Reactions of cyanothioformamide and thiohydantoin derivatives with some arylidenes of cyanothioacetamide and other elecetrophilic and nucleophilic reagents

Article abstract of DOI:10.1080/104265090517343

N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyanothioformamide was synthesized from the corresponding 4-amino-pyrazole. Various cyanothioformamides were reacted with different arylidenes of cyanothioacetamide to produce either 4-imino-5-th

Full text of DOI:10.1080/104265090517343

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Phosphorus, Sulfur, and Silicon
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Reactions of
Cyanothioformamide and
Thiohydantoin Derivatives
With Some Arylidenes of
Cyanothioacetamide and Other
Elecetrophilic and Nucleophilic
Reagents
A. M. Sh. El-Sharief a , F. F. Mahmoud b , N. M. Taha b
& E. M. Ahmed b
a Chemistry Department , Faculty of Science, Al-
Azhar University (for Boys) , Cairo, Egypt
b Chemistry Department , Faculty of Science, Al-
Azhar University (for Girls) , Cairo, Egypt
Published online: 21 Dec 2010.
To cite this article: A. M. Sh. El-Sharief , F. F. Mahmoud , N. M. Taha & E. M. Ahmed
(2005) Reactions of Cyanothioformamide and Thiohydantoin Derivatives With
Some Arylidenes of Cyanothioacetamide and Other Elecetrophilic and Nucleophilic
Reagents, Phosphorus, Sulfur, and Silicon and the Related Elements, 180:2, 573-589,
DOI: 10.1080/104265090517343
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Phosphorus, Sulfur, and Silicon, 180:573–589, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090517343
Reactions of Cyanothioformamide and Thiohydantoin
Derivatives With Some Arylidenes of
Cyanothioacetamide and Other Elecetrophilic
and Nucleophilic Reagents
A. M. Sh. El-Sharief
Chemistry Department, Faculty of Science, Al-Azhar University
(for Boys), Cairo, Egypt
F. F. Mahmoud
N. M. Taha
E. M. Ahmed
Chemistry Department, Faculty of Science, Al-Azhar University
(for Girls), Cairo, Egypt
N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)cyanothioformamide
was synthesized from the corresponding 4-amino-pyrazole. Various cyanothiofor-
mamides were reacted with different arylidenes of cyanothioacetamide to produce
either 4-imino-5-thioxo-3-(pyrroline
& pyrrolidine)carbonitrile or pyrrolo[3,2-
d]thiazole. Interaction of thiohydantoin with the arylidenes of either malononitrile
or cyanothioacetamide furnished the same 5-aminothiopyrano[2,3-d]-imidazole-
6-carbonitriles. Also, thiohydantoin reacted with the anilide of chloroacetic
acid and with anthranilic acid to produce thieno[2,3-d]-imidazole-2-one and
imidazo[4,5-b]quinoline-2,9-dione, respectively.
INTRODUCTION
A variety of heterocyclic ring closure reactions with cyanothio-
formamides1–3 give rise to imidazoles,4 oxazoles5 thiazoles6,7 and other
Received June 1, 2004.
Many thanks for Prof. Dr. E. Schaumann, Institu¨t fur Organische Chemie, Technis-
che Universitat Claushthal, Leibnizstra Be 6 for his great help in making 1HNMR and
13CNMR.
Many thanks for Prof. Dr. Roger Katcham, Prof. of Chem. and Pharm. Chem. Dept. of
Pharm. Chem. School of pharmacy, Univ. of California, San Francisco, CA 94143-0446,
USA. I began the work in this field at his lab. under his supervision since 1981, when I
was a visiting Professor there.
Address correspondence to A. M. Sh. El-Sharief, Chemistry Department, Faculty of
Science, Al-Azhar University (for Boys), Cairo, Egypt. E-mail: hmadian@hotmail.com
573

