Synthesis, complete NMR spectral assignments, and antifungal screening of new 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one oxime derivatives

Article abstract of DOI:10.1007/s00706-009-0221-8

A series of differently substituted 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9- one oximes have been synthesized and their ¹H and ¹³C NMR chemical shifts have been unambiguously assigned using H,H-COSY, NOESY, HSQC, and HMBC spectral data

Full text of DOI:10.1007/s00706-009-0221-8

Monatsh Chem (2010) 141:79–93
DOI 10.1007/s00706-009-0221-8
ORIGINAL PAPER
Synthesis, complete NMR spectral assignments, and antifungal
screening of new 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one oxime
derivatives
•
Paramasivam Parthiban Paramasivam Rathika
•
•
Keun Soo Park Yeon Tae Jeong
Received: 28 August 2009 / Accepted: 19 November 2009 / Published online: 14 January 2010
Ó Springer-Verlag 2010
Abstract A series of differently substituted 2,4-diaryl-3-
azabicyclo[3.3.1]nonan-9-one oximes have been synthe-
sized and their 1H and 13C NMR chemical shifts have been
unambiguously assigned using H,H-COSY, NOESY,
HSQC, and HMBC spectral data. On the basis of the NMR
studies, irrespective of the nature and position of the sub-
stituents, all reported compounds exist in twin-chair
conformation with equatorial disposition of the phenyl
groups at C-2 and C-4 of the 3-azabicyclononane moiety.
Among the synthesized oxime derivatives, compounds
with halo-substituents at ortho/para positions of the phenyl
showed good antifungal profile against all tested organisms.
local anaesthetic activity of 3-azabicyclononanes has
occupied much attention in the recent past [1–6]. The
3-azabicyclononane pharmacophore is present in numerous
naturally abundant diterpenoid/norditerpenoid alkaloids
and is responsible for their wide variety of pharmacological
actions. Because the biological activity depends mainly on
the stereochemistry of the molecules, it is very important to
establish the configuration and conformation of the syn-
thesized molecules; in this respect, NMR spectroscopy is a
versatile tool for structural and stereochemical analysis of
organic compounds [7–11].
Stereochemical investigations have been carried out on a
few synthesized 3-azabicyclononane moieties with different
substituents [12–19]. However, there are lacunae in the
synthesis, spectral assignments, and stereochemistry of
the 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one oximes and
oxime ethers. Hence, in this study, a series of 2,4-diaryl-3-
azabicyclo[3.3.1]nonan-9-one oximes, 3-methyl-2,4-diphe-
nyl-3-azabicyclo[3.3.1]nonan-9-one oxime, and 2,4-diphenyl-
3-azabicyclo[3.3.1]nonan-9-one O-methyloxime were synthe-
sized with various electron donating/withdrawing substituents
at ortho/meta/para positions of the phenyl groups at C-2 and
C-4. Further, because of the antifungal efficacy of oxime
derivatives of nitrogen heterocycles [20–22], the synthesized
oxime derivatives 17–33 were screened for their antifungal
activity against a panel of fungal strains.
Keywords 2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-one
oxime ꢀ O-Methyloxime ꢀ N-Methylation ꢀ 2D NMR ꢀ
Conformation ꢀ Antifungal activity
Introduction
The broad spectrum of biological activity, for example
antifungal, antibacterial, analgesic, narcotic antagonism,
antitussive, anti-inflammatory, sedative, antipyretic, an-
tiphologistic, calcium antagonist, and hypotensive, and
P. Parthiban ꢀ K. S. Park ꢀ Y. T. Jeong (&)
Division of Image Science and Information Engineering,
Pukyong National University, Busan 608-739,
Republic of Korea
Results and discussion
Synthesis
e-mail: ytjeong@pknu.ac.kr
According to Scheme 1, all the compounds were synthe-
sized, and characterized by use of their analytical and
P. Rathika
Department of Microbiology, Annamalai University,
Annamalainagar, Chidambaram 608002, India
1
spectral data (IR, H NMR, 13C NMR, and MS). For the
123

80
P. Parthiban et al.
O
7
O
8
6
Ethanol
Warm
Stirring
9
R1
R1
H
O
O
H
1
2
5
4
2'
R2
R3
R2
R3
2'
3
R1
R2
R1
R2
1'
3'
1'
N
H
3'
4'
6'
6'
4'
5'
5'
1 15
-
R3
R3
MeONH2 . HCl
NaOAc . 3H2O
Ethanol
NH2OH . HCl
NH4OAc
NaOAc . 3H2O
Ethanol
Reflux
Reflux
Compound R1
R2
H
H
F
H
H
Cl
H
H
Br
H
H
H
H
OMe
H
R3
H
H
H
F
H
H
Cl
H
H
Br
H
Me
H
1, 17
2, 18
3, 19
4, 20
5, 21
6, 22
7, 23
8, 24
9, 25
10, 26
11, 27
12, 28
13, 29
14, 30
15, 31
H
F
H
H
Cl
H
H
Br
H
H
Me
H
OMe
H
Me
O
7
7
OH
N
8
6
N
8
6
9
9
R1
R1
1
2
5
4
5
4
1
2
2'
1'
2''
R2
R2
R3
2'
2''
3
3
3'
1''
1'
1''
3'
N
H
3''
3''
N
H
4'
6''
6'
6''
4'
4''
6'
4''
R3
5'
5''
5'
5''
17 31
-
33
H
OMe
H
7
7
N
9
OH
O
8
6
8
6
NH2OH . HCl
MeI
9
NaOAc . 3H2O
Ethanol
Anhyd. K2CO3
Dry MeCOMe
Reflux
1
2
5
5
4
1
2
2'
2'
2'
2''
4
3
Reflux
3
1'
1'
1'
1''
1
3'
4'
3'
4'
3'
3''
N
N
6'
4'
6''
6'
Me
Me
4''
6'
5'
5'
5'
5''
16
32
Scheme 1
representative compound 19, H,H-COSY, NOESY, HSQC,
and HMBC were recorded to assign all the signals unam-
biguously, and to establish the stereochemistry. The H,H-
COSY/NOESY and HSQC/HMBC correlations are repro-
duced in Tables 1 and 2. Most of the synthesized
3-azabicyclic ketones 1–16 are reported for the first time,
and for a few of the previously reported compounds
complete 1H and 13C spectral data are not available. Hence,
the complete 1H and 13C spectral assignments of 1–16 were
carried out; for unambiguous assignment, H,H-COSY and
HSQC have been recorded for compounds 5, 6, 8, 9, 11, 13,
and 14.
Assignment of proton chemical shifts
and stereochemistry
In 19, the broad singlet at 8.55 ppm (1H) has neither H,H-
correlation nor NOE with any other protons and it has no
123

Synthesis, complete NMR spectral assignments, and antifungal screening
81
Table 1 Correlations in the H,H-COSY and NOESY spectra of 19
Signal (d (ppm))
Correlations in H,H-COSY
Correlations in NOESY
–
8.55 (br s, 1H, N–OH)
–
7.34 (m, 6H, H-20/200, H-50/500, H-60/600) 7.00
4.40 (s), 4.33 (s), 3.58, 2.72, 2.56 (w), 1.81–1.71
7.00 (t, 2H, H-40/400)
7.34
–
4.40 (s, 1H, H-2a)
2.56, 1.60–1.49 (w)
7.34a (s), 4.33, 2.56 (s), 1.81–1.71 (w)
7.34b (s), 4.40, 3.58 (s), 1.81–1.71 (w)
7.34b (s), 4.33 (s), 1.81–1.71, 1.60–1.49
7.34a (w), 1.41
7.34a (w), 4.40 (s), 1.60–1.49 (w)
7.34a (w),1.60–1.49
4.33 (s, 1H, H-4a)
3.58, 1.60–1.49 (w)
4.33 (s), 2.56 (w), 1.81–1.71c (w), 1.60–1.49d
3.58 (br s, 1H, H-5)
2.72 (m, 1H, H-7a)
1.81–1.71, 1.41
4.40 (s), 3.58 (w), 1.81–1.71e (w), 1.69–1.49f
3.58 (w), 2.72, 1.60–1.49
2.56 (br s, 1H, H-1)
1.81–1.71 (m, 3H, H-6e, H-8e, NH)
1.60–1.49 (m, 2H, H-6a, H-8a)
1.41 (quin, 1H, H-7e)
4.40 (w), 4.33 (w), 3.58, 2.56, 1.81–1.72, 1.41 (w) 1.81–1.71
2.72 2.72 (s)
s, strong correlation; w, weak correlation
a
Correlation with the lower frequency region of the multiplet (H-20/200)
b
Correlation with the higher frequency region of the multiplet (H-50/500, H-60/600)
c
Correlation with the lower frequency region of the multiplet (H-6e)
d
Correlation with the lower frequency region of the multiplet (H-6a)
e
Correlation with the higher frequency region of the multiplet (H-8e)
f
Strong correlation with the higher frequency region of the multiplet (H-8a) and weak correlation with H-6a
Table 2 Correlations in the HSQC and HMBC spectra of 19
Signal (d (ppm))
Correlations in HSQC
Correlations in HMBC
–
8.55 (br s, 1H, N–OH)
7.34 (m, 6H, H-20/200, H-50/
500, H-60/600)
–
130.14a, 130.07a, 122.77, 122.64, 114.18b,
114.07b, 113.95b, 113.85b
164.40, 161.96 (a, b, c), 145.07, 145.01 (a, b), 122.27, 122.64
(a), 114.48–114.27 (a, b)
7.00 (t, 2H, H-40/400)
114.48, 114.27
65.07
164.40, 161.96 (a),122.27, 122.64 (b), 114.18–113.85 (b)
4.40 (s, 1H, H-2a)
145.13, 145.07, 145.01 (a), 122.27, 122.64 (b), 114.18–113.85
(b), 43.10 (b), 28.16 (b)
4.33 (s, 1H, H-4a)
63.10
145.13, 145.07, 145.01 (a), 122.27, 122.64 (b), 114.18–113.85
(b), 36.27 (a), 26.66 (b)
3.58 (br s, 1H, H-5)
2.72 (m, 1H, H-7a)
2.56 (br s, 1H, H-1)
36.27
–
21.61
28.16 (a), 26.66 (a)
43.10
28.16a, 26.66b
–
1.81–1.71 (m, 3H, H-6e,
H-8e, NH)
165.00 (b), 43.10 (a), 36.27 (a), 28.16 (b), 26.66 (b), 21.61 (a)
1.60–1.49 (m, 2H, H-6a,
H-8a)
28.16a, 26.66b
21.61
65.07 (b), 63.10 (b), 43.10 (a), 36.27 (a), 21.61 (a)
43.10 (b), 36.27 (b), 28.16 (a), 26.66 (a)
1.41 (quin, 1H, H-7e)
a: a-Correlation; b: b-correlation; c: c-correlation
a
Correlation with the higher frequency region of the multiplet
b
Correlation with the lower frequency region of the multiplet
correlation with any carbon signals. Also, it disappeared in
1
the D2O exchange H NMR spectrum; consequently, the
There are two broad singlets at 3.58 (1H) and 2.56
(1H) ppm with the half-width W1/2 of 11.36 and
11.60 Hz, respectively. The broad singlet nature and half-
width values suggest that they are due to the bridgehead
protons H-1 and H-5. Further, the observed weak corre-
lation between 3.58 and 2.56 ppm strongly implies that
the correlation is due to long-range coupling between the
broad singlet is unequivocally assigned to the oxime pro-
ton. According to the D2O exchange NMR, the multiplet at
1.81–1.71 ppm corresponding to three protons is reduced
to two protons, because of D2O exchange, which indicates
that the NH proton resonance also overlapped the multiplet.
123

