Cyanothioacetanilide intermediates in heterocyclic synthesis, part 1: Synthesis and biological evaluation of some novel thiazole, thiophene, pyrazole, and pyrazolo[1,5-a]pyrimidine derivatives

Article abstract of DOI:10.1080/10426500902953938

Some novel thiophenes (4a,b, 5, and 9a,b) were obtained from the cycloalkylation of the thiocarbamoyl group in the cyanothioacetanilide derivative (1) with -halocarbonyl compounds. Also, the reaction of cyanothioacetanilide derivative with phenyl isothiocyanate in the presence of potassium hydroxide followed by in situ heterocyclization of the resulting adduct with -halocarbonyl compounds furnished the corresponding thiazole (12, 14, and 15), pyrazole (19), and pyraozlo[1,5-a]pyrimidine (22, 25, and 26) derivatives. Compounds (4b, 5, 9a, 12, 13, 18, 22, 25, and 26) were tested to evaluate their antimicrobial activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902953938

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Cyanothioacetanilide Intermediates in
Heterocyclic Synthesis, Part 1: Synthesis
and Biological Evaluation of Some Novel
Thiazole, Thiophene, Pyrazole, and
Pyrazolo[1,5-a]Pyrimidine Derivatives
Y. A. Ammar a , H. Kh. Thabet a , M. M. Aly a , Y. A. Mohamed a , M.
A. Ismail a & M. A. Salem a
a Chemistry Department, Faculty of Science, Al-Azhar University,
Nasr City, Cairo, Egypt
Published online: 23 Mar 2010.
To cite this article: Y. A. Ammar , H. Kh. Thabet , M. M. Aly , Y. A. Mohamed , M. A. Ismail & M. A.
Salem (2010) Cyanothioacetanilide Intermediates in Heterocyclic Synthesis, Part 1: Synthesis and
Biological Evaluation of Some Novel Thiazole, Thiophene, Pyrazole, and Pyrazolo[1,5-a]Pyrimidine
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:4, 743-753, DOI:
10.1080/10426500902953938
To link to this article: http://dx.doi.org/10.1080/10426500902953938
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Phosphorus, Sulfur, and Silicon, 185:743–753, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902953938
CYANOTHIOACETANILIDE INTERMEDIATES IN
HETEROCYCLIC SYNTHESIS, PART 1: SYNTHESIS AND
BIOLOGICAL EVALUATION OF SOME NOVEL THIAZOLE,
THIOPHENE, PYRAZOLE, AND
PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
Y. A. Ammar, H. Kh. Thabet, M. M. Aly, Y. A. Mohamed,
M. A. Ismail, and M. A. Salem
Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City,
Cairo, Egypt
Some novel thiophenes (4a,b, 5, and 9a,b) were obtained from the cycloalkylation of the
thiocarbamoyl group in the cyanothioacetanilide derivative (1) with α-halocarbonyl com-
pounds. Also, the reaction of cyanothioacetanilide derivative with phenyl isothiocyanate in
the presence of potassium hydroxide followed by in situ heterocyclization of the resulting
adduct with α-halocarbonyl compounds furnished the corresponding thiazole (12, 14, and
15), pyrazole (19), and pyraozlo[1,5-a]pyrimidine (22, 25, and 26) derivatives. Compounds
(4b, 5, 9a, 12, 13, 18, 22, 25, and 26) were tested to evaluate their antimicrobial activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Biological activity; cyanothioacetanilide; pyrazolo[1,5-a]pyrimidines; thiazoles;
thiophenes
INTRODUCTION
Cyanothioacetanilide derivatives are highly reactive reagents, and their utility in
heterocyclic synthesis has recently received considerable attention.1–3 The combination
of NH-C S and CH2CN groups in cyanothioacetanilide molecules opens a variety of
synthetic opportunities for further reaction and utilization as a starting materials in the
synthesis of heterocyclic compounds. The development of effective therapeutic agents for
the treatment of inflammation continues to be challenging problem in medicinal chem-
istry. Compounds containing thiophene, thiazole, and pyrazole functionalities have been
reported to exhibit anti-inflammation activities.4–9 In our laboratory, a series of thiazole and
pyrazole derivatives has been synthesized and evaluated in the search for new non-steroidal
anti-inflammation.10–16 Furthermore, the antimicrobial activity of thiophene, thiazole, and
pyrazole are well documented.17,18 The present investigation deals with the synthesis of
Received 20 January 2009; accepted 5 April 2009.
