N-silylation of 2,4,6-trialkyl-2,4,6,8-tetraazabicyclo-|3.3.0|octane-3,7-diones

Article abstract of DOI:10.1023/A:1021789731836

N-Trimethylsilyl derivatives of 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones have been prepared for the first time and the electrophilic substitution reaction of the trimethylsilyl group has been studied.

Full text of DOI:10.1023/A:1021789731836

Chemistry of Heterocyclic Compounds, Vol. 38, No. 10, 2002
N-SILYLATION OF 2,4,6-TRIALKYL-
2,4,6,8-TETRAAZABICYCLO-
[3.3.0]OCTANE-3,7-DIONES
K. Yu. Chegaev, A. N. Kravchenko, O. V. Lebedev, Yu. A. Strelenko, and P. A. Belyakov
N-Trimethylsilyl derivatives of 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones have been prepared for
the first time and the electrophilic substitution reaction of the trimethylsilyl group has been studied.
Keywords: 2,4,6-trialkyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones, silylation, electrophilic
substitution, nuclear Overhauser effect.
The silylation of 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones (TABOD) has not been reported in the
literature. The trimethylsilyl derivatives of TABOD attracted our attention most particularly because, on the
basis of data obtained by the QSAR method, these compounds had been shown to be potentially promising
psychotropically active materials [1]. On the other hand, they are of interest both from a practical and from a
theoretical viewpoint as novel, chiral species.
The silylation reaction was studied for the case of the tri-N-alkyl-substituted TABOD 1a-c, whose
synthesis has been described by us previously [2]. Trimethylchlorosilane was chosen as the most readily
available silylating agent. We have studied the effect of different proton acceptors (pyridine, triethylamine, and
hexamethyldisilazane) and solvents (CH2Cl2, CHCl3, and acetone) on the yield. The optimum yields of the
trimethylsilyl derivatives of TABOD 2a-c (85-93%) are achieved with hexamethyldisilazane and CH2Cl2.
R2
N
R1
N
R2
N
R1
N
i
O
O
O
O
N
N
H
N
N
R1
1a–c
R1
SiMe3
2a–c
1, 2 a R1 = R2 = Me; b R1 = Me, R2 = Et; c R1 = Et, R2 = Me
i = CH2Cl2; Me3SiCl; (Me3Si)2NH; ~20°C, 1 h
An example has been reported in the literature for the formation of O-derivatives of TABOD in
alkylation reactions [3]. We have shown that the silylation of 1a-c occurs not at an oxygen but at the nitrogen
atom. The structure of the synthesized compounds 2a-c was proved by experimental NOE measurement [4]. The
signal for the trimethylsilyl protons was saturated and changes in the intensity of the signals for the central H1
proton and the protons of the substituent R1 (Scheme 1) were observed. As a result it was shown that the
trimethylsilyl group is situated on the nitrogen atom.
__________________________________________________________________________________________
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913, Russia;
e-mail: mnn@cacr.ioc.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1417-1420,
October, 2002. Original article submitted January 14, 2000; revision submitted November 12, 2001.
1250
0009-3122/02/3810-1250$27.00©2002 Plenum Publishing Corporation

