Syntheses of some novel imidazolidinethiones and condensed imidazoles containing arylazo moieties starting from cyanothioformamides

Article abstract of DOI:10.1002/hc.20113

Cyclocondensation of cyanothioformamides (1) with arylhydrazonomalononitriles (2) afforded the novel imidazole derivatives (4a-e) in good yields. Isothiocyanatoazobenzene (6) was allowed to react with potassium cyanide and gave the new cyanothioformamide (7) which was reacted with 4-chlorophenyl isocyanate to yield imidazolidinethione (8). Compound (8) was subjected to react with hydrochloric acid, o-phenylenediamine, 4-methylaniline, and hydrogen sulfide and furnished compounds (10), (11), (12), and (15), respectively. Also, the reactivity of thiohydantoin (15) toward some electrophilic reagents such as N,N-dimethylformamide-dimethyl-acetal and arylidene-malononitriles was investigated. The structure of the synthesized compounds was established by analytical and spectral data.

Full text of DOI:10.1002/hc.20113

Heteroatom Chemistry
Volume 16, Number 3, 2005
Syntheses of Some Novel
Imidazolidinethiones and Condensed
Imidazoles Containing Arylazo Moieties
Starting from Cyanothioformamides
Ahmed M. Sh. El-Sharief,1 Mohamed S. A. El-Gaby,2
Ahmed A. Atalla,2 and Abu-Bakr A. A. M. El-Adasy2
1Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
2Department of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
Received 6 October 2003; revised 18 October 2004
of both natural and synthetic origin [1]. Hydan-
ABSTRACT: Cyclocondensation of cyanothiofor-
toin derivatives are used in therapy as anticon-
mamides (1) with arylhydrazonomalononitriles (2) af-
vulsants and chemotherapeutics [2]. Antimicrobial
forded the novel imidazole derivatives (4a–e) in good
activity was stated among derivatives possessing aro-
yields. Isothiocyanatoazobenzene (6) was allowed to
matic substituents at the imidazole nitrogen e.g. N-
react with potassium cyanide and gave the new
acyl and 5-arylidene derivatives of hydantoin and
cyanothioformamide (7) which was reacted with 4-
4-thiohydantoin [3–5]. Moreover, previous reports
chlorophenyl isocyanate to yield imidazolidinethione
demonstrated that synthetic imidazoles act either
(8). Compound (8) was subjected to react with hy-
as inhibitors of ꢀ-adrenoceptor mediated events in
drochloric acid, o-phenylenediamine, 4-methylaniline,
platelets [6] or inducers of platelets activation [7].
and hydrogen sulfide and furnished compounds (10),
Also, in the literature it is well documented that azo
(11), (12), and (15), respectively. Also, the reactivity
compounds have been widely utilized as dyes and
of thiohydantoin (15) toward some electrophilic
analytical reagents [8]. They can also be used as ma-
reagents such as N,N-dimethylformamide-dimethyl-
terials for nonlinear optics and for storage of opti-
acetal and arylidene-malononitriles was investigated.
cal information in laser disks [9]. As an extension
The structure of the synthesized compounds was es-
to our interest [10–16] on the chemistry of cyanoth-
ꢀ
C
tablished by analytical and spectral data. 2005Wiley
ioformamides 1, we report herein the synthesis of
Periodicals, Inc. Heteroatom Chem 16:218–225, 2005; Pub-
novel imidazolidinethione and condensed imidazole
lished online in Wiley InterScience (www.interscience.
derivatives containing arylazo moieties.
wiley.com). DOI 10.1002/hc.20113
RESULTS AND DISCUSSION
INTRODUCTION
Cyclocondensation of cyanothioformamides 1 with
arylhydrazonomalono-nitriles 2 in ether in the
presence of triethylamine at room temperature af-
forded the novel imidazolidinethiones 4a–e in good
yields (68–82%) (Scheme 1). The structures of com-
pounds 4a–e have been confirmed by elemental anal-
Imidazoles and their fused derivatives are key com-
ponents of a great many bioactive compounds
Correspondence to: Mohamed S. A. El-Gaby; e-mail: m-elgaby@
hotmail.com
1
c
ꢀ
2005 Wiley Periodicals, Inc.
ysis, IR, H NMR, and mass spectra. The infrared
218

