The highly regioselective synthesis of novel imidazolidin-2-ones via the intramolecular cyclization/electrophilic substitution of urea derivatives and the evaluation of their anticancer activity

Article abstract of DOI:10.3390/molecules26154432

A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regiosele

Full text of DOI:10.3390/molecules26154432

molecules
Article
The Highly Regioselective Synthesis of Novel Imidazolidin-2-
Ones via the Intramolecular Cyclization/Electrophilic
Substitution of Urea Derivatives and the Evaluation of Their
Anticancer Activity
Almir S. Gazizov 1,
*
, Andrey V. Smolobochkin 1 , Elizaveta A. Kuznetsova 1, Dinara S. Abdullaeva 2,
Alexander R. Burilov 1, Michail A. Pudovik 1, Alexandra D. Voloshina 1, Victor V. Syakaev 1, Anna P. Lyubina 1,
Syumbelya K. Amerhanova 1 and Julia K. Voronina 3,4
1
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of
Sciences, Arbuzova Str. 8, 420088 Kazan, Russia; smolobochkin@iopc.ru (A.V.S.); sherlok@live.ru (E.A.K.);
burilov@iopc.ru (A.R.B.); pudovik@iopc.ru (M.A.P.); microbi@iopc.ru (A.D.V.); vvs@iopc.ru (V.V.S.);
anna.l@mail.ru (A.P.L.); s.amerkhanova@mail.ru (S.K.A.)
Chemistry Department, Kazan Federal University, Kremlyovskaya Str. 18, 420008 Kazan, Russia;
dinka0902@mail.ru
N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninsky Ave. 31,
119991 Moscow, Russia; juliavoronina@mail.ru
G.V. Plekhanov Russian University of Economics, Stremyanny Per. 36, 117997 Moscow, Russia
Correspondence: agazizov@iopc.ru
2
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
3
Citation: Gazizov, A.S.;
Smolobochkin, A.V.; Kuznetsova,
E.A.; Abdullaeva, D.S.; Burilov, A.R.;
Pudovik, M.A.; Voloshina, A.D.;
Syakaev, V.V.; Lyubina, A.P.;
Amerhanova, S.K.; et al. The Highly
Regioselective Synthesis of Novel
Imidazolidin-2-Ones via the
Intramolecular Cyclization/
Electrophilic Substitution of Urea
Derivatives and the Evaluation of
Their Anticancer Activity. Molecules
2021, 26, 4432.
4
*
Abstract: A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed
reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed
approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available
starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by
quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained
compounds was tested in vitro.
Keywords: imidazolidine-2-one; regioselectivity; urea; cyclization; anti-tumor activity; anti-cancer
activity; cytotoxicity
https://doi.org/10.3390/
molecules26154432
Academic Editor: Jacek Nycz
1. Introduction
Received: 29 June 2021
Accepted: 20 July 2021
Published: 22 July 2021
Various cyclic ureas are the well-established pivotal functionalities in the drug dis-
covery and medicinal chemistry. Among them, the imidazolidine-2-one scaffold is often
found in bioactive compounds and constitute the key structural part of a plethora of FDA
approved drugs, such as emicerfont, imidapril, azlocillin and others (Figure 1). Moreover,
these compounds may serve as precursors for vicinal diamines, which are valuable build-
ing blocks in organic and medicinal chemistry [1,2]. Taking these into account, it is not
surprising that a lot of effort is devoted to the development of the methods of synthesis of
imidazolidinones [3].
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iations.
The most straightforward approach to cyclic ureas is the carbonylation of variously
substituted diamines. This approach is somewhat controversial due to the abovemen-
tioned utility of imidazolidine-2-ones as 1,2-diamines precursors. However, it is still
Copyright:
© 2021 by the authors.
used in some cases, especially with chiral diamines [4–7]. Novel approaches to these
compounds have been developed in 2019–2020 by various research groups, indicating a
growing area of interest. These include silver-catalyzed cycloaddition of nitrones with
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Attribution (CC BY) license (https://
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4.0/).
methylene isocyanides [
and Rh-catalyzed intramolecular C–H amination of N-oxyurea derivatives [10
catalyzed amidation of vinylethylcarbamates followed by cyclization of intermediate
8], stereoselective diamination of alkenes with 1,3-ditosylurea [
9]
,11]. Pd-
Molecules 2021, 26, 4432. https://doi.org/10.3390/molecules26154432
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4432
2 of 17
allyl ureas should also be mentioned [12]. Finally, the amidoalkylation of indoles by
hydroxyimidazolidin-2-one under the Lewis acid catalysis has also been reported [13].
Figure 1. Some known drugs possessing imidazolidin-2-one moiety.
Nitrogen-containing aldehydes and acetals are widely used in the heterocycles synthe-
sis [14
based on the in situ generation of a cyclic iminium ion from 4-aminobutanal acetals (4,4-
diethoxybutan-1-amines) and its trapping by various nucleophiles [16 18]. Our preliminary
,15]. Earlier, we have described the approach to 2-substituted pyrrolidine derivatives
–
studies indicate that N-(2,2-dialkoxyethyl) ureas are also capable of the formation of cyclic
imidazolinium cations and the reaction results in cyclic urea derivatives—imidazolidinones
or benzo [d] [1,3] diazepinones [19]. As the continuation of our efforts, herein, we report
the successful application of this methodology to the synthesis of the series of 4-(hetero)
arylimidazolidin-2-ones starting from N-(2,2-dialkoxyethyl) ureas and (hetero) aromatic nu-
cleophiles (Scheme 1). The main advantages of the described method are the mild reaction
conditions, good to high product yield and the high regioselectivity. Notably, N-(2,2-
dialkoxyethyl) ureas are easily accessible from commercially available 2,2-dimethoxyethan-
1-amine and amines or isocyanates in just one step, which also adds value to the proposed
approach. Some considerations on the regioselectivity of the reaction are discussed based
on quantum chemistry calculations, as well as evaluation of the in vitro anti-cancer activi-
ties of the obtained compounds.
Scheme 1. The proposed synthetic approach to 4-(hetero) arylimidazolidine-2-ones.
2. Results and Discussion
2.1. Chemistry
We initiated our studies with the expanding the scope of the starting N-(2,2-dialkoxyethyl)
ureas
1
(Scheme 2). Di- and trisubstituted ureas possessing various aryl (1a–f) and aryl/alkyl
(1g–m) groups were easily obtained from appropriate isocyanates by known procedures [20].
Scheme 2. The synthesis of starting N-(2,2-dialkoxyethyl)ureas 1.

Molecules 2021, 26, 4432
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Next, we investigated the reaction of the ureas 1a
–
m
with various electron-rich aro-
matic and heterocyclic C-nucleophiles (Scheme 3). In all cases, the reaction provided the
desired imidazolidinones in good to high yield. The previously reported conditions were
2
employed, i.e., refluxing toluene and a triflouroacetic acid (TFA) as catalysts [19]. Notably,
the 15-fold excess of catalyst was used in these preliminary experiments. However, the
further screening of reaction conditions allowed us to decrease the amount of catalyst
significantly without a loss of yield. Moreover, during our preliminary studies, we found
that this reaction leads to the mixture of 4- and 5-substituted imidazolidin-2-ones, with
4-substituted regioisomer
the improved regioselectivity, so that only 4-substituted imidazolinones
2
being the major one. Decreasing the amount of TFA led to
were observed
2
in the reaction mixture. The isolated yields of target compounds varied somewhat. In
general, ureas possessing unsubstituted nitrogen atom tend to provide higher yields of
imidazolidinones 2. However, no correlation was observed between the yields and the
substituents in the aryl moiety of the starting ureas.
5
Nu
4
O
TFA (1 equiv.), PhMe, reflux, 64 h
R2 N
R2
OMe
R1 OMe
3
+
Nu H
O
2
1
N
N
N
R1
2-8
H
O
O
OH
Ar = Ph (g), 91%
4-Cl-C6H4 (h), 24%
4-Me-C6H4 (j), 32%
4-MeO-C6H4 (k), 49%
3-Me-C6H4 (l), 50%
3-Cl-C6H4 (m), 77%
O
O
Cl
Ar = Ph (a), 86%
4-Cl-C6H4 (b), 89%
4-Me-C6H4 (c), 78%
4-MeO-C6H4 (d), 72%
3-Me-C6H4 (e), 53%
3-Cl-C6H4 (f), 48%
HO
HO
HO
NH
N Me
NH
N
N
Ar
O
Ar
N
2a-f
O
O
2g-m
Ar
O
3a,d,e
Ph
Ph
Ar = Ph (a), 49%
4-MeO-C6H4 (d), 36%
3-Me-C6H4 (e), 51%
Me
Me
Me Ar = Ph (g), 60%
4-Cl-C6H4 (h), 43%
N
N
N
N
Ar = Ph (a), 44%
O
4-Cl-C6H4 (b), 64%
4-Me-C6H4 (c), 47%
4-MeO-C6H4 (d), 50%
3-Me-C6H4 (e), 57%
4-Me-C6H4 (j), 24%
4-MeO-C6H4 (k), 31%
3-Me-C6H4 (l), 26%
Me
O
Me
N
NH
HO
N
N
Ar
Ar
O
O
O 4g-l
4a-e
Me
O
Ar
N
NH
O
O
O
O
7b,c,f
Ar = Ph (a),41%
O
O
Me
OH
4-Cl-C6H4 (b), 66%
4-Me-C H4 (c), 86%
Ar = 4-Cl-C6H4 (b), 86%
4-Me-C6H4 (c), 60%
3-Cl-C6H4 (f), 83%
OH
6
OH
HN
O
NH
HO
N
4-MeO-C6H4 (d), 84%
3-Cl-C6H4 (f), 53%
NH
N
N
Ar
Ar
6a,h,j
O
O
Ar = Ph (a), 91%
5d',
8% by 1H NMR
5a-d,f
4-Cl-C6H4 (h), 58%
OMe
Me
4-Me-C H4 (j), 68%
6
OH
89%, dr = ~ 1 : 1 (1H NMR data)
16% isolated yield of single diastereomer
Ph
Ph
N
O
N
O
NH
HN
8
Scheme 3. The synthesis of imidazolidine-2-ones 2. The isolated yields are given, unless noted otherwise.
The chemical shifts of methyne and methylene protons for 4- and 5-substituted
imidazolidin-2-ones differ notably [19] (see Supplementary Materials, Figure S2). Thus,
the substitution site of the imidazolidinone ring for the N-methyl substituted compounds
2h–m
and 4h
–
l
was determined by the comparison of their NMR spectra with the spectra
of previously described 4-substituted imidazolidin-2-ones, 2g and 4g
[
19] (for example,
see Supplementary Materials, Figures S3 and S4). Additionally, the structures of the
compounds 2j and 2k were confirmed by X-ray analysis (Figure 2; for details, see Supple-
mentary Materials, pp. S2–S3 and Figure S1).

Molecules 2021, 26, 4432
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Figure 2. Molecular structure of the compounds 2j
(
A
) and 2k
(
B). Ellipsoids are given with a 50%
probability.
In order to determine the substitution pattern on imidazolidine-2-one ring correctly for
other compounds, a complete structure elucidation of the compound 2c was accomplished
by a variety of 1D/2D NMR correlation experiments (1H-1H COSY, NOESY, 1H-13C HSQC,
1
1H-13C HMBC, H-15N HMBC). First, the signals of protons and carbon atoms were
assigned used the set of 2D homo- and heteronuclear correlation experiments. Then,
the 1D NOESY experiment was carried out. Selective excitation of ortho-protons (Ha) of
aryl fragment provided NOE between these protons and Hb, H’b protons of the methylene
group (Hb 2.0%, H’b 2.1%), which indicates the 4-substitution of imidazolidin-2-one ring
(Figure 3).
Figure 3.
(A) 1D NOESY spectrum of compound 2c (irradiation of ortho-aromatic protons resonance)
(500 MHz, (CD3)2SO, 303 K); (B) 1H NMR spectrum of compound 2c (400 MHz, (CD3)2SO, 303 K).

