Single-stage synthesis of 3-hydroxy- and 3-alkoxy-5-arylimidazolidine-2,4-diones by reaction of arylglyoxal hydrates with N-hydroxy- and N-alkoxyureas

Article abstract of DOI:10.1007/s10593-015-1735-0

[Figure not available: see fulltext.] Arylglyoxal hydrates interact with N-alkoxyureas and N-hydroxyurea in acetic acid with selective formation of 3-alkoxy-5-arylimidazolidine-2,4-diones and 5-aryl-3-hydroxyimidazolidine-2,4-diones, respectively. The str

Full text of DOI:10.1007/s10593-015-1735-0

DOI 10.1007/s10593-015-1735-0
Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
Single-stage synthesis of 3-hydroxy- and 3-alkoxy-
5-arylimidazolidine-2,4-diones by reaction of arylglyoxal hydrates
with N-hydroxy- and N-alkoxyureas
Vasiliy G. Shtamburg1*, Viktor V. Shtamburg1, Andrey A. Anishchenko2, Roman I. Zubatyuk3,
Aleksander V. Mazepa4, Eugene A. Klotz5, Svetlana V. Kravchenko6, Remir G. Kostyanovsky7
1 Ukrainian State University of Chemical Technologies, 8 Gagarina Ave., Dnipropetrovsk 49005, Ukraine;
e-mail: stamburg@gmail.com
2 Oles' Gonchar Dnipropetrovsk National University,
25 Nauchnaya St., Dnipropetrovsk 49050, Ukraine; e-mail: koloxai@gmail.com
3 State Scientific Institution "Institute for Single Crystals" of National Academy of Sciences of Ukraine, 60 Lenina Ave., Kharkiv 61001,
Ukraine; e-mail: zubatyuk@gmail.com
4 A. V. Bogatskii Physicochemical Institute, National Academy of Sciences of Ukraine,
86 Lyustdorfskaya Road, Odessa 65060, Ukraine; e-mail: almazepa@rambler.ru
5 Kirovohrad Volodymyr Vinnichenko State Pedagogical University, 1 Shevchenko St., Kirovohrad 25006, Ukraine;
e-mail: klotspgf@rambler.ru
6 Dnipropetrovsk State Agrarian and Economic University,
Voroshilova str. 25, Dnipropetrovsk 49600, Ukraine; e-mail: svtailor@ukr.net
7 N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences,
4 Kosygina St., Moscow 119991, Russia; e-mail: kost@chph.ras.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
Submitted April 6, 2015
2015, 51(6), 553–559
Accepted June 4, 2015
Ar
O
O
H
N
AcOH
OH
OH
H2N
+
Ar
OR
HN
N
OR
13–27°C, 21–120 h
O
O
Ar = Ph, 4-XC6H4 (X = Cl, Br, F, Me, OMe), 2-thienyl; R = H, Me, Et, Bu
Arylglyoxal hydrates interact with N-alkoxyureas and N-hydroxyurea in acetic acid with selective formation of 3-alkoxy-5-aryl-
imidazolidine-2,4-diones and 5-aryl-3-hydroxyimidazolidine-2,4-diones, respectively. The structures of 3-methoxy-5-phenyl-
imidazolidine-2,4-dione, 3-ethoxy-5-phenylimidazolidine-2,4-dione, and 3-butoxy-5-(4-chlorophenyl)imidazolidine-2,4-dione were
studied by X-ray structural analysis.
Keywords: 3-alkoxy-5-arylimidazolidine-2,4-diones, N-alkoxyureas, arylglyoxals, 5-aryl-3-hydroxyimidazolidine-2,4-diones, N-hydroxy-
urea, cyclization, X-ray structural analysis.
The reactions of arylglyoxals with binucleophilic
reagents are well known methods for the preparation of
nitrogen heterocycles. Condensation of glyoxals with ureas
can, depending on the conditions, lead either to substituted
hydantoins,1,2 or to 2,4,6,8-tetraazabicyclo[3.3.0]octane-
3,7-diones,3 while 4,5-dihydroxyimidazolidine-2-thiones are
formed in reactions with thioureas.4
The goal of this work was to study the possibilities for a
selective single-stage synthesis of 5-aryl-3-hydroxyimid-
azolidine-2,4-diones and 3-alkoxy-5-arylimidazolidine-2,4-di-
ones from arylglyoxals, as well as to study the structure of
3-alkoxy-5-arylimidazolidine-2,4-diones.
