Ultrasonics Sonochemistry 17 (2010) 55–57

Contents lists available at ScienceDirect

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
Received 24 March 2009 EtOH under ultrasound irradiation. Compared to the method using stirring, the main advantage of the
Received in revised form 19 April 2009 present procedure is milder conditions and shorter reaction time.
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-

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.
* Corresponding author. Fax: +86 312 5079628.
E-mail address: lijitai@hbu.cn (J.-T. Li).
ful protocol in organic synthesis during the last three decades,
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].
1
H 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]).

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

O Table 1
The effect of reaction conditions on the synthesis of glycoluril under ultrasound
O Ar1
O O O HN NH Ar2 irradiationa.
KOH 40 oC
+ Ar1 Ar 2 +
Ar 1 Ar2 H2 N NH2 u. s. HN NH Entry Substrate/urea/ Frequency, Temp., Time, Isolated yield %
HN NH KOH, molar ratio kHz °C h
Glycoluril Hydantoin
O
O 1 1:4:0.6 40 40 2 75 14
1 2 3 2 1:6:0.6 40 40 2 74 18
3 1:3:0.6 40 40 2 71 11
Scheme 1. The synthesis of glycoluril. 4 1:4:0.4 40 40 2 73 3
5 1:4:0.8 40 40 2 76 10
7 1:4:0.6 25 40 2 76 14
8 1:4:0.6 Stirring 40 6 74 5
2.2. General procedure for synthesis of glycoluril 9 1:4:0.6 40 30 2 74 6
10 1:4:0.6 40 20 2 75 10
A 25 mL round flask was charged with benzil (1, 1 mmol), urea 11 1:4:0.6 40 40 1 75 3
12 1:4:0.6 40 40 2.5 74 14
(4 mmol), KOH (0.033 g, 0.6 mmol) and C2H5OH (4 mL) in one por-
13 1:4:0.6 40 40 3 74 6
tion. The reaction flask was located in the cleaner bath, where the
a
surface of reactants is slightly lower than the level of the water. Substrate: 1,2-diphenyl-1,2-ethandione.
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- and hydantoin was 75%, 3% with the ratio changing to 1:4:0.6.
tion temperature was controlled by addition or removal of water With the increasing of KOH, the yield of glycoluril and hydantoin
from ultrasonic bath. The mixture was irradiated in the ultrasonic was increased unconspicuously.
cleaning bath at 40 ± 2 °C for the period as indicated in Table 2 (The We also did the experiments in silent condition. The glycoluril
reaction was monitored by TLC, petroleum ether: ethyl ace- was given only 74% yield with benzil to urea to KOH ratios of
tate = 1:1 (V/V)). After the completion of the reaction, the solvent 1:4:0.6 using strong stirring for 6 h at 40 °C (Table 1, Entry 8).
was removed by evaporation under reduced pressure to give the While under sonication, the glycoluril was obtained in 75% yield
white solid, then poured water (10 mL) into the reaction flask within 2 h. The yield of 2e was 41% using strong stirring for 8 h,
and filtered, washed by water and ethyl ether to give the products whereas under ultrasound irradiation 2e was obtained in 60% yield
glycoluril 2. The filtrate was neutralized by acetic acid and filtered for 2 h (Table 2, Entry e). It is apparent that the condensation can
to get another white solid 5,5-diarylhydantoin 3. The authenticity be finished in shorter time under ultrasound.
of the glycoluril was established by their 1H NMR and MS. The effect of irradiation frequency on the reaction was ob-
Compound 2a: white solid, 1H NMR (400 MHz, CD3SOCD3):dH served. When the irradiation frequency was 40 kHz, the synthesis
7.01–7.04 (m, 10H, Ph–H), 7.75 (s, 4H, N–H), m/z (ESI): 295 [M + 1]+. of glycoluril was completed in 2 h with 75% yield, while with
Compound 2b: white solid, 1H NMR (400 MHz, CD3SOCD3):dH 25 kHz irradiation the yield was 76%. This indicates that the irradi-
2.11 (s, 3H, Ph–CH3), 7.03–7.06 (m, 9H, Ph–H), 7.69 (s, 4H, N–H), ation frequency has small influence in the reaction.
