A complete 1D and 2D NMR studies of variously substituted 3-azabicyclo[3.3.1]nonan-9-ones

Article abstract of DOI:10.1016/j.molstruc.2011.08.006

Variously substituted 3-azabicyclo[3.3.1]nonan-9-ones viz, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones, 2,4-diaryl-1-methyl-3-azabicyclo[3. 3.1]nonan-9-ones and 2,4-diaryl-7-methyl-3-azabicyclo[3.3.1]nonan-9-ones were conveniently synthesized by a modified

Full text of DOI:10.1016/j.molstruc.2011.08.006

Journal of Molecular Structure 1005 (2011) 31–44
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
A complete 1D and 2D NMR studies of variously substituted
3-azabicyclo[3.3.1]nonan-9-ones
a,b,
Dong Ho Park a, Yeon Tae Jeong b, , Paramasivam Parthiban
⇑
⇑
a Department of Biomedicinal Chemistry, Inje University, Gimhae 621-749, Gyeongnam, Republic of Korea
b Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2011
Received in revised form 2 August 2011
Accepted 2 August 2011
Available online 10 August 2011
Variously substituted 3-azabicyclo[3.3.1]nonan-9-ones viz, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones,
2,4-diaryl-1-methyl-3-azabicyclo[3.3.1]nonan-9-ones and 2,4-diaryl-7-methyl-3-azabicyclo[3.3.1]nonan-
9-ones were conveniently synthesized by a modified and an optimized one-pot Mannich condensation of
cyclohexanones, benzaldehydes and ammonium acetate in 1:2:1.5 M ratio. All the synthesized bicycles
were examined by their physical and spectral (IR, HR-MS, 1H NMR and 13C NMR) techniques. In order to
establish their unambiguous stereochemical assignments, H,H-COSY, HET-COSY, HMBC, NOESY and
dynamic NMR investigations have been carried out for some of the representative compounds. The detailed
NMR analysis proved that all the synthesized 3-azabicycles exist in a twin-chair conformation with an
equatorial orientation of the substituents, regardless the incorporation of either linear or bulkier groups
on the phenyl and/or methyl on the heterocycle or carbocycle. The electronic effects of methylation on
the azabicycle as well as the ortho substitution on the phenyl provided some useful insights.
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
2D NMR
Dynamic NMR
Methylation effect
Conformation
Stereochemistry
3-Azabicycle
1. Introduction
Since the biological actions mainly depend on the stereochemis-
try of the molecules, it is desperately needed to establish the config-
The 3-azabicyclo[3.3.1]nonane pharmacophore is present in a
wide variety of naturally occurring diterpenoid/norditerpenoid
alkaloids such as aconitine, condelphine, delcorine, deltaline, dels-
amine, delsoline, elatine, hetisine, inuline, kobusine, karacoline
lappaconitine, lycoctonine, and nudicauline, and the pharmaco-
phore has been isolated from a range of plants including aconitum,
delphinium, consolida, thalictrum and spiraea species [1–4]. The
wide-spread nature and diverse biological actions of this heterocy-
cle attracted more attention in the recent years [5–12], and as a
consequence, synthesis of a large number of analogous molecules
to improve their biological efficacy is under practice [13–20]. There
are diverse possibilities in conformation of the 3-azabicycle such as
chair–chair [21–24], chair–boat [25] and boat–boat [26] besides a
number of possible stereomers as witnessed by their stereogenic
centers.
uration and conformation of the synthesized molecules. Although
our earlier reports related to these heterocycles [8–11,21–24],
herein, we report the synthesis, complete spectral assignments
and stereochemistry of some 2,4-diaryl-3-azabicycles with various
new substituents on the phenyl groups along with/without methyl
on the bridge-head as well as other position of the hetero-bicycle.
This study will be much useful for the development in the
construction of new biologically active molecules, using this
pharmacophore as a building block.
Since the NMR spectroscopy is proved as a versatile tool for the
structural and stereochemical diagnosis of organic compounds, we
employed 1H NMR, 13C NMR, and various 2D NMR techniques such
as H,H-COSY, HET-COSY, HMBC and NOESY, and also the variable-
temperature 1H NMR, to explore the complete 1H/13C chemical
shift assignments and stereochemistry of the synthesized mole-
cules 1–16 by Scheme 1.
Abbreviations: 1D NMR, one-dimensional nuclear magnetic resonance spectros-
copy; 2D NMR, two-dimensional nuclear magnetic resonance spectroscopy; s,
singlet; br s, broad singlet; d, doublet; dd, doublet of doublets; ddd, doublet of
doublet of doublets; dt, doublet of triplets; t, triplet; td, triplet of doublets; q,
quartet; quint, quintet; m, multiplet; unr m, unresolved multiplet; SF, spectrometer
frequency; AQ, acquisition time; NS, number of transients (Number of scans); DS,
dummy scans; SW, spectral width; DR, digital resolution; RD, relaxation delay; RG,
receiver gain.
2. Experimental
All the reported melting points were taken in open capillaries
and are uncorrected. FT-IR spectra were recorded on a Varian
1000 FT-IR Scimitar Series spectrophotometer. High-resolution
mass spectra (HRMS) were performed on JEOL JMS-700 mass
spectrometer. Elemental analyses were performed on Heraeus
Carlo Erba 1108 CHN analyzer, their results were found to be
⇑
Corresponding authors.
E-mail addresses: ytjeong@pknu.ac.kr (Y.T. Jeong), parthisivam@yahoo.co.in
(P. Parthiban).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.08.006