We have previously shown that interaction of
arylglyoxal hydrates with N-hydroxyurea in aqueous
medium at room temperature involves the formation of
substituted N-hydroxyureas 1a–c, followed by cyclization
to 5-aryl-3,4,5-trihydroxyimidazolidin-2-ones 2, 3 a–c,
which then undergo elimination of water molecule,
forming 5-aryl-3-hydroxyimidazolidine-2,4-diones (5-aryl-
3-hydroxyhydantoins) 4a–c (Scheme 1).5
However, performing the reaction at 20–23°С,
depending on the nature of arylglyoxal, may in some cases
produce either a mixture of substituted N-hydroxyureas 1
and 5-aryl-3-hydroxyhydantoins 4 (X = Me,5 OMe), i.e.,
products of the first and third step of the mechanism, or a
diastereomeric mixture of 5-aryl-3,4,5-trihydroxyimid-
azolidin-2-ones, for example, compounds 2, 3 (X = Cl)5 or
their mixture with products of the third step, 5-aryl-
0009-3122/15/5106-0553©2015 Springer Science+Business Media New York
553

Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
Scheme 1
Scheme 2
H
N
Ar
O
H2N
O
OH
H
H
OH
N
AcOH
O
HO
O
OH
OH
H2N
N
+
O
Ar
OH
HN
N
OH
OH
OH
15–20°C
24–96 h
O
Ar
O
H2O, rt
O
4a–g
Ar H2N
1a–c
Table 1. Yields of 5-aryl-3-hydroxyimidazolidine-2,4-dione
monohydrates 4a–g
HO
Ar
HN
Ar
OH
OH
Ar
HN
O
H
H
HO
+
HN
N
N
N
Com-
pound
OH
OH
OH
–H2O
Ar
Temperature, °С
Time, h
Yield, %
O
O
O
Ph
18–19
18–19
19–20
19–20
17–18
16–17
15–16
24
24
24
96
26
24
24
76
69
63
95
77
63
40
4a
2a–c
3a–c
4a–c
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-FC6H4
4b
Ar = 4-XC6H4, a X = H, b X = Cl, c X = Me
4c
3-hydroxyhydantoins 4 (X = H).
4d
In the latter case, performing the reaction with gentle
heating or removal of water from the reaction mixture by
distillation at elevated temperature under vacuum
facilitated the complete conversion of 3,4,5-trihydroxy-
5-phenylimidazolidin-2-one diastereomers 2a and 3a to
3-hydroxy-5-phenylimidazolidine-2,4-dione 4а.5
4e
4f
2-Thienyl
4g
The major product of reaction between (4-chlorophenyl)-
glyoxal hydrate and N-hydroxyurea in aqueous medium at
15–23°С was 5-(4-chlorophenyl)-3,4,5-trihydroxyimidazo-
lidin-2-one diastereomer with cis orientation of hydroxy
groups at С-4,5 carbon atom, compound 2b, which was
characterized by X-ray structural analysis.5 The ratio of
diastereomers 2b and 3b was determined by the intensity
ratio of the CHOH proton doublets in the 1Н NMR spectra,
which was equal to 97:3. Compounds 2b, 3b were
converted quantitatively to 5-(4-chlorophenyl)-3-hydroxy-
imidazolidine-2,4-dione (4b) by refluxing in MeCN
solution.
The reaction of arylglyoxals with N-alkoxyureas could
be expected to produce the respective 3-alkoxyhydantoins.
Indeed, the reaction of anhydrous phenylglyoxal with
N'-ethoxy-N-phenylurea in CH2Cl2 at 20°С gave 1,5-bis-
(phenyl)-3-ethoxyimidazolidine-2,4-dione in moderate
yield (46%).6 Thus, the reaction of arylglyoxals with
N-hydroxy- and N-alkoxyureas could be generally
applicable to the preparation of 3-hydroxy- and 3-alkoxy-
5-arylimidazolidine-2,4-diones, and could compete with
the very few known methods for the preparation of
3-hydroxy- and 3-alkoxyhydantoins and their derivatives.7–13
The practical challenges were associated with the difficult
removal of impurities formed in the first and second stages
of this synthesis.
as the only products, formed in the third step of Scheme 1
(Scheme 2, Table 1). Products of the first and second steps
were absent in the reaction mixture.
A complete conversion of arylglyoxal hydrate is
typically observed after maintaining the reaction mixture
for 1 day at room temperature. Longer time was required in
the case of (4-methoxyphenyl)glyoxal hydrate (Table 1),
that probably could be explained by deactivation of
β-carbonyl group in glyoxal by the p-methoxyphenyl
substituent, creating an obstacle to cyclization in the
second stage of the reaction (Scheme 1).
The conversion of intermediates 2, 3 a–g to 5-aryl-
3-hydroxyimidazolidine-2,4-diones 4a–g, i.e., the third
stage of the mechanism (Scheme 1), could be facilitated by
acidic catalysis (AcOH) and may involve the formation of
intermediate "benzyl" cation А in acidic medium followed
by 1,2-hydride shift (Scheme 3).
The interaction of arylglyoxal hydrates with N-alkoxy-
ureas in acetic acid at room temperature for several days
led to a selective formation of 3-alkoxy-5-arylimidazolidine-
2,4-diones 5a–j (Scheme 4, Table 2), probably according to
the mechanism shown in Schemes 1 and 3.
The structure of 3-hydroxy- and 3-alkoxy-5-aryl-
imidazolidine-2,4-diones was confirmed by 1Н and 13С NMR
spectroscopy, mass spectrometry, and in the case of
compounds 5a,b,f also by X-ray structural analysis (Fig. 1, 3,
Table 3).
