Advancements in synthesis of pharmacologically active imidazolidin-4-ones and stereochemistry of their Reactions with some Reagents

Article abstract of DOI:10.1002/jhet.3871

1-Aryl, 1,3-diaryl- and 5-(2-oxo-2-arylethyl)-2-thioxo-imidazolidin-4-ones 2 were prepared as before, nevertheless, equivalent amounts of potassium hydroxide were added to the reaction conditions. This change, dramatically, reduced the reaction time and h

Full text of DOI:10.1002/jhet.3871

Received: 1 November 2019
DOI: 10.1002/jhet.3871
Revised: 6 December 2019
Accepted: 7 December 2019
A R T I C L E
Advancements in synthesis of pharmacologically active
imidazolidin-4-ones and stereochemistry of their Reactions
with some Reagents
Khaled F. Saied1
| Salwa S. Abdelwahab2
| Heba E. Hashem3
|
Kamal A. Kandeel4
1Basic Science Department, Faculty of
Oral and Dental Medicine, Nahda
University, Beni-Suef, Egypt
2Faculty of Pharmaceutical Sciences and
Pharmaceutical industries, Future
University, Cairo, Egypt
3Department of Chemistry, Faculty of
Women, Ain Shams University, Cairo,
Egypt
Abstract
1-Aryl, 1,3-diaryl- and 5-(2-oxo-2-arylethyl)-2-thioxo-imidazolidin-4-ones 2 were
prepared as before, nevertheless, equivalent amounts of potassium hydroxide
were added to the reaction conditions. This change, dramatically, reduced the
reaction time and highly increased the yield of some derivatives. Treatment of
2 with sulfuric acid converted them into their analogous (E)/(E,Z)-5-(2-oxo-
2-arylethylidene) derivatives 3. Reactions of 2 and/or 3 with chromium trioxide
affected their conversion into the corresponding 2,4-diones 4 and 5, respectively.
Treatment of 2 and/or 3 with ethyl bromoacetate affected conversion of the for-
mer into their respective 2,4-diones 4, whereas it gave the respective 2-alkylthio
derivatives of the latter. Reactions of 2b with aromatic aldehydes gave mixtures
of spiro-1H- and 2H-pyrrole diastereomers. Structures of the new products were
4Department of Chemistry, Faculty of
Since, Ain Shams University, Cairo, Egypt
Correspondence
Khaled F. Saied, Basic Science
Department, Faculty of Oral and Dental
Medicine, Nahda University, Beni-Suef
62511, Egypt.
evidenced by infrared, EI-MS, H- and 13C-NMR spectroscopic measurements.
1
Email: fathykhaled905_7@yahoo.com
Many of the selected compounds showed good antimicrobial activity.
1 | INTRODUCTION
oxidized giving the respective C O class. The presence of
the NH─C S group is also suitable in synthesis of a
Imidazolidin-4-ones are characterized by different
biological activities. Some of these activities are
antimicrobial,[1,2] antitumor,[3] antifungal[4] and anti-par-
asitic.[5] There are other pharmacological applications
have been cited in reviews.[6,7] The imidazolidin-4-ones
2 are antimicrobial active derivatives have been pre-
variety of derivatives by alkylation[9] with halides or via
Mannich reaction.[10] However, compounds 2 had not
received further study since they have been
synthesized.[2]
Thus, compounds 2 were treated with sulfuric acid,
chromium trioxide, ethyl bromoacetate, and aromatic
aldehyde, in some attempts to prepare new imidazolidin-
4-ones of anticipated biological activity. Chromium triox-
ide has been, successfully, used[11] to convert the C S, in
some 1,3-thiazolidin-4-ones, into C O group, without
any side changes occurred when other reagents are
used.[12–15] Hence, the reactions of this reagent with
2 were performed to generalizing its utility with different
thioxoheterocycles. Comparing the antimicrobial poten-
tial of the products with those, previously investigated,
was another target of the study.
pared[2]
from
(3H)/3-phenyl-5-(2-oxo-2-arylethyl)-
2-phenylimino-1,3-thiazolidin-4-ones 1a-f, by reflux in
dimethyl formamide. The stability of the transition state
has been manifested by the presence of the aryl group at
C-2; thus, the 2-imino-1e gave poor yield of 2e.[2] Herein,
we explored the preparation of 2, with a slight modifica-
tion in the reaction conditions and investigated their
behavior towards some reagents. These derivatives
include 1,4-diketone system, which is useful in Paal-
Knorr synthesis[2,8]; the C S moiety, which could be
J Heterocycl Chem. 2020;1–17.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
SAIED ET AL.
2 | RESULTS AND DISCUSSION
correlated with two C O and another band for NH
groups. Further support was added by the H-NMR spec-
1
The
starting
compound
5-(2-(4-chlorophenyl)-
trum which showed the signals of the splitting pattern of
the AMX protons.[17,18] The structure was also confirmed
by 13C-NMR spectrum and mass spectrum which
exhibited a correct molecular ion peak at m/z = 310. On
the other hand, the structure of 2a-e was confirmed by
comparing (T.L.C) and melting points with authentic
samples.[2]
2-oxoethyl)-2-(4-tolylimino)-1,3-thiazolidin-4-one 1c was
prepared from ammonium 4-tolyldithiocarbamate with
4-(4-chlorophenyl)-4-oxobut-2-enoic acid,[16] following
the method used before.[2] The H-NMR spectrum of 1c
1
showed the signals characteristic of the CH-CH2 pro-
tons.[17,18] The structure of 1c was further supported by
IR, EI-MS and 13C-NMR spectra (cf Section 5).
Following Paal-Knorr furan synthesis,[8] compounds
2a-c were treated with concentrated sulfuric acid. The
desired furo[2,3-d]-imidazole [VI] did not formed
(Scheme 3, pathway ii), while the corresponding (E,Z)-
5-(2-oxo-2-arylethylidene)-derivatives 3a-c were isolated
(Scheme 3, pathway i). The IR spectra of 3 displayed
Reflux of 1a-f in dimethyl formamide, with molar
amounts of potassium hydroxide, for 5 minutes, gave fair
yields of 1-aryl-, 1,3-diaryl- and 5-(2-aryl-2-oxoethyl)-
2-thioxoimidazolidin-4-ones 2a-f via the mechanistic
steps 1 to 3 (Scheme 1). The gain of this approach is
observed in the reaction time which has decreased from
4 to 10 hours[2] to 5 minutes and in the yield of 2e, which
has increased from 10% to 75%. This dramatic change has
occurred, most likely, by the contact of potassium ions
with sulfur, which promote the ring cleavage, followed
by losing of a proton, leading to the formation of a stable
ionic transition state, while the prime factor, that acceler-
ated the reactions, in 1e, was the imposition of a perma-
nent negative charge resonates close to two lone pairs of
electrons at the N-atoms. This situation enhanced break-
ing of the ring, into a stable thiolate intermediate, [III]
which, immediately, endured 5-exodig cyclization,[19] for-
ming the imidazole ring (Scheme 2). It was, also, believed
that the match in size of orbitals between C─N, com-
pared with C─S[20] had another role in accelerating this
process. The nondeposition of 2, unless by acidification,
disclosed the acidic nature of 1 and 2.[2,21]
SCHEME 2 Conversion of 1e ! 2e in the presence of KOH
The structure of 2a was established by studying its
spectral data. Its IR spectrum showed absorption bands
SCHEME 1 Synthesis of compounds 2 in the absence and
presence of KOH
SCHEME 3 Formation of compound 3

SAIED ET AL.
3
absorption bands for (NH) at 3194; (C O, ketone) at
Moreover, reactions of 2 and/or 3, with chromium tri-
oxide, were performed in boiled acetic acid. As antici-
pated[11] this treatment converted 2 and 3 into their
1685 and (C O, imide) at 1651 cm−1
.
1
Moreover, the H-NMR spectra exhibited one singlet
signal in each of 3a and 3c, with a correct integration
ratio for an olefinic proton, at 5.94 and 5.89 ppm, respec-
tively. However, in 3b, the olefinic proton was represen-
ted by two singlet signals, at δ = 5.89 and 6.55 ppm;
likewise, the NH proton was represented by two broad
signals, at δ = 12.98 and 12.76 ppm. This inferred that 3b
existed as E,Z mixture, in 35:65%, as indicated from the
integration ratios. The configuration assignment was
corresponding 2,4-diones
(Scheme 4).
4
and 5, respectively
The IR spectra of the structures 4 and 5 displayed
absorption bands corresponding to three C O groups.
The EI-MS showed their molecular ion peak values as lit-
tle as by 16 atomic units, compared with their respective
starting materials.
All of these data were in harmony with the prospect
1
1
assisted on the H-NMR spectra of (E,Z)-cycloaryliden-
that the C S has converted into C O groups. The H-
4-ones[22,23] in which, the olefinic singlets, of the Z-iso-
mers, existed at lower field, compared with the equiva-
lent proton of the E-isomers, due to the deshielding effect
of the C O groups, at C-4. According to the chemical
shift values of the olefinic signals in 3b, it was indicated
that 3a and 3c are pure E-isomers. Further evidence was
gained from the mass spectra which showed molecular
ion peak values, for 3a-c, as less as by two atomic units,
compared with their starting parent 2a-c. In addition, the
structure of 3a was proved authentically.[2]
Formation of 3a-c was expected to occur by a
sulphonation process at C-5, in the enole form [III] giv-
ing the sulfonic acid intermediate [IV] (not isolated).
Thus, by elimination of sulfonic acid,[24–26] compounds
3 were formed (Scheme 3, pathway i).
NMR spectra of 4a and 4c showed the predicted signals
of the AMX protons[17,18]; however, instead of the AMX
pattern, the spectrum of 4d showed two doublets for
geminal protons.[17,27]
This phenomenon was explained by existence of this
derivative in the furo[2,3-d]imidazole [V] (see Scheme 3).
1
Moreover, the H-NMR data showed that 4b existed as a
mixture of the open and the cyclic structures, in 50:50%
ratios.
Since the infrared spectra of 4a-d showed three C O,
for each, it was expected that the furo-[V] structure has
only formed during measuring the 1H-NMR.
1
On the other hand, the H-NMR spectra of (E,Z)-5a-f
exhibited two signals for the olefinic protons, at δ ≈ 5.9
and 6.5 ppm for E- and Z-isomers, respectively.[22,23] This
SCHEME 4 Conversion of compounds 2 and 3 into 4 and 5