32
D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
Scheme 1. Synthesis of variously substituted 3-azabicyclo[3.3.1]nonan-9-ones 1–16.
in good agreement with the calculated values. All the chemicals
used were of high grade and purchased from Aldrich and Alfa
Aesar. Solvents used were of commercial grade and used after
purification. Sturat melting point apparatus (Barloworld Scien-
tific, UK) was used to determine the melting point of the synthe-
sized compounds.
pre scan delay 0.1 s; NOESY: Spectral width of 3815.3 Hz was used
in both dimensions and the number of data points are 1024 ꢀ 73,
mixing time 700 ms, NS 32, AQ 0.26 s (F2), 33.54 ms (F1), RD 7 s,
RG 11, G. shape sine, G. type 2, DR 3.72 (F2), 52.26 Hz (F1), DS 4
(F2), 0 (F1), pre scan delay 1 s; HET-COSY (HSQC): Spectral width
of 3815.3 Hz in F2 and 18181.8 Hz in F1 were used. The experiment
was optimized for CAH coupling of 140.0 Hz. Acquisition data size
was 1024 points, and the number of increments for evolution was
512. The number of scans per increment was 4, with a 2.0 s delay
between transients, AQ 0.26 (F2), 28.16 (F1), DS 4 (F2), 0 (F1), RG 31,
G. recover 0.1 ms, pre scan delay 0.1 ms; HMBC: The parameters
were very similar to those used in the HSQC experiment, and
long-range 13C, 1H chemical shift correlations were obtained by
optimizing for a coupling of 8 Hz. The acquisition data size was
1024 points, and the number of increments for evolution was
256. The number of scans per increment was 8 with a 2.0 s delay
between transients.
2.1. Recording of one-dimensional NMR spectra
1D NMR spectra of all the synthesized compounds were re-
corded on JEOL JNM ECP 400 NMR spectrometer at 294 K. The 1H
and 13C NMR spectra were measured on 0.03 M and 0.05 M solu-
tions, respectively in CDCl3 with TMS as internal reference in
5 mm NMR tubes for all compounds. The pulse conditions were
as follows: 1H NMR spectra: SF 399.78 MHz, AQ 2.73 s, NS 32, DS
0, SW 5998.8 Hz, pulse 4.65 ls, angle 45°, width 9.3 ls, DR
0.366 Hz, RD 5 s, RG 13, data points 16,384, pre scan delay 1 s;
13C NMR spectra: SF 100.52 MHz, AQ 1.25 s, NS 250, DS 4, SW
26178.01 Hz, Pulse 3.13 ls, angle 30°, width 9.4 ls, DR 0.798 Hz,
RD 1 s, RG 25, data points 32,768, pre scan delay 1 s.
2.3. Recording of dynamic NMR spectra
2.2. Recording of two-dimensional NMR spectra
The variable temperature 1H NMR of compound 1 recorded at
every 5 °C intervals by the same 1H NMR parameters as mentioned
above with a temperature range of 218–318 K (ꢁ55 to 55 °C).
All the 1H and 13C chemical shift values are given in d scale
(ppm) and referred to TMS, via the solvent signals (1H, residual
CHCl3 at 7.26 ppm; 13C, CHCl3 at 77.16 ppm). Coupling constants
J are reported in Hz.
All 2D NMR spectra were recorded on the same instrument
using 0.05 M solution. The pulse conditions were as follows: H,H-
COSY: Spectral width of 3815.3 Hz was used in both dimensions
and the acquisition data points are 1024 ꢀ 256, NS 64, AQ 0.26 s
(F2), 67.09 ms (F1), P1, P2 90°, RD 1 s, RG 14, G. selection 1:1, G.
shape sine, G. type 2, DR 3.72 (F2), 14.90 Hz (F1), DS 4 (F2), 0 (F1),

Table 1
Proton chemical shift values of compounds 1–16 in CDCl3 [d (ppm)].
Com- H-1
pound
H-2a
H-4a H-5
H-6a
H-8a H-6e
H-8e
H-7a
H-7e
NH
Aryl protons at C-2 and C-4
CH3 at
C-1/ C-7
Substituents on phenyl
H-20a,
H-40a
H-20b,
H-40b
H-20c
H-40c
H-20d
H-40d
H-20e,
H-40e
1
2.69
4.82
s
2.69
br s
1.75–1.65
m
1.89
dd
2.96–2.83
m
1.31
1.46
br s
–
6.86
7.26
7.04
7.96
–
4.10–3.98, m (OCH2A);
1.43, t (CH3 of OEt)
[6.96]
br s
quint
d
dt
dt
dd,
W1/2 = 8.80
W1/2 = 8.80
[14.28,
5.12]
[8.04]
[7.32,
1.48]
[7.68,
1.48]
[7.68,
1.44]
2
3
2.41
4.34
2.41
1.74–1.65
m
1.95
2.95–2.82
m
1.39
1.83
br s
7.45
6.92
–
6.92
7.45
–
–
4.04, q (OCH2A); 1.43, t
(CH3 of OEt) [6.96]
br s
W1/2 = 8.06
d
br s
W1/2 = 8.06
dd
[15.02,
5.52]
quint
d
d
d
d
[2.56]
[8.80]
[8.80]
[8.80]
[8.80]
2.41
4.34
2.41
1.76–1.65
1.95
2.95–2.82
1.39
1.82a
7.45
6.93
–
6.93
7.45
3.93, t (OCH2A) [6.56];
1.82, sextet
(OACH2ACH2A); 1.05, t
(CH3 of OPr)
[7.72, 7.32]
br s
W1/2 = 8.42
d
br s
W1/2 = 8.42
m
dd
[14.40,
5.12]
m
quint
1.39
d
d
d
d
[2.20]
[8.76]
[8.44]
[8.44]
[8.76]
4
5
6
2.41
4.34
2.41
1.75–1.65
1.95
2.95–2.82
1.83
7.45d
6.93
–
–
–
6.93
7.45
–
–
–
3.98, t (OCH2A) [6.56];
1.81–1.75, m
(OACH2ACH2A); 1.55–
1.46, m (OACH2A
CH2ACH2A); 0.98, t
(CH3 of OBu) [7.68,
7.32]
br s
W1/2 = 8.60
d
br s
W1/2 = 8.60
m
dd
[13.56,
4.40]
m
quint
1.39
br s
[8.44]
7.46b
d
d
d
[1.44]
[8.80]
[8.80]
[8.44]
2.42
4.34
2.42
1.75–1.65
1.95
2.94–2.81
1.83
7.01
7.01
7.46b
5.08, s (OCH2A); 7.45b,
d (ortho protons
of O-Bn) [6.96]; 7.39, dt
(meta protons of
O-Bn) [8.08, 1.44]; 7.34,
td (para protons
of O-Bn) [6.96]
br s
W1/2 = 8.24
d
br s
W1/2 = 8.24
m
dd
[14.32,
4.76]
m
quint
1.39
br s
d
d
d
d
[2.56]
[7.68]
[8.76]
[8.76]
[7.68]
2.42
4.34
2.42
1.75–1.65
1.95
2.94–2.81
1.84
7.45
6.95
6.95
7.45
4.55, td (OCH2A) [5.12,
1.48]; 6.12–6.02, m
(OACH2ACH@CH2);
5.43, ddd
(@CHH0) [17.20, 2.92,
1.48],5.30, ddd
(@CHH0) [10.28, 2.56,
1.44]
br s
W1/2 = 8.24
d
br s
W1/2 = 8.24
m
dd
[14.28,
4.76]
m
quint
br s
d
d
d
d
[2.56]
[8.76]
[8.76]
[8.76]
[8.76]
7
2.49
4.39
br s
2.49
1.78–1.69
m
1.98
2.89–2.78
m
1.42
1.93
br s
7.09
s
–
–
–
–
7.20
7.08
–
3.86, s (OCH3); 2.33, s
(OCOCH3)
br s
W1/2 = 8.88
br s
W1/2 = 8.88
dd
[14.28,
5.12]
1.93
ddd
[15.40,
5.88,
1.48]
quint
dd
[8.04,
1.44]
7.29
d
[8.44]
d
[8.08]
8
2.44
unr m
4.37
d
[2.56]
2.44
unr m
1.75–1.66
m
2.93–2.79
m
1.39
quint
1.86
br s
7.47
d
[8.44]
7.29
d
[8.44]
7.47
d
[8.44]
–
2.80, s (SCH3)
9
2.46
4.38
2.46
1.74–1.65
m
1.96
2.99–2.86
m
1.37
1.87
br s
7.47
7.27
7.27
7.47
–
2.99–2.86, m(ACHA);
1.42, d(CH3 of iPr)
br s
d
br s
dd
quint
d
d
d
d
W1/2 = 7.32
[2.20]
W1/2 = 7.32
[13.92,
4.76]
[8.08]
[8.04]
[8.04]
[8.08]
10
–
4.69
4.77 2.79
1.76–1.66
1.46– 1.90
1.39c
2.21
3.27–3.12
1.46–1.39c
1.63d
–
6.85
7.28–7.20e 7.05
7.99
0.82
4.09–3.94,
m(AOCH2A); 1.46–
1.39c, m (CH3 of OEt)
(continued on next page)