Compounds 5a,b,f had related structures (Fig. 1). The
five-membered ring in all three structures was planar, the
We found that performing the reaction of N-hydroxyurea
with arylglyoxal hydrates in acetic acid at 15–20°С
produced 5-aryl-3-hydroxyimidazolidine-2,4-diones 4a–g
Scheme 3
H
+
H
Ar
OH
O
H
N
H
N
Ar
O
Ar
O
+
H
H
N
HO
Ar
HN
OH
OH
OH
OH
AcOH
OH
H2N
+
HN
Ar
OH
HN
HN
N
N
–H+
OH
OH
–H2O
OH
O
O
O
O
O
2, 3 a–g
A
4a–d
554

Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
Scheme 4
Ar
O
O
H
N
AcOH
OH
OH
H2N
+
Ar
OR
HN
N
OR
13–27°C
21–120 h
O
O
5a–j
Table 2. Yields of 3-alkoxy-5-arylimidazolidine-2,4-diones 5a–j
5a
Com-
pound
Time,
h
Yield,
%
Ar
R
Temperature, °С
Ph
Ph
Me
Et
14–15
17–18
13–14
26–27
26–27
25–26
26–27
26–27
15–16
20–21
74
118
45
69
99
63
78
78
88
78
99
85
64
5a
5b
5c
5d
5e
5f
Ph
n-Bu
Me
Et
4-ClC6H4
4-ClC6H4
92
98
4-ClC6H4 n-Bu
95
4-FC6H4
4-FC6H4
4-BrC6H4
2-Thienyl
Me
Et
21
5g
5h
5i
91
5b
Et
68
Et
120
5j
endocyclic torsion angles did not exceed 4°. The alkyl
substituent at the О(2) atom was oriented orthogonally to the five-
membered ring plane (the torsion angle С(10)–O(2)–N(1)–C(2)
was –87.6(4)°, –83.2(2)°, and –87.3(2)° for compounds
5a,b,f, respectively). At the same time, the butyl
substituent in compound 5f was disordered over the two
positions А and В with the relative occupancy 0.59(1):0.41(1)
due to a rotation around О(2)–С(10) bond, with slightly
different conformations at positions А and В. The respective
torsion angles N(1)–O(2)–C(10)–C(11) (158.6(4)° and
–166.1(5)° at positions А and В) and С(10)–С(11)–С(12)–С(13)
(–91.3(9)° and 85.3(17)°) have opposite signs, while the
torsion angles O(2)–C(10)–C(11)–C(12) are practically
equal (–175.7(5)° and 178.7(7)°).
We should note that the configuration of the N(1)
nitrogen atom in 3-methoxy-5-phenylimidazolidine-2,4-
dione (5a) was planar, while in compounds 5b,f it was slightly
pyramidal. The Winkler–Dunitz pyramidality parameters χ,14
representing angles between the planes drawn through the
nitrogen atom and two adjacent atoms, were 0.3(7)°, 17.7(3)°,
and 9.2(4)° for compounds 5a,b,f, respectively. Thus, the
pyramidality of the N(1) atom increased in the series of
substituents Me→Bu→Et. The higher pyramidality in the
case of ethyl substituent, compared to butyl, apparently
could be explained by the differences in C(10)–C(11) bond
orientation relative to the N(1)–O(2) bond: it was syn-clinal
in N-ethoxyhydantoin 5b and anti-periplanar in
N-butoxyhydantoin 5f (the values of the respective torsion
angles were 65.1(3)° for compound 5b and 158.6(4)°;
–166.1(5)° for the two disordered positions of compound
5f). The connection between rotation angle along the O(2)–C(10)
bond and the degree of nitrogen atom pyramidality was
confirmed by quantum-chemical calculations using the the
B97-D3/def2-SVP density functional method. Scanning of
5f
Figure 1. Molecular structure of compounds 5a,b,f with non-
hydrogen atoms represented by thermal vibration ellipsoids of
50% (compounds 5a,b) and 30% (compound 5f) probability.
the relaxed potential energy surface during variation of the
torsion angle N–O–C–C in molecule of 3-ethoxy-
5-phenylimidazolidine-2,4-dione 5b (Fig. 2) showed that
the nitrogen atom was most pyramidal when the C–C bond
had syn-clinal orientation relative to the С–О bond, and
least pyramidal when the orientation was syn- and anti-
periplanar. This dependence could probably be explained
by interaction between the nitrogen lone electron pair and a
methyl group hydrogen atom, which is attractive precisely
at syn-clinal orientation. According to X-ray structural data,
the N···H distance in 3-ethoxy-5-phenylimidazolidine-2,4-
dione (5b) was equal to 2.65 Å, corresponding to the sum of
van der Waals radii of the atoms.15 The graph of energy vs.
torsion angle also showed two minima at syn-clinal and anti-
periplanar areas, corresponding to the conformations of
molecules 5b,f observed in the crystalline state.
The crystals of 3-alkoxy-5-arylimidazolidine-2,4-diones
contained molecules linked by intermolecular N(2)–H···O(3)
hydrogen bonds. More specifically, molecular chains along
the screw axis 21 were observed in 3-alkoxy-5-phenyl-
imidazolidine-2,4-diones 5a,b, while the molecules were
arranged in 3-butoxy-5-(4-chlorophenyl)imidazolidine-2,4-
dione (5f) in centrally symmetric dimers (Fig. 3).
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Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
Table 3. The characteristic bond lengths in 3-alkoxy-
5-arylimidazolidine-2,4-diones 5a,b,f
Bond lengths, Å
Com-
pound
N(1)–O(2)
1.386(4)
1.379(2)
1.374(2)
N(2)–C(3)
1.330(4)
1.323(3)
1.341(2)
N(1)–C(3)
1.403(4)
1.412(2)
1.400(3)
N(1)–C(2)
1.354(5)
1.368(3)
1.362(3)
5a
5b
5f
established, and the non-equivalence of amide N–C bonds
in the ring system was observed.