4
SAIED ET AL.
problem, clearly, appeared in the 13C-NMR spectrum of
5b, as it showed twice of the expected number of carbon
signals.
of the three membered ring, into an open dipolar inter-
mediate [IX] which, rapidly, has cyclized into a four-
membered ring [X]. However, the proper overlap of C/O
orbitals, compared with C/S,[36] resulted in splitting of
the four-membered ring, providing the analogous
2,4-diones 4 and 5, along with the sulfone intermediate
[XI] which gave SO2 gas via a dehydrogenative single
electron cyclization, followed by hydrolysis, then, oxida-
tive degradation step ! CrIII (Scheme 4).
It is worth to notice that the E-isomer was the chief con-
stituent in each of these mixtures. The conversion of pure
(E)-3a and 3c into (E,Z)-5a and 5c was understood in light
of the isomerization around the olefinic linkage,[28–30]
whereas formation of the largest ratio of E-isomer was
rationalized in terms of the existence of 5 as two equili-
brated mesoionic [XII] and [XIII] forms (Figure 1). These
forms have involved, separately, with chromium ions in
some bonding[31]; however, the probable bonding of a chro-
mium ion, with the imidic and the ketonic C O groups, of
the same molecule, trapped some portion of conformation
[XIII] out the equilibrium. Thus, by working the reactions
out, additional ratios of E-isomers were added to the bal-
anced mixture, which resulted in an increase of the E- over
the Z-isomer in the total ratio of the mixture. Formation of
(E,Z)-5b (E-isomer, 60%) from (E,Z)-3b (E-isomer, 35%)
supported this interpretation.
These reactions began with effervescence, without
generation of hydrogen sulfide, whereas we smelled the
distinctive odor of burnt sulfur, for SO2 gas. This observa-
tion was verified when these effervescences turned the
orange color of an acidified chromate solution into green.
We proposed the mechanism in light of the oxidation
by oxochromiumVI compounds,[32] the oxidation of thio-
ureas[33] and the evolution of SO2 (Scheme 4). Other fac-
tors were considered; (a) the rapid evolution of SO2 gas
which indicated that the oxidation of sulfur was an ear-
lier step; (b) absence of any traces of elemental sulfur
which revealed that oxidation of sulfur has occurred
while it was linked to some intermediate; therefore, we
ignored that sulfur was separated, in the elemental form,
then has oxidized[34]; (c) sulfur functions are capable to
behave free radical reactions[33]; and (d) the transition
metal ions induce free radical reactions.[32] Thus, it was
proposed that the reaction started by the attack of the
lone pair of electrons, in the C S, at the chromium
ions[35]; the originated chromate anion, in turn, attacked
the electron deficient sulfur affording the intermediate
[VI]. Resonating of [VII] into [VIII] stimulated cleaving
In addition, reactions of 2a and 2b as well as 3a-c,
with ethyl bromoacetate, were conducted in ethanol plus
equivalent amounts of potassium hydroxide (Scheme 5).
This treatment affected alkylation of 3a-c into the
esters 6a-c, whereas it transformed 2a and 2b into their
respective 2,4-diones 4a and 4b. This was confirmed by
comparing the melting point and the spectral data of
these products with 4a and 4b, previously prepared.
This conversion was believed to occur, first, by the for-
mation of the S-alkyl 7, as momentary intermediate, which
has hydrolyzed, at the S─C bond, giving 4 (Scheme 5). In
this context, it should be noted that alkylation of the
2-thioxo-1,3-thiazolidin-4-ones[37] and 2-thioxoimidazolidin-
4-ones[38] was an earlier method used for preparation of the
respective 2,4-diones of these heterocyclic classes.
Moreover, alkylation of 3a-c proceeded, as
expected[21,39–41] giving the S-alkyl products 6a-c. The
1H-NMR spectra of 6 exhibited the splitting patterns
characteristic of the CH2─S and the COOC2H5 protons.
The IR spectra of 6 exposed absorption bands for three
carbonyl groups in between 1770 and 1685 cm−1. The sin-
glet signals of the CH2─S protons have overlapped by the
quartet patterns of the ─OCH2 protons. Additionally, the
spectra showed two singlet signals for the olefinic pro-
tons, revealing that 6a-c are mixtures of E- and Z-iso-
mers.[22,23] Furthermore, the EI-MS of 6a-c showed
molecular ion peak values and fragmentation pattern in
agreement with the expected values (cf Section 5).
There are two notable points in the formation of 6;
(a) Z-isomer was the major quantity in both of the
4-chlorobenzoyl-esters 6b and 6c, whereas, E-isomer was
the major portion in the benzoyl-6a and (b) stability of
6 against hydrolysis, compared with 7 (nonisolated).
These phenomena were explained in view of the pres-
ence of intermediate forms [XIV] and [XV] in case of 6a
(Figure 2) and [XVII] and [XVIII] forms in case of 6b
and 6c (Figure 3).
As for the first problem, in the benzoyl 6a, the form
[XV], which has the proper orientation for cyclization,
currently, was trapped in the cyclic furo-structure [XVI]
1
(see H-NMR of 4d). Therefore, the bulk of the mixture
was made of E-isomer (Figure 2). However, in the
4-chlorobenzoyl 6b and 6c, the chloro functions accrued
negative charges at the ketonic C O, so that the repulsion
FIGURE 1 Bonding of Cr ions with (E)/(E,Z)-3 ! (E,Z)-5

SAIED ET AL.
5
SCHEME 5 Formation of esters 6 and the hydrolyzed nonisolated 7
FIGURE 3 Cl function in 6b and 6c shifts the equilibrium to
[XVII] form ! (Z) isomer
FIGURE 2 Cyclization in 6a shifts the equilibrium to [XV]
form ! (E) isomer
between the oxygen atoms shifted the equilibrium to the
[XVIII] form (Figure 3). Thus, the bulk of the mixture was
made of Z-isomer. The significant increment of Z-isomer
ratio in 6b (85%), compared with its ratio in the starting
material 3b (65%), is in harmony with this elucidation.
The second problem was rationalized in terms of the
hetero ring aromaticity. This property has achieved, in 6,
by the conjugation in the C C─C O moiety into reso-
nating [XIX] forms (Figure 4), whereas the hetero ring in
7 would attain the aromatic property by the development
of the enol form [XX] (Figure 5).
FIGURE 4 The conjugation of C C─C O moiety in 6,
induced aromatization
However, the enol forms, in general, are less stable
than their ketone tautomers and slowly are formed.[42]
In addition, imidazolidin-4-one 2b was conducted to
the reactions with 4-chloro- and
4-methoxybenzaldehydes. The reactions were carried out
in boiled toluene, catalyzed by addition of ammonium
acetate.[37] Each reaction gave two products which were
separated by column chromatography.
Moreover, if we assumed that [XX] was developed, it
would undergo successive 1,3-hydrogen shifts into non-
aromatic forms (Figure 5). Thus, esters 6, which, tempo-
rary, existed in an aromatic structure, were less
susceptible[43] for the nucleophilic attack by water mole-
cules, compared with structure 7, which was unable to
gain the aromatic characters and has hydrolyzed.
The reaction of 4-chlorobenzaldehyde afforded a mix-
ture of compounds 10a and 11a (Scheme 6). The IR

6
SAIED ET AL.
spectra showed an absorption band for C O group, at
1
1754 cm−1 in 10a and 1668 cm−1 in 11a. The H-NMR
spectrum, in CDCl3, showed in 10a, a broad signal at
δ = 8.11 ppm for NH; multiplets for the expected number
of the aromatic protons 7.78 to 7.30 ppm; two doublets
for two geminal protons[17,27]; a singlet signal at
δ = 5.75 ppm, for C─H proton. On the other hand, the
spectrum of 11a exhibited two broad signals for two NH
groups, at 8.78 and 8.01 ppm; multiplets 7.68 to 7.16 ppm,
equivalent to 14 protons (13 aromatic protons plus an
olefinic proton); a singlet signal, at δ = 6.89 ppm equiva-
lent to a highly deshielded C─H proton. It was
FIGURE 5 Enole form of the nonisolated 7 does not achieve
aromatization
SCHEME 6 Formation of spiro-2H-pyrrole 10 and spiro-1H-pyrrole 11 from 2b