Syntheses of Some Novel Imidazolidinethiones and Condensed Imidazoles Containing Arylazo Moieties 219
hydrazo form 4 (Scheme 1). The 1H NMR spectrum
of compound 4b for example exhibited two singlets
at ꢁ = 8.40 ppm (C NH) and 9.50 ppm (NH imida-
zole ring) along with two singlets at ꢁ = 2.47 ppm
(CH3) and 3.84 ppm (OCH3) in addition to aromatic
protons. The final elucidation of the structure 4b
was carried out by its mass spectrum that showed a
molecular ion peak at m/z 376 (6.10%) together with
a base peak at m/z 108, and its fragmentation pattern
is illustrated in Chart 1. The reaction mechanism was
assumed to proceed through a nucleophilic attack of
the nitrogen atom of the cyanothioformamide moi-
ety 1 to the Sp carbon of the cyano in 2 to form 3 fol-
lowed by the addition of the imino group to the cyano
group to yield the cyclized product 4 (Scheme 1).
4-Isothiocyanatoazobenzene 6 was synthesized
by treatment of 4-aminoazobenzene 5 with thio-
phosgene in 1:1 mixture of dichloromethane and
chloroform [17]. Compound 6 was allowed to re-
act with potassium cyanide in aqueous medium at
room temperature and gave the novel azo deriva-
tive 7. Cyclocondensation of compound 7 with 4-
SCHEME 1
spectra of these compounds revealed absorption
bands characteristic for NH, C N, C N, and C S
functional groups. On the basis of 1H NMR spectra,
these compounds exist in azo form 4a–e rather than
chlorophenyl isocyanate in tetrahydrofuran in the
presence of triethylamine afforded the new imi-
dazolidinethione derivative 8 in good yield. Also,
in a similar manner isothiocyanate 6 was cyclized
CHART 1 Fragmentation pattern of compound 4b.

220 El-Sharief et al.
SCHEME 2
with cyanothioformamide 1 (Ar = C6H4CH3-p) at
room temperature and yielded the 2,4-dithioxo-
imidazolidine derivative 9 (Scheme 2). Mass spec-
trum of compound 9 exhibited a molecular ion peak
at m/z 415 (18.2%) in addition to a base peak at m/z
77 characteristic for phenyl moiety (Chart 2).
Hydrolysis of imino group in compound 8 was
achieved by its treatment with hydrochloric acid
CHART 2 Fragmentation pattern of compound 9.

Syntheses of Some Novel Imidazolidinethiones and Condensed Imidazoles Containing Arylazo Moieties 221
SCHEME 3
in ethanol at room temperature and produced the
2,5-imidazolidinedione derivative 10. Cyclization of
compound 8 with 1,2-phenylenediamine under re-
flux in ethanol yielded the imidazo[4,5-b]quinoxaline
derivative 11, via elimination of hydrogen sulfide and
ammonia [15]. Condensation of compound 8 with
two molecules of 4-methylaniline furnished the novel
di-imine derivative 12 (Scheme 3).
the presence of triethylamine at room temperature
(Scheme 4).
Reactivity of thiohydantoin 15 toward some
electrophilic reagents was investigated. Thus, N,N-
dimethylamino derivative 16 was obtained by
treatment of methylene function in 15 with
dimethylformamide-dimethylacetal (DMF-DMA) as
1
electrophile in dry m-xylene under reflux. The H
The cyclization of compound 8 with malononi-
trile in refluxing ethanol in the presence of triethy-
lamine afforded the novel pyrrolo[2,3-d]imidazole
derivative 14. The assignment of structure 14 was
based on analytical and spectral data. Thus, the in-
frared spectrum of compound 14 revealed absorp-
tion characteristics for NH (3330 cm−1), C N (2202
cm−1), and C O (1725 cm−1). The 1H NMR spectrum
recorded in DMSO-d6 showed singlet at ꢁ = 10.00
ppm (NH) in addition to aromatic protons (m, 13H).
Also, the mass spectrum revealed a molecular ion
peak at m/z 435 (M-NH; 2.6%) with a base peak at m/z
107. This reaction is assumed to proceed via elimina-
tion of hydrogen sulfide (lead acetate paper) to form
13 followed by nucleophilic attack by the imino ni-
trogen on one of cyano groups to give 14 (Scheme 4).
The imino functional group in compound 8 was con-
verted into active methylene functional group [15]
by treatment with hydrogen sulfide in ethanol in
NMR spectrum of compound 16 recorded in DMSO-
d6 revealed the presence of singlet at ꢁ = 3.35 ppm
due to N,N-dimethylamino moiety and was free
methylene function. Thiopyrano[2,3-d]imidazol-6-
carbonitriles 19a,b were achieved by cycloconden-
sation of compound 14 with arylidenemalononi-
triles 17 in ethanol in the presence of catalytic
amount triethylamine under reflux. Structures of
compounds 19 were established based on the an-
alytical and spectral data. Thus, the infrared spec-
tra of the synthesized compounds displayed char-
acteristic absorption bands for NH2, C N, C O,
and N N functional groups. The 1H NMR spec-
trum of compound 19a showed singlet at ꢁ = 4.10
ppm attributed to the presence of thiopyrano pro-
ton and the lack of signal due to methylene pro-
tons. The formation of thiopyranoimidazole 19 is
assumed to proceed via the Michael addition of
the nucleophilic carbon atom of methylene on

