Synthesis of 2-monofunctionalized 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7- diones

Article abstract of DOI:10.1023/A:1022473004714

New (1R*,5S*)-2-R-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7- diones containing the terminal carboxy or hydroxy group in the substituent R were synthesized by cyclocondensation of 4,5-dihydroxyimidazolidin-2-one with 1-R-ureas. Single-crystal X-ray diffraction analysis showed that 2-carboxyethyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione crystallizes as a racemate.

Full text of DOI:10.1023/A:1022473004714

192
Russian Chemical Bulletin, International Edition, Vol. 52, No. 1, pp. 192—197, January, 2003
Synthesis of 2ꢀmonofunctionalized
2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdiones
a
a
a
a
A. N. Kravchenko,a E. Yu. Maksareva, P. A. Belyakov, A. S. Sigachev, K. Yu. Chegaev,
ꢀ
K. A. Lyssenko,b O. V. Lebedev,a and N. N. Makhovaa
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@xrlab.ineos.ac.ru
New (1R*,5S*)ꢀ2ꢀRꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdiones containing the terꢀ
minal carboxy or hydroxy group in the substituent R were synthesized by cyclocondensation of
4,5ꢀdihydroxyimidazolidinꢀ2ꢀone with 1ꢀRꢀureas. Singleꢀcrystal Xꢀray diffraction analysis
showed that 2ꢀcarboxyethylꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdione crystallizes as a
racemate.
Key words: synthesis, 2ꢀmonofunctionalized 2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀ
diones, glycolurils, carboxyꢀ and hydroxyalkyl groups, racemate, Xꢀray diffraction analysis.
Earlier, we have demonstrated that Nꢀsubstituted biꢀ
Chiral 2,6ꢀdimethylꢀ and diethylglycolurils form conꢀ
glomerates and, consequently, these compounds are caꢀ
pable of spontaneous separation into enantiomers.5,6 The
preparation of individual enantiomers is necessary for the
design of chiral drugs.7
The present study was aimed at synthesizing new types
of chiral glycolurils, viz., 2ꢀmonosubstituted derivatives 1
containing functional groups (COOH or OH)* in the subꢀ
stituents. Only diꢀ and tetraꢀNꢀhydroxymethyl derivatives
of glycolurils containing similar substituents were deꢀ
scribed in the literature.9 Data on the synthesis of monoꢀ
Nꢀhydroxymethylglycolurils are lacking. A series of
2ꢀNꢀmonoalkylglycolurils (R = Me,6,10 Et,6 Pr,6 Bu,11 or
CH2Ph6,10,12) were synthesized as powders, whereas their
highꢀquality crystals were not prepared.6
cyclic bisꢀureas represent a new promising class of comꢀ
pounds possessing psychoꢀ and cardiotropic activities.1,2
2,4,6,8ꢀTetramethylꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]ocꢀ
taneꢀ3,7ꢀdione belonging to bicyclic bisꢀureas of the ocꢀ
tane series, viz., 2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀ
diones (glycolurils), has been already integrated into mediꢀ
cal practice as a daytime tranquilizer (Mebicar).2 Other
glycolurils exhibiting various psychotropic activities were
also synthesized. Due to rigidity of the heterocyclic core
and cisꢀfusion of the fiveꢀmembered rings, these comꢀ
pounds adopt a conformation of a halfꢀopen book.3,4 Beꢀ
cause of this, many glycoluril derivatives contain the asymꢀ
metric C(1) and C(5) atoms. Only glycolurils having a
symmetry plane (σ1 or σ2, Fig. 1) are achiral.
Derivatives of type 1 are of interest as potential physiꢀ
ologically active compounds and synthons for the conꢀ
struction of compounds containing fragments of glycolꢀ
urils and other biologically active compounds.13 In addiꢀ
tion, one would expect that the introduction of functional
groups into the alkyl substituents will facilitate the prepaꢀ
ration of crystals suitable for Xꢀray diffraction analysis and
allow one to elucidate their ability to form conglomerates.
Compounds 1a—g were synthesized by condensation
of monosubstituted ureas 2 with 4,5ꢀdihydroxyimidꢀ
azolidinꢀ2ꢀone (3) (Scheme 1).
* The synthesis of some of these compounds has been described
earlier.8
Fig. 1. Symmetry planes in glycolurils.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 180—185, January, 2003.