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D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44

D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
35
Fig. 1. Important COSY and nOe correlations of compounds 1, 2, 10, 11, 15 and 16. The thin arrows represent the nOe correlations while the thick arrows represent the long-
range couplings of protons from the H,H-COSY by their ‘‘W’’ arrangement.
2.4. Synthesis of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones 1–9
3. Result and discussion
Mixture of cyclohexanone, substituted benzaldehydes and
ammonium acetate in 1:2:1.5 M ratio in ethanol was very gently
warmed and stirred until the completion of the reaction. Thus,
the formed products were filtered and washed with cold ethanol,
ether (1:5) mixture. According to our earlier report [10], we have
optimized the reaction conditions to afford the higher yield of
2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones as a single product as
well as single isomer, without the chalcone byproduct.
3.1. Proton NMR spectral analysis of compounds 1–9
Compounds 2,4-bis(2-ethoxyphenyl)-3-azabicyclo[3.3.1]nonan-
9-one 1 and 2,4-bis(4-ethoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-
one 2 are positional isomers regarding the substitution on the phe-
nyl at C-2 and C-4. The 1H NMR spectra of 1 and 2 have been char-
acterized with the help of their H,H-COSY/NOESY spectra and the
chemical shifts are reproduced in Table 1.
Compounds 2–9 are para or meta and para substituted com-
pounds; of them, 2 is considered as the representative compound.
In 1H NMR, the bridge-head protons H-1 and H-5 together appear
as a broad singlet at 2.41 ppm (2H) with a half of the spectral width
‘‘W1/2’’ of 8.06 Hz. The magnitude of W1/2 supports the twin-chair
conformation [15]. In H,H-COSY, a long-range coupling by W
arrangement of protons are observed between the doublet at
4.34 ppm (2H, J = 2.56 Hz) and multiplet at 1.74–1.65 ppm (2H).
Besides, the doublet and multiplet have nOe with the bridge-head
protons. They suggest that the doublet and multiplet are due to H-
2a/4a and H-6a/8a. Further, the nOe between the doublets at 4.34
and 7.45 ppm (4H, J = 8.80 Hz) clearly suggest that the latter is due
to the protons meta to the ethoxy substituents (i.e., H-20a, H-20e,
2.5. Synthesis of 2,4-diaryl-1-methyl-3-azabicyclo[3.3.1]nonan-9-ones
10–14
By adopting the above method, all the Mannich bases were syn-
thesized using 2-methtylcyclohexanone, instead of cyclohexanone.
2.6. Synthesis of 2,4-diaryl-7-methyl-3-azabicyclo[3.3.1]nonan-9-ones
15–16
According to the above method, compounds 15 and 16 were ob-
tained by 4-methtylcyclohexanone, instead of cyclohexanone.

36
D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
Fig. 2. 1H NMR spectrum of 2,4-bis(4-allyloxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one 6.
Fig. 3. 1H NMR spectrum of compound 1.

D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
37
(a)
(b)
(c)
(d)
Fig. 4. (a) and (c) Interactions between the benzylic/bridge-head hydrogens and ortho substituents on the phenyl at C-2/C-4; (b) and (d) The distances (in Å) between
benzylic/bridge-head hydrogen and oxygen atoms of analogous compounds [21,22].
Fig. 5. 1H NMR spectrum of compound 10.

