Cyanoacetanilides intermediates in heterocyclic synthesis. Part 2: Preparation of some hitherto unknown ketene dithioacetal, benzoazole and pyridone derivatives

Article abstract of DOI:10.1002/jccs.200500081

Ketene dithioacetal 3, aminopyrazole 5, tetrazine 7, benzoazole 9 and pyridone 11, 12, 13 and 16 derivatives were pre pared from cyanoacetanilide 1 as a starting material.

Full text of DOI:10.1002/jccs.200500081

Journal of the Chinese Chemical Society, 2005, 52, 553-558
553
Cyanoacetanilides Intermediates in Heterocyclic Synthesis. Part 2:
Preparation of Some Hitherto Unknown Ketene Dithioacetal, Benzoazole
and Pyridone Derivatives
Y. A. Ammar,a A. M. Sh. El-Sharief,a A. G. Al-Sehemi,b
Y. A. Mohamed,a M. A. Senussia and M. S. A. El-Gabyc*
aDepartment of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
bDepartment of Chemistry, Teachers Colleges, Abha, Saudia
cDepartment of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
Ketene dithioacetal 3, aminopyrazole 5, tetrazine 7, benzoazole 9 and pyridone 11, 12, 13 and 16 deriva-
tives were prepared from cyanoacetanilide 1 as a starting material.
Keywords: Ketene dithioacetal; Benzoazole; Aminopyrazole and pyridone derivatives.
INTRODUCTION
Cyanoacetanilides are important and versatile reagents
NMR spectrum of 3 in DMSO-d6 revealed the presence of a
singlet at d = 2.37, 2.48 ppm characteristic for two methylthio
groups in addition to the expected signals attributed to NH,
ethoxy and aromtic protons. Also, the structure 3 is supported
by its mass spectrum which showed a molecular ion peak at
m/z = 308 (12.4%) corresponding to the formula C14H16N2O2S2.
Also, the base peak was found in the spectrum at m/z = 75.
The reactivity of compound 3 towards some nitrogen
and carbon nucleophiles was studied. Thus, treatment of
compound 3 with aromatic amine in refluxing ethanol gave
acrylamide derivatives 4a,b, through Michael addition fol-
lowed by elimination of methyl mercaptan.10 The mass spec-
trum of compound 4a showed a molecular ion peak at m/z =
367 (48.7%) with base peak at m/z = 137 (H2NC6H4OC2H5-
4). Cyclocondensation of compound 3 with phenyl hydrazine
furnished the novel aminopyrazole derivative 5. The isolated
product was established by analytical and spectral data. In the
mass spectrum of compound 5 a molecular ion peak was
found at m/z = 368 (39%) with base peak at m/z = 232 (M-
HNC6H4OC2H5). The formation of 5 is assumed to proceed
through Michael addition of the amino group to the ethylenic
bond in 3 with elimination of methyl mercaptan followed by
intramolecular cyclization at the cyano group to form 5. On
which have been especially used for the synthesis of poly-
functionalized heterocycles.1-3 Aminopyrazole,4 benzoazole5
and 3-cyanopyridine-2-one6 derivatives have been reported
to exhibit biological activities. In view of the above and in
continuation of our studies on the synthesis of heterocyclic
compounds exhibiting biological activity,7-9 we report here
the synthesis of novel ketene dithioacetal, benzoazole and
pyridone derivatives from cyanoacetanilide derivative 1 as
readily available starting material.