82
P. Parthiban et al.
signals to H-2 and H-4. Further, they have close proximity
(NOE) with each other, hence indicating their orientation as
axial. Except for axial orientation of the protons at C-2 and
C-4, there is otherwise no possibility of NOE between them
in the chair conformation. As a consequence of the observed
NOE, we can conclude that the orientation of the phenyl
groups on the same carbons should be equatorial. Moreover,
1,3-diequatorial orientation of the bulkier substituents is
more favorable in the chair conformation. Further, the
observed strong NOE of the ortho protons with H-7a/H-8e/
H-6e also supports the equatorial orientation of the phenyl
groups and the twin-chair conformation.
OH
N
H
H
5
1
Ha
Ha
Ha
Ha
Ar
6
2
8
4
He
He
He
Ar
3
N
7
Ha
H
In addition to the ‘‘W’’ correlation, both H-1 and H-5 have
correlations with the multiplets at 1.81–1.71 (3H, due to
overlapped NH) and 1.60–1.49 (2H) ppm. It is usually
observed that the chemical shift difference of protons in the
Fig. 1 Correlations between the protons that are in ‘‘W’’ arrange-
ments, from the H,H-COSY spectrum of 19
bridgehead protons because of the ‘‘W’’ arrangement of
those protons (Fig. 1).
cyclohexane chair conformation is positive (Ddeq,ax
=
deq - dax, is *0.3 ppm), owing to the leading hyperconju-
gation of the C–C single bond [23]. The multiplets with
average difference of 0.22 ppm suggest that they are due to
C-6 and C-8 protons. Specifically, the lower and higher
frequency regions of both multiplets have correlations with
H-5 and H-1. Hence, the lower and higher-frequency regions
of the multiplets are assigned to H-6e/6a and H-8e/8a. Fur-
ther, the assignments and chair conformation of the
cyclohexane part are confirmed by their NOE (Fig. 3).
A strong correlation between the proton resonances at
2.72 (m, 1H) and 1.41 (quin, 1H) ppm clearly confirms that
the signals are due to C-7 protons, and the multiplet only
correlates with H-6a/H-8a and H-6e/H-8e. The NOE
between the multiplet and the aryl protons supports attri-
bution of the multiplet to H-7a (endocyclic proton, which is
spatially very close to the ortho protons), hence, the
1.41 ppm quintet is attributed to H-7e. But the difference
The difference between H-1 and H-5, i.e., Dd, is 1.02 ppm
whereas in the corresponding bicyclic ketone, the bridgehead
protons H-1 and H-5 appear together at 2.49 ppm (2H) as a
broad singlet with a W1/2 of 11.54 Hz. Because of allylic
interaction (A1,3) between the N–OandC(5)-H bonds (Fig. 2),
the H-5 proton is deshielded, the deshielding magnitude is
quite large (1.09 ppm). But there is no change in another
bridgehead proton H-1, except for slight deshielding of
0.07 ppm. The positions, appearance, spectral width, and
correlations strongly suggest that the signals at 3.58 and
2.56 ppm are due to the bridgehead protons H-5 (syn a) and
H-1 (anti a). Though the bridgehead protons appear as two
separate signals, both are broad singlets and their half-widths
arealsosimilartothatofitsprecursor. Hence,thissuggeststhat
the bicyclic oxime also adopts the twin-chair conformation.
The signals at 4.40 and 4.33 ppm are due to benzylic
protons and they only have correlations with the bridgehead
protons H-1 and H-5; hence, we can unequivocally assign the
H
O
1,3
N
A
interaction
9
δ
H
δ
syn
anti
5
1
4
8
2
6
Ar
Ar
3
Fig. 3 Twin-chair conformation with equatorial orientation of the
phenyl groups at C-2 and C-4; supported by the NOE observed in the
NOESY spectrum of 19. For clarity, the NOE between the ortho and
ring protons is shown by dashed lines
N
H
7
Fig. 2 Interaction between the N–O and C(5)-H bonds
123

Synthesis, complete NMR spectral assignments, and antifungal screening
83
between H-7a and H-7e is quite large (1.31 ppm), more-
over, in contrast with other cyclohexane ring protons, H-7a
appears at almost twice the chemical shift magnitude of
H-7e. This is neither in accordance with the hyperconju-
gation effect of the C–C single bond of the cyclohexane in
the chair conformation nor only because of the magnetic
anisotropy of the nitrogen lone pair [12, 13]. Hence, it
should be mainly because of the steric interaction implied
by the endocyclic bond. Thus the steric interaction polar-
izes C–H(7a) bond and, as a result, H-7a acquires positive
charge and C-7 acquires negative charge. Hence, H-7a is
deshielded and C-7 is shielded; as a consequence, H-7e
also shielded by *0.4 ppm more than the other equatorial
protons H-6e/H-8e.
the methinic and ipso carbons (b to the ring nitrogen)/C-9
(c to the ring nitrogen) are respectively deshielded and
shielded by around 1 ppm. In 32, vicinal coupling con-
stants J2a,1 = 3.28 and J4a,5 = 2.92 Hz are appreciably
higher than corresponding non-N-Me oxime 17; for 17,
vicinal coupling constants are 1.44 and 1.84 Hz. The
higher magnitude of coupling constants for 32 is because of
the lower electronegativity of the NMe group than that of
NH. Besides, owing to the higher population of N-Me
equatorial conformations [13], the interaction between the
nitrogen lone pair and the ortho protons will be increased
and, as a consequence, one set of the ortho protons is de-
shielded by 0.24 ppm relative to its non-N-Me analogue
and appears as a broad singlet at 7.83 ppm (2H).
1
Of the two sets of aryl signals, a multiplet centered at
7.34 (6H) and a triplet at 7.00 (2H) ppm, the triplet has no
NOE with any of the protons in the molecule whereas it has
H,H-correlation with the higher-frequency region of the
multiplet. Hence the triplet is assigned to para protons
(H-40/400). The lower-frequency region of the multiplet
has NOE with H-1/H-2a/H-7a/H-8e whereas the higher-
frequency region has NOE with H-4a/H-5. Accordingly,
the lower and higher-frequency regions are assigned to the
ortho protons H-20/200 and H-60/600, respectively.
Careful analysis of the H NMR data reveals that the
benzylic and bridgehead protons of the ortho substituted
compounds are more deshielded than their meta/para
analogues. The deshielding of H-1/H-5 and H-2a/H-4a is,
respectively, about 0.1–0.3 and 0.2–0.4 ppm for all com-
pounds, except 24, because of a solvent effect. The
maximum deshielding is observed for Cl-substituted com-
pound 21, because of its higher electronegativity (H-1/H-5
and H-2a/H-4a are 0.33/0.34 and 0.42/0.43 ppm, respec-
tively) and lower for methyl substituted compound 27
(H-1/H-5 and H-2a/H-4a are 0.08/0.09 and 0.18/0.19 ppm,
respectively) than for their respective para analogues 23
and 28. Moreover in ortho substituted compounds, the
ortho protons, i.e., H-60/6600, are experiencing unusual
deshielding and appear as a separate signal at around
8 ppm compared to the same ortho protons in 17. The
deshielding is not only due to the electronic effect of the
ortho substituent, because such deshielding is not observed
in para/meta compounds; moreover, the effect is more for
halogen substituents, where the halogen atom prefers to be
syn to the benzylic proton to avoid dipole–dipole interac-
tion between C–X and C–N bonds. As an outcome, the
ortho protons H-60/600 are deshielded by the nitrogen lone
pair.
Overall, the chemical shifts, splitting pattern, H,H-
correlation, and NOE suggest that the compound is in
twin-chair conformation with equatorial orientation of the
phenyl groups, as depicted in Fig. 3. Further, the twin-chair
conformation is evidenced by the W1/2 of H-1 and H-5;
these values are in good agreement with the corresponding
ketone and with literature values for the flattened twin-
chair conformation of similar bicycles. If one of the cycles
adopts a boat conformation, the resonances for the
bridgehead protons H-1 and H-5 should be apparent dou-
blets with coupling constants of about 18 Hz [12]. In
addition, the observed long-range couplings between H-2a
and H-8a and between H-4a and H-6a are due to the ‘‘W’’
arrangement of those protons and this is only possible
when the bicycle is in the twin-chair conformation (Fig. 1).
Apart from this, the correlations support the axial orien-
tation of the protons at C-2 and C-4.
In 24, the oxime and NH protons appear at abnormally
higher frequencies than in the rest of the compounds. This
deshielding is because of the effect of DMSO solvent. The
oxygen atom in the sulfoxide may be interacting with the
protons in the oxime and NH. Owing to this, the oxime and
NH protons are deshielded by 2 ppm compared with
analogous compounds.
The order of chemical shift magnitude of the bicyclic
protons of 19 is H-2a [ H-4a [ H-5 [ H-7a [ H-1 [
1
H-8e [ H-6e [ H-8a [ H-6a [ H-7e. Similarly, H NMR
signals of other bicyclic oximes 17–31 and oxime ether 33
are assigned and summarized in the Experimental section
whereas in the N-Me derivative 32, because of the intro-
duction of electron-donating methyl group on the
heterocyclic ring nitrogen of 17, both the benzylic protons
H-2a and H-4a are shielded by 0.81 and 0.80 ppm but the
methinic protons H-1 and H-5 are shielded by 0.13 and
0.14 ppm, respectively. Also, the benzylic carbons (a to the
ring nitrogen) are deshielded by 10.03 and 10.12 ppm but
Assignment of carbon chemical shifts
All the carbon signals of the representative compound 19
were unambiguously assigned using HSQC and HMBC
spectra. The carbon signals from 21.61 to 65.07 ppm have
cross peaks with the bicyclic ring protons; carbon signals
between 114.27 and 130.14 ppm show cross peaks with
123

84
P. Parthiban et al.
precursors 1–16. In general, because of the decrease in the
electronegativity of a particular group in the ring skeleton,
the a-carbons are shielded and the b- and c-carbons are
deshielded [24]. Accordingly in oximes 17–32 and oxime
ether 33, the a-carbons are shielded. Specifically, in our
compounds, the shielding of a syn a-carbon is more pro-
nounced (*17–18 ppm) than that of an anti a-carbon
(*10–11 ppm) because of the interaction between N–O
and syn a C–H bonds (Fig. 2). Owing to this, the syn a-
proton (H-5) acquires an appreciable positive charge and
the C-5 carbon acquires negative charge; hence, the syn a-
carbon is more shielded than the anti a-carbon by *7 ppm.
According to the general pattern, in 17–33 the anti b-
carbons are deshielded but the syn b-carbons are shielded.
This contrast is because of the transmittance of excess
negative charge from the syn a-carbon to the syn b-carbon.
This negative charge results in shielding of the syn b-car-
bon, hence this effect prevails over the deshielding
produced by the electronegativity effect. For the same
reason, the syn c-carbon experiences less deshielding than
the anti c-carbon; however, it is not enough to overcome
the deshielding produced by the electronegativity effect.
The effects of oximation/oximination on the ring carbons
are summarized in Table 3.
OH
N
9
5
1
Ha
Ha
6
2
8
4
H
He
He
2'
H
6''
3
2''
6'
7
N
H
H
F
F
H
H
H
Fig. 4 Typical connectivities found in the HMBC spectrum of 19
phenyl protons and, hence, are assigned unambiguously.
However, signals beyond 130.14 ppm have no correlations
in the HSQC spectrum and, hence, they were assigned with
the help of HMBC correlations (Fig. 4). The carbon signals
of all other oximes/oxime ether are assigned by comparison
with oxime 19 and summarized in the Experimental sec-
tion. The HSQC and HMBC correlations are reproduced in
Table 2.
As a consequence of the N–O and C(5)-H interaction,
the oximation effect is strong fo the a-protons and less for
the b-protons. Especially, the syn a-proton H-5 is de-
shielded by 1 ppm compared with the corresponding 3-
azabicyclo[3.3.1]nonan-9-ones. Furthermore, the differ-
ence between a-protons (Dd5,1) is quite large and found to
be above 1 ppm whereas the difference between b-protons
(Dd2a,4a) is only B0.1 ppm.
Effect of oximation/oximination
Because C=N is less polar than C=O, the electronegativity
of the C=N group of our synthesized oximes/oxime ether
17–33 must be less than that of the C=O group of their
Table 3 13C chemical shift
difference between 3-
azabicyclo[3.3.1]nonan-9-ones
1–16 and their corresponding
oxime derivatives 17–33
Compounds
C-1
C-2
C-4
1.13
C-5
C-6
C-7
C-8
C-9
C-10
C-100
17
18
19
20
21
22
23
24a
25
26
27
28
29
30
31
32
33
10.75
10.66
10.68
10.66
10.66
10.63
10.67
9.98
-0.87
-0.96
-0.88
-0.92
-1.18
-0.96
-0.91
-1.87
-0.85
-0.97
-1.27
-0.89
-0.94
-0.89
-0.81
-1.22
-0.82
17.50
17.46
17.51
17.50
17.29
17.39
17.54
16.75
17.31
17.51
17.64
17.75
17.48
17.66
17.60
17.31
16.98
2.42
2.69
2.48
2.40
2.81
2.47
2.43
1.84
2.52
2.43
2.68
2.39
2.57
2.38
2.40
2.39
2.37
-0.48
-0.39
-0.44
-0.48
-0.34
-0.45
-0.46
-1.13
-0.38
-0.47
-0.41
-0.37
-0.47
-0.48
-0.49
-0.90
-0.38
0.94
1.12
0.98
0.92
1.18
0.98
0.96
0.34
1.02
0.94
1.16
0.90
1.03
0.91
0.93
0.93
0.90
51.74
51.92
51.48
51.66
56.34
51.48
51.59
54.07
54.10
51.52
51.53
51.93
53.70
52.29
52.03
51.75
53.49
-1.27
-1.10
-1.25
-1.23
-1.26
-1.25
-1.22
-2.89
-1.13
-1.24
-1.30
-1.12
-1.31
-1.33
-1.38
-1.02
-1.30
-1.22
-1.00
-1.19
-1.16
-1.22
-1.19
-1.17
-2.84
-1.09
-1.19
-1.30
-1.05
-1.31
-1.28
-1.33
-0.97
-1.20
0.86
1.09
1.08
0.62
1.02
1.09
-0.06
1.15
1.05
0.65
1.08
0.83
1.09
1.20
0.69
1.16
[(d3-ABN-9-one - doxime/oxime ether
(ppm)]
)
10.73
10.64
10.88
10.97
10.66
10.77
10.86
10.70
10.89
A negative sign denotes
deshielding
a
Deviation is because of the
effect of solvent; oxime 24 was
recorded in DMSO-d6 whereas
its corresponding ketone 8 was
recorded in CDCl3
123

