Synthesis of glycoluril catalyzed by potassium hydroxide under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2009.04.010

Synthesis of the glycolurils catalyzed by potassium hydroxide was carried out in 17-75% yield at 40 °C in EtOH under ultrasound irradiation. Compared to the method using stirring, the main advantage of the present procedure is milder conditions and shorter reaction time.

Full text of DOI:10.1016/j.ultsonch.2009.04.010

Ultrasonics Sonochemistry 17 (2010) 55–57
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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Synthesis of glycoluril catalyzed by potassium hydroxide
under ultrasound irradiation
*
Ji-Tai Li , Xiao-Ru Liu, Ming-Xuan Sun
College of Chemistry and Environmental Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province,
Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education, No. 180 Wusi East Road, Baoding 071002, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of the glycolurils catalyzed by potassium hydroxide was carried out in 17–75% yield at 40 °C in
EtOH under ultrasound irradiation. Compared to the method using stirring, the main advantage of the
present procedure is milder conditions and shorter reaction time.
Received 24 March 2009
Received in revised form 19 April 2009
Accepted 24 April 2009
Ó 2009 Elsevier B.V. All rights reserved.
Available online 3 May 2009
Keywords:
Synthesis
Glycoluril
Cyclic condensation
Ultrasound irradiation
1. Introduction
Ultrasound irradiation has been considered as a clean and use-
ful protocol in organic synthesis during the last three decades,
The glycolurils have been received a great deal of attention due
to their practical applications, such as fertilizers [1], polymer cross-
linking [2,3], explosives [4], stabilizers of organic compounds
against photodegradation [5], combinatorial chemistry [6], radio-
iodination agents for biomolecules, psychotropic agents, catalysts,
bleaching activators [7], and they have also been using for the
monomer in supramolecular chemistry [8]. The synthesis of glyco-
lurils via condensation of benzils with urea catalyzed by classical
acid, such as H2SO4 [9], HCl [8,10], CF3COOH [6,11], has been re-
ported. However, in spite of their potential utility, some of the re-
ported methods suffer from drawbacks such as longer reaction
times, harsh conditions and corruption. The base-catalyzed con-
densation of benzil with urea gives 3a,6a-diarylglycoluril and
5,5-diarylhydantoin in general. Dunnavant et al. studied the effect
of varied reaction conditions on the relative yields of 5,5-diphenyl-
hydantoin and 3a,6a-diphenylglycoluril from the condensation of
benzil with urea, and found that 5,5-diphenylhydantoin and
3a,6a-diphenylglycoluril were obtained in 75% and 23% yield
respectively in the presence of potassium hydroxide [12]. There
still appears a need to introduce novel methods to permit better
selectivity under milder conditions and with easy work-up
procedures.
compared with traditional methods, the procedure is more conve-
nient. A large number of organic reactions can be carried out in
higher yield, shorter reaction time or milder conditions under
ultrasonic irradiation [13]. We have shown that ultrasonic irradia-
tion afforded
a significant amelioration for the synthesis of
5,5-disubstituted hydantoin via Bucherer–Bergs reactions [14].
Herein, we wish to report the synthesis of glycolurils catalyzed
by potassium hydroxide via the condensation of benzil with urea
under ultrasound irradiation (Scheme 1).
2. Methods
2.1. Apparatus and analysis
The starting materials benzils were prepared according to liter-
atures [15,16].
1H NMR spectra were measured on a Bruker AVANCE 400
(400 MHz) spectrometer using TMS as the internal standard and
CD3SOCD3 as a solvent. MS were determined on SHIMADZU
GCMS-QP2010 spectrometer (ESI). Sonication was performed in
Shanghai Branson BUG25-06 ultrasonic cleaner (with a frequency
of 25 kHz and a nominal power 250 W, the total acoustic power in-
jected into the sample solution was found to be 0.63 W by calorim-
etry [17]) and Branson BUG40-06 ultrasonic cleaner (with a
frequency of 40 kHz and a nominal power 250 W, the total acoustic
power injected into the sample solution was found to be 1.53 W by
calorimetry [17]).
* Corresponding author. Fax: +86 312 5079628.
E-mail address: lijitai@hbu.cn (J.-T. Li).
1350-4177/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2009.04.010

