Synthesis of glycolurils and hydantoins by reaction of urea and 1, 2-dicarbonyl compounds using etidronic acid as a “green catalyst”

Article abstract of DOI:10.1002/jhet.4132

Most of the known methods for the synthesis of heterocyclic compounds have disadvantages, such as a long reaction time and aggressive conditions. We have developed a new, rather simple and efficient method for the synthesis of a number of glycoluryls and hydantoins in water using a etidronic acid (HEDP) as “Green catalyst.” So, for the first time, the condensation reaction of ureas with 1, 2-dicarbonyl compounds was carried out in the presence of HEDP. Also based on NMR studies, a chemism of these reactions, which is stepwise, is proposed. It has been established that the optimal conditions for the synthesis of glycoluryls and hydantoins using HEDP are: temperature 80°C-90°C, 40-20 minutes, and the ratio of urea and HEDP is 1:1. In all cases, the remaining aqueous filtrate containing HEDP after the reaction can be reused for other cycles synthesis of glycoluril and other compounds, because HEDP is not converted during the reaction.

Full text of DOI:10.1002/jhet.4132

FULL PAPER
Synthesis of Glycolurils and Hydantoins by Reaction of Urea
and 1, 2-Dicarbonyl Compounds using Etidronic acid as a “Green
catalyst”.
Abdigali Bakibaev,[a] Artur Uhov,[a] Victor Malkov,[a] and Svetlana Panshina*[a, b]
[a]
[b]
Prof. A.A. Bakibaev, A.I. Uhov, V.S. Malkov, S.Yu.Panshina
Department of Chemistry
National Research Tomsk State University
Tomsk, 634050, Russian Federation
S.Yu.Panshina
Department of Chemistry
National Research Tomsk Polytechnic University
Tomsk, 634050, Russian Federation
E-mail: janim_svetatusik@mail.ru
Supporting information for this article is given via a link at the end of the document.
Abstract: Most of the known methods for the synthesis of
heterocyclic compounds have disadvantages, such as a long
reaction time and aggressive conditions. We have developed a new,
rather simple and efficient method for the synthesis of a number of
glycoluryls and hydantoins in water using a Etidronic acid (HEDP) as
“Green catalyst”. So, for the first time, the condensation reaction of
ureas with 1, 2-dicarbonyl compounds was carried out in the
presence of HEDP. Also based on NMR studies, a chemism of these
reactions, which is stepwise, is proposed.
It has been established that the optimal conditions for the synthesis
of glycoluryls and hydantoins using HEDP are: temperature 80–
90°C, 40–20 minutes, and the ratio of urea and HEDP is 1 : 1.
In all cases, the remaining aqueous filtrate containing HEDP after
the reaction can be reused for other cycles synthesis of glycoluril
and other compounds, because HEDP is not converted during the
reaction.
and aggressive conditions. Recently, the search for new
synthetic strategies for the production of glycoluryls with good
selectivity, in mild conditions and with easy processing is
determined by the environmental necessity of chemical
processes [38], which is also true for methods for the production
of glycoluryls.
An efficient approach to the green synthesis of glycoluryls in an
aqueous medium using P4O10 as
a catalyst, under mild
conditions with the possibility of recycling both solvent and
catalyst, is reported in [39].
More recently, in a number of works [40–42] it was found that
Etidronic acid (HEDP) proved to be a convenient “green” catalyst
in 3-component reactions of the formation of dihydropyrimidones
using carbonyl compounds with an active methylene group, urea
and aldehydes as under traditional conditions [40, 41], and
under microwave synthesis [42]. However, examples of the use
of HEDP as a catalyst in the reactions of 1, 2-dicarbonyl
compounds with ureas are still not known.
Introduction
As mentioned above, we first carried out the condensation
reaction of urea 1a with glyoxal 2a in water to obtain glycoluril 3a
in the presence of HEDP as a “green” catalyst (Scheme 1).
In the chemistry of heterocyclic compounds, bicyclic bisureas
have a special place, among which the most interesting are
2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione (glycoluril) 3a
(Scheme 1) and its derivatives.
The chemistry of glycolurils, first of all, due to polyfunctionality of
their structure, has developed rapidly. It was reflected in the
creation of valuable substances in various fields of human
activity such as fertilizers [1], disinfectors [2], drugs [3, 4],
stabilizers of organic compounds against photodegradation [5, 6]
of independent explosives or their components [7-10] and other
important substances and materials (polymer crosslinking
agents [11], catalysts [12], bleaching activators [13-15] and their
use in combinatorial chemistry [6, 16]). The synthesis and study
of the chemical properties of bicyclic bisureas makes it possible
to obtain new classes of nitrogen-containing heterocyclic
compounds with practically useful properties, an example of
which are polycyclic condensed systems such as cucurbit[n]urils
[17-23] and bambus[n]urils [24, 25], the construction unit of
which is glycoluryl 3a.
