Activated anilide in heterocyclic synthesis: Synthesis of new dihydropyridines, dihydropyridazines and thiourea derivatives

Article abstract of DOI:10.1002/cjoc.201190216

A series of new dihydropyridines, butanamide, dihydropyridazines and thiourea derivatives have been prepared through the reactions of 3-aminopyridine (1) and N-(pyridin-3-yl)-3-(pyridin-3-ylimino)butanamide 3 with some electrophilic reagents, aryl diazonium salts and isothiocyanates. Elementary analysis, MS, IR, and ¹H NMR spectra confirmed the identity of the products. Copyright

Full text of DOI:10.1002/cjoc.201190216

FULL PAPER
Activated Anilide in Heterocyclic Synthesis: Synthesis of New
Dihydropyridines, Dihydropyridazines and
Thiourea Derivatives
Hafiz, Ibrahim S. A.*,a
Ramiz, Mahmoud M. M.b
Sarhan, Ahmed A. M.a
a Department of Chemistry, Faculty of Education, Suez Canal University, Arish, Egypt
b Faculty of Electronic Engineering, Menofia University, Menouf, Egypt
A series of new dihydropyridines, butanamide, dihydropyridazines and thiourea derivatives have been prepared
through the reactions of 3-aminopyridine (1) and N-(pyridin-3-yl)-3-(pyridin-3-ylimino)butanamide 3 with some
electrophilic reagents, aryl diazonium salts and isothiocyanates. Elementary analysis, MS, IR, and 1H NMR spectra
confirmed the identity of the products.
Keywords lactones, oxygen heterocycles, cis-Wittig olefination, mono and di-O-benzyl ethers, cryptofolione
stereoisomers
Introduction
ratus and uncorrected. The purity of compound was
confirmed by TLC using Merck silica gel 60 F254
plates using toluene, ethyl acetate and methanol as a
mobile phase and spots were visualized under UV ra-
diation. IR spectra (KBr) were recorded on a
Bruker-Vector 22 instrument (Bruker) and frequencies
are expressed in cm . H NMR spectra were recorded
with a Varian Gemini spectrometer at 300 MHz and 200
MHz with TMS as the internal reference. Chemical
shifts were reported on a δ scale relative to TMS as a
standard. EI-mass spectra were recorded with an HP
D5988 A 1000 MHz instrument (Hewlett-Packard).
Elemental analyses were performed at the Microana-
lytical Centre at the Faculty of Science, Cairo Univer-
sity, Egypt.
Polyfunctionally substituted azines and azoles are
biologically interesting molecules and their chemistry
has received a considerable attention,1-5 especially
1,4-dihydropyridine (DHP) and condensed pyridazi-
nones.6-12 1,4-DHPs have received much attention due
to their wide range of pharmaceutical and biological
activity and were used in therapeutics such as blood
pressure control on chronic, nondiabetic nephropa-
thies,13,14 hypnotic, anti-inflammator,15 antihypoxic and
antiischemic drugs16 and calcium channel modulators of
the nifedipine type17 which are the best selling drugs
used in the treatment of cardiovascular diseases.18 Gen-
erally, 1,4-DHPs are synthesized by the Hantszch
method, which involves one pot condensation of an al-
dehyde with ethyl acetoacetate, and ammonia either in
acetic acid or refluxing in alcohol.19 However, the yields
of 1,4-dihydropyridines obtained by this method are
generally low and several methods have been described
for the synthesis of 1,4-dihydropyridine.20-24
Also heterocyclic thiourea derivatives are known to
exhibit diverse bioactivities such as antiviral,25 antitu-
bercular,26 fungicidal,27 and herbicidal28 activities. In
conjunction with our interest in the synthesis of azines
and condensed azines,29,30 we study here the readily ob-
tainable butanamide and pyridine derivatives as starting
materials for the synthesis of a new series of polyfunc-
tionally substituted 1,4-dihydropyridines, 2,5-dihydro-
pyridazines and thiourea derivatives in a good yields.
－1
1
Preparation of 3-oxo-N-(pyridin-3-yl)butanamide (2)
A mixture of 3-aminopyridine (0.94 g, 0.01 mol) and
ethyl acetoacetate (1.3 g, 0.01 mol) was heated in re-
fluxing benzene (30 mL) for 2 h. The reaction mixture
was allowed to cool and the separated solid product was
collected by filtration and crystallized from n-hexane to
give compound 2 as white crystals, yield 66%, m.p.
1
133—134 ℃; H NMR (DMSO-d6) δ: 2.21 (s, 3H,
CH3), 3.72 (s, 2H, CH2), 7.30—8.94 (m, 4H, aromatic
H), 10.24 (s, 1H, NH); IR (Film) v: 3200—3154 (NH),
－1
3019 (CH-arom)＋, 2996 (CH-aliph), 1650 (C＝O) cm ;
MS m/z: 177 (M －1). Anal. calcd for C9H10N2O2 (178):
C 60.66, H 5.66, N 15.72; found C 60.90, H 5.50, N
15.50%.
Preparation of N-(pyridin-3-yl)-3-(pyridin-3-ylimino)-
Experimental
butanamide (3)
Melting points were determined using a Büchi appa-
A mixture of 3-aminopyridine (1.88 g, 0.02 mol) and
*
E-mail: dr_ibrahim_saad@maktoob.com
Received August 20, 2010; revised January 27, 2011; accepted February 17, 2011.
1154
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1154— 1162

Synthesis of New Dihydropyridines, Dihydropyridazines and Thiourea Derivatives
ethyl acetoacetate (1.3 g, 0.01 mol) was heated in re-
fluxing xylene (30 mL) for 5 h. The reaction mixture
was allowed to cool and the separated solid product was
collected by filtration and crystallized from n-hexane to
give compound 3 as white crystals, yield 80%., m.p.
