Synthesis of pyridine-2,6-bis((E)-2-benzylidene-3-oxopropanenitrile) and its behavior towards nitrogen binucleophiles

Article abstract of DOI:10.3987/COM-12-12515

Several new pyrazole, isoxazole and pyrimidine derivatives attached to pyridine ring at 2,6-positions have been synthesized by the reactions of the versatile multifunctional unreported pyridine-2,6-bis((E)-2-benzylidene-3- oxopropanenitrie)(2a) with several nitrogen binucleophiles. A novel one-pot three- component reaction of an aldehyde, pyridine-2,6-bis(3-oxopropanenitrile) (1) and electron-rich heterocyclic amines including [3-phenyl-1H-pyrazol-5-amine (12) and 2-aminobenzimedazole (16)] in DMF have been described.

Full text of DOI:10.3987/COM-12-12515

HETEROCYCLES, Vol. 85, No. 8, 2012
1975
HETEROCYCLES, Vol. 85, No. 8, 2012, pp. 1975 - 1986. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 22nd May, 2012, Accepted, 18th June, 2012, Published online, 26th June, 2012
DOI: 10.3987/COM-12-12515
SYNTHESIS
OF
PYRIDINE-2,6-BIS((E)-2-BENZYLIDENE-3-OXO-
PROPANENITRILE) AND ITS BEHAVIOR TOWARDS NITROGEN
BINUCLEOPHILES
Korany A. Ali*
Applied Organic Chemistry Department, National Research Centre, 12622-Cairo,
Egypt. Fax: +202-33370-93. E-mail: kornykhlil@yahoo.com
Abstract – Several new pyrazole, isoxazole and pyrimidine derivatives attached to
pyridine ring at 2,6-positions have been synthesized by the reactions of the versatile
multifunctional unreported pyridine-2,6-bis((E)-2-benzylidene-3-oxopropane-
nitrie) (2a) with several nitrogen binucleophiles. A novel one-pot three-component
reaction of an aldehyde, pyridine-2,6-bis(3-oxopropanenitrile) (1) and electron-rich
heterocyclic amines including [3-phenyl-1H-pyrazol-5-amine (12) and
2-aminobenzimedazole (16)] in DMF have been described.
INTRODUCTION
Binucleophiles are an important reagents in heterocyclic chemistry, and their reactions with electrophiles
are a facile synthetic approach for obtaining divers heterocyclic systems containing azole and condensed
azole moieties.1-5 An interest on these heterocycles is attributed to their known biological activities.6-12
Multicomponent condensation reactions (MCRs) consider as a powerful method for the synthesis of
organic compounds, since the products are formed in a single step.13,14 Such reactions offer a wide range of
possibilities for the efficient construction of highly complex molecules in a single procedure step.15-18 In the
last decade great deal of interest has been focused on the synthesis of the functionalized pyridine
derivatives due to their biological activities.19-22 In view of these observations and in continuation of our
current interest in the synthesis of poly substituted heterocycles for biological evaluations,23-30 we described
herein a facile synthesis of novel 2.6-disubstituted pyridines with expected biological activity starting from
pyridine-2,6-bis(2-benzylidene-3-oxopropanenitrile) (2a). Previously we have reported the synthesis of

1976
HETEROCYCLES, Vol. 85, No. 8, 2012
2,6-bis[3-oxopropanenitrile-2(N,N-dimethylamino)methylene]pyridine and its reactivity towards some
nitrogen binucleophiles.31 As part of our current studies on the developments of different routes to
heterocyclic systems bearing deferent type and number of substituents, we described herein a facile
synthesis of pyridine-2,6-bis(2-benzylidene-3-oxopropanenitrile) (2a) and its reactivity towards some
nitrogen binucleophiles to increase the number of substituent on the synthesized heterocycles and then
study the effect of number of substituent in the biological activity. Herein we described also, a facile
synthesis of fused pyridine derivatives (including pyrazolo[3,4-b]pyridine and pyrido[2,3-d]pyrimidine)
by three-component one-pot reaction of benzaldehyde, pyridine-2,6-bis(3-oxopropanenitrile) (1), and
electron-rich amino heterocycles in DMF under mild conditions.
