β-Enaminonitriles in heterocyclic synthesis: Synthesis of new 1,4-dihydropyridine, tetrahydropyridine, nicotinonitrile and aminopyrazole derivatives

Article abstract of DOI:10.1002/jccs.201100537

A series of new pyridine, dihydropyridine, tetrahydropyridine, nicotinonitrile and pyrazole derivatives with expected biological activity were prepared through the reactions of 3-aminopent-2-enenitrile 1 with some electrophilic reagents, nucleophilic reagents, and aryl diazonium salts. The newly synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR and mass spectral studies.

Full text of DOI:10.1002/jccs.201100537

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
b-Enaminonitriles in Heterocyclic Synthesis: Synthesis of New 1,4-Dihydropyridine,
Tetrahydropyridine, Nicotinonitrile and Aminopyrazole Derivatives
Mahmoud M. M. Ramiz,a,* Ibrahim S. Abdel Hafizb and Mohamed A. Elianb
aDepartment of Physics and Mathematical Engineering, Faculty of Electronic Engineering, Minoufyia University,
Menouf, Egypt
bDepartment of Chemistry, Faculty of Education, Suez Canal University, Arish, Egypt
(Received: Sept. 5, 2011; Accepted: Jan. 2, 2012; Published Online: ??; DOI: 10.1002/jccs.201100537)
A series of new pyridine, dihydropyridine, tetrahydropyridine, nicotinonitrile and pyrazole derivatives
with expected biological activity were prepared through the reactions of 3-aminopent-2-enenitrile 1 with
some electrophilic reagents, nucleophilic reagents, and aryl diazonium salts. The newly synthesized com-
pounds were characterized by IR, 1H-NMR, 13C-NMR and mass spectral studies.
Keywords: b-Enaminonitrles; 1,4-Dihydropyridine; Tetrahydropyridine; Nicotinonitrile;
Aminopyrazole.
INTRODUCTION
In recent years, much synthetic heterocyclic organic
tion, nitrogen-linked heterocyclic compounds received
considerable attention in recent years because of their me-
dicinal and pesticidal importance.15,16 It is well known that
the study of pyrazole derivatives is significant in pesticide
chemistry, and some pyrazole derivatives were widely used
because of their antiviral,17 antitumor,18 anti-inflamma-
tory,19 antibacterial,20 herbi-cidal,21 insecticidal,22 and fun-
gicidal activities.23 It was also found that the o-phthalimide
nucleus, which incorporates a pyrazole ring, exhibits a
large number of biological activities, especially herbicidal
activities.21 In addition, it was reported that the antibiotics
pyrazole C-glycoside (pyrazofurin), possess a broad spec-
trum of antimicrobial and antiviral activities with consider-
able activity against several tumor cell lines.24
chemistry involves specially designed reagents which are
readily generated and used to provide molecules as func-
tional moieties for further exploitation. Important exam-
ples of such reagents are b-enaminonitriles, which have
proven to be valuable reagents in the synthesis of a wide
variety of unique heterocyclic systems such as pharmaceu-
ticals, fungicides and solavtochromatic dyes. A number of
papers and patents concerning the importance of b-enami-
nonitriles in the synthesis of biologically active com-
pounds such as; dihydropyridines analogous to nifedipine
and amlodipine which considered as a potential calcium
channel blockers in the treatment of angina and hyperten-
sion.1-5
Therefore, our interest was to develop an efficient
synthesis method utilizing the readily obtainable b-enami-
nonitrile as a starting material for the synthesis and charac-
terization of polyfunctionally substituted Pyridines, Nico-
tinonitriles and pyrazoles and some new derivatives of
these compounds.
Pyridine derivatives occur in numerous natural prod-
ucts which are of fundamental importance to living systems
(e.g., nicotinamide adenine dinucleotide (NAD)). They
display interesting physiological activities with attractive
applications as pharmaceuticals and agro-chemicals, as
well as general synthetic building blocks.6,7 Nicotinonitrile
like pyridine derivatives are of special synthetic impor-
tance,8 the interest in further developing novel routes for
the synthesis of these compounds has been revived.9 The
potent biological activity of various vitamins and drugs10-12
is primarily contributed to the presence of pyridine ring in
their molecular make-up. Also, the pyridine ring was found
in the skeleton of many compounds that have potent anti-
bacterial, antifungal and anticancer properties.13,14 In addi-
EXPERIMENTAL
Melting points were determined using a Büchi appa-
ratus and are 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 radiation. IR spectra
(KBr) were recorded on a Bruker-Vector 22 instrument
(Bruker) and frequencies are expressed in cm-1. NMR spec-
* Corresponding author. E-mail: dr.m.ramiz@gmail.com
J. Chin. Chem. Soc. 2012, 59, 000-000
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Article
Ramiz et al.
tra 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 d scale (ppm) relative to
TMS as a standard. EI-mass spectra were recorded with a
HP D5988 A 1000MHz instrument (Hewlett-Packard). El-
emental analyses were performed at the Microanalytical
Centre at the Faculty of Science, Cairo University, Egypt.
Preparation of 2-((dimethylamino)methylene)-3-imino-
pentanenitrile (2)
7.85 (s, 1H, NH); 13C NMR (CDCl3): d 12.00, 21.75, 44.00,
44.00, 54.70, 56.90, 75.50, 114.60, 114.60, 152.50,
155.00; MS: m/z (%) 217 (M+); Anal. calcd. for C11H15N5
(217.27): C, 60.81; H, 6.96; N, 32.23; Found: C, 60.70; H,
6.87; N, 32.19.
2-Amino-6-ethylpyridine-3,5-dicarbonitrile (8)
A mixture of 3-aminopent-2-enenitrile 1 (0.96 g, 0.01
mol) and ethoxymethylenemalononitrile (0.01 mol) in eth-
anol (80 mL) containing catalytic amount of piperidine (5
drops) was heated under reflux for 7 h. The reaction mix-
ture was allowed to cool and poured into crushed ice then
acidified with HCl. The separated solid was filtered, washed
with water and crystallized from ethanol (yellowcrystals).
