Synthesis and properties of 3-substituted 3-azabicyclo-[3.3.1]nonan-9- amines

Article abstract of DOI:10.1134/S1070428011070062

Catalytic hydrogenation of 3-benzyl- and 3-tert-butoxycarbonyl-3- azabicyclo[3.3.1]nonan-9-one oximes over Raney nickel gave the corresponding 3-substituted 3-azabicyclo[3.3.1]nonan-9-amines which were converted into amides via reactions with acetyl and c

Full text of DOI:10.1134/S1070428011070062

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 7, pp. 1003–1010. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.I. Moskalenko, A.Yu. Chashchin, V.I. Boev, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 7, pp. 989–996.
Synthesis and Properties of 3-Substituted 3-Azabicyclo-
[3.3.1]nonan-9-amines
A. I. Moskalenko, A. Yu. Chashchin, and V. I. Boev
Lipetsk State Pedagogical University, ul. Lenina 42, Lipetsk, 398020 Russia
e-mail: kaf_himii@lspu.lipetsk.ru
Received November 16, 2009
Abstract—Catalytic hydrogenation of 3-benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-one
oximes over Raney nickel gave the corresponding 3-substituted 3-azabicyclo[3.3.1]nonan-9-amines which were
converted into amides via reactions with acetyl and chloroacetyl chlorides and maleic and succinic anhydrides,
into Schiff bases by condensation with benzaldehyde and 4-chlorobenzaldehyde, and into isothiocyanates
by treatment with thiophosgene in the presence of K2CO3. 3-Benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo-
[3.3.1]nonan-9-yl isothiocyanates readily reacted with methanol, aniline, and sodium azide to produce methyl
thiocarbamate, thiourea, and dihydrotetrazole-5-thione derivatives having a 3-azabicyclo[3.3.1]nonane
fragment.
DOI: 10.1134/S1070428011070062
In continuation of our studies on 3-azabicyclo-
[3.3.1]nonane derivatives [1, 2] as potential biologi-
cally active compounds [3], in the present work we
synthesized for the first time some 3-substituted 3-aza-
bicyclo[3.3.1]nonan-9-amines having a primary amino
group and obtained a number of their derivatives at the
amino group. The optimal procedure for the synthesis
of 3-azabicyclo[3.3.1]nonan-9-amines IIa and IIb is
catalytic reduction of the corresponding accessible
3-azabicyclo[3.3.1]nonan-9-one oximes Ia and Ib [2]
with hydrogen over Raney nickel. This procedure
ensured smooth formation of target amines IIa and IIb
in 73–76% yield (Scheme 1).
3370–3360 cm–1 due to stretching vibrations of N–H
bonds. In the 1H NMR spectra of IIa and IIb, the NH2
protons resonated as a broadened singlet at δ 4.23 ppm,
and a new signal appeared in the region δ 3.62–
3.80 ppm due to 9-H (no such signal was observed in
the spectra of the initial compounds).
Diverse chemical transformations of amines IIa
and IIb provided additional proofs for their structure
and demonstrated wide potential of their application in
organic synthesis for the preparation of new com-
pounds having an azabicyclic fragment. Amines IIa
and IIb readily reacted with acetyl and chloroacetyl
chlorides in the presence of triethylamine, as well as
with maleic and succinic anhydrides on heating in
anhydrous chloroform. As a result, N-substituted
amides III–VI were obtained. Maleamic and succin-
amic acid derivatives Va, Vb, VIa, and VIb were
subjected to intramolecular cyclization on heating in
acetic anhydride. We thus isolated the corresponding
N-substituted maleimides VIIa and VIIb and succin-
amides VIIIa and VIIIb (Scheme 2).
Scheme 1.
OH
N
NH2
[H], Raney nickel
THF, 50 atm, 60°C
N
N
R
R
Ia, Ib
IIa, IIb
Schiff bases IXa, IXb, Xa, and Xb were synthe-
sized by condensation of amines IIa and IIb with
benzaldehyde and 4-chlorobenzaldehyde on heating in
boiling anhydrous ethanol. Compounds IXa, IXb,
Xa, and Xb are promising as intermediate products in
organic synthesis. Their reduction with sodium tetra-
hydridoborate afforded secondary aromatic amines
R = PhCH2 (a), t-BuOC(O) (b).
The purity and structure of compounds IIa and IIb
were confirmed by their elemental analyses and IR, 1H
NMR, and mass spectra (GC–MS). The IR spectra of
IIa and IIb contained absorption bands in the region
1003

MOSKALENKO et al.
1004
Scheme 2.
NHCOR'
R'COCl, NEt3, THF
–Et3N·HCl
N
R
IIIa, IIIb, IVa, IVb
O
COOH
O
O
HN
N
, CHCl3
O
O
O
Ac2O
–H2O
IIa, IIb
N
R
N
R
Va, Vb
VIIa, VIIb
O
O
N
O
HN
COOH
, CHCl3
O
O
O
Ac2O
–H2O
N
R
N
R
VIa, VIb
VIIIa, VIIIb
R = PhCH2 (a), t-BuOC(O) (b); III, Me; IV, R′ = ClCH2.
Scheme 3.
HN
NaBH4
R'
N
R
N
CHO
XIa, XIb, XIIa, XIIb
EtOH
–H2O
R'
IIa, IIb
+
S
R'
N
O
N
R
R'
IXa, IXb, Xa, Xb
HSCH2COOH
N
R
XIIIa, XIIIb, XIVa, XIVb
R = PhCH2 (a), t-BuOC(O) (b); IX, XI, XIII, R′ = H; X, XII, XIV, R′ = Cl.