56
J.-T. Li et al. / Ultrasonics Sonochemistry 17 (2010) 55–57
Table 1
O
The effect of reaction conditions on the synthesis of glycoluril under ultrasound
Ar1
Ar2
O
irradiationa.
O
O
O
HN NH
KOH 40 oC
u. s.
+
Ar1
Ar2
+
Entry Substrate/urea/
Frequency, Temp., Time, Isolated yield %
HN NH
H2N NH
Ar1
Ar2
2
HN NH
KOH, molar ratio kHz
°C
h
Glycoluril Hydantoin
O
O
1
2
3
4
5
7
8
9
10
11
12
13
1:4:0.6
1:6:0.6
1:3:0.6
1:4:0.4
1:4:0.8
1:4:0.6
1:4:0.6
1:4:0.6
1:4:0.6
1:4:0.6
1:4:0.6
1:4:0.6
40
40
40
40
40
25
Stirring
40
40
40
40
40
40
40
40
40
30
20
40
40
40
2
2
2
2
2
2
6
2
2
1
2.5
3
75
74
71
73
76
76
74
74
75
75
74
74
14
18
11
3
10
14
5
6
10
3
3
2
1
Scheme 1. The synthesis of glycoluril.
2.2. General procedure for synthesis of glycoluril
40
40
40
A 25 mL round flask was charged with benzil (1, 1 mmol), urea
(4 mmol), KOH (0.033 g, 0.6 mmol) and C2H5OH (4 mL) in one por-
tion. The reaction flask was located in the cleaner bath, where the
surface of reactants is slightly lower than the level of the water.
Observation of the surface of the reaction solution during vertical
adjustment of vessel depth will show the optimum position by
the point at which maximum surface disturbance occurs. The reac-
tion temperature was controlled by addition or removal of water
from ultrasonic bath. The mixture was irradiated in the ultrasonic
cleaning bath at 40 2 °C for the period as indicated in Table 2 (The
reaction was monitored by TLC, petroleum ether: ethyl ace-
tate = 1:1 (V/V)). After the completion of the reaction, the solvent
was removed by evaporation under reduced pressure to give the
white solid, then poured water (10 mL) into the reaction flask
and filtered, washed by water and ethyl ether to give the products
glycoluril 2. The filtrate was neutralized by acetic acid and filtered
to get another white solid 5,5-diarylhydantoin 3. The authenticity
of the glycoluril was established by their 1H NMR and MS.
Compound 2a: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
7.01–7.04 (m, 10H, Ph–H), 7.75 (s, 4H, N–H), m/z (ESI): 295 [M + 1].+
Compound 2b: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
2.11 (s, 3H, Ph–CH3), 7.03–7.06 (m, 9H, Ph–H), 7.69 (s, 4H, N–H),
m/z (ESI): 309 [M + 1]+.
14
6
a
Substrate: 1,2-diphenyl-1,2-ethandione.
and hydantoin was 75%, 3% with the ratio changing to 1:4:0.6.
With the increasing of KOH, the yield of glycoluril and hydantoin
was increased unconspicuously.
We also did the experiments in silent condition. The glycoluril
was given only 74% yield with benzil to urea to KOH ratios of
1:4:0.6 using strong stirring for 6 h at 40 °C (Table 1, Entry 8).
While under sonication, the glycoluril was obtained in 75% yield
within 2 h. The yield of 2e was 41% using strong stirring for 8 h,
whereas under ultrasound irradiation 2e was obtained in 60% yield
for 2 h (Table 2, Entry e). It is apparent that the condensation can
be finished in shorter time under ultrasound.
The effect of irradiation frequency on the reaction was ob-
served. When the irradiation frequency was 40 kHz, the synthesis
of glycoluril was completed in 2 h with 75% yield, while with
25 kHz irradiation the yield was 76%. This indicates that the irradi-
ation frequency has small influence in the reaction.
From the results above, the optimum reaction conditions were
chosen: benzil (1 mmol), urea (4 mmol, 0.24 g), KOH (0.6 mmol),
C2H5OH (4 mL), at 40 °C. Under this condition, a series of experi-
ments of the synthesis with 40 kHz ultrasound irradiation were
performed. The results are summarized in Table 2.
Compound 2c: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
3.29 (s, 3H, Ph–OCH3), 7.03–7.05 (m, 9H, Ph–H), 7.69 (s, 4H, N–
H), m/z (ESI): 325 [M + 1]+.
Compound 2d: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
2.12 (s, 3H, Ph–CH3), 7.01–7.19 (m, 8H, Ph–H), 7.82 (s, 4H, N–H),
m/z (ESI): 344 [M + 1]+.
As shown in Table 2, the synthesis of glycolurils was carried out
in good yield under ultrasound irradiation. From the results in
Table 2, it seems that the benzils containing electron-donating
group were found to be more reactive and could be condensed
more easily (2b and 2c). In contrast, the benzils containing elec-
tron-withdrawing group have shown lower reactivity (2e and 2f).
This shows that the electronic effects of substitutents have a signif-
icant effective on the reaction. On the other hand, the yields
of 3a,6a–bis(3-chlorophenyl)tetrahydroimidazo[4,5-d]imidazole-
2,5(1H,3H)-dione (Table 2, 2f), 3a,6a–bis(3,4-dichlorophenyl)
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (2g) and
3a,6a-di(benzo[d][1,3]dioxol-5-yl)tetrahydroimidazo[4,5-d]imidaz-
ole-2,5(1H,3H)-dione (2i) were obviously lower than others. It may
be that the steric hindrance of substituents in benzil inhibits the
condensation.
Compound 2e: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
7.05–7.19 (m, 8H, Ph–H), 7.82 (s, 4H, N–H), m/z (ESI): 364 [M + 1]+.
Compound 2f: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
7.01–7.16 (m, 8H, Ph–H), 7.90 (s, 4H, N–H), m/z (ESI): 364 [M + 1]+.
Compound 2h: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
6.21–6.23 (m, 4H, 3,4-furural-H), 7.42(m, 2H, 5-furural-H) 7.82
(s, 4H, N–H), m/z (ESI): 275 [M + 1]+.
Compound 2i: white solid, 1H NMR (400 MHz, CD3SOCD3):dH
5.89 (s, 4H, CH2) 6.49–6.71 (m, 6H, Ph–H), 7.71 (s, 4H, N–H), m/z
(ESI): 383 [M + 1]+.
3. Results and discussion
The effect of molar ratio of materials was studied by considering
benzil to urea ratios of 1:3, 1:4, 1:6 respectively in C2H5OH (4 mL)
at 40 °C under ultrasound irradiation. As shown in Table 1, the
yield increases from 71% to 75% with increasing ratios from 1:3
to 1:4 within 2 h. At the benzil to urea ratio of 1:4, the best yield
of 3a,6a-diphenyl-glycoluril was achieved (Table 1, Entry 1), the
byproduct 5,5-diphenplhydantoin was obtained in 14% yield.
Exceeding which urea has a little effect on yield of glycoluril. The
account of KOH influenced the reaction also. When the ratio of
materials (benzil:urea) to KOH was 1:4:0.4, the yield of glycoluril
and hydantoin was 73% and 3%, respectively. The yield of glycoluril
Sonochemistry can be defined as chemistry in a liquid medium
in presence of pressure waves. The increasing interest for sono-
chemistry is due to the positive chemical and mechanical effects
that can be observed when ultrasonic waves propagate in a liquid
medium. Collapsing bubbles are generated, localized ‘‘hot spots”
with a transient high temperature and pressures are formed,
inducing molecular fragmentation, and highly reactive species
are locally produced, which are responsible for the chemical effects
of ultrasound on homogeneous solutions. In the some case, sonica-
tion can probably provide more efficient stirring [13b,18]. All of
these can cause the reaction to take place rapidly.