(OH), 3325 (NH2), 3058 (CH-arom), 2935 (CH-aliph),
＋
－1
2190 (CN) cm ; MS m/z: 442 (M ). Anal. calcd for
C24H19ClN6O (442.90): C 65.08, H 4.32, N 18.97, Cl
8.00; found C 65.05, H 4.28, N 18.90, Cl 8.01.
2-Amino-4-(2-chlorophenyl)-6-hydroxy-1-(pyri-
din-3-yl)-5-(1-(pyridin-3-ylimino)ethyl)-1,4-dihydro-
pyridine-3-carbonitrile (8d) Formed as yellow crys-
1
140—142 ℃; H NMR (DMSO-d6, 300 MHz) δ: 2.06
(s, 3H, CH3), 4.95 (s, 2H, CH2), 7.26—8.74 (m, 8H,
aromatic H), 9.79 (s, 1H, NH); IR (Film) v: 3208—3161
(NH), 3026 (CH-arom), 2986＋(CH-aliph), 1647 (C＝O)
cm － 1; MS m/z: 253 (M －1). Anal. calcd for
C14H14N4O (254.29): C 66.13, H 5.55, N 22.03; found C
66.06, H 5.50, N 22.02.
1
tals from ethanol; yield 70%, m.p. 150—152 ℃; H
NMR (DMSO-d6, 300 MHz) δ: 1.99 (s, 3H, CH3), 4.43
(s, 2H, NH2), 5.04 (s, 1H, H-4 pyridine), 7.33—8.69 (m,
12H, aromatic H), 12.15 (s, 1H, OH); IR (Film) v: 3463
(OH), 3325 (NH2), 3193 (CH-aro＋m), 2964 (CH-aliph),
－1
2180 (CN) cm ; MS m/z: 441 (M －1). Anal. calcd for
General procedure for the synthesis of dihydropy-
ridine derivatives 8a— 8e
C24H19ClN6O (442.90): C 65.08, H 4.32, N 18.97, Cl
8.00; found C 65.33, H 4.57, N 18.85, Cl 8.15.
Procedure (A) A mixture of butanamide 3 (0.94 g,
0.01 mol) and arylidenemalononitryles 4a—4e (0.01
mol) in ethanol (75 mL) containing catalytic amount of
piperidine was heated under reflux for 6 h. The reaction
mixture was allowed to cool and poured into crushed ice
then acidified with dilute HCl, The separated solid was
filtered, washed and crystallized from ethanol from the
proper solvent.
Procedure (B) A mixture of malononitrile (0.66 g,
0.01 mol) and Shiff's base 9a—9e (0.01 mol) in ethanol
containing catalytic amount of piperidine was heated
under reflux for 2 h, left to cool in ice bath for 1 h. The
solid product formed was collected by filtration and
crystallized from the proper solvent.
2-Amino-4-(2,4-dichlorophenyl)-6-hydroxy-1-(py-
ridin-3-yl)-5-(1-(pyridin-3-ylimino)ethyl)-1,4-dihy-
dropyridine-3-carbonitrile (8e) Formed as pale yel-
low crystals from ethanol; yield 72%, m.p. 174—176
1
℃; H NMR (CDCl3, 300 MHz) δ: 1.88 (s, 3H, CH3),
4.30 (s, 2H, NH2), 5.05 (s, 1H, H-4 pyridine), 7.27—
8.67 (m, 11H, aromatic H), 12.19 (s, 1H, OH); IR (Film)
v: 3463 (OH), 3325 (NH2), 3186 (CH-arom), 2966
＋
－1
(CH-aliph), 2171 (CN) cm ; MS m/z: 477 (M ). Anal.
calcd for C24H18Cl2N6O (477.35): C 60.49, H 3.78, N
17.64, Cl 14.91; found C 60.33, H 3.77, N 17.59, Cl
14.87.
General procedure for the synthesis of Shiff's bases
9a— 9e
2-Amino-6-hydroxy-4-phenyl-1-(pyridine-3-yl)-5-
(1-(pyridine-3-ylimino)ethyl)-1,4-dihydro-pyridine-
3-carbonitrile (8a) Formed as greenish yellow crys-
A mixture of compound 3 (0.94 g, 0.01 mol), aro-
matic aldehydes (0.01 mol) in ethanol (75 mL) and a
catalytic amount of piperidine was heated under reflux
for 3 h. The reaction mixture was allowed to cool and
poured into crushed ice then acidified with HCl. The
separated solid was filtered, washed and crystallized
from ethanol from the proper solvent.
1
tals from ethanol; yield 70%, m.p. 122—124 ℃; H
NMR (DMSO-d6, 300 MHz) δ: 1.93 (s, 3H, CH3), 4.18
(s, 2H, NH2), 4.5 (s, 1H, H-4 pyridine), 7.26—8.65 (m,
13H, aromatic H), 12.14 (s, 1H, OH); IR (Film) v: 3460
(OH), 3328 (NH2), 3031 (CH-arom), 2858—2927
＋
－1
(CH-aliph), 2179 (CN) cm ; MS m/z: 405 (M －3).
Anal. calcd for C24H20N6O (408.46): C 70.57, H 4.89, N
20.56; found C 70.80, H 4.93, N 20.74.