SAIED ET AL.
7
TABLE 1 Chemoffice measurements for spiro-2H-pyrrole
diastereomers 10a
interesting that the EI-MS exhibited the same molecular
ion peak value m/z = 465 for each, revealing a relation-
ship of isomerism between these compounds.
Configuration φa
Atoms,b ꢀ/A
Atoms,b ꢀ/A
Missing of the CH─CH2 pattern and disappearance of
C O group inferred that C-5 and the ketone C O were
involved in the reaction, while, arising of additional HN
group, in 11a, indented that NH3 gas, evolved from ammo-
nium acetate, participated the reaction. This rationaliza-
tion was proposed in light of the reactions
2-thioxothiazolidin-4-ones with aldehydes, under the same
conditions.[44] Since by evolution of HN3 base, the reac-
tions have fulfilled the conditions of Mannich reaction,[10]
the structure of 10a was expected to be a spiro-2H-pyrrole,
while the structure of 11a was expected to be a spiro-1H-
pyrrole tautomer. Formation of these pyrroles was
suggested to tack place as illustrated (Scheme 6).
By boiling, ammonium acetate generated NH3 which
abstracted the acidic proton at the chiral C-5. The formed
carbanion [XI] attacked, by any of its sides, at the ─CHO
group, from above and/or below; therefore, another chi-
ral center is formed. Accordingly, four hydroxyl (5S,6S)-,
(5S,6R)-, (5R,6S)- and (5R,6R)-diasteromers 8 are formed.
Again, ammonia was involved in the reaction and rep-
laced the OH groups giving four diastereomers of Man-
nich base 9, via SN1 mechanism (taking into account the
inversion of configuration that occurs during these nucle-
ophilic substitution reactions). Thus, condensation of the
amino group and the ketonic C O furnished (5S,6S)-,
(5S,6R)-, (5R,6S)-, and (5R,6R)-diastereomers of spiro-2H-
pyrrole 10a via 5-exo-trig[45] cyclization.
(5S,6S)-
−1.96ꢀ
O(10)-H
(33)/2.467
C(4)-H
(33)/2.443
(5R,6R)-
1.96ꢀ
O(10)-H
(33)/2.466
C(4)-H
(33)/2.446
(5R,6S)-
(5S,6R)-
117.42ꢀ
–
–
–
–
−117.42ꢀ
aThe torsion angle including O(10)-C(4)-C(5)-C(6)-H(33).
bThe distance between the given atoms.
TABLE 2 Chemoffice measurements for spiro-1H-pyrrole
diastereomers 11a
Configuration
(5S,6S)-
φa
Atoms,b ꢀ/A
−0.514ꢀ
0.517ꢀ
115.97ꢀ
−115.97ꢀ
C(4)-H(33)/2.556
(5R,6R)-
C(4)-H(33)/2.556
(5R,6S)-
–
–
(5S,6R)-
aThe torsion angle including C(4)-C(5)-C(6)-H(33).
bThe distance between the given atoms.
Thus, 1,3-proton shift across the CH2─C N group, in
10a gave (5S,6S)-, (5S,6R)-, (5R,6S)- and (5R,6R)-spiro-
1H-pyrrole 11a tautomers.
This problem of diastereomers has solved by consult-
ing the software program Chemoffice,[46] depending on
the IR spectra. The program measurements for 10a and
11a were listed in Tables 1 and 2, respectively; the C O
was denoted by C(4) and O(10); H-6 by H(33); (φ) is the
torsion angle including the C O group, and H-6 and the
distance between them are also recorded.
As showed, the recorded length[47,48] and φ ≈ ( 2ꢀ)
permitted the formation of H-bond between H-6 and the
C O, in (5S,6S)- and (5R,6R)-isomers, whereas in
(5R,6S)- and (5S,6R)-isomers, the C O and H-6 are too
apart to undergo H-bonding φ ≈ ( 115ꢀ − 117ꢀ).
Accordingly, and because we did not separate further
products, we expected that 10a, with the greater vC O, was
a mixture of 50:50% (5R,6S)/(5S,6R)-enantiomers, whereas
11a was a 50:50% mixture of (5S,6S)/(5R,6R)-enantiomers.
Since the conversion between cyclic conformers
occurs with retention of configuration,[49] we concluded
that the (5S,6S)- and (5R,6R)-2H-pyrroles 10a have
changed into the respective 1H-pyrrole 11a, while the
FIGURE 6 Configuration of 10a and 11a mixtures
(5R,6S)- and (5S,6R)-2H-pyrroles 10a stayed unchanged
(Figure 6).
As for the stereogenic sp3 nitrogen-atoms, they have no
specific stereochemistry because they are labile and rapidly

8
SAIED ET AL.
interconvert between the S and R configuration.[50] On the
other hand, the reaction of 4-methoxybenzaldehyde and 2b
afforded a mixture of two products. Their 1H-NMR spectra,
in DMSO, were identical and resemble the spectrum of
11a, in DMSO (cf Section 5).
Furthermore, their EI-MS exhibited the same molecu-
lar ion peak value m/z = 461. However, the IR spectra
showed an absorption band for C O, at 1752, in one of
them and 1672 cm−1, in the other.
In light of the previous discussion, we ended that all
the produced (5S,6S)-, (5S,6R)-, (5R,6S)- and (5R,6R)-
spiro-2H-pyrrole diasteromers 10b have changed into the
respective 1H-pyrrole diasteromers 11b, which were iso-
lated into two pairs of 50:50% enantiomeric mixtures; the
mixture with the greater vC O (1752 cm−1, nonbonded)
was assigned the (5R,6S)/(5S,6R)-configuration, while the
isomeric mixture with the lower vC O (1672 cm−1) was
assigned the (5S,6S)/(5R,6R)-configuration (Figure 7).
The great difference between the chemical shift
values of signals in 10a and 11a, in CDCl3 compared with
dimethyl sulfoxide, was rationalized in terms of the effect
of the solvent. Dimethyl sulfoxide acts as a Lewis base
that abstracts protons from NH, OH, or even from C─H
groups and may affect the displacement of the chemical
shift of signals up to 3 to 5 ppm, to lower field, compared
with CDCl3.[51–54]
FIGURE 7 Configuration of 1H-pyrrole mixtures 11b
TABLE 3 Antimicrobial activity of
the samples/ Inhibition zone diameter
Microorganism
(mm/mg Sample)
Bacterial Species G−
Bacterial Species G+
Fungi
Sample
Ia
IIb
0.0
21
–
IIIc
0.0
25
–
IVd
0.0
26
–
Ve
0.0
–
VIf
0.0
–
DMSO
0.0
26
g
†
h
‡
17
21
0.0
11
0.0
9
3a
3c
6a
6b
6c
4a
4b
4d
4f
31
26
22
23
22
10
10
13
15
23
27
21
20
17
16
14
0.0
0.0
0.0
11
15
17
23
21
19
17
15
0.0
9
24
20
17
16
17
0.0
10
0.0
11
17
19
0.0
0.0
0.0
10
10
11
0.0
0.0
0.0
0.0
10
13
0.0
0.0
0.0
0.0
0.0
13
0.0
13
15
18
5b
5c
aBacillus subtilis.
bStaphylococcus aureus.
cPseudomonas aeruginosa.
dEscherichia coli.
eAspergillus flavus.
fCandida albicans.
gAmpicillin standard antibacterial agent.
hAmphotericin standard antifungal agent.

