Regioselective reactions of N-(carboxyalkyl)- and N-(aminoethyl)ureas with glyoxal and 1,2-dioxo-1,2-diphenylethane

Article abstract of DOI:10.1007/s11172-014-0446-5

Regioselective reactions of N-(carboxyalkyl)ureas (ureido acids) and N-(aminoethyl)ureas with 1,2-dioxo-1,2-diphenylethane (benzyl) and glyoxal are studied in detail. The structure of the reactants affects the reaction regioselectivity. Acid-catalyzed rea

Full text of DOI:10.1007/s11172-014-0446-5

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 416—421, February, 2014
416
Regioselective reactions of Nꢀ(carboxyalkyl)ꢀ
and Nꢀ(aminoethyl)ureas with glyoxal and 1,2ꢀdioxoꢀ1,2ꢀdiphenylethane*
A. N. Kravchenko,a V. V. Baranov,a G. A. Gazieva,a I. E. Chikunov,a and Yu. V. Nelyubinab
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: unelya@xrlab.ineos.ac.ru
Regioselective reactions of Nꢀ(carboxyalkyl)ureas (ureido acids) and Nꢀ(aminoethyl)ureas
with 1,2ꢀdioxoꢀ1,2ꢀdiphenylethane (benzyl) and glyoxal are studied in detail. The structure of
the reactants affects the reaction regioselectivity. Acidꢀcatalyzed reactions of glyoxal with 1ꢀ[2ꢀ(diꢀ
methylamino(acetylamino))ethyl]ureas and benzene with ureido acids result mainly in 2,6ꢀdiꢀ
substituted glycolurils. The structure of 2,6ꢀdi(methoxycarbonylethyl)glycoluril is unambiguꢀ
ously established by Xꢀray diffraction.
Key words: Nꢀ(carboxyalkyl)ureas (ureido acids), 1ꢀ{2ꢀ[dimethylamino(acetylamino)]ꢀ
ethyl}ureas, glyoxal, benzyl, 2,6ꢀ and 2,8ꢀdisubstituted glycolurils, regioselective reactions.
Recently, we elaborated synthetic methods to access
tained glucoluril diesters were hydrolyzed to 2,8ꢀdi(carbꢀ
oxymethyl)ꢀ1,5ꢀdiphenylglucolurils.
monofunctional glycolurils bearing aminoalkyl, hydroxyalkyl,
and carboxyalkyl groups at the nitrogen atoms.1—7 Among
synthesized compounds, substances exhibiting neurotropic
(sedative, anxiolytic), neuroprotective, nootropic (superiꢀ
or than Nootropil) activities were found.8,9 Glycolurils
bearing the 2ꢀacetylaminoethyl8 and 3ꢀcarboxypropyl moiꢀ
eties9 at the same nitrogen atom turned out to be the most
effective. This fact demonstrates the feasibility of search
for the new promising compounds in this series; therefore,
the introduction of one more acetylaminoethyl and carbꢀ
oxyalkyl groups into glycoluril is of interest. Earlier,10,11
2,6ꢀ and 2,8ꢀdi(carboxyalkyl)glycolurils were synthesized
by the reaction of Nꢀcarbamoylglycine and its esters with
glyoxal and 1,2ꢀdioxoꢀ1,2ꢀdiphenylethane (benzyl). From
the reaction mixture obtained in the reaction of Nꢀcarbaꢀ
moylglycine with glyoxal at 100 C for 0.2 h,10 some prodꢀ
uct was isolated in 14% yield. Based on the melting point
and elemental analysis, to this compound, the structure of
2,6ꢀ and/or 2,8ꢀdi(carboxymethyl)glycoluril was ascribed.
Predominant formation of 2,8ꢀdi(carboxymethyl)ꢀ1,5ꢀ
diphenylglycoluril diesters was demonstrated on the exꢀ
ample of several reactions of Nꢀcabamoylglycinates with
benzyl derivatives.11 The reactions were carried out in
benzene in the presence of trifluoroacetic acid. The obꢀ
With the aim to develop novel regioselective syntheses
of 2,6ꢀtrans (1) or 2,8ꢀcis difunctionally substituted** (2)
glycolurils, in the present work we first studied in detail
the diastereoselective condensations of glyoxal and benzꢀ
yl with 1ꢀ[2ꢀ(dimethylamino(acetylamino))ethyl]ureas
3a,b and Nꢀ(carboxyalkyl)ureas (ureido acids) 3c—e
(Schemes 1 and 2).
