New functional glycoluril derivatives

Article abstract of DOI:10.1070/MC2001v011n01ABEH001357

Functional glycoluril (2,4,6,8-tetraazabicyclo[3.3.0]octan-3,7-dione) derivatives containing 2-hydroxyethyl, carboxyl and amino groups were synthesised.

Full text of DOI:10.1070/MC2001v011n01ABEH001357

, 2001, 11(1), 32–33
New functional glycoluril derivatives
Konstantin Yu. Chegaev, Angelina N. Kravchenko, Oleg V. Lebedev and Yurii A. Strelenko
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119992 Moscow, Russian Federation.
Fax: +7 095 135 5328
10.1070/MC2001v011n01ABEH001357
Functional glycoluril (2,4,6,8-tetraazabicyclo[3.3.0]octan-3,7-dione) derivatives containing 2-hydroxyethyl, carboxyl and amino
groups were synthesised.
It is well known that glycoluril derivatives (2,4,6,8-tetraaza-
R
O
R
O
bicyclo[3.3.0]octan-3,7-diones, TABODs) show a wide range
of biological activity,1,2 for example, 2,4,6,8-tetramethyl-
2,4,6,8-tetraazabicyclo[3.3.0]octan-3,7-dione is used in clinical
practice as the tranquilliser Mebicar.3 The capability of TABODs
to exhibit simultaneously both hydrophilic and lipophilic pro-
perties is responsible for the physiological action of these
compounds. On the one hand, they can easily penetrate into the
body and, on the other hand, readily overcome the hemato-
encephalic barrier. It is interesting to perform a combinatorial
synthesis of TABODs with other known classes of biological
substances in order to refine the mechanism of biological ef-
fects. To solve this problem, we prepared functional TABOD
derivatives containing amino, 2-hydroxyethyl and carboxyl
groups for the first time.
The addition of functional groups to nitrogen atoms of
TABODs was almost not described in the literature. Only
particular examples of N-hydroxymethyl derivatives, which
were prepared by the reaction of TABODs with an alkaline
formaldehyde solution, are known.4 For the most part, di-N-
hydroxymethyl and tetra-N-hydroxymethyl derivatives of
TABODs were synthesised.
i
(CH2)n
(CH2)n
H2N
OH
HN
OH
O
NH2
1a
n = 1, R = H
1b = 0, R = H
n
n
1c = 0, R = Me
Scheme 2 Reagents and conditions: i, H2O, KCNO, reflux for 20 min,
addition of HCl to pH 3.
Ureas 1a–e were entered into a bicyclization reaction with
dihydroxyimidazolidin-2-ones 2a,b. As a result, new functional
TABOD derivatives 3a–g were obtained (Scheme 3).
It is interesting to note that the reaction of S(–) 1c with 2a is
diastereoselective. The 1H NMR spectrum of 3e exhibits signals
due to protons of two diastereoisomers. An analysis of the most
Me
NH
Me
NH
O
Two approaches may be suggested to prepare TABOD
derivatives of interest. One of them consists in the introduction
of a functional group into a completed TABOD molecule,
which is used for the hydroxymethyl derivatives of TABODs.
The other uses a bicyclization reaction involving specially syn-
thesised ureas containing functional groups at nitrogen atoms.
We decided on the latter method because the nitrogen atoms of
TABODs exhibit a weak nucleophilicity.
O
HN
HN
NH
OH
O
Me
1e
1d
It is well known that TABODs can be prepared by the reac-
tion of ureas with α-dicarbonyl compounds or 4,5-dihydroxy-
imidazolidin-2-ones in aqueous or aqueous-ethanol media in
the presence of acids5 (Scheme 1).
1
informative portion of the H NMR spectrum (the range 4.0–
4.5 ppm of signals due to CH protons) indicated that according
to integral intensities the ratio between diastereoisomers in the
reaction mixture is 2:5. This ratio remained almost unchanged
in the course of isolation of 3e.†
R
R
R
O
O
NH
R1
R3
R1
R3
O
H+
HO
HO
R
R
NH
N
N
N
N
N
NH
R
R
R
i
O
O
O
O
N
N
N
N
N
NH
R2
O
O
R2
R3
R3
H+
R
R
R
R
R
R
1
2
3
NH
N
N
HO
HO
1: a R1 = H, R2 = CH2CH2COOH
b R1 = H, R2 = CH2COOH
O
O
NH
R
c R1 = H, R2 = CH(Me)COOH
R
d R1 = Me, R2 = CH2CH2NHCOMe
e R1 = Me, R2 = CH2CH2OH
Scheme 1
2: a R3 = H
b R3 = Me
The syntheses of ureas containing amino acid units starting
from amino acid esters are known.6,7 We developed a simple
procedure for preparing ureas directly from relevant amino
acids 1a–c (Scheme 2).
With the use of S(+)-α-alanine, the S(–) isomer of 1c was
isolated, as found by polarimetry ([a]D23 –8.25°, c = 2, H2O).
Other ureas 1d and 1e containing 2-(N-acetyl)aminoethyl and
2-hydroxyethyl groups, respectively, were prepared according
to standard procedures.8,9
3: a R1 = R3 = H, R2 = CH2CH2COOH
b R1 = H, R2 = CH2CH2COOH, R3 = Me
c R1 = R3 = H, R2 = CH2COOH
d R1 = H, R2 = CH2COOH, R3 = Me
e R1 = R3 = H, R2 = CH(Me)COOH
f R1 = Me, R2 = CH2CH2OH, R3 = H
g R1 = R3 = Me, R2 = CH2CH2NHCOMe
Scheme 3 Reagents and conditions: i, H2O, pH 1, 90 °C, 1 h.
– 32 –

