A new and efficient method for the preparation of 2,4,6,8- Tetraazabicyclo[3.3.0]octane-3,7-diones (Glycolurils) catalyzed by keggin, wells-dawson, and preyssler heteropolyoxometalates, effect of structure on the reactivity

Article abstract of DOI:10.2174/157017812800167475

Some important cis- and trans-alkyl substituted glycolurils were prepared via condensation of vicinal dicarbonyl compounds with urea and/or methylurea catalyzed by 0.95 mol% of Keggin- type H₃PW₁₂O ₄₀ under environmentally benign and simple condition. Proficiency of structurally different heteropolyoxometalates, including Keggin, Wells-Dawson, and Preyssler, was investigated in the reaction of urea with 2, 3-butanedione. A common method was introduced for the isolation of cis- and trans-isomers, role of different solvents was studied, and effect of catalyst mol% was also investigated in this reported.

Full text of DOI:10.2174/157017812800167475

Letters in Organic Chemistry, 2012, 9, 183-191
183
A New and Efficient Method for the Preparation of 2,4,6,8-Tetra-
azabicyclo[3.3.0]octane-3,7-diones (Glycolurils) Catalyzed by Keggin,
Wells-Dawson, and Preyssler Heteropolyoxometalates, Effect of Structure
on the Reactivity
Reza Tayebee*, Rezaei-Seresht Esmaeil and Maleki Behrooz
Department of Chemistry, School of Sciences, Sabzevar Tarbiat Moallem University, Sabzevar 96179-76487, Iran
Received October 03, 2011: Revised November 04, 2011: Accepted November 21, 2011
Abstract: Some important cis- and trans-alkyl substituted glycolurils were prepared via condensation of vicinal
dicarbonyl compounds with urea and/or methylurea catalyzed by 0.95 mol% of Keggin- type H PW12O40 under
3
environmentally benign and simple condition. Proficiency of structurally different heteropolyoxometalates, including
Keggin, Wells-Dawson, and Preyssler, was investigated in the reaction of urea with 2, 3-butanedione. A common method
was introduced for the isolation of cis- and trans-isomers, role of different solvents was studied, and effect of catalyst
mol% was also investigated in this reported.
Keywords: Condensation, diketone, glycoluril, heteropolyoxometalate, urea.
INTRODUCTION
Recently, it has been claimed that heteropoly compounds
could be used as effective catalysts for the synthesis of
substituted glycolurils [13]. In continuation of the previous
report, a systematic and more special study is introduced for
the production and isolation of the structural isomers of
some important N-alkyl substituted glycolurils via
condensation of glyoxal and/or vicinal diketones with urea
and methylurea under mild and environmentally friendly
The chemistry of glycolurils (2,4,6,8-tetraazabicyclo
[
3.3.0]octane-3,7-diones) has received a great deal of interest
due to their widespread applications in chemical industries
and laboratory research. These immporant compounds would
be used as promoters and polymer crosslinking agents [1],
stabilizers of organic compounds against photodegradation
[
2], radioiodination agents for biomolecules, psychotropic
3
conditions by employing 0.95 mol% of H PW12O40. Effect of
agents, bleaching activators [3], explosives [4], starting
materials for the preparation of cucurbit[n]uril-type
macrocycles, and several applications in combinatorial
chemistry [5, 6]. Moreover, some glycolurils have been
applied as molecular templates for intra-molecular Claisen-
type condensations and preparation of a wide variety of
supramolecular systems, including molecular clips, the
cucurbit[n]urils, and molecular capsules [7-9].
catalyst structure on the reactivity, role of solvent
characteristics, and effect of catalyst mol% is discussed in
the synthesis of 3a, 6a-dimethylglycoluril, 3c, through
condensation of 2, 3-butanedione with urea under simple
aerobic conditions. Scheme 1 shows a general reaction
scheme for the preparation of glycolurils. The first step for
the synthesis of these compounds is the cyclization reaction
of urea with dicarbonyl compound at pH values below 4 via
formation of a monocyclic intermediate.