The starting ureas 3a—e were synthesized by Nꢀcarbaꢀ
moylation of the corresponding ethylenediamines (2ꢀ(diꢀ
methylamino)ethylꢀ and 2ꢀ(acetylamino)ethylamines) and
amino acids (Gly, ꢀAla, ꢀaminobutyric acid) in the presꢀ
ence of KOCN similarly to earlier developed procedures.12
2ꢀ(Acetylamino)ethylamine was obtained by ethylenediꢀ
amine acetylation.13
Condensations of glyoxal with 1ꢀ[2ꢀ(dimethylaminoꢀ
(acetylamino))ethyl]ureas 3a,b and ureido acids 3c—e (see
Scheme 1) were performed in water under conditions used
previously14 for the synthesis of 2,6ꢀdialkylglycolurils, i.e.,
pH 1—2, reaction time of 1 h. Regioselectivity of the reacꢀ
1
tions was estimated by H NMR spectroscopy of the reꢀ
action mixtures evaporated to dryness. The most informaꢀ
tive signals of the compounds synthesized are the signals
** Since the cisꢀfusing of the imidazolidine rings in glycoluris is
well known, the terms 2,8ꢀcisꢀ and 2,6ꢀtransꢀ are used to
describe the orientation of substituents at the cyclic nitrogen
atoms.
* On the occasion of the 80th anniversary 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. 0416—0421, February, 2014.
1066ꢀ5285/14/6302ꢀ0416 © 2014 Springer Science+Business Media, Inc.

Reactions of Nꢀ(carboxy(amino)alkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
417
Scheme 1
of the protons of the CH—CH glycoluril groups, namely,
the doublet of doublets for cisꢀisomers and singlet for transꢀ
isomer, and variable chemical shifts of the NH group
singlets. It is shown that the reaction of glyoxal with 1ꢀ[2ꢀ(diꢀ
methylamino)ethyl]urea 3a yields transꢀ (1a) and cisꢀglyꢀ
colurils (2a) in an 1 : 1 ratio. The separation of these isoꢀ
mers failed due to the proximity of physicoꢀchemical propꢀ
erties. Moreover, 1H NMR spectrum contains also the
signals of the known hydantoin 4a.15 Isolated yields of the
mixture of isomers 1a and 2a and hydantoin 4a are 49 and
31%, respectively.
It is found that the reactions of glyoxal with both
1ꢀ(2ꢀacetylaminoethyl)urea 3b and ureido acid 3c are reꢀ
giospecific and result in transꢀisomers 1b,c in the yields
of 51 and 26%, respectively. Even traces of the corꢀ
responding cisꢀisomers 2b,c were not detected. Glyoxꢀ
al reacts with ureido acid 3c to give hitherto unknown
compound, 3,3´ꢀbi[(1R*,5S*)ꢀ2,4ꢀdioxaꢀ6,8ꢀdiazaꢀ7ꢀ
oxobicyclo[3.3.0]octꢀ6ꢀyl)acetic acid] (5). The structure
of bisbicycle 5 was established by 1H and 13C NMR specꢀ
troscopy and mass spectrometry taking in account the
data for the previously synthesized 3,3´ꢀbi(6,8ꢀdialkylꢀ
2,4ꢀdioxaꢀ7ꢀthiaꢀ6,8ꢀdiazabicyclo[3.3.0]octaneꢀ7,7ꢀdiꢀ
oxides).16
Similar reactions between either Nꢀcarbamoylꢀꢀalanꢀ
ine (3d) or Nꢀcarbamoylꢀꢀbutyric acid (3e) afford the
complex mixtures of the unidentified products.