Molecules 2021, 26, 4432
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Interestingly, the reaction of the urea 1d with 4-hydroxy-6-methylpyran-2-one resulted
in the mixture of regioisomeric 4-(2-oxopyran-3-yl)- and 4-(2-oxopyran-5-yl)imidazolidinones
5d and 5d0 (~10:1 molar ratio according to NMR data). The structure of regioisomers was
unequivocally determined by 1H-13C HMBC experiments (Figure 4). Thus, in compound
5d, a cross-peak is observed between the protons of the methyl group of the pyran-2-one
fragment and 50-C carbon atom, which is bonded to hydrogen. At the same time, in the
compound 5d0, the cross-peak between the protons of the same methyl group and the
substituted 50-C carbon atom is present (see Supplementary Materials, Figure S98, for the
HMBC spectrum). Additionally, there are cross-peaks between the 50-C carbon atom and
protons of the methyne (4-CH) and methylene (5-CH2) groups of the imidazolidin-2-one ring.
1
Figure 4. Structure determination of the compounds 5d and 5d0. Key cross-peaks in the H-13
C
HMBC spectra are indicated by arrows.
The reaction of urea 1a with 2-methylesorcinol possessing two reactive sites resulted
in the disubstituted imidazolinone . The compound was obtained as the mixture of the
8
8
(R,S)- and (S,S)-, (R,R)-diastereomers (dr = 1:1 according to NMR data), from which one
diastereomer was isolated in the individual form in 16% yield. Unfortunately, we were not
able to obtain the crystals suitable for the X-ray analysis; thus, the absolute configuration
of the isolated compound could not be determined.
2.2. Mechanism Discussion and Quantum Chemistry Calculations
The proposed mechanism of the formation of imidazolidine-2-ones from ureas
1 is
depicted in Scheme 4 using phenol as the model nucleophile. The first stage of the reaction
is the formation of the oxonium cation and its subsequent intramolecular cyclization to
give 5-methoxyimidazolidine-2-one
molecule furnishes iminium cation
A
. The acid-promoted elimination of the methanol
B. This intermediate may further undergo two con-
current reactions. The first one is the interaction with phenol molecule, which results in
the intermediate via transition state TS2. Further deprotonation of this intermediate
results in the 5-substituted imidazolidine-2-one. Alternatively, iminium cation may
undergo deprotonation-protonation steps to give isomeric cation via imidazoline-2-one
. The subsequent reaction of cation with phenol results in the intermediate via
F
B
D
C
D
G
transition state TS3. Finally, deprotonation of this intermediate furnishes 4-substituted
imidazolidine-2-ones 2.
Quantum chemistry calculations were performed for iminium ions
for O-protonated ion to justify the regioselectivity of the reaction. The relative energies of
the intermediates are given in Scheme 4. The oxonium ion appeared to be the most stable,
which is in accordance with the preferred protonation of the ureas at the oxygen atom [21].
The energy of the iminium ion is 7.3 kcal/mol higher compared to cation . Surprisingly,
the isomeric iminium ion B appeared to be somewhat lower in energy (6.8 kcal/mol).
Next, energies of the intermediates and , as well as energies of the appropriate
B and D, as well as
E
E
D
E
F
G
transition states TS2 and TS3, were calculated. ortho-Substitution of the phenol was mod-
elled to reflect the presence of the hydroxy group next to the reactive center in the most
of the used nucleophiles. Again, the relative energy of the intermediate
F was lower than
that of the intermediate . At the same time, the relative energy of the transition state
G
TS3 appeared to be lower than the energy of transition state TS2 by circa 5 kcal/mol. Ac-
cording to the Curtin–Hammett principle [22], the product distribution for the two rapidly
interconverting intermediates depends both on their relative energies and energies of the

Molecules 2021, 26, 4432
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respective transition states. Thus, the observed regioselective formation of 4-substituted
imidazolidine-2-ones may be attributed to its lower activation energy.
Scheme 4. Plausible mechanism for the formation of regioisomeric imidazolidin-2-ones and relative
energies of the intermediates (kcal/mol), as obtained from quantum chemistry calculations (B3LYP/6-
311++G(d,p), Gaussian16).
2.3. Biological Studies
Some of the resulting compounds were tested for cytotoxicity against normal and
cancer human cell lines at concentrations of 1–100 µM. As seen from the Table 1, most of
the obtained compounds exhibited little to no cytotoxicity against both normal and cancer
cells. Compounds 2h and 2k appeared to be the most active. The selectivity index (SI) was
calculated for them as the ratio between the IC50 value for normal cells and the IC50 value
for cancer cells. The cytotoxicity of the compound 2h against the HuTu 80 cancer cell line
was almost two-fold higher than the cytoxicity against normal cells (SI = 1.7). This is better
than the selectivity of the reference compound Arglabin (SI = 1.2). Notably, the replacement
of the methyl substituent at the nitrogen atom by hydrogen lowers the cytotoxicity against
cancer cells, whereas the cytotoxicity against normal cells tends to remain the same or even
increases (compare, e.g., 2h and 2b, 2k and 2d and 2j and 2c). Thus, it appears to be one of
the key factors influencing the activity of the compounds under study.

Molecules 2021, 26, 4432
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Table 1. Cytotoxic effects of imidazodin-2-ones 2 on the cancer and normal human cell lines 1.
Cancer Cell Lines Normal Cell Line
Test Compounds
M-HeLa
IC50 (µM)
HuTu 80
IC50 (µM)
56b ± 5
>100
56.8 ± 4.5
>100
Chang Liver
IC50 (µM)
98.7 ± 8.8
>100
SI
1
SI
1.7
–
2h
93.6 ± 8.2
>100
2j
–
2k
59.5 ± 4.8
96.3 ± 8.2
>100
1.1
–
1.1
–
63.2 ± 5.6
>100
2l
2a
–
>100
–
95.6 ± 8.2
87.7 ± 7.2
58.4 ± 4.7
>100
2b
>100
–
>100
–
2c
>100
–
>100
–
2d
>100
–
>100
–
2e
>100
–
>100
–
>100
4h
98.7 ± 8.7
90.7 ± 7.8
94.7 ± 8.8
97 ± 8.6
>100
–
>100
–
>100
4j
–
>100
–
>100
4k
–
>100
–
85.8 ± 6.9
>100
4l
–
>100
–
4c
–
>100
–
>100
4d
>100
–
>100
–
>100
5b
>100
–
>100
–
>100
5c
>100
–
>100
–
>100
5d
6j
>100
–
>100
–
>100
>100
–
>100
–
>100
7c
>100
–
>100
–
>100
Tamoxifen
Arglabin
28.0 ± 2.5
41.6 ± 3.2
1.6
0.6
NA
–
46.2 ± 3.5
26.3 ± 2.1
22.7 ± 1.8
1.2
1
Three independent experiments were carried out—means no selectivity; NA means no activity.
3. Materials and Methods
3.1. Chemistry
IR spectra were recorded on a UR-20 spectrometer in a 400–3600 cm−1 range in KBr.
1H NMR spectra were recorded on a Bruker MSL 400 spectrometer (400 MHz) with respect
to the signals of residual protons of deuterated solvent (CDCl3, DMSO-d6). 13C NMR
spectra were recorded on a Bruker Avance 600 (151 MHz) spectrometer relative to signals of
residual protons of deuterated solvent (CDCl3, DMSO-d6). Elemental analysis is performed
on a Carlo Erba device EA 1108. The melting points are determined in glass capillaries on
a Stuart SMP 10 instrument.
The X-ray diffraction data for the crystals of 2j and 2k were collected on a Bruker D8
Venture automatic diffractometer using graphite monochromated radiation. The struc-
tures were solved by direct methods and refined by full-matrix least-squares using the
SHELXL97 [23] program. All the non-hydrogen atoms were refined with anisotropic atomic
displacement parameters. All figures were made using the program OLEX2 [24]. Crys-
tallographic data for the structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Center (2068964–2068965).
Crystal data for 2j: C22H24N4O2, M = 376.45, monoclinic, space group P21/n,
Z = 4, a = 7.3485(4), b = 21.8110(10), c = 12.3569(6)Å,
β
= 104.398(2)◦, V = 1918.34(17)Å3,
$
calc = 1.303 g/cm3 =0.086 mm−1, 15151 reflections collected (
,
µ
±
h,
±
k,
±
l), 3768 inde-