Synthesis and characterization of various self-assembling
molecular capsules and several substituted glycolurils have
been the subject of great attention and some strong inorganic
acids [10-12] have been applied as catalyst for the
preparation of these compounds. Although, many of the
reported methods were almost effective, some of them
RESULTS AND DISCUSSION
During the past few decades, polyoxometalates have
been constituted an interesting class of inorganic compounds
extended to catalysis research owing to their wide industrial
applications as heterogeneous and homogeneous catalysts for
the preparation of organic commodities [14]. Furthermore,
the high solubility of polyoxometalates in various organic
solvents caused more options for the choice of
environmentally less harmful solvent and consequently
leading to the environmentally benign industrial procedures.
Heteropolyoxometalates, as inorganic porphyrin analogues,
owing interesting redox and super-acidic properties and have
effectively been used as catalysts in a wide range of
oxidation reactions, transformation of various kinds of
functional groups, cyclization, esterification, olefin
epoxidation, and wide applications in fine chemical
consequenced
disadvantages
such
as
corruption,
environmental hazards, and long reaction times. Moreover,
one of the main drawbacks of the above protocols has been
the formation of unwanted 5, 5-diphenylhydantoin (B) as a
major by-product accompanied with the desired glycoluril
(
A) (Scheme 1) [12]. Therefore, still appears a need to
introduce novel methods to permit better selectivity under
milder conditions and with easy work-up procedures.
*
Address correspondence to this author at the Department of Chemistry,
School of Sciences, Sabzevar Tarbiat Moallem University, Sabzevar 96179-
6487, Iran; Tel: +98-571-4410110; Fax: +98-571-4410300;
E-mail: rtayebee@yahoo.com
7
1
875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

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84 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Tayebee et al.
7
O
O
O
O
O
O
O
H+
HN
NH
HN 2 3NH
1
H N
NH2
HN
O
NH
+
2
3
a
R1
R2
R
R
R1
R2
1
2
+
H N
NH2
6a
2
+
H , -2H O
2
6
4
NH
HN
5
R2
HO
OH
R1
(B)
R , R = Aryl, Alkyl
1
2
(A)
O
8
Scheme 1.
production, such as fragrances, pharmaceuticals and foods
14].
tetramethylglycolurils with complete conversion after 24 h.
2, 3-hexanedione, 1c, was also subjected to the reaction with
urea and methylurea. 1c produced the corresponding
glycoluril with 83% yield after 36 h; while, methylurea
showed lower reactivity in the reaction with 1c and resulted
in 50% conversion after 48 h. 2, 3-Octanedione (1d) showed
the lowest reactivity toward urea and generated 48% of
product after 36 h. Definitely, both electronic and steric
influences induced by the methylene substituents around the
carbonyl groups of diketones and urea affected their
reactivity toward the condensation reactions. Increasing
[
As previously described [13], vicinal dicarbonyl
compounds easily contribute to the cyclocondensation
reactions with urea and methyl urea according to the
conventional procedure in methanol at room temperature in
3
the presence of 0.95 mol% H PW12O40. Preliminary findings
revealed the high efficacy of heteropolyacids as catalysts in
the preparation of glycoluril derivatives via condensation
reaction of dicarbonyl compounds (1a-1d) with ureas (2a-
2
b). According to Scheme 2, two structural cis- and trans-
n
steric hindrances as Pr > Et > Me in the examined
isomers (3 and 4) would be formed in the cyclocondensation
diketones, led to lowering isolated yield% and lengthening
of the reaction times. Moreover, in spite of the higher
basicity of methyl urea rather than urea, the first provided
lower conversions, presumably, due to the steric hindrances
originated when methyl urea was approached to the
corresponding diketones.
of vicinal dicarbonyl compounds such as 2, 3-butanedione
(
1b), 2, 3-hexanedione (1c), and 2, 3-heptanedione (1d) with
urea and methylurea; whereas, glyoxal (1a) led to only one
product (3a).
To isolate the structural isomers, the crude reaction
1
products were purified, then, were analyzed by H NMR
Although, there are only a few reports [10-12, 15] on the
preparation of glycoluril derivatives under catalytic
conditions, to the best of our knowledge there isn't
systematic and efficient catalytic rute for the synthesis of N-
substituted glycolurils by the mediation of green catalysts.