Acidꢀcatalyzed condensations of benzyl with 1ꢀ[2ꢀ(diꢀ
methylamino(2ꢀacetylamino))ethyl]ureas 3a,b and ureido
acids 3c—e were carried out in MeOH or PriOH because
benzyl is insoluble in water. Attempted reaction of benzyl
with ureas 3a,b failed and the starting compounds were
recovered. Cyclocondensations of ureido acids 3c—e with
benzyl (Scheme 2) were performed in MeOH since in
PriOH no reaction occurred. Refluxing of the reactants for
1 h yielded methyl esters of transꢀ (1d—f) and cisꢀ (2d—f)
glycoluril derivatives. The ratios of the isomers, 1d : 2d =
= 1 : 2, 1e : 2e = 3.3 : 1, and 1f : 2f = 4.4 : 1, clearly indiꢀ
cate the regioselectivity of the reactions. The ratios of the
2,6ꢀ and 2,8ꢀsubstituted products were determined by
1H NMR spectroscopy. It is found that the alkyl chain
elongation in ureido acids 3c—e leads to the increase in
the content of 2,6ꢀdi(methoxycarbonylalkyl)glycolurils
1d—f. Compounds 1d—f and 2d—f were separated by fracꢀ
tional crystallization in the yields of 11—50% for 1d—f
and 8—22% for 2d—f. Along with glucoluril derivatives,
from the reaction mixtures, the following compounds were
isolated: benzyl, ureido acid 3e, and known products of

418
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Kravchenko et al.
Scheme 2
n = 1 (1d, 2d, 3c), 2 (1e, 2e, 3d), 3 (1f, 2f, 3e)
ureido acid cyclization, namely, hydantoin 4b (in the case
of ureido acid 3c)1 and dihydropyrimidineꢀ2,4(1H,3H)ꢀ
dione 4c (in the case of ureido acid 3d).17
171.0(3)—172.8(3)). The C—H...O, C—H..., and
weak interactions connect these chains into a 3D network
(Fig. 2).
The structures of the synthesized compounds were esꢀ
tablished by microanalysis data, 1H and 13C NMR spectroꢀ
scopy, and mass spectrometry. The structure of the major
isomer 1e was also confirmed by Xꢀray diffraction (Fig. 1).
According to Xꢀray data, in crystal 1e, one and a half
molecules are crystallographically independent with the
slightly different geometrical parameters.* Thus, the hetꢀ
erocycle conformation in both cases is an envelope with
a deviation from the mean plane of 0.33(1)—0.35(1) Å
for the C(1) and C(3) atoms and the angles between
these planes of 69.9(3) and 70.6(3). Therefore, the
mutual imidazolidine cycle arrangement characterisꢀ
tic of these type of compounds2—4,7,14 can be regarded
as "halfꢀopen book". The C(17)N(2)N(4)C(21) and
C(18)C(17)C(21)C(22) dihedral angles describing the
mutual orientation of the ester groups are 101.4(3)/
38.2(3) and 108.8(3)/45.3(3) in two molecules, respecꢀ
tively. Like the previously studied glycolurils,7 the phenyl
groups at the bridgehead carbons adopt cis orientation.
The crystals of compound 1e contain the endless chains
formed by the N—H...O hydrogen bonds (the NO disꢀ
tance is 2.805(3)—2.826(3) Å, the NHO angle is
In summary, the detail study of the reactions of amiꢀ
noethylꢀ and carboxyalkylureas with glyoxal and benzyl
reveals the effect of the reactant structure on regioselectivꢀ
ity of formation of 2,6ꢀ and 2,8ꢀdisubstituted glycolurils.
It is shown that both 2ꢀacetylaminoethylureas and
Nꢀcarbamoylglycine regiospecifically react with glyoxal
to give exclusively 2,6ꢀdisubstituted glycolurils, while
2ꢀdimethylaminoethylureas react with glyoxal to yield the
mixture of 2,6ꢀ and 2,8ꢀisomers in an 1 : 1 ratio. Condenꢀ
sation of benzyl with ureido acids regioselectively producꢀ
es methyl esters of 2,6ꢀ and 2,8ꢀisomers; wherein the longer
the alkyl chain of the ureido acid, the higher the content
of 2,6ꢀdi(methoxycarbonylalkyl)glycolurils.