Yield 84%; mp 182-184 °C; IR (KBr): u cm-1 3430,
3300 (NH2), 3036 (CH-arom), 2988 (CH-aliph), 2223
(2CN); 1H-NMR (CDCl3): d 1.17 (t, 3H, CH3), 2.60 (q, 2H,
CH2), 7.05-7.97 (m, 3H, Ar H and NH2); MS: m/z (%) 172
(M+); Anal. calcd. for C9H8N4 (172.19): C, 62.78; H, 4.68;
N, 32.54; Found: C, 62.73; H, 4.62; N, 32.49.
Amixture of 3-aminopent-2-enenitrile 1 (0.96 g, 0.01
mol) and N,N-Dimethyl-formamide Dimethylacetal (1.19
g, 0.01 mol) was refluxed in ethanol (30 mL) for 4 h. The
reaction mixture was allowed to cool and the separated
solid product was collected by filtration and crystallized
from ethanol (white crystals); Yield 82%; mp 145-147 °C;
IR (KBr): u cm-1 3341 (NH), 2927 (CH-aliph), 2229 (CN);
1H-NMR (CDCl3): d 1.24 (t, 3H, CH3), 2.01 (s, 6H, 2CH3);
2.71 (q, 2H, CH2); 3.99 (br, 1H, NH); 6.09 (s, 1H, CH-
olifinic); MS: m/z (%) 151 (M+, 100), 136 (80), 123 (50),
109 (30), 95 (33), 68 (25), 54 (65); Anal. calcd. for
C8H13N3 (151.21): C, 63.54; H, 8.67; N, 27.79; Found: C,
63.48; H, 8.53; N, 27.67.
Preparation of 3-amino-2-(diethoxymethyl)pent-2-
enenitrile (9)
Amixture of 3-aminopent-2-enenitrile 1 (0.96 g, 0.01
mol) and triethoxymethane (1.48 g, 0.01 mol) was refluxed
in acetic anhydride (30 mL) for 5 h. The reaction mixture
was allowed to cool and the separated solid product was
collected by filtration and crystallized from ethanol (white
crystals); Yield 77%; mp 243-245 °C; IR (KBr): u cm-1
3337, 3300 (NH2), 2973 (CH-aliph), 2219 (CN); 1H-NMR
(CDCl3): d 1.18 (t, 6H, 2CH3), 1.29 (t, 3H, CH3); 2.64 (q,
2H, CH2); 2.73 (q, 4H, 2CH2), 4.87 (s, 1H, CH); 6.11 (s,
2H, NH2); MS: m/z (%) 198 (M+); Anal. calcd. for
C10H18N2O2 (198.26): C, 60.58; H, 9.15; N, 14.13; Found:
C, 60.53; H, 9.09; N, 14.10.
General procedure for the synthesis of 2-amino-4-
(dimethylamino)-6-ethyl-1,4-dihydropyridine-3,5-di-
carbonitrile (5)
Procedure (A)
A mixture of iminopentanenitrile derivatives 2 (1.51
g; 0.01 mol) and benzylidene malononitriles 3 (0.01 mol) in
ethanol (80 mL) containing catalytic amount of piperidine
(5 drops) was heated under reflux for 6 h. The reaction mix-
ture was allowed to cool and poured into crushed ice then
acidified with HCl. The separated solid was filtered, washed
with water and crystallized from the proper solvent to give
the dihydropyridine 6.
General procedure for the synthesis of tetrahydro-
pyridine derivatives (11a-c)
Procedure (B)
A mixture of iminopentanenitrile derivatives 2 (1.51
g; 0.01 mol) and malononitrile (0.01 mol) in ethanol (80
mL) containing catalytic amount of piperidine (5 drops)
was heated under reflux for 2 h. The reaction mixture was
allowed to cool and poured into crushed ice then acidified
with HCl. The separated solid was filtered, washed with
water and crystallized from ethanol (brown crystals); Yield
80%; mp 152-154 °C; IR (KBr): u cm-1 3363, 3300 (NH2),
3102 (NH), 2925 (CH-aliph), 2219 (2CN); 1H-NMR
(CDCl3): d 1.31 (t, 3H, CH3), 2.53 (s, 6H, 2CH3), 3.20 (q,
2H, CH2), 4.56 (s, 1H, H-4 pyridine), 5.66 (s, 2H, NH2),
A mixture 3-amino-2-(diethoxymethyl)pent-2-ene-
nitrile 9 (1.98 g; 0.01 mol) and benzylidenemalononitriles
3a-c (0.01 mol) in ethanol (60 mL) containing catalytic
amount of piperidine (5 drops) was heated under reflux for
5 h. The reaction mixture was allowed to cool and poured
into crushed ice then acidified with HCl. The separated
solid was filtered, washed with water and crystallized from
ethanol (yellow crystals).
4,4-Diethoxy-6-ethyl-3-phenyl-1,2,3,4-tetrahydropyr-
idine-2,5-dicarbonitrile (11a)
Yield 87%; mp 114-116 °C; IR (KBr): u cm-1 3343
2
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b-Enaminonitriles in Heterocyclic Synthesis
(NH), 2934 (CH-aliph), 2192 (2CN); 1H-NMR (DMSO-
d6):d 1.20 (t, 6H, 2CH3), 1.45 (t, 3H, CH3), 4.53 (q, 2H,
CH2), 4.55 (q, 4H, 2CH2), 6.77 (d, 1H, C-2), 7.15 (d, 1H,
C-3), 7.20-7.70 (m, 6H, Ar H and NH); 13C NMR (DMSO-
d6):d 12.00, 15.90, 15.90, 23.10, 44.80, 51.00, 61.40,
51.40, 84.00, 111.00, 115.50, 117.60, 127.00, 128.30,
128.30, 129.50, 129.50, 137.00, 160.40; MS: m/z (%) 325
(M+);Anal. calcd. for C19H23N3O2 (325.40): C, 70.13; H,
7.12; N, 12.91; Found: C, 70.09; H, 7.07; N, 12.86;
3-(4-Chlorophenyl)-4,4-diethoxy-6-ethyl-1,2,3,4-tetra-
hydropyridine-2,5 dicarbonitrile (11b)
Yield 80%; mp 121-123 °C; IR (KBr): u cm-1 3352
(NH), 3172 (CH-arom), 2954 (CH-aliph), 2210 (2CN);
1H-NMR (DMSO-d6): d 1.29 (t, 6H, 2CH3), 1.35 (t, 3H,
CH3), 4.43 (q, 2H, CH2), 4.45 (q, 4H, 2CH2), 6.80 (d, 1H,
C-2), 7.15 (d, 1H, C-3), 7.27-7.57 (m, 5H, Ar H and NH);
MS: m/z (%) 359 (M+); Anal. calcd. for C19H22ClN3O2
(359.85): C, 63.42; H, 6.16; Cl, 9.85; N, 11.68,; Found: C,
63.20; H, 6.20; Cl, 9.80; N, 11.75.
