Diethylamine Dess-Martin periodinane: An efficient catalyst-oxidant combination in a sequential, one-pot synthesis of difficult to access 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines at ambient temperature

Article abstract of DOI:10.1039/c7ra07738f

Herein, diethylamine Dess-Martin periodinane has been demonstrated for the first time as an efficient catalyst-oxidant combination in a sequential, one-pot synthesis of medicinally privileged but difficult to access 2-amino-3,5-dicarbonitrile-6-sulfanylpy

Full text of DOI:10.1039/c7ra07738f

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Diethylamine Dess–Martin periodinane: an efficient
catalyst–oxidant combination in a sequential, one-
pot synthesis of difficult to access 2-amino-3,5-
dicarbonitrile-6-sulfanylpyridines at ambient
temperature†
Cite this: RSC Adv., 2017, 7, 38877
a
R. V. Kupwade,a S. S. Khot,a M. A. Kulkarni,a U. V. Desai
and P. P. Wadgaonkarb
Herein, diethylamine Dess–Martin periodinane has been demonstrated for the first time as an efficient
catalyst–oxidant combination in a sequential, one-pot synthesis of medicinally privileged but difficult to
access 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines via a pseudo-four component reaction between
2,6-disubstituted benzaldehydes, malononitrile, and thiols. Ambient reaction conditions, excellent yields,
and total avoidance of conventional isolation as well as purification are the noteworthy merits of this
developed protocol.
Received 14th July 2017
Accepted 26th July 2017
DOI: 10.1039/c7ra07738f
rsc.li/rsc-advances
drugs useful in the treatment of Parkinson's disease, hypoxia/
ischemia, asthma, kidney disease, and epilepsy.9 This wide
Introduction
range of applications of pyridine-3,5-dicarbonitriles has
inspired many researchers to develop efficient methods for their
synthesis (Fig. 1).
Rapid assembly of molecular diversity, obeying the demands of
green chemistry is an important area of current research in
organic synthesis. A rational pathway to this goal begins with
the design and implementation of appropriate multicomponent
reactions.1 Multicomponent reactions for the generation of
complex products involve the formation of several bonds with
concomitant elimination of simple molecules such as water,
ammonia, and alcohol that can be very easily removed from the
resultant product. The usefulness of multicomponent reactions
increases many fold when they provide an easy access towards
medicinally privileged scaffolds that can act as ligands for
structurally diverse biological receptors and consequently assist
in drug discovery.2 Pyridine-3,5-dicarbonitriles, possessing
amino and sulfanyl moieties at the positions C2 and C6,
respectively, and aryl or heteroaryl substitution at C4 have long
been recognised as one such medicinally important scaffolds.
Compounds belonging to this class are known to exhibit diverse
pharmacological activities and are useful as anti-prion,3 anti-
hepatitis B virus,4 anti-bacterial,5 and anticancer6 agents and
as potassium channel openers in the treatment of urinary
incontinence.7 A few compounds of this class have been re-
ported to serve as high potency agonists for human adenosine
receptors8 and are, therefore, used in the development of new
As far as synthesis of 2-amino-3,5-dicarbonitrile-6-
sulfanylpyridines is concerned, the most preferred pathway is to
perform a multicomponent reaction between an aldehyde,
malononitrile, and thiol.10 The synthesis follows the Knoevenagel-
carba–Michael-thia–Michael
addition-oxidation
pathway.11
Taking into account the fact that Knoevenagel as well as Michael
addition reactions are typically base-catalyzed reactions, many
protocols using the aforementioned substrates have been subse-
quently developed employing the catalysts such as Et3N, DABCO,10
piperidine, TBAH,11 DBU,12a {(bmim)OH},12b KF-Al2O3,12c nano-
crystalline-MgO,12d ethanolic KOH,12e and diethylamine12f
(Scheme 1). Although these reported protocols are efficient, they
are associated with a common drawback that using 2,6-disubsti-
tuted benzaldehyde as an aldehyde component, instead of the
aDepartment of Chemistry, Shivaji University, Kolhapur, Maharashtra, India. E-mail:
uvdchem2011@gmail.com; uprabhu_desai@rediffmail.com
bPolymer Science and Engineering Division, CSIR National Chemical Laboratory, Pune,
India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra07738f
Fig. 1 Medicinally privileged pyridine-3,5-dicarbonitrile scaffold.