Address correspondence to Dr. H. Kh. Thabet, Chemistry Department, Faculty of Science, Al-Azhar Uni-
versity, Nasr City, Cairo, Egypt. E-mail: h khamees@hotmail.com
743

744
Y. A. AMMAR ET AL.
compounds having thiophene, thiazole, and pyrazole incorporated in their structures in
order to investigate their effect on antimicrobial activity.
RESULTS AND DISCUSSION
Cyanothioacetanilide (1) has three nucleophilic sites, which may potentially undergo
initial attack; the methylene group carbon and thioamide nitrogen and sulfur atoms. On the
whole, under cyclocondensation or cycloaddition, cyanothioacetanilide acts a C,N-, C,S-,
or S,N-binucleophile. Also, the cyanothioacetanilide contains a cyano group as electrophile
center. In the course of our study of synthetic scope of cyanothioacetanilide (1), we inves-
tigated its reaction with different reagents as well as the structure and transformation of the
reaction product.
α-Halocarbonyl compounds are highly versatile intermediates for the synthesis of a
variety of heterocyclic compounds.19 Treatment of cyanothioacetanilides (1a,b) with ethyl
chloroacetate in alcoholic sodium acetate under reflux afforded a single product in each
case. The structure of the isolated products was established by analytical and spectro-
scopic data as the thiophene derivatives (4a,b) instead of the thiazole derivative (3). The
infrared spectrum of compound 4a showed the absence of a C≡N group, which supports
the thiophene structure and the presence of the following absorption bands: 3294–3000
1
(br; OH/NH), 2920 (CH-aliph.), and 1707cm−1(C O; COOH). Also, the H NMR spec-
trum of compound 4a in DMSO-d6 displayed three singlets at 2.23, 3.68, and 5.78 ppm
attributed to CH3 and 2H of thiophene protons, respectively. The aromatic protons were
observed as a multiplet at 7.08–7.46; also three singlets were identified at 9.73, 10.07, and
11.48 ppm attributed to 2NH and OH carboxylic group (disappeared with D2O). This sug-
gested that the reaction starts with a nucleophilic substitution of the chlorine atom by the
thiolate group of (1) to give the non-isolable intermediate 2, which cyclizes through the
addition on the cyano group. Also, the reaction involves the hydrolysis of an ester group
under the reaction conditions. The structure of the latter compound 4a,b was further con-
firmed by another route via alkylation of compound 1 with chloroacetic acid under the same
conditions (Scheme 1). In a similar manner, thiophene derivative 5 was obtained by the
cycloalkylation of cyanothioacetanilide derivative (1b) with p-nitrophenacyl bromide. The
structure of 5 was identified on the basis of satisfactory elemental analysis and spectral data.
The infrared spectrum showed the absence of the C≡N functional group and indicated the
presence of absorption bands at 3102 (NH) and 1660 cm−1 (C O). The mass spectrum of
5 showed a molecular ion peak at m/z = 373 (7%), which is characteristic for the molecular
formula C17H12ClN3O3S together with base peak at m/z 219.
The reactivity of the methylene group in cyanothioacetanilide derivative (1) towards
isothiocyanate in the presence of potassium hydroxide followed by in situ heterocyclization
with α-halocarbonyl compounds was studied. Thus, the reaction of cyanothioacetanilide
derivative (1b) with phenyl isothiocyanate in the presence of potassium hydroxide at room
temperature gave the non-isolable potassium salt (6).