(q, 2H, CH2), 5.20 (s, 2H, NH2), 7.22-8.01 (m, 5H, Ar H);
13C NMR (CDCl3): d 13.00, 30.40, 85.60, 101.00, 116.50,
118.70, 125.00, 128.50, 128.50, 132.40, 132.40, 140.00,
161.30, 170.20, 172.50; MS: m/z (%) 248 (M+); Anal.
calcd. for C15H12N4 (248.28): C, 72.56; H, 4.87; N, 22.57;
Found: C, 72.50; H, 4.82; N, 22.50.
2-Amino-4-(4-chlorophenyl)-6-ethylpyridine-3,5-dicar-
bonitrile (14b)
Yield 67%; mp 136-138 °C; IR (KBr): u cm-1 3338,
3300 (NH2), 3070 (CH-arom), 2952 (CH-aliph), 2195
(2CN); 1H-NMR (CDCl3): d 1.25 (t, 3H, CH3), 3.70 (q, 2H,
CH2), 5.59 (s, 2H, NH2), 7.20-8.00 (m, 4H, Ar H); MS: m/z
(%) 282 (M+); Anal. calcd. for C15H11ClN4 (282.73): C,
63.72; H, 3.92; Cl, 12.54; N, 19.82; Found: C, 63.72; H,
3.92; Cl, 12.54; N, 19.82.
2-Amino-4-(3-chlorophenyl)-6-ethylpyridine-3,5-dicar-
bonitrile (14c)
Yield 62%; mp 110-112 °C; IR (KBr): u cm-1 3345,
3300 (NH2), 3090 (CH-arom), 2928 (CH-aliph), 2198
(2CN); 1H-NMR (CDCl3): d 1.42 (t, 3H, CH3), 3.70 (q, 2H,
CH2), 5.70 (s, 2H, NH2), 7.22-7.42 (m, 4H, Ar H); MS: m/z
(%) 282 (M+); Anal. calcd. for C15H11ClN4 (282.73): C,
63.72; H, 3.92; Cl, 12.54; N, 19.82; Found: C, 63.72; H,
3.92; Cl, 12.54; N, 19.8.
3-(2-Chlorophenyl)-4,4-diethoxy-6-ethyl-1,2,3,4-tetra-
hydropyridine-2,5-dicarbonitrile (11c)
Yield 83%; mp 130-132 °C; IR (KBr): u cm-1 3465
(NH), 3050 (CH-arom), 2957 (CH-aliph), 2302 (2CN);
1H-NMR (DMSO-d6): d 1.27 (t, 6H, 2CH3), 1.40 (t, 3H,
CH3), 4.45 (q, 2H, CH2), 4.53 (q, 4H, 2CH2), 6.77 (d, 1H,
C-2), 7.14 (d, 1H, C-3), 7.20-7.60 (m, 5H, Ar H and NH);
MS: m/z (%) 359 (M+); Anal. calcd. for C19H22ClN3O2
(359.85): C, 63.42; H, 6.16; Cl, 9.85; N, 11.68; Found: C,
63.35; H, 6.10; Cl, 9.95; N, 11.60.
2-Amino-6-ethyl-4-(4-nitrophenyl)pyridine-3,5-dicar-
bonitrile (14d)
Yield 83%; mp 116-118 °C; IR (KBr): u cm-1 3354,
1
3300 (NH2), 2940 (CH-aliph), 2209 (2CN); H-NMR
(CDCl3): d 1.98 (t, 3H, CH3), 3.44 (q, 2H, CH2), 5.50 (s,
2H, NH2), 7.26-8.40 (m, 4H, Ar H); MS: m/z (%) 293 (M+);
Anal. calcd. for C15H11N5O2 (293.28): C, 61.43; H, 3.78; N,
23.88 Found: C, 61.39; H, 3.72; N, 23.84.
General procedure for the synthesis of pyridine de-
rivatives (14a-l)
Amixture of 3-aminopent-2-enenitrile 1 (0.96 g; 0.01
mol) and arylidenemalononitriles 3a-e (0.01 mol) or ethyl
2-cyano-3-phenylacrylate derivatives 3f-h (0.01 mol) or
2-cyano-3-phenylprop-2-enethioamide derivatives 3i-l
(0.01 mol) in ethanol (60 mL) containing catalytic amount
of piperidine (5 drops) was refluxed for 5 h. The reaction
mixture was allowed to cool and poured into crushed ice
then acidified with HCl, the solid product so formed was
collected by filtration and crystallized from the proper sol-
vent (Brown crystals).
2-Amino-4-(2,4-dichlorophenyl)-6-ethylpyridine-3,5-
dicarbonitrile(14e)
Yield 88%; mp 124-126 °C; IR (KBr): umax = 3343,
3300 (NH2), 3076 (CH-arom), 2931 (CH-aliph), 2195
(2CN); 1H-NMR (CDCl3): d 1.22 (t, 3H, CH3), 3.45 (q, 2H,
CH2), 5.90 (s, 2H, NH2), 7.24-7.66 (m, 3H, Ar H); MS: m/z
(%) 317 (M+); Anal. calcd. for C15H10Cl2N4 (317.17): C,
56.80; H, 3.18; Cl, 22.36; N,17.66; Found: C, 56.80; H,
3.18; Cl, 22.36; N, 17.66.
