K2CO3-Mediated, One-Pot, Multicomponent Synthesis of Medicinally Potent Pyridine and Chromeno[2,3-b]pyridine Scaffolds

Article abstract of DOI:10.1080/00397911.2011.555284

An efficient one-pot, multicomponent synthesis of 3,5-dicyanopyridines has been developed from the reaction of malononitrile and different thiophenol or thiols with a variety of aldehydes (aromatic including hindered ones, heteroaromatic, and aliphatic) i

Full text of DOI:10.1080/00397911.2011.555284

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K2CO3-Mediated, One-Pot,
Multicomponent Synthesis of Medicinally
Potent Pyridine and Chromeno[2,3-
b]pyridine Scaffolds
Sarita Mishra a & Rina Ghosh a
a Department of Chemistry, Jadavpur University, Kolkata, India
Available online: 15 Dec 2011
To cite this article: Sarita Mishra & Rina Ghosh (2012): K2CO3-Mediated, One-Pot, Multicomponent
Synthesis of Medicinally Potent Pyridine and Chromeno[2,3-b]pyridine Scaffolds, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 42: 2229–2244, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.555284
K2CO3-MEDIATED, ONE-POT, MULTICOMPONENT
SYNTHESIS OF MEDICINALLY POTENT PYRIDINE
AND CHROMENO[2,3-b]PYRIDINE SCAFFOLDS
Sarita Mishra and Rina Ghosh
Department of Chemistry, Jadavpur University, Kolkata, India
GRAPHICAL ABSTRACT
Abstract An efficient one-pot, multicomponent synthesis of 3,5-dicyanopyridines has been
developed from the reaction of malononitrile and different thiophenol or thiols with a variety
of aldehydes (aromatic including hindered ones, heteroaromatic, and aliphatic) in the pres-
ence of 20 mol% of K2CO3 in refluxing 50% aqeuous ethanol. KMnO4 has been utilized as a
readily available, inexpensive oxidant for the in situ transformation of the initially formed
dihydropyridine intermediate. K2CO3 also mediates the one-pot formation of chrome-
no[2,3-b]pyridines from reaction of salicylaldehyde or its analogs with malononitrile and
thiol or thiophenols. Both of these conditions also work equally well under 50-fold scale-up
conditions.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Chromeno[2,3-b]pyridines; 3,5-dicyanopyridines; K2CO3; one-pot multicom-
ponent synthesis
Received November 25, 2010.
Address correspondence to Rina Ghosh, Department of Chemistry, Jadavpur University, Kolkata
700 032, India. E-mail: ghoshrina@yahoo.com; ghosh_rina@hotmail.com
2229

2230
S. MISHRA AND R. GHOSH
INTRODUCTION
Compounds having basic pyridine skeletons are medicinally potent hetero-
cycles. Among these, 2-amino-3,5-dicyanopyridines of general structure P (Fig. 1)
are of particular importance as these exhibit several biological activities such as anti-
bacterial,[1] anticancer,[2] anti–hepatitis B viral,[3] antiprion,[4] and potassium channel
opening (for treatment of urinary incontence)[5] activities. Moreover, some act as
[6a,b]
[6c]
adenosine A1
and A2B receptor binding ligands. It is worth mentioning here
that adenosine receptors have been attractive targets for drug development, parti-
cularly for treatment of Parkinson disease, asthma, hypoxia=ischemia, epilepsy,
cancer, and kidney diseases.[6a,c] Introduction of diverse functionalities on such
framework may generate compound libraries, which are capable of binding at differ-
ent receptor sites; thus, these compounds could be considered as medicinal leads for
drug development.
Several multistep procedures on the synthesis of 3,5-dicyanopyridines were
reported,[7] which have disadvantages in terms of yield, energy, time, use of toxic
reagents, and generality. Because of many advantages such as atom economy, green
conditions, procedural simplicity, and cost-effectiveness over conventional multistep
synthesis, one-pot multicomponent reactions have gained much attention, parti-
cularly for heterocyclic library compounds.[8] They are thus attractive alternatives
for rapid diversified assembly of medicinally privileged pyridine scaffolds. After the
first one-pot synthesis of 3,5-dicyanopyridines using Et3N or 1,4-diazabicyclo[2.2.2]-
octane (DABCO) as catalyst,[9] which afforded poor yields of products, other
one-pot syntheses based on organic bases (Et3N and pyridine),[10] ionic bases
(bmImOH[11] and Bu4NOH[12]), SiO2 nanoparticles,[13] Lewis acid (ZnCl2),[14] 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU),[15] and very recently cetyl triethylammonium
bromide (CTAB)–boric acid[16] have also been reported, each having its own merits
and demerits. Some are excellent in some substrates but give poor yields of products
with other substrates, or some have used toxic chemicals.[17] Astonishingly, when we
started our work, none of the then-reported[9–14] one-pot procedures exploited aque-
ous conditions for these one-pot syntheses. Thus, we thought to start our investi-
gation on one-pot syntheses of pyridine scaffolds in aqueous solvents using
inexpensive, nontoxic inorganic bases. In this article, we report an efficient, one-pot,
multicomponent synthesis of 3,5-dicyanopyridines from reactions of malanonitrile
and thiols with a variety of aldehydes using inexpensive K2CO3 as base catalyst
and KMnO4 as added oxidant in refluxing 50% aqueous ethanol (Scheme 1).
Figure 1. 3,5-Dicyanopyridine.