RESULTS AND DISCUSSION
Reaction of compound 1 with carbon disulfide in di-
methylformamide and in the presence of potassium hydrox-
ide gave the non-isolable intermediate 2. The latter was con-
verted into 2-cyano-N-(4-ethoxyphenyl)-3,3-bis(methylsul-
fanyl)acrylamide 3 by treatment with dimethyl sulfate at
room temperature in good yield, Scheme I. The structure of 3
was confirmed by analytical and spectroscopic data. The 1H
Scheme I
O
O
ArNH C
CN
SK
ArNH C
CN
CS2
(CH3)2SO4
C
C
C
C
ArNHCOCH2
KOH / DMF
CN
KS
H3CS
SCH3
1
2
3
Ar= C6H4OC2H5-4

554 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Ammar et al.
the other hand, reaction of compound 3 with thiocarbohy-
drazide in ethanol under reflux gave the tetrazine derivative 7
and discarded the other possible structure 6 on the basis of an-
alytical and spectral data. The infrared spectrum of com-
pound 7 was characterized by the appearance of absorption
bands corresponding to NH, CºN and C=O at 3174, 2191 and
1660 cm-1, respectively. Also, the mass spectrum of 7 showed
a molecular ion peak at m/z = 312 (M-2; 5.1%) with base peak
at m/z = 146.
Scheme III
NH2
XH
NH
8a-c
CN
C
X
EtOH / reflux
CONHAr
9a-c
3
CN
SCH3
CH2CONH2
NC
O
CN
Scheme II
10
O
EtOH / EtONa
reflux
N
NH2
SCH3
ArNHC
Ar'NH2
Ar
C
C
EtOH / reflux
11
NC
NHAr'
8a and 9a; X= NH
b; X= O
4a,b
c; X= S
H3CS
CONHAr
NH2
PhNHNH2
EtOH / reflux
The reactivity of compound 1 towards certain nucleo-
N
N
Ph
5
philic and electrophilic reagents was studied. Thus, cyclo-
condensation of compound 1 with acetylacetone as nucleo-
phile in ethanol in the presence of triethylamine12 yielded
pyridone derivative 12 in excellent yield. Condensation of
compound 12 with excess dimethylformamide-dimethyl-
acetal in refluxing m-xylene furnished 4,6-bis-(2-dimethyl-
amino-vinyl)-1-(4-ethoxyphenyl)-2-oxo-1,2-dihydropyridine-
3-carbonitrile 13. Also, compound 1 was cyclized with acti-
vated nitriles 14 to furnish pyridone derivatives 15a-d. The
novel azomethine 16 was achieved by treatment of compound
15b with dimethylformamide-dimethylacetal in refluxing
dioxane. On refluxing compound 16 with hydrazine hydrate
in ethanol, N-amino derivative 18 was obtained. The forma-
tion of compound 18 is assumed to proceed via loss of a
dimethylamine to form non-isolated intermediate 17 which
undergoes intramolecular cyclization into 18, Scheme IV.
3
H3CS
CONHAr
NH2
N
C
N
CSNHNH2
(NH2NH)2CS
EtOH / reflux
6
O
N
N
N
N
ArNHC
S
-2CH3SH
NC
4a; Ar'= C6H4CH3-4
4b; Ar'= C6H4NH2-4
7
Our investigation was extended to include the behavior
of 3 towards bifunctional nucleophilic reagents. When com-
pound 3 was treated with 1,2-phenylenediamine 8a in re-
fluxing ethanol containing triethylamine, the benzimidazole
derivative 9a was obtained. The reaction is assumed to pro-
ceed via a nucleophilic attack of the NH2 to the ethylenic
bond in 3 with elimination of two moles of methyl mercap-
tan.10 In a similar manner, the reactions of 2-aminophenol 8b
and 2-aminothiophenol 8c with compound 3 led to the forma-
tion of benzoazole derivatives 9b and 9c, respectively. Com-
pound 3 reacted with cyanoacetamide 10 as carbon nucleo-
phile in refluxing in the presence of sodium ethoxide to yield
the pyridine derivative 11. The formation of 11 was suggested
to proceed via the addition of the active methylene group of
10 to the ethylenic bond with elimination of methyl mercap-
tan followed by loss of water11 to form 11, Scheme III.
