Synthesis and Stereochemistry of Some 3-Azabicyclo[3.3.1]nonane Derivatives

Article abstract of DOI:10.1023/A:1023438511753

Michael reactions of methyl (ethyl) 1-benzyl-4-oxopiperidine-3- carboxylates with a number of α,β-unsaturated carbonyl compounds result in formation of 6- and 6,8-substituted methyl (ethyl) 3-benzyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylates. Stereochemical aspects of these reactions were studied, and some further transformations of the products were performed.

Full text of DOI:10.1023/A:1023438511753

Russian Journal of Organic Chemistry, Vol. 39, No. 1, 2003, pp. 49 56. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 1, 2003,
pp. 60 66.
Original Russian Text Copyright
2003 by Vafina, Yakhina, Khakimova, Spirikhin, Galin, Yunusov.
Synthesis and Stereochemistry
of Some 3-Azabicyclo[3.3.1]nonane Derivatives
G. F. Vafina, G. R. Yakhina, T. V. Khakimova, L. V. Spirikhin,
F. Z. Galin, and M. S. Yunusov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: chemorg@anrb.ru
Received October 24, 2001
Abstract Michael reactions of methyl (ethyl) 1-benzyl-4-oxopiperidine-3-carboxylates with a number of
,
-unsaturated carbonyl compounds result in formation of 6- and 6,8-substituted methyl (ethyl) 3-benzyl-
-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylates. Stereochemical aspects of these reactions were studied, and
some further transformations of the products were performed.
9
The ease of preparation of 3-azabicyclo[3.3.1]-
nonanes (3-ABN) from accessible and cheap starting
compounds, the unique reactivity of this bicyclic
system, and wide spectrum of biological activity of
The Michael reactions of methyl vinyl ketone with
compounds IIa and IIb in methanol in the presence
of 1.1 equiv of triethylamine [2] afforded 6-hydroxy-
6-methyl-3-azabicyclo[3.3.1]nonane-1-carboxylates
IIIa/IIIb and IVa/IVb as mixtures of stereoisomers at
a ratio of 1:8 and 1.5:8, respectively (yield 80 92%;
Scheme 2).
3
-ABN derivatives make them convenient models for
studying target-oriented transformations with the goal
of obtaining new structures with desired properties.
We have studied Michael reaction of methyl and
ethyl 1-benzyl-4-oxopiperidine-3-carboxylates IIa and
IIb with various alkyl vinyl ketones and unsaturated
aldehydes. A practical procedure for preparation of
esters IIa and IIb is based on the reaction of methyl
Scheme 2.
(
8
or ethyl) acrylate with benzylamine, which gives
8 90% of amines Ia and Ib, and subsequent Dieck-
mann cyclization of the latter. The intramolecular con-
densation of Ia and Ib was effected by the action of
sodium methoxide in benzene [1], and esters IIa and
IIb were obtained in 56 93% yield (Scheme 1).
Scheme 1.
IIa, IIIa, IIIb, R = Me; IIb, IVa, IVb, R = Et.
Compound IIIa was isolated as individual isomer
in the crystalline state, and its stereochemical structure
and intramolecular interactions were examined. In the
one-dimensional J-modulation 13C NMR spectrum of
IIIa, the multiplicities of all signals were consistent
R = Me (a), Et (b).
1
070-4280/03/3901-0049$25.00 2003 MAIK Nauka/Interperiodica

5
0
VAFINA et al.
2.57 ppm corresponds to C . As might be ex-
2
6
C
2
pected, the coupling mode of protons on C indicates
that they are relatively distant from the other protons:
1
they appear in the H NMR spectrum as an ABX spin
system with a geminal constant of 11.5 Hz and
a long-range constant of 2.2 Hz. These data mean that
2
the axial proton on C is coupled with the axial proton
8
2
on C . The equtorial proton on C is characterized
4
by a long-range coupling ( J = 1.6 Hz) with the
equatorial proton on C . The W-like arrangement of
the above protons on C and C and on C and C
4
2
8
2
4
suggests that conformational equilibrium is displaced
toward the chair chair conformer. Evidences in favor
of this conformation are the long-range coupling con-
stants J2-ax, 8-ax and J2-eq, 8-eq, Bohlmann bands in the
region 2600 2800 cm 1 of the IR spectrum of IIIa
in KBr [3], and the results of AM1 calculations. The
6
-hydroxy group in IIIa occupies equatorial position,
and the methyl group is axial. In keeping with the
calculated interatomic distances, Overhauser effect
should be observed for 5-H and axial methyl protons.
This was confirmed by the results of NOEDIFF
experiments.
1
1
Fig. 1. Two-dimensional H H NMR correlation spectrum
COSY) of methyl 3-benzyl-6-hydroxy-6-methyl-9-oxo-
-azabicyclo[3.3.1]nonane-1-carboxylate (IIIa).