As a rule, the synthesis of glycoluryls are carried out by
condensation of 1, 2-dicarbonyl compounds with ureas in the
presence of acidic (H2SO4 [26-28], HCl [29-31] and CF3COOH
[32-35]) and alkaline catalysts [36]. There is evidence of the use
of heteropolyoxometals in MeOH [37]. However, in recent years
the problem of environmental pollution has been growing
progressively, which makes it necessary to take this
circumstance into account in experimental and industrial
practice. Most of the known methods for the synthesis of
glycoluryls have disadvantages, such as a long reaction time
Scheme 1. Synthesis of glycoluril 3a
Results and Discussion
In the course of our studies, we found that the synthesis of
glycoluril 3a using HEDP as a catalyst (Scheme 1) proceeds for
40 minutes 3a.
In order to search for conditions allowing to direct the process to
the selective formation of glycoluril 3a with the greatest yield, we
studied the interaction of urea 1a with glyoxal 2a in the form of a
40% aqueous solution. It was found that the optimal conditions
for the synthesis of glycoluril 3a (yield 99% 100%) using HEDP
are temperature 80° C, 40 minutes and the ratio of urea 1a and
HEDP is 1: 1. An attempt to reduce the amount of HEDP to 0.5
equivalents showed that the total yield of glycoluril 3a drops to
87%.
It is important to note that the remaining aqueous filtrate after
the reaction containing HEDP can be used again for other cycles
synthesis of glycoluril 3a, because, after a week-long standing
1
(according to 13C, H and 31P, NMR spectroscopy of the crude
This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1002/jhet.4132
This article is protected by copyright. All rights reserved.

FULL PAPER
reaction mixture after filtering product 3a) chemical shifts of
HEDP (Fig. S1-S4) did not change. Analysis of concentrated
stock solutions after the synthesis of glycoluryl 3a by 13C and 1H
NMR showed that with prolonged heating of the reaction mass,
the filtrate always contains a trace amount of hydantoin 6a
together with HEDP (Fig S5-S6), which is probably due to the
presence of a competitive reaction or the opening of bicycle 3a
may be present (Scheme 2).
The authors of [39] synthesized glycoluryls using a large excess
(12 mmol) of an 85% aqueous solution of H3PO4 compared to
P4O10, but after 2 hours, they obtained products with a lower
yield (45–55%) relative to those obtained in the presence of
P4O10 (70%). They associated this circumstance with the greater
stability of the cyclic five-coordinated phosphate intermediate
based on P4O10 and glyoxal than the corresponding acyclic five-
coordinated compound associated with H3PO4. In contrast to this
work, we have shown that the use of HEDP gives high yields
(95-99%), and this fact indicates that the intermediate is not
connected with the acyclic structure of the catalyst.
The authors of [39] also proposed a reaction mechanism for the
preparation of glycoluril 3a, where the initial stage involves
hydration of the aldehyde 2a and then phosphorylation of the
latter with P4O10 to obtain a cyclic five-coordinated phosphate
intermediate, which decomposes in the process, since at the
beginning and at the end of the reaction, the 31P NMR spectrum
of the reaction a constant P4O10 signal was observed in the
mixture (d = - 23 ppm), but they did not conduct NMR
registration of the obtained phosphate complex. It is important to
note that P4O10 is prone to hydrolysis with conversion to
phosphoric acid, while HEDP remains unchanged both with
weekly boiling and with monthly standing in solution.
To study the specific features of the catalytic effect of HEDP in
the synthesis of glycoluril 3a, we carried out this reaction with
stepwise addition of reagents, and the process was monitored
by NMR.
It is known [43–44] that glyoxal 2a exists in various hydrated
forms in aqueous solutions, and bishemidiol glyoxal 2a'
(Scheme 2) prevails in highly diluted aqueous solutions.
Scheme 2. The chemism of synthesis of glycoluril 3a
We believe that the chemical shift at 4.48 ppm in the 1H
spectrum (Fig. 1) corresponds to the proton CH(OH)2 of the
bishemdiol fragment of complex A, and the two signals are
176.59 and 165.61 ppm in the 13C spectrum (Fig. 2) corresponds
to the carbonyl C=O-group of complex A, the pairing of which
can be explained by tautomeric equilibria in complex A, or by
double complexation with HEDP.
1
We found that when HEDP was added to glyoxal 2a in the H
and 13C NMR spectra of the analyte, peaks uncharacteristic of
the starting materials instantly appeared: chemical shift of 4.48
1
ppm in the H spectrum (Fig. 1) and 176.59 and 165.61 ppm in
the 13C spectrum (Fig. 2), which disappear in the further course
of the reaction.
To explain the observed changes, we believe that the initial
stage includes the process of complete hydration of glyoxal 2a in
water with the formation of bishemdiol 2a' (Fig S7-S8) and then
HEDP, that is prone to hydrate formation [45], binds one water
molecule to the formation of an intermediate complex
A
(Scheme 2, Fig. 1, 2), which is stabilized due to the appearance
of a developed system of hydrogen bonds.
This article is protected by copyright. All rights reserved.

