Synthesis of new chiral mono-, di-, tri-, and tetraalkylglycolurils

Article abstract of DOI:10.1007/s11172-005-0307-3

Two general procedures were developed for the synthesis of chiral N-mono-, N, N′-di-, N, N′ N″-tri-, and N, N′, N″, N′″-tetraalkylglycolurils based on the reactions of 4,5-dihydroxy-imidazolidin-2-ones or glyoxal with one or two moles of alkylureas, respectively, by acid catalysis. The reactions of N-monoalkyl- and N, N′-dialkylureas with glyoxal proceed regioselectively. The mechanism of these reactions was suggested and partly confirmed by quantum-chemical calculations and experimental data. The enantiomeric separation of some chiral glycolurils by chiral-phase HPLC was carried out for the first time.

Full text of DOI:10.1007/s11172-005-0307-3

Russian Chemical Bulletin, International Edition, Vol. 54, No. 3, pp. 691—704, March, 2005
691
Synthesis of new chiral monoꢀ, diꢀ, triꢀ, and tetraalkylglycolurils
a
a
a
a
a
A. N. Kravchenko,a A. S. Sigachev, E. Yu. Maksareva, G. A. Gazieva, N. S. Trunova, B. V. Lozhkin ,
T. S. Pivina,a M. M. Il´in,b K. A. Lyssenko,b Yu. V. Nelyubina,b V. A. Davankov,b O. V. Lebedev,a
N. N. Makhova,a and V. A. Tartakovskya
ꢀ
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 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 (095) 135 5085. Eꢀmail: kostya@xray.ineos.ac.rukostya@xrlab.ineos.ac.ru
Two general procedures were developed for the synthesis of chiral Nꢀmonoꢀ, N,N´ꢀdiꢀ,
N,N´N´´ ꢀtriꢀ, and N,N´,N´´ ,N´´´ ꢀtetraalkylglycolurils based on the reactions of 4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀones or glyoxal with one or two moles of alkylureas, respectively, by acid
catalysis. The reactions of Nꢀmonoalkylꢀ and N,N´ꢀdialkylureas with glyoxal proceed
regioselectively. The mechanism of these reactions was suggested and partly confirmed by
quantumꢀchemical calculations and experimental data. The enantiomeric separation of some
chiral glycolurils by chiralꢀphase HPLC was carried out for the first time.
Key words: glycolurils, chirality, 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones, monoꢀ and dialkylꢀ
ureas, quantumꢀchemical calculations, enantiomeric analysis and separation, regioselectivity.
It is well known that Nꢀalkylꢀsubstituted 2,4,6,8ꢀtetraꢀ
azabicyclo[3.3.0]octaneꢀ3,7ꢀdiones (glycolurils) exhibit a
wide spectrum of biological activities,1—5 in particular,
they possess psychotropic activity.1—3 Some compounds
of this class influence the cytochromeꢀPꢀ450ꢀdependent
liver monooxygenase system: 2,6´ꢀBu2ꢀglycoluril exhibits
activity suppressesing the liver monooxygenase system,
whereas 2,6ꢀBz2ꢀglycoluril, on the contrary, stimulates
the enzymeꢀinducing activity.4 In addition, 2ꢀBuꢀ and
2,6ꢀMe2ꢀglycolurils are used as the starting compounds
in the synthesis of glycidyl derivatives (for example,
4,8ꢀdi(1,2ꢀepoxypropyl)ꢀ2,6ꢀdimethylglycoluril) showing
cytostatic effects.5 The aboveꢀmentioned glycolurils, like
most glycolurils, are chiral.6 In biological assays, these
compounds were used, apparently, as racemates, because
the enantiomeric separation was not discussed. However,
it is known that racemates and individual enantiomers
involved in medicines can differ substantially in activity,
toxicity, and side effects.7
The problem of preparation of pure Nꢀalkylglycolurils
has received attention only in the very recent past. Earꢀ
lier, we have found two compounds, viz., 2,6ꢀdiꢀ
methylꢀ and 2,6ꢀdiethylglycolurils, which can crystallize
as conglomerates.8,9 Data on the conglomerateꢀforming
properties of other Nꢀalkylglycolurils containing chiral
atoms are lacking in the literature. This can be attributꢀ
able to the fact that, in spite of numerous publications on
the synthesis and biological properties of Nꢀalkylglycolꢀ
urils,1—22 representatives of this type of compounds are
scarce, most of them being covered by patents5,13,14,18—20
or described in brief communications.7,12,16,21 These comꢀ
pounds have not been characterized spectroscopically and
procedures for their synthesis have not been optimized.
The aim of the present study was to develop a general
approach to the synthesis of monoꢀ, diꢀ, triꢀ, and tetraꢀ
alkylꢀsubstituted glycolurils and extend the range of comꢀ
pounds by introducing various alkyl substituents.
Known procedures for the synthesis of glycolurils are
based on condensation of ureas with glyoxal2,4,10—15,18,19
and 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones.2,10,13,18—21 To
prepare new representatives of chiral 2ꢀmonoalkylglycolꢀ
urils 1, we decided to use a procedure based on cycloꢀ
condensation of 1ꢀalkylureas 2a—f with 4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀone (3a), which was prepared according
to a known procedure (Scheme 1).23 The reactions of the
latter with compounds 2a,b were carried out in water,
whereas the reactions with compounds 2c—f were perꢀ
formed in isopropanol at 80—90 °C for 1—1.5 h. In both
cases, a catalytic amount of hydrochloric acid was added.
An analogous approach was used to synthesize 2,4ꢀdiꢀ
alkylglycolurils 4. In this case, the reactions of 4,5ꢀdiꢀ
hydroxyimidazolidinꢀ2ꢀone 3a were carried out with
1ꢀalkylꢀ3ꢀmethylureas 5a—f, the reactions with comꢀ
pounds 5a—c,f being performed in water, whereas the
reactions with compounds 5d,e being carried out in isoꢀ
propanol. These reactions, like the aboveꢀdescribed reacꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 680—692, March, 2005.
1066ꢀ5285/05/5403ꢀ0691 © 2005 Springer Science+Business Media, Inc.

