4,5-Dihydroxyimidazolidin-2-ones in the α-ureidoalkylation reaction of N-(carboxyalkyl)-, N-(hydroxyalkyl)-, and N-(aminoalkyl)ureas 1. α-Ureidoalkylation of N-(carboxyalkyl)ureas

Article abstract of DOI:10.1007/s11172-010-0022-6

The α-ureidoalkylation of N-(carboxyalkyl)ureas (ureido acids) with 1,3-H₂ ^s-, 1,3-Me ₂ ^s-, and 1,3-Et₂ ^s-4,5-dihydroxyimidazolidin-2-ones was systematically studied. The yields of glycolur

Full text of DOI:10.1007/s11172-010-0022-6

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 395—405, February, 2009
395
4,5ꢀDihydroxyimidazolidinꢀ2ꢀones in the αꢀureidoalkylation reaction
of Nꢀ(carboxyalkyl)ꢀ, Nꢀ(hydroxyalkyl)ꢀ, and Nꢀ(aminoalkyl)ureas
1. αꢀUreidoalkylation of Nꢀ(carboxyalkyl)ureas*
A. N. Kravchenko,a K. A. Lyssenko,b I. E. Chikunov,a P. A. Belyakov,a M. M. Il´in,b V. V. Baranov,a
Yu. V. Nelyubina,b V. A. Davankov,b T. S. Pivina,a N. N. Makhova,a and M. Yu. Antipinb
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: kani@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5058. Eꢀmail: kostya@xrlab.ineos.ac.ru
The αꢀureidoalkylation of Nꢀ(carboxyalkyl)ureas (ureido acids) with 1,3ꢀH2ꢀ, 1,3ꢀMe2ꢀ,
and 1,3ꢀEt2ꢀ4,5ꢀdihydroxyimidazolidinꢀ2ꢀones was systematically studied. The yields of
glycolurils were shown to decrease both in going from 1,3ꢀH2ꢀ to 1,3ꢀMe2ꢀ and 1,3ꢀEt2ꢀ4,5ꢀ
dihydroxyimidazolidinꢀ2ꢀones and with elongation and branching of the carboxyalkyl chain
in the ureido acids under study. The optimal reaction time for most of ureido acids is 3 h. The
reaction mechanism was proposed. This mechanism was partially confirmed by quantum
1
chemical methods and H NMR spectroscopy. Crystals of a number of the newly synthesized
compounds were studied by Xꢀray diffraction, and two new conglomerates were found. A
method was developed for the enantiomeric analysis of some racemic Nꢀ(carboxyalkyl)ꢀ
glycolurils by chiralꢀphase HPLC.
Key words: glycolurils, 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones, Nꢀ(carboxyalkyl)ureas (ureido
acids), racemates, conglomerates, enantiomers, quantum chemical calculations, Xꢀray difꢀ
fraction and enantiomeric analysis.
Glycolurils (2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ
3,7ꢀdione derivatives) belong to a wellꢀknown class of
psychotropic compounds.1—3 Hence, the search for new
derivatives and the development of procedures for the
enantiomeric resolution of racemic glycolurils are importꢀ
ant for drug design. Recently,4 we have developed a
method for the diastereoselective synthesis of 1R,5Sꢀ and
1S,5Rꢀglycolurils by the acidꢀcatalyzed αꢀureidoalkylation
of Sꢀ or RꢀNꢀcarbamoylꢀαꢀamino acids, respectively, with
the use of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀone (DHI) as the
ureidoalkylating agent and have found the conditions
allowing the reaction to proceed diastereospecifically.5
This opened a route to enantiomerically pure glycolurils
with the desired configurations of the bridgehead C(1)
and C(5) atoms of the bicyclic moiety. Another proceꢀ
dure for the synthesis of enantiomerically pure compounds
is based on their spontaneous crystallization as a mixture
of crystals of individual enantiomers (the conglomerate
formation).6—8 In a series of cooperative works, we sucꢀ
ceeded in synthesizing first representatives of enantioꢀ
merically pure glycolurils, viz., 2,6ꢀdimethylꢀ and 2,6ꢀdiꢀ
ethylglycolurils, according to this method.9,10 The methylꢀ
ation of enantiomers of the latter compound with (Me)2SO4
afforded enantiomers of 4,8ꢀdiethylꢀ2,6ꢀdimethylglycolꢀ
uril, which is the new promising tranquilizer Albicar.11
To found new conglomerateꢀforming Nꢀalkylglycolꢀ
urils, we have suggested12 two general approaches to the
synthesis of chiral Nꢀmonoꢀ, N,N´ꢀdiꢀ, N,N´,N″ꢀtriꢀ, and
N,N´,N″,N´´´ꢀtetraalkylglycolurils based on the acidꢀcataꢀ
lyzed reaction of DHI or glyoxal with one or two moles of
the corresponding alkylureas. Unfortunately, the crystalꢀ
lization of these compounds in water, aqueousꢀalcoholic
media, ethyl acetate, dioxane, or CHCl3 did not afford
new conglomerates.
One of approaches to the synthesis of glycolurils, which
can crystallize as conglomerates, could be based on the
introduction of functional groups capable of participating
in hydrogen bonding (for example, carboxy, hydroxy, or
amino groups) into substituents at the nitrogen atoms.