K2CO3-MEDIATED, ONE-POT SYNTHESIS
2231
Scheme 1. One-pot synthesis of 3,5-dicyanopyridines.
RESULTS AND DISCUSSION
At the outset, the choice of catalyst was made from a couple of reactions of a
mixture of benzaldehyde, malononitrile, and thiophenol (1:2:1) in refluxing aqueous
ethanol in the presence of different bases such as basic Al2O3, CaO, KOH, Na2CO3,
NaOH, and K2CO3 (entries 1–12, Table 1); use of 20 mol% K2CO3 in aqueous etha-
nol (1:1) furnished the best result (entry 10, Table 1). Although the reaction based on
benzaldehyde, malononitrile, and thiophenol (2:3:1) furnished the corresponding
pyridine derivative in excellent yield (92% based on PhSH, entry 12, Table 1), syn-
thesis of pyridines derived from expensive aldehyde is not cost-effective, as it
demands the use of extra equivalents of aldehyde. To improve the yield of the pro-
duct from condensation of benzaldehyde, malononitrile, and thiophenol (1:2:1),
fresh sets of reactions were conducted in the presence of different oxidants (entries
1–8, Table 2). Thus, under the optimized condition, a mixture of benzaldehyde, mal-
ononitrile, and thiophenol (1:2:1) in the presence of 20 mol% of K2CO3 was refluxed
in 50% aqueous ethanol followed by addition of KMnO4 (1 M, 1.1 equiv) as an oxi-
dant after 30 min of reaction (at this time, a solid again started appearing after its
initial disappearance from the reaction mixture; appearance of the solid in the reac-
tion mixture for the second time could thus also be considered for the time of the
Table 1. Choice of catalyst and optimization of catalyst load
Entry
Base (20 mol%)
EtOH–H2O
Time (h)
Yielda (%)
1
2
Morpholine
Al2O3
CaO
1–1
1–1
1–1
1–1
1–1
1–1
1–2
0–1
1–1
1–1
1–1
1–1
2.0
2.0
1.5
1.5
1.5
1.5
2.0
4.0
1.5
1.0
1.0
1
46
41
49
31
39
38
62
21
56
68
68
92d
3
4
NaOH
Na2CO3
KOH
5
6
7
K2CO3
K2CO3
K2CO3
8
b
9
10
11
12
K2CO3
K2CO3
K2CO3
c
aReactions based on benzaldehyde–malanonitrile–thiophenol 1:2:1 (unless mentioned otherwise).
bUse of 10 mol%.
cUse of 30 mol%.
dReaction based on benzaldehyde–malanonitrile–thiophenol 2:3:1; yield based on PhSH.

2232
S. MISHRA AND R. GHOSH
Table 2. Choice of the oxidant and standardization of the reaction condition
Entry
Added oxidant
Time of addition of the oxidant
Yielda (%)
1
2
3
4
5
6
7
8
Bubbled air
Full reaction time
After 30 min
After 30 min
After 20 min
After 30 min
After 45 min
After 30 min
After 30 min
70
77
76
71
80
76
70
60
1 M KMnO4 (2 equiv)
1 M KMnO4 (1.5 equiv)
1 M KMnO4 (1.1 equiv)
1 M KMnO4 (1.1 equiv)
1 M KMnO4 (1.1 equiv)
NaClO2 (1 equiv)
DDQ (1 equiv)
aReactions based on benzaldehyde–malanonitrile–thiophenol 1:2:1 using 20 mol % K2CO3 in EtOH–
H2O (1:1) with added oxidant.
addition of the oxidant), which produced 2-amino-3,5-dicyano-4-phenyl-5-thiophe-
nylpyridine (P1, entry 5, Table 2, and entry 1, Table 3) in 80% yield. It is also worth
mentioning here that the time of addition of KMnO4 to the reaction mixture is cru-
cial, as evidenced from entries 4–6, in Table 2. Under standard protocol, other aro-
matic aldehydes with substituents on the phenyl ring having þR effect (entries 2–9,
Table 3) and related substituents having–R effect (entries 10 and 11, Table 3) also
efficiently reacted with malononitrile and thiophenol, yielding the corresponding
densely functionalized pyridines in very good yields. Various other thiophenols
(entries 12–20, Table 3) and thiols (entries 21 and 22) were also used to react with
aromatic aldehydes and malononitrile under similar conditions. In general, reactions
from thiophenols were more productive than those from thiols; this could be due to
the better acidity of ArSH under the reaction condition. The generality of the present
synthesis was further established from similar synthesis of pyridine scaffolds using
heterocyclic aldehydes. Thus, thiophene-2-carboxaldehyde (entries 23–25) or pyri-
dine 3-carboxaldehyde (entry 26) reacted with malononitrile and different thiophe-
nols, affording the corresponding pyridine derivatives in good yields. It is
interesting to note that the presence of 4-Cl=3-OH=4-OH on the phenyl ring of
the starting aldehyde enhances the anticancer activity of functionalized pyridine pro-
duct;[2c] whereas products derived from 2-hydroxy-ethanethiol and aromatic alde-
hydes have affinity for human adenosine A2B receptor.[6b] In general, substitution
in the 3-position caused more effective binding than substitution in the 4-position
of the phenyl ring. The present methodology was also exploited for generation of
substituted pyridine in good yield from an aliphatic aldehyde such as octanal (entry
27, Table 3) in reaction with malononitrile and thiophenol. To check the efficacy of
the present procedure, hindered aldehyde 2,6-dichlorobenzaldehyde was allowed to
react with malononitrile and different thiophenols (entries 28 and 29, Table 3),
but excess KMnO4 (2.0 equiv.) was necessary for producing the corresponding sub-
stituted pyridines in excellent yield (84–90%, entries 28 and 29, Table 3). In both of
these cases, the reactions required more time for completion in comparison to other
reactions. The efficiency of the present procedure was further established when the
reaction of a mixture of benzaldehyde, malononitrile, and thiophenol was scaled
up (50-fold), which afforded the corresponding product in good yield (84%, entry 1,
in parentheses, Table 3).