Experimental
Commercially available (Acros) amino acids, N,Nꢀ(diꢀ
methyl)ethylamine hydrochloride, glyoxal trimer dihydrate, and
40% aqueous glyoxal were used. Ureido acids 3a—e were synꢀ
thesized by treatment of the corresponding amines with KOCN
as earlier described.12
NMR spectra were run on Bruker AMꢀ250 (1H, 250 MHz)
and Bruker AMꢀ300 (13C, 75.5 MHz) instruments in DMSOꢀd6,
the chemical shifts are given in the  scale relative to Me4Si
(internal standard). The melting points were determined on
a GALLENKAMP apparatus (Sanyo).
* The numbering scheme for glycolurils in the Xꢀray experiment
differs from the IUPAC numbering scheme.
O(2)
C(9)
C(4)
N(3)
C(10)
C(21)
C(23)
O(5)
C(12)
C(11)
N(4)
O(4)
C(13)
C(14)
C(5)
C(3)
C(22)
C(8)
C(7)
C(18)
C(24)
O(6)
C(20)
C(1)
N(2)
C(19)
O(3)
N(1)
C(6)
C(17)
C(16)
C(15)
C(2)
O(1)
Fig. 1. Molecular structure of compound 1e, displacement ellipsoids are given with 30% probability.

Reactions of Nꢀ(carboxy(amino)alkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
419
O(7C)
N(8C)
N(3A)
O(1A)
O(2A)
N(1A)
N(1)
O(2)
N(6B)
N(3)
O(1)
O(7B)
Fig. 2. HꢀBonded chain in crystal 1e.
1
Xꢀray diffraction study of compound 1e was performed on
a SMART 1000 CCD diffractometer (MoK radiation,  scanꢀ
ning mode). The structure was solved by the direct methods and
refined using the fullꢀmatrix least squares on F2hkl in anisotropic
approximation. Hydrogen atoms of the NH groups were localꢀ
ized from difference Fourier syntheses of electron density, other
hydrogen atoms were positioned geometrically. The positions of
all hydrogen atoms were refined isotropically using the riding
model. The Xꢀray data collection and refinement statistic
are given in Table 1. All calculations were performed using
SHELXTL PLUS program package.18
Synthesis of 2,6(2,8)ꢀdi[2ꢀ(dimethylamino)ethyl]ꢀ (1a and 2a)
and 2,6ꢀdi(2ꢀacetylaminoethyl)ꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]ꢀ
octaneꢀ3,7ꢀdiones (1b) (general procedure). To a solution of glyꢀ
oxal trimer dihydrate (0.0033 mol) or 40% aqueous glyoxal
(0.01 mol, 1.15 mL, d = 1.265) in water (10 mL), 1ꢀ[2ꢀ(diꢀ
methylamino)ethyl]ꢀ (3a) or 1ꢀ(2ꢀacetylaminoethyl)urea (3b)
(0.02 mol) was added followed by addition of concentrated HCl to
pH 1, and the reaction mixture was heated at 80 C for 1 h. The
solvent was removed in vacuo to give the oily residue. The residue
was treated with isopropyl alcohol and methanol, the resulted
precipitate of glycolurils 1a, 2a or 1b was collected by filtration.
Slow concentration of the filtrate afforded crystalline compound 4a.
Mixture of isomers 1a and 2a. Yield 49%. H NMR, : 2.79
(s, 12 H, NMe2); 2.81 (s, 12 H, NMe2); 3.00—3.09 (m, 1 H,
NCH2); 3.13—3.41 (m, 12 H, NCH2); 3.46—3.57 (m, 2 H,
NCH2); 3.72—3.83 (m, 1 H, NCH2); 5.30 (d, 1 H, CH, J = 8.2 Hz);
5.40 (s, 2 CH); 5.62 (d, 1 H, CH, J = 8.2 Hz); 7.73 (s, 2 H,
2 NH); 7.87 (s, 2 H, 2 NH). Found (%): C, 50.64; H, 8.48;
N, 29.58. C12H24N6O2. Calculated (%): C, 50.69; H, 8.51;
N, 29.55.