FULL PAPER
In further studies, we found that a 3-day standing of the reaction
mixture in an ampoule at room temperature led to the
disappearance of the signal at 4.90 ppm in the 1H NMR
spectrum, but chemical shifts of low intensity of hydantoin 6a
appear in the reaction mixture (singlet of the CH2 group at 3.84
ppm) and an extended triplet j = 52.2 Hz at 6.88, 6.75, 6.62 ppm,
which indicates the presence of the NH3+ ion in the test sample.
Thus, based on the data of NMR spectroscopy, we believe that
the chemical signal at 4.90 ppm corresponds to the protons of
CH-CH of monocycle 5 with a linear ureide fragment (Scheme 2),
the conversion of which is probably associated with a more
thermodynamically favorable salt formation of urea 1a and
HEDP. This is evidenced by the NMR analysis of a model
mixture of urea 1a and HEDP, in the 1H NMR spectrum of which
there is a similar signal of the NH3+ ion (triplet J = 52.2 Hz at
6.88, 6.75, 6.62 ppm) (Fig. S13-S14).
Figure 1. 1H NMR spectrum of complex A based on glyoxal 2a and HEDP.
To determine the formation path of hydantoin 6a in the reaction
mixture, chromatographically pure glycoluril 3a (Fig. S15) with
HEDP was boiled for 1 hour at various ratios (Table 1).
1
According to the integrated intensity in the H NMR spectra, it
was shown (Table 1) that glycoluril 3a partially decomposes into
hydantoin 6a and urea 1a. This circumstance is probably
associated with the more thermodynamically favorable salt
formation of urea 1a and HEDP described above, which occurs
through the opening of the imidazolinone ring of glycoluril 3a
with the formation of intermediate
5
with its further
rearrangement into substance 6a (Scheme 2).
Table 1. The yield of hydantoin 6a and urea 1a as a result of the
interaction of glycoluril 3a with HEDP in various ratios,
calculated from the integrated intensity of 1H NMR spectrum.
The ratio of reagents Yield, %
Yield, %
Figure 2. 13C NMR spectrum of complex A based on glyoxal 2a and HEDP
glycoluril
HEDP
3a
and
6a
10
25
4
1a
9
Further, we found that when an equimolar amount of urea 1a
1
1:0.05
1:1
was added to the resulting mixture, the peak in the H spectra
was at 4.48 ppm begins to decrease, and the peak at 4.70 ppm,
13
3
related
to
the
signals
of
CH-CH-protons
4, 5-
dihydroxyimidazolidin-2-one
4
increase (Fig. S11). This
1:2
observation is obviously associated with the nucleophilic attack
of urea 1a of activated HEDP C=O group (as shown in Scheme
2), which subsequently leads to condensation and cyclization
with the formation of intermediate 4, which may, under acidic
conditions, partially undergo rearrangement to hydantoin 6a [46],
but under the studied conditions, it predominates to glycoluril 3a
after the addition of another mole of urea 1a. After the
disappearance of the chemical shift at 4.48 ppm and reaching a
peak at 4.70 ppm of the maximum intensity, the second
equivalent of urea 1a was introduced into the reaction vial in
order to trace the stepwise process of obtaining glycoluril 3a. A
low-intensity peak at 4.90 ppm appeared in the 1H spectral
pattern, the nature of which was initially unclear. Peak formation
at 5.32 ppm (corresponding to CH-CH protons of glycoluril 3a)
was not observed at room temperature, and only after heating
the reaction ampule to 60–80° C, this signal was recorded in the
PMR spectrum. Unfortunately, the increase in the singlet
intensity at 5.32 ppm could not be traced, because substance 3a
is poorly soluble in water and immediately precipitates.
The end of the reaction is indicated by the disappearance of the
peak at 4.70 ppm corresponding to CH-CH protons of 4, 5-
dihydroxyimidazolidin-2-one 4, at the same time, the peak at
4.90 ppm was recorded in the spectrum simultaneously with the
residual signal of glycoluril 3a (Fig S12). Thus, the obtained
experimental data support the fact that the synthesis of glycoluril
3a proceeds stepwise and passes through the stages of
stepwise condensation of urea 1a with glyoxal 2a and 4,5-
dihydroxyimidazolidin-2-one 4.
1:3
3
3
In order to determine the preparative possibilities of the found
bicyclization reactions of glyoxal 2a with urea 1a (Scheme 1) we
extended this reaction to a number of glycoluryl derivatives
3b-g, 3c’ using various urea 1a-d and dicarbonyl compounds
2a-d (Scheme 3) in the presence of HEDP.
The products 3b g, 3c’ with 26-96% yields were isolated
(Scheme 3). Low yields for 3d, g can be explained by the
presence of bulky substituents of reagents. So phenyl
substituents in benzyl 2d can inhibit the formation of complex A
(Scheme 2), and the nucleophilic attack of phenylurea 1d is
limited due to spatial difficulties. Another limiting factor is the low
solubility of the starting reagents 1d, 2d in water, although with
an increase in the reaction time the yields of 3d, g increase (up
to 50%).
It is known [36] that the base-catalyzed synthesis of glycoluryl
3g gives a mixture of 1, 5-diphenyl glycoluryl 3g and 5, 5-
diphenylhydantoin in a ratio of about 1: 2. In this case, the
formation of 5, 5-diphenylhydantoin was not observed.