EXPERIMENTAL
Melting points are recorded on a Fisher-John melting
points apparatus and are uncorrected. IR spectra were re-
corded on a Shimadzu 470 spectrophotometer using KBr
pellets. 1H NMR spectra were recorded on a Varian Gemini
Spectrometer 200 (200 MHz) using TMS as internal standard
and mass spectra on a Jeol-JMS-600 mass spectrometer. Ele-
mental analyses were performed on a Perkin-Elmer 240 C mi-
cro-analyzer. The physical and spectral data are collected in
Tables 1 and 2, respectively.

Cyanoacetanilides in Heterocyclic Synthesis
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 555
Scheme IV
CH3
CH=CHN
CH3
N
CH3
CN
CN
O
CH2(COCH3)2
DMFDMA
m-xylene
reflux
1
EtOH / TEA
HC
N
O
H3C
H3C
H3C
reflux
N
CH Ar
Ar
13
12
R
R
X
RCH=C
NC
X
NC
O
CN
DMFDMA
15b
CN
14
CH3
CH3
EtOH / TEA
piperidine
O
N
NH2
N
N=CHN
Ar
Ar
16
15a-d
NH2NH2
EtOH
R
N
R
NH
N
NC
O
NC
O
C
N
NH2
NH NH2
N
N=CH
N
Ar
17
Ar
18
15a; R= CH3
15b; R= C6H4Cl-2
, X = CN
, X= CN
15c; R= C6H4OCH3-4 , X= CN
15d; R= C6H4Cl-2 , X= COOEt
Formation of 2-cyano-N-(4-ethoxyphenyl)-3,3-bis(methyl-
sulfanyl)-acrylamide (3)
product was recrystallized to give 4.
MS (4a): 367 (M+; 48%), 368 (M+1; 11.7%), 369
(M+2; 8.5%); 320 (M-SCH3; 19.3%), 231 (29.3%), 137
(H2NC6H4OC2H5; 100%), 108 (56%), 91 (27%), 107 (37.7%),
76 (5.9%).
To a stirred suspension of finely powdered potassium
hydroxide (0.01 mole) in dry dimethyformamide (10 mL)
cooled to 0 °C the active methylene 1 (0.01 mole) and next
carbon disulfide were added gradually. The reaction mixture
was stirred at room temperature for 3 h, then cooled again to 0
°C, treated with dimethyl sulfate and stirred at room tempera-
ture for an additional 6 h. Then it was poured into ice/water;
the resulting precipitate was filtered off, dried and recrystal-
lized to give 3.
MS (4b): 354 [M-14(N); 9.5%], 218 (10%), 190 (10%),
137 (H2NC6H4OC2H5; 100%), 108 (38%), 76 (1.9%), 75
(1.6%).
Synthesis of 5-amino-3-methylsulfanyl-1-phenyl-1H-
pyrazole-4-carboxylic acid (4-ethoxyphenyl)amide (5)
and 2-cyano-N-(4-ethoxyphenyl)-2-(6-thioxo-6H-[1,2,4,5]-
tetrazine-3-ylidene)acetamide (7): General procedure
A mixture of 3 (0.01 mole) and phenyl hydrazine or
thiocarbohydrazide was heated at 100 °C for 0.5 h. The ob-
tained product was collected and recrystallized to give 5 or 7,
respectively.
MS (5): 368 (M+; 39%), 369 (M+1; 8.5%), 323 (M-
HNC6H4OC2H5; 100%), 137 (H2NC6H4OC2H5; 32%), 108
(6.8%), 119 (24%), 91 (5.3%), 76 (1.3%), 75 (1.5%).
MS (7): 312 (M-2; 5.1%), 292 (47%), 246 (16%), 218
(10%), 163 (12%), 146 (100%), 137 (76%), 108 (65%), 76
MS (3): 308 (M+; 12.4%), 309 (M+1; 2.3%), 310 (M+2;
1.5%), 261 (M-SCH3; 1.2%), 172 (M-NHC6H4OC2H5; 54%),
137 (H2NC6H4OC2H5; 8.9%), 76 (3.6%), 75 (100%).