222 El-Sharief et al.
SCHEME 4
1
benzylidene moiety to give the Michael adduct [15]
18 followed by intramolecular cyclization to form
the final product 19 (Scheme 5).
tometer. H NMR spectra were recorded on Varian
Gemini spectrometer 200 (200 MHz), using DMSO-
d6 as a solvent and TMS as internal standard. Chemi-
cal shifts are expressed as ꢁ ppm units. Mass spectra
were recorded on Shimadzu GC-MS-QP 100 EX (70
eV). Microanalytical data were obtained from the Mi-
croanalytical Data Unit at Cairo University. Found: C,
H, N for all compounds were within 0.4% from the
EXPERIMENTAL
Melting points are uncorrected. IR spectra were
recorded (KBr) on a Perkin Elmer 1650 spectropho-
SCHEME 5

Syntheses of Some Novel Imidazolidinethiones and Condensed Imidazoles Containing Arylazo Moieties 223
theoretical value. Physical data for the synthesized
cold water, and recrystallized from proper solvent to
compounds are given in Table 1. Also, the spectral
data are collected in Table 2.
give 7.
1-(4-Chlorophenyl)-3-azobenzene-5-imino-4-
thioxo-2-imidazolidinone (8)
[1-(4-Substituted phenyl)-4-imino-5-thioxo-4,5-
dihydro-1H-imidazol-2-yl]- (4-substituted
phenylhydrazono)acetonitriles (4a–e)
A mixture of N-(azobenzene)cyanothioformamide 7
(0.01 mole), p-chlorophenyl isocyanate (0.01 mole),
and equivalent amount of triethylamine (0.01 mole)
in tetrahydrofuran (25 mL) was stirred at room tem-
perature for 15 min. The product was collected and
recrystallized from proper solvent to give 8.
A mixture of substituted cyanothioformamide 1
(0.01 mole), arylhydrazonomalononitriles 2 (0.01
mole), and triethylamine in ether was stirred at room
temperature for 15 h. The solid product was collected
and recrystallized from proper solvent to give 4a–e.
1-(Azobenzene)-3-(4-methylphenyl)-5-imino-2,4-
imidazoli-dinedithione (9)
N-(Azobenzene)cyanothioformamide (7)
Equivalent amounts of 6 (0.01 mole) and cyanothio-
formamide 1 (Ar=C6H4CH3-p) (0.01 mole) in 20 mL
ether were treated with triethylamine (0.01 mole). Af-
ter stirring at room temperature for 24 h, the product
was collected, washed with n-hexane, and recrystal-
lized from proper solvent to give 9.
A mixture of potassium cyanide (0.01 mole in 10 mL
H2O) and isothiocyanate 6 (0.01 mole) in ethanol was
stirred at room temperature for 3 h. The reaction
mixture was then poured into ice/HCl (3 mL, 12%),
and the obtained product was collected, washed with
TABLE 1 Characterization Data for Newly Synthesized Compounds
Compd.
No.
Mp
Solvent
Cryst.
Yield
(%)
Formula
(Mol. Wt.)
( ◦C)
Color
4a
4b
4c
4d
4e
7
268–270
252–253
290–291
265–267
300–302
178–180
216–218
331–332
196–197
295–297
192–192
198–200
185–187
145–147
155–156
143–144
Dioxan
Violet
Violet
Violet
Violet
Violet
Orange
Orange
Yellow
Red
82
70
74
72
68
80
83
70
70
68
65
67
70
66
62
70
C18H13BrN6S
(425.31)
Ethanol
Ethanol
Ethanol
Dioxan
C
19H16N6OS
(376.44)
18H13ClN6S
(380.5.86)
17H10BrClN6S
(445.73)
17H12BrN7O2S2
(490.36)
14H10N4S2
C
C
C
Chloroform
Chloroform
Ethanol
Dioxan
C
(266.32)
C21H14ClN5OS
(419.90)
8
9
C
22H17N5S2
(415.53)
21H13ClN4O2S
(420.88)
27H17ClN6O
(476.92)
35H27ClN6O
(583.10)
24H14ClN7O
(451.87)
21H15ClN4OS
(406.90)
24H20ClN5OS
(461.98)
32H23ClN6OS
(575.10)
32H23ClN6O2S
(591.10)
10
11
12
14
15
16
19a
19b
C
Ethanol
Benzene
Ethanol
Ethanol
Ethanol
Benzene
Ethanol
Yellow
Yellow
Brown
Yellow
Orange
Yellow
Yellow
C
C
C
C
C
C
C