Synthesis, complete NMR spectral assignments, and antifungal screening
85
Table 4 Antifungal profile of
Compound
Candida
albicans
Candida-6
Candida-51
Rhizopus sp.
Aspergillus
niger
Aspergillus
flavus
the synthesized oxime
derivatives by the disc diffusion
method
17
- -
? ?
-
- - -
? ? ?
?
- - -
? ? ?
? ? ?
? ? ?
? ? ?
? ?
? ?
? ? ?
?
- - -
?
- - -
? ? ?
? ?
? ? ?
?
- - -
? ?
-
18
19
- -
?
20
? ?
? ? ?
? ?
? ? ?
?
? ?
? ?
-
?
21
? ?
?
? ? ?
? ?
? ? ?
?
22
- -
? ?
? ?
-
23
? ?
?
? ?
?
24
25
-
- -
-
-
?
26
?
? ?
?
?
?
? ? ?
?
27
?
?
? ?
?
-
28
-
?
-
?
?
29
?
?
?
?
? ?
-
-
Activity index: - - - :
B3 mm; - - : B6 mm; - :
B10 mm; ? : B15 mm; ? ? :
B20 mm; ? ? ? : B25 mm;
Ketoconazole has activity in the
range 19–23 mm against all
strains; DMSO has activity of
B1 mm for all strains
30
?
-
- -
? ?
- -
-
?
- -
-
31
?
-
?
?
32
?
- -
- - -
? ? ?
?
- -
- -
? ? ?
- - -
- - -
? ? ?
33
?
- -
? ?
Ketoconazole
? ? ?
? ? ?
Antifungal activity
stereochemistry of the synthesized compounds were
established. All compounds exist in the twin-chair con-
formation with equatorial orientation of the aryl
substituents at C-2 and C-4. The observed effect on the ring
carbons/their associated protons due to oximation and N-
methylation are significant, whereas there are no significant
changes due to O-methylation.
All synthesized oxime derivatives 17–33 were screened for
their antifungal activity against a panel of fungal strains—
Candida albicans, Candida-6, Candida-51, Rhizopus sp.,
Aspergillus niger, and Aspergillus flavus—by the disc
diffusion method using ketoconazole as positive reference
standard. Ketoconazole has an inhibition range of 19–
23 mm against all treated strains whereas the negative
solvent control DMSO has B1 mm of inhibition zone.
Table 4 provides in vitro antifungal profile of the synthe-
sized oxime derivatives. Compound 17 with unsubstituted
phenyl groups on either sides of the secondary amino group
has no activity against all strains; however, replacement of
H by a methyl group at the ring nitrogen in 32 or the oxime
functionality of 33 has improved activity; in particular,
their activity is noticeable against C. albicans. But more
surprisingly, the activity is abruptly increased when
incorporating the halogen substituents on the phenyl groups
of 17. Specifically, the fluoro/chloro/bromo substituents at
ortho/para positions (18, 20, 21, 23, 24, and 26) inhibit the
growth of the tested fungal strains significantly.
According to the preliminary screening carried out by
the disc diffusion method, oxime derivatives with electron-
withdrawing substituents at the ortho/para position of the
phenyl groups at C-2 and C-4 of the 3-azabicyclononane
pharmacophore had remarkable activity against all tested
fungal strains.
Experimental
All reported melting points were taken in open capillaries.
FT-IR spectra were recorded on a Perkin–Elmer Spectrum
GX FT-IR spectrophotometer. Electron-impact mass
spectra (EIMS) were recorded with a Jeol JMS-700 mass
spectrometer, whereas chemical ionization mass spectra
(CIMS) were recorded with a Pesciex API 3000 series mass
spectrometer. Elemental analyses were performed with an
Heraeus Carlo Erba 1108 CHN analyzer; results were
found to be in good agreement with the calculated values.
Unless otherwise stated, all reagents and solvents used
were of high grade and purchased from Aldrich and Alfa
Aesar.
Conclusion
All compounds (1–33) were characterized by use of their
IR, mass, and NMR spectral data. Based on the 1D and 2D
NMR data, complete proton/carbon chemical shifts and
123

86
P. Parthiban et al.
Recording of NMR spectra
spectrometer frequency, AQ: acquisition time, NS: number
of transients, DS: dummy scans, SW: spectral width, DR:
digital resolution, RD: relaxation delay, RG: receiver gain.
All 1D NMR spectra of synthesized compounds were
recorded on a Jeol JNM ECP 400 NMR spectrometer at
1
294 K. The H and 13C NMR spectra were measured from
Synthesis of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones
1–15
0.03 and 0.05 M solutions, respectively, in CDCl3 with
TMS as internal reference in 5 mm NMR tubes for all
compounds except 24, which was recorded in DMSO-d6
because of its insolubility in CDCl3. The pulse conditions
A mixture of cyclohexanone, substituted benzaldehyde,
and ammonium acetate in 1:2:1.5 ratio in ethanol was very
gently warmed and stirred until the completion of the
reaction. The crude products formed were filtered and
washed with an ethanol–ether (1:5) mixture. Then the
bicyclic ketones were recrystallized from ethanol–chloro-
form–acetone to obtain the pure compounds. In this study,
we optimized the reaction conditions to afford higher
yields of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones,
absolutely as a single product and as a single isomer,
without the chalcone byproduct when using 1.5 equiv of
NH4OAc for 1 equiv cyclohexanone with moderate stirring
at *30–35 8C during the entire course of reaction.
1
were as follows: H NMR spectra: SF 399.78 MHz, AQ
2.73 s, NS 32, DS 0, SW 5,998.8 Hz, pulse 4.65 ls, angle
458, 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 26,178.01 Hz,
Pulse 3.13 ls, angle 308, width 9.4 ls, DR 0.798 Hz, RD
1 s, RG 25, data points 32,768, pre scan delay 1 s.
All 2D NMR spectra were recorded on a Jeol JNM ECP
400 NMR spectrometer at 294 K using 0.05 M solutions in
CDCl3 with TMS in a 5 mm NMR tube. The pulse con-
ditions were as follows: SF of protons and carbons are
399.78 and 100.52 MHz for all experiments; H,H-COSY:
Spectral width of 3,815.3 Hz was used in both dimensions
and the acquisition data points were 1,024 9 256, NS 60,
AQ 0.26 s (X), 67.09 ms (Y), P1, P2 908, RD 1 s, RG 14,
G. selection 1:1, G. shape sine, G. type 2, DR 3.72 (X),
14.90 Hz (Y), DS 4 (X), 0 (Y), pre scan delay 0.1 s; NO-
ESY: Spectral width of 3,815.3 Hz was used in both
dimensions and the number of data points were
1,024 9 73, mixing time 700 ms, NS 16, AQ 0.26 s (X),
33.54 ms (Y), RD 7 s, RG 11, G. shape sine, G. type 2, DR
3.72 (X), 52.26 Hz (Y), DS 4 (X), 0 (Y), pre scan delay 1 s;
HSQC: Spectral width of 3,815.3 Hz in X and 18,181.8 Hz
in Y was used. The experiment was optimized for C–H
coupling of 140.0 Hz. Acquisition data size was 1,024
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 (X), 28.16 (Y), DS 4
(X), 0 (Y), RG 31, G. recover 0.1 ms, pre scan delay
0.1 ms; HMBC: The conditions 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 1,024
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.
2,4-Diphenyl-3-azabicyclo[3.3.1]nonan-9-one
(1, C20H21NO)
Yield: 49%; m.p.: 185 °C; IR (KBr): vꢀ ¼ 3;315 (N–H
stretching), 3,057, 3,026, 2,926, 2,857, 2,794 (C–H
stretching), 1,708 (C=O stretching), 1,598 (C=C stretch-
ing-Ph), 1,491, 1,454, 1,433, 1,373, 1,346, 1,302, 1,283,
1,257, 1,236, 1,165, 1,127, 1,071, 1,024, 1,005, 929, 853,
779, 760, 722, 701, 675 cm-1 1H NMR (400 MHz,
;
CDCl3): d = 7.54 (d, J = 7.32 Hz, H-20, H-60), 7.39 (t,
J = 7.52 Hz, H-30, H-50), 7.30 (t, J = 7.32 Hz, H-40), 4.39
(d, J = 2.40 Hz, H-2a, H-4a), 2.89 (m, H-7a), 2.47 (br s,
H-1, H-5), 1.93 (dd, J = 5.86, 1.46 Hz, H-8e), 1.90 (dd,
J = 5.88, 1.48 Hz, H-6e), 1.87 (br s, NH), 1.74–1.64 (m,
H-6a, H-8a), 1.38 (quin, H-7e) ppm; 13C NMR
(100.5 MHz, CDCl3): d = 217.58 (C-9), 141.37 (C-10),
128.61 (C-30, C-50), 127.62 (C-40), 126.96 (C-20, C-60),
64.81 (C-2, C-4), 54.05 (C-1, C-5), 29.14 (C-6, C-8), 21.21
(C-7) ppm; MS (EI): m/z = 291.2 (M?).
2,4-Bis(2-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(2, C20H19F2NO)
Yield: 52%; m.p.: 187 °C; IR (KBr): vꢀ ¼ 3;310 (N–H
stretching), 3,068, 3,039, 2,973, 2,933, 2,857, 2,826 (C–H
stretching), 1,735, 1,716 (C=O stretching), 1,611, 1,581
(C=C stretching-Ph), 1,486, 1,455, 1,436, 1,380, 1,348,
1,277, 1,255, 1,221, 1,173, 1,130, 1,090, 1,033, 1,003, 979,
948, 927, 893, 881, 845, 814, 763, 751, 735, 687, 666,
1
The H and 13C chemical shift values are given as d
(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. The expansions
for the abbreviations used are s: singlet, br s: broad singlet,
d: doublet, dd: doublet of doublet, ddd: doublet of doublet
of doublet, dt: doublet of triplet, t: triplet, td: triplet of
doublet, q: quartet, quin: quintet, m: multiplet, SF:
573 cm-1 1H NMR (400 MHz, CDCl3): d = 7.95 (dt,
;
J = 7.32, 1.84 Hz, H-60), 7.33–7.22 (m, H-40, H-50), 7.07
(dd, J = 8.04, 1.38 Hz, H-30), 4.80 (s, H-2a, H-4a), 2.85
(m, H-7a), 2.63 (br s, H-1, H-5), 1.93 (dd, J = 5.86,
1.46 Hz, H-8e), 1.89 (dd, J = 5.86, 1.46 Hz, H-6e), 1.82–
1.72 (m, H-6a, H-8a), 1.65 (br s, NH), 1.39 (quin, H-7e)
123

