Synthesis of new substituted 5-methyl-3,5-diphenylimidazolidine-2,4-diones from substituted 1-(1-cyanoethyl-1-phenyl)-3-phenylureas

Article abstract of DOI:10.1002/jhet.5570420523

The reaction of substituted phenyl isocyanates with 2-amino-2- phenylpropanenitrile and 2-amino-2-(4-nitrophenyl)propanenitrile has been used to prepare substituted 1-(1-cyanoethyl-1-phenyl)-3-phenylureas. In anhydrous phosphoric acid the first products t

Full text of DOI:10.1002/jhet.5570420523

Synthesis of New Substituted 5-Methyl-3,5-diphenylimidazolidine-2,4-
diones from Substituted 1-(1-Cyanoethyl-1-phenyl)-3-phenylureas
Jul-Aug 2005
899
Miloš Sedlák*, Roman Keder, Jiří Hanusek and Aleš Růžička
University of Pardubice, Faculty of Chemical Technology, Department of Organic Chemistry, Nám. Čs. Legií
565, 532 10 Pardubice, Czech Republic
Fax: +420 466 037 068; Tel: +420 466 037 015; E-mail: Milos.Sedlak@upce.cz.
Received November 19, 2004
The reaction of substituted phenyl isocyanates with 2-amino-2-phenylpropanenitrile and 2-amino-2-(4-
nitrophenyl)propanenitrile has been used to prepare substituted 1-(1-cyanoethyl-1-phenyl)-3-phenylureas. In
anhydrous phosphoric acid the first products to be formed from 1-(1-cyanoethyl-1-phenyl)-3-phenylureas
are phosphates of 4-methyl-4-phenyl-2-phenylimino-5-imino-4,5-dihydro-1,3-oxazoles, which on subse-
quent hydrolysis give the respective ureidocarboxylic acids. On prolongation of the reaction time, the phos-
phates of 4-methyl-4-phenyl-2-phenylimino-5-imino-4,5-dihydro-1,3-oxazoles rearrange to give phosphates
of 5-methyl-4-imino-3,5-diphenylimidazolidin-2-ones, and these are subsequently hydrolysed to the respec-
tive substituted 5-methyl-3,5-diphenylimidazolidin-2,4-diones. The ureidocarboxylic acids were also
prepared by alkaline hydrolysis of 5-methyl-3,5-diphenylimidazolidin-2,4-diones. The 5-methyl-3,5-
1
13
diphenylimidazolidin-2,4-diones and ureidocarboxylic acids were characterised by their H and C NMR
spectra. Structure of the 5-methyl-5-(4-nitrophenyl)-3-phenylimidazolidine-2,4-dione was verified by X-ray
d i ffraction. The alkaline hydrolysis of individual imidazolidine-2,4-diones was studies spectrophoto-
metrically in sodium hydroxide solutions at 25 °C. The rate-limiting step of the base catalysed hydrolysis
consists in decomposition of the tetrahedral intermediate. The reaction is faster if electron-acceptor sub-
stituents are present in the 3-phenyl group of imidazolidine-2,4-dione cycle. The pK values of individual
a
5-methyl-3,5-diphenylimidazolidine-2,4-diones have been determined kinetically.
J. Heterocyclic Chem., 42, 899 (2005).
1
Introduction
were characterised by their H, 13C NMR spectra and
elemental analyses.
Substituted imidazolidine-2,4-diones (hydantoins),
like barbiturates, belong among cyclic ureas with a wide
spectrum of applications [1]. The oldest known imidazo-
lidine-2,4-diones represent a significant group of psy-
chopharmaceuticals [2], analgesics [3], cytostatics [4],
antihypertensives [5] and herbicides [6]. However, in
recent years increasing attention has been paid to the sub-
stituted imidazolidine-2,4-diones having bacteriostatic
e ffects particularly against Mycobacterium tuberculosis,
which is connected with the spread of new resistant
strains [7]. The aim of the present paper is to verify the
direct synthesis of new substituted 5-methyl-3,5-
diphenylimidazolidine-2,4-diones from 1-(1-cyanoethyl-
1-phenyl)-3-phenylureas without the necessity of prelim-
inary transformation of the nitrile group into carboxylic
or ester group. Another part of this paper covers the char-
acterisation of the new substituted 5-methyl-3,5-
diphenylimidazolidine-2,4-diones, inclusive of estima-
tion of their hydrolytic stability and determination of pKa
values of the individual 5-methyl-3,5-diphenylimidazoli-
dine-2,4-diones.
1, 2, 3
a
b
c
d
e
f
g
h
1
R
4-NO 4-NO 4-NO
4-OCH
4-NO
4-NO 4-NO 4-NO
2
H
H
2
2
2
2
2
2
2
R
H
3-CF 4-COCH 4-NO 3,4-Cl 2,4-Cl
3 3 2 2 2
3
Scheme 1
Results and Discussion.