3-(4-Ethoxyphenylamino)-2-methylsulfanyl-2-(4-tolyl-
amino-methylene)-but-3-enenitrile (4a) and 3-(4-amino-
phenylamino)-2-cyano-N-(4-ethoxyphenyl)-3-(methylsul-
fanyl)-acrylamide (4b): General procedure
A mixture of 3 (0.01 mole) and the aromatic amine
(0.01 mole) in ethanol (30 mL) was heated under reflux for 1
h. The reaction mixture was concentrated and the obtained

556 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Ammar et al.
Table 1. Physical and analytical data of the synthesized compounds
Elemental analyses
Compd.
No.
Molecular formula
(Mol. Wt.)
M.p.
(°C)
Yield
(%)
Solvent
EtOH
C%
H%
N%
3
080-2
150-1
170-2
120-3
> 300
275-6
210-2
240-1
190-2
230-1
115-6
268-9
> 300
> 300
230-2
247-8
260-1
87
82
76
68
70
74
87
80
74
84
88
72
76
75
73
76
65
C14H16N2O2S2
(308.42)
C20H21N3O2S
(367.47)
C19H20N4O2S
(368.46)
C19H20N4O2S
(368.46)
C13H10N6O2S
(314.33)
C18H16N4O2
(320.35)
C18H15N3O3
(321.34)
C18H15N3O2S
(337.40)
C16H14N4O2S
(326.38)
C16H16N2O2
(268.32)
C22H26N4O2
(378.48)
C16H14N4O2
(294.32)
C21H15ClN4O2
(390.83)
C22H18N4O2
(370.41)
C23H20ClN3O4
(437.89)
C24H20ClN5O2
(445.91)
54.52
54.60
65.37
65.30
61.94
61.80
61.94
61.80
49.68
49.60
67.49
67.10
67.28
67.20
64.08
64.20
58.88
58.70
71.62
71.60
69.82
69.70
65.30
65.30
64.54
64.60
71.34
71.30
63.09
63.10
64.65
64.60
66.49
66.30
5.23
5.10
5.76
5.70
5.47
5.40
5.47
5.50
3.21
3.10
5.03
5.00
4.71
4.70
4.48
4.50
4.32
4.40
6.01
6.00
6.92
6.80
4.79
4.70
3.87
3.70
4.90
4.80
4.60
4.60
4.52
4.50
4.31
4.60
09.08
09.00
11.43
11.40
15.21
15.10
15.21
15.20
26.74
26.60
17.49
17.40
13.08
13.00
12.45
12.40
17.17
17.10
10.44
10.40
14.80
14.90
19.04
19.10
14.34
14.30
15.13
15.10
09.60
09.60
15.71
15.70
21.15
21.40
4a
4b
5
EtOH
EtOH
EtOH
7
EtOH
9a
9b
9c
11
12
13
15a
15b
15c
15d
16
18
EtOH
EtOH
EtOH
EtOH
EtOH
Dioxane
Benzene
Benzene
Benzene
Benzene
EtOH
EtOH
C22H17N6O2
(397.43)
(11%), 60 (54%).
6-Amino-1-(4-ethoxyphenyl)-4-methylsulfanyl-2-oxo-1,2-
dihydropyridine-3,5-dicarbonitrile (11)
2-Cyano-2-(1,3-dihydro-benzimidazol-2-ylidene)-N-(4-
ethoxyphenyl)acetamide (9a), 2-(3H-benzoxazol-2-
ylidene)-2-cyano-N-(4-ethoxyphenyl)acetamide (9b) and
2-(3H-benzothiazol-2-ylidene)-2-cyano-N-(4-ethoxyphenyl)-
acetamide (9c): General procedure
A mixture of compound 3 (0.01 mole), cyanoacetamide
(0.01 mole) and sodium ethoxide (0.01 mole) in ethanol (30
mL) was heated under reflux for 3 h, then allowed to cool and
poured into cold water (50 mL) and acidified with HCl to give
11.