According to the results of 13C, 1H NMR and 31P NMR analyzes,
it was shown that in all cases HEDP in solution after the reaction
does not degrade and does not undergo changes. In the case of
the isolation of methyl derivatives of glycoluryls 3b, c, 3c’ after
the completion of the reaction, HEDP was converted into the
sodium salt, which was filtered off and then regenerated.
This article is protected by copyright. All rights reserved.

FULL PAPER
Scheme 3. Synthesis of glycoluril and its derivatives 3b-g, 3c’
To study the possibility of opening the cycles of substances
3b-g, 3c’ and rearrangement into a compound of type 5
(Scheme 2), an experiment was carried out during which it was
established that with the presence of substituents in glycoluril,
the reaction with HEDP is difficult and trace amounts of
hydantoins were observed only for glycoluryls 3c, 3c', 3e, 3f.
Since the formation of hydantoins was observed in the course of
the above studies, we attempted to directly synthesize these
compounds using HEDP as a catalyst (Scheme 4).
vacuum followed by freezing (6a, b) or extraction of the aqueous
residue with ethyl acetate solution. The yields of 6a-e, 6d’, e’
about 20–60%, and upon repeated extraction, the yields
increase. When using N-methylurea 1c, we obtained a mixture
of two isomers 6d and 6d’ (or 6e and 6e’) in a relative molar
ratio of 2 : 1 ([47] 70 : 30) (Scheme 4).
It should be noted that it was not possible to preparatively isolate
the intermediate component of the reaction
-
4, 5-
dihydroxyimidazolidin-2-one 4 and its analogues (in case of use
urea 1a-d and dicarbonyl compounds 2a-d) in the synthesis of
glycoluryls and hydantoins.
The reactions shown in Scheme 4 were carried out at a
temperature of 80–90°
C for 2 hours. The synthesized
hydantoins 6a-e, 6d’, e’ were separated from the reaction
mixture after partial removal of water by lyophilization under
Scheme 4. Synthesis of hydantoin and its derivatives 6a-e, 6d’, e’
This article is protected by copyright. All rights reserved.

FULL PAPER
СН), 1.45 (s. 3Н, СН3). 13C NMR (101 MHz, D2O): δ = 158.10
(С=О), 69.92 (СН), 66.50 (СН), 24.43 (СН3).
1,5-Dimethyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione
3f. Substance 3f is light-beige powder, yield 95%. T. decomp.
Conclusion
1
more 360 оC ([26]: 360° C). H NMR (400 MHz, [D6]DMSO): δ =
7.11 (s. 4H, NH), 1.33 (s. 6H, CH3). 13C NMR (101 MHz,
[D6]DMSO): δ = 159.90 (С=О), 75.83 (СН), 27.74 (CH3).
Thus, the chemistry of the synthesis of glycoluril 3a using HEDP
as a catalyst was proposed, where, according to NMR results
(Fig. 1, 2), the intermediate formation of the complex based on
glyoxal 2a and HEDP is shown (Scheme 2, complex A). The
chemistry of the reaction is stepwise and partially confirmed by
NMR with model processes of the formation of glycoluril 3a.
It was found that the optimal conditions for the synthesis of
glycoluril 3a (yield 99% - 100%) using HEDP are: temperature
80° C, 40 minutes and the ratio of urea 1a and HEDP is 1 : 1.
Under the found conditions the monocyclic intermediate 4
(Scheme 2) is formed mainly at room temperature (as in the
presence of the mineral acid HCl, pH = 4–7 [48]), and for the
further reaction of which the temperature is a decisive factor.
The optimal conditions for the synthesis of 3b-g, 3c’ glycoluryls
and 6a-e, 6d, e’ hydantoins using HEDP are: temperature
80-90° C, 40-120 minutes and urea 1a and HEDP ratio is 1: 1.
It is important to note that in all cases, the remaining aqueous
filtrate containing HEDP after the reaction can be used again for
other synthesis cycles to form the same glycoluril 3a and other
compounds. It is shown that, during a week-long standing (as
evidenced by 13С, 1Н and 31Р NMR spectroscopy of the crude
reaction mixture after filtration of product 3a), the chemical shifts
of the HEDP do not change.
1, 5-Diphenyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione -
3g. Substance 3g is light beige powder, yield 26%. T. decomp.
1
more 350оC ([50]: 378° C). H NMR (400 MHz, [D6]DMSO): δ =
7.82 (c. 4H, NH), 7.09-7.02 (м, 10Н, Ph). 13C NMR (101 MHz,
[D6]DMSO): δ = 161.22 (С=О), 138.71, 128.25, 127.81, 127.47
(Ph), 82.26 (CН).
Due to the high solubility of compounds 3b, c, 3c’ in water, their
isolation procedure is different, where at the end of the reaction
the reaction mass was dried at 2/3 parts with a vacuum and
treated with a solution of 20% NaOH to pH = 9-10. The product
was isolated from the crude residue by several extraction with
ethyl acetate. The reaction was monitored by TLC.