Comparison of the results obtained in Table 1 with other
previously reported protocols (considering catalyst mol%,
reaction time, and yield%) confirmed the high efficacy of the
present HPA-catalyzed cyclocondensation procedure for the
synthesis of N-substituted glycolurils under mild and simple
reaction conditions (Table 2). These results revealed that
spectroscopy. The high efficacy of the present protocol was
confirmed when 40% aqueous glyoxal solution (1a) was
reacted with urea and gave the simplest form of glycoluril
(
3a) with 85 % yield after 2 h. In this report we tried to
separate the cis-(3b) and trans-(4b) isomers obtained from
the reaction of glyoxal with methylurea which occurred
regioselectively. Findings revealed the trans isomer as the
major product with the ratio of 4b/3b as ~3 : 1. 2, 3-
butanedione (1b) reacted quantitatively with urea and led to
1
00% of 3c after 5.5 h; whereas, methylurea showed lower
reactivity and gave a mixture of cis- and trans-isomers of
O
O
O
R3
R3
O
O
N
N
NH
N
NH
R3
H PW O (0.95 mol%)
3
12 40
+
2
H N
2
N
R
1
R
2
+
R1
R2
H
R1
R2
MeOH, RT
NH
HN
N
R3
R
3
diketone
urea
O
O
cis-glycoluril
trans-glycoluril
3
3
a: R , R , R = H
1
2
3
1
1
1
1
a R , R = H
1 2
b, 4b: R , R = H; R = Me
1
2
3
b R , R = Me
1
2
2a R = H
3
3c: R , R = Me; R = H
3d, 4d: R , R , R = Me
1 2 3
1 2 3
c R , R = Et
1
2
2b R = Me
3
d R , R = n-Pr
1
2
3
3
3
3
e: R , R = Et, R = H
f, 4f: R , R = Et, R = Me
g: R , R = nPr; R = H
h, 4h: R , R =nPr; R =Me
1 2 3
1
2
3
1
2
3
1
2
3
Scheme 2.

A New and Efficient Method for the Preparation
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
185
Table 1. Condensation Reaction of Some Dicarbonyl Compounds (1a-1d) with Urea (2a) and Methylurea (2b)
O
O
O
O
O
R3
H PW12O40 (0.95 mol%)
R3
O
O
N
N
NH
N
NH
R3
3
+
2
H N
2
N
R
1
R
2
+
R1
R2
H
R1
R2
MeOH, RT
NH
HN
N
R3
R
3
n
R , R = H, Me, Et, Pr
R = H, Me
3
1
2
(
2a)+Diketone
(2b)+Diketone
Trans:
Cis
ratio
Time
Conv.
(%)
Yield
(%)
Selec.
(%)
Time
(h)
Conv.
(%)
Yield
(%)
Selec.
(%)
Diketone
Product
Products
(
h)
O
O
O
O
Me
Me
O
O
HN
NH
N
N
NH
N
NH
H
H
H
H
H
H
2
88
100
89
85
100
83
96
100
93
12
24
48
100
100
100
100
92
3:1
5:1
6:1
H
H
HN
NH
NH
HN
N
Me
Me
Me
Me
1
a
O
O
3
a
4b
3b
O
O
O
Me
Me
Me
O
O
HN
Me
NH
N
NH
N
NH
Me
Me
Me Me
NH
HN
Me
5
.5
100
100
N
N
Me
Me
HN
NH
1
b
O
O
O
3
c
3d
4d
O
O
O
Me
Me
Me
O
O
HN
NH
N
N
NH
Et
N
NH
Et
HN
Et
NH
Et
Et
HN
Et
a
3
6
54
50
NH
N
Et
Et
1c
O
O
O
3
e
4f
3f
O
O
O
Me
Me
O
O
N
N
NH
N
NH
nPr
HN
NH
nPr
Me
nPr nPr
nPr
nPr
a
3
6
56
48
86
48
59
55
93
7:1
nPr
nPr
NH
HN
N
HN
NH
Me
1
d
O
O
O
3g
4h
3
h
a
The solution was first heated for 1 h on a steam bath, then, was stirred for 47 h at room temperature. Then, the solvent was removed and the residue was re-crystallized from dioxane.
only 0.95 mol% of H
condensation of 2,3-butanedione (1b) with urea after 5.5 h.