Next, we treated the substituted 1-(1-cyanoethyl-1-
phenyl)-3-phenylureas 1a-h with anhydrous phosphoric
acid, presuming a ring closure reaction to take place giving
substituted 4-methyl-4-phenyl-2-phenylimino-4,5-dihydro-
1,3-oxazol-5-ones. In this way, analogous ring closure reac-
tions proceed in strongly acid anhydrous media transform-
ing substituted 2-cyanophenylureas [9] and N-(1-cyano-1,1-
The reaction of racemic 2-amino-2-phenylpropaneni-
trile [8] and 2-amino-2-(4-nitrophenyl)propanenitrile [8]
with substituted phenyl isocyanates was used to prepare
the substituted 1-(1-cyanoethyl-1-phenyl)-3-phenylureas
1a-h (Scheme 1). In all the cases, the addition reactions
gave high yields (51 to 93%). The ureas prepared (1 a-h)

900
M. Sedlák, R. Keder, J. Hanusek and A. Růžička
Vol. 42
dialkylmethyl)benzamides [10] into benzoxazines and 4,4-
dialkyl-2-phenyl-4,5-dihydro-1,3-oxazol-5-ones, respec-
tively. In our case we found out that in anhydrous phos-
phoric acid the first reaction is ring closure (kinetic control)
between the oxygen atom of urea and the protonated nitrile
group, giving phosphates of 4-methyl-4-phenyl-2-
phenylimino-5-imino-4,5-dihydro-1,3-oxazoles. The subse-
quent slower step (thermodynamic control) involves a
rearrangement of the imonium salt to give phosphates of
substituted 5-methyl-4-imino-3,5-diphenylimidazolidin-2-
ones (Scheme 2). The rearrangement probably proceeds by
a mechanism analogous to that described for transforma-
tions of benzoxazines into quinazolindiones in anhydrous
phosphoric acid [11]. However, in our attempts at isolation
of the individual 4-methyl-4-phenyl-2-phenylimino-5-
imino-4,5-dihydro-1,3-oxazoles we only isolated, after the
hydrolysis of the salts, either the ureidocarboxylic acids 3a-
g (Method A) or the substituted 5-methyl-3,5-diphenylimi-
dazolidine-2,4-diones 2a-h, depending on the reaction time
in phosphoric acid (Scheme 2). The fact that the hydrolysis
produces ureidocarboxylic acids 3a-g can be considered a
piece of indirect evidence in favour of the reaction path via
the intermediates represented by the phosphates of 4-
methyl-4-phenyl-2-phenylimino-5-imino-4,5-dihydro-1,3-
oxazoles. 5-Methyl-3,5-diphenylimidazolidine-2,4-diones
2a-h are not hydrolysed at measurable rate in diluted phos-
phoric acid, and also the hydrolysis of nitrile group in this
medium at room temperature is very slow, hence the only
educts for the ureidocarboxylic acids 3a-g can be deriva-
tives of substituted 4,5-dihydro-1,3-oxazoles (Scheme 2).
Another piece of indirect evidence in favour of formation of
the phosphates of substituted 5-methyl-4-imino-3,5-
diphenylimidazolidin-2-ones by the rearrangement is the
fact that during the spectrophotometric monitoring of this
reaction in anhydrous phosphoric acid it takes place as a
system of two consecutive reactions, i.e. the ring closure
and rearrangement. This monitoring of the reaction of 1-[1-
cyano-1-(4-nitrophenyl)ethyl]-3-phenylurea (1 b) at first
shows an isosbestic point at 244 nm. However, after c a. 2
hrs of reaction, the spectra taken at regular intervals gradu-
ally ceaseto cross the isosbestic point, which indicates that a
consecutive reaction is taking place (Scheme 2).
Structure of the 5-methyl-5-(4-nitrophenyl)-3-phenylimi-
dazolidine-2,4-dione (2b) was verified by means of X-ray
diffraction (ORTEP). The geometry of imidazolidine-2,4-
dione fragment of 2b (Figure 1) stands in a good agreement
with those of several previously published hydantoins. The
structurally closely related imidazolidine-2,4-diones [12]
reveal comparable bond lengths and interatomic angles as
those observed in 2b. An important difference in this respect
is the system of two intermolecular hydrogen bonds. These
two hydrogen bonds in 2b connect each molecule in the
crystal unit cell with a molecule from another crystal unit
….
cell via O1 N3 bridges (N3 H3 O1 0.837(19) 2.072(19)
2.8829(15) 163.1(17)). The same arrangement is present
also in compounds described elsewhere [12].
Figure 1. Molecular structure of 2 b, ORTEP 50% probability level.
Selected interatomic distances [Å] and angles [°]: N1 C5 1.3668(17), N1
C2 1.4074(16), N1 C13 1.4339(17), C2 O1 1.2161(16), C2 N3 1.3382(17),
N3 C4 1.4529(16), N3 H3 0.837(19), C4 C7 1.5275(19), C4 C6 1.532(2),
C4 C5 1.5364(18) C5 O2 1.2053(17), N2 O22 1.207(3), N2 O21 1.218(3),
C5 N1 C2 111.56(11), C5 N1 C13 124.54(11), O1 C2 N3 128.87(12), O1
C2 N1 124.13(12), N3 C2 N1 106.99(11), C2 N3 C4 113.75(11), N3 C4 C7
113.05(11), N3 C4 C6 111.87(12), C7 C4 C6 110.07(12), N3 C4 C5
100.65(10), C7 C4 C5 111.15(11), O21 N2 C10 118.6(2), hydrogen bond
N3 H3 O1 0.837(19) 2.072(19) 2.8829(15) 163.1(17).
Crystallography.
The single crystals were obtained by vapour diffusion of
hexane into ca. 3% dichloromethane solution of 2b. The
X-ray data were collected on the Nonius KappaCCD
Scheme 2

Jul-Aug 2005
Synthesis of New Substituted 5-Methyl-3,5-diphenylimidazolidine-2,4-diones
901
carbonyl oxygen atom of amide group in the neighbouring
molecule, which in our case results in formation of dimers;
in similar way, formation of trimers was described in the
case of 1,3-nonsubstituted imidazolidine-2,4-diones [16].