S
S
CN
CN
S K
KOH/PhNCS
DMF
N
Cl
N
H
Cl
H
PhHN
(1b)
(6)

CYANOTHIOACETANILIDE INTERMEDIATES
745
The potassium sulfide salt (6) was exploited to synthesize new thiophene and thiazole
derivatives. Treatment of the intermediate 6 with p-nitrophenacyl bromide (7a) and N-(4-
nitrophenyl)chloroacetamide (7b) at room temperature gave the novel 3-aminothiophene
derivatives (9a,b) in good yields (Scheme 2). The structure of the isolated products was
confirmed on the basis of elemental analysis and spectral data. The infrared spectrum of
9a revealed absorption bands at 3393, 3320, 3280 (NH/NH2) and 1660 cm−1 (C O) with
1
the absence of a C≡N absorption band. Also, the H NMR spectrum of 9a in DMSO-
d6 exhibited a broad singlet at 8.01 (2H, NH2) and a D2O exchangeable 2NH at 9.94,
10.11 ppm. Also, compound 9b gave a molecular ion peak at m/z 507 [M-16(NH2); 20%]
and the base peak was found in the spectrum at m/z 343. The formation of 9 is assumed to
proceed through the initial alkylation of intermediate 6 to afford the non-isolable thioether
derivative (8) followed by in situ heterocyclization via a Dieckmann-type reaction.20,21 On
the other hand, the isolable thioether derivative (10) was obtained via alkylation of salt (6)
with N-(4-methoxyphenyl)-chloroacetamide in good yield. The structure of thioether (10)
was confirmed by examining spectral data. Its infrared spectrum indicated the presence
of NH, C N, and C O absorption bands. In addition the structure 10 was supported by
1H NMR spectrum, which revealed a singlet at δ = 3.67 ppm assigned to the methylene
moiety. 4-Thiazolidinone derivative (12) was obtained via refluxing of thioether derivative
(10) in ethanolic piperidine, and the other possible thiophene structure (11) was excluded
on the basis of analytical and spectral data. Infrared spectrum exhibited absorption bands at
2199 (C≡N) and 1737 cm−1 (C O; thiazolidinone), while its 1H NMR spectrum showed
a singlet at δ 4.00 (2H, CH2-thiazole). The reaction mechanism is assumed to proceed via
intramolecular cyclization and elimination of p-anisidine molecule. The structure of the
COCH2Br
CN
S
ClCH2CO2Et
CH3CO2Na
NO2
Ar
CN
C
Ar
N
N
H
S
COOEt
CH3CO2Na
H
(1a,b)
(2)
C
l
C
H
2 C
O
H
2 H
3 C
O
2 N
CN
S
a
Cl
NH
NO2
NH
Ar
N
Ar
N
H
S
N
S
COOH
H
H
H
O
O
(3)
NH2
O
Cl
NO2
NH2
N
H
S
Ar
N
S
COOH
H
(5)
(4a,b)
4a; Ar = C6H4CH3-p
4b; Ar = C6H4Cl-p
Scheme 1

746
Y. A. AMMAR ET AL.
NHCOCH2Cl
S
S
Ar
CN
Ar
CN
OCH3
N
N
H
H
H
N
PhNH
S
PhNH
(6)
S K
O
OCH3
(10)
C
XCH2COR
(7a,b)
l
p
-
C
)
H
2
3
H
C
C
-
O
E
O
2
(
2
t
O
H
E
N
4
H
S
t
H
6
C
-
Ar
CN
S
N
H
PhNH
S
S
N
R
Ar
NH2
N
Ar
CN
S
H
N
H
N
H
O
PhNH
S
(8)
Ph
O
OCH3
S
O
(11)
Ar
NH2
R
N
(12)
H
PhNH
S
O
(9a,b)
9a
; R = C6H4NO2-p
9b; R = NHC6H4NO2-p
Scheme 2
latter compound was further confirmed by synthetic route via cycloalkylation of salt (6)
with ethyl chloroacetate.