574
A. M. Sh. El-Sharief et al.
heterocycles.8,9 Our interest in activated nitriles10,11 and the chem-
istry of cyanothioformamide12–22 led us to synthesize a new cyanothio-
formamide which contain a heterocyclic ring (pyrazole) and reacted it
with different types of activated nitriles.
Thus, N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-
cyanothioformamide I (Scheme 1) was prepared by the same procedure
1
reported in Ref. (23). Its structure was demonstrated by IR, HNMR,
13CNMR, mass spectra and elemental analyses. Reaction of I with
p-fluorobenzylidene cyanothioacetamide IIa in EtOH/TEA (TEA =
triethylamine), furnished a product for which its elemental and spec-
1
tral data (IR, HNMR, 13CNMR, and mass spectra) were compatible
with structure III (Scheme 1) viz., l-(l,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-lH-4-pyrazolyl)-4-imino-2-(p-fluorophenyl)-5-thioxo-3-thioam-
ido-3-pyrrolidinecarbonitrile. This product III could easily lose one
molecule of thioformamide H.CS.NH2 to give the 2-pyrroline 3-
carbonitrile derivative which appeared as the first fragment in its
mass spectrum and also could be isolated with other derivatives.
Similarly, reaction of N(p-anisyl)cyanothioformamide with p-anisyl-
idinecyanothioacetamide IIc yielded the 4-imino-l,2-di (p-anisyl)-5-
thioxo-4,5-dihydro-lH-2-pyrroline-3-carbonitrile, IV (Scheme 1). Its
structure was confirmed by IR, 1HNMR, mass spectra and elemen-
tal analyses. Also, reaction of N(p-tolyl) and (p-chlorophenyl)cyanothio-
formamide with arylidene II (a & c) produced in each case one prod-
uct in which its IR, 1HNMR, mass spectra and elemental analyses
were compatible with structure V as 1-(p-tolyl)-2,5-di-(p-fluorophenyl)-
pyrrolo[3,2-d]thiazole-3-carbonitrile dihydrate (Va) and l-(p-chloro-
phenyl)-2,5-di(p-anisyl)pyrrolo[3,2-d]thiazole-3-carbonitrile dihydrate
Vb (Scheme 1). The mechanism of formation of V can be rationalized
as described in Scheme 2. This pyrrolo[3,2-d]thiazole structure was ob-
tained by the authors15 through interaction of pyrrolidineimino- thione
with p-chlorobenzoyl chloride.
Cyanothioformamide I was also reacted with o-amino phenol as a
nucleophilic reagent to produce a product with elemental and spectral
data compatible with the 3-(l,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
lH-4-pyrazolylamino)benzo[l,4]-oxazin-2-one VI (Scheme 1).
The known higher activity of thiohydantoin that contains adja-
cent active methylene and thione groups influenced us to couple it
with different reagents to produce various fused heterocyclic sys-
tems having potential biological interest. Thus 5-iminoimidazolidine-
4-thiones which were prepared by the reaction of the correspond-
ing cyanothioformamides with phenyl isocyanate, were reacted with
H2S/TEA4 to produce the respective thiohydantoin derivatives VIIa–f
(Scheme 3).

Derivatives of Cyanothioacetamide
575
SCHEME 1
Reaction of VII with various arylidenes of malononitrile VIII
furnished the corresponding 5-amino-3,7-diaryl-2-oxo-1-phenyl-
1,2,3,4-tetrahy-drothiopyrano[2,3-d]imidazole-6-carbonitriles, IXa–d
(Scheme 3). There is a point of interest with respect to compounds

576
A. M. Sh. El-Sharief et al.
SCHEME 2
IXa,b & c: The base peak in all of them is M-l which sheds some light
on the stability of these compounds. Another important observation
is the ratio between M: M + 2 in IXb–d which is about 3:1 due to the
presence of the chlorine atom.
Reaction of VIIb,c with VIII (Arꢀ-C6H4OCH3-p) furnished in each
case one product wherein its elemental and spectral data were consis-
tent with the monohydrate of 5-amino-3-[m-tolyl Xa and p-tolyl Xb]-7-
(p-methoxyphenyl)-2-oxo-1-phenyl-1,2,3,4-tetrahydrothiopyrano-[2,3-
d]imidazole-6-carbonitrile (Scheme 3). Mass spectra of Xb showed a

Derivatives of Cyanothioacetamide
577
SCHEME 3
peak at m/z 484 corresponding to (M + H2O. 65%) that then lost water
to give a molecular ion peak at m/z 466 (43%) and a base peak at
m/z 464 (100%, M-2). On using the arylidenes of cyanothioacetamide
IIa–c instead of the arylidene derivatives of malononitrile VIII to
react with VII, H2S was liberated during the reaction period and the
same products were obtained (if they have the same Ar & Arꢀ groups)
(m.p., mixed m.p and TLC) which were in complete agreement with
our previous finding.17
Reaction of VIIe with triethyl orthoformate gave the 1-(p-chloro-
phenyl)-4-(1-ethoxymethylidene)-3-phenyl-5-thioxoperhydro-2-imidaz-
olone XI (Scheme 3). Also VIIc was reacted with p-chlorobenzaldehyde
to yield the 4-(p-chlorobenzylidene)-1-(p-tolyl)-3-phenyl-5-thioxoperhy-
dro-2-imidazol one XII, (Scheme 3). Reaction of VIIc with chloroacetic
acid gave imidazole derivative XIII, (Scheme 3) which could be
obtained by alkylation followed by decarboxylation. Repetition of