2-Amino-6-ethyl-4-phenylpyridine-3,5-dicarbonitrile
Ethyl 2-amino-5-cyano-6-ethyl-4-(4-nitro-phenyl)-
(14a)
Yield 64%; mp 132-134 °C; IR (KBr): u cm-1 3341,
3300 (NH2), 3076 (CH-arom), 2929 (CH-aliph), 2173,
nicotinate (14f)
Yield 87%; mp 119-121 °C; IR (KBr): u cm-1 3422,
3300 (NH2), 3032 (CH-arom), 2992 (CH-aliph), 2225
(CN), 1720 (C=O); 1H-NMR (CDCl3): d 1.38 (t, 3H, CH3),
1
2200 (2CN); H-NMR (CDCl3): d 1.25 (t, 3H, CH3), 3.43
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Article
Ramiz et al.
1.41 (t, 3H, CH3), 3.70 (q, 2H, CH2), 4.40 (q, 2H, CH2),
5.20 (s, 2H, NH2), 7.26-8.37 (m, 4H, Ar H); 13C NMR
(CDCl3): d 13.30, 14.40, 30.50, 62.00, 95.10, 99.00,
132.70, 132.70, 128.30, 131.00, 131.00, 139.60, 145.10,
154.00, 167.30, 168.70, 171.20; MS: m/z (%) 340 (M+);
Anal. calcd. for C17H16N4O4 (340.33): C, 59.99; H, 4.74; N,
16.46, Found: C, 59.94; H, 4.69; N, 16.43.
C15H13ClN4S (316.81): C, 56.87; H, 4.14; Cl, 11.19; N,
17.68; S, 10.12, Found: C, 56.80; H, 4.10; Cl, 11.25; N,
17.75; S, 10.15.
2-Amino-5-cyano-6-ethyl-4-(4-methoxy-phenyl)-pyri-
dine-3-carbothioamide (14k)
Yield 79%; mp 136-138 °C; IR (KBr): u cm-1 3377,
3277, 3166 (2NH2), 2940 (CH-aliph), 2226 (CN); 1H-
NMR (CDCl3): d 1.83 (t, 3H, CH3), 3.49 (q, 2H, CH2), 3.89
(s, 3H, OCH3), 6.86-8.05 (m, 4H, Ar H), 8.74 (s, 2H, NH2),
10.00 (s, 2H, NH2); MS: m/z (%) 312 (M+); Anal. calcd. for
C16H16N4OS (312.39): C, 61.52; H, 5.16; N, 17.93, S,
10.26, Found: C, 61.46; H, 5.11; N, 17.90, S, 10.19 %.
2-Amino-5-cyano-4-(2,4-dichlorophenyl)-6-ethyl-pyri-
dine-3-carbothioamide (14l)
Yield 76%; mp 121-123 °C; IR (KBr): u cm-1 3480,
3337, 3170 (2NH2), 3090 (CH-arom), 2924 (CH-aliph),
2215 (CN); 1H-NMR (CDCl3): d 1.22 (t, 3H, CH3), 3.45 (q,
2H, CH2), 7.30-7.66 (m, 3H, Ar H), 8.90 (s, 2H, NH2),
10.20 (s, 2H, NH2); MS: m/z (%) 351 (M+); Anal. calcd. for
C15H12Cl2N4S (351.25): C, 51.29; H, 3.44; Cl, 20.19; N,
15.95; S, 9.13, Found: C, 51.35; H, 3.50; Cl, 20.15; N,
15.90; S, 9.15.
Ethyl 2-amino-4-(4-chlorophenyl)-5-cyano-6-ethyl-
nicotinate (14g)
Yield 92%; mp 131-33 °C; IR (KBr): u cm-1 3441,
3300 (NH2), 3036 (CH-arom), 2990 (CH-aliph), 2223
1
(CN), 1724 (C=O); H-NMR (CDCl3): d 1.40 (t, 3H, CH3),
1.52 (t, 3H, CH3), 4.22 (q, 2H, CH2), 4.40 (q, 2H, CH2),
7.27-8.20 (m, 6H, Ar H and NH2); MS: m/z (%) 329 (M+);
Anal. calcd. for C17H16N3ClO2 (329.78): C, 61.91; H, 4.89;
N, 12.74; Cl, 10.75, Found: C, 61.85; H, 4.95; N, 12.80;
Cl, 10.85.
Ethyl 2-amino-5-cyano-4-(2,4-dichlorophenyl)-6-
ethylnicotinate (14h)
Yield 90%; mp 128-130 °C; IR (KBr): u cm-1 3441,
3300 (NH2), 3076 (CH-arom), 2934 (CH-aliph), 2219
(CN), 1725 (C=O); 1H-NMR (CDCl3): d 1.45 (t, 3H, CH3),
1.60 (t, 3H, CH3), 4.20 (q, 2H, CH2), 4.45 (q, 2H, CH2),
7.27-8.20 (m, 5H, Ar H and NH2); MS: m/z (%) 364 (M+);
Anal. calcd. for C17H15Cl2N3O2 (364.23): C, 56.06; H,
4.15; Cl, 19.47; N, 11.54, Found: C, 56.10; H, 4.20; Cl,
19.55; N, 11.60.
General procedure for the synthesis of diazenyl de-
rivatives (16a-e)
Acold suspension of aryl diazonium salts 15a-e (0.01
mol) (prepared from 0.01 mol of aromatic amine in 5 mL
concentrated HCl with the appropriate quantities of sodium
nitrite 0.7 g in 10 mL H2O) was gradually added to a cold
solution (0-5 °C) of 1 (0.01 mol) in ethanol (50 mL) con-
taining anhydrous sodium acetate (5 g) with continuous
stirring for 1 hr. The resulting reaction product was filtered
off, washed with water and crystallized from the proper
solvent (reddish brown).
2-Amino-5-cyano-6-ethyl-4-phenylpyridine-3-carbo-
thioamide (14i)
Yield 86%; mp 260-262 °C; IR (KBr): u cm-1 3274,
3116 (NH2), 2926 (CH-aliph), 2216 (CN); 1H-NMR
(DMSO-d6): d 1.63 (t, 3H, CH3), 3.00 (q, 2H, CH2), 7.41-
7.59 (m, 5H, Ar H), 8.21 (s, 2H, NH2), 12.74 (s, 2H, NH2);
13C-NMR (DMSO-d6): d 13.00, 29.70, 100.50, 116.00,
117.60, 126.20, 128.50, 128.50,133.40, 133.40, 139.00,
155.70, 164.70, 167.00, 194.20; MS: m/z (%) 282 (M+);
Anal. calcd. for C15H14N4S (282.36): C, 63.80; H, 5.00; N,
19.84, S, 11.36, Found: C, 63.75; H, 4.93; N, 19.79, S,
11.31.