m/z (ESI): 309 [M + 1]+. From the results above, the optimum reaction conditions were
Compound 2c: white solid, 1H NMR (400 MHz, CD3SOCD3):dH chosen: benzil (1 mmol), urea (4 mmol, 0.24 g), KOH (0.6 mmol),
3.29 (s, 3H, Ph–OCH3), 7.03–7.05 (m, 9H, Ph–H), 7.69 (s, 4H, N– C2H5OH (4 mL), at 40 °C. Under this condition, a series of experi-
H), m/z (ESI): 325 [M + 1]+. ments of the synthesis with 40 kHz ultrasound irradiation were
Compound 2d: white solid, 1H NMR (400 MHz, CD3SOCD3):dH performed. The results are summarized in Table 2.
2.12 (s, 3H, Ph–CH3), 7.01–7.19 (m, 8H, Ph–H), 7.82 (s, 4H, N–H), As shown in Table 2, the synthesis of glycolurils was carried out
m/z (ESI): 344 [M + 1]+. in good yield under ultrasound irradiation. From the results in
Compound 2e: white solid, 1H NMR (400 MHz, CD3SOCD3):dH Table 2, it seems that the benzils containing electron-donating
7.05–7.19 (m, 8H, Ph–H), 7.82 (s, 4H, N–H), m/z (ESI): 364 [M + 1]+. group were found to be more reactive and could be condensed
Compound 2f: white solid, 1H NMR (400 MHz, CD3SOCD3):dH more easily (2b and 2c). In contrast, the benzils containing elec-
7.01–7.16 (m, 8H, Ph–H), 7.90 (s, 4H, N–H), m/z (ESI): 364 [M + 1]+. tron-withdrawing group have shown lower reactivity (2e and 2f).
Compound 2h: white solid, 1H NMR (400 MHz, CD3SOCD3):dH This shows that the electronic effects of substitutents have a signif-
6.21–6.23 (m, 4H, 3,4-furural-H), 7.42(m, 2H, 5-furural-H) 7.82 icant effective on the reaction. On the other hand, the yields
(s, 4H, N–H), m/z (ESI): 275 [M + 1]+. of 3a,6a–bis(3-chlorophenyl)tetrahydroimidazo[4,5-d]imidazole-
Compound 2i: white solid, 1H NMR (400 MHz, CD3SOCD3):dH 2,5(1H,3H)-dione (Table 2, 2f), 3a,6a–bis(3,4-dichlorophenyl)
5.89 (s, 4H, CH2) 6.49–6.71 (m, 6H, Ph–H), 7.71 (s, 4H, N–H), m/z tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (2g) and
(ESI): 383 [M + 1]+. 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
3. Results and discussion be that the steric hindrance of substituents in benzil inhibits the
condensation.
The effect of molar ratio of materials was studied by considering Sonochemistry can be defined as chemistry in a liquid medium
benzil to urea ratios of 1:3, 1:4, 1:6 respectively in C2H5OH (4 mL) in presence of pressure waves. The increasing interest for sono-
at 40 °C under ultrasound irradiation. As shown in Table 1, the chemistry is due to the positive chemical and mechanical effects
yield increases from 71% to 75% with increasing ratios from 1:3 that can be observed when ultrasonic waves propagate in a liquid
to 1:4 within 2 h. At the benzil to urea ratio of 1:4, the best yield medium. Collapsing bubbles are generated, localized ‘‘hot spots”
of 3a,6a-diphenyl-glycoluril was achieved (Table 1, Entry 1), the with a transient high temperature and pressures are formed,
byproduct 5,5-diphenplhydantoin was obtained in 14% yield. inducing molecular fragmentation, and highly reactive species
Exceeding which urea has a little effect on yield of glycoluril. The are locally produced, which are responsible for the chemical effects
account of KOH influenced the reaction also. When the ratio of of ultrasound on homogeneous solutions. In the some case, sonica-
materials (benzil:urea) to KOH was 1:4:0.4, the yield of glycoluril tion can probably provide more efficient stirring [13b,18]. All of
and hydantoin was 73% and 3%, respectively. The yield of glycoluril 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 C6H5 C6H5 2 2a 75 3a 14
b C6H5 4-CH3C6H4 2 2b 72 3b 18
c C6H5 4-CH3OC6H4 2 2c 75 3c 15
d 4-ClC6H4 4-CH3C6H4 2 2d 64 3d 14
e 4-ClC6H4 4-ClC6H4 2 2e 60 3e 37
4-ClC6H4 4-ClC6H4 8(stir.) 2e 41 3e 12
f 3-ClC6H4 3-ClC6H4 8 2f 44 3f 36
g 3,4-Cl2C6H3 3,4-Cl2C6H3 8 2g 17 3g 1
3,4-Cl2C6H3 3,4-Cl2C6H3 13(stir.) 2g 17 3g 8
h Furanyl Furanyl 2 2h 61 3h 3
i 3,4-(OCH2OC6H3) 3,4-(OCH2OC6H3) 3 2i 44 3i 20