2,4,6,8-Tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-
dione 3b. To an aqueous solution of 8,8 г (0.1 mol) of 1,3-
dimethylurea 1b and 7.3 g of a 40% aqueous solution of glyoxal
2a (0.05 mol) while stirring, 20.6 g (0.1 mol) of HEDP are added.
The reaction mixture is heated to 80° C and maintained the
reaction mixture for 60 minutes. The reaction is monitored by
TLC. After completion of the reaction, the solvent was distilled
off, the remaining reaction mass was treated with 20% NaOH
solution to pH = 9, and the product 3b was extracted with
methylene chloride. Colorless crystals 3b were obtained, yield
62%. M. p. 228оC ([ 51]: 228 °C). 1H NMR (400 MHz,
To summarize, we have developed a new, rather simple and
efficient method for the synthesis of a number of glycoluryls
3а-g, 3c’ and hydantoins 6a-e, 6d, e’ in water using a “green”
HEDP catalyst, which makes this approach an interesting
alternative way to these important heterocycles.
[D6]DMSO): δ = 5.02 (s. 2Н, СН), 2.78 (s. 12Н, СН3). 13C NMR
(101 MHz, [D6]DMSO): δ = 159.11 (С=О), 71.99 (СH), 30.51
(СН3).
2,6-Dimethyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione
3c and 2,8-dimethyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-
dione 3c’. Substances 3c and 3c’ are powders of white, light
beige color. Yield of 3c is 60%, m. p. 270 оC ([52]: 270° C). 1H
NMR (400 MHz, [D6]DMSO): δ = 5.19 (s. 2H, СН), 2.55 (s. 6H,
CH3). 13C NMR (101 MHz, [D6]DMSO): δ = 158.53 (С=О), 76.59
(СH), 28.56 (СН3). Yield of 3c’ is 30%, m. p. 301 оC ([52]:
300°C). 1H NMR (400 MHz, [D6]DMSO): δ = 5.28 (д. J = 8.4 Hz,
Experimental Section
NMR spectra for substances 3a-g, 3c’(Fig. S16-S31), 6a-e,
6d’, e’ (Fig. S32-S41) were recorded on a Bruker AVANCE III
HD spectrometer (Bruker Corporation, Germany) with an
operating frequency of 400 and 100 MHz for H and 13C nuclei
1
1H, СН), 5.16 (д. J = 8.4 Hz, 1H, СН), 2.72. (с. 6Н, СН3). 13
C
respectively, in a solutions of DMSO-d6 and D2O. The internal
standard is tetramethylsilane (TMS).
Melting points are determined on a Buchi instrument. The
reaction progress was monitored by TLC on Silufol UV-254
plates (eluent PhH – EtOH, 8: 2), visualization in iodine vapor
and UV light (254 nm).
NMR (101 MHz, [D6]DMSO): δ = 160.96 (С=О), 76.59 (СH),
62.54 (СH), 28.56 (СН3).
Synthesis of hydantoins using HEDP.
Imidazolin-2,4-dione (hydantoin) 6a. To an aqueous solution
of 3.0 g (0.05 mol) of urea 1a and 7.3 g of a 40% aqueous
solution of glyoxal 2a (0.05 mol) while stirring, 10.3 g (0.05 mol)
of HEDP are added. The reaction mixture is heated to 90° C and
maintained for two hours, after which the solvent was distilled
off. The reaction mass is treated with 20% solution of NaOH to
pH = 8. The reaction mass is kept in the cold for a day and then
the precipitate is filtered off. Product 6a is colorless crystals,
yield 50%, m. p. 221оC ([47]: 222° C). 1H NMR (400 MHz,
[D6]DMSO): δ = 10.66 (s. 1Н, NH), 7.70 (s. 1Н, NH), 3.83 (s. 2Н,
СН2). 13C NMR (101 MHz, [D6]DMSO): δ = 174.50 (С=О),
158.91 (С=О), 47.73 (СН2).
Synthesis of glycoluryls using HEDP.
2,4,6,8-Tetraazabicyclo[3.3.0.]octan-3,7-dione
(glycoluryl)
3a. To an aqueous solution of 6.0 g (0.1 mol) of urea 1a and 7.3
g of a 40% aqueous solution of glyoxal 2a (0.05 mol) while
stirring, 20.6 g (0.1 mol) of HEDP are added. The reaction
mixture is heated to 80° C and maintained for 40 minutes. After
10 minutes, product 3a begins to precipitate. After 40 minutes,
the reaction mixture is cooled, the precipitate is filtered off and
washed with water. Substance 3a is white powder, yield
99-100%. T. decomp. more 360 ° C ([26]: decomp. more 360°
5-Methylimidazolin-2,4-dione 6b.
The preparation of
1
C). H NMR (400 MHz, [D6]DMSO): δ = 7.17 (s. 4H, NH), 5.24
substance 6b was carried out similarly to 6a, where substance
6b is colorless crystals, yield 60%.1H NMR (400 MHz, D2O): δ =
4.09 (q, J = 7.1 Hz, 1H, СН), 1.21 (d, J = 7.1 Hz, 3H, СН3). 13C
NMR (101 MHz, D2O): δ =176.70 (С=О), 157.60 (С=О), 53.25
(СН), 15.80 (СН3).