The 5-methyl-3,5-diphenylimidazolidine-2,4-diones 2a-
h prepared by us were also characterised by means of 1H,
13C NMR spectra and elemental analyses. The 13C NMR
spectra of 5-methyl-3,5-diphenylimidazolidine-2,4-diones
show chemical shifts typical of carbonyl carbon atoms
C2=O (δ ∼154.0) and C4=O (δ ∼173.0) [17]. Also mea-
sured was the 15N NMR spectrum for derivative 2b, where
the nitrogen atoms N1 and N3 exhibit chemical shifts that
are comparable with those given in literature [16]. We also
prepared and characterised substituted ureidocarboxylic
acids 3a-h as products of alkaline hydrolysis of 5-methyl-
3,5-diphenylimidazolidine-2,4-diones 2a-h (Method B).
diffractometer, MoKα radiation (λ = 0.71073 Å, graphite
monochromator) at 150(2) K. Absorption corrections were
carried out for both data sets using a multiscan procedure
(SORTAV) [13]. The structure was solved by direct meth-
ods (SIR92) [14], full-matrix least-squares refinements on
F2 were carried out using the program SHELXL97 [15].
All non-hydrogen atoms are refined anisotropically, all
hydrogen atoms on carbons were calculated into idealised
positions (riding model) and assigned displacement factors
Hiso(H) = 1.2 Ueq(pivot atom) or of 1.5Ueq for the methyl
moiety. The positions of remaining hydrogen atoms were
found using difference Fourier map and refined as riding
on nitrogen with isotropic displacement factors.
Crystallographic parameters for compound 2 b: formula:
C16H13N3O4, M: 311.29, crystal system: triclinic, space
group: P-1(No 2.), a: 7.8840(3)Å, b: 9.9340(3)Å, c:
10.9630(3)Å, α: 69.8400(19)˚, β: 69.3200(17)˚, γ:
79.5170(19)˚, Z: 2, V: 752.31(4)Å3, Dc: 1.374 g.cm-3,
dimensions: 0.5 x 0.4 x 0.4 mm, µ: 0.101 mm-1, Tmin = 0.88,
Tmax = 0.979 reflections measured: 12416, independent
(Rint)a: 3295 (0.043), observed [I > 2σ(I)]: 7413, parameters
refined: 400, S valuea: 1.177, R(F obs. data): 0.065, wR(F2):
0.154, Δρmax; Δρmin: 1.275; -1.225 eÅ-3.
Study of Hydrolysis of 5-Methyl-3,5-diarylsubstituted
Imidazolidine-2,4-diones 2a-h.
For a wide variety of applications of substituted imida-
zolidine-2,4-diones it is of considerable significance to
estimate their stabilities in aqueous media at various pH
values. The hydrolysis of the 5-methyl-3,5-diphenylimida-
zolidine-2,4-diones 2a-g prepared by us was studied spec-
trophotometrically under the conditions of the psudo-first-
order reaction. No spectral changes occurred for a period
of several months in aqueous solutions of hydrochloric
acid at 25 °C. The spectral recordings of 5-methyl-3,5-
diphenylimidazolidine-2,4-diones 2a-g in aqueous solu-
tions of sodium hydroxide (0.01-1.00 mol.l–1) at 25 °C
exhibited changes with time and well developed isosbestic
points, the only hydrolytic products being sodium ureido-
carboxylates 3a-g. Figure 3 presents the dependences of
observed rate constants (kobs, s–1) on sodium hydroxide
concentration for individual derivatives carrying various
substituents at 3-phenyl group of the imidazolidine-2,4-
dione cycle. From the kinetic dependences it can be seen
that with derivatives 2a,b and 2h the observed rate con-
stant at first increases with increasing sodium hydroxide
concentration, but at a certain concentration the hydrolysis
becomes independent of hydroxide concentration. The fol-
lowing general Scheme 2 can be formulated for the
hydroxide-ion-catalysed hydrolysis. By action of sodium
hydroxide, the proton is split off from the first nitrogen
atom of the imidazolidine-2,4-dione heterocycle in an
equilibrium reaction (K). However, the reactive species is
the starting protonated substrate (SH), which underg o e s
addition reaction with hydroxide ion (k1[OH–]) to give the
negatively charged intermediate (In–), which is decom-
posed into the reaction product in the rate-limiting reaction
step (k2). In the cases of the imidazolidine-2,4-diones 2c-g
having electron-acceptor substituents, an increasing
sodium hydroxide concentration causes further accelera-
tion of the hydrolysis proportionally to the increasing σ
Figure 2. Crystal packing diagram of 2b with hydrogen bonding system.
In the crystal lattice of 2b (Figure 2) we found an inter-
molecular hydrogen bond between amide proton and

902
M. Sedlák, R. Keder, J. Hanusek and A. Růžička
Vol. 42
EXPERIMENTAL
value of the substituents. In accordance with literature
[18], this acceleration of hydrolysis can be explained by
operation of another reaction path: the OH– ion splits off
another proton from the intermediate In– (k3[OH–]) to give
a doubly charged intermediate In2–, which is decomposed
into the product (k4).
Unless otherwise stated, all the isocyanates were obtained
from Aldrich and used without further purification. Both
2-amino-2-phenylpropanenitrile and 2-amino-2-(4-nitro-
phenyl)propanenitrile were prepared by a known method [8].
Scheme 3
The experimental points given in Figure 3 are fitted with
curves, which correspond to the following rate equation
(1). By optimisation of these kinetic dependences we
determined the parameters of rate equation; moreover, it
was possible to determine the pKa values from K values
(pKa = 14 – pK) for the individual derivatives, the maxi-
mum error being ±0.05 pKa unit (see Table). The absolute
values of constants k2 and k3 cannot be determined mathe-
matically, but it is possible to determine the ratios k3/k2
(see Table). The k3/k2 values express the ratios of opera-
tion of the first and the second reaction paths (the decom-
positions of In– and In2–, respectively). For instance, with
derivative 2a (4-OCH3) the second reaction path forms
only 4 %, whereas with derivative 2e (4-NO2) it forms as
much as 40 % of overall transformation.