3
PW12
O
40 was capable of complete
principally constituted by molybdenum, tungsten or
vanadium as polyatoms (M), phosphorus and silicon as
central atom or heteroatom (X). The Keggin unit is formed
Now, we wish to discuss about the role of
heteropolyoxometalate structure on its catalytic efficacy.
There are three important classes of heteropoly compounds.
Fig. (1) shows the general structures of Keggin, Wells–
Dawson, and Preyssler– type heteropoly compounds. The
Keggin-type heteropoly compounds with the general formula
by a central tetrahedral XO
MO [16]. The Wells–Dawson heteropolyanion has the
general formula of [(X )
represents central atom, such as phosphorous(V),
4
surrounded by 12 octahedral
6
n+
(16-2n)-
n+
2
M
18
O
62
]
,
where
X
a
arsenic(V), and sulfur(VI), surrounded by a cage of M
addenda atoms, such as tungsten(VI) and molybdenum(VI)
or a mixture of elements, each of them composing MO (M-
6
V
VI
V
(3+x-y)-
of H
y
[X M (12-x)
V
x
O
40
]
are polynuclear complexes

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86 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Tayebee et al.
Table 2. Comparison of the Catalytic Efficiency of H
Reaction of Glyoxal with Urea
3
PW12
O
40 with Some Different Catalysts Reported for the Cyclocondensation
O
O
O
R3
R3
O
O
R3
N
N
NH
R2
NH
N
NH
R2
+
2
H N
2
N
R1
R1
HN
+
H
R1
R2
N
R3
R
3
O
O
Catalyst
Catalyst mol(%)
R
1
,R
2
R
3
Time(h)
Yield%
Condition
Ref.
H
H
3
3
PW12
O
O
40
40
<1
<1
Me
H
H
5.5
12
100
100
50-60
51
RT
RT
This work
PW12
Me
Me
Me
Me
H
This work
HCl(Conc.)
HCl(Conc.)
HCl(Conc.)
KOH
>50
>50
>70
>60
H
48
80-90 ˚C
RT
19
10
18
14
Me
H
1.45
72
71
20 ˚C
Ph
2
75
Ultrasonic, 40 ˚C
oxygen) octahedral units. This structure is composed of two
identical “half units” of the central atom surrounded by nine
H
3
PW12
O
40, and H
4
SiMo
3
W
9
O
40 (Keggin), H14NaP
5 30 110
W O
(Preyssler), and
6 2
K P Mo18O62 (Wells-Dawson) reacted
octahedral units XM
The Preyssler polyanion [MP
central metal ion, M) consists of a cyclic assembly of five
9
O
31 linked through oxygen atoms [17].
satisfactory with urea after 5.5 h; whereas, other
heteropolyoxometalates displayed 30-80% of conversion
under the same reaction condition. Clearly, tungsten-
substituted polyoxometalates showed higher catalytic
activity than molybdenum analogues. Although, heteropoly
compounds in their acidic forms were more effective than
their corresponding soluble ionic salts, high catalytic activity
x-
5
30
W O110] , (x depends on the
3
-
PW
by removal of two sets of three corner shared WO
18].
6
O
22 units, each derived from Keggin anion, [PW12
O40] ,
6
octahedra
[
Particular characteristics of heteropolyoxometalates such
of K
totally acid catalyzed. Moreover, H
heteropolyacid was obviously less efficient than H
The first, led to 60% of product; whereas, H
6
P
2
Mo18
O
62 indicated that the present protocol was not
as their solubility in solvents of different polarities, inherent
stability, lack of corrosion, ease of handling, simple recovery
and regeneration constitute an attractive class of inorganic
compounds that have been used as catalysts in the
transformation of various kinds of functional groups. To
obtain more insights on the role of kind and concentration of
catalyst in the introduced condensation protocol, the reaction
of 1b with urea was used as a model reaction. The reaction
of 1.15 mmol of compound 1b with 2.53 mmol of urea in 1
ml methanol at room temperature in the presence of 0.011
mmol of different heteropolyacid catalysts was investigated
3
PMo12O
40 as a strong
3
PW12
40
O .