Cycloalkylation of non-isolable salt (6) with chloroacetone afforded 4-methylthiazole
derivative (14). The other possible structure (13) was ruled out on the basis of infrared spec-
trum, which showed the characteristic absorption band at 2182 cm−1 for C≡N functional
group and 1H NMR spectrum, which revealed a singlet at δ = 1.84 ppm assigned to CH3
with singlet at δ 6.37 ppm assigned to (CH-thiazole). Similarly, treatment of non-isolable
salt (6) with α-chloroethylacetoacetate afforded 4-methylthiazle derivative (15), and the two
other possible structures (16 and 17) were excluded on the basis of elemental analysis and
spectral data. The infrared spectrum of compound 15 showed the characteristic absorption
band at 2184 and 1712 cm−1 for C≡N and (C O, ester) groups. Also, 1H NMR revealed
a triplet at 1.31 ppm and quartet at 4.32 ppm assigned to the ester moiety. Formation of 15
was assumed to proceed through initial alkylation followed by intramolecular cyclization
through dehydration (Scheme 3).
Pyrazole derivatives have attracted the attention of organic chemists due to their
biological and chemotherapeutic importance.22 Also, the pyrazolo[1,5-a]pyrimidine struc-
tural motif may be found in a large number of pharmacological agents with a diverse
range of physiological activities, for example the treatment of pain, including inflammatory
and neuropathic pain.23 The study was extended to synthesize some novel pyrazolo[1,5-
a]pyrimidines from readily obtainable inexpensive starting materials. The key starting
material for this part of the research was obtained when the non-isolable 6 was treated
with dimethyl sulfate. The isolated product was identified as N-(4-chlorophenyl)-2-cyano-
3-(methylthio)-3-(phenylamino)prop-2-enethioamide (18) on the basis of: (a) the infrared
spectrum showed absorption bands at 3134 (NH), 2950 (CH-aliph.) and 2198 cm−1 (C≡N),
1
(b) H NMR spectrum in DMSO-d6 displayed three singlets at 2.26 assigned for methyl

CYANOTHIOACETANILIDE INTERMEDIATES
747
S
Ar
NH2
N
H
PhNH
S
COCH3
CH2COCH3
Cl
(13)
S
Ar
CN
N
H
Ph
N
S
H3C
(14)
S
(6)
Ar
CN
S
N
H
Ph
N
CO2Et
Cl
CO2Et
H3C
(15)
COCH3
S
Ar
CN
S
N
H
Ph
N
COCH3
O
H
(16)
S
Ar
NH
N
H
PhNH
COCH3
S
CO2Et
Ar = C6H4Cl-p
(17)
Scheme 3
sulfanyl group, (c) it is converted into the aminopyrazole (19) by refluxing with hydrazine
in ethanol (Scheme 4). The infrared spectrum of compound 19 showed the absence of
characteristic absorption bands for C≡N, with the presence of absorption bands at 3252,
3111 cm−1 (NH/NH2). 1H NMR spectrum of compound 19 revealed the following signals:
δ 6.15 (s, 2H, NH2) and D2O exchangeable 3 NH at 9.15, 9.80, and 10.00 ppm. Also,
compound 19 gave a molecular ion peak at m/z 343, which fitted exactly with the expected
molecular weight. The reactivity of aminopyrazole derivative 19 towards some electrophilic
reagents was investigated to afford pyrazolo[1,5-a]pyrimidine derivatives. Thus, reaction
of 19 with α-cyano-2-chlorocinnamonitrile (20) yielded a product for which structure 22
or 24 seemed possible. Structure 22 appears more likely than 24 on the basis that ring nitro-
gen is the most nucleophilic center in the molecule.24 The structure of 22 was established
by elemental analysis and spectral data. Infrared spectrum of compound 22 showed the

748
Y. A. AMMAR ET AL.
following absorption bands: 3305, 3252, 3179 (NH/NH2) and 2219 cm−1 (C≡N). 1H NMR
spectrum of compound 22 in DMSO-d6 revealed D2O exchangeable signals at 9.25, 9.38,
and 9.95 ppm for NH2 and 2NH. The formation of 22 is assumed to proceed via initial
Michael addition of endocyclic NH of 19 to the activated double bond of 20 to afford the
intermediate 21 followed by intramolecular cyclization and auto-oxidation Scheme 4.