SAIED ET AL.
9
3 | BIOLOGICAL ACTIVITY
recorded on Perkin Elmer 1600 FTIR spectrophotome-
1
ter; H-NMR on Varian 300 MHz instrument and 13C-
Antimicrobial activity was run in Micro Analytical Cen-
ter, Cairo University, Giza, Egypt.
NMR at 75 MHz, in (DMSO-d6), otherwise stated;
chemical shifts (δ) are reported in ppm downfield from
(TMS) chemical shifts δ in ppm (s, singlet; d, doublet;
dd, doublets of doublet; t, triplet; q, quartet; appt.t,
apparently triplet; m, multiplet; br, broad), coupling
constants (Hz). Mass spectra were operated on a
Shimadzu GC-MS-QP 1000X spectrometer operating at
70 eV. The solvents were purchased from EL-Nasr Phar-
maceutical and chemical company (Adwic), Egypt and
Loba Chemie India and used without further purifica-
tion. The reagents were purchased from Sigma-Aldrich,
Alpha Chemika, India. Reactions were monitored by
T.L.C. on Merck silica gel 60-F254 aluminum backed
plates, developed under UV absorption. Light petroleum
refers to 60/80 fraction. 1,3-Thiazolidin-4-ones 1a-f were
synthesized following to literature.[2]
The tested samples were evaluated using a modified
Kirby-Bauer disc diffusion method,[55] following documented
techniques,[56,57] against four bacteria types: two negative
gram (Bacillus subtilis and Staphylococcus aureus) and two
positive gram (Escherichia coli and Pseudomonas aeruginosa).
The samples were also tested against two types of fungi
(Aspergillus flavus and Candida albicans) (Table 3).
Mueller-Hinton agar was used according to well-known
recommendations.[58] Blank paper disks and susceptibility
tests were performed by stated disc diffusion method.[59–62]
Standard discs of ampicillin and amphotericin B were
used as antibacterial and antifungal agents, respectively,
for positive controls. Filter impregnated with 10 μL of dis-
tilled water, chloroform, and DMSO solvents were applied
as a negative control. According to the recorded data,
3-unsubstituted imidazolidin-2,4-diones 4a, 4b, and 4d
were the least potent derivatives; they are also less potent
than their respective 2-thioxo-homologs which have been
previously evaluated[2]; however, they exhibited moderate
antibacterial activity against some bacteria species.
Specimens 4c, 12, and 13 did not realize any antimi-
crobial activity. By the comparison with new documented
antimicrobial studies,[63–65] we can say that the tested
samples of class 3, 5, 6, and 4f exhibited good
antibacterial activity against the four types of bacteria.
In addition, 3c, 6b, 6c, 5b, and 5c showed remarked
effect against C albicans fungus, while 5b, 5c, and 5c are
the derivatives which showed interesting potential
against pathogen A flavus (Table 3).
5.1 | Compound 1c
5.1.1 | 5-(2-(4-Chlorophenyl)-2-oxoethyl)-
2-(4-methylphenyl-imino)-1,3-thiazolidin-
4-one (1c)
White powder, mp < 300ꢀC (dioxane); yield 80% (0.8 g),
IR spectrum (KBr); ѵ, cm−1 3494 (NH), 3046 ( CH),
2924, (C─H), 1762 (C O ketone), 1695 (br, C O imide,
C N); 1591 (C C); 817 (δ2-H). 1H-NMR spectrum
(300 MHz, DMSO-d6); δ, ppm, (J, Hz): 7.80, 7.35 each
(dd, J = 6.9, 1.8 Hz, 2H); 6.16-7.21 (m, 5H); 5.23 (apt.t,
J = 4.5, 1H); 3.62, 3.38 each (dd, J = 18, 4.5 2H). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 358 [M]+ (3.2);
330 [M─CO]+ (43); [M─CO─H2]+ (100); 326 [M─S]+ (7);
283 [M─S─NHCO]+ (10); 139 [4-ClC6H4─CO]+ (8). Anal.
calcd. for C18H15ClN2O2S (358): C, 60.25; H, 4.21; N, 7.81;
found C, 60.57; H, 4.08; N, 7.77.
4 | CONCLUSIONS
The research comprised an easy quick route for synthesis
of biologically valuable compounds and confirmed that
chromium trioxide can be used to convert the C S into
C O group, in different heterocyclic compounds. Fur-
thermore, the study described facile conditions useful in
synthesis of pure E-isomers of imidazolidin-4-ones. Most
of the tested compounds showed good results against the
5.2 | Synthesis of compounds 2
A round-bottomed flask containing 50 mL of dimethyl
formamide and 1 g of 1a, 1b, 1c, 1d, 1e, or 1f was heated
till solvation has completed and left to cool at ≈50ꢀC,
then an aqueous solution of KOH (2 mL, 1.1 equiv.) was
added and the heating was continued with stirring for
5 minutes. The solution was left to cool at ≈50ꢀC and fil-
tered off to remove any impurities. The clear solution
was poured onto crushed ice water, acidified with excess
of acetic acid and left for ≈15 minutes for complete pre-
cipitation. The formed crystals were filtered off, well
dried, and recrystallized from dioxane/toluene to give:
screened
microbes,
particularly,
the
5-(2-aryl-
2-oxoethylidene)-derivatives of classes 3, 5, and 6 which
showed a promising interest against the fungi.
5 | EXPERIMENTAL SECTION
All recorded melting points are uncorrected. Reflux was
performed on hot plate. The spectra of IR were

10
SAIED ET AL.
5.2.1 | 5-(2-Phenyl-2-oxoethyl)-1-phenyl-
2-thioxoimidazolidin-4-one (2a)
5.2.4 | 5-(2-Phenyl-2-oxoethyl)-
1,3-diphenyl-2-thioxoimidazolidin-
4-one (2d)
Creamy crystals, mp 224ꢀC-226ꢀC (toluene/light petro-
leum) (Lit.[2] 226-228), yield (0.85 g, 85%), IR spectrum
(KBr); ѵ, cm−1 3236; 3190 (NH); 3047 ( CH); 2927; 2812
(C─H); 1739 (br, C O ketone, C O imide); 1678 (C N);
1597 (C C); 1404; 752; 698 (δ5-H). 1H-NMR spectrum
(300 MHz, DMSO-d6); δ, ppm, (J, Hz): 11.28 (br.s, 1H,
NH); 7.81 (d, 2H, Ar─H, J = 7.20); 7.56 (t, 1H, ArH,
J = 7.20); 7.30-7.54 (m, 6H, ArH); 7.10 (t, 1H, ArH,
J = 7.20); 5.25 (appt.t, 1H, HA, J = 4.5); 3.67 (dd, 1H, HM,
JMX = 18, JAM = 4.5); 3.60 (dd, 1H, HM, JMX = 18,
JAM = 4.5, 2H). 13C-NMR, δ, 196.13 (C S); 173.45 (C O);
155.08 (C O); 135.75 (C Ar); 135.70 (C Ar); 133.57
(C Ar); 128.83 (2C Ar); 128.63 (2C Ar); 127.75 (2C Ar);
124.74 (C Ar); 122.22 (2C Ar); 56.08 (C-5); 35.98 (C─C-5).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 310 [M]+ (100);
308 [M─H2]+ (7); 105 [PhCO]+ (11); [Ph]+ (13).
Creamy crystals, mp 155ꢀC (toluene/light petroleum)
(Lit.[2] 152-154), yield (0.80 g, 80%).
5.2.5 | 5-(2-(4-Bromophenyl)-2-oxoethyl)-
2-thioxoimidazolidin-4-one (2e)
Creamy crystals, mp 208ꢀC (toluene/light petroleum)
(Lit.[2] 206ꢀC-208ꢀC), yield (0.75 g, 75%).
5.2.6 | 5-(2-(4-Bromophenyl)-2-oxoethyl)-
1-phenyl-2-thioxoimi-dazolidin-4-one (2f)
Creamy crystals, mp 247ꢀC (toluene/light petroleum)
(Lit.[2] 247ꢀC-249ꢀC), yield (0.85 g, 85%).
5.2.2 | 5-(2-(4-Chlorophenyl)-2-oxoethyl)-
1-phenyl-2-thioxoimidazolidin-4-one (2b)
5.3 | Synthesis of 3a-c
Creamy crystals, mp 248ꢀC (toluene/light petroleum)
(Lit.[2] 238ꢀC-240ꢀC), yield (0.80 g, 80%).
In 50-mL conical flask containing 10 mL of concentrated
sulfuric acid, 1 g of 2a, 2b, or 2c was added with gentle
shaking till the substance completely was dissolved, then
few drops of acetic anhydride were added. The reaction
mixture was left at room temperature overnight, and then
poured onto 50-g ice water. The fine precipitate was fil-
tered off, well dried, and recrystallized from glacial acetic
acid to afford:
5.2.3 | 5-(2-(4-Chlorophenyl)-2-oxoethyl)-
2-thioxo-1-(4-methylphenyl)-imidazolidin-
4-one (2c)
Creamy crystals, mp 196ꢀC-198ꢀC (toluene/light petro-
leum), yield (0.80 g, 80%); IR spectrum, ν, cm−1: 3209, 3159
(NH), 3093, 3039 ( C─H), 2987, 2920 (C─H), 1735. 1685
(two C O), 813 (2H, C─H Ar, oop). 1H-NMR spectrum, δ,
ppm (J, Hz): 8.74, 7.54 each (2H, d, J = 8.6, 2H, H Ar); 7.20,
7.15 each (2H, d, J = 8.4, 2H, H Ar); 5.24 (1H, appt.,
JAX = 4.4, JMX = 4.4, 5-CHX); 3.63 (1H, dd, JAM = 18.8,
JMX = 4.4, 1-CHM); 3.38 (1H, dd, JAM = 18.8, JAX = 4.4,
1-CHA). 13C-NMR spectrum, δ, ppm: 21.09 (CH3); 37.22
(CH2); 62.27 (C-5); 127.37 (2C); 129.34 (2C); 129.96 (2C);
130.35 (2C); 134.33 (C); 134.63 (C); 137.69 (C); 139.22 (C);
174.68 (C O amid); 182.07 (C S); 195.40 (C O ketone).
5.3.1 | (E)-5-(2-Oxo-2-phenylethylidene)-
1-phenyl-2-thioxoimidazolidin-4-one (3a)
Bright orange crystals, mp 190ꢀC-192ꢀC (glacial acetic
acid), yield (0.82 mg, 82%); IR spectrum (KBr); ѵ,
cm−1:3194; 3136 (NH); 3051( CH); 2958; 2920 (C─H);
1
1685 (C O, ketone); 1651 (C O, imide); 821 (δ2-H). H-
NMR spectrum (300 MHz, DMSO-d6); δ, ppm, (J, Hz):
12.75 (s, 1H, NH); 7.95 (d, 2H, Ar─H, J = 7.20 Hz);
7.62-7.48 (m, 8H, Ar─H); 5.94 (s, 1H, CH). 13C-NMR, δ,
191.30 (C Ar O); 179.03 (C S); 162.01 (HNC O); 136.41
(C Ar); 136.28 (C Ar); 134.22 (C Ar); 133.59 (C Ar); 129.67
(2C Ar); 129.33 (C Ar); 128.84 (4C Ar); 128.57 (2C Ar);
111.86 ( C). Mass spectrum (EI, 70 eV), m/z (Irel, %):
308 [M]+ (100); 144 [M─CS─NHCO─Ph]+ (11) 105
[PhCO]+ (62); 77 [Ph]+ (42) Anal. calcd. for
C17H12N2O2S (308): C, 66.22; H, 3.92; N, 9.08 C, 66.65;
H, 4.97; N, 8.64.
Mass
spectrum
(EI,
70 eV),
m/z
(Irel,
%):
296 [M─CH2 CHCl─H2]+ (3); 217 [M─4-ClC6H4─CO
─H2]+ (4); 193 [M─4-MeC6H4NCSNH─H]+ (6);
149 [4-MeC6H4NCS]+ (13); 139 [4-ClC6H4CO]+ (43);
111 [4-ClC6H4]+ (69); 139 [4-ClC6H4─CO]+ (43);
91 [4-MwC6H4]+ (96); 65 [C5H5]+ (100); Anal. calcd. for
C18H15ClN2O2S (358): C, 60.25; H, 4.21; N, 7.81; found C,
60.45; H, 4.11; N, 7.89.