Table
Values of Ratios k /k and Values of pK of 5-Methyl-3,5-
3
2
a
diphenylimidazolidine-2,4-diones 2a-h
–1
–1
Figure 3. Dependence of k (s ) on NaOH concentration (mol·l ) for
obs
2
a
b
c
d
e
f
h
hydrolysis of 5-methyl-3,5-difenylimidazolidine-2,4-diones ( 2a,  2b,
 2c,  2d,  2e, 2f, 2h).
k /k
0.040
11.69
0.047
11.37
0.216
11.31
0.314
11.35
0.695
11.02
0.269
11.43
0.023
12.08
3
2
pK
a
The kinetic measurements were carried out on HP UV/VIS
Diode Array apparatus in 1 cm closed cells at 25 °C. First, a suit-
able wavelength was chosen for the kinetics runs on the basis of
the spectra scanned from 200 to 1000 nm. Then the cell was
always charged with 2 ml aqueous solution of sodium hydroxide.

Jul-Aug 2005
Synthesis of New Substituted 5-Methyl-3,5-diphenylimidazolidine-2,4-diones
903
After attaining the chosen temperature, a methanolic solution of
substrate 2a-h was added. The observed pseudo-first-order rate
123.9; 127.2; 127.4; 127.8; 128.5; 129.6; 135.0; 138.1; 147.3;
148.8; 155.3; 166.2; 197.6.
constants k
dence of absorbance with the help of an optimisation program.
were calculated from the measured time depen-
Anal. Calcd. for C
15.90. Found: C, 61.12; H, 4.49; N, 15.76.
H N O (352.4): C, 61.36; H, 4.58; N,
obs
18 16 4 4
1
The H and C NMR spectra were measured in hexadeu-
13
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-(4-nitrophenyl)urea (1e).
This compound was obtained in 81 % yield, m.p. 203-206 °C;
teriodimethyl sulphoxide (DMSO-d ), on a Bruker AMX 360
6
apparatus and a Bruker 500 Avance apparatus, respectively.
The full crystallographic data of compound 2b were deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC-248304. Copies of the
data can be obtained free of charge on request; e-mail:
deposit@ccdc.ca.ac.uk.
1
H NMR: 1.97 (s, CH ); 7.88 (d, 2H, H-2´); 7.93 (d, 2H, H-2);
3
8.32 (d, 2H, H-3); 8.34 (d, 2H, H-3´); 8.89 (s, 1H, NH); 9.12 (s,
13
1H, NH´); C NMR: 24.0; 65.7; 123.9; 124.1; 124.9; 127.3;
127.4; 131.0; 131.3; 140.9; 146.8; 147.3; 147.5; 167.4.
Anal. Calcd. for C H N O (355.3): C, 54.09; H, 3.69; N,
16 13 5 5
19.71. Found: C, 54.18; H, 3.60; N, 19.91.
Syntheses of Substances.
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-(3,4-dichlorphenyl)urea
(1f).
Sytheses of Substitututed Ureas 1a-h.
A saturated solution of 0.01 mol 2-amino-2-(4-nitrophenyl)-
propanenitrile (2-amino-2-phenylpropanenitrile) in 4 ml dry ace-
tone was treated with a saturated solution of 0.01 mol substituted
phenyl isocyanate in 2-4 ml dry acetone. The reaction proceeded
at room temperature with gradual separation of the crystalline
ureidonitrile, which was finally collected by suction and washed
with 10 ml ether. The raw product was recrystallized from an
ethanol/water mixture.
This compound was obtained in 63 % yield, m.p. 165-167 °C;
H NMR: 1.89 (s, CH ); 7.48 (d, 1H, H-5´); 7.69 (d, 1H, H-6´);
1
3
7.78 (s, 1H, H-2´); 7.87 (d, 2H, H-2); 8.27 (d, 2H, H-3); 8.62 (s,
13
1H, NH); 8.94 (s, 1H, NH´); C NMR: 24.86; 62.2; 123.6;
123.9; 127.6; 127.7; 128.7; 129.2; 129.5; 130.4; 130.8; 131.5;
132.0; 134.0; 147.3; 148.8; 155.1; 166.0.
Anal. Calcd. for C H Cl N O (379.2): C, 50.68; H, 3.19;
16 12 2 4 3
N, 14.77. Found: C, 50.53; H, 3.13; N, 14.50.
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-(4-methoxyphenyl)urea
(1a).
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-(2,4-dichlorphenyl)urea
(1g).
This compound was obtained in 87 % yield, m.p. 211-213 °C;
H NMR: 1.86 (s, CH ); 3.77 (s, OCH ); 7.00 (d, 2H, H-3´); 7.21
This compound was obtained in 78 % yield, m.p. 187-190 °C;
H NMR: 1.94 (s, CH ); 7.32 (dd, 1H, H-5´); 7.62 (d, 1H, H-3´);
1
1
3
(d, 2H, H-2´); 7.31 (s, 1H, NH); 7.88 (d, 2H, H-2); 8.27 (d, 2H,
3
3
7.81 (d, 2H, H-2); 8.06 (dd, 1H, H-6´); 8.34 (d, 2H, H-3); 8.51 (s,
13
1H, NH); 8.54 (s, 1H, NH´); C NMR: 29.2; 53.4; 53.5; 119.9;
13
H-3); 8.78 (s, 1H, NH´); C NMR: 25.2; 27.9; 55.6; 62.1; 114.0;
121.5; 122.3; 124.1; 125.8; 126.2; 127.6; 128.5; 134.7; 134.8;
147.2; 148.0; 152.8; 152.9.
115.1; 123.8; 124.0; 126.8; 127.5; 129.2; 129.8; 147.3; 149.4;
150.0; 155.6; 156.3; 159.4; 158.4; 164.7; 167.2.