Synthesis, complete NMR spectral assignments, and antifungal screening
87
ppm; 13C NMR (100.5 MHz, CDCl3): d = 216.48 (C-9),
161.08, 158.62 (C-20), 128.44, 128.40 (C-40), 129.09,
129.01 (C-60), 128.32 (C-10), 124.22, 124.18 (C-50),
115.81, 115.60 (C-30), 57.51 (C-2, C-4), 51.30 (C-1,
C-5), 29.82 (C-6, C-8), 21.12 (C-7) ppm; MS (EI):
m/z = 327.14 (M?).
1.20 Hz, H-60), 7.39 (dt, J = 7.00, 1.60 Hz, H-30, H-50),
7.27 (dt, J = 7.60, 1.80 Hz, H-40), 4.85 (d, J = 2.40 Hz,
H-2a, H-4a), 2.88 (m, H-7a), 2.77 (br s, H-1, H-5), 1.90 (d,
J = 4.80 Hz, H-8e), 1.87 (dd, J = 4.80, 1.60 Hz, H-6e),
1.81–1.71 (m, H-6a, H-8a), 1.66 (br s, NH), 1.41 (quin,
H-7e) ppm; 13C NMR (100.5 MHz, CDCl3): d = 216.34
(C-9), 138.17 (C-10), 132.69 (C-20), 130.17 (C-60), 128.90
(C-30), 128.78 (C-40), 126.92 (C-50), 61.01 (C-2, C-4),
49.67 (C-1, C-5), 29.65 (C-6, C-8), 20.93 (C-7) ppm; MS
(EI): m/z = 359.08 (M?).
2,4-Bis(3-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(3, C20H19F2NO)
Yield: 46%; m.p.: 192 °C; IR (KBr): vꢀ ¼ 3;315 (N–H
stretching), 3,073, 2,978, 2,930, 2,910, 2,852, 2,815 (C–H
stretching), 1,712 (C=O stretching), 1,614, 1,589 (C=C
stretching-Ph), 1,488, 1,462, 1,443, 1,381, 1,344, 1,325,
1,270, 1,255, 1,237, 1,171, 1,141, 1,123, 1,071, 1,024,
1,003, 971, 937, 889, 857, 823, 777, 746, 698, 661, 625,
2,4-Bis(3-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(6, C20H19Cl2NO)
Yield: 56%; m.p.: 180 °C; IR (KBr): vꢀ ¼ 3;315 (N–H
stretching), 2,984, 2,926, 2,887, 2,805 (C–H stretching),
1,711 (C=O stretching), 1,593, 1,572 (C=C stretching-Ph),
1,433, 1,346, 1,276, 1,239, 1,126, 1,071, 945, 890, 790,
1
574 cm-1; H NMR (400 MHz, CDCl3): d = 7.40–7.27
(m, H-20, H-50, H-50), 7.02 (dt, J = 7.80, 1.80 Hz, H-40),
4.42 (d, J = 1.60 Hz, H-2a, H-4a), 2.80 (m, H-7a), 2.49 (br
s, H-1, H-5), 1.94 (d, J = 4.80 Hz, H-8e, NH), 1.90 (d,
J = 5.20 Hz, H-6e), 1.78–1.68 (m, H-6a, H-8a), 1.42
(quin, H-7e) ppm; 13C NMR (100.5 MHz, CDCl3):
d = 216.48 (C-9), 164.40, 161.95 (C-30), 143.88, 143.82
(C-10), 130.31, 130.23 (C-50), 122.58, 122.56 (C-60),
114.75, 114.54 (C-20), 114.04, 113.82 (C-40), 64.19 (C-2,
C-4), 53.78 (C-1, C-5), 29.14 (C-6, C-8), 21.17 (C-7) ppm;
MS (EI): m/z = 327.14 (M?).
769, 697, 662 cm-1
;
1H NMR (400 MHz, CDCl3):
d = 7.54 (s, H-60), 7.40 (d, J = 7.68 Hz, H-20), 7.34 (t,
J = 7.70 Hz, H-40), 7.30 (td, J = 7.68 Hz, H-50), 4.38 (s,
H-2a, H-4a), 2.80 (m, H-7a), 2.47 (br s, H-1, H-5), 1.93
(dd, J = 5.88, 1.48 Hz, H-8e), 1.90 (br s, NH, H-6e), 1.77–
1.68 (m, H-6a, H-8a), 1.42 (quin, H-7e) ppm; 13C NMR
(100.5 MHz, CDCl3): d = 216.35 (C-9), 143.16 (C-10),
134.67 (C-30), 130.01 (C-50), 127.97 (C-20), 127.02 (C-60),
125.18 (C-40), 64.23 (C-2, C-4), 53.66 (C-1, C-5), 29.05
(C-6, C-8), 21.18 (C-7) ppm; MS (EI): m/z = 359.08 (M?).
2,4-Bis(4-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(4, C20H19F2NO)
2,4-Bis(4-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(7, C20H19Cl2NO)
Yield: 48%; m.p.: 198 °C; IR (KBr): vꢀ ¼ 3;310 (N–H
stretching), 3,073, 2,973, 2,924, 2,852 (C–H stretching),
1,708 (C=O stretching), 1,603 (C=C stretching-Ph), 1,506,
1,459, 1,440, 1,336, 1,285, 1,220, 1,156, 1,130, 1,092,
Yield: 47%; m.p.: 174 °C; IR (KBr): vꢀ ¼ 3;314 (N–H
stretching), 3,063, 2,921, 2,852, 2,800 (C–H stretching),
1,709 (C=O stretching), 1,590 (C=C stretching-Ph), 1,489,
1,438, 1,404, 1,340, 1,294, 1,241, 1,194, 1,163, 1,133,
1,088, 1,012, 924, 880, 856, 823, 807, 777, 720, 691, 655,
1,014, 925, 895, 848, 822, 796, 765, 714, 692, 661 cm-1
;
1H NMR (400 MHz, CDCl3): d = 7.51 (dd, J = 8.44,
5.52 Hz, H-20, H-60), 7.10 (t, J = 8.60 Hz, H-30, H-50),
4.40 (d, J = 2.20 Hz, H-2a, H-4a), 2.83 (m, H-7a), 2.44 (br
s, H-1, H-5), 1.92 (d, J = 5.48 Hz, H-8e), 1.88 (d,
J = 5.48 Hz, H-6e, NH), 1.76–1.67 (m, H-6a, H-8a),
1.41 (quin, H-7e) ppm; 13C NMR (100.5 MHz, CDCl3):
d = 216.90 (C-9), 163.46, 161.01 (C-40), 136.94, 136.92
(C-10), 128.49, 128.41 (C-20, C-60), 115.61, 115.40 (C-30,
C-50), 64.17 (C-2, C-4), 53.95 (C-1, C-5), 28.97 (C-6, C-8),
21.15 (C-7) ppm; MS (CI): m/z = 328.0 (M ? 1).
630 cm-1 1H NMR (400 MHz, CDCl3): d = 7.48 (d,
;
J = 8.44 Hz, H-20, H-60), 7.38 (d, J = 8.80 Hz, H-30, H-
50), 4.39 (d, J = 2.20 Hz, H-2a, H-4a), 2.80 (m, H-7a),
2.44 (br s, H-1, H-5), 1.90 (d, J = 4.76 Hz, H-8e), 1.87 (d,
J = 4.76 Hz, H-6e, NH), 1.76–1.66 (m, H-6a, H-8a), 1.40
(quin, H-7e) ppm; 13C NMR (100.5 MHz, CDCl3):
d = 216.64 (C-9), 139.63 (C-10), 133.43 (C-40), 128.88
(C-20, C-60), 128.28 (C-30, C-50), 64.17 (C-2, C-4), 53.77
(C-1, C-5), 29.00 (C-6, C-8), 21.14 (C-7) ppm; MS (EI):
m/z = 359.08 (M?).
2,4-Bis(2-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(5, C20H19Cl2NO)
2,4-Bis(2-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(8, C20H19Br2NO)
Yield: 57%; m.p.: 218 °C; IR (KBr): vꢀ ¼ 3;305 (N–H
stretching), 3,063, 2,973, 2,931, 2,905, 2,852, 2,821 (C–H
stretching), 1,720, 1,706 (C=O stretching), 1,589, 1,567
(C=C stretching-Ph), 1,467, 1,434, 1,373, 1,341, 1,270,
1,236, 1,194, 1,168, 1,131, 1,076, 1,045, 1,032, 1,000, 950,
927, 893, 882, 845, 777, 764, 749, 735, 700, 664 cm-1; 1H
NMR (400 MHz, CDCl3): d = 8.05 (dd, J = 8.00,
Yield: 51%; m.p.: 214 °C; IR (KBr): vꢀ ¼ 3;305 (N–H
stretching), 3,068, 2,968, 2,933, 2,900, 2,857, 2,826 (C–H
stretching), 1,719, 1,703 (C=O stretching), 1,585, 1,564
(C=C stretching-Ph), 1,462, 1,434, 1,370, 1,340, 1,320,
1,269, 1,257, 1,234, 1,194, 1,171, 1,134, 1,076, 1,040,
1,021, 1,000, 961, 945, 921, 890, 880, 845, 775, 763, 747,
123