SAIED ET AL.
11
5.3.2 | (E,Z)-5-(2-(4-Chlorophenyl)-
2-oxoethylidene)-1-phenyl-2-thioxo-
imidazolidin-4-one (3b)
5.4.1 | 5-(2-Oxo-2-phenylethyl)-
1-phenylimidazolidine-2,4-dione (4a)
White crystal, mp 175ꢀC-177ꢀC (toluene/methanol);
yield (0.8 g, 80%) IR spectrum (KBr); ѵ, cm−1 3189
(NH); 3066 ( CH); 2927 (C-H); 1765 (C O, ketone);
1712 (br. two C O, imide); 1595; 1497; 1391; 759;
Bright orange crystals, mp 216ꢀC-218ꢀC (glacial acetic
acid), yield (0.82 g, 82%); IR spectrum (KBr); ѵ, cm−1
3167 (NH); 3024 ( CH); 2924 (C─H); 1755 (C O,
ketone); 1654 (C O, imide); 1585 (C C); 794 (δ2-H);
1
689 (δ5-H). H-NMR spectrum (300 MHz, DMSO-d6); δ,
1
690 (δ5-H); H-NMR, δ, 7.99 (d, 2H, Ar─H, J = 6.60 Hz);
ppm, (J, Hz): 11.22 (br.s, 1H, NH); 7.83-7.80 (m, 2H,
Ar─H); 7.57 (appt.t, 1H, Ar─H, J = 7.5); 7.47-7.30
(m, 6H, Ar─H); 7.11 (appt.t, 1H, J = 7.2); 5.24-5.21
(m, 1H, HA); 3.65 (dd, 1H, HM, JMX = 16.8, JAM = 4.8);
3.57 (dd, 1H, HX, JMX = 16.8, JAX = 3.6). Mass spec-
trum (EI, 70 eV), m/z (Irel, %): 294 [M]+ (95);
189 [M─PhCO]+ (100); 118 [C6H4NCHCH2]+ (90);
105 [PhCO]+ (86); 77 [Ph]+ (93). Anal. calcd. for
C17H14N2O3. (294): C, 69.38; H, 4.79; N, 9.52; found C,
69.79; H, 4.82; N, 9.33.
7.62-7.05 (m, 7H, Ar─H); for Z-isomer (35%); 12.98 (br.s,
1H, NH); 6.55 (s, 1H, CH); for E-isomer (65%) 12.76 (br.
s, 1H, NH); 5.89 (s, 1H, CH). Mass spectrum (EI,
70 eV), m/z (Irel, %): 344 [M + 2]+ (33); 342 [M]+ (100);
139 [ClC6H4─CO]+ (6); 111 [ClC6H4]+ (5). Anal. calcd.
for C17H11ClN2O2S (342): C, 59.56; H, 3.23; N, 8.17;
found C, 59.04; H, 3.15; N, 8.22.
5.3.3 | (E)-5-(2-(4-Chlorophenyl)-
2-oxoethylidene)-2-thioxo-
1-(4-methylphenyl)-imidazolidin-4-one (3c)
5.4.2 | 5-(2-(4-Chlorophenyl)-2-oxoethyl)-
1-phenylimidazolidine-2,4-dione (4b)
Bright orange crystals, mp 196ꢀC-198ꢀC (glacial acetic acid);
yield (0.82 g, 82%); IR spectrum (KBr); ѵ, cm−1 3174 (NH);
3043 ( CH); 2924, 2854 (C─H); 1732 (C O imide); 1666
(C O, ketone); 1446; 798 (δ2-H). 1H-NMR spectrum
(300 MHz, DMSO-d6); δ, ppm, (J, Hz): 12.73 (br.s, 1H, NH);
7.97, 7.55 each (dd, 2H, Ar─H, J = 6.6, 1.80); 7.44-7.40 (m,
5H, Ar─H); 5.89 (s, 1H, CH); 2.36 (s, 3H, CH3); 13C-NMR,
δ, 190.47 (C Ar O); 179.15 (C S); 162.07 (HNC O);
138.95 (C Ar); 138.48 (C Ar); 136.69 (C Ar); 135.25 (C Ar);
131.54 (C Ar); 130.65 (2C Ar); 130.15 (2C Ar); 128.67
(2C Ar); 128.51 (2C Ar); 110.97 ( C); 20.77 (Ar─CH3).
Mass spectrum (EI, 70 eV), m/z (Irel, %): [M + 2]+ 358 (9);
[M]+ 356 (28); 330 [M─CO + 2]+ (33); 328 [M─CO]+ (100);
189 [M─Cl-C6H4CO─CO]+ (20); 139 [4-ClC6H4─CO]+ (14).
Anal. calcd. for C18H13ClN2O2S (356): C, 60.59; H, 3.67; N,
7.85; found C, 60.29; H, 4.00; N, 7.94.
White crystal, mp 178ꢀC-180ꢀC, (toluene/methanol);
yield (0.75 g, 78%) IR spectrum (KBr); ѵ, cm−1 3186
(NH); 3051 ( CH); 2920 (C─H); 1708; (C O, ketone);
1708; 1681 (br. two C O, imide); 794 (δ2-H), 690 (δ5-H).
1H-NMR spectrum (300 MHz, DMSO-d6) (J, Hz): 11.27
(br.s, 1H, NH); 7.815 (m, 2H, Ar─H); 7.54-7.11 (m, 7H,
Ar─H); 5.23 (br.s, 1H, HA); 3.65-3.54 (m, 3H, HM, HX,
Hfuro); for furo-structure; 3.45 (d, 1H, Hfuro, J = 18.6 Hz).
13C-NMR, δ, 138.69 (C Ar); 135.69 (C Ar); 134.41 (C Ar);
134.19 (C Ar); 129.75 (3C Ar); 129.62 (3C Ar); 128.81
(6C Ar); 126.67 (C Ar); 125.87 (3C Ar); 124.80 (C Ar);
122.30 (3C Ar); for diketo form: 195.72 (C Ar O); 173.38
(C O, imide); 155.05 (C O, imide); 57.12 (C-5); 36.06
(CH2); for enol form: 173.06 (C O, ketone); 155.05
(C O, imide); 86.35 (C-5); 42.06 (CH2). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 328 [M]+ (34);
189 [M─4-ClC6H4CO]+ (86); 149 [M─4-ClC6H4C3H2]+
(100); 118 [C6H4NCHCH2]+ (82); 111 [ClC6H4]+ (826);
77 [Ph]+ (93); for found 328. Anal. calcd. for
C17H13ClN2O3 (328): C, 62.11; H, 3.99; N, 8.52; found C,
61.89; H, 4.02; N, 8.60.
5.4 | Reactions of 2 and 3 with
chromium trioxide: Synthesis of (4a-f,
method A) and 5a-c
In 50 mL of glacial acetic acid containing 1 g of 2a, 2b,
2c, 2d, 2f, 3a, 3b, or 3c, 0.50 g of CrO3 was added, with
stirring, into two portions. The reaction mixture was
heated for an hour on water bath. The mixture was left to
cool, and then added to cold water; the greenish-white
precipitated solid was filtered on water pump, succes-
sively washed with water. The dry solid was crystallized
with charcoal from toluene/methanol to give 4 from
2 and 5 from 3.
5.4.3 | 5-(2-(4-Chlorophenyl)-2-oxoethyl)-
1-(p-tolyl)imidazolidine-2,4-dione (4c)
White crystal, mp 222ꢀC-224ꢀC (toluene/methanol); yield
(0.78 g, 80%), IR spectrum (KBr); ѵ, cm−1 3179 (NH);
3070 ( CH); 2921; 2794 (C─H); 1719 (br. three C O
ketone, two imide); 1588 (C C); 816 (δ2-H). 1H-NMR