Figure 2. The dependence of N(1) (χ) atom pyramidality and energy
(ΔE) of 3-ethoxy-5-phenylimidazolidine-2,4-dione (5b) molecule on
the torsion angle С(11)–С(10)–O(2)–N(1), calculated by the B97-D3/
def2-SVP method.
Experimental
The N(1)–C(2) amide bond in all three compounds was
much shorter than the N(1)–C(3) bond. This was probably
caused by the greater conjugation between lone electron
pair of the N(1) atom and the С(2)=О(1) carbonyl bond
IR spectra were recorded on a UR-20 spectrometer in
1
KBr pellets. Н and 13С NMR spectra were acquired on a
Varian VXP-300 spectrometer (300 and 75 MHz,
respectively). The solvents were DMSO-d6 (compounds
1d, 2b, 3b, 4a–g, 5a,g; 1H NMR spectra of compounds 5h–j)
and CDCl3 (compounds 5b–e; 13С NMR spectra of
compounds 5h–j), with TMS as internal standard.
13С NMR spectra of compounds 2b, 4e,g, 5b,с were
recorded in APT mode. Mass spectra were recorded on a
VG 70-70EQ mass spectrometer in fast atom bombardment
mode. Elemental analysis for C, H, and N was performed
on a Carlo Erba analyzer. Melting points were determined
in a capillary with a PTOP sulfuric acid apparatus.
1
compared to the С(3)=О(3) carbonyl bond (Table 3). Н
NMR signals of N(1)–H and C(1)–H protons in 3-alkoxy-
5-arylimidazolidine-2,4-diones 5a,b,f were singlets,
similarly as in the case of other 3-alkoxyhydantoins and
3-hydroxyhydantoins. This was in good agreement with the
planar conformation of the N(1) atom observed in the
crystal structure.
The proposed single-stage synthesis of 3-hydroxy-5-aryl-
imidazolidine-2,4-diones and 3-alkoxy-5-arylimidazolidine-
2,4-diones by reactions of aryl glyoxals with N-hydroxyurea
and N-alkoxyureas in acetic acid at room temperature can
be considered to be quite promising. Structural features of
3-alkoxy-5-arylimidazolidine-2,4-diones were studied, in
particular the planarity of five-membered ring was
N-Hydroxyurea16 (stored at –26°С), N-methoxyurea,17
N-ethoxyurea,18 and N-n-butoxyurea18 were obtained
according to published procedures. 2-Thienylglyoxal
hydrate was obtained by a published procedure,19 then
purified by vacuum distillation, converted to hydrate, and
recrystallized from benzene. Phenylglyoxal hydrate was
obtained according to a published procedure,20 then
purified by vacuum distillation and conversion to hydrate.
The rest of the arylglyoxal hydrates were obtained
analogously. The solvents were purified according to
standard procedures.
Preparation of cis- and trans-5-(4-chlorophenyl)-3,4,5-
trihydroxyimidazolidin-2-ones 2b, 3b. A solution of
N-hydroxyurea (90 mg, 1.180 mmol) in H2O (20 ml) was
stirred with (4-chlorophenyl)glyoxal hydrate (220 mg,
1.180 mmol) at 20–25°С for 27 h (the precipitate of glyoxal
hydrate dissolved nearly completely). Then additional
N-hydroxyurea (80 mg, 1.052 mmol) was added, and the
mixture was stirred for 30 min until precipitate formed. The
obtained white precipitate was maintained for 24 h at 20°С,
then filtered off and dried under vacuum (3 mmHg),
yeilding a mixture of diastereomers 2b and 3b (218 mg,
66%) in 97:3 ratio (according to 1Н NMR data).
5a
5b
The aqueous filtrate was evaporated under vacuum
(3 mmHg) at 20°С to one half volume, the precipitate that
formed was filtered off and dried under vacuum (3 mmHg),
giving additional crop of diastereomers 2b, 3b (38 mg,
11%) as 97:3 mixture. The obtained diastereomers 2b, 3b
were combined and recrystallized from 1:1 THF–hexane
mixture. The cis-diastereomer 2b was finally isolated, as
identified by 1Н NMR spectroscopy and mass
spectrometry.5
5f
Figure 3. Hydrogen bonds in the crystal structures of 3-alkoxy-
5-arylimidazolidine-2,4-diones 5a,b,f.
556

Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
cis-Diastereomer 2b. Yield 167 mg (53%), colorless
Synthesis of compound 4d in neutral aqueous
medium. A solution of (4-methoxyphenyl)glyoxal hydrate
(911 mg, 5.00 mmol) in Н2О (50 ml) was heated to 45°С
and treated with a solution of N-hydroxyurea (380 mg,
5.00 mmol) in Н2О (7 ml). The reaction mixture was
stirred for 2 h at 27–30°С, then maintained without stirring
for 40 h at 27–30°С, and the obtained precipitate of
N-hydroxy-N-[hydroxy(4-methoxybenzoyl)]methylurea
(1d) was filtered off. The remaining aqueous filtrate was
maintained for another 24 h at 27–30°С, then cooled to 0°С
and maintained for 5 days. The crystalline precipitate that
formed was filtered off and dried under vacuum, giving
3-hydroxy-5-(4-methoxyphenyl)imidazolidine-2,4-dione
crystals, mp 104–106°С (decomp.) (mp 103–106°С (THF–
hexane)).5 13C NMR spectrum, δ, ppm: 82.1 (C(OH)Ar);
89.7 (CHOH); 128.0, 128.1 (CH Ar); 132.8, 141.7 (C Ar);
159.6 (C=O).
trans-Diastereomer 3b. 1H NMR spectrum, δ, ppm
(J, Hz): 4.84 (1H, d, CHOH, J = 5.7); 6.41 (1H, d, J = 5.7,
CHOH); 6.60 (1H, s, 5-OH); 7.34–7.51 (4Н, m, H Ar);
8.01 (1H, s, NH); 9.07 (1H, s, NOH).