Compound 1b. Yield 51%, m.p. 255—257 C. 1H NMR,
: 1.78 (s, 6 H, 2 Ac); 2.94—2.98 (m, 2 H, NCH2); 3.05—3.09
(m, 2 H, NCH2); 3.20—3.28 (m, 4 H, 2 NCH2); 5.25 (s, 2 H,
2 CH); 7.49 (s, 2 H, 2 NH); 7.83 (t, 2 H, 2 NHAc, J = 4.9 Hz).
13C NMR, : 169.41 (CONH), 159.17 (CO), 65.42 (CH), 39.93
(NCH2), 36.53 (NCH2), 22.64 (CH3). MS, m/z (Irel (%)): 253
[M – NH2Ac]+ (21.94), 211 (28.39), 169 (58.06), 126 (88.39),
114 (50.32), 110 (50.32), 85 (100), 73 (61.94), 56 (58.71),
43 (84.52). Found (%): C, 46.05; H, 6.49; N, 26.88. C12H20N6O4.
Calculated (%): C, 46.15; H, 6.45; N, 26.91.
Compound 4a. Yield 31%, m.p. 237—239 C (cf. Ref. 15:
238—239 C). 1H NMR spectral data are in agreement with those
published previously.15
Synthesis of (6ꢀcarboxymethylꢀ3,7ꢀdioxoꢀ2,4,6,8ꢀtetraazaꢀ
bicyclo[3.3.0]octanꢀ2ꢀyl)acetic acid (1c) and 3,3´ꢀbi(7ꢀoxoꢀ2,4ꢀ

420
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Kravchenko et al.
Table 1. Crystallographic characteristic, Xꢀray data colꢀ
lection, and refinement parameters for compound 1e
benzyl (0.005 mol) and the corresponding ureido acid 3c—e
(0.01 mol) in MeOH (15—25 mL), HCl (1.8 mL) was added,
and the stirred mixture was refluxed for 2 h and then kept for
3 days. The precipitate formed was filtered and washed with
diethyl ether. 2,6ꢀ and 2,8ꢀDisubstituted glycolurils were sepaꢀ
rated by crystallization from MeOH.
Methyl 2ꢀ[6ꢀ(methoxycarbonyl)methylꢀ1,5ꢀdiphenylꢀ3,7ꢀdiꢀ
oxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octanꢀ2ꢀyl]acetate (1d). Yield
11%, m.p. 279—281 C. 1H NMR, : 3.50 (d, 2 H, CH2,
J = 17.6 Hz); 3.59 (s, 6 H, OMe); 3.92 (d, 2 H, CH2, J = 17.7 Hz);
6.98—7.15 (m, 10 H, Ph); 8.28 (s, 2 H, NH). 13C NMR, : 41.90
(CH2); 51.63 (OMe); 83.70 (CPh); 127.19, 127.66, 128.37 (Ph);
135.22 (C(Ph)); 158.69 (CO); 169.14 (COO). Found (%):
C, 60.24; H, 5.05; N, 12.83. C22H22N4O6. Calculated (%):
C, 60.27; H, 5.06; N, 12.78.
Parameter
Value
Molecular formula
Molecular weight
T/K
C24H26N4O6
466.49
296
Crystal system
Space group
Monoclinic
C2/c
Z
12
a/Å
b/Å
c/Å
/deg
22.444(5)
11.080(3)
30.118(7)
90.00
/deg
94.29(2)
90.00
7469(3)
1.245
0.91
2952
56
37952
9022
4857
Methyl 2ꢀ[8ꢀ(methoxycarbonyl)methylꢀ1,5ꢀdiphenylꢀ3,7ꢀdiꢀ
oxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octanꢀ2ꢀyl]acetate (2d). Yield
22%, m.p. 322—324 C. 1H NMR, : 3.05 (d, 2 H, CH2,
J = 17.5 Hz); 3.66 (s, 6 H, OMe); 3.72 (d, 2 H, CH2, J = 17.7 Hz);
6.98—7.15 (m, 10 H, Ph); 8.29 (s, 2 H, NH). 13C NMR, : 42.78
(CH2); 51.80 (OMe); 79.95, 88.28 (CPh); 127.17, 127.32, 127.75,
128.13, 128.54, 129.46 (Ph); 133.35, 137.28 (C(Ph)); 159.00
(CO); 169.79 (COO). Found (%): C, 60.29; H, 5.07; N, 12.74.
C22H22N4O6. Calculated (%): C, 60.27; H, 5.06; N, 12.78.