S
S
Ar
CN
S K
Ar
CN
(CH3)2SO4
DMF
N
N
H
H
PhNH
(6)
PhNH
SCH3
(18)
S
S
NH2
NH2NH2.H2O
EtOH/reflux
Ar
N
NH2
CN
Ar
Ar'
N
H
N
N
H
N
N
CN
PhNH
PhNH
N
S
NC
Ar'
Ar'
Ar
NH2
CN
CN
N
(22)
(21)
H
Ar'
N
PhNH
N
H
S
(20)
S
CN
CN
N
Ar'
Ar
HN
(19)
N
H
PhNH
Ar
N
H
N
N
NH
CN
N
NH2
PhNH
(23)
(24)
Ar = C6H4Cl-p, Ar' = C6H4Cl-o
Scheme 4
Also, the reactivity of the aminopyrazole derivative (19) towards the 1,3-dicarbonyl
compounds was also discussed. Thus, cyclocondensation of aminopyrazole (19) with acety-
lacetone in refluxing glacial acetic acid gave the pyrazolo[1,5-a]pyrimidine derivative
(25). Finally the reaction of 19 with ethyl acetoacetate in refluxing glacial acetic yielded
pyrazolo[1,5-a]pyrimidine derivative (26) (Scheme 5).
EXPERIMENTAL
All melting points are uncorrected. IR spectra (KBr) were recorded on a FTIR 5300
spectrometer (v, cm−1). The 1H NMR spectra were recorded in DMSO-d6 at 200 MHz on
a Varian Gemini NMR spectrometer (δ, ppm) using TMS as an internal standard. Mass
spectra were obtained on GC MS-QP 1000 EX mass spectrometer at 70 eV. Elemental
analyses were carried out by the Microanalytical Research Centre, Faculty of Science,
Cairo University.
General Procedure for the Formation of Compounds (4a,b)
Method A. A mixture of cyanothioacetanilide derivatives 1a,b25 (0.01 mol), ethyl
chloroacetate (0.01 mol), and fused sodium acetate (0.01 mol) was refluxed in ethanol
(30 mL) for 1 h. The solid product, which precipitated upon heating, was collected and
recrystallized from the proper solvent to give 4a,b.

CYANOTHIOACETANILIDE INTERMEDIATES
749
COCH3
S
Ar
N
CH3
COCH3
AcOH
N
H
PhNH
N
N
CH3
(25)
(19)
COCH3
S
H
N
Ar
O
N
H
CO2Et
AcOH
N
PhNH
N
CH3
(26)
Scheme 5
Method B. A mixture of cyanothioacetanilide derivatives 1a,b (0.01 mol),
chloroacetic acid (0.01 mol), and fused sodium acetate (0.01 mol) was refluxed in ethanol
(30 mL) for 1 h. The solid product, which was produced upon heating, was collected and
recrystallized from the proper solvent to give 4a,b.
3-Imino-5-(p-tolylamino)-2,3-dihydrothiophene-2-carboxylic acid 4a.
This compound was crystallized from dioxane and obtained in 60% yield as white
crystals, mp 240–242◦C, IR (KBr): ν = 3294–3000 (br; OH/2NH), 2920 (CH-aliph.) and
1707 cm−1 (C O, COOH); 1H NMR (DMSO-d6): δ = 2.23, (s, 3H, CH3), 3.68, 5.78 (2s,
2H, thiophene-H), 7.08–7.46 (m, 4H, Ar-H), 9.73, 10.07, 11.48 ppm (3s, 3H, 2NH + OH;
disappeared with D2O). Anal. Calcd. for C12H12N2O2S (248): C, 58.06; H, 4.83; H, 11.29.
Found: C, 58.00; H, 4.70; H, 11.20.
3-Imino-5-(p-chlorophenylamino)-2,3-dihydrothiophene-2-carboxylic
acid 4b. This compound was crystallized from acetic acid and obtained in 65% yield as
white crystals, mp 270–272◦C, IR (KBr): ν = 3300–3000 (br; OH carboxylic, 2NH) and
1708 cm−1 (C O, COOH); 1H NMR (DMSO-d6): δ = 3.92, 5.85 (2s, 2H, thiophene-H),
7.27–7.67 (2d, 4H, Ar-H), 10.04 (s, 1H, NH; disappeared with D2O), 11.20 (br, 2H, NH +
OH; disappeared with D2O). Anal. Calcd. for Cl1H9ClN2O2S (268.5): C, 49.16; H, 3.35;
H, 10.42. Found: C, 49.10; H, 3.30; H, 10.30.