(
3
Scheme 3.
with the assumed structure: 2 quartets, 5 triplets,
1
6
doublets, and 4 singlets were present. The H and
1
3
6
C signals from the methyl group on C , carbonyl
9
carbon atom (C ), as well as from the ester carbon
atoms and those of the benzyl group, can readily be
assigned. The detailed assignment of the skeletal
carbon atoms in structure IIIa was performed on
the basis of the COSYHH45 and CHCORR spectra
(
Figs. 1, 2). The upfield region of the CHCORR
spectrum (Fig. 2) contains two triplets with 31.87
C
and 34.67 ppm, to which two pairs of diastereotopic
protons correspond. Taking into account , -effects
7
of the substituents, we can contend that the C signal
8
is located in a weaker field relative to the C signal.
The difference in the chemical shifts of protons on C7
is relatively greater due to effect of the methyl and
hydroxy groups in the -position. Moreover, the
The NMR spectra of isomer IIIb are characterized
by quite different chemical shifts of almost all protons
and carbon nuclei. A different coupling system is
1
7
observed in the H NMR spectrum, so that we con-
downfield shift of the axial proton on C in 3-aza-
cluded that conformational equilibrium of compound
IIIb is displaced toward the chair boat conformer.
There is no J2-ax, 8-ax constant, but the long-range
bicyclo[3.3.1]nonane derivatives is caused by the
effect of lone electron pair on the nitrogen [4]. The
AB quartet from geminal protons at the carbon atom
2-Heq 4-Heq coupling (J 1.6 Hz) in the piperidine
with
61.85 ppm is typical of benzyl methylene
group. The 5-H proton should be coupled with those
attached to C , and the two-dimensional spectrum
ring is retained. The difference in the chemical shifts
4
7
of protons on C decreases (
0.42 ppm), for the
(
Fig. 1) contains to cross peaks from 5-H. Then, the
effect of lone electron pair on the nitrogen is insignif-
doublets of doublets at 2.40 and 3.04 ppm belong
to protons on C ( C 56.13 ppm), and the signal at
icant in the chair boat conformation. The chemical
4
2
shifts of protons on C change to the reverse values,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

SYNTHESIS AND STEREOCHEMISTRY OF SOME 3-AZABICYCLO[3.3.1]NONANE
51
1
13
Fig. 2. Two-dimensional H C NMR correlation spectrum (CHCORR) of methyl 3-benzyl-6-hydroxy-6-methyl-9-oxo-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate (IIIa).
presumably due to change of orientation of the
methoxycarbonyl group in the -position. The upfield
6,8-substituted 3-azabicyclononanes Va, Vb, VIa
VId, and VIIb VIId (Scheme 4). The reactions were
carried out by two procedures: (1) in methanol in the
presence of triethylamine and (2) in acetone in the
presence of potassium carbonate.
9
shift of the carbonyl carbon signal (C ) by 4 ppm in
the 13C NMR spectrum can be regarded as an indirect
7
proof for the change of conformation [4]. The C and
8
C signals are displaced downfield by 6 7 ppm, and
The product obtained from acrolein in methanol in
2
4
those from C and C shift upfield. Thus the hydroxy
group tends to occupy equtorial position. We have
revealed no appreciable displacement of conforma-
tional equilibria for compounds IIIa and IIIb by
the presence of Et N in quantitative yield was a mix-
3
ture of epimers Va and Vb at a ratio of 4:1. When
the reaction was performed in acetone in the presence
of potassium carbonate, the ratio Va:Vb was 1:4.
Thus the stereoselectivity of Michael addition of IIa
to acrolein changes to the reverse on variation of the
reaction conditions. The isomer ratio was determined
1
recording the H NMR spectra at various temperatures
(25 55 C).
By reaction of methyl 1-benzyl-4-oxopiperidine-3-
carboxylate (IIa) with acrolein, crotonaldehyde, and
1
from the 6-H signal intensity in the H NMR spec-
cinnamaldehyde, we obtained in high yields 6- and
trum. The structure of Va and Vb was confirmed by
Scheme 4.
Va, Vb, R = H; VIa VId, R = Me; VIIb VIId, R = Ph.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

5
2
VAFINA et al.
the H and 13C NMR spectra (both one- and two-
dimensional). The hydroxy group in isomer Va is
equatorial, as follows from the position and multi-
plicity of the 6-H signal. The axial proton gives
a more upfield signal than the equatorial one. The 6-H
signal in the spectrum of Va is a doublet of triplets
characterized by a large axial axial coupling constant
1
on the reaction conditions. When triethylamine was
used as a base, stereoisomer VIb prevails in the
mixture (a:b:c:d = 3.6:5:1:1.2), while potassium
carbonate as catalyst favors predominant formation of
structure VId with equatorial orientation of the sub-
6
8
stituents on C and C (a:b:c:d = 1.8:0.5:3.5:4).
