3- substituted 3- azabicyclo[3.3.1]nonan- 9- ols and their transformations involving the hydroxy group

Article abstract of DOI:10.1134/S1070428010100143

The reduction of 3-benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1] nonan-9-ones with sodium tetrahydridoborate gave the corresponding alcohols as mixtures of a- and ae-epimers at a ratio of 2: 3. The resulting alcohols reacted with acetyl chloride a

Full text of DOI:10.1134/S1070428010100143

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 10, pp. 1527–1533. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.I. Moskalenko, V.I. Boev, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 10, pp. 1521–1527.
3-Substituted 3-Azabicyclo[3.3.1]nonan-9-ols and Their
Transformations Involving the Hydroxy Group
A. I. Moskalenko 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—The reduction of 3-benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-ones with
sodium tetrahydridoborate gave the corresponding alcohols as mixtures of α- and β-epimers at a ratio of 2:3.
The resulting alcohols reacted with acetyl chloride and methanesulfonyl chloride at the hydroxy group to form
O-acetyl and O-methylsulfonyl derivatives. Reactions of the latter with potassium iodide and sodium azide
afforded 3-substituted 9-iodo(azido)-3-azabicyclo[3.3.1]nonanes. 9-Iodo derivatives were treated with tri-
phenylphosphine to obtain triphenylphosphonium salts which were converted into the corresponding phospho-
nium ylides by the action of sodium methoxide in methanol, and the ylides readily reacted with benzaldehyde
according to Wittig.
DOI: 10.1134/S1070428010100143
We previously developed [1] a convenient proce-
dure for the synthesis of 3-substituted 3-azabicyclo-
[3.3.1]nonan-9-ones that are promising as synthons
due to the presence of functional groups in their mole-
cules. Interest in compounds possessing a 3-azabicyclo-
[3.3.1]nonane system is determined by their structural
similarity to terpene alkaloids [2] which exhibit high
biological activity.
3.98 ppm. We failed to separate epimer mixtures into
individual compounds, so that further chemical trans-
formations were performed with mixtures α-IIa/β-IIa
and α-IIb/β-IIb, and epimeric composition of the
products was determined on the basis of their 1H NMR
spectra (see Experimental).
Alcohols IIa and IIb reacted with acetyl chloride
and methanesulfonyl chloride in the presence of pyri-
dine to give the corresponding 9-O-acetyl- and
9-O-methylsulfonyl derivatives III and IV (Scheme 2)
which were subjected to further chemical transforma-
tions. By heating compounds IVa and IVb with potas-
sium iodide in acetone or with sodium azide in di-
methyl sulfoxide (DMSO) we obtained iodides Va and
Vb and azides VIa and VIb as a result of nucleophilic
replacement of the methylsulfonyl group.
By reduction of ketones Ia and Ib with sodium
tetrahydridoborate in methanol we obtained a mixture
of α- and β-epimeric alcohols IIa and IIb in almost
quantitative yield (Scheme 1). In both cases, the ratios
of α- and β-epimers were fairly similar (~2:3); the
epimer ratio was determined from the intensities of
two doublets belonging to the 9-H proton in the
1H NMR spectra. According to published data [3–5],
the 9-H proton in the major β-epimer resonates in
a stronger field, at δ 3.67–3.71 ppm, and the corre-
sponding signal of the α-epimer is observed at δ 3.95–
1
The H NMR spectra of compounds III and IV
contained singlets from methyl protons in the acetyl
and methylsulfonyl groups. The ratio of α- and
Scheme 1.
O
H
OH
HO
H
NaBH4, MeOH
+
N
N
N
R
R
R
Ia, Ib
α-IIa, α-IIb
β-IIa, β-IIb
R = PhCH2 (a), Me3COC(O) (b).
1527

MOSKALENKO, BOEV
1528
Scheme 2.
OAc
AcCl
MsCl
N
R
I
CH2Cl2, pyridine
R'I, Me2CO
IIIa, IIIb
IIa, IIb
N
OMs
R
R
Va, Vb
N
R
N3
NaN3, DMSO
IVa, IVb
N
VIa, VIb
β-epimers for compounds III–VI was the same as for
the initial alcohols. In the IR spectra of III–VI we
observed absorption bands typical of vibrations of
bonds in the acetyl, methylsulfonyl, and azido groups
(see Experimental). The structure of compounds V and
VI was confirmed by their chemical transformations.
In particular, by heating iodides Va and Vb with
triphenylphosphine in tetrahydrofuran (THF) under
pressure we synthesized triphenylphosphonium salts
VIIa and VIIb. Treatment of the latter with sodium
methoxide in methanol readily produced unstable
phosphonium ylides VIIIa and VIIIb which reacted in
situ with benzaldehyde according to Wittig. As a result,
unsaturated 9-benzylidene derivatives IXa and IXb
were formed in high yield (Scheme 3).
phosphine oxide (Scheme 4). Schiff bases XIa and
XIb were also obtained by reduction of azides VIa and
VIb with lithium tetrahydridoaluminate in anhydrous
THF at room temperature, followed by reaction of
primary amines XIIa and XIIb with benzaldehyde
(Scheme 5).
Scheme 4.
