Synthesis of Novel Fused Heterocycles Based on 6-Amino-4-phenyl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile

Article abstract of DOI:10.1002/jhet.2522

Under phase transfer catalysis conditions, 6-amino-4-phenyl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) was allowed to react with halo compounds, acrylonitrile, chloroacetyl chloride, ethyl cyanoacetate, formamide, triethylorthoformate, or formic acid to give new derivatives of fused pyridines 2–22, respectively. Acetylation of compound 1 using acetic anhydride afforded product 23, which in turn underwent intramolecular cyclization in pyridine to give the corresponding pyrido[2,3-d]pyrimidine 24.

Full text of DOI:10.1002/jhet.2522

Month 2015
Synthesis of Novel Fused Heterocycles Based on 6-Amino-4-phenyl-
2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile
*
H. Abdel-Ghany, A. M. El-Sayed, A. A. Amer, and A. M. Ahmed
Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
*
E-mail: Amer_chem@yahoo.com
Received May 19, 2015
DOI 10.1002/jhet.2522
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Under phase transfer catalysis conditions, 6-amino-4-phenyl-2-thioxo-1,2-dihydropyridine-
3,5-dicarbonitrile (1) was allowed to react with halo compounds, acrylonitrile, chloroacetyl chloride, ethyl
cyanoacetate, formamide, triethylorthoformate, or formic acid to give new derivatives of fused pyridines
2–22, respectively. Acetylation of compound 1 using acetic anhydride afforded product 23, which in turn
underwent intramolecular cyclization in pyridine to give the corresponding pyrido[2,3-d]pyrimidine 24.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
phenylpyridin-2-yl)thio]acetate (2), 2-[(6-amino-3,5-dicyano-
4-phenylpyridin-2-yl)thio]acetamide (5), 2-amino-6-[(2-
oxo-2-phenylethyl)thio]-4-phenyl-pyridine-3,5-dicarbonitrile
(7), or 2-amino-6-[(cyanomethyl)thio]-4-phenylpyridine-3,5-
dicarbonitrile (9), respectively. Compounds 2, 5, 7, and 9
underwent intramolecular cyclization on heating under similar
PTC conditions to give ethyl 3,6-diamino-5-cyano-4-
phenylthieno[2,3-b]pyridine-2-carboxylate (3), 3,6-diamino-
5-cyano-4-phenylthieno[2,3-b] pyridine-2-carboxamide (6),
3,6-diamino-2-benzoyl-4-phenylthieno[2,3-b]pyridine-5-
carbonitrile (8), or 3,6-diamino-4-phenylthieno[2,3-b]pyr-
idine-2,5-dicarbonitrile (10), respectively. Compounds 3, 6,
8, or 10 were synthesized directly in one step by heating
compound 1 with ethyl chloroacetate, chloroacetamide,
phenacyl bromide or chloroacetonitrile, respectively, under
PTC conditions. Ethyl 3-amino-5-cyano-6-[(2-ethoxy-2-
oxoethyl)-amino]-4-phenylthieno[2,3-b]pyridine-2-car-
boxylate 4 was obtained on heating compound 3 with ethyl
chloroacetate under similar PTC conditions. Also, com-
pound 4 was synthesized directly in one step by heating
compound 1 with ethyl chloroacetate in 1:2 molar ratio
(Scheme 2).
Fused heterocyclic containing pyrazolopyridine systems
have been described associated with several biological and
medicinal activities including anxiolytic [1], antiviral [2,3],
antileishmanial [4], antimalarial [5], antiproliferative [6],
antimicrobial [7–9], cardiovascular [10–12], and anti-
inflammatory [13] profiles. In particular, thienopyridines
have been reported to have biological activities [14],
including antibacterial [15], anti-inflammatory [16], anti-
viral [17], antiparasitic [18,19], and immune-stimulating
activities [20]. Others are useful as gonadotropin-
releasing hormone antagonists [21] and as lipoxygenases
inhibitors [22].
In view of the previous applications, we aim to use
6-amino-4-phenyl-2-thioxo-1, 2-dihydropyridine-3,5-
dicarbonitrile (1) as building blocks for the synthesis
of some new family of fused heterocyclic compounds
incorporating pyridine moiety with the hope to possess
better antimicrobial activity.
RESULTS AND DISCUSSIONS
The IR spectra of compounds 2, 5, 7, and 9 showed the
absence of absorption bands corresponding to C¼S but
exhibited new absorption bands at 2977–2926 cmꢀ1 corre-
sponding to aliphatic C–H and at 1719–1643 cmꢀ1 corre-
sponding to the C¼O group. The 1HNMR spectra of
compounds 2, 5, 7, and 9 revealed new singlet signals at
4.21–3.90ppm corresponding to the S–CH2 groups. In the
case of compound 2, a quartet signal at 4.19–4.12ppm
corresponding to the CH2 ester and a triplet signal at
1.28–1.20ppm corresponding to the CH3 ester appeared.