XIa, XIb, XIIa, XIIb, and the reaction with 2-sul-
fanylacetic acid in boiling anhydrous benzene led to
the formation of bicyclic thiazolidin-4-one derivatives
XIIIa, XIIIb, XIVa, and XIVb (Scheme 3).
An important synthetic transformation of primary
amino group is achieved via reaction with thiophos-
gene. In such a way we obtained bicyclic isothiocy-
anates XVa and XVb. As might be expected, com-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

SYNTHESIS AND PROPERTIES OF 3-SUBSTITUTED 3-AZABICYCLO[3.3.1]NONAN-...
1005
Scheme 4.
S
HN
OMe
MeOH
N
R
XVIa, XVIb
S
S
·
HN
NHPh
N
S
PhNH2, PhH
K2CO3, Me2CO
IIa, IIb
+
Cl
Cl
N
N
R
R
XVIIa, XVIIb
XVa, XVb
N
NH
N
S
N
NaN3
N
R
XVIIIa, XVIIIb
R = PhCH2 (a), t-BuOC(O) (b).
the presence of highly reactive functional groups the
products may be used to create combinatorial libraries
with a view to perform broader biological screening.
pounds XVa and XVb turned out to be highly reactive
toward various nucleophiles. By heating isothiocy-
anates XVa and XVb in anhydrous methanol we syn-
thesized methyl thiocarbamates XVIa and XVIb in
quantitative yield; the reaction of XVa and XVb with
aniline in boiling anhydrous benzene gave thiourea
derivatives XVIIa and XVIIb, and treatment of the
same substrates with sodium azide in water afforded
1-substituted dihydrotetrazole-5-thiones XVIIIa and
XVIIIb (Scheme 4).
EXPERIMENTAL
The IR spectra were recorded in KBr on a Specord
1
75IR spectrometer. The H NMR spectra were meas-
ured on a Varian Mercury Plus-400 spectrometer
(400 MHz) from solutions in CDCl3 using hexamethyl-
disiloxane as internal reference. The mass spectra (at-
mospheric pressure chemical ionization) were obtained
on a Thermo Finnigan Surveyor MSQ GC–MS instru-
ment (USA). The purity of the isolated compounds
was checked by thin-layer chromatography on Silufol
UV-254 plates using hexane–ethyl acetate (1:1) as
eluent; spots were visualized under UV light or by
treatment with iodine vapor.
Compounds IIb–XVIIIb having a tert-butoxycar-
bonyl group (Boc) on the nitrogen atom were readily
deprotected by treatment with a saturated solution of
hydrogen chloride in anhydrous dioxane to produce the
corresponding 3-azabicyclo[3.3.1]nonane derivatives
having no substituent on N3 as hydrochlorides. Anal-
ogous water-soluble hydrochlorides were obtained
from compounds IIa–XVIIIa with conservation of the
initial structure.
3-Benzyl-3-azabicyclo[3.3.1]nonan-9-amine
(IIa). A high-pressure reactor was charged with 24.4 g
(0.1 mol) of oxime Ia [2] and 10 g of Raney nickel in
250 ml of anhydrous THF, and hydrogen was supplied
The structure of the newly synthesized compounds
was confirmed by analytical and spectral data. Due to
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

MOSKALENKO et al.
1006
Compounds IIIb, IVa, and IVb were synthesized in
a similar way.
at a pressure of 50 atm at 60°C over a period of 10 h
until the initial oxime disappeared (according to the
TLC data) and hydrogen was no longer absorbed. The
catalyst was filtered off and washed with 100 ml of
THF, the filtrate was evaporated under reduced pres-
sure, and the oily residue was dissolved in ethyl acetate
and purified by chromatography on silica gel using
ethyl acetate–hexane (1:1) as eluent. Yield 16.82 g
(73%), mp 66–68°C. IR spectrum, ν, cm–1: 3369, 3358
tert-Butyl 9-acetylamino-3-azabicyclo[3.3.1]-
nonane-3-carboxylate (IIIb). Yield 92%, mp 135–
137°C. IR spectrum, ν, cm–1: 3401 (NH); 1698, 1683
1
(C=O). H NMR spectrum, δ, ppm: 1.31 s (9H, t-Bu),
1.46–2.14 m (6H, CH2), 2.03 s (3H, CH3), 2.35–2.42 m
(2H, CH), 3.41 d (2H, NCH2), 3.61 d (2H, NCH2),
3.98 m (1H, 9-H), 7.01 br.s (1H, NH). Mass spectrum,
m/z: 283 [M + H]+, 182 [M – 101 + H]+. Found, %:
C 63.71; H 9.36; N 9.81. C15H26N2O3. Calculated, %:
C 63.83; H 9.22; N 9.93. M 282.
1
(NH2). H NMR spectrum, δ, ppm: 1.36–2.05 m (6H,
CH2), 2.12–2.21 m (2H, CH), 2.78 d (2H, NCH2),
2.85 d (2H, NCH2), 3.35 s (2H, PhCH2), 3.74 m (1H,
9-H), 4.24 br.s (2H, NH2), 7.04–7.18 m (5H, C6H5).
Mass spectrum: m/z 231 [M + H]+. Found, %: C 78.13;
H 9.45; N 12.08. C15H22N2. Calculated, %: C 78.26;
H 9.57; N 12.17. M 230.
N-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)-2-
chloroacetamide (IVa). Yield 90%, mp 114–116°C.
IR spectrum, ν, cm–1: 3398 (NH), 1698 (C=O).
