4,5-Dihydroxyimidazolidin-2-ones in a-ureidoalkylation of N-carboxy-, N-hydroxy-, and N-aminoalkylureas 2. α-Ureidoalkylation of N-(hydroxyalkyl)ureas

Article abstract of DOI:10.1007/s11172-009-0165-5

sThe a-ureidoalkylation of N-(hydroxyalkyl)ureas (ureido alcohols) with 1,3-H₃-and 1,3-Me₂-4,5-dihydroxyimidazolidin-2-ones was systematically studied. The yields of glycolurils decrease both in going from 1,3-H₂-to 1,3-Me₂-4,5-dihydroxyimidazolidin-2-one and with increasing length (or with branching) of the hydroxyalkyl chain in ureido alcohols. The optimal reaction time for ureido alcohols is 1 h. The X-ray diffraction study showed that 2-(2-hydroxy-1,1-dimethylethyl)glycoluril crystallizes as a conglomerate. The enantiomeric analysis of 2-(2-hydroxyethyl)glycoluril was carried out by chiral-phase HPLC. ; 2009 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s11172-009-0165-5

Russian Chemical Bulletin, International Edition, Vol. 58, No. 6, pp. 1264—1269, June, 2009
1264
4,5ꢀDihydroxyimidazolidinꢀ2ꢀones in αꢀureidoalkylation
of Nꢀcarboxyꢀ, Nꢀhydroxyꢀ, and Nꢀaminoalkylureas
2.* αꢀUreidoalkylation of Nꢀ(hydroxyalkyl)ureas**
A. N. Kravchenko,a A. S. Sigachev,a P. A. Belyakov,a M. M. Ilyin,b K. A. Lyssenko,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 (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(hydroxyalkyl)ureas (ureido alcohols) with 1,3ꢀH2ꢀ and
1,3ꢀMe2ꢀ4,5ꢀdihydroxyimidazolidinꢀ2ꢀones was systematically studied. The yields of glycolurils
decrease both in going from 1,3ꢀH2ꢀ to 1,3ꢀMe2ꢀ4,5ꢀdihydroxyimidazolidinꢀ2ꢀone and with
increasing length (or with branching) of the hydroxyalkyl chain in ureido alcohols. The
optimal reaction time for ureido alcohols is 1 h. The Xꢀray diffraction study showed that
2ꢀ(2ꢀhydroxyꢀ1,1ꢀdimethylethyl)glycoluril crystallizes as a conglomerate. The enantiomeric
analysis of 2ꢀ(2ꢀhydroxyethyl)glycoluril was carried out by chiralꢀphase HPLC.
Key words: Nꢀ(hydroxyalkyl)glycolurils, 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones, Nꢀ(hydroxyꢀ
alkyl)ureas (ureido alcohols), racemates, enantiomers, conglomerate, Xꢀray diffraction and
enantiomeric analysis.
Since glycolurils (2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ
ureido alcohols) with 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones
(DHI).6,7
3,7ꢀdiones) belong to a new class of psychotropic comꢀ
pounds,2—4 the development of procedures for the enanꢀ
tiomeric resolution of glycolurils is necessary for the
design of optically pure drugs. The formation of conꢀ
glomerates (mixtures of enantiomerically pure crystals) is
the simplest way of preparing enantiomerically pure comꢀ
pounds. As has been demonstrated in our previous study,1
one of approaches to the synthesis of glycolurils capable
of crystallizing as conglomerates could be based on the
functionalization of the substituents at the nitrogen atoms
by introducing such groups that can be involved in hydroꢀ
gen bonding (for example, carboxy, hydroxy, or amino
groups). We have thoroughly developed this approach
based on the synthesis of Nꢀ(carboxyalkyl)glycolurils,
among which we have found two conglomerates.1,5 To
search for new conglomerates among glycolurils, it is of
interest to introduce hydroxyalkyl groups at the nitrogen
atoms of glycolurils. Previously, we have synthesized
several representatives of this type of compounds by the
αꢀureidoalkylation of Nꢀ(hydroxyalkyl)ureas (hereinafter,
With the aim of extending the range of conglomerateꢀ
forming glycolurils, in the present study we investigated
in detail the αꢀureidoalkylation of ureido alcohols using
various DHI as ureidoalkylating agents and developed
an optimal procedure for the preparation of Nꢀ(hydroxyꢀ
alkyl)glycolurils.