3-Amino-2-(phenyldiazenyl)pent-2-enenitrile (16a)
Yield 69%; mp 113-115 °C; IR (KBr): u cm-1 3433,
3106 (NH2), 2924 (CH-aliph), 2194 (CN); 1H-NMR (CDCl3):
d 1.27 (t, 3H, CH3), 3.33 (q, 2H, CH2), 7.17-7.41 (m, 7H,
Ar H and NH2); MS: m/z (%) 200 (M+); Anal. calcd. for
C11H12N4 (200.24): C, 65.98; H, 6.04; N, 27.98; Found: C,
65.94; H, 5.97; N, 27.91.
2-Amino-4-(4-chlorophenyl)-5-cyano-6-ethyl-pyridine-
3-carbothioamide (14j)
3-Amino-2-((4-nitrophenyl)diazenyl)pent-2-enenitrile
Yield 83%; mp 140-142 °C; IR (KBr): u cm-1 3415,
3400, 3194 (2NH2), 3076 (CH-arom), 2934 (CH-aliph),
2195 (CN); 1H-NMR (DMSO-d6): d 1.60 (t, 3H, CH3), 3.10
(q, 2H, CH2), 7.40-7.60 (m, 4H, Ar H), 8.35 (s, 2H, NH2),
12.70 (s, 2H, NH2); MS: m/z (%) 316 (M+); Anal. calcd. for
(16b)
Yield 72%; mp 118-120 °C; IR (KBr): u cm-1 3401,
3116 (NH2), 2908 (CH-aliph), 2204 (CN); 1H-NMR (CDCl3):
d 1.25 (t, 3H, CH3), 2.22 (q, 2H, CH2), 4.80 (s, 2H, NH2),
7.26-8.43 (m, 4H, Ar H); MS: m/z (%) 245 (M+); Anal.
4
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b-Enaminonitriles in Heterocyclic Synthesis
calcd. for C11H11N5O2 (245.24): C, 53.87; H, 4.52; N,
28.56; Found: C, 53.81; H, 4.49; N, 28.53.
32.22.
5-Ethyl-4-(p-tolyldiazenyl)-1H-pyrazol-3-amine (18b)
Yield 65%; mp 180-182 °C; IR (KBr): u cm-1 3407,
3390 (NH2), 3154 (NH), 2923 (CH-aliph); 1H-NMR
(CDCl3): d 0.88 (t, 3H, CH3), 1.26 (s, 3H, CH3), 2.39 (q,
2H, CH2), 7.06-7.26 (m, 6H, Ar H and NH2), 11.59 (s, 1H,
NH); MS: m/z (%) 229 (M+); Anal. calcd. for C12H15N5
(229.28): C, 62.86; H, 6.59; N, 30.54, Found: C, 62.84; H,
6.57; N, 30.47.
3-Amino-2-((4-bromophenyl)diazenyl)pent-2-enenitrile
(16c)
Yield 67%; mp 115-117 °C; IR (KBr): u cm-1 3266,
3192 (NH2), 2956 (CH-aliph), 2212 (CN); 1H-NMR (CDCl3):
d 1.25 (t, 3H, CH3), 2.08 (q, 2H, CH2), 5.00 (s, 2H, NH2),
7.06-8.28 (m, 4H, Ar H); MS: m/z (%) 279 (M+); Anal.
calcd. for C11H11N4Br (279.14): C, 47.33; H, 3.97; Br,
28.63; N, 20.07; Found: C, 47.40; H, 4.00; Br, 28.60; N,
20.0.
4-((4-Chlorophenyl)diazenyl)-5-ethyl-1H-pyrazol-3-
amine (18c)
Yield 57%; mp 129-131 °C; IR (KBr): u cm-1 3300,
3277 (NH2), 3110 (NH), 2992 (CH-aliph); 1H-NMR
(CDCl3): d 1.32 (t, 3H, CH3), 2.13 (q, 2H, CH2), 5.80 (s,
2H, NH2), 7.08-8.08 (m, 4H, Ar H), 12.78 (s, 1H, NH); MS:
m/z (%) 249 (M+); Anal. calcd. for C11H12N5Cl (249.70): C,
52.91; H, 4.84; N, 28.05; Cl, 14.20, Found: C, 52.87; H,
4.80; N, 27.97, Cl, 14.16.
3-Amino-2-(p-tolyldiazenyl)pent-2-enenitrile (16d)
Yield 79%; mp 126-128 °C; IR (KBr): u cm-1 3435,
3194 (NH2), 2924 (CH-aliph), 2213 (CN); 1H-NMR
(CDCl3): d 1.25 (s, 3H, CH3), 1.60 (t, 3H, CH3), 2.28 (q,
2H, CH2), 3.90 (s, 2H, NH2), 7.07-8.32 (m, 4H, Ar H); MS:
m/z (%) 214 (M+); Anal. calcd. for C12H14N4 (214.27):
C,67.27; H,6.59; N,26.15, Found: C, 67.22; H, 6.52; N,
26.11.
General procedure for the synthesis of nicotino-nitrile
derivatives (21a-c)
3-Amino-2-((4-chlorophenyl)diazenyl)pent-2-enenitrile
A mixture of compounds 16 (0.01 mole), ammonium
acetate (0.01 mole) and malononitrile (0.66 g, 0.01 mole)
was fused in domestic microwave oven for 3 minutes. The
solid precipitate so formed was treated with ethanol and fil-
tered out and crystallized from the proper solvent (reddish
brown).