38
D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
H-40a and H-40e). Likewise, another doublet at comparatively up-
field region of 6.92 ppm (4H, J = 8.80 Hz) has nOe with the methy-
lene protons of the ethoxy group. Thus, the upfield aryl doublet is
assigned to the protons ortho to the ethoxy substituents (i.e., H-20b,
H-20d, H-40b and H-40d). The protons at C-7 are identified by the
correlation between them. Of them, the axially oriented endocyclic
proton has nOe with the aryl protons, which justifies allocating the
multiplet (2.95–2.82 ppm, 1H) to H-7a and 1.39 ppm quintet to H-
7e. But, according to the cyclohexane chair conformation, the dif-
ference between equatorial and axial protons of C-6/8 is
0.26 ppm only, owing to the leading hyperconjucation of CAC sin-
functionalized compound with OCH3 and OCOCH3 groups at meta
and para positions. Owing to the diverse bulkier substitutions on
the phenyl, 7 is expected to deviate some extent from the stereo-
chemistry of compound 2. As witnessed by its vicinal couplings
(3J2a/4a,H-1/5 = zero) of the benzylic protons and W1/2 (8.88 Hz) of
the bridge-head protons, there is a more flattening observed on
the benzylic and bridge-head bonds of 7 than 2, otherwise a similar
stereochemistry is exist.
In order to assess the impact on the stereochemistry of the 3-
azabicycle by the bulkier substitution on the ortho position of the
phenyl at C-2 and C-4, we have synthesized the ortho-OEt com-
pound 1.
gle bond [27], whereas here, the
Ddeq,ax of C-7 protons is
ꢁ1.49 ppm; this vast difference and in fact reverted effect is abso-
lutely not possible by the lone pair of electrons on the nitrogen
atom. Indeed, this must be due to the polarization of H-7a as a con-
sequence of the steric interaction experienced by the endocyclic
bond C7AH7a. This prompts to acquire a positive charge on H-7a
and thus deshielded nearly 1.8 ppm than the expected resonance
according to the foresaid effect. Overall, the vicinal coupling con-
stant, W1/2 of the bridge-head protons and 2D NMR correlations
(Fig. 1) are clearly indicate that compound 2 adopts a twin-chair
conformation with an equatorial orientation of the para-ethoxy-
phenyl group on both sides of the secondary amino group of the
bicycle.
Similarly, other para substituted compounds 3, 4, 5, 6 (Fig. 2), 8
and 9 were analyzed and their proton chemical shifts are repro-
duced in Table 1. A careful analysis of the splitting pattern, chem-
ical shifts, vicinal coupling constants and W1/2 of the bridge-head
protons undoubtedly evidence that all the compounds adopt very
similar stereochemistry as compound 2. However, 7 is a highly
In its 1H NMR spectrum as shown in Fig. 3, the bridge-head pro-
tons H-1 and H-5 appear together as a broad singlet at 2.69 ppm as
para isomer 2 with the W1/2 of 8.24 Hz. In H,H-COSY (Fig. 1), a long-
range coupling between the singlet at 4.82 ppm and the multiplet
at 1.75–1.65 ppm is observed by the W arrangement of those pro-
tons. Further, the nOe correlations (Fig. 1) between the bridge-
head protons with those protons clearly indicate that the singlet
and multiplet are due to H-2a/4a and H-6a/8a, respectively. How-
ever, in this ortho isomer 1, H-2a/4a appear as a singlet in contrary
to the doublet with J = 2.56 Hz of the para isomer 2. Besides, there
are some significant deshielding noticed on H-2a/4a and H-20e/40e
by 0.48 and 0.51 ppm, respectively than 2, and a 0.28 ppm deshiel-
ding also noted on the bridge-head protons.
Indeed, the foresaid deshieldings are not feasible by the elec-
tronic effect of the ortho substitution. It is mainly by the orienta-
tion of the ortho substituent. In order to avoid the dipole–dipole
interaction between the CAO and CAN bonds, the (CAO bond of
the) OEt substituent prefers to be syn to the benzylic proton as
H-7e, H-8a,
O-CH2-CH3
(upfi eld
region)
1.46-1.39, m
O
H-6a
H-6e
2.79
quintet
(downf ield
4.09-3.94, m
r egion)
0.82
s
H-8e
4.69
s
H
H3C
H3C
CH3
1
5
4.77, d
1.76-1.66, m
J = 2.92 Hz
H2C
Ha
Ha
Ha
O
CH2
1.46-1.39, m
Ha
O
H-5
4
6
8
2
2.21, ddd
2'a
4'a
J = 12.96,
He
Ha
2'
He
He
3
7
H2'b
4'
H-7a
6.85, d
H
5.52, 1.84 Hz
1.46-1.39, m
N
2'e
4'b
J = 8.08 Hz
H4'e
H
H
1.63
br s
2'c
H
4'c
H
1.90, tt
3.27-
3.12
m
2H'd
7.28-7.20, m
(overlapping
of two dt )
4'dH
7.83, dd
J = 13.92,
2.56 Hz
J = 7.68,
1.48 Hz 7.05, t
O-CH2-CH3
7.99, dd
J = 7.72,
1.12 Hz
J = 7.50 Hz
6.84, d
J = 8.04 Hz
6.98, t
J = 7.50 Hz
H-2a
H-4a
H-2’b/4’b
H-2’d
H-4’d
H-4’c, H-2’c
H-2’e
H-4’e
Fig. 6. H,H-COSY spectrum of compound 10.