N-(4-Chlorophenyl)-4-imino-5-(4-nitrobenzoyl)-4,5-dihydrothiophen-2-amine
(5)
A mixture of cyanothioacetanilide 1b (0.01 mol), p-nitrophena-cyl bromide (0.01
mol), and fused sodium acetate (0.01 mol) was refluxed in ethanol (30 mL) for 1 h. The
solid product, which was produced upon heating, was collected and recrystallized from
acetic acid to give 5.
Yield (50%), mp 220–222◦C, IR (KBr): ν = 3102 cm−1 (NH) and 1660 cm−1 (C O);
MS, m/z (%): 373 (7), 219 (100, base peak), 355 (7), 221 (9) and 150 (37). Anal. Calcd.

750
Y. A. AMMAR ET AL.
for C17H12ClN3O3S (373.5): C, 54.61; H, 3.21; N, 11.24. Found: C, 54.50; H, 3.10; N,
11.20.
Preparation of 9a,b, 10, 12, 13, and 15: General Procedure
To a suspension of finely powdered potassium hydroxide (0.01 mol) in dry dimethyl-
formamide (15 mL), cyanothioacetanilide derivative 1b (0.01 mol) and then the phenyl
isothiocyanate (0.01 mol) were added in portions. The reaction mixture was stirred at room
temperature with α-halocarbonyl compound (0.01 mol) and left at room temperature for
3 h. Then it was poured into ice/water and acidified with 0.1 N HCl at pH 3–4. The resulting
precipitate was filtered off, dried, and recrystallized from the proper solvent.
Alternative Method for Preparation of Compound 12
A mixture of compound 10 (0.01 mol) and piperidine (0.01 mol) in ethanol (30 mL)
was heated under reflux for 1 h. The solid product, which was produced upon heating, was
collected and recrystallized to give 12.
4-Amino-N-(4-chlorophenyl)-5-(4-nitrobenzoyl)-2-(phenylamino)-thio-
phene-3-carbothioamide (9a). This compound was crystallized from benzene and
obtained in 70% yield as brown crystals, mp >300◦C, IR (KBr): ν = 3393, 3280 cm−1
(NH2/NH) and 1660 cm−1 (C O); 1H NMR (DMSO-d6): δ = 7.11–8.29 (m, 13H, Ar-H),
8.01 (br, 2H, NH2, disappeared with D2O), 9.94, 10.11 (2s, 2H, 2NH, disappeared with
D2O). Anal. Calcd. for C24H17ClN4O3S2 (508.5): C, 56.63; H, 3.34; N, 11.01. Found: C,
56.50; H, 3.20; N, 11.00
3-Amino-4-(4-chlorophenylcarbamothioyl)-N-(4-nitro-phenyl)-5-(phenyl-
amino)thiophene-2-carboxamide (9b). This compound was crystallized from
benzene and obtained in 65% yield as brown crystals, mp >300◦C, IR (KBr): ν = 3306
(br, NH2/NH) 3063 (CH-aromatic) and 1650 cm−1 (C O; amide). Anal. Calcd. for
C24H18ClN5O3S2 (523.5): C, 55.01; H, 3.43; N, 13.37. Found: C, 55.00; H, 3.30; N, 13.20.
MS, m/z (%) = 507 [M-16 (NH2) 20], 343 (100, base peak), 508 (67.7), 216 (52.7) and
127 (71).
2-(3-(4-Chlorophenylamino)-2-cyano-1-(phenylamino)-3-thioxo-prop-1-
enylthio)-N-(4-methoxyphenyl)acetamide (10). This compound was obtained in
75% yield as white crystals (acetic acid), mp 200–202◦C. IR (KBr): ν = 3259 (NH), 2200
1
(C≡N) and 1639 cm−1 (C O). H NMR (DMSO-d6): δ = 3.67 (s, 3H, OCH3), 3.73 (s,
2H, SCH2), 6.75–7.54 (m, 13H, Ar-H), 9.74, 10.08, 11.20 (3s, 3H, 3NH, disappeared with
D2O). Anal. Calcd. for C25H21ClN4O2S2 (508.5): C, 58.99; H, 4.12; N, 11.01. Found: C,
58.80; H, 4.00; N, 10.70.