224 El-Sharief et al.
TABLE 2 Spectral Data of the Synthesized Compounds
Compd No.
IR(νmax) (cm−1
)
1HNMR (δ(ppm)) (DMSO-d6)
4a
4b
4c
4d
4e
3414 (NH), 2235 (C≡N), 1672 (C N), 1591
(N N), 1470, 1244 (C S)
2.30 (s, 3H, CH3), 6.72, 7.13, 7.24, 7.78 (4d, 8H,
Ar-H), 8.54, 9.48 (2s, 2H, two NH)
2.47 (s, 3H, CH3), 3.48 (s, 3H, OCH3), 6.78–7.80
(m, 8H, Ar-H), 8.40, 9.50 (2s, 2H, two NH)
3405 (NH), 2210 (C≡N), 1675 (C N), 1590
(N N), 1420, 1238 (C S)
3410 (NH), 2207 (C≡N), 1680 (C N), 1592
(N N), 1475, 1235 (C S)
3450 (NH), 2250 (C≡N), 1668 (C N), 1578
6.76, 7.34, 7.40, 7.79 (4d, 8H, Ar-H), 8.71, 9.65
(2s, 2H, two NH)
6.80 (s, 2H, SO2NH2), 7.20–7.67 (m, 8H, Ar-H),
8.60, 9.50 (2s, 2H, two NH)
7.57–8.16 (m, 9H, Ar-H), 13.60 (Hump, 1H, NH)
7.61–8.70 (m, 13H, Ar-H), 10.03 (s, 1H, NH)
(N N), 1480, 1250 (C S)
3413, 3346, 3257 (NH, NH2), 2214 (C≡N), 1685
(C N), 1596 (N N), 1487, 1251 (C S)
3267 (NH), 2233 (C≡N), 1542 (N N)
3365 (NH), 1743 (C O), 1678 (C N), 1542
(N N), 1458, 1214 (C S)
7
8
9
3220 (NH), 1651 (C N), 1512 (N N), 1384,
1280 (C S)
2.40 (s, 3H, CH3), 7.37–8.04 (m, 13H, Ar-H), 9.90
(s, 1H, NH)
10
1797, 1743 (C O), 1542 (N N), 1384, 1288
(C S)
7.44–8.08 (m, 13H, Ar-H)
11
12
1752 (C O), 1600 (C N), 1508 (N N)
1747 (C O), 1569 (N N)
7.61–8.17 (m, 17H, Ar-H)
2.26, 2.27 (2s, 6H, 2CH3), 6.58–8.19 (m, 21H,
Ar-H)
14
3330 (NH), 2202 (C≡N), 1725 (C O), 1620
(C N), 1542 (N N)
7.07–7.87 (m, 13H, Ar-H), 10.00 (s, 1H, NH)
15
2929 (CH-aliph), 1747 (C O), 1542 (N N),
1432, 1253 (C S)
4.96 (s, 2H, CH2), 6.65–7.99 (m, 13H, Ar-H)
16
3060 (CH-arom), 2925 (CH-aliph), 1715 (C O),
1488 (N N)
3.35 (s, 6H, N(CH3)2), 6.91–7.94 (m, 13H, Ar-H),
8.07 (s, 1H, CH)
19a
19b
3332, 3250 (NH2), 2214 (C≡N), 1743 (C O),
2.49 (s, 3H, CH3), 3.45 (s, 2H, NH2), 4.10 (s, 1H,
thiopyran-H), 6.89–8.01 (m, 17H, Ar-H)
3.38 (s, 2H, NH2), 3.61 (s, 1H, thiopyran), 3.83 (s,
3H, OCH3), 7.11–7.92 (m, 17H, Ar-H)
1596 (N N)
3345, 3230 (NH2), 2220 (C≡N), 1741 (C O),
1503 (N N)
and NH3 were evolved, then allowed to cool and
poured into water (100 mL) and acidified with hy-
drochloric acid. The product was collected and re-
crystallized from proper solvent to give 12.
3-(Azobenzene)-1-(4-chlorophenyl)-4-thioxo-2,5-
imidazolidinedione (10)
