An efficient green multi-component reaction strategy for the synthesis of highly functionalised pyridines and evaluation of their antibacterial activities

Article abstract of DOI:10.1248/cpb.c13-00412

An efficient green multi-component reaction (MCR) method has been developed for the synthesis of 2-amino-4-aryl/heteroaryl-6-(pyridin-2-ylthio)pyridine-3, 5-dicarbonitrile(s) via a 3-component reaction of aryl aldehyde(s), malononitrile and 2-mercaptopyridine in the presence of K₂CO ₃ under solvent free reaction conditions (SFRC) using grinding technique at room temperature in a single step. The advantages of the present protocol is operationally simple, environmentally benign, solvent-free reaction conditions (SFRC), simple work up, excellent isolated yields of desired products and viable method for large scale applications in pharmaceutical industry. Interestingly, the synthesized compounds showed moderate to excellent antibacterial activities against Gram-positive and Gram-negative bacterial strains.

Full text of DOI:10.1248/cpb.c13-00412

1114
Regular Article
Chem. Pharm. Bull. 61(11) 1114–1120 (2013)
Vol. 61, No. 11
An Efficient Green Multi-Component Reaction Strategy for the
Synthesis of Highly Functionalised Pyridines and Evaluation of Their
Antibacterial Activities
Lakkireddy Srinivasula Reddy,a,b Tirumalareddy Ram Reddy,b Reddy Bodireddy Mohan,c
,c
Avula Mahesh,b Yeramanchi Lingappa,a and Nallagondu Chinna Gangi Reddy*
b
a Department of Chemistry, Sri Venkateswara University; Tirupati–517 502, Andhra Pradesh, India: Dr. Reddy’s
c
Laboratories Limited; Bollaram Road, Miyapur, Hyderabad–500 049, Andhra Pradesh, India: and Department of
Chemistry, School of Physical Sciences, Yogi Vemana University; Kadapa–516 003, Andhra Pradesh, India.
Received May 28, 2013; accepted August 8, 2013
An efficient green multi-component reaction (MCR) method has been developed for the synthesis of
2-amino-4-aryl/heteroaryl-6-(pyridin-2-ylthio)pyridine-3,5-dicarbonitrile(s) via a 3-component reaction of
aryl aldehyde(s), malononitrile and 2-mercaptopyridine in the presence of K2CO3 under solvent free reac-
tion conditions (SFRC) using grinding technique at room temperature in a single step. The advantages of the
present protocol is operationally simple, environmentally benign, solvent-free reaction conditions (SFRC),
simple work up, excellent isolated yields of desired products and viable method for large scale applications
in pharmaceutical industry. Interestingly, the synthesized compounds showed moderate to excellent anti-
bacterial activities against Gram-positive and Gram-negative bacterial strains.
Key words pyridine; solvent-free synthesis; green chemistry; multi-component reaction; grindstone chemis-
try; antibacterial activity
The pharmaceutical industry is increasingly under pres- when compared to base-catalyzed reactions. Ultrasonic-as-
sure to minimise its environmental impact.1) Demands for sisted synthesis also reported in literature.25–29) However, this
sustainable and environmental friendly organic syntheses2,3) reported method is not accessible for large scale applications
are stimulating the search for alternatives to the use of organic in pharmaceutical industry. Since grindstone chemistry30) is
solvents in synthetic organic chemistry. Performing reaction inexpensive and viable method for scale-up process when
under solvent-free reaction conditions (SFRC) using grind- compared to Ultrasonic-assisted synthesis. Nevertheless, to
ing technique is an important and interesting alternative, the best of our knowledge, no reports on one-pot synthesis
but reaction pathways, as well as the products formed may of 2-amino-4-aryl/heteroaryl-6-(pyridin-2-ylthio)pyridine-3,5-
be modified significantly.4–11) 2-Amino-3,5-dicarbonitrile- dicarbonitrile via MCR under SFRC using grindstone technol-
6-thiopyridines are among the most important N-heterocycles ogy.