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Scheme 1 Two step and sequential, one-pot, two-step synthesis of pyridine 3,5-dicarbonitriles.
desired 2-amino-3,5-dicarbonitrile-6-sulfanylpyridine 5, the cor- KMnO4 as the base–oxidant combination.13 All these protocols
responding 2-amino-3,5-dicarbonitrile-6-sulfanyldihydropyridine, are associated with the limitations of elevated temperature and
4 is obtained (Scheme 1a). A logical approach towards the mainly the generation of undesired waste as well as difficulties
synthesis of this difficult to access 2-amino-3,5-dicarbonitrile-6- in the isolation of the product from the reaction mixture. These
sulfanylpyridines would be either to synthesize respective dihy- limitations clearly highlight the need as well as scope for the
dropyridines, 4, and to oxidize them to the corresponding pyri- development of an easily adaptable and high yielding protocol
dine derivatives 5 in two separate steps (Scheme 1a) or to perform for the synthesis of this difficult to access 2-amino-3,5-
their sequential, one-pot synthesis involving a multicomponent dicarbonitrile-6-sulfanylpyridines, 5. Due to our continuous
condensation-oxidation approach (Scheme 1b). From a practical interest in the development of practical and problem solving
viewpoint, the latter approach is certainly advantageous; however, synthetic methodologies,14a–e we planned to undertake the
its success depends upon the correct choice of the catalyst– development of an easily adaptable protocol for the synthesis of
oxidant combination.
pyridine-3,5-dicarbonitriles (5, R1 s H).
Literature studies have revealed that there are only three
In recent years, there has been considerable growth in the
protocols available for the synthesis of pyridine-3,5- exploration of applications of hypervalent iodine reagents in
dicarbonitriles, 5. However, two of these protocols are two organic transformations.15 Amongst various hypervalent iodine
step protocols and involve the oxidation of 3,5-dicyanodihy- reagents, Dess–Martin periodinane [1,1,1-tris (acetyloxy)-1,1-
dropyridines, 4, prepared in the rst step to corresponding dihydro-1,2-benziodoxol-3-(1H)-one, DMP] (X, Scheme 2) is
pyridines, 5, using TCBQ/DDQ or MnO2 as oxidants.3a,10b,11b On a highly useful hypervalent iodine reagent customarily used in
the other hand, Mishraet et al. have reported a sequential one- the oxidation of alcohols.16 A literature survey revealed two
pot synthesis of pyridine-3,5-dicarbonitriles using Na2CO3– earlier reports on the use of DMP in the oxidation of Hantzsch
Scheme 2 Oxidation of dihydropyridines to pyridines using a Dess–Martin periodinane.
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Table 1 Base-catalyzed oxidation of dihydropyridine, 4a, to pyridine,
dihydropyridines to pyridines. Heravi et al. reported the use of
a DMP-silica gel-HNO3 combination,17a whereas Karade et al.
demonstrated the use of a DMP-iodine (or KBr) combination17b
for this oxidation (Scheme 2A). However, to the best of our
knowledge, there are no reports on the use of DMP in the
oxidation of 3,5-dicyanodihydropyridines, 4, to pyridine-3,5-
dicarbonitriles, 5.
