6.82.
N-(4-Amino-5-cyano-3-phenylpyridin-2-yl)-N-(3-chlorophenyl)-
4-methylbenzenesulfonamide (4f). Colourless solid, mp: 240–
1
ꢀ
241 C; H NMR (300 MHz, CDCl3) d ¼ 8.37 (1H, s, Py-H), 7.61
(2H, d, J ¼ 8.1 Hz, Ar-H), 7.26–7.15 (4H, m, Ar-H), 7.11 (1H, t, J ¼
7.2 Hz, Ar-H), 7.06–6.94 (4H, m, Ar-H), 6.67 (2H, d, J ¼ 7.8 Hz, Ar-
H), 4.81 (2H, s, Ar-H), 2.43 (3H, s, CH3), 2.40 (3H, s, CH3); 13C
NMR (100 MHz, CDCl3) d ¼ 155.4, 154.9, 150.7, 143.2, 139.0,
138.6, 136.4, 129.9, 129.5, 128.9, 128.6, 128.4, 128.2, 127.7,
127.2, 120.5, 115.4, 93.3, 21.5, 21.2; IR (KBr, cmꢁ1): 3487, 3384,
3230, 3070, 3035, 2921, 2221, 1598, 1577, 1487, 1463, 1419,
1352, 1159, 1095, 825, 678, 565; anal. calcd (%) for C26H22N4O2S:
C, 68.70; H, 4.88; N, 12.33; S, 7.05; found: C, 68.55; H, 4.81; N,
12.38; S, 7.01.
Notes and references
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J. A. J. K. Mills, Heterocyclic Chemistry, Wiley India Pvt.
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J. Chen, Q. Pang, Y. Sun and X. Li, J. Org. Chem., 2011, 76,
3523.
3 (a) S. Schwartz, D. C. Brater, D. Pound, P. K. Green,
W. G. Kramer and D. Rudy, Clin. Pharmacol. Ther., 1993,
54, 90; (b) M. D. Murray, M. M. Deer, J. A. Ferguson,
P. R. Dexter, S. J. Bennett, S. M. Perkins, F. E. Smith,
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Am. J. Med., 2001, 111, 513.
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2001, 297, 267; (b) K. F. Rabe, E. D. Bateman, D. O'Donnell,
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366, 563.
N-(4-Amino-5-cyano-3-phenylpyridin-2-yl)-4-methyl-N-(p-tolyl)-
benzenesulfonamide (4g). Colourless solid, mp: 201–203 ꢀC; 1H
NMR (300 MHz, CDCl3) d ¼ 8.39 (s, 1H), 7.63 (d, J ¼ 8.1 Hz, 2H),
7.52–7.38 (m, 3H), 7.22 (d, J ¼ 8.1 Hz, 2H), 7.15–7.03 (m, 3H),
6.94 (t, J ¼ 8.1 Hz, 1H), 6.63 (s, 1H), 6.56 (d, J ¼ 8.1 Hz, 1H), 4.84
(s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) d ¼ 154.9, 154.8,
151.0, 143.6, 140.0, 136.1, 133.7, 130.5, 129.6, 129.4, 129.0,
128.9, 128.8, 128.8, 128.4, 127.5, 126.2, 120.3, 115.2, 93.6, 21.5;
IR (KBr, cmꢁ1): 3473, 3377, 3321, 3228, 3199, 3056, 2871, 2732,
2237, 1635, 1571, 1467, 1413, 1352, 1286, 1159, 1087, 1074,
1012, 973, 680, 576; anal. calcd (%) for C25H19ClN4O2S: C, 63.22;
H, 4.03; N, 11.80; S, 6.75; found: C, 63.01; H, 4.08; N, 11.83; S,
6.71.
N-(4-Amino-5-cyano-3-phenylpyridin-2-yl)-N-(4-chlorophenyl)-
4-methylbenzenesulfonamide (4h). Colourless solid, mp: 236–
1
ꢀ
237 C; H NMR (300 MHz, CDCl3) d ¼ 8.38 (1H, s, Py-H), 7.61
(2H, d, J ¼ 8.2 Hz, Ar-H), 7.51–7.36 (3H, m, Ar-H), 7.21 (2H, d, J ¼
8.1 Hz, Ar-H), 7.17–7.06 (2H, m, Ar-H), 6.98 (2H, d, J ¼ 8.7 Hz, Ar-
H), 6.58 (2H, d, J ¼ 8.7 Hz, Ar-H), 4.84 (2H, s, Py-NH2), 2.41 (3H,
s, CH3); 13C NMR (100 MHz, CDCl3) d ¼ 155.0, 154.8, 150.9,
143.6, 137.5, 136.0, 133.3, 130.7, 129.7, 129.5, 129.4, 128.9,
128.8, 128.4, 120.3, 115.2, 93.6, 21.5; IR (KBr, cmꢁ1): 3481, 3375,
3232, 3053, 2921, 2227, 1620, 1573, 1562, 1415, 1346, 1163,
1163, 1089, 1014, 678, 576; anal. calcd (%) for C25H19ClN4O2S C,
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