that exhibit miscellaneous pharmacological activities such
The present communication describes an one-pot
as anti-prion,12,13) anti-hepatitis B,14) anticancer agents15) and three component synthesis of 2-amino-4-aryl/heteroaryl-6-
some of these compounds are recognized as highly selective (pyridin-2-ylthio)pyridine-3,5-dicarbonitrile (4) from aryl
ligands for adenosine receptors,16) which are renowned as pos- aldehyde (1), malononitrile (2) and 2-mercaptopyridine (3) in
sible targets for the development of new drugs in the treatment presence of K2CO3 under SFRC using grinding technique at
of Parkinson’s disease, asthma, kidney disease, epilepsy, and room temperature as shown in Chart 1.
cancer.17) These utilities continue to drive the interest in the
Mechanistically, the reaction seems to proceed (Chart 2) via
development of new synthetic routes for 2-amino-3,5-dicarbo- in situ generation of 2-alkylidenemalononitrile i.e., Knoeve-
nitrile-6-thiopyridines which include a multi-component reac- nagal adduct (5) from aryl aldehyde (1) and malononitrile (2)
tions (MCRs) under basic conditions18–21) or basic ionic liquid under basic conditions employed. Further, firstly, 1,2-addition
medium22) and also MCR using Lewis acid catalysts such between the thiol group of 2-mercaptopyridine and one of the
as (ZnCl2)23) and boric acid,24) which show improved results nitrile group of another malononitrile and secondly, Michael
Chart 1. Green MCR Strategy for the Synthesis of 2-Amino-4-aryl/Heteroaryl-6-(pyridin-2-ylthio)pyridine-3,5-dicarbonitriles
The authors declare no conflict of interest.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: ncgreddy@yogivemanauniversity.ac.in

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1115
Chart 2. Plausible Mechanism19) for the Formation of 2-Amino-4-aryl/Heteroaryl-6-(pyridin-2-ylthio)pyridine-3,5-dicarbonitrile
addition between carbanion of malononitrile and Knoevenagel of yield in water and highest yield of 87% of product 4a was
adduct (5) followed by cyclization afforded the intermediate obtained under SFRC at room temperature. The use of other
(7) which tautomerises to 1,4-dihydropyridine intermediate bases such as N-methyl-2-pyrrolidone, L-proline, basic Al2O3
(8) and subsequent aromatization in the presence of base and and Cs2CO3 were examined, but were found to be less ef-
Knoevenagel adduct 5 (an in situ-oxidizing agent) provided fective as the expected product 4a was isolated in 30–50%
the desired product 2-amino-4-aryl/heteroaryl-6-(pyridin-2- of yield (entries 3–6) in water and 40–70% of yield under
ylthio)pyridine-3,5-dicarbonitrile(s) 4a–i and compound 9.
SFRC. We also carried out the same reaction using tetra-n-
butylammonium fluoride, KH2PO4, BaCl2 both in water and
under SFRC, but the obtained yield was not satisfactory (en-
Results and Discussion
In our initial study, the reaction of benzaldehyde (1a), tries 7–9). From the above study we concluded that K2CO3 is
malononitrile (2) and 2-mercaptopyridine (3) was carried out the best option to get maximum yield of the desired product
in the presence of Na2CO3 at room temperature give rise to 4a under SFRC using grinding technique at room temperature.
2-amino-3,5-dicarbonitrile-4-phenyl-6-thio pyridine 4a. It was
Further, the effect of temperature was examined under
isolated and yield is 42% in water and 63% under solvent- SFRC using K2CO3 (also with other bases stated in Table 1).