578
A. M. Sh. El-Sharief et al.
this reaction using VIId furnished a product for which its elemental
and spectral data were compatible with structure XIV (Scheme 3)
viz., 2-[5-carboxy-methyl-3-(p-methoxyphenyl)-2-oxo-1-phenyl-2,3-
dihydro-1H-4-imida-zolyldisulphanyl]-1-(p-methoxypheny1)-2-oxo-3-
phenyl-2,3-dihydro- lH-4-imidazolylacetic acid. The formation of
XIV can be attributed to air oxidation of the thiohydantion to give
diimidazolyl disulphide which then reacted with chloroacetic acid
to give XIV. On using a chloroacetic acid derivative such as its
p-methoxyanilide to react with thiohydantoin VIId we produced
the 3-(p-methoxyphenyl)-6-(p-methoxyphenyl-amino)-1-phenyl-2,3-di-
hydro-lH-thieno[2,3-d]imidazol-2-one XV, (Scheme 3). Thiohydantoin
VIIc was reacted with anthranilic acid through elimination of H2S and
H2O to produce XVI (Scheme 4) as 1-phenyl-3-(p-tolyl)-l,4-dihydro-
SCHEME 4

Derivatives of Cyanothioacetamide
579
3H-imidazo[4,5-b]quinoline-2,9-dione, and it was also coupled with
p-toluenediazonium chloride to give the 5-(p-tolylazo)-4-thiohydantoin
XVII, (Scheme 4). Some by-products could be isolated from the reac-
tions of thiohydantoin which can be attributed to facile air oxidation
of thiohydantoin under the reaction conditions. These by-products are
the disulphides XVIII, the monosulphide XIX and the diimidazolone
XX derivatives (Scheme 4). The mechanism of formation of XX can
be rationalized as described in Scheme 4 and these are in complete
agreement with the previous findings obtained by Katcham et al.4
EXPERIMENTAL
Melting points were taken on a Stuart apparatus and are uncorrected.
IR spectra were determined with a Jasco FT/IR 5300 spectrophotome-
1
ter using the KBr technique. HNMR spectra were measured using a
Jeol FX-100 spectrometer 60 MHz and a Varian Gemini 200 instru-
ment 200 MHz (Cairo University) and 250 & 300 MHz with TMS as an
internal reference. Mass spectra were obtained by use of a Schimadzu-
GC MS-QP 1000 EX instrument using the direct inlet system (Cairo
University). Microanalyses were performed by the microanalytical
unit at Cairo University. All compounds gave satisfactory elemental
analyses.
N-(l,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-
cyano-thioformamide (I)
This compound was prepared by the same procedure reported in
ref. 23. The obtained product was recrystallized from ethanol to give
1
I (Table IV). The HNMR spectrum of I (CDCl3) exhibited signals at:
δ = 2.20 (3H, s, CH3-C), 3.35 (3H, s, CH3-N), 7.45 (6H, m, Ar H +
NH which disappeared following the addition of D2O). 13CNMR spec-
troscopy exhibited the following signals: 13.4 (Me-C); 34.8 (Me-N), 106.9
( C N), 113.5 (C-4), 126.1 and 126.3 (2C-8), 128.7 (C-9), 129.6 and
129.7 (2C-7), 133.1 (C-5), 148.7 (C S), 160.4 (C-6) and 164.8 (C O).
Mass spectrum of I (C13H12N4OS, 272) showed a molecular ion peak
at m/z 272 (2.07%) with a base peak at m/z 56 (100%) other significant
peaks were observed at m/z 245 (95.09%), 203 (3%), 187 (1.7%), 171
(6.0%) and 119 (2.6%).
General Procedure for the Preparation of Compounds (III–VI)
A mixture of the requisite cyanothioformamide (0.01 mol), arylidene
of cyanothioacetamide (in case of III–V) or o-aminophenol (in case of