5aa
From a mechanistic viewpoint, we surmised that instead of
using a DMP-silica gel-HNO3 or DMP-iodine (or KBr) combi-
nation, the use of a base-Dess–Martin periodinane combination
would be more appropriate for the oxidation of dihydropyr-
idines (Scheme 2B). It was speculated that during the oxidation
of dihydropyridines to pyridines using the aforementioned
combination, the added base catalyst would abstract the acidic
proton attached to nitrogen to generate an anion, which upon
rearrangement followed by elimination of hydride ion would
yield the corresponding pyridine derivative. This hydride ion on
attack over iodine in Dess–Martin periodinane would cause the
release of acetate ion. It was also surmised that the synthesis of
intermediate dihydropyridines, 4, typically being a base-
catalyzed reaction (Scheme 1a), success to the speculated
base-catalyzed oxidation of dihydropyridines, 4, to pyridines, 5,
would provide us an opportunity to achieve sequential, one-pot
synthesis of pyridine-3,5-dicarbonitriles, 5 (Scheme 1B). Based
upon this speculation, we initially tested the feasibility of
a base-Dess–Martin periodinane combination in the oxidation
No.
Catalyst (20 mol%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
Na2CO3
K3PO4
DBU
DABCO
20
20
10
10
10
15
5
10
240
240
84
86
87
89
90
92
93
91
65
20
Piperidine
Triethylamine
Diethylamine
Diethylamineb
c
—
10
Diethylamined
a
Reaction conditions: dihydropyridine, 4a (1 mmol), DMF (2 mL),
b
Dess–Martin periodinane (1 mmol), base, RT. Using 15 mol%
diethylamine. c In the absence of base. d Using Oxone as an oxidant.
of
3,5-dicyanodihydropyridines,
4,
to
pyridine-3,5- (Table 1, entry 10). From the results summarized in Table 1, it is
evident that as compared to inorganic bases such as potassium
phosphate and sodium carbonate, with organobasic catalysts,
the oxidation proceeded well. Furthermore, the organic bases,
(e.g., triethylamine, diethylamine, DBU, and piperidine), with
dicarbonitriles, 5 (Scheme 2B).
Results and discussion
For preliminary studies, representative 3,5-dicyanodihydropyr- very close pKb values, were found to be equally effective (Table 1)
idine, 4a, was prepared employing 2,6-dichlorobenzaldehyde, as catalysts in this oxidation. From the results, it is also evident
malononitrile, and thiophenol as substrates and diethylamine that from economic as well as environmental viewpoints,
as the catalyst.12f Subsequently, a set of model reactions was diethylamine is the best suited basic catalyst in Dess–Martin
carried out using Dess–Martin periodinane as an oxidant and periodinane-mediated oxidation of dihydropyridine, 4a, to
Na2CO3, K3PO4, DBU, DABCO, piperidine, triethylamine, and pyridine, 5a.
diethylamine as representative base catalysts. Thus, to a well
The primary objective of this study was not limited to the
stirred solution of 4a (1 mmol) in dimethylformamide (2 mL) oxidation of 3,5-dicyanodihydropyridines, 4, to the corre-
and chosen base catalyst (20 mol%), Dess–Martin periodinane sponding pyridine derivatives 5, but was mainly the develop-
(1 mmol) was added. Stirring was continued at ambient ment of a sequential, one-pot protocol for the synthesis of
temperature, and the reactions were monitored by TLC. Upon pyridine-3,5-dicarbonitriles, 5. In this regard, another model
completion of each reaction (TLC), water (10 mL) was added, reaction was carried out wherein, to a well stirred solution of
and stirring was continued for further half an hour. The resul- 2,6-dichlorobenzaldehyde, malononitrile, and thiophenol
tant free owing solid was ltered, washed with water, dried, (1 : 2 : 1 equiv.) in ethanol (3 mL), diethylamine (20 mol%) was
washed with chloroform, and dried again. Spectral analysis of added, and stirring was continued at ambient temperature.