3
3
3
The reaction of compound IIa and cinnamaldehyde
in the presence of triethylamine gave three isomers
VIIb VIId (according to the NMR data). As in the
preceding case, the major isomer is VIIb (b:c:d =
(
J6-ax, 7-ax = 13 Hz, J
all coupling constants for the 6-H proton in isomer
Vb fall into the range from 4 to 6 Hz (W = 9 Hz).
The H and C NMR spectra of the reaction
mixture obtained from piperidinone IIa and croton-
aldehyde suggest the presence of four isomers of
product VI. As with compound VII, the following
stereoisomeric structures of azabicyclononane VI in
the chair chair conformation are possible: OHax,
Meax (a); OH , Me (b); OH , Me (c); OHeq,
= 5 Hz, J
= 5 Hz);
6-ax, 7-eq
6-ax, 5
1
/2
1
13
7
:2.3:1). Presumably, isomer VIIa is not formed for
steric reasons. Isomer VIId having the phenyl and
hydroxy groups in equatorial positions is formed in
trace amounts. The same reaction performed in the
presence of K CO3 resulted in formation of two
2
isomers VIIc and VIId at a ratio of 3:2.
eq
ax
ax
eq
Isomer mixtures Va/Vb and VIa VId (obtained in
the presence of triethylamine) were converted into the
corresponding acetates VIIIa/VIIIb and IXa IXd,
following a standard procedure. Their yield was 85
Meeq (d) (Scheme 5).
Scheme 5.
8
8%, and the ratio was the same as for the initial
alcohols.
We also tried to reduce the carbonyl group (C9 O)
in the prepared 3-ABN derivatives with sodium tetra-
hydridoborate. The reduction of IIIb was carried out
in anhydrous methanol and 2-propanol. No reaction
in methanol was observed. In 2-propanol, we obtained
a mixture of epimeric alcohols Xa and Xb at a ratio of
3
:2 (overall yield 60%). The reduction with LiAlH4
afforded 35% of pure alcohol Xb (Scheme 6). Deben-
zylation of compound IIIb in methanol over Pd/C
(10% of Pd) in the presence of ammonium formate [7]
led to formation of product XI in 40% yield. The
structure of Xa, Xb, and XI was established by com-
paring their 13C NMR spectra with that of initial
N-benzyl derivative IIIb.
VI, R = Me; VII, R = Ph.
The most characteristic signals of isomers VIa VId
in both proton and carbon resonance spectra are those
from the 6-hydroxy proton ( 4.0 4.4 ppm) and C6
( C 72 76 ppm). According to the calculation results
Scheme 6.
[
5] and published data [6], the most upfield among
these signals, 69.8 ppm, belongs to structure VIa,
and the most downfield,
C
*
75.16 ppm, to VId.
C
Intermediate values, 70.53 and 74.57 ppm, corre-
C
spond to isomers VIb and VIc, respectively. The ratio
of isomers VIa VId was determined from the intens-
ities of doublet signals from the 8-CH protons in the
3
1
H NMR spectrum. This ratio was found to depend
_
*
___________
13
All signals in the C NMR spectra of compounds VId and
VIId are displaced upfield due to complex formation with
triethylamine.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

SYNTHESIS AND STEREOCHEMISTRY OF SOME 3-AZABICYCLO[3.3.1]NONANE
53
EXPERIMENTAL
Methyl 1-benzyl-4-oxopiperidine-3-carboxylate
IIa). Yield 93%. According to the GLC data, the
(
The H and 13C NMR spectra were recorded on
a Bruker AMX-III 300 instrument operating at 300.13
and 75.47 MHz, respectively; chloroform-d was used
as solvent (10 20% solutions), and tetramethylsilane,
as internal reference. The IR spectra were obtained on
UR-20 and Specord M-80 spectrometers from samples
prepared as thin films, Nujol mulls, KBr pellets, or
solutions in chloroform. The mass spectra (70 eV)
were run on an MKh-1306 spectrometer (ion source
temperature 150 200 C). GLC analysis was per-
formed on a Chrom-5 chromatograph equipped with
a flame-ionization detector; 12-m column; stationary
phase 5% of SE-30 on Inerton Super (0.12 0.16 mm);
carrier gas flow rate 60 ml/min; oven temperature
programming from 50 to 300 C.
1
product was a mixture of stereoisomers at a ratio of
97 : 3. Solvent system C was used as eluent for
1
3
column chromatography. C NMR spectrum, C,
2
6
3
ppm: 48.76 t (C ), 49.95 t (C ), 52.28 d (C ), 55.61 t
5
(C ), 56.53 q (COOMe), 61.59 t (CH Ph), 126.46
2
128.30 d, 138.07 s (Ph), 170.48 s (CO, ester), 204.10 s
(CO, ketone).