N
PPh3, PhH
PPh3
VIa, VIb
N
R
Xa, Xb
N
PhCHO
–Ph3P=O
CHPh
N
R
XIa, XIb
Scheme 3.
PPh3 I–
Scheme 5.
PPh3, THF
NH2
Va, Vb
N
R
LiAlH4, THF
VIa, VIb
N
VIIa, VIIb
R
XIIa, XIIb
PPh3
PhCHO
–H2O
MeONa, MeOH
XIa, XIb
N
R
VIIIa, VIIIb
Azides VIa and VIb reacted with methyl prop-2-
ynoate in boiling toluene to give 1,2,3-triazoles XIIIa
and XIIIb (Scheme 6). In the 1H NMR spectra of com-
pounds XI–XIII, the 9-H signal is doubled, indicating
that these compounds are mixtures of α- and β-epimers
Ph
PhCHO
N
–Ph3P=O
R
IXa, IXb
Azides VIa and VIb also reacted with triphenyl-
phosphine, but under milder conditions, on heating in
boiling benzene. The reaction was accompanied by
evolution of nitrogen (Staudinger reaction), and the
products were phosphazo compounds Xa and Xb
whose reaction with benzaldehyde (aza-Wittig) afford-
ed bicyclic Schiff bases XIa and XIb and triphenyl-
Scheme 6.
VIa, VIb
Toluene
+
HC
COOMe
COOMe
R
N
N
N
N
XIIIa, XIIIb
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

3-SUBSTITUTED 3-AZABICYCLO[3.3.1]NONAN-9-OLS AND THEIR TRANSFORMATIONS
1529
whose ratio was determined from the signal intensities
(see Experimental).
The extracts were combined with the organic phase,
washed with water, and dried over anhydrous sodium
sulfate, and the solvent was removed under reduced
pressure to isolate compound IIa as a mixture of α-
and β-epimers, which was crystallized from hexane on
cooling to –20°C. Yield 23 g (100%), α/β ratio 2:3. IR
Compounds IIb–VIIb, XIIb, and XIIIb having
a tert-butoxycarbonyl group (Boc) on the nitrogen
readily lost that group on treatment with a saturated
solution of hydrogen chloride in anhydrous dioxane,
and the corresponding NH derivatives were formed in
high yield as hydrochlorides IIc–VIIc, XIIc, and
XIIIc. Analogous N-benzyl derivatives under similar
conditions were converted into water-soluble hydro-
chlorides without elimination of the substituent at the
nitrogen atom.
1
spectrum: ν 3428 cm–1 (OH). H NMR spectrum, δ,
ppm: 1.41–2.08 m (6H, CH2), 2.28–2.32 m (2H, CH),
2.83 d (2H, NCH2), 2.95 d (2H, NCH2), 3.40 s (2H,
PhCH2), 3.67 d (9-H, β), 3.95 d (9-H, α), 7.21–7.38 m
(5H, C6H5). Mass spectrum: m/z 232 [M + H]+. Found,
%: C 77.83; H 9.01; N 6.28. C15H21NO. Calculated, %:
C 77.92; H 9.09; N 6.06.
R
tert-Butyl 9-hydroxy-3-azabicyclo[3.3.1]nonane-
3-carboxylate (IIb) was synthesized in a similar way.
Yield 99%, α/β ratio 38:62. IR spectrum, ν, cm–1: 3431
· nHCl
HN
1
IIc–VIIc, XIIc, XIIIc
(OH), 1681 (C=O). H NMR spectrum, δ, ppm: 1.30 s
(9H, t-Bu), 1.46–2.07 m (6H, CH2), 2.36–2.42 m (2H,
CH), 3.40 d (2H, NCH2), 3.62 d (2H, NCH2), 3.71 d
(9-H, β), 3.98 d (9-H, α). Mass spectrum, m/z: 242
[M + H]+, 185 [M – 57 + H]+, 141 [M – 101 + H]+.
Found, %: C 64.68; H 9.47; N 5.63. C13H23NO3. Cal-
culated, %: C 64.73; H 9.54; N 5.81.
II, R = HO; III, R = AcO; IV, R = MeSO2; V, R = I; VI, R = N3;
O
N
VII, R = I– Ph3P+; XII, R = H3N+; XIII, R =
;
N
N
MeO
II–V, VII, n = 1; VI, XII, XIII, n = 2.
Apart from IR and 1H NMR spectra, the structure of
the newly synthesized compounds was confirmed by
elemental analyses and mass spectra (electrospray
ionization).
3-Benzyl-3-azabicyclo[3.3.1]non-9-yl acetate
(IIIa). A solution of 0.24 g (3 mmol) of acetyl chloride
in 3 ml of methylene chloride was added under stirring
at 0–5°C to a mixture of 0.46 g (2 mmol) of alcohol
IIa and 0.2 g (2.5 mmol) of anhydrous pyridine in 5 ml
of anhydrous methylene chloride. The mixture was
allowed to warm up to room temperature and was
stirred for 2 h until the initial alcohol disappeared com-
pletely (TLC). The mixture was poured into 20 ml of
water, the organic phase was separated, and the
aqueous phase was extracted with methylene chloride
(2 ×10 ml). The extracts were combined with the
organic phase and dried over anhydrous sodium
sulfate, and the solvent was removed under reduced
pressure to isolate 0.42 g (77%) of compound IIIa as
a mixture of α- and β-epimers at a ratio of 2 :3. IR
EXPERIMENTAL
The IR spectra were recorded in KBr on a Specord
1
75IR spectrometer. The H NMR spectra were meas-
ured on a Bruker DPX-400 instrument (400 MHz)
from solutions in CDCl3 (II–VI, IX–XIII) or
DMSO-d6 (VIIa, VIIb, IIc–VIIc, IXc–XIIIc) using
hexamethyldisiloxane as internal reference. The mass
spectra (atmospheric pressure chemical ionization)
were obtained on a Thermo Finnigan Surveyor MSQ
mass spectrometer. The purity of the products was
checked by TLC on Silufol UV-254 plates using
hexane–ethyl acetate (2:1) as eluent.