the resultant product conrmed it as the desired pyridine-3,5- Upon completion of the reaction, the resultant dihydropyridine
dicarbonitrile 5a. To conrm the role of the base as a catalyst, 4a was directly dissolved in dimethylformamide (2 mL), and
the model reaction was then carried out in the absence of the Dess–Martin periodinane (1 mmol) was added to it. Stirring was
catalyst. However, the oxidation reaction took a very long time continued, and the reaction was monitored by TLC. Upon
(4 h) and furnished the desired pyridine derivative in an unac- completion of the reaction (TLC), followed by workup as
ceptable yield (Table 1, entry 9). In addition, we have most described earlier, the desired product 5a was obtained in
recently reported diethylamine-Oxone as an efficient catalyst– excellent yield (93%). Based on this result, it can be concluded
oxidant combination in the oxidation of suldes to sulfones.18 that diethylamine Dess–Martin periodinane can serve as an
Hence, the same combination was also screened in the oxida- efficient catalyst–oxidant combination in a sequential, one-pot
tion of dihydropyridine, 4a, to pyridine, 5a. However, the reac- synthesis of easily non-accessible 2-amino-3,5-dicarbonitrile-6-
tion furnished the desired pyridine derivative in very poor yield sulfanylpyridines, 5 (Scheme 2).
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Next, we explored the scope and generality of the protocol. aer isolation of the product at any of these two stages, the
Accordingly, 2,6-dichloro, 2,6-dimethyl, 2,6-dimethoxy, and 2,6- resultant product did not require any further purication.
diuoro benzaldehyde were chosen as aldehyde components
while keeping malononitrile xed as the second component.
Thiols such as thiophenol, 4-bromothiophenol, 4-methyl-
Conclusion
thiophenol, 4-chlorothiophenol, 4-methoxy-thiophenol, and
cyclohexyl, n-butyl, and ethane thiol were allowed to react under
the established reaction conditions. In each case, the corre-
sponding 2-amino-3,5-dicarbonitrile-6-sulfanyl pyridine 5b–r
was obtained in excellent yields (Table 2). It was noticed that
yield of the desired pyridine derivative did not depend upon the
nature of the substituent, either an aldehyde or thiol, on the
aromatic ring. Even the aliphatic thiols equally worked well. The
key advantages of this sequential one-pot protocol were asso-
ciated with the facts that (i) each reaction could be arrested at
the stage of the formation of the intermediate dihy-
drodicyanopyridine (4a–r) or may be directed towards the
synthesis of the corresponding pyridine derivative (5a–r) and (ii)
2-Amino-3,5-dicarbonitrile-6-sulfanylpyridines have been re-
ported to possess a very wide range of medicinal and biological
properties. However, the main issues involved in their syntheses
are associated with the choice of an aldehyde component as well
as the oxidation of intermediate dihydropyridines. In the
present study, we have demonstrated for the rst time that
diethylamine Dess–Martin periodinane served as an extremely
useful catalyst–oxidant combination in a sequential, one-pot
synthesis of difficult to access 2-amino-3,5-dicarbonitrile-6-
sulfanylpyridines. Possible arrest of the reaction at an inter-
mediate stage to isolate dihydropyridines, obtain excellent
yields, and avoid conventional isolation as well as a purication
procedure are the noteworthy merits of this approach.
Employing the results obtained in this study, the development
Table 2 One-pot synthesis of 2-amino-4,6-dicyanodihydropyridines, 4, and 2-amino-4,6-dicyanopyridines, 5ab
Product (4)b
Product (5)
Product (5)c
Thiol (3)
(R1¼)
Melting point
(ꢀC)
No.