Ethyl 1-benzyl-4-oxopiperidine-3-carboxylate
IIb). Yield 56%. H NMR spectrum, , ppm: 1.25 t
1
(
(
Me), 2.60 t (2H, 2-H), 3.25 t (2H, 6-H), 3.50 m (1H,
13
3
-H), 4.25 q (2H, CH ), 7.35 m (Ph). C NMR spec-
2
2
trum, , ppm: 14.34 q (Me), 48.56 t (C ), 49.95 t
C
6
3
5
(
C ), 51.40 d (C ), 55.00 t (C ), 61.59 t (CH CH ),
2 3
6
1
2.21 t (CH Ph), 126.53 127.88 d, 138.12 s (Ph),
70.48 s (CO, ester), 204.04 s (CO, ketone). The
2
The progress of reactions was monitored by TLC
on Silufol UV-254 plates. Individual compounds were
isolated by column chromatography on neutral Al O3
product was purified via transformation into the corre-
sponding hydrochloride.
2
Ethyl 1-benzyl-4-oxopiperidine-3-carboxylate
hydrochloride. Compound IIb, 4.4 g, was dissolved
in 12 ml of diethyl ether, and 3 ml of an alcoholic
solution of HCl was added. The colorless precipitate
was filtered off and repeatedly washed with ether.
Yield 3.7 g, mp 155 C.
using the following solvent systems: A: methylene
chloride methanol (100, 100:1, 50:1, 25:1, 10:1);
B: benzene ether methanol (1:2, 2:1, 20:10:3); and
C: benzene methanol (100, 100:1, 50:1, 25:1, 10:1).
Bis(2-alkoxycarbonylethyl)benzylamines Ia and
Ib. Freshly distilled benzylamine, 46 ml (1.0 mol),
was added with stirring to 95 ml (2.1 mol) of freshly
distilled methyl or ethyl acrylate in 100 ml of an-
hydrous methanol. The mixture was heated for 4.5 h
under stirring, the solvent was distilled off under
reduced pressure, and the residue was purified by
column chromatography using eluent system A. Yield
Methyl (ethyl) 9-oxo-3-azabicyclo[3.3.1]nonane-
1-carboxylates (general procedure). a. Freshly dis-
tilled triethylamine, 17.5 ml (0.11 mmol), and freshly
distilled ketone or aldehyde, 0.15 mmol, were added
in succession under stirring to a solution of 0.1 mmol
of compound IIa or IIb in 40 ml of anhydrous
methanol. The mixture was stirred for 24 h (6 8 h in
the reaction with acrolein) at room temperature, the
solvent was distilled off, and the residue was purified
by column chromatography using solvent system B.
1
13.85 g (80.7%).
Bis(2-methoxycarbonylethyl)benzylamine (Ia).
C NMR spectrum, C, ppm: 32.39 t and 49.05 t
1
3
(
1
CH ), 51.43 q (COOMe), 58.21 t (CH Ph), 127.19
2
2
1
Methyl 3-benzyl-6-hydroxy-6-methyl-9-oxo-3-
28.22 d and 138.62 s (Ph), 172.73 s (COO). H
NMR spectrum: 2.80 t and 2.48 t (4H, CH ), 3.55 q
2H, AB system CH Ph), 3.63 s (3H, COOMe),
.20 s (Harom).
azabicyclo[3.3.1]nonane-1-carboxylate (IIIa/IIIb).
2
1
IR spectrum (CHCl ), , cm : 832, 848, 1535, 1704,
(
7
3
2
1
1
736, 2508, 3600 (OH ), 3680 (OH ). Isomer ratio
:8. Isomer IIIa: mp 118 121 C (from ether). H
eq ax
1
Alkyl 1-benzyl-4-oxopiperidine-3-carboxylates
NMR spectrum, , ppm: 1.22 s (3H, Me), 1.70 d.d
IIa and IIb. Amine Ia, 10.3 g, was added dropwise
under stirring to a suspension of 3.0 g of sodium
methoxide in 15 ml of dry benzene. The mixture was
stirred for 3.5 h under reflux, cooled to 10 C, and
carefully poured into 28 ml of water. The mixture was
stirred until the ketone sodium salt dissolved com-
pletely, the organic phase was separated, and the
aqueous phase was neutralized with 3.1 ml of acetic
acid and extracted with benzene (3 100 ml). The
solvent was distilled off from the extract under
reduced pressure, and the residue was purified by
column chromatography on Al O .
2
3
(
1H, 7-H , J = 13.6, J
= 6.3 Hz), 2.02 d.d
= 6.3 Hz), 2.29 br.s
eq
7-eq, 8-eq
2
3
(1H, 8-H , J = 13.6, J
eq
8-eq, 7-eq
2
3
(
1H, 5-H), 2.40 d.d (1H, 4-H , J = 11.9, J
=
ax
4-ax, 5
3
2
.2 Hz), 2.74 d.d.d.d (1H, 8-H , J = 13.6, 13.5, 6.6,
ax
2
4
.2 Hz), 2.97 d.d (1H, 2-H , J = 11.5, J
=
=
eq
2-eq, 4-eq
3
2
1.6 Hz), 3.04 d.d.d (1H, 4-H , J = 11.9, J
eq
4-eq, 5
.5, 4J
2
2
= 1.6 Hz), 3.05 d.d.d (1H, 7-H , J =
4
3
-eq, 2-eq
ax
3
1
3.6, J7
= 13.5, J
= 6.6 Hz), 3.24 d.d
= 2.2 Hz), 3.40 and
-ax, 8-ax
7-ax, 8-eq
2
4
(1H, 2-H , J = 11.5, J
2
3
ax
2-ax, 8-ax
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

5
3
4
VAFINA et al.