1
spectrum: ν 1692 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.42–1.82 m (6H, CH2), 2.01 s (3H, CH3), 2.29–
2.34 m (2H, CH), 2.85 d (2H, NCH2), 2.94 d (2H,
NCH2), 3.42 s (2H, PhCH2), 3.72 s (9-H, β), 4.05 s
(9-H, α), 7.24–7.43 m (5H, C6H5). Mass spectrum: m/z
274 [M + H]+. Found, %: C 74.82; H 8.51; N 5.06.
C17H23NO2. Calculated, %: C 74.72; H 8.42; N 5.13.
3-Benzyl-3-azabicyclo[3.3.1]nonan-9-ol (IIa).
Compound Ia, 22.9 g (0.1 mol), was dissolved in
180 ml of anhydrous methanol, 11.3 g (0.3 mol) of
sodium tetrahydridoborate was added under stirring
over a period of 50 min, and the mixture was stirred
for 3 h (until the initial ketone disappeared according
to the TLC data). The mixture was diluted with 300 ml
of water, 200 ml of methylene chloride was added, the
organic phase was separated, and the aqueous phase
was extracted with methylene chloride (2×100 ml).
tert-Butyl 9-acetoxy-3-azabicyclo[3.3.1]nonane-
3-carboxylate (IIIb) was synthesized in a similar way.
Yield 82%, α/β ratio 41 :59. IR spectrum, ν, cm–1:
1
1695, 1682 (C=O). H NMR spectrum, δ, ppm: 1.32 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

MOSKALENKO, BOEV
1530
(9H, t-Bu), 1.48–2.10 m (9H, CH2, CH3CO), 2.38–
2.47 m (2H, CH), 3.42 d (2H, NCH2), 3.65 d (2H,
NCH2), 3.82 d (9-H, β), 4.08 d (9-H, α). Mass spec-
trum, m/z: 284 [M + H]+, 227 [M – 57 + H]+, 183 [M –
101 + H]+. Found, %: C 63.48; H 8.76; N 4.85.
C15H25NO4. Calculated, %: C 63.60; H 8.83; N 4.95.
distilled off under reduced pressure to isolate com-
pound Va as a mixture of α- and β-epimers at a ratio of
42:58. Yield 4.62 g (90%). 1H NMR spectrum, δ, ppm:
1.41–2.08 m (6H, CH2), 2.17–2.21 m (2H, CH), 2.85 d
(2H, NCH2), 2.98 d (2H, NCH2), 3.40 s (2H, PhCH2),
3.65 s (9-H, β), 3.97 s (9-H, α), 7.26–7.43 m (5H,
C6H5). Mass spectrum: m/z 342 [M + H]+. Found, %:
C 52.65; H 5.78; N 3.86. C15H20IN. Calculated, %:
C 52.79; H 5.87; N 4.11.
3-Benzyl-3-azabicyclo[3.3.1]non-9-yl methane-
sulfonate (IVa). A solution of 2.9 g (25 mmol) of
methanesulfonyl chloride in 10 ml of methylene
chloride was added under stirring at 15–20°C to a mix-
ture of 4.6 g (20 mmol) of alcohol IIa and 2 g
(25 mmol) of anhydrous pyridine in 30 ml of anhy-
drous methylene chloride. The mixture was stirred for
12 h until the initial alcohol disappeared completely
(TLC) and poured into 300 ml of water, the organic
phase was separated, and the aqueous phase was
extracted with methylene chloride (2×50 ml). The ex-
tracts were combined with the organic phase, washed
with water, and dried over anhydrous sodium sulfate.
Removal of the solvent under reduced pressure gave
4.92 g (80%) of compound IVa as a mixture of α- and
β-epimers at a ratio of 35:65. IR spectrum, ν, cm–1:
tert-Butyl 9-iodo-3-azabicyclo[3.3.1]nonane-3-
carboxylate (Vb) was synthesized in a similar way.
Yield 90%, α/β ratio 2:3. IR spectrum: ν 1681 cm–1
1
(C=O). H NMR spectrum, δ, ppm: 1.32 s (9H, t-Bu),
1.47–2.10 m (6H, CH2), 2.38–2.45 m (2H, CH), 3.42 d
(2H, NCH2), 3.64 d (2H, NCH2), 3.68 s (9-H, β), 3.98 s
(9-H, α). Mass spectrum, m/z: 352 [M + H]+, 295 [M –
57 + H]+, 251 [M – 101 + H]+. Found, %: C 44.28;
H 6.17; N 4.05. C13H22INO2. Calculated, %: C 44.44;
H 6.27; N 3.99.