K2CO3-MEDIATED, ONE-POT SYNTHESIS
2233
Table 3. One-pot preparation of 3,5-dicyanopyridines
Crystallized yield
(%)a=mp (ꢀC)
Entry
R
R0
Product
Time (x þ y) min
80 (84)b=218–220
87=243–245
85=227–229
81=238–240
76=317–319
76=262–264
81=222–224
87=223–225
87=256–258
85=272–273
70=221–223
78=230–232
85=284–286
80=340–342
82=261–263
84=237–239
89=249–251
81=308–310
80=228–230
88=284–286
60=226–228
61=167–169
[11b,16]
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
P1
(30 þ 30)
(30 þ 40)
(35 þ 40)
(35 þ 40)
(30 þ 30)
(30 þ 45)
(25 þ 25)
(30 þ 30)
(30 þ 30)
(15 þ 25)
(25 þ 25)
(30 þ 30)
(35 þ 25)
(25 þ 25)
(30 þ 40)
(30 þ 45)
(30 þ 40)
(20 þ 40)
(25 þ 35)
(30 þ 40)
(40 þ 50)
(35 þ 40)
[11b,18]
[11b,16]
[11b]
4-OMe-Ph
3,4-OMe-Ph
3,4,5-OMe-Ph
4-OH-Ph
3-OH-Ph
4-Cl-Ph
P2
P3
P4
P5
P6
P7
P8
P9
3
4
[11b,17]
5
6
[11b,18]
[12,16]
[17]
7
8
4-F-Ph
4-Br-Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-CN-Ph
3-NO2-Ph
Ph
P10
P11
P12
P13
P14
P15
P16
P17
P18
P19
P20
P21
P22
[17]
[13]
4-Cl-Ph
4-Cl-Ph
4-OH-Ph
4-CN-Ph
3,4-OMe-Ph
Ph
4-Cl-Ph
4-Cl-Ph
[17]
[17]
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-NH2-Ph
HO-(CH2)2-
HO-(CH2)2-
4-Cl-Ph
4-CN-Ph
3,4-OMe-Ph
3,4-OMe-Ph
4-OH-Ph
4-Cl-Ph
[11b]
[8b]
[11b,15]
[11b,16]
23
24
25
Ph
P23
(30 þ 30)
(20 þ 50)
(30 þ 45)
88=208–210
80 =230–232
81=196–198
[6b,12]
4-Cl-Ph
4-Me-Ph
P24
P25
[11b,15]
26
27
Ph
Ph
P26
(30 þ 30)
(30 þ 60)
79=305–307
CH3(CH2)6
P27
80=136–138
(Continued )

2234
S. MISHRA AND R. GHOSH
Table 3. Continued
Crystallized yield
(%)a=mp (ꢀC)
Entry
R
R0
Product
Time (x þ y) min
90c=212–214
84c=216–218
[11b,13]
28
29
2,6-(Cl)2-Ph
2,6-(Cl)2-Ph
Ph
4-Cl-Ph
P28
P29
(40 þ 140)
(40 þ 140)
aYield based on aldehyde–malanonitrile–mercaptan 1:2:1.
bUnder scale-up (50-fold) condition.
cUsing 2.0 equiv. of KMnO4.
The mechanism of K2CO3-mediated, one-pot synthesis of substituted pyridine is
supposed to follow a base-catalyzed pathway as proposed earlier12 (Scheme 2). The
reaction is initiated by K2CO3-mediated Knovenagel condensation of aldehyde and
malononitrile, generating intermediate I1 (proved by its isolation from an incomplete
reaction mixture), which reacts with another molecule of malononitrile producing the
corresponding dihydropyridine intermediate I2 [evidenced from LC-MS, m=z
(MþNaþ) 352.97]. This is finally oxidized to the 3,5-dicyanopyridine (P1). H transfer
from the dihydropyridine intermediate (I2) to the Knovenagel intermediate (I1) may be
correlated with the similar H transfer in NAD (nicotinamide adenine dinucleotide—
oxidized form) to NADH (nicotinamide adenine dinucleotide—reduced form) trans-
formation.[18] This step causes the involvement of an extra equivalent of aldehyde
and malononitrile, for the reaction done without the use of added KMnO4, to get a
good yield of the product (comparison of entries 10 and 12, Table 1).
Scheme 2. Probable mechanistic pathway for the formation of 3,5-dicyanopyridine.