Molecules 2021, 26, 4432
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pendent (Rint 0.0387) and 3013 observed reflections [I
≥
2
\
s (I)], 257 refined parameters,
R1 = 0.0457, wR2 = 0.1049, max. residual electron density is 0.267 (−0.231) eÅ−3
.
Crystal data for 2k: C22H24N4O3, M = 392.45, monoclinic, space group P21/c,
Z = 4, a = 7.5009(5), b = 21.8592(14), c = 12.5236(9)Å,
β
= 107.237(3)◦, V = 1961.2(2)Å3,
h, k, l), 5225 inde-
s (I)], 266 refined parameters,
$
calc = 1.329 g/cm3 =0.091 mm−1, 19745 reflections collected (
,
µ
±
±
±
pendent (Rint 0.0637) and 3528 observed reflections [I
≥ \
2
R1 = 0.0479, wR2 = 0.1170, max. residual electron density is 0.258 (−0.249) eÅ−3
.
General method for the synthesis N-(2,2-dimethoxyethyl)ureas 1
To a solution of 2,2-dimethoxyethan-1-amine or 2,2-dimethoxy-N-methylethan-1-
amine (11.0 mmol) in benzene (10 mL), aryl isocyanate (11.0 mmol) was added dropwise
under cooling (5–8 ◦C). The reaction mixture was stirred for 6 h at room temperature, the
solvent was removed in vacuum (20 mm Hg). The resulting bright fusible solid was dried
in vacuum (1 h, 0.01 mm Hg) to a constant weight.
1-(2,2-Dimethoxyethyl)-3-phenylurea (1a). Yield 93%. The spectral characteristics were in
agreement with the previously published data [25].
1-(4-Chlorophenyl)-3-(2,2-dimethoxyethyl)urea (1b). Yield 95%; 1H-NMR (400 MHz,
CHCl3,
δ ppm) 3.41 (s, 6H, CH3), 3.36-3.45 (m, 2H, CH2), 4.40 (t, 1H, J = 4.7 Hz, CH),
5.68 (br s, 1H, NH), 7.17–7.25 (m, 4H, Ar-H), 7.48 (br s, 1H, NH); 13C-NMR (151 MHz,
CHCl3, δ ppm) 41.87, 54.73, 103.69, 121.24, 128.18, 128.98, 137.52, 156.12.
1-(2,2-Dimethoxyethyl)-3-(p-tolyl)urea (1c). Yield 93%. The spectral characteristics were
in agreement with the previously published data [26].
1
1-(2,2-Dimethoxyethyl)-3-(4-methoxyphenyl)urea (1d). Yield 97%; H-NMR (400 MHz,
CHCl3,
δ ppm) 3.39 (s, 6H, CH3), 3.32–3.44 (m, 2H, CH2), 3.77 (s, 3H, CH3), 4.40 (t, 1H,
J = 5.0 Hz, CH), 5.44 (br s, 1H, NH), 6.82 (d, 2H, J = 9.0 Hz, Ar-H), 7.08 (br s, 1H, NH), 7.19
(d, 2H, J = 9.1 Hz, Ar-H); 13C-NMR (151 MHz, CHCl3,
δ
ppm) 41.90, 54.53, 55.51, 103.56,
114.45, 123.49, 131.47, 156.43, 156.83.
1
1-(2,2-Dimethoxyethyl)-3-(m-tolyl)urea (1e). Yield 86%; H-NMR (400 MHz, CHCl3,
δ
ppm) 2.27 (s, 3H, CH3), 3.40 (s, 6H, CH3), 3.35-3.45 (m, 2H, CH2), 4.42 (t, 1H, J = 5.2 Hz,
CH), 5.82 (br s, 1H, NH), 6.84 (d, 1H, J = 7.2 Hz, Ar-H), 7.07–7.18 (m, 3H, Ar-H), 7.51 (br
s, 1H, NH); 13C-NMR (151 MHz, CHCl3,
124.02, 128.84, 138.83, 138.89, 156.49.
δ ppm) 21.39, 41.84, 54.48, 103.56, 117.37, 120.99,
1-(3-Chlorophenyl)-3-(2,2-dimethoxyethyl)urea (1f). Yield 82%; 1H-NMR (400 MHz, CHCl3,
ppm) 3.42 (s, 6H, CH3), 3.37-3.46 (m, 2H, CH2), 4.41 (t, 1H, J = 4.9 Hz, CH), 5.77 (br s, 1H,
δ
NH), 6.96 (d, 1H, J = 7.4 Hz, Ar-H), 7.10–7.19 (m, 2H, Ar-H), 7.39 (s, 1H, Ar-H), 7.65 (br s, 1H,
NH); 13C-NMR (151 MHz, CHCl3,
134.56, 140.37, 155.98.
δ ppm) 41.86, 54.69, 103.66, 117.59, 119.62, 122.84, 129.92,
1-(2,2-Dimethoxyethyl)-1-methyl-3-phenylurea (1g). Yield 96%. The spectral characteris-
tics were in agreement with the previously published data [27].
3-(4-Chlorophenyl)-1-(2,2-dimethoxyethyl)-1-methylurea (1h). Yield 91%; 1H-NMR (400
MHz, CHCl3,
δ ppm) 3.03 (s, 3H, CH3), 3.43 (d, 2H, J = 5.0 Hz, CH2), 3.51 (s, 6H, CH3), 4.48
(t, 1H, J = 5.0 Hz, CH), 7.20–7.24 (m, 2H, Ar-H), 7.25–7.30 (m, 2H, Ar-H), 7.69 (br s, 1H,
NH); 13C-NMR (151 MHz, CHCl3,
137.83, 155.97.
δ ppm) 35.55, 52.29, 55.04, 103.81, 119.95, 126.72, 128.20,
1-(2,2-Dimethoxyethyl)-1-methyl-3-(p-tolyl)urea (1j). Yield 90%; 1H-NMR (400 MHz,
CHCl3, ppm) 2.29 (s, 3H, CH3), 3.03 (s, 3H, CH3), 3.43 (d, 2H, J = 5.0 Hz, CH2), 3.50 (s,
δ
6H, CH3), 4.48 (t, 1H, J = 5.0 Hz, CH), 7.07 (d, 2H, J = 8.0 Hz, Ar-H), 7.22 (d, 2H, J = 8.2 Hz,
Ar-H), 7.47 (br s, 1H, NH); 13C-NMR (151 MHz, CHCl3,
104.39, 119.55, 129.30, 131.92, 137.07, 156.76.
δ ppm) 20.72, 36.06, 52.75, 55.45,
1-(2,2-Dimethoxyethyl)-3-(4-methoxyphenyl)-1-methylurea (1k). Yield 96%; 1H-NMR
(400 MHz, CHCl3, ppm) 3.00 (s, 3H, CH3), 3.40 (d, 2H, J = 5.0 Hz, CH2), 3.47 (s, 6H, CH3),
δ

Molecules 2021, 26, 4432
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3.75 (s, 3H, CH3), 4.46 (t, 1H, J = 5.0 Hz, CH), 6.80 (d, 2H, J = 9.0 Hz, Ar-H), 7.21 (d, 2H,
J = 8.9 Hz, Ar-H), 7.36 (br s, 1H, NH); 13C-NMR (151 MHz, CHCl3,
δ ppm) 36.05, 52.61,
55.38, 55.51, 104.34, 114.08, 121.53, 132.78, 155.42, 157.00.
1
1-(2,2-Dimethoxyethyl)-1-methyl-3-(m-tolyl)urea (1l). Yield 79%; H-NMR (400 MHz,
CHCl3, ppm) 2.32 (s, 3H, CH3), 3.03 (s, 3H, CH3), 3.43 (d, 2H, J = 4.7 Hz, CH2), 3.50 (s, 6H,
δ
CH3), 4.48 (t, 1H, J = 4.7 Hz, CH), 6.81 (d, 1H, J = 7.4 Hz, Ar-H), 7.02–7.11 (m, 1H, Ar-H),
7.12–7.17 (m, 1H, Ar-H), 7.21 (s, 1H, Ar-H), 7.53 (br s, 1H, NH); 13C-NMR (151 MHz, CHCl3,
δ
ppm) 21.50, 36.05, 52.76, 55.47, 104.37, 116.46, 120.10, 123.30, 128.60, 138.60, 139.58, 156.67.
3-(3-Chlorophenyl)-1-(2,2-dimethoxyethyl)-1-methylurea (1m). Yield 80%; 1H-NMR (400
MHz, CHCl3, ppm) 3.03 (s, 3H, CH3), 3.42 (d, 2H, J = 5.0 Hz, CH2), 3.31 (s, 6H, CH3), 4.48
δ
(t, 1H, J = 4.9 Hz, CH), 6.93–6.98 (m, 1H, Ar-H), 7.14–7.21 (m, 2H, Ar-H), 7.43 (s, 1H, Ar-H),
7.75 (br s, 1H, NH); 13C-NMR (151 MHz, CHCl3,
119.28, 122.36, 129.73, 134.42, 140.99, 156.37.
δ ppm) 36.09, 52.82, 55.59, 104.31, 117.24,
General method for the synthesis of imidazolidin-2-ones 2
To a solution of urea (0.40 g, 1.66 mmol) in toluene (10 mL), the appropriate C-
1
nucleophile (1.66 mmol) and TFA (0.19 g, 1.66 mmol) were added and the mixture was
refluxed for 64 h. Volatiles were removed under vacuum and the residue was washed with
acetone, then recrystallized from absolute ethanol and dried under vacuum (10.1 Torr, r.t.,
3 h) to give imidazolidin-2-ones 2.
4-(6-Hydroxybenz◦o[d][1,3]dioxol-5-yl)-1-phenylimidazolidin-2-one (2a). Beige solid, yield
86%, m.p. 225–226 C; IR (ν
, cm−1): 1598, 1615, 2929, 3113, 3203; 1H-NMR (400 MHz, DMSO-
d6,
δ ppm) 3.48 (dd, 1H, J = 6.3 Hz, J = 9.1 Hz, Ha3), 4.23 (dd, 1H, J = 8.9 Hz, J = 9.1 Hz,
Hb3), 4.96 (dd, 1H, J = 3.6 Hz, J = 8.9 Hz, H4), 5.90 (m, 2H, H9), 6.48 (s, 1H, H11), 6.79 (s,
1H, H7), 6.97 (t, 1H, J = 7.9 Hz, H16), 7.28 (t, 2H, J = 7.9 Hz, H15), 7.36 (s, 1H, NH5), 7.54 (d,
2H, J = 7.9 Hz, H14), 9.44 (s, 1H, OH); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 46.6 (C4),
52.0 (C3), 97.6 (C11), 100.7 (C9), 105.6 (C7), 117.0 (C14), 120.1 (C6), 121.5 (C16), 128.5 (C15),
139.8 (C8), 140.5 (C13), 146.6 (C10), 149.2 (C12), 158.4 (C1); Elemental analysis: calc. for
C16H14N2O4 (298): C, 64.42; H, 4.73; N, 9.39; found C, 64.64; H, 4.89; N, 9.27.
1-(4-Chlorophenyl)-4-(6-hydroxybenzo[d][1,3]dioxol-5-yl)imidazolidin-2-one (2b). Beige
◦
solid, yield 89%, m.p. 252 C; IR (
DMSO-d6, ppm) 3.44-3.51 (m, 1H, Ha3), 4.18–4.26 (m, 1H, Hb3), 4.92–4.98 (m, 1H, H4),
5.89 (m, 2H, H9), 6.48 (s, 1H, H11), 6.78 (s, 1H, H7), 7.32 (d, 2H, J = 9.0 Hz, H15), 7.46 (s,
1H, NH5), 7.58 (d, 2H, J = 9.1 Hz, H16), 9.46 (s, 1H, OH); 13C-NMR (151 MHz, DMSO-d6,
ν
, cm−1): 1599, 1617, 2906, 3143, 3255; 1H-NMR (400 MHz,
δ
δ
ppm) 46.56 (C4), 51.87 (C3), 97.61 (C11), 100.67 (C9), 105.64 (C7), 118.47 (C14), 119.87 (C6),
125.17 (C16), 128.26 (C15), 139.46 (C8), 139.76 (C13), 146.62 (C10), 149.19 (C12), 158.17 (C1);
Elemental analysis: calc. for C16H13ClN2O4 (332.5): C, 57.76; H, 3.94; Cl, 10.65; N, 8.42;
found C, 57.91; H, 4.14; Cl, 10.83; N, 8.59.
4-(6-Hydroxybenz◦o[d][1,3]dioxol-5-yl)-1-(p-tolyl)imidazolidin-2-one (2c). Beige solid, yield
78%, m.p. 257–258 C; IR (ν
, cm−1): 1597, 1627, 2974, 3154, 3275; 1H-NMR (400 MHz, DMSO-
d6, δ ppm) 2.24 (s, 3H, H17), 3.45 (dd, 1H, J = 6.2 Hz, J = 9.0 Hz, Ha3), 4.20 (dd, 1H, J = 8.9
Hz, J = 9.0 Hz, Hb3), 4.95 (dd, 1H, J = 3.7 Hz, J = 8.9 Hz, H4), 5.90 (d, 2H, J = 17.1 Hz, H9),
6.47 (s, 1H, H11), 6.78 (s, 1H, H7), 7.09 (d, 2H, J = 8.4 Hz, H15), 7.29 (br s, 1H, NH5), 7.43 (d,
2H, J = 8.6 Hz, H14), 9.43 (s, 1H, OH); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 20.20 (C17),
46.6 (C4), 52.1 (C3), 97.6 (C11), 100.6 (C9), 105.6 (C7), 117.1 (C15), 120.1 (C6), 128.9 (C14),
130.3 (C16), 138.1 (C13), 139.8 (C8), 146.5 (C10), 149.1 (C12), 158.5 (C1); Elemental analysis:
calc. for C17H16N2O4 (312): C, 65.38; H, 5.16; N, 8.97; found C, 65.47; H, 5.26; N, 9.19.
4-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)imidazolidin-2-one (2d). Beige
solid, yield 72%, m.p. 227–228 ◦C; IR ( , cm−1): 1597, 1618, 3153, 3284; 1H-NMR (400 MHz,
ν
DMSO-d6, δ ppm) 3.39–3.48 (m, 1H, Ha3), 3.71 (s, 3H, H17), 4.14–4.22 (m, 1H, Hb3), 4.90–4.99
(m, 1H, H4), 5.90 (d, 2H, J = 19.8 Hz, H9), 6.48 (s, 1H, H11), 6.79 (s, 1H, H7), 6.86 (d, 2H,
J = 9.1 Hz, H15), 7.21 (br s, 1H, NH5), 7.44 (d, 2H, J = 9.0 Hz, H14), 9.42 (s, 1H, OH18); 13C-