RESULTS AND DISCUSSION
Substituted β-keto nitriles are highly reactive multifunctional synthetic intermediates which undergo a wide
range of condensation and cyclization reactions.32-36 Recently, we have reported the preparation of
pyridine-2,6-bis(3-oxopropanenitrile) (1) via the Claisen condensation of diethyl 2,6-pyridinedicarboxylate
with acetonitrile in dry THF, in the presence of sodium hydride as strong base.30 The active methylene
moiety of the β-keto nitrile 1 condensed with the appropriate aromatic aldehydes in EtOH and in the
presence of a catalytic amount of piperidine to afford the corresponding Knoevenagel products:
pyridine-2,6-bis-((E)-2-arylidene-3-oxopropanenitrile) (2a-f) (Scheme 1). The structure of the isolated
Knoevenagel products (2a-f) were assigned as the E-isomer based on the previous reported paper.37 The IR
spectrum of compound 2a, taken as a typical example of the series, exhibited a strong carbonyl and nitrile
bands at 1721 and 2188 cm-1, respectively. The 1H NMR spectrum of 2a revealed signal at δ 8.22 due to a
methine proton, in addition to an multiplet at δ 6.77-8.01 due to phenyl and pyridine protons. On the other
hand, treatment of pyridine-2,6-bis(3-oxopropanenitrile) (1) with salicylaldehyde afforded the coumarin
derivative 4 based on the spectral data and similarity to the well-established behavior of 4-antipyrinyl
acetonitrile on the reaction with salicylaldehyde to form 2-imino-2H-chromene derivatives.38 The absence
of cyano group signal at 2100-2200 cm-1 in the IR spectrum of compound 4 support its structure. The
formation of compounds 4 could be explained by the reaction sequence as in Scheme 1. First a
Knoevenagel condensation followed by intramolecular cyclization to coumarin derivative 4.
Subsequent addition of nitrogen-containing reagents that possess two nucleophilic centers provides a
means to convert pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) (2a) to functionalized
heterocycles. Thus, treatment of 2-benzylidene-3-oxopropanenitrile 2a taken as a typical example of the
synthesized serieswith hydrazine hydrate, in refluxing EtOH, afforded the pyrazole derivative 5 as shown in
Scheme 2.

HETEROCYCLES, Vol. 85, No. 8, 2012
1977
O
O
O
O
N
N
EtOH/Piperidine
rt
+
ArCHO
Ar
Ar
CN
CN
CHO
CN
CN
1
EtOH/
Piperidine
2
OH
rt
Yield
Ar
Ph
2
a
%
O
NH
82
91
O
Ph/4-F
Ph/4-Me
b
c
OH
CN HO
NC
NH
88
77
O
N
Ph/4-OMe
O
d
e
f
N
Ph/3,4-OMe
80
79
Ph/3,4,5-OMe
O
O
4
82%
3
Scheme 1
The formation of compound 5 was assumed to proceed by a sequence of 1,4-addition, cyclization with loss
of water, followed by late stage oxidation that is driven by the formation of an aromatic heterocycle.
Pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) (2a) reacts also with phenyl hydrazine in
refluxing EtOH, in the presence of sodium acetate to afford the pyrazole derivative 7. This reaction
proceeds by initial 1,4-addition of phenyl hydrazine, followed by rapid oxidation to provide firstly stable
vinylogous amide-like structure 6 due to the steric hindrance of phenyl group, then the vinylogous
amide-like structure 6 converted to product 7 by loss of water (Scheme 2). The structures of the products 5,
6 and 7 were confirmed on the bases of their elemental analysis and spectral data (See experimental part).