1H NMR spectrum, δ, ppm: 1.38–2.05 m (6H, CH2),
2.15–2.24 m (2H, CH), 2.83 d (2H, NCH2), 2.89 d
(2H, NCH2), 3.41 s (2H, PhCH2), 3.85 m (1H, 9-H),
4.45 s (2H, CH2Cl), 6.97 br.s (1H, NH), 7.11–7.24 m
(5H, C6H5). Mass spectrum: m/z 307 [M + H]+. Found,
%: C 66.38; H 7.42; N 9.26. C17H23ClN2O. Calculated,
%: C 66.56; H 7.50; N 9.14. M 306.
tert-Butyl 9-amino-3-azabicyclo[3.3.1]nonane-3-
carboxylate (IIb) was synthesized in a similar way.
Yield 71%, mp 87–90°C. IR spectrum, ν, cm–1: 3365,
1
3351 (NH2); 1684 (C=O). H NMR spectrum, δ, ppm:
1.31 s (9H, t-Bu), 1.46–2.12 m (6H, CH2), 2.36–
2.42 m (2H, CH), 3.42 d (2H, NCH2), 3.60 d (2H,
NCH2), 3.81 m (1H, 9-H), 4.25 br.s (2H, NH2). Mass
spectrum, m/z: 241 [M + H]+, 140 [M – 101 + H]+.
Found, %: C 64.83; H 10.14; N 11.52. C13H24N2O2.
Calculated, %: C 65.00; H 10.00; N 11.67. M 240.
tert-Butyl 9-(chloroacetylamino)-3-azabicyclo-
[3.3.1]nonane-3-carboxylate (IVb). Yield 87%,
mp 128–130°C. IR spectrum, ν, cm–1: 3402 (NH);
1
1701, 1684 (C=O). H NMR spectrum, δ, ppm: 1.32 s
(9H, t-Bu), 1.47–2.15 m (6H, CH2), 2.36–2.44 m (2H,
CH), 3.42 d (2H, NCH2), 3.60 d (2H, NCH2), 4.01 m
(1H, 9-H), 4.48 s (2H, CH2Cl), 7.03 br.s (1H, NH).
Mass spectrum, m/z: 317 [M + H]+, 216 [M – 101 + H]+.
Found, %: C 56.71; H 7.69; N 8.74. C15H25ClN2O3.
Calculated, %: C 56.87; H 7.90; N 8.85. M 316.
N-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)acet-
amide (IIIa). A solution of 0.47 g (6 mmol) of acetyl
chloride in 5 ml of methylene chloride was added un-
der stirring at 0–5°C to a solution of 1.15 g (5 mmol)
of amine IIa and 0.6 g (6 mmol) of triethylamine in
20 ml of anhydrous methylene chloride. The mixture
was then allowed to warm up to room temperature,
stirred for 1 h until the initial amine disappeared com-
pletely (TLC), and poured into 100 ml of water. The
organic phase was separated, the aqueous phase was
extracted with methylene chloride (2×30 ml), the ex-
tracts were combined with the organic phase and dried
over anhydrous sodium sulfate, and the solvent was
distilled off under reduced pressure. The oily residue
crystallized on storage and was recrystallized from
hexane–ethyl acetate (4:1). Yield 1.27 g (93%),
mp 101–103°C. IR spectrum, ν, cm–1: 3396 (NH),
4-(3-Benzyl-3-azabicyclo[3.3.1]non-9-ylamino)-
4-oxobut-2-enoic acid (Va). Maleic anhydride,
0.216 g (2.2 mmol), was added to a solution of 0.5 g
(2.2 mmol) of amine IIa in 5 ml of anhydrous chloro-
form, and the mixture was heated for 1 h under reflux
until the initial amine disappeared completely (TLC).
The solvent was removed under reduced pressure, and
the residue was recrystallized from hexane–ethyl
acetate (1:1). Yield 0.46 g (64%), mp 116–117°C. IR
spectrum, ν, cm–1: 3482 (OH); 3404 (NH); 1728, 1719
(C=O); 1622 (C=C). 1H NMR spectrum, δ, ppm: 1.38–
2.07 m (6H, CH2), 2.09–2.24 m (2H, CH), 2.93 d (2H,
NCH2), 3.05 d (2H, NCH2), 3.41 s (2H, PhCH2),
3.89 m (1H, 9′-H), 6.05 d (1H, 3-H, J = 15.1 Hz),
6.74 d (1H, 2-H, J = 15.1 Hz), 6.98 br.s (1H, NH),
7.12–7.26 m (5H, C6H5), 11.78 br.s (1H, COOH).
Mass spectrum: m/z 329 [M + H]+. Found, %: C 69.38;
H 7.36; N 8.31. C19H24N2O3. Calculated, %: C 69.51;
H 7.32; N 8.54. M 328.
1
1697 (C=O). H NMR spectrum, δ, ppm: 1.38–2.06 m
(6H, CH2), 1.98 s (3H, CH3), 2.14–2.24 m (2H, CH),
2.81 d (2H, NCH2), 2.87 d (2H, NCH2), 3.39 s (2H,
PhCH2), 3.87 m (1H, 9-H), 6.94 br.s (2H, NH2), 7.10–
7.23 m (5H, C6H5). Mass spectrum: m/z 273 [M + H]+.
Found, %: C 75.18; H 8.67; N 10.42. C17H24N2O. Cal-
culated, %: C 75.00; H 8.82; N 10.29. M 272.
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SYNTHESIS AND PROPERTIES OF 3-SUBSTITUTED 3-AZABICYCLO[3.3.1]NONAN-...
1007
Compounds Vb, VIa, and VIb were synthesized in
NCH2), 3.42 s (2H, PhCH2), 3.87 m (1H, 9′-H), 5.98 d
a similar way.
(2H, CH=CH, J = 12.3 Hz), 7.08–7.18 m (5H, C6H5).
Mass spectrum: m/z 311 [M + H]+. Found, %: C 73.46;
H 7.16; N 8.85. C19H22N2O2. Calculated, %: C 73.55;
H 7.10; N 9.03. M 310.