Molecules 2021, 26, 4432
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NMR (151 MHz, DMSO-d6,
δ
ppm) 47.22 (C4), 52.92 (C3), 55.68 (C17), 98.14 (C11), 101.18
(C9), 106.12 (C7), 114.31 (C15), 119.38 (C14), 120.70 (C6), 134.41 (C13), 140.30 (C8), 147.06
(C10), 149.65 (C12), 154.83 (C16), 159.14 (C1); Elemental analysis: calc. for C17H16N2O5
(328): C, 62.19; H, 4.91; N, 8.53; found C, 62.35; H, 5.09; N, 8.75.
4-(6-Hydroxybenzo◦[d][1,3]dioxol-5-yl)-1-(m-tolyl)imidazolidin-2-one (2e). Beige solid,
yield 53%, m.p. 213 C; IR (ν
, cm−1): 1595, 1613, 3153, 3205; 1H-NMR (400 MHz, DMSO-d6,
δ
ppm) 2.27 (s, 3H, H19), 3.42–3.49 (m, 1H, Ha3), 4.18–4.27 (m, 1H, Hb3), 4.91–4.99 (m,
1H, H4), 5.90 (d, 2H, J = 13.7 Hz, H9), 6.48 (s, 1H, H11), 6.78 (s, 1H, H7), 6.80 (br s, 1H,
NH5), 7.11–7.21 (m, 1H, H14), 7.26–7.41 (m, 3H, H16,17,18), 9.44 (s, 1H, OH20); 13C-NMR
(151 MHz, DMSO-d6, δ ppm) 21.75 (C19), 47.10 (C4), 52.61 (C3), 98.13 (C11), 101.15 (C9),
106.04 (C7), 114.79 (C14), 118.16 (C16), 120.68 (C18), 122.76 (C17), 128.81 (C15), 138.15
(C8), 140.28 (C13), 147.07 (C10), 149.63 (C12), 158.91 (C1); Elemental analysis: calc. for
C17H16N2O4 (312): C, 65.38; H, 5.16; N, 8.97; found C, 65.24; H, 5.32; N, 8.86.
1-(3-Chlorophenyl)-4-(6-hydrox◦ybenzo[d][1,3]dioxol-5-yl)imidazolidin-2-one (2f). Beige
1
solid, yield 48%, m.p. 201–202 C; IR (
ν
, cm−1): 1597, 1615, 2943, 3183, 3287; H-NMR
(400 MHz, DMSO-d6,
δ ppm) 3.46–3.56 (m, 1H, Ha3), 4.18–4.29 (m, 1H, Hb3), 4.92–5.02 (m,
1H, H4), 5.90 (d, 2H, J = 15.8 Hz, H9), 6.48 (s, 1H, Ar-H), 6.78 (s, 1H, Ar-H), 6.97–7.04 (m,
1H, Ar-H), 7.26–7.31 (m, 1H, Ar-H), 7.33–7.39 (m, 1H, H11), 7.54 (s, 1H, H7), 7.81 (br s, 1H,
NH5), 9.47 (s, 1H, OH19); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 46.58 (C4), 51.79 (C3),
97.62 (C11), 100.67 (C9), 105.70 (C7), 115.06 (C16), 116.58 (C17), 119.79 (C18), 121.01 (C6),
130.08 (C14), 133.08 (C15), 139.77 (C8), 141.94 (C13), 146.66 (C10), 149.23 (C12), 158.09 (C1);
Elemental analysis: calc. for C16H13ClN2O4 (332.5): C, 57.76; H, 3.94; Cl, 10.65; N, 8.42;
found C, 57.88; H, 4.19; Cl, 10.44; N, 8.42.
1-Phenyl-4-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-methylimidazolidin-2-one (2g). Yield
91%. The spectral characteristics were in agreement with the previously published data [19].
1-(4-Chlorophenyl)-4-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-methylimidazolidin-2-one (2h).
◦
Beige solid, yield 24%, m.p. 218–219 C; IR (
ν
, cm−1): 1596, 1617, 2976, 3181, 3298; 1H-NMR
(400 MHz, DMSO-d6, ppm) 2.60 (s, 3H, H5), 3.46–3.55 (m, 1H, Ha3), 4.08–4.17 (m, 1H,
δ
Hb3), 4.86–4.94 (m, 1H, H4), 5.92 (d, 2H, J = 11.1 Hz, H9), 6.49 (s, 1H, H11), 6.68 (s, 1H, H7),
7.33 (d, 2H, J = 9.0 Hz, H15), 7.61 (d, 2H, J = 9.1 Hz, H14), 9.50 (s, 1H, OH17); 13C-NMR
(151 MHz, DMSO-d6,
δ ppm) 28.93 (C5), 49.43 (C4), 52.40 (C3), 97.82 (C11), 100.81 (C9),
106.34 (C7), 116.52 (C14), 118.29 (C15), 125.18 (C16), 128.32 (C14), 139.57 (C8), 140.17 (C13),
147.15 (C10), 150.33 (C12), 157.06 (C1); Elemental analysis: calc. for C17H15ClN2O4 (346.5):
C, 58.88; H, 4.36; Cl, 10.22; N, 8.08; found C, 59.00; H, 4.45; Cl, 10.34; N, 8.16.
4-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-3-methyl-1-(p-tolyl)imidazolidin-2-one (2j). Beige
◦
solid, yield 32%, m.p. 182–183 C; IR (
ν
, cm−1): 1597, 1618, 2904, 3101, 3189;1H-NMR
(400 MHz, DMSO-d6, ppm) 2.24 (s, 3H, H17), 2.59 (s, 3H, H5), 3.42–3.48 (m, 1H, Ha3),
δ
4.05–4.14 (m, 1H, Hb3), 4.83–4.91 (m, 1H, H4), 5.91 (d, 2H, J = 14.5 Hz, H9), 6.49 (s, 1H,
H11), 6.67 (s, 1H, H7), 7.10 (d, 2H, J = 8.1 Hz, H15), 7.46 (d, 2H, J = 8.5 Hz, H14), 9.45 (s, 1H,
OH18); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 20.75 (C17), 29.62 (C5), 50.20 (C4), 53.01
(C3), 98.37 (C11), 101.33 (C9), 106.64 (C7), 117.35 (C6), 117.54 (C15), 129.48 (C14), 130.94
(C16), 138.73 (C13), 140.73 (C8), 147.59 (C10), 150.79 (C12), 157.96 (C1); Elemental analysis:
calc. for C18H18N2O4 (326): C, 66.25; H, 5.56; N, 8.58; found C, 66.39; H, 5.67; N, 8.47.
4-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-3-methylimidazolidin-2-one
(2k). Beige solid, yield 49%, m.p. 186–187 ◦C; IR ( , cm−1): 1597, 1617, 2978, 3104, 3257;
ν
1H-NMR (400 MHz, DMSO-d6,
δ ppm) 2.59 (s, 3H, H5), 3.43–3.48 (m, 1H, Ha3), 3.71 (s, 3H,
H17), 4.05–4.12 (m, 1H, Hb3), 4.80–4.90 (m, 1H, H4), 5.91 (d, 2H, J = 14.7 Hz, H9), 6.49 (s,
1H, H11), 6.68 (s, 1H, H7), 6.88 (d, 2H, J = 9.0 Hz, H15), 7.47 (d, 2H, J = 8.9 Hz, H14), 9.46 (s,
1H, OH18); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 29.69 (C5), 50.53 (C4), 53.07 (C3), 55.69
(C17), 98.37 (C11), 101.32 (C9), 106.62 (C7), 114.37 (C15), 117.35 (C6), 119.31 (C14), 134.52
(C16), 140.73 (C13), 147.57 (C8), 150.79 (C10), 154.90 (C12), 158.16 (C1); Elemental analysis:
calc. for C18H18N2O5 (342): C, 63.15; H, 5.30; N, 8.18; found C, 63.37; H, 5.41; N, 8.21.