Ph Ph
HN
Ph Ph
O
O
CN NC
N
NH
PhNHNH2
N
N
N
H
Ph
Ph
H
sodium acetate
EtOH/reflux
CN
CN
O
O
2a
50%
NH2NH2
6
80%
EtOH/reflux
74%
-H2O
Ph
Ph
NH
Ph
N
Ph
CN NC
CN NC
N
HN
N
N
N
N
N
N
Ph
Ph
5
7
Scheme 2

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HETEROCYCLES, Vol. 85, No. 8, 2012
Compound 2a reacts also with hydroxylamine hydrochloride, in the presence of sodium acetate, to afford
white solid of 2,6-bis(4-cyano-3-phenylisoxazol-5-yl)pyridine (9) that is not readily soluble in DMSO,
chloroform or methanol (therefore, it is difficult to measure its NMR spectra). Compound 9 is assumed to
be formed via formation of non-isolable intermediate 8 which underwent condensation and intramolecular
cyclization followed by oxidation that is driven by the formation of an aromatic heterocycle, to afford the
isoxazole derivative 9 (Scheme 3). The IR spectrum of the later product revealed the lack of absorption
band corresponding to carbonyl group and showed band at 2205 cm-1 corresponding to nitrile function and
its mass spectrum revealed molecular ion peak at m/z 415. 2-Benzylidene-3-oxopropanenitrile 2a reacts
also with guanidine in refluxing EtOH, in the presence of anhydrous potassium carbonate to give a single
productthat was identified as 2,6-bis(2-amino-5-cyano-6-phenylpyrimidin-4-yl)pyridine (11) according to
its elemental analysis and spectral data (See experimental part) (Scheme 3).
O
O
Ph
O
Ph
O
Ph
N
Ph
N
N
CN NC
N
HO
CN NC
N
OH
Ph
Ph NH2OH
75%
N
N
H
H
CN
CN
-H2O
O
O
K2CO3
reflux
2a
9
8
NH
NH2
NH2
N
NH2
N
NH Ph
Ph NH
H2N
72%
-H2O
N
N
CN NC
N
H2N
N
N
H
NH2
N
H
K2CO3
reflux
Ph
Ph
O
O
CN
CN
11
10
Scheme 3
The behaviors of the benzylidene-3-oxopropanenitrile derivative 2a towards electron-rich amino
heterocycles were also investigated. Thus, treatment of compound 2a with 5-amino-3-phenyl-1H-pyrazole
(12), in refluxing EtOH in the presence of a catalytic amount of triethylamine, furnished a product
identified as 2,6-bis[5-cyano-4,7-dihydro-3,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]pyridine (14)
1
(with 45% yield) and not 15 (Scheme 4) on the basis of its elemental analysis and spectral data. The H
NMR spectrum of 14 revealed two-D2O-exchangeable signals at δ 10.37 and 12.38 due to NH protons of
pyridine and pyrazole, respectivly. Furthermore, compound 14 was prepared with 85% yield by
three-component one-pot reaction of aldehyde, 3-oxopropanenitrile 1, and 5-amino-3-phenyl-1H-pyrazole
(12), in DMF at room temperature. The formation of compounds 14 could be explained by the reaction
sequence as in Scheme 4. First, a Knoevenagel condensation reaction of benzaldehydewith
3-oxopropanenitrile 1 is proposed to give (E)-2-benzylidene-3-phenyl-3-oxopropanenitrile (2a) followed

HETEROCYCLES, Vol. 85, No. 8, 2012
1979
by Michael addition of electron-rich amino heterocyclic compound 12 to provide intermediate 13a, that
underwent condensation and intramolecular cyclization to afford compound 14 (Scheme 4).