D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
39
shown in Fig. 4. As a result, the phenyl protons H-20e and H-40e are
deshielded by the nitrogen lone pair. By the non-bonded interac-
tions between the benzylic/bridge-head protons and CAO bond
of the OEt groups, both the benzylic and bridge-head protons are
deshielded, however, due to proximity, the benzylic protons H-
2a/4a are deshielded significantly than the bridge-head protons
H-1/5.
The absence of doublet for the benzylic protons and an incre-
ment in the W1/2 of the bridge-head protons indicate that the ortho
isomer is flattened more than the para isomer and, of course the
broadenings might probably be due to the restricted rotation of
the benzylic/bridge-head protons through the significant non-
bonded interactions with the CAO bonds. All correlations from
the COSY as well as NOESY suggest that 1 also adopts a similar con-
formation as 2 with an equatorial disposition of the ortho-ethoxy-
phenyl groups at C-2 and C-4, whereas the C1AC2 and C4AC5
bonds are flattened by the bulkier ortho substitution.
2,4-bis(2-ethoxyphenyl)-1-methyl-3-azabicyclo[3.3.1]nonan-9-one 10
and 2,4-bis(4-ethoxyphenyl)-1-methyl-3-azabicyclo[3.3.1]nonan-
9-one 11 are chosen as representative compounds to explore the im-
pact on the chemical shifts and stereochemistry of the azabicycle by
the incorporation of a methyl group on the bridge-head.
Dissimilar to 2, separate signals obtained for all ring protons of
11. Also in the aryl region, instead of the two sets of doublets in 2,
two doublets at 7.46 (2H, H-40a/40e) and 7.41 (2H, H-20a/20e), and a
doublets of a doublet at 6.90 ppm (4H, H-20b/20d and H-40b/40d) are
noticed. Of the bridge-head positions C-1 and C-5, the C-1 is occu-
pied by the methyl group and which appears as a singlet at
0.79 ppm. Hence the consecutive proton H-2a appears as a singlet
at 3.88 ppm, which shows a long-range W correlation with the
multiplet at 1.45 ppm (2H); of the two protons, one is identified
as H-8a according to the W correlation. From the H,H-COSY, H-8e
is identified at 2.07 ppm as a doublets of doublets of a doublet,
and it leads to identify the H-6e (1.96, tt) by their W arrangement.
These factors clearly notify the twin-chair conformation and equa-
torial orientation of the para-ethoxyphenyl at C-2.
3.2. Proton NMR spectral analysis of compounds 10–14
Another benzylic proton H-4a appears as a doublet at 4.33 ppm
(1H, 3J = 2.92 Hz) by the interaction with the benzylic proton H-5,
which appears as a quintet at 2.50 ppm. The vicinal coupling con-
stant witness the axial orientation of the hydrogen at C-4, accord-
Compounds 10–14 lost their symmetry by the introduction
of a methyl group on one of the bridge-heads of 1–3 and 8–9.
Similar to the previous series, an ortho and para OEt compounds
Fig. 7. NOESY spectrum of compound 10.

40
D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
ingly, equatorial orientation of the para-ethoxyphenyl at C-4 is
authenticated.
the quintet at 2.79 (1H), thus the quintet is allocated to H-5. Unlike
the broad singlet for the bridge-head protons in 1, the H-5 of 10 ap-
pears as a quintet.
As in 11, the W correlations observed in the H,H-COSY spectrum
of 10 (Fig. 6) between H-2a and H-8a as well as H-6e and H-8e. But
the H-8a and H-7e are merged with the multiplet of the CH3 of OEt
at 1.46–1.39 ppm; however they are unambiguously assigned by
their COSY/nOe correlations (Figs. 1 and 7). The doublets of dou-
blets at 7.99 and 7.83 ppm are respectively designated to H-40e
and H-20e by corresponding correlations.
Similar to 1, its 1-methylated analog 10 also experiences an
identical effect by the ortho substitution owing to the non-bonded
interactions between the benzylic as well as bridge-head protons
with CAO bonds of the OEt group (Fig 4). Therefore, H-4a is
deshielded by 0.44 ppm like H-2a/4a of 1, whereas the H-2a
deshielded by 0.81 ppm, which is almost twice than H-4a. In fact,
this is a sum of the effects by the introduction of methyl at C-1
and interaction between the H-2a and CAO bonds. Compare to
benzylic protons, the bridge-head proton is less deshielded
(0.28 ppm) by their less proximity with CO of OEt. The phenyl pro-
tons H-20e/40e are deshielded by 0.51 ppm than H-20e/40e of the
para isomer due to the nitrogen lone pair electrons. Because of
the non-bonded interaction between the benzylic/bridge-head
protons and CAO, there may be a restricted rotation in the mole-
cule, and thus the ortho protons H-20e/40e are particularly deshield-
ed by the nitrogen lone pair.
By the introduction of methyl at C-1 of 2, the syn
2a as well as H-8a and H-8e are shielded and deshielded signifi-
cantly by 0.46/0.24 and 0.12 ppm whereas the anti b- and -pro-
a-protons H-
c
tons are deshielded and shielded marginally by 0.09 and
0.01 ppm, respectively.
By considering the effect of methylation on 2 along with the
assignment of 11, all other para compounds viz, 1-methyl-2,4-
bis(4-propoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
methyl-2,4-bis(4-thioanisyl)-3-azabicyclo[3.3.1]nonan-9-one 13
and 1-methyl-2,4-bis(4-isopropylphenyl)-3-azabicyclo[3.3.1]
12,
1-
nonan-9-one 14 are assigned. All of them adopt the same stereo-
chemistry as compound 11.
Owing to the introduction of a methyl group on one of the
bridge-heads of 1, we expected that there may be a severe impact
on the chemical shifts and stereochemistry of 10. Hence, we re-
corded all the 2D NMR spectra along with the 1H/13C NMR and dy-
namic 1H NMR spectra for 10 to establish its stereochemistry
unambiguously.
In 1H NMR (Fig. 5), the methyl group at C-1 appears as a singlet
at 0.82 ppm and it has a strong nOe to the singlet at 4.69 ppm.
Accordingly, the singlet is designated to the proton at C-2 and it
shows a strong nOe on the doublet at 4.77 ppm (J = 2.92 Hz), thus
the doublet is designated to the proton at C-4. This nOe proves that
the protons at C-2 and C-4 are in axial position and thus directs to
designate an equatorial disposition to the ortho-ethoxyphenyl
groups at C-2 and C-4. Further, the H-4a shows a strong nOe on
On the whole, the COSY, NOESY correlations and vicinal cou-
pling constants clearly indicate that the orhto-ethoxyphenyl along
Fig. 8. 1H NMR spectrum of compound 15.

D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
41
Fig. 9. NOESY spectrum of compound 15.
O
51.43
218.80
50.71
9
19.61
63.42
H3C
H3C
CH3
1
5
61.24
58.38
30.24
37.57
H2C
CH
2 14.90
4'a155.51
4' b 110.99
O
O
4
6
8
2
14.93
156.602' a
2'
3
7
4'
4'e
2'b
110.99
N
H
2'e
21.63
127.90 2'c
120.11
127.66
4' c
2'd
128.35
4'd
120.09
129.97
129.62,
129.00
Fig. 10. 13C NMR spectrum of compound 10.