(16e)
Yield 82%; mp 120-122 °C; IR (KBr): u cm-1 3434,
3192 (NH2), 2964 (CH-aliph), 2201 (CN); 1H-NMR
(CDCl3): d 1.24 (t, 3H, CH3), 2.07 (q, 2H, CH2), 5.20 (s,
2H, NH2), 7.17-8.10 (m, 4H, Ar H), MS: m/z (%) 234 (M+);
Anal. calcd. for C11H11ClN4 (234.68): C,56.30; H,4.72; Cl,
15.11; N,23.87, Found: C,56.35; H,4.80; Cl, 15.10; N,
23.90.
2,4-Diamino-6-ethyl-5-(phenyldiazenyl)nicotino-nitrile
(21a)
Yield 64%; mp 130-132 °C; IR (KBr): u cm-1 3480,
3400, 3337, 3300 (2NH2), 3064 (CH-arom), 2934 (CH-
aliph), 2193 (CN); 1H-NMR (CDCl3): d 1.20 (t, 3H, CH3),
3.20 (q, 2H, CH2), 5.40 (s, 4H, 2 NH2), 7.40-8.00 (m, 5H,
ArH); MS: m/z (%) 266 (M+); Anal. calcd. for C14H14N6
(266.30): C, 63.14; H, 5.30; N, 31.56, Found: C, 63.11; H,
5.28; N, 31.51.
General procedure for the synthesis of pyrazole de-
rivatives (18a-c)
A mixture of compounds 16 (0.01 mole), ammonium
acetate (0.01 mole) and hydrazine hydrate (0.5 g 0.01
mole) was fused in domestic microwave oven for 3 min-
utes. The solid precipitate so formed was treated with etha-
nol and filtered out and crystallized from the proper sol-
vent.
2,4-Diamino-6-ethyl-5-((4-nitrophenyl)diazenyl)-nico-
tinonitrile (21b)
Yield 61%; mp 280-282 °C; IR (KBr): u cm-1 3495,
3400, 3343, 3300 (2NH2), 3090 (CH-arom), 2921 (CH-
aliph), 2194 (CN); 1H-NMR (CDCl3): d 1.20 (t, 3H, CH3),
3.30 (q, 2H, CH2), 5.60 (s, 4H, 2 NH2), 7.80-8.40 (m, 4H,
Ar H); MS: m/z (%) 311 (M+); Anal. calcd. for C14H13N7O2
(311.30): C, 54.02; H, 4.21; N, 31.50, Found: C, 53.88; H,
4.19; N, 31.46.
5-Ethyl-4-((4-nitrophenyl)diazenyl)-1H-pyrazol-3-
amine (18a)
Yield 68%; mp 230-232 °C; IR (KBr): u cm-1 3485,
3377 (NH2), 3102 (NH), 2991 (CH-aliph); 1H-NMR
(CDCl3): d 1.45 (t, 3H, CH3), 2.61 (q, 2H, CH2), 4.60 (s,
2H, NH2), 7.21-8.38 (m, 4H, Ar H), 11.45 (s, 1H, NH);
13C-NMR (CDCl3): d 13.10, 18.7, 123.20, 123.20, 126.00,
126.00, 130.20, 145.60, 151.20, 153.70, 170.50; MS: m/z
(%) 260 (M+); Anal. calcd. for C11H12N6O2 (260.25): C,
50.77; H, 4.65; N, 32.29, Found: C, 50.71; H, 4.61; N,
2,4-Diamino-5-((4-bromophenyl)diazenyl)-6-ethylnico-
tinonitrile (21c)
Yield 66%; mp 125-127 °C; IR (KBr): u cm-1 3400,
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Article
Ramiz et al.
3356, 3266 (2NH2), 3090 (CH-arom), 2934 (CH-aliph),
2193 (CN); 1H-NMR (CDCl3): d 1.20 (t, 3H, CH3), 3.30 (q,
2H, CH2), 5.60 (s, 4H, 2 NH2), 7.40-7.90 (m, 4H, Ar H);
MS: m/z (%) 345 (M+); Anal. calcd. for C14H13 BrN6
(345.20): C, 48.71; H, 3.80; Br, 23.15; N, 24.35, Found: C,
48.68; H, 3.76; Br, 23.12 ; N, 24.31.
and ammonium thiocyanate in refluxing acetone) was
added. The reaction mixture was refluxed for 3 hrs, and
then poured onto cold water. The solid product was col-
lected by filtration, washed with water and crystallized
from the proper solvent (white crystals).
6-Ethyl-4-methyl-2-thioxo-1,2-dihydropyrimidine-5-
General procedure for the synthesis of pyridine de-
rivatives (24a-c)
carbonitrile (28a)
Yield 62%; mp 130-132 °C; IR (KBr): u cm-1 3389
(NH), 2924 (CH-aliph), 2206 (CN); 1H-NMR (CDCl3): d
1.22 (t, 3H, CH3), 2.07 (s, 3H, CH3), 2.82 (q, 2H, CH2),
10.22 (s, 1H, NH); 13C-NMR (CDCl3): d 11.50, 20.50,
23.00, 93.70, 116.20, 166.20, 174.70, 182.90; MS: m/z (%)
179 (M+); Anal. calcd. for C8H9N3S (179.24): C, 53.61; H,
5.06; N, 23.44, S, 17.89, Found: C, 53.58; H, 4.94; N,
23.41, S, 17.86.
A mixture of compounds 16 (0.01 mole), ammonium
acetate (0.01mole) and ethyl cyanoacetate (1.13 g, 0.01
mole) was fused in domestic microwave oven for 3 min-
utes. The solid precipitate so formed was treated with etha-
nol and filtered out and crystallized from the proper solvent
(brown crystals).