4-(3-tert-Butoxycarbonyl-3-azabicyclo[3.3.1]non-
9-ylamino)-4-oxobut-2-enoic acid (Vb). Yield 69%,
mp 131–132°C. IR spectrum, ν, cm–1: 3483 (OH);
3402 (NH); 1726, 1708, 1685 (C=O); 1622 (C=C).
1H NMR spectrum, δ, ppm: 1.30 s (9H, t-Bu), 1.47–
2.16 m (6H, CH2), 2.36–2.44 m (2H, CH), 3.43 d (2H,
NCH2), 3.62 d (2H, NCH2), 3.97 m (1H, 9′-H), 6.05 d
(1H, 3-H, J = 14.9 Hz), 6.75 d (1H, 2-H, J = 14.9 Hz),
6.98 br.s (1H, NH), 11.83 br.s (1H, COOH). Mass
spectrum, m/z: 339 [M + H]+, 238 [M – 101 + H]+.
Found, %: C 60.43; H 7.74; N 8.16. C17H26N2O5. Cal-
culated, %: C 60.36; H 7.69; N 8.28. M 338.
Compounds VIIb, VIIIa, and VIIIb were synthe-
sized in a similar way.
tert-Butyl 9-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-
yl)-3-azabicyclo[3.3.1]nonane-3-carboxylate (VIIb).
Yield 79%, mp 121–122°C. IR spectrum, ν, cm–1:
1
1724, 1720, 1688 (C=O); 1621 (C=C). H NMR spec-
trum, δ, ppm: 1.30 s (9H, t-Bu), 1.48–2.17 m (6H,
CH2), 2.35–2.46 m (2H, CH), 3.42 d (2H, NCH2),
3.64 d (2H, NCH2), 3.98 m (1H, 9′-H), 6.04 d (2H,
CH=CH, J = 12.5 Hz). Mass spectrum, m/z: 321
[M + H]+, 220 [M – 101 + H]+. Found, %: C 63.57;
H 7.58; N 8.61. C17H24N2O4. Calculated, %: C 63.75;
H 7.50; N 8.75. M 320.
4-(3-Benzyl-3-azabicyclo[3.3.1]non-9-ylamino)-
4-oxobutanoic acid (VIa). Yield 74%, mp 121–
122°C. IR spectrum, ν, cm–1: 3486 (OH); 3401 (NH);
1
1726, 1713 (C=O). H NMR spectrum, δ, ppm: 1.36–
2.08 m (6H, CH2), 2.10–2.23 m (2H, CH), 2.42–
2.73 m (4H, CH2CH2), 2.95 d (2H, NCH2), 3.06 d (2H,
NCH2), 3.42 s (2H, PhCH2), 3.89 m (1H, 9′-H),
6.97 br.s (1H, NH), 7.10–7.24 m (5H, C6H5), 12.02 br.s
(1H, COOH). Mass spectrum: m/z 331 [M + H]+.
Found, %: C 68.82; H 7.64; N 8.53. C19H26N2O3. Cal-
culated, %: C 69.09; H 7.88; N 8.48. M 330.
1-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)pyrroli-
dine-2,5-dione (VIIIa). Yield 69%, mp 98–100°C.
1
IR spectrum, ν, cm–1: 1725, 1710 (C=O). H NMR
spectrum, δ, ppm: 1.35–2.05 m (6H, CH2), 2.11–
2.34 m (6H, CH, CH2CH2), 2.97 d (2H, NCH2), 3.08 d
(2H, NCH2), 3.43 s (2H, PhCH2), 3.88 m (1H, 9-H),
7.12–7.25 m (5H, C6H5). Mass spectrum: m/z 313 [M +
H]+. Found, %: C 73.18; H 7.56; N 8.74. C19H24N2O2.
Calculated, %: C 73.08; H 7.69; N 8.97. M 312.
4-(3-tert-Butoxycarbonyl-3-azabicyclo[3.3.1]non-
9-ylamino)-4-oxobutanoic acid (VIb). Yield 76%,
mp 141–142°C. IR spectrum, ν, cm–1: 3485 (OH);
tert-Butyl 9-(2,5-dioxopyrrolidin-1-yl)-3-azabicy-
clo[3.3.1]nonane-3-carboxylate (VIIIb). Yield 74%,
mp 110–112°C. IR spectrum, ν, cm–1: 1726, 1711,
1
3398 (NH); 1727, 1712, 1686 (C=O). H NMR spec-
trum, δ, ppm: 1.31 s (9H, t-Bu), 1.46–2.15 m (6H,
CH2), 2.37–2.45 m (2H, CH), 2.48–2.75 m (4H,
CH2CH2), 3.42 d (2H, NCH2), 3.62 d (2H, NCH2),
3.97 m (1H, 9′-H), 7.01 br.s (1H, NH), 12.04 br.s (1H,
COOH). Mass spectrum, m/z: 341 [M + H]+, 240
[M – 101 + H]+. Found, %: C 59.91; H 8.33; N 8.17.
C17H28N2O5. Calculated, %: C 60.00; H 8.24; N 8.24.
M 340.
1
1687 (C=O). H NMR spectrum, δ, ppm: 1.31 s (9H,
t-Bu), 1.47–2.15 m (6H, CH2), 2.17–2.28 m (4H,
CH2CH2), 2.38–2.46 m (2H, CH), 3.43 d (2H, NCH2),
3.64 d (2H, NCH2), 4.01 m (1H, 9-H). Mass spectrum,
m/z: 323 [M + H]+, 222 [M – 101 + H]+. Found, %:
C 63.52; H 7.94; N 8.73. C17H26N2O4. Calculated, %:
C 63.35; H 8.07; N 8.70. M 322.