3J
2
.60 d (2H, CH Ph, J = 12.9 Hz), 3.72 s (3H,
= 4.1 Hz), 2.61 m (1H, 5-H), 2.91 d.d (1H,
4-ax, 5
2
1
3
2
4
COOMe), 7.35 m (Ph). C NMR spectrum, C, ppm:
2
2-H , J = 10.6, J
= 1.6 Hz), 2.99 d.d.d (1H,
eq
2-eq, 4-eq
8
7
8.04 q (Me); 31.88 t (C ); 34.67 t (C ); 52.34 q
2
3
3
7
-H , J = 13.0 Hz, J
= 13.0, J
=
=
4
1
5
ax
7-ax, 8-ax
7-ax, 8-eq
(COOMe); 56.13 t (C ); 58.24 s (C ); 59.00 d (C );
2
4
2
6
6.7 Hz), 3.10 d.d (1H, 2-H , J = 12.0, J
ax
2-ax, 8-ax
6
1
1.85 t (CH Ph); 62.57 t (C ); 78.69 s (C ); 127.51 d,
28.75 d, 128.92 d, 137.99 s (Ph); 171.26 s (CO,
2
2
2
.2 Hz), 3.35 d and 3.58 d (2H, CH Ph, J =
2
2
4
ester), 210.36 s (CO, ketone).
13.0 Hz), 3.50 d.d (1H, 4-Heq, J = 12.1, J4-eq, 2-eq =
.6 Hz), 3.68 s (3H, COOMe), 4.10 d.t (1H, 6-H ,
J6-ax, 7-ax = 13.0, J
1
1
Isomer IIIb: H NMR spectrum, , ppm: 2.10 s
ax
2
3
3
3
(3H, Me), 2.22 m (1H, 2-H , J = 11.6 Hz), 2.32
= 5.0, J
= 5.0 Hz),
ax
6-ax, 7-eq
6-ax, 5
2
1
3
2
.41 m (2H, 8-H , 5-H), 2.46 m (1H, 7-H , J =
1
.65 d.d.d (1H, 8-H , J = 10.4, J
eq eq
7.35 m (Ph). C NMR spectrum, , ppm: 30.05 t
C
2
7
8
4
0.6 Hz), 2.47 m (1H, 4-H , J = 10.8 Hz),
(C ); 30.38 t (C ); 52.28 q (COOMe); 54.13 t (C );
ax
2
3
5
1
2
2
= 10.3,
ax
8-ax, 7-ax
54.42 d (C ); 58.17 s (C ); 61.15 t (C ); 61.76 t
3
J8-ax, 7-eq = 5.1 Hz), 2.88 m (1H, 7-H ), 3.01 m (1H,
6
ax
(CH Ph); 72.30 d (C ); 127.43 d, 128.20 d, 128.54 d,
2
2
4
4-H ), 3.34 d.d (1H, 2-H , J = 11.6, J =
2-eq, 4-eq
137.83 s (Ph); 171.06 s (CO, ester); 209.23 s (CO,
ketone).
eq
eq
2
1
1
.6 Hz), 3.55 d and 3.62 d (2H, CH Ph, J =
2
1
3
Isomer Vb. 13C NMR spectrum, , ppm: 26.14 t
2.8 Hz), 3.73 s (3H, COOMe), 7.30 m (Ph).
C
C
8
7
8
5
NMR spectrum, , ppm: 29.92 q (Me); 38.84 t (C );
4
C
(C ); 31.70 t (C ); 54.86 q (COOMe); 54.86 d (C );
7
4
0.47 t (C ); 52.32 q (COOMe); 53.66 t (C ); 58.92 d
1
4
2
5
6.56 s (C ); 58.74 t (C ); 61.70 t (C ); 61.87 t
5
2
1
(C ); 60.40 s (C ); 61.21 t (CH Ph); 61.71 t (C );
6
2
(
CH Ph); 76.28 d (C ); 127.37 s, 128.45 s, 128.92 s,
6
2
7
5.55 s (C ); 127.45 d, 128.69 d, 128.85 d, 137.78 s
1
37.93 s (Ph); 171.09 s (CO, ester); 210.01 s (CO,
ketone).
Methyl 3-benzyl-6-hydroxy-8-methyl-9-oxo-3-
(
Ph); 172.07 s (CO, ester), 206.37 s (CO, ketone).