Methyl 3ꢀ[6ꢀ(2ꢀmethoxycarbonyl)ethylꢀ1,5ꢀdiphenylꢀ3,7ꢀdiꢀ
oxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octanꢀ2ꢀyl]propionate (1e).
/deg
V/Å3
dcalc/g cm–3
/cm–1
F(000)
2max/deg
Number of measured reflections
Number of independent reflections
Number of reflections with I > 2(I)
Number of refined parameters
R1
wR2
468
1
0.0764
0.2063
1.042
Yield 50%, m.p. 288—290 C. H NMR, : 2.43—2.62 (m, 4 H,
CH2); 2.88—3.00 (m, 2 H, CH2); 3.35—3.51 (m, 2 H, CH2);
3.54 (s, 6 H, OMe); 6.76—7.48 (m, 10 H, Ph); 8.35 (s, 2 H, NH).
13C NMR, : 33.25, 36.41 (CH2); 51.46 (OMe); 83.87 (CPh);
127.34, 127.99, 128.53 (Ph); 135.39 (C(Ph)); 158.87 (CO); 171.47
(COO). Found (%): C, 61.83; H, 5.60; N, 12.03. C24H26N4O6.
Calculated (%): C, 61.79; H, 5.62; N, 12.01.
GOF
Residual electron
density/e Å–3 (min/
–0.528/1.029
)
max
Methyl 3ꢀ[8ꢀ(2ꢀmethoxycarbonyl)ethylꢀ1,5ꢀdiphenylꢀ3,7ꢀdiꢀ
oxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octanꢀ2ꢀyl]propionate (2e).
Yield 15%, m.p. 187—190 C. 1H NMR, : 2.76 (t, 4 H, CH2,
J = 7.6 Hz); 3.13—3.27 (m, 2 H, CH2); 3.33—3.49 (m, 2 H, CH2);
3.57 (s, 6 H, OMe); 6.73—6.84 (m, 2 H, Ph); 6.94—7.02 m, 2 H,
Ph); 7.03—7.16 (m, 6 H, Ph); 8.21 (s, 2 H, NH). 13C NMR,
: 33.68, 38.20 (CH2); 51.39 (OMe); 79.33, 89.84 (CPh); 127.11,
127.42, 127.74, 128.13, 128.25, 128.58 (Ph); 133.25, 137.19
(C(Ph)); 159.68 (CO); 171.23 (COO). Found (%): C, 61.80;
H, 5.58; N, 12.05. C24H26N4O6. Calculated (%): C, 61.79;
H, 5.62; N, 12.01.
dioxaꢀ6,8ꢀdiazabicyclo[3,3,0]octanꢀ6ꢀyl)acetic acid (5). To a soꢀ
lution of glyoxal trimer dehydrate (0.033 mol) or 40% aqueous
glyoxal (0.01 mol, d = 1.265) in water (10 mL), Nꢀcarbamoyl
glycine (0.02 mol) was added followed by dropwise addition of
concentrated HCl (0.1 mL). The reaction mixture was heated at
80 C for 1 h. After cooling down, precipitated compound 5 was
collected by filtration and washed with water. The filtrate was
concentrated to 1/4 of its initial volume and precipitated comꢀ
pound 1c was collected.
2ꢀ((1S*,5S*)ꢀ6ꢀCarboxymethylꢀ3,7ꢀdioxoꢀ2,4,6,8ꢀtetraꢀ
azabicyclo[3.3.0]octanꢀ2ꢀyl)acetic acid (1c). Yield 26%, m.p.
288—289 C. 1H NMR, : 3.66 (d, 2 H, CH2, 3J = 18.1 Hz); 3.96
(d, 2 H, CH2, 3J = 18.1 Hz); 5.30 (br.s, 2 H, 2 CH); 7.61 (s, 2 H,
2 NH); 12.75 (br.s, 2 H, 2 CH). Found (%): C, 37.25; H, 3.91;
N, 21.65. C8H10N4O6. Calculated (%): C, 37.22; H, 3.90;
N, 21.70.
Methyl 4ꢀ[6ꢀ(3ꢀmethoxycarbonyl)propylꢀ1,5ꢀdiphenylꢀ3,7ꢀ
dioxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octanꢀ2ꢀyl]butanoate (1f).