N-(4-Chlorophenyl)-2-cyano-2-(4-oxo-3-phenylthiazolidin-2-ylidene)-
ethanethioamide (12). This compound was obtained in 55% yield as yellow crystals
(benzene), mp 240–242◦C. IR (KBr): ν = 3330 (NH), 2198 (C≡N) and 1737 cm−1 (C O;
1
thiazolidinone). H NMR (DMSO-d6): δ = 4.00 (s, 2H, SCH2), = 7.32–7.58 (m, 9H,
Ar-H), 9.58 (s, 1H, NH; disappeared with D2O). Anal. Calcd. for C18H12ClN3OS2 (385.5):
C, 56.03; H, 3.11; N, 10.89. Found: C, 55.90; H, 3.00; N, 10.80.
N-(4-Chlorophenyl)-2-cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene)-
ethanethioamide (13). This compound was obtained in 55% yield as yellow crystals
(benzene), mp 237–240◦C. IR (KBr): ν = 3305 (NH), 2182 (C≡N) and 1304 cm−1 (C S).
1H NMR (DMSO-d6): δ = 1.84 (s, 3H, CH3), 6.94 (s, 1H, thiazole-H), 7.25–7.59 (m, 9H,

CYANOTHIOACETANILIDE INTERMEDIATES
751
Ar-H), 8.87 (s, 1H, NH; disappeared with D2O). Anal. Calcd. for C19H14ClN3S2 (383.5):
C, 59.45; H, 3.65; N, 10.95. Found: C, 59.30; H, 3.60; N, 10.80.
Ethyl 2-(2-(4-Chlorophenylamino)-1-cyano-2-thioxoethylidene)-4-meth-
yl-3-phenyl-2,3-dihydrothiazole-5-carboxylate (15). This compound was obtained
in 60% yield as brown crystals (benzene), mp 245–247◦C. IR (KBr): ν = 3409 (NH), 2184
(C≡N) and 1712 (C O; ester), 1301 cm−1 (C S). 1H NMR (DMSO-d6): δ = 1.31 (t, 3H,
CH3), 2.16 (s, 3H, CH3), 4.32 (q, 2H, CH2), 7.29–7.62 (m, 9H, Ar-H), 9.11 (s, 1H, NH;
disappeared with D2O). Anal. Calcd. for C22H18ClN3O2S2 (455.5): C, 57.95; H, 3.95; N,
9.22. Found: C, 57.80; H, 3.80; N, 9.30.
N-(4-Chlorophenyl)-2-cyano-3-(methylthio)-3-(phenylamino)prop-2-ene-
thioamide (18)
To a stirred suspension of finely powdered potassium hydroxide (0.01 mol) in dry
dimethylformamide (15 mL) at room temperature, the active methylene 1b (0.01 mol) and
next phenyl isothiocyanate (0.01 mol) were added gradually. The reaction mixture was
stirred at room temperature for 3 h, then treated with dimethylsulfate (0.01 mol) and stirred
at room temperature for an additional 3 h. Then it was poured into ice/water, the resulting
product was filtered off, dried, and recrystallized from EtOH as white crystals.
Yield 80%, mp 140–143◦C. IR (KBr): ν = 3334 (NH), 2950 (CH-aliph.) and 2198
(C≡N), 1359 cm−1 (C S). 1H NMR (DMSO-d6): δ = 2.26 (s, 3H, CH3), 6.52–7.61 (m, 9H,
Ar-H), 9.76, 11.67 (2s, 2H, 2NH; disappeared with D2O). Anal. Calcd. for C17H14ClN3S2
(359.5): C, 56.74; H, 3.89; N, 11.68. Found: C, 56.70; H, 3.90; N, 11.50.