The reaction of phenylglyoxal hydrate with N-hydroxy-
urea in water at 20°С gave a mixture of diastereomers 2а
and 3а (4:1−9:1) and hydantoin 4а, which were difficult to
separate due to the similar solubility of these compounds in
water. Compounds 2а and 3а could be readily and
selectively converted upon gentle heating to hydantoin 4а.
Preparation of 5-aryl-3-hydroxyimidazolidine-2,4-di-
ones 4a–g (General method). A mixture of N-hydroxyurea
(118 mg, 1.546 mmol) and arylglyoxal hydrate (1.546 mmol)
with AcOH (10 ml) was stirred until complete dissolution,
the obtained solution was maintained at 15–20°С for 24–96 h
(Table 1). The solvent was evaporated under vacuum
(3 mmHg) at 20°С, the residue was washed with cold water
(5 ml) and dried under vacuum (3 mmHg). For additional
purification, compounds 4a–g were recrystallized from 1:2
mixture of THF and hexane.
1
hydrate (4d) (211 mg, 18%), which was identified by Н
NMR spectroscopy and mass spectrometry.
Compound 1d. Yield 489 mg (41%), white crystals, mp
145–147°С (decomp.). IR spectrum, ν, cm–1: 1660 (C=O),
1680 (C=O), 3295 (NH2), 3346 (ОН), 3450 (OH). 1H NMR
spectrum, δ, ppm (J, Hz): 3.85 (3H, s, ОCH3); 5.88 (1H, d,
J = 8.4, CHOH); 6.53 (1H, d, J = 8.4, CHOH); 6.54 (2H,
br. s, NH2); 7.06 (2H, d, J = 9.0, H); 7.99 (2H, d, J = 9.0,
H Ar); 9.24 (1H, s, NOH). Mass spectrum, m/z (Irel, %):
241 [M+H]+ (50), 223 (18), 180 (76), 176 (46), 165 (57),
120 (48), 107 (31), 105 (44), 89 (86), 77 (100). Found, %:
C 49.85; H 5.16; N 11.49. C10H12N2O5. Calculated, %:
C 50.00; H 5.04; N 11.66.
3-Hydroxy-5-phenylimidazolidine-2,4-dione
(4a).
Colorless crystals, mp 170–172°С (decomp.), after second
recrystallization 175–176°С (decomp.) (mp 175–176°С
(decomp., THF–hexane)).5 13С NMR spectrum, δ, ppm:
57.7 (C-5); 126.9, 128.6, 128.8, 135.5 (C Ph); 154.4
(C=O); 167.8 (C=O). Mass spectrum, m/z (Irel, %): 193
[M+H]+ (100), 175 [M+H–H2O]+ (10).
5-(4-Chlorophenyl)-3-hydroxyimidazolidine-2,4-dione (4b).
Colorless crystals, mp 167–169°С (decomp.) (mp 132–134°С
(decomp.)).5 13C NMR spectrum, δ, ppm: 57.0 (C-5); 128.7,
128.8, 133.2, 134.3 (C Ar); 154.4 (C=O); 167.5 (C=O).
Also the hydrate of 5-(4-chlorophenyl)-3-hydroxy-
imidazolidine-2,4-dione 4b was formed in 100% yield after
refluxing a solution of 5-(4-chlorophenyl)-3,4,5-trihydroxy-
imidazolidine-2-one (2b) in MeCN for 2 h, followed by
removing the solvent under vacuum (10 mmHg).
3-Hydroxy-5-(4-methylphenyl)imidazolidine-2,4-di-
one (4с). Colorless crystals, mp 141–143°С (decomp.) (mp
136–139°С (decomp.)).5 13C NMR spectrum, δ, ppm: 20.6
(CH3); 57.4 (C-5); 126.8, 129.4, 132.4, 137.9 (C Ar); 154.5
(C=O); 167.8 (C=O). Mass spectrum, m/z (Irel, %): 207 [M+H]
+ (49), 119 (100), 91 (36).
5-(4-Bromophenyl)-3-hydroxyimidazolidine-2,4-dione
(4e). Colorless crystals, mp 175–177°С (decomp.).
1H NMR spectrum, δ, ppm (J, Hz): 5.28 (1H, s, 5-CH);
7.32 (2H, d, J = 8.4, H Ar); 7.64 (2H, d, J = 8.4, H Ar);
8.78 (1H, s, NH); 10.70 (1H, br. s, NOH). 13C NMR
spectrum, δ, ppm: 56.9 (C-5); 121.6 (C Ar); 128.8 (CH
Ar); 131.5 (CH Ar); 134.7 (C Ar); 154.1 (C=O); 167.1
(C=O). Mass spectrum, m/z (Irel, %): 273 [M(81Br)+H]+
(100), 271 [M(79Br)+H]+ (92). Found, %: C 37.14; H 3.45;
N 9.55. C9H7BrN2O3·H2O. Calculated, %: C 37.39; H 3.14;
N 9.69.