Previously,13—15 we have synthesized several comꢀ
pounds 1 by the αꢀureidoalkylation of Nꢀ(carboxyalkyl)ꢀ,
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 390—399, February, 2009.
1066ꢀ5285/09/5802ꢀ0395 © 2009 Springer Science+Business Media, Inc.

396
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Kravchenko et al.
Scheme 1
Nꢀ(hydroxyalkyl)ꢀ, and Nꢀ(2ꢀacetylamino)ethylꢀsubstiꢀ
tuted ureas, primarily, with 4,5ꢀdihydroxyimidazolidinꢀ
2ꢀone. However, these reactions were carried out by analogy
with the synthesis of Nꢀalkylglycolurils and the reaction
conditions were not optimized.
With the aim of extending the range of conglomerateꢀ
forming Nꢀ(carboxyalkyl)glycolurils 1 and optimizing the
conditions of the αꢀureidoalkylation reactions of Nꢀ(carꢀ
boxyalkyl)ureas (hereinafter, ureido acids) 2 with various
DHI 3, in the present study we investigated in detail the
dependence of the yields of Nꢀ(carboxyalkyl)glycolurils 1
on the reaction time, the type of substitution at the nitroꢀ
gen atoms of DHI 3, and the length and branching of the
alkyl chain in ureido acids 2 and examined the ability
of Nꢀ(carboxyalkyl)glycolurils to form conglomerates
depending on the crystallization conditions.
Glycolurils 1a—k were synthesized in an aqueous
acidic medium (pH 1—2) at 85 °C at different reaction
times (1, 2, and 3 h). The reactions were carried out with
4,5ꢀdihydroxyimidazolidinꢀ2ꢀones 3a—c and ureido acids
2a—c, which were synthesized according to the previꢀ
ously developed procedure14 by the reaction of KOCN
with amino acids (glycine, βꢀalanine, γꢀaminobutyric acid,
and βꢀaminoisobutyric acid) (Scheme 1, Table 1).
As can be seen from Table 1, the yield of glycoluril 1a,
which was synthesized by the reaction of DHI 3a with
Nꢀcarbamoylglycine (2a), increases by 3% and 8% with
increasing reaction time from 1 h to 2 and 3 h, respecꢀ
tively. In the reaction of 3a with Nꢀcarbamoylꢀβꢀalanine
(2b), the yield of glycoluril 1b decreases with increasing
reaction time from 58% (1 h) to 30% (3 h), whereas
the yield of 1c in the reaction of 3a with Nꢀcarbamoylꢀ
γꢀaminobutyric acid (2c) increases by 7% (2 h) and
1
a
b
c
d
e
f
g
h
i
R
H
H
H
Me
H
H
R´
H
H
H
H
Me
Me
Me
n
1
2
3
1
1
2
3
1
1
2
3
2
a
b
c
d
R
H
H
H
n
1
2
3
1
3
a
b
c
R´
H
Me
Et
Me
4
a
b
c
d
e
R
H
H
H
Me
H
R″
H
Me
Et
H
n
1
1
1
1
2
H
Me Me
H
H
H
Et
Et
Et
j
k
H
11% (3 h). The yield of glycoluril 1d, which was syntheꢀ
sized by the reaction of DHI (3a) with Nꢀcarbamoylꢀ
βꢀaminoisoꢀbutyric acid (2d), increases from 33% to 40%
Table 1. Dependence of the yields of Nꢀ(carboxyalkyl)glycolurils 1a—k on the reaction time, the type of substitution
at the nitrogen atoms of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones 3a—c, and the length of the alkyl chain in ureido
acids 2a—d
Reagents
t/h
Glycoluril
Yield (%)
Reagents
t/h
Glycoluril
Yield (%)
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2a
2a
2a
2b
2b
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
60
63
68
58
50
30
52
59
63
33
40
38
39
42
55
38
45
2b 3b
2c 3b
2c 3b
2c 3b
2d 3b
2d 3b
2d 3b
2a 3c
2a 3c
2a 3c
2b 3c
2b 3c
2b 3c
2c 3c
2c 3c
2c 3c
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1f
24
21
30
39
15
20
29
5
1g
1g
1g
1h
1h
1h
1i
1i
1i
9
15
—
—
5
5
40
20
—
—
1j
1k
1k
1k
1f

αꢀUreidoalkylation of Nꢀ(carboxyalkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
397
as the reaction time is increased from 1 to 2 h and slightly
decreases (to 38%) after the storage of the reaction mixꢀ
ture for 3 h. In the reaction of DHI 3b with ureido acids
2a,c,d, the yields of glycolurils 1e,g,h increase with
increasing reaction time to 2 and 3 h, respectively, by
3% and 16% for 1e, by 7% and 18% for 1g, and by 5% and
14% for 1h. In the reaction with ureido acid 2b, the yield
of glycoluril 1f increases by 7% as the reaction time is
increased to 2 h and decreases by 16% with increasing
reaction time to 3 h. The αꢀureidoalkylation of ureido
acids 2a—c with DHI 3c affords the target products in low
yields: 5—15% for 1i, 5—20% for 1g, and 5% for 1j, the
latter reaction product being obtained only at the reaction
time of 3 h (Fig. 1). Ureido acid 2d is not involved in the
condensation with DHI 3c regardless of the reaction time,
which is apparently attributed to steric factors.