42
D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
with a methyl substitution on one of the bridge-heads did not alter
the conformation of the bicycle.
4.82 ppm of 1, here a doublet is observed for H-2a/4a at
4.80 ppm with a vicinal coupling of 1.84 Hz. In fact, the 3J of 16
is 2.60 Hz whereas it is only 1.84 Hz for the ortho counterpart 15.
The decrease in the magnitude of vicinal coupling constant indi-
cates that in 15, the bonds between the benzylic and bridge-head
protons are flattened, however, less flattened than 1 (3J = 0.0 Hz).
The variable temperature 1H NMR study has been carried out
for compound 10 to examine the restricted rotation in the mole-
cule. As seen in Supplementary Figure S1, there are no significant
broadenings and the coalescence is not very indicative. Hence, it
can be convincing that the restricted rotation and energy barrier
are not significant factors in this molecule.
3.4. 13C NMR spectral analysis of compounds 1–16
3.3. Proton NMR spectral analysis of compounds 15–16
The 13C NMR analysis of all the synthesized compounds has
been carried out with an aid of 1HA13C one and multiple bond cor-
relations of some of the representative compounds. Of them, the
13C NMR and HMBC spectra of compound 10 are reproduced in
Figs. 10 and 11. The complete carbon chemical shift assignments
of 1–16 are represented in Table 2.
A careful analysis of Table 2 provides some information about
the effect of an introduction of a methyl group at C-1 and C-7 as
well the impact of ortho substitution on phenyl groups at C-2
and C-4. In all cases, compare to para isomer, the ortho analogs’
benzylic and bridge-head carbons are shielded significantly. In
compound 1, the C-2/4 and C-1/5 are shielded by 6.15 and
3.84 ppm whereas C-6/8 is deshielded by 1.11 ppm. Similarly in
7-methylated compound 15, the C-2/4 and C-1/5 are shielded by
6.25 and 3.86 ppm, respectively and the C-6/8 is deshielded by
1.16 ppm than the para analog 16. Because of the interactions be-
tween the ortho substituent and benzylic/bridge-head protons,
their CAH bonds polarized and as a consequence that protons ac-
quired partial positive charge and the carbons acquired partial neg-
ative charge and thus shielded (Fig. 4). Of them, due to spatial
The chemical shift assignments and stereochemistry of 2,4-
bis(2-ethoxyphenyl)-7-methyl-3-azabicyclo[3.3.1]nonan-9-one 15
and 2,4-bis(4-ethoxyphenyl)-7-methyl-3-azabicyclo[3.3.1]nonan-
9-one 16 were carried out by their COSY/NOESY spectral analysis
along with the comparison of corresponding non-methylated ana-
logs 1 and 2.
The para-OEt compound 16 is adopted the twin-chair confor-
mation with equatorial orientations of the aryl groups at C-2 and
C-4, and methyl group at C-7 of the 3-azabicycle. Along with nOe
correlations (Fig. 1), the vicinal coupling of 2.60 Hz of both the
H-2a and H-4a, and W1/2 of 8.06 Hz of the H-1/5 further confirm
the twin-chair conformation.
The 1H NMR and NOESY spectra of 15 are reproduced in Figs. 8
and 9. The chemical shifts are very similar to that of its non-meth-
ylated counterpart 1. The nOes and H,H-correlations (Fig. 1) of 15
further confirm the twin-chair conformation of the bicycle with
an equatorial orientation of the ortho-ethoxyphenyl groups at C-2
and C-4 as well as the methyl at C-7. Unlike a singlet at
Fig. 11. HMBC spectrum of compound 10.