1
Yield 35%, m.p. 276—278 C. H NMR, : 1.69—1.81 (m, 4 H,
CH2); 2.26 (t, 4 H, CH2, J = 7.7 Hz); 2.56—2.73 (m, 2 H, CH2);
3.20—3.47 (m, 2 H, CH2); 3.56 (s, 6 H, OMe); 6.88—7.02 (m, 4 H,
Ph); 7.03—7.14 (m, 6 H, Ph); 8.21 (s, 2 H, NH). 13C NMR,
: 24.34, 30.87, 39.67 (CH2); 51.17 (OMe); 83.94 (CPh); 127.14,
127.75, 128.25, 129.47, 129.54 (Ph); 135.41, 135.49 (C(Ph));
158.98 (CO); 172.91 (COO). Found (%): C, 63.12; H, 6.13;
N, 11.30. C26H30N4O6. Calculated (%): C, 63.15; H, 6.11;
N, 11.33.
3,3´ꢀBi[((1R*,5S*)ꢀ2,4ꢀdioxaꢀ6,8ꢀdiazaꢀ7ꢀoxobicyclo[3.3.0]ꢀ
octanꢀ6ꢀyl)acetic acid] (5). Yield 20%, m.p. 330—332 C (deꢀ
comp.). 1H NMR, : 3.77 (d, 2 H, CH2, 3J = 17.7 Hz); 3.92 (d, 2 H,
3
CH2, J = 17.7 Hz); 4.88 (s, 2 H, 2 CH); 5.71 (s, 4 H, 4 CH);
8.08 (s, 2 H, 2 NH); 12.80 (br.s, 2 OH, 2 COOH). MS, m/z
(Irel (%)): 187 1/2[M]+ (6.91), 158 (5.91), 114 (26.83), 113 (32.63),
85 (24.92), 56 (45.25), 44 (71.77), 43 (32.96), 42 (100). Found (%):
C, 38.48; H, 3.79; N, 14.97. C12H14N4O10. Calculated (%):
C, 38.51; H, 3.77; N, 14.97.
Methyl 4ꢀ[8ꢀ(3ꢀmethoxycarbonyl)propylꢀ1,5ꢀdiphenylꢀ3,7ꢀ
dioxoꢀ2,4,6,8ꢀtetraazabicyclo[3.3.0]octanꢀ2ꢀyl]butanoate (2f).
1
Yield 8%, m.p. 165—167 C. H NMR, : 1.82—2.06 (m, 4 H,
CH2); 2.32 (t, 4 H, CH2, J = 7.3 Hz); 2.87—3.02 (m, 2 H, CH2);
3.10—3.24 (m, 2 H, CH2); 3.55 (s, 6 H, OMe); 6.70—6.80
(m, 2 H, Ph); 6.80—7.02 (m, 2 H, Ph); 7.03—7.16 (m, 6 H, Ph);
Synthesis of methyl esters of 2,6ꢀ (1d—f) and 2,8ꢀdi(carbꢀ
oxyalkyl)glycolurils (2d—f) (general procedure). To a solution of

Reactions of Nꢀ(carboxy(amino)alkyl)ureas
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
421
8.08 (s, 2 H, NH). 13C NMR, : 24.65, 30.77, 41.56 (CH2);
51.17 (OMe); 79.16, 89.97 (CPh); 127.06, 127.41, 127.73, 128.06,
128.44 (Ph); 133.59, 137.35 (C(Ph)); 159.93 (CO); 172.80
(COO). Found (%): C, 63.16; H, 6.10; N, 11.35. C26H30N4O6.
Calculated (%): C, 63.15; H, 6.11; N, 11.33.
8. A. N. Kravchenko, G. A. Gazieva, V. V. Baranov, L. V.
Anikina, Yu. B. Vikharev, Abstr. of Sci. Conf. "Biologically
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Svet, AR Crimea, Ukraine, May 23—28, 2011), Novy Svet,
Ukraine, 2011, 92.
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gachev, A. N. Kravchenko, Yu. V. Shklyaev, N. N. Makhoꢀ
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12 (in Russian).
This work was financially supported by the Division of
Chemistry and Materials Science of the Russian Academy
of Sciences (Program "Medicinal Chemistry").
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Received October 28, 2013;
in revised form December 6, 2013