The starting compound 6-amino-4-phenyl-2-thioxo-1,2-
dihydropyridine-3,5-dicarbonitrile (1) was prepared by
the reaction of benzaldehyde with cyanothioacetamide in
1:2 molar ratio in ethanol and piperidine as a catalyst [23].
Under phase transfer catalysis (PTC) conditions using di-
oxane as the organic phase, potassium carbonate as the solid
phase and tetrabutylammonium bromide as a catalyst,
compound 1 was allowed to react at room temperature with
halo compounds containing active methylene group, namely
ethyl chloroacetate, chloroacetamide, phenacyl bromide, or
chloroacetonitrileto give ethyl [(6-amino-3,5-dicyano-4-
1
The HNMR spectrum of compound 5 was characterized
as a new broad signal at 3.80–3.60 ppm corresponding to
© 2015 HeteroCorporation

H. Abdel-Ghany, A. M. El-Sayed, A. A. Amer, and A. M. Ahmed
Vol 000
Scheme 1
the NH2 group. The IR spectra of compounds 3, 6, 8,
and 10 showed the absence of absorption bands corre-
sponding to C¼S but exhibited new absorption bands
at 3487–3147 cmꢀ1 corresponding to the NH2 group.
1
The HNMR spectra of these compounds were consistent
1
with the purposed structures. The IR and HNMR spectra
of compound 4 were consistent with the purposed struc-
tures. Moreover, the mass spectrum of compound 4 gave
m/z 424 [M+] (Irel 87.07%), which corresponds to the
molecular weight of the molecular formula C21H20N4O4S
of the assigned structure.
Diazotization of compound 10 using sodium nitrite and
HCl/AcOH mixture gave 4,10-dichloro-11-phenyl[1,2,3]
triazino-[5″,4″:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]tri-
azine (11). Compound 10 was allowed to react with 2,5-
dimethoxytetrahydrofuran to give 4-phenyl-3,6-di(pyrrol-1-
yl)-thieno[2,3-b]-pyridine-2,5-dicarbonitrile (12) (Scheme 1).
The IR spectrum of compound 12 showed the absence of
the absorption bands corresponding to the NH2 group. The
1HNMR spectrum showed the absence of the signal corre-
sponding to the NH2 group but revealed new signals at
7.4–7.2, 6.3–5.9, and 5.5–5.2 ppm corresponding to the
pyrrole protons.
Under similar PTC reaction conditions, compound 1
was cycloalkylated on heating with some dihalo reagents,
namely 1,2-dibromoethane, 1,3-dibromopropane, 1,4-
dibromobutane, 2,3-dichloro-1,4-naphthoquinone, or
2,3,5,6-tetrachloro-1,4-benzoquinone to give 5-imino-7-
phenyl-2,3-dihydro-5H-[1,3]thiazolo-[3,2-a]pyridine-6,8-
dicarbonitrile (13), 6-imino-8-phenyl-3,4-dihydro-2H,6H-
pyrido[2,1-b][1,3]thiazine-7,9-dicarbonitrile (14), 7-imino-9-
phenyl-2,3,4,5-tetrahydro-7H-pyrido[2,1-b] [1,3]thiazepine-
8,10-dicarbonitrile (15), 4-imino-6,11-dioxo-2-phenyl-6,11-
dihydro-4H-naphtho[2′,3′:4,5][1,3]thiazolo[3,2-a]pyridine-
1,3-dicarbonitrile (16), and 7,8-dihydroxy-1-imino-6,9-
dioxo-3-phenyl-6,9-dihydro-1H-pyrido[2,1-b] [1,3]-benzothiazole-
2,4-dicarbonitrile (17), respectively (Scheme 2).
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of New Heterocyclic Compounds
The IR spectra of compounds 13–17 showed the absence
of absorption bands corresponding to the C¼S and NH2
groups but exhibited new absorption bands at 2932–
2928 cmꢀ1 corresponding to aliphatic C–H, in the case of
compounds 13–17 at 1675–1625 cmꢀ1 corresponding to
C¼O, in the case of compounds 16 and 17. Also, the IR
spectrum of compound 17 exhibited new absorption bands
at 3559 and 3447cmꢀ1 corresponding to two OH groups.
The 1HNMR spectra of compounds 13–17 showed the ab-
sence of the signal corresponding to the NH2 group but re-
vealed aliphatic cyclic protons signals at 4.15–1.60 ppm, in
the case of compounds 13–17, and aromatic proton signals
at 7.8–7.0ppm, in the case of compound 16. The 1HNMR
spectrum of compound 17 showed new singlet signals at
3.5ppm corresponding to two OH groups.
Compound 1 was allowed to react with acrylonitrile in
ethanol and triethylamine as a catalyst to give 2-amino-
6-[(2-cyanoethyl)thio]-4-phenylpyridine-3,5-dicarbonitrile
18; however, the cyclized compound 19 was not obtained
via heating compound 18 in DMF solution. In order to con-
struct new derivatives of the interesting 1,8-naphthyridines
[24], we have synthesized a new family of 1,8-
naphthyridines via the reaction of compound 1 with
chloroacetyl chloride or ethyl cyanoacetate to give the cor-
responding 1,8-naphthyridines 20 and 21, respectively.