D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
43
Table 2
13C chemical shift values of compounds 1–16 inCDCl3 [d (ppm)].
C
om
C-1
C-2
C-4
C-5
C-6
C-7
C-8
C-9
C-20/
C-40
C-20a/
C-40a
C-20b/
C-40b
C-20c/
C-40c
C-20d/
C-40d
C-20e/
C-40e
CH3
at
Substituents on phenyl
C-1/
C-7
1
2
3
50.39 58.19
54.23 64.34
54.23 64.34
50.39 30.14 21.01 30.14 218.91 128.91 155.55 111.09 128.05 120.16 127.83
54.23 29.03 21.20 29.03 217.89 133.34 127.92 114.42 158.33 114.42 127.92
54.23 29.02 21.19 29.02 217.78 133.28 127.88 114.43 158.53 114.43 127.88
–
–
–
63.47 (CH2 of OEt);
14.93 (CH3 of OEt)
63.43 (CH2 of OEt);
14.90 (CH3 of OEt)
69.49 (OCH2); 22.63
(OCH2ACH2ACH3);
10.57 (OCH2ACH2ACH3)
67.74 (OCH2); 31.42
(OCH2ACH2ACH2ACH3);
19.33
4
54.29 64.41
54.29 29.07 21.25 29.07 217.91 133.31 127.93 114.48 158.60 114.48 127.93
–
(OCH2ACH2ACH2ACH3);
13.92
(OCH2ACH2ACH2ACH3)
70.15 (OCH2-Ph); 137.07
(ipso carbon of O-Bn);
128.69, 128.09, 127.57
(OCH2-Ph)
5
54.27 64.43
54.27 29.12 21.28 29.12 217.96 133.84 128.08 114.92 158.28 114.92 128.08
–
6
7
54.29 64.43
54.01 64.68
54.29 29.12 21.28 29.12 217.99 133.74 128.03 114.79 158.09 114.79 128.03
54.01 29.21 21.17 29.21 217.24 140.12 111.08 151.27 139.17 118.94 122.93
–
–
68.94 (OCH2ACH@CH2);
133.39 (OCH2ACH@CH2);
117.81 (OCH2ACH@CH2)
55.98 (OCH3); 20.79
(OCOCH3); 169.19 (OCOCH3)
15.90 (SCH3)
8
9
53.96 64.39
54.07 64.62
53.96 29.06 21.18 29.06 217.29 137.68 127.43 126.73 138.16 126.73 127.43
54.07 29.10 21.18 29.10 217.62 138.73 126.81 126.48 148.00 126.48 126.81
–
–
i
33.96 (CH of Pr); 24.01
i
(CH3 of Pr)
10 51.43 61.24 58.38 50.71 30.24 21.63 37.57 218.80 129.62, 156.60, 110.99 128.35, 120.11, 129.97, 19.61 63.42 (CH2 of OEt); 14.93,
129.00 155.51 127.90 120.09 127.66 14.90 (CH3 of OEt)
11 50.89 70.67 64.44 54.59 29.02 21.47 36.79 217.95 133.29, 129.96, 114.32, 158.58, 114.32, 129.96, 20.32 63.34 (CH2 of OEt); 14.86
131.83 127.77 113.86 158.20 113.86 127.77 (CH3 of OEt)
12 50.82 70.64 64.41 54.55 28.97 21.43 36.74 217.69 133.20, 129.89, 114.31, 158.74, 114.31, 129.89, 20.27 69.36 (OCH2); 22.57
131.74 127.68 113.85 158.36 113.85 127.68
(OCH2ACH2ACH3);
10.52 (OCH2ACH2ACH3)
13 50.72 70.68 64.44 54.22 28.99 21.38 36.73 217.25 138.00, 129.41, 126.58, 138.07, 126.58, 129.41, 20.24 15.78, 15.65 (SCH3)
137.38 127.21 125.98 136.51 125.98 127.21
14 50.82 71.02 64.79 54.42 29.12 21.47 36.88 217.72 138.68, 128.97, 126.39, 148.30, 126.39, 128.97, 20.35 33.73 (CH of Pr);
i
i
137.23 126.70 125.97 147.83 125.97 126.70
24.03, 24.01 (CH3 of Pr)
15 50.19 57.79
16 54.05 64.04
50.19 38.40 26.38 38.40 218.99 129.76 155.50 111.08 128.00 120.16 127.77 22.61 63.43 (CH2 of OEt);
14.89 (CH3 of OEt)
54.05 37.24 26.74 37.24 217.98 133.30 127.85 114.41 158.32 114.41 127.85 22.54 63.39 (CH2 of OEt);
14.89 (CH3 of OEt)
proximity between the ortho substituent and benzylic protons,
their carbons shielded more than that of the bridge-head carbons.
While compare the 1-methylated compounds 10 and 11, ex-
cept a 0.54 deshielding of C-1, the C-2, C-4 and C-5 of 10 are
shielded by 9.43, 6.06 and 3.88 ppm, respectively. In this, the
shielding magnitude of C-4 and C-5 are similar to 1 and 15.
The higher magnitude of shielding on C-2 and a deshielding of
C-1 are due to the electronic effect of the methyl at C-1. This im-
pact is evaluated by a comparison of analogous compounds 2
(non-methylated) and 11 (1-methylated). In 2, the bridge-head
protons C-1 and C-5 appear at 54.23 ppm whereas by the intro-
presence of the carbonyl group adjacent to methyl, which caused
a gauche interaction between the methyl and adjacent carbonyl.
However, another b-carbon (benzylic carbon) was not influenced
by the carbonyl group and hence which appeared very closer to
the benzylic carbon of piperidine. Increasing substitution on the
a-carbon of the piperidin-4-one 18 slightly (0.4 ppm) inverted
the -effect. Similarly in the bicycle, although the -carbon is
a
a
quaternary, it is a bridge-head and thus, deals out the methyl
in its stereochemical position, not in an exact equatorial position
as in piperidin-4-ones. This result in an inversion of the
a-effect,
nearly 3 ppm for the 1-methylated compounds but it is as ex-
pected for 7-methylated compounds. All the above methylation
effects are systematically depicted in Fig. 12.
duction of
a methyl at C-1, the a-carbon C-1 shielded by
3.34 ppm. The b-carbons C-2 and C-8 deshielded by 6.33 and
7.76 ppm, respectively whiles the other b-carbon C-9 deshielded
The comparison of methylation effects on 10 and 11 reveals the
ortho substitution effect. The b-carbon C-2 is reduced to half of 11
by the interaction of ethoxy substituent with H-2a whereas no
such variation between 15 and 16. Also this interaction shielded
the methyl at C-1 of 10 about 3 ppm related to the methyl at C-7
of 15 (Fig. 4c).
only 0.06 ppm. The
c-carbons C-5 and C-7 deshielded by 0.36
and 0.24 ppm, respectively whereas the C-20 is shielded
1.51 ppm. The literature reveal that the introduction of an equa-
torial methyl substituent in the cyclohexane deshielded
b-carbons significantly and either shielded or deshielded the
-carbon with a smaller magnitude. Accordingly noted by the
a and
c
introduction of an equatorial methyl substitution on C-3 of cis-
2,6-diphenylpiperidine as well as cis-2,6-diphenylpiperidin-
4. Conclusion
4-one 17 [28]. However in piperidin-4-one, the
a-effect is re-
duced to half but the b-effect on one of the b-carbons (carbonyl
carbon) reduced severely than piperidine. This is due to the
As a result of complete 1D and 2D NMR spectral analysis, the
proton as well as carbon chemical shifts and stereochemistry of