692
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Kravchenko et al.
Scheme 1
1.0000
5.3
9.7656
5.2
5.7
5.6
5.5
5.4
5.1
5.0
δ
Fig. 1. Region of the signals for the protons of the CH—CH
groups in a concentrated reaction mixture of compounds 6b
(δ 5.18, s) and 7b (δ 5.17 and 5.32, both d).
i. HCl (cat.)
R = Et (a), Pr (b), Bus (c), But (d), cycloꢀC6H11 (e), C12H25 (f)
The investigation of the reaction of 1ꢀmethylureas 2h
with glyoxal has demonstrated11 that cyclocondensation
afforded a mixture of 2,6ꢀ and 2,8ꢀdimethylglycolurils 6h
(trans isomer) and 7h (cis isomer) in a ratio of 7 : 4 with
respect to the products isolated. Hence, to develop a genꢀ
eral method for the synthesis of chiral 2,6ꢀdialkylꢀ
glycolurils 6, it was necessary to study the regioselectivity
of the reactions of glyoxal with 1ꢀalkylureas containing
various alkyl substituents 2a,b,d,e,g,h (Scheme 3).
tions, were performed by acid catalysis at 80—90 °C
(Scheme 2). In both cases, the target glycolurils 1 and 4
were prepared in 60—92% yields.
Scheme 2
The reaction was carried out according to a convenꢀ
tional procedure by heating the reaction mixture in water
or isopropanol at 80—90 °C in the presence of a catalytic
amount of hydrochloric acid. The reaction products were
1
analyzed by H NMR spectroscopy of the reaction mixꢀ
tures concentrated to dryness. The trans to cis isomer
ratios (compounds 6 and 7) were estimated from the
ratios of the signals for the protons of the CH—CH
groups at δ 4.8—5.5. The signals for these protons in the
trans isomers appear as singlets, whereas the correspondꢀ
ing signals for the cis isomers appear as AMX systems (see
Figs 1 and 2).
It was found that the reactions of glyoxal with monoꢀ
alkylureas 2a,b,d,e,g always occur regioselectively to give
trans isomers 6 as the major products; the ratios were as
follows: 6a : 7a = 3 : 1, 6b : 7b ≈ 9 : 2, 6d : 7d = 5 : 2,
i. HCl (cat.)
R = Et (a), Pr (b), Bus (c), But (d), cycloꢀC6H11 (e), Bu (f)
Scheme 3
R = Et (a), Pr (b), But (d), cycloꢀC6H11 (e), Bu (g), Me (h)

Synthesis of new chiral akylglycolurils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
693
monoalkylureas 2 always produced mixtures of transꢀ and
cisꢀglycolurils 6 and 7. In addition, the reactions yielded
hydantoins 8 as byꢀproducts, which were formed from the
carbonium cation C as a precursor. Hence, the first reacꢀ
tion pathway through the formation of 1ꢀalkylꢀ4,5ꢀ
dihydroxyimidazolidinꢀ2ꢀones 3 seems to be more likely.
This conclusion is also indirectly supported by the followꢀ
ing facts:
— earlier, we have synthesized 5ꢀsubstituted arylꢀ
sulfonyliminoimidazolidinꢀ2ꢀones by the reaction of
1ꢀalkylꢀ4,5ꢀdihydroxyimidazolidinꢀ2ꢀones with arylꢀ
sulfamides,17 which confirms higher stability of the
carbocation bearing a charge on the carbon atom adjacent
to the alkylꢀsubstituted nitrogen atom;
— we have described24 the regioselective reaction
of 1ꢀmethylurea with acetaldehyde giving rise to both
2,5,7,8ꢀtetramethylꢀ and 2,5,7,10ꢀtetramethylꢀ2,4,8,10ꢀ
tetraazabicyclo[4.4.0]decaneꢀ3,9ꢀdiones, which is eviꢀ
dence that not only the NH2 group but also the H—N—Alk
fragment are involved in condensation of 1ꢀmethylurea
with aldehyde.
In addition to the sequence of transformations of a
particular intermediate shown in Scheme 4, the order in
which the NH fragments of the starting 1ꢀalkylurea 2 are
involved in condensation with glyoxal is also of fundaꢀ
mental importance for the possible formation of the
trans or cis isomers (2,6ꢀ (6) or 2,8ꢀdialkylglycolurils (7),
respectively). It was hypothesized12,16 that this condensaꢀ
tion first occurs at the free NH2 group of the starting
urea 2. If this is the case, the reactions would always
afford only the trans isomers, viz., 2,6ꢀdialkylglycolurils 6,
in accordance with Scheme 4. The formation of 2,8ꢀdiꢀ
alkylglycolurils 7 along with glycolurils 6 is indicative of
the possible condensation of glyoxal with the H—N—Alk
fragment of urea 2.
0.8173
3.1627
1.0000
5.52 5.44 5.36 5.28 5.20 5.12
5.04 4.96
δ
Fig. 2. Region of the signals for the protons of the CH—CH
groups in a concentrated reaction mixture of compounds 6g
(δ 5.26, s) and 7g (δ 4.99 and 5.39, both d).
6e : 7e = 7 : 2, and 6g : 7g ≈ 2 : 1. The ratio of compounds
6 and 7 was determined from the integral intensity ratios
of the signals for the protons of the CH—CH groups at
δ 4.8—6.0. The isolation of 2,6ꢀ and 2,8ꢀdimethylꢀ
glycolurils 6 and 7 in pure form was carried out by fracꢀ
tional crystallization. The yields of transꢀ and cisꢀglycolꢀ
urils were 40—63 and 12—20%, respectively. Hydantoins 8
were obtained as byꢀproducts.*
The mechanism of formation of the bicyclic systems
of 2,6ꢀ and 2,8ꢀdialkylglycolurils, as well as the mechaꢀ
nism of formation of glycolurils from glyoxal and ureas, is
still debated.10,12,16 Two main pathways of these reactions
were suggested in the literature:10,12,16 1) through the interꢀ
mediate formation of 1ꢀalkylꢀ4,5ꢀdihydroxyimidazolidinꢀ
2ꢀone 3 from glyoxal and one 1ꢀalkylurea molecule and
2) through the linear product B prepared by the reaction
of glyoxal with two urea molecules. Ureidocarbinol A was
assumed to be the precursor of both intermediates 3 and B
(Scheme 4).
To elucidate the possible direction of the first step of
condensation of glyoxal with 1ꢀalkylureas 2, we calcuꢀ
lated the threeꢀdimensional and electronic structures of
compounds 2a,b,e,g,h by semiempirical quantumꢀchemiꢀ
cal methods (MNDO and PM3) using the MOPAC and
WinMOPAC program packages. The results of calculaꢀ
tions are given in Table 1. Analysis of the charge distribuꢀ
tions showed that the more negative charge is always loꢀ
calized on the nitrogen atom of the NH—Alk fragments.
The dipole moments of the compounds under study deꢀ
pend only slightly on the length of the alkyl fragment,
whereas the enthalpies of formation are indicative of an
increase in thermochemical stability with increasing length
of the alkyl chain. These data confirm our hypothesis that
the reaction of glyoxal with ureas occurs at the NH—Alk
fragment.
If the reaction follows the first pathway, intermediate
3 that formed in the second step of the reaction is protoꢀ
nated in the presence of an acid followed by elimination
of the water molecule to generate the carbonium ion C.
The latter reacts with the second urea molecule and gives
the final glycoluril through the intermediate D and the
second carbonium ion Е. Two alternative reaction pathꢀ
ways through the intermediates D,E or D″,E″ are possible
depending on which urea fragment, NH2 or NHR, is
bound to the carbonium ion C to give trans isomer 6 or
cis isomer 7, respectively.
If the reaction follows the second pathway, glycolurils
are, apparently, produced by two successive cyclizations
of the linear intermediate B. The first cyclization affords
the intermediate D´, which is transformed into the carꢀ
bonium ion E´. The latter undergoes cyclization to the
final glycoluril 6. However, the reactions of glyoxal with
To elucidate the factors responsible for the fact
that cyclization follows the first pathway, the threeꢀdiꢀ
mensional and electronic structures of the intermediꢀ
ates (D, D´, and DІ″) and the corresponding cations
* The synthesis of hydantoins will be published elsewhere, and
here we do not report their physicochemical characteristics.