, 2001, 11(1), 32–33
Me Me
It would be expected that not only compound 3g, but also
alternative compounds 3g' and 3g'' result from the reaction
between 1d and 2b.
O
Me
O
Me
Me
Me
N
N
N
N
N
N
N
The structure of 3g was supported by 15N NMR spectro-
scopy. Thus, in an INEPT experiment adjusted to the direct
coupling constant 15N–1H, the 15N NMR spectrum exhibited a
N
N
O
O
O
O
N
NH
N
N
Me
Me
Me
O
†
1
The H, 13C and 15N NMR spectra of solutions in [2H6]DMSO were
O
NHMe
Me
HN
Me
recorded on a Bruker AM 300 spectrometer. Chemical shifts were
measured with reference to the signals of the solvent at d 2.50 ppm
O
3g
3g'
3g''
1
([2H6]DMSO, H NMR) and 39.50 ppm (13C NMR) or with the use of
an external standard (MeNO2, 15N NMR). The structures of new com-
pounds were confirmed by elemental analysis.
doublet of the NH group at –266.8 ppm with the constant
1J(15N–1H) = 91.9 Hz. On the selective polarisation transfer from
the protons of the MeCO group (1.72 ppm in the 1H NMR
spectrum), the 15N NMR signal was observed with the same
chemical shift and splitting due to direct NH coupling, J 91.9 Hz,
and antiphase splitting, J 2.0 Hz, due to long-range coupling
with Me protons. This is indicative of the presence of the
MeCONH unit in the molecule of only compound 3g.
Compounds 3a–g are of special interest as biologically active
substances, and the introduced functional groups make it
possible to combine TABODs with a wide variety of natural
compounds.
1a: yield 96%, mp 180–182 °C. 1H NMR ([2H6]DMSO) d: 2.30 (t,
2H, CH2), 3.17 (q, 2H, CH2), 5.70 (s, 2H, NH2), 6.22 (t, 1H, NH).
1b: yield 98%, mp 193–195 °C. 1H NMR ([2H6]DMSO) d: 3.65 (d,
2H, CH2), 5.69 (s, 2H, NH2), 6.22 (t, 1H, NH).
1c: yield 84%, mp 224–226 °C. 1H NMR ([2H6]DMSO) d: 1.22 (d,
3H, Me), 4.05 (m, 1H, CH), 5.57 (s, 2H, NH2), 6.22 (d, 1H, NH), 12.0–
12.8 (br. s, 1H, COOH).
1d: yield 76%, mp 155–157 °C. 1H NMR ([2H6]DMSO) d: 1.76 (s,
3H, MeCO), 2.43 (s, 3H, Me), 3.02 (m, 4H, 2CH2), 5.48 (s, 2H, NH2),
6.01 (d, 1H, NH).
1
1e: yield 93%. H NMR ([2H6]DMSO) d: 2.48 (d, 3H, Me), 3.01 (q,
2H, CH2), 3.35 (t, 2H, CH2), 4.4 (br. s, OH), 5.05 (d, H, CH), 6.0 (br. s,
2H, 2NH).
This work was supported by INTAS (grant no. 99-0157).
3a: yield 58%, mp 215–217 °C. 1H NMR ([2H6]DMSO) d: 2.3–2.6
(m, 2H, CH2), 2.9–3.3 (m, 2H, CH2), 5.12 (d, 1H, CH), 5.23 (d, 1H,
CH), 7.11 (s, 1H, NH), 7.20 (s, 1H, NH), 7.28 (s, 1H, NH).