Molecules 2021, 26, 4432
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4-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-3-methyl-1-(m-tolyl)imidazolidin-2-one (2l). Beige
◦
solid, yield 50%, m.p. 180 C; IR (
ν
, cm−1): 1595, 1615, 2893, 3101, 3179; 1H-NMR (400 MHz,
DMSO-d6, ppm) 2.27 (s, 3H, H19), 2.60 (s, 3H, H5), 3.46–3.54 (m, 1H, Ha3), 4.07–4.15 (m,
δ
1H, Hb3), 4.85–4.91 (m, 1H, H4), 5.91 (d, 2H, J = 11.5 Hz, H9), 6.50 (s, 1H, H11), 6.66 (s, 1H,
H7), 6.76–6.82 (m, 1H, Ar-H), 7.13–7.20 (m, 1H, Ar-H), 7.36–7.43 (m, 2H, Ar-H), 9.47 (s, 1H,
OH20); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 21.79 (C19), 29.56 (C5), 50.20 (C3), 52.99
(C4), 98.38 (C11), 101.33 (C9), 106.64 (C7), 114.71 (C14), 117.34 (C6), 118.05 (C18), 122.83
(C16), 128.88 (C17), 138.23 (C15), 140.72 (C13), 141.11 (C8), 147.61 (C10), 150.80 (C12), 157.87
(C1); Elemental analysis: calc. for C18H18N2O4 (326): C, 66.25; H, 5.56; N, 8.58; found C,
66.16; H, 5.70; N, 8.68.
1-(3-Chlorophenyl)-4-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-methylimidazolidin-2-one (2m)
Beige solid, yield 77%, m.p. 210 ◦C; IR ( , cm−1): 1596, 1617, 3134, 3233; 1H-NMR (400 MHz
DMSO-d6, ppm) 2.60 (s, 3H, H5), 3.49–3.57 (m, 1H, Ha3), 4.09–4.18 (m, 1H, Hb3), 4.86–4.94
.
ν
,
δ
(m, 1H, H4), 5.92 (d, 2H, J = 9.4 Hz, H9), 6.49 (s, 1H, H11), 6.70 (s, 1H, H7), 6.98–7.05 (m,
1H, Ar-H), 7.27–7.37 (m, 1H, Ar-H), 7.38–7.46 (m, 1H, Ar-H), 7.79–7.86 (m, 1H, Ar-H), 9.49
(s, 1H, OH19); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 28.83 (C5), 49.35 (C3), 52.43 (C4),
97.82 (C11), 100.81 (C9), 106.45 (C7), 114.93 (C18), 116.37 (C17), 116.42 (C16), 121.02 (C6),
130.11 (C14), 133.14 (C15), 140.16 (C13), 142.04 (C8), 147.18 (C10), 150.37 (C12), 156.92 (C1);
Elemental analysis: calc. for C17H15ClN2O4 (346.5): C, 59.88; H, 4.36; Cl, 10.22; N, 8.08;
found C, 58.99; H, 4.49; Cl, 10.46; N, 8.20.
4-(5-Chloro-2,4-dihydroxyphenyl)-1-phenylimidazolidin-2-one (3a). Beige solid, yield
◦
49%, m.p. 213–214 C; IR (
ν
, cm−1): 1597, 1625, 2902, 3182, 3248, 3348; 1H-NMR (400 MHz,
DMSO-d6, ppm) 3.46–3.54 (m, 1H, Ha3), 4.18–4.26 (m, 1H, Hb3), 4.83–4.92 (m, 1H, H4),
δ
6.56 (s, 1H, H10), 6.97 (t, 1H, J = 7.3 Hz, H17), 7.11 (s, 1H, H7), 7.28 (t, 2H, J = 7.4 Hz, H16),
7.37 (br s, 1H, NH5), 7.54 (d, 2H, J = 7.8 Hz, H15), 9.80 (s, 1H, OH12), 9.94 (s, 1H, OH13);
13C-NMR (151 MHz, DMSO-d6,
δ ppm) 46.32 (C4), 51.78 (C3), 103.70 (C10), 109.32 (C8),
117.00 (C15), 120.62 (C6), 121.48 (C7), 126.60 (C17), 128.47 (C16), 140.48 (C4), 152.71 (C11),
154.02 (C9), 158.29 (C1); Elemental analysis: calc. for C15H13ClN2O3 (304.5): C, 59.12; H,
4.30; Cl, 11.63; N, 9.19; found C, 59.37; H, 4.54; Cl, 11.81; N, 9.37.
4-(5-Chloro-2,4-dihydroxyphenyl)-1-(4-methoxyphenyl)imidazolidin-2-one (3d). Beige
◦
1
solid, yield 36%, m.p. 225–226 C; IR (
ν
, cm−1): 1594, 1626, 3182, 3249, 3345; H-NMR
(400 MHz, DMSO-d6, ppm) 3.42–3.50 (m, 1H, Ha3), 3.47 (s, 3H, H18), 4.15–4.23 (m, 1H,
δ
Hb3), 4.83-4.91 (m, 1H, H4), 6.56 (s, 1H, H10), 6.86 (d, 2H, J = 9.2 Hz, H16), 7.12 (s, 1H, H7),
7.24 (br s, 1H, NH5), 7.44 (d, 2H, J = 9.1 Hz, H15), 9.81 (s, 1H, OH12), 9.95 (s, 1H, OH13);
13C-NMR (151 MHz, DMSO-d6,
δ ppm) 46.40 (C4), 52.21 (C3), 55.12 (C18), 103.69 (C10),
109.34 (C8), 113.77 (C16), 118.82 (C15), 120.70 (C6), 126.58 (C7), 133.83 (C14), 152.67 (C11),
154.00 (C17), 154.29 (C9), 158.52 (C1); Elemental analysis: calc. for C16H15ClN2O4 (334.5):
C, 57.41; H, 4.52; Cl, 10.59; N, 8.37; found C, 57.50; H, 4.61; Cl, 10.78; N, 8.36.
4-(5-Chloro-2,4-dihydroxyphenyl)-1-(m-tolyl)imidazolidin-2-one (3e). Beige solid, yield
◦
51%, m.p. 201–202 C; IR (
ν ,
, cm−1): 1591, 1628, 2932, 3141, 3209, 3323; 1H-NMR (400 MHz
DMSO-d6, ppm) 3.27 (s, 3H, H20), 3.42–3.52 (m, 1H, Ha3), 4.15–4.24 (m, 1H, Ha3), 4.81–
δ
4.92 (m, 1H, H4), 6.56 (s, 1H, H10), 6.76–6.81 (m, 1H, Ar-H), 7.10 (s, 1H, H7), 7.25–7.53 (m,
4H, Ar-H, NH), 9.80 (s, 1H, OH12), 9.94 (s, 1H, OH13); 13C-NMR (151 MHz, DMSO-d6,
δ
ppm) 21.24 (C20), 46.31 (C4), 51.90 (C3), 103.70 (C10), 109.32 (C8), 114.25 (C17), 117.60
(C19), 120.69 (C6), 122.25 (C15), 126.55 (C7), 128.30 (C18), 137.64 (C16), 140.44 (C14), 152.70
(C11), 154.00 (C9), 158.32 (C1); Elemental analysis: calc. for C16H15ClN2O3 (318.5): C, 60.29;
H, 4.74; Cl, 11.12; N, 8.79; found C, 60.56; H, 4.80; Cl, 11.26; N, 8.99.
1,5-Dimethyl-4-(2-oxo-1-phenylimidazolidi◦n-4-yl)-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
(4a). Beige solid, yield 44%, m.p. 199–200 C; IR (ν
, cm−1): 1598, 1613, 2969, 3316, 3379;
1H-NMR (400 MHz, DMSO-d6,
δ ppm) 2.29 (s, 3H, H9), 3.08 (s, 3H, H10), 3.95–4.10 (m, 2H,
H3), 4.70–4.79 (m, 1H, H4), 6.97 (t, 1H, J = 7.3 Hz, H14), 7.13 (br s, 1H, NH5), 7.27–7.35 (m,
5H, Ar-H), 7.48 (t, 2H, J = 7.8 Hz, Ar-H), 7.58 (d, 2H, J = 8.4 Hz, Ar-H); 13C-NMR (151 MHz,

Molecules 2021, 26, 4432
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DMSO-d6,
δ
ppm) 10.63 (C9), 35.36 (C10), 42.61 (C4), 48.74 (C3), 106.39 (C6), 116.85 (C16),
121.29 (C14), 123.50 (C12), 126.12 (C18), 128.45 (C13), 128.94 (C17), 134.99 (C11), 140.61
(C15), 154.84 (C7), 158.10 (C1), 163.78 (C8); Elemental analysis: calc. for C20H20N4O2 (348):
C, 68.95; H, 5.79; N, 16.08; found C, 69.11; H, 5.96; N, 16.22.
4-(1-(4-Chlorophenyl)-2-oxoimidazolidin-4-yl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
◦
pyrazol-3-one (4b). Beige solid, yield 64%, m.p. 203–204 C; IR (
ν
, cm−1): 1597, 1612,
2954, 3101, 3322; 1H-NMR (400 MHz, DMSO-d6,
δ
ppm) 2.28 (s, 3H, H9), 3.07 (s, 3H, H10),
3.92–4.00 (m, 1H, H3), 4.02–4.09 (m, 1H, H3), 4.72–4.79 (m, 1H, H4), 7.24 (br s, 1H, NH5),
7.27–7.38 (m, 5H, Ar-H), 7.46–7.51 (m, 2H, Ar-H), 7.61 (d, 2H, J = 9.0 Hz, Ar-H); 13C-NMR
(151 MHz, DMSO-d6,
δ ppm) 10.59 (C9), 35.35 (C10), 42.51 (C4), 48.62 (C3), 106.22 (C6),
118.26 (C16), 123.51 (C12), 124.96 (C18), 126.14 (C14), 128.25 (C13), 128.94 (C17), 134.95
(C11), 139.56 (C15), 154.80 (C7), 157.87 (C1), 163.72 (C8); Elemental analysis: calc. for
C20H19ClN4O2 (382.5): C, 62.75; H, 5.00; Cl, 9.26; N, 14.63; found C, 62.98; H, 5.21; Cl, 9.29;
N, 14.49.
1,5-Dimethyl-4-(2-oxo-1-(p-tolyl)imidazolidin-4-yl)-2-phenyl-1,2-dihydro-3H-pyrazol-3-
◦
one (4c). Beige solid, yield 47%, m.p. 213–214 C; IR (
ν
, cm−1): 1595, 1615, 3310, 3328;
1H-NMR (400 MHz, DMSO-d6,
δ
ppm) 2.24 (s, 3H, H19), 2.28 (s, 3H, H9), 3.07 (s, 3H, H10),
3.92–3.98 (m, 1H, H3), 3.99–4.05 (m, 1H, H3), 4.69–4.77 (m, 1H, H4), 7.05 (br s, 1H, NH5),
7.10 (d, 2H, J = 8.3 Hz, Ar-H), 7.28–7.34 (m, 3H, Ar-H), 7.44–7.52 (m, 4H, Ar-H); 13C-NMR
(151 MHz, DMSO-d6,
δ ppm) 10.64 (C9), 20.21 (C19), 35.37 (C10), 42.66 (C4), 48.85 (C3),
106.44 (C6), 116.94 (C16), 123.49 (C12), 126.11 (C14), 128.86 (C13), 128.94 (C17), 130.11 (C18),
135.00 (C11), 138.18 (C15), 154.84 (C7), 158.18 (C1), 163.79 (C8); Elemental analysis: calc. for
C21H22N4O2 (362): C, 69.59; H, 6.12; N, 15.46; found C, 69.77; H, 6.27; N, 15.55.
4-(1-(4-Methoxyphenyl)-2-oxoimidazolidin-4-yl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
◦
pyrazol-3-one (4d). Beige solid, yield 50%, m.p. 155 C; IR (
ν
, cm−1): 1598, 1613, 2969, 3316,
3379; 1H-NMR (400 MHz, DMSO-d6,
δ
ppm) 2.29 (s, 3H, H9), 3.07 (s, 3H, H10), 3.72 (s, 3H,
H19), 3.92–4.07 (m, 2H, H3), 4.68–4.76 (m, 1H, H4), 6.88 (d, 2H, J = 9.0 Hz, Ar-H), 6.99 (br s,
1H, NH5), 7.29–7.35 (m, 3H, Ar-H), 7.46–7.51 (m, 4H, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
δ
ppm) 10.65 (C9), 35.37 (C10), 42.73 (C4), 49.18 (C3), 55.15 (C19), 106.48 (C6), 113.76 (C16),
118.65 (C12), 123.49 (C13), 126.10 (C14), 128.94 (C17), 134.00 (C11), 135.01 (C15), 154.17
(C18), 154.85 (C7), 158.32 (C1), 163.81 (C8); Elemental analysis: calc. for C21H22N4O3 (378):
C, 66.65; H, 5.86; N, 14.81; found C, 66.41; H, 5.88; N, 14.87.
1,5-Dimethyl-4-(2-oxo-1-(m-tolyl)imidazolidin-4-yl)◦-2-phenyl-1,2-dihydro-3H-pyrazol-
3-one (4e). Beige solid, yield 57%, m.p. 185–186 C; IR (ν
, cm−1): 1595, 1617, 2969,
3319; 1H-NMR (400 MHz, DMSO-d6, δ ppm) 2.28 (s, 3H,H21), 2.29 (s, 3H, H9), 3.08 (s, 3H,
H10), 3.93–4.09 (m, 2H, H3), 4.69–4.77 (m, 1H, H4), 6.79 (d, 1H, J = 7.5 Hz, Ar-H), 7.10 (br s,
1H, NH), 7.17 (t, 1H, J = 7.8 Hz, Ar-H), 7.29–7.34 (m, 3H, Ar-H), 7.36–7.41 (m, 2H, Ar-H),
7.47–7.50 (m, 2H, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 10.63 (C9), 21.30 (C21),
35.37 (C10), 42.60 (C4), 48.86 (C3), 106.46 (C6), 114.11 (C16), 117.44 (C20), 122.05 (C18),
123.49 (C12), 126.11 (C19), 128.28 (C14), 128.94 (C13), 135.00 (C17), 137.57 (C11), 140.57
(C15), 154.84 (C7), 158.12 (C1), 163.79 (C8); Elemental analysis: calc. for C21H22N4O2 (362):
C, 69.59; H, 6.12; N, 15.46; found C, 69.72; H, 6.26; N, 15.29.
4-(1-phenyl-3-methyl-2-oxoimidazolidin-4-yl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (4g). Yield 60%. The spectral characteristics were in agreement with the
previously published data [19].
4-(1-(4-Chlorophenyl)-3-methyl-2-oxoimidazolidin-4-yl)-1,5-dimethyl-2-phenyl-1,2-dihydro-
3H-pyrazol-3-one (4h). Beige solid, yield 43%, m.p. 245–247 ◦C; IR ( , cm−1): 1595, 1613;
ν
1H-NMR (400 MHz, DMSO-d6,
3.91–4.06 (m, 2H, H3), 4.62–4.70 (m, 1H, H4), 7.30–7.37 (m, 5H, Ar-H), 7.46–7.53 (m, 2H,
Ar-H), 7.59–7.66 (m, 2H, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
ppm) 10.87 (C9), 28.73
δ ppm) 2.31 (s, 3H, H9), 2.62 (s, 3H, H10), 3.13 (s, 3H, H5),
δ
(C5), 35.81 (C10), 46.63 (C3), 48.97 (C4), 102.99 (C6), 118.62 (C16), 124.32 (C12), 125.56 (C18),
126.86 (C14), 128.85 (C13), 129.49 (C17), 135.44 (C11), 140.13 (C15), 156.25 (C7), 157.10 (C1),