J.-T. Li et al. / Ultrasonics Sonochemistry 17 (2010) 55–57
57
Table 2
The synthesis of glycolurils from benzils and urea under ultrasound irradiation.
Entry
Ar1
Ar2
Time, h
Products
Glycoluril
Isolated yield %
Hydantoin
Isolated yield %
a
b
c
d
e
C6H5
C6H5
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
3,4-Cl2C6H3
3,4-Cl2C6H3
Furanyl
C6H5
2
2
2
2
2a
2b
2c
2d
2e
2e
2f
2g
2g
2h
2i
75
72
75
64
60
41
44
17
17
61
44
3a
3b
3c
3d
3e
3e
3f
3g
3g
3h
3i
14
18
15
14
37
12
36
1
4-CH3C6H4
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
3,4-Cl2C6H3
3,4-Cl2C6H3
Furanyl
2
8(stir.)
8
8
13(stir.)
2
3
f
g
8
3
20
h
i
3,4-(OCH2OC6H3)
3,4-(OCH2OC6H3)
the method using stirring, the main advantage of the present pro-
cedure is milder conditions and shorter reaction time.
O
O
HN NH
Ar1 Ar
HN NH
2
Acknowledgements
H2N NH
2
O
O
-2-OH
--OH
O
Natural Science Foundation of Hebei Province (B2006000969),
China, supported the project.
HN NH
O
O
H2N NH
-OH
Ar2
2
Ar1
Ar2
2
O- O-
Ar1
4
References
1
O-
Ar
2
Ar
1
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substrate and/or reagent can suffer hemolytic bond breakage to
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mechanism. In view of the point, we added the radical trap in
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4. Conclusion
In summary, we have found a facile and efficient method for the
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