Aldehyde (1)
Time (h)
Time (min)
Yield (%)
a
b
c
d
e
f
g
h
i
Phenyl
2.5
1.5
1.5
2
2
2
2
2
1.5
1.5
2
10
5
5
93
94
95
96
96
95
90
95
93
96
95
190–192
206–208
174–178
184–186
192–194
142–144
164–166
210–212
260–264
216–218
243–245
4-Methylphenyl
4-Chlorophenyl
4-Bromophenyl
Cyclohexyl
n-Butyl
Ethyl
5
10
10
10
5
5
5
Phenyl
4-Bromophenyl
4-Chlorophenyl
4-Methoxyphenyl
j
k
10
l
m
n
Phenyl
4-Chlorophenyl
4-Methylphenyl
2
1.5
1.5
5
5
5
94
96
96
196–198
208–210
194–196
o
p
q
r
Phenyl
2
10
5
5
92
95
94
96
274–276
280–282
196–198
164–166
4-Chlorophenyl
4-Methylphenyl
Cyclohexyl
1.5
1.5
2
5
a
Reaction conditions: aldehyde (1 mmol), malononitrile (2 mmol), thiol (1 mmol), diethylamine (20 mol%), RT; aer completion of reaction (step 1,
product 4), add dimethylformamide (2 mL) and Dess–Martin periodinane (1 mmol), rt (step 2, product 5). b Reaction can be arrested at step 1 to
isolate dihydropyridine, 4 or may be continued to obtain the corresponding pyridine derivative, 5.; for detailed characterization of product 4, see
ESI. c Total time of the reaction is the sum of the time in columns 4 and 5.
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of another sequential one-pot protocol for the synthesis of HRMS (ESI): m/z [M + H]+ calcd for C19H10N4Cl3S: 430.9686;
medicinally privileged compounds is being carried out by our found mass: 430.9684.
group.
2-Amino-6-[(4-bromophenyl)sulfanyl]-4-(2,6-dichlorophenyl)
pyridine-3,5-dicarbonitrile, 5d. Off white solid; mp 184–186 ꢀC;
1H-NMR (DMSO-d6, 300 MHz): 7.58 (d, 2H, J ¼ 7.8 Hz), 7.69 (d,
4H, J ¼ 8.1 Hz), 7.86–8.11 (m, 3H); 13C-NMR (DMSO-d6, 75
MHz): 92.6, 98.3, 118.7, 129.0, 131.2, 131.4, 134.0, 135.3, 136.3,
136.8, 137.5, 138.0, 139.4, 142.1, 159.3, 164.7, 171.2 ppm; HRMS
(ESI): m/z [M + H]+ calcd for C19H9N4Br Cl2S: 476.8613; found
mass: 476.8613.
2-Amino-6-(cyclohexylsulfanyl)-4-(2,6-dichlorophenyl)pyridine-
3,5-dicarbonitrile, 5e. Pale yellow solid; mp 192–194 ꢀC; 1H-
NMR (DMSO-d6, 300 MHz): 1.47–1.68 (broad doublet, 7H),
2.00 (s, 3H), 4.46 (merged in DMSO, 1H), 7.65–8.02 (m, 5H);13C-
NMR (DMSO-d6, 75 MHz): 25.5, 25.8, 32.7, 44.9, 86.0, 93.9,
114.4, 120.7, 126.6, 129.2, 133.1, 135.1, 141.0, 145.8, 150.0,
154.2, 160.0.; HRMS (ESI): m/z [M + H]+ calcd for C19H17N4Cl2S:
403.0505; found mass: 403.0542.
Experimental
General
All the chemicals were commercially available and used as
received. Melting points were obtained using a Kumar melting
point apparatus and were uncorrected. IR spectra were obtained
1
using a Thermo Scientic Nicolet iS10 FT-IR Spectrometer. H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were obtained
using a Bruker Avance II spectrometer. High resolution mass
spectra (HRMS) were obtained using a Thermo Scientic Q-
Exactive, Accela 1250 pump, instrument.