580
A. M. Sh. El-Sharief et al.
VI) (0.001 mol) and 0.1 ml piperidine in absolute ethanol (30 ml) was
refluxed for 4 hrs. The reaction mixture was then cooled, poured into
crushed ice (50 gm), neutralized with dil. HCl (5 molar) and the obtained
product was recrystallized from ethanol to give (III, IV, Va,b & VI)
(Table IV).
l-(l,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-4-pyrazolyl)-4-
imi-no-2-(p-fluorophenyl)-5-thioxo-3-thioamido-3-
pyrrolidinecarbonitrile (III)
1H NMR; δ = 2.0 (3H, s, CH3-C), 3.35 (3H, s, CH3-N), 5.0 (1H, s, CH),
7.05–7.70 (10H, m, Ar-H + NH, disappeared following the addition of
D2O) and 8.30 ppm (2H, hump, NH2, disappeared following the addition
of D2O). 13CNMR; at δ = 10.3 (Me-C); 34.8 (Me-N); 83.6 (C-13); 103.2
(C N); 106.4 (C-14); 114.9 (C-4); 115.5, 115.9 (2C-16); 117.9 (C-15);
119.4 (C-9); 123.6, 123.7 (2C-17); 125.3, 125.4 (2C-8); 128.3 (C-5); 130.5,
130.7 (2C-7); 134 (C-18); 149 (CS-NH2); 152.7 (C S; pyrrole); 158.1
(C NH) and 162.9 (C O). The mass spectrum of III (C23H19N6S2OF)
showed a peak at m/z 417 (3.8%) corresponding to [M-(H.CS.NH2)] with
a base at m/z 56 (100%). Other significant beaks were apparent at m/z
272 (2.4%), 245 (1.7%), 213 (1.1%). 187 (1.0%) and 145 (2.5%).
4-Imino-l,2-di-(p-anisyl)-5-thioxo-4,5-dihydro-1H-2-pyrroline-3-
carbonitrile (IV)
1HNMR; at δ = 3.69 (3H, s, CH3-O C6H4-C p), 3.77 (3H, s, CH3-
O C6H4-N-p), 4.11(1H, a broad signal which disappeared following the
addition of D2O, NH), 6.79–7.00 ppm (8H, 2 A-B q, 2 p-substituted).
Mass spectrum of IV (C19H15N3O2S) exhibited a molecular ion peak at
m/z (349, 8.2%) with a base peak (350, M + 1, 100%). Other significant
peaks appeared at 351 (M + 2, 81%) and 352 (M + 3, 34.4%).
Vb
1HNMR in (DMSO-d6 + D2O); at δ = 3.74 & 3.75 (6H, 2s, 2-OCH3) and
6.6–7.3 ppm (12H, m, Ar-H). Mass spectrum of Vb (C26H22N3O4SCl)
showed a molecular ion peak (base peak) at m/z 508 (100%). Va; Mass
spectrum (C25H19N3O2SF2) revealed a molecular ion peak at m/z 463
(72.6%) with a base peak at m/z 292 (100%) and other significant peaks
were appeared at m/z 322 (58%), 307 (34%), 306 (20%), 297 (10.5%), 250
(9%) and 211 (5.1%).

Derivatives of Cyanothioacetamide
581
3-(l,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-4-
pyrazolylamino)-benzo[l,4]oxazin-2-one (VI)
Mass spectrum (C19H16N4O3) exhibited a molecular ion peak at m/z 348
(21.5%), a base peak at m/z 56 (100%), 203 (11.9%), 149 (19.7%), 146
(9.3%), 119 (17.3%), 103 (13.5%) and 77 (62.8%). 1HNMR spectra of VI
revealed the following signals at δ = 2.1 (3H, s, CH3-C), 3.4 (3H, s, CH3-
N), 4.1 (1H, a broad signal which disappeared following the addition of
D2O, NH) and 6.2–7.8 ppm (9H, m, Ar H).
Synthesis of Thiohydantoin Derivatives (Vlla–f)
To a solution of 3-aryl-l-phenyl-2-oxo-5-iminoimidazolidine-4-thione
(0.001 mol) in ethanol or benzene (30 ml), triethylamine (3 drops)
was added. A stream of H2S was bubbled into the solution with stir-
ring. The obtained products were recrystallized from the proper sol-
1
vent to give VIIa–f, (Table IV). The HNMR spectrum of compound
VIIc exhibited the following signals at δ = 2.4 (3H, s, CH3-Ar), 4.9
(2H, s, CSCH2N), 7.0–7.6 ppm (9H, m, Ar H). Mass spectrum of Vlld
(C16H14N2O2S) showed a molecular ion peak at m/z 298 (100%), 149
(80.6%; H3COC6H4NCO-p); 133 (3% H3CO-C6H4NC-p) and 103 (5.5%
Ph NC).Mass spectrum of VIIe (C15H11N2SOCl) exhibited a molecular
ion peak at m/z 302 (18.8%), a base peak 139 (100%), 303 (18.8%), 286
(41.7%), 111 (25%) and 77 (36.8%).
Synthesis of Thiopyrano[2,3-d]imidazole Derivatives IXa–d &
Xa,b: Method (A)
A mixture of substituted thiohydantoin (VII; 0.001 mol), substituted
arylidene derivatives of malononitrile (0.001 mol) and piperidine
(0.1 ml) in absolute ethanol (30 ml) was refluxed for 4 h. The reaction
mixture was then cooled, poured in to crushed ice (50 gm), neutralized
with dil. HC1 (5 molar) and the obtained product was recrystallized
from the proper solvent to give IXa–d and Xa,b (Table IV).
Method (B)
A mixture of substituted thiohydantoin (Vll; 0.001 mol), arylidene
of cyanothioacetamide (0.001 mol) and piperidine (0.1 ml) in ethanol
(30 ml) was refluxed for 4 h. The reaction mixture was worked
as above to give IXa–d and Xa,b. 1HNMR spectrum of IXb exhib-
ited the following signals at δ = 2.15 (3H, s, CH3), 3,52 (2H, hump,
NH2, disappeared following the addition of D2O), 4.37 (1H, s, CH),