88
P. Parthiban et al.
730, 696, 675, 665, 601 cm-1
;
1H NMR (400 MHz,
stretching), 1,714, 1,700 (C=O stretching), 1,610, 1,581
(C=C stretching-Ph), 1,478, 1,457, 1,428, 1,375, 1,344,
1,310, 1,289, 1,273, 1,222, 1,160, 1,136, 1,060, 1,043, 987,
908, 893, 861, 821, 783, 760, 736, 723, 672, 620,
CDCl3): d = 8.02 (dd, J = 7.88, 1.64 Hz, H-60), 7.57
(dd, J = 8.06, 1.10 Hz, H-30), 7.42 (dt, J = 7.52, 1.10 Hz,
H-50), 7.18 (dt, J = 7.52, 1.64 Hz, H-40), 4.77 (s, H-2a,
H-4a), 2.88 (m, H-7a), 2.79 (br s, H-1, H-5), 1.90 (dd,
J = 6.40, 1.28 Hz, H-8e), 1.86 (dd, J = 5.16, 1.08 Hz,
H-6e), 1.81–1.71 (m, H-6a, H-8a), 1.67 (s, NH), 1.40 (quin,
H-7e) ppm; 13C NMR (100.5 MHz, CDCl3): d = 216.17
(C-9), 139.56 (C-10), 133.54 (C-30), 129.28 (C-60), 129.19
(C-40), 127.51 (C-50), 122.97 (C-20), 63.38 (C-2, C-4),
49.59 (C-1, C-5), 29.54 (C-6, C-8), 20.90 (C-7) ppm; MS
(EI): m/z = 446.98 (M?).
574 cm-1 1H NMR (400 MHz, CDCl3): d = 8.00 (d,
;
J = 8.00 Hz, H-60), 7.31 (dt, J = 6.96, 1.02 Hz, H-50),
7.23–7.17 (m, H-30, H-40), 7.18 (dt, J = 7.52, 1.64 Hz, H-
40), 4.60 (d, J = 1.48 Hz, H-2a, H-4a), 3.01 (m, H-7a),
2.50 (br s, H-1, H-5), 2.34 (s, Me-C-20), 1.99 (dd, J = 6.24,
1.28 Hz, H-8e), 1.96 (d, J = 5.12 Hz, H-6e), 1.79–1.69
(m, H-6a, H-8a), 1.63 (br s, NH), 1.42 (quin, H-7e) ppm;
13C NMR (100.5 MHz, CDCl3): d = 217.77 (C-9), 139.09
(C-10), 134.87 (C-20), 130.91 (C-30, C-40), 127.25 (C-60),
126.05 (C-50), 61.42 (C-2, C-4), 50.82 (C-1, C-5), 29.36
(C-6, C-8), 21.13 (C-7), 19.15 (Me-C-20) ppm; MS (EI):
m/z = 319.19 (M?).
2,4-Bis(3-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(9, C20H19Br2NO)
Yield: 47%; m.p.: 180 °C; IR (KBr): vꢀ ¼ 3;310 (N–H
stretching), 3,063, 2,973, 2,931, 2,852 (C–H stretching),
1,710 (C=O stretching), 1,588, 1,564 (C=C stretching-Ph),
1,470, 1,434, 1,383, 1,344, 1,297, 1,278, 1,241, 1,197,
1,168, 1,126, 1,063, 1,034, 995, 942, 890, 840, 790, 767,
2,4-Bis(4-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(12, C22H25NO)
Yield: 57%; m.p.: 160 °C; IR (KBr): vꢀ ¼ 3;315 (N–H
stretching), 3,024, 2,939, 2,859 (C–H stretching), 1,714
(C=O stretching), 1,599, 1,564 (C=C stretching-Ph), 1,508,
1,442, 1,311, 1,267, 1,197, 1,154, 1,139, 1,062, 958, 909,
748, 733, 699, 680, 664 cm-1 1H NMR (400 MHz,
;
CDCl3): d = 7.68 (s, H-20), 7.46 (d, J = 8.08 Hz, H-40,
H-60), 7.28 (t, J = 7.68 Hz, H-50), 4.37 (d, J = 2.20 Hz,
H-2a, H-4a), 2.79 (m, H-7a), 2.47 (br s, H-1, H-5), 1.93 (d,
J = 4.76 Hz, H-8e), 1.89 (d, J = 4.40 Hz, H-6e, NH),
1.77–1.68 (m, H-6a, H-8a), 1.40 (quin, H-7e) ppm; 13C
NMR (100.5 MHz, CDCl3): d = 216.20 (C-9), 143.41
(C-10), 130.92 (C-20), 130.31 (C-50), 129.93 (C-40), 125.64
(C-60), 122.91 (C-30), 64.20 (C-2, C-4), 53.64 (C-1, C-5),
29.03 (C-6, C-8), 21.18 (C-7) ppm; MS (EI): m/z = 447.0
(M?).
868, 817, 758, 730, 706, 660, 608 cm-1 1H NMR
;
(400 MHz, CDCl3): d = 7.43 (d, J = 8.04 Hz, H-20,
H-60), 7.21 (d, J = 7.68 Hz, H-30, H-50), 4.37 (d,
J = 2.20 Hz, H-2a, H-4a), 2.89 (m, H-7a), 2.44 (br s,
H-1, H-5), 2.36 (s, Me-C-40), 1.95 (dd, J = 5.86, 1.46 Hz,
H-8e), 1.92 (dd, J = 5.32, 1.64 Hz, H-6e, NH), 1.75–1.65
(m, H-6a, H-8a), 1.37 (quin, H-7e) ppm; 13C NMR
(100.5 MHz, CDCl3): d = 217.99 (C-9), 138.46 (C-10),
137.22 (C-40), 129.29 (C-30, C-50), 126.90 (C-20, C-60),
64.71 (C-2, C-4), 54.21 (C-1, C-5), 29.18 (C-6, C-8), 21.27
(C-7), 21.22 (Me-C-40) ppm; MS (EI): m/z = 319.20 (M?).
2,4-Bis(4-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(10, C20H19Br2NO)
Yield: 55%; m.p.: 198 °C; IR (KBr): vꢀ ¼ 3;310 (N–H
stretching), 3,057, 2,984, 2,921, 2,852, 2,800, 2,763 (C–H
stretching), 1,705 (C=O stretching), 1,603, 1,572 (C=C
stretching-Ph), 1,486, 1,449, 1,438, 1,400, 1,370, 1,340,
1,323, 1,294, 1,278, 1,241, 1,192, 1,163, 1,134, 1,105,
1,071, 1,008, 963, 924, 880, 857, 818, 806, 774, 717, 681,
658, 634 cm-1; 1H NMR (400 MHz, CDCl3): d = 7.54 (d,
J = 8.40 Hz, H-20, H-60), 7.42 (d, J = 8.44 Hz, H-30, H-50),
4.37 (d, J = 1.49 Hz, H-2a, H-4a), 2.79 (m, H-7a), 2.44 (br
s, H-1, H-5), 1.91 (d, J = 4.76 Hz, H-8e), 1.87 (br s, H-6e,
NH), 1.76–1.66 (m, H-6a, H-8a), 1.40 (quin, H-7e) ppm;
13C NMR (100.5 MHz, CDCl3): d = 216.48 (C-9), 140.12
(C-10), 131.80 (C-30, C-50), 128.61 (C-20, C-60), 121.51
(C-40), 64.17 (C-2, C-4), 53.67 (C-1, C-5), 28.99 (C-6, C-8),
21.12 (C-7) ppm; MS (EI): m/z = 448.0 (M ? 1).
2,4-Bis(2-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(13, C22H25NO3)
Yield: 49%; m.p.: 217 °C; IR (KBr): vꢀ ¼ 3;300 (N–H
stretching), 3,073, 2,934, 2,831 (C–H stretching), 1,711
(C=O stretching), 1,598, 1,585 (C=C stretching-Ph), 1,488,
1,459, 1,436, 1,391, 1,373, 1,336, 1,283, 1,244, 1,232,
1,192, 1,161, 1,134, 1,106, 1,071, 1,050, 1,026, 941, 906,
847, 760, 746, 696, 673, 649, 602 cm-1 1H NMR
;
(400 MHz, CDCl3): d = 7.95 (dd, J = 7.50, 1.26 Hz,
H-60), 7.28 (dt, J = 7.68, 1.08 Hz, H-40), 7.05 (t,
J = 7.52 Hz, H-50), 6.88 (d, J = 8.04 Hz, H-30), 4.79 (d,
J = 2.20 Hz, H-2a, H-4a), 3.81 (s, OMe-C-20), 2.89 (m,
H-7a), 2.67 (br s, H-1, H-5), 1.90 (d, J = 5.12 Hz, H-8e),
1.87 (d, J = 5.48 Hz, H-6e), 1.74–1.65 (m, H-6a, H-8a),
1.45 (br s, NH), 1.31 (quin, H-7e) ppm; 13C NMR
(100.5 MHz, CDCl3): d = 219.21 (C-9), 156.21 (C-20),
129.71 (C-10), 128.17 (C-40), 127.79 (C-60), 120.33 (C-50),
110.25 (C-30), 58.12 (C-2, C-4), 55.21 (OMe-C-20), 50.36
2,4-Bis(2-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(11, C22H25NO)
Yield: 51%; m.p.: 194 °C; IR (KBr): vꢀ ¼ 3;305 (N–H
stretching), 3,052, 3,021, 2,973, 2,929, 2,852 (C–H
123

Synthesis, complete NMR spectral assignments, and antifungal screening
89
(C-1, C-5), 30.08 (C-6, C-8), 21.01 (C-7) ppm; MS (EI):
m/z = 351.19 (M?).
1,070, 1,025, 1,001, 930, 853, 779, 761, 712, 675,
1
630 cm-1; H NMR (400 MHz, CDCl3): d = 7.81 (br s,
H-20, H-60), 7.57 (d, J = 7.36 Hz, H-20, H-60), 7.39–7.28
(m, H-30, H-50), 3.74 (d, J = 3.36 Hz, H-2a, H-4a), 2.91
(m, H-7a), 2.42 (br s, H-1, H-5), 1.97 (s, NMe), 1.92 (dt,
J = 5.92, 1.48 Hz, H-6e, H-8e), 1.69–1.60 (m, H-6a,
H-8a), 1.46 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 216.96 (C-9), 140.76 (C-10), 128.58 (C-30,
C-50), 127.59 (C-40), 127.33 (C-20, C-60), 74.49 (C-2, C-4),
54.67 (C-1, C-5), 29.65 (C-6, C-8), 20.27 (C-7) ppm; MS
(EI): m/z = 305.2 (M?).
2,4-Bis(3-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(14, C22H25NO3)
Yield: 56%; m.p.: 160 °C; IR (KBr): vꢀ ¼ 3;310 (N–H
stretching), 3,073, 2,933, 2,930, 2,826 (C–H stretching),
1,708 (C=O stretching), 1,609, 1,583 (C=C stretching-Ph),
1,485, 1,440, 1,373, 1,339, 1,272, 1,231, 1,192, 1,144,
1,128, 1,079, 1,044, 1,005, 995, 953, 894, 859, 806, 778,
748, 715, 683 cm-1
;
1H NMR (400 MHz, CDCl3):
d = 7.31 (t, J = 7.86 Hz, H-50), 7.12 (m, H-20, H-60),
6.84 (ddd, J = 7.96, 2.38, 0.86 Hz, H-40), 4.37 (d,
J = 2.20 Hz, H-2a, H-4a), 3.84 (s, OMe-C-30), 2.86 (m,
H-7a), 2.48 (br s, H-1, H-5), 1.97 (dd, J = 5.68, 1.48 Hz,
H-8e), 1.93 (dd, J = 4.76, 1.48 Hz, H-6e), 1.90 (s, NH),
1.75–1.65 (m, H-6a, H-8a), 1.38 (quin, H-7e) ppm;
13C NMR (100.5 MHz, CDCl3): d = 217.55 (C-9),
159.83 (C-30), 143.03 (C-10), 129.61 (C-50), 119.27
(C-60), 112.97 (C-20), 114.6 (C-40), 64.65 (C-2, C-4),
55.29 (OMe-C-30), 54.03 (C-1, C-5), 29.23 (C-6, C-8),
21.18 (C-7) ppm; MS (EI): m/z = 351.18 (M?).
Synthesis of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one
oximes 17–32
To a hot solution of the corresponding 2,4-diphenyl-3-
azabicyclo[3.3.1]nonan-9-one (0.005 mol) in ethanol,
0.417 g hydroxylamine hydrochloride (0.006 mol) and
2.04 g sodium acetate trihydrate (0.015 mol) were added
and the mixture was heated under reflux until completion
of the reaction. After that, water was added to the con-
centrated reaction mixture, and the precipitated oxime was
separated by filtration, washed with excess water, and
dried. The crude oxime obtained was purified by recrys-
tallization from ethanol.
2,4-Bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(15, C22H25NO3)
Yield: 45%; m.p.: 174 °C; IR (KBr): vꢀ ¼ 3;307 (N–H
stretching), 3,005, 2,968, 2,933, 2,831 (C–H stretching),
1,705 (C=O stretching), 1,610, 1,584 (C=C stretching-Ph),
1,553, 1,509, 1,452, 1,344, 1,301, 1,289, 1,247, 1,163, 1,131,
1,026, 966, 871, 831, 814, 792, 764, 737, 695, 684 cm-1; 1H
NMR (400 MHz, CDCl3): d = 7.46 (d, J = 8.80 Hz, H-20,
H-60), 6.93 (d, J = 8.80 Hz, H-30, H-50), 4.34 (d,
J = 2.56 Hz, H-2a, H-4a), 3.28 (s, OMe-C-40), 2.88 (m,
H-7a), 2.41 (br s, H-1, H-5), 1.96 (d, J = 4.40 Hz, H-8e),
1.92 (d, J = 4.76 Hz, H-6e), 1.87 (br s, NH), 1.74–1.64 (m,
H-6a, H-8a), 1.38 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 217.88 (C-9), 158.98 (C-40), 136.51 (C-10),
132.27 (C-20, C-60), 113.89 (C-30, C-50), 64.36 (C-2, C-4),
55.29 (OMe-C-40), 54.24 (C-1, C-5), 29.05 (C-6, C-8), 21.22
(C-7) ppm; MS (EI): m/z = 351.18 (M?).
2,4-Diphenyl-3-azabicyclo[3.3.1]nonan-9-one oxime
(17, C20H22N2O)
Yield: 90%; m.p.: 196 °C; IR (KBr): vꢀ ¼ 3;311 (N–H
stretching), 3,080, 3,063, 3,022, 2,960, 2,931, 2,894, 2,857,
2,800 (C–H stretching), 1,668 (C=N stretching), 1,598
(C=C stretching-Ph), 1,491, 1,451, 1,432, 1,345, 1,263,
1,251, 1,240, 1,175, 1,144, 1,068, 1,029, 1,000, 964, 938,
893, 852, 819, 782, 750, 702, 683, 633, 593 cm-1; H
1
NMR (400 MHz, CDCl3): d = 8.53 (br s, N–OH), 7.59
(dd, J = 11.72, 7.68 Hz, H-20, H-200, H-60, H-600), 7.40 (dt,
J = 7.32, 1.84 Hz, H-30 H-300, H-50, H-500), 7.30 (dt,
J = 7.32, 1.84 Hz, H-40, H-400), 4.40 (d, J = 1.44 Hz,
H-2a), 4.34 (d, J = 1.84 Hz, H-4a), 3.58 (br s,
W1/2 = 9.56 Hz, H-5), 2.82 (m, H-7a), 2.55 (br s,
W1/2 = 9.88 Hz, H-1), 1.80–1.72 (m, H-6e, H-8e, NH),
1.58–1.46 (m, H-6a, H-8a), 1.39 (quin, H-7e) ppm; 13C
NMR (100.5 MHz, CDCl3): d = 165.84 (C-9), 142.64/
142.59 (C-10/C-100), 128.52 (C-30, C-300, C-50, C-500), 127.39
(C-40, C-400), 127.20/127.08 (C-20, C-60/C-200, C-600), 65.68
(C-2), 63.68 (C-4), 43.30 (C-1), 36.55 (C-5), 28.20 (C-8), 26.72
(C-6), 21.69 (C-7) ppm; MS (EI): m/z = 307.2 (M ? 1).
3-Methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one
(16, C21H23NO)
A mixture of 2.914 g 2,4-diphenyl-3-azabicyclo[3.3.1]
nonan-9-one (1, 0.01 mol), 2 g anhydrous potassium
carbonate, and 1.42 g iodomethane (0.01 mol) in 30 cm3
dry acetone was heated under reflux for 3 h in an inert
atmosphere. Removal of acetone by distillation, dilution
with water, and treatment with aqueous ammonia afforded
the corresponding N-methylated 3-azabicyclononan-9-one
16. Yield: 78%; m.p.: 198 °C; IR (KBr): vꢀ ¼ 3;057; 3,026,
2,926, 2,857, 2,794 (C–H stretching), 1,710 (C=O stretch-
ing), 1,599 (C=C stretching-Ph), 1,490, 1,454, 1,434,
1,373, 1,346, 1,300, 1,283, 1,257, 1,236, 1,165, 1,127,
2,4-Bis(2-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (18, C20H20F2N2O)
Yield: 92%; m.p.: 191 °C; IR (KBr): vꢀ ¼ 3;303 (N–H
stretching), 3,068, 3,039, 2,965, 2,936, 2,911, 2,857 (C–H
stretching), 1,670 (C=N stretching), 1,613, 1,586 (C=C
stretching-Ph), 1,487, 1,453, 1,432, 1,382, 1,337, 1,278,
123