1066ꢀ5285/03/5201ꢀ192 $25.00 © 2003 Plenum Publishing Corporation

Functionalization of glycolurils
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 1, January, 2003
193
Scheme 1
Table 1. Yields and selected characteristics of 2ꢀmonosubstiꢀ
tuted glycolurils 1a—g
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular
formula
(%)
C
H
N
1a
1b
1c
1d
1e
1f
60 273—275 35.87 4.03 28.04 С6Н8N4O4
36.00 4.03 27.99
58 215—217 37.72 4.92 25.16 C7H10N4O4•
37.67 4.97 25.10 •0.5 Н2О
58 145—147 42.12 5.41 24.61 C8H12N4O4
42.10 5.30 24.55
52 220—222 44.46 5.77 23.20 C9H14N4O4
44.63 5.83 23.13
40 251—252 37.38 4.40 27.18 C8H11N5O5
37.36 4.31 27.23
55 172—173 38.80 5.45 30.11 C6H10N4O3
38.71 5.41 30.09
R = CH2COOH (a), (CH2)2COOH (b), (CH2)3COOH (c),
(CH2)4COOH (d), CH2C(O)NHCH2COOH (e), (CH2)2OH (f),
CMe2CH2OH (g)
1g
47 227—229 44.91 6.63 26.13 C8H14N4O3
44.85 6.59 26.15
We intended to introduce fragments of amino acids
(glycine, βꢀalanine, γꢀaminobutyric, and δꢀaminovaleric
acids), dipeptide (glycylglycine), and amino alcohols
(ethanolamine and 2ꢀhydroxy(1,1ꢀdimethyl)ethylamine)
into ureas 2a—g. The most general procedure for the
preparation of compounds 2 involves the reactions of urea
with the corresponding amino acids14 or amino alcohols.15
According to the known data, these reactions are carꢀ
ried out in a concentrated alkaline solution (∼50%) at
110—140 °C during several hours. In addition, the proceꢀ
dure for the synthesis of mono(2ꢀhydroxyalkyl)ureas 2f,g
by the reaction of nitrourea with ethanolamine or 2ꢀhydrꢀ
oxy(1,1ꢀdimethyl)ethylamine (at 100—170 °C in argon)
was covered by a patent.16 Ureas based on glycine and
βꢀalanine were also prepared by Nꢀcarbomoylation of
amino acids with KOCN at 40—50 °C and pH 7—10 for
5—15 h.17 We modified the latter method and applied it
to the synthesis of ureas 2a—g (see Scheme 1). The reacꢀ
tions of KOCN with amino acids, dipeptide, and amino
alcohols were carried out on refluxing in water for
20—30 min. Under these conditions, ureido acids 2a—e
and ureas 2f,g were obtained in virtually quantitative
yields.
Cyclocondensation of substituted ureas 2a—g with
imidazolidinone 3 was carried out in a aqueousꢀacidic
medium for 1 h (see Scheme 1). Compounds 1a—e preꢀ
cipitated from the reaction mixtures upon cooling. After
recrystallization from water, these compounds were obꢀ
tained in 40—60% yields (Table 1). Compounds 1f,g were
isolated only after the removal of water and recrystallizaꢀ
tion from a MeOH—AcOEt mixture.
The structures of products 1a—g were confirmed by
the results of elemental analysis and spectroscopic data
(Tables 1 and 2, respectively). The IR spectra of the reꢀ
sulting compounds have characteristic intense absorption
bands of the CO groups in the region of 1640—1740 cm–1
Table 2. Spectroscopic characteristics of compounds 1a—g
Compound
IR,
ν/сm–1
1H NMR (DMSOꢀd6),
MS,
m/z (Irel (%))
δ (J/Hz)
(1R*,5S*)ꢀ(3,7ꢀDioxoꢀ
2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octꢀ2ꢀ
yl)ethanoic acid
(1a)
624, 652, 700, 744, 760,
768, 804, 824, 848, 888,
896, 904, 920, 960, 1032,
1108, 1128, 1136, 1160,
1232, 1284, 1308, 1324,
1344, 1380, 1404, 1432,
1456, 1464, 1500, 1560,
1648, 1676, 1700, 1712,
2536, 2688, 2928, 3032, 3256
3.64, 4.00 (both d, 1 H each, СН2, 200 [М]+ (2), 159 (2),
J = 18.2); 5.27 (s, 2 Н, CHCH);
7.24, 7.26, 7.50
142 (8), 129 (4), 113 (52),
112 (34), 99 (24), 84 (24),
70 (19), 58 (100), 56 (52),
55 (34)
(all s, 1 H each, 3 NH);
12.72 (br.s, 1 Н, COOH)
(to be continued)

194
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 1, January, 2003
Kravchenko et al.