A new family of fused pyrido[2,3-d]pyrimidines was
prepared via the reaction of compound 1 with formamide
or formic acid to give the corresponding pyrido[2,3-d]py-
rimidines 22 and 23, respectively. The formation of com-
pound 23 was assumed to proceed via the amide
formation [25], followed by an intramolecular cyclization
with formic acid to furnish the desired product
(cf. Scheme 3). The acetylation of compound 1 using acetic
anhydride afforded the diacetylated compound N-(1-ace-
tyl-3,5-dicyano-4-phenyl-6-thioxo-1, 6-dihydropyridin-2-
yl)acetamide 24, which in turn underwent cyclization in
pyridine followed by hydrolysis of an acetyl group to give
4-hydroxy-2-methyl-5-phenyl-7-thioxo-7,8-dihydropyrido[2,3-
d]pyrimidine-6-carbonitrile 25 (cf. Scheme 3).
The IR spectrum of compound 25 showed the absence of
absorption band corresponding to the C¼O group but ex-
hibited new absorption band at 3471 cmꢀ1 corresponding
to the OH group. The 1HNMR spectrum showed the disap-
pearance of the signal corresponding to one CH3 group and
revealed new broad signal at 4.3–3.7 ppm corresponding to
the OH group.
Compound
1
was allowed to react with
triethylorthoformate using acetic anhydride as a catalyst
to give 1-diethoxymethyl-6-[1-ethoxymethylideneamino]-
4-phenyl-2-thioxo-1,2-dihydro-3,5-pyridinedicarbonitrile
(26). The IR spectrum of compound 26 showed the
absence of absorption bands corresponding to the NH2
and NH groups but exhibited new absorption bands at
2926–2864 cmꢀ1 corresponding to aliphatic C–H and at
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Abdel-Ghany, A. M. El-Sayed, A. A. Amer, and A. M. Ahmed
Vol 000
Scheme 4
stirred for 2h at r.t. The reaction mixture was filtered off,
the filtrate was evaporated in vacuo, and the resulting
product was washed with water and recrystallized from
ethanol.
Ethyl [(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)thio]acetate
(2). Yield: 90%, mp 194°C; IR: 3356, 3218 (NH2),
3054 (CHarom.), 2977 (CHaliph.), 2211 (CN), 1719
1
(C¼O) cmꢀ1; HNMR: 7.98 (s, 2H, NH2), 7.6–7.4 (m,
5H, arom.), 4.21 (s, 2H, –CH2–S), 4.19–4.12 (q, 2H,
CH2ester), 1.28–1.20 (t, 3H, CH3ester). Anal. Calcd for
C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56; S, 9.48.
Found: C, 60.18; H, 4.20; N, 16.32; S, 9.33.
2-[(6-Amino-3,5-dicyano-4-phenylpyridin-2-yl)-thio]acetamide
(5). Yield: 68%, mp 231°C; IR: 3398, 3322, 3214 (2NH2),
1241 cmꢀ1 corresponding to C–O–C. The 1HNMR
spectrum revealed a new quartet signal at 4.52–4.44 ppm
corresponding to the ¼C–OCH2 group, multiplet signal
at 3.41–3.32 ppm corresponding to the 2CH2 groups,
and multiplet signals at 1.43–1.35 ppm corresponding to
the 3CH3 groups.
Compound 26 was treated at room temperature
with phenyl hydrazine or benzohydrazide to give
6-amino-2-mercapto-4-phenyl-2-(2′-phenylhydrazino)-
1,2-dihydropyridine-3,5-dicarbonitrile (27) and 7-amino-
3,9-diphenyl-4-oxa-1,2,6-triazaspiro[4.5]deca-2,7,9-triene-
8,10-dicarbonitrile (28), respectively. The IR spectra of
compounds 27 and 28 showed the absence of absorp-
tion bands corresponding to aliphatic C–H but exhibited
new absorption bands at 3461–3212cmꢀ1 corresponding
to the NH2 and NH groups. The 1HNMR spectra of
compounds 27 and 28 showed the absence of the sig-
nals corresponding to aliphatic protons but revealed
new signals corresponding to NH2 and NH groups
(Scheme 4).
3060 (CHarom.), 2928 (CHaliph.), 2211 (CN), 1643 (C¼O)
cmꢀ1 1HNMR: 8.05 (s, 2H, NH2), 7.79–7.28 (m, 5H,
;
arom.), 3.9 (s, 2H, CH2), 3.80–3.60 (br, 2H, CONH2).
Anal. Calcd for C15H11N5OS: C, 58.24; H, 3.58; N, 22.64;
S, 10.37. Found: C, 58.36; H, 3.49; N, 22.53; S, 10.22.
2-Amino-6-[(2-oxo-2-phenylethyl)thio]-4-phenylpyridine-3,5-
dicarbonitrile (7). Yield: 65%, mp 292°C; IR: 3345, 3216
(NH2), 3056 (CHarom.), 2926 (CHaliph.), 2210 (CN), 1676
(C¼O) cmꢀ1
;
1HNMR: 8.2 (s, 2H, NH2). 7.8–7.0 (m,
10H, arom.), 4.7 (s, 2H, CH2). Anal. Calcd for
C21H14N4OS: C, 68.09; H, 3.81; N, 15.12; S, 8.66.