90
P. Parthiban et al.
1,259, 1,232, 1,173, 1,138, 1,099, 1,080, 1,039, 996, 941,
895, 822, 754, 680, 636, 609, 568 cm-1 1H NMR
;
CDCl3): d = 165.24 (C-9), 163.39, 160.95 (C-40, C-400),
138.17/138.10 (C-10/C-100), 128.68, 128.60, 128.57, 128.49
(C-20, C-200, C-60, C-600), 115.51, 115.30 (C-30, C-300, C-50,
C-500), 65.09 (C-2), 63.09 (C-4), 43.26 (C-1), 36.45 (C-5),
28.05 (C-8), 26.57 (C-6), 21.63 (C-7) ppm; MS (EI):
m/z = 342.16 (M?).
(400 MHz, CDCl3): d = 7.91 (dt, J = 7.32, 1.80 Hz, H-
60, H-600), 7.74 (br s, N–OH), 7.32–7.21 (m, H-40, H-400,
H-50, H-500), 7.10–7.04 (m, H-30 H-300), 4.73 (s, H-2a),
4.68 (s, H-4a), 3.73 (br s, W1/2 = 11.00 Hz, H-5), 2.75
(m, H-7a), 2.68 (br s, W1/2 = 11.36 Hz, H-1), 1.78–1.70
(m, H-6e, H-8e), 1.63–1.52 (m, H-6a, H-8a, NH), 1.39
(quin, H-7e) ppm; 13C NMR (100.5 MHz, CDCl3):
d = 164.56 (C-9), 161.38, 158.92/161.36, 158.90 (C-20/
C-200), 129.44, 129.40/129.32 (C-10/C-100), 128.84/128.76
(C-60/C-600), 128.52, 128.48/128.43, 128.39 (C-40/C-400),
124.17, 124.13/124.10 (C-50/C-500), 115.71/115.50 (C-30/
C-300), 58.47 (C-2), 56.65 (C-4), 40.64 (C-1), 33.84 (C-5),
28.70 (C-8), 27.13 (C-6), 21.51 (C-7) ppm; MS (ES):
m/z = 342.2 (M?).
2,4-Bis(2-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (21, C20H20Cl2N2O)
Yield: 87%; m.p.: 256 °C; IR (KBr): v ¼ 3;311 (N–H
stretching), 3,055, 2,965, 2,932, 2,857, 2,824 (C–H
stretching), 1,674 (C=N stretching), 1,592, 1,568 (C=C
stretching-Ph), 1,465, 1,435, 1,374, 1,343, 1,275, 1,257,
1,238, 1,193, 1,173, 1,144, 1,082, 1,047, 1,033, 998, 937,
895, 819, 760, 749, 735, 707, 688, 669, 635, 600 cm-1; 1H
NMR (400 MHz, CDCl3): d = 8.01 (d, J = 7.68 Hz, H-60,
H-600), 7.41–7.35 (m, H-30 H-300, H-50, H-500), 7.26 (dt,
J = 5.88, 1.84 Hz, H-40, H-400), 7.13 (br s, N–OH), 4.78 (s,
H-2a), 4.73 (s, H-4a), 3.87 (br s, W1/2 = 11.16 Hz, H-5),
2.83 (s, H-1), 2.79 (m, H-7a), 1.71 (dt, J = 20.52, 4.76 Hz,
H-6e, H-8e), 1.63–1.51 (m, H-6a, H-8a, NH), 1.40 (quin,
H-7e) ppm; 13C NMR (100.5 MHz, CDCl3): d = 160.00
(C-9), 139.43/139.39 (C-10/C-100), 132.96 (C-20, C-200),
130.05 (C-60, C-600), 128.94/128.86 (C-30/C-300), 128.54
(C-40, C-400), 126.88/126.82 (C-50/C-500), 62.19 (C-2), 60.39
(C-4), 39.01 (C-1), 32.38 (C-5), 28.47 (C-8), 26.81 (C-6),
21.27 (C-7) ppm; MS (ES): m/z = 375.1 (M ? 1).
ꢀ
2,4-Bis(3-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (19, C20H20F2N2O)
Yield: 86%; m.p.: 219 °C; IR (KBr): vꢀ ¼ 3;307 (N–H
stretching), 3,068, 3,039, 2,969, 2,931, 2,907, 2,861, 2,833,
2,808 (C–H stretching), 1,668 (C=N stretching), 1,611,
1,589 (C=C stretching-Ph), 1,484, 1,447, 1,432, 1,376,
1,341, 1,325, 1,288, 1,267, 1,254, 1,177, 1,141, 1,123,
1,070, 1,000, 967, 938, 923, 887, 864, 833, 798, 782, 754,
1
707, 680, 648, 609, 592, 572 cm-1; H NMR (400 MHz,
CDCl3): d = 8.55 (br s, N–OH), 7.34 (m, H-20, H-200, H-50,
H-500, H-60, H-600), 7.00 (t, J = 7.72 Hz, H-40 H-400), 4.40
(s, H-2a), 4.33 (s, H-4a), 3.58 (br s, W1/2 = 11.36 Hz, H-
5), 2.72 (m, H-7a), 2.56 (br s, W1/2 = 11.60 Hz, H-1),
1.81–1.71 (m, H-6e, H-8e, NH), 1.60–1.49 (m, H-6a, H-
8a), 1.41 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 165.00 (C-9), 164.40, 161.96 (C-30, C-300),
130.14/130.07 (C-50/C-500), 122.77/122.64 (C-60/C-600),
114.48/114.27 (C-40/C-400), 114.18, 114.07/113.95, 113.85
(C-20/C-200), 65.07 (C-2), 63.10 (C-4), 43.10 (C-1), 36.27
(C-5), 28.16 (C-8), 26.66 (C-6), 21.61 (C-7) ppm; MS (CI):
m/z = 343.2 (M ? 1).
2,4-Bis(3-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (22, C20H20Cl2N2O)
Yield: 95%; m.p.: 197 °C; IR (KBr): vꢀ ¼ 3;308 (N–H
stretching), 2,952, 2,925, 2,854, 2,800 (C–H stretching),
1,666 (C=N stretching), 1,594, 1,574 (C=C stretching-Ph),
1,467, 1,454, 1,432, 1,375, 1,342, 1,286, 1,257, 1,203,
1,139, 1,094, 1,076, 1,001, 933, 905, 899, 867, 787, 777,
1
725, 716, 703, 680, 645, 613 cm-1; H NMR (400 MHz,
CDCl3): d = 7.99 (br s, N–OH), 7.56 (d, J = 8.44 Hz, H-
60, H-600), 7.45 (dd, J = 15.76, 7.68 Hz, H-20, H-200), 7.36–
7.26 (m, H-40, H-400), 4.35 (s, H-2a), 4.29 (s, H-4a), 3.56 (br
s, W1/2 = 8.80 Hz, H-5), 2.71 (m, H-7a), 2.53 (br s,
W1/2 = 9.16 Hz, H-1), 1.78–1.70 (m, H-6e, H-8e, NH),
1.59–1.48 (m, H-6a, H-8a), 1.42 (quin, H-7e) ppm; 13C
NMR (100.5 MHz, CDCl3): d = 164.87 (C-9), 144.41/
144.35 (C-10/C-100), 134.57 (C-030 0, C-300), 129.91/129.89
(C-50/C-500), 127.74 (C-20, C-2 ), 127.23/127.13 (C-60/
C-600), 125.38/125.24 (C-40/C-400), 65.19 (C-2), 63.21
(C-4), 43.03 (C-1), 36.27 (C-5), 28.07 (C-8), 26.58 (C-6),
21.63 (C-7) ppm; MS (EI): m/z = 374.1 (M?).
2,4-Bis(4-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (20, C20H20F2N2O)
Yield: 88%; m.p.: 204 °C; IR (KBr): vꢀ ¼ 3;296 (N–H
stretching), 3,068, 3,031, 3,006, 2,977, 2,927, 2,899, 2,861,
2,804, 2,771 (C–H stretching), 1,675 (C=N stretching),
1,603 (C=C stretching-Ph), 1,506, 1,455, 1,440, 1,343,
1,323, 1,295, 1,263, 1,216, 1,155, 1,144, 1,094, 1,014,
1,001, 944, 928, 895, 827, 796, 749, 724, 695, 669, 627,
1
609 cm-1; H NMR (400 MHz, CDCl3): d = 8.72 (br s,
N–OH), 7.54 (m, H-20, H-200, H-60, H-600), 7.09 (dt,
J = 8.62, 1.84 Hz, H-30, H-300, H-50, H-500), 4.37 (s,
H-2a), 4.31 (s, H-4a), 3.53 (br s, W1/2 = 9.16 Hz, H-5),
2.74 (m, H-7a), 2.50 (br s, W1/2 = 9.12 Hz, H-1), 1.84 (br
s, NH), 1.80–1.70 (m, H-6e, H-8e), 1.59–1.47 (m, H-6a,
H-8a), 1.40 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
2,4-Bis(4-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (23, C20H20Cl2N2O)
Yield: 94%; m.p.: 183 °C; IR (KBr): vꢀ ¼ 3;298 (N–H
stretching), 2,960, 2,927, 2,907, 2,894, 2,845 (C–H stretch-
ing), 1,672 (C=N stretching), 1,594 (C=C stretching-Ph),
123