The yields of glycolurils decrease both in changing
from 3a to 3b,c (see Table 1 and Fig. 1) and with an
elongation and branching of the carboxyalkyl chain in
ureido acids 2a—d. The optimal reaction time for the
synthesis of glycolurils 1a,c,e,g—j is 3 h; of glycoluril 1b,
1 h; of glycolurils 1d,f,k, 2 h.
All αꢀureidoalkylation reactions under consideration
are accompanied by the following two known side proꢀ
Scheme 2

398
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Kravchenko et al.
Y (%)
However, the attack of the carbocation A (or A´) on
the NH groups of ureido acid and, consequently, the
formation of the enantiomeric intermediates D and D″,
D´ and D´´´ cannot be ruled out as well. For clarity, let
us consider the latter intermediates separately.
68
70
60
50
40
30
20
10
63
59
1a
1b
1c
1d
1e
1f
1g
1h
1i
60
63
55
58
50
52
45
42
38
39
39
38
30
29
24
40
30
33
21
1j
1k
20
20
9
15
15
5
0
5
0
0.5
1.5
2.5
3.5 t/s
Fig. 1. Plot of the yields (Y) of Nꢀcarboxyalkylglycolurils 1a—k
vs the reaction time and depending on the type of substitution
at the nitrogen atoms of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones
(3a—c) and the length and branching of the alkyl chain in ureido
acids (2a—d).
cesses: the rearrangement of compounds 3a—c into
hydantoins 4a—c and the cyclization of ureido acids 2a,b,d
to hydantoins 4a,d,e. A decrease in the yield of the target
glycolurils 1 is accompanied by an increase in the yield
of products 4 of the side processes. NꢀCarbamoylꢀβꢀalanꢀ
ine 2b proved to be the least reactive compound in the
αꢀureidoalkylation reactions with DHI 3b and 3c, and
these reactions give dihydropyrimidineꢀ2,4(1H,3H)ꢀdione
(4d) as the major product.16 NꢀCarbamoylꢀγꢀaminobutyric
acid 2c does not form a cyclic product. The reaction of 3c
with ureido acid 2d affords hydantoins 4c and 4e as the
major products in a ratio of 1 : 1.
Previously,14 we have proposed the possible mechaꢀ
nism of formation of glycolurils in the acidꢀcatalyzed
reaction of glyoxal with Nꢀalkylureas, which involves the
formation of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones. Unlike
Nꢀalkylureas, ureido acids 2a—d contain the electronꢀ
withdrawing carboxy group. Consequently, the NH2 group
in these compounds should be more nucleophilic and will
add mainly to the carbocation A (or A´) (Scheme 2).
Based on this fact, we proposed a hypothetical mechaꢀ
nism of the reaction of ureido acid 2a with DHI 3a. It is
known that transꢀ4,5ꢀdihydroxyimidazolidinꢀ2ꢀone (3a)
exists as enantiomers 3a´ and 3a″ and as the cis form
(3a´´´).17,18 The trans and cis forms are present in soluꢀ
tion in a ratio of 95 : 5. Hence, the intermediates can have
the trans (B and B″) and cis configurations (B´ and B´´´).
It should be noted that these pairs are enantiomeric and
would form the corresponding enantiomers 1a´ and 1a″
of Nꢀ(carboxymethyl)glycoluril. In the step of formation of
the carbocations C and C´, the configuration of the chiral
center bound to the carboxymethylureido fragment changes
due to a change in the seniority of the substituents.
H(6N)
H(6N)
N(6)
H(4N)
N(4)
H(4N)
N(4)
N(6)
O(2)
O(1) O(2)
C(5)
C(1)
C(5)
C(1)
C(3)
O(1)
C(3)
C(7)
C(7)
N(8)
N(2)
N(2)
C(1N)
N(8)
C(1N)
O(4)
H(8N)
O(3)
H(8N)
C(2N)
H(4O)
H(4O)
O(4)
O(3)
C(3N)
C(4N)
C(2N)
1a
1d
C(8)
H(4N)
N(4)
H(4N)
C(8)
C(5)
N(6)
C(7)
N(6)
C(5)
N(4)
O(1)
C(3)
C(1N)
O(2)
O(1)
C(1)N(2)
C(7)
O(2)
N(8)
C(3)
C(1)
N(8)
C(9)
C(9)
N(2)
C(1N)
C(2N)
O(3)
C(2N)
H(1NA) C(3N)
O(3)
H(4O)
O(4)
H(4O)
O(4)
1f
1e
C(9)
N(6) C(5)
O(2)
H(4N)
N(4)
O(1)
C(3)
C(1)
C(7)
N(2)
N(8)
C(3N)
C(10)
C(1N)
O(4)
O(3)
C(2N)
H(4O)
C(4N)
1h
Fig. 2. Molecular structures of compounds 1a,d,e,f,h shown as
thermal displacement ellipsoids (p = 50%).