Ethyl 3-benzyl-6-hydroxy-6-methyl-9-oxo-3-aza-
bicyclo[3.3.1]nonan-1-carboxylate (IVa/IVb). Yield
azabicyclo[3.3.1]nonane-1-carboxylate (VIa VId)
was synthesized follwing the general procedure,
method a. Yield 96% (95% according to b). Isomer
1
78%. Isomer ratio 1.5:8. Isomer IVb: H NMR spec-
trum, , ppm: 1.17 t (3H, CH CH ), 2.04 s (3H,
2
3
1
3
6
-Me), 4.13 q (2H, CH CH ), 7.22 m (Ph). C NMR
2 3
1
ratio a:b:c:d = 3.6:5:1:1.2. IR spectrum, , cm :
spectrum, , ppm: 13.94 q (CH Me); 25.56 q (Me);
2
5
6
1
C
2
6
80, 692, 1080, 1728, 1736, 3432 (film); 3688, 3696
8
7
4
1
9.66 t (C ); 38.60 t (C ); 40.32 t (C ); 52.06 s (C );
3.44 d (C ); 60.22 t (CH Ph); 60.95 t (CH Me);
1.21 t (C ); 61.57 s (C ); 127.21, 128.46, 128.68 d,
37.69 s (Ph); 171.35 s (CO, ester), 207.13 s (CO,
+
(
CHCl ). m/z 317 [M] . C H O N. Major isomer
3 18 23 4
5
1
2
2
VIb: H NMR spectrum, , ppm: 0.83 d (3H, Me,
J = 6.6 Hz), 3.70 s (3H, COOMe), 4.00 m (1H, 6-H),
7
2
6
.30 m (Ph). 13C NMR spectrum, C, ppm: 16.22 q
8
7
ketone).
(
Me); 34.15 d (C ); 38.47 t (C ); 52.03 q (COOMe);
5
1
4
2
b. Potassium carbonate, 1.5 mmol, was added
53.6 d (C ); 54.00 s (C ); 54.08 t (C ); 62.08 t (C );
6
under argon to a solution of 1 mmol of compound IIa
in 10 ml of anhydrous acetone, and the mixture was
stirred for 15 min at room temperature. A solution of
62.36 t (CH Ph); 70.44 d (C ); 126.94 128.81 d,
2
137.96 s (Ph), 170.92 s (CO, ester); 209.57 s (CO,
ketone). Isomer mixture VIa VId was converted into
the corresponding hydrochloride (see above), mp 176
1.5 mmol of acrolein in 2 ml of anhydrous acetone
was slowly added in a dropwise manner. The mixture
was stirred for 7 h, the precipitate was filtered off,
and the solvent was removed from the filtrate under
reduced pressure. Yield of Va/Vb 99.9%.
1
78 C.
Isomer VIa. H NMR spectrum, , ppm: 0.95 d
Me, J = 6.42 Hz), 3.60 s (3H, COOMe), 4.20 m (1H,
1
(
13
6-H). C NMR spectrum, C, ppm: 18.67 q (Me);
8
7
Methyl 3-benzyl-6-hydroxy-9-oxo-3-azabicyclo-
3
6.20 d (C ); 41.13 t (C ); 51.80 q (COOMe); 55.92 d
5
1
2
[
3.3.1]nonane-1-carboxylate (Va/Vb). IR spectrum,
(
C ); 55.97 s (C ); 58.70 (C ); 62.11 t (CH Ph);
1
2
,
cm : 744, 948, 1028, 1044, 1076, 1088, 1108,
4
6
6
3.63 t (C ); 69.84 d (C ); 127.33 128.72 d, 137.56 s
1
268, 1356, 1456, 1688, 1720, 1728, 1744, 3448.
(
Ph); 170.82 s (CO, ester); 206.43 s (CO, ketone).
1
Isomer Va: H NMR spectrum, , ppm: 1.90 2.11 m
1
2
Isomer VIc. H NMR spectrum, , ppm: 1.05 d
(
1H, 7-H ), 2.18 d.d.d (1H, 8-H , J = 13.1,
J8-eq, 7-ax = 6.7, J
eq
eq
(Me, J = 7.14 Hz), 3.65 s (3H, COOMe), 4.27 br.s
3
3
= 2.2 Hz), 2.27 d.d.d.d (1H,
13
8-eq, 7-eq
(1H, 6-H). C NMR spectrum, C, ppm: 16.48 q
(Me); 35.11 d (C ); 37.40 t (C ); 51.41 q (COOMe);
56.73 s (C ); 58.16 t (C ); 61.18 t (C ); 61.98 t
2
3
= 13.0, 3J
8
7
8
-H , J = 13.1, J
= 6.0,
ax
8-ax, 7-ax
8-ax, 7-eq
4J
= 2.2 Hz), 2.46 d.d (1H, 4-H , J = 12.1,
2
1
2
4
8
-ax, 2-ax
ax
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

SYNTHESIS AND STEREOCHEMISTRY OF SOME 3-AZABICYCLO[3.3.1]NONANE
55
6
5
6
(
CH Ph); 74.57 d (C ); 127.39 128.75 d, 137.76 s
52.36 d (C ); 61.65 t (CH Ph); 78.00 d (C ); 127.89
2
2
(
Ph); 172.87 s (CO, ester); 209.30 s (CO, ketone).