O the method using stirring, the main advantage of the present pro-
cedure is milder conditions and shorter reaction time.
O HN NH
Ar 1 Ar2
H2N NH2 HN NH
Acknowledgements
O
O
HN NH -2- OH O Natural Science Foundation of Hebei Province (B2006000969),
O O H2 N NH2
Ar 1 Ar2 2 China, supported the project.
Ar 1 Ar 2 - O- O-
OH - -OH
1 4 References
O- Ar2
Ar 1
[1] T.M. Addiscott, V.H. Thomas, Chem. Ind. (1979) 29.
HN N [2] G.G. Parekh, US Patent 4105708 (1978).
O Ar1 O Ar 1 [3] A. Wang, D. Bassett, US Patent 4310450 (1982).
Ar 2 H+ Ar2 O [4] J. Boileau, M. Carail, E. Wimmer, R. Gallo, M. Pierrot, Propell. Explos. Pyrotech.
HN NH HN N 10 (1985) 118.
[5] A. Krause, A. Aumueller, E. Korona, H. Trauth, US Patent 5670613 (1997).
-
O O [6] K.E. Pryor, J. Rebek, Org. Lett. 1 (1999) 39.
[7] (a) S. Sun, J.F. Britten, C.N. Cow, C.F. Matta, P.H.M. Harrison, Can. J. Chem. 76
3 (1998) 301;
(b) W. Jacobs, D. Foster, S. Sansur, R.G. Lees, Prog. Org. Coat. 29 (1996) 127;
Scheme 2. The formation of glycoluril and hydantoin under basic conditions. (c) J. Yinon, S. Bulusu, T. Axenrod, H. Yazdekhasti, Org. Mass Spectrom. 29
(1994) 625;
(d) S. Karcher, A. Kornmuller, M. Jekel, Water Sci. Technol. 40 (1999) 425.
The mechanism of condensation of benzils and urea by base- [8] A.X. Wu, J.C. Fettinger, L. Isaacs, Tetrahedron 58 (2002) 9769.
catalyzing is not yet understood. In sonochemical process, the [9] Y.Z. Xia, S.K. Jiao, J. Beijing Inst. Chem. Technol. 17 (1990) 73.
[10] (a) F.B. Slezaka, A. Hirsch, I. Rosen, J. Org. Chem. 25 (1960) 660;
substrate and/or reagent can suffer hemolytic bond breakage to (b) F.B. Slezak, H. Bluestone, T.A. Magee, J.H. Wotiz, J. Org. Chem. 27 (1962)
generate radical, which can induce the reaction via a free radical 2181;
mechanism. In view of the point, we added the radical trap in (c) C.A. Burnett, J. Lagona, A.X. Wu, J.A. Shaw, D. Coady, J.C. Fettinger, A.I. Day,
L. Isaacs, Tetrahedron 59 (2003) 1961.
the condensation of benzil with urea, the 3a,6a-diphenylglycoluril [11] (a) B.A. Murraya, G.S. Whelana, Pure Appl. Chem. 68 (1996) 1561;
was obtained in 73% yield, which was similar to the prior without (b) J. Kang, R.S. Meissner, R. Wyler, J. Mendoza, J.R. Jr, Bull. Korean Chem. Soc.
radical trap (2a). However, there is a possible course as shown in 21 (2000) 221;
(c) B.M. O’Leary, T. Szabo, N. Svenstrup, C.A. Schalley, A. Ltzen, M. Schfer, J.
Scheme 2 [12,19]. The first step would involve condensation of
Rebek, J. Am. Chem. Soc. 123 (2001) 11519;
urea with the benzil by nucleophilic attack on a carbonyl carbon (d) K. Moon, W.Z. Chen, T. Ren, A.E. Kaifer, Cryst. Eng. Commun. 5 (2003) 451.
resulting in the formation of 4, which then could be condensed [12] W.R. Dunnavant, F.L. James, J. Am. Chem. Soc. 78 (1956) 2740.
[13] (a) T.J. Mason, Practical Sonochemistry, Ellis Horwood, New York, 1991;
with the second mole of urea to form the glycoluril (2). The forma-
(b) J.T. Li, S.X. Wang, G.F. Chen, T.S. Li, Curr. Org. Synth. 2 (2005) 415.
tion of the hydantoin (3) involves a molecular rearrangement in [14] (a) J.T. Li, L.L. Li, T.S. Li, H.Z. Li, J.K. Liu, Ultrason. Sonochem. 3 (1996) 141;
the intermediate (4) in which an aryl undergoes a 1,2-shift. (b) J.T. Li, S. Wang, L.J. Li, Chin. J. Org. Chem. 15 (1995) 558.
[15] Department of Chemistry, Lanzhou and Fudan University, Experimental
Organic Chemistry, second ed., Higher Education Press, Beijing, 1994, pp. 236.
4. Conclusion [16] J.T. Li, X.R. Liu, W.F. Wang, Ultrason. Sonochem. 16 (2009) 331.
[17] T. Kimura, T. Sakamoto, J.M. Leveque, H. Sohmiya, M. Fujita, S. Ikeda, T. Ando,
Ultrason. Sonochem. 3 (1996) 157.
In summary, we have found a facile and efficient method for the [18] O. Dahlem, J. Reisse, V. Halloin, Chem. Eng. Sci. 54 (1999) 2829.
synthesis of glycoluril from some benzils and urea by potassium [19] G.G. Muccioli, J.H. Poupaert, J. Wouters, B. Norberg, W. Poppitz, G.K.E. Scriba,
hydroxide as catalyst under ultrasound irradiation. Compared to D.M. Lambert, Tetrahedron 59 (2003) 1301.