5-(4-Fluorophenyl)-3-hydroxyimidazolidine-2,4-dione (4f).
Colorless crystals, mp 198–199°С (decomp.). 1H NMR
spectrum, δ, ppm (J, Hz): 5.27 (1H, s, 5-CH); 7.26 (2Н, dd,
J = 8.4, J = 10.3, H Ar); 7.34 (2Н, dd, J = 8.4, J = 5.8,
H Ar); 8.74 (1H, s, NH); 10.60 (1H, br. s, NOH). 13C NMR
spectrum, δ, ppm (J, Hz): 56.9 (C-5); 115.6 (d, JCF = 21.8,
C-3,5 Ar); 128.9 (d, JCF = 9.0, C-2,6 Ar); 131.6 (C-1 Ar);
154.3 (C=O); 162.2 (d, JCF = 250.5, C-4 Ar); 167.7 (C=O).
Mass spectrum, m/z (Irel, %): 211 [M+H]+ (100), 193 [M+H–
H2O]+ (11). Found, %: С 47.41; H 4.07; N 12.13.
C9H7FN2O3·H2O. Calculated, %: C 47.37; H 3.98; N 12.28.
3-Hydroxy-5-(4-methoxyphenyl)imidazolidine-2,4-di-
one (4d). Pinkish-white crystals, mp 158–159°С
(decomp.). IR spectrum, ν, cm–1: 1715 (C=O), 1770 (C=O),
3-Hydroxy-5-(2-thienyl)imidazolidine-2,4-dione
(4g).
Yellowish crystals, unstable at room temperature, mp 98–
103°С (decomposition at 176–178°С, with loss of water)
(mp 107–108°С (decomp.)).5 13C NMR spectrum, δ, ppm:
54.1 (C-5); 126.5, 126.6, 127.3 (C-3,4,5 thiophene); 138.0
(C-2 thiophene); 154.1 (C=O); 167.0 (C=O). Mass
spectrum, m/z (Irel, %): 199 [M+H]+ (100), 181 [M+H–H2O]+
(9). Found, %: C 38.70; H 3.95; N 12.73. C7H6N2O3S·H2O.
Calculated, %: C 38.89; H 3.73; N 12.96.
1
3260 (N–H), 3580 (O–H). H NMR spectrum, δ, ppm
(J, Hz): 3.77 (3H, s, ОCH3); 5.17 (1Н, s, 5-СН); 6.99 (2H,
d, J = 8.7, H Ar); 7.25 (2H, d, J = 8.7, H Ar); 8.69 (1H, s,
NH); 10.59 (1H, s, NOH). 13C NMR spectrum, δ, ppm:
55.2 (ОCH3); 57.2 (C-5); 114.2, 127.3, 128.1 (C Ar); 154.4
(C=O); 159.4 (C-4 Ar); 168.1 (C=O). Mass spectrum, m/z
(Irel, %): 223 [M+H]+ (100), 205 [M+H–H2O]+ (34). Found,
%:
С
49.74;
Н
5.28;
N
11.57. C10H10N2O4·H2O.
Preparation of 3-alkoxy-5-arylimidazolidine-2,4-di-
ones 5a–j (General method). A mixture of N-alkoxyurea
Calculated, %: C 50.00; H 5.04; N 11.66.
557

Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
(0.965 mmol), arylglyoxal hydrate (0.965 mmol), and
131.8, 135.8 (C Ar); 154.2 (C=O); 166.5 (C=O). Mass
spectrum, m/z (Irel, %): 257 [M(37Cl)+Н]+ (32), 255
[M(35Cl)+Н]+ (100). Found, %: C 51.75; H 4.58; N 10.85.
C11H11ClN2O3. Calculated %: C 51.88; H 4.35; N 11.00.
3-n-Butoxy-5-(4-chlorophenyl)imidazolidine-2,4-dione (5f).
Colorless crystals, mp 151–152°С (decomp.). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 0.93 (3H, t, J =7.4,
O(CH2)3CH3); 1.45 (2H, sextet, J = 7.4, O(CH2)2CH2Me);
1.69 (2H, quin, J = 7.4, OCH2CH2Et); 4.12 (2H, td, J = 7.4,
J = 2.4, NOCH2); 5.03 (1H, s, 5-CH); 6.61 (1H, br. s, NH);
7.32 (2H, d, J = 8.4, H Ar); 7.40 (2H, d, J = 8.4, H Ar). 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 0.89 (3H, t, J = 7.4,
O(CH2)3CH3); 1.40 (2H, sextet, J = 7.4, O(CH2)2CH2Me); 1.59
(2H, quin, J = 7.2, OCH2CH2Et); 4.03 (2H, td, J = 7.4, J = 2.1,
NOCH2); 5.29 (1H, s, 5-CH); 7.39 (2H, d, J = 8.4, H Ar); 7.50
(2H, d, J = 8.4, H Ar); 8.89 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 13.6 (O(CH2)3CH3); 18.7 (O(CH2)2CH2Me);
29.8 (OCH2CH2Et); 58.1 (C-5); 78.0 (NOCH2); 127.8, 129.4,
131.8, 135.4 (C Ar); 154.0 (C=O); 166.3 (C=O). Mass
spectrum, m/z (Irel, %): 283 [M(35Cl)+H]+ (100). Mass
spectrum (FAB, KI), m/z (Irel, %): 321 [M(35Cl)+K]+ (33),
283 [M(35Cl)+H]+ (41), 134 (100). Found, %: C 55.01;
H 5.36; N 9.85. C13H15ClN2O3. Calculated, %: C 55.23;
H.35; N 9.91.