3
PW12 40 gave
O
complete conversion during the same time. Vanadium-
substituted heteropolyoxometalates disclosed less catalytic
activity and resulted in <55% of the corresponding
glycoluril.
Even though, it is difficult to offer a clear explanation for
different catalytic reactivity patterns observed for these three
structural types of heteropolyanions, there is a complex
relationship between the catalytic activity, structure,
stability, and solubility of the heteropoly compounds. By
changing the constituent elements of polyanion (both hetero
and addenda atoms), the acid strength of heteropolyacid, as
(
Fig. 2). 1b led to ~10% of product in the absence of catalyst
after 24 h. As is described in Fig. (2), the examined
heteropolyoxometalates exhibited different different catalytic
activities. Among the introduced heteropolyoxometalates,
(a)
(b)
(c)
Fig. (1). The primary structures of Keggin (a), Wells–Dawson (b), and Preyssler (c) heteropolyacids.

A New and Efficient Method for the Preparation
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
187
(0.95 mol%)
O
O
O
HN
HN
NH
O
+
2
Me
Me
H2N
NH2
MeOH, RT
NH
Me
Me
O
Fig. (2). Reaction of 2, 3-butanedione with urea in the presence of different heteropolyoxometalates.
well as its catalytic activity and solubility, change in a wide
range [19]. Several studies have shown that the acidity of
heteropolyacids slightly affected by their structural
composition. Many heteropolyacids, in particular those
possessing the Keggin structure, are close to the spherical
shape and behave as strong acids [20]. Surprisingly, high
It is well known that efficiency of many homogeneous
and heterogeneous catalytic systems would be influenced by
the nature of solvent in liquid phase. Effect of the nature of
solvent was studied in the present protocol, and the obtained
findings revealed that solvent has a profound effect on the
yield% of the desired glycolurils. Experiments were
performed to find the best solvent for the reaction of 1b with
urea (Table 3). The series of solvents were organised in
decreasing dielectric constant, which is a measurement of the
6 2 4 9 2
catalytic activity of K P Mo18O62 and K SiW Mo O39 salts
could not be explained considering Bronsted acidity of
heteropolyacids. This behavior would be demonstrated
regarding approach of the substrate into the bulk of the
heteropolyacid. It seems that polar reactant molecules
penetrate into the bulk of the heteropolyacid crystallites,
then, after chemical transformation, the products release to
the outside of the solid bulk.
3
solvent polarity. H PW12O40 is completely soluble in polar
solvents (high dielectric constant) such as water and
methanol, partially soluble in acetone, acetonitrile, and
ethanol and non soluble in non polar solvents (ꢀ<5) such as
3
carbon tetrachloride and hexane. Since, H PW12O40 is soluble
in a wide range of polar solvents, especially in water, there is
more option for the choice of solvent and consequently cause
less harm to the environment. Interestingly, 85% of 3c was
provided in normal tap water. Therefore, due to the non-
volatile, inflammable, and non-toxic nature of water, this
solvent may be the most preferred, and would be a good
choice for the synthetic purposes from the green points of
view. However, as shown in Table 3, methanol was the best
solvent and 3c was obtained in 100% yield; whereas, other
polar solvents showed lower efficacy toward the
condensation reaction. When non-polar solvents, such as
carbon tetrachloride and hexane, were used as a solvent, the
catalytic reaction didn't take place efficiently, presumably,
To study effect of catalyst quantity on the progress and
efficacy of the catalytic system, a set of experiments where
carried out using different mol% of H PW12O40 in the
3
reaction of 1b (1.15 mmol) with urea (2.53 mmol) under the
standard reaction condition in MeOH (1 ml) at room
temperature. As mentioned earlier, the catalytic system was
inefficient in the absence of catalyst and <10% of product
was obtained after 24 h. A clear increase in the yield % was
occurred in the presence of 0.5 mol % of H
2% of the corresponding glycoluril was produced after 2 h
Fig. 3). Higher amount of the catalyst, resulted in a smooth
increase in the product yield%, and the maximum conversion
5% was obtained in the presence of 10 mol% H
after 2 h.