1,3-Dimethylimidazolin-2,4-dione 6с. To an aqueous solution
of 4,4 г (0.05 mol) of 1,3-dimethylurea 1b and 7.3 g of a 40%
aqueous solution of glyoxal 2a (0.05 mol) while stirring, 10.3 g
(0.05 mol) of HEDP are added. The reaction mixture is heated to
90° C and maintained the reaction mixture for two hours. The
reaction is monitored by TLC. After completion of the reaction,
the solvent was distilled off, the reaction mass was treated with
20% NaOH solution to pH = 9, and the product 6с was extracted
with ethyl acetate. Product 6c is light yellow hygroscopic
(s. 2H, CH). 13С NMR (101 MHz, [D6]DMSO): δ = 161.72 (С=О),
65.05 (CH).
The synthesis of 3d-g substances was carried out in a similar
manner using the appropriate reagents for 60 minutes.
2,6-Diphenyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione
3d. Substance 3d is light-beige powder, yield 44%. T. decomp.
more 370оC ([26]: 375 - 380° C). 1H NMR (400 MHz,
[D6]DMSO): δ = 8.51 (s, 2H, NH), 7.56 (d, J = 8.0 Hz, 4H, Ph),
7.36 (t, J = 7.9 Hz, 4H, Ph), 7.10 (t, J = 7.5 Hz, 2H, Ph), 6.05 (s,
2H, CH). 13C NMR (101 MHz, [D6]DMSO): δ = 157.27 (С=О),
138.37, 129.24, 123.63, 119.64 (Ph), 65.67 (CН).
1-Methyl-2,4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione
3е.
Substance 3е is light-beige powder, yield 96%. T. decomp. more
270оC ([49]: 254° C).1H NMR (400 MHz, D2O): δ = 4.43 (s. 1Н,
This article is protected by copyright. All rights reserved.

FULL PAPER
crystals, yield 40%, m. p. 45 оC. ([52]: 43° C). 1H NMR (400
MHz, [D6]DMSO): δ = 3.84 (s. 2Н, СН2), 2.75 (s. 3Н, СН3), 2.74
(s. 3Н, СН3). 13C NMR (101 MHz, [D6]DMSO): δ = 173.70 (С=О),
158.49 (С=О), 51.75 (СН2), 29.01 (СН3), 24.59 (СН3).
The synthesis and isolation of substances 6d, 6d’, 6e, 6e’ was
carried out similarly to 6c.
[19] K.I. Assaf, W.M. Nau, Chem. Soc. Rev. 2015, 44, 394-418,
DOI: 10.1039/C4CS00273C
[20] S.J. Barrow, S. Kasera, M.J. Rowland; del J. Barrio, O.A. Scherman,
Chem. Rev.
2015,
115,
12320-12406,
DOI: 10.1021/acs.chemrev.5b00341
[21] H. Isobe, N. Tomita, J.W. Lee, H.-J. Kim, K. Kim, E. Nakamura, Angew.
Chem. Int. Ed. 2000, 39, 4257-4260.
1-Methylimidazolin-2,4-dione 6d and 3-Methylimidazolin-2,4-
dione 6d’. Substances 6d and 6d' are colorless crystals.
Yield of 6d is 55%, m. p. 159° С ([47]: 158° С). 1H NMR (400
MHz, D2O): δ = 3.87 (s. 2Н, СН2), 2.71 (s. 2Н, СН2). 13C NMR
(101 MHz, D2O): δ = 175.39 (С=О), 160.96 (С=О), 46.56 (СН2),
28.56 (СН3). Yield of 6d' is 25%, т.пл. 185° С. ([48]: 185–186°
С). 1H NMR (400 MHz, D2O): δ = 3.84 (s. 2Н, СН2), 2.74 (s. 2Н,
СН2). 13C NMR (101 MHz, D2O): δ = 174.93 (С=О), 160.08
(С=О), 48.90 (СН2), 29.08 (СН3).
[22] C. Chen, F. Liu, X. Zhang, Z. Zhao, S. Liu, Beilstein J. Org. Chem.
2019, 15, 992-999, DOI: 10.3762/bjoc.15.97
[23] D. Tuncel in Cucurbituril-based Functional Materials (Eds.: D. Tuncel),
Royal
Society
of
Chemistry,
London,
2019.
p.
303,
DOI: 10.1039/978178801595028
[24] V. Havel, M. Babiak, V. Sindelar, Chemistry-A European Journal 2017,
23(37), 8963-8968, DOI: 10.1002/chem.201701316
[25] J. Svec, M. Necas, V. Sindelar, Angew. Chem. Int. Ed. 2010, 122,
2428-2431, DOI: 10.1002/anie.201000420
1,5-Dimethylimidazolin-2,4-dione
6e
and
3, 5-
dimethylimidazolin-2,4-dione 6e'. Substances 6e and 6e' are
colorless crystals. Yield of 6e is 50%, m. p. 134°С ([47]: 132° С).