Table 2 (continued)
Compound
IR,
ν/сm–1
1H NMR (DMSOꢀd6),
MS,
m/z (Irel (%))
δ (J/Hz)
214 [М+ – 0.5 Н2О] (3),
171 (9), 153 (38), 125 (38),
112 (38), 99 (63), 84 (66),
70 (22), 59 (10), 55 (100)
ꢀ
2.50 (m, 2 Н, СН2СО);
(1R*,5S*)ꢀ3ꢀ(3,7ꢀDioxoꢀ
2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octꢀ2ꢀ
yl)propanoic acid
(1b)
608, 672, 708, 736, 752,
768, 800, 808, 848, 884,
3.22, 3.42 (both m, 2 H, NСН2);
3
896, 920, 976, 1056, 1068,
1096, 1120, 1132, 1156, 1204,
1228, 1252, 1296, 1328, 1344,
1360, 1400, 1408, 1416, 1440,
1460, 1500, 1552, 1664, 1684,
1700, 1720, 2568, 2640, 2936,
3000, 3304, 3600, 3640
5.19 (d, 1 Н, С(5)H, J = 8.2);
3
5.29 (d, 1 Н, С(1)H, J = 8.2);
7.29, 7.34, 7.38
(all br.s, 1 H each, 3 NH);
12.30 (br.s, 1 H, COOH)
(1R*,5S*)ꢀ4ꢀ(3,7ꢀDioxoꢀ
2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octꢀ2ꢀ
yl)butanoic acid
(1c)
664, 720, 736, 796, 816, 840,
888, 908, 928, 976, 1008,
1.67 (m, 2 Н, ССH2C);
2.17 (t, 2 H, CH2CO, J = 7.5);
—
3
1020, 1068, 1080, 1112, 1156,
1196, 1208, 1224, 1232, 1252,
1272, 1284, 1296, 1304, 1320,
1328, 1336, 1352, 1392, 1508,
1564, 1680, 1690, 1712, 1720,
2656, 2736, 2944, 2944, 3008,
3264, 3384, 3456
2.97, 3.17 (both m, 1 H each,
NCH2); 5.19, 5.25 (both d,
1 H each, CHCH, 3J = 8.3);
7.28, 7.30, 7.41
(all s, 1 H each, 3 NH);
12.06 (br.s, 1 Н, COOH)
(1R*,5S*)ꢀ5ꢀ(3,7ꢀDioxoꢀ
2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octꢀ2ꢀ
yl)pentanoic acid
(1d)
664, 712, 736, 752, 760, 800,
816, 848, 888, 964, 1076, 1088, 2.22 (br.s, 2 Н, CH2CO); 2.94,
1120, 1152, 1208, 1220, 1256,
1296, 1348, 1376, 1408, 1424,
1504, 1564, 1692, 2840, 2860,
2980, 2952, 3000, 3210, 3248
1.44 (br.s, 4 Н, C(CH2)2C);
—
—
3.16 (both br.s, 1 H each, NCH2);
5.19 (br.m, 2 Н, CHCH);
7.25 (br.s, 2 Н, 2 NH);
7.41 (s, 1 Н, NH);
12.00 (br.s, 1 Н, COOH)
(1R*,5S*)ꢀNꢀ[(3,7ꢀDioxoꢀ
2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octꢀ2ꢀ
yl)acetyl]aminoꢀ
ethanoic acid