3
PW12O40 and
4
(
9
3 40
PW12O
due to the non solubility of H
non-polar solvents.
3
PW12O40 on the mentioned

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88 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Tayebee et al.
100
90
80
70
60
50
40
30
20
10
0
0
2
4
6
8
10
12
Catalyst (mol%)
3
Fig. (3). Effect of H PW12O40 (mol%) on the reaction of 2, 3-butanedione with urea after 2 h.
Table 3. Effect of Different Solvents on the Reaction of 1b with Urea in the Presence of H
3
PW12
O
40 (0.95 mol%)
a
Solvent
Dielectric constant, ꢀ
Dipole moment (D)
Solubility of H
3
PW12
O
40
Yield%
Time (h)
MeOH Methanol
32.6
78.5
38.8
24.3
20.7
5.8
1.7
1.87
4.03
1.7
S
100
85
83
73
68
53
18
15
5.5
5.5
5.5
5.5
5.5
5.5
5.5
5.5
H
2
O Water
S
MeCN Acetonitrile
EtOH Ethanol
PS
PS
PS
PS
NS
NS
CH
EtOAc Ethyl acetate
CCl Carbon tetrachloride
14 Hexane
3
COCH
3
Acetone
2.85
1.88
-
4
2.2
C
6
H
1.9
0.08
Data from ref. RC Weast (Ed.), Handbook of Chemistry and Physics, CRC Press, Boca Raton, FL, 1987, p E-44; S: soluble, PS: partially soluble, NS: not soluble.
The mechanism of the formation of glycolurils from
glyoxal and ureas was studied by Kravchenko et al. [20].
They proposed a reasonable reaction pathway as described in
Scheme 3. In the first step, an intermediate formulated as 1-
alkyl-4,5-dihydroxyimidazolidin-2-one would be appeared
from the reaction of diketone and mono-alkylurea molecules.
Then, this intermediate was protonated in the presence of an
acid catalyst followed by elimination of a water molecule to
generate the carbonium ion. The latter reacted with the
second urea molecule and generated the final glycoluril
through a new carbonium ion intermediate. Two alternative
cyclization through the formation of the trans-intermediates
was more favorable, both in the orbital- and charge-
controlled reactions, resulting in the formation of trans-
glycolurils.
Stability and reusability of H
means of infrared spectroscopy. The PO
3 40
surrounded by four W 13 groups in the Keggin H PW12O ,
3
PW12
O
40 was studied by
4
tetrahedron
3
O
gives rise to four types of oxygen infrared bands in the
-1
fingerprint region between 1200 and 700 cm . These
-1
characteristic bands were observed at ca. 1075 cm (P-O in
-1
central tetrahedral), 980 cm (terminal W
d
O), 885 and 810
reaction pathways through these two intermediates are
-1
'
cm (W-O-W) associated with the asymmetric vibrations.
These bands could be used as an indicator of the stability of
possible depending on which urea fragment, NH
2
or NHR, is
bound to the final carbonium ion to give cis- and trans-
isomers. However, the reactions of glyoxal with
monoalkylureas always produced mixtures of trans- and cis-
glycolurils. In addition, the reactions produced hydantoins,
as minor by-products, which was formed from the primary
carbonium ion. Kravchenko [20] demonstrated that the
3 40
the catalyst. The stability and deactivation of H PW12O
under the reaction could be evaluated by reusing the recycled
catalyst after completion of the first run. When the reaction
was repeated using the recovered catalyst, the resultant
conversion was comparable to the value obtained for the first
run. Comparison of the infrared spectra of the recovered
catalyst after five runs revealed that the Keggin structure was
retained almost completely.