582
A. M. Sh. El-Sharief et al.
6.65–7.75 ppm (8H, m, Ar H). Mass spectrum of IXb (C26H19N4OSCl)
exhibited a molecular ion peak at m/z 470 (44%) with a base peak
at 469 (100%, M − 1), 471 (39.5% M + 1), 472 (12.4% M + 2), 187
[33%, p Cl C6H4-CH C(CN)2-1], 119 (4.2%, C6H5NCO), 117 (2.6%,
m CH3-C6H4NC) and 111 (2.3%; p ClC6H4 ). Mass spectrum of IXa
(C26H19N4OSF) showed a molecular ion peak at m/z 454 (33.7%) with
a base peak at 453 (M − l; 100%). Other significant peaks were ap-
peared at 421 (3.8%), 376 (4.3%). 333 (6.2%), 300 (4.9%), 119 (5.2%), 117
(27%), 105 (2.7%) and 95 (1.4%). Mass spectrum of IXc (C26H19N40SCl)
showed a molecular ion peak at 470 (40.4%) with a base peak 469
(M − 1; 100%). Other significant peaks 472 (14.8%, M + 2), 282 (5.3%),
250 (3.3%), 188 [2.3%, p Cl-C6H4-CH C(CN)CSNH2], 149 (4.2%,
p CH3C6H4NCS), 119 (14.0% C6H5NCO), 113 (2.0%, Cl C6H5) and 91
(43.3%. p CH3C6H4). Mass spectrum of IXd (C26H19N402SCl) assigned
a molecular ion peak at 486(43%) with a base peak at 484 (100%, M − 2),
487 (36.8%, M + 1),488 (10%, M + 2), 302 (30%), 184 [5.3%, p CH3-
O-C6H4CH C:(CN)CSNH2], 150 [1.7% p CH3-O C6H4-CH C:(CN)2],
169 (2.1%, p-Cl C6H4NCS) and 119 (1.8%, PhNCO). Mass spectrum of
Xb (C27H24N4O3S) exhibited peaks at m/z 484 (M + H2O, 65%), a molec-
ular ion peak at 466 (43%) base peak at 464 (100%, M − 2), 465 (M − l,
84.8%), 463(M − 3, 57.6%), 184 [9.1%, p CH3-OC6H4-CH:C (CN)2], 119
(8.4%, C6H5NCO) and 117 (6.7%, p CH3-C6H4NC) (Scheme 5).
Formation of l-(p-Chlorophenyl)-4-(1-ethoxymethylidene)-3-
phenyl-5-thioxoperhydro-2-imidazolone (XI)
A mixture of substituted thiohydantoin VIId; (0.001 mol; 0.3 gm) and
triethylorthoformate (0.002 mol; 0.3 gm) in acetic anhydride (10 ml) was
refluxed for 1 h. The obtained solid was recrystallized from petroleum
1
ether 60/80 to give XI (Table IV). HNMR spectrum of XI exhibited
the following signals: δ = 1.18 (3H, t, CH3), 4.09 (2H, q, CH2), 6.97–
7.53 ppm (10H, m, Ar H + CH). Mass spectrum of (XI; C18H15N2O2SCl)
exhibited a molecular ion peak at m/z 358 (53.7%), a base peak at 315
(100%), 359 (33.4%, M + l) and 360 (20%, M + 2).
Synthesis of 4-[(p-Chlorophenyl)methylidene]-l-(p-tolyl)-3-
phenyl-5-thioxoperhydro-2-imidazolone XII
A mixture of substituted thiohydantoin VIId (0.001 mol; 0.3 gm) p-
chlorobenzaldehyde (0.001 mol; 0.14 gm) and fused sod. acetate (0.1 gm)
in Ac2O/AcOH mixture (10:20 ml) was refluxed for 2 h. The obtained
product was recrystallized from ethanol to give XII (Table IV). Mass
spectrum of XII (C23H17N2OSCl) exhibited a peak at 405 (2.18%,