Found: C, 68.15; H, 3.96; N, 15.03; S, 8.72.
2-Amino-6-[(cyanomethyl)thio]-4-phenylpyridine-3,5-dicarbonitrile
(9). Yield: 75%, mp 214°C; IR: 3330, 3229 (NH2), 3050
(CHarom.), 2973 (CHaliph.), 2205 (CN) cmꢀ1 1HNMR:
;
8.26 (s, 2H, NH2), 7.65–7.42 (m, 5H, arom.), 4.3 (s, 2H,
CH2). Anal. Calcd for C15H9N5S: C, 61.84; H, 3.11; N,
24.04; S, 11.01. Found: C, 61.91; H, 3.02; N, 4.10; S,
10.94.
Ethyl 3-amino-5-cyano-6-[(2-ethoxy-2-oxoethyl)amino]-4-
phenylthieno[2,3-b]-pyridine-2-carboxylate
A.
(4).
Method
A mixture of compound 1 (0.001 mol, 0.252g),
ethyl chloroacetate (0.002 mol, 0.22mL), anhydrous
potassium carbonate (3 g), catalytic amount of
EXPERIMENTAL
a
tetrabutylammonium bromide, and dioxane (20 mL) was
stirred for 1h at r.t. The reaction mixture was further
stirred for 2 h at 60–70°C and treated as previously
mentioned.
All melting points are uncorrected and were recorded on
Melt-Temp II melting point apparatus (USA). IR spectra
were measured as KBr pellets on a Shimadzu DR-8001
spectrometer. 1HNMR spectra were recorded in deuterated
chloroform or dimethyl sulfoxide at 60 MHz on a Varian
EM 360L and also at 200 MHz on a Varian Gemini
NMR spectrometer using tetramethylsilane as an internal
reference. Mass spectra analyses were performed on a
Shimadzu GCMS-QP 1000 mass spectrometer at 70eV.
The elemental analyses were carried out on a Perkin-Elmer
240C. All compounds were checked for their purity on
thin-layer chromatography plates.
Method B.
A mixture of compound 3 (0.001 mol,
0.338 g), ethyl chloroacetate (0.001mol, 0.11 mL), anhy-
drous potassium carbonate (3 g), a catalytic amount of
tetrabutylammonium bromide, and dioxane (20 mL)
was stirred for 1 h at r.t. The reaction mixture was fur-
ther stirred for 2 h at 60–70°C, then filtered off, and the
filtrate was evaporated in vacuo, and the resulting prod-
uct was washed with water and crystallized from
ethanol.
Synthesis of compounds 2, 5, 7, and 9. General
procedure. A mixture of compound 1 (0.001 mol, 0.252 g),
the appropriate halo compound (0.001 mol), anhydrous
Yield: 80%, mp 235°C; IR: 3488, 3406, 3352 (NH2,
NH), 3051 (CHarom.), 2978 (CHaliph.), 2211 (CN), 1732
1
(C¼O), 1667 (C¼O) cmꢀ1; HNMR: 7.98 (s, 1H, NH),
potassium carbonate (3 g),
a catalytic amount of
7.64–7.46 (m, 5H, arom.), 5.49 (s, 2H, NH2), 4.25–4.14
tetrabutylammonium bromide, and dioxane (20 mL) was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of New Heterocyclic Compounds
(m, 6H, 2CH2ester +CH2–N), 1.27–1.20 (t, 6H, 2CH3ester).
Mass spectrum, m/z (%): 424 (M+, 87.09), 338 (97.33),
291 (100). Anal. Calcd for C21H20N4O4S: C, 59.42; H,
4.75; N, 13.20; S, 7.55. Found: C, 59.31; H, 4.62; N,
13.34; S, 7.39.
sodium nitrite solution 10% (2mL) was added with
stirring for 5min. The stirring was continued at 5°C for
3h. The formed precipitate was collected by filtration and
crystallized from dioxane as yellow crystals, 0.2g (52%
yield), mp 224°C; IR: 3060 (CHarom.) cmꢀ1 1HNMR:
;
Synthesis of compounds 3, 6, 8, and 10. Method A.
A
7.5–7.0 (m, 5H, arom.). Anal. Calcd for C15H5Cl2N7S: C,
46.65, H, 1.30; N, 25.39; S, 8.30. Found: C, 46.72; H,
mixture of compound (0.001mol, 0.252g), the
1
appropriate halo compound, anhydrous potassium
carbonate (3g), a catalytic amount of tetrabutylammonium
bromide, and dioxane (20mL) was stirred for 1h at r.t.
The reaction mixture was further stirred for a period of
time at 60–70°C, then filtered off, and the filtrate was
evaporated in vacuo, and the resulting product was washed
with water and crystallized from ethanol or dioxane.
1.42; N, 25.48; S, 8.25.