Some Nꢀ(carboxylalkyl)glycolurils are known to exist
as conglomerates. The latter were prepared with the use
of 1,3ꢀH2ꢀ and 1,3ꢀMe2ꢀDHI. Hence, Nꢀ(hydroxyalkyl)ꢀ
glycolurils 1a—l were synthesized by the αꢀureidoalkylꢀ
ation of ureido alcohols 2a—g with DHI 3a,b at 85 °C in
an aqueous medium at pH 1—2 (Scheme 1).
The results of research on the dependence of the yields
of compounds 1a—l on the reaction time and the characꢀ
ter of substitution at the nitrogen atoms of 4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀones 3a,b and in ureido alcohols 2a—g,
as well as on the lengths and branching of the alkyl chain
in ureido alcohols, are presented in the diagram (Fig. 1).
The dependence of the yield of Nꢀ(hydroxyalkyl)glycolꢀ
urils 1 on the reaction time was investigated with the
use of the most readily accessible ureido alcohol 2a and
4,5ꢀdihydroxyimidazolidinꢀ2ꢀone 3a. The investigation
showed that the yield of 1a is 55% (1 h), 56% (2 h), and
* For Part 1, see Ref. 1.
** Dedicated to Academician O. N. Chupakhin on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1229—1233, June, 2009.
1066ꢀ5285/09/5806ꢀ1264 © 2009 Springer Science+Business Media, Inc.

αꢀUreidoalkylation of Nꢀ(hydroxyalkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1265
Scheme 1
Y (%)
55
1
2
3
4
54
50
49
46
45
46
43
40
42
38
34
30
26
40
35
34
31
30
24
1a 1i 1f 1j 1b 1c 1k 1g 1l 1d 1e 1h
Fig. 1. Diagram of the yields (Y) of Nꢀ(hydroxyalkyl)glycolurils
1a—l (average values) versus the character of substitution at the
nitrogen atoms of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones 3a,b and
the length and branching of the alkyl chain in ureido alcohols
2a—g: 1, 3a + ureido alcohol, 2, 3a + Nꢀmethylureido alcohol,
3, 3b + ureido alcohol, 4, 3b + Nꢀmethylureido alcohol.
i. pH 1—2, 1 h, 85 °C
Compound
1a
1b
1c
1d
1e
1f
R1
H
H
H
H
R2
(CH2)2OH
(CH2)3OH
CMe2CH2OH
CHEtCH2OH
(CH2)2C6H4OHꢀp
(CH2)2OH
CMe2CH2OH
(CH2)2C6H4OHꢀp
(CH2)2OH
CMe2CH2OH
(CH2)2OH
CMe2CH2OH
(CH2)2OH
(CH2)3OH
CMe2CH2OH
CHEtCH2OH
(CH2)2C6H4OHꢀp
(CH2)2OH
CMe2CH2OH
—
R3
H
H
H
H
and 1k (40%), and of 1j (30%) and 1l (24%) confirms that
the branching of the alkyl substituents in ureido alcohols
2 results in a decrease in the yields of glycolurils 1. The
replacement of the hydroxyalkyl substituent in ureido
alcohols by the pꢀhydroxyphenylethyl substituent (2e)
leads to a slight decrease (1a (55%) and 1e (49%)) or to
no decrease (1f (34%) and 1h (35%)) in the yields of the
corresponding glycolurils 1e,h. All the processes under
consideration were accompanied by the formation of the
well known hydantoins 4a,b as byꢀproducts that were
formed through the pinacol rearrangement of DHI 3a,b.4
We did not isolate compounds 4a,b, but they were detected
H
H
H
Me
Me
Me
H
1g
1h
1i
1j
1k
H
H
Me
Me
Me
Me
H
H
Me
Me
—
—
—
—
—
—
—
H
1l
2a
2b
2c
H
H
2d
2e
2f
2g
3a
3b
4a
4b
H
H
1
by H NMR spectroscopy of the oily residues obtained
Me
Me
—
—
—
—
after the removal of the solvent from the mother liquors.
Hence, the yield of glycolurils 1 in the αꢀureidoꢀ
alkylation of ureido alcohols 2 decreases with increasing
length and branching of the alkyl chain in the hydroxyalkyl
substituents of these ureido alcohols, as well as in the
presence of an alkyl substituent at the second nitrogen
atom of the starting ureido alcohol and the methyl groups
in DHI.