12
SAIED ET AL.
spectrum (300 MHz, DMSO-d6); δ, ppm, (J, Hz): 11.18
(br.s, 1H, NH); 7.83 (dd, 2H, Ar─H, J = 7.8, 1.6); 7.23 (dd,
2H, Ar─H, J = 8.4,1.8); 5.18-5.19 (m, 1H, HA); 3.59 (dd,
1H, HM JMX = 18.6, JAM 4.8); 3.49 (dd, 1H, HA, JMX = 18.3,
JAX = 3.6); 2.22 (s, 3H, Ar─CH3); 13C-NMR, δ, 195.25
(C Ar O); 173.40 (HNC O); 154.98 (Ar─NC O); 138.55
(C Ar); 134.40 (C Ar); 134.16 (C Ar); 133.07 (C Ar);
129.75 (2C Ar); 129.27 (2C Ar); 128.77 (2C Ar), 122.57
(2C Ar); 57.28 (C-5); 36.08 (CH2); 20.33 (Ar─CH3).
(Shimadzu QP-2010 Plus) Mass spectrum (EI, 70 eV), m/
z (Irel, %): 342 [M]+ (100); 203 [M─4-ClC6H4CO]+ (98);
139 [4-ClC6H4CO]+ (91); 132 [4-CH3C6H4NCHCH2]+
(95); 111 [4-ClC6H4]+ (78). Anal. calcd. for C18H15ClN2O3
(342): C, 63.07; H, 4.41; N, 8.17; (362) found C, 63.85; H,
4.76; N, 8.27.
(24); 293 [M─Br]+ (29); 222 [M─Br─NH(CO)2]+ (86);
219
[M─HBr─NH(CO)2─H2]+
(65);
149 [M─BrC2H─PhNCO]+ (38); 63 [CH≡C─CH─C≡CH]+
(100); Anal. calcd. for C17H13BrN2O3 (372): C, 54.71; H,
3.51; N, 7.51 found C, 54.46; H, 3.86; N, 7.74.
5.4.6 | (E,Z) 5-(2-oxo-
2-phenylethylidene)-
1-phenylimidazolidine-2,4-dione (5a)
White crystal, mp 191ꢀC-193ꢀC (toluene/methanol);
yield: (0.75 g, 80%) IR spectrum (KBr); ѵ, cm−1 3197,
3136 (NH), 3024 ( CH); 1751 (br. two C O, ketone,
amide); 1651 (C O, amide); 756, 698 (δ5-H). 1H-NMR
spectrum (300 MHz, DMSO-d6); δ, ppm, for E-isomer
67%; 11.92 (s, 1H, NH); 8.0 (d, 2H, Ar─H, J = 8.0 Hz);
7.68 (appt, 2H, Ar─H, J = 8.0); 7.59-7.40 (m, 6H, Ar─H);
6.02 (s, 1H, CH); for Z-isomer 33%; 11.99 (s, 1H, NH);
7.97 (d, 2H, Ar─H, J = 8.0); 7.62 (appt, 2H, Ar─H,
J = 8.0); 7.59-7.40 (m, 6H, Ar─H); 6.66 (s, 1H, CH).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 292 [M]+ (2);
280 [(M + 2)─NH]+ (39); 279 [(M + 1)─NH]+ (31);
105 [PhCO] (42); 77 [Ph] (100). Anal. calcd. for
C17H12N2O3 (292): C, 69.86; H, 4.14; N, 9.58; found C,
69.62; H, 3.97; N, 9.55.
5.4.4 | 5-(2-Oxo-2-phenylethyl)-
1,3-diphenylimidazolidine-2,4-dione (4d)
White crystal, mp 136ꢀC-138ꢀC (toluene/methanol); yield
(0.75 g, 80%). IR spectrum (KBr); ѵ, cm−1 3479 (OH);
3225 (NH); 3062 ( CH); 2893 (C─H); 1752 (br. two C O;
ketone, imide); 1676 (C O, imide); 1494; 1425; 1303; 750;
1
688 (δ5-H). H-NMR spectrum (300 MHz, DMSO-d6); δ,
ppm, (J, Hz): 8.13 (s, 1H, OH); 7.91 (dd, 2H, Ar─H,
J = 7.20, 1.2); 7.67-7.24 (m, 13 H, Ar─H); 3.87, 3.50 each
(d, 1H, Hfuro, J = 18.9). 13C-NMR, δ, 196.42 (C Ar O);
182.53 (C O, imide); 171.53 (C O, imide); 135.26
(C Ar); 135.20 (C Ar); 134.08 (C Ar); 133.85 (C Ar);
129.13 (2C Ar); 128.91 (2C Ar); 128.83 (2C Ar); 128.69
(2C Ar); 128.64 (3C Ar); 128.39 (2C Ar); 127.59 (2C Ar);
86.51 (C-5); 43.82 (CH2). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 371 [M + 1]+ (21); 370 [M]+ (14); 345 [(M
5.4.7 | (E,Z) 5-(2-(4-Chlorophenyl)-
2-oxoethylidene)-1-phenylimidazolidine-
2,4-dione (5b)
White crystal, mp 173ꢀC-175ꢀC (toluene/methanol);
yield: (0.78 g, 80%) IR spectrum (KBr); ѵ, cm−1 3170
(NH), 3055 ( CH); 1774 (C O, ketone); 1732 (br. two
+ 1)─CH≡CH]+
(75);
331
[M─C3H3]+
(49);
292 [M─C6H5─H]+ (21); 175 [(M + 1)─Ph─PhNCO]+
(100); 119 [PhNCO]+ (35); 117 [PhNCO─H2]+ (59). Anal.
calcd. for C23H18N2O3 (370): C, 74.58; H, 4.90; N, 7.56
found C, 74.26; H, 4.86; N, 7.50.
1
C O, amide); 1643; 1593; 1492; 757; 692 (δ5-H). H-NMR
spectrum (300 MHz, DMSO-d6); δ, ppm, (J, Hz): 7.96-7.92
(m, 2H, Ar─H); 7.64-7.45 (m, 5H, Ar─H); 7.20-7.07 (m,
2H, Ar─H); for E-isomer 11.52 (s, 1H, NH); 5.96 (s, 1H,
CH) 55%; for Z-isomer 13.17 (s, 1H, NH); 6.58 (s, 1H,
CH) 45%. 13C-NMR, δ, 131.08 (C Ar); 130.62 (C Ar);
130.08 (C Ar); 129.62 (C Ar); 128.67 (C Ar); 128.63
(C Ar); 128.54 (C Ar); 127.74 (C Ar); 127.01 (C Ar); for E-
isomer 60%: 190.93 (Ar─C O); 166.40 (HNC O); 161.84
(N C─OH); 153.20 (Ar─NC O); 138.26 (C Ar); 136.92
(C Ar); 136.18 (C Ar); 135.61 (C Ar); 132.64 (C Ar);
108.14 (C C-5); for Z-isomer 40%: 188.64 (Ar─C O);
163.86 (HN─C O), 154.23 (Ar─NC O); 138.19 (C Ar);
137.74 (C Ar); 135.56 (C Ar); 134.38 (C Ar); 128.35
(C Ar); 102.65 (C C-5). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 326 [M]+ (100); 324 [M─H2]+ (28);
5.4.5 | 5-(2-(4-Bromophenyl)-2-oxoethyl)-
1-phenylimidazolidine-2,4-dione (4f)
White crystal, mp 217ꢀC-219ꢀC (toluene/methanol); yield
(40%, 0.34 g); IR spectrum (KBr); ѵ, cm−1 3427 (OH);
3187 (NH); 3069 ( CH), 2927 (C─H); 1724 (br. two C O,
ketone, imide); 1683 (C O, imide); 1494, 804 (δ2-H);
1
691 (δ5-H). H-NMR spectrum (300 MHz, DMSO-d6); δ,
ppm, (J, Hz): 12.19 (br.s, 1H, NH, 40%); 11.23 (br.s, 1H,
NH, 60%), 7.76-7.64 (m, 4H, Ar-H); 7.39-7.12 (m, 5H,
Ar─H); 5.26-523 (m, 1H, HA), 3.65-3.65 (m, 2H, HM, HA).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 296 [M─Ph]+
283
[M─HNCO]+
(19);
298
[M─CO]+
(20);

