Synthesis of selenium analogs of 1-Azabicyclo[3.3.1]nonane

Full text of DOI:10.1134/S0012500812030044

ISSN 0012ꢀ5008, Doklady Chemistry, 2012, Vol. 443, Part 1, pp. 80–81. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.N. Proshin, I.V. Serkov, S.O. Bachurin, 2012, published in Doklady Akademii Nauk, 2012, Vol. 443, No. 2, pp. 189–190.
CHEMISTRY
Synthesis of Selenium Analogs of 1ꢀAzabicyclo[3.3.1]nonane
A. N. Proshin, I. V. Serkov, and Corresponding Member of the RAS S. O. Bachurin
Received October 6, 2011
DOI: 10.1134/S0012500812030044
The synthesis of organoselenium compounds,
especially seleniumꢀcontaining heterocycles, have
lately attracted considerable attention due to their
chemical properties and a wide spectrum of biological
activity [1]. In particular, they show antioxidant [2],
antiꢀinflammatory [3], and antiviral [4] properties.
Isoselenocyanates are efficient reagents for the prepaꢀ
ration of seleniumꢀcontaining heterocyclic comꢀ
pounds on account of their high reactivity, low toxicꢀ
ity, and relative stability [5]. For example, isoselenocyꢀ
anates were used in the synthesis of selenazolidines
and selenadiazines [6].
Selenium analogs (2а–2с) of such bicyclic moleꢀ
cules in the series of 1ꢀazabicyclo[3.3.1]nonane were
obtained by the condensation of aryl isoselenocyanꢀ
ates (4а
isoselenocyanates (4а
corresponding formamides (3а
–
4с) with 3ꢀbromomethylpiperidine (
4с) were prepared from the
3с) by refluxing in
6). Aryl
–
–
toluene with phosgene and selenium (powder) in the
presence of triethylamine [8]. 3ꢀBromomethylpiperiꢀ
dine (6) was synthesized in quantitative yield from the
corresponding alcohol (
5) by heating at reflux with
hydrobromic acid. The condensation of the initial
compounds was carried out in an ethanol solution in
the presence of sodium hydrogen carbonate. Resulting
We reported recently the synthesis of bicyclic tetꢀ
selenourea (7а–7с) immediately undergoes intramoꢀ
rahydrothiazines (1), which can be considered as
lecular alkylation at the selenium atom, transformation
into isoselenourea, and ring closure to give a bicyclic
structure of Nꢀaryl(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ
cyclic derivatives of isothiourea [7]. This paper deals
with the synthesis of previously unknown seleniumꢀ
containing heterocyclic compounds.
2ꢀyliden)amine (2а–2с).
O
NH2
H
NCSe
N
COCl2
Se
R
R
R
4a–4c
NaHCO3
3a–3c
HN
N
Br
HBr
Se
N
OH
N
Br
·HBr
7a–7c
5
6
He Ha
1
HN
N
8
7
N
2 N
Ar
Ha
9
6
He
S
3
Se
5
4
1
Ha He
2a–2c
(R = H (a), 3'ꢀClꢀ4'ꢀMe (b), 4'ꢀF (c))
Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severnyi pr. 1,
Chernogolovka, Moscow oblast, 142432 Russia
80

SYNTHESIS OF SELENIUM ANALOGS OF 1ꢀAZABICYCLO[3.3.1]NONANE
81
The obtained bicyclic compounds (2а–2с) were
Nꢀ(3'ꢀChloroꢀ4'ꢀmethylphenyl)(3ꢀselenaꢀ1ꢀazabiꢀ
found to show high inhibitory activity in the cyclo[3.3.1]nonꢀ2ꢀyliden)amine 2b. Brown oil, yield
glutamateꢀstimulated 45Ca2+ uptake by rat cerebral
cortex synaptosomes, which affects pathological proꢀ
cesses in various neurodegenerative diseases [9]. Thus,
it was shown for compound 2b that Kinh = 5.6% (Kinh is
the percentage of 45Са2+ uptake by rat cerebral cortex
88.4%.
1H NMR (CDCl3,
Harom), 6.80 (d, 1H, J 2.0 Hz, Harom), 6.64 (dd, 1H,
2.0, 8.0 Hz, Harom), 4.21 (dm, 1H, 12.2 Hz,
C(9)He), 3.63 (dq, 1H, 1.9, 13.7 Hz, C(8)He),
3.21 (m, 3H, C(4)He, C(8)Ha, C(9)Ha), 2.84 (dd, 1H,
2.8, 11.6 Hz, C(4)Ha), 2.33 (s, 3H, CH3), 2.30 (dd,
1H, 2.8, 10.9 Hz, C(5)H), 1.81 (m, 3H, C(6)He,
C(7)H2), 1.47 (m, 1H, C(6)Ha).
ꢀ(4ꢀFluorophenyl)(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ
δ
, ppm): 7.14 (d, 1H, J 8.0 Hz,
J
J
J
synaptosomes relative to control, control = 100%) and
IC50 = 34.7
used in the treatment of Alzheimer disease, for examꢀ
ple Memantin ( inh = 8%, IC50 = 22.9 M).
µM are at the level of those for compounds
J
J
K
µ
N
2ꢀyliden)amine 2c. Colorless crystals, mp 106–108°C,
yield 93.5%.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker CXPꢀ
200 spectrometer (Germany), chemical shifts are
given on the δ scale using Me4Si as a reference. Meltꢀ
ing points were determined with the use of a Boetius
hotꢀstage apparatus and they were uncorrected. Soluꢀ
tions were concentrated by rotary evaporation in a
vacuum of a waterꢀjet pump.
1H NMR (CDCl3,
6.82 (m, 2H, Harom), 4.25 (dd, 1H,
C(9)He), 3.67 (dd, 1H, 2.2, 13.7 Hz, C(8)He),
3.26 (m, 3H, C(4)He, C(8)Ha, C(9)Ha), 2.88 (dd, 1H,
2.7, 11.5 Hz, C(4)Ha), 2.33 (dd, 1H, 2.8, 10.8 Hz,
δ, ppm): 7.03 (m, 2H, Harom),
J
2.3, 12.8 Hz,
J
J
J
C(5)H), 1.89 (m, 3H, C(6)He, C(7)H2), 1.51 (m, 1H,
C(6)Ha).
Synthesis of
Nꢀaryl(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ
2ꢀyliden)amines (2a–2c) (general procedure).
ACKNOWLEDGMENTS
Aryl isoselenocyanate 4а–4с (0.01 mol) and 3ꢀbroꢀ
This work was supported by the Russian Foundaꢀ
tion for Basic Research (project no. 01–03–00863ꢀa)
and the Ministry of Education and Science of the Rusꢀ
sian Federation (State Contract no. 14.740.11.0810).
momethylpiperidine (2.56 g, 0.01 mol) were disꢀ
6
solved in 30 mL of methanol. A solution of sodium
hydrogen carbonate (1.85 g, 0.022 mol) in a minimal
amount of water was added dropwise to the resultant
solution and the mixture was stirred at ambient temꢀ
perature for 1 h. The reaction mixture was diluted with
water (20 mL), the methanol was evaporated, and the
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DOKLADY CHEMISTRY Vol. 443
Part 1
2012