To a solution of compound 8 (0.01 mole) in boiling
dioxane (20 mL), conc. HCl (3 mL) was added. The
reaction mixture was allowed overnight. The product
was collected, washed with cold water, and recrystal-
lized from proper solvent to give 10.
3-(4-Chlorophenyl)-5-imino-2-oxo-1-(4-
phenylazophenyl)-1,2,3,5-tetrahydro-
pyrrolo[2,3-d]imidazol-6-carbonitrile (14)
A mixture of compound 8 (0.01 mole) and malonon-
itrile (0.01 mole) in 30 mL absolute ethanol in the
presence of few drops of triethylamine was refluxed
until hydrogen sulfide evolved (18 h). The obtained
product was recrystallized from proper solvent to
give 14.
3-(Azobenzene)-1-(4-chlorophenyl)-1H-
imidazo[4,5-b]-quinoxalin-2-one (11)
A mixture of compound 8 (0.01 mole), o-phenyl-
enediamine (0.01 mole) in absolute ethanol (30 mL)
was refluxed until H2S and NH3 were evolved. The
solid that obtained was recrystallized from proper
solvent to give 11.
3-(Azobenzene)-1-(4-chlorophenyl)-4-
thiohydantoin (15)
Through a suspension of compound 8 (0.01 mole)
in 20 mL absolute ethanol containing triethylamine
(0.02 mole) was passed a stream of hydrogen sulfide
until the system became clear (0.5 h). The obtained
product was collected and washed with ethanol to
give 15.
3-(Azobenzene)-1-(4-chlorophenyl)-4,5-bis(4-
methylphenyl-imino)-2-imidazolidinone (12)
To a solution of compound 8 (0.01 mole) in 20 mL
absolute ethanol was added 4-methylaniline (0.02
mole). The reaction mixture was refluxed until H2S

Syntheses of Some Novel Imidazolidinethiones and Condensed Imidazoles Containing Arylazo Moieties 225
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The N,N-dimethylformamide-dimethylacetal (0.02
mole) is added to a solution of the thiohydantoin 15
(0.01 mole) in 30 mL dry m-xylene, and the reaction
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A mixture of thiohydantoin (15; 0.01 mole), substi-
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(0.5 mL) in 30 mL absolute ethanol was refluxed for
6 h. The reaction mixture was then cooled, poured
into crushed ice, neutralized with dil HCl (3 mL,
12%) and the obtained product was collected,
washed with cold water, and recrystallized from
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