4-Phenyl-3,6-di-1H-pyrrol-1-ylthieno[2,3-b]-pyridine-2,5-
dicarbonitrile (12). A mixture of compound 10 (0.001mol,
0.291g) and 2,5-dimethoxytetrahydrofuran (0.002mol,
0.26mL) in 20mL of glacial acetic acid was heated under
reflux for 4h and left to cool. The precipitated crystals
were collected by filtration and crystallized from dioxane
as pale yellow crystals, 0.22g (57% yield), mp 224°C; IR:
Method B.
To a solution of the appropriate com-
3070 (CHarom.), 2220 (CN) cmꢀ1; HNMR: 7.4–7.2 (d,
1
pounds 2, 5, 7, or 9 (0.001mol) in dioxane (20 mL), anhy-
drous potassium carbonate (3 g) and a catalytic amount of
tetrabutylammonium bromide were added. The reaction
mixture was stirred for 2 h at 60–70°C and then filtered
off. The filtrate was evaporated in vacuo, and the resulting
product was washed with water and crystallized from
4H, 2 ¼CH–N–CH¼), 7.0–6.6 (m, 5H, arom.), 6.3–5.9 (t,
2H, ¼CH–CH¼), 5.5–5.2 (t, 2H, ¼CH–CH¼). Anal.
Calcd for C23H13N5S: C, 70.57, H, 3.35; N, 17.89; S,
8.19. Found: C, 70.45; H, 3.46; N, 17.97; S, 8.21.
Synthesis of compounds 13–17. General procedure.
A
mixture of compound 1 (0.001mol, 0.252g, 0.001mol) of
the appropriate halo compound, anhydrous potassium
carbonate (3g), a catalytic amount of tetrabutylammonium
bromide, and dioxane (20mL) was stirred for 1h at r.t.
The reaction mixture was further stirred for a period of
time at 60–70°C, then filtered off, and the filtrate was
evaporated in vacuo. The resulting product was washed
with water, dried, and crystallized from ethanol.
5-Imino-7-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-
6,8-dicarbonitrile (13). Yield: 61%, mp >300°C (decomp.);
IR: 3328 (NH), 3056 (CHarom.), 2928 (CHaliph.), 2212 (CN)
cmꢀ1; 1HNMR: 7.50 (s, 1H, NH), 7.30–7.00 (m, 5H, arom.),
4.15–3.80 (t, 2H, CH2–N), 3.50–3.25 (t, 2H, CH2–S). Anal.
Calcd for C15H10N4S: C, 64.73, H, 3.62; N, 20.13; S, 11.52.
ethanol.
Ethyl 3,6-diamino-5-cyano-4-phenylthieno[2,3-b]pyridine-2-
carboxylate (3). Yield: 90%, mp 278°C; IR: 3487, 3359,
3291, 3147 (2NH2), 3050 (CHarom.), 2983 (CHaliph.),
2210 (CN), 1677 (C¼O) cmꢀ1; HNMR: 7.66–7.5 (m,
1
7H, arom. + NH2), 5.49 (s, 2H, NH2), 4.24–4.13 (q, 2H,
CH2ester), 1.27–1.20 (t, 3H, CH3 ester). Anal. Calcd for
C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56; S, 9.48.
Found: C, 60.18; H, 4.25; N, 16.60; S, 9.33.
3,6-Diamino-5-cyano-4-phenylthieno[2,3-b]pyridine-2-carboxamide
(6). Yield: 60%, mp 269°C; IR: 3458, 3346, 3204 (3NH2),
3050 (CHarom.), 2217 (CN), 1640 (C¼O) cmꢀ1; HNMR:
1
7.6–7.4 (m, 5H, arom.), 6.5 (s, 2H, NH2-exchanged by
D2O), 6.2 (s, 2H, NH2-exchanged by D2O), 5.4 (s, 2H,
NH2-exchanged by D2O). Anal. Calcd for C15H11N5OS:
C, 58.24, H, 3.58; N, 22.64; S, 10.37. Found: C, 58.13; H,
Found: C, 64.62; H, 3.73; N, 20.24; S, 11.45.
6-Imino-8-phenyl-3,4-dihydro-2H,6H-pyrido[2,1-b][1,3]thiazine-
7,9-dicarbonitrile (14). Yield: 86%, mp 155°C; IR: 3353
3.66; N, 22.73; S, 10.29.
3,6-Diamino-2-benzoyl-4-phenylthieno[2,3-b]pyridine-5-
carbonitrile (8). Yield: 72%, mp >300°C; IR: 3471, 3345,
(NH), 3050 (CHarom.), 2929 (CHaliph.), 2210 (2CN) cmꢀ1
;
1HNMR: 7.5 (s, 1H, NH), 7.4–7.0 (m, 5H, arom.), 3.4–3.0
(t, 2H, CH2–N), 3.0–2.8 (t, 2H, CH2–S), 2.3–2.0 (m, 2H,
CH2). Anal. Calcd for C16H12N4S: C, 65.73, H, 4.14; N,
3211 (2NH2), 3067 (CHarom.), 2209 (CN), 1678 (C¼O)
cmꢀ1 1HNMR: 7.9 (s, 2H, NH2), 7.6–7.4 (m, 10H,
;
19.16; S, 10.97. Found: C, 65.64; H, 4.05; N, 19.21; S, 11.05.