694
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Kravchenko et al.
Scheme 4
i. Rapidly.
(E, E´, and E″) were calculated by the quantumꢀchemiꢀ
cal MNDO method. The results of calculations are given
in Table 2.
Analysis of the results of calculations demonstrated
that the isomer D is the thermochemically most stable
compound, which is characterized by the deepest miniꢀ
mum on the potential energy surface (Е = –2735.292 eV),
whereas the isomer D´ is the least stable compound
(Е = –2734.887 eV).
A comparison of the stabilities of the corresponding
cations shows that the cation E is the most stable species
(the total energy of the molecule was –2392.762 eV),
whereas the cation E´ is the least stable species and has
the energy of –2392.351 eV. The cation E is characterized
by the highest positive charge on the cationic C center
(0.437), whereas the cation E´ is characterized by the
lowest positive charge on the C atom (0.406). As for the
ionization potentials, the cations E and E´ are characterꢀ
ized by the lowest and highest potentials (10.617 and
10.778 eV, respectively). These data suggest that cyclizaꢀ
tion occuring through the formation of the intermediates
D and E is most favorable both in the orbitalꢀ and
chargeꢀcontrolled reactions, resulting in the formation of
transꢀglycolurils, whereas cyclization through the interꢀ
mediates D´ and E´ is least favorable. Hence, the formaꢀ
tion of cisꢀglycolurils can occur, although it is less
probable.
Therefore, both the calculated and experimental data
demonstrate that the regioselectivity of the formation of
bicyclic compounds 6 or 7 is virtually independent of the
length of the alkyl chain or the volume of the substituent
in 1ꢀalkylureas 2.

Synthesis of new chiral akylglycolurils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
695
Table 1. Calculated characteristics of the electronic structures of 1ꢀalkylureas 2
с
Comꢀ Charges on atoms
Molecular
formula (M)
µ/Da
PIb
/eV
EHOMO/ELUMO
(ELUMO – EHOMO)/eV
–∆Hf°
/kcal mol–1
pound
(MNDO)
MNDO PM3 MNDO PM3
MNDO
PM3 MNDO PM3
2a
2b
2e
2h
2g
С3H8N2O
(88.109)
3.79
3.77
3.95
3.83
3.79
3.63
3.61
4.14
3.64
3.60
10.269
10.265
10.216
10.305
10.261
9.548
9.553
9.581
9.604
9.553
–10.269/ –9.548/ 45.33
1.824 1.146
(11.509) (10.693)
48.819
54.03
62.406
42.62
59.46
C4H10N2O
(102.136)
–10.265/ –9.553/ 50.05
1.831
1.136
(12.096) (10.690)
C7H14N2O2
(142.200)
–10.216/ –9.581/ 54.91
1.784
1.239
(12.000) (10.821)
C2H6N2O
(74.082)
–10.305/ –9.604/ 40.32
1.882
1.154
(12.187)
C5H12N2O
(116.163)
–10.261/ –9.553/ 54.71
1.825 1.131
(11.510) (10.685)
a The dipole moment.
b The ionization potential.
c The enthalpy of formation.
Earlier, we have demonstrated21 that triꢀNꢀalkylꢀ
glycolurils can be synthesized according to two proceꢀ
dures: (1) by the reaction of 1,3ꢀdialkylꢀ4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀones (3b,c) (which were synthesized by
the reactions of the corresponding ureas with glyoxal)10,17
with 1ꢀalkylureas 2a,h or (2) by the oneꢀpot reaction of
1ꢀalkylꢀ4,5ꢀdihydroxyimidazolidinꢀ2ꢀones 3d,e (which
were synthesized by the reactions of 1ꢀalkylureas 2a,h
with glyoxal) with 1,3ꢀdialkylureas 9a,b (Scheme 5). We
used both these approaches to synthesize triꢀNꢀalkylꢀ
glycolurils and studied these approaches in more detail.
The former reaction was carried out in an aqueous meꢀ
dium by acid catalysis with heating to 90 °C followed by
keeping for 1 h. Under these conditions, we prepared
Scheme 5
2a
—
Et
2h
—
Me
3b
Me
—
3c
Et
—
3d
—
Et
3e
—
Me
9a
Me
—
9b 10a 10b 10c 10d
R
R1
Et
—
Me
Et
Et
Et
Me
Me Me
Et

696
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Kravchenko et al.
Table 2. Characteristics of the electronic structures of the compounds calculated by the MNDO method
Comꢀ
pound
Charges on atoms
(MNDO)
Molecular
formula (M)
µ/D
PI
/eV
EHOMO/ELUMO
(ELU MO – EHOMO
/eV
∆Hf°
Etotal/eV
)
/kcal mol–1
D´
C6H12N4O3
(188.186)
5.25
10.262
–10.262/
0.948
–141.83
–2734.887
(11.210)
D
C6H12N4O3
(188.186)
10.53
9.89
7.51
10.476
10.320
10.778
–10.476/
1.041
(11.517)
–152.51
–144.14
41.836
–2735.292
–2734.937
–2392.351
D″
E´
C6H12N4O3
(188.186)
–10.320/
0.742
(11.062)
C6H11N4O2
(171.179)
–10.778/
–1.030
(9.748)
E
C6H11N4O2
(171.179)
13.35
14.12
10.617
10.744
–10.617/
–0.732
(9.885)
30.07
37.63
–2392.762
–2392.455
E″
C6H11N4O2
(171.179)
–10.744/
–0.866
(9.878)
the following 2,4,6ꢀtrialkylglycolurils: 10a (44—46%),
10b (37—39%), 10c (47—49%), and 10d (40—42%)
(Scheme 5).
These conditions were used in the oneꢀpot synthesis
of glycolurils 10a—d. First, we synthesized 3d,e by the
reaction of 2a,h with glyoxal and used these compounds
(without isolation) in the reactions with 1,3ꢀdimethyl(diꢀ
ethyl)ureas 9a,b; рH was changed to 1, and the reaction
mixture was kept at 90 °C for 1 h. The yields of the target
glycolurils were as follows: 10a, 50—52%; 10b, 37—39%;
10c, 32—35%; and 10d, 60—61%. A comparative analysis
demonstrated that the first reaction is a method of choice
for the synthesis of compound 10c, whereas compounds
10a,d are more convenient to prepare according to the
second procedure. Both methods are suitable for the synꢀ
thesis of compound 10b, because these methods afforded
10b in nearly equal yields. The physicochemical characꢀ
teristics of glycolurils 10 have been described in detail in
our earlier publication.21
The second procedure was carried out using TLC and
1H NMR control of the reaction mixtures. First, we studꢀ
ied the reactions of methylꢀ and ethylureas 2h,a with
glyoxal under the conditions of the reaction giving rise to
4,5ꢀdihydroxyimidazolidinꢀ2ꢀones (рH 4—5, a 40% aqueꢀ
ous solution of glyoxal, an equimolar reagent ratio, and
heating of the reaction mixture at 50 °C).23 The reaction
was monitored based on the disappearance of the signals
for the Nꢀmethyl protons of the starting ureas 2 (at δ 3.72,
3
singlet (2h), and at δ 1.00, triplet J = 8 Hz (2a)) in the
1H NMR spectra of the reaction mixtures. The results of
1H NMR spectroscopy combined with the TLC control
demonstrated that the starting ureas 2h,a were completely
1
consumed within 2 h, and the H NMR spectra showed
Earlier, we have established the structure of glycoluril
10a by Xꢀray diffraction and demonstrated that crystalliꢀ
only signals of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones 3d,e.