Derivatives of Cyanothioacetamide
583
referred to M + l), a base peak at 91 (100%, p CH3-C6H4 ), 285 (3.3%),
275 (2.4%) and 209 (2.6%).
Formation of Imidazole Derivative (XIII)
A mixture of substituted thiohydantoin VIIb (0.001 mol; 0.3 gm)
chloroacetic acid (0.001 mol; 0.1 gm) and sodium ethoxide (0.001 mol;
0.07 gm) in absolute ethanol (30 ml) was refluxed for 7 h. The obtained
1
solid was recrystallized from ethanol to give XIII (Table IV). HNMR
spectrum exhibited the following signals at δ = 2.21 (3H, s, CH3-Ar),
2.5 (3H, s, S CH3), 6.6 (1H, s, CH), and 6.8–7.58 ppm (9H, m, Ar H).
Synthesis of (XIV)
A mixture of thiohydantoin VIId (0.001 mol; 0.3 gm), chloroacetic acid
(0.001 mol; 0.1 gm) and sodium ethoxide (0.001 mol; 0.07 gm) in absolute
ethanol (30 ml) was reacted as above to give XIV (Table IV). Mass
spectrum of XIV (C36H30N8S2) exhibited a molecular ion peak-2H (M-
H2, 708, 1.3%) also a molecular ion peak-water (M H2O) was observed
at m/z 692 (3.6%). Other significant peaks were appeared at m/z 648
(2%), 620 (1%), 588 (7.7%), 574 (7.8%), 542 (9.6%) and 528 (100%, base
peak). (Scheme 6).
Formation of 3-(p-Methoxyphenyl)-6-(p-methoxyphenyl
Amino)-l-phenyl-2,3-dihydro-1H-thieno[2,3-d]imidazol-2-one
(XV)
A mixture of substituted thiohydantoin VII-d (0.001 mol; 0.3 gm), p-
methoxy- γ -chloroacetanilide (0.001 mol; 0.2 gm) and sodium ethoxide
(0.001 mol; 0.07 gm) in absolute ethanol (30 ml) was refluxed for 6h.
The obtained solid was recrystallized from ethanol to give XV (Table IV).
1HNMR spectra of XV exhibited the following signals at δ = 3.7 (6H, s,
2CH3OC6H5), and 6.4–7.3 ppm (14H, m, Ar H). The NH proton was ap-
peared underneath the Ar H. Mass spectrum of XV exhibited a molec-
ular ion peak at 443 (7%) a base peak at (77, 100%), 445 (27%), 187
(10%), 179 (66%), 165 (36%), 149 (20%), 133 (4%) and 119(20%).
Synthesis of l-Phenyl-3-(p-tolyl)-l,4-dihydro-3-H-imidazo[4,5-
b]-quinoline-2,9-dione (XVI)
A mixture of the thiohydantoin VIIc (0.001 mol; 0.28 gm) anthranilic
acid (0.001 mol; 0.14 gm) and sodium ethoxide (0.001 mol; 0.07 gm) in
absolute ethanol (20 ml) was refluxed for 12 h. The reaction mixture was
then cooled poured into crushed ice (50 gm), neutralized with dil. HCl

584
A. M. Sh. El-Sharief et al.
(5 molar) and the obtained product was recrystallized from ethanol to
give XVI (Table IV). Mass spectrum of XVI (C23H17N3O2, 367) exhibited
peaks at 368 (M + 1, 2.64%), 266 (100%), 263 (3.9%), 133 (24.6%), 119
(73.5%), 117 (6%) and 105 (66.3%).
Synthesis of 5-(p-Tolylazo)-4-thiohydantion Derivative (XVII)
p-Toluidine (0.01 mol; 1.1 gm) was dissolved in a mixture of HCl (4 ml;
10 molar) and H2O (5 ml) then cooled to 0◦C. To this a cold aqueous
solution of sodium nitrite (0.69 g) was then added. The diazonium salt
so obtained was added dropwise to a cold mixture of sodium acetate (1 g)
TABLE I Antibacterial Activity of Synthesized Compounds
Staphylococcus
aureus
(NCTC-7447)
Serratia
Marcescens
(IMRU-70)
Proteus
mirabilis
(NTCC-289)
Bacillus cereus
(ATCC-14579)
Compd. no.
I
III
IV
Va
Vb
VI
VIIb
VIIc
IXa
IXb
IXc
IXd
Xa
Xb
XI
XII
XIV
XV
++
++
+++
+++
++
++
++
+++
++
+++
++
++
++
+++
++
++
++
++
++
+++
+++
+++
+++
+++
++
+++
++
++
+++
+
++
++
++
++
++
+++
+++
+++
+
+++
++
+++
++
++
+
++
+++
++
+++
++
++
+++
++
++
+
+++
++
+++
++
+++
+++
++
++
++
+++
+++
+++
+++
++
+++
+++
+++
+++
++
+++
++
++
XVI
XVII
XVIII
XIX
Ampicillin
(25 µg)
++
++
++
++
+++
++
+++
++
++
+
+++
++++
++++
++++
++++
+: Less active (0.2–0.5 cm).
++: Moderately active (0.6–1.4 cm).
+++: Highly active (1.5–3.0 cm).
++++: Very highly active (over 3.0 cm).
Standard for Gram positive and gram negative bacteria: Ampicillin 25 µg.