To examine the ability of glycolurils 1 to crystallize as
conglomerates, we studied the crystallization of these
compounds from 50% aqueous methanol, anhydrous
methanol, chloroform, and ethyl acetate and investigated
the complexation of some glycolurils 1 with transition
metal salts. The crystallization of glycolurils 1 did not give
crystals suitable for Xꢀray diffraction; in all cases we
obtained powders. In attempting to prepare the coordinaꢀ
tion compound of glycoluril 1c with CdCl2, we carried
out the reaction under the conditions analogous to those
used in the synthesis of the complexes (80 °C, 1.5 h, H2O
instead of EtOH as the solvent)8 during 2 days and isoꢀ
—
—
—
Me
H
Me
58% (3 h), i.e., the yield increases only slightly with time.
Hence, all subsequent studies were carried out by storing
the reaction mixtures for 1 h. The reactions of ureido
alcohols 2a and 2b containing the hydroxyethyl and
hydroxypropyl substituent, respectively, with 4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀone 3a afford glycolurils in 55% (1a) and
40% (1b) yields, respectively, which indicates that the
yields of Nꢀ(hydroxyalkyl)glycolurils substantially decrease
with increasing length of the hydroxyalkyl substituent in
ureido alcohols. A comparison of the yield of glycoluril 1a
(55%) with the yields of 1c (46%) or 1d (43%) shows that
the use of ureido alcohols 2c or 2d containing branched
hydroxyalkyl substituents in these reactions leads to a
decrease in the yield of glycolurils. A comparison of the
yields of glycolurils 1f (34%) and 1g (31%), of 1i (45%)

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Kravchenko et al.
O(3)
O(1W)
O(1W)
C(5)
C(1)
N(2)
C(2N)
C(3N)
N(6)
N(8)
N(4)
C(7)
C(3)
O(1)
O(2)
C(4N)
Fig. 2. Molecular structure of hydrate 1c.
Fig. 3. Fragment of the hydrogenꢀbonded homochiral layer in
the crystal structure of 1c.
lated transparent crystals from the mother liquor. The
melting point of these crystals differs by 80 °C from that
of the starting racemic compound 1c. Nevertheless, the
IR spectroscopic data did not provide evidence for
the formation of the complex. The singleꢀcrystal Xꢀray
diffraction study showed that the compound thus obtained
is the starting glycoluril 1c crystallized as a solvate in
the chiral space group P212121 (Z = 4, Z´ = 1) (Fig. 2,
Table 1). The principal geometric parameters of 1c are
similar to the expected values.1,5,9,10 The fiveꢀmembered
rings C(1)N(2)C(3)N(4)C(5) and C(1)C(5)N(6)C(7)N(8)
adopt an envelope conformation with the N(4) and C(1)
atoms, respectively, deviating from the mean planes by
0.10 and 0.12 Å, respectively.
In the crystal, the molecules are linked by N—H...O
hydrogen bonds (N...O, 2.724(2)—2.931(2)A) to form
homochiral layers having pores of a size of 6.49Ѕ9.28 Å.
The pores are occupied by water molecules hydrogenꢀ
bonded to the C=O groups of 1c and to the hydroxy
groups of the molecules from the adjacent layers, resultꢀ
ing in the formation of a threeꢀdimensional framework
(Fig. 3).
In this case, the unexpected formation of the conꢀ
glomerate can be attributed to the influence of CdCl2 on
the kinetics of the growth of homoꢀ and heterochiral crysꢀ
tals of 1c. Thus, CdCl2 can inhibit the growth of racemic
crystals due to the coordination to the molecules on its
surface. Similar effects were considered in detail for the
crystal growth of amino acids.11 The role of the reversible
complexation with CdCl2, which can preorganize the
molecules through the formation of supramolecular assoꢀ
ciates favorable for the growth of homochiral crystals,
cannot be ruled out as well. Since the solution of this
problem requires information on the structural features
(including the morphology, the energy of the faces, etc.)
of both homochiral and heterochiral crystals, it is nowaꢀ
days impossible to reveal with certainty the role of CdCl2.
We plan to consider this problem in the future.
Racemic Nꢀ(hydroxyalkyl)glycolurils, which do not
form conglomerates, were resolved by chiralꢀphase HPLC.
We have used this method for the first time for the enanꢀ
tiomeric analysis of functionalized glycolurils in the case
of Nꢀ(carboxyalkyl)glycolurils. In spite of considerable
technical difficulties, which have been discussed in detail
in the study,1 we examined the possibility of the use of
chiralꢀphase HPLC for Nꢀ(hydroxyalkyl)glycolurils.