Synthesis of new chiral akylglycolurils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
697
pounds 3b,c with 1ꢀalkylꢀ3ꢀmethylureas afforded tetraꢀ
alkylglycolurils 11 in 57—72% yields (Scheme 6). The
reactions of dialkylureas 5d,e with glyoxal occurred
regioselectively to give transꢀtetraalkylglycolurils 12 as the
major products. The reactions also produced isomeric
cisꢀtetraalkylglycolurils 13 and hydantoins 14 and 15
C(11)
C(1)
C(5)
N(2)
N(6)
C(8)
N(4)
C(10)
N(8)
C(9)
C(7)
C(3)
1
O(2)
(Scheme 7), which was confirmed by H NMR spectroꢀ
O(1)
scopy of the reaction mixtures concentrated to dryness.
Hydantoins 14 and 15 were not isolated, but the 1H NMR
spectra showed the signals for their protons: two singlets
of the CH2 groups at δ 3.9—4.1, whose integral intensities
correspond to the intensities of the signals for other groups
of protons of hydantoins 14 and 15. Glycolurils 12d and
13d were isolated by fractional crystallization. Glycolurils
12e and 13e were isolated by preparative column chromaꢀ
tography on SiO2. Compounds 12 and 13 were syntheꢀ
sized in 32—39 and 24—28% yields, respectively. Eviꢀ
dently, the regioselective formation of compounds 12 is
controlled by the steric factors.
Fig. 3. Overall view of molecule 10a.
zation of the racemate is accompanied by the spontaneꢀ
ous enantiomeric separation. Compound 10a crystallizes
in the space group Р–1 with four independent molecules
per asymmetric unit. Molecules 10a have no symmetry
elements and exist as one of the possible enantiomers.25
The presence of four independent molecules per asymꢀ
metric unit suggests that other polymorphs can exist along
with the aboveꢀconsidered crystal modification. Because
of this, we repeated Xꢀray diffraction analysis of comꢀ
pound 10a (Fig. 3), which unexpectedly demonstrated
that 10a crystallizes in the centrosymmetric space group Р–1
with two independent molecules and the identical unit
cell parameters (see Ref. 25 and Table 6). Therefore, the
spontaneous separation of 10a was not observed and the
earlier Xꢀray diffraction data are incorrect. The main geoꢀ
metric parameters, including the conformation of molꢀ
ecule 10a, are similar to the previous data.25 In the crysꢀ
tal, the independent molecules are linked to each other by
N—H...O hydrogen bonds (2.865(3)—2.888(3) Å) to form
dimers. Other contacts in the crystal of 10a belong to
usual van der Waals interactions.
Scheme 6
Only one procedure for the synthesis of chiral tetraꢀ
alkylglycolurils was described in the literature.7,22 This
procedure is based on alkylation of 2,6ꢀdialkylglycolurils 6.
In the present study, we synthesized chiral tetraalkylꢀ
glycolurils 11 and 12 using two procedures: (1) cycloꢀ
condensation of 1,3ꢀdimethyl(diethyl)ꢀ4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀones 3b,c with 1ꢀalkylꢀ3ꢀmethylureas
5b,d,e,h or (2) the reaction of 5d,e with glyoxal. In both
cases, the reactions were carried out in isopropanol at
80—82 °C using acid catalysis (in the latter case, glyoxal
was used as trimeric dihydrate). The reactions of comꢀ
R = Pr (5b, 11a), But (5d, 11b,d), cycloꢀC6H11 (5e, 11c,e),
(5h, 11f)
R´ = Me (3b, 11a,b,c,f); Et (3c, 11d,e)
Scheme 7
R = But (d), cycloꢀC6H11 (e)

698
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Kravchenko et al.
C(5)
C(13)
polar eluents, for example, mixtures of hexane and isoꢀ
propanol, were recommended for most of these columns.
In these media, the solubility of glycolurils is too low,
whereas these compounds are poorly retained on most of
chiral phases in polar media (mixtures of water and acetoꢀ
nitrile). A Chirobiotic TAG column (250×4 mm) (Adꢀ
vanced Separation Technologies Inc.), in which the macꢀ
rocyclic antibiotic Teicoplanin Aglycone containing eight
chiral centers covalently bound to silica gel served as the
sorbent, proved to be a column of choice. On this colꢀ
umn, glycolurils were retained for a rather long period of
time with the use a 50% aqueous MeOH solution as the
standard eluent (an UV detector, 206 nm). Of the twelve
racemates under study, five compounds showed a satisꢀ
factory enantiomeric separation in this eluent. Selected
results are given in Table 3. For seven racemates, the
peaks of enantiomers overlap to a substantial extent, and
an improvement of separation requires further optimizaꢀ
tion of the conditions. When examining the possibility of
the separation of the racemate of "albicar" (after prelimiꢀ
nary preclinical studies), in spite of a poor peak resolution
(Rs = 1.2), we succeeded in isolating individual enantiꢀ
omers for a more detailed investigation by repeated chroꢀ
matography on an analytical column. We performed
the successful enantiomeric separation of 2ꢀEtꢀ (1a),
2ꢀPrnꢀ (1b), 2ꢀButꢀ4ꢀMeꢀ (4d), and 2,6ꢀMe2ꢀsubstituted
glycolurils (6h).
C(12)
C(11)
C(1)
N(4)
C(9)
N(8)
N(2)
C(10)
C(8)
C(3)
C(7)
N(6)
C(14)
O(2)
C(15)
O(1)
Fig. 4. Overall view of molecule 11c.
C(16)
The structure of one of the resulting tetraalkylꢀ
glycolurils was established by Xꢀray diffraction analysis.
The singleꢀcrystal investigation of 11c demonstrated that
this compound crystallizes in the racemic space group as
a hydrate (Fig. 4). The bond lengths and bond angles in
11c are close to the corresponding values in alkyl derivaꢀ
tives of glycolurils studied earlier.7—9 The hydrogen atꢀ
oms at the C(1) and C(5) atoms are in the cis arrangeꢀ
ment. The fiveꢀmembered rings adopt an envelope conꢀ
formation with the C(1)/C(5) atoms deviating by 0.11 Å.
The angle between the planes of the fiveꢀmembered rings
is 123°. The nitrogen atoms in the ring are planar with the
maximum deviation observed for the N(8) atom (the deꢀ
viation of the C(1), C(7), and C(11) atoms from the plane
is 0.12 Å), which is, apparently, associated with the presꢀ
ence of the cyclohexane ring.
Analysis of the crystal packing showed that molecules
11c are linked to each other to form dimers by mediumꢀ
strength O—H...O hydrogen bonds (O...O, 2.842 Å) inꢀ
volving the water solvate molecule located at the inverꢀ
sion center.
Most of the chiral glycolurils synthesized in the present
study have not been described in the literature. The yields,
melting points, elemental analysis data, and spectroscopic
characteristics, which confirmed the structures of all these
compounds, are given in Tables 4 and 5.
Compound
"Albicar"
1a
R1
Me
Et
R2
Et
H
R3
Et
H
R4
Me
H
Experiments on crystallization of compounds 1, 4,
6, 7, and 10—13 allowed us to grow highꢀquality crystals
of only compounds 10a and 11c, whereas crystals of the
other compounds are unsuitable for Xꢀray diffraction
study. Hence, the separation of racemic mixtures presents
a special problem.
1b
4d
6h
Pr
Me
Me
H
H
H
H
H
H
Me
But
H
To summarize, we developed two general procedures
for the synthesis of previously unknown chiral monoꢀ,
2,4ꢀ; 2,6ꢀdiꢀ, 2,4,6ꢀtriꢀ, and tetraalkylglycolurils by the
To solve this problem, we examined, for the first time,
the possibility of using chiral HPLC for the enantioꢀ
meric separation of racemates of chiral Nꢀalkylꢀsubstiꢀ
tuted glycolurils 2ꢀMeꢀ,10 2ꢀEtꢀ (1a), 2ꢀPrꢀ (1b),
2ꢀButꢀ4ꢀMeꢀ (4d), 2,6ꢀEt2ꢀ (6a), 2,6ꢀBu2ꢀ (6g),
2,6ꢀcycloꢀC6H11ꢀ (6e), 2,6ꢀMe2ꢀ (6h), 2,4,6ꢀEt3ꢀ (10b),
2,4,6ꢀMe3ꢀ8ꢀPrꢀ (11a), 2,4,6ꢀMe3ꢀ8ꢀcycloꢀC6H11ꢀglycolꢀ
urils (11c), and "albicar" (2,6ꢀMe2ꢀ4,8ꢀEt2ꢀglycoluril).
The aims were to evaluate the prospects of the preparative
separations and develop convenient procedures for the
enantiomeric analysis of chiral products. A series of comꢀ
mercial chiral HPLC columns, primarily, based on celluꢀ
lose and amylose derivatives, were tested. However, nonꢀ
Table 3. Results of enantiomeric separation of glycolurils by
HPLC on a Chirobiotic TAG column (250×4 mm)
Compound
k1
k2
α
Rs
"Albicar"
1.32
1.05
1.29
1.71
0.74
1.57
2.0
1.65
3.39
0.85
1.19
1.91
1.28
1.98
1.15
1.2
3.5
1.5
3.7
0.8
1a
1b
4d
6h
Note. ki is the retention factor, α is the separation factor, and
Rs is the peak resolution.

