Synthesis of new imidazolidin-2,4-dione and 2-thioxoimidazolidin-4-ones via C-phenylglycine derivatives

Article abstract of DOI:10.3390/molecules15010128

Hydantoins and their derivatives constitute a group of pharmaceutical compounds with anticonvulsant and antiarrhythmic properties, and are also used against diabetes. N-3 and C-5 substituted imidazolidines are examples of such products. As such, we have developed a synthesis of 2,4-dione and 2-thioxo-4-one imidazolidinic derivatives by reaction of amino acids with C-phenylglycine, phenyl isocyanate and phenyl isothiocyanate. Four amino-derivatives IG(1-4) and eight imidazolidinic derivatives, IM(1-8), were obtained in yields of 70-74%. The mass, infrared, ¹H and ¹³C-NMR spectra of representative products are discussed.

Full text of DOI:10.3390/molecules15010128

Molecules 2010, 15, 128-137; doi:10.3390/molecules15010128
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of New Imidazolidin-2,4-dione and 2-Thioxo-
imidazolidin-4-ones via C-Phenylglycine Derivatives
José Alixandre de Sousa Luis 1,2, José Maria Barbosa Filho 1, Bruno Freitas Lira 1, Isac Almeida
Medeiros 1, Liana Clébia Soares Lima de Morais 1, Alexsandro Fernandes dos Santos 3,
Cledualdo Soares de Oliveira 3 and Petrônio Filgueiras de Athayde-Filho 1,3,
*
1
Laboratório de Tecnologia Farmacêutica, Universidade Federal da Paraíba, João Pessoa - PB, CEP
58.051-970, Brazil
2
3
Centro de Educação e Saúde, Unidade Acadêmica de Saúde, Universidade Federal de Campina
Grande, Cuité - PB, CEP 58.175-000, Brazil
Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa - PB, CEP
58059-900, Brazil
* Author to whom correspondence should be addressed; E-Mail: athayde-filho@quimica.ufpb.br.
Received: 13 October 2009; in revised form: 1 December 2009 / Accepted: 2 December 2009 /
Published: 30 December 2009
Abstract: Hydantoins and their derivatives constitute a group of pharmaceutical
compounds with anticonvulsant and antiarrhythmic properties, and are also used against
diabetes. N-3 and C-5 substituted imidazolidines are examples of such products. As such,
we have developed a synthesis of 2,4-dione and 2-thioxo-4-one imidazolidinic derivatives
by reaction of amino acids with C-phenylglycine, phenyl isocyanate and phenyl
isothiocyanate. Four amino-derivatives IG(1-4) and eight imidazolidinic derivatives,
IM(1-8), were obtained in yields of 70–74%. The mass, infrared, 1H and 13C-NMR spectra
of representative products are discussed.
Keywords: hydantoins; C-phenylglycine; imidazolidines; 2-thioxoimidazolidine-4-ones

Molecules 2010, 15
129
Introduction
Nowadays, there is an incessant search for biological functional compounds suitable for treating
diverse illnesses. The development of more efficient and less toxic products often involves the study of
new synthetic routes or structural modifications of existing molecules and medicinal drugs are often
manufactured by modification or molecular variation using bioisosterism [1]. The influence of an atom
or an atom group modification by bioisosters can be analyzed based on the biological activity
presented by the drug, having an identical or exact antagonistic effect. The synthesis of heterocyclic
2,4-imidazolidinones or hydantoins (1) has been studied intensively for their important
pharmacological properties [2]. Substances that contain these heterocyclic moieties present significant
biological activities as antifungal [3], antibacterial and anti-inflammatory [4] drugs, for the treatment
of hypoglycemia [5], or as plant growth inhibitors [6], among other properties. Thiohydantoins are
sulfur analogs of hydantoins with one or two carbonyl groups replaced by thiocarbonyl groups. The 2-
thiohydantoins have been widely evaluated due to their applications as hypolipidemic, anti-
carcinogenic, antiviral (e.g., herpes virus, HSV, HIV and tuberculosis), antimicrobial, anti-ulcer and
anti-inflammatory agents [7].