Representative procedure for the sequential, one-pot
synthesis of 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines
2-Amino-6-(butylsulfanyl)-4-(2,6-dichlorophenyl)pyridine-
3,5-dicarbonitrile, 5f. Pale yellow solid; mp 142–144 ꢀC; 1H-NMR
(DMSO-d6, 300 MHz): 0.92 (t, 3H, J ¼ 7.2 Hz), 1.43 (s, 2H, J ¼ 7.2
Hz), 1.66 (quintet, 2H, J ¼ 7.2 Hz), 3.22 (t, 2H, J ¼ 7.2 Hz), 7.56–
7.64 (m, 3H), 8.00–8.06 (m, 2H); 13C-NMR (DMSO-d6, 75 MHz):
13.9, 21.9, 30.0, 31.1, 86.3, 114.3, 129.0, 132.2, 132.9, 133.3,
154.0, 159.9, 168.1; HRMS (ESI): m/z [M + H]+ calcd for
To a well-stirred solution of 2,6-disubstituted benzalldehyde,
malononitrile and thiol (1 : 2 : 1 mmol) in ethanol (3 mL),
diethylamine (20 mol%) was added, and stirring was continued
at ambient temperature. Upon completion of the reaction
(TLC), resultant dihydropyridine, 4, was (may be isolated and
identied) dissolved in dimethylformamide (2 mL). To the
resulting solution, Dess–Martin periodinane (1 mmol) was
added, and stirring was continued. Upon completion of oxida-
tion (TLC), water (10 mL) was added, and stirring was continued
till free owing solid separated out. Resultant solid was ltered,
washed with water, dried, washed again with chloroform, and
dried. Resultant 2-amino-3,5-dicarbonitrile-6-sulfanylpyridine,
5, was found to be pure and did not require any further
purication.
C
17H15N4Cl2S: 377.0389; found mass: 377.0387.
2-Amino-4-(2,6-dichlorophenyl)-6-(ethylsulfanyl)pyridine-
3,5-dicarbonitrile, 5g. Pale yellow solid; mp 164–166 ꢀC; 1H-
NMR (DMSO-d6, 300 MHz): 1.34 (s, 3H), 2H merged in DMSO,
7.73–7.85 (m, 3H), 7.96–8.02 (m, 2H); 13C-NMR (DMSO-d6, 75
MHz): 14.6, 24.8, 86.3, 114.3, 120.8, 126.6, 129.1, 130.5, 131.5,
132.2, 133.3, 134.7, 140.9, 160.0, 168.0 ppm; HRMS (ESI): m/z [M
+ H]+ calcd for C15H11N4Cl2S: 349.0076; found mass: 349.0074.
2-Amino-4-(2,6-dimethylphenyl)-6-(phenylsulfanyl)pyridine-
3,5-dicarbonitrile, 5h. Pale yellow solid; mp 210–212 ꢀC; 1H-
NMR (DMSO-d6, 300 MHz): 2.08 (s, 6H), 7.24 (d, 2H, J ¼ 7.5
Hz), 7.33 (t, 2H, J ¼ 7.5 Hz), 7.41 (t, 2H, J ¼ 3 Hz), 7.35–7.53 (m,
Spectral data of pyridine 3,5-dicarbonitriles, 5, is summarized
below. For the original spectra of all the products (step 1 and
step 2), please see the ESI†
2-Amino-4-(2,6-dichlorophenyl)-6-(phenylsulfanyl)pyridine- 2H); 13C-NMR (DMSO-d6, 75 MHz): 19.7, 87.9, 94.5, 114.5, 127.5,
3,5-dicarbonitrile, 5a. Off white solid; mp 190–192 ꢀC; 1H-NMR 128.1, 129.4, 129.7, 129.7, 133.7, 134.8, 135.3, 159.1, 160.0,
(DMSO-d6, 300 MHz): 7.62 (s, 2H), 7.84–7.9 (m, 5H), 8.03 (d, 3H); 167.4 ppm; HRMS (ESI): m/z [M + H]+ calcd for C21H17N4S:
13C-NMR (DMSO-d6, 75 MHz):87.9, 93.6, 114.6, 125.9, 129.0, 357.1168; found mass: 357.1167.
129.7, 130.6, 132.1, 132.5, 132.8, 133.3, 135.6, 137.0, 141.0,
2-Amino-6-[(4-bromophenyl)sulfanyl]-4-(2,6-dimethylphenyl)-
154.4, 159.9, 166.6 ppm; HRMS (ESI): m/z [M + H]+ calcd for pyridine-3,5-dicarbonitrile, 5i. Yellow solid; mp 260–262 ꢀC; 1H-
C
19H11N4Cl2S: 397.0076; found mass: 397.0073.