A mixture of compound 3 (0.01 mole) and binucleo-
phile (0.01 mole) in ethanol (30 mL) was heated under reflux
for 48 h. The reaction mixture was concentrated and the ob-
tained product was collected and recrystallized to give 9a-c.
1-(4-Ethoxyphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyri-
dine-3-carbonitrile (12)
A mixture of compound 1 (0.01 mole), acetylacetone

Cyanoacetanilides in Heterocyclic Synthesis
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 557
Table 2. Spectral data of the synthesized compounds
Compd
No.
IR/nmax (cm-1)
1H NMR (DMSO-d6; d/ppm)
3
3373 (NH), 2980 (CH-aliph),
2202 (CºN), 1660 (C=O).
3224 (NH), 2977, 2923 (CH-
aliph), 2191 (CºN), 1620 (C=O).
3399, 3178 (NH2), 2174 (CºN),
1640 (C=O).
1.34 (t, 3H, CH3), 2.37, 2.48 (2s, 6H, 2SCH3), 4.12 (q, 2H,
CH2), 6.91-7.15 (m, 4H, Ar-H), 9.34 (s, 1H, NH).
4a
4b
1.41 (t, 3H, CH3), 2.53 (s, 3H, SCH3), 4.12 (q, 2H, CH2),
6.91-7.39 (m, 8H, Ar-H), 8.29, 8.33 (2s, 2H, 2NH), 12.56
(hump, 2H, NH2).
5
3425, 3363, 3317 (NH/NH2), 3047
(CH-arom), 2923 (CH-aliph),
1643 (C=O).
1.45 (t, 3H, CH3), 2.58 (s, 3H, SCH3), 4.18 (q, 2H, CH2),
6.72 (s, 2H, NH2), 6.94-7.59 (m, 9H, Ar-H), 9.41 (s, 1H,
NH).
7
3174 (NH), 2977, 2923 (CH-
aliph), 2191 (CºN), 1660 (C=O).
3250, 3420 (2NH), 2169 (CºN),
1643 (C=O).
3301, 3201 (2NH), 2985, 2923
(CH-aliph), 2214 (CºN), 1674
(C=O).
1.18 (t, 3H, CH3), 4.01 (q, 2H, CH2), 6.81, 7.49 (2d, 4H,
Ar-H), 8.79 (s, 1H, NH).
1.40 (t, 3H, CH3), 4.11 (q, 2H, CH2), 6.90-7.45 (m, 8H, Ar-
H), 8.15, 8.32, 12.40 (3s, 3H, 3NH).
9a
9b
9c
11
3402, 3201 (2NH), 2183 (CºN),
1651 (C=O).
3306, 3204 (NH2), 2984, 2928
(CH-aliph), 2214 (CºN), 1670
(C=O).
1.41 (t, 3H, CH3), 4.12 (q, 2H, CH2), 7.01-7.85 (m, 8H, Ar-
H), 8.28, 8.39 (2s, 2H, 2NH).
1.19 (t, 3H, CH3), 2.81 (s, 3H, SCH3), 4.07 (q, 2H, CH2),
6.81-7.55 (m, 4H, Ar-H), 7.89 (hump, 2H, NH2).
12
13
3064 (CH-arom), 2984, 2910
(CH-aliph), 2218 (CºN), 1600
(C=O).
2916 (CH-aliph), 2191 (CºN),
1630 (C=O).
1.37 (t, 3H, CH3), 1.99, 2.39 (2s, 6H, 2CH3), 4.08 (q, 2H,
CH2), 6.45 (s, 1H, pyridine-H), 7.04, 7.24 (2d, 4H, Ar-H).