2-Benzylidene-N-(pyridin-3-yl)-3-(pyridine-3-yli-
mino)butanamide(9a)
Formed as brown crystals
1
from ethanol; yield 60%, m.p. 100—103 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 1.76 (s, 3H, CH3), 6.30 (s, 1H,
alkenyl proton), 7.20—8.70 (m, 13H, aromatic H),
10.30 (s, 1H, NH); IR (Film) v: 3415 (NH), 3120
(CH-arom), 3045－(CH-alkenyl proton＋), 2945 (CH-aliph),
2-Amino-4-(4-chlorophenyl)-6-hydroxy-1-(pyri-
din-3-yl)-5-(1-(pyridin-3-ylimino)ethyl)-1,4-dihydro-
pyridine-3-carbonitrile (8b) Formed as yellow crys-
1
tals from ethanol; yield 77%, m.p. 126—128 ℃; H
1
NMR (DMSO-d6, 300 MHz) δ: 1.89 (s, 3H, CH3), 4.08
(s, 2H, NH2), 4.45 (s, 1H, H-4 pyridine), 7.21—8.67 (m,
12H, aromatic H), 12.13 (s, 1H, OH); IR (Film) v: 3460
(OH), 3325 (NH2), 3051 (CH-arom), 2966, (CH-aliph),
1655 (C＝O) cm ; MS m/z: 341 (M －1). Anal. calcd
for C21H18N4O (342.15): C 73.67, H 5.30, N 16.36;
found C 73.40, H 5.50, N 16.50.
2-(4-Chlorobenzylidene)-N-(pyridin-3-yl)-3-(pyri-
dine-3-ylimino)butanamide (9b) Formed as yellow
crystals from ethanol; yield 66%, m.p. 138—140 ℃; 1H
NMR (DMSO-d6, 300 MHz) δ: 1.66 (s, 3H, CH3), 6.17
(s, 1H, alkenyl proton), 7.3—8.78 (m, 12H, aromatic H),
10.24 (s, 1H, NH); IR (Film) v: 3421 (NH), 3120
(CH-arom), 3058－(CH-alkenyl proton＋), 2935 (CH-aliph),
＋
－1
2179 (CN) cm ; MS m/z: 441 (M －1). Anal. calcd for
C24H19ClN6O (442.90): C 65.08, H 4.32, N 18.97, Cl
8.00; found C 65.02, H 4.28, N 18.96, Cl 7.90.
2-Amino-4-(3-chlorophenyl)-6-hydroxy-1-(pyri-
din-3-yl)-5-(1-(pyridin-3-ylimino)ethyl)-1,4-dihydro-
pyridine-3-carbonitrile (8c) Formed as brown crys-
1
1
tals from ethanol; yield 70%, m.p. 250—252 ℃; H
1665 (C＝O) cm ; MS m/z: 378 (M ＋2). Anal. calcd
NMR (DMSO-d6, 300 MHz) δ: 1.99 (s, 3H, CH3), 4.57
(s, 2H, NH2), 5.77 (s, 1H, H-4 pyridine), 7.30—8.73 (m,
12H, aromatic H), 12.02 (s, 1H, OH); IR (Film) v: 3420
for C21H17ClN4O (376.84): C 66.93, H 4.55, N 14.87, Cl
9.41; found C 66.87, H 4.51, N 14.86, Cl 9.42.
2-(3-Chlorobenzylidene)-N-(pyridin-3-yl)-3-(pyri-
Chin. J. Chem. 2011, 29, 1154— 1162
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1155

Hafiz, Ramiz & Sarhan
FULL PAPER
dine-3-ylimino)butanamide (9c) Formed as brown
crystals from ethanol; yield 70%, m.p. 118—120 ℃; 1H
NMR (DMSO-d6, 300 MHz) δ: 1.64 (s, 3H, CH3), 6.20
(s, 1H, alkenyl proton), 7.3—8.89 (m, 12H, aromatic H),
10.06 (s, 1H, NH); IR (Film) v: 3255 (NH), 3120
(CH-arom), 3058－(CH-alkenyl proton), 2935 (CH-aliph),
MS m/z: 392 (M＋ ). Anal. calcd for C20H17ClN6O
(392.84): C 61.15, H 4.36, N 21.39, Cl 9.02; found C
61.09, H 4.32, N 21.38, Cl 9.03.
N-(Pyridin-3-yl)-3-(pyridin-3-ylimino)-2-(2-o-
tolylhydrazono)butanamide (15c) Formed as yellow
crystals from ethanol; yield 65%, m.p. 144—146 ℃; 1H
NMR (DMSO-d6, 300 MHz) δ: 2.35 (s, 3H, CH3), 2.53
(s, 3H, CH3), 7.13—8.80 (m, 12H, aromatic H), 11.39 (s,
1H, NH), 14.44 (s, 1H, NH); IR (Film) v: 3404 (NH),
＋
1
1671 (C＝O) cm ; MS m/z: 376 (M ). Anal. calcd for
C21H17ClN4O (376.84): C 66.93, H 4.55, N 14.87, Cl
9.41; found C 66.82, H 4.48, N 14.89, Cl 9.50.
－1
2-(2-Chlorobenzylidene)-N-(pyridin-3-yl)-3-(pyri-
din-3-ylimino)butanamide (9d) Formed as yellowish
crystals from ethanol; yield 65%, m.p. 121—122 ℃; 1H
NMR (DMSO-d6, 300 MHz) δ: 1.07 (s, 3H, CH3),
7.42—8.69 (m, 13H, alkenyl and aromatic H), 10.58 (s,
1H, NH); IR (Film) v: 3310 (NH), 3120 (CH-arom),
3060 (CH-alkenyl proton), 291＋0 (CH-aliph), 1682 (C＝
3076 (CH-arom)＋, 2978 (CH-aliph), 1656 (C＝O) cm ;
MS m/z: 372 (M ). Anal. calcd for C21H20N6O (372.42):
C 67.73, H 5.41, N 22.57; found C 67.66, H 5.37, N
22.55.