αꢀUreidoalkylation of Nꢀ(carboxyalkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
399
Scheme 3
To estimate the thermodynamic stability of the posꢀ
sible configurations of the intermediates, we carried out
semiempirical quantum chemical calculations (AM1,
MNDO, and PM3)19 of the threeꢀdimensional structures,
the enthalpies of formation (ΔHf0/kcal mol–1), and the
total energies (Etot/eV). To found the most stable interꢀ
mediates as the starting configurations, we used molecules
containing the hydroxy groups in the transoid (B and D)
and cisoid (B´ and D´) orientations with respect to the
plane of the imidazolidine ring.
For both isomers calculated based on different startꢀ
ing configurations, the deepest minima on the potential
energy surface correspond to the intermediates B and D
with the C(O)N(H)C1C2(OH) torsion angle of approxiꢀ
mately 120° (Fig. 2).
Therefore, the αꢀureidoalkylation of ureido acid 2a
with DHI 3a involves the attack of the primary amino
group of the ureido acid on the carbocation A (or A´)
giving rise to the intermediate B (or B″) as the first step.
The formation of the bicyclic structures of glycolurils 1a´
and 1a″ is completed with the intramolecular ureidoalkylꢀ
ation with the second carbocationic center in the intermeꢀ
diate C (or C´) at the NH group of the ureido fragment.
With the aim of searching for conglomerates in the
series of glycolurils 1, we investigated the crystallization
from water and 30% aqueous methanol. Crystals suitable
for Xꢀray diffraction were grown by crystallization of comꢀ
pounds 1a,c,d,e,g,h,k from water.
Supramolecular synthons are widely used in the crysꢀ
tal engineering20,21 By supramolecular synthons are meant
stable associates, which are strongly bound via specific
interactions between particular functional groups. These
associates are formed in crystals with high probability
and, consequently, can serve as building blocks, which
makes it possible to achieve a particular arrangement of
A comparison of the calculated enthalpies of formꢀ
ation and the total energies of the molecules allows the
conclusion that the intermediate B containing the asymꢀ
metric carbon atoms in the trans configuration is the most
stable one (Table 2).
The enantiomeric intermediate B″ has the opposite
configuration. Based on the calculated data, the mechaꢀ
nism of formation of enantiomers of 2ꢀ(carboxyalkyl)ꢀ
glycolurils can be represented by simpler Scheme 3.
molecules and/or ions in the crystals. In the crystal strucꢀ
...
tures, a centrosymmetric dimer formed through N—H
O
hydrogen bonds is the most typical assembly of amide
groups.22 Such synthons are evidently unsuitable for the
design of nonꢀcentrosymmetric crystals.
Based on this fact and in the context of investigation
of the spontaneous resolution in the series of glycolurils,
we complicated the structure of the latter compounds by
introducing an additional functional group, which could
compete with the amide group for the hydrogen bonding
and analyzed the influence of the number of N—H groups
on the resulting supramolecular associates. Actually, our
previous studies of the crystals of 1b,g,k have shown that
the molecules of hydrate 1b form centrosymmetric dimers
Table 2. Energy characteristics of the intermediates
(ΔHf0/kcal mol–1, Etot/eV)
Interꢀ
mediate
AM1
Etot
MNDO
ΔHf0
Etot
PM3
ΔHf0
ΔHf0
Etot
B
D
–188.14 –3336.75 –203.38–3350.08 –212.58 –2984.15
–182.81 –3336.52 –193.73–3349.65 –207.33 –2983.93

400
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Kravchenko et al.
...
O(3)
through N—H O bonds, whereas molecules 1g and 1k
are arranged in homochiral layers. However, it should be
noted that the homochiral association is a necessary but
not sufficient condition for the spontaneous resolution.
Actually, glycoluril 1g crystallizes in the chiral space group
P21, whereas the crystal structure of compound 1k conꢀ
sists of homochiral layers composed of opposite enantioꢀ
mers.15 To study the stability of the homochiral layer,
which was found in the structure of glycoluril 1g, as a
function of the length of the alkyl chain at the nitrogen
atom of the bicycle for the series of substituents under
consideration, we investigated compounds 1e,f,h and
monosubstituted analogs 1a,d (see Fig. 2).
Like glycolurils 1b14 and 1c15 studied previously, comꢀ
pounds 1d,e,f crystallize as hydrates with one water
molecule. Selected geometric parameters of these comꢀ
pounds are similar to the expected values for this class of
compounds.9—12,14,15,23—26 All bicyclic molecules have a
halfꢀopen book conformation; the conformation of the
fiveꢀmembered rings varies from planar to envelope, which
agrees well with the flexibility of these rings.26
O(1)
N(2)
N(4)
N(6)
N(8)
O(2)
...
Fig. 4. Centrosymmetric N—H Oꢀbonded dimers in the crystal
structure of 1h.
An analysis of the crystal packings of the compounds
showed that even a minimal change in the length of the
alkyl chain with retention of the substituents at the other
nitrogen atoms leads to a principal change in the type of
the supramolecular organization. For example, in the crysꢀ
tal structure of 1f, the molecules are linked together by
...
...
strong (O=)C—OH O=CN2 hydrogen bonds (O(4) O(1),
2.610(3) Å) to form a homochiral associate, but this assoꢀ
ciate has a chain rather than a layer structure (as opposed
to 1g,h). However, like in the crystal structure of 1h, the
existence of homochiral associates is insufficient for
the spontaneous resolution of enantiomers, because the
chains of opposite chirality are linked together by hydroꢀ
gen bonds formed by molecules 1f and water molecules
1d
...