612, 624, 648, 668, 688, 724,
740, 752, 768, 796, 816, 848,
880, 888, 904, 924, 944, 960,
992, 1024, 1052, 1068, 1116,
1164, 1248, 1288, 1296, 1312,
1336, 1352, 1368, 1384, 1400,
1416, 1432, 1440, 1496, 1500,
1520, 1540, 1580, 1664, 1672,
1704, 1720, 1728, 1740, 2544,
2696, 2928, 2952, 3008, 3296,
3368, 3392
3.53, 3.96 (both d, 1 H each, NCH2,
2J = 17.2); 3.77 (d, 2 Н, NHCH2,
3J = 5.6); 5.33, 5.38 (both d, 2 Н,
CHCH, 3J = 8.3); 7.32 (br.s, 2 Н,
2 NH); 7.52 (s, 1 Н, NH);
8.30 (t, 1 H, NHCH2, 3J = 5.6);
12.70 (br.s, 1 Н, COOH)
(1e)
(1R*,5S*)ꢀ2ꢀ(2ꢀHydroxyꢀ
ethyl)ꢀ2,4,6,8ꢀtetraazaꢀ
bicyclo[3.3.0]octaneꢀ
3,7ꢀdione
684, 716, 736, 784, 792, 844,
864, 876, 888, 928, 1016, 1032, 3.45 (m, 2 Н, СН2O);
3.03, 3.21 (both m, 2 Н, NСН2);
186 [М]+ (2), 156 (82),
155 (70), 143 (13), 126 (6),
113 (20), 112 (100), 100 (20),
98 (6), 84 (56), 83 (63),
82 (20), 71 (16), 69 (57),
58 (80), 56 (58)
1064, 1084, 1112, 1168, 1248,
1256, 1264, 1288, 1344, 1360,
1368, 1388, 1500, 1560, 1680,
1712, 1732, 2928, 2992, 3280,
3392, 3416
4.75 (t, 1 H, OH, 3J = 5.2);
3
5.19 (d, 1 H, C(5)H, J = 8.2);
(1f)
5.30 (d, 1 Н, С(1)H, 3J = 8.2);
7.29 (br.m, 3 H, 3 NH)
(1R*,5S*)ꢀ2ꢀ[2ꢀHydroxyꢀ
(1,1ꢀdimethyl)ethyl]ꢀ
2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octaneꢀ
3,7ꢀdione
720, 748, 764, 860, 888, 928,
1016, 1028, 1064, 1080, 1112,
1160, 1184, 1208, 1260, 1312,
1348, 1384, 1498, 1560, 1664,
1676, 1692, 2928, 2960,
3008, 3240
1.22, 1.24 (both s, 3 H each, 2 Me);
3.34, 3.62 (both dd, 1 H each, СН2,
2J = 10.7, 3J = 4.2); 4.89 (br.t,
—
3
1 Н, ОН, J = 4.2); 5.11 (d, 1 Н,
С(5)H, 3J = 8.2); 5.46 (d, 1 Н,
3
(1g)
С(1)H, J = 8.2); 7.17 (br.s, 1 Н,
NH); 7.26 (br.s, 2 H, 2 NH)
1
The signals overlap with the signal of the solvent; because of this, the H NMR spectrum in D2O and the 13C NMR spectrum were
ꢀ
1
additionally recorded. H NMR (D2O), δ: 2.14 (t, 2 H, CH2CO, J = 6.7 Hz); 2.82—2.12 (m, 2 H, NCH2); 5.02 and 5.10 (both d,