free reaction conditions (SFRC) (entry 1, Table 1). Then, we In this connection, we raised the temperature of the reac-
conducted the same reaction using K2CO3 and afforded 52% tion to 70–80°C and maintained at the same temperature for
Table 1. Optimization of Reaction Conditions for Synthesis of 2-Amino-4-phenyl-6-(pyridin-2-ylthio)pyridine-3,5-dicarbonitrile (4a) via MCR of 1a, 2
and 3a)
Time (min)
Yieldb) (%)
Entry
Base
Solvent (H2O)
SFRCc)
Solvent (H2O)
SFRCc)
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
150
120
210
250
300
330
250
270
400
60
30
65
70
60
60
55
60
70
42
52
48
35
20
40
46
45
30
63
87
68
57
46
61
70
71
52
NMP
L-Proline
Basic Al2O3
Cs2CO3
TBAF
K2H2PO4
BaCl2
a) Reaction conditions: Benzaldehyde (1a) (0.00188mol), malononitrile (2) (0.00377mol), 2-mercaptopyridine (3) (0.0015mol), base (1eq) and H2O (10vol) or SFRC at
room temperature. b) Isolated yields of the product. c) Reaction carried out under stirring. d) Reaction carried out under solvent free reaction conditions (SFRC) using grinding
technique.

1116
Vol. 61, No. 11
Table 2. Effect of Base Load on Synthesis of 2-Amino-4-phenyl-6-
(−Ve) bacteria. Compounds 4a, 4b and 4h exhibited least ac-
tivity against both bacteria.
(pyridin-2-ylthio)pyridine-3,5-dicarbonitrile (4a)a)
On the other hand, the results of preliminary antibacterial
testing of compounds 4a–i as shown in Table 4 revealed that,
compounds 4d and 4i exhibited good activity against Gram
(+Ve) bacteria (inhibitory zone >27mm) and excellent activ-
ity against Gram (−Ve) bacteria (inhibitory zone >31mm).
Compounds 4c, 4e and 4g showed moderate activity towards
Gram (+Ve) bacteria (19–27mm) and moderate to good activ-
ity (23–29mm) towards Gram (−Ve) bacteria.
Entry
K2CO3 (eq)
Time (min)
Yieldb) (%)
1
2
3
4
5
0.5
0.75
1
70
60
30
40
40
40
58
87
82
78
1.5
2.0
a) Reaction conditions: Benzaldehyde (1a) (0.00188mol), malononitrile (2)
(0.00377mol), 2-mercaptopyridine (3) (0.0015mol), K2CO3 at room temperature
under SFRC. b) Isolated yields of product (4a).
The MIC values were determined as the lowest concentra-
tion that completely inhibited visible growth of the microor-
ganisms as presented in Table S1. The structure–antimicrobial
30–70min. The obtained yield of product 4a was compara- activity relationship of the synthesized compounds revealed
tively low (50–65%). Based on obtained results, we concluded that presence of electron withdrawing groups (F, Br, NO2 on
that room temperature is optimum for maximum conversion 4′-aryl substituent or presence of 4′-heterocycle of pyridine
and highest isolated yield of product 4a.
core displayed high activity. The compounds having electron
Base concentration was optimized by varying its concentra- donating groups (OH, OMe) on 4′-aryl substituent of pyridine
tion from 0.5 to 2.0eq (entries 1–5, Table 2). Increase in the core or without substitution exhibited low activity. Excellent
product (4a) yield was observed on apply of 0.5 to 1.0eq of activity was attained with the compounds (4c–d) having –F
base. Decrease in yield of the product 4a was observed on in- (fluorine) substituent on the 4′-aryl substituent of pyridine
crease of base concentration (entries 4–5). Hence, 1eq of base core. The maximum activity was observed with compound
was considered as an optimum base concentration (entry 3).
To test the generality and scope of this MCR a range of aryl
aldehydes (1a–i) were employed and obtained results were
presented in Table 3. Consistent with the results in the opti-
(4i) having 4′-heterocycle substituent of pyridine core.