1-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)-1H-pyr-
role-2,5-dione (VIIa). A mixture of 0.5 g (1.5 mmol)
of compound Va, 0.2 g of anhydrous sodium acetate,
and 3 ml of acetic anhydride was heated for 1 h at
100°C (until the initial compound disappeared com-
pletely according to the TLC data). The mixture was
treated with 10 ml of water and left to stand for 12 h at
room temperature, and the precipitate was filtered off,
washed with water, and recrystallized from aqueous
ethanol. Yield 0.36 g (77%), mp 102–103°C. IR spec-
trum, ν, cm–1: 1722, 1718 (C=O); 1620 (C=C). 1H NMR
spectrum, δ, ppm: 1.35–2.06 m (6H, CH2), 2.07–
2.25 m (2H, CH), 2.94 d (2H, NCH2), 3.04 d (2H,
3-Benzyl-N-benzylidene-3-azabicyclo[3.3.1]-
nonan-9-amine (IXa). A solution of 0.24 g (2.2 mmol)
of freshly distilled benzaldehyde in 3 ml of anhydrous
ethanol was added under stirring to a solution of 0.5 g
(2.2 mmol) of amine IIa in 5 ml of anhydrous ethanol.
The mixture was heated for 12 h under reflux with
stirring, the solvent was distilled off under reduced
pressure, and the residue was dissolved in hexane–
ethyl acetate (3:1) and purified by column chromatog-
raphy on silica gel. Yield 0.48 g (69%), oily substance.
1
IR spectrum: ν 1608 cm–1 (C=N). H NMR spectrum,
δ, ppm: 1.39–2.08 m (6H, CH2), 2.17–2.26 m (2H,
CH), 2.82 d (2H, NCH2), 2.93 d (2H, NCH2), 3.41 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

MOSKALENKO et al.
1008
(2H, PhCH2), 3.95 m (1H, 9-H), 6.78 s (1H, N=CH),
7.00–7.43 m (10H, C6H5). Mass spectrum: m/z 319
[M + H]+. Found, %: C 82.91; H 8.03; N 8.74.
C22H26N2. Calculated, %: C 83.02; H 8.18; N 8.81.
M 318.
NCH2), 2.90 d (2H, NCH2), 3.38 s (2H, PhCH2),
3.93 m (1H, 9-H), 4.98 s (2H, NHCH2), 5.24 br.s (1H,
NH), 7.02–7.34 m (10H, C6H5). Mass spectrum:
m/z 321 [M + H]+. Found, %: C 82.35; H 8.64; N 8.57.
C22H28N2. Calculated, %: C 82.50; H 8.75; N 8.75.
M 320.
Compounds IXb, Xa, and Xb were synthesized in
a similar way.
Compounds XIb, XIIa, and XIIb were synthesized
in a similar way.
tert-Butyl 9-benzylideneamino-3-azabicyclo-
[3.3.1]nonane-3-carboxylate (IXb). Yield 70%,
mp 74–76°C. IR spectrum, ν, cm–1: 1684 (C=O), 1608
tert-Butyl 9-benzylamino-3-azabicyclo[3.3.1]-
nonane-3-carboxylate (XIb). Yield 80%, mp 56–
57°C. IR spectrum, ν, cm–1: 3354 (NH), 1685 (C=O).
1H NMR spectrum, δ, ppm: 1.31 s (9H, t-Bu), 1.46–
2.12 m (6H, CH2), 2.34–2.42 m (2H, CH), 3.40 d (2H,
NCH2), 3.60 d (2H, NCH2), 3.94 m (1H, 9-H), 5.08 s
(2H, PhCH2), 5.36 br.s (1H, NH), 7.05–7.21 m (5H,
C6H5). Mass spectrum, m/z: 331 [M + H]+, 230 [M –
101 + H]+. Found, %: C 72.78; H 8.93; N 8.39.
C20H30N2O2. Calculated, %: C 72.73; H 9.09; N 8.48.
M 330.
1
(C=N). H NMR spectrum, δ, ppm: 1.30 s (9H, t-Bu),
1.46–2.10 m (6H, CH2), 2.37–2.45 m (2H, CH), 3.42 d
(2H, NCH2), 3.62 d (2H, NCH2), 3.98 m (1H, 9-H),
6.81 s (1H, N=CH), 7.02–7.21 m (5H, C6H5). Mass
spectrum, m/z: 329 [M + H]+, 228 [M – 101 + H]+.
Found, %: C 73.26; H 8.48; N 8.39. C20H28N2O2. Cal-
culated, %: C 73.17; H 8.54; N 8.54. M 328.
3-Benzyl-N-(4-chlorobenzylidene)-3-azabicyclo-
[3.3.1]nonan-9-amine (Xa). Yield 73%, mp 51–53°C.
1
IR spectrum: ν 1610 cm–1 (C=N). H NMR spectrum,
3-Benzyl-N-(4-chlorobenzyl)-3-azabicyclo[3.3.1]-
nonan-9-amine (XIIa). Yield 80%, oily substance. IR
δ, ppm: 1.38–2.09 m (6H, CH2), 2.18–2.27 m (2H,
CH), 2.85 d (2H, NCH2), 2.97 d (2H, NCH2), 3.45 s
(2H, PhCH2), 3.98 m (1H, 9-H), 6.84 s (1H, N=CH),
7.18–7.82 m (9H, Harom). Mass spectrum: m/z 353 [M +
H]+. Found, %: C 74.67; H 7.01; N 7.82. C22H25ClN2.