Synthesis, complete NMR spectral assignments, and antifungal screening
91
1,489, 1,454, 1,432, 1,411, 1,341, 1,294, 1,255, 1,236, 1,168,
1,138, 1,089, 1,014, 998, 942, 936, 910, 893, 872, 816, 779,
CDCl3): d = 164.68 (C-9), 144.54/144.50 (C-10/C-100),
130.63 (C-20, C-200), 130.13, 129.98 (C-40, C-400), 130.07
(C-50, C-500), 122.78 (C-30, C-300), 65.05 (C-2), 63.05 (C-4),
42.91 (C-1), 36.33 (C-5), 28.01 (C-8), 26.51 (C-6), 21.56
(C-7) ppm; MS (EI): m/z = 462.0 (M?).
1
721, 685, 656, 619 cm-1; H NMR (400 MHz, CDCl3):
d = 8.18 (br s, N–OH), 7.51 (dd, J = 11.72, 8.36 Hz, H-20,
H-200, H-60, H-600), 7.37 (dd, J = 8.44, 2.20 Hz, H-30, H-300,
H-50, H-500), 4.36 (s, H-2a), 4.30 (s, H-4a), 3.53 (br s,
W1/2 = 9.92 Hz, H-5), 2.70 (m, H-7a), 2.50 (br s,
W1/2 = 10.28 Hz, H-1), 1.77–1.69 (m, H-6e, H-8e), 1.58–
1.46 (m, H-6a, H-8a, NH), 1.40 (quin, H-7e) ppm; 13C NMR
(100.5 MHz, CDCl3): d = 165.05 (C-9), 140.85/140.80
(C-10/C-100), 133.17 (C-40, C-400), 128.78, 128.75 (C-20,
C-200, C-60, C-600), 128.49/128.37 (C-30, C-50/C-300, C-500),
65.08 (C-2), 63.08 (C-4), 43.10 (C-1), 36.23 (C-5), 28.04
(C-8), 26.57 (C-6), 21.60 (C-7) ppm; MS (EI): m/z = 375.1
(M ? 1).
2,4-Bis(4-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (26, C20H20Br2N2O)
Yield: 85%; m.p.: 192 °C; IR (KBr): vꢀ ¼ 3;298 (N–H
stretching), 2,960, 2,925, 2,911, 2,903, 2,849, 2,800 (C–H
stretching), 1,672 (C=N stretching), 1,588 (C=C stretching-
Ph), 1,486, 1,453, 1,433, 1,407, 1,370, 1,341, 1,296, 1,259,
1,263, 1,169, 1,137, 1,097, 1,071, 1,010, 998, 909, 891,
1
874, 815, 776, 763, 749, 719, 685, 646, 616 cm-1; H
NMR (400 MHz, CDCl3): d = 7.98 (br s, N–OH), 7.52
(dd, J = 8.14, 2.02 Hz, H-20, H-200, H-60, H-600), 7.45 (dd,
J = 11.72, 8.40 Hz, H-30, H-300, H-50, H-500), 4.34 (s, H-
2a), 4.28 (s, H-4a), 3.53 (br s, W1/2 = 9.56 Hz, H-5), 2.69
(m, H-7a), 2.49 (br s, W1/2 = 10.28 Hz, H-1), 1.76–1.67
(m, H-6e, H-8e, NH), 1.58–1.46 (m, H-6a, H-8a), 1.39
(quin, H-7e) ppm; 13C NMR (100.5 MHz, CDCl3):
d = 164.96 (C-9), 141.36/141.31 (C-10/C-100), 131.71
(C-30, C-300, C-50, C-500), 128.85, 128.73 (C-20, C-200,
C-60, C-600), 121.27 (C-40, C-400), 65.10 (C-2), 63.12 (C-4),
43.03 (C-1), 36.16 (C-5), 28.05 (C-8), 26.56 (C-6), 21.59
(C-7) ppm; MS (CI): m/z = 463.0 (M ? 1).
2,4-Bis(2-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (24, C20H20Br2N2O)
Yield: 91%; m.p.: 237 °C; IR (KBr): vꢀ ¼ 3;290 (N–H
stretching), 3,068, 2,993, 2,965, 2,931, 2,899, 2,849 (C–H
stretching), 1,671 (C=N stretching), 1,584, 1,563 (C=C
stretching-Ph), 1,464, 1,434, 1,372, 1,342, 1,321, 1,257,
1,197, 1,171, 1,140, 1,082, 1,043, 1,021, 997, 947, 921, 894,
868, 816, 782, 749, 728, 687, 662, 633, 599 cm-1; 1H NMR
(400 MHz, DMSO-d6): d = 10.35 (s, N–OH), 8.04 (t,
J = 6.38 Hz, H-60, H-600), 7.62 (d, J = 8.08 Hz, H-30, H-
300), 7.50 (t, J = 7.32 Hz, H-50, H-500), 7.25 (t, J = 7.32 Hz,
H-40, H-400), 4.45 (s, H-2a), 4.38 (s, H-4a), 3.69 (br s,
W1/2 = 10.28 Hz, H-5), 2.97 (br s, NH), 2.76 (m, H-7a), 2.65
(br s, W1/2 = 10.24 Hz, H-1), 1.51 (dd, J = 12.84, 4.76 Hz,
H-6e, H-8e), 1.46–1.33 (m, H-6a, H-8a), 1.28 (quin, H-7e)
ppm; 13C NMR (100.5 MHz, DMSO-d6): d = 162.10 (C-9),
142.45/142.40 (C-10/C-100), 134.24 (C-30, C-300), 131.20/
131.09 (C-60/C-600), 130.36 (C-40, C-400), 129.04/128.96
(C-50/C-500), 123.62/123.56 (C-20/C-200), 65.25 (C-2), 63.44
(C-4), 39.61 (C-1), 32.84 (C-5), 29.20 (C-8), 27.70 (C-6),
22.03 (C-7) ppm; MS (EI): m/z = 463.0 (M ? 1).
2,4-Bis(2-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (27, C22H26N2O)
Yield: 91%; m.p.: 221 °C; IR (KBr): vꢀ ¼ 3;296 (N–H
stretching), 3,068, 3,026, 2,965, 2,935, 2,853, 2,812 (C–H
stretching), 1,679 (C=N stretching), 1,601 (C=C stretching-
Ph), 1,484, 1,455, 1,429, 1,377, 1,346, 1,292, 1,273, 1,255,
1,175, 1,143, 1,081, 1,049, 1,003, 955, 934, 894, 866, 823,
1
800, 755, 743, 731, 689, 679, 639, 604 cm-1; H NMR
(400 MHz, CDCl3): d = 7.97 (t, J = 6.96 Hz, H-60, H-600),
7.65 (br s, N–OH), 7.30 (t, J = 6.96 Hz, H-50, H-500), 7.23–
7.17 (m, H-30, H-300), 4.55 (s, H-2a), 4.48 (s, H-4a), 3.64
(br s, W1/2 = 8.98 Hz, H-5), 2.92 (m, H-7a), 2.56 (br s,
W1/2 = 9.56 Hz, H-1), 2.41 (s, Me-C-20), 2.38 (s, Me-
C-200), 1.80 (dt, J = 15.18, 4.76 Hz, H-6e, H-8e), 1.66 (br
s, NH), 1.60–1.48 (m, H-6a, H-8a), 1.42 (quin, H-7e) ppm;
13C NMR (100.5 MHz, CDCl3): d = 166.24 (C-9), 140.39
(C-10, C-100), 135.26/135.18 (C-20/C-200), 130.79 (C-40,
C-400), 127.24/127.18 (C-30/C-300), 127.06 (C-50, C-500),
126.07/125.99 (C-60/C-600), 62.69 (C-2), 60.77 (C-4), 39.94
(C-1), 33.18 (C-5), 28.20 (C-8), 26.68 (C-6), 21.54
(C-7), 19.38, 19.18 (Me-C-20, Me-C-200) ppm; MS (EI):
m/z = 334.2 (M?).
2,4-Bis(3-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (25, C20H20Br2N2O)
Yield: 87%; m.p.: 188 °C; IR (KBr): vꢀ ¼ 3;307 (N–H
stretching), 2,961, 2,923, 2,853 (C–H stretching), 1,670
(C=N stretching), 1,592, 1,567 (C=C stretching-Ph), 1,471,
1,454, 1,436, 1,427, 1,370, 1,341, 1,321, 1,288, 1,259,
1,195, 1,142, 1,088, 1,069, 1,017, 953, 930, 895, 851, 790,
776, 725, 704, 683, 667, 638, 603 cm-1 1H NMR
;
(400 MHz, CDCl3): d = 7.69 (d, J = 11.36 Hz, H-20,
H-200, N–OH), 7.50 (dd, J = 13.56, 7.72 Hz, H-60, H-600),
7.44 (d, J = 7.72 Hz, H-40, H-400), 7.27 (dt, J = 7.68,
1.84 Hz, H-50, H-500), 4.33 (d, J = 2.20 Hz, H-2a), 4.28 (d,
J = 2.56 Hz, H-4a), 3.55 (br s, W1/2 = 9.34 Hz, H-5), 2.69
(m, H-7a), 2.52 (br s, W1/2 = 9.36 Hz, H-1), 1.75 (dt,
J = 18.72, 5.52 Hz, H-6e, H-8e), 1.60–1.47 (m, H-6a,
H-8a, NH), 1.41 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
2,4-Bis(4-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (28, C22H26N2O)
Yield: 90%; m.p.: 186 °C; IR (KBr): vꢀ ¼ 3;304 (N–H
stretching), 3,027, 2,961, 2,939, 2,859, 2,815 (C–H
123