SAIED ET AL.
13
275 [M─HN─HCl]+ (19); 255 [M─HNCO─CO]+ (16);
111 [4-ClC6H4]+ (9); 77 [Ph]+ (18). Anal. calcd. for
C17H11ClN2O3 (326) C, 62.49; H, 3.39; N, 8.57 found C,
62.53; H, 3.37; N, 8.77.
5.5 | Reactions of 2a, 2b and 3a-c with
ethyl bromoacetate (4a, b, method B)
A hot ethanolic solution (40 mL) containing 0.20 g of potas-
sium hydroxide was added to a stirred suspension of (1 g,
3 mmol) of 2a, b, 3a, 3b, or 3c in ethanol (10 mL per drops
of H2O). The whole mixture was wormed till the starting
compounds were solvated, then (0.5 g, 3 mmol) of ethyl
bromoacetate acetate was added. The reaction mixture was
refluxed for 30 minutes, left to cool at room temperature,
and then decanted onto crushed ice (approximately 30 g)
containing 2 mL of concentrated hydrochloric acid. The
pale yellow solids precipitated from 3a-c were filtered off,
dried, and crystalized from ethanol to give 6a-c. The acidi-
fied reaction mixture of 2 was extracted twice with 50 mL
of ethyl acetate; the two organic layers were added together,
washed, separated, and dried (anhydrous CaCl2) and fil-
tered. The filtrate was left to slow evaporation over night;
the organic residue was triturated with 10 mL of methanol
and left in the refrigerator overnight. The solid products
were filtered off, dried to give 4a and 4b. After slow evapo-
ration, the filtrate gave unknown viscous oil with unpleas-
ant dour (under investigation).
5.4.8 | (E,Z) 5-(2-(4-Chlorophenyl)-
2-oxoethylidene)-1-(p-tolyl)-imidazolidine-
2,4-dione (5c)
White crystal, mp 169ꢀC-171ꢀC (toluene/methanol);
yield: (0.75 g, 80%). IR spectrum (KBr); ѵ, cm−1 3228
(NH); 3086 ( CH); 1735 (C O, ketone); 1662 (br. two
1
C O, amide); 1516; 1400; 825; 655 (δ5-H). H-NMR spec-
trum (300 MHz, DMSO-d6); δ, ppm, (J, Hz): 11.77 (s, 1H,
NH); 7.94, 7.46 each (d, 2H, Ar─H, J = 8.4 Hz); 7.46, 6.95
each (d, 2H, Ar─H, J = 5.4 Hz); for E-isomer: 5.91 (s, 1H,
CH) 53%; for Z-isomer: 6.53 (s, 1H, CH) 47%. Mass
spectrum (EI, 70 eV), m/z (Irel, %): 342 [M + 2]+ (5);
310 [M─H2─CO]+ (100); 269 [M─NHCO─CO]+ (11);
255 [(M + 2)─CH2:CHClCH2 CH]+ (18); 236 [M─CH2:
CHCl-NHCO]+ (17); 111 [M─H2─CO]+ (10). Anal. calcd.
for C18H13ClN2O3 (340): C, 63.45; H, 3.85; N, 8.22;
found C, 63.68; H, 3.80; N, 8.34.
5.5.1 | Imidazolidine-2,4-dione (4a)
Yield (50%, 0.4 g); mp, T.L.C., and IR are identical with
5.4.9 | (E,Z) 5-(2-(4-Bromophenyl)-
2-oxoethylidene)-1-phenylimidazolidine-
2,4-dione (5f)
4a previously prepared.
5.5.2 | Imidazolidine-2,4-dione (4b)
White crystal, mp 173ꢀC-175ꢀC (toluene/methanol);
yield: (0.78 g, 80%). IR spectrum (KBr); ѵ, cm−1 3165
(NH); 1750 (br. two C O, ketone, amide); 1649
Yield (45%, 0.35 g); mp, T.L.C. and IR are identical with
4b, previously prepared. 1H-NMR spectrum (400 MHz,
DMSO-d6); δ, ppm, (J, Hz): 11.30 (s, 1H, NH); 7.82, 7.50
each (d, 2H, Ar─H, J = 8.8); 7.40 (d, 2H, Ar─H, J = 8.4)
(m, 1H, HA); 7.33 (appt, 2H, Ar─H, J = 8.40); 7.11 (appt,
1H, Ar─H, J = 8.4); 5.26-5.24 (m, 1H, HA), 3.66 (dd, 1H,
HM, JMX = 18.8, JAM = 4.8); 3.54 (dd, 1H, HX, JMX = 18.8,
JAX = 3.6). 13C-NMR, δ, 195.72 (C Ar─C O); 173.91,
155.57 (C O, imide); 139.13 (C Ar); 136.21 (C Ar); 134.86
(C Ar); 130.24 (2C Ar); 129.37 (2C Ar); 129.28 (2C Ar);
125.31 (C Ar); 122.77 (2C Ar); 57.60 (C-5); 36.45 (CH2).
1
(br. C O, amide); 1643; 1593; 1435; 757; 692 (δ5-H). H-
NMR spectrum (300 MHz, DMSO-d6); δ, ppm, (J, Hz):
7.89; 7.68 each (dd, 2H, Ar─H, J = 8.7, 1.8 Hz); 7.70, 7.07
(m, 5H, Ar─H); for E-isomer: 12.78 (s, 1H, NH); 5.89 (s,
1H, CH) 68%; for Z-isomer: 13.0 (s, 1H, NH); 6.55 (s,
1H, CH) 32%. 13C-NMR, δ, for E-isomer: 191.28, 179.63,
162.64 (C O); 137.17 (C Ar); 136.07 (C Ar); 134.68
(C Ar); 132.16 (2C Ar); 131.31 (2C Ar); 130.20 (2C Ar);
129.36 (2C Ar); for Z-isomer: 189.78, 181.09, 164.56
(C O); 136.16 (C Ar); 136.13 (C Ar); 135.85 (C Ar);
132.02 (2C Ar); 130.83 (2C Ar); 129.89 (2C Ar); 129.15
(C Ar); Mass spectrum (EI, 70 eV), m/z (Irel, %):
5.5.3 | Ethyl (E,Z)-2-((4-oxo-5-(2-oxo-
2-phenylethylidene)-1-phenyl-4,5-dihydro-
1H-imidazol-2-yl)thio)acetate (6a)
370
[M]+
(12);
325
[M─HNCO─H2]+
(42);
324 [M─H─HNCO─H2]+ (100); 187 [M─p-BrC6H5CO]+
(48); 179 [p-BrC6H5C≡C]+ (74); 149 [M─BrC2H─
PhNCO]+ (38); Anal. calcd. for C17H11BrN2O3
(370): C, 55.01; H, 2.99; N, 7.55; found C, 55.16; H,
3.06; N, 7.44.
Pale yellow crystals, mp 156ꢀC-157ꢀC (ethanol); yield
(1.1 g, 85%). IR spectrum (KBr); ѵ, cm−1 3035 ( CH);
2972 (C─H); 1738 (br, two C O, ester, ketone); 1662