Several studies [8–10] have described the synthesis of amino acid compounds, their importance and
applications as intermediates for the synthesis of heterocyclics [11,12]. The present study aimed to
contribute with the chemical and pharmacological studies of imidazolidinic compounds, whereby
imidazolidinic bioisosters obtained from amino acids were synthesized and characterized as
imidazolidin-2,4-dione and 2-thioxo-imidazolidin-4-one derivatives. Among the compounds
synthesized we evaluated 3-phenyl-5-(4-isopropylphenyl)-imidazolidin-2,4-dione (IM-7), and a focus of
this study was to investigate the acute cardiovascular effects induced by IM-7 in rats. In addition, the
effects of 5-(4-ethylphenyl)-3-phenylimidazolidin-2,4-dione (IM-3) on the Central Nervous System was
investigated, and its possible involvement in antinociception was considered based on results obtained
with early pharmacological screening [13].
Results and Discussion
Eight 3,5-di-substituted-imidazolidinic compounds were obtained in 70–74% yield by means of
amino acids via Strecker synthesis. Of these imidazolidinic compounds, one (IM-5) was previously
reported [14], but its structure was not elucidated by the usual physical techniques. All samples were
obtained in two steps: first, a Strecker synthesis was performed using sodium cyanide, ammonium chloride
and 4-arylaldehydes, followed by an acid hydrolysis to form the corresponding C-arylglycine derivative
(IG). C-4-Methoxyphenylglycine (IG-1), C-4-ethylphenylglycine (IG-2), C-4-methylphenylglycine (IG-3)
and C-4-isopropylphenylglycine (IG-4) were thus obtained. In the second part, the amino acids reacted
with phenyl isocyanate or phenyl isothiocyanate, followed by an acid hydrolysis reaction (Scheme 1). Eight
imidazolidinic compounds (IM) were thus obtained: 3-phenyl-5-(4-methylphenyl)-imidazolidin-2,4-dione
(IM-1); 3-phenyl-5-(4-methylphenyl)-2-thioxoimidazolidin-4-one (IM-2); 5-(4-ethylphenyl)-3-phenyl-
imidazolidin-2,4-dione (IM-3); 3-phenyl-5-(4-ethylphenyl)-2-thioxoimidazolidin-4-one (IM-4); 5-(4-
methoxyphenyl)-3-phenylimidazolidin-2,4-dione (IM-5); 3-phenyl-5-(4-metoxyphenyl)-2-thioxo-
imidazolidin-4-one (IM-6); 5-(4-isopropylphenyl)-3-phenylimidazolidin-2,4-dione (IM-7); 3-phenyl-5-(4-
isopropylphenyl)-2-thixo-imidazolidin-4-one (IM-8) (Scheme 1).

Molecules 2010, 15
130
Scheme 1. Synthesis of imidazolidines.
R
6
5'
5
4
HClaq
+
CHO
KCN
R
+
NH4Cl
4'
3
*
H2N CH-COOH
8
'
9
7'
8
IC-(1-4)
+
6
O
7
N
4
3
'
11
12
'
*
5
2
X
10
11
HClaq
N
H
1
13
XCN
R
12
X = O or S
IM-(1- 8)
Compound
IG-1
R
X
−
−
−
−
O
S
O
S
O
S
CH3O
C2H5
CH3
i-Pr
CH3
IG-2
IG-3
IG-4
IM-1
IM-2
IM-3
IM-4
IM-5
IM-6
CH3
C2H5
C2H5
CH3O
CH3O
IM-7
IM-8
i-Pr
i-Pr
O
S
Mass spectral data support the proposed structures. Scheme 2 shows the fragmentation pattern for 3-
phenyl-5-(4-methylphenyl)-imidazolidin-2,4-dione (IM-1) which serves as an example for all the
compounds mutatis mutandis.
Scheme 2. MS fragmentation pattern for the imidazolidines.
CO
C H N
N
C
O
6
5
m/z = 91
N
m/z = 119
CO
N
O
m/z = 238
PhNCO
H
O
NCO
N
N
O
CH2N
H
H
NH
C
m/z = 226
M
m/z =77
m/z = 119
m/z = 91

Molecules 2010, 15
131
The IR spectra are in agreement with the organic functionalities present. The principal features
observed in the intermediates IG(1-4) are the carboxylic acid group C=O and C-O- stretches at
1,753–1,740 and 1,422–1,398 cm-1, whereas the N-H stretch of the amine group is observed at
3,165–3,100 cm-1. Mainly N-H, C=O and C=S stretches were detected in the imidazolidinic rings. The
heterocyclic N-H was characterized by the absorption band at 3,317–3,154 cm–1. The C=O groups
were characterized by absorptions at 1,773 – 1,711 cm-1. The C=S absorptions in IM-2, IM-4, IM-6
and IM-8 were characterized by bands at 1,513, 1,518, 1,515 and 1,517 cm-1, respectively. The absorption
bands at 1,025 and 1,029 cm-1 refer the C-O stretch of methoxyl groups of the compounds IM-5 and
IM-6.
The 1H-NMR spectra are useful for the determination of structures. In the intermediates IG-(1-4) and
imidazolidinic compounds IM(1-8), the benzene ring hydrogens show peaks at δ 6.93–7.54 ppm. In IG(1-4),
the α-hydrogen signals are at δ 4.83, 4.98, 4.96 and 4.78 ppm. The methoxyl groups in IG-1, IM-5 and IM-6
is characterized by singlets at 3.72, 3.71 and 3.73 ppm, respectively. The ethylic group in IG-2, IM-3 and
IM-4 is characterized by triplets at 1.07, 1.16 and 1.18 ppm coupled with quartets at 2.53, 2.60 and 2.64 ppm.
The methylic groups in IG-3, IM-1 and IM-2 were characterized by singlets at 2.27, 2.49 and 2.27 ppm. The
isopropyl group in IG-4, IM-7 and IM-8 is characterized by doublets at 0.84, 1.22 and 1.21 ppm,
respectively, coupled with septets at 2.18 and 2.90 ppm for the last two compounds. In all imidazolinic
compounds the single hydrogen linked to the heterocyclic ring occur as singlet in the range 5.16 – 5.58 ppm
13
and the N-H signals occur as singlets in the range 8.86–10.99 ppm (Table 1). The significant C-NMR
spectra signals are listed in Table 2 and are in agreement with the proposed structures.
Table 1. 1H-NMR spectra data (DMSO-d6): Chemical shifts δ (ppm) from TMS, J (Hz).
1H
H- C*
4.83
-C6H4–R
-C6H5
H-N
-R
IG-1, R = OCH3
IG-2, R = CH3CH2
6.93 – 7.39 (m, 4H)
7.17 – 7.33 (m, 4H)
-
-
8.92 (s, 2H)
3.72 (s, 3H)
4.98
8.92 (s, 2H) 1.07 (t, 3H); 2.53 (q, 2H); J
= 7.6 Hz
IG-3, R = CH3
4.96
4.78
7.21 (d, 2H); 7.39 (d,
2H), J= 8,2 Hz
7.01 (d, 2H); 7.11 (d,
2H), J= 8.0 Hz
7.41 (m, 4H)
-
9.02 (s, 2H)
9.44 (s, 2H)
9.21 (s, 1H)
2.27 (s, 3H)
IG-4, R = (CH3)2CH
-
0.84 (d, 6H); 2.18 (sept,
1H); J = 6.4 Hz
2.49 (s, 3H)
IM-1, R = CH3
IM-2, R = CH3
IM-3, R = CH3CH2
5.52 (s, 1H)
5.49 (s, 1H)
5.33 (s, 1H)
7.71(m, 5H)
7.24 (m, 4H)
7.47(m, 5H) 10.99 (s, 1H)
7.51 (m, 5H) 8.97 (s, 1H)
2.27 (s, 3H)
7.24 (m, 4H)
1.16 (t, 3H);
2.60 (q, 2H); J = 7,6 Hz
1.18 (t, 3H);
IM-4, R = CH2CH3
5.58 (s, 1H)
7.28 (m, 4H)
7.54 (m, 5H) 11.04 (s, 1H)
2.64 (q, 2H); J = 7,6 Hz
3.71 (s, 3H)
IM-5, R = OCH3
IM-6, R = OCH3
5.16 (s, 1H)
5.49 (s, 1H)
6.95 (m, 4H)
7.27 (m, 4H)
7.16 (m, 4H)
7.32 (m, 5H) 8.86 (s, 1H)
7.51 (m, 5H) 10.96 (s,1H)
7.50 (m, 5H) 8.97 (s, 1H)
3.73 (s, 3H)
IM-7, R = (CH3)2CH 5.38 (s, 1H)
1.22(d,6H);
2.90 (sept, 1H); J = 6.,8 Hz
1.21(d,6H);
IM-8, R = (CH3)2CH 5.55 (s, 1H)
7.28 (m, 4H)
7.54 (m, 5H) 10.98 (s, 1H)
2.90 (sept, 1H); J = 6,8 Hz

Molecules 2010, 15
Table 2. 13C-NMR spectra data (DMSO-d6): Chemical shifts δ (ppm) from TMS.
132
13C
C*
CAr-N
-
CAr-C*
130.3
130.6
130.4
128.5
133.0
133.7
132.2
133.4
130.2
133.6
133.2
133.4
CAr-R
164.9
145.3
138.8
151.0
138,4
138,9
144,3
144,6
159,4
159,9
148,9
149,2
-R
C=S
C=O
174.9
169.8
169.8
170.0
IG-1, R = OCH3
IG-2, R = CH3CH2
IG-3, R = CH3
60.4
55.6
55.3
60.3
60.2
63.1
59.8
62.6
59.9
62.7
59.8
62.6
60.0
-
-
15.8; 28.1
20.9
-
-
-
IG-4, R = (CH3)2CH
IM-1, R = CH3
-
23.9; 30.9
21.1
-
132.4
131.7
133.1
131.7
130.2
133,6
132.2
131.8
-
183.1
-
156.2; 172.3
173.4
IM-2, R = CH3
21.2
IM-3, R = CH3CH2
IM-4, R = CH3CH2
IM-5, R = OCH3
IM-6, R = OCH3
IM-7, R = (CH3)2CH
IM-8, R = (CH3)2CH
15.7; 27.9
15.7; 28.0
55.5
155.8; 171.9
172.9
182.7
-
154.8; 173.2
173.5
55.6
182.9
-
23.9; 33.2
23.9; 33.2
155.7; 171.8
172.9
182.7
The pharmacological studies, in vivo, with non-anesthetized rats, IM-7 (1, 5, 10, 20, 30 mg/kg, i.v.)
induced hypotension (-3.6 ± 1.6, -4.2 ± 1.4, -4.4 ± 1.6, -24.6 ± 10.9, -32 ± 9.2 %). Compound IM-7
(20, 30 mg/kg, i.v.) also induced bradycardia (-28 ± 15, -50 ± 15 %). Both responses were completely
abolished in rats treated with atropine (2 mg/Kg, i.v.). In mesenteric rings IM-7 (10-12–10-3 M) induced
relaxation of phenylephrine (10 mM) induced tone (EC50 = 2.9 ± 0.4x10-5 M). This effect was
significantly attenuated after removal of the vascular endothelium, 100 mM L-NAME, or 1 nM
atropine (EC50 = 1.2 ± 0.1 × 10-4; 1.4 ± 0.2 × 10-4; 1.3 ± 0.3 × 10-4 M, respectively). However, IM-7
induced relaxant effect was not attenuated by indomethacin (30 mM).
The present study showed that treatment of mice with 5-(4-ethylphenyl)-3-phenylimidazolidin-2,4-
dione IM-3 in doses of 250 and 500 mg/kg, i.p caused a significant decrease in writhing numbers after
administration (7.3 ± 2.3; 3.6 ± 1.7, respectively) in relation to control (22.1 ± 6.0), indicating a
antinociceptive effect, however, the central depressant effect was not confirmed because this
compound did not increase the response time in the Hot Plate Test in comparison with a standard drug
(morphine 6 mg/kg, i.p).
Experimental
General
Mass spectra were obtained using a Finnigan GCQ Mat type quadrupole-ion trap spectrometer. IR
spectra were obtained by means of a Bruker IFS66 spectrometer with the samples in KBr discs.
13
1H- and C-NMR spectra were recorded on a Varian Unity Plus 200 MHz spectrometer operating at
200 MHz for 1H and 50 MHz for 13C, the sample being dissolved in DMSO-d6 with TMS as reference.
Elemental analysis was carried out using a Perkin Elmer Elemental Microanalyser. The melting points
were determined using a Kofler hot-plate apparatus combined with a Carl-Zeiss microscope and are
uncorrected. In the pharmacological studies with IM-7, male Wistar rats (250–300 g) were
anesthetized and the abdominal aorta and inferior vena cava were cannulated for pressure recordings
and administration of drugs. Rat superior mesenteric rings (1-2 mm) were suspended by cotton threads

Molecules 2010, 15
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for isometric tension recordings in Tyrode´s solution, 37 ºC, gassed with 95% O2 and 5% CO2, resting
tension 0.75 g. For the pharmacological studies of IM-3, Male Swiss mice (25–35 g) were treated with
increased doses of IM-3 (125, 250 and 500 mg/kg) in the toxicological Test, for calculus of Median
Letal Dose (LD50), a posteriori writhing and Hot Plate Tests were realized. The parameters utilized
were writhing numbers, reaction time(s) and latency(s).
General method for the preparation of C-arylglycines
Appropriate amounts of KCN and ammonium chloride were dissolved in distilled H2O (100 mL).
Equimolar quantities of the arylaldehyde in MeOH (100 mL), were added under vigorous stirring and
the reaction continued for 120 minutes. H2O (250 mL) was added and the resulting mixture was then
added to toluene (250 mL). The toluene phase was separated and then extracted with HCl (6N,
3 × 100 mL). The combined acid extract was refluxed for 8 hours, giving the desired product in the
form of white crystals after cooling. These were filtered off, washed with CHCl3 and air-dried.
(±)C-(4-Methoxyphenyl)glycine (IG-1). KCN (24.80 g; 381 mmol), NH4Cl (20.38 g; 381 mmol) and
4-methoxybenzaldehyde (50.00 g, 367 mmol), were reacted according to the general procedure. Yield:
70.30% (46.80 g); recrystallization from EtOH/H2O (1:1); Mp 230 – 232 °C. IR νmax 3,165 (NH);
1
2,960 and 2,839 (CH3); 1,748 (C=O); 1,413 (CAr-O); 1,028 (CH3-O) cm-1. H-NMR δ 3.72 (s, 3H,
13
CH3O); 4.83 (s, 1H, H2); 6.93–7.39 (m, 4H, aromatics); 8.92 (s, 2H, NH2) ppm. C-NMR δ 60.0
(CH3O); 60.4 (C2); 119.2 (C4-4’); 130.3 (C3); 134.7 (C5-5’); 164.9 (C6); 174.9 (C1).
(±)C-(4-Ethylphenyl)-glycine (IG-2). KCN (12.37 g; 190 mmol), NH4Cl (10.16 g; 190 mmol) and
4-ethylbenzaldehyde (25 g; 186 mmol), were reacted according to the general procedure. Yield:
73.10% (24.40 g); recrystallization from EtOH/H2O (1:1); Mp 228–230 ºC. IR νmax 3,139 (NH); 2,976
1
and 2,945 (CH2, CH3); 1,745 (C=O); 1,422 (C-O) cm-1. H-NMR δ 1.07 (t, 3H, CH3CH2 J = 7.6 Hz);
2.53 (q, 2H, CH3CH2 J = 7.6 Hz); 4.98 (s, 1H, H2); 7.17–7.33 (m, 4H, aromatics); 8.92 (s, 2H, NH2)
13
ppm. C-NMR δ 15.8 (CH3CH2); 28.1 (CH3CH2); 55.6 (C2); 128.5 (C4-4’ and C5-5’); 130.6 (C3);
145.3 (C6); 169.8 (C1) ppm.
(±)C-(4-Methylphenyl)-glycine (IG-3). KCN (16.27 g; 250 mmol), NH4Cl (13.37 g; 250 mmol) and
4-methylbenzaldehyde (30 g; 250 mmol), were reacted according to the general procedure. Yield:
o
74.64% (30.80 g); recrystallization from EtOH/H2O (1:1); Mp 287 – 289 C. IR νmax 3,100 (NH);
1,740 (C=O); 1,405 (C-O); 2,967 (CH3) cm-1. 1H-NMR δ 2.27 (s, 3H, CH3); 4.96 (s, 1H, H2); 7.21 (d,
2H, H4-4` J = 8.2 Hz); 7.39 (d, 2H, H5-5` J = 8.2 Hz); 9.02 (s, 2H, NH2) ppm. 13C-NMR δ 20.9 (CH3);
55.3 (C2); 128.2 (C4-4`); 129.4 (C5-5´); 130.4 (C3); 138.8 (C6); 169.8 (C1) ppm.
(±)C-(4-Isopropylphenyl)-glycine (IG-4). KCN (7.16 g; 110 mmol), NH4Cl (5.88 g; 110 mmol) and
4-isopropylbenzaldehyde (16.60 g; 112 mmol), were reacted according to the general procedure.
Yield: 72.30% (15.64 g); recrystallization from EtOH/H2O (1:1); Mp 182 °C. IR νmax 3,153 (NH);
1
1,753 (C=O); 1,398 (C-O) cm-1. H-NMR δ 0.84 (d, 6H, CH(CH3)2, J = 6.4 Hz); 2.18 (septet, 1H,
CH(CH3)2, J = 6.4 Hz); 4.78 (s, 1H, C*H); 7.01 (d, 2H, aromatics, J = 8.0 Hz); 7,11(d, 2H, aromatics,

Molecules 2010, 15
134
J = 8.0 Hz), 9.44 (s, 2H, NH2) ppm. 13C-NMR δ 23.9 (CH(CH3)2); 30.9 (CH(CH3)2); 60.3 (C-2); 127.5
(C-4, 4’); 128.5 (C-3); 128.90 (C-5, 5’); 151.0 (C-6); 170.0 (C-1) ppm.
General method for the preparation of 3-phenyl-5-arylimidazolidinic derivatives
C-Arylglycine was dissolved in the minimum amount of aqueous NaOH (10%) with stirring which
was continued for an additional 120 minutes. Equimolar quantities of the required phenyl isocyanate or
phenyl isothiocyanate was added in small amounts and stirring continued for a further 4 h. After 24
hours the precipitate was separated by filtration and the remaining solution was acidified with HCl.
The aroylimidazilidinic acid obtained was refluxed for 1 h with 40 mL of 6N HCl solution. The white
crystalline product was filtered off, washed with H2O, air-dried and recrystallized from ethanol/H2O
(1:1).
(±)-3-Phenyl-5-(4-methylphenyl)-imidazolidine-2,4-dione (IM-1). C-4-Methylphenylglycine (1.48 g;
9 mmol) and PhNCO (1.07 g; 9 mmol), were reacted according to the general procedure. Yield:
77.50% (1.85 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 198–199 °C. IR νmax
3,236 (NH); 2,921 (CH3); 1,715 (C=O) cm-1. 1H-NMR δ 2.49 (s, 3H, Ar-CH3); 5.52 (s, 1H, C5); 7.41–
13
7.71 (m, 9H, aromatics); 9.21 (s, 1H, NH) ppm. C-NMR δ 21.1 (CH3); 60.2 (C5); 127.2 (C12-12´);
127.3 (C11-11´); 128.4 (C9); 129.3 (C8-8´); 129.8 (C7-7´); 132.4 (C10); 133.0 (C6); 138.4 (C13);
156.2 (C4); 172.3 (C2) ppm. EIMS, m/z 266 [M] + (41.79); 238 (8.58); 119 (100); 195 (4.34); 103
(2.95); 132 (7.72); 104 (2.27); 77 (8.58); 91 (29.04); 147 (3.40).
(±)3-Phenyl-5-(4-methylphenyl)-2-thioxo-imidazolidine-4-one (IM-2). C-4-Methylphenylglycine (1.65 g;
10 mmol) and PhNCS (1.35 g; 10 mmol), were reacted according to the general procedure. Yield: 78.60%
(2.26 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 215–216 °C. IR νmax 3,154 (NH),
2,986 (CH3); 1,759 (C=O); 1,513 (C=S) cm-1. 1H-NMR δ 2.27 (s, 3H, CH3); 5.49 (s, 1H, H5); 7.24–7.47
13
(m, 9H, aromatics); 10.99 (s, 1H, NH) ppm. C-NMR δ 21.2 (CH3-Ar); 63.1 (C5); 127.4 (C12-12´);
129.2 (C11-11´); 129.3 (C9); 129.4 (C8-8´); 130.1 (C7-7´); 131.7 (C10); 133.7 (C6); 138.9 (C13);
173.4 (C4); 183.1 (C2) ppm. EIMS, m/z 282 [M] + (48.8); 254 (7.63); 135 (8.23); 119 (24.13); 103
(4.87); 132 (100); 104 (10.63); 77 (12.73); 91 (13.80); 163 (2.14).
(±)3-Phenyl-5-(4-ethyphenyl)-imidazolidine-2,4-dione (IM-3). C-4-Ethylphenylglycine (1.61 g;
9 mmol) and PhNCO (1.07 g; 9 mmol), were reacted according to the general procedure. Yield:
78.64% (1.98 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 216–218 ºC. IR νmax
1
3,241 (NH); 2,966 and 2,930 (CH2, CH3); 1,773 and 1,711 (C=O) cm-1. H-NMR δ 1.16 (t, 3H,
CH3CH2 J = 7.6 Hz); 2.60 (q, 2H, CH3CH2 J = 7.6 Hz); 5.33 (s, 1H, H5); 7.24-7.51 (m, 9H,
13
aromatics); 8.97 (s, 1H, NH) ppm. C-NMR δ 15.7 (CH3CH2); 27.9 (CH3CH2); 59.8 (C5); 126.8
(C12-12’); 127.1 (C11-11’); 127.9 (C9); 128.2 (C8-8’); 128.8 (C7-7’); 132.2 (C10); 133.1 (C6); 144.3
(C13); 155.8 (C2); 171.9 (C=O) ppm. EIMS, m/z 280 [M] + (47.51); 252 (11.03); 119 (29.75); 209
(9.82); 105 (9.76); 133 (100); 117 (10.28); 146 (2.14); 118 (14.41); 77 (12.49); 91 (40.75); 189 (1.22);
161 (1.97).

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(±)3-Phenyl-5-(4-ethylphenyl)-2-thioxo-imidazolidine-4-one (IM-4). C-4-Ethylphenylglycine (1.61 g;
9 mmol) and PhNCS (1.22 g; 9 mmol), were reacted according to the general procedure. Yield: 73.30 %
(1.95 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 246–248 °C. IR νmax 3,162
(NH); 2,965 and 2,931 (CH2, CH3). 1,761 (C=O); 1,518 (C=S) cm-1. 1H-NMR δ 1.18 (t, 3H, CH3CH2,
J = 7.4 Hz); 2.64 (q, 2H, CH3CH2, J = 7.4 Hz); 5.58 (s, 1H, H5); 7.28-7.54 (m, 9H, aromatics); 11.04
13
(s, 1H, NH) ppm. C-NMR δ 15.7 (CH3CH2); 28.0 (CH3CH2); 62.6 (C5); 127.1 (C12-12´); 128.4
(C11-11´); 128.7 (C9); 128.8 (C8-8´); 128.9 (C7-7´); 131.7 (C10); 133.4 (C6); 144.6 (C13); 172.9
(C4); 182.7 (C2) ppm. EIMS, m/z 296 [M] + (94.29); 268 (5.81); 135 (100); 209 (10.98); 105 (13.61);
133 (33.49); 117 (21.71); 146 (3.33); 118 (13.80); 119 (20.87); 77 (58.80); 91 (38.59); 267 (23.38);
177 (12.76).
(±)3-Phenyl-5-(4-methoxyphenyl)-imidazolidine-2,4-dione (IM-5). C-4-Methoxyphenylglycine (2.54 g;
14 mmol) and PhNCO (1.67 g; 14 mmol), reacted according to the general procedure. Yield: 87.60%
(3.47 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 182–183 °C. IR νmax 3,317
1
(NH); 1,773, 1,718 (C=O); 1,249 (CAr-O); 1,025 (CH3-O) cm-1. H-NMR (DMSO-d6) δ 3.71 (s, 3H,
CH3O); 5.16 (s, 1H, H5); 6.95 (m, 4H, aromatics); 7.32 (m, 5H, aromatics); 8.86 (s, 1H, NH) ppm.
13C-NMR (DMSO-d6) δ 55.5 (CH3O); 59.9 (C5); 114.4 (C12-12’); 128.3 (C9); 128.7 (C8-8’); 129.1
(C7-7’); 129.2 (C11-11’); 130.2 (C10); 140.2 (C6); 154.8 (C2); 159.4 (C13); 173.2 (C4) ppm. EIMS,
m/z 282 [M] + (32.43); 254 (5.47); 119 (9.27); 211 (2.28); 107 (1.70); 135 (100); 77 (11.43); 91 (9.62);
163 (1.20).
(±)-3-Phenyl-5-(4-methoxyphenyl)-2-thioxo-imidazolidine-4-one (IM-6). C-4-Methoxyphenylglycine
(2.54 g; 14 mmol) and PhNCS (1.89 g; 14 mmol), were reacted according to the general procedure.
Yield: 85.20% (3.56 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 226–228 °C. IR
1
νmax 3,154 (NH); 1,717 (C=O); 1,515 (C=S); 1,244 (CAr-O); 1,029 (CH3-O) cm-1. H-NMR δ 3.73 (s,
13
3H, OCH3); 5.49 (s, 1H, C5); 7.27-7.51 (m, 9H, aromatics); 10.96 (s, 1H, NH) ppm. C-NMR δ 55.6
(CH3O); 62.7 (C5); 114.8 (C12-12´); 122.8 (C11-11´); 128.8 (C9); 129.2 (C8-8´); 129.3 (C7-7´); 126.5
(C10); 133.6 (C6); 159.9 (C13); 173.5 (C4); 182.9 (C2) ppm. EIMS, m/z 298 [M] + (37.65); 135 (60.9)
119 (14.14); 148 (6.71); 77 (22.23); 91 (17.62); 207 (100); 163 (6.32); 267 (9.46).
(±)-3-Phenyl-5-(4-isopropylphenyl)-imidazolidine-2,4-dione (IM-7). C-4-Isopropylphenylglycine
(1.93 g; 10 mmol) and PhNCO (1.19 g; 10 mmol), were reacted according to the general procedure.
Yield: 90.80% (2.67 g) as white crystals; recrystallization from EtOH/H2O (1:1); Mp 215 °C. IR νmax
1
3,314 (NH); 1,783 and 1,711(C=O) cm-1. H-NMR δ 1.22 (d, 6H, CH(CH3)2); 2.90 (septet, 1H,
CH(CH3)2); 5.38 (s, 1H, H5); 7.16 (m, 4H, aromatics); 7.50 (m, 5H, aromatics); 8.97 (s, 1H, NH) ppm.
13C-NMR δ 23.9 (CH(CH3)2); 33.2 (CH(CH3)2); 59.8 (C5); 126.8 (C12-12’); 127.9 (C9); 127.1 (C8-
8’); 126.9 (C7-7’); 128.9 (C11-11’); 132.2 (C10); 133.2 (C6); 155.7 (C2); 148.9 (C13); 171.8 (C4)
ppm. EIMS, m/z 294 [M] + (54.5); 266(11.5); 147 (76.6); 119 (31.8).
(±)3-Phenyl-5-(4-isopropylphenyl)-2-thioxo-imidazolidine-4-one (IM-8). C-4-Isopropylphenylglycine
(1.35 g; 7 mmol) and PhNCS (0.95 g; 7 mmol), were reacted according to the general procedure.
Yield: 74.70% (1.62 g) as gray crystals; recrystallization from EtOH/H2O (1:1); Mp 255 ºC. IR νmax

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1
3,157 (NH); 1,783 (C=O); 1,517 (C=S) cm-1. H-NMR δ 1.21 (d, 6H, CH(CH3)2); 2.90 (septet, 1H,
CH(CH3)2); 5.55 (s, 1H, H5); 7.28 (m, 4H, aromatics); 7.54 (m, 5H, aromatics); 10.98 (s, 1H, NH)
13
ppm. C-NMR δ 23.9 (CH(CH3)2); 33.2 (CH(CH3)2); 62.6 (C5); 127.0 (C12-12’); 128.7 (C9); 128.8
(C8-8’); 128.9 (C7-7’); 128.7 (C11-11’); 131.8 (C10); 133.4 (C6); 182.7 (C2); 149.2 (C13); 172.9
(C4) ppm. EIMS, m/z 310 [M] + (100.0); 297(6.70); 147 (11.5); 120 (6.40); 135 (12.9).
Conclusions
Four new C-phenylglycine derivatives IG(1-4) containing different groups and obtained via
Strecker synthesis were subjected to reactions with phenyl isocyanate and phenyl isothiocyanate to
furnish eight imidazolidinic compounds IM(1-8), seven of which were new, and one, IM-5, whose
1
13
structure was not previously elucidated. Their structures were confirmed by infrared, H- and C-
NMR and mass spectroscopies. The pharmacological studies with IM-3 and IM-7 show that these
compounds are bioactive structures. In the cardiovascular system IM-7 induced a marked hypotension
and bradycardia which are probably due to decrease of the peripheral resistances. Likewise in vivo, the
relaxant effect of this compound seems to involve endothelial muscarinic receptor activation and
consequent NO release. The results obtained with pharmacological and behavior tests suggest that IM-3
showed peripheral antinociceptive effect considering the negative results in the Hot Plate test.
Acknowledgements
The authors acknowledge the Brazilian National Research Council (CNPq) for financial support.
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