N-(Pyridin-3-yl)-3-(pyridin-3-ylimino)-2-(2-p-
tolylhydrazono)butanamide (15d) Formed as orange
crystals from ethanol; yield 70%, m.p. 110—112 ℃; 1H
NMR (DMSO-d6, 300 MHz) δ: 2.31 (s, 3H, CH3), 2.51
(s, 3H, CH3), 7.22—8.83 (m, 12H, aromatic H), 11.28 (s,
1H, NH), 13.83 (s, 1H, NH); IR (Film) v: 3420 (NH),
－ 1
O) cm ; MS m/z: 374 (M －2). Anal. calcd for
C21H17ClN4O (376.84): C 66.93, H 4.55, N 14.87, Cl
9.41; found C 66.80, H 4.55, N 14.74, Cl 9.38.
－1
2-(2,4-Dichlorobenzylidene)-N-(pyridin-3-yl)-3-
(pyridine-3-ylimino)butanamide (9e)
3028 (CH-arom)＋, 2916 (CH-aliph), 1654 (C＝O) cm ;
Formed as
MS m/z: 372 (M ). Anal. calcd for C21H20N6O (372.42):
C 67.73, H 5.41, N 22.57; found C 67.70, H 5.40, N
22.48.
pale yellow crystals from ethanol; yield 72%, m.p.
1
110—112 ℃; H NMR (DMSO-d6, 300 MHz) δ: 1.70
(s, 3H, CH3), 6.25 (s, 1H, alkenyl proton), 7.30—8.80
(m, 11H, aromatic H), 10.40 (s, 1H, NH); IR (Film) v:
3430 (NH), 3120 (CH-arom), 3058－(CH-alkenyl proton),
N-(pyridin-3-yl)-2-(2-(pyridin-3-yl)hydrazono)-3-
(pyridin-3-ylimino)butanamide (15e)
Formed as
yellow crystals from ethanol; yield 87%, m.p. 160—
162 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 2.29 (s, 3H,
CH3), 7.47—8.92 (m, 12H, aromatic H), 11.91 (s, 1H,
NH), 12.51 (s, 1H, NH); IR (Film) v: 3434 (NH－), 3026
1
2927 (CH-aliph), 1650 (C＝O) cm ; MS m/z: 410 (M
－1). Anal. calcd for C21H16Cl2N4O (411.28): C 61.33,
H 3.92, N 13.62, Cl 17.24; found C 61.20, H 3.70, N
13.51, Cl 17.29.
1
(CH-arom), 2916 (CH-aliph), 1643 (C＝O) cm ; MS
m/z: 359 (M＋). Anal. calcd for C19H17N7O (359.15): C
General procedure for the synthesis of hydrazo de-
rivatives 15a— 15e
63.44, H 4.73, N 27.28; found C 63.48, H 4.70, N 27.26.
General procedure for the synthesis of pyridazinone
A solution of the diazonium salt 14a—14e (prepared
from 0.01 mol of aromatic amine with the appropriate
quantities of sodium nitrite and hydrochloric acid) was
added to a cold solution (0—5 ℃) of 3 (0.01 mol) in
ethanol (50 cm3) containing anhydrous sodium acetate
(5 g) with continuous stirring for 1 h. The separated
solid was filtered, washed with water and crystallized
from the proper solvent to give compounds 15a—15e.
2-(2-Phenylhydrazono)-N-(pyridin-3-yl)-3-(pyri-
din-3-ylimino)butanamide (15a) Formed as orange
crystals from ethanol; yield 60%, m.p. 154—156 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.47 (s, 3H, CH3),
7.03—8.53 (m, 13H, aromatic H), 11.49 (s, 1H, NH),
12.93 (s, 1H, NH); IR (Film) v: 3429 (NH), 3062
derivatives (18a— 18e)
A mixture of compounds 15a—15e (0.01 mol), am-
monium acetate (0.01 mol) and ethyl cyanoacetate (1.13
g, 0.01 mol) was fused in domestic microwave oven for
5 min. The precipitate solid was treated with water and
filtered off, washed with water and crystallized from the
proper solvent.
3-Oxo-2-phenyl-5-(pyridin-3-ylamino)-6-(1-(pyri-
din-3-ylimino)ethyl)-2,3-dihydropyridazine-4-carbo-
nitrile (18a) Formed as orange crystals from ethanol;
1
yield 63%, m.p. 156—158 ℃; H NMR (CDCl3, 300
MHz) δ: 2.29 (s, 3H, CH3), 7.11—8.71 (m, 13H,
arom-H), 11.80 (s, 1H, NH); IR (Film) v: 3400 (NH2),
3034 (CH-－arom), 2916 (CH-aliph), 2200 (CN), 1743 (C
＝O) cm 1; MS m/z: 407 (M＋ ). Anal. calcd for
C23H17N7O (407.15): C 67.80, H 4.21, N 24.06; found C
67.95, H 4.50, N 24.00
－1
(CH-arom), ＋2927 (CH-aliph), 1654 (C＝O) cm ; MS
m/z: 357 (M －1). Anal. calcd for C20H18N6O (358.40):
C 67.02, H 5.06, N 23.45; found C 66.86, H 5.00, N
23.30.
2-(2-(4-Chlorophenyl)hydrazono)-N-(pyridin-3-
yl)-3-(pyridin-3-ylimino) butanamide (15b) Formed
as yellow crystals from ehanol/dioxane; yield 70%, m.p.
2-(4-Chlorophenyl)-3-oxo-5-(pyridin-3-ylamino)-
6-(1-(pyridin-3-ylimino)ethyl)-2,3-dihydro-pyrida-
zine-4-carbonitrile (18b) Formed as yellow crystals
1
1
184—186 ℃; H NMR (DMSO-d6, 300 MHz) δ: 2.54
from ethanol; yield 67%, m.p. 158—160 ℃; H NMR
(s, 3H, CH3), 7.39—8.84 (m, 12H, aromatic H), 11.14 (s,
1H, NH), 13.41 (s, 1H, NH); IR (Film) v: 3430 (NH),
(CDCl3, 300 MHz) δ: 2.06 (s, 3H, CH3), 7.15—8.75 (m,
12H, aromatic H), 11.53 (s, 1H, NH); IR (Film) v: 3300
(NH), 3028 (CH-arom), 2916 (CH-aliph), 2210 (CN),
－1
3065 (CH-arom), 2927 (CH-aliph), 1666 (C＝O) cm ;
1156
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1154— 1162

Synthesis of New Dihydropyridines, Dihydropyridazines and Thiourea Derivatives
＋
－1
1745 (C＝O) cm ; MS m/z: 441 (M ). Anal. calcd for
C23H16ClN7O (441.11): C 62.52, H 3.65, N 22.19, Cl
8.02; found C 62.90, H 3.85, N 22.30, Cl 8.30.