7-Imino-9-phenyl-2,3,4,5-tetrahydro-7H-pyrido[2,1-b][1,3]thiazepine-
8,10-dicarbonitrile (15). Yield: 57%, mp 140°C; IR: 3342
arom.), 5.2 (s, 2H, NH2). Anal. Calcd for C21H14N4OS: C,
68.09, H, 3.81; N, 15.12; S, 8.66. Found: C, 68.02; H,
3.89; N, 15.21; S, 8.75.
(NH), 3061 (CHarom.), 2932 (CHaliph.), 2208 (CN) cmꢀ1
;
3,6-Diamino-4-phenylthieno[2,3-b]pyridine-2,5-dicarbonitrile
(10). Yield: 91%, mp 286°C; IR: 3414, 3338, 3232 (2NH2),
1HNMR: 7.50 (s, 1H, NH), 7.30–6.90 (m, 5H, arom.),
3.85–3.50 (t, 2H, CH2–N), 3.40–3.00 (t, 2H, CH2–S),
2.10–1.60 (m, 4H, CH2–CH2). Anal. Calcd for
C17H14N4S: C, 66.64, H, 4.61; N, 18.29; S, 10.47.
1
3050 (CHarom.), 2189 (CN) cmꢀ1; HNMR: 7.66–7.56 (m,
7H, arom. +NH2), 5.28 (s, 2H, NH2). Anal. Calcd for
C15H9N5S: C, 61.84, H, 3.11; N, 24.04; S, 11.01. Found:
C, 61.77; H, 3.21; N, 24.11; S, 24.11.
4,10-Dichloro-11-phenyl[1,2,3]triazino[5″,4″:5′,6′]pyrido[3′,2′:4,5]-
thieno[3,2-d]-[1,2,3]triazine (11). To a chilled solution of
Found: C, 66.61; H, 4.69; N, 18.37; S, 10.39.
4-Imino-6,11-dioxo-2-phenyl-6,11-dihydro-4H-naphtho[2′,3′:4,
5][1,3]thiazolo-[3,2-a]pyridine-1,3-dicarbonitrile (16). Yield:
compound 10 (0.001mol, 0.291g) in a mixture of acetic
acid (10mL) and concentrated hydrochloric acid (7mL), a
81%, mp 274°C; IR: 3442 (NH), 3070 (CHarom.), 2210
(CN), 1675 (C¼O) cmꢀ1
;
1HNMR: 7.8–7.0 (m, 10H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Abdel-Ghany, A. M. El-Sayed, A. A. Amer, and A. M. Ahmed
Vol 000
arom. +NH). Anal. Calcd for C23H10N4O2S: C, 67.97; H,
2.48; N, 13.79; S, 7.89. Found: C, 67.92; H, 2.39; N,
13.85; S, 7.93.
7,8-Dihydroxy-1-imino-6,9-dioxo-3-phenyl-6,9-dihydro-1H-
pyrido[2,1-b][1,3]-benzothiazole-2,4-dicarbonitrile (17). Yield:
cool and poured onto ice cold water. The obtained solid
product was filtered, washed with water, and crystallized
from ethanol to yield 22 (0.11g, 45%); mp 210°C; IR:
3456, 3372, 3162 (NH2, NH), 3050 (CHarom.), 2220 (CN),
1
1565 (C¼S) cmꢀ1; HNMR: 8.0 (s, 1H, N¼CH), 7.8 (s,
89%, mp 279°C; IR: 3559, 3447 (2OH), 3215 (NH), 3066
1H, NH), 7.4–6.7 (m, 5H, arom.), 6.0 (s, 2H, NH2). Anal.
Calcd for C14H9N5S: C, 60.20, H, 3.25; N, 25.07; S,
11.48. Found: C, 60.11; H, 3.32; N, 25.12; S, 11.36.
4-Oxo-5-phenyl-7-thioxo-3,4,7,8-tetrahydropyrido[2,3-
d]pyrimidine-6-carbonitrile (23). A mixture of compound 1
(CHarom.), 2213 (2CN), 1629 (2C¼O) cmꢀ1
;
1HNMR:
7.7–7.0 (m, 6H, arom. +NH), 3.5 (s, 2H, 2OH). Anal.