Calculated, %: C 74.89; H 7.09; N 7.94. M 352.5.
spectrum: ν 3358 cm–1 (NH). H NMR spectrum, δ,
1
ppm: 1.35–2.08 m (6H, CH2), 2.13–2.25 m (2H, CH),
2.84 d (2H, NCH2), 2.95 d (2H, NCH2), 3.42 s (2H,
PhCH2), 3.95 m (1H, 9-H), 5.08 s (2H, C6H4CH2),
5.25 br.s (1H, NH), 7.16–7.80 m (9H, Harom). Mass
spectrum: m/z 355 [M + H]+. Found, %: C 74.32;
H 7.55; N 7.78. C22H27ClN2. Calculated, %: C 74.47;
H 7.62; N 7.90. M 354.5.
tert-Butyl 9-(4-chlorobenzylideneamino)-3-aza-
bicyclo[3.3.1]nonane-3-carboxylate (Xb). Yield 78%,
mp 88–90°C. IR spectrum, ν, cm–1: 1685 (C=O), 1610
1
(C=N). H NMR spectrum, δ, ppm: 1.32 s (9H, t-Bu),
tert-Butyl 9-(4-chlorobenzylamino)-3-azabicyclo-
[3.3.1]nonane-3-carboxylate (XIIb). Yield 77%,
mp 73–74°C. IR spectrum, ν, cm–1: 3356 (NH), 1685
1.48–2.12 m (6H, CH2), 2.41–2.48 m (2H, CH), 3.45 d
(2H, NCH2), 3.71 d (2H, NCH2), 4.03 m (1H, 9-H),
6.95 s (1H, N=CH), 7.42–7.84 m (4H, C6H4). Mass
spectrum, m/z: 363 [M + H]+, 262 [M – 101 + H]+.
Found, %: C 66.13; H 7.52; N 7.64. C20H27ClN2O2.
Calculated, %: C 66.21; H 7.45; N 7.72. M 362.5.
1
(C=O). H NMR spectrum, δ, ppm: 1.31 s (9H, t-Bu),
1.42–2.09 m (6H, CH2), 2.32–2.41 m (2H, CH), 3.44 d
(2H, NCH2), 3.65 d (2H, NCH2), 3.95 m (1H, 9-H),
5.12 s (2H, C6H4CH2), 5.38 br.s (1H, NH), 7.38–
7.79 m (4H, C6H4). Mass spectrum, m/z: 365 [M + H]+,
264 [M – 101 + H]+. Found, %: C 65.71; H 7.98;
N 7.43. C20H29ClN2O2. Calculated, %: C 65.84;
H 7.96; N 7.68. M 364.5.
N,3-Dibenzyl-3-azabicyclo[3.3.1]nonan-9-amine
(XIa). Sodium tetrahydridoborate, 0.1 g (2.7 mmol),
was added to a solution of 0.64 g (2 mmol) of Schiff
base IXa in 20 ml of a 1:1 mixture of anhydrous
methanol and tetrahydrofuran, and the mixture was
stirred for 5 h, poured into 50 ml of water, and
extracted with ethyl acetate (2×30 ml). The combined
extracts were dried over anhydrous sodium sulfate, the
solvent was removed under reduced pressure, and the
oily residue was dissolved in hexane–ethyl acetate
(3:1) and purified by column chromatography on silica
gel. Yield 0.52 g (81%), oily substance. IR spectrum:
3-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)-
2-phenyl-1,3-thiazolidin-4-one (XIIIa). A mixture of
0.64 g (2 mmol) of Schiff base IXa and 0.2 g
(2.2 mmol) of sulfanylacetic acid in 20 ml of anhy-
drous benzene was heated for 10 h under reflux with
stirring. The solvent was removed under reduced pres-
sure, the residue was treated with hot hexane, and the
precipitate was filtered off and recrystallized from
aqueous ethanol (1:2). Yield 0.38 g (49%), mp 164–
1
ν 3352 cm–1 (NH). H NMR spectrum, δ, ppm: 1.32–
1
2.04 m (6H, CH2), 2.15–2.23 m (2H, CH), 2.80 d (2H,
166°C. IR spectrum: ν 1705 cm–1 (C=O). H NMR
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SYNTHESIS AND PROPERTIES OF 3-SUBSTITUTED 3-AZABICYCLO[3.3.1]NONAN-...
1009
spectrum, δ, ppm: 1.38–2.09 m (6H, CH2), 2.18–
2.25 m (2H, CH), 2.84 d (2H, NCH2), 2.95 d (2H,
NCH2), 3.41 s (2H, PhCH2), 3.96 m (1H, 9-H), 4.10 s
(2H, CH2S), 6.24 s (1H, SCHN), 7.04–7.46 m (10H,
C6H5). Mass spectrum: m/z 393 [M + H]+. Found, %:
C 73.22; H 6.85; N 7.04. C24H28N2OS. Calculated, %:
C 73.47; H 7.14; N 7.14. M 392.
chloride (3×50 ml). The combined extracts were dried
over anhydrous sodium sulfate, and the solvent was
removed under reduced pressure. Yield 6.12 g (90%),
oily substance. IR spectrum: ν 2092 cm–1 (NCS).
1H NMR spectrum, δ, ppm: 1.38–2.07 m (6H, CH2),
2.15–2.26 m (2H, CH), 2.83 d (2H, NCH2), 2.87 d
(2H, NCH2), 3.38 s (2H, PhCH2), 3.78 m (1H, 9-H),
7.08–7.24 m (5H, C6H5). Mass spectrum: m/z 273 [M +
H]+. Found, %: C 70.42; H 7.18; N 10.13. C16H20N2S.
Calculated, %: C 70.59; H 7.35; N 10.29. M 272.