NMR (DMSO-d6, 300 MHz): 2.08 (s, 6H), 7.15 (d, 2H, J ¼ 7.5 Hz),
2-Amino-4-(2,6-dichlorophenyl)-6-[(4-methylphenyl)sulfanyl] 7.25 (t, 1H, J ¼ 8.4 Hz), 7.48 (d, 2H, J ¼ 8.4 Hz), 7.58 (d, 3H, J ¼
pyridine-3,5-dicarbonitrile, 5b. Light grey solid; mp 206–208 ꢀC; 8.4 Hz); HRMS (ESI): m/z [M + H]+ calcd for C21H16N4BrS:
1H-NMR (DMSO-d6, 300 MHz): 2.36, (s, 3H), 7.27–8.01 (m, 9H); 435.0274; found mass: 432.0272 [due to very poor solubility of
13C-NMR (DMSO-d6, 75 MHz): 21.4, 87.6, 93.6, 114.2, 123.6, compound in d6-DMSO/d6-acetone, 13C-NMR was not obtained].
126.7, 129.1, 130.4, 131.5, 132.1, 132.9, 133.3, 134.6, 135.4,
140.0, 141.1, 154.4, 159.9 ppm; HRMS (ESI): m/z [M + H]+ calcd pyridine-3,5-dicarbonitrile, 5j. Pale yellow solid; mp 216–218 ꢀC;
for C20H13N4Cl2S: 411.0232; found mass: 411.0230.
1H-NMR (DMSO-d6, 300 MHz): 2.06 (s, 6H), 6.97 (s, 2H), 7.1 (d,
2-Amino-6-[(4-chlorophenyl)sulfanyl]-4-(2,6-dimethylphenyl)
2-Amino-6-[(4-chlorophenyl)sulfanyl]-4-(2,6-dichlorophenyl) 2H, J ¼ 7.5 Hz), 7.21 (t, 1H, J ¼ 7.5 Hz), 7.38 (d, 2H, J ¼ 8.4 Hz),
pyridine-3,5-dicarbonitrile, 5c. Light grey solid; mp 174–178 ꢀC; 7.49 (d, 2H, J ¼ 8.7 Hz); 13C-NMR (DMSO-d6, 75 MHz): 19.7,
1H-NMR (DMSO-d6, 300 MHz): 7.55–7.57 (d, 1H, J ¼ 7.8 Hz), 114.5, 114.6, 126.5, 128.2, 129.7, 129.8, 130.4, 131.5, 133.9,
7.65–7.85 (m, 3H), 7.93–8.02 (m, 3H), 8.17 (s, 2H); 13C-NMR 134.9, 135.5, 137.0, 159.2, 160.1, 166.5 ppm; HRMS (ESI): m/z [M
(DMSO-d6, 75 MHz): 87.8, 93.3, 114.1, 114.3, 125.7, 129.4, + H]+ calcd for C21H16N4ClS: 391.0779; found mass: 391.0778.
130.0, 131.9, 133.1, 133.6, 135.6, 137.4, 154.8, 159.9, 166.8 ppm;
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87.1, 95.1, 112.3, 112.7, 114.7, 126.5, 128.2, 130.4, 132.6, 133.4,
133.6, 133.7, 134.5, 141.0, 147.1, 157.5, 157.5, 159.8, 160.7,
160.8, 167.9; HRMS (ESI): m/z [M + H]+ calcd for C19H17N4F2S:
371.1137; found mass: 371.1136.