9-Azido-3-benzyl-3-azabicyclo[3.3.1]nonane
(VIa). A mixture of 4.63 g (15 mmol) of compound
IVa and 2.93 g (45 mmol) of sodium azide in 12 ml of
DMSO was stirred for 6 h at 100°C (until the initial
compound disappeared completely according to the
TLC data). The mixture was cooled, diluted with
150 ml of water, and extracted with methylene chloride
(2×50 ml). The extracts were combined, washed with
three portions of water, and dried over anhydrous
sodium sulfate, and the solvent was distilled off under
reduced pressure to isolate 3.41 g (89%) of compound
VIa as a mixture of α- and β-epimers at a ratio of 2:3.
1
1358, 1172 (SO2). H NMR spectrum, δ, ppm: 1.39–
2.08 m (6H, CH2), 2.27–2.39 m (2H, CH), 2.94 s (3H,
H3CSO2), 2.98 d (2H, NCH2), 3.08 d (2H, NCH2),
3.43 s (2H, PhCH2), 3.78 s (9-H, β), 4.07 s (9-H, α),
7.25–7.42 m (5H, C6H5). Mass spectrum: m/z 310 [M +
H]+. Found, %: C 62.24; H 7.32; N 4.61. C16H23NO3S.
Calculated, %: C 62.14; H 7.44; N 4.53.
tert-Butyl 9-methylsulfonyloxy-3-azabicyclo-
[3.3.1]nonane-3-carboxylate (IVb) was synthesized
in a similar way. Yield 83%, α/β ratio 38:62. IR spec-
trum, ν, cm–1: 1683 (C=O); 1360, 1173 (SO2). 1H NMR
spectrum, δ, ppm: 1.34 s (9H, t-Bu), 1.42–2.12 m (6H,
CH2), 2.38–2.42 m (2H, CH), 2.95 s (3H, H3CSO2),
2.99 d (2H, NCH2), 3.08 d (2H, NCH2), 3.81 d (9-H,
β), 4.10 d (9-H, α). Mass spectrum, m/z: 320 [M + H]+,
263 [M – 57 + H]+, 219 [M – 101 + H]+. Found, %:
C 52.71; H 7.58; N 4.32. C14H25NO5S. Calculated, %:
C 52.66; H 7.84; N 4.39.
1
IR spectrum: ν 2108 cm–1 (N3). H NMR spectrum, δ,
ppm: 1.39–2.03 m (6H, CH2), 2.16–2.21 m (2H, CH),
2.82 d (2H, NCH2), 2.96 d (2H, NCH2), 3.42 s (2H,
PhCH2), 3.58 s (9-H, β), 3.81 s (9-H, α), 7.24–7.36 m
(5H, C6H5). Mass spectrum: m/z 257 [M + H]+. Found,
%: C 70.24; H 7.93; N 21.47. C15H20N4. Calculated, %:
C 70.31; H 7.81; N 21.88.
tert-Butyl 9-azido-3-azabicyclo[3.3.1]nonane-3-
carboxylate (VIb) was synthesized in a similar way.
Yield 87%, α/β ratio 2:3. IR spectrum, ν, cm–1: 2106
3-Benzyl-9-iodo-3-azabicyclo[3.3.1]nonane (Va).
A mixture of 4.63 g (15 mmol) of compound IVa and
7.47 g (45 mmol) of anhydrous potassium iodide in
50 ml of anhydrous acetone was heated for 12 h under
reflux with stirring (until the initial compound disap-
peared completely according to the TLC data). The
mixture was cooled, diluted with 200 ml of water, and
extracted with methylene chloride (3×80 ml). The
extracts were combined, washed with water, and dried
over anhydrous sodium sulfate, and the solvent was
1
(N3), 1682 (C=O). H NMR spectrum, δ, ppm: 1.30 s
(9H, t-Bu), 1.47–2.09 m (6H, CH2), 2.37–2.42 m (2H,
CH), 3.41 d (2H, NCH2), 3.62 d (2H, NCH2), 3.72 d
(9-H, β), 3.97 d (9-H, α). Mass spectrum, m/z: 267
[M + H]+, 210 [M – 57 + H]+, 166 [M – 101 + H]+.
Found, %: C 58.43; H 8.16; N 20.85. C13H22N4O2. Cal-
culated, %: C 58.65; H 8.27; N 21.05.
(3-Benzyl-3-azabicyclo[3.3.1]non-9-yl)triphenyl-
phosphonium iodide (VIIa). A mixture of 3.41 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

3-SUBSTITUTED 3-AZABICYCLO[3.3.1]NONAN-9-OLS AND THEIR TRANSFORMATIONS
1531
(10 mmol) of compound Va and 2.62 g (10 mmol) of
triphenylphosphine in 15 ml of anhydrous THF was
heated for 10 h at 120°C in a sealed ampule. The
ampule was cooled and opened, the mixture was
diluted with 100 ml of anhydrous diethyl ether and left
to stand for 15 h, and the precipitate was filtered off,
washed with 50 ml of diethyl ether, and dried. Yield
4.25 g (71%), mixture of α- and β-epimers at a ratio of
2.08 m (6H, CH2), 2.37–2.44 m (2H, CH), 3.41 d (2H,
NCH2), 3.60 d (2H, NCH2), 6.65 s (1H, =CH), 7.01–
7.12 m (5H, C6H5). Mass spectrum, m/z: 314 [M + H]+,
257 [M – 57 + H]+, 213 [M – 101 + H]+. Found, %:
C 76.51; H 8.46; N 4.38. C20H27NO2. Calculated, %:
C 76.43; H 8.63; N 4.47.