Derivatives of Cyanothioacetamide
585
and substituted thiohydantoin VIlb (0.01 mol; 2.8 gm) in ethanol. The
resulting solid was washed with water and recrystallized from ethanol
to give XVII (Table IV). Mass spectrum of XVII (C23H20N4OS, 400)
showed a molecular ion peak at 400 (35%) with a base peak at 91 (100%)
and other significant at m/z 401 (M + 1, 43%), 402 (M + 2, 15%), 385 (M-
CH3,17%),149 (20%), 133 (23%), 119 (33%), 105 (22%) and 91 (79%).
Antimicrobial Activity
1-Antibacterial Activity
The newly synthesized compounds were screened for their antibac-
terial activity against two species of Gram positive bacteria, namely
TABLE II Antifungal Activity of Synthesized Compounds
Aspergillus ochraceus
Wilhelm
Penicillium
chrysogenum Thom
(AUCC-530)
Compd. no.
(AUCC-230)
I
III
IV
Va
Vb
VI
VIIb
VIIc
IXa
IXb
IXc
IXd
Xa
Xb
XI
XII
XIV
XV
++
++
++
+
+
++
+
+
+++
+
++
+++
+
+
+++
++
+
+++
+++
+
+++
++
+
+
++
+
++
+
++
+++
+++
+
++
++
+
+
XVI
XVII
XVIII
XIX
Mycostatin
(30 µg)
++
+++
++
+
+
++
++
++
++++
++++
+: Less active (0.2–0.5 cm).
++: Moderately active (0.6–1.4 cm).
+++: Highly active (1.5–3.0 cm).
++++: Very highly active (over 3.0 cm).
Standard: for fungi: Mycostatin.

586
A. M. Sh. El-Sharief et al.
Staphylococcus aureus (NCTC-7447), Bacillus cereus (ATCC-14579)
and two species of Gram negative bacteria Serratia marcescens (IMRU-
70) and Proteus mirabilis (NTCC-289) using Ampicillin (25 µg) as the
reference compound. Table I Shows the effect of compounds I, III, IV,
Va, Vb, VI, VIIb,c, IXa–d, Xa,b, XI, XII, XIV–XVIII, and XIX on the
microorganisms tested. It was found that all compounds were shown to
exhibit an activity pattern which suggests that they may have a broad
spectrum antibacterial effect with a sustained high degree of inhibition,
giving almost + + + ratings against all of the test organisms.
2-Antifungal Activity
The newly synthesized compounds were screened for their antifungal
activity against two species of fungi, Aspergillius ochraceus Wilhelm
TABLE III IR Spectra of Synthesized Compounds
Compd. no.
ν
(cm−1
)
max
I
3150 (NH), 2950 (CH-aliph.), 2207 (C N), 1690 (C O), 1490, 1120
(S N).
3270–3109 (NH), 3030 (CH-arom.), 2922, 2860 (CH-aliph.), 2214 (C N),
1684 (C O), 1630 (C N), 1421, 1124 (S N).
3248 (NH), 2933, 2837 (CH-aliph.), 2216 (C N), 1412, 1149 (S
C
III
C
IV
C N).
Vb
3030 (CH-arom), 2922, 2854 (CH-aliph.), 2214 (C N), 1612 (C N), 1530
(C C).
VI
3250(NH), 2950 (CH-aliph.), 1710 (C O).
VIIb
IXa
2927 (CH-aliph.), 1757 (C O), 1490, 1150 (S C N).
3330, 3150 (NH2), 3050 (CH-arom.), 2927 (CH-aliph.), 2218 (C N), 1743
(C O).
IXb
3317, 3197 (NH2), 3034 (CH-arom.), 2931 (CH-aliph.), 2213 (C N), 1741
(C O).
IXc
IXd
3325, 3190 (NH2), 3050 (CH-arom.), 2218 (C N), 743 (C O).
3323, 3140 (NH2), 3063 (CH-arom.), 2931 (CH-aliph), 2217 (C N), 1745
(C O).
Xb
XI
3400, 3200 (NH2), 3067, 3026 (CH-arom.), 2930, 2836 (CH-aliph), 2218
(C N), 1745 (C O).
3060 (CH-arom.), 2923, 2852 (CH-aliph), 1712 (C O), 1595 (C C), 1490,
1130 (S
C N).
XII
3050 (CH-arom.), 1712 (C O), 1560 (C C), 1492, 1150 (S
2990 (CH-aliph.), 1709 (C O), 1595 (C C).
3200–2500 (OH), 1708, 1670 (C O).
3300 (NH), 3050 (CH-arom.), 2930 (CH-aliph.), 1680 (C O).
3200 (NH), 3030 (CH-arom.), 2950 (CH-aliph.), 1710 (C O).
C N).
XIII
XIV
XV
XVI
XVII
3400 (NH), 3033 (CH-arom.), 2918, 2827 (CH-aliph.), 1717 (C O), 1615
(C N), 1498, 1124 (S N).
C