11.35 (s, 1H, NH), 12.27 (s, 1H, NH); IR (Film) v:
3425—3554 (NH), 3131 (CH-arom), 1685 (C＝O),
＋
－1
1560 (C＝S) cm ; MS m/z: 291 (M ). Anal. calcd for
C13H10ClN3OS (291.76): C 53.52, H 3.45, N 14.40, S
10.99, Cl 12.15; found C 53.60, H 3.60, N 14.50, S
10.90, Cl 12.25.
3-Oxo-5-(pyridin-3-ylamino)-6-(1-(pyridin-3-yli-
mino)ethyl)-2-o-tolyl-2,3-dihydropyridazine-4-carbo-
nitrile (18c) Formed as yellow crystals from ethanol;
1
yield (65%), m.p. 154—156 ℃; H NMR (CDCl3, 300
N-(Pyridin-3-ylcarbamothioyl)acetamide
(21c)
MHz) δ: 2.26 (s, 3H, CH3), 2.41 (s, 3H, CH3),
7.20—8.70 (m, 12H, arom-H), 11.10 (s, 1H, NH); IR
(Film) v: 3404 (NH2), 3079 (CH-arom), 2926
Formed as colourless crystals from ethanol/dioxane;
1
yield 66%, m.p. 212—214 ℃; H NMR (CDCl3, 300
MHz) δ: 2.17 (s, 3H, CH3), 7.46—8.69 (m, 4H, aro-
matic H), 11.61 (s, 1H, NH), 12.37 (s, 1H, NH); IR
(Film) v: 3425—3554 (NH), 3131 (CH-arom), 2930
－1
(CH-ali＋ph), 2200 (CN), 1740 (C＝O) cm ; MS m/z:
421 (M ). Anal. calcd for C24H19N7O (421.17): C 68.40,
H 4.54, N 23.26; found C 68.60, H 4.60, N 23.40.
3-Oxo-5-(pyridin-3-ylamino)-6-(1-(pyridin-3-yli-
mino)ethyl)-2-p-tolyl-2,3-dihydropyridazine-4-carbo-
nitrile (18d) Formed as yellow crystals from ethanol;
－1
(CH-ali＋ph), 1712 (C＝O), 1544 (C＝S) cm ; MS m/z:
195 (M ). Anal. calcd for C8H9N3OS (195.24): C 49.21,
H 4.65, N 21.52, S 16.42; found C 49.40, H 4.60, N
21.50, S 16.50.
1
yield 60%, m.p. 100—102 ℃; H NMR (CDCl3, 300
1-(Pyridin-3-yl)-2-thioxoimidazolidin-4-one (22)
Formed as colourless crystals from ethanol/dioxane;
MHz) δ: 2.24 (s, 3H, CH3), 2.33 (s, 3H, CH3), 7.19—
8.76 (m, 12H, aromatic H), 11.55 (s, 1H, NH); IR (Film)
v: 3250 (NH2), 3031 (CH-arom), 2920 (CH-aliph), 2200
1
yield 55%, m.p. 234—236 ℃; H NMR (CDCl3, 300
MHz) δ: 4.06 (s, 2H, CH2), 7.23—8.54 (m, 4H, aro-
matic H), 9.08 (s, 1H, NH); IR (Film) v: 3129 (NH),
3042 (CH-arom), 2916 (CH-aliph), 1632 (C＝O), 1403
＋
－1
(CN), 1748 (C＝O) cm ; MS m/z: 421 (M ). Anal.
calcd for C24H19N7O (421.17): C 68.40, H 4.54, N 23.26;
found C 68.55, H 4.65, N 23.40.
＋
－1
(C＝S) cm ; MS m/z: 194 (M ＋1). Anal. calcd for
C8H7N3OS (193.23): C 49.73, H 3.62, N 21.75, S 16.57;
found C 49.68, H 3.62, N 21.73, S 16.56.
3-Oxo-5-(pyridin-3-ylamino)-6-(1-(pyridin-3-yli-
mino)ethyl)-2-(pyridin-4-yl)-2,3dihydropyrida-zine-
4-carbonitrile (18e) Formed as yellow crystals from
ethanol; yield 63%, m.p. 142—143 ℃; 1H NMR
(CDCl3, 300 MHz) δ: 2.24 (s, 3H, CH3), 7.20—8.80 (m,
12H, aromatic H), 11.70 (s, 1H, NH); IR (Film) v: 3340
(NH2), 3030 (CH-arom), 2925 (CH-aliph), 2210 (CN),
General procedure for the synthesis of compounds
24a— 24d
Procedure (A) A mixture of 3-aminopyridine (1)
(0.94 g, 0.01 mol) and arylidenemalononitriles (0.01
mol) in dioxane (70 mL) was treated with few drops of
piperidine and heated under reflux for 3 h. The reaction
mixture was allowed to cool and poured into crushed ice,
then acidified with dilute HCl. The separated solid was
filtered and crystallized from the proper solvent.