92
P. Parthiban et al.
stretching), 1,671 (C=N stretching), 1,598 (C=C stretching-
Ph), 1,506, 1,444, 1,310, 1,271, 1,195, 1,156, 1,142, 1,060,
OMe-C-300), 3.57 (br s, W1/2 = 8.44 Hz, H-5), 2.77 (m, H-
7a), 2.53 (br s, W1/2 = 8.24 Hz, H-1), 1.79 (dt,
J = 14.64 Hz, H-6e, H-8e), 1.55–1.45 (m, H-6a, H-8a,
NH), 1.38 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 165.26 (C-9), 159.834/159.826 (C-30/C-300),
144.27/144.26 (C-10/C-100), 129.55/129.51 (C-50/C-500),
119.62/119.44 (C-60/C-600), 113.10/113.01 (C-20/C-200),
112.37/112.28 (C-40/C-400), 65.54 (C-2), 63.56 (C-4),
55.40, 55.38 (OMe-C-30, OMe-C-300), 43.26 (C-1), 36.37
(C-5), 28.32 (C-8), 26.85 (C-6), 21.66 (C-7) ppm; MS (EI):
m/z = 366.2 (M?).
1
960, 909, 868, 817, 760, 732, 707, 660, 612 cm-1; H
NMR (400 MHz, CDCl3): d = 8.61 (br s, N–OH), 7.45
(dd, J = 10.94, 7.68 Hz, H-20, H-200, H-60, H-600), 7.20 (dd,
J = 7.72, 2.16 Hz, H-30, H-300, H-50, H-500), 4.37 (s, H-2a),
4.29 (s, H-4a), 3.55 (br s, W1/2 = 9.18 Hz, H-5), 2.80 (m,
H-7a), 2.48 (br s, W1/2 = 9.12 Hz, H-1), 2.380 (s, Me-C-
40), 2.377 (s, Me-C-400), 1.80–1.70 (m, H-6e, H-8e, NH),
1.58–1.47 (m, H-6a, H-8a), 1.38 (quin, H-7e) ppm; 13C
NMR (100.5 MHz, CDCl3): d = 166.06 (C-9), 139.58/
139.51 (C-10/C-100), 136.65/136.63 (C-40/C-400), 129.21 (C-
30, C-300, C-50, C-500), 126.97/127.02 (C-20, C-60/C-200, C-
600), 65.60 (C-2), 63.63 (C-4), 43.24 (C-1), 36.46 (C-5),
28.28 (C-8), 26.79 (C-6), 21.64 (C-7), 19.83, 19.81 (Me-C-
40, Me-C-400) ppm; MS (EI): m/z = 334.2 (M?).
2,4-Bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (31, C22H26N2O3)
Yield: 94%; m.p.: 195 °C; IR (KBr): vꢀ ¼ 3;306 (N–H
stretching), 2,985, 2,959, 2,940, 2,923, 2,861, 2,835 (C–H
stretching), 1,679 (C=N stretching), 1,610, 1,584 (C=C
stretching-Ph), 1,509, 1,465, 1,457, 1,439, 1,348, 1,325,
1,299, 1,259, 1,241, 1,179, 1,170, 1,142, 1,103, 1,084,
1,036, 1,000, 934, 896, 822, 790, 745, 729, 698, 689,
2,4-Bis(2-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (29, C22H26N2O3)
Yield: 89%; m.p.: 221 °C; IR (KBr): vꢀ ¼ 3;303 (N–H
stretching), 3,002, 2,952, 2,936, 2,923, 2,837 (C–H stretch-
ing), 1,674 (C=N stretching), 1,601, 1,585 (C=C stretching-
Ph), 1,489, 1,460, 1,435, 1,378, 1,339, 1,298, 1,284, 1,259,
1,235, 1,169, 1,142, 1,080, 1,050, 1,026, 1,025, 996, 940,
1
667, 630 cm-1; H NMR (400 MHz, CDCl3): d = 8.05
(br s, N–OH), 7.50 (t, J = 10.20 Hz, H-20, H-200, H-60,
H-600), 6.94 (t, J = 8.44 Hz, H-30, H-300, H-50, H-500), 4.33
(s, H-2a), 4.27 (s, H-4a), 3.830 (s, OMe-C-40), 3.826 (s,
OMe-C-400), 3.51 (br s, W1/2 = 10.24 Hz, H-5), 2.81 (m,
H-7a), 2.47 (br s, W1/2 = 9.88 Hz, H-1), 1.75 (t,
J = 15.40 Hz, H-6e, H-8e, NH), 1.59–1.47 (m, H-6a,
H-8a), 1.40 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 165.85 (C-9), 158.78 (C-40, C-400), 134.83/
134.78 (C-10/C-100), 128.19, 128.07 (C-20, C-600), 113.77
(C-30, C-300, C-50, C-500), 65.17 (C-2), 63.16 (C-4), 55.34
(OMe-C-40, OMe-C-400), 43.38 (C-1), 36.64 (C-5), 28.12
(C-8), 26.65 (C-6), 21.71 (C-7) ppm; MS (CI): m/z = 367.2
(M ? 1).
1
926, 895, 821, 793, 745, 690, 639, 599 cm-1; H NMR
(400 MHz, CDCl3): d = 7.93 (d, J = 6.96 Hz, H-60, H-600),
7.27 (t, J = 7.02 Hz, H-40, H-400), 7.13 (br s, N–OH), 7.05
(t, J = 6.96 Hz, H-50, H-500), 6.89 (dd, J = 7.86, 4.76 Hz,
H-30, H-300), 4.73 (s, H-2a), 4.67 (s, H-4a), 3.86 (s, OMe-C-
20), 3.83 (s, OMe-C-200), 3.76 (br s, W1/2 = 8.44 Hz, H-5),
2.81 (m, H-7a), 2.72 (br s, W1/2 = 9.16 Hz, H-1), 1.73 (t,
J = 13.92 Hz, H-6e, H-8e, NH), 1.56–1.45 (m, H-6a,
H-8a), 1.32 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 165.51 (C-9), 156.61/156.59 (C-20, C-200),
131.02 (C-10, C-100), 127.97 (C-40, C-400, C-60, C-600), 120.42
(C-50/C-500), 110.39/110.24 (C-30/C-300), 59.06 (C-2), 57.29
(C-4), 55.57, 55.39 (O OMe-C-20, OMe-C-200), 39.70 (C-1),
32.88 (C-5), 29.05 (C-8), 27.51 (C-6), 21.48 (C-7) ppm; MS
(EI): m/z = 366.2 (M?).
3-Methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-one
oxime (32, C21H24N2O)
Yield: 85%; m.p.: 206 °C; IR (KBr): vꢀ ¼ 3;030; 2,962,
2,930, 2,856, 2,780 (C–H stretching), 1,653 (C=N stretch-
ing), 1,601 (C=C stretching-Ph), 1,492, 1,450, 1,356,
1,220, 1,143, 1,042, 920, 873, 801, 756, 701, 611 cm-1
;
2,4-Bis(3-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
oxime (30, C22H26N2O3)
1H NMR (400 MHz, CDCl3): d = 9.30 (br s, N–OH), 7.83
(br s, H-60, H-600), 7.57 (d, J = 8.80 Hz, H-20, H-200), 7.40–
7.27 (m, H-30, H-300, H-40, H-400, H-50, H-500), 3.59 (d,
J = 3.28 Hz, H-2a), 3.54 (d, J = 2.92 Hz, H-4a), 3.44 (br
s, W1/2 = 10.12 Hz, H-5), 2.78 (m, H-7a), 2.42 (br s,
W1/2 = 9.94 Hz, H-1), 1.89 (s, N-Me), 1.68–1.58 (m, H-6e,
H-8e), 1.45–1.33 (m, H-6a, H-8a, H-7e) ppm; 13C NMR
(100.5 MHz, CDCl3): d = 165.21 (C-9), 141.78/141.73
(C-10/C-100), 128.48, 128.41 (C-30, C-300, C-50, C-500),
127.41 (C-40, C-400), 127.17/127.11 (C-20, C-60/C-200,
C-600), 75.71 (C-2), 73.80 (C-4), 43.97 (C-1), 43.80
(N-Me), 37.36 (C-5), 28.72 (C-8), 27.26 (C-6), 21.17
(C-7) ppm; MS (EI): m/z = 320.2 (M?).
Yield: 92%; m.p.: 176 °C; IR (KBr): vꢀ ¼ 3;305 (N–H
stretching), 2,969, 2,926, 2,854, 2,808, 2,783 (C–H
stretching), 1,658 (C=N stretching), 1,607, 1,593, 1,582
(C=C stretching-Ph), 1,487, 1,464, 1,450, 1,433, 1,370,
1,339, 1,315, 1,274, 1,249, 1,233, 1,191, 1,181, 1,151,
1,139, 1,109, 1,083, 1,048, 1,041, 1,025, 995, 950, 942,
921, 903, 883, 845, 801, 774, 752, 702, 689, 649,
600 cm-1 1H NMR (400 MHz, CDCl3): d = 7.32 (dt,
;
J = 7.68, 2.56 Hz, H-50, H-500, N–OH), 7.16 (dt,
J = 10.62, 2.20 Hz, H-20, H-200, H-60, H-600), 6.84 (td,
J = 7.32 Hz, H-40, H-400), 4.35 (d, J = 2.56 Hz, H-2a),
4.29 (d, J = 2.20 Hz, H-4a), 3.85 (s, OMe-C-30), 3.84 (s,
123

Synthesis, complete NMR spectral assignments, and antifungal screening
93
Acknowledgments This work was supported by Corporate-affiliated
Research Institute of Academic-Industrial-Institutional Cooperation
Improvement Business No. S7080008110.
2,4-Diphenyl-3-azabicyclo[3.3.1]nonan-9-one
O-methyloxime (33, C21H24N2O)
Amixtureof1.457 g2,4-diphenyl-3-azabicyclo[3.3.1]nonan-
9-one (1, 0.005 mol), 0.50 g methoxylamine hydrochloride
(0.006 mol), and 2.04 g sodium acetate trihydrate
(0.015 mol) in ethanol was heated under reflux. After
completion of the reaction, the contents of the flask were
concentrated, water was added, and the mixture was extracted
with ether. The ethereal layer was dried with anhydrous
sodium sulfate to afford the crude product. Then, the crude
oxime ether 33 was purified by column chromatography on
neutral alumina using petroleum ether (b.p.: 40–60 °C)/
n-hexane, 1:2, as eluent. Yield: 91%; m.p.: 124 °C; IR (KBr):
vꢀ ¼ 3;310 (N–H stretching), 3,067, 3,022, 2,971, 2,929,
2,894, 2,857, 2,806 (C–H stretching), 1,660 (C=N stretching),
1,598 (C=C stretching-Ph), 1,492, 1,451, 1,431, 1,345, 1,265,
1,250, 1,241, 1,175, 1,145, 1,068, 1,030, 1,001, 964, 938, 895,
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852, 820, 782, 750, 706, 685, 633, 590 cm-1; H NMR
1
(400 MHz, CDCl3): d = 7.56 (t, J = 6.96, 5.12 Hz, H-20, H-
200, H-60, H-600), 7.37 (t, J = 7.32 Hz, H-30, H-300, H-50, H-500),
7.27 (t, J = 7.32, 6.96 Hz, H-40, H-400), 4.34 (s, H-2a), 4.26 (s,
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(m, H-7a), 2.48(br s, W1/2 = 9.88 Hz, H-1), 1.79–1.74 (m, H-
8e, NH), 1.68 (dd, J = 15.04, 4.40 Hz, H-6e), 1.54–1.40 (m,
H-6a, H-8a), 1.34 (quin, H-7e) ppm; 13C NMR (100.5 MHz,
CDCl3): d = 164.90 (C-9), 142.67/142.57 (C-10/C-100),
128.43/128.38 (C-30, C-50/C-300, C-500), 127.26 (C-40, C-400),
127.08/126.94 (C-20, C-60/C-200, C-600), 65.63 (C-2), 63.65 (C-
4), 61.26 (OMe), 43.16 (C-1), 37.07 (C-5), 28.24 (C-8), 26.77
(C-6), 21.59 (C-7) ppm; MS (ES): m/z = 320.2 (M?).
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Antifungal analysis
The antifungal activity [25] of the synthesized oximes was
tested using Sabouraud dextrose agar (SDA) medium. The
sterilized (autoclaved at 120 °C for 30 min) medium was
inoculated (1 cm3/100 cm3 of medium) with a suspension
of the microorganism (matched to McFarland barium sul-
fate standard) and poured into Petri dishes to give a depth
of 3–4 mm. Paper discs impregnated with the test com-
pounds (1 mg/cm3 in dimethyl sulfoxide) were placed on
the solidified medium. The plates were pre incubated for
1 h at room temperature and incubated at 37 1 °C for
about 48 h for antifungal activity. Ketoconazole (100 lg/
disc) was used as positive reference standard. Negative
controls were also prepared by impregnating discs of the
same size with DMSO solvent.
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Acta Cryst E 64:1710
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