Conclusion
In summary, we demonstrated an efficient Green MCR
mization studies, the reactions smoothly proceeded to afford strategy for the synthesis of highly functionalized pyridines
2-amino-4-aryl/heteroaryl-6-(pyridin-2-ylthio)pyridine-3,5- (4a–i) of potential medicinal interest via a three component
dicarbonitriles in good to excellent isolated yields. Various reaction under SFRC by adopting Grindstone chemistry in
electron donating e.g. OMe, Br, OH (entries 2, 5, 6, 8, Table presence of K2CO3 in a single step. The advantages of the
3) or electron withdrawing groups e.g. F, NO2 (entries 3, 4, 7) grindstone technique include high yields, environmentally
present on the aryl aldehydes were well tolerated. The reaction benign procedure, shorter reaction time, simpler workup pro-
proceeded well irrespective of the substituents present on aryl cedure and less energy consumption. The methodology is
aldehydes (entries 1 vs. 2–8). The use of heteroaromatic alde- also useful in constructing a diversity based library of mol-
hyde was also successful and afforded the desired product 4i ecules related to Pyridine framework. Among the synthetic
in good yield (entry 9).
analogues, compounds 4d and 4i showed excellent inhibition
Antibacterial Activity Studies The primary antimicro- against multidrug resistant Gram-negative bacteria, E. coli
bial activity screen was carried out by agar disc-diffusion and K. pneumoniae, nearly equivalent to that of reference drug
method.31–34) All the synthesized compounds were tested by Chloramphenicol. We have discerned that the inhibition rate
the disk diffusion method against Gram-positive bacterial was directly proportional either to strength of electron with-
strains: Micrococcus luteus (MTCC 106) and Staphylococ- drawing groups on 4-aryl substituent or presence 4-heteroa-
cus aureus (MTCC 737) and Gram-negative bacterial strains: ryl group of 2-amino-4-aryl-6-(pyridin-2-ylthio)pyridine-3,5-
Escherichia coli (MTCC 443), Klebsiella pneumoniae (MTCC dicarbonitrile, 4c–e, 4g and 4i.
109). Chloramphenicol was used as positive control and di-
methyl sulfoxide (DMSO) was used as negative control. The
susceptibility was assessed on the basis of diameter of zone of
Experimental
Melting points were determined using Buchi (B-540) melt-
inhibition against Gram-positive and Gram-negative strains of ing point analyzer (Postfach, Flawil, Switzerland) and are
bacteria. Inhibition zones were measured and compared with uncorrected. NMR spectra were recorded on Varian 400MHz
the controls. The minimum inhibitory concentration (MIC) for (Varian, Inc., NMR Systems, Palo Alto, CA, U.S.A.). Chemi-
the most active compounds 4c, 4d, 4g and 4i against the same cal shifts were expressed in parts per million (ppm), coupling
microorganisms used in the preliminary screening was carried constants were expressed in Hertz (Hz). Splitting patterns
out using microdilution susceptibility method32) and presented describe apparent multiplicities and were designated as s
in Table 4.
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and
The results of preliminary antibacterial testing of com- br (broad). High Resolution Mass Spectra were recorded on
pounds 4a–i are shown in Table S1 (see supplementary in- a LCT-Premier XE mass spectrometer (Waters, Milford, MA,
formation). The results revealed that, compounds 4c, 4d, 4g U.S.A.)-single quadrupole system equipped with electrospray
and 4i displayed good activity against Gram-positive bacteria ionization (ESI) source. Thin-layer chromatography was per-
(inhibitory zone >25mm) and excellent activity against Gram formed on 0.25mm Merck silica gel plates and visualized
(−Ve) bacteria (inhibitory zone >27mm). Compound 4e dis- with UV light. All chemicals and solvents are purchased from
played low to moderate activity towards Gram (+Ve) bacteria Sigma-Aldrich (St. Louis, MO, U.S.A.) and Merck (Mumbai,
(18–21mm) and moderate activity (20–23mm) towards Gram India) and are used without further purification.

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1117
Table 3. Synthesis of 2-Amino-4-aryl/Heteroaryl-6-(pyridin-2-ylthio)pyridine-3,5-dicarbonitrile (4a–i)a)
Entry
Aryl aldehyde (R) (1)
Time (min)
Product(s) (4)
Yieldb) (%)
1
30
87
2
3
4
20
25
30
82
91
90
5
20
88
6
28
83

1118
Vol. 61, No. 11
Table 3. Continued
Entry
Aryl aldehyde (R) (1)
Time (min)
Product(s) (4)
Yieldb) (%)
7
35
85
8
15
92
9
20
90
a) Reaction conditions: Aryl aldehyde(s) (1a–i) (0.00188mol), malononitrile (2) (0.00377mol), 2-mercaptopyridine (3) (0.0015mol), K2CO3 (1eq) at room temperature under
SFRC. b) Isolated yields of product(s) (4a–i).