Anal. Calcd. for C H Cl N O (379.2): C, 50.68; H, 3.19;
16 12 2 4 3
N, 14.77. Found: C, 50.96; H, 2.98; N, 14.82.
Anal. Calcd. for C
16.46. Found: C, 60.07; H, 4.59; N, 16.59.
H N O (340.3): C, 60.00; H, 4.74; N,
17 16 4 4
1-(1-Cyano-1-phenylethyl)-3-phenylurea (1h).
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-phenylurea (1b).
This compound was obtained in 88 % yield, m.p. 148-152 °C;
H NMR: 1.82 (s, CH ); 6.93 (m, 1H, NH); 7.22 (t, 2H, H-2);
This compound was obtained in 93 % yield, m.p. 194-197 °C;
H NMR: 1.90 (s, CH ); 6.98 (m, 2H, H-4´); 7.27 (m, 2H, H-
1
1
3
7.33-7.36 (m, 3H, H-3´, 4´); 7.41-7.45 (m, 3H, H-3, 4); 7.51 (d,
3
3´);7.39 (d, 2H, H-2´); 7.73 (s, 1H, NH); 7.80 (d, 2H, H-2); 8.33
13
2H, H-2´); 8.66 (s, 1H, NH´); C NMR: 29.9; 53.4; 117.9; 120.9;
121.8; 124.3; 125.5; 128.0; 128.7; 139.4; 141.0; 153.4.
13
(d, 2H, H-3); 8.85 (s, 1H, NH´); C NMR: 25.0; 27.7; 62.0; 62.1;
123.7; 124.0; 127.3; 127.4; 127.8; 128.6; 129.8; 134.1; 147.2;
147.3; 149.1; 149.8; 155.8; 163.4; 166.7.
Anal. Calcd. for C H N O (310.3): C, 61.93; H, 4.55; N,
16 14 4 3
18.06. Found: C, 62.12; H 4.54; N, 18.24.
A n a l. Calcd. for C
15.84. Found: C, 72.58; H, 5.98; N, 15.73.
H N O (265.3): C, 72.43; H, 5.70; N,
16 15 3
Syntheses of Substituted Imidazolidine-2,4-diones 2a-h.
The respective ureidonitrile 1a-h (0.01 mol) was added to 10
ml polyphosphoric acid, and the reaction mixture was intensively
stirred and heated to a temperature of 100 °C for 5-8 hours. After
cooling, the reaction mixture was hydrolysed in a mixture of 100
g ice and water. The separated crystalline imidazolidine-2,4-
dione was collected by suction and washed with 20 ml water. The
raw product was recrystallized from ethanol.
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-(3-trifluormehtylphenyl)-
urea (1c).
This compound was obtained in 54 % yield, m.p. 186-188 °C;
H NMR: 1.90 (s, CH ); 7.67-7.76 (m, 3H, H-4´,5´,6´); 7.84 (s,
1
3
1H, H-2´); 7.88 (d, 2H, H-2); 8.28 (d, 2H, H-3); 8.57 (s, 1H, NH);
13
8.93 (s, 1H, NH´); C NMR: 24.8; 62.1; 123.9; 127.5; 129.8;
131.5; 134.6; 147.3; 148.7; 155.3; 166.2.
3-(4-Methoxyphenyl)-5-methyl-5-(4-nitrophenyl)imidazolidine-
2,4-dione (2a).
Anal. Calcd. for C
14.81. Found: C, 53.88; H, 3.69; N, 14.99.
H F N O (378.3): C, 53.97; H, 3.46; N,
17 13 3 4 3
This compound was obtained in 92 % yield, m.p. 178-180 °C;
3
H NMR: 1.91 (s, 3H, CH ), 3.82 (s, 1H, OCH ), 7.05 (d, J = 9.0
1-[1-Cyano-1-(4-nitrophenyl)ethyl]-3-(4-acetylphenyl)urea (1d).
1
3
3
Hz, 2H, H-3´), 7.33 (d, J = 8.9 Hz, 2H, H-2´), 7.93 (d, J = 8.9
3
3
This compound was obtained in 51 % yield, m.p. 180-182 °C;
H NMR: 1.95 (s, CH ); 2.64 (s, 4´-CH ); 7.65 (d, 2H, H-2´);
1
3
Hz, 2H, H-2), 8.33 (d, J = 8.9 Hz, 2H, H-3), 9.39 (s, 1H, NH);
3
7.92 (d, 2H, H-2); 8.05 (d, 2H, H-3´); 8.34 (d, 2H, H-3); 8.69 (s,
3
13
C NMR: 25.4, 55.5, 62.9, 114.2, 123.8, 124.5, 127.3, 128.4,
146.9, 147.4, 154.8, 158.9, 173.8.
13
1H, NH); 8.99 (s, 1H, NH´); C NMR: 24.9; 26.9; 62.1; 123.6;

904
M. Sedlák, R. Keder, J. Hanusek and A. Růžička
Vol. 42
Anal. Calcd. for C
12.31. Found: C, 60.01; H, 4.36; N, 12.27.
H
N O (341.3): C, 59.82; H, 4.43; N,
NMR: 24.7, 26.0, 63.7, 124.0, 127.5, 128.6, 129.7, 132.7, 133.4,
135.1, 145.9, 146.5, 147.5, 153.5, 172.9.
Anal. Calcd. for C H Cl N O (380.2): C, 50.55; H, 2.92; N,
17 15
3 5
16 11
2 3 4
5-Methyl-5-(4-nitrophenyl)-3-phenylimidazolidine-2,4-dione (2 b) .
This compound was obtained in 72 % yield, m.p. 187-189 °C;
11.05. Found: C, 50.35; H, 3.14; N, 10.97.
5-Methyl-3,5-diphenylimidazolidine-2,4-dione (2h).