Synthesis of new chiral akylglycolurils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
699
Synthesis of chiral glycolurils: 2ꢀethylꢀ (1a), 2ꢀpropylꢀ (1b),
2ꢀsecꢀbutylꢀ (1c), 2ꢀtertꢀbutylꢀ (1d), 2ꢀcyclohexylꢀ (1e),
2ꢀdodecylꢀ (1f), 4ꢀethylꢀ2ꢀmethylꢀ (4a), 2ꢀmethylꢀ4ꢀpropylꢀ (4b),
2ꢀsecꢀbutylꢀ4ꢀmethylꢀ (4c), 2ꢀtertꢀbutylꢀ4ꢀmethylꢀ (4d),
4ꢀcyclohexylꢀ2ꢀmethylꢀ (4e), 2ꢀbutylꢀ4ꢀmethylꢀ (4f), 6ꢀethylꢀ2,4ꢀ
dimethylꢀ (10a), 2,4,6ꢀtriethylꢀ (10b), 2,4ꢀethylꢀ6ꢀmethylꢀ (10d),
2,4,6ꢀtrimethylꢀ8ꢀpropylꢀ (11a), 2ꢀtertꢀbutylꢀ4,6,8ꢀtriꢀ
methylꢀ (11b), 8ꢀcyclohexylꢀ2,4,6ꢀtrimethylꢀ (11c), 2ꢀtertꢀbuꢀ
tylꢀ6,8ꢀdiethylꢀ4ꢀmethylꢀ (11d), 4ꢀcyclohexylꢀ6,8ꢀdiethylꢀ2ꢀ
methylꢀ 11(e), and 2ꢀ[(2E,6E,10E)ꢀ3,7,11,15ꢀtetramethylhexaꢀ
decaꢀ2,6,10,14ꢀtetraenyl]ꢀ4,6,8ꢀtrimethylꢀ2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octaneꢀ3,7ꢀdione (11f) (general procedure). Concenꢀ
trated hydrochloric acid (0.2 mL) was added (in an aqueous
medium to рH of 1) to a solution of the corresponding urea 2
(2a,b—f, 5a—h) (0.02 mol) and 1,3ꢀHꢀ, 1,3ꢀMe2ꢀ, or 1,3ꢀEt2ꢀ
4,5ꢀdihydroxyimidazolidinꢀ2ꢀone (3a—c) (0.02 mol) in the miniꢀ
mum amount of water or isopropanol (depending on the solubilꢀ
ity of the starting compounds). In the synthesis of compounds
1a—c,f, 4a—c,f, 10a,b,d, and 11a—f, the reaction mixture was
kept at reflux temperature for 1 h. In the synthesis of compounds
1d,e and 4d,e the reaction mixture was kept at reflux temperaꢀ
ture for 1.5 h. Then the reaction mixture (1a—c, 4a—c,f, 10a,b,d,
and 11a,b,d,f) was concentrated to oneꢀhalf of the initial volꢀ
ume and kept in a refrigerator for 12 h. The precipitate that
formed (1a—c, 4a—c,f, or 11a,b,d) was filtered off and recrysꢀ
tallized from water. Compounds 10a,b,d were extracted ten times
with chloroform (the volumes were equal to the volumes of the
evaporated reaction mixtures). The chloroform extracts were
concentrated to dryness and the residues were recrystallized from
dioxane. In the case of compounds 1d,e, 4d,e, and 11c, the
reactions afforded precipitates, which were filtered off and reꢀ
crystallized from MeOH.
reactions of the corresponding monoalkylꢀ and 1ꢀalkylꢀ
3ꢀmethylureas with glyoxal or 4,5ꢀdihydroxyimidazolidinꢀ
2ꢀones in water or isopropanol using acid catalysis, which
substantially extends the range of chiral glycolurils conꢀ
taining alkyl substituents at the nitrogen atoms. When
studying the reactions of monoalkylꢀ and 1ꢀalkylꢀ3ꢀ
methylureas with glyoxal, we observed the regioselectivity
of the formation of 2,6ꢀdialkylꢀ and 2,6ꢀdialkylꢀ4,8ꢀ
dimethylglycolurils. The mechanism of formation of
dialkylglycolurils was proposed based on experimental
data and results of quantumꢀchemical calculations. We
demonstrated for the first time that chiral glycolurils
can be separated into enantiomer by analytical chiralꢀ
phase HPLC.
Experimental
Commercial (Acros) urea, dimethylurea, diethylurea, a 40%
aqueous glyoxal solution, and glyoxal trimeric dihydrate were
used. 1ꢀAlkylureas 2a—h and 1ꢀalkylꢀ3ꢀmethylureas 5a—g were
synthesized by the reactions of the corresponding amines with
KOCN and MeNCO.26,27 4,5ꢀDihydroxyimidazolidinꢀ2ꢀones 3
were prepared by the reactions of the corresponding ureas with
glyoxal according to procedures described earlier.17,23,28
The NMR spectra were recorded on Bruker AMꢀ250
(1H, 250 MHz) and Bruker AMꢀ300 (13C, 75.5 MHz) spectromꢀ
eters; the chemical shifts are given in the δ scale relative to
Me4Si as the internal standard. The mass spectra were obtained
on a Varian MAT CHꢀ6 mass spectrometer (70 eV). The melting
point was determined on a GALLENKAMP instrument (Sanyo).
The enantiomeric analysis of compounds 1a,b, 4d, and 6h and
"albicar" was carried out by HPLC on a Chirobiotic TAG
(250×4 mm) column (Advanced Separation Technologies Inc.),
in which the macrocyclic antibiotic Teicoplanin Aglycone conꢀ
taining eight chiral centers covalently bound to silica gel was
used as the sorbent (50% aqueous MeOH solution as the eluent,
an UV detector, 206 nm).
In the case of compound 1f, water was evaporated in vacuo
until an oily residue formed. The latter was triturated in a 1 : 3
acetone—diethyl ether mixture (10 mL). The precipitate of 1f
that formed was filtered off and recrystallized from MeOH. The
yields and physicochemical characteristics of compounds 1a—f,
4a—f, and 11a—f are given in Tables 4 and 5.
Synthesis
of
2,4,6ꢀtrimethylꢀ2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octaneꢀ3,7ꢀdione (10c). A 20% aqueous NaOH soꢀ
Table 4. Yields and selected physicochemical characteristics of monoꢀ, diꢀ, triꢀ, and
tetraalkylglycolurils
Comꢀ
pound
Yields
(%)
M.p.
/°С
Found
Calculated
Molecular
formula
(%)
C
H
N
1a
1b
1c
1d
1e
68—70
60—63
70—72
89—91
87—90
278—280
250—252
303—305
279—280
300—303
42.27
42.35
45.22
45.64
48.43
48.47
48.53
48.47
53.49
53.56
5.97
5.92
6.32
6.57
7.15
7.12
7.18
7.12
7.30
7.19
33.10
32.92
30.98
30.42
27.99
28.26
28.31
28.26
25.07
24.98
C6H10N4O2
C7H12N4O2
C8H14N4O2
C8H14N4O2
C10H16N4O2
(to be continued)