Table 4. Minimum Inhibitory Concentration (MIC), µg/mL of 4
Minimum inhibitory concentration (µg/mL)
Compound
Gram-positive bacteria
Gram-negative bacteria
M. luteus
S. aureus
E. coli
K. pneumoniae
4c
100
100
50
100
75
100
100
100
25
100
200
100
50
4d
4g
4i
100
50
25
Chloramphenicol
6.5
6.5
6.25
6.0
1
General Experimental Procedure for Synthesis of zylmalononitrile (9a) was confirmed by H-NMR and GC-MS.
Compounds 4a–i mixture of benzaldehyde (1a) The same procedure for experimental and purification was fol-
A
(0.00188mol, 0.2g), malononitrile (2) (0.00377mol, 0.249g), lowed for the preparation of all other compounds (4b–i). The
K2CO3 (0.00188mol, 0.138g) and 2-mercaptopyridine (3) synthesised compounds (4a–i) gave satisfactory spectroscopic
(0.00150mol, 0.167g) were thoroughly ground with a pestle in data in accordance with their proposed structures.
a mortar at room temperature in an open atmosphere until the
2-Amino-4-phenyl-6-(pyridine-2-ylthio)pyridine-3,5-dicar-
mixture turned into a thick mass. The progress of the reaction bonitrile (4a): Off-white solid Yield=87%; mp 224–227°C;
was monitored by TLC. The mixture continued to be ground 1H-NMR (400MHz, DMSO-d6) δ: 8.57 (d, 1H, J=3.6Hz, arom
occasionally until completion of the reaction. After completion H), 7.98 (br, 2H, –NH2), 7.87 (t, 1H, J=8.0Hz, arom H), 7.8
of the reaction as from TLC, water (100mL) was added to (d, 1H, J=8.0Hz, arom H), 7.58 (s, 5H, arom H), 7.43 (t, 1H,
the crude mass and product was extracted using ethyl acetate J=6.0Hz, arom H); 13C-NMR (100MHz, DMSO-d6) δ: 164.2,
(3×50mL). The organic layer was collected, dried over anhy- 159.8, 158.9, 152.4, 150.2, 137.8, 133.9, 130.5, 129.6, 129.4,
drous Na2SO4 and the solvent was removed under vacuum. 128.8 (2C), 128.6, 128.4 (2C), 123.5, 95.6, 88.0; high resolution
Pure product 4a was obtained from crude mass after recrystal- (HR)-MS (ESI): m/z (M+H)+ Calcd for C18H12N5S: 330.0813,
lisation from a mixture of EA–n-hexane (1:1 ratio, 10vol) and Found 330.0808.
the crude 2-benzylmalononitrile (9a) was isolated from the fil-
2-Benzylmalononitrile (9a): White solid; mp 88–90°C;
trate and purified by column chromatography using a mixture 1H-NMR (400MHz, CDCl3) δ: 7.43–7.38 (m, 2H, arom H),
of EA–n-hexane (1:99 ratio). The obtained by-product 2-ben- 7.36–7.30 (m, 2H, arom H), 3.90 (t, J=6.8Hz, 1H), 3.27 (d,

November 2013
1119
J=6.8Hz, 2H); GC-MS: m/z (M)+ 156.