3-Amino-N-(4-chlorophenyl)-5-(phenylamino)-1H-pyrazole-4-carbothio-
amide (19)
A mixture of 18 (0.01 mol) and hydrazine hydrate (0.01 mol) in ethanol (30 mL) was
heated under reflux for 3 h. The reaction was concentrated, and the obtained product was
collected and recrystallized from benzene as yellow crystals.
Yield 70%, mp 180–182◦C. IR (KBr): ν = 3252, 3111 (NH2/NH), 3065 (CH-arom.)
1
and 1620 cm−1 (C N) 1350 cm−1 (C S). H NMR (DMSO-d6): δ = 5.35 (s, 2H, NH2;
disappeared with D2O), 6.46–7.68 (m, 9H, Ar-H), 9.15 (s, 1H, NH; disappeared with D2O),
9.80 (br, 2H, 2NH, disappeared with D2O). Anal. Calcd. for C16H14ClN5S (343.5): C,
55.89; H, 4.07; N, 20.37. Found: C, 55.80; H, 4.00; N, 20.00.
5-Amino-7-(2-chlorophenyl)-N-(4-chlorophenyl)-6-cyano-2-(phenylami-
no)pyrazolo[1,5-a]pyrimidine-3-carbothioamide (22)
To a solution of 19 (0.01 mol) in ethanol (30 mL), α-cyano-2-chlorophenylcinnamoni-
trile 20 (0.01 mol) and piperidine (0.5 mL) were added, and the mixture was heated under
reflux for 3 h. The solid product was collected and recrystallized from dioxane as brown
crystals.
Yield 50%, mp 220–222◦C. IR (KBr): ν = 3305, 3252, 3179 (NH2/NH) and 2219
(C≡N), 1340 cm−1 (C S). 1H NMR (DMSO-d6): δ = 7.01–7.93 (m, 13H, Ar-H), 9.25 (s,
2H, NH2, disappeared with D2O), 9.38, 9.95 (2s, 2H, 2NH, disappeared with D2O). Anal.
Calcd. for C26H17Cl2N7S (530): C, 58.86; H, 3.20; N, 18.49. Found: C, 58.70; H, 3.20; N,
18.40.

752
Y. A. AMMAR ET AL.
Preparation of Compounds 25 and 26: General Procedure
A mixture of compound 19 (0.01 mol) and 1,3-dicarbonyl compounds (namely,
acetylacetone, ethyl acetoacetate, 0.01 mol) in glacial acetic acid (10 mL) was heated under
reflux for 1 h. The solid product, which was produced upon heating, was collected and
recrystallized from the proper solvent to give 25 and 26.
N-(4-Chlorophenyl)-5,7-dimethyl-2-(phenylamino)pyrazolo[1,5-
a]pyramidine-3-carbothioamide (25). This compound was obtained in 75%
yield as brown crystals (dioxane), mp 225–227◦C. IR (KBr): ν = 3289 (NH), 2934
1
(CH-aliph.) and 1620 (C N), 1295 cm−1 (C S). H NMR (DMSO-d6): δ = 2.50, 2.64
(2s, 6H, 2CH3), 5.92 (s, 1H, pyrimidine-H), 7.02–7.86 (m, 9H, Ar-H), 8.90, 10.04 (2s, 2H,
2NH; disappeared with D2O). Anal. Calcd. for C21H18ClN5S (407.5): C, 61.84; H, 4.41;
N, 17.17. Found: C, 61.70; H, 4.30; N, 17.10.
N-(4-Chlorophenyl)-7-methyl-5-oxo-2-(phenylamino)-4,5-dihydro-pyra-
zolo[1,5-a]pyrimidine-3-carbothioamide (26). This compound was obtained in
65% yield as brown crystals (DMF), mp >300◦C. IR (KBr): ν = 3290 (NH), 2927
(CH-aliph.) and 1657 cm−1 (C O), 1295 cm−1 (C S). Anal. Calcd. for C20H16ClN5OS
(409.5): C, 58.60; H, 3.90; N, 17.09. Found: C, 58.50; H, 3.80; N, 16.90. MS, m/z (%) =
409 (2.5%) 265 (100, base peak), 391 (35), 374 (10), 264 (34).
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