...
(O O, 2.790(3)—2.844(3) Å; N O, 2.797(3) Å) to form
a threeꢀdimensional framework (Fig. 3).
O(1A)
O(4)
A further decrease in the length of the carboxyalkyl
chain in 1e, as well as the branching of this chain in 1h,
results in the formation of the aboveꢀdescribed centrosymꢀ
...
...
metric N—H Oꢀbonded dimers (N O, 2.785(4) and
2.836(4) Å) (see, for example, Fig. 4). The replacement
N(2)
O(1)
N(4)
N(6)
N(8)
O(2)
O(1)
O(4)
O(3)
1g
Fig. 5. Homochiral layers in the crystal structures of 1d and 1g.
In the structure of 1d, the solvent molecules are indicated by
large dashed circles.
Fig. 3. Homochiral chains in the crystal structure of 1f.

αꢀUreidoalkylation of Nꢀ(carboxyalkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
401
of the alkyl groups at the nitrogen atom by hydrogen
atoms in 1a also does not lead to the homochiral molecular
packing, and, like in the structures of 1e,h, the presence
racemic Nꢀ(carboxyalkyl)glycolurils by chiral HPLC preꢀ
sents considerable difficulties. The recognition of enantioꢀ
mers by a chiral selector requires the establishment of at
least three interactions between these components. Of
several dozens of modern commercially available chiral
phases, most phases are oriented to the formation of πꢀπ
interactions between aromatic systems of enantiomers and
selectors. However, the glycolurils under consideration
contain no aromatic substituents. The hydrogen bonding
is the second most widely used type of interactions.
Glycolurils provide this possibility, but hydrogen bonds
ensure good retention of sorbates only in lowꢀpolarity
aprotic media, where glycolurils are insoluble. In aqueous
and alcoholic media, the solvent by itself saturates the
protonꢀreleasing and protonꢀwithdrawing potencies of
both the selector and the enantiomer with hydrogen bonds.
Yet another popular group of chiral phases contains
cyclodextrin or its derivatives as chiral selectors. These
phases prone to form clathrates with enantiomers, resultꢀ
ing in the localization of hydrophobic fragments of the
enantiomers within the hydrophobic ring of the selector.
However, the methyl and ethyl substituents in the glycolꢀ
urils under study are too small to be retained in the
cyclodextrin ring. Therefore, the range of promising chiral
HPLC phases for the enantiomeric resolution of glycolurils
is extremely narrow. Another difficulty is that there are no
characteristic absorption bands in the UV spectra of
glycolurils, which would allow the detection of these
compounds with high sensitivity against the background
of polar solvents. Hence, one would have to use a less
selective and less sensitive refractometric sensor for the
detection.
Electrostatic interactions between the acidic group and
the tertiary nitrogen atom of the quinuclidine fragment of
the alkaloid quinine, which is used as a chiral selector in
the HPLC phase ProntoSIL Chiral AX QNꢀ1 (Bischoff,
Germany) proved to be efficient for Nꢀ(carboxyalkyl)ꢀ
glycolurils 1a,b,e. The ionic bonding is rather efficient
even in aqueous and alcoholic media. Two other interactꢀ
ions necessary for the chiral recognition are evidently
provided by a weaker hydrogen bond and steric contacts
between glycolurils and the selector. The ionꢀexchange
mode of chromatography is provided by the presence
of competitive ions of acetic acid and ammonium acetate
in the methanolic eluent. The successful resolution is
illustrated by Fig. 6. Interestingly, the presence of the
methyl substituents in glycoluril 1e enhances the selectꢀ
ivity, whereas the separation of the carboxy group from
the heterocycle by one methylene unit in 1b decreases
the selectivity of enantiomeric resolution compared to
glycine derivatives 1a. The available data are insufficient
for the construction of a threeꢀdimensional model of a
labile complex of the selector with enantiomers responsꢀ
ible for the recognition of the latter. Of the three interactꢀ
ions between the components of the complex, the strongꢀ
...
of centrosymmetric hydrogenꢀbonded (N O, 2.883(3) Å)
dimers gives rise to the racemic packing of molecules.
However, the introduction of the 2ꢀcarboxypropanꢀ
2ꢀyl substituent into glycoluril 1d unexpectedly led to the
crystallization of this compound as a conglomerate. In
the crystal structure of 1d, the molecules form homochiral
layers (Fig. 5), although the type of intermolecular
hydrogen bonds in 1d somewhat differs from that in 1g.
The hydrogenꢀbonded graphs of these layers are virtually
identical (Fig. 5). In the crystal structure of 1d, the solꢀ
vent molecules, which hinder the spontaneous resolution
in 1f, are located in the channels within the layers and
link the layers into a threeꢀdimensional framework. Moreꢀ
over, the solvent water molecules in the crystal structure
of 1d are apparently responsible for the retention of this
type of association taking into account a decrease in the
length of the carboxyalkyl fragment by two methylene
units compared to 1g.