(2C), 128.7, 123.9 (2C), 123.6, 114.9, 114.5, 95.1, 87.8; HR-MS
2-Amino-4-(4-methoxyphenyl)-6-(pyridine-2-ylthio)- (ESI): m/z (M+H)+ Calcd for C18H11N6O2S: 375.0664, Found:
pyridine-3,5-dicarbonitrile (4b): Off-white solid; Yield=82%; 375.0657.
mp 250–253°C; 1H-NMR (400MHz, DMSO-d6) δ: 8.57 (d, 1H,
2-Amino-4-(3,4,5-trimethoxyphenyl)-6-(pyridine-2-ylthio)-
J=4.0Hz, arom H), 7.93 (br, 2H, –NH2), 7.86 (td, 1H, J=8.0, pyridine-3,5-dicarbonitrile (4h): Off-white solid; Yield=92%;
1
2.0Hz, arom H), 7.80 (d, 1H, J=8.0Hz, arom H), 7.53 (d, mp 265–268°C; H-NMR (400MHz, DMSO-d6) δ: 8.57 (dd,
2H, J=8.8Hz, arom H), 7.42 (q, 1H, J=4.8Hz, arom H), 7.13 1H, J=4.8, 1.2Hz, arom H), 7.95 (br, 2H, –NH2), 7.87 (td, 1H,
(d, 2H, J=8.0Hz, arom H), 3.85 (s, 3H, –OCH3); 13C-NMR J=8.0, 1.6Hz, arom H), 7.79 (d, 1H, J=8.0Hz, arom H), 7.43
(100MHz, DMSO-d6) δ: 164.2, 160.9, 159.9, 158.5, 152.5. (td, 1H, J=5.6, 2.4Hz, arom H), 6.94 (s, 2H, arom H), 3.82
150.2, 137.8, 130.3 (2C), 128.5, 125.7, 123.4, 115.5, 115.2, 114.1 (s, 6H, –2OCH3), 3.76 (s, 3H, –OCH3); 13C-NMR (100MHz,
(2C), 95.7, 87.9, 55.4; HR-MS (ESI): m/z (M+H)+ Calcd for DMSO-d6) δ: 164.1, 159.7, 158.5, 152.7, 152.4, 150.1, 138.8,
C19H14N3OS: 360.0919, Found: 360.0906.
137.7, 128.8, 128.6 (2C), 123.4, 115.4, 115.0, 106.4 (2C), 95.5,
2-Amino-4-(4-f luorophenyl)-6-(pyridine-2-ylthio)- 87.9, 60.1, 56.1 (3C), HR-MS (ESI): m/z (M+H)+ Calcd for
pyridine-3,5-dicarbonitrile (4c): Off-white solid; Yield= C21H18N5O3S: 420.1130, Found: 420.1117.
1
91%; mp 246–249°C; H-NMR (400MHz, DMSO-d6) δ: 8.57
2-Amino-4-(pyridine-2-ylthio)-4-(pyridine-4-ylthio)-
(d, 1H, J=4.0Hz, arom H), 8.0 (br, 2H, –NH2), 7.87 (td, pyridine-3,5-dicarbonitrile (4i): Off-white solid; Yield=90%;
1
1H, J=8.0, 2.0Hz, arom H), 7.80 (d, 1H, J=8.0Hz, arom mp 233–235°C; H-NMR (400MHz, DMSO-d6) δ: 8.82 (dd,
H), 7.67–7.64 (m, 2H, arom H), 7.46–7.41 (m, 3H, arom H); 2H, J=4.4, 1.6Hz, arom H), 8.58 (dd, 1H, J=4.8, 1.2Hz, arom
13C-NMR (100MHz, DMSO-d6) δ: 164.2, 159.7, 157.9, 152.4, H), 8.1 (br, 2H, –NH2), 7.88 (td, 1H, J=7.6, 2.0Hz, arom H),
150.2, 137.8 (2C), 131.2, 131.1, 128.6 (2C), 123.5, 116.0, 115.8, 7.81 (d, 1H, J=8.4Hz, arom H), 7.61 (d, 2H, J=6.4Hz, arom
115.2, 114.8, 95.7, 88.1; HR-MS (ESI): m/z (M+H)+ Calcd for H), 7.45–7.42 (m, 1H, arom H).; 13C-NMR (100MHz, DMSO-
C18H11N5FS: 348.0719, Found: 348.0704.
d6) δ: 164.3, 159.5, 156.3, 152.1, 150.2 (3C), 141.6, 137.8, 128.6,
2-Amino-4-(3,4-difluorophenyl)-6-(pyridine-2-ylthio)- 123.5, 122.8 (2C), 114.8, 114.4, 94.8, 87.5.; HR-MS (ESI): m/z
pyridine-3,5-dicarbonitrile (4d): Off-white solid; Yield=90%; (M+H)+ Calcd for C17H11N6S: 331.0766, Found: 331.0754.