O
O
Ph
N
NH2
+
+
Ph
O
N
N
H
CN
CN
12
1
DMF
85%
Ph
N
Ph
HN N
Ph
Ph
H
N
HN
O
Ph
CN
N
H
N
NH OH
CN
OH HN
CN
N
HN
H
N
N
Ph
Ph
Ph
O
NH
H
CN
13a
13b
85%
-H2O
Ph
N
Ph
Ph
Ph
Ph
Ph
N
CN NC
N
N
N
N
N
N
N
N
N
N
H
N
H
H
H
N
Ph
Ph
CN
CN
14
15
12
EtOH/piperidine
45%
2a
Scheme 4
The yield of compound 14 from method B was lower compared to one pot synthesis of method A due to the
solvent effect, DMF consider as aprotic solvent that enhance Michael addition of electron-rich amino
heterocyclic compound 12 to provide intermediate 13a.
Three-component one-pot condensation of an aldehyde, β-ketonitrile (1) instead of β-ketoester and
2-aminobenzimidazole, instead of thiourea in Biginelli and Biginelli like reactions,39 in DMF at room
temperature, afforded triheterocyclic dihydropyrimidine (DHPs) derivative (17) (Scheme 5).
CN
NH
Ph
H
H
N
CN
CN
CN
Ph
N
DMF
N
NH2
O
+
+
N
Ph
N
N
rt
HN
H
O
O
N
75%
N
16
1
17
Scheme 5

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HETEROCYCLES, Vol. 85, No. 8, 2012
The latter reaction proceeds in two steps: first, Knoevenagel condensation of benzaldehyde with 1 followed
by Michael addition of 2-aminobenzimidazole 16 followed by intramolecular cyclization to afford
4H-pyrimido[1,2-a]benzimidazole derivative 17 (Scheme 6).
H
N
H2N
CN
CN
N
CN
CN
DMF
rt
16
Ph
Ph
O
+
Ph
N
N
O
O
H
O
O
H
1
2a
NC
Ph
N
CN
NH
Ph
H
H
N
CN
NC
N
N
O
N
N
H2N
-H2O
Ph
Ph
O
N
HN
H
H
N
NH2
N
N
18
17
Scheme 6
CONCLUSION
The present study describes syntheses of pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) (2a)
and its reactivity towards nitrogen binucleophiles such hydrazine, phenylhydrazine, hydroxylamine and
guanidine to afford 2,6-bis(4-cyano-1H-3-phenylpyrazole-5-yl)pyridine (5), 2,6-bis(4-cyano-1H-1,3-
diphenylpyrazole-5-yl)pyridine (7), 2,6-bis(4-cyano-3-phenylisoxazol-5-yl)pyridine (9) and 2,6-bis(2-
amino-5-cyano-6-phenylpyrimidin-4-yl)pyridine (11). We have described also an efficient synthesis of
one-pot three-component reaction of aldehyde, 3-oxoprobaoenitrile (1), and electron-rich amino
heterocycles, such as 5-aminopyrazole or 2-aminobenzimedazole, in DMF for the synthesis of
1H-pyrazolo[3,4-b]pyridine (14) and pyrimido[1,2-a]benzimidazole (17) derivative, respectively. This
method has the advantages of higher yields, milder reaction conditions and shorter reaction time.
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting point apparatus. The infrared spectra were
recorded in potassium bromide discs on a PyeUnicam SP3-300 and Shimadzu FT IR 8101 PC infrared
spectrophotometers. The NMR spectra were recorded on a Varian Mercury VXR-300 NMR spectrometer.
1H NMR (300 MHz) and 13C NMR (75.46 MHz) were run in deuterated chloroform (CDCl3) or dimethyl
sulfoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a
Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV. Elemental analyses were carried out at the

HETEROCYCLES, Vol. 85, No. 8, 2012
1981
Micro-analytical Centre of Cairo University, Giza, Egypt and recorded on Elementar-Vario EL (Germany)
automatic analyzer. All reactions were followed by TLC (Silica gel, Aluminum Sheets 60 F254, Merck).
Compounds 130 and 1240-42 were prepared according to literature procedures.