AcOH (10 ml) was stirred until complete dissolution, the
obtained solution was maintained at 13–27°С for 21–120 h
(Table 2), then AcOH was removed by evaporation under
vacuum (3 mmHg) at 20°С, the residue was washed with
cold (5°С) water (10 ml) and dried under vacuum (3 mmHg).
For additional purification, the obtained compounds were
recrystallized from CH2Cl2 (compound 5g), CCl4
(compounds 5e,j), or 1:2 mixture of CH2Cl2–hexane (the
rest of the compounds).
3-Methoxy-5-phenylimidazolidine-2,4-dione
(5a).
Colorless crystals, mp 161–162°С. 1H NMR spectrum, δ, ppm
(J, Hz): 3.85 (3H, s, OСН3); 5.25 (1H, s, 5-CH); 7.35–7.45
(5H, m, H Ph); 8.90 (1H, s, NH). 13C NMR spectrum, δ, ppm:
57.8 (C-5); 64.7 (OСН3); 126.9, 128.6, 128.8, 134.8 (C Ph);
152.6 (C=O); 166.7 (C=O). Mass spectrum, m/z (Irel, %): 207
[M+H]+ (100). Found, %: C 58.02; H 4.98; N 13.37.
C10H10N2O3. Calculated %: C 58.25; H 4.89; N 13.59.
3-Ethoxy-5-phenylimidazolidine-2,4-dione
(5b).
Colorless crystals, mp 130–131°С. IR spectrum, ν, cm–1: 1740
1
(C=O), 1770 (C=O), 3320 (N–H). H NMR spectrum, δ,
ppm (J, Hz): 1.34 (3H, t, J = 7.0, OCH2CH3); 4.19 (2H, dq,
J = 1.8, J = 7.0, OCH2CH3); 5.03 (1H, s, 5-CH); 6.54 (1H,
br. s, NH); 7.34–7.48 (5H, m, H Ph). 13C NMR spectrum,
δ, ppm: 13.3 (OCH2CH3); 58.7 (C-5); 73.7 (OCH2CH3);
126.4, 129.0, 129.1 (CH Ph); 133.3 (C-1 Ph); 154.2 (C=O);
166.8 (C=O). Mass spectrum, m/z (Irel, %): 221 [M+H]+
(100). Found, %: C 60.14; H 5.02; N 12.43. C11H12N2O3.
Calculated %: C 59.99; H 5.49; N 12.72.
5-(4-Fluorophenyl)-3-methoxyimidazolidine-2,4-dione
(5g). Colorless crystals, mp 163–164°С (decomp.).
1H NMR spectrum, δ, ppm (J, Hz): 3.88 (3H, s, OCH3);
5.29 (1H, s, 5-CH); 7.28 (2H, t, J = 8.7, H Ar); 7.43 (2H,
dd, J = 8.7, J = 5.7, H Ar); 8.94 (1H, s, NH). 13C NMR
spectrum, δ, ppm (J, Hz): 57.2 (C-5); 64.9 (OCH3); 115.8 (d,
3-n-Butoxy-5-phenylimidazolidine-2,4-dione
(5c).
Colorless crystals, mp 78–80°С. IR spectrum, ν, cm–1: 1730
JCF = 21.8, C-3,5 Ar); 129.2 (d, JCF = 8.8, C-2,6 Ar); 131.1
1
(C=O), 1775 (C=O), 3240 (N–H). H NMR spectrum, δ, ppm
(C-1 Ar); 152.7 (C=O); 162.3 (d, JCF = 243.4, C-4 Ar);
166.8 (C=O). Mass spectrum, m/z (Irel, %): 225 [M+H]+ (100).
Found, %: C 53.39; H 4.22; N 12.32. C10H9FN2O3.
Calculated %: C 53.57; H 4.05; N 12.50.
(J, Hz): 0.92 (3H, t, J = 7.2, O(CH2)3Me); 1.44 (2H, sextet,
J = 7.2, O(CH2)2CH2Me); 1.68 (2H, quin, J = 7.2,
OCH2CH2Et); 4.04–4.15 (2H, m, NOCH2); 5.02 (1H, s, 5-CH);
7.03 (1H, s, NH); 7.34–7.44 (5H, m, H Ph). 13C NMR
spectrum, δ, ppm: 13.5 (O(CH2)3CH3); 18.5 (O(CH2)
2CH2Me); 29.7 (OCH2CH2Et); 58.6 (C-5); 77.4 (OCH2);
126.4, 129.1, 129.2 (CH Ph); 133.4 (C-1 Ph); 154.1 (C=O);
166.7 (C=O). Mass spectrum, m/z (Irel, %): 249 [M+H]+
(100). Found %: C 63.12; H 6.67; N 11.14. C13H16N2O3.
Calculated %: C 62.89; H 6.50; N 11.28.
5-(4-Chlorophenyl)-3-methoxyimidazolidine-2,4-dione
(5d). Colorless crystals, mp 142–145°С (decomp.)