1H NMR (400 MHz, D2O): δ = 3.97 (q, J = 7.1 Hz, 1H, СН), 1.19
(d, J = 7.1 Hz, 3H, СН3). 13C NMR (101 MHz, D2O): δ = 178.44
(С=О), 160.82 (С=О), 58.76 (СН2), 26.55 (СН3), 13.53 (СН3).
[26] A.A. Bakibaev, R.R. Akhmedzhanov, A.Yu. Yagovkin, T.P.
Novozheeva, V.D. Filimonov, A.S. Saratikov, Pharmaceutical Chemistry
Journal, 1993, 27(6), 401-406, DOI: 10.1007/BF00780658
[27] Y. Xia, S. Jiao, Beijing Huagong Xueyuan Xuebao, Ziran Kexueban,
1990, 17, 73-76.
1
Yield of 6e' is 20%, m. p. 113°С ([48]: 111–113° С). H NMR
[28] A.X. Wu, J.C. Fettinger, L. Isaacs, Tetrahedron, 2002, 58, 9769-9777,
DOI: 1016/S0040-4020(02)01307-8
(400 MHz, D2O): δ = 4.05 (q, J = 7.1 Hz, 1H, СН), 1.23 (d, J =
7.1 Hz, 3H, СН3). 13C NMR (101 MHz, D2O): δ = 178.53 (С=О),
157.60 (С=О), 53.25 (СН), 26.70 (СН3), 15.80 (СН3).
[29] F.B. Slezak, A. Hirsch, I. Rosen, J. Org. Chem. 1960, 25, 660-661.
[30] F.B. Slezak, H. Bluestone, T.A. Magee, J.H. Wotiz, J. Org. Chem. 1962,
27, 2181-2183, DOI: 10.1021/jo01053a069
Supporting Information Summary. The NMR spectra are
provided in the supporting information
[31] C.A. Burnett, J. Lagona, A.X. Wu, J.A. Shaw, D. Coady, J.C. Fettinger,
A.I. Day, L. Isaacs, Tetrahedron, 2003, 59, 1961-1970,
DOI: 10.1016/S0040-4020(03)00150-9
Acknowledgements. We thank Tomsk State University for
financial support to our research groups.
[32] B.A. Murraya, G.S. Whelena, Pure Appl. Chem. 1996, 68, 1561-1567,
DOI: 10.1351/pac199668081561
[33] J. Kang, R.S. Meissner, R. Wyler, J. De Mendoza, J. Rebek, Jr. Korean
Chem. Soc. 2000, 21, 221-224.
Conflict of Interest. The authors declare no conflict of interest.
[34] B.M. O’Leary, T. Szabo, N. Svenstrup, C.A. Schalley, A. Ltzen, M.
Schfer, J. Rebek, J. Am. Chem. Soc. 2001, 123, 11519-11533,
DOI: 10.1021/ja011651d
Keywords: catalysis, condensation, Etidronic acid (HEDP),
glycoluryls, green chemistry; hydantoins, NMR
[35] K. Moon, W.Z. Chen, T. Ren, A.E. Kaifer, Cryst. Eng. Commun. 2003, 5,
451-453, DOI: 10.1351/pac199668081561
[1]
[2]
T. A. Addiscott, V. H. Thomas, Chem. Ind. 1979, 1, 29-30
W. Beilfuss, R. Gradtke, I. Krull, K. Steinhauer, DE-102004059041(A1),
2006.
[36] J.T. Li, X.R. Liu, M.X. Sun, Ultrason. Sonochem. 2010, 17, 55-57,
DOI: 10.1016/j.ultsonch.2009.04.010
[3]
[4]
[5]
B.D. Mashkovsky in Pharmaceuticals, Vol. 1 (Eds.: B.D. Mashkovsky),
Meditsina (in Russian), Moscow, 1993, pp. 99
[37] E. Rezaei-Seresht, R. Tayebee, J. Chem. Pharm. Res. 2011, 3,
103-107.
A.A. Prokopov, N.V. Kostebelov, A.S. Berland, Pharmaceutical
Chemistry Journal. 2002, 36, 170-171, DOI: 10.1023/A:1019820218645
A.A. Bakibaev, A.Yu. Yagovkin, S.N. Vostretsov, Russ. Chem. Rev.
1998, 67(4), 295–314, DOI: 10.1070/RC1998v067n04ABEH000295
A. Krause, A. Aummueller, E. Korona, H. Trauth, US-5.670.613, 1997.
K. Cui, G. Xu, Z. Xu, P. Wang, M. Xue, Z.Meng, J. Li, B. Wang, Z.
Ge, G. Qin, Propellant Explos. Pyrotech, 2014, 39(5), 662-669.
DOI: 10.1002/prep.201300100
[38] U.M.
DOI: 10.1021/cr010122p
[39] G. Micheletti, C. Delpivo,
Letters and Reviews,
DOI: 10.1080/17518253.2012.718803
Lindstrom,
Chem.
Rev.