700
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Kravchenko et al.
Table 4 (continued)
Comꢀ
pound
Yields
(%)
M.p.
/°С
Found
Calculated
Molecular
formula
(%)
C
H
N
1f
78—80
75—77
86—88
85—86
85—86
90—92
88—89
48—50
53—55
40—42
61—63
42—44
16—18
12—14
15—17
18—20
20—22
57—59
63—65
70—72
59—61
65—66
60—61
32—35
37—39
24—25
26—28
255—256
248—250
270—272
274—276
264—266
256—258
238—240
292—294
293—295
340—341
365—367
319—322
300—301
287—289
332—335
355—357
312—314
126—128
118—120
120—122
138—140
131—135
286—287
248—250
260—262
239—241
254—256
61.81
61.90
45.75
45.64
48.37
48.47
50.87
50.93
50.85
50.93
55.51
55.44
51.04
50.93
48.44
48.47
53.11
53.08
56.74
56.67
62.68
62.72
31.27
31.31
48.52
48.47
53.00
53.08
56.70
56.67
62.73
62.72
56.61
56.67
51.00
50.93
55.01
54.98
58.65
58.62
58.22
58.18
61.18
61.20
70.51
70.55
59.48
59.55
64.71
64.64
59.61
59.55
64.63
64.64
9.53
9.74
6.68
6.57
7.14
7.12
7.57
7.60
7.71
7.60
7.64
7.61
7.68
7.60
7.09
7.12
7.95
8.02
8.75
8.72
8.56
8.55
2.58
2.63
7.15
7.12
7.98
8.02
8.69
8.72
8.52
8.55
8.75
8.72
7.58
7.60
8.40
8.39
8.30
8.33
9.04
9.01
8.94
8.90
9.59
9.56
9.27
9.28
9.08
9.04
9.23
9.28
9.07
9.04
17.89
18.05
30.55
30.42
28.12
28.26
26.31
26.40
26.37
26.40
23.46
23.51
26.52
26.40
28.31
28.26
24.81
24.76
21.97
22.03
18.32
18.29
24.27
24.35
28.21
28.26
24.81
24.76
22.07
22.03
18.30
18.29
22.06
22.03
26.45
26.40
23.27
23.32
21.05
21.04
20.95
20.88
18.99
19.03
12.65
12.66
19.82
19.84
16.73
16.75
19.83
19.84
16.72
16.75
C16H30N4O2
C7H12N4O2
C8H14N4O2
C9H16N4O2
C9H16N4O2
C11H18N4O2
C9H16N4O2
C8H14N4O2
C10H18N4O2
C12H22N4O2
C16H26N4O2
C6H6N4O6
4a
4b
4c
4d
4e
4f
6a
6b
6d
6e
6g
7a
C8H14N4O2
C10H18N4O2
C12H22N4O2
C16H26N4O2
C12H22N4O2
C9H16N4O2
C11H20N4O2
C13H24N4O2
C13H22N4O2
C15H26N4O2
C26H42N4O2
C14H26N4O2
C18H30N4O2
C14H26N4O2
C18H30N4O2
7b
7d
7e
7g
11a
11b
11c
11d
11e
11f
12d
12e
13d
13e