3-Benzyl-9-(triphenyl-λ5-phosphanylidene-
amino)-3-azabicyclo[3.3.1]nonane (Xa). A mixture of
2.56 g (10 mmol) of azide VIa and 2.62 g (10 mmol)
of triphenylphosphine in 30 ml of benzene was heated
for 10 h under reflux (until the initial compounds dis-
appeared according to the TLC data). The solvent was
distilled off under reduced pressure, and the residue
was crystallized from ethyl acetate–hexane (1:5).
Compound Xa was isolated as a mixture of α- and
β-epimers at a ratio of 41:59. Yield 3.68 g (75%),
1
46:54, mp 172–176°C. H NMR spectrum, δ, ppm:
1.45–2.14 m (6H, CH2), 2.37–2.45 m (2H, CH), 2.91 d
(2H, NCH2), 3.06 d (2H, NCH2), 3.42 s (2H, PhCH2),
3.84 m (9-H, β), 4.12 m (9-H, α), 7.32–7.54 m (5H,
+
C6H5), 7.92–8.63 m (15H, PPh3). Mass spectrum:
m/z 477 [M + H]+. Found, %: C 65.31; H 5.68; N 2.36.
C33H35INP. Calculated, %: C 65.67; H 5.80; N 2.32.
(3-tert-Butoxycarbonyl-3-azabicyclo[3.3.1]non-9-
yl)triphenylphosphonium iodide (VIIb) was synthe-
sized in a similar way. Yield 66%, α/β ratio 42:58. IR
1
mp 125–128°C. H NMR spectrum, δ, ppm: 1.38–
2.04 m (6H, CH2), 2.16–2.23 m (2H, CH), 2.83 d (2H,
NCH2), 2.97 d (2H, NCH2), 3.43 s (2H, PhCH2), 3.61 s
(9-H, β), 3.84 s (9-H, α), 7.23–8.02 m (20H, C6H5).
Mass spectrum: m/z 491 [M + H]+. Found, %: C 80.73;
H 7.04; N 5.62. C33H35N2P. Calculated, %: C 80.82;
H 7.14; N 5.71.
tert-Butyl 9-(triphenyl-λ5-phosphanylidene-
amino)-3-azabicyclo[3.3.1]nonane-3-carboxylate
(Xb) was synthesized in a similar way. Yield 78%,
α/β ratio 45:55. IR spectrum: ν 1681 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 1.32 s (9H, t-Bu), 1.48–
2.08 m (6H, CH2), 2.35–2.44 m (2H, CH), 3.41 d (2H,
NCH2), 3.58 d (2H, NCH2), 3.74 s (9-H, β), 3.98 s
(9-H, α), 7.32–8.04 m (15H, C6H5). Mass spectrum,
m/z: 501 [M + H]+, 444 [M – 57 + H]+, 400 [M – 101 +
H]+. Found, %: C 74.24; H 7.32; N 5.46. C31H37N2O2P.
Calculated, %: C 74.40; H 7.40; N 5.60.
1
spectrum: ν 1681 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.38 s (9H, t-Bu), 1.52–2.21 m (6H, CH2), 2.45–
2.51 m (2H, CH), 3.54 d (2H, NCH2), 3.68 d (2H,
NCH2), 3.88 m (9-H, β), 4.15 m (9-H, α), 8.02–8.76 m
(15H, Ph). Mass spectrum, m/z: 487 [M + H]+, 430
[M – 57 + H]+, 386 [M – 101 + H]+. Found, %:
C 60.31; H 5.93; N 2.19. C31H37INO2P. Calculated, %:
C 60.68; H 6.04; N 2.28.
3-Benzyl-9-benzylidene-3-azabicyclo[3.3.1]-
nonane (IXa). Phosphonium salt VIIa, 2.38 g
(5 mmol), was dissolved in 20 ml of anhydrous metha-
nol, a solution of 5.5 mmol of sodium methoxide in
10 ml of anhydrous methanol was added under argon,
and the mixture was stirred for 3 h. Benzaldehyde,
0.53 g (5 mmol), was added to the resulting orange
solution of ylide VIIIa, the mixture was heated for 6 h
under reflux, the solvent was removed under reduced
pressure, and the residue was dissolved in ethyl acetate
and subjected to chromatography on silica gel using
ethyl acetate–hexane (1:3) as eluent. Yield 1.12 g
(74%), mp 98–100°C (from hexane). IR spectrum:
3-Benzyl-N-benzylidene-3-azabicyclo[3.3.1]-
nonan-9-amine (XIa). A mixture of 0.98 g (2 mmol)
of compound Xa and 0.21 g (2 mmol) of benzaldehyde
in 10 ml of toluene was heated for 6 h under reflux
(until the initial compounds disappeared according to
the TLC data), the solvent was distilled off under
reduced pressure, and the residue was dissolved in
ethyl acetate and purified by chromatography on silica
gel using ethyl acetate–hexane (1:2) as eluent. Com-
pound XIa was isolated as a mixture of α- and
β-epimers at a ratio of 38:62. Yield 0.53 g (83%). IR
1
ν 1618 cm–1 (C=C). H NMR spectrum, δ, ppm: 1.38–
2.05 m (6H, CH2), 2.16–2.25 m (2H, CH), 2.79 d (2H,
NCH2), 2.87 d (2H, NCH2), 3.38 s (2H, PhCH2), 6.62 s
(1H, =CH), 6.98–7.42 m (10H, C6H5). Mass spectrum:
m/z 304 [M + H]+. Found, %: C 86.93; H 8.16; N 4.45.