Compounds XIIIb, XIVa, and XIVb were synthe-
sized in a similar way.
tert-Butyl 9-(4-oxo-2-phenyl-1,3-thiazolidin-
3-yl)-3-azabicyclo[3.3.1]nonane-3-carboxylate
(XIIIb). Yield 52%, mp 183–185°C. IR spectrum, ν,
tert-Butyl 9-isothiocyanato-3-azabicyclo[3.3.1]-
nonane-3-carboxylate (XVb). Yield 96%, mp 58–
60°C. IR spectrum, ν, cm–1: 2095 (NCS), 1686 (C=O).
1H NMR spectrum, δ, ppm: 1.30 s (9H, t-Bu), 1.47–
2.15 m (6H, CH2), 2.35–2.48 m (2H, CH), 3.45 d (2H,
NCH2), 3.64 d (2H, NCH2), 3.86 m (1H, 9-H). Mass
spectrum, m/z: 283 [M + H]+, 182 [M – 101 + H]+.
Found, %: C 59.67; H 7.61; N 10.04. C14H22N2O2S.
Calculated, %: C 59.57; H 7.80; N 9.93. M 282.
1
cm–1: 1705, 1685 (C=O). H NMR spectrum, δ, ppm:
1.30 s (9H, t-Bu), 1.45–2.12 m (6H, CH2), 2.36–
2.47 m (2H, CH), 3.44 d (2H, NCH2), 3.65 d (2H,
NCH2), 3.96 m (1H, 9-H), 4.12 s (2H, CH2S), 6.28 s
(1H, SCHN), 7.14–7.39 m (5H, C6H5). Mass spectrum,
m/z: 403 [M + H]+, 302 [M – 101 + H]+. Found, %:
C 65.71; H 7.35; N 6.92. C22H30N2O3S. Calculated, %:
C 65.67; H 7.46; N 6.97. M 402.
O-Methyl (3-benzyl-3-azabicyclo[3.3.1]non-9-yl)-
carbamothioate (XVIa). A mixture of 0.272 g
(1 mmol) of isothiocyanate XVa and 10 ml of anhy-
drous methanol was heated for 10 h under reflux, and
the solvent was distilled off under reduced pressure.
Yield 0.3 g (98%), mp 118–120°C. IR spectrum:
3-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)-2-
(4-chlorophenyl)-1,3-thiazolidin-4-one (XIVa). Yield
46%, mp 178–180°C. IR spectrum, ν, cm–1: 1705
1
(C=O). H NMR spectrum, δ, ppm: 1.37–2.09 m (6H,
CH2), 2.19–2.27 m (2H, CH), 2.86 d (2H, NCH2),
2.96 d (2H, NCH2), 3.41 s (2H, PhCH2), 3.97 m (1H,
9-H), 4.10 s (2H, CH2S), 6.26 s (1H, SCHN), 7.03–
7.48 m (9H, Harom). Mass spectrum: m/z 427 [M + H]+.
Found, %: C 67.28; H 6.29; N 6.34. C24H27ClN2OS.
Calculated, %: C 67.53; H 6.33; N 6.57. M 426.5.
1
ν 3358 cm–1 (NH). H NMR spectrum, δ, ppm: 1.36–
2.08 m (6H, CH2), 2.13–2.25 m (2H, CH), 2.81 d (2H,
NCH2), 2.88 d (2H, NCH2), 3.40 s (2H, PhCH2),
3.74 m (1H, 9-H), 3.96 s (3H, OCH3), 7.02–7.21 m
(5H, C6H5), 9.05 s (1H, NH). Mass spectrum: m/z 305
[M + H]+. Found, %: C 66.93; H 7.76; N 9.17.
C17H24N2OS. Calculated, %: C 67.11; H 7.89; N 9.21.
M 304.
tert-Butyl 9-[2-(4-chlorophenyl)-4-oxo-1,3-thia-
zolidin-3-yl]-3-azabicyclo[3.3.1]nonane-3-carbox-
ylate (XIVb). Yield 47%, mp 185–186°C. IR spec-
1
trum, ν, cm–1: 1705, 1685 (C=O). H NMR spectrum,
tert-Butyl 9-(methoxycarbonothioylamino)-3-
azabicyclo[3.3.1]nonane-3-carboxylate (XVIb) was
synthesized in a similar way. Yield 99%, mp 136–
138°C. IR spectrum, ν, cm–1: 3359 (NH), 1685 (C=O).
1H NMR spectrum, δ, ppm: 1.31 s (9H, t-Bu), 1.48–
2.16 m (6H, CH2), 2.36–2.49 m (2H, CH), 3.45 d (2H,
NCH2), 3.65 d (2H, NCH2), 3.85 m (1H, 9-H), 4.01 s
(3H, OCH3), 9.12 s (1H, NH). Mass spectrum, m/z:
315 [M + H]+, 214 [M – 101 + H]+. Found, %:
C 57.19; H 8.38; N 8.76. C15H26N2O3S. Calculated, %:
C 57.32; H 8.28; N 8.92. M 314.
δ, ppm: 1.30 s (9H, t-Bu), 1.46–2.14 m (6H, CH2),
2.35–2.46 m (2H, CH), 3.46 d (2H, NCH2), 3.68 d
(2H, NCH2), 3.97 m (1H, 9-H), 4.12 s (2H, CH2S),
6.28 s (1H, SCHN), 7.43–7.84 m (4H, C6H4). Mass
spectrum, m/z: 437 [M + H]+, 336 [M – 101 + H]+.
Found, %: C 60.56; H 6.77; N 6.23. C22H29ClN2O3S.
Calculated, %: C 60.48; H 6.64; N 6.41. M 436.5.