K2CO3-MEDIATED, ONE-POT SYNTHESIS
2235
Figure 2. Some medicinally important compounds having the chromeno[2,3-b]pyridine skeleton.
Chromeno[2,3-b]pyridines show a wide variety of biological activities such as
antimyopic,[19] antihistaminic,[20] hypotensive,[21] antirheumatic,[22] antiasthmatic,[23]
and antibacterial (including antitubercular)[24] activities. Some of these are inhibitors
of protein kinase,[25] and some also inhibit histamine-stimulated gastric acid secretion
in animals.[26] Mention may be made of amlexanox and prosnoprofen (Fig. 2) having
the chromeno[2,3-b]pyridine framework, which are two established therapeutic drugs;
some others having this skeleton exhibit gastric antisecretary properties (Fig. 2).
Although several reports have been made on the multistep synthesis of chrome-
no[2,3-b]pyridines,[27] because of some disadvantages of such conventional multistep
procedures, exploration of one-pot multicomponent synthesis of these compounds is
an attractive alternative for the preparation of medicinally potent leads having such a
skeleton. Astonishingly, in spite of a few earlier reports of the one-pot syntheses of
3,5-dicyanopyridines,[9–16] to the best of our knowledge no other reports except those
made by Evdokimov et al.[9b,28] have included one-pot syntheses of medicinally potent
compounds having the chromeno[2,3-b]pyridine molecular framework. K2CO3
(20 mol%) has also been found to catalyze efficiently the one-pot synthesis of chrome-
no[2,3-b]pyridines (C1–C11) from reaction of salicylaldehyde or its derivatives or
2-hydroxynaphthylaldehyde with a variety of thiophenol and malononitrile in reflux-
ing aqueous ethanol, and the results are summarized in Scheme 3 and Tables 4 and 5.
K2CO3 (20 Mol%) was used for the synthesis of chromeno[2,3-b]pyridine (C1)
from a reaction under reflux in 50% aqueous ethanol of a mixture of salicylaldehyde,
malononitrile, and thiophenol (1:2:1), which furnished excellent yield of C1(92%,
entry 1, Table 4). A comparison of this result with those done with the previous
mixture of ingredients but in the presence of other catalysts such as Bu4NOH,[11]
Scheme 3. K2CO3-catalyzed one-pot synthesis of chromeno[2,3-b]pyridines.

2236
S. MISHRA AND R. GHOSH
Table 4. Synthesis of chromeno[2,3-b]pyridine: Comparison based on different catalysts
Entry
Catalyst
Time (h)
Yielda of C1%
1
2
K2CO3
3
4
92
52
Bu4NOH
bmImOH
CTAB-H3BO3
DBU
3
3
47
4
4
27b
47
5
4
6
ZnCl2
FeCl3
4
nilc
45c
61
7
6
8
Pyridine
Morpholine
Et3N9b
4
9
3.5
4
72
10
11
12
86c
50
Basic Al2O3
CaO
4
4
76
aFrom a reaction of a mixture of aldehyde–malononitrile–thiophenol 1:2:1 in the presence of 20 mol% of
the catalyst in refluxing 50% aqueous ethanol (until stated otherwise).
bReaction in water.
cReaction in EtOH.
bmImOH,[12] CTAB–H3BO3,[16] DBU,[15] ZnCl2,[14] and Et3N,[9a,b] (entries 2–6 and
10, Table 4, which catalyze one-pot synthesis of 3,5-dicyanopyridines), along with
a variety of other catalysts such as FeCl3, pyridine, morpholine, basic Al2O3 and
CaO (entries 7–9, 11, and 12, Table 4) reveals that K2CO3 is the catalyst of choice
for one-pot synthesis of chromeno[2,3-b]pyridine. Under similar conditions, salicy-
laldehyde (entries 2 and 3, Table 5) and its derivatives with electron-withdrawing
Table 5. K2CO3 catalyzed one-pot synthesis of chromeno[2,3-b]pyridines
Entry
Aldehyde
R0
Product
Time (h)
Yield (%)a=mp (ꢀC)
92 (93)b=220–222
67=226–228
63=223–225
78=216–218
70=208–210
65=218–219
68=252–254
60=212–213
70=181–183
73=222–224
78=235–236
[9b]
1
2
Salicyaldehyde
Salicyaldehyde
Salicyaldehyde
Ph
C1
3
3.5
2.5
3.5
3.5
3
4-Cl-Ph
4-Me-Ph
Ph
C2
C3
C4
C5
C6
3
4
5-NO2-salicyaldehyde
5-NO2-salicyaldehyde
5-NO2-salicyaldehyde
3-OMe-salicyaldehyde
3-OMe-salicyaldehyde
5-Cl-salicyaldehyde
2-OH-naphthaldehyde
2-OH-naphthaldehyde
5
4-Cl-Ph
4-Me-Ph
Ph
6
[9b]
7
C7
C8
3.5
3
8
4-Me-Ph
Ph
Ph
9
C9
4
10
11
C10
C11
3
4-Me-Ph
3
aIsolated yield based on starting aldehyde.
bUnder scale-up (50-fold) condition.