14
SAIED ET AL.
1
(C O, amide); 1590 (C C); 678 (δ5-H). H-NMR spec-
trum (300 MHz, DMSO-d6); δ, ppm, (J, Hz): 7.94 (dd, 2H,
ArH, J = 8.4, 1.2 Hz); 7.67-7.51 (m, 6H, Ar─H); 7.54
(appt.t, 2H, Ar─H, J = 7.8 Hz); 4.16-4.2 (m, 4H, OCH2, S-
CH2); 1.19 (t, 3H, CH3, J = 7.2 Hz); for Z-isomer: 6.84 (s,
1H, CH, 12%); for E-isomer: 6.32 (s, 1H, CH, 88%).
13C-NMR, δ, 192.01 (C O, ketone); 181.35 (C O, amide);
172.27 (C O, ester); 167.29 (C N); 138.18 (C-5); 133.64
(C Ar); 132.86 (C Ar); 130.30 (C Ar); 129.24 (C Ar); 128.72
(C Ar); 128.60 (C Ar); 128.11 (C Ar); 114.51 ( C); 61.51
(OCH2); 33.775 (SCH2); 13.889 (CH3); for Z-isomer 136.20
(C-5); 128.30 (C Ar); 127.46 (C Ar). Mass spectrum (EI,
70 eV), m/z (Irel, %): 394 [M]+ (17); 362 [M─S]+ (64);
308 [(M + 1)─CH2COOEt]+ (44); 144 [N≡CSCH2COOEt]+
(68); 105 [PhCO]+ (100); 77 [Ph]+ (93). Anal. calcd. for
C21H18N2O4S (394): C, 63.95; H, 4.60; N, 7.10 (394):
found C, 64.05; H, 4.66; N, 7.32.
( CH); 2981, 2924 (C─H); 1728 (br. two C O, ketone,
ester), 1662 (C O, imide); 1593 (C C); 1485; 821 (δ2-H).
1H-NMR spectrum (300 MHz, DMSO-d6); δ, ppm, (J, Hz):
7.47, 7.60 each (d, 2H, Ar─H, J = 7.2); 7.04 (br.s, 4H,
Ar─H); 4.15-4.13 (m, 4H, OCH2, S─CH2); 1.20 (t, 3H,
CH3, J = 7.2); for Z-isomer; 7.84 (s, 1H, CH, 89%);
for E-isomer 6.32 (s, 1H, CH, 11%). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 442 [M]+ (97);
355 [M─CH2COOEt]+ (26); 340 [M─CH:CS─OEt]+
(44);
269
308
[M─NHCO─CH3C6H4]+
(49);
369;
(100);
[M─SCH2COOEt─CN─CO]+
139 [4-ClC6H4CO]+ (30); 355 [M─CH2COOEt]+ (26);
111 [4-ClC6H4]+ (15); 77 [Ph]+ (20). Anal. calcd. for
C22H19ClN2O4S (442): C, 59.66; H, 4.32; N, 6.32; found C,
59.52; H, 4.14; N, 6.21.
5.6 | Reactions of 2b with aldehyde:
Synthesis of 10a and 11a,b
5.5.4 | Ethyl (E,Z)-
2-((5-(2-(4-chlorophenyl)-2-oxoethylidene)-
4-oxo-1-phenyl-4,5-dihydro-1H-imidazol-
2-yl)thio)acetate (6b)
In 100-mL round-bottomed flask, a mixture of 2b (1.0 g,
10 mmol) and 4-chlorobenzaldehyde (0.40 g, 3 mmol) or
4-methoxybenzaldehyde (0.40 g, 3 mmol) was boiled in
50 mL of toluene plus ammonium acetate (0.5 g) and gla-
cial acetic acid (2 mL), for 3 hours on water bath. Then,
the reaction mixture was poured on 30 mL of water and
extracted twice with 30 mL of toluene. The organic layers
were added together, washed, separated, dried (anhy-
drous CaCl2), and concentrated (2 mL). The residue was
chromatographed with ethyl acetate/light petroleum (v:
v/15:85), monitored by T.L.C., giving 11a followed by
10a, from the reaction of 4-chlorobenzaldehyde and
(5R,6R)/(5S,6S)-11b followed by (5S,6R)/(5R,6S)-11b,
from the reaction of 4-methoxybenzaldehyde.
Pale yellow crystals, mp 195ꢀC-196ꢀC (ethanol); yield
(1.1 g, 87%). IR spectrum (KBr); ѵ, cm−1 3186, 3062
( CH); 2920 (C─H); 1766 (C O, ester); 1708 (C O,
ketone); 1685 (C O, amide); 1593 (C C); 1493;
810 (δ2-H); 678 (δ5-H). 1H-NMR spectrum (300 MHz,
DMSO-d6); δ, ppm, (J, Hz): 7.63, 7.47 each (d, 2H,
Ar─H, J = 8.7 Hz); 7.28-7.21 (m, 5H, Ar─H); 4.15-4.13
(m, 4H, OCH2, S─CH2); (t, 3H, CH3, J = 7.2 Hz); for
Z-isomer, 6.79 (s, 1H, CH, 87%); for E-isomer 6.19 (s,
1H, CH, 13%). 13C-NMR, δ, 189.47 (C O, ketone);
185.01 (C O, amide); 175.01 (C O, ester); 167.71
(C N); 139.09 (C-5); 138.20 (C Ar); 135.59 (C Ar);
135.02 (C Ar); 130.74 (2C Ar); 130.13 (C Ar); 129.80
(2C Ar); 129.24 (2C Ar); 128.04 (2C Ar); 109.73 ( C);
62.08 (OCH2); 34.74 (SCH2);14.44 (CH3). Mass spec-
trum (EI, 70 eV), m/z (Irel, %): 430 [M + 2]+ (7);
428 [M]+ (28); 327 [M─CH3─CH2 CHClCH2 CH]+
(63); 326 [M─CH2:CHCl─NCO] (100); 111 [4-ClC6H4]+
(62); 77 [Ph]+ (52). Anal. calcd. for C21H17ClN2O4S (428): C,
63.95; H, 4.60; N, 7.10; found C, 64.05; H, 4.46; N, 7.33.
5.6.1 | (5S,6R)/(5R,6S)-6,8-bis
(4-chlorophenyl)-1-phenyl-2-thioxo-
1,3,7-triazaspiro[4.4]non-7-en-4-one (10a)
White crystals, mp 194ꢀC-196ꢀC, yield (0.6 g, 90%). IR
spectrum (KBr); ѵ, cm−1 3061 ( CH), 2922, 2855 (C-H);
1752 (C O); 1617 (C N); 1089 (C S); 1381; 823 (δ2-H);
1
687 (δ5-H). H-NMR spectrum (300 MHz, DMSO-d6); δ,
ppm, (J, Hz): 8.15 (br.s, 1H, NH); 7.76 (d, 2H, Ar─H,
J = 8.4 Hz); 7.26-7.77 (m, 11H, Ar─H); 5.75 (s, 1H, H-6);
3.70, 3.04 each (d, 1H, Haliph.). 13C-NMR, δ, 181.85
(C O); 173.40 (C S); 170.42 (C N); 136.22 (C Ar);
135.48 (2C Ar); 132.54 (C Ar); 131.39 (C Ar); 130.31
(C Ar); 129.58 (2C Ar); 129.46 (2C Ar); 129.20 (2C Ar);
129.14 (2C Ar); 128.71 (C Ar); 128.27 (C Ar); 128.05
(2C Ar); 79.53 (C-5); 78.36 (C-6); 42.98 (C-9). Mass spec-
trum (EI, 70 eV), m/z (Irel, %): 465 [M]+ (4);
5.5.5 | Ethyl (E,Z)-
2-((5-(2-(4-chlorophenyl)-2-oxoethylidene)-
4-oxo-1-(p-tolyl)-4,5-dihydro-1H-imidazol-
2-yl)thio)acetate (6c)
Pale yellow crystals, mp 135ꢀC-137ꢀC (ethanol); yield
(1.1 g, 87%). IR spectrum (KBr); ѵ, cm−1 3089, 3062

SAIED ET AL.
15
406 [M─NHCS]+ (4); 314 [M─NHCS─C6H6N]+ (100);
287 [M─NHCS─PhNCS]+ (60); 93 [C6H5NH2]+ (64);
77 [Ph]+ (20); 59 [NHCS]+ (5). Anal. calcd. for
C24H17Cl2N3OS (465): C, 61.81; H, 3.67; N, 9.01; found C,
61.68; H, 3.88; N, 8.99.
5.6.4 | (5R,6R)/(5S,6S)-
8-(4-chlorophenyl)-6-(4-methoxyphenyl)-
1-phenyl-2-thioxo-1,3,7-triazaspiro[4.4]non-
8-en-4-one (11b)
White crystals, mp 198ꢀC-200decopm.ꢀC, yield (0.55 g, 88%).
IR spectrum (KBr); ѵ, cm−1 3198 (NH), 3061, 3038 ( CH),
2965 (C─H), 1752 (C O); 1613 (C C); 1066 (C S);
1
5.6.2 | (5R,6R)/(5S,6S)-6,8-bis
828 (δ2-H), 737, 695 (δ5-H). H-NMR spectrum (300 MHz,
(4-chlorophenyl)-1-phenyl-2-thioxo-
1,3,7-triazaspiro[4.4]non-8-en-4-one (11a)
DMSO-d6); δ, ppm, (J, Hz): 12.72 (br.s, 1H, 50% NHCO);
12.08 (br.s, 1H, 50%, N─OH); 11.71, 10.37 each (s, 1H,
50%, NHamine); 7.83-6.97 (m, 15H: 13H, Ar─H + 1H,
CH + 1H, H-6). 13C-NMR, δ, 179.02 (C S); 165.40
(C O); 159.58 (C-8); 139.07 (C Ar); 138.05 (C Ar); 131.00
(C Ar); 130.49 (C Ar); 130.38 (C Ar); 128.69 (C Ar), 128.56
(C Ar); 1126.03; (C Ar), 125.48 (C Ar); 124.02; (C Ar);
123.43 (C Ar); 120.71 (C Ar); 113.66 (C-5); 113.51 (C-9);
108.41 (C-6); 55.29. (OCH3). Mass spectrum (EI, 70 eV),
m/z (Irel, %): 461 [M]+ (9); 402 [M─NHCS]+ (9);
311 [M─NHCS─C6H5N]+ (25); 310 [M─NHCS─C6H6N]+
(100); 93 [C6H5NH2]+ (69); 77 [Ph]+ (14); 59 [NHCS]+
(36). Anal. calcd. for C25H20ClN3O2S (461): C, 65.00; H,
4.36; N, 9.10; found C, 64.72; H, 4.61; N, 9.05.
White crystals, mp 205ꢀC-206decopm.ꢀC, yield (0.6 g, 90%).
IR spectrum (KBr); ѵ, cm−1 3278 (NH); 3096, 3019
( CH); 1668 (C O); 1509; 1085 (C S); 829 (δ2-H);
1
735, 684 (δ5-H). H-NMR spectrum (300 MHz, CDCl3); δ,
ppm, (J, Hz): 8.80 (br.s, 1H, NHamide); 8.66 (s, 1H,
NHamine); 7.84-7.16 (m, 14 H, 13H, Ar─H + 1H, CH);
6.89 (s, 1H, H-6). 13C-NMR, δ, 179.14 (C O); 165.11
(C S); 138.04 (C Ar); 137.62 (C Ar); 133.03 (C Ar); 131.28
(C Ar); 131.22 (C Ar); 131.08 (C Ar); 130.24 (C Ar);
130.10 (C Ar); 128.86 (C Ar); 128.74 (C Ar); 128.55
(C Ar); 128.15 (C Ar); 127.96 (C Ar); 127.55 (C Ar);
126.05, 125.96 (C C); 125.49 (C Ar); 124.07 (3C Ar);
114.03 (C-5); 108.86 (C-6). Mass spectrum (EI, 70 eV), m/
ORCID
z
(Irel, %): 465 [M]+ (1); 406 [M─NHCS]+ (8);
Khaled F. Saied https://orcid.org/0000-0001-7319-2777
Salwa S. Abdelwahab https://orcid.org/0000-0002-
5392-689X
315 [M─NHCS─C6H5N]+ (19); 314 [M─NHCS─C6H6N]+
(56); 93 [C6H5NH2]+ (100); 77 [Ph]+ (18); 59 [NHCS]+
(77). Anal. calcd. for C24H17Cl2N3OS (465): C, 61.81; H,
3.67; N, 9.01 found C, 61.75; H, 3.73; N, 9.15.
Heba E. Hashem https://orcid.org/0000-0002-9324-4404
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16
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How to cite this article: Saied KF,
Abdelwahab SS, Hashem HE, Kandeel KA.
Advancements in synthesis of pharmacologically
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