isomer C
than C , based on the theoretical analysis of the potential
energy surface calculations. These data suggested that
1
is the thermochemically more stable intermediate
2

A New and Efficient Method for the Preparation
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
189
O
O
O
HN
NR'
O
O
H+
O
'
R N
NH
'
R N
NH
+
R
R
'
R
-
H O
R
R
R
R
H
2
N
NH
2
HO
OH
R
OH
OH
R
R= H, CH , C H , C H
3
2
5
3
9
O
R'= H, CH3
O
'
R
H N
NH
'
2
R
H N
2
NH
O
O
RN
NH
RN
NH
O
O
R
R
R
R
'
NR'
RHN
NH
OH
H
2
N
OH
H+
-
H O
H+
-
H O
2
2
O
O
RN
NH
O
RN
NH
R
R
O
R
R
'
RHN
NH
H N
2
NR'
O
O
R'
R'
N
NH
N
NH
R
HN
R
R
R
N
N
NH
R'
R'
O
O
Scheme 3.
In order to study the reusability of H
separated from the reaction mixture, washed with
chloroform, was dried, and was reused again. The recovered
catalyst was found to be reusable after seven cycles without
significant loss of activity. Reusability studies revealed that
the activity of the exhausted catalyst was close to the new
one, demonstrating the efficiency of the catalyst (Fig. 4).
3
PW12
O
40, it was
resources and were used as received. All products were
characterized by comparison of their spectral and physical
data with those previously reported. Melting points were
recorded on an Electrothermal type 9200 melting point
apparatus. Infrared spectra were run on a 8700 Shimadzu
Fourier Transform spectrophotometer. H and C NMR
spectra were recorded on a Bruker AVANCE 300-MHz
instrument using TMS as an internal reference.
Heteropolyoxometalates were prepared and characterized
according to literature procedures [21].
1
13
EXPERIMENTAL
Materials and Methods
2
.1. General Procedure for Synthesis of the Glycoluril 3a
Commercial urea, methylurea, 40% aqueous glyoxal
solution, and glyoxal trimeric dihydrate were used. Other
reagents needed to prepare the examined catalysts, solvents,
and starting materials were purchased from commercial
Compound 1a (1.15 mmol), urea (2.53 mmol),
H
5
3
PW12
O
40 (0.011 mmol), and MeOH (1 ml) were added to a
ml round bottomed flask equipped with a magnetic stirrer.
Progress of the reactions was monitored by TLC under

1
90 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
00
Tayebee et al.
1
9
8
7
6
0
0
0
0
Yield% 50
40
30
20
10
0
1
2
3
4
5
6
7
8
Number of cycles
3
Fig. (4). Studying reusability of H PW12O40 in the reaction of 2,3-butanedione with urea after 5.5 h.
1
83
ambient temperature. After completion, the reaction mixture
including the insoluble crude product was poured into water
W-NMR, confirmed that 90–95% of the solid product is in
31
the ꢁ-form. P-NMR: ꢁ= -12.7 ppm, ꢂ= -11 and -11.6 ppm,
1
83
(
10 ml) and filtered off. Then, the solid crude product was
W-NMR: ꢁ= -125 and -170 ppm, ꢂ= -112,-131,-171 and -
191 ppm.
washed with water and subsequently with ether. The pure
product, if needed, could be obtained by re-crystallization
from ethanol-water mixture. Products were identified by
2
.4. Preparation of Preyssler’s Anion K12Na
2 5 30 110
[NaP W O ]
1
and Its Acidic Form H14[NaP
5 30 110
W O ]
means of IR and H NMR spectroscopy and/or comparison
of their melting points with those reported in the literature.