This compound was obtained in 78 % yield, m.p. 145-147 °C;
1
H NMR: 1.92 (s, 3H, CH ), 7.41-7.50 (m, 4H, H-2´, H-4´), 7.52
3
3
(t, J = 7.6 Hz, 1H, H-3´), 7.94 (d, J = 9.0 Hz, 2H, H-2), 8.35 (d,
3
3
13
J = 9.0 Hz, 2H, H-3), 9.44 (s, 1H, NH); C NMR: 25.3, 62.9,
123.9, 127.0, 127.3, 128.2, 128.9, 131.9, 146.7, 147.4, 154.4,
1
3
H NMR: 1.82 (s, 3H, CH ), 7.35-7.50 (m, 8H), 7.57 (d, J = 7.6
3
13
Hz, 2H, H-2‘), 9.23 (s, 1H, NH); C NMR: 24.9, 62.8, 125.5,
126.8, 128.0, 128.2, 128.7, 128.8, 132.0, 139.6, 154.6, 174.5.
15
173.6. N NMR: –10 (NO ), –221 (N-3), –275 (N-1).
2
Anal. Calcd. for C
13.50. Found: C, 61.94; H 4.25; N, 13.46.
H N O (311.3): C, 61.73; H, 4.21; N,
16 13 3 4
Anal. Calcd. for C
H N O (266.3): C, 72.17; H, 5.30; N,
16 14 2 2
10.52. Found: C, 72.24; H, 5.22; N, 10.41.
Syntheses of Substituted Acids 3a-h.
Method A.
5-Methyl-5-(4-nitrophenyl)-3-(3-trifluoromethylphenyl)imida-
zolidine-2,4-dione (2c).
This compound was obtained in 75 % yield, m.p. 161-163 °C;
H NMR: 1.94 (s, 3H, CH ), 7.75-7.82 (m, 3H, H-4´, H-5´, H-6´),
The respective ureidonitrile 1a-h (0.01 mol) was added to 10
ml polyphosphoric acid and the reaction mixture was intensively
stirred at room temperature for 2-4 hours. Then the reaction mix-
ture was hydrolysed with a 100 g mixture of ice and water. The
separated solid was collected by suction and washed with 20 ml
water. The raw product was recrystallized from aqueous ethanol.
1
3
7.92-7.96 (m, 3H, H-2, H-2´), 8.33 (d, J = 9.0 Hz, 2H, H-3), 9.56
3
13
(s, 1H, NH); C NMR: 25.3, 63.1, 123.8, 123.8, 123.9, 124.8,
127.4, 129.7, 130.2, 131.0, 132.8, 146.6, 147.5, 154.0, 173.4.
Anal. Calcd. for C
11.08. Found: C, 53.97; H, 3.19; N, 10.91.
H F N O (379.3): C, 53.83; H, 3.19; N,
17 12 3 3 4
Method B.
3-(4-Acetyphenyl)-5-methyl-5-(4-nitrophenyl)imidazolidine-
2,4-dione (2d).
A solution of the respective 5-methyl-3,5-diphenylimidazoli-
dine-2,4-dione 2a-h (0.01 mol) in 10 ml methanol was added to
–1
200 ml aqueous sodium hydroxide solution (c = 1 mol⋅l ). The
reaction mixture was stirred at room temperature 24 hours. The
resulting solution was cooled and gradually acidified with con-
centrated hydrochloric acid to pH ~ 1-2. The separated crystals of
ureidocarboxylic acid were collected by suction and washed with
10 ml water. The raw product was recrystallized from ethanol.
This compound was obtained in 83 % yield, m.p. 163-166 °C;
3
H NMR: 1.94 (s, 3H, CH ), 2.64 (s, 1H, COCH ), 7.63 (d, J =
1
3
3
8.5 Hz, 2H, H-2´), 7.94 (d, J = 8.8 Hz, 2H, H-2), 8.09 (d, J = 8.5
3
3
3
Hz, 2H, H-3´), 8.33 (d, J = 8.8 Hz, 2H, H-3), 9.58 (s, 1H, NH);
13
C NMR: 25.4, 26.9, 63.1, 123.9, 126.7, 127.4, 128.9, 136.0,
146.4, 146.6, 154.0, 154.0, 173.4, 197.4.
Anal. Calcd. for C
11.89. Found: C, 60.96; H, 4.20; N, 11.65.
H N O (353.3): C, 61.19; H, 4.28; N,
18 15 3 5
2 - ( 4 - M e t h o x y p h e n y l c a r b a m o y l ) a m i n o - 2 - ( 4 - n i t r o p h e n y l )-
propanoic Acid (3a).
5-Methyl-3,5-di(4-nitrophenyl)imidazolidine-2,4-dione (2e).
This compound was obtained in 92 % (method A) and 90 %
1
(method B) yields, m.p. 168-171 °C (decomp.); H NMR: 2.00
1
This compound was obtained in 83 % yield, m.p. 217-219 °C; H
3
3
NMR: 1.95 (s, 3H, CH ), 7.82 (d, J = 9.2 Hz, 2H, H-2´), 7.94 (d, J
3
= 9.0 Hz, 2H, H-2), 8.33 (d, J = 9.0 Hz, 2H, H-3), 8.37 (d, J = 9.2
3
(s, 3H, CH ), 3.71 (s, 1H, OCH ), 6.83 (d, J = 9.0 Hz, 2H, H-2´),
3
3
3
7.26 (d, J = 8.9 Hz, 2H, H-3´), 7.20 (s, 1H, NH), 7.76 (d, J = 8.9
3
3
3
13
Hz, 2H, H-3´), 9.66 (s, 1H, NH); C NMR: 25.3, 63.0, 123.7,
124.0, 127.0, 127.2, 137.7, 146.0, 146.4, 147.4, 153.5, 173.0.