Electrostatic interactions between the acidic group and
the tertiary nitrogen atom of the quinuclidine residue of
the quinine alkaloid, which is used as a chiral selector for
the HPLC phase ProntoSIL Chiral AX QNꢀ1 (Bischoff,
Germany), proved to be useful in the case of Nꢀ(carbꢀ
oxyl)ꢀcontaining compounds. The ionꢀexchange mode of
chromatography is provided by the presence of competꢀ
ing ions of acetic acid and ammonium acetate in the
methanol eluent. Hydroxylꢀcontaining glycoluril 1a inꢀ
capable of electrostatic binding is not retained on the phase
ProntoSIL Chiral AX QNꢀ1 and is not resolved even in
pure MeOH. In 50% aqueous MeOH, racemate 1a was
unexpectedly easily resolved on a Chirobiotic TAG column
(250×4 mm; Advanced Separation Technologies Inc.,
Table 1. Selected bond lengths (d) and bond angles (ω) in the
structure of 1c
Bond
d/Å
Bond angle
ω/deg
O(1)—C(3)
C(1)—N(8)
C(1)—N(2)
C(1)—C(5)
1.235(2) N(8)—C(1)—N(2) 114.56(17)
1.452(3) N(8)—C(1)—C(5) 102.99(16)
1.456(3) N(2)—C(1)—C(5) 103.25(16)
1.568(3) C(3)—N(2)—C(1) 111.28(16)
C(1N)—N(2) 1.486(3) O(1)—C(3)—N(4) 123.94(19)
N(2)—C(3)
O(2)—C(7)
C(3)—N(4)
N(4)—C(5)
C(5)—N(6)
N(6)—C(7)
C(7)—N(8)
1.365(3) O(1)—C(3)—N(2) 126.46(19)
1.239(2) N(4)—C(3)—N(2) 109.58(17)
1.359(3) C(3)—N(4)—C(5) 112.28(17)
1.440(3) C(7)—N(6)—C(5) 113.35(18)
1.448(3) C(7)—N(8)—C(1) 112.10(18)
1.348(3)
1.363(3)

αꢀUreidoalkylation of Nꢀ(hydroxyalkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1267
Table 2. Yields, melting points, 1H NMR spectroscopic data (DMSOꢀd6), and elemental analysis data for Nꢀ(hydroxyalkyl)glycolurils
Comꢀ M.p.
pound /°С
Found
Calculated
Molecular
formula
δ (J/Hz)
(%)
C
H
N
1a*
1b
172—1737
139—141 42.02 6.01 28.02 C7H12N4O3 1.57 (m, 2 Н, СН2); 2.98 (m, 1 Н, СН2); 3.16 (m, 1 Н, СН2);
42.00 6.04 27.99
3.36 (m, 2 Н, СН2); 4.42 (m, 1 Н, ОН); 5.17, 5.24 (both d, 2 Н,
2 СН, J = 7.9); 7.25 (br.s, 2 Н, 2 NH); 7.40 (br.s, 1 Н, NH)
1c*
227—2297
1d
338—340 44.88 6.60 26.12 C8H14N4O3 0.80 (m, 3 Н, С—СН3); 1.38, 1.47 (both m, 1 Н each, С—СН2);
44.85 6.59 26.15
3.19, 3.53 (both, 1 Н each, СН2—ОН); 4.42 (m, 1 Н, ОН);
5.18, 5.32 (both d, 1 Н each, 2 СН, J = 7.9); 7.17 (br.s, 3 Н, 3 NH)
1e
302—305 54.99 5.41 21.35 C12H14N4O3 2.58, 2.78 (both m, 1 Н each, СН2); 3.18, 3.51 (both m, 1 Н each, СН2);
54.96 5.38 21.36
4.45 (br.s, 1 Н, ОН); 5.07, 5.12 (both d, 1 Н each, 2 СН, J = 8.3);
6.71, 6.97 (both d, 2 Н each, 4 СН, J = 8.7); 7.42 (br.s, 2 Н, 2 NH);
7.62 (br.s, 1 Н, NH)
1f
160—162 44.84 6.57 26.13 C8H14N4O3 2.70 (s, 2 Н, СН3); 2.83 (s, 6 Н), 2.60 (s, 3 Н, СН3); 2.68 (s, 3 Н,
44.85 6.59 26.15