K2CO3-MEDIATED, ONE-POT SYNTHESIS
2237
(entries 4–6, Table 5) or electron-releasing groups (entries 7–9, Table 5) on the
phenyl ring, and also 2-hydroxynaphthaldehyde (entries 10 and 11, Table 5), reacted
fruitfully with malononitrile and thiophenol or its derivatives, producing the corre-
sponding chromeno[2,3-b]pyridines (C2–C11) in good yields. The reaction of salicy-
laldehyde with malononitrile and thiophenol under 50-fold scale-up condition also
proceeded equally well, generating the corresponding chromenopyridine (C1) in
excellent yield (93%, entry 1, in parentheses, Table 5).
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded respectively on 300-MHz and
75-MHz NMR Bruker spectrometers in dimethylsulfoxide (DMSO-d6) and in some
cases in a mixture of DMSO-d6 and CDCl3. High-resolution mass spectroscopic
(HRMS) data were recorded on a Q-tof-Micro mass spectrometer by the electron
spray ionization (ESI) method. Infrared (IR) spectra were run on a Fourier trans-
form (FT-IR) spectrometer.
General Procedure for Synthesis of 3,5-Dicyanopyridines (P)
K2CO3 (0.2 equiv) was added to a solution of aldehyde (1 equiv), malononitrile
(2 equiv), and thiol (1 equiv) in 50% aqueous ethanol (3 ml). The reaction mixture was
refluxed untill the appearance of the solid. Then 1 M aqueous KMnO4 (1.1 equiv) was
added to the reaction mixture, and the mixture was refluxed further until completion
(Table 2). The resulting solid was filtered and washed with water (2 ꢁ 2 ml). To
remove MnO2 (by-product) from the residue, the product was dissolved in hot
MeOH, and undissolved MnO2 was filtered off. The residue was washed with hot
MeOH (2 ꢁ 2 ml), and the combined filtrate and washings were concentrated to
crystallize out the pure products (P1–P29).
2-Amino-4-(3-hydroxyphenyl)-6-(phenylsulfanyl)-3,5-pyridinedicarboni-
trile (p6). Yield 76%, pale yellow solid, mp 262–264 ꢀC (MeOH). 1H NMR
(300 MHz, DMSO-d6) d (ppm): 6.86–6.95 (m, 3H), 7.32–7.76 (m, 8H), 9.87 (s,
1H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 166.6, 160.2, 159.1, 157.9, 135.6,
135.3, 130.5, 130.1, 129.9, 127.7, 119.4, 117.8, 115.7, 115.6, 115.5, 93.8, 87.5. HRMS
m=z (ESI) calc. for C19H12N4OSNa [M þ Na]þ: 367.0630. Found: 367.0634. IR
(KBr): v 3458, 3314, 3211, 2210, 1620, 1549, 1508, 1462, 1261, 1078, 1011 cmꢂ1
.
2-Amino-4-(4-cyanophenyl)-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile
(p10). Yield 85%, white crystal, mp 272–273 ꢀC (MeOH). 1H NMR (300 MHz,
CDCl3þDMSO-d6) d (ppm): 7.53-7.54 (m, 7H), 7.75 (d, J 7.8 Hz, 2H), 8.01 (d, J
7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3 þDMSO-d6) d (ppm): 171.6, 164.1, 160.9,
142.7, 139.4, 137.0, 134.0, 133.9, 133.7, 131.6, 122.3, 119.1, 119.0, 118.2, 97.7, 91.2.
HRMS m=z (ESI) calc. for C20H12N5S [M þ Hþ]: 354.0813. Found: 354.0806. IR
(KBr) 3606, 3532, 3390, 3227, 3223, 2215, 1649, 1544, 1421, 1263, 1022 cmꢂ1
.
2-Amino-4-(4-hydroxyphenyl)-6-(4-chlorophenylsulfanyl)-3,5-pyridine-
1
dicarbonitrile (p13). Yield 85%, white crystal, mp 284–286 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 6.90–6.94 (m, 2H), 7.37–7.40 (m, 2H), 7.51–7.60

2238
S. MISHRA AND R. GHOSH
(m, 4H), 7.75 (br s, 2H), 10.1 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 165.6,
159.7, 159.4, 158.5, 136.6, 134.6, 130.2, 129.9, 129.8, 129.3, 129.1, 128.7, 126.1, 124.0,
115.5, 115.3, 115.2, 115.1, 93.1, 86.8. HRMS m=z (ESI) calc. for C19H11ClN4OSNa
[M þ Na]þ: 401.0240. Found: 401.0243. IR (KBr) 3476, 3337, 3219, 2220, 1640,
1613, 1549, 1510, 1474, 1416, 1287, 1263, 1233, 1179, 1090, 1010 cmꢂ1
.
2-Amino-4-(4-cyanophenyl)-6-(4-chlorophenylsulfanyl)-3,5-pyridinedi-
1
carbonitrile (p14). Yield 80%, yellow solid, mp 340–342 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 7.53–7.61 (m, 4H), 7.77 (d, J 8.0 Hz, 2H), 7.96 (br
s, 2H), 8.06-8.08 (d, J 7.9 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) d (ppm):
165.7, 159.4, 157.0, 138.4, 136.6, 134.8, 132.6, 129.5, 129.4, 125.8, 118.0, 114.8,
114.5, 113.1, 92.3, 86.9. HRMS m=z (ESI) calc. for C20H10ClN5SNa [M þNa]þ:
410.0243. Found: 410.0247. IR (KBr) 3426, 3340, 3240, 2214, 1651, 1549, 1471,
1258, 1089, 1035, 1011 cmꢂ1
.
2-Amino-4-(3,4-dimethoxyphenyl)-6-(4-chlorophenylsulfanyl)-3,5-pyri-
1
dinedicarbonitrile (p15). Yield 82%, white crystal, mp 261–263 ꢀC (MeOH). H
NMR (300 MHz, DMSO-d6) d (ppm): 3.82 (d, J 13.3 Hz, 6H), 7.13–7.20 (m, 3H),
7.53–7.62 (m, 4H), 7.79 (br s, 2H). 13C NMR (75 MHz, DMSO-d6) d (ppm):
166.3, 160.3, 158.9, 151.1, 148.9, 137.3, 135.3, 130.0, 126.7, 126.3, 122.2, 116.1,
115.9, 112.9, 112.1, 93.9, 87.7, 56.3, 56.2. HRMS m=z (ESI) calc. for
C21H15ClN4O2SNa [M þ Na]þ: 445.0502. Found: 445.0503. IR (KBr) 3414, 3331,
3231, 2214, 1639, 1551, 1526, 1250 cmꢂ1
.
2-Amino-4-(4-cyanophenyl)-6-(4-methylphenylsulfanyl)-3,5-pyridinedi-
1
carbonitrile (p18). Yield 81%, white crystal, mp 308–310 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 2.36 (s, 3H), 7.30 (d, J 7.8 Hz, 2H), 7.46 (d, J
7.9 Hz, 2H), 7.78 (d, J 8.1 Hz, 2H), 7.89 (br s, 2H), 8.07 (d, J 8.1 Hz, 2H). 13C
NMR (75 MHz, DMSO-d6) d (ppm): 160.4, 153.2, 150.7, 133.4, 132.3, 128.7,
126.5, 123.9, 123.4, 117.1, 111.9, 108.7, 108.4, 106.9, 86.6, 80.6, 14.7. HRMS m=z
(ESI) calc. for C21H13N5SNa [M þ Na]þ: 390.0789. Found: 390.0792. IR (KBr)
3402, 3323, 3229, 2218, 1639, 1544, 1319, 1260, 1017 cmꢂ1
.
2-Amino-4-(3,4-dimethoxyphenyl)-6-(4-methylphenylsulfanyl)-3,5-pyri-
1
dinedicarbonitrile (p19). Yield 80%, white crystal, mp 228–230 ꢀC (MeOH). H
NMR (300 MHz, DMSO-d6) d (ppm): 2.35 (s, 3H), 3.81 (d, J 12 Hz, 6H),
7.12–7.19 (m, 3H), 7.29 (d, J 7.9 Hz, 2H), 7.46 (d, J 7.9 Hz, 2H), 7.71 (br s,
2H).13C NMR (75 MHz, DMSO-d6) d (ppm): 171.7, 164.9, 163.4, 155.6, 153.5,
144.6, 140.1, 135.2, 130.9, 128.7, 126.7, 120.7, 120.5, 117.5, 116.7, 98.4, 92.0, 60.8,
60.7, 26.2. HRMS m=z (ESI) calc. for C22H17N4O2S [M þ H]þ: 403.1229. Found:
403.1222. IR (KBr) 3637, 3524, 3363, 3179, 2210, 1655, 1515, 1460, 1308, 1258,
1143, 1020 cmꢂ1
.
2-Amino-4-(thiophen-2-yl)-6-(4-methylphenylsulfanyl)-3,5-pyridinedi-
1
carbonitrile (p25). Yield 81%, yellow crystal, mp 196–198 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 2.35 (s, 3H), 7.28 (d, J 7.1 Hz, 3H), 7.46 (d, J
7.6 Hz, 2H), 7.56 (s, 1H), 7.80 (br s, 2H), 7.94 (d, J 4.7 Hz, 1H).13C NMR
(75 MHz, DMSO-d6) d (ppm): 167.0, 159.7, 150.7, 139.5, 134.9, 132.6, 131.2,
130.7, 130.0, 127.8, 123.3, 115.3, 115.1, 92.9, 86.6, 20.8. HRMS m=z (ESI) calc.