Procedure (B) A mixture of chalcones 27 (0.01
mol) and malononitrile (0.01 mol) in dioxane (70 mL)
was treated with few drops of piperidine and heated un-
der reflux for 3 h. The reaction mixture was allowed to
cool and poured into crushed ice, then acidified with
HCl. The separated solid was filtered and crystallized
from the proper solvent.
＋
－1
1740 (C＝O) cm ; MS m/z: 408 (M ). Anal. calcd for
C22H16N8O (408.14): C 64.70, H 3.95, N 27.44; found C
64.90, H 3.10, N 27.60.
Preparation of thiourea derivatives (21a— 21c) and
imidazolidine (22)
To a solution of 3-aminopyridine 1 (0.94 g, 0.01 mol)
in dry acetone (50 mL), aroyl or alkoyl isothiocyanate
20 (0.01 mol) (prepared in situ by refluxing aroyl or
alkoyl chloride with ammonium thiocyanate in dry ace-
tone) was added. The reaction mixture was refluxed for
2 h, and then poured into cold water. The separated
solid was filtered, washed with water and crystallized
from the proper solvent to give thiourea derivatives
21a— 21c or 22.
2-Cyano-3-phenyl-3-(pyridin-3-ylamino)propane-
mide (24a) Formed as brown crystals from etha-
1
nol/DMF; yield 60%, m.p. 191—193 ℃; H NMR
N-(Pyridin-3-ylcarbamothioyl)benzamide (21a)
Formed as colourless crystals from ethanol/dioxane;
(DMSO-d6, 300 MHz) δ: 3.10 (d, J＝3.10 Hz, 1H, CH),
4.70 (d, J＝5.5 Hz, 1H, CH), 6.99—7.99 (m, 11H, aro-
matic H and NH2), 9.99 (s, 1H, NH); IR (Film) v: 3256
(NH), 3032 (CH-arom)－, 2857—2942 (CH-＋aliph), 2180
1
yield 65%, m.p. 184—186 ℃; H NMR (CDCl3, 300
MHz) δ: 7.45—8.78 (m, 9H, aromatic H), 11.71 (s, 1H,
NH), 12.53 (s, 1H, NH); IR (Film) v: 3406 (NH),
300－1—3085 (CH-arom), 1674 (C＝O), 1589 (C＝S)
cm 1; MS m/z: 258 (M ＋ ＋1). Anal. calcd for
C13H11N3OS (257.31): C 60.68, H 4.31, N 16.33, S
12.46; found C 60.60, H 4.20, N 16.30, S 12.40.
1
(CN), 1690 (C＝O) cm ; MS m/z: 264 (M －2). Anal.
calcd for C15H14N4O (266.12): C 67.63, H 5.26, N 21.04;
found C 67.59, H 5.25, N 21.02.
3-(4-Chlorophenyl)-2-cyano-3-(pyridin-3-ylami-
no)propanamide (24b) Formed as brown crystals
1
2-Chloro-N-(pyridin-3-ylcarbamothioyl)benzami-
de (21b) Formed as colorless crystals from etha-
from dioxane; yield 60%, m.p. 150—152 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 3.2 (d, J＝5.5 Hz, 1H, CH),
4.70 (d, J＝5.6 Hz, 1H, CH), 6.98—8.14 (m, 10H, aro-
matic H and NH2), 9.99 (s, 1H, NH); IR (Film) v: 3400
1
nol/dioxane; yield 70%, m.p. 182—184 ℃; H NMR
(CDCl3, 300 MHz) δ: 7.47—8.80 (m, 8H, aromatic H),
Chin. J. Chem. 2011, 29, 1154— 1162
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Hafiz, Ramiz & Sarhan
FULL PAPER
(NH), 3032 (CH-arom), 2857— 2942 (CH-aliph), 2227
N-(2,4-Dichlorobenzylidene)pyridin-3-amine (27d)
＋
－1
Formed as colorless crystals from ethanol; yield 68%,
(CN), 1660 (C＝O) cm ; MS m/z: 300 (M ). Anal.
calcd for C15H13ClN4O (300.08): C 59.98, H 4.33, N
18.66, Cl 11.83; found C 59.85, H 4.32, N 18.62, Cl
11.80.
1
m.p. 115—117 ℃; H NMR (CDCl3, 300 MHz) δ:
7.26—8.86 (m, 8H, alkenyl and aromatic H); IR (Fil－m)
1
v: 3040 (＝CH), 3＋029 (CH-arom), 2160 (C＝N) cm ;
MS m/z: 251 (M ＋1). Anal. calcd for C12H8Cl2N2
(250.01): C 57.60, H 3.20, N 11.20, Cl 25.60; found C
57.37, H 3.18, N 11.15, Cl 25.50.
3-(2-Chlorophenyl)-2-cyano-3-(pyridin-3-ylami-
no) propanamide (24c) Formed as yellow crystals
1
from dioxane; yield 55%, m.p. 162—164 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 3.1 (d, J＝5.7 Hz, 1H, CH),
4.7 (d, J＝5.5 Hz, 1H, CH), 7.06—8.74 (m, 10H, aro-
matic H and NH2), 10.40 (s, 1H, NH); IR (Film) v: 3352
(NH), 3032 (CH－-arom), 2940 (CH-aliph), 2193 (CN),
Results and discussion
Chemistry
＋
1
The starting material N-(pyridin-3-yl)-3-(pyridin-3-
ylimino)butanamide (3) was synthesized by refluxing 2
mol of 3-aminopyridine (1) with one mol of ethyl ace-
toacetate in xylene for 5 h. The analytical and spectra
data of 3 were in accordance with the proposed structure.
1650 (C＝O) cm ; MS m/z: 302 (M ＋2). Anal. calcd
for C15H13ClN4O (300.08): C 59.98, H 4.33, N 18.66, Cl
10.66; found C 59.60, H 4.30, N 18.54, Cl 10.60.