Synthesis of pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) dreivatives (2a-f)
To a stirred solution of pyridine-2,6-bis(3-oxo-3-propanenitrile) (1) (0.21 g, 1 mmol) and the appropriate
aldehyde (2 mmol) in EtOH (20 mL), few drops of piperidine were added. The resulting mixture was stirred
for 2-4 h at rt and the solid that precipitate was collected by filtration, washed with EtOH, dried and finally
recrystallized from EtOH to afford the corresponding 2-benzylidene-3-oxopropanenitrile dreivatives
(2a-f).
Pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) (2a)
Yield (0.32 g, 82%); brown solid (from EtOH); mp: 134-135 °C. IR (KBr, cm-1): v 2188 (CN), 1721 (C=O).
1H NMR (DMSO-d6): δ 7.14-7.31 (m, 10H, Ar-H), 7.65-8.12 (m, 3H, pyridine-H), 8.22 (s, 2H, 2C=CH).
13C NMR (DMSO-d6): δ 116.46, 125.19, 125.40, 129.44, 139.44, 140.2, 148.43, 150.49, 151.14, 165.40,
190.45. MS m/z (%): 389 [M+] (15), 232 (20), 128 (50), 77 (100). Anal. Calcd for C25H15N3O2 (389.41): C,
77.11; H, 3.88; N, 10.79. Found: C, 77.29; H, 3.97; N, 10.91.
Pyridine-2,6-bis-((E)-2-(4-fluorobenzylidene)-3-oxopropanenitrile) (2b)
Yield (0.39 g, 91%); orange crystals (from EtOH); mp: 263-265 °C. IR (KBr, cm-1): v 2171 (CN), 1717
1
(C=O). H NMR (DMSO-d6): δ 7.01-7.33 (m, 8H, Ar-H), 7.51-8.01 (m, 3H, pyridine-H), 8.11 (s, 2H,
2C=CH). MS m/z (%): 425 [M+] (53), 343 (15), 302 (33), 223 (48), 174 (63), 126 (90), 76 (100). Anal.
Calcd for C25H13F2N3O2 (425.39): C, 70.59; H, 3.08; N, 9.88. Found: C, 70.35; H, 3.18; N, 9.71.
Pyridine-2,6-bis-((E)-2-(4-methylbenzylidene)-3-oxopropanenitrile) (2c)
Yield (0.37 g, 88%); brown crystals (from EtOH); mp: 128-129 °C. IR (KBr, cm-1): v 2203 (CN), 1717
1
(C=O). H NMR (DMSO-d6): δ 2.41 (s, 6H, 2CH3), 6.75-7.34 (m, 8H, Ar-H), 7.71-8.10 (m, 3H,
pyridine-H), 8.35 (s, 2H, 2C=CH). 13C NMR (DMSO-d6): δ 25.3, 116.4, 126.2, 126.3, 129.4, 139.1, 145.2,
149.3, 150.9, 152.2, 165.1, 188.5. Anal. Calcd for C27H19N3O2 (417.46): C, 77.68; H, 4.59; N, 10.01.
Found: C, 77.61; H, 4.62; N, 10.11.
Pyridine-2,6-bis-((E)-2-(4-methoxybenzylidene)-3-oxopropanenitrile) (2d)
Yield (0.34 g, 77%); yellow crystals (from EtOH); mp: 138-139 °C. IR (KBr, cm-1): v 2176 (CN), 1720
1
(C=O). H NMR (DMSO-d6): δ 3.35 (s, 6H, 2OCH3), 6.82-7.23 (m, 8H, Ar-H), 7.77-8.10 (m, 3H,
pyridine-H), 8.31 (s, 2H, 2C=CH). Anal. Calcd for C27H19N3O4 (449.46): C, 72.15; H, 4.26; N, 9.35. Found:
C, 72.05; H, 4.46; N, 9.21.