1 H each, CHCH, 3J = 8.5 Hz). 13C NMR, δ: 32.7, 36.7 (2 CH2); 62.4, 68.1 (2 CH); 159.2, 161.3 (2 CO); 173.1 (COOH).

Functionalization of glycolurils
O(3)
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 1, January, 2003
195
Table. 3. Selected bond lengths (d) and bond angles (ω) in the
structure of 1b
C(11)
O(4)
Bond
d/Å
Bond
d/Å
O(1)—C(3)
O(2)—C(7)
C(1)—N(2)
C(1)—N(8)
C(1)—C(5)
C(3)—N(2)
C(3)—N(4)
1.238(2)
1.236(2)
1.451(2)
1.442(2)
1.559(2)
1.354(2)
1.353(2)
C(5)—N(4)
C(5)—N(6)
C(7)—N(6)
C(7)—N(8)
O(3)—C(11)
O(4)—C(11)
N(2)—C(9)
1.437(2)
1.441(2)
1.345(2)
1.355(2)
1.212(2)
1.322(2)
1.456(2)
C(10)
C(9)
N(2)
C(1)
N(8)
Angle
ω/deg
Angle
ω/deg
N(8)—C(1)—C(5) 103.3(1)
N(2)—C(1)—C(5) 102.8(1)
C(3)—N(2)—C(1) 111.9(1)
C(3)—N(2)—C(9) 122.5(1)
C(1)—N(2)—C(9) 123.1(1)
O(1)—C(3)—N(4) 125.4(1)
O(1)—C(3)—N(2) 125.3(1)
N(4)—C(3)—N(2) 109.3(1)
C(3)—N(4)—C(5) 112.5(1)
N(4)—C(5)—N(6) 114.4(1)
N(4)—C(5)—C(1) 103.1(1)
N(6)—C(5)—C(1) 102.3(1)
C(7)—N(6)—C(5) 112.8(1)
O(2)—C(7)—N(6) 125.7(1)
O(2)—C(7)—N(8) 125.3(1)
N(6)—C(7)—N(8) 108.9(1)
C(7)—N(8)—C(1) 111.9(1)
O(1)
C(3)
C(5)
N(4)
C(7)
N(6)
O(2)
Fig. 2. Overall view of molecule 1b.
and bands, which might be assigned to skeletal vibraꢀ
tions of the bicyclic systems (1500—1508 cm–1). In the
1H NMR spectra of compounds 1b,c,e—g, the signals for
the methine protons (CH—CH fragment) are observed as
an AB system (δ 5.0—5.5). A singlet for these protons in
the spectrum of compound 1a and a broadened multiplet
in the spectrum of compound 1d are attributed to the
similarity of their chemical shifts. The protons of the
NCH2 groups are diastereotopic and are manifested as an
AMX2 system due to spinꢀspin coupling with the protons
of the adjacent CH2 group. The positions of other signals
and their intensities are in complete agreement with their
structures (see Table 2).
Hꢀbonded threeꢀdimensional framework. It should be
noted that not only the NH and COH groups but also the
methine H atom at the C(5) atom can be involved in
hydrogen bonding (Table 4).
Of chemical transformations of glycolurils 1, we studꢀ
ied esterification of products 1a,b (Scheme 2). Comꢀ
pounds 4a—d were prepared according to standard proceꢀ
dures and their structures were confirmed by elemental
analysis and spectroscopic methods.
Scheme 2
Attempts to crystallize compounds 1a—g from water
allowed us to grow crystals of 1a,b and 1d suitable for
Xꢀray diffraction analysis. Xꢀray diffraction study demꢀ
onstrated that product 1b crystallized as a water solvate in
the centrosymmetrical space group P21/c. The principal
bond lengths and bond angles in the bicyclic system
(Fig. 2, Table 3) are close to the expected values.5 The
introduction of the (CH2)2COOH group has virtually no
effect on the conjugation in the N—C(=O)—N fragment,
which is manifested in the similarity of the corresponding
N—C and C=O bond lengths. By contrast, the N—C(H)
bond length appears to be more sensitive to the introducꢀ
tion of the substituent.
4: R´ = Me, n = 1 (a); R´ = Et, n = 1 (b);
R´ = Me, n = 2 (c); R´ = Et, n = 2 (d)
To summarize, cyclocondensation of 4,5ꢀdihydroxyꢀ
imidazolidinꢀ2ꢀone with 1ꢀRꢀureas afforded new monoꢀ
functionally substituted glycolurils, which are of interest
as potentially physiologically active compounds and
synthons for the preparation of other derivatives of this
class. Singleꢀcrystal Xꢀray diffraction study showed that
2ꢀcarboxyethylꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octaneꢀ3,7ꢀ
dione (1b) crystallized as a racemate.
Both fiveꢀmembered rings adopt a strongly flattened
envelope conformation with the C(3) and C(7) atoms
deviating from the corresponding planes by 0.08 and
0.11 Å. The dihedral angle between the planes of the fiveꢀ
membered rings is 119.1°.
The presence of four protons and three carbonyl groups
capable of hydrogen bonding gives rise to the expected

196
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 1, January, 2003
Kravchenko et al.