3
Hz, 2H, H-2), 8.26 (d, J = 8.8 Hz, 2H, H-3), 8.80 (s, 1H, NH´);
13
C NMR: 24.2, 55.3, 61.1, 114.0, 119.1, 119.2, 123.3, 127.6,
133.5, 146.6, 150.2, 154.1, 173.6.
Anal. Calcd. for C
15.72. Found: C, 53.93; H, 3.30; N, 15.56.
H N O (356.3): C, 53.94; H, 3.39; N,
16 12 4 6
Anal. Calcd. for C
H N O (359.34): C, 56.82; H, 4.77; N,
17 17 3 6
11.69. Found: C, 56.75; H, 4.63; N, 11.54.
3-(3,4-Dichlorophenyl)-5-methyl-5-(4-nitrophenyl)imidazoli-
dine-2,4-dione (2f).
2-(Phenylcarbamoyl)amino-2-(4-nitrophenyl)propanoic Acid
(3b).
This compound was obtained in 80 % yield, m.p. 165-167 °C;
1
3
H NMR: 1.92 (s, 3H, CH ), 7.51 (dd, J = 8.4 Hz, J = 1.7 Hz 1H,
4
3
H-5´), 7.79 (d, J = 8.9 Hz, 1H, H-6´), 7.84 (d, J = 1.7 Hz, 1H, H-
This compound was obtained in 87 % (method A) and 92 %
1
(method B) yields, m.p. 167-168 °C (decomp.); H NMR: 2.02
3
4
3
3
2´), 7.93 (d, J = 8.6 Hz, 2H, H-2), 8.33 (d, J = 8.7 Hz, 2H, H-3),
3
(s, 3H, CH ), 7.24 (t, J = 7.9 Hz, 1H, H-3´), 7.36-7.38 (m, 3H,
13
9.55 (s, 1H, NH); C NMR: 25.3, 63.0, 123.8, 127.1, 127.4,
3
H-2´, NH), 7.78 (d, J = 8.8 Hz, 2H, H-2), 8.27 (d, J = 8.7 Hz,
3
3
128.7, 130.7, 131.1, 131.8, 146.5, 147.4, 153.6, 153.8, 173.2.
Anal. Calcd. for C H Cl N O (380.2): C, 50.55; H, 2.92; N,
13
2H, H-3), 9.05 (s, 1H, NH´); C NMR: 23.7, 61.1, 117.5, 121.4,
16 11
11.05. Found: C, 50.40; H, 3.04; N, 11.15.
2 3 4
123.3, 127.6, 128.8, 140.2, 146.6, 150.1, 153.8, 173.6.
Anal. Calcd. for C
H N O (329.31): C, 58.36; H, 4.59; N,
16 15 3 5
12.76. Found: C, 58.18; H, 4.49; N, 12.64.
3-(2,4-Dichlorophenyl)-5-methyl-5-(4-nitrophenyl)imidazoli-
dine-2,4-dione (2g).
2-(3-Trifluoromethylphenylcarbamoyl)amino-2-(4-nitrophenyl)-
propanoic Acid (3c).
This compound was obtained in 74 % yield, m.p. 202-204 °C;
H NMR: 1.93 and 1.96 (2×s, 1H, CH ), 7.59-7.63 (m, 1H, H-6´),
1
3
4
3
7.67 and 7.74 (d and dd, J = 8.5 Hz, J = 1.7 Hz 1H, H-5´), 7.86-
This compound was obtained in 85 % (method A) and 70 %
1
(method B) yields, m.p. 174-176 °C; H NMR: 2.00 (s, 3H,
4
7.93 (2×d, J = 2.2 Hz, 1H, H-3´), 7.95 (2×d, J = 8.9 Hz, 2H, H-2),
3
3
8.36 (m, J = 8.6 Hz, 2H, H-3), 9.53 and 9.60 (2×s, 1H, NH);
13
3
CH ), 7.26 (d, J = 6.1 Hz, 1H, H-4´), 7.47-7.50 (m, 2H, H-5´,H-
C
3

Jul-Aug 2005
Synthesis of New Substituted 5-Methyl-3,5-diphenylimidazolidine-2,4-diones
905
3
6´), 7.64 (s, 1H, NH), 7.79 (d, J = 8.5 Hz, 2H, H-2), 7.96 (s,1H,
Anal. Calcd. for C H N O (284.31): C, 67.59; H, 5.67; N,
16 16 2 3
9.85. Found: C, 67.86; H, 5.67; N, 9.68.
3
H2´), 8.27 (d, J = 8.6 Hz, 2H, H-3), 9.84 (s, 1H, NH´);
13
C
NMR: 24.1, 61.3, 113.5, 117.8, 121.3, 123.5, 127.8, 130.1, 141.3,
146.9, 150.0, 154.0, 173.6.
Conclusion.
The reaction of 1-(1-cyanoethyl-1-phenyl)-3-phenylureas
1a-h in the medium of anhydrous phosphoric acid at first
gives phosphates of 4-methyl-4-phenyl-2-phenylimino-5-
imino-4,5-dihydro-1,3-oxazoles, which subsequently, after a
longer reaction time, rearrange to phosphates of substituted 5-
methyl-4-imino-3,5-diphenylimidazolidin-2-ones. The
hydrolysis of the reaction mixture produces (depending on the
reaction time) either ureidocarboxylic acids 3a-g or substi-
tuted 5-methyl-3,5-diphenylimidazolidine-2,4-diones 2a-h.