Therefore, the Xꢀray diffraction study of the supramoꢀ
lecular organization in the crystals of homologs of carboxyꢀ
alkylglycolurils allows the following conclusions to be
drawn:
1) the homochiral association appeared to be a necesꢀ
sary but not sufficient condition for the spontaneous resoꢀ
lution (see structure 1f);
2) the simple replacement of the substituents does
not provide the crystallization in a chiral space group, i.e.,
the contribution of weak hydrogen bonds (in the limit,
van der Waals interactions) to stabilization of a particular
crystal packing appeared to be a more important factor
compared to strong hydrogen bonds;
3) solvent molecules, whose presence in the crystal
structure is difficult to control, add a degree of freedom
and can play both the “positive” and “negative” role in
the stabilization of a homochiral packing.
It should be noted that the percentage of the spontaꢀ
neously resolved molecules in this series of compounds is
somewhat higher than that usually observed for organic
molecules. However, since the sample is not fully repreꢀ
sentative in statistical meaning, it cannot be stated with
certainty that the packing in chiral groups for this class
of bicyclic molecules is more probable than it could be
expected from the known probability distribution for the
space groups.
The Xꢀray diffraction study revealed the following new
conglomerates: 2ꢀ(3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazabicycloꢀ
[3.3.0]octꢀ2ꢀyl)isobutyric acid (1d) and 4ꢀ(6,8ꢀdimethylꢀ
3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octꢀ2ꢀyl)butyric
acid (1g).
Racemates of Nꢀ(carboxyalkyl)glycolurils, which do
not form conglomerates, were resolved by chiralꢀphase
HPLC. The enantiomeric resolution of the synthesized

402
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Kravchenko et al.
to form conglomerates. Seven compounds were studied
by Xꢀray diffraction, and two new conglomerates, viz.,
1d,g, were found. The mechanism of αꢀureidoalkylation
of Nꢀcarbamoylglycine 2a with DHI 3a was proposed
and partially confirmed by quantum chemical methods.
A method was developed for the enantiomeric analysis
of a series of the synthesized racemic glycolurils by chiralꢀ
phase HPLC.
H
R = CH2CH2COOH (1a),
CH2COOH (1b,e)
R´ = H (1a,b), Me (1e)
a
U/mV
160
Experimental
130
100
70
Amino acids, urea, 1,3ꢀdimethylurea, and a 40% aqueous
glyoxal solution were commercially available (Acros).
1,3ꢀDiethylurea was prepared by passing gaseous ethylamine
into an urea melt at 140—150 °C by analogy with the synthesis
of 1,3ꢀdimethylureas.29 Ureido acids 2a—d were synthesized
by the reaction of the corresponding amino acids with KOCN
analogously to procedures described in the literature.13,14
4,5ꢀDihydroxyimidazolidinꢀ2ꢀones 3a—c were synthesized by
the reactions of the corresponding ureas with glyoxal according
to known procedures.17,30,31
The NMR spectra were recorded on Bruker AMꢀ250 (1H,
250 MHz) and Вruker AMꢀ300 (13C, 75.5 MHz) spectrometers;
the chemical shifts are given on the δ scale with respect to Me4Si
as the internal standard. The melting points were determined on
a Gallenkamp instrument (Sanyo).
40
10
–25.2
0.5
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 t/s
b
U/mV
90
70
50
30
10
Xꢀray diffraction studies of compounds 1a,d,e,f,h were carꢀ
ried out on a SMART 1000 CCD diffractometer (MoKα radiaꢀ
tion, graphite monochromator, ωꢀscanning technique); comꢀ
pound 1h was studied on a SMART APEX II CCD diffractometer
(MoKα radiation, graphite monochromator, ωꢀscanning techꢀ
nique). The structures were solved by direct methods and
refined anisotropically by the fullꢀmatrix leastꢀsquares method
based on F 2hkl. The hydrogen atoms were located in difference
Fourier maps and refined isotropically using a riding model.
Principal crystallographic data and the data collection and
refinement statistics are given in Table 3. All calculations
were carried out with the use of the SHELXTL PLUS program
package.32
–19.8
2.0
4.0
6.0
t/s
c
U/V
0.42
0.34
0.26
0.18
0.1
0.02
–0.05
2.0
4.0
6.0 t/s
The enantiomeric resolution of compounds 1a,b,e was
performed by liquid chromatography on chiral phases of ionꢀ
exchange HPLC using a ProntoSIL Chiral AX QNꢀ1 column
(Bischoff, Germany), where the residues of substituted quinine
were fixed on silica gel as a chiral selector. Methanol with the
addition of 2% acetic acid and 0.5% ammonium acetate was
used as the eluent. A refractometric sensor was used for the
detection.
Synthesis of glycolurils 1a—k (general procedure). Concenꢀ
trated HCl was added to an aqueous solution of the correspondꢀ
ing ureido acid 2a—d (0.02 mol) and the corresponding
4,5ꢀdihydroxyimidazolidinꢀ2ꢀone 3a—c (0.02 mol) to pH 1, and
the reaction mixture was kept at 85 °C during a certain time.