Table 4. Principal geometric parameters (bond lengths (d) and bond angles) of the hydrogen bonds (D—H...A) in the
structure of 1b
Bond
d(D...A)
d(H...A)
D—H—A angle
/deg
Å
N(4)—H(4N)...O(1) (–x + 1, –y + 1, –z)
N(6)—H(6N)...O(3) (x + 1, –y + 1.5, z – 0.5)
N(8)—H(8N)...O(1) (–x + 1, y + 0.5, –z + 0.5)
O(4)—H(4O)...O(2) (x – 1, –y + 1.5, z + 0.5)
O(1W)—H(1WA)...O(1)
2.882(2)
2.924(2)
3.054(2)
2.626(2)
2.780(3)
3.310(3)
3.231(3)
2.06
2.06
2.29
1.69
1.85
2.36
2.17
163
156
165
170
152
152
172
O(1W)—H(1WB)...N(4) (x – 1, y, z)
C(5)—H(5)...O(2) (2 – x, y – 0.5, –z + 0.5)
Note. D is a donor and A is an acceptor. The symmetry operations are given in parentheses.
cooled to ∼20 °C, and kept for 12 h. The precipitates of comꢀ
pounds 1a—e that formed were filtered off and recrystallized
from water. In the case of compounds 1f,g, the reaction mixture
was concentrated in vacuo until an oily residue formed. The
precipitate was triturated with a 1 : 3 Me2CO—Et2O mixture
(10 mL). Products 1f,g that precipitated were filtered off and
recrystallized from a 4 : 1 MeOH—AcOEt mixture (15 mL). The
yields and physicochemical characteristics of compounds 1a—g
are given in Table 1. The spectroscopic characteristics of these
compounds are listed in Table 2.
Experimental
The IR spectra were recorded on a Specord Mꢀ80 spectromꢀ
eter in KBr pellets. The NMR spectra were measured on Bruker
AMꢀ250 (250 MHz (1H)) and Bruker AMꢀ300 (300 MHz for 1H
and 75.5 MHz for 13C) spectrometers in DMSOꢀd6; the chemiꢀ
cal shifts are given in the δ scale relative to Me4S as the internal
standard. The mass spectra were obtained on an MSꢀ30 mass
spectrometer. The melting points were measured on a Boetius
PHMKꢀ05 instrument.
Synthesis of monosubstituted ureas 2a—g (general proceꢀ
dure). An aqueous solution of the corresponding amino acid
(dipeptide or amino alcohol) (0.05 mol) was heated to boiling
and then KOCN (4.5 g, 0.052 mol) was added in five portions to
the gently refluxing solution. After the addition of a total amount
of KOCN, the reaction mixture was refluxed for 20 min (in the
case of dipeptide, for 30 min), cooled to ∼20 °C, and treated
with an equimolar amount (4.5 mL) of concentrated HCl to
pH ∼1. Then the reaction mixture was kept at ∼20 °C for 7 h and
crystals of compounds 2a—e that precipitated were filtered off.
In the case of 2f,g, the reaction mixture was concentrated to
dryness in vacuo, MeOH (20 mL) was added, and a precipitate
of KCl was filtered off. The filtrate was concentrated in vacuo,
the oily residue was triturated with a 1 : 2 MeOH—Et2O mixture
(15 mL), and products 2f,g that formed were filtered off.
Ureidoethanoic acid (2a). The yield was 95%, m.p.
173—175 °C (cf. lit. data17: m.p. 165 °C).
Synthesis of methyl esters of 2ꢀsubstituted (1R*,5S*)ꢀ2,4,6,8ꢀ
tetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdiones 4a,c (general proceꢀ
dure). Concentrated H2SO4 (1 mmol) was added to a solution of
compounds 1a,b (5 mmol) in MeOH (0.5 mol) and the reaction
mixture was refluxed for 5 h under conditions precluding expoꢀ
sure to atmospheric moisture. Then the reaction mixture was
concentrated to ∼1/3 of the initial volume and kept at ∼20 °C for
7 h. The precipitates that formed were filtered off and washed
with MeOH (3—5 mL). Compounds 4a and 4с were obtained in
yields of 0.95 g (88%) and 0.85 g (75%), respectively.