C22H25N. Calculated, %: C 87.13; H 8.25; N 4.62.
1
tert-Butyl 9-benzylidene-3-azabicyclo[3.3.1]-
nonane-3-carboxylate (IXb) was synthesized in
a similar way. Yield 72%, mp 133–135°C (from hex-
ane). IR spectrum, ν, cm–1: 1682 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 1.31 s (9H, t-Bu), 1.45–
spectrum: ν 1608 cm–1 (C=N). H NMR spectrum, δ,
ppm: 1.39–2.08 m (6H, CH2), 2.18–2.28 m (2H, CH),
2.82 d (2H, NCH2), 2.93 d (2H, NCH2), 3.40 s (2H,
PhCH2), 3.81 s (9-H, β), 4.02 s (9-H, α), 6.78 s (1H,
=CH), 6.99–7.43 m (10H, C6H5). Mass spectrum:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

MOSKALENKO, BOEV
1532
m/z 319 [M + H]+. Found, %: C 82.87; H 8.05; N 8.67.
C22H26N2. Calculated, %: C 83.02; H 8.18; N 8.81.
3 mmol of freshly distilled benzaldehyde in 10 ml of
toluene was heated under reflux over a period of 5 h.
The solvent was slowly distilled off under atmospheric
pressure, the residue was dissolved in ethyl acetate and
subjected to chromatography on silica gel. Compound
XIa or XIb was eluted with ethyl acetate–hexane
(1:2); their yields were 78 and 83%, respectively.
tert-Butyl 9-benzylideneamino-3-azabicyclo-
[3.3.1]nonane-3-carboxylate (XIb) was synthesized
in a similar way. Yield 79%, α/β ratio 43:57. IR spec-
1
trum, ν, cm–1: 1684 (C=O), 1608 (C=N). H NMR
spectrum, δ, ppm: 1.30 s (9H, t-Bu), 1.46–2.10 m (6H,
CH2), 2.38–2.42 m (2H, CH), 3.42 d (2H, NCH2),
3.62 d (2H, NCH2), 3.92 s (9-H, β), 4.05 s (9-H, α),
6.81 s (1H, =CH), 7.01–7.18 m (5H, C6H5). Mass spec-
trum, m/z: 329 [M + H]+, 272 [M – 57 + H]+, 228 [M –
101 + H]+. Found, %: C 73.31; H 8.45; N 8.37.
C20H28N2O2. Calculated, %: C 73.17; H 8.54; N 8.54.
Methyl 1-(3-benzyl-3-azabicyclo[3.3.1]non-9-yl)-
1H-1,2,3-triazole-4-carboxylate (XIIIa). A mixture
of 0.77 g (3 mmol) of azide VIa and 0.3 g (3.5 mmol)
of methyl prop-2-ynoate in 5 ml of toluene was heated
for 10 h under reflux (until the initial azide disap-
peared according to the TLC data). The solvent was
distilled off under reduced pressure, and the residue
was dissolved in ethyl acetate and purified by chroma-
tography on silica gel. Compound XIIIa was isolated
as a mixture of α- and β-epimers at a ratio of 45:55.
Yield 0.52 g (51%), mp 148–152°C (from hexane). IR
3-Benzyl-3-azabicyclo[3.3.1]nonan-9-amine
(XIIa). A solution of 2.56 g (10 mmol) of azide VIa in
20 ml of THF was added under argon to a suspension
of 0.2 g (5.2 mmol) of lithium tetrahydridoaluminate in
10 ml of anhydrous THF, and the mixture was stirred
for 5 h at room temperature (until the initial com-
pounds disappeared according to the TLC data). The
mixture was then treated with 30 ml of 10% aqueous
ammonium chloride, stirred for 1 h, and filtered, and
the filtrate was extracted with ethyl acetate (2×50 ml).
The extracts were combined, washed with water, and
dried over anhydrous sodium sulfate, the solvent was
distilled off under reduced pressure, and the residue
was crystallized from hexane on cooling to –20°C.
Compound XIIa was isolated as a mixture of α- and
β-epimers at a ratio of 35:65. Yield 1.48 g (64%),
mp 65–68°C. IR spectrum, ν, cm–1: 3367, 3358 (NH2).
1H NMR spectrum, δ, ppm: 1.36–2.04 m (6H, CH2),
2.12–2.21 m (2H, CH), 2.78 d (2H, NCH2), 2.85 d
(2H, NCH2), 3.36 s (2H, PhCH2), 3.62 m (9-H, β),
3.86 m (9-H, α), 4.22 br.s (2H, NH2), 7.02–7.17 m
(5H, C6H5). Mass spectrum: m/z 231 [M + H]+. Found,
%: C 78.41; H 9.36; N 12.08. C15H22N2. Calculated, %:
C 78.26; H 9.57; N 12.17.