Synthesis of new chiral akylglycolurils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
701
Table 5. Spectroscopic characteristics of monoꢀ, diꢀ, triꢀ, and tetraalkylglycolurils
Glycolꢀ
uril
MS
m/z (I (%))
1H NMR
(δ, (DMSOꢀd6), J/Hz)
1a
1b
1c
170 (43), 155 (100), 126 (10),
112 (22), 85 (13)
1.03 (t, 3 H, СMe, J = 7.1); 2.98 (m, 1 H, СH2); 3.22 (m, 1 H, СH2);
5.19, 5.28 (both d, 1 H each, СHСH, J = 8.5); 7.28 (s, 2 H, 2NH);
7.45 (s, 1 H, NH)
0.80 (t, 3 H, СMe, J = 7.3); 1.45 (m, 2 H, СH2); 2.92, 3.10 (both m,
1 H each, NСH2); 5.19, 5.26 (both d, 1 H each, 2 СH, J = 6.8); 7.26 (s,
2 H, 2 NH); 7.42 (s, 1 H, NH)
0.79, 1.11 (both m, 3 H each, Me); 1.46 (m, 2 H, СH2); 3.59 (m, 1 H,
СH); 5.24 (m, 2 H, 2 СH); 7.20 (s, 1 H, NH); 7.25 (s, 1 H, NH);
7.33 (s, 1 H, NH)
184 (23), 155 (61), 112 (100),
86 (10), 84 (10), 82 (10),
73 (10), 69 (52)
1d
1e
1f
1.31 (s, 9 H, 3 Me); 5.10, 5.45 (both d, 1 H each, 2 СH, J = 8.1); 7.03
(br.s, 2 H, 2 NH); 7.23 (br.s, 1 H, NH)
1.18 (m, 4 H, 2 СH2); 1.60 (m, 6 H, 3 СH2); 3.38 (m, 1 H, N—СH);
5.24, 5.32 (both d, 1 H each, 2 СH, J = 7.7); 7.18, 7.22 7.32 (s, 1 H, NH)
0.87 (m, 3 H, СMe); 1.26 (br.s, 18 H, 9 СH2); 1.45 (m, 2 H, СH2);
2.95, 3.17 (both m, 1 H each, NСH2); 5.19, 5.24 (both d, 1 H each, 2 СH,
J = 8.3); 7.09 (br.s, 2 H, 2 NH); 7.30 (br.s, 1 H, NH)
0.96 (m, 3 H, Me); 2.52 (s, 3 H, NMe); 2.98 (m, 2 H, СH2); 5.12, 5.23
4a
4b
3
(both d, 1 H each, 2 СH, J = 8.5); 7.58 (br.s, 2 H, 2 NH)
169 (59), 126 (10), 113 (15),
112 (100), 85 (23), 84 (27),
71 (12), 69 (35)
0.80 (t, 3 H, СMe, J = 6.6); 1.45 (m, 2 H, СH2); 2.62 (s, 3 H, NMe);
3.00 (m, 2 H, NСH2); 5.10, 5.21 (both d, 1 H each, 2 СH, 3J = 8.5); 7.50
(br.s, 2 H, 2 NH)
4c
4d
0.78 (m, 3 H, СH2СH3); 1.10 (d, 3 H, СHСH3, J = 7.3); 1.49 (m, 2 H,
СH2); 2.61 (s, 3 H, NMe); 3.56 (m, 1 H, NCH); 5.19, 5.73 (both d,
1 H each, 2 СH, J = 8.6); 7.39 (s, 1 H, NH); 7.50 (br.s, 1 H, NH)
1.30 (s, 9 H, 3 СMe), 2.59 (s, 3 H, NMe); 4.97, 5.40 (both d, 1 H each,
2 СH, J = 7.9); 7.42, 7.52 (both s, 1 H each, NH)
198 (15), 197 (95), 156 (10),
154 (13), 141 (10), 140 (100),
114 (25), 113 (13), 112 (13),
98 (10), 97 (22), 84 (38),
71 (17), 67 (12), 59 (19)
4e
4f
183 (100), 140 (26), 126 (77),
84 (16), 83 (31), 73 (10),
71 (11), 70 (17), 69 (11)
1.11 (m, 4 H, 2 СH2); 1.62 (m, 6 H, 3 СH2); 2.58 (s, 3 H, NMe); 3.43
(m, 1 H, СH); 4.94, 5.37 (both d, 1 H each, 2 СH, J = 8.2); 7.33, 7.48
(both s, 1 H each, NH)
0.86 (m, 3 H, СMe); 1.23, 1.39 (both m, 2 H each, СH2); 2.62 (s, 3 H,
NMe); 3.08 (m, 2 H, NСH2); 5.10, 5.21 (both d, 1 H each, 2 СH, J = 7.9);
7.5 (br.s, 2 H, 2 NH)
6a
6b
1.03 (t, 6 H, 2 Me, J = 7.1); 3.00, 3.21 (both m, 2 H each, 2 СH2);
5.23 (s, 2 H, СHСH); 7.48 (br.s, 2 H, 2 NH)
0.81 (m, 6 H, 2 Me); 1.50 (m, 4 H, 2 ССH2); 2.98, 3.17 (both m, 1 H each,
NCH2); 5.18 (s, 2 H, СHСH); 8.00 (br.s, 2 H, 2 NH)
1.31 (s, 18 H, 6 Me); 5.24 (s, 2 H, СHСH); 8.08 (br.s. 2 H, 2 NH)
1.16 (m, 8 H, 4 СH2); 1.55 (m, 12 H, 6 СH2); 3.38 (m, 2 H, СH); 5.27
(s, 2 H, СHСH); 7.36 (br.s, 2 H, 2 NH)
6d
6e
225 (14), 220 (10), 167 (15),
166 (100), 163 (12), 142 (12),
141 (22), 138 (12), 112 (10),
99 (12), 98 (12), 84 (36),
83 (16), 81 (12), 73 (10),
71 (16), 69 (22), 67 (17)
6g
7a
7b
0.89 (m, 6 H, 2 Me); 1.32, 1.45 (both m, 4 H each, 2 СH2); 2.98 (m, 2 H,
СH2); 3.28 (m, 2 H, СH2); 5.26 (s, 2 H, СHСH); 7.51 (br.s, 2 H, 2 NH)
0.95 (m, 6 H, 2 Me); 2.97, 3.29 (both m, 2 H each, 2 СH2); 5.15, 5.35
(both d, 2 H each, СHСH, J = 8.3)
0.82 (m, 6 H, 2 Me); 1.51 (m, 4 H, 2 СH2); 3.10 (m, 2 H, СH2); 3.29
(m, 2 H, NСH2); 5.17, 5.32 (both d, 2 H each, СHСH, J = 7.7); 7.83
(br.s, 2 H, 2 NH)
(to be continued)