44
D.H. Park et al. / Journal of Molecular Structure 1005 (2011) 31–44
CH3
-5.54
-0.24
-7.76
CH3
O
O
O
-8.21
-8.21
0.18
CH3
-1.4
-7.4
Ar
0.2
0.18
-0.36
Ar
-0.5
Ar
3.34
-6.33
Ar
-0.06
-1.7
0.30
Ar
0.30
Ar
N
H
N
H
N
H
1.51
17
16
11
CH3
-5.73
O
CH3
-0.62
O
CH3
0.4
-7.43
CH3
-4.9
O
-7.10
-7.10
0.20
-8.5
Ar
3.0
Ar
N
H
0.20
-0.32
Ar
-1.04
-3.05
Ar
0.11
0.40
Ar
0.40
Ar
18
N
H
N
H
-0.08
15
10
Fig. 12. Effect of methylation on the carbon chemical shifts.
the synthesized compounds 1–16 are make known in an unambig-
uous manner. Accordingly, all compounds exist in a twin-chair
conformation with an equatorial orientation of the aryl groups at
C-2 and C-4 despite the nature and position of the substituents
at ortho or meta and/or para positions of the phenyl. Likewise,
the stereochemistry is not altered by the introduction of a methyl
group either on the bridge-head C-1 or tail-position C-7 of the
3-azabicycle, and the methyl group adopts an exocyclic disposition.
References
[1] R. Jeyaraman, S. Avila, Chem. Rev. 81 (1981) 149.
[2] A. Henry, Plant Alkaloids, Churchill, London, 1966.
[3] S.W. Pelletier, in: M.H. Benn, J.M. Jacyno (Eds.), The Alkaloids: Chemical and
Biological Perspectives, vol. 1, Wiley, New York, 1983, p. 120.
[4] S.W. Pelletier, in: S.W. Pelletier, N.V. Mody, B.S. Joshi, L.C. Schramm (Eds.), The
Alkaloids: Chemical and Biological Perspectives, vol. 2, Wiley, New York, 1983,
p. 205.
[5] S.W. Pelletier, in: S.W. Pelletier, B.S. Joshi (Eds.), The Alkaloids: Chemical and
Biological Perspectives, vol. 7, Wiley, New York, 1991, p. 297.
[6] D.J. Hardick, I.S. Blagbrough, G. Cooper, B.V.L. Potter, T. Critchley, S. Wonnacott,
J. Med. Chem. 39 (1996) 4860.
[7] D. Barker, D.H-S. Lin, J.E. Carland, C.P-Y. Chu, M. Chebib, M.A. Brimble, G.P.
Savage, M.D. Mc Leod, Bioorg. Med. Chem. 13 (2005) 4565.
[8] P. Parthiban, G. Aridoss, P. Rathika, V. Ramkumar, S. Kabilan, Bioorg. Med.
Chem. Lett. 19 (2009) 6981.
[9] P. Parthiban, P. Rathika, V. Ramkumar, S.M. Son, Y.T. Jeong, Bioorg. Med. Chem.
Lett. 20 (2010) 1642.
[10] P. Parthiban, V. Subalakshmi, K. Balasubramanian, Md.N. Islam, J.S. Choi, Y.T.
Jeong, Bioorg. Med. Chem. Lett. 21 (2011) 2287.
[11] P. Parthiban, P. Rathika, K.S. Park, Y.T. Jeong, Monatsh. Chem. 141 (2010) 79.
[12] R. Ramachandran, M. Rani, S. Kabilan, Bioorg. Med. Chem. Lett. 19 (2009) 2819.
[13] N.S. Zefirov, Russian Chem. Rev. 44 (1975) 413.
[14] R. Jeyaraman, M. Manoharan, Heterocycles 29 (1989) 1191.
[15] I. Iriepa, A.I. Madrid, E. Galvez, J. Bellanato, J. Mol. Struct. 651–653 (2003) 579.
and references cited therein.
[16] M.S. Arias, Y.G. Smeyers, M.S. Fernandez, N.J. Smeyers, E. Galvez, I. Fonseca, J.S.
Aparicio, J. Org. Chem. 59 (1994) 2565.
3
The observed vicinal coupling constant J2a/4a,H-1/5 of the ortho-
OEt compounds 1 (0.0 Hz) and 15 (1.84 Hz) and para-OEt com-
pounds 2 (2.56 Hz) and 16 (2.60 Hz) show that the piperidone ring
is flattened by the bulkier ortho substitution along with a puckered
cyclohexanone part, but it is relatively less flattened by the similar
or even bulkier para substituents. This is further advocated by the
reasonable higher magnitude of W1/2 of the bridge-head protons of
the ortho compounds. The W1/2 of 1 and 15 are 8.80 and 8.62 Hz
whereas they are only 8.06 Hz for 2 and 16. As 1, compound 7
(meta-methoxy and para-acetyloxy substituted phenyl) also has
the 3J of zero and W1/2 of 8.88 Hz. They indicate that compound
7 also more flattened from the normal chair.
The effect of methylation played a vital role on the chemical
shifts of the protons/carbons of the bicycle while no conforma-
tional/configurational changes occurred. Similarly, the bulkier
ortho-substitution could not alter the twin-chair conformation;
however, significantly flattened the piperidone ring and polarized
the benzylic/bridge-head CAH bonds.
[17] M.S. Arias-Perez, A. Alejo, E. Galvez, S.M. Perez, M.J. Santos, J. Mol. Struct. 349
(1995) 69.
[18] T. Polonski, M. Pham, M.J. Milewska, M. Gdaneic, J. Org. Chem. 61 (1996) 3766.
[19] K.J. Goodall, M.A. Brimble, D. Barker, Magn. Reson. Chem. 44 (2006) 980.
[20] A.I. Moskalenko, V.I. Boev, Russian J. Org. Chem. 45 (2009) 472.
[21] P. Parthiban, V. Ramkumar, M.S. Kim, S.M. Son, Y.T. Jeong, Acta Cryst. E65
(2009) o1383.
[22] P. Parthiban, V. Ramkumar, Y.T. Jeong, Acta Cryst. E65 (2009) o3103.
[23] P. Parthiban, V. Ramkumar, Y.T. Jeong, Acta Cryst. E67 (2011) o635.
[24] P. Parthiban, V. Ramkumar, Y.T. Jeong, Acta Cryst. E67 (2011) o790.
[25] P. Smith-Verdier, F. Florencio, S. Garcia-Blanco, Acta Cryst. C39 (1983) 101.
[26] S.J. Padegimas, P. Kovacic, J. Org. Chem. 37 (1972) 2672.
[27] S. Klod, A. Koch, E. Kleinpeter, J. Chem. Soc., Perkin Trans 2 (2002) 1506.
[28] K. Pandiarajan, A. Manimekalai, Magn. Reson. Chem. 29 (1991) 904. and
references cited therein.
Appendix A. Supplementary material
Physical parameters, IR data and mass/elemental analyses re-
port of 1–16 were summarized and provided in the Supplementary
material. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2011.
08.006.