3-Benzyl-9-isothiocyanato-3-azabicyclo[3.3.1]-
nonane (XVa). A solution of 2.9 g (25.2 mmol) of
thiophosgene in 30 ml of anhydrous acetone was
cooled to 0–5°C, a solution of 5.75 g (25 mmol)
of amine IIa in 30 ml of acetone was added under
stirring, and 3.6 g (26 mmol) of anhydrous potassium
carbonate was then added in small portions. The mix-
ture was stirred for 3 h at room temperature, poured
into 200 ml of water, and extracted with methylene
1-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)-3-
phenylthiourea (XVIIa). A mixture of 0.272 g
(1 mmol) of isothiocyanate XVa and 0.093 g (1 mmol)
of aniline in 5 ml of anhydrous benzene was heated for
7 h under reflux. The solvent was distilled off under
reduced pressure, and the residue was treated with hot
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

MOSKALENKO et al.
1010
hexane. The precipitate was filtered off and recrystal-
lized from ethyl acetate. Yield 0.21 g (58%), mp 156–
158°C. IR spectrum, ν, cm–1: 3356, 3268 (NH).
1H NMR spectrum, δ, ppm: 1.37–2.09 m (6H, CH2),
2.11–2.24 m (2H, CH), 2.83 d (2H, NCH2), 2.89 d (2H,
NCH2), 3.38 s (2H, PhCH2), 3.74 m (1H, 9-H), 7.03–
7.43 m (10H, C6H5), 8.04 s (1H, NH), 9.18 s (1H, NH).
Mass spectrum: m/z 366 [M + H]+. Found, %: C 72.24;
H 7.52; N 11.33. C22H27N3S. Calculated, %: C 72.33;
H 7.40; N 11.51. M 365.
m/z 316 [M + H]+. Found, %: C 60.73; H 6.45; N 21.80.
C16H21N5S. Calculated, %: C 60.95; H 6.67; N 22.22.
M 315.
tert-Butyl 9-(5-thioxo-4,5-dihydro-1H-tetrazol-
1-yl)-3-azabicyclo[3.3.1]nonane-3-carboxylate
(XVIIIb) was synthesized in a similar way. Yield 86%,
mp 196–198°C. IR spectrum, ν, cm–1: 3406 (NH),
1687 (C=O), 1528 (N=N). 1H NMR spectrum, δ, ppm:
1.32 s (9H, t-Bu), 1.48–2.15 m (6H, CH2), 2.36–
2.52 m (2H, CH), 3.46 d (2H, NCH2), 3.68 d (2H,
NCH2), 3.89 m (1H, 9-H). Mass spectrum, m/z: 326
[M + H]+, 225 [M – 101 + H]+. Found, %: C 52.01;
H 7.23; N 21.43. C14H23N5O2S. Calculated, %:
C 51.69; H 7.08; N 21.54. M 325.
tert-Butyl 9-(phenylcarbamothioylamino)-3-
azabicyclo[3.3.1]nonane-3-carboxylate (XVIIb) was
synthesized in a similar way. Yield 63%, mp 171–
173°C. IR spectrum, ν, cm–1: 3362, 3274 (NH), 1687
1
(C=O). H NMR spectrum, δ, ppm: 1.31 s (9H, t-Bu),
Reaction of compounds IIb–XVIIIb with HCl.
Compound IIb–XVIIIb, 2 mmol, was dissolved in
5 ml of anhydrous ethanol, 10 ml of a saturated
(~16%) solution of hydrogen chloride in anhydrous
dioxane was added, and the mixture was stirred for 1 h
and then heated for 1 h under reflux. The solvent was
removed under reduced pressure, the residue was
dissolved in 3 ml of hot propan-2-ol, the solution was
cooled, 15 ml of anhydrous diethyl ether was added,
and the mixture was left to stand for 20 h. The precip-
itate was filtered off, washed with diethyl ether, and
dried under reduced pressure over P2O5. The yields of
the corresponding 3-unsubstituted 3-azabicyclo[3.3.1]-
nonane derivatives ranged from 87 to 98%.
1.47–2.15 m (6H, CH2), 2.34–2.50 m (2H, CH), 3.44 d
(2H, NCH2), 3.66 d (2H, NCH2), 3.87 m (1H, 9-H),
7.02–7.28 m (5H, C6H5), 8.06 s (1H, NH), 9.21 s (1H,
NH). Mass spectrum, m/z: 376 [M + H]+, 275 [M –
101 + H]+. Found, %: C 63.85; H 7.84; N 11.07.
C20H29N3O2S. Calculated, %: C 64.00; H 7.73;
N 11.20. M 375.
1-(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)-4,5-di-
hydro-1H-tetrazole-5-thione (XVIIIa). A mixture of
0.272 g (1 mmol) of isothiocyanate XVa and 0.098 g
(1.5 mmol) of sodium azide in 5 ml of water was
heated for 4 h under reflux. The mixture was cooled
and washed with 20 ml of diethyl ether. The aqueous
solution was acidified with 10% hydrochloric acid to
pH 2–3 and left to stand for 10 h in a refrigerator, and
the precipitate was filtered off, washed with cold water
and diethyl ether, and dried. Yield 0.28 g (89%),
mp 187–190°C. IR spectrum, ν, cm–1: 3405 (NH),
REFERENCES
1. Moskalenko, A.I. and Boev, V.I., Russ. J. Org. Chem.,
2009, vol. 45, p. 472.
1
1528 (N=N). H NMR spectrum, δ, ppm: 1.38–2.10 m
2. Moskalenko, A.I. and Boev, V.I., Russ. J. Org. Chem.,
(6H, CH2), 2.12–2.26 m (2H, CH), 2.85 d (2H, NCH2),
2.92 d (2H, NCH2), 3.39 s (2H, PhCH2), 3.85 m (1H,
9-H), 7.04–7.26 m (5H, C6H5). Mass spectrum:
2009, vol. 45, p. 895.
3. Jeyaraman, R. and Avila, S., Chem. Rev., 1981, vol. 81,
p. 149.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011