4-Amino-6-ethyl-2-hydroxy-5-((4-nitrophenyl)-diazen-
yl)nicotinonitrile (24a)
6-Ethyl-4-phenyl-2-thioxo-1,2-dihydropyrimidine-5-
Yield 65%; mp 140-142 °C; IR (KBr): u cm-1 3493
(OH), 3373, 3300 (NH2), 2924 (CH-aliph), 2212 (CN);
1H-NMR (CDCl3): d 1.25 (t, 3H, CH3), 2.35 (q, 2H, CH2),
4.60 (s, 2H, NH2), 7.40-8.30 (m, 4H, Ar H), 11.33 (s, 1H,
OH), MS: m/z (%) 312 (M+); Anal. calcd. for C14H12N6O3
(312.28): C, 53.85; H, 3.87; N, 26.91, Found: C, 53.82; H,
3.84; N, 26.89.
carbonitrile (28b)
Yield 60%; mp 162-64 °C; IR (KBr): u cm-1 = 3311
(NH), 3060 (CH-arom), 2908 (CH-aliph), 2224 (CN); 1H-
NMR (DMSO-d6): d 1.16 (t, 3H, CH3), 2.39 (q, 2H, CH2),
7.29-7.62 (m, 5H, Ar H), 10.63 (s, 1H, NH); MS: m/z (%)
241 (M+); Anal. calcd. for C13H11N3S (241.31): C, 64.70;
H, 4.59; N, 17.41, S, 13.29, Found: C, 64.68; H, 4.55; N,
17.38, S, 13.24.
4-Amino-6-ethyl-2-hydroxy-5-(p-tolyldiazenyl)-nico-
tinonitrile (24b)
4-(2-Chlorophenyl)-6-ethyl-2-thioxo-1,2-dihydropyr-
Yield 69%; mp 279-281 °C; IR (KBr): u cm-1 3584
(OH), 3435, 3400 (NH2), 2923 (CH-aliph), 2206 (CN);
1H-NMR (CDCl3): d 1.26 (t, 3H, CH3), 1.33 (s, 3H, CH3),
2.30 (q, 2H, CH2), 4.40 (s, 2H, NH2), 7.20-8.39 (m, 4H, Ar
H), 11.33 (s, 1H, OH); MS: m/z (%) 281 (M+); Anal. calcd.
for C15H15N5O (281.31): C, 64.04; H, 5.37; N, 24.90,
Found: C, 63.98; H, 5.34; N, 24.88.
imidine-5-carbonitrile (28c)
Yield 65%; mp 230-232 °C; IR (KBr): u cm-1 3433
(NH), 3071 (CH-arom), 2921 (CH-aliph), 2222 (CN); 1H-
NMR (CDCl3): d 1.20 (t, 3H, CH3), 2.60 (q, 2H, CH2),
7.40-7.80 (m, 4H, Ar H), 10.30 (s, 1H, NH); MS: m/z (%)
275 (M+); Anal. calcd. for C13H10ClN3S (275.76): C, 56.62;
H, 3.66; Cl, 12.86; N, 15.24, S, 11.63, Found: C, 56.59; H,
3.63; Cl, 12.81; N, 15.21, S, 11.58.
4-Amino-5-((4-chlorophenyl)diazenyl)-6-ethyl-2-hy-
droxynicotinonitrile (24c)
Yield 61%; mp 131-33 °C; IR (KBr): u cm-1 3500
(OH), 3423, 3300 (NH2), 3050 (CH-arom), 2926 (CH-
aliph), 2211 (CN); 1H-NMR (CDCl3): d 1.19 (t, 3H, CH3),
2.11 (q, 2H, CH2), 4.60 (s, 2H, NH2), 7.00-8.20 (m, 4H, Ar
H), 11.21 (s, 1H, OH); MS: m/z (%) 301 (M+); Anal. calcd.
for C14H12ClN5O (301.73): C, 55.73; H, 4.01; Cl, 11.75; N,
23.21, Found: C, 55.71; H, 3.89; Cl, 11.71 ; N, 23.18.
General procedure for the synthesis of dihydropyr-
imidine derivatives (28a-c)
RESULTS AND DISCUSSION
It was found that enaminonitrile 1 react with dimeth-
ylformamide dimethyl acetal to give a compound with mo-
lecular formula C8H13N3 = 151. This was considered to be
2-((dimethylamino)methylene)-3-iminopentanenitrile 2
based on its elemental and spectral analyses. Also, the 1H-
NMR of compound 2 revealed the presence of a triplet sig-
nal at d = 1.24 ppm corresponding to methyl group, a sin-
glet signal at d = 2.01 ppm corresponding to two methyl
groups, a quartet signal at d = 2.71 ppm corresponding to
methylene group, a singlet signal at d = 3.99 ppm corre-
sponding to amino function and a singlet signal at d = 6.09
Amixture of 3-aminopent-2-enenitrile 1 (0.96 g; 0.01
mol) in dry acetone (50 mL), aroyl or alkoyl isothiocyanate
(0.01 mol) (prepared in situ from aroyl or alkoyl chloride
6
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ppm corresponding to olifinic proton. The mass spectrum
of the same product is in accordance with the proposed
structure. It shows a very intense molecular ion peak at
151. Compound 2 was allowed to reflux with malononitrile
in ethanol containing a catalytic amount of piperidine to
give a compound with molecular formula C11H15N5 = 217.
This was considered to be 1,4-dihydropyridine 5. The
1H-NMR spectra of compound 5 revealed the presence of a
triplet signal at d = 1.31 ppm corresponding to methyl
group, a singlet signal at d = 2.53 ppm corresponding to
two methyl groups, a quartet signal at d = 3.20 ppm corre-
sponding to methylene group, a singlet signal at d = 4.56
ppm corresponding to H-4 pyridine, a singlet signal at d =
5.66 ppm corresponding to NH2 and a singlet signal at d =
7.85 ppm corresponding to NH. The 13C NMR data of
compounds 5 showed chemical shift values conform to
the suggested structure, also the mass spectrum and IR
spectrum of the same product agrees with the proposed
structure. Formation of 5 from the reaction of malono-
nitrile with 2 is believed to be formed via initial addition
of malononitrile on the double bond system of 2 which
give the acyclic intermediate 3 that cyclized in the same
reaction condition to give 4 which tautomerizes into 5.
(Scheme I).
ppm corresponding to methyl function, a quartet signal at d
= 2.60 ppm corresponding to methylene group and a multi-
plet signal at d = 7.05-7.97 ppm corresponding to aromatic
proton and amino function. Formation of 8 is believed to be
formed via initial addition of enaminonitrile 1 on the dou-
ble bond of ethoxymethylenemalononitrile to give the non
isolable intermediate 6 which gives the pyridine 8 via los-
ing ethanol and subsequent tautomerism.