Derivatives of Cyanothioacetamide
587
TABLE IV Physical Data of the Synthesized Compounds
Elemental analyses
calcd./found [%]
Compd. Yield
M.p.
[◦C]
Cryst.
solvent
Mol. formula
(Mol. Wt)
no.
(%)
c
h
n
s
I
85
175
218
218
220
300
180
153
160
136
170
180
210
313
200
232
153
170
78
Ethanol
Ethanol
Benzene
Ethanol
Benzene
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Benzene
Benzene
Ethanol
Ethanol
Ethanol
C13H12N4OS
272.33
57.34
57.40
57.73
57.90
65..31 4.33 12.03
4.30 12.00
4.44 20.57 11.77
4.40 20.60 11.80
4.00 17.56 13.40
4.00 17.30 13.20
III
65
70
75
80
75
70
85
65
70
75
65
70
80
80
75
80
70
85
60
85
85
C23H19N6OS2
478.57
IV
C
19H15N3O2S
349.42
9.18
9.00
6.92
7.00
6.31
6.20
—
65.20
64.78
64.50
61.47
61.70
65.51
65.70
68.06
68.10
68.06
68.10
64.41
64.40
59.50
59.60
71.68
71.70
68.71
68.90
66.31
66.50
66.31
66.60
64.13
64.20
66.92
67.10
66.92
67.00
60.25
60.30
68.22
68.10
68.89
69.00
60.83
60.90
67.70
67.40
Va
C25H19N3O2SF2
462.51
C26H22N3O4SCl
508
4.13
4.10
4.37
4.20
4.63 16.08
4.60 16.10
9.07
9.10
8.27
8.10
Vb
VI
C19H16N4O3
348.37
C16H14N2OS
282.37
—
VIIb
VIIc
VIId
VIIe
VIIf
IXa
IXb
IXc
IXd
Xa
4.99
5.00
4.99
5.00
4.73
4.70
3.66
3.60
4.43
4.40
9.92 11.36
9.90 11.40
9.92 11.36
9.90 11.50
9.39 10.75
9.40 10.95
9.25 10.59
9.20 11.70
8.79 10.07
8.80 10.00
C16H14N2OS
282.37
C16H14N2O2S
298.37
C15H11N2OSCl
302.78
C
C
C
C
19H14N2SO
318.39
26H19N4OSF
454.53
26H19N4OSCl
470.98
4.21 12.33
4.20 12.30
4.07 11.90
4.00 11.90
4.07 11.90
4.10 12.00
3.93 11.51
3.90 11.50
4.99 11.56
4.70 11.50
4.99 11.56
4.90 11.70
7.05
7.00
6.81
6.70
6.81
6.90
6.58
6.40
6.62
6.50
6.62
6.40
8.94
9.00
7.92
8.00
26H19N4OSCl
470.98
C26H19N4O2SCl
486.98
C27H24N4O3S
484.58
Xb
C
C
C
C
27H24N4O3S
484.58
18H15N2O2SCl
358.85
23H17N2OSCl
404.92
XI
Pet.ether
60/80
Ethanol
4.21
4.20
4.23
4.20
5.44
5.30
4.25
4.20
4.77
4.70
7.81
7.80
6.92
6.90
9.45 10.82
9.50 10.70
8.00
7.89
9.47
9.40
XII
XIII
XIV
XV
160
200
206
200
Ethanol
Ethanol
Ethanol
17H16N2OS
296.39
C36H30N4O8S2
710.79
C25H21N3O3S
443.53
9.02
9.00
7.23
7.10
(Continued on next page)

588
A. M. Sh. El-Sharief et al.
TABLE IV Physical Data of the Synthesized Compounds (continued)
Elemental analyses
Calcd./found [%]
Compd. Yield
M.p.
[◦C]
Cryst.
solvent
Mol. formula
(Mol. Wt)
no.
%
c
h
n
s
XVI
75
162
180
200
160
200
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
C23H17N3O2
367.41
C23H20N4O
400.5
75.19
75.00
68.98
68.80
68.30
68.40
72.43
72.60
72.44
72.50
4.66 11.44
4.70 11.50
5.03 13.99
5.00 13.90
—
—
8.01
8.00
XVII
XVIII
XIX
85
65
60
75
C32H26N4O2S2
4.66
4.60
9.96 11.40
9.90 11.30
562.72
C32H26N4O2S
530.66
4.94 10.56
4.90 10.30
4.94 10.56
5.00 10.70
6.04
6.00
—
XX
C32H26N4O4
530.59
—
(AUCC-230) and Penicillium chrysogemim Thorn (AUCC-530) using the
Mycostatin (30 ug) as the reference compound. Table II Showed the
effect of compounds I, III, IV, Va, Vb, VI, VIIb,c, IXa–d, Xa,b, XI,
XII, XIV–XVIII, and XIX on the microorganisms tested. It was found
that all compounds were shown to exhibit an activity pattern which
suggested that they may have broad spectrum antifungal action with a
sustained high degree of inhibition, giving almost ++ ratings against
all of the test organisms.
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