1
spectrum: ν 1698 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.38–2.08 m (6H, CH2), 2.14–2.22 m (2H, CH),
2.79 d (2H, NCH2), 2.86 d (2H, NCH2), 3.38 s (2H,
PhCH2), 3.56 s (3H, OCH3), 3.72 s (9-H, β), 3.92 s
(9-H, α), 7.05–7.36 m (6H, 5-H, C6H5). Mass spec-
trum: m/z 341 [M + H]+. Found, %: C 65.84; H 7.15;
N 16.31. C19H24N4O2. Calculated, %: C 67.06; H 7.06;
N 16.47.
Methyl 1-(3-tert-butoxycarbonyl-3-azabicyclo-
[3.3.1]non-9-yl)-1H-1,2,3-triazole-4-carboxylate
(XIIIb) was synthesized in a similar way. Yield 49%,
α/β ratio 42:58. IR spectrum, ν, cm–1: 1698, 1684
1
(C=O). H NMR spectrum, δ, ppm: 1.32 s (9H, t-Bu),
1.48–2.15 m (6H, CH2), 2.34–2.39 m (2H, CH), 3.42 d
(2H, NCH2), 3.58 d (2H, NCH2), 3.68 s (3H, OCH3),
3.91 s (9-H, β), 4.08 s (9-H, α), 7.11 s (1H, 5-H). Mass
spectrum, m/z: 351 [M + H]+, 294 [M – 57 + H]+, 250
[M – 101 + H]+. Found, %: C 58.12; H 7.27; N 15.86.
C17H26N4O4. Calculated, %: C 58.29; H 7.43; N 16.00.
9-Hydroxy-3-azoniabicyclo[3.3.1]nonane
chloride (IIc). Compound IIb, 1.16 g (5 mmol), was
dissolved in 10 ml of anhydrous ethanol, 20 ml of
a saturated solution (16%) 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 treated with 30 ml of anhydrous diethyl
ether, and the mixture was left to stand for 20 h. The
precipitate was filtered off, washed with 20 ml of
diethyl ether, and dried under reduced pressure over
P2O5. Yield 0.82 g (92%), decomposition point 178–
183°C. IR spectrum, ν, cm–1: 3431 (OH), 3382 (+NH2).
1H NMR spectrum, δ, ppm: 1.51–2.24 m (6H, CH2),
tert-Butyl 9-amino-3-azabicyclo[3.3.1]nonane-3-
carboxylate (XIIb) was synthesized in a similar way.
Yield 62%, mp 87–90°C, α/β ratio 48:52. IR spectrum,
1
ν, cm–1: 3364, 3351 (NH2); 1684 (C=O). H NMR
spectrum, δ, ppm: 1.31 s (9H, t-Bu), 1.47–2.12 m (6H,
CH2), 2.36–2.41 m (2H, CH), 3.41 d (2H, NCH2),
3.60 d (2H, NCH2), 3.90 m (9-H, β), 4.06 m (9-H, α),
4.25 br.s (2H, NH2). Mass spectrum, m/z: 241 [M + H]+,
184 [M – 57 + H]+, 140 [M – 101 + H]+. Found, %:
C 64.83; H 9.93; N 11.52. C13H24N2O2. Calculated, %:
C 65.00; H 10.00; N 11.67.
Reaction of amines XIIa and XIIb with benzal-
dehyde. A mixture of 3 mmol of amine Xa or Xb and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

3-SUBSTITUTED 3-AZABICYCLO[3.3.1]NONAN-9-OLS AND THEIR TRANSFORMATIONS
1533
2.29–2.38 m (2H, CH), 3.41 d (2H, NCH2), 3.62–
(3-Azoniabicyclo[3.3.1]non-9-yl)triphenylphos-
phonium chloride iodide (VIIc). Yield 92%, decom-
position point 204–208°C. IR spectrum: ν 3386 cm–1
+
3.96 m (3H, NCH2, 9-H), 9.50 br.s (2H, NH2) Mass
spectrum: m/z 142 [M + H]+. Found, %: C 53.67;
H 8.83; N 7.76. C8H15NO · HCl. Calculated, %:
C 54.08; H 9.01; N 7.89.
1
(+NH2). H NMR spectrum, δ, ppm: 1.52–2.24 m (6H,
CH2), 2.46–2.53 m (2H, CH), 3.68 d (2H, NCH2),
3.74–4.05 m (3H, NCH2, 9-H), 8.08–8.83 m (15H, Ph),
9.61 br.s (2H, H2N+). Mass spectrum: m/z 387 [M + H]+.
Found, %: C 56.60; H 5.34; N 2.47. C26H29INP·HCl.
Calculated, %: C 56.78; H 5.46; N 2.55.
Hydrochlorides IIIc–VIIc, XIIc, and XIIIc were
synthesized in a similar way.