2-Cyano-3-(2,4-dichlorophenyl)-3-(pyridin-3-yla-
mino)propanamide (24d) Formed as brown crystals
from ethanol/dioxane; yield 60%, m.p. 159—161 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 3.2 (d, J＝5.5 Hz,
1H, CH), 4.8 (d, J＝5.8 Hz, 1H, CH), 7.41—8.18 (m,
7H, aromatic H), 10.40 (s, 1H, NH); IR (Film) v: 3367
(NH), 3028 (CH－-arom), 2936 (CH-aliph), 2215 (CN),
1
Thus, H NMR spectrum of compound 3 revealed the
presence of three singlet signals at δ 2.06, 4.95 and 9.79
corresponding to methyl, methylene and NH groups
respectively. The mass spectrum of the same product
showed a molecular ion peak at m/z 253 (M＋－1). For-
mation of 3 from the reaction of 3-aminopyridine (1)
and ethyl acetoacetate is believed to be formed via ini-
tial condensation and subsequent elimination of ethanol
to give 2 that condenses with another molecule of
3-aminopyridine (1) to give 3 via elimination of water
and subsequent tautomerism as shown in Scheme 1.
Trial to prepare compound 2 was succeeded under a
variety of mild conditions (cf. experimental part).
＋
1
1650 (C＝O) cm ; MS m/z: 316 (M －1). Anal. calcd
for C15H10Cl2N4 (317.17): C 56.75, H 3.15, N 17.65, Cl
20.17; found C 56.60, H 3.14, N 17.61, Cl 20.12.
General procedure for the synthesis of compounds
27a— 27d
A mixture of 3-aminopyridine (1) (0.94 g, 0.01 mol)
and aldhyde (0.01 mol) in ethanol (75 mL) was treated
with few drops of piperidine and heated under reflux for
3 h. The reaction mixture was allowed to cool and
poured into crushed ice, then acidified with dilute HCl.
The separated solid was filtered and crystallized from
the proper solvent.
Scheme 1
N-Benzylidenepyridin-3-amine (27a) Formed as
colorless crystals from ethanol; yield 40%, m.p. 90—92
℃; 1H NMR (CDCl3, 300 MHz) δ: 7.20—8.80 (m, 10H,
alkenyl and aromatic H); IR (Film)－v: 3050 (＝CH),
1
3030 (CH-arom), 2155 (C＝N) cm ; MS m/z: 182
(M＋). Anal. calcd for C12H10N2 (182.08): C 79.10, H
5.53, N 15.37; found C 79.30, H 5.70, N 15.40.
N-(4-Bhlorobenzylidene)pyridin-3-amine
(27b)
Formed as colorless crystals from ethanol; yield 46%,
m.p. 78—80 ℃; 1H NMR (CDCl3, 300 MHz) δ:
7.25—8.48 (m, 9H, alkenyl and aromatic H); IR (Fil－m)
1
v: 3040 (＝CH),＋3028 (CH-arom), 2160 (C＝N) cm ;
MS m/z: 216 (M ). Anal. calcd for C12H9ClN2 (216.05):
C 66.65, H 4.16, N 12.95, Cl 14.81; found C 66.46, H
4.15, N 12.92, Cl 14.76.
N-(2-Chlorobenzylidene)pyridin-3-amine
(27c)
Formed as colorless crystals from ethanol; yield 45%,
m.p. 80—82 ℃; 1H NMR (CDCl3, 300 MHz) δ:
7.30—8.70 (m, 9H, alkenyl and aromatic H); IR (Fil－m)
The behavior of 3 towards some electrophilic re-
agents such as arylidinemalononitriles was investigated.
Thus, compound 3 reacted with benzylidenemalononi-
trile 4a in refluxing ethanol containing a catalytic
amount of piperidine to give 1,4-dihydropyridine de-
1
v: 3055 (＝CH),＋3040 (CH-arom), 2170 (C＝N) cm ;
MS m/z: 216 (M ). Anal. calcd for C12H9ClN2 (216.05):
C 66.52, H 4.19, N 12.93, Cl 16.36; found C 66.60, H
4.30, N 12.90, Cl 16.40.
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Chin. J. Chem. 2011, 29, 1154— 1162

Synthesis of New Dihydropyridines, Dihydropyridazines and Thiourea Derivatives
rivative 8a rather than its tautomeric structure 13a.
Structure 13a was ruled out and structure 8a was estab-
lished as the sole product of this reaction based on its
spectral analysis. Thus, the 1H NMR spectrum of com-
pound 8a confirmed the presence of a singlet signal at δ
4.5 corresponding to 4H pyridine, and a singlet signal at
δ 12.14 corresponding to phenolic proton. The presence
of amino function in the ortho position shifts the pheno-
lic proton absorption downfield to δ 12.14 because of
intramolecular hydrogen bonding. The mass spectrum
of 8a showed a molecular ion peak at m/z 405 (M＋－3).
The formation of 8a is believed to be formed via initial
addition of the methylene group of 3 on the double bond
of the arylidene 4 to give the Michael adduct 5 that un-
derwent intramolecular cyclization and subsequent
tautomerisation to give 8a which is stabilized by in-
tramolecular hydrogen bonding. Similarly arylidene-
malononitriles 4b—4e reacted with 3 under the same
reaction conditions to give the dihydropyridine deriva-
tives 8b—8e (Scheme 2). Condensation of 3 with aro-
matic aldehydes in refluxing ethanol containing a cata-
lytic amount of piperidine resulted in the formation of
9a—9e. Compounds 9a—9e add readily malononitrile
in refluxing ethanol to give 1,4-dihydropyridine deriva-
tives 8a—8e (Scheme 2). Establishing structures
8a—8e for the reaction of 9a—9e with malononitrile
was based on their spectral data and mixed melting
points of the authentic samples prepared from the reac-
tion of 3 with arylidinemalononitriles 4a—4e (Scheme
2).
of 3-aminopyridine (1) towards isothiocyanate reagents.