Ortho-phosphoric acid 90% (75 mL, 1.2 mol) was slowly
added to 50 mL of an aqueous solution of Na WO .2H O (99
g, 0.3 mol) at 45 ºC, and the resulting mixture was refluxed
for 5 h. The obtained solution was then diluted by 15 mL of
water. Thereafter, powdered KCl (22.5 g, 0.32 mol) was
slowly added to the vigorously stirred above solution during
35 min at room temperature. The pale green impure
2
4
2
2
.2. Preparation of Tetramethylglycolurils and Separation
of the cis-(3d) and trans-(4d) Isomers[9]
A 10 ml round flask was charged with compound 1b (5.7
mmol), methyl urea (12.6 mmol), H PW12O40 catalyst (0.05
3
mmol), and MeOH (5 ml). The reaction was carried out at
ambient temperature for 48 h. After completion of the
reaction, the mixture was cooled to 0 ºC for 30 min. The
solid product was collected by vacuum filtration, washed
with cooled ethanol (2 ꢀ 0.6 ml), then exhaustively with
dichloromethane and dried to give 0.3 g of a mixture of cis-
and trans-isomers. The cis-isomer was isolated from the
reaction mixture in the pure form through re-crystallization
from ethanol. Isolation of the trans-isomer was carried out
by heating mixture of the two isomers (0.3 g) with acetic
anhydride (3 ml) under reflux for 20 h. After cooling to room
temperature, the solid material was collected and washed
3
precipitate was filtered off and was washed with CH COOK
(0.1 M). The white needlelike crystals of potassium salt of
the Preyssler anion were re-crystallized from hot water. The
free acid was prepared via the passage of a solution of 11.4 g
potassium salt in 20 mL of water through a column
+
(50cmꢀ1cm) of Dowex 50WX8 in the H form. Evaporation
of the eluent to dryness in vacuum, resulted in
H
14[NaP
5
W
30
2 5 30
O110]. Calcd (Found) for K12Na [NaP W O110].
15H
66.95 (66.83); H
1070(m), 1010(w), 980(vw), 920(vs), 890(vs), 760(vs).
Calcd (Found) for H14[NaP O: Na, 0.27
O, 12.27 (12.40)
2
O: K, 5.69 (5.81); Na, 0.84 (0.71); P, 1.88 (1.74); W,
-
1
2
O, 3.28 (3.35). FT-IR (cm ): 1160(s),
with CHCl
3
, THF and cold ethanol, to give the trans-form.
5 30 2
W O110].58H
(
[
0.32); P, 1.82 (1.90); W, 64.8 (64.92); H
21].
2
2
.3. Preparation of K P W O62.10H
6 2 18 2
O and its Acidic form
6 2 18 2
H P W O62.24H O
Na
the solution was heated to boiling. Then, 150 ml of 85%
PO was added and the resulting yellow-green solution
was refluxed for 13 h. The solution was cooled, and the
product was precipitated by addition of 100 g of solid KCl.
The light green precipitate was collected and re-dissolved in
a minimum amount of hot water and allowed to crystallize at
2 4 2
WO .2H O (100g) was added to 350 ml of water and
CONCLUSION
H
3
4
The present protocol introduced a new approach to the
synthesis of some important alkyl-substituted glycolurils via
condensation of glyoxal and/or vicinal diketones with urea
and methylurea under mild and environmentally friendly
conditions by using 0.95 mol% of some important
heteropolyoxometalates with Keggin, Wells–Dawson, and
Preyssler structures. Using an environmentally benign
catalyst instead of hazardous classical inorganic acids, high
selectivity of the catalytic system to the formation of
glycolurils, high stability and reusability of the
heteropolyoxometalates, and high efficacy of tap water as
5
8
˚C overnight. The typical yield was 70 g after drying at
0˚C under vacuum for several hours. The K
6 2 18 62
P W O
prepared by this way is always a mixture of ꢁ and ꢂ isomers.
The acid H O was prepared from an aqueous
solution of ꢁ/ꢂ K 62 salt by passing of it from a
cationic resin. Characterization of this product with P- and
6 2 18 2
P W O62.24H
6 2 18
P W O
3
1

A New and Efficient Method for the Preparation
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
191
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solvent in this catalytic system are highlight points of the
present methodology.
ACKNOWLEDGEMENT
Partial financial support from the Research Council of
Sabzevar Tarbiat Moallem University is greatly appreciated.
Special thanks to Vahid Tayebee for English editing of the
manuscript.
[13]
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CONFLICT OF INTEREST
Declared none.
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