K2CO3-MEDIATED, ONE-POT SYNTHESIS
2239
for C18H13N4S2 [M þ H]þ: 349.0582. Found: 349.0586. IR (KBr) 3433, 3346, 2211,
1639, 1543, 1507, 1259, 1010 cmꢂ1
.
2-Amino-4-(n-heptyl)-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile (p27).
Yield 80%, pale yellow crystal, mp 136–138 ꢀC (MeOH). 1H NMR (300 MHz,
DMSO-d6) d (ppm): 0.82–0.85 (m, 3H), 1.25–1.31 (m, 8H), 1.58 (d, J 6.6 Hz, 2H),
2.69–2.74 (m, 2H), 7.45–7.47 (m, 4H), 7.53–7.56 (m, 1H), 7.67 (br s, 2H). 13C
NMR (75 MHz, DMSO-d6) d (ppm): 165.8, 161.2, 159.6, 134.7, 129.5, 129.4,
127.2, 114.9, 114.6, 93.4, 87.0, 33.2, 30.96, 28.8, 28.6, 28.1, 22.0, 13.9. HRMS m=z
(ESI) calc. for C20H23N4S [M þ H]þ: 351.1643. Found: 351.1641. IR (KBr) 3493,
3378, 2918, 2852, 2211, 1609, 1558, 1529, 1466, 1418, 1329, 1265, 1018 cmꢂ1
.
2-Amino-4-(2,6-dichlorophenyl)-6-(4-chlorophenylsulfanyl)-3,5-pyridi-
nedicarbonitrile (p29). Yield 84%, pale yellow crystal, mp 216–218 ꢀC (MeOH).
1H NMR (300 MHz, DMSO-d6) d (ppm): 7.55 (d, J 8.3 Hz, 2H), 7.60–7.70 (m,
3H), 7.74 (d, J 8.0 Hz, 2H), 8.16 (br s, 2H). 13C NMR (75 MHz, DMSO-d6) d
(ppm): 166.8, 159.9, 154.8, 137.4, 135.6, 133.5, 133.1, 131.9, 130.0, 129.4, 125.8,
114.3, 114.1, 93.3, 87.8. HRMS m=z (ESI) calc. for C19H9Cl3N4SNa [M þ Na]þ:
452.9511. Found: 452.9519. IR (KBr) 3642, 3392, 3216, 2218, 1651, 1554, 1476,
1428, 1260, 1093, 1012 cmꢂ1
.
General Procedure for Synthesis of Chromeno[2,3-b]pyridines (C)
K2CO3 (0.2 equiv) was added to a solution of selected salicyaldehyde (1 equiv),
malononitrile (1 equiv), and desired thiophenol or thiol (1 equiv) in 50% aqueous
ethanol (4 ml) at room temperature, and the resulting mixture was refluxed. After
30 min another equivalent of malononitrile was added, and the reaction was contin-
ued under reflux untill completion (Table 4). The reaction mixture was then cooled,
and the solid was filtered and washed well with water. The residue was dissolved in
dimethylformaide (DMF), (2 ml), the undissolved part in DMF was filtered off, and
water (3 ml) was added to the filtrate. The resulting precipitate was filtered and dried
well under vacuum pump, which was almost pure. In some cases, it was further
recrystallized from hot MeOH.
2,4-Diamino-5-(4-chlorophenylsulfanyl)-5H-chromeno[2,3-b]pyridine-3-
1
carbonitrile (C2). Yield 67%, yellow crystal, mp 226–228 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 5.76 (s, 1H), 6.50 (s, 2H), 6.70–6.73 (m, 2H), 6.82
(d, J 7.9 Hz, 2H), 6.95 (s, 2H), 7.10–7.21 (m, 3H), 7.36–7.48 (m, 1H). 13C NMR
(75 MHz, DMSO-d6) d (ppm): 159.9, 159.7, 156.4, 150.9, 137.7, 134.2, 129.7,
129.5, 129.2, 128.64, 128.60, 128.3, 123.9, 121.5, 116.5, 115.8, 86.0, 70.4, 43.1.
HRMS m=z (ESI) calc. for C19H14ClN4OS [M þ H]þ: 381.0577. Found: 381.0576.
IR (KBr): 3343, 3199, 2205, 1582, 1473, 1404, 1320, 1261, 1230, 1154 cmꢂ1
.
2,4-Diamino-5-(4-methylphenylsulfanyl)-5H-chromeno[2,3-b]pyridine-3-
1
carbonitrile (C3). Yield: 63%, yellow solid, mp 220–222 ꢀC. H NMR (300 MHz,
DMSO-d6) d (ppm): 2.20 (s, 3H), 5.67 (s, 1H), 6.45 (br s, 2H), 6.63 (d, J 7.8 Hz,
2H), 6.79 (d, J 7.9 Hz, 1H), 6.90 (s, 4H), 7.09 (d, J 6.8 Hz, 1H), 7.17 (d, J 7.3 Hz,
2H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 159.7, 159.5, 156.3, 150.8, 138.3,
135.9, 128.8, 128.6, 128.2, 127.0, 123.6, 121.8, 116.4, 115.7, 86.3, 70.3, 42.6, 20.6.