Methyl
(1R*,5S*)ꢀ(3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazabicycꢀ
lo[3.3.0]octꢀ2ꢀyl)ethanoate (4a). M.p. 250—252 °C. Found (%):
C, 39.31; H, 4.65; N, 26.27. C7H10N4O4. Calculated (%):
1
C, 39.25; H, 4.71; N, 26.16. H NMR, δ: 3.64 (s, 3 H, OMe);
3.77 and 4.06 (both d, 1 H each, CH2, 2J = 18.1 Hz); 5.27 (s,
2 H, CHCH); 7.30, 7.32, and 7.60 (all s, 1 H each, 3 NH). MS,
m/z (Irel (%)): 214 [M]+ (5), 185 (5), 171 (17), 156 (79), 155
(72), 143 (5), 126 (12), 113 (16), 112 (100), 100 (24), 84 (19), 83
(71), 82 (24), 70 (21), 69 (60), 58 (92), 56 (63).
3ꢀUreidopropanoic acid (2b). The yield was 96%, m.p.
178—180 °C.
4ꢀUreidobutanoic acid (2с). The yield was 92%, m.p.
190—192 °C.
5ꢀUreidopentanoic acid (2d). The yield was 87—88%, m.p.
195—197 °C.
Ureidoacetylaminoethanoic acid (2e). The yield was 85—86%,
m.p. 220—222 °C.
Methyl (1R*,5S*)ꢀ3ꢀ(3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazabicycꢀ
lo[3.3.0]octꢀ2ꢀyl)propanoate (4с). M.p. 196—197 °C. Found (%):
C, 42.24; H, 5.35; N, 24.47. C8H12N4O4. Calculated (%):
C, 42.10; H, 5.30; N, 24.55. 1H NMR, δ: 2.53 (m, 2 H, CH2CO);
3.32 and 3.45 (both m, 2 H each, NCH2); 3.66 (s, 3 H, OMe);
5.17 (d, 1 H, C(5)H, 3J = 8.2 Hz); 5.25 (d, 1 H, C(1)H, 3J =
8.2 Hz); 7.19, 7.25, and 7.31 (all br.s, 1 H each, 3 NH).
1ꢀ(2ꢀHydroxyethyl)urea (2f). The yield was 78—80%, m.p.
85—86 °C.
Synthesis of ethyl esters of 2ꢀsubstituted (1R*,5S*)ꢀ2,4,6,8ꢀ
tetraazabicyclo[3.3.0]octaneꢀ3,7ꢀdiones 4b,d (general proceꢀ
dure). Concentrated H2SO4 (10 mmol) was added to a solution
of compounds 1a,b (5 mmol) in anhydrous EtOH (0.5 mol).
The reaction mixture was refluxed for 2 h and then toluene
(0.25 mol) was added. The mixture was concentrated to dryness
by azeotropic distillation and the residue was dissolved in anꢀ
hydrous EtOH (5 mL). The resulting solution was kept at ∼20 °C
1ꢀ[2ꢀHydroxy(1,1ꢀdimethyl)ethyl]urea (2g). The yield was
76—77%, m.p. 60—62 °C.
Synthesis of 2ꢀsubstituted (1R*,5S*)ꢀ2,4,6,8ꢀtetraazabiꢀ
cyclo[3.3.0]octaneꢀ3,7ꢀdiones 1a—g (general procedure). Conꢀ
centrated HCl was added to an aqueous solution of the correꢀ
sponding urea 2 (0.05 mol) and 4,5ꢀdihydroxyimidazolidinꢀ2ꢀone
(3) (0.05 mol) to pH 1—2. The solution was refluxed for 1 h,

Functionalization of glycolurils
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 1, January, 2003
197
for 12 h and the precipitates of esters 4b,d that formed were
filtered off and washed with anhydrous EtOH. Compounds 4b
and 4d were obtained in yields of 0.91 g (77%) and 0.89 g (74%),
respectively.
References
1. O. V. Lebedev, L. I. Khmel´nitskii, L. V. Epishina, L. I.
Suvorova, I. V. Zaikonnikova, I. E. Zimakova, S. V. Kirshin,
A. M. Karpov, V. S. Chudnovskii, M. V. Povstyanoi, and
V. A. Eres´ko, in Tselenapravlennyi poisk novykh neiroꢀ
tropnykh preparatov [Targeted Search for New Neurotrophic
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and Yu. T. Struchkov, Acta Crystallogr., Sect. C, 1994,
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Galitskii, A. I. Verenich, L. I. Khmel´nitskii, O. V. Lebedev,
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O. V. Lebedev, A. N. Kravchenko, I. I. Chervin, and V. R.