As compared with the classical method, this new synthetic
procedure of preparation of imidazolidine-2,4-diones does not
require preliminary hydrolysis of the nitrile group to car-
boxylic or ester group. The 5-methyl-3,5-diphenylimidazoli-
dine-2,4-diones obtained are practically stable in solutions of
strong mineral acids. In aqueous solutions of sodium hydrox-
ide, they undergo hydrolysis to give salts of substituted urei-
docarboxylic acids 3a-g.
Anal. Calcd. for C
N, 10.58. Found: C, 51.09; H, 3.63; N, 10.76.
H F N O : (397.31): C, 51.39; H, 3.55;
17 14 3 3 5
2-(4-Acetylphenylcarbamoyl)amino-2-(4-nitrophenyl)propanoic
Acid (3d).
This compound was obtained in 79 % (method B) yield, m.p.
1
165-168 °C; H NMR: 2.02 (s, 3H, CH ), 2.52 (s, 1H, COCH ),
3
7.48 (d, J = 8.8 Hz, 2H, H-2´), 7.56 (s, 1H, NH), 7.78 (d, J = 8.9
3
3
3
3
3
Hz, 2H, H-2), 7.87 (d, J = 8.7 Hz, 2H, H-3´), 8.27 (d, J = 8.9
13
Hz, 2H, H-3), 9.59 (s, 1H, NH´); C NMR: 23.4, 26.8, 61.1,
122.1, 123.4, 127.5, 132.2, 136.5, 139.4, 146.6, 150.1, 153.0,
173.4, 197.8.
Anal. Calcd. for C H N O (372.35): C, 58.22; H, 4.61; N,
18 17 3 6
11.32. Found: C, 58.23; H, 4.48; N, 11.46.
2-(4-Nitrophenylcarbamoyl)amino-2-(4-nitrophenyl)propanoic
Acid (3e).
This compound was obtained in 76 % (method B) yield, m.p.
Acknowledgments.
1
214-216 °C; H NMR: 2.04 (s, 3H, CH ), 7.58 (d, J = 9.2 Hz,
3
3
2H, H-2´), 7.64 (s, 1H, NH), 7.78 (d, J = 8.8 Hz, 2H, H-2), 8.16
3
The authors wish to thank Dr. Ivana Císařová for the determi-
nation of X-ray diffraction. The financial support provided by the
Grant Agency of the Czech Republic (Grant No. 203/04/0646) is
gratefully acknowledged.
3
(d, J = 9.1 Hz, 2H, H-3´), 8.27 (d, J = 8.8 Hz, 2H, H-3), 9.85 (s,
3
13
1H, NH´); C NMR: 23.2, 61.1, 116.9, 123.3, 125.2, 127.4,
140.6, 146.6, 146.7, 150.1, 152.9, 173.2.
Anal. Calcd. for C H N O (374.3): C, 51.34; H, 3.77; N,
16 14 4 7
14.97. Found: C, 51.33; H, 3.70; N, 15.04.
REFERNCES AND NOTES
2-(3, 4-Dichlorophenylcarbamoyl)amino-2-(4-nitrophenyl) -
propanoic Acid (3f).
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1
(method B) yields, m.p. 166-167 °C; H NMR: 2.00 (s, 3H,
3
CH ), 7.19 (d, J = 7.4 Hz, 1H, H-6´), 7.47 (d, J = 8.8 Hz, 1H, H-
3
3
5´), 7.54 (s, 1H, NH), 7.77 (d, J = 8.5 Hz, 2H, H-2), 7.81 (s, 1H,
3
3
H-2´), 8.26 (d, J = 8.6 Hz, 2H, H-3), 9.56 (s, 1H, NH´);
13
C
NMR: 23.6, 61.1, 117.6, 117.7, 122.6, 123.4, 127.6, 130.6, 131.1,
140.4, 146.6, 149.8, 153.5, 173.5.
Anal. Calcd. for C H Cl N O (398.2): C, 48.26; H, 3.29;
16 13 2 3 5
N, 10.55. Found: C, 48.17; H, 3.07; N, 10.31.
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2-(2, 4-Dichlorophenylcarbamoyl)amino-2-(4-nitrophenyl) -
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1
165-166 °C; H NMR: 1.99 (s, 3H, CH ), 7.29 (d, J = 7.5 Hz,
3
3
1H, H-5´), 7.57 (s, 1H, NH), 7.79 (d, J = 8.6 Hz, 2H, H-2), 8.08
3
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3
(d, J = 8.9 Hz, 1H, H-6´), 8.24-8.29 (m, 3H, H-3, H-3´), 8.77 (s,
13
1H, NH´); C NMR: 23.9, 61.4, 121.8, 122.1, 123.3, 125.5,
127.4, 127.6, 128.5, 135.7, 146.6, 149.6, 153.5, 173.3.
H Cl N O (398.2): C, 48.26; H, 3.29;
16 13 2 3 5
Anal. Calcd. for C
N, 10.55. Found: C, 48.20; H, 3.11; N, 10.44.
2-(Phenylcarbamoyl)amino-2-phenylpropanoic Acid (3h).
This compound was obtained in 80 % (method A) and 72 %
1
(method B) yields, m.p. 181-184 °C; H NMR: 1.97 (s, 3H, CH ),
3
6.93 (t, J = 7.3 Hz, 1H, H-4´), 7.11 (s, 1H, NH), 7.25 (t, J = 7.6
3
3
3
Hz, 2H, H-3‘), 7.33-7.44 (m, 5H, H-2, H-3, H-4), 7.53 (d, J = 7.5
13
Hz, 2H, H-2´), 8.93 (s, 1H, NH´); C NMR: 23.7, 61.2, 117.5,
121.2, 125.9, 127.4, 128.4, 128.8, 140.5, 142.3,154.1, 174.5.

906
M. Sedlák, R. Keder, J. Hanusek and A. Růžička
Vol. 42
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