Calcd for C19H8N4O4S: C, 58.76; H, 2.08; N, 14.43; S,
8.26. Found: C, 58.72; H, 1.98; N, 14.51; S, 8.32.
2-Amino-6-[(2-cyanoethyl)thio]-4-phenylpyridine-3,5-dicarbonitrile
(18). A mixture of compound 1 (0.00125mol, 0.315g),
(0.001mol, 0.252g) and excess of formic acid (10mL)
was heated under reflux for 23h. The reaction mixture was
left to cool. The obtained crystals were filtered and
recrystallized from ethanol to yield 23 (0.13g, 54%); mp
260°C; IR: 3378 (NH), 3203 (NH), 3040 (CHarom.), 2212
acrylonitrile (0.00125mol, 0.066g), triethylamine as a
catalyst, and ethanol (20mL) was refluxed for 3h. After
cooling, the separated crystals were collected by filtration
and recrystallized from ethanol to yield 18 (0.23g, 69%);
mp 208°C (ethanol); IR: 3432, 3310 (NH2), 3016
1
(CN), 1655 (C¼O), 1530 (C¼S) cmꢀ1; HNMR: 7.6–7.2
(m, 7H, arom.+2NH), 6.4 (s, 1H, ¼CH–). Anal. Calcd for
(CHarom.), 2917 (CHaliph.), 2218 (CN) cmꢀ1 1HNMR:
;
C14H8N4OS: C, 59.99; H, 2.88; N, 19.99; S, 11.44.
8.16 (s, 2H, NH2), 7.59–7.58 (m, 5H, arom.), 3.54–3.46 (t,
2H, CH2CN), 3.09–3.00 (t, 2H, CH2–S). Anal. Calcd for
C16H11N5S: C, 62.93; H, 3.63; N, 22.93; S, 10.50. Found:
C, 62.84; H, 3.75; N, 22.84; S, 10.42.
Found: C, 60.06; H, 2.72; N, 19.84; S, 11.57.
N-(1-Acetyl-3,5-dicyano-4-phenyl-6-thioxo-1,6-dihydropyridin-
2-yl)acetamide (24). A solution of compound 1 (0.001mol,
0.252g) in acetic anhydride (20mL) was heated under
reflux for 4h. The reaction mixture was left to cool and
poured onto ice cold water. The obtained solid product
was filtered, washed with water, and recrystallized from
ethanol to yield 24 (0.21g, 73%); mp 276°C; IR: 3210
(NH), 3056 (CHarom.), 2964 (CHaliph.), 2231 (2CN), 1705
5-Amino-6-chloro-7-oxo-4-phenyl-2-thioxo-1,2,7,8-tetrahydro-
1,8-naphthyridine-3-carbonitrile (20).
To a solution of
compound 1 (0.001mol, 0.252g) in pyridine (15mL),
chloroacetyl chloride (0.001mol, 0.11g) was added
dropwise with stirring at room temperature for 30min and
then refluxed for 6h. The reaction mixture was left to
cool, poured onto ice cold water, and neutralized by HCl.
The obtained solid product was filtered, washed with
water, and recrystallized from ethanol to yield 20 (0.24g,
85%); mp 226°C; IR: 3434, 3337, 3227 (NH2, 2NH), 3050
(CHarom.), 2215 (CN), 1714 (C¼O), 1541 (C¼S), 700
1
(2C¼O), 1579 (C¼S) cmꢀ1; HNMR: 11.34 (s, 1H, NH),
7.67–7.60 (m, 5H, arom.), 2.23 (s, 3H, CH3), 2.16 (s, 3H,
CH3). Anal. Calcd for C17H12N4O2S: C, 60.70; H, 3.60;
N, 16.66; S, 9.53. Found: C, 60.61; H, 3.49; N, 16.58; S,
9.42.
4-Hydroxy-2-methyl-5-phenyl-7-thioxo-7,8-dihydropyrido[2,3-
d]pyrimidine-6-carbonitrile (25). A solution of compound 24
1
(C–Cl) cmꢀ1; HNMR: 7.6–6.8 (m, 7H, arom. + 2NH),
(0.001mol, 0.336g) in pyridine (15mL) was heated under
reflux for 2h. The reaction mixture was left to cool and
poured onto ice cold water. The medium was acidified
with HCl. The solid product was filtered, crystallized from
ethanol, and then recrystallized from dioxane to yield 25
(0.14g, 46%); mp 168°C; IR: 3471 (OH), 3381 (NH),
3051 (CHarom.), 2931 (CHaliph.), 2208 (CN), 1537 (C¼S)
4.9–4.3 (br, 2H, NH2). Anal. Calcd for C15H9ClN4OS:
C, 54.80; H, 2.76; N, 17.04; S, 9.75. Found: C, 54.72;
H, 2.81; N, 17.11; S, 9.63.
4-Amino-2-oxo-5-phenyl-7-thioxo-1,2,7,8-tetrahydro-1,8-
naphthyridine-3,6-dicarbonitrile (21).
A
mixture of
compound 1 (0.001mol, 0.252g), ethyl cyanoacetate
(0.001mol, 0.11g), DMF (10mL), and piperidine (0.5mL)
was heated under reflux for about 3h. The reaction
mixture was left to cool and poured onto ice cold water.
The medium was acidified with two drops of HCl. The
solid product was filtered and crystallized from dioxane to
yield 21 (0.21g, 77%); mp 244°C; IR: 3401, 3324, 3197
1
cmꢀ1; HNMR: 8.2 (s, 1H, NH), 7.2–6.9 (m, 5H, arom.),
4.3–3.7 (br, 1H, OH), 2.4 (s, 3H, CH3). Anal. Calcd for
C15H10N4OS: C, 61.21; H, 3.42; N, 19.04; S, 10.89.