1
mp 251–254°C; H-NMR (400MHz, DMSO-d6) δ: 8.58 (d, 1H,
J=4.8Hz, arom H), 8.06 (br, 2H, –NH2), 7.88 (t d, 2H, J=8.0,
Acknowledgment The authors thank Dr. A. K. Roy, Dr.
2.0Hz, arom H), 7.80 (d, 1H, J=7.6Hz, arom H), 7.73–7.6 (m, K. V. Raghu, Dr. V. Dahanukar and Analytical group of Dr.
1H, arom H), 7.5–7.43 (m, 2H, arom H); 13C-NMR (100MHz, Reddy’s Laboratories, Hyderabad, India, for spectral data and
DMSO-d6) δ: 164.2, 159.6, 156.6, 152.2 (2C), 150.2, 137.8, DAE-BRNS (BARC), Govt. of India, Mumbai, for providing
128.7, 126.2, 123.6, 118.49, 118.43, 118.3, 118.2, 115.0, 114.6, financial assistance (No. 2011/37C/52/BRNS/2264).
95.5, 88.2; HR-MS (ESI): m/z (M+H)+ Calcd for C18H10N5F2S:
366.0625, Found: 366.0606.
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1
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mp 260–263°C; H-NMR (400MHz, DMSO-d6) δ: 8.57 (d,
1H, J=4.0Hz, arom H), 8.0 (br, 2H, –NH2), 7.87 (td, 2H,
J=8.0, 1.6Hz, arom H), 7.81 (d,t, 2H, J=8.4, 6.0Hz, arom H),
7.54 (d, 2H, J=8.4Hz, arom H), 7.44–7.41 (m, 1H, arom H);
13C-NMR (100MHz, DMSO-d6) δ: 164.2, 159.7, 157.7, 152.3,
150.2, 137.8, 133.1, 131.8 (2C), 130.6 (2C), 128.6, 124.2, 123.5,
115.1, 114.8, 95.4, 87.9; HR-MS (ESI): m/z (M+H)+ Calcd for
C18H11N5SBr: 407.9919, Found: 407.9904, other isotopic peaks
found: 409.8890, 410. 9925
2-Amino-4-(3-hydroxyphenyl)-6-(pyridine-2-ylthio)-
pyridine-3,5-dicarbonitrile (4f): Off-white solid; Yield=83%;
1
mp 222–226°C; H-NMR (400MHz, DMSO-d6) δ: 9.89 (s, 1H,
–OH), 8.56 (d, 1H, J=3.6Hz, arom H), 7.95 (br, 2H, –NH2),
7.87 (td, 1H, J=8.0, 2.0Hz, arom H), 7.80 (d, 1H, J=8.0Hz,
arom H), 7.43–7.35 (m, 2H, arom H), 6.97–6.89 (m, 3H, arom
H); 13C-NMR (100MHz, DMSO-d6) δ: 164.1, 159.8, 158.8,
157.3, 152.5, 150.1, 137.8, 135.0, 130.0, 128.5, 123.4, 118.9,
117.3, 115.2, 115.0, 114.8, 95.5, 87.9; HR-MS (ESI): m/z (M+
H)+ Calcd for C18H12N5OS: 346.0763, Found: 346.0746.
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2-Amino-4-(4-nitrophenyl)-6-(pyridine-2-ylthio)-
pyridine-3,5-dicarbonitrile (4g): Off-white solid; Yield=85%;
1
mp 245–248°C; H-NMR (400MHz, DMSO-d6) δ: 8.58 (d,
1H, J=4.0Hz, arom H), 8.44 (d, 2H, J=8.8Hz, arom H), 8.11
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