The optimal reaction time for the synthesis of glucolurils
1a,c,d,e,g,i,j is 3 h; for the synthesis of 1b, 1 h; for the synthesis
of 1h,f,k, 2 h. Glycolurils 1a—d were isolated from the reaction
mixture as precipitates upon cooling and storage in a refrigerator
for 10 h. The precipitates were crystallized from water. In the
case of 1e,f,g,i,j, the reaction mixtures were concentrated to 1/2
of the initial volume (in the case of 1h, the reaction mixture was
Fig. 6. Chromatograms of glycolurils 1a (a), b (b), and e (c).
est interaction determines primarily the stability of the
complex (i.e., the retention of enantiomers on a column),
whereas the weakest interaction provides the selectivity of
enantiomeric resolution.28 Evidently, the energy of the
weak interaction in the complex (a hydrogen bond or a
steric interaction) strongly depends on the slightest structꢀ
ural changes of the substituents in glycolurils.
To sum up, we systematically studied the αꢀureidoꢀ
alkylation of ureido acids with the involvement of DHI
derivatives as ureidoalkylating agents, revealed the
dependence of the yields of Nꢀ(carboxyalkyl)glycolurils
on the reaction time, the character of substitution at the
nitrogen atoms of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones, and
the length and branching of the alkyl chain in ureido
acids, and examined the ability of the resulting glycolurils

αꢀUreidoalkylation of Nꢀ(carboxyalkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
403
Table 3. Principal crystallographic characteristics and the data collection and refinement statistics for 1a,d,e,f,h
Parameter
1a
1d
1e
1f
1h
Molecular formula
Molecular weight
T/K
C6H8N4O4
200.16
120
C8H14N4O5
246.23
120
C8H14N4O5
246.23
C9H16N4O5
260.26
C10H16N4O4
256.27
120
120
100
Crystal system
Space group
Monoclinic
C2/c
Monoclinic
P21
Monoclinic
P21/c
Orthorhombic
Pna21
Monoclinic
P21/c
a/Å
b/Å
c/Å
β/deg
V/Å3
Z
21.144(4)
8.3123(17)
9.1806(18)
92.69(3)
1611.8(6)
8
6.1168(8)
9.7434(13)
8.8440(12)
97.943(3)
522.03(12)
2
10.4493(15)
11.6265(17)
10.6141(15)
116.066(2)
1158.3(3)
4
8.6418(6)
20.8479(14)
6.4730(5)
90.00
1166.20(14)
4
13.4992(15)
5.8966(6)
15.5307(17)
90.150(3)
1236.2(2)
4
dcalc/g cm–3
μ/cm–1
1.650
1.4
1.566
1.31
1.412
1.18
1.482
1.22
1.377
1.08
F(000)
832
260
520
552
544
2θmax/deg
50
60
58
60
60
Number of reflections
measured
independent
1779
1411
6117
1600
6727
3052
6577
1781
13784
3592
Number of reflections with I > 2σ(I)
1190
1325
2460
1703
1579
Number of refined parameters
159
158
221
227
171
R1
wR2
GOOF
0.0353
0.1047
1.048
0.0433
0.0979
1.004
0.0438
0.1113
1.013
0.0322
0.0763
1.080
0.0452
0.0770
0.927
Residual electron density,
0.247/–0.216
0.324/–0.227
0.232/–0.203
0.251/–0.185
0.239/–0.216
e Å–3(dmin/dmax
)
Table 4. Yields, melting points, and elemental analysis data for Nꢀ(carboxyalkyl)glycolurils
Comꢀ
pound
Yield
(%)
M.p.
/°С
Found
Calculated
Molecular
formula
(%)
N
C
H
1a
1b
1c
1d
60—68
30—58
52—63
33—40
273—27513,14
215—21713,14
145—14713—15
273—275
*
*
*
*
*
*
*
*
*
*
*
*
39.01
39.02
39.05
39.02
44.56
41.54
46.85
46.87
46.86
46.87
46.87
46.87
48.86
48.88
50.67
50.69
5.69
5.73
5.71
5.73
6.22
6.20
6.29
6.29
6.27
6.29
6.30
6.29
6.69
6.71
7.06
7.09
22.73
22.75
22.77
22.75
21.55
21.53
21.87
21.86
21.88
21.86
21.87
21.86
20.74
20.73
19.73
19.71
C8H14N4O5
1e
1f
39—55
24—38
21—39
15—29
5—15
5
258—26013
187—19113
232—23315
263—265
C8H14N4O5
C9H16N4O5
C10H16N4O4
C10H16N4O4
C10H16N4O4
C11H18N4O4
C12H20N4O4
1g
1h
1i
215—217
1j
221—223
1k
5—20
187—18915
* The elemental analysis data and the molecular formula were reported previously.14

404
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Kravchenko et al.