Thus compound 1 reacted with benzoylisothiocyanate
(20a) to afford a product with a molecular formula
C13H11N3OS＝257 which was considered to be the
acyclic thiourea derivative 21a based on its spectral
1
analysis. Thus, the H NMR spectrum of 21a revealed
the presence of a multiplet signals at δ 7.45—8.78 cor-
responding to aromatic protons and two singlet signals
at δ 11.71 and 12.53 corresponding to two NH groups.
Trials to cyclise the acyclic thiourea derivative 21a
failed under a variety of experimental conditions. Simi-
larly, isothiocynate derivatives 20b—20c reacted with 1
to give the acyclic thiourea derivatives 21b—21c. The
structures of 21a—21c were confirmed by studying
their elemental and spectral analyses (Scheme 4).
In contrast to the behaviour of 1 towards isothiocy-
anate reagents 20a—20c, compound 1 reacted with
isothiocyanate 20d in refluxing acetone to give imida-
zolidine derivative 22. Formation of 22 is believed to be
formed via the loss of HCl from 21d followed by sub-
sequent cyclization. Establishing structure 22 was based
1
on its spectral analysis. Thus, the H NMR spectrum of
22 showed the appearance of a singlet signal at δ 4.06
corresponding to CH2 group. The mass spectrum of 22
showed a molecular ion peak at m/z 194 (M＋＋1) in
agreement with its molecular formula C8H7N3OS.
The behavior of 3-aminopyridine (1) towards
arylidenemalononitrile reagents 4 was also investigated.
Thus, 3-aminopyridine (1) reacted with benzylidine-
malononitrile (4a) to give propanamide derivative 24a,
via intermediacy of Michael adduct 23a. The structure
of 24a was established based on its elemental analysis
Compound 3 coupled readily with aryl diazonium
salts 14a—14e to form the corresponding hydrazo
compounds 15a—15e rather than their potentially
tautomeric azo structures 19a—19e based on their spec-
1
and spectral data. Thus, the H NMR spectrum of 24a
revealed the presence of a two doublet signals at δ 3.10
and 4.70 corresponding to two sp3 protons, a multiplete
signal at δ 6.99—7.99 corresponding to aromatic pro-
tons and the NH group appeared as singlet signal at δ
9.99. The mass spectrum of 24a ＋showed a very intense
molecular ion peak at m/z 264 (M －2) and a number of
fragments in agreement with the proposed structure.
Formation of 24a from the reaction of 3-aminopyridine
(1) and benzylidinemalononitrile (4a) is believed to be
formed via initial addition of 3-aminopyridine on the
double bond system of benzylidinemalononitrile to give
the non isolable intermediate 23a which formulated into
24a via the addition of one water molecule, from the
aqueous medium of the reaction, on the nitrile group to
give 24a. Similarly, 3-aminopyridine (1) reacted with
arylidinemalononitriles 4b—4d to give 24b—24d via
intermediacy of 23b—23d. Trials to cyclize the acyclic
derivative 24 into pyridopyridine derivatives 25 failed
under a variety of experimental conditions (Scheme 5).
Propanamide derivatives 24a—24d were prepared in
a good yields from the reaction of 3-aminopyridine (1)
with aldehydes 26a—26d in refluxing dioxane contain-
ing catalytic amount of pipridine to give chalcons
1
tral analyses. Thus, the H NMR spectrum of 15a re-
vealed the presence of two signals at δ 11.49 and 12.93
corresponding to two NH groups. Furthermore, the IR
spectrum of the same product further supports the hy-
drozo structure. Fusion of 15a—15e with ethyl
cyanoacetate in domestic micro wave oven for 5 min
gives rise to the 2,5-dihydropyridazine derivatives
18a—18e. The structure of 18a was confirmed by
1
studying its spectral data. For example the H NMR of
18a showed the presence of two singlet signals at δ 2.29
and 11.80 corresponding to a methyl and amino groups
respectively. The mass spectrum of 18a showed a mo-
lecular ion peak at m/z 407 (M＋) in agreement with its
molecular formula C23H17N7O. Formation of
2,5-dihydropyridazine derivatives 18 from the reaction
of 15 with ethyl cyanoacetate is believed to be formed
via initial addition of methylene group of ethyl
cyanoacetate on the carbonyl group of 15 to give the
non isolable intermediate 16 that loses ethanol and wa-
ter under the same reaction condition to give 18 via in-
termediacy of 17.
The behavior of compound 3 towards electrophilic
reagents prompted us to investigate further the behavior
Chin. J. Chem. 2011, 29, 1154— 1162
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1159

Hafiz, Ramiz & Sarhan
FULL PAPER
Scheme 2
Conclusion
27a—27d. Refluxing of 27a—27d with malononitrile in
dioxane/piperidine afforded the non isolable intermedi-
ates 23a—23d which add one water molecule to give
24a—24d. Establishing structures 24a—24d for the
reaction of 27 with malononitrile was based on their
spectral data and mixed melting points of the authentic
samples prepared from the reaction of 1 with arylidine-
malononitriles 4a—4d (Scheme 5).
New dihydropyridines, dihydropyridazines and thio-
urea derivatives were accomplished by the reaction of
butanamide and pyridine derivatives as starting materi-
als with selected electrophilic reagents.
Acknowledgement
Authors wish their deep great acknowledgments to
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Chin. J. Chem. 2011, 29, 1154— 1162

Synthesis of New Dihydropyridines, Dihydropyridazines and Thiourea Derivatives
Scheme 3
Scheme 4
Scheme 5
Prof. Dr. Ahmed Ismail Khodair Professor of Organic
Chemistry, Suez Canal University, Faculty of Science,
for his valuable assistance during the course of this
study.
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