Scheme 1
R2
N
R1
N
O
O
N
N
H1
R1
SiMe3
NOE
1
The H NMR spectra fully confirm the structure of the compounds 2a-c obtained. The protons of the
SiMe3 groups appear as singlets with chemical shifts of 0.38 (2a), 0.08 (2b), and 0.02 (2c) ppm. Due to their
nonequivalence, the methine protons form an AB system with the following constants, δ, ppm, J (Hz): for
compound 2a δA 4.95 and δB 5.05, JAB = 8.01; for compound 2b δA 4.85 and δB 4.91, JAB = 7.82; for compound
2c δA 4.88 and δB 5.96, JAB = 7.85. The N-methyl groups protons appear in the spectrum of compound 2a as
three singlets with chemical shifts 2.71, 2.80, and 3.00 ppm; in the spectrum of compound 2b as two singlets at
2.55 and 2.71 ppm; in the spectrum of compound 2c as one singlet at 2.52 ppm. Due to the diastereotopic nature
1
of the methylene protons of the ethyl groups they form an AMX3 spectroscopic system. Hence, the H NMR
spectrum (δ, ppm; J, Hz) of compound 2b shows a triplet (δ 0.90, JAX = JAM = 6.40) and a doublet of sextets
(δ 2.95 and 3.20, JAM = 2JAX = 12.80). The spectrum of compound 2c shows two AMX3 systems with the
following parameters: A'M'X'3 triplet (δX' 0.81, JA'X' = JA'M' = 7.11) and doublet of sextets (δA' 2.71, δM' 2.95,
J
A'M' = 2JA'X' = 14.22) and A''M''X''3 triplet (δX'' -0.92, JA''X'' = JA''M'' = 7.11) and doublet of sextets (δA'' 3.20,
δM'' 3.32, JA''M'' = 2JA''X'' = 14.22).
Hence we have synthesized for the first time the 4,6,8-trimethyl-2-trimethylsilyl-2,4,6,8-tetraazabicyclo-
[3.3.0]octane-3,7-dione (2a), 4-ethyl-6,8-dimethyl-2-trimethylsilyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-
dione (2b), and 6,8-diethyl-4-methyl-2-trimethylsilyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (2c) which
are novel, chiral species and show interest in connection with the problem of preparing optically pure
biologically active materials.
From a chemical viewpoint, the greatest interest is in the electrophilic substitution reaction of the
trimethylsilyl group. In a study of the desilylation of compounds 2a-c it was found that they are stable in
methanol but readily protodesilylated in an acidic medium (pH 3). This behavior can be incorporated when
carrying out biological experiments on animals to reveal psychotropic activity. The electrophilic substitution of
the trimethylsilyl group for an alkyl was studied for the example of the best known representative of this class of
compound which is the 2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (mebicar) [5]:
R1
N
Me
N
R1
N
SiMe3
N
ii
O
O
O
O
N
N
N
N
R2
R1
R2
R1
3a
2a
R1 = R2 = Me. ii = MeI, AgClO4, ~20°C, 2 h
The physicochemical properties of compound 3a correspond to data in [6]. Hence we have shown the
basis for the introduction of an alkyl substituent at the nitrogen atoms in TABOD and this opens up novel
synthetic possibilities for varying the substituent and for broadening out this class of compound.
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EXPERIMENTAL
1H NMR spectra of compound solutions were measured on a Bruker AM 300 (300 MHz) instrument
using CDCl3. Calibration was carried out using the signal for the residual protons of the solvent at 7.27 ppm.
29Si NMR spectra were recorded using selective polarization transfer from the protons. TLC was carried out on
Silufol UV-254 plates and CHCl3–MeOH (10:1).
Preparation of Compounds 2a-c. Each of compound 1a-c (8.15 mmol) was dissolved in CH2Cl2
(15 ml). (Me3Si)2NH (2 ml, 1.54 g, 9.5 mmol) was added followed by trimethylchlorosilane (1.35 ml, 1.15 g,
10.6 mmol) dropwise with stirring. The reaction product was stirred at room temperature for a further 1 h and
the NH4Cl precipitate was filtered off. The filtrate was evaporated in vacuo and the product was washed with
ether and dried in a desiccator over NaOH.
4,6,8-Trimethyl-2-trimethylsilyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (2a). Yield 93%;
mp 55°C (decomp.), Rf 0.64. 29Si NMR spectrum, δ, ppm: 9.90 (s, SiMe). Found, %: C 46.75; H 7.94; N 21.93.
C10H20N4O2Si. Calculated, %: C 46.88; H 7.81; N 21.88.
4-Ethyl-6,8-dimethyl-2-trimethylsilyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (2b). Yield 91%;
mp 58°C (decomp.), Rf 0.72. Found, %: C 48.82; H 8.23; N 20.83. C11H22N4O2Si. Calculated, %: C 48.89;
H 8.15; N 20.74.
6,8-Diethyl-4-methyl-2-trimethylsilyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (2c). Yield 85%;
mp 52°C (decomp.), Rf 0.81. Found, %: C 50.63; H 8.52; N 19.87. C12H24N4O2Si. Calculated, %: C 50.70;
H 8.45; N 19.72.
Preparation of Compound 3a. Compound 2a (1 g, 3.9 mmol) was dissolved in CH3I (5 ml). AgClO4
(0.9 g, 4.3 mmol) was added with stirring. The reaction mixture was left at room temperature for 2 h and then
diluted with MeOH (10 ml). The precipitated AgI was filtered off, the filtrate evaporated, and the product was
washed with Et2O to give compound 3a (0.41 g, 53%); mp 230-232°C (mp 231-232°C in [6]), Rf 0.54.
REFERENCES
1.
I. V. Svitan'ko, I. L. Zyryanov, M. I. Kumskov, L. I. Khmel'nitskii, L. I. Suvorova, A. N. Kravchenko,
T. B. Markova, O. V. Lebedev, G. A. Orekhova, and S. V. Belova, Mendeleev Commun., No. 2, 49
(1995).
2.
3.
A. N. Kravchenko, O. V. Lebedev, and E. Yu. Maksareva, Mendeleev Commun., No. 1, 27 (2000).
L. I. Suvorova, L. V. Epishina, O. V. Lebedev, L. I. Khmel'nitskii, and S. S. Novikov in O-Alkyl
Derivatives of Saturated Condensed Bisureas [in Russian], Summary Documents. II Moscow
Conference for Chemistry and Technology, D. I. Mendeleev VKO, Moscow (1979), p. 50.
L. Birkofer, A. Ritter, and H. Kuhlthau, Chem. Ber., 97, 934 (1964).
4.
5.
6.
M. D. Mashkovskii, Medicinal Compounds [in Russian], Meditsina, Moscow (1993), p. 99.
J. Nematolahi and R. Ketcham, J. Org. Chem., 28, 2378 (1963).
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