СН3); 3.02 (m, 2 Н, СН2); 3.53 (m, 2 Н, СН2); 4.07 (br.m, 1 Н, ОН);
5.07, 5.59 (both d, 1 Н each, 2 СН, J = 6.6); 6.60 (br.s, 1 Н, NH)
1g
1h
198—200 49.59 7.51 23.11 C10H18N4O3 1.20 (s, 3 Н, СН3); 1.21 (s, 3 Н, СН3); 2.71 (s, 3 Н, СН3); 2.84
49.57 7.49 23.13
(s, 3 Н, СН3); 3.40, 3.62 (both m, 1 Н each, СН2); 4.85 (m, 1 Н, ОН);
5.11, 5.44 (both d, 1 Н each, 2 СН, J = 8.0); 7.25 (br.s, 1 Н, NH)
289—291 57.91 6.27 19.32 C14H18N4O3 2.60, 2.77 (both m, 1 Н each, СН2); 2.62 (s, 3 Н, СН3); 2.79 (s, 3 Н,
57.92 6.25 19.30
СН3); 3.17, 3.48 (both m, 1 Н each, СН2), 4.43 (br.s, 1 Н, ОН); 5.03,
5.11 (both d, 1 Н each, 2 СН, J = 8.5); 6.67, 7.00 (both d, 2 Н each,
4 СН, J = 8.6); 7.62 (br.s, 1 Н, NH)
1i**
142—1446 41.98 6.06 28.01 C7H12N4O3
42.00 6.04 27.99
1j
211—212 47.37 7.10 24.52 C9H16N4O3 1.24, 1.26 (both s, 3 Н each, 2 CH3); 2.78 (s, 3 Н, СН3);
47.36 7.07 24.55
3.29, 3.65 (both m, 1 Н each, СН2); 4.82 (m, 1 Н, ОН); 5.10, 5.54
(both d, 1 Н each, 2 СН, J = 8.0); 7.23 (br.s, 2 H, 2 NH)
1k
1l
135—137 47.33 7.05 24.53 C9H16N4O3 2.70 (s, 3 Н, СН3); 2.83 (br.s, 6 Н, 2 СН3); 3.15 (m, 1 Н, СН2);
47.36 7.07 24.55
3.53 (m, 1 Н, СН2); 3.70 (m, 2 Н, 2 СН2); 4.91 (br.m, 1 Н, ОН);
5.09, 5.84 (both d, 1 Н each, 2 СН, J = 7.2)
184—186 51.53 7.88 21.85 C11H20N4O3 1.23 (s, 3 Н, СН3); 1.26 (s, 3 Н, СН3); 2.69 (s, 3 Н, СН3); 2.72
51.55 7.87 21.86
(s, 3 Н, СН3); 2.80 (s, 3 Н, СН3); 3.42, 3.61 (both m, 1 Н each, СН2);
4.91 (m, 1 Н, ОН); 5.02, 5.61 (both d, 1 Н each, 2 СН, J = 8.1)
1
* The H NMR spectrum and the elemental analysis data have been published earlier.7
** 1H NMR spectrum was published in the study.6
U/mV
54
USA), in which the macrocyclic antibiotic Teicoplanin
Aglycone with eight chiral centers covalently bound to
silica gel was used as the sorbent (UV detector, 206 nm)
(Fig. 4). On the contrary, glycoluril 1a was not retained
and not resolved on the ligandꢀexchange sorbent with the
copper complex of Nꢀdecylhydroxyproline in aqueous
methanol. Evidently, the ability of 1a to form the chelate
complex with copper is very low.
To sum up, the systematic study of the αꢀureidoꢀ
alkylation of 4,5ꢀdihydroxyimidazolidinꢀ2ꢀones with
ureido alcohols showed that the yields of Nꢀ(hydroxyꢀ
alkyl)glycolurils depend on the reaction time and the charꢀ
acter of substitution at the nitrogen atoms of 4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀones, as well as on the length and branchꢀ
ing of the alkyl chain in ureido alcohols. The general
procedure was developed for the synthesis of the target
48
42
36
30
24
18
12
6
0
—6
1
2
3
4
5
6
7
8
9
10 11 12 t/min
Fig. 4. Chromatogram of glycoluril 1a.