Pyridine-2,6-bis-((E)-2-(3,4-dimethoxybenzylidene)-3-oxopropanenitrile) (2e)
Yield (0.41 g, 80%); yellow crystals (from EtOH); mp: 151-152 °C. IR (KBr, cm-1): v 2181 (CN), 1720
(C=O). 1H NMR (DMSO-d6): δ 3.65, 3.75 (s, 12H, 2OCH3), 6.81-7.31 (m, 4H, Ar-H), 7.65-8.11 (m, 3H,

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HETEROCYCLES, Vol. 85, No. 8, 2012
pyridine-H), 8.17 (s, 2H, 2C=CH). MS m/z (%): 509 [M+] (25), 77 (100). Anal. Calcd for C29H23N3O6
(509.51): C, 68.36; H, 4.55; N, 8.25. Found: C, 68.26; H, 4.61; N, 8.31.
Pyridine-2,6-bis-((E)-2-(3,4,5-trimethoxybenzylidene)-3-oxopropanenitrile) (2f)
Yield (0.45 g, 79%); pale yellow crystals (from EtOH); mp: 160-161 °C. IR (KBr, cm-1): v 2182 (CN), 1714
1
(C=O). H NMR (DMSO-d6): δ 3.60-3.85 (3s, 18H, 6 OCH3), 6.59 (s, 4H, Ar-H), 7.77-8.15 (m, 3H,
pyridine-H), 8.21 (s, 2H, 2C=CH). MS m/z (%): 569 [M+] (5.4), 536 (2), 391 (16), 324 (4), 181 (27), 145
(47), 84 (100). Anal. Calcd for C31H27N3O8 (569.56): C, 65.37; H, 4.78; N, 7.38. Found: C, 65.31; H, 4.82;
N, 7.35.
Pyridine-2,6-bis(1-imino-1H-isochromen-3-yl-methanone) (4)
Yield (0.33 g, 78%); pale yellow crystals (from EtOH); mp: 225-227 °C. IR (KBr, cm- 1): v 3415 (NH), 1720
(C=O). 1H NMR (DMSO-d6): δ 4.81 (s, 2H, 2NH, D2O-exchangable), 6.70-8.05 (m, 8 Ar-H, 3 pyridine-H),
8.18 (s, 1H, CH). MS m/z (%): 421 [M+] (10), 317 (30), 250 (35), 172 (72), 89 (60), 51 (100). Anal. Calcd
for C25H15N3O4 (421.40): C, 71.25; H, 3.59; N, 9.97. Found: C, 71.05; H, 3.72; N, 9.72.
2,6-Bis(4-cyano-1H-3-phenylpyrazole-5-yl)pyridine (5)
Hydrazine hydrate (80%, 2 mL) was added to a stirred solution of compound 2a (0.39 g, 1 mmol) in EtOH
(10 mL). Stirring was continued for 4 h at rt and the obtained solid was filtered off, washed with cold water,
dried and finally recrystallized from EtOHto affordcompound 5. Yield (0.31 g, 75%); pale yellow powder
(from EtOH); mp: 155-156 °C. IR (KBr, cm-1): v 3273 (NH), 2191 (CN). 1H NMR (DMSO-d6): δ 6.71-8.13
(m, 13H, Ar-H and pyridine-H), 10.29 (br s, 2H, 2NH, D2O-exchangeable). MS m/z (%): 413 [M+] (15),
372 (25), 245 (55), 223 (45), 179 (75), 165 (67), 129 (93), 76 (100). Anal. Calcd for: C25H15N7 (413.43): C,
72.63; H, 3.66; N, 23.72. Found: C, 72.77; H, 3.51; N, 23.87.
2,6-Bis(4-cyano-1H-1,3-diphenylpyrazole-5-yl)pyridine (7)
To a solution of the compound 2a (0.39 g, 1 mmol) in EtOH (10 mL), were added phenyl hydrazine (0.32 g,
3 mmol) and sodium acetate (0.3 g). The reaction mixture was refluxed for 5 h, then left to cool and 10 mL
of water was added. The yellowish solid precipitate was collected by filtration, washed with EtOH, dried,
and finally recrystallized from EtOH to afforded 2,6-bis(4-cyano-1H-1,3-diphenylpyrazole-5-yl)pyridine)
(7). Compound 6 was separated after 1 h.