1H NMR spectrum, δ, ppm (J, Hz): 4.00 (3H, s, OСН3);
5.06 (1H, s, 5-CH); 6.28 (1H, s, NH); 7.35 (2H, d, J = 8.4,
H Ar); 7.43 (2H, d,J = 8.4, H Ar). 13C NMR spectrum, δ, ppm:
58.2 (C-5); 65.3 (OСН3); 127.8, 129.4, 131.6, 135.6 (C);
153.1 (C=O); 165.6 (C=O). Mass spectrum, m/z (Irel, %): 243
[M(37Cl)+Н]+ (35), 241 [M(35Cl)+Н]+ (100). Found, %:
C 49.84; H 3.95; N 11.55. C10H9ClN2O3. Calculated %:
C 49.91; H 3.77; N 11.64.
3-Ethoxy-5-(4-fluorophenyl)imidazolidine-2,4-dione
(5h). Colorless crystals, mp 126–129°С (decomp.).
1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.0,
OCH2CH3); 4.09 (2H, q, J = 7.0, OCH2CH3); 5.29 (1H, s,
5-CH); 7.26 (2H, t, J = 8.7, H Ar); 7.43 (2H, dd, J = 8.1,
J =5.7, H Ar); 8.89 (1H, s, NH). 13C NMR spectrum, δ, ppm
(J, Hz): 13.4 (OCH2CH3); 58.1 (C-5); 73.8 (OCH2CH3);
116.2 (d, JCF = 21.8, C-3,5 Ar); 128.3 (d, JCF = 8.5, C-2,6
Ar); 129.0 (C-1 Ar); 153.8 (C=O); 163.1 (d, JCF = 247.1,
C-4 Ar); 166.5 (C=O). Mass spectrum, m/z (Irel, %): 239
[M+H]+ (100). Found, %: C 55.25; H 4.82; N 11.63.
C11H11FN2O3. Calculated %: C 55.46; H 4.65; N 11.76.
5-(4-Bromophenyl)-3-ethoxyimidazolidine-2,4-dione
(5i). Colorless crystals, mp 140–142°С. 1H NMR spectrum,
δ, ppm (J, Hz): 1.21 (3H, t, J = 6.9, OCH2CH3); 4.08 (2H,
q, J = 6.9, OCH2CH3); 5.29 (1H, s, 5-CH); 7.33 (2H, d,
J = 8.1, H Ar); 7.62 (2H, d, J = 8.1, H Ar); 8.92 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 13.4 (OCH2CH3); 58.2
(C-5); 73.9 (OCH2CH3); 123.5, 128.1, 132.2, 132.4 (C);
154.1 (C=O); 166.3 (C=O). Mass spectrum, m/z (Irel, %): 301
[M(81Br)+H]+ (100), 299 [M(79Br)+H]+ (99), 255 [M(81Br)+
H–EtOH]+ (14), 253 [M(79Br)+H–EtOH]+ (15). Found, %:
C 44.02; H 3.98; N 9.16. C11H11BrN2O3. Calculated %:
C 44.17; H 3.71; N 9.37.
5-(4-Chlorophenyl)-3-ethoxyimidazolidine-2,4-dione
(5e). Colorless crystals, mp 115–118°С. 1H NMR
spectrum, δ, ppm (J, Hz): 1.34 (3H, t, J = 7.5, OCH2CH3);
4.19 (2H, dq, J = 1.2, J = 7.1, OCH2CH3); 5.04 (1H, s,
5-CH); 6.66 (1H, s, NH); 7.32 (2H, d, J = 8.4, H Ar); 7.40
(2H, d, J = 8.4, H Ar). 13C NMR spectrum, δ, ppm: 13.3
(OCH2CH3); 58.1 (C-5); 73.9 (OCH2CH3); 127.8, 129.4,
558

Chemistry of Heterocyclic Compounds 2015, 51(6), 553–559
3-Ethoxy-5-(2-thienyl)imidazolidine-2,4-dione
(5j).
References
Yellowish crystals, mp 100–102°С. 1H NMR spectrum, δ, ppm
(J, Hz): 1.22 (3H, t, J = 7.1, OCH2CH3); 4.09 (3H, q, J = 7.1,
OCH2CH3); 5.58 (1H, s, 5-CH); 7.07 (1H, t, J = 4.2, H thio-
phene); 7.14 (1H, d, J = 3.3, H thiophene); 7.58 (1H, d, J = 4.2,
H thiophene); 9.09 (1H, s, NH). 13C NMR spectrum, δ, ppm:
13.2 (OCH2CH3); 55.0 (C-5); 73.7 (OCH2CH3); 126.5,
126.6, 127.4, 135.9 (C thiophene); 153.5 (C=O); 165.7
(C=O). Mass spectrum, m/z (Irel, %): 227 [M+H]+ (100), 225
[M–H]+ (68). Found, %: C 47.52; H 4.31; N 12.53.
C9H10N2O3S. Calculated, %: C 47.78; H 4.46; N 12.38.
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Quantum-chemical calculations for a molecule of
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method.22–26 Scanning of potential energy surface was
accomplished by a sequence of geometry optimizations
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This work received financial support from the Ministry
of Education and Science of Ukraine (grant
0115U003159), Ukraine State Foundation for Basic
Research (grant F-53.3/001), and the Russian Foundation
for Basic Research (grant 13-03-90460).
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559