Found: C, 61.28; H, 3.35; N, 19.12; S, 10.96.
1-Diethoxymethyl-6-[1-ethoxymethylideneamino]-4-phenyl-
2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile (26). A mixture
(NH2, 2NH), 2220 (CN), 1646 (C¼O), 1562 (C¼S) cmꢀ1
;
1HNMR: 7.6 (s, 1H, NH), 7.5–7.0 (m, 8H, arom. +NH
+NH2). Anal. Calcd for C16H9N5OS: C, 60.18; H, 2.84;
N, 21.93; S, 10.04. Found: C, 60.27; H, 2.76; N, 21.80; S,
of compound 1 (0.005mol, 1.26g), triethylorthoformate
(15mL), and acetic anhydride (2 drops) was refluxed for
8h. The reaction mixture was left to cool. The solid
product was filtered and recrystallized from ethanol to
afford 26 (0.76g, 43%); mp 145°C; IR: 2926, 2864
10.10.
4-Amino-5-phenyl-7-thioxo-7,8-dihydropyrido[2,3-d]pyrimidine-
6-carbonitrile (22). A mixture of compound 1 (0.001mol,
0.252g) and excess of formamide (10mL) was heated
(CHaliph), 2220 (2CN), 1521 (C¼S), 1241 (C–O) cmꢀ1
;
1HNMR: 8.81 (s, 1H, N¼CH), 7.64–7.62 (m, 6H, arom.
+CH–N), 4.52–4.44 (q, 2H, ¼C–OCH2), 3.41–3.32 (m,
under reflux for 30min. The reaction mixture was left to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of New Heterocyclic Compounds
[5] El-Essawy1, F. A.; Rady S. I. M. Chem Heterocycl Compd
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4H, 2OCH2), 1.43–1.35 (m, 9H, 3CH3). Anal. Calcd for
C21H22N4O3S: C, 61.44; H, 5.40; N, 13.65; S, 7.81.
Found: C, 61.53; H, 5.52; N, 13.73; S, 7.89.
6-Amino-2-mercapto-4-phenyl-2-(2-phenylhydrazino)-1,2-
dihydropyridine-3,5-dicarbonitrile (27) and 7-amino-3,9-diphenyl-
4-oxa-1,2,6-triazaspiro[4.5]deca-2,7,9-triene-8,10-dicarbonitrile
(28). General procedure. To a mixture of compound 26
(0.001mol, 0.41g), phenyl hydrazine, or benzohydrazide
(0.003mol) in ethanol (20mL), TEA (2 drops) was added.
The reaction mixture was stirred for 4h at r.t. The product
that formed was collected by filtration and then
crystallized from ethanol.
6-Amino-2-mercapto-4-phenyl-2-(2-phenylhydrazino)-1,2-
dihydropyridine-3,5-dicarbonitrile (27).
Yield: 53%, mp
233°C; IR: 3459, 3320, 3212 (NH2, NH), 3073 (CHarom.),
1
2553 (SH), 2208 (CN) cmꢀ1; HNMR: 10.1 (s, 1H, NH),
8.5 (s, 1H, NH), 7.4–6.7 (m, 10H, arom.), 5.9 (s, 2H,
NH2), 4.3 (s, 1H, NH), 2.4 (s, 1H, SH). Anal. Calcd for
C19H16N6S: C, 63.31, H, 4.47; N, 23.32; S, 8.90. Found:
C, 63.45; H, 4.42; N, 23.40; S, 8.88.
7-Amino-3,9-diphenyl-4-oxa-1,2,6-triazaspiro[4.5]deca-2,7,9-
triene-8,10-dicarbonitrile (28). Yield: 40%, mp 244°C; IR:
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I. C. P. P. Heterocycl Commun 2004, 10, 407.
[18] Bernardino, A. M. R.; Pinheiro, L. C. S.; Rodrigues, C. R.;
Loureiro, N. I. V.; Castro, H. C.; Lanfredi-Rangel, A.; Sabatini-Lopes, J.;
Borges, J. C.; Carvalho, J. M.; Romeiro, G. A.; Ferreira, V. F.;
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[19] Bruno, L.; Ilídio, F. A.; Carlos, R. R.; Paula, A. A.; Rafael, G.;
Luiz, C. S. P.; Alexandre, R. A.; Julio, C. B.; Percilene, F. V.; Cláudio, C. C. S.;
Francisco, C. A.; Lúcio, M. C.; Izabel, C. P. P.; Alice, M. R.; Dilvani, O. S.;
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3459, 3326, 3215 (NH2, NH), 3072 (CHarom.), 2214 (CN)
cmꢀ1 1HNMR: 7.5 (s, 2H, NH2), 7.4–7.0 (m, 10H,
;
arom.), 4.3 (s, 1H, NH). Anal. Calcd for C20H14N6O: C,
67.79; H, 3.98; N, 23.72. Found: C, 67.61; H, 4.07;
N, 23.63.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet