Efficient synthesis of 5-arylmethyl-5-phenylimidazolidine-2,4-dione (or 5-arylmethyl-5-phenyl-2-thioxoimidazolidin-4-one) from chalcone oxides under ultrasound irradiation

Article abstract of DOI:10.2174/157017811795038403

Synthesis of 5-arylmetlryl-5-phenylirnidazolidine-2,4-dione (or 5-arylmethyl-5-phenyl-2-thoxoimidazolidin-4- one) via the reaction of 3-aryl-2,3-epoxyl-1-phenyl-1-propanone and urea (or thiourea) was carried out in 57-98% yields at 50 °C in EtOH in the pr

Full text of DOI:10.2174/157017811795038403

198
Letters in Organic Chemistry, 2011, 8, 198-201
Efficient Synthesis of 5-Arylmethyl-5-phenylimidazolidine-2,4-dione (or
5-Arylmethyl-5-phenyl-2-thioxoimidazolidin-4-one) from Chalcone Oxides
Under Ultrasound Irradiation
Ji-Tai Li*, Xiao-Ya Xu and Ying Yin
Key Laboratory of Analytical Science and Technology of Hebei Province, Key Laboratory of Medical Chemistry and
Molecular Diagnosis, Ministry of Education, College of Chemistry and Environmental Science, Hebei University,
Baoding 071002, P. R. China
Received July 05, 2010: Revised September 27, 2010: Accepted October 13, 2010
Abstract: Synthesis of 5-arylmethyl-5-phenylimidazolidine-2,4-dione (or 5-arylmethyl-5-phenyl-2-thioxoimidazolidin-4-
one) via the reaction of 3-aryl-2,3-epoxyl-1-phenyl-1-propanone and urea (or thiourea) was carried out in 57-98% yields
at 50 oC in EtOH in the presence of KOH under ultrasound irradiation. The procedure has the advantages of mild
conditions, short reaction time and high yield.
Keywords: Substituted hydantoin, synthesis, chalcone oxide, ultrasound irradiation.
INTRODUCTION
Muccioli et al. also described the microwave-assisted
synthesis of phenytoin and structurally related derivatives
from benzil and alkylurea (or alkylthiourea) catalyzed by
KOH in 42-74% yield [5]. In 2006，Bhat et al. used 3-
Since, Merritt et al. discovered phenytoin’s usefulness
for controlling seizures, without the sedative effects
associated with phenobarbital, phenytoin was attracted by
more and more people. As phenytoin could act on the brain
and nervous system, it is often used to treat various types of
convulsions and seizures, such as epilepsy [1] and anxiety
[2]. It can also be used to treat arrhythmias (irregular
heartbeat), migraine headaches and facial nerve pain.
Recently antidepressant, antiviral activities as well as
benzyl-2,3-epoxyl-1-(4-methoxyphenyl)-1-propanone
and
urea to prepare 5-benzyl-5-(4-methoxyphenyl)imidazolidine-
2,4-dione in 81% yield by stirring in THF for 5h in the
presence of NaH [6]. However, in spite of their potential
utility, some methods suffer from drawbacks such as lower
yield and longer reaction time.
O
O
O
KOH
u.s. 50 oC
95%EtOH
H2N
NH2
C
X
HN
NH
R
R
X
1a-e
2a-b
3a-j
X=O or S
Scheme 1. Synthesis of 5-arylmethyl-5-phenylimidazolidine-2,4-dione or 5-arylmethyl-5-phenyl-2-thioxoimidazolin-4-one.
inhibited binding of HIV to lymphocytes were also reported
for hydantoins [3].
Ultrasound irradiation has been considered as a useful
protocol, compared with traditional methods, in organic
synthesis in the last three decades [7]. A large number of
organic reactions can be carried out in higher yield, shorter
reaction time or milder conditions under ultrasonic
irradiation [8].
The main structural challenge for the synthesis of these
compounds is the construction of the hydantoin ring. One of
the methods for constructing the hydantoin ring is the
reaction of chalcone oxides and urea. In 1958, Enebäck
reported the synthesis of 5-benzyl-5-phenylimidazolidine-2,4-
dione from chalcone oxides and urea by refluxing in ethanol
for 2h in the presence of KOH in 75% yield [4]. In 2003,
Herein, we wish to report an efficient and facile
procedure
for
the
synthesis
of
5-benzyl-5-
phenylimidazolidine-2,4-dione (or 5-arylmethyl-5-phenyl-2-
thioxoimidazolidin-4-one) from 3-aryl-2,3-epoxyl-1-phenyl-
1-propanone, urea (or thiourea) and KOH under ultrasound
irradiation (Scheme 1).
*Address correspondence to this author at the College of Chemistry and
Environmental Science, Hebei University, Wusi East Road No. 180,
Baoding 071002, P.R. China; Tel: +86-312-5079361: Fax: +86-312-
5079628; E-mail: lijitai@hbu.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Synthesis of 5-Arylmethyl-5-phenylimidazolidine-2,4-dione
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
199
RESULTS AND DISCUSSION
°C. Using this system, we did a series of experiments to
prepare 5-arylmethyl-5-phenylimidazolidine-2,4-dione (or 5-
arylmethyl-5-phenyl-2-thioxoimidazolidin-4-one). The results
are summarized in Table 2.
To examine the effect of reaction conditions on the
synthesis of title compounds, the reaction of 2,3-epoxyl-1,3-
diphenyl-1-propanone (1a) and urea (2a) was selected as the
model reaction under ultrasound irradiation. The results are
summarized in Table 1.
As shown in Table 2, the reactions were carried out in
good yields in the presence of potassium hydroxide under
ultrasound irradiation. In order to verify the effect of
ultrasound irradiation, some reactions of 3-aryl-2,3-epoxyl-
1-phenyl-1-propanone (Table 2, Entries 1, 3 and 8), urea (or
thiourea) and potassium hydroxide were carried out by
stirring alone at refluxed temperature under silent condition,
3a, 3c and 3h were obtained in 60%, 80% and 61% yield,
respectively; while under ultrasound, these reactions can be
completed in 83%, 94% and 76% yield, respectively within
the same time (Table 2, Entries 1, 3 and 8). It showed that
ultrasound irradiation can accelerate the reaction and
improve the result (except for 3j).
As shown in Table 1, the yield of 3a increased from 56%
to78% by changing the reaction time from 35 min to 45 min
(Entries 1 and 2). When the reaction time was 55 min, the 3a
was obtained in 67% yield (Entry 3). The results showed that
45 min was the appropriate time for this reaction.
The effect of temperature on the reaction yield was
observed. With the increase of temperature from 30°C to
50°C (Entries 2, 4 and 5), higher yield (78%) was obtained
and we chose 50°C as the appropriate temperature.
With the increase of the molar ratio of 2,3-epoxyl-1,3-
diphenyl-1-propanone and potassium hydroxide from 1: 1 to
1: 2 (Entries 2, 6 and 7), the higher yield (83 %) was
achieved within 45 min (Entry 7). Further increase of the
molar ratio to 1: 2.5, does not modify the yield (Entry 8).
The results showed that changing the molar ratio of 1a with
potassium hydroxide had significant effect on the yield of
3a, and the optimum molar ratio was 1: 2.
In the present procedure, 3-aryl-2,3-epoxyl-1-phenyl-1-
propanone carrying electron-donating substituents in the
benzene ring reacted with thiourea to afford products in
higher yields, whereas the reaction of chalcone oxide with
urea does not follow the trend. It is noted that 3-(4-
nitrophenyl)-2,3-epoxyl-1-phenyl-1-propanone does not
react with both urea and thiourea.
Similarly, we changed the molar ratio of 2,3-epoxyl-1,3-
diphenyl-1-propanone and urea from 1: 2 to 1: 2.5, the
higher yield (75%) was observed in the latter case (Table 1,
Entries 9 and 10). By increasing the molar ratio to 1: 3, the
yield did not change (Entry 11). The optimum molar ratio of
1a with urea was 1: 2.5.
From these results, we can deduce that the yields are in
general, similar or higher than those described in the
literature. Compared with reported methods, the main
advantages of the procedure are the milder conditions and
the shorter reaction time than classical methods. For
example, under refluxing in KOH-EtOH for 2 h, 3a and 3c
were obtained in 75% and 86% yield, respectively [4];
whereas present method can give 3a and 3c in 83% and 94%
yield respectively within 45 min.
We also examined the effects of irradiation frequency on
the reaction. When the frequency was 25 kHz, the yield of
3a was 83% (Table 1, Entry 7), when the frequency was 40
kHz, the yield of 3a was 75% (Table 1, Entry 10). The result
showed that 25 kHz was the appropriate frequency for this
reaction.
The found structure is apparently
a result of a
rearrangement with a migration of an aromatic- ring in the
proximity of the carbonyl functionality (Ar-group in position
3). The possible mechanism for the formation of hydantoin is
suggested, as shown in Scheme 2 [6, 11].
From the above results, a typical experimental procedure
was chosen: 2,3-epoxyl-1,3-diphenyl-1-propanone (1a, 2
mmol), urea (2, 5 mmol), potassium hydroxide (4 mmol) and
95% EtOH (4 mL) under 25 kHz ultrasound irradiation at 50
In conclusion, we have found an efficient and convenient
procedure for the preparation of 5-arylmethyl-5-
Table 1. The Effect of Reaction Conditions on the Yield of 3a
Entry
Substrate/ urea/KOH (molar ratio)
Time (min)
Temperature (oC)
Frequency (kHz)
Yield (%)
1
2
1: 2.5: 1.5
1: 2.5: 1.5
1: 2.5: 1.5
1: 2.5: 1.5
1: 2.5: 1.5
1: 2.5 :1.0
1: 2.5: 2.0
1: 2.5: 2.5
1: 2.0: 2.0
1: 2.5: 2.0
1: 3.0: 2.0
35
45
55
45
45
45
45
45
45
45
45
50
50
50
40
30
50
50
50
50
50
50
25
25
25
25
25
25
25
25
40
40
40
56
78
67
48
27
71
83
82
72
75
75
3
4
5
6
7
8
9
10
11

200 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Li et al.
Table 2. The Synthesis of 3a-j from 3-Aryl-2,3-epoxyl-1-phenyl-1-propanone and Urea (or Thiourea)
Entry
R
X
Method*
Time (min.)
Product
Isolated yield (%)
m.p. (oC) (Lit.)
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
45
45
83
60
84
64
94
80
81
63
80
67
67
62
98
57
76
61
62
45
57
57
1
H
O
3a
210 (210-211) [9]
45
2
3
2-OCH3
4-OCH3
2-Cl
O
O
O
O
S
3b
3c
3d
3e
3f
185
45
45
231-233 (206-208) [4]
45
45
4
230-232
45
45
5
4-Cl
216 (212-213) [9]
45
120
120
45
6
H
226-228 (229-230) [10]
7
2-OCH3
4-OCH3
2-Cl
S
3g
3h
3i
156
210
45
45
8
S
45
120
120
120
120
9
S
202
10
4-Cl
S
3j
202-204
*The molar ratio of 1, 2 and KOH, 1: 2.5: 2. Method: A. ultrasound irradiation, 50 oC.; B. refluxing without ultrasound.
O
O
O
O
OH
O
O
O
-H2O
Ar
Ar
Ar
Ar
Ph
Ph
Ar
Ph
Ph
Ph
OH
O
O
O
OH
X
O
Ph
Ph
N
X
XH
NH
Ph
N
N
Ph
Ar
NH2
NH2
H2N
HN
O
XH+
NH
N
H
X
O
Ar
Ar
Ar
O
Scheme 2. Formation of 5-arylmethyl-5-phenylimidazolidine-2,4-dione or 5-arylmethyl-5-phenyl-2-thioxoimidazolidin-4-one.
phenylimidazolidine-2,4-dione (or 5-arylmethyl-5-phenyl-2-
thioxoimidazolidin-4-one) from chalcone oxides and urea (or
thiourea) under ultrasound irradiation. Compared with the
classical methods, the main advantages of the present
procedure are higher yields and shorter reaction period.
Sonication was performed in Shanghai BUG 40-06 or
BUG 25-06 ultrasonic cleaner (with a frequency of 40 or 25
kHz and a nominal power 250 W). The reaction flask was
located in the ultrasonic bath, where the surface of reactants
is slightly lower than the level of water. The reaction
temperature was controlled by the addition or removal of
circulated water from ultrasonic bath.
EXPERIMENTAL
Apparatus and Analysis
Typical Procedure for the Preparation of 5-benzyl-5-
phenylimidazolidine-2,4-dione (3a)
Melting points were uncorrected. The H and 13C NMR
1
spectra were recorded at 600 MHz and 150 MHz,
respectively on a Bruker AVANCE 600 spectrometer using
TMS as internal standard and DMSO as solvent. LC-MS
were determined on SHIMADZU (LCMS-2010EA,
UVD/ELSD) using CH3CN and H2O (0.05% TFA) as mobile
phase.
The 3-phenyl-2,3-epoxyl-1-phenyl-1-propanone (1a, 2
mmol) and 95% ethanol (2 mL) were added to a 50 mL
Pyrex and irradiated in the ultrasonic cleaning at 50 °C (bath
temperature), then added the solution of potassium
hydroxide (4 mmol) and urea (2a, 5 mmol) in 95% ethanol
(2 mL). Sonication was continued for 45 min until epoxide

Synthesis of 5-Arylmethyl-5-phenylimidazolidine-2,4-dione
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
201
chalcone had disappeared as indicated by TLC. After
completion of the reaction, the mixture was poured into
water and filtered. The filtrate was neutralized to pH=5~6 by
3 mol/L hydrochloric acid and filtered. The solid was
washed with water (3ꢀ15 mL) and dried to give the product
3a.
129.2, 129.2, 128.8, 126.5, 125.9, 125.9, 113.9, 111.9, 72.0,
55.4, 42.9 ppm.
Compound 3i
5-(2-chlorobenzyl)-5-phenyl-2-thioxoimidazolidin-4-one
o
1
Yellow solid, m.p.202 C; m/z (ESI): 317 [M+H]+; H
NMR (DMSO): ꢁH 2.51-2.53 (1H, d, J=12 Hz, CH2), 3.71-
3.73 (1H, d, J=12 Hz, CH2), 7.25-7.60 (9H, m, Ar-H), 10.77
(1H, s, NH), 11.68 (1H, s, NH); 13C NMR (DMSO): ꢁC
181.7, 175.8, 137.9, 134.8, 132.6, 132.5, 129.9, 129.6, 129.2,
129.2, 128.9, 127.3, 126.6, 126.6, 71.5, 31.2 ppm.
The authenticity of the product 3b, 3c, 3d and 3g-j was
1
established by their H NMR, 13C NMR and MS, the rest
known compounds (3a, 3e and 3f) were established by their
melting points compared with that reported in literature [4, 9,
10].
Compound 3j
Compound 3b
5-(4-chlorobenzyl)-5-phenyl-2-thioxoimidazolidin-4-one
5-(2-methoxybenzyl)-5-phenylimidazolidine-2,4-dione
o
Yellow solid, m.p.202-204 C; m/z (ESI): 317 [M+H]+;
o
1
Yellow solid, m.p.185 C; m/z (ESI): 297 [M+H]+; H
NMR (DMSO): ꢁH 3.17-3.19 (1H, d, J=12 Hz, CH2), 3.44-
3.46 (1H, d, J=12 Hz, CH2), 3.73 (3H, s, OCH3), 6.83-7.63
(9H, m, Ar-H), 8.34 (1H, s, NH), 10.48 (1H, s, NH); 13C
NMR (DMSO): ꢁC 175.4, 157.8, 155.9, 139.6, 131.2, 128.5,
128.3, 128.3, 127.8, 125.6, 125.6, 123.1, 119.9, 110.8, 68.1,
55.3, 37.4 ppm.
1H NMR (DMSO): ꢁH 3.10-3.12 (1H, d, J=12 Hz, CH2),
3.51-3.53 (1H, d, J=12 Hz, CH2), 7.24-7.58 (9H, m, Ar-H),
10.81 (1H, s, NH), 11.69 (1H, s, NH); 13C NMR (DMSO): ꢁC
181.7, 175.9, 138.1, 138.1, 133.7, 132.6, 132.6, 129.3, 129.3,
128.9, 128.5, 128.5, 125.9, 125.9, 71.7, 42.7 ppm.
Compound 3c
ACKNOWLEDGEMENT
5-(4-methoxybenzyl)-5-phenylimidazolidine-2,4-dione
Yellow solid, m.p. 231-233 (206-208 [4]) oC; m/z (ESI):
The project was supported by Natural Science
Foundation of Hebei Province (B2006000969), China.
1
297 [M+H]+; H NMR (DMSO): ꢁH 2.91-2.93 (1H, d, J=12
Hz, CH2), 3.44-3.46 (1H, d, J=12 Hz, CH2), 3.73 (3H, s,
OCH3), 6.85-7.64 (9H, m, Ar-H), 8.64 (1H, s, NH), 10.44
(1H, s, NH); 13C NMR (DMSO): ꢁC 175.3, 158.3, 155.8,
139.4, 131.4, 128.4, 127.9, 126.6, 125.5, 113.4, 68.5, 54.9,
42.9 ppm.
REFERENCES
[1]
(a) Browne, T. R. Drug therapy reviews: drug therapy of status
epilepticus. Am. J. Hosp. Pharm., 1978, 35, 915; (b) Browne, T. R.
Drug therapy reviews: clinical pharmacology of antiepileptic drugs.
Am. J. Hosp. Pharm., 1978, 35, 1048.
[2]
[3]
Krall, R. L.; Penry, J. K.; White, B. G.; Kupferberg, H. J.;
Swinyard, E. A. Antiepileptic drug development: ii. Anticonvulsant
drug screening. Epilepsia, 1978, 19, 409.
Kashem Liton, A.; Rabiul Islaml, M. Synthesis of hydantoin and
thiohydantoin related compounds from benzyl and study of their
cycotoxicity. Bangladesh T. Pharmacol, 2006, 1, 10.
Compound 3d
5-(2-chlorobenzyl)-5-phenylimidazolidine-2,4-dione
o
Yellow solid, m.p.230-232 C; m/z (ESI): 301 [M+H]+;
1H NMR (DMSO): ꢁH 3.31-3.33 (1H, d, J=12 Hz, CH2),
3.66-3.68 (1H, d, J=12 Hz, CH2), 7.26-7.65 (9H, m, Ar -H),
8.70 (1H, s, NH), 10.66 (1H, s, NH); 13C NMR (DMSO): ꢁC
175.6, 156.3, 139.4, 135.0, 133.3, 132.4, 129.9, 129.4, 129.0,
129.0, 128.6, 127.3, 126.1, 126.1, 68.6, 31.1 ppm.
[4]
[5]
Enebäck, C. Hydantoins from chalcone oxides. Acta. Chem.
Scand., 1958, 12, 1528.
Muccioli, G. G.; Poupaert, J. H.; Wouters, J.; Norberg, B.; Poppitz,
W.; Scriba, G. K. E.; Lambert, D. M. A rapid and efficient
microwave-assisted synthesis of hydantoins and thiohydantoins.
Tetrahedron, 2003, 59, 1301-1307.
[6]
Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Spiteller, M. A novel one-pot
rearrangement reaction of 2,3-epoxydiaryl ketones: Synthesis of
(±)-5,5-disubstituted imidazolones and 5,5-disubstituted hydantoins
Synlett., 2006, 17, 2723.
(a) Luche, J. L. Synthetic Organic Sonochemistry, Plenum, New
York, NY, 1998; (b) Mason, T. J.; Peters, D. Practical
Sonochemistry, 2nd ed., Ellis Horwood, London, 2002.
(a) Li, J.T.; Wang, S. X.; Chen, G. F.; Li, T. S. Some application of
ultrasound irradiation in organic synthesis. Curr. Org. Synth., 2005,
2, 175; (b) Ratoarinoro, N.; Wilhelm, A. M.; Berlan, J.; Delmas, H.
Effects of ultrasound emitter type and power on a heterogeneous
reaction. Chem. Eng. J., 1992, 50, 27.
Goodson, L.H.; Honigberg, I. L.; Lehman, J. J.; Burton W. H.
Potential growth antagonists I. Hydantoins and disubstituted
glycines. J. Org. Chem., 1960, 25, 1920.
Enebäck, C.; Alberty, J. E. Synthesis and anticonvulsive properties
of substituted 5-phenyl-5-benzyl-hydantoins. Arzneim. Forsch.,
1965, 15, 1231.
Compound 3g
5-(2-methoxybenzyl)-5-phenyl-2-thioxoimidazolidin-4-one
Yellow solid, m.p.156 C; m/z (ESI): 313 [M+H]+; H
NMR (DMSO): ꢁH 3.23-3.25 (1H, d, J=12 Hz, CH2), 3.48-
3.50 (1H, d, J=12 Hz, CH2), 3.76 (3H, s, OCH3), 6.83-7.59
(9H, m, Ar -H), 10.48 (1H, s, NH), 11.50 (1H, s, NH); 13C
NMR (DMSO): ꢁC 181.5, 176.2, 158.3, 138.6, 131.9, 129.2,
129.1, 129.1, 128.7, 126.0, 126.0, 123.0, 120.4, 111.4, 71.7,
56.0, 37.7 ppm.
o
1
[7]
[8]
[9]
Compound 3h
5-(4-methoxybenzyl)-5-phenyl-2-thioxoimidazolidin-4-one
[10]
[11]
Yellow solid, m.p.210 C; m/z (ESI): 313 [M+H]+; H
NMR (DMSO): ꢁH 2.51-2.53 (1H, d, J=12 Hz, CH2), 3.02-
3.04 (1H, d, J=12 Hz, CH2), 3.73 (3H, s, OCH3), 6.85-7.59
(9H, m, Ar -H), 10.77 (1H, s, NH), 11.50 (1H, s, NH); 13C
NMR (DMSO): ꢁC 181.6, 176.1, 158.9, 138.5, 131.8, 131.8,
o
1
(a) Jörlander, H. Ifber das anisoyl-phenyl-oxidolthan und andere
keto-oxidoverbindungen. Ber., 1917, 50, 406; (b) Dunnavant, W.
R.; James, F. L. Molecular rearrangements. I. The base-catalyzed
condensation of benzil with urea. J. Am. Chem. Soc., 1956, 78,
2740.