Molecules 2021, 26, 4432
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164.26 (C8); Elemental analysis: calc. for C21H21ClN4O2 (396.5): C, 63.55; H, 5.33; Cl, 8.93;
N, 14.12; found C, 63.69; H, 5.20; Cl, 9.06; N, 14.12.
1,5-Dimethyl-4-(3-methyl-2-oxo-1-(p-tolyl)imidazolidin-4-yl)-2-phenyl-1,2-dihydro-3H-
◦
1
pyrazol-3-one (4j). Beige solid, yield 24%, m.p. 248 C; IR (
NMR (400 MHz, DMSO-d6, ppm) 2.24 (s, 3H, H9), 2.30 (s, 3H, H19), 2.60 (s, 3H, H10),
3.12 (s, 3H, H5), 3.90–3.98 (m, 2H, H3), 4.59–4.65 (m, 1H, H4), 7.10 (d, 2H, J = 8.1 Hz, Ar-H),
7.29–7.35 (m, 3H, Ar-H), 7.44–7.51 (m, 4H, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
ppm)
ν
, cm−1): 1592, 1614; H-
δ
δ
10.93 (C9), 20.75 (C19), 28.91 (C5), 35.86 (C10), 46.77 (C3), 49.22 (C4), 103.21 (C6), 117.34
(C12), 124.30 (C16), 126.84 (C14), 129.48 (C13), 129.51 (C17), 130.78 (C18), 135.50 (C11),
138.80 (C15), 156.31 (C7), 157.49 (C1), 164.38 (C8); Elemental analysis: calc. for C22H24N4O2
(376): C, 70.19; H, 6.43; N, 14.88; found C, 70.23; H, 6.49; N, 14.88.
4-(1-(4-Methoxyphenyl)-3-methyl-2-oxoimidazolidin-4-yl)-1,5-dimethyl-2-phenyl-1,2-
◦
dihydro-3H-pyrazol-3-one (4k). Beige solid, yield 31%, m.p. 209–210 C; IR (
ν
, cm−1):
1595, 1613; 1H-NMR (400 MHz, DMSO-d6,
δ
ppm) 2.31 (s, 3H, H9), 2.61 (s, 3H, H10), 3.12
(s, 3H, H5), 3.72 (s, 3H, H19), 3.90–3.99 (m, 2H, H3), 4.56–4.65 (m, 1H, H4), 6.90 (d, 2H,
J = 9.1 Hz, Ar-H), 7.32–7.36 (m, 3H, Ar-H), 7.42–7.52 (m, 4H, Ar-H); 13C-NMR (151 MHz,
DMSO-d6,
δ ppm) 28.95 (C9), 31.13 (C5), 35.82 (C10), 47.06 (C3), 49.29 (C4), 55.66 (C19),
103.18 (C6), 114.35 (C12), 119.04 (C16), 124.29 (C13), 126.82 (C14), 129.49 (C17), 134.58 (C11),
135.45 (C15), 154.76 (C19), 156.25 (C7), 157.65 (C1), 164.37 (C8); Elemental analysis: calc. for
C22H24N4O3 (392): C, 67.33; H, 6.16; N, 14.28; found C, 67.51; H, 6.29; N, 14.40.
1,5-Dimethyl-4-(3-methyl-2-oxo-1-(m-tolyl)imidazolidin-4-yl)-2-phenyl-1,2-dihydro-3H-
◦
pyrazol-3-one (4l). Beige solid, yield 26%, m.p. 215–216 C; IR (
ν
, cm−1): 1592, 1613;
1H-NMR (400 MHz, DMSO-d6,
δ
ppm) 2.28 (s, 3H, H9), 2.30 (s, 3H, H21), 2.61 (s, 3H, H10),
3.12 (s, 3H, H5), 3.91–4.01 (m, 2H, H3), 4.58–4.67 (m, 1H, H4), 6.80 (d, 1H, J = 6.9 Hz, Ar-H),
7.17 (t, 1H, J = 7.5 Hz, Ar-H), 7.30– 7.36 (m, 3H, Ar-H), 7.38–7.43 (m, 2H, Ar-H), 7.48 (t, 2H,
J = 7.4 Hz, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 10.92 (C9), 21.83 (C21), 28.87
(C5), 35.86 (C10), 46.78 (C3), 49.12 (C4), 103.23 (C6), 114.52 (C16), 117.82 (C18), 122.68 (C20),
124.30 (C12), 126.84 (C14), 128.89 (C19), 129.51 (C13), 135.50 (C17), 138.19 (C11), 141.18
(C15), 156.31 (C7), 157.40 (C1), 164.37 (C8); Elemental analysis: calc. for C22H24N4O2 (376):
C, 70.19; H, 6.43; N, 14.88; found C, 70.37; H, 6.61; N, 14.71.
4-(4-Hydroxy-6-methyl-◦2-oxo-2H-pyran-3-yl)-1-phenylimidazolidin-2-one (5a). Beige solid,
yield 41%, m.p. 182–183 C; IR (ν
, cm−1): 1598, 1613, 3145, 3271; 1H-NMR (400 MHz, DMSO-
d6, δ ppm) 2.17 (s, 3H, H11), 3.75–3.82 (m, 1H, Ha3), 3.99–4.07 (m, 1H, Hb3), 4.97–5.05 (m,
1H, H4), 6.01 (s, 1H, H8), 6.92 (br s, 1H, NH5), 6.94 (t, 1H, J = 7.2 Hz, H15), 7.27 (t, 2H,
J = 7.7 Hz, H14), 7.57 (d, 2H, J = 8.4 Hz, H13), 11.75 (s, 1H, OH16); 13C-NMR (151 MHz,
DMSO-d6,
δ ppm) 19.87 (C11), 42.57 (C4), 48.84 (C3), 100.41 (C6), 100.79 (C8), 117.04 (C14),
121.38 (C15), 128.92 (C13), 141.44 (C12), 158.81 (C1), 162.54 (C9), 163.44 (C7), 167.55 (C10);
Elemental analysis: calc. for C15H14N2O4 (286): C, 62.93; H, 4.93; N, 9.79; found C, 63.12;
H, 5.13; N, 9.91.
1-(4-Chlorophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)imidazolidin-2-one (5b)
.
1
Beige solid, yield 66%, m.p. 190–191 ◦C; IR (
ν
, cm−1): 1592, 1613, 3102, 3228; H-NMR
(
400 MHz, DMSO-d6,
Hb3), 4.96–5.05 (m, 1H, H4), 6.02 (s, 1H, H8), 7.05 (br s, 1H, NH5), 7.32 (d, 2H, J = 9.1 Hz,
H14), 7.61 (d, 2H, J = 9.0 Hz, H13), 11.80 (s, 1H, OH16); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 2.18 (s, 3H, H11), 3.77–3.80 (m, 1H, Ha3), 4.00–4.10 (m, 1H,
δ
ppm) 19.84 (C11), 42.46 (C4), 48.80 (C3), 100.38 (C6), 100.69 (C8), 118.45 (C14), 125.03 (C15),
128.70 (C13), 140.36 (C12), 158.59 (C1), 162.57 (C9), 163.39 (C7), 167.55 (C10); Elemental
analysis: calc. for C15H13ClN2O4 (320.5): C, 56.17; H, 4.09; Cl, 11.05; N, 8.73; found C, 55.98;
H, 3.95; Cl, 10.87; N, 8.68.
4-(4-Hydroxy-6-methyl-◦2-oxo-2H-pyran-3-yl)-1-(p-tolyl)imidazolidin-2-one (5c). Beige solid,
yield 86%, m.p. 184–185 C; IR (ν
, cm−1): 1593, 1620, 3132, 3288; 1H-NMR (400 MHz, DMSO-
d6,
δ ppm) 2.17 (s, 3H, H11), 2.24 (s, 3H, H16), 3.74–3.82 (m, 1H, Ha3), 3.96–4.05 (m, 1H,
Hb3), 4.95–5.02 (m, 1H, H4), 6.01 (s, 1H, H8), 6.84 (br s, 1H, NH5), 7.08 (d, 2H, J = 8.4 Hz,