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6. R. G. Kostyanovsky, K. A. Lyssenko, A. N. Kravchenko,
O. V. Lebedev, G. K. Kadorkina, and V. R. Kostyanovsky,
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Ethyl
(1R*,5S*)ꢀ(3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazabicycꢀ
lo[3.3.0]octꢀ2ꢀyl)ethanoate (4b). M.p. 224—225 °C. Found (%):
C, 42.15; H, 5.27; N, 24.57. C8H12N4O4. Calculated (%):
C, 42.10; H, 5.30; N, 24.55. 1H NMR, δ: 1.21 (t, 3 H, Me, 3J =
2
7.2 Hz); 3.73 and 4.05 (both d, 1 H each, CH2, J = 18.1 Hz);
4.12 (q, 2 H, MeCH2, 3J = 7.2 Hz); 5.29 (s, 2 H, CHCH); 7.26,
7.36, and 7.62 (all s, 1 H each, 3 NH). MS, m/z (Irel (%)): 228
[M]+ (2), 199 (5), 186 (15), 185 (83), 171 (5), 156 (21), 155
(85), 126 (10), 112 (100), 99 (7), 84 (36), 83 (30), 82 (21), 69
(46), 58 (64), 56 (39).
Ethyl
(1R*,5S*)ꢀ3ꢀ(3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazabicycꢀ
lo[3.3.0]octꢀ2ꢀyl)propanoate (4d). M.p. 205—207 °C. Found (%):
C, 44.41; H, 5.75; N, 23.26. C9H14N4O4. Calculated (%):
C, 44.63; H, 5.83; N, 23.13. 1H NMR, δ: 1.18 (t, 3 H, Me, 3J =
7.3 Hz); 2.63 (m, 2 H, CH2CO); 3.19 and 3.34 (both m, 2 H,
NCH2); 4.05 (q, 2 H, MeCH2, 3J = 7.3 Hz); 5.18 (d, 1 H,
C(5)H, 3J = 8.0 Hz); 5.29 (d, 1 H, C(1)H, 3J = 8.0 Hz); 7.29
(br.s, 1 H, NH); 7.37 (br.s, 2 H, 2 NH).
Xꢀray diffraction analysis of compound 1b. Single crystals
were prepared by crystallization from H2O. Crystals of 1b
(C7H10N4O4•0.5 H2O, M = 223.20) are monoclinic, space group
P21/c, at T = 163 K: a = 7.656(2) Å, b = 11.263(4) Å, с =
7. R. G. Kostyanovsky, G. K. Kadorkina, K. A. Lyssenko,
V. Yu. Torbeev, A. N. Kravchenko, O. V. Lebedev, G. V.
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Commun., 2002, 6.
10.764(3) Å, β = 101.45(2)°, V = 909.7(5) Å3, Z = 4, dcalc
=
1.630 g cm–3. The intensities of 1912 independent reflections
were measured on an automated Syntex P21 diffractometer
(graphite monochromator, λ(MoꢀKα) = 0.71073 Å, θ/2θ scan
technique, θmax = 26°). The structure was solved by direct methꢀ
ods and refined by the fullꢀmatrix leastꢀsquares method based
on F 2hkl with anisotropic thermal parameters for all nonhydrogen
atoms. The H atoms were revealed from the difference electron
density synthesis and refined isotropically. Analysis of the differꢀ
ence electron density synthesis in the region of the water molꢀ
ecule of solvation located in an inversion center showed disorꢀ
dering of the H atoms, and their positions were refined using the
riding model. The final reliability factors were as follows:
R1 = 0.0427 (based on F 2 for 1585 observed reflections with
I > 2σ(I )), wR2 = 0.1282, GOF = 1.082, the number of the
refinable parameters was 188. All calculations were carried out
on a personal computer with the use of the SHELXTL PLUS
program package.
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17. J. Taillades, L. Boiteau, I. Beuzelin, O. Lagrille, J. Biron,
W. Vayaboury, O. VandenabeeleꢀTrambouze, O. Giani, and
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This study was financially supported by the INTAS
European Foundation (Grant 99ꢀ0157) and the Russian
Foundation for Basic Research (Project Nos. 02ꢀ03ꢀ33257
and 00ꢀ15ꢀ97359).
Received May 18, 2002;
in revised form August 29, 2002