Isomer VId. H NMR spectrum, , ppm: 0.90 d
128.97 d, 138.95 s (Ph); 170.11 s (CO, acetate);
1
1
71.20 s (CO, ester); 208.53 s (CO, ketone).
(
(
(
(
3H, Me, J = 6.18 Hz), 3.73 s (3H, CO Me), 4.48 br.s
Methyl 6-acetoxy-3-benzyl-8-methyl-9-oxo-3-aza-
2
1
3
*
1H, 6-H). C NMR spectrum, C, ppm: 19.38
bicyclo[3.3.1]nonane-1-carboxylate (IXa IXd) was
synthesized by a standard procedure from isomer
mixture VIa VId (obtained according to method a).
Yield 88%. Major isomer IXb: 13C NMR spectrum,
8
19.16) q (Me); 36.91 (29.04) d (C ); 38.86 (40.69) t
7
5
C ); 51.50 (52.03) q (COOMe); 54.09 d (C ); 56.50 s
1
4
2
(C ); 58.28 t (C ); 61.90 t (CH Ph); 62.85 t (C );
2
6
, ppm: 16.37 q (Me); 21.12 q (MeCO); 33.95 d
C
7
1
5.16 d (72.08) (C ); 127.39 128.75 d, 137.87 s (Ph);
70.79 s (CO, ester); 207.50 s (CO, ketone).
8
7
5
(
C ); 35.01 t (C ); 50.85 d (C ); 52.40 q (COOMe);
2
4
1
5
4.83 (C ); 56.45 t (C ); 61.86 s (C ); 62.40 t
CH Ph); 71.87 d (C ); 126.68 128.45 d, 137.84 s
Methyl 3-benzyl-6-hydroxy-9-oxo-8-phenyl-3-
6
(
(
azabicyclo[3.3.1]nonane-1-carboxylate (VIIb VIId)
was synthesized following the general procedure,
method a. Yield 75%. Isomer ratio b:c:d = 7:2.3:1.
m/z 379 [M] . C H O N. Major isomer VIIb:
NMR spectrum, , ppm: 37.18 t (C ); 45.16 d (C );
2
Ph); 169.93 s (CO, acetate); 175.97 s (CO, ester);
2
07.80 s (CO, ketone).
+
13
Isomer IXa. 13C NMR spectrum, , ppm: 18.64 q
C
2
3
25
4
C
7
8
7
8
(
Me); 21.21 q (MeCO); 34.56 t (C ); 36.49 d (C );
0.67 d (C ); 52.14 q (COOMe); 52.87 t (C ); 53.79 t
(C ); 61.48 s (C ); 62.08 t (CH Ph); 77.30 d (C );
5
1
5
2
5
1.48 q (COOMe); 54.33 d (C ); 54.60 s (C ); 57.35 t
5
4
2
6
4
1
6
(C ); 62.25 t (CH Ph); 62.77 t (C ); 70.28 d (C );
2
2
1
26.14 131.39 d, 136.58 137.54 s (Ph); 172.91 s
1
26.45 128.64 d, 137.59 s (Ph); 169.76 s (CO,
acetate), 170.13 s (CO, ester); 205.17 s (CO, ketone).
(CO, ester); 208.55 s (CO, ketone).
1
3
Isomer VIIc. C NMR spectrum, , ppm: 35.99 t
C
Methyl 6-acetoxy-3-benzyl-8-methyl-9-oxo-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate (IXa IXd) hydro-
chloride, mp 174 176 C.
Methyl 3-benzyl-6,9-dihydroxy-6-methyl-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate (Xa/Xb).
a. Compound IIIb, 0.5 g, was dissolved in 25 g of
8
7
5
(C ); 45.93 d (C ); 51.90 q (COOMe); 54.22 d (C );
4
2
5
(
1
8.15 t (C ); 62.20 t (CH Ph); 63.35 t (C ); 73.97 d
2
6
C ); 126.93 131.23 d, 133.97 134.67 s (Ph);
69.79 s (CO, ester); 209.44 s (CO, ketone).
Isomer VIId. 1 C NMR spectrum, , ppm: 38.63 t
3
C
8
7
4
(C ); 44.99 d (C ); 51.78 q (COOMe); 57.92 t (C );
anhydrous isopropyl alcohol, and 0.2 g of NaBH was
4
2
6
6
1
1.43 t (CH Ph); 62.98 t (C ); 72.15 t (C ); 126.55
added with stirring under a stream of argon. The mix-
ture was heated for 6 h under reflux, a saturated solu-
2
31.83 d, 134.89 s, 145.03 s (Ph); 170.57 s (CO,
ester); 210.33 s (CO, ketone).
tion of NaHCO was added, and the mixture was
3
extracted with methylene chloride. After appropriate
treatment, the residue was subjected to column
chromatography using solvent system C as eluent.