Molecules 2021, 26, 4432
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H14), 7.45 (d, 2H, J = 8.5 Hz, H13), 11.74 (s, 1H, OH17); 13C-NMR (151 MHz, DMSO-d6,
δ
ppm) 19.32 (C11), 20.19 (C16), 42.08 (C4), 48.36 (C3), 99.88 (C6), 100.25 (C8), 116.57 (C14),
128.79 (C13), 129.59 (C15), 138.49 (C12), 158.34 (C1), 161.96 (C9), 162.89 (C7), 167.00 (C10);
Elemental analysis: calc. for C16H16N2O4 (300): C, 63.99; H, 5.37; N, 9.33; found C, 64.09;
H, 5.47; N, 9.49.
4-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-1-(4-methoxyphenyl)imidazolidin-2-one (5d)
Beige solid, yield 84%, m.p. 184–185 ◦C; IR ( , cm−1): 1593, 1614, 3218; 1H-NMR (400 MHz,
DMSO-d6, ppm) 2.17 (s, 3H, H11), 3.71 (s, 3H, H16), 3.76–3.78 (m, 1H, Ha3), 3.96–4.02 (m,
.
ν
δ
1H, Hb3), 4.94–5.00 (m, 1H, H4), 6.01 (s, 1H, H8), 6.78 (br s, 1H, NH5), 6.86 (d, 2H, J = 9.2
Hz, H14), 7.47 (d, 2H, J = 9.1 Hz, H13), 11.74 (s, 1H, OH17); 13C-NMR (151 MHz, DMSO-d6,
δ
ppm) 19.32 (C11), 42.11 (C4), 48.62 (C3), 55.14 (C16), 99.90 (C6), 100.26 (C8), 113.71 (C14),
118.22 (C13), 134.37 (C12), 153.84 (C15), 158.44 (C1), 161.93 (C9), 162.90 (C7), 167.01 (C10);
Elemental analysis: calc. for C16H16N2O5 (316): C, 60.76; H, 5.10; N, 8.86; found C, 60.87;
H, 5.26; N, 8.99.
1-(3-Chlorophenyl)-4-(4-hydro◦xy-6-methyl-2-oxo-2H-pyran-3-yl)imidazolidin-2-one (5f)
.
Beige solid, yield 53%, m.p. 194 C; IR (ν
, cm−1): 1598, 1613, 3125, 3221; 1H-NMR (400 MHz,
DMSO-d6, δ ppm) 2.17 (s, 3H, H11), 3.74–3.80 (m, 1H, Ha3), 4.02–4.10 (m, 1H, Hb3), 4.93–
5.04 (m, 1H, H4), 6.01 (s, 1H, H8), 6.95–7.00 (m, 1H, Ar-H), 7.12 (br s, 1H, NH5), 7.27–7.32
(m, 1H, Ar-H), 7.33–7.37 (m, 1H, Ar-H), 7.86 (s, 1H, H13), 11.79 (s, 1H, OH18); 13C-NMR
(151 MHz, DMSO-d6, δ ppm) 19.34 (H11), 41.92 (H4), 48.27 (H3), 99.86 (H6), 100.18 (H8),
114.55 (H17), 116.00 (H15), 120.37 (H16), 130.05 (H13), 133.06 (H14), 142.27 (H12), 158.00
(H1), 162.08 (H9), 162.89 (H7), 167.05 (H10); Elemental analysis: calc. for C15H13ClN2O4
(320): C, 56.17; H, 4.09; Cl, 11.05; N, 8.73; found C, 56.15; H, 4.14; Cl, 11.05; N, 8.81.
4-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-1-phenylimidazolidin-2-one (6a). Beige solid, yield
91%, m.p. 193–194 ◦C; IR ( , cm−1): 1596, 1614, 3131, 3203; 1H-NMR (400 MHz, DMSO-d6,
ν
δ
ppm) 3.87–3.95 (m, 1H, Ha3), 4.08–4.17 (m, 1H, Hb3), 5.21–5.29 (m, 1H, H4), 6.96 (t, 1H,
J = 7.3 Hz, Ar-H), 7.04 (br s, 1H, NH5), 7.27–7.33 (m, 2H, Ar-H), 7.36–7.42 (m, 2H, Ar-H),
7.61 (d, 2H, J = 7.8 Hz, Ar-H), 7.63–7.67 (m, 1H, Ar-H), 8.04 (dd, 1H, J = 7.8, J = 1.6, Hz,
Ar-H); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 42.77 (C4), 48.47 (C3), 104.51 (C6), 116.10
(C8), 116.29 (C12), 116.53 (C16), 120.97 (C9), 123.51 (C10), 123.92 (C18), 128.43 (C17), 132.51
(C11), 140.80 (C15), 152.32 (C13), 158.34 (C1), 161.03 (C7), 162.09 (C14); Elemental analysis:
calc. for C18H14N2O4 (322): C, 67.08; H, 4.38; N, 8.69; found C, 67.19; H, 4.50; N, 8.75.
1-(4-Chlorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)imidazolidin-2-one (6h). Beige
◦
1
solid, yield 58%, m.p. 199–200 C; IR (
DMSO-d6, ppm) 3.85–3.93 (m, 1H, Ha3), 4.08–4.16 (m, 1H, Hb3), 5.23–5.31 (m, 1H, H4),
7.15 (br s, 1H, NH5), 7.32–7.35 (m, 2H, Ar-H), 7.36–7.42 (m, 2H, Ar-H), 7.62–7.67 (m, 3H,
Ar-H), 8.03 (dd, 1H, J = 8.0, J = 1.5, Hz, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
ppm) 42.67
ν
, cm−1): 1597, 1616, 3284; H-NMR (400 MHz,
δ
δ
(C4), 48.44 (C3), 104.41 (C6), 116.09 (C8), 116.30 (C12), 117.96 (C17), 123.53 (C9), 123.93
(C10), 124.66 (C18), 128.24 (C16), 132.53 (C11), 139.74 (C15), 152.33 (C13), 158.17 (C1), 161.05
(C7), 162.17 (C14); Elemental analysis: calc. for C18H13ClN2O4 (356.5): C, 60.60; H, 3.67; Cl,
9.94; N, 7.85; found C, 60.65; H, 3.64; Cl, 9.91; N, 7.94.
4-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-1-(p-tolyl)imidazolidin-2-one (6j). Beige solid, yield
◦
68%, m.p. 194–196 C; IR (ν δ
, cm−1): 1598, 1612, 3124, 3244; 1H-NMR (400 MHz, DMSO-d6,
ppm) 2.25 (s, 3H, H19), 3.84–3.94 (m, 1H, Ha3), 4.03–4.14 (m, 1H, Hb3), 5.19–5.29 (m, 1H,
H)4, 6.96 (br s, 1H, NH5), 7.10 (d, 2H, J = 8.1 Hz, Ar-H), 7.33–7.42 (m, 2H, Ar-H), 7.49 (d,
2H, J = 8.3 Hz, Ar-H), 7.65 (t, 1H, J = 7.1 Hz, Ar-H), 8.00–8.07 (m, 1H, Ar-H); 13C-NMR
(151 MHz, DMSO-d6, δ ppm) 20.75 (C19), 43.41 (C4), 49.12 (C3), 105.03 (C6), 116.66 (C8),
116.82 (C12), 117.18 (C17), 124.04 (C9), 124.45 (C10), 129.38 (C16), 130.31 (C18), 133.02 (C11),
138.94 (C15), 152.87 (C13), 158.94 (C1), 161.55 (C7), 162.61 (C14); Elemental analysis: calc.
for C19H16N2O4 (336): C, 67.85; H, 4.80; N, 8.33; found C, 68.08; H, 4.96; N, 8.45.
2-(1-(4-Chlorophenyl)-2-oxoimidazolidin-4-yl)-3-hydroxynaphthalene-1,4-dione (7b). Beige
◦
1
solid, yield 86%, m.p. 234–235 C; IR (ν
, cm−1): 1598, 1600, 1613, 3154, 3221; H-NMR

Molecules 2021, 26, 4432
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(400 MHz, DMSO-d6,
δ
ppm) 3.82–3.91 (m, 1H, Ha3), 4.12–4.21 (m, 1H, Hb3), 5.15–5.24 (m,
1H, H4), 7.13 (br s, 1H, NH5), 7.34 (d, 2H, J = 9.0 Hz, H18), 7.63 (d, 2H, J = 9.0 Hz, H17),
7.79–7.88 (m, 2H, Ar-H), 7.98–8.02 (m, 2H, Ar-H); 13C-NMR (151 MHz, DMSO-d6,
δ
ppm)
41.76 (C4), 48.58 (C3), 117.96 (C18), 120.97 (C6), 124.66 (C13), 125.72 (C9), 125.81 (C12),
128.26 (C17), 129.77 (C8), 132.02 (C19), 133.24 (C11), 134.88 (C10), 139.74 (C16), 156.86 (C15),
158.12 (C1), 181.19 (C14), 183.39 (C7); Elemental analysis: calc. for C19H13ClN2O4 (368.5):
C, 61.88; H, 3.55; Cl, 9.61; N, 7.60; found C, 62.09; H, 3.77; Cl, 9.57; N, 7.47.
2-Hydroxy-3-(2-oxo-1-(p◦-tolyl)imidazolidin-4-yl)naphthalene-1,4-dione (7c). Beige solid,
yield 60%, m.p. 223–224 C; IR (ν
, cm−1): 1597, 1600, 1622, 3133, 3287; 1H-NMR (400 MHz,
DMSO-d6, δ ppm) 2.25 (s, 3H, H20), 3.82–3.90 (m, 1H, Ha3), 4.08–4.19 (m, 1H, Hb3), 5.15–
5.23 (m, 1H, H4), 6.94 (br s, 1H, NH5), 7.10 (d, 2H, J = 8.3 Hz, H18), 7.48 (d, 2H, J = 8.6 Hz,
H17), 7.79–7.83 (m, 1H, Ar-H), 7.85–7.90 (m, 1H, Ar-H), 7.97–8.04 (m, 2H, Ar-H); 13C-NMR
(151 MHz, DMSO-d6,
δ ppm) 20.22 (C20), 41.89 (C4), 48.71 (C3), 116.63 (C18), 120.51 (C13),
121.18 (C6), 125.70 (C9), 125.81 (C12), 128.85 (C17), 129.78 (C8), 132.02 (C11), 133.23 (C10),
134.88 (C19), 138.39 (C16), 156.74 (C15), 158.37 (C1), 181.21 (C14), 183.44 (C7); Elemental
analysis: calc. for C20H16N2O4 (348): C, 68.96; H, 4.63; N, 8.04; found C, 69.15; H, 4.73;
N, 8.13.
1-(3-Chlorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)imidazolidin-2-one (7f). Beige
1
solid, yield 83%, m.p. 199 ◦C; IR (
ν
, cm−1): 1594, 1618, 3176, 3293; H-NMR (400 MHz,
DMSO-d6, δ ppm) 3.85–3.95 (m, 1H, Ha3), 4.08–4.19 (m, 1H, Hb3), 5.22–5.30 (m, 1H, H4),
6.98–7.02 (m, 1H, Ar-H), 7.22 (br s, 1H, NH5), 7.29–7.33 (m, 1H, Ar-H), 7.36–7.42 (m, 3H,
Ar-H), 7.62–7.67 (m, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 8.01–8.06 (m, 1H, Ar-H); 13C-NMR
(151 MHz, DMSO-d6, δ ppm) 42.65 (C4), 48.42 (C3), 104.40 (C6), 114.61 (C19), 116.05 (C8),
116.10 (C12), 116.31 (C18), 120.50 (C20), 123.54 (C9), 123.93 (C10), 130.09 (C17), 132.54 (C11),
133.10 (C16), 142.19 (C15), 152.33 (C13), 158.10 (C1), 161.05 (C7), 162.19 (C14); Elemental
analysis: calc. for C18H13ClN2O4 (356.5): C, 60.60; H, 3.67; Cl, 9.94; N, 7.85; found C, 60.78;
H, 3.81; Cl, 10.09; N, 7.86.
4,40-(4,6-Dihydroxy-5-methyl-1,3-phenylene)bis(1-(4-chlorophenyl)imidazolidin-2-one)
(8). Beige solid, yield 16%, m.p. > 250 ◦C; IR ( , cm−1): 1594, 1627, 3089, 3171, 3276; 1H-
ν
NMR (400 MHz, DMSO-d6,
2H, Hb3), 5.00–5.08 (m, 2H, H4), 7.16 (s, 1H, H9), 7.32 (d, 4H, J = 8.9 Hz, H13), 7.52 (br s, 2H,
NH5), 7.59 (d, 4H, J = 8.9 Hz, H12), 7.50 (s, 2H, OH15); 13C-NMR (151 MHz, DMSO-d6,
δ ppm) 2.10 (s, 3H, H10), 3.42–3.51 (m, 2H, Ha3), 4.21–4.30 (m,
δ
ppm) 10.20 (C10), 47.62 (C4), 52.76 (C3), 113.55 (C8), 118.87 (C13), 120.73 (C6), 121.45 (C14),
125.61 (C9), 128.82 (C12), 140.09 (C11), 152.68 (C7), 158.73 (C1); Elemental analysis: calc.
for C25H22Cl2N4O4 (513): C, 58.49; H, 4.32; Cl, 13.81; N, 10.91; found C, 58.78; H, 4.58; Cl,
13.99; N, 11.09.
3.2. Biological Studies
Cytotoxic effects of the test compounds on human cancer and normal cells were
estimated by means of the multifunctional Cytell Cell Imaging system (GE Health Care
Life Science, Sweden) using the Cell Viability Bio App, which precisely counts the number
of cells and evaluates their viability from fluorescence intensity [28]. DAPI and propidium
iodide purchased from Sigma were used to detect cell viability. IC50 was calculated
using an online tool: “Quest Graph™ IC50 Calculator.” AAT Bioquest, Inc, https://www.
aatbio.com/tools/ic50-calculator, accessed on 6 April 2021. The M-HeLa clone 11 human,
epithelioid cervical carcinoma, strain of HeLa, clone of M-HeLa; human duodenal cancer
cell line (HuTu 80) from the Type Culture Collection of the Institute of Cytology (Russian
Academy of Sciences) and Chang liver cell line (Human liver cells) from the N. F. Gamaleya
Research Center of Epidemiology and Microbiology were used in the experiments. The
cells were cultured in a standard Eagle’s nutrient medium manufactured at the Chumakov
Institute of Poliomyelitis and Virus Encephalitis (PanEco company) and supplemented
with 10% fetal calf serum and 1% nonessential amino acids. The cells were plated into
a 96-well plate (Nanc) at a concentration of 1
×
105 cells/mL, 150
µL of medium per