2240
S. MISHRA AND R. GHOSH
IR (KBr): n 3461, 3354, 2371, 2202, 1624, 1594, 1566, 1480, 1403,1259 cmꢂ1. HRMS
ESI [M þ H]þ calcd. for C20H17N4OS 361.1123; found 361.1131.
2,4-Diamino-7-nitro-5-(phenylsulfanyl)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (C4). Yield 78%, yellow solid, mp 216–218 ꢀC (MeOH). 1H NMR
(300 MHz, DMSO-d6) d (ppm): 5.07 (d, J 3.5 Hz, 1H), 6.86 (s, 2H), 7.25-7.29 (m,
3H), 7.54 (s, 5H), 7.78 (s, 1H), 8.14 (m, 1H). 13C NMR (75 MHz, DMSO-d6) d
(ppm): 159.5, 153.2, 152.9, 143.7, 136.6, 133.3, 133.2, 129.6, 129.4, 124.3, 124.2,
122.8, 119.3, 118.3, 117.6, 85.0, 53.7, 36.3. HRMS m=z (ESI) calc. for C19H14N5O3S
[M þ H]þ: 392.0817. Found: 392.0819. IR (KBr): 3480, 3376, 3208, 2370, 2191, 1655,
1545, 1523, 1477, 1409, 1343, 1258 cmꢂ1
.
2,4-Diamino-7-nitro-5-(4-chlorophenylsulfanyl)-5H-chromeno[2,3-b]pyri-
dine-3-carbonitrile (C5). Yield 70%, yellow solid, mp 208–210 ꢀC (MeOH). 1H
NMR (300 MHz, DMSO-d6) d (ppm): 5.06 (s, 1H), 6.85 (br s, 2H), 7.24–7.28 (m,
3H), 7.52 (m, 4H), 7.76 (d, J 1.9 Hz, 1H), 8.13 (dd, J 2.3 Hz, 9.0 Hz, 1H). 13C
NMR (75 MHz, DMSO-d6) d (ppm): 159.5, 153.2, 152.9, 143.7, 133.3, 133.2,
132.0, 129.6, 129.4, 129.3, 124.3, 124.2, 122.7, 119.3, 118.3, 117.6, 85.0, 53.7, 36.3.
HRMS m=z (ESI) calc. for C19H12ClN5O3SNa [M þ Na]þ: 448.0247. Found:
448.0248. IR (KBr): 3482, 3374, 3206, 2207, 1659, 1578, 1545, 1474, 1410, 1343,
1256 cmꢂ1
.
2,4-Diamino-7-nitro-5-(4-methylphenylsulfanyl)-5H-chromeno[2,3-b]pyri-
dine-3-carbonitrile (C6). Yield 65%, yellow solid, mp 218–219 ꢀC (MeOH). 1H
NMR (300 MHz, DMSO-d6) d (ppm): 2.32 (s, 3H), 5.06 (s, 1H), 6.60 (s, 2H),
7.21–7.27 (m, 5H), 7.46 (d, J 8.0 Hz, 2H), 7.76 (d, J 2.1 Hz, 1H), 8.12 (dd, J 2.6 Hz,
9.0 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 160.1, 155.3, 153.5, 144.3,
139.4, 133.2, 130.8, 126.9, 124.8, 124.7, 123.5, 119.9, 119.1, 118.2, 84.5, 54.5, 36.6,
21.2. HRMS m=z (ESI) calc. for C20H15N5O3SNa [M þ Na]þ: 428.0793. Found:
428.0794. IR (KBr): 3456, 3353, 2134, 1652, 1640, 1546, 1405, 1324, 1251 cmꢂ1
.
2,4-Diamino-9-methoxy-5-(4-methylphenylsulfanyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile (C8). Yield 60%, yellow solid, mp 212–213 ꢀC (MeOH).
1H NMR (300 MHz, DMSO-d6) d (ppm): 2.29 (s, 3H), 3.80 (S, 3H), 4.89 (s, 1H), 6.67
(d, J 7.7 Hz, 1H), 6.89–6.96 (m, 5H), 7.07 (t, J 7.9 Hz, 1H), 7.20 (d, J 8.0 Hz, 2H),
7.33 (d, J 8.0 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 160.5, 150.0,
146.9, 138.0, 137.5, 130.8, 129.9, 127.8, 124.3, 122.0, 120.2, 120.1, 119.3, 110.9,
89.5, 55.5, 52.9, 33.4, 20.5. HRMS m=z (ESI) calc. for C21H18N4O2SNa [M þ Na]þ:
: 413.1048. Found: 413.1051. IR (KBr): 3445, 3324, 2178, 1659, 1622, 1553, 1485,
1402, 1333, 1275, 1219 cmꢂ1
.
2,4-Diamino-7-chloro-5-(phenylsulfanyl)-5H-chromeno[2,3-b]pyridine-3-
1
carbonitrile (C9). Yield 70%, yellow crystal, mp 181–183 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 5.32 (s, 1H), 6.80 (d, J 8.7 Hz, 1H), 7.02–7.04 (m,
2H), 7.10 (br s, 2H), 7.21–7.37 (m, 7H). 13C NMR (75 MHz, DMSO-d6) d (ppm):
162.4, 148.3, 136.5 (2), 135.8, 130.8, 129.9, 129.6, 129.1, 128.9, 128.7, 128.5, 128.1,
127.7, 123.9, 119.9, 117.9, 53.7, 46.8. HRMS m=z (ESI) calc. for C19H13ClN4OSNa
[M þ Na]þ: 403.0396. Found: 403.0393. IR (KBr): 3459, 3333, 3279, 3072, 2201,
1655, 1602, 1570, 1477, 1417, 1263, 1220, 1180 cmꢂ1
.