9-Acetoxy-3-azoniabicyclo[3.3.1]nonane chloride
(IIIc). Yield 96%, decomposition point 186–191°C. IR
spectrum, ν, cm–1: 3385 (+NH2), 1700 (C=O). 1H NMR
spectrum, δ, ppm: 1.52–2.25 m (9H, CH2, CH3), 2.30–
2.39 m (2H, CH), 3.42 d (2H, NCH2), 3.64–4.01 m
(3H, NCH2, 9-H), 9.56 br.s (2H, H2N+). Mass spec-
trum: m/z 184 [M + H]+. Found, %: C 54.53; H 8.14;
N 6.27. C10H17NO2 ·HCl. Calculated, %: C 54.67;
H 8.20; N 6.38.
3-Azoniabicyclo[3.3.1]non-9-ylammonium di-
chloride (XIIc). Yield 97%, decomposition point 208–
211°C. IR spectrum, ν, cm–1: 3398, 3387, 3378 (+NH2,
1
+NH3). H NMR spectrum, δ, ppm: 1.51–2.25 m (6H,
CH2), 2.48–2.56 m (2H, CH), 3.67 d (2H, NCH2),
3.82–4.07 m (3H, NCH2, 9-H), 8.93 br.s (3H, H3N+),
9.73 br.s (2H, H2N+). Mass spectrum: m/z 141 [M + H]+.
Found, %: C 44.83; H 8.26; N 13.08. C8H16N2·2HCl.
Calculated, %: C 45.07; H 8.45; N 13.15.
9-Methylsulfonyloxy-3-azoniabicyclo[3.3.1]-
nonane chloride (IVc). Yield 98%, decomposition
point 175–178°C. IR spectrum, ν, cm–1: 3388 (+NH2);
1-(3-Azoniabicyclo[3.3.1]non-9-yl)-4-methoxy-
carbonyl-1H-1,2,3-triazolium dichloride (XIIIc).
Yield 94%, decomposition point 218–221°C. IR spec-
trum, ν, cm–1: 3396, 3382 (+NH2, +NH), 1705 (C=O).
1H NMR spectrum, δ, ppm: 1.54–2.28 m (6H, CH2),
2.47–2.55 m (2H, CH), 3.69 d (2H, NCH2), 3.78 s (3H,
OCH3), 3.92–4.10 m (3H, NCH2, 9-H), 7.68 s (1H,
CH), 9.08 br.s (1H, NH+), 9.64 br.s (2H, H2N+). Mass
spectrum: m/z 251 [M + H]+. Found, %: C 44.36;
H 6.08; N 17.28. C12H18N4O2·2HCl. Calculated, %:
C 44.58; H 6.19; N 17.34.
1
1361, 1178 (SO2). H NMR spectrum, δ, ppm: 1.52–
2.26 m (6H, CH2), 2.32–2.41 m (2H, CH), 2.98 s (3H,
H3CSO2), 3.44 d (2H, NCH2), 3.64–3.98 m (3H, NCH2,
9-H), 9.52 br.s (2H, H2N+). Mass spectrum: m/z 220
[M + H]+. Found, %: C 42.17; H 6.93; N 5.46.
C9H17NO3S·HCl. Calculated, %: C 42.27; H 7.05;
N 5.48.
9-Iodo-3-azoniabicyclo[3.3.1]nonane chloride
(Vc). Yield 82%, decomposition point 168–172°C. IR
1
spectrum: ν 3386 cm–1 (+NH2). H NMR spectrum, δ,
ppm: 1.50–2.25 m (6H, CH2), 2.30–2.38 m (2H, CH),
3.42 d (2H, NCH2), 3.62–3.95 m (3H, NCH2, 9-H),
9.50 br.s (2H, H2N+). Mass spectrum: m/z 252
[M + H]+. Found, %: C 33.43; H 4.68; N 4.75.
C8H14IN·HCl. Calculated, %: C 33.39; H 4.87; N 4.87.
REFERENCES
1. Moskalenko, A.I. and Boev, V.I., Russ. J. Org. Chem.,
2009, vol. 45, p. 472.
2. Jeyaraman, R. and Avila, S., Chem. Rev., 1981, vol. 81,
9-Azido-3-azabicyclo[3.3.1]nonane dihydro-
chloride (VIc). Yield 94%, decomposition point 158–
163°C. IR spectrum, ν, cm–1: 3384 (+NH2), 2112 (N3).
1H NMR spectrum, δ, ppm: 1.51–2.24 m (6H, CH2),
2.30–2.37 m (2H, CH), 3.44 d (2H, NCH2), 3.66–
4.01 m (3H, NCH2, 9-H), 9.53 br.s (2H, H2N+). Mass
spectrum: m/z 167 [M + H]+. Found, %: C 39.72;
H 5.68; N 23.34. C8H14N4 · 2 HCl. Calculated, %:
C 40.17; H 5.86; N 23.43.
p. 149.
3. Omarov, T.T., Konformatsionnye effekty azotistykh gete-
rotsiklov (Conformational Effects in Nitrogen-Containing
Heterocycles), Alma-Ata: Nauka, 1988.
4. Vafina, G.F., Yakhina, G.R., Spirikhin, L.V., Galin, F.Z.,
and Yunusov, M.S., Russ. J. Org. Chem., 2005, vol. 41,
p. 1208.
5. Arias-Perez, M.S., Alejo, A., and Maroto, A., Tetra-
hedron, 1997, vol. 53, p. 13099.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010