Molecules 2021, 26, 4432
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well, and cultured in a CO2 incubator at 37 ◦C. Twenty-four hours after seeding the cells
into wells, the compound under study was added at a preset dilution, 150 µL to each
well. The dilutions of the compounds were prepared immediately in nutrient media; 5%
DMSO, which does not induce inhibition of cells at this concentration, was added for better
solubility. The experiments were repeated three times. Intact cells cultured in parallel with
experimental cells were used as a control.
3.3. Quantum Chemistry Calculations
All calculations have been performed with the Gaussian 16 package [29]. The initial
structures were fully optimized at the B3LYP/6-311++G(d,p) theory level. All optimizations
were followed by frequency calculations at the same level of theory in order to check that
optimized structures really correspond to true minima.
4. Conclusions
In conclusion, a series of novel 4-(het) arylimidazolidines were obtained via tri-
fluoroacetic acid catalyzed intramolecular cyclization/Mannich-type reaction of N-(2,2-
diethoxyethyl) ureas with high regioselectivities. The plausible mechanism was discussed
using quantum chemistry calculations and the choice of the solvent and catalyst amount
was found to have a crucial effect on the regioselectivity. The anti-cancer activities of the
obtained compounds were tested in vitro, and the substitution of the nitrogen atom was
identified as one the key factors influencing the cytotoxicity against normal and cancer
human cell lines.
Supplementary Materials: The following are available online. Figure S1: Bifurcate CH . . .
O
interaction in the crystals of the studied compounds, Table S1: CH . . . O interactions in crystals of
investigated compounds, Figures S2–S98: copies of the NMR spectra of all synthesized compounds.
Author Contributions: A.S.G., supervision (chemistry), conceptualization, writing and funding
acquisition; A.V.S., E.A.K. and D.S.A., investigation (chemistry); A.R.B. and M.A.P., project admin-
istration; A.D.V., supervision (in vitro anti-cancer studies); V.V.S., NMR studies; A.P.L. and S.K.A.,
investigation (in vitro anti-cancer studies); J.K.V., investigation (X-ray studies and QC calculations).
All authors have read and agreed to the published version of the manuscript.
Funding: The synthetic part of this work, the NMR studies and the biological studies were funded
by the Russian Science Foundation, grant number 21-73-20020. The NMR studies were performed
in the Assigned Spectral-Analytical Center of the FRC Kazan Scientific Center of RAS. The X-ray
studies were supported by the Ministry of Science and Higher Education of Russia as part of the state
assignment of the Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy
of Sciences.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds 2–7 are available from the authors.
References
1.
Saibabu Kotti, S.R.S.; Timmons, C.; Li, G. Vicinal Diamino Functionalities as Privileged Structural Elements in Biologically Active
Compounds and Exploitation of their Synthetic Chemistry. Chem. Biol. Drug Des. 2006, 67, 101–114. [CrossRef] [PubMed]
Lucet, D.; Le Gall, T.; Mioskowski, C. The Chemistry of Vicinal Diamines. Angew. Chemie Int. Ed. 1998, 37, 2580–2627. [CrossRef]
Smolobochkin, A.V.; Gazizov, A.S.; Burilov, A.R.; Pudovik, M.A.; Sinyashin, O.G. Advances in the synthesis of heterocycles with
an endocyclic urea moiety. Russ. Chem. Rev. 2021, 90, 395–417. [CrossRef]
2.
3.
4.
5.
Wen, W.; Luo, M.-J.; Yuan, Y.; Liu, J.-H.; Wu, Z.-L.; Cai, T.; Wu, Z.-W.; Ouyang, Q.; Guo, Q.-X. Diastereodivergent chiral aldehyde
catalysis for asymmetric 1,6-conjugated addition and Mannich reactions. Nat. Commun. 2020, 11, 5372. [CrossRef] [PubMed]
Zhou, M.; Li, K.; Chen, D.; Xu, R.; Xu, G.; Tang, W. Enantioselective Reductive Coupling of Imines Templated by Chiral Diboron.
J. Am. Chem. Soc. 2020, 142, 10337–10342. [CrossRef] [PubMed]

Molecules 2021, 26, 4432
17 of 17
6.
7.
Li, J.; Zhang, D.; Chen, J.; Ma, C.; Hu, W. Enantioselective Synthesis of Fluoroalkyl-Substituted syn -Diamines by the Asymmetric
gem -Difunctionalization of 2,2,2-Trifluorodiazoethane. ACS Catal. 2020, 10, 4559–4565. [CrossRef]
Du, M.; Yu, L.; Du, T.; Li, Z.; Luo, Y.; Meng, X.; Tian, Z.; Zheng, C.; Cao, W.; Zhao, G. N -Protecting group tuning of the
enantioselectivity in Strecker reactions of trifluoromethyl ketimines to synthesize quaternary α-trifluoromethyl amino nitriles by
ion pair catalysis. Chem. Commun. 2020, 56, 1581–1584. [CrossRef]
8.
9.
Chen, Y.; Wu, Y.; Shatskiy, A.; Kan, Y.; Kärkäs, M.D.; Liu, J.-Q.; Wang, X.-S. Cooperative Silver- and Base-Catalyzed Diastere-
oselective Cycloaddition of Nitrones with Methylene Isocyanides: Access to 2-Imidazolinones. Eur. J. Org. Chem. 2020, 2020,
3475–3479. [CrossRef]
Tao, Z.; Gilbert, B.B.; Denmark, S.E. Catalytic, Enantioselective syn- Diamination of Alkenes. J. Am. Chem. Soc. 2019, 141,
19161–19170. [CrossRef]
10. Ivanovich, R.A.; Polat, D.E.; Beauchemin, A.M. Photocatalytic Intramolecular C–H Amination Using N -Oxyureas as Nitrene
Precursors. Org. Lett. 2020, 22, 6360–6364. [CrossRef]
11. Zhou, Z.; Tan, Y.; Yamahira, T.; Ivlev, S.; Xie, X.; Riedel, R.; Hemming, M.; Kimura, M.; Meggers, E. Enantioselective Ring-Closing
C–H Amination of Urea Derivatives. Chem 2020, 6, 2024–2034. [CrossRef]
12. Taily, I.M.; Saha, D.; Banerjee, P. Palladium-catalyzed regio- and stereoselective access to allyl ureas/carbamates: facile synthesis
of imidazolidinones and oxazepinones. Org. Biomol. Chem. 2020, 18, 6564–6570. [CrossRef]
13. Sviridova, L.A.; Protopopova, P.S.; Akimov, M.G.; Dudina, M.S.; Melnikova, E.K.; Kochetkov, K.A. Synthesis of new physiologi-
cally active (2-oxoimidazolidin-5-yl)indoles. Mendeleev Commun. 2020, 30, 347–349. [CrossRef]
14. Gazizov, A.S.; Burilov, A.R.; Pudovik, M.A.; Sinyashin, O.G. Reactions of nitrogen-containing acetals with aromatic nucleophiles.
Russ. Chem. Rev. 2017, 86, 75–98. [CrossRef]
15. Liu, D.-Y.; Zhu, S.-M.; Li, R.-Q.; Tian, J.-S.; Loh, T.-P.
α-Amino Acetal: A Synthetic Intermediate for the Construction of
Aza-Polycycles. Org. Lett. 2019, 21, 6357–6360. [CrossRef] [PubMed]
16. Smolobochkin, A.; Gazizov, A.; Sazykina, M.; Akylbekov, N.; Chugunova, E.; Sazykin, I.; Gildebrant, A.; Voronina, J.; Burilov, A.;
Karchava, S.; et al. Synthesis of Novel 2-(Het)arylpyrrolidine Derivatives and Evaluation of Their Anticancer and Anti-Biofilm
Activity. Molecules 2019, 24, 3086. [CrossRef] [PubMed]
17. Smolobochkin, A.V.; Rizbayeva, T.S.; Gazizov, A.S.; Voronina, J.K.; Dobrynin, A.B.; Gildebrant, A.V.; Strelnik, A.G.; Sazykin,
I.S.; Burilov, A.R.; Pudovik, M.A.; et al. Acid-Catalyzed Intramolecular Imination/Nucleophilic Trapping of 4-Aminobutanal
Derivatives: One-Pot Access to 2-(Pyrazolyl)pyrrolidines. Eur. J. Org. Chem. 2019, 2019, 5709–5719. [CrossRef]
18. Smolobochkin, A.V.; Turmanov, R.A.; Abdullaeva, D.S.; Gazizov, A.S.; Voronina, J.K.; Appazov, N.O.; Buzyurova, D.N.; Burilov,
A.R.; Pudovik, M.A. 2-(Het)aryl- N -phosphorylpyrrolidines via Cyclization of Phosphorus Acid Amides: A Regioselective
Approach. ChemistrySelect 2020, 5, 12045–12050. [CrossRef]
19. Smolobochkin, A.V.; Gazizov, A.S.; Otegen, N.K.; Voronina, J.K.; Strelnik, A.G.; Samigullina, A.I.; Burilov, A.R.; Pudovik,
M.A. Nucleophilic Cyclization/Electrophilic Substitution of (2,2-Dialkoxyethyl)ureas: Highly Regioselective Access to Novel
4-(Het)arylimidazolidinones and Benzo[d][1,3]diazepinones. Synthesis 2020, 52, 3263–3271. [CrossRef]
20. Gazizov, A.S.; Smolobochkin, A.V.; Burilov, A.R.; Pudovik, M.A. Interaction of 2-Naphthol with γ-Ureidoacetals. A New Method
for the Synthesis of 2-Arylpyrrolidines. Chem. Heterocycl. Compd. 2014, 50, 707–714. [CrossRef]
21. Grant, H.M.; Mctigue, P.; Ward, D.G. The basicities of aliphatic amides. Aust. J. Chem. 1983, 36, 2211–2218. [CrossRef]
22. Chakraborty, S.; Saha, C. The Curtin-Hammett principle. Resonance 2016, 21, 151–171. [CrossRef]
23. Sheldrick, G.M. SHELXTL v.6.12, Structure Determination Software Suite; Bruker AXS: Madison, WI, USA, 2000.
24. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement
and analysis program. J. Appl. Crystallogr. 2009, 42, 339–341. [CrossRef]
25. Llopart, C.C.; Ferrer, C.; Joule, J.A. Lithiation of 1-arylimidazol-2(1 H )-ones and 1-aryl-4,5-dihydroimidazol-2(1 H )-ones. Can. J.
Chem. 2004, 82, 1649–1661. [CrossRef]
26. Hu, Y.-C.; Liang, C.-F.; Tsai, J.-H.; Yap, G.P.A.; Chang, Y.-T.; Ong, T.-G. Zirconium Complexes Supported by Imidazolones:
Synthesis, Characterization, and Application of Precatalysts for the Hydroamination of Aminoalkenes. Organometallics 2010, 29,
3357–3361. [CrossRef]
27. Burilov, A.R.; Khakimov, M.S.; Gazizov, A.S.; Pudovik, M.A.; Syakaev, V.V.; Krivolapov, D.B.; Konovalov, A.I. Reactions of
resorcinol derivatives with 1-methyl-3-phenylimidazol-2-one as a new method for the synthesis of 5-arylimidazolidin-2-ones.
Mendeleev Commun. 2008, 18, 54–55. [CrossRef]
28. Voloshina, A.D.; Sapunova, A.S.; Kulik, N.V.; Belenok, M.G.; Strobykina, I.Y.; Lyubina, A.P.; Gumerova, S.K.; Kataev, V.E.
Antimicrobial and cytotoxic effects of ammonium derivatives of diterpenoids steviol and isosteviol. Bioorgan. Med. Chem. 2021
32, 115974. [CrossRef] [PubMed]
,
29. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.;
Nakatsuji, H.; et al. Gaussian 16, Revision C.01; Gaussian, Inc.: Wallingford, CT, USA, 2016.