Enehydrazine of pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) (6)
Yield (0.31 g, 50%); pale yellow solid; mp: 147-148 °C. IR (KBr, cm-1): v 3305 (2NH), 2258 (CN), 1707
(C=O). 1H NMR (DMSO-d6): δ 6.71-8.17 (m, 20H, Ar-H and 3H, pyridine), 7.82, 10.30 (s, 2H, 2NH-D2O
exchangable). MS m/z (%): 601 [M+] (3), 503 (83), 371 (51), 186 (67), 128 (46), 91 (47), 77 (100). Anal.
Calcd for C37H27N7O2 (601.66): C, 73.86; H, 4.52; N, 16.30. Found: C, 73.93; H, 4.32; N, 16.21.
2,6-Bis(4-cyano-1H-1,3-diphenylpyrazole-5-yl)pyridine (7)
Yield (0.42 g, 74%); pale yellow; mp: 165-166 °C. IR (KBr, cm-1): v 2194 (CN). 1H NMR (DMSO-d6): δ

HETEROCYCLES, Vol. 85, No. 8, 2012
1983
7.11-7.70 (m, 20H, Ar-H), 7.95-8.03 (m, 3H, pyridine). 13C NMR (DMSO-d6): δ 108.5, 115.3, 119.5, 120.4,
126.2, 126.3, 127.1, 129.5, 132.5, 135.1, 137.4, 139.2, 149.2, 150.9, 154.2, MS m/z (%): 569 [M+] (54), 467
(36), 141 (11), 141 (47), 92 (76), 76 (100). Anal. Calcd for C37H27N7 (569.66): C, 78.01; H, 4.88; N, 17.21.
Found: C, 78.11; H, 4.70; N, 17.31.
Reaction of pyridine-2,6-bis-((E)-2-benzylidene-3-oxopropanenitrile) (2a) with hydroxylamine
hydrochloride and guanidine.
To a mixture of compound 2a (0.39 g, 1 mmol) and hydroxylamine hydrochloride (0.14 g, 2 mmol) or
guanidine hydrochloride (0.19 g, 2 mmol) in EtOH (20 mL), was added anhydrous potassium carbonate
(0.28 g, 2 mmol). The resulting mixture was refluxed for 6-10 h, and allowed to cool to rt then diluted with
water (30 mL). The solid products that formed were collected by filtration, washed with water, dried and
finally recrystallized from the proper solvent to afford compounds 9 and 11 respectively.
2,6-Bis(4-cyano-3-phenylisoxazol-5-yl)pyridine (9)
Yield (0.31 g, 75%); white solid (DMF); mp: 230-232 °C. IR (KBr, cm-1): v 2205 (CN). MS m/z (%): 416
(M++1) (5), 415 [M+] (10), 272 (13), 234 (41), 206 (21), 190 (16) 122 (63), 105 (54), 77 (74), 51 (100). Anal.
Calcd for C25H13N5O2 (415.4): C, 72.28; H, 3.15; N, 16.86. Found: C, 72.38; H, 3.25; N, 16.71.
2,6-Bis(2-amino-5-cyano-6-phenylpyrimidin-4-yl)pyridine (11)
Yield (0.34 g, 72%); brown solid (from DMF); mp:>300 °C. IR (KBr, cm-1): v 3392-3100 (NH2), 2200
1
(CN). H NMR (DMSO-d6): δ 4.33 (br s, 4H, 2NH2, D2O-exchangeable), 7.11-8.08 (m, 13H, Ar-H and
pyridine-H), 13C NMR (DMSO-d6): δ 95.1, 115.2, 120.1, 125.4, 127.3, 129.5, 130.1, 135.7, 150.1, 167.5,
169.8, 171.1. MS m/z (%): 467 [M+] (5), 430 (10), 360 (11), 319 (7), 272 (36) 233 (29), 173 (16), 128 (41),
105 (66), 77 (100). Anal. Calcd for C27H17N9 (467.48): C, 69.37; H, 3.67; N, 26.97. Found: C, 69.23; H,
3.52; N, 26.81.