1.36 (t, 3H, CH3), 2.71, 3.00 (2s, 12H, 2N(CH3)2), 4.10 (q,
2H, CH2), 6.54 (s, 1H, pyridine-H), 6.99 (s, 4H, Ar-H),
7.43, 7.71 (2d, 4H, ethylene-H).
15a
15c
15d
3309, 3193 (NH2), 2977 (CH-
aliph), 2214 (CºN), 1660 (C=O).
3320, 3186 (NH2), 2206 (CºN),
1640 (C=O).
3420, 3224 (NH2), 2229 (CºN),
1700 (C=O; ester), 1658 (C=O;
pyridone).
1.28 (t, 3H, CH3), 3.26 (s, 3H, CH3), 3.81 (s, 2H, NH2),
4.02 (q, 2H, CH2), 6.87, 7.42 (2d, 4H, Ar-H).
1.37 (t, 3H, CH3), 3.85 (s, 3H, OCH3), 4.12 (q, 2H, CH2),
7.08-7.51 (m, 8H, Ar-H), 7.67 (hump, 2H, NH2).
0.61, 1.38 (2t, 6H, 2CH3), 3.80, 4.14 (q, 4H, 2CH2), 7.12-
7.58 (m, 10H, Ar-H and NH2).
16
18
2977, 2931 (CH-aliph), 3214
(CºN), 1651 (C=O).
3448, 3178 (NH2), 2977 (CH-
aliph), 2221 (CºN), 1658 (C=O).
1.37 (t, 3H, CH2), 2.71, 3.06 (2s, 6H, 2CH3), 4.10 (q, 2H,
CH2), 7.01-7.73 (m, 8H, Ar-H), 8.22 (s, 1H, CH=N).
1.35 (t, 3H, CH3), 4.13 (q, 2H, CH2), 7.10-7.71 (m, 11H,
Ar-H+NH2+NH), 7.98 (s, 1H, pyrimidine-H).
(0.01 mole) and triethylamine (0.01 mole) in ethanol (40 mL)
was heated under reflux for 4 h; the solid product which was
produced on heating was collected and recrystallized to give
12.
mL) was heated under reflux for 3 h; the solid product which
was produced on heating was collected and recrystallized to
give 13.
6-Amino-1-(4-ethoxyphenyl)-2-oxo-4-R-1,2-dihydropyri-
dine-3,5-dicarbonitriles (15a-c) and ethyl 6-amino-3-
cyano-1-(4-ethoxyphenyl)-2-oxo-4-(2-chlorophenyl)-1,2-
dihydropyridine-5-carboxylate (15d): General procedure
A mixture of compound 1 (0.01 mole), activated nitrile
4,6-Bis(2-dimethylamino-vinyl)-1-(4-ethoxyphenyl)-2-oxo-
1,2-dihydropyridine-3-carbonitrile (13)
A mixture of compound 12 (0.01 mole) and dimethyl-
formamide-dimethylacetal (0.02 mole) in dry m-xylene (30

558 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Ammar et al.
14 (0.01 mole) and piperidine (0.01 mole) in ethanol (40 mL)
was heated under reflux for 1 h; the solid product which was
produced on heating was collected and recrystallized to give
15a-c.
Received October 13, 2004.
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Gh. W. Phosphorus, Sulfur and Silicon 2000, 164, 189.
12. Ammar, Y. A.; El-Sharief, A. M.; Mohamed, Y. A.; Salem,
M. A.; Al-Schemi, A. G.; El-Gaby, M. S. A. J. Chin. Chem.
Soc. 2004, Proof.
3-Amino-8-(4-ethoxyphenyl)-4-imino-7-oxo-5-(2-chloro-
phenyl)-3,4,7,8-tetra-hydropyrido[2,3-d]pyrimidine-6-
carbonitrile (18)
A mixture of compound 16 (0.01 mole) and hydrazine
hydrate (0.01 mole) in ethanol (30 mL) was refluxed for 3 h,
and then allowed to cool. The solid product was collected and
recrystallized to give 18.