702
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Kravchenko et al.
Table 5 (continued)
Glycolꢀ
uril
MS
m/z (I (%))
1H NMR
(δ, (DMSOꢀd6), J/Hz)
7d
7e
7g
1.22 (s, 9 H, 3 CMe); 5.06, 5.41 (both d, 2 H each, СHСH, J =8.1); 7.32
(br.s, 2 H, 2 NH)
1.12 (m, 8 H, 4 СH2); 1.65 (m, 12 H, 6 СH2); 2.88 (m, 2 H, 2 СH); 5.15,
5.33 (both d, 2 H each, СHСH, J = 7.9); 7.28 (br.s, 2 H, 2 NH)
0.94 (m, 6 H, 2 Me); 1.35 (m, 4 H, 2 СH2); 1.47 (m, 4 H, 2 СH2); 3.11
(m, 2 H, СH2); 3.37 (m, 2 H, СH2); 4.99, 5.39 (both d, 2 H each, СHСH,
J = 7.4); 7.62 (br.s, 2 H, 2 NH)
11a
0.82 (t, 3 H, СMe, J = 7.6); 1.42 (m, 2 H, СH2); 2.76 (s, 6 H, 2 Me);
2.88 (s, 3 H, Me); 2.94, 3.12 (both m, 1 H each, NСH2); 5.19, 5.26 (both d,
1 H each, 2 СH, J = 7.0)
11b
11c
11d
1.35 (s, 9 H, 3 Me); 2.83 (s, 6 H, 2 Me); 2.85 (s, 3 H, Me); 5.41, 5.84
(both d, 1 H each, СHСH, J = 7.3)
1.13 (m, 4 H, 2 СH2); 1.71 (m, 6 H, 3 СH2); 2.85 (s, 6 H, 2 Me); 2.91 (s,
3 H, Me); 3.47 (m, 2 H, 2 СH); 5.39, 5.44 (both d, 1 H each, СHСH, J = 8.0)
1.00, 1.11 (both t, 3 H each, 2 Me, J = 6.7); 2.71 (s, 3 H, NMe); 1.37 (s, 9 H,
3 Me); 3.05 (m, 2 H, СH2); 3.40 (m, 2 H, СH2); 5.46, 5.90 (both d, 1 H each,
СHСH, J = 7.6)
11e
1.04 (m, 6 H, 2 СMe); 1.21 (m, 4 H, 2 СH2); 1.67 (m, 6 H, 3 СH2); 2.75
(s, 3 H, NMe); 3.14 (m, 3 H, 2 NCH2); 3.35 (m, 3 H, 2 NCH2); 5.13, 5.28
(both d., 1 H each, СHСH, J = 8.6)
11f*
1.58 (br.s, 6 H, 3 СH2(9,14,20)); 1.85 (s, 3 H, СH3(4)); 1.87 (br.s, 1 H,
С(19)H); 2.02 (m, 12 H, С(5)H2, C(6)H2, C(10)H2, C(11)H2, C(15)H2,
C(16)H2); 2.79 (s, 6 H, 2 NMe); 2.93 (s, 3 H, NMe); 3.74 (m, 3 H, С(1)H3);
5.09 (m, 5 H, С(7)H, C(12)H, C(17)H, СHСH); 5.20 (m, 3 H, С(2)H3)
1.35 (s, 18 H, 6 CMe); 2.80 (s, 6 H, NMe); 5.26 (s, 2 H, СHСH)
1.21 (m, 8 H, 4 СH2); 1.62 (m, 12 H, 6 СH2); 2.75 (s, 6 H, 2 Me); 3.27
(m, 1 H, СH); 3.37 (m, 1 H, СH); 5.14 (s, 2 H, СHСH)
12d
12e
334 (12), 252 (19), 180 (95),
170 (27), 127 (13), 113 (19),
99 (12), 98 (100), 85 (10),
83 (10), 82 (12), 69 (17)
13d
13e
1.21 (s, 18 H, 6 СMe); 2.72 (s, 6 H, NMe); 4.99, 5.39 (both d, 1 H each,
СHСH, J = 8.2)
1.19 (m, 8 H, 4 СH2); 1.72 (m, 12 H, 6 СH2); 2.80 (s, 6 H, 2 Me); 3.79 (m,
1 H, СH); 3.85 (s, 1 H, СH); 4.98, 5.25 (both d, 1 H each, СHСH, J = 8.4)
*
lution was added to a solution of methylurea 2h (0.02 mol) in
40% aqueous glyoxal (0.02 mol) to рH 4—5 (a universal indicaꢀ
tor). The reaction mixture was heated at 50 °C for 2 h. Then рH
of the reaction mixture was brought to 1 (with 18% aqueous
HCl) at the same temperature, 1,3ꢀdimethylurea (0.02 mol) was
added, and the reaction mixture was kept at 90 °C for 1 h. Then
the reaction mixture was cooled to room temperature and exꢀ
tracted with CHCl3 (0.5 volume of the reaction mixture was
added 10 times). The combined portions were concentrated to
an oily consistency and triturated with a mixture of diethyl ether
and ethyl acetate (in a ratio of 2 : 1). The precipitate of comꢀ
pound 10c was recrystallized from dioxane.
Synthesis of chiral glycolurils, viz., 2,6ꢀdiethylꢀ (6a),
2,6ꢀdipropylꢀ (6b), 2,6ꢀdiꢀtertꢀbutylꢀ (6d), 2,6ꢀdicyclohexylꢀ (6e),
2,6ꢀdibutylꢀ (6g), 2,6ꢀdimethylꢀ (6h), 2,6ꢀdiꢀtertꢀbutylꢀ4,8ꢀdiꢀ
methylꢀ (12d), and 4,8ꢀdicyclohexylꢀ2,6ꢀdimethylꢀ2,4,6,8ꢀtetraꢀ
azabicyclo[3.3.0]octaneꢀ3,7ꢀdione (12e), and achiral glycolurils,
viz., 2,8ꢀdiethylꢀ (7a), 2,8ꢀpropylꢀ (7b), 2,8ꢀdiꢀtertꢀbutylꢀ (7d),
2,8ꢀdicyclohexylꢀ (7e), 2,8ꢀdibutylꢀ (7g), 2,8ꢀdimethylꢀ (7h),
2,8ꢀdiꢀtertꢀbutylꢀ4,6ꢀdimethylꢀ (13d), and 4,6ꢀdicyclohexylꢀ2,8ꢀ

Synthesis of new chiral akylglycolurils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
703
Table 6. Selected crystallographic characteristics and parameters of structure refinement of 10a and 11c
Parameter
10а
11c
Molecular formula
M
T/K
C8H14N4O2
198.23
298
C13H22N4O2•1/2H2O
275.35
120
Diffractometer
Crystal system
Space group
Siemens P3/PC
Triclinic
Р1
Smart CCD
Monoclinic
C2/с
Z (Z´)
4 (2)
8 (1)
a/Å
b/Å
с/Å
α/deg
8.544 (2)
9.723 (2)
12.994 (3)
78.43 (3)
79.74 (3)
71.37 (3)
994.6 (3)
1.324
16.922 (3)
12.187 (2)
15.793 (3)
—
119.520 (3)
—
β/deg
γ/deg
V/Å3
2834.2 (8)
1.291
dcalc/g cm–3
µ/cm–1
0.98
0.91
F(000)
424
1192
2θmax/deg
54
60
Scanning mode
θ/2θ
ω
Number of measured reflections
4600
8637
(Rint
)
(0.0494)
4311
(0.0206)
4065
Number of independent reflections
Number of observed reflections
1706
2920
Number of parameters in refinement
268
269
R1
wR2
GOOF
0.0418
0.1875
0.870
0.0518
0.1276
1.007
Residual electron density
(emax/emin)/e Å–3
–0.118/0.112
–0.279/0.338
dimethylꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdione (13e)
(general procedure). Concentrated hydrochloric acid (0.2 mL;
in aqueous medium, рH 1) was added to a solution of the correꢀ
sponding urea 2 (2a,b,d,e,g,h) (0.02 mol) in water or isoproꢀ
panol (depending on the solubility) and 40% aqueous glyoxal
(0.01 mol) (in the synthesis of 12d,e and 13d,e, glyoxal diꢀ
hydrate (trimer) was added). The reaction mixture was kept
with stirring at 80—90 °C for 1 h. After cooling, the reaction
mixture was kept in a refrigerator for 48 h. Compound 6a
(6b,d,e,g,h) that precipitated was filtered off and recrystallized
from water. In all cases, the filtrate was concentrated to oneꢀhalf
of the initial volume and cooled at +4 °C for 12 h. The crystalꢀ
line precipitate of the corresponding compound 7 (7a,b,d,e,g,h)
was filtered off and recrystallized from a mixture of methanol
and water (5 : 2). Compounds 6 (6a,b,d,e,g,h) and 7 (7a,b,d,g,h)
were recrystallized from water.
structure of 10a were calculated geometrically. The hydrogen
atoms in the structure of 11c were revealed from difference
Fourier syntheses. All calculations were carried out using the
SHELXTL PLUS 5.0 program package.29
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ33257)
and the Russian Academy of Sciences (Program "Fundaꢀ
mental Studies in Medicine").
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Received November 23, 2004