Three component one pot synthesis of fused pyridine and pyrimidine derivatives 14 and 17
General Procedure: Method A: a mixture of benzaldehyde (0.22 g, 2 mmol), 3-oxopropanenitrile 1 (0.21 g,
1 mmol) and the appropriate heterocyclic amine 12 or 16 (1 mmol) in dry DMF (10 mL) was stirred at rt for
4-7 h to complete the reaction (monitored by TLC), then 50 mL water was added. The solid was filtered off
and washed with water. The crude product was purified by recrystallization from EtOH to give 14 and 17,
respectively. Method B: To a mixture of the 2-benzylidene-3-oxopropanenitrile (2) (0.39 g, 1 mmol) and
5-amino-3-phenyl-1H-pyrazole 13 (0.32 g, 2 mmol) in EtOH (20 mL), was added a few drops of piperidine.
The resulting mixture was refluxed for 5 h, and allowed to cool to rt. The solid product that formed was
collected by filtration, washed with EtOH, dried and finally recrystallized from EtOH to afford
2,6-bis[6-cyano-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl]pyridine 14.
2,6-Bis[5-cyano-4,7-dihydro-3,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]pyridine (14)
Yield [method A (0.57 g, 85%), method B (0.30 g, 45%)]; pale yellow crystals (from MeOH); mp:

1984
HETEROCYCLES, Vol. 85, No. 8, 2012
265-267 °C. IR (KBr, cm-1): v 3328, 3242 (2NH), 2191 (CN). 1H NMR (DMSO-d6): δ 5.69 (s, 2H, 2CH),
7.23-7.49 (m, 20H, Ar-H), 7.51-8.02 (m, 3H, pyridine-H), 10.37, 12.38 (s, 2H, 2NH-D2O-exchangable).
13C NMR (DMSO-d6): δ 29.11, 81.47, 100.14, 111.52, 119.13, 124.13, 126.85, 127.38, 128.01, 128.45,
128.62, 134.11, 135.17, 139.13, 145.76, 148.13, 151.06, 161.07. MS m/z (%): 671 [M+] (15), 669 (15) 579
(20), 343 (4), 127 (12), 104 (53), 90 (67), 76 (100). Anal. Calcd for C43H29N9 (671.75): C, 76.88; H, 4.35; N,
18.77. Found: C, 76.93; H, 4.27; N, 18.81.
2,6-Bis[4-phenyl-3-cyano-1,4-dihydropyrimido[1.2-a]benzimidazol-2-yl]pyridine (17)
1
Yield (0.49 g, 75%, pale yellow crystals); mp: 244-246 °C. IR (KBr, cm-1): v 3433 (NH) 2187 (CN). H
NMR (DMSO-d6): δ 4.59 (d, 2H, 2CH), 6.54-7.10 (m, 18H, Ar-H), 7.97-8.13 (m, 3H, pyridine-H), 8.33 (s,
13
2H, 2NH-D2O-exchangeable). C NMR (DMSO-d6): δ 47.12, 95.11, 112.1, 118.12, 118.5, 119.7, 119.9,
120.11, 122.11, 127.12, 128.30, 128.6, 133.21, 135.12, 140.11, 142.5, 159.11, 161.41, 165.14. Anal. Calcd
for C39H25N9 (619.68): C, 75.59; H, 4.07; N, 20.34. Found: C, 75.35; H, 4.19; N, 20.23.
ACKNOWLEDGEMENTS
Financial support for this work was provided by the program of the Science and Technology Development
Fund (STDF) - Egypt (project No.170). The program is financed through the Ministry of State for Scientific
Research and is administered by Higher Council for Science & Technology.
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