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Kravchenko et al.
volume and then kept in a refrigerator for 12 h. The precipitate
of 1a (1b—j) that formed was filtered off and crystallized from
water. The reaction mixture containing 1f (1g) was concenꢀ
trated to the oily state and triturated with MeOH. The precipiꢀ
tate of 1f (1g) that formed was filtered off and crystallized from
MeOH. Glycolurils 1k,l were extracted with CHCl3, and the
extracts were concentrated to dryness. 2ꢀ(3ꢀHydroxyethyl)ꢀ (1a),
2ꢀ(3ꢀhydroxypropyl)ꢀ (1b), 2ꢀ(2ꢀhydroxyꢀ1,1ꢀdimethylethyl)ꢀ
(1c), 2ꢀ(1ꢀ(hydroxymethyl)propyl)ꢀ (1d), 2ꢀ(2ꢀ(4ꢀhydroxyꢀ
phenyl)ethyl)ꢀ (1e), 6ꢀ(2ꢀhydroxyethyl)ꢀ2,4ꢀdimethylꢀ (1f),
glycolurils. The ability of glycolurils to form conglomerꢀ
ates was investigated. The Xꢀray diffraction study showed
that 2ꢀ[2ꢀhydroxyꢀ1,1ꢀ(dimethyl)ethyl]glycoluril (1c)
crystallizes as the conglomerate. The enantiomeric analyꢀ
sis of 2ꢀ(2ꢀhydroxyethyl)glycoluril (1a) was carried out
by chiralꢀphase HPLC.
Experimental
6ꢀ(2ꢀhydroxyꢀ1,1ꢀdimethylethyl)ꢀ2,4ꢀdimethylꢀ
(1g),
6ꢀ(2ꢀ(4ꢀhydroxyphenyl)ethyl)ꢀ2,4ꢀdimethylꢀ (1h), 2ꢀ(2ꢀhyꢀ
droxyꢀ1,1ꢀdimethylethyl)ꢀ4ꢀmethylꢀ (1j), 2ꢀ(2ꢀhydroxyethyl)ꢀ
4,6,8ꢀtrimethylꢀ (1k), and 2ꢀ(2ꢀhydroxyꢀ1,1ꢀdimethylethyl)ꢀ
4,6,8ꢀtrimethylꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdiones
(1l) were synthesized.
Amino alcohols, urea, dimethylurea, and 40% aqueous
glyoxal were commercially available (Acros). Ureido alcohols
2a—e were synthesized by the reaction of the corresponding
amino alcohols with KOCN according to procedures described
in the literature.7 1ꢀMethylureido alcohols 2f,g were syntheꢀ
sized by the reactions of the corresponding amino alcohols with
MeCNO according to the procedure used for the synthesis of
1ꢀalkylꢀ3ꢀmethylureas.12 4,5ꢀDihydroxyimidazolidinꢀ2ꢀones
3a,b were synthesized by the reactions of the corresponding
ureas with glyoxal according to known procedures.13,14
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).
The physicochemical characteristics and the elemental
analysis data for compounds 1a—l are given in Table 2.
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”).
References
Xꢀray diffraction data. Crystals of 1c (C8H16N4O4,
M = 232.25) are rhombic, space group P212121 at 120 K
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a = 9.1423(16) Å, b = 10.6687(18) Å, c = 10.9582(18) Å,
3
V = 1068.8(3) Å , Z = 4 (Z´ = 1), dcalc = 1.443 g cm–3
,
μ(MoꢀKα) = 1.16 cm–1, F(000) = 496. The intensities of 14444
reflections were measured on a Bruker SMART 1000 CCD
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2θ < 60°), and 1786 independent reflections (Rint = 0.0354)
were used in the refinement. The structure was solved by direct
methods and refined with anisotropic and isotropic displaceꢀ
ment parameters by the fullꢀmatrix leastꢀsquares method based
on F2. The hydrogen atoms were located in difference Fourier
maps and refined isotropically. The final R factors for 1c were
wR2 = 0.1044 and GOOF = 1.110 for all independent reflections
(R1 = 0.0513 based on F for 1578 observed reflections with
I > 2σ(I)). All calculations were carried out with the use of the
SHELXTL PLUS 5.0 program package.15
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out in 50% aqueous MeOH with the UV detection at 210 nm.
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was added (in an aqueous medium to pH 1 of the reaction
mixture) to a solution of the corresponding ureido alcohol 2a
(2b—g) (0.02 mol) and the corresponding 1,3ꢀH2ꢀ or 1,3ꢀMe2ꢀ
4,5ꢀdihydroxyimidazolidinꢀ2ꢀone (3a,b) (0.02 mol) in a miniꢀ
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formed upon the storage of the reaction mixture in a refrigerator
for 10 h and then crystallized from H2O. The reaction mixture
containing 1a (1b—g) was concentrated to oneꢀhalf of the initial

αꢀUreidoalkylation of Nꢀ(hydroxyalkyl)ureas
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Received July 10, 2008;
in revised form December 16, 2008