2-Amino-6-[(4-methoxyphenyl)sulfanyl]-4-(2,6-dimethylphenyl)-
pyridine-3,5-dicarbonitrile, 5k. Pale yellow solid; mp 243–
245 ꢀC; 1H-NMR (DMSO-d6, 300 MHz): 2.08 (s, 6H), 3.82 (s, 3H),
7.06 (d, 2H, J ¼ 8.7 Hz), 7.23 (d, 2H, J ¼ 7.5 Hz), 7.32 (t, 1H, J ¼
8.4 Hz), 7.56 (d, 2H, J ¼ 8.7 Hz), 7.85 (s, 2H); 13C-NMR (DMSO-
d6, 75 MHz): 19.6, 55.9, 87.5, 114.8, 115.6, 117.4, 128.4, 129.9,
134.1, 134.9, 137.5, 159.2, 160.2, 161.1, 168.1 ppm.
Acknowledgements
Authors S. S. K. and U. V. D. are thankful to UGC, New Delhi, for
the junior research fellowship and nancial assistance [F. No.
43-221/2014 (SR)], respectively.
2-Amino-4-(2,6-dimethoxyphenyl)-6-(phenylsulfanyl)pyridine-
1
ꢀ
3,5-dicarbonitrile, 5l. Off white solid; mp 196–198 C; H-NMR
(DMSO-d6, 300 MHz): 3.78 (s, 6H), 6.81 (s, 1H), 7.5 (d, 7H),
7.85–8.00 (broad signal, 2H); HRMS (ESI): m/z [M + H]+ calcd for
C
21H17O2N4S: 389.1067; found mass: 389.1063 [due to very poor
References
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pyridine-3,5-dicarbonitrile, 5n. Off white solid; mp 194–196 ꢀC;
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3,5-dicarbonitrile, 5o. Grey solid; mp 274–276 ꢀC; 1H-NMR
(DMSO-d6, 300 MHz): 7.36 (t, 2H), 7.5 (s, 3H), 7.61–7.86 (m,
3H), 8.00 (broad singlet, 2H); 13C-NMR (DMSO-d6, 75 MHz):
88.6, 94.5, 112.7, 113.0, 114.4, 114.6, 127.2, 129.8, 130.2, 131.5,
134.2, 135.4, 147.7, 159.8, 167.0 ppm; HRMS (ESI): m/z [M + H]+
calcd for C19H11N4F2S: 365.0667; found mass: 365.0665.
2-Amino-6-[(4-chlorophenyl)sulfanyl]-4-(2,6-diuorophenyl)
pyridine-3,5-dicarbonitrile, 5p. Grey solid; mp 280–282 C; H-
NMR (DMSO-d6, 300 MHz): 7.23 (s, 2H), 7.46–7.56 (m, 4H),
7.83 (s, 2H), 8.03 (s, 1H); 13C-NMR (DMSO-d6, 75 MHz): 88.8,
94.6, 112.4, 112.7, 114.4, 125.9, 129.7, 133.8, 135.6, 137.0, 147.6,
159.8, 166.6 ppm; HRMS (ESI): m/z [M + H]+ calcd for C19H10-
N4ClF2S: 399.0277; found mass: 399.0276.
2-Amino-4-(2,6-diuorophenyl)-6-[(4-methylphenyl)sulfanyl]
pyridine-3,5-dicarbonitrile, 5q. Light grey solid; mp 196–198 ꢀC;
1H-NMR (DMSO-d6, 300 MHz): 2.37 (s, 3H), 7.28–7.34 (m, 4H),
7.48 (d, 2H, J ¼ 7.5 Hz), 7.69–7.73 (m, 1H), 7.85–8.02 (m, 2H);
13C-NMR (DMSO-d6, 75 MHz): 21.4, 88.5, 94.3, 112.7, 113.0,
114.5, 114.6, 123.5, 130.6, 131.5, 135.5, 140.14, 147.6, 159.8,
167.4 ppm; HRMS (ESI): m/z [M + H]+ calcd for C20H13N4F2S:
379.0823; found mass: 379.0820.
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1
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Frijtag
Drabbe
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T.
Mulder
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38882 | RSC Adv., 2017, 7, 38877–38883
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