Yield 60%. According to the GLC data, the ratio of
epimeric alcohols Xa and Xb was 6:4.
Methyl 3-benzyl-6-hydroxy-9-oxo-8-phenyl-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate (VIIb VIId)
hydrochloride, mp 134 137 C.
Methyl 6-Acetoxy-3-benzyl-9-oxo-3-azabicyclo-
[
3.3.1]nonan-9-one (VIIIa/VIIIb) was synthesized
by a standard procedure from isomer mixture Va/Vb
obtained by method a). Yield 85%. The isomer ratio
b. Lithium aluminum hydride, 0.06 g, was added
with stirring to 0.5 g of compound IIIb in 10 ml of
anhydrous THF. The mixture spontaneously warmed
up to 30 C. It was heated for 6 h and treated as
described above in a. Yield of Xb 35%. C H NO .
(
1
3
remained unchanged. Major isomer VIIIa: C NMR
spectrum, , ppm: 20.92 q (MeCO); 26.58 d (C );
3
(
7
1
8
C
7
5
1
8
24
4
0.10 t (C ); 51.45 q (COOMe); 52.31 d (C ); 54.45 s
C ); 58.09 t (C ); 58.18 t (C ); 61.53 t (CH Ph);
+
13
1
4
2
m/z 319 [M] . Isomer Xa: C NMR spectrum, C,
2
8
7
6
ppm: 26.50 t (C ); 31.13 q (Me); 36.98 t (C ); 45.24 d
3.23 d (C ); 127.45 128.94 d, 136.35 s (Ph);
69.61 s (CO, acetate); 170.54 s (CO, ester); 207.13 s
5
1
2
(
5
C ); 46.40 s (C ); 52.33 q (COOMe); 54.52 t (C );
4
6
9.94 t (C ); 62.46 t (CH Ph); 71.29 s (C ); 74.70 d
(
CO, ketone).
2
9
Isomer VIIIb. 13C NMR spectrum, C, ppm:
(C ); 127.21 128.80 d, 138.07 s (Ph); 176.89 s (CO).
Alcohol Xb. 13C NMR spectrum, C, ppm: 23.31 q
8
2
_
*
2.50 q (MeCO); 27.00 d (C ); 51.27 q (COOMe);
___________
8
7
(
Me); 44.32 t (C ); 48.91 t (C ); 51.81 q (COOMe);
52.26 t (C ); 52.87 s (C ); 59.87 d (C ); 62.66 t
(CH2Ph); 68.44 s (C ); 72.80 d (C ); 127.67
2
1
5
13
In parentheses are given the C chemical shifts from the
6
9
spectrum of the reaction mixture obtained according to
method a.
128.58 d, 138.07 s (Ph); 176.89 s (CO).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

5
6
VAFINA et al.
Methyl 6-hydroxy-6-methyl-9-oxo-3-azabicyclo-
3.3.1]nonane-1-carboxylate (XI) was synthesized by
REFERENCES
[
the procedure described in [7]. Anhydrous ammonium
formate, 15 mmol, was added in one portion to
a suspension of 3 mmol of compound IIIb and
an equal (by weight) amount of 10% Pd/C in 20 ml
of anhydrous methanol, stirred in a stream of argon.
The mixture was stirred for 45 min at the boiling
point, the catalyst was filtered off and washed with
chloroform, and the filtrate was combined with the
1. Preobrazhenskii, N.A., Malkov, K.M., Maurit, M.E.,
Vorob’ev, M.A., and Vlasov, A.S., Zh. Obshch. Khim.,
1957, vol. 27, p. 3162.
2
3
.
.
Becker, H.G.O., J. Prakt. Chem., 1964, vol. 23, p. 259.
Azerbaev, I.N. and Omarov, T.T., Zh. Org. Khim.,
976, vol. 12, p. 1207.
1
4
.
Jeyaraman, R., Heterocycles, 1989, vol. 29, p. 1191.
1
3
washings and evaporated. Yield 40%. C NMR spec-
5. Boschke, F.L., Fresenius, W., Huber, J.F.K., Pun-
gor, E., Rechnitz, G.A., Simon, W., and West, Th.S.,
Tables of Spectral Data for Structure Determination of
Organic Compounds, Berlin: Springer, 1990, 2nd ed.
8
trum, , ppm: 29.85 q (Me); 32.13 t (C ); 33.29 t
C
7
4
1
(
C ); 51.86 q (COOMe); 52.01 t (C ); 60.26 s (C );
0.41 t (C ); 74.62 s (C ); 170.19 s (CO, ester),
06.93 s (CO, ketone).
2
6
6
2
6. Filippini, M.-H., Faure, R., and Rodriques, J., J. Org.
Chem., 1995, vol. 60, p. 6872.
This study was financially supported by the
Ministry of Industry and Science of the Russian
Federation (State Contract no. 41.002.1.1.1401).
7. Ram, S. and Spicer, L.D., Tetrahedron Lett., 1987,
vol. 28, p. 515.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003