K2CO3-MEDIATED, ONE-POT SYNTHESIS
2241
2,4-Diamino-5-(phenylsulfanyl)-5H-naphthopyrano[2,3-b]pyridine-3-
1
carbonitrile (C10). Yield 73%, yellow solid, mp 222–224 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 6.37–6.46 (m, 5H), 6.90–7.00 (m, 3H), 7.13 (s, 2H),
7.22 (t, J 7.3 Hz, 1H), 7.49 (t, J 7.4 Hz, 1H), 7.66 (t, J 7.5 Hz, 1H), 7.79 (d, J
8.9 Hz, 1H), 7.92 (d, J 8.0 Hz, 1H), 8.40 (d, J 8.5 Hz, 1H). 13C NMR (75 MHz,
DMSO-d6) d (ppm): 159.4 (2), 156.3, 149.0, 136.5, 130.3, 129.8, 129.2, 128.9, 128.4,
127.8, 126.6, 124.6, 123.9, 116.6, 113.0, 86.4, 70.4, 40.6. IR (KBr): 3486, 3371,
3433, 3300, 3159, 2205, 1649, 1622, 1581, 1568, 1481, 1437, 1404, 1329, 1240 cmꢂ1
.
HRMS m=z (ESI) calc: for C23H17N4OS [M þ H]þ: 397.1123. Found: 397.1128.
2,4-Diamino-5-(4-methylphenylsulfanyl)-5H-naphthopyrano[2,3-b]pyri-
1
dine-3-carbonitrile (C11). Yellow solid; 78%; mp 235–236 ꢀC (MeOH). H NMR
(300 MHz, DMSO-d6) d (ppm): 2.17 (s, 3H), 6.26 (d, J 7.5 Hz, 2H), 6.33 (s, 1H),
6.47 (br s, 2H), 6.78 (d, J 7.5 Hz, 2H), 6.93 (d, J 8.9 Hz, 1H), 7.12 (br s, 2H), 7.49
(t, J 7.4 Hz, 1H), 7.65 (t, J 7.5 Hz, 1H), 7.79 (d, J 8.9 Hz, 1H), 7.92 (d, J 8.0 Hz,
1H), 8.39 (d, J 8.4 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 160.0, 156.9,
149.5, 138.9, 137.0, 130.9, 130.4, 129.7, 129.1, 129.0, 127.4, 127.1, 125.1, 124.5,
117.2, 113.7, 87.0, 70.9, 41.0, 21.2. IR (KBr): 3486, 3375, 3155, 2206, 1622, 1569,
1480, 1407, 1240 cmꢂ1
.
CONCLUSION
In summary, we have developed an efficient one-pot synthesis of densely
functionalized medicinally potent pyridines including chromeno[2,3-b]pyridines using
inexpensive reagents such as 20 mol% K2CO3 as base (and KMnO4 as the added
oxidant for formation of 3,5-dicyanopyridines) from the reaction of a variety of alde-
hydes (salicylaldehyde or its derivatives for chromenopyridine) with malanonitrile and
thiophenols or thiols in refluxing 50% aqueous ethanol. The advantages of the present
procedure are the generally good yields, mild and environmentally benign inexpensive
benchtop chemicals or solvents, and operational simplicity. The present protocol is
also equally efficient under a scale-up (ꢃ50-fold) condition, with cost-effective,
large-scale production of these medicinally privileged heterocyclic compounds.
ACKNOWLEDGMENTS
S. M. is grateful to the University Grants Commision (UGC), India, for her
research fellowship. Center for Advanced Studies (CAS)-UGC and Funding for
Infrastructure in Science and Technology–Department of Science and Technology
(FIST-DST), New Delhi, India, are acknowledged for supporting research facilities
at the Department of Chemistry, Jadavpur University.
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