2002,
102(8),
2751-2772,
G. Baccolini, Green Chemistry
2013, 6(2), 135-139,
[6]
[7]
[40] A.M. Pansuriya, M.M. Savant, C.V. Bhuva, J. Singh, Y.T. Naliapara,
Arkivoc, 2009, 7, 79–85, DOI: 10.3998/ark.5550190.0010.707
[41] K.V. Vilapara, S.P. Gami, S.A. Gadara, and Y.T. Naliapara,
ChemistrySelect, 2019, 4, 11235–11238, DOI: 10.1002/slct.201902997
[42] М.M. Savant, A.M. Pansuriya, C.V. Bhuva, N.P. Kapuriya, Y.T.
Naliapara, Catal. Lett. 2009, 132, 281–284, DOI: 10.1007/s10562-009-
0112-y
[8]
[9]
J. Boileau, M. Carail, E. Wimmer, R. Gallo, M. Pierrot, Prop. Explos.
Pyrotec. 1985, 10, 118-120, DOI: 10.1002/prep.19850100407
M.N. Zharkov, I.V. Kuchurov, I.V. Fomenkov, S.G. Zlotin, V.A.
Tartakovsky,
Mendeleev
Commun.
2015,
25,
15-16,
DOI: 10.1016/j.mencom.2015.01.004
[43] J.Р. Guette, G. Mattioda, В. Metivier. Actualite Chimique, 1982, 5,
23-31.
[10] Y. Fang, F. Li, Hanneng cailiao Energ. Mater. 1996, 4(2), 62-67.
[11] G.G. Paekh, US-4.105.708,1978.
[44] E.B. Whipple. J. Amer. Chem. Soc. 1970, 92(24), 7183-7186,
https://doi.org/10.1021/ja00727a027
[12] S. Moradi, M.A. Zolfigol, M. Zarei, D.A. Alonso, A. Khoshnood,
ChemistrySelect 2018, 3(11), 3042-3047, DOI: 10.1002/slct.201702544
[13] S. Sun, J.F. Britten, C.N. Cow, C.F. Matta, P.H.M. Harroson, Can. J.
Chem. 1998, 29, 301-306.
[45] L.P. Loginova, I.V. Levin, A.G. Matveeva, S.A. Pisareva, and E.E.
Nifant´evb,
Russ
Chem
Bull,
2004,
53,
2000–2007,
DOI: 10.1007/s11172-005-0062-5
[14] W. Jacobs, D. Foster, S. Sansur, R.G. Lees, Prog. Org. Coat. 1996, 29,
127-138, DOI: 10.1016/S0300-9440(96)00643-1.
[46] A.N. Kravchenko, A.S. Sigachev, P.A. Belyakov, M.M. Ilyin, K.A.
Lyssenko, V.A. Davankov, O.V. Lebedev, N.N. Makhova, and V.A.
Tartakovsky, Russ. Chem. Bull., Int. Ed., 2009, 58(6), 1264–1269,
DOI: 10.1007/s11172-009-0165-5
[15] J. Yinon, S. Bulusu, T. Axenrod, Yazdekhasti, Org. Mass Spect. 1994,
29, 625-631, DOI: 10.1002/oms.1210291109
[16] Q. Yan, W. Liu, H. Wen, X. Zhibin, Z. Meng, ChemistrySelect, 2020,
5(6), 1878-1883, DOI: 10.1002/slct.201904902
[47] G. Baccolini, C. Boga, C. Delpivo, G. Micheletti, Tetrahedron Letters,
2011, 52, 1713–1717, DOI: 10.1016/j.tetlet.2011.02.002
[17] S. Nandi, P. Patel, A. Jakhar, N. H. Khan, A.V. Biradar, R.I.
Kureshy, H.C. Bajaj, ChemistrySelect, 2017, 2(31), 9911-9919,
DOI: 10.1002/slct.201702196
[48] H.
Peterson,
Lieb.
Ann.
Chem.,
1969,
726(1),
89-99,
DOI: 10.1002/jlac.19697260114
[18] A. Kornmuller, S. Karcher, M. Jekel, Water Res. 2001, 35(14),
3317-3324, DOI: 10.1016/S0043-1354(01)00039-2
This article is protected by copyright. All rights reserved.

FULL PAPER
[49] K. Jansen, A. Ego, H.-J. Buschmann, E. Schollmeyer, D. Dopp,
Designed Monomers and Polymers, 2003, 6(1), 43–55,
DOI: 10.1163/156855503321127529
[50] S. Arrous, I. Boudebouz, I. V. Parunov, Russ. J. Org. Chem., 2019, 55,
1874–1877, DOI: 10.1134/S1070428019120108
[51] L.I. Suvorova, V.A. Eres'ko, L.V. Epishina, O.V. Lebedev, L.I.
Khmel'nitskii, S.S. Novikov, M.B. Povstyanoi, V.D. Krylov, G.V.
Korotkova, L.V. Lapshina, A.F. Kulik, Bull. Acad. Sci. USSR, Div. Chem.
Sci., 1979, 28, 1222-1224, DOI: 10.1007/BF00947390
[52] N.
Shigeyoshi,
S.
Hidetaka,
S.
Tetsuro,
Y.
Kimihiko,
US2010010233 (A1), 2010.
This article is protected by copyright. All rights reserved.