1
Table 5. H and 13C NMR spectra (DMSOꢀd6) of Nꢀ(carboxyalkyl)glycolurils*
Glycoluril
NMR, δ (J/Hz)
1H
—
13С
(3,7ꢀDioxoꢀ2,4,6,8ꢀtetraazabicycloꢀ
[3.3.0]octanꢀ2ꢀyl)acetic acid (1a)
2ꢀ(3,7ꢀDioxoꢀ6,8ꢀdimethylꢀ2,4,6,8ꢀ
tetraazabicyclo[3.3.0]octꢀ2ꢀyl)ꢀ
isobutyric acid (1d)
175.15 (COOH); 161.39 (CO); 159.51 (CO);
68.41 (CH); 62.39 (CH); 43.01 (CH2)
175.57 (COOH); 161.30 (CO); 158.94 (CO);
66.99 (CH); 62.66 (CH); 56.94 (C);
24.67 (Me); 23.69 (Me)
1.37 (s, 3 H, CH3); 1.39 (s, 3 H,
CH3); 5.22 and 5.49 (both d, 1 H,
2 CH, J = 8.3); 7.30 (s, 1 H, NH);
7.34 (s, 1 H, NH); 7.45 (s, 1 H, NH);
12.21 (br.s, 1 H, COOH)
—
(6,8ꢀDimethylꢀ3,7ꢀdioxoꢀ2,4,6,8ꢀ
tetraazabicyclo[3.3.0]octanꢀ2ꢀyl)ꢀ
acetic acid (1e)
171.17 (COOH); 160.05 (CO); 158.08 (CO);
71.85 (CH); 65.93 (CH); 44.35 (CH2);
29.37 (Me); 28.02 (Me)
2ꢀ(4,6ꢀDimethylꢀ3,7ꢀdioxoꢀ6,8ꢀ
dimethylꢀ2,4,6,8ꢀtetraazabicycloꢀ
[3.3.0]octꢀ2ꢀyl)isobutyric acid (1h)
1.46 (s, 3 H, CH3); 1.49 (s, 3 H,
CH3); 2.66 (s, 3 H, CH3); 2.80
(s, 3 H, CH3); 5.18 and 5.41 (both d, 30.24 (Me); 27.93 (Me); 25.42 (Me);
175.60 (COOH); 160.09 (CO); 158.45 (CO);
70.54 (CH); 66.51 (CH); 58.06 (C);
1 H, 2 CH, J = 8.1); 7.77 (s, 1 H,
NH); 12.35 (br.s, 1 H, COOH)
0.99—1.11 (m, 6 H, 2 CH3);
3.29—3.40 (m, 4 H, 2 CH2); 3.94
(br.s, 2 H, CH2); 5.31 (br.s, 2 H,
2 CH); 7.86 (s, 1 H, NH); 12.49
(br.s, 1 H, COOH)
1.02 (m, 6 H, 2 CH3); 2.31—2.63 (m,
2 H, CH2); 3.00—3.58 (m, 6 H, 3 CH2);
5.22 and 5.36 (both d, 1 H, 2 CH,
J = 8.8); 7.48 (s, 1 H, NH); 12.60
(br.s, 1 H, COOH)
24.24 (Me)
(6,8ꢀDiethylꢀ3,7ꢀdioxoꢀ2,4,6,8ꢀ
tetraazabicyclo[3.3.0]octanꢀ2ꢀyl)ꢀ
acetic acid (1i)
—
—
2ꢀ(6,8ꢀDiethylꢀ3,7ꢀdioxoꢀ2,4,6,8ꢀ
tetraazabicyclo[3.3.0]octanꢀ2ꢀyl)ꢀ
propionic acid (1j)
1
* Earlier, we have reported the H NMR spectroscopic data for glycolurils 1a,b,c,13,14 1e,f,13 and 1g,k.15
concentrated to 2/3 of the initial volume) and kept in a refrigꢀ
erator for 12 h. The precipitate of 1e (or 1f—j) was filtered off
and crystallized from water. In the case of 1k, the reaction
mixture was concentrated to the oily state and triturated with
MeOH. The precipitate that formed was filtered off and crystalꢀ
lized from MeOH.
4. A. N. Kravchenko, K. Yu. Chegaev, I. E. Chikunov, P. A.
Belyakov, E. Yu. Maksareva, K. A. Lyssenko, O. V. Lebedev,
N. N. Makhova, Mendeleev Commun., 2003, 269.
5. I. E. Chikunov, A. N. Kravchenko, P. A. Belyakov, K. A.
Lyssenko, V. V. Baranov, O. V. Lebedev, N. N. Makhova,
Mendeleev Commun., 2004, 253.
The yields and physicochemical characteristics of comꢀ
pounds 1a—k are given in Tables 4 and 5.
6. V. Yu. Torbeev, K. A. Lyssenko, O. N. Kharybin, M. Yu.
Antipin, R. G. Kostyanovsky, J. Phys. Chem., B, 2003, 107,
13523.
This study was financially supported by the Russian
Academy of Sciences (Program of the Division of Chemꢀ
istry and Materials Science of the Russian Academy of
Sciences “Biomolecular and Medical Chemistry”).
7. (a) P. A. Levkin, Yu. A. Strelenko, K. A. Lyssenko,
V. Schurig, R. G. Kostyanovsky, Tetrahedron: Asymm., 2003,
14, 2059; (b) P. A. Levkin, E. Schweda, H.ꢀJ. Kolb,
V. Schurig, R. G. Kostyanovsky, Tetrahedron: Asymm., 2004,
15, 1445.
8. R. G. Kostyanovsky, V. R. Kostyanovsky, G. K. Kadorkina,
K. A. Lyssenko, Mendeleev Commun., 2003, 111.
9. R. G. Kostyanovsky, K. A. Lyssenko, G. K. Kadorkina,
O. V. Lebedev, A. N. Kravchenko, I. I. Chervin, V. R.
Kostyanovsky, Mendeleev Commun., 1998, 231.
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in revised form September 3, 2008