The reactivity of enaminonitrile 1 toward triethyl-
orthoformate was also investigated. So, when 1 is allowed
to react with triethylorthoformate in refluxing acetic anhy-
dride, a product with a molecular formula C10H18N2O2 =
198 was obtained. This was considered to be 9 based on its
elemental analysis and spectral data (Scheme II). The 1H-
NMR of compound 9 revealed the presence of a triplet sig-
nal at d = 1.18 ppm corresponding to two methyl group, a
triplet signal at d = 1.29 ppm corresponding to methyl
group, a quartet signal at d = 2.64 ppm corresponding to
methylene group, a quartet signal at d = 2.73 ppm corre-
sponding to two methylene group, a singlet signal at d =
4.87 ppm corresponding to CH and a singlet signal at d =
6.11 ppm characteristic for NH2. The mass spectrum is in
accordance with the proposed structure which shows a mo-
lecular ion peak at 198 (M+).
The behaviour of 9 toward benzylidenemalononitrile
was also investigated. When 9 is allowed to reflux with
benzylidenemalononitrile 10a in ethanol containing a cata-
lytic amount of piperidine, a compound with molecular for-
mula C19H23N3O2 = 325 was formed. This was considered
to be tetrahydropyridine 11a based on its spectral and ele-
mental analysis. Similarly 9 reacted with benzylidene-
malononitrile 10b,c in the same reaction condition to give
tetrahydropyridine derivatives 11b,c (Scheme II).
Scheme I Synthesis of compounds 2,5,8
Scheme II Synthesis of compounds 9 and 11a-c
On the other hand enaminonitrile 1 reacted with eth-
oxymethylenemalononitrile in ethanol-reflux containing a
catalytic amount of piperidine to give pyridine derivative 8
via intermediacy of non-isolable intermediates 6 and 7
(Scheme I). Confirming structures 8 was based on its ele-
1
mental analysis and spectral data. The H-NMR of com-
pound 8 revealed the presence of a triplet signal at d = 1.17
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7

Article
Ramiz et al.
The results obtained from the reaction 9 with ben-
diazenyl 16b-e. Establishing structure 16 was based on ele-
mental analysis and spectral data. Aryl diazenyl 16b,d,e
were allowed to react with hydrazine hydrate to give
pyrazole derivatives 18a-c via intermediacy of non-iso-
lable acyclic intermediate 17 (Scheme IV). The structure of
18 was established on the basis of its elemental analysis and
spectral data. Furthermore the behavior of aryl diazenyl
16a-c toward active methylene reagents was also investi-
gated. When 16a fused with malononitrile, it affords pyri-
dine derivatives 21a via intermediacy of 19 that cyclizes to
20 which tautomerizes into 21. Establishing structure 21
was based on its elemental analysis. Similarly, 16b,c re-
acted with malononitrile to give pyridine derivatives 1b,c.
In contrast to this, aryl diazenyl 16b,d,e reacted with ethyl
cyanoacetate by fusion to give pyridine derivative 24 via
intermediacy of 22 that cyclizes to 23 which tautomerizes
into 24 (Scheme IV).
zylidenemalononitrile prompted us to investigate further
the behaviour of enaminonitrile 1 toward benzylidenemal-
ononitrile derivatives. Thus, when 1 reacted with benzyli-
denemalononitrile 10a under reflux in ethanol containing a
catalytic amount of piperidine afforded the pyridine deriva-
tive 14a via intermediacy of 12 and 13 (Scheme III). Estab-
lishing structure 14a was based on its elemental and spec-
tral analysis. Similarly, enaminonitrile 1 reacted with aryli-
denes 10b-h to give pyridine derivatives 14b-h via inter-
mediacy of 12 and 13. Similar to the behavior of arylidenes
10a-h, enaminonitrile 1 reacted with arylidenecyanothio-
acetamide 10i-l to give pyridine derivatives 14i-l via inter-
mediacy of 12 and 13. Establishing structure 14i-l was
based on the elemental analyseis and spectral data. For ex-
ample, the 1H NMR of compound 14a revealed the pres-
ence of a triplet signal at d = 1.25 ppm corresponding to
methyl function, a quartet signal at d = 3.43 ppm corre-
sponding to methylene function, a singlet function at d =
5.20 ppm corresponding to amino function and a multiplet
signal at d = 7.22-8.01 ppm corresponding to aromatic pro-
tons. The mass spectrum of the same product is in accor-
dance with the proposed structure. Thus, it showed a mo-
lecular ion peaks at 248 and a number of fragments agree
with the proposed structure (Scheme III). The 13C NMR
data of compounds 14a showed chemical shift values con-
form to the suggested structure.
Synthesis of compounds 18a-c, 21a-c,
Scheme IV
24a-c
Scheme III Synthesis of compounds 14a-l
Coupling of enaminonitrile 1 with aryl diazonium
salts 15a-e was also investigated. When enaminonitrile 1
is allowed to couple with aryl diazonium salt 15a aryl
diazenyl 16a was obtained based on its spectral data. Simi-
larly, aryl diazonium salts 15b-e coupled with 1 to give aryl
The behavior of enaminonitrile 1 toward isothio-
cyanate reagents was also investigated. Thus, when 1 re-
8
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acted with acyl isothiocyanate 25a in refluxing acetone,
dihydropyrimidine 28a was obtained rather than its tauto-
Suez Canal University, Ismailia, Egypt, for valuable sup-
port and reviewing this manuscript.
1
meric structure 31a based on its spectral data. The H-
NMR spectrum of 28a revealed the presence of a singlet
signal for methyl function at higher field at d = 2.07 ppm,
one would expect if the reaction product was 31a the
methyl function appears at lower field. Formation of
dihydropyrimidine 28 formed from the reaction of 1 with
acyl isothiocyanate is believed to be formed via initial addi-
tion of enaminonitrile 1 on 25 to give the non isolable inter-
mediate 26 that cyclizes in the same reaction condition to
give 27 which readily loses a water molecule to give 28.
Similarly, enaminonitrile 1 reacted with isothiocyanate
25b,c in acetone-reflux to give dihydropyrimidine deriva-
tives 28b,c (Scheme V).
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Scheme V Synthesis of compounds 28a-c
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 000-000