3b: yield 28%, mp 187–191 °C. 1H NMR ([2H6]DMSO) d: 2.35–2.60
(m, 2H, CH2), 2.64 (s, 3H, Me), 2.83 (s, 3H, Me), 3.20–3.60 (m, 2H,
CH2), 5.09 (d, 1H, CH), 5.22 (d, 1H, CH), 7.68 (s, 1H, NH), 12.2–12.4
(br. s, 1H, COOH).
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 neirotropnykh preparatov (Directed Search for Novel
Neurotropic Drugs), Zinatne, Riga, 1983, p. 81 (in Russian).
2 Uspekhi khimii v sozdanii novykh biologicheski aktivnykh soedinenii
(Chemical Advances in the Development of New Biologically Active
Compounds), ed. A. A. Bakibaev, Tomsk Polytechnic University, Tomsk,
1998, p. 67 (in Russian).
3 M. D. Mashkovskii, Lekarstvennye sredstva (Drugs), Meditsina, Moscow,
1993, p. 99 (in Russian).
4 H. Petersen, Text. Res. J., 1971, 41, 239.
5 H. Petersen, Synthesis, 1973, 243.
6 C. Harries and M. Weiss, Liebigs Ann. Chem., 1903, 355.
7 H. Knolker and T. Braxmeier, Synlett, 1997, 925.
3c: yield 60%, mp 273–275 °C. 1H NMR ([2H6]DMSO) d: 3.62 (d,
1H, CH2), 3.97 (d, 1H, CH2), 5.28 (s, 2H, CH–CH), 7.29 (s, 2H, 2NH),
7.51 (s, 1H, NH).
3d: yield 31%, mp 258–260 °C. 1H NMR ([2H6]DMSO): 2.66 (s, 3H,
Me), 2.76 (s, 3H, Me), 3.83 (d, 1H, CH2), 4.03 (d, 1H, CH2), 5.14–5.23
(m, 2H, CH–CH), 7.90 (s, 1H, NH).
3e: yield 37%. 1H NMR ([2H6]DMSO) d: diastereomer 1: 1.38 (d, 3H,
Me), 4.02 (q, 1H, CH), 5.21 (d, 1H, CH), 5.30 (d, 1H, CH), 7.19 (s, 1H,
NH), 7.23 (s, 1H, NH), 7.41 (s, 1H, NH); diastereomer 2: 1.41 (d, 3H,
Me), 4.31 (q, 1H, CH). 13C NMR: diastereomer 1: 14.66 (Me), 51.82
(CH), 62.68 (CH), 67.68 (CH), 158.73 (CO), 160.95 (CO), 172.05
(COOH); diastereomer 2: 15.83 (Me), 51.96 (CH), 62.80 (CH), 67.08
(CH), 159.35 (CO), 161.21 (CO), 172.38 (COOH).
3f: yield 21%, mp 142–144 °C. 1H NMR ([2H6]DMSO) d: 2.66 (s,
3H, Me), 3.05–3.25 (m, 2H, CH2), 3.46 (t, 2H, CH2), 5.21 (d, 1H, CH),
5.29 (d, 1H, CH), 7.25–7.50 (br. s, 2H, NH).
8 T. L. Davis and K. C. Blachard, J. Am. Chem. Soc., 1923, 45, 1818.
9 F. Arndt, C. R. Noller and J. Georgsteinsson, Org. Synth., 1953, 15, 48.
3g: yield 34%, mp 127–130 °C. 1H NMR ([2H6]DMSO) d: 1.72 (s,
3H, COMe), 2.68 (s, 3H, Me), 2.71 (s, 3H, Me), 2.75 (s, 3H, Me), 2.95–
3.15 (m, 2H, CH2), 3.28–3.42 (m, 2H, CH2), 4.78 (d, 1H, CH), 5.06 (d,
1H, CH), 7.18 (t, H, NH). 13C NMR, d: 22.15 (Me), 37.31 (CH2), 42.41
(CH2), 68.88 (CH), 71.91 (CH), 158.35 (CO), 158.76 (CO), 170.07 (CO).
Received: 7th July 2000; Com. 00/1683
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