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P. Parthiban et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6452–6458
bridge-head protons (H-1 and H-5) as well as carbons differ lar-
gely. Compared to 1 (H-2,4/H-6,8/H-1,5 and C-2,4/C-6,8/C-1,5 are
4.39/4.74/2.89 and 63.28/58.64/61.76 ppm), the 1H and 13C of 2
indicates that the impact of A1,3-interaction is significantly better
than the electronegativity effect on the b carbons; in fact, the desh-
ielding might be about 2.1 ppm since the anti-b carbon C-2 is
deshielded by 0.91 ppm. Of the two syn-b carbons, one in the chair
form C-4 is more shielded than the C-6 in the boat form, rational-
ized by the comparative shorter bond length of C(5)–C(4) [1.557
(2) Å] than C(5)–C(6) [1.566 (2) Å]. In accordance with the above
(4.68/4.98/3.18 and 57.89/53.55/57.07),
5 (4.73/5.28/3.52 and
60.54/55.82/55.70) and 8 (4.68/5.31/3.62 and 62.74/55.44/57.89)
are deshielded and shielded, respectively, according to the varying
impact on the chemical shifts with varying magnitude of the elec-
tronegativity of the substituents. This deshielding of protons is rea-
sonably attributed by the interaction between the halogens and
benzylic/bridge-head protons, indeed, which is more with the
bridge-head protons than the benzylic protons, by their spatial
proximity. In the above cases, in fact, the C–X bonds prefer to be
syn to the benzylic protons to avoid the C–X and C–N dipole–dipole
interaction. Owing to this, the ortho protons in the chair are more
exposed to the axially oriented nitrogen lone pair, thus deshielded,
and appear at 8.06, 8.21 and 8.22 ppm of 2, 5 and 8, respectively,
than 7.60 ppm of 1. Though the bridge-head and ortho protons
are deshielded in the CH3 and OCH3/OC2H5 bispidines 11 and 16/
19 by spatial proximity, particularly in 16/19, the benzylic protons
in the chair are significantly shielded by the electronic effect of
OCH3/OC2H5 groups attached b to them.
electronegativity rule, all the
are deshielded by 0.71, 0.61, 0.82 and 0.95 ppm, respectively.
However, the syn-
carbons C-40 and C-60 are less deshielded than
corresponding anti-
carbons C-20 and C-80 by the transmittance of
c
carbons C-20, C-40, C-60 and C-80
c
c
a small magnitude of negative charge from C-5 to C-40/C-60 through
C-4/C-6 as a consequence of the above mentioned effect of
A1,3-interaction. However, the impact experienced by them is les-
ser than the b carbons. Another interesting observation is, of the
anti-b carbons, the C-2 is deshielded by 0.91 ppm in accordance
with the rule, whereas, another anti-b carbon C-8 is shielded by
1.10 ppm. Moreover, this shielding is very closer to the syn-b car-
bon C-6 (1.19 ppm) by the consequence of A1,3-interaction but
such effect is not possible at C-8 if the molecule is rigid, instead
of the dynamic behavior as outlined in Figure 6.
The oximes and oxime ethers of bispidines5a were synthesized
as depicted in Scheme 1, using sodium acetate trihydrate as base
(method A). Since the reaction required up to three days for the
completion, alternatively tried with pyridine as base (method B).
As an outcome, the desired product was achieved by 5–6 h reflux,
but the yield reduced largely.
The complete proton and carbon chemical shifts of all com-
pounds were assigned by 1D/2D NMR spectra (refer Supplementary
data). Because of oximation, the ring carbons and their protons ap-
pear as distinct signals. Moreover, due to A1,3-interaction (Fig. 3),
Other than 0.1 ppm less deshielding of the H-5, a similar effect
is observed in 51 by the introduction of a methyl group on oxime
functionality of 26. Further, in 13C, the methyl group shields the
oximino carbon C-9 and deshields the syn-a carbon C-5 by 1.13
and 0.72 ppm, respectively. Likewise, all other oximes 27–50 and
oxime ethers 52–75 are exhibiting the trend. The 1H and 13C
NMR chemical shifts of 53 are represented in Figures 4 and 5. On
the basis of 1D/2D NMR studies in solution, we perceived that
the oximes 26–50 and oxime ethers 51–75 are exist in an intercon-
vertable dynamic chair-boat conformation with equatorial disposi-
tion of the aryl groups at C-2/C-4 (in the chair form) and axial-like
orientation at C-6/C-8 (in the boat form) as in Figure 6.
the syn-
by 1.13 ppm but the anti-
1. Thus the difference between the bridge-head protons
1.13 ppm, obviously by the allylic interaction since there was no
impact by the electronegativity effect on the protons.
In general, decrease in electronegativity of a particular group in
a six-membered ring shields the -carbons and deshields the b and
carbons.6 Accordingly, the
carbons are shielded by the reduc-
tion of C@O as C@N, however, the trend violated in the b and car-
a
proton H-5 is deshielded. In 26, the H-5 is deshielded
proton H-1 appears at 2.88 ppm as in
d5,1 is
a
D
Single-crystal analysis of 26 (Figs. 7 and 8) shows that one of the
piperidine rings C1–C7–C4–C5–N2–C6 adopts a near ideal chair
conformation with the deviation of ring atoms N2 and C7 from
the best plane C1–C4–C5–C6 by ꢁ0.657 and 0.673 Å, respectively.
According to Nardelli,7 the smallest displacement asymmetry
parameters q2 and q3 are 0.0391(17) and 0.6133(17) Å, respec-
tively. In accordance with Cremer and Pople,8 the ring puckering
parameters such as total puckering amplitude ‘QT’ and the phase
angle ‘h’ are 0.6145(17) Å and 176.32(6)°. Thus all parameters
strongly support the near ideal chair conformation. Likewise, the
puckering analysis of another piperidine ring C1–C2–N1–C3–C4–
C7 indicates that the ring adopts a boat conformation with the
deviation of ring atoms N1 (ꢁ0.652 Å) and C7 (0.708 Å) from the
best plane C1–C2–C3–C4. Further, it is confirmed by the
QT = 0.7681(17) Å and h = 89.43(13)° as well as q2 [0.768(17)] and
q3 [0.0077(17) Å]. Thus, the detailed crystallographic studies such
as asymmetry parameters, ring puckering parameters, torsion an-
gles and least-square planes calculated for 26 proved that the bicy-
cle exists in a chair-boat conformation with equatorial orientation
of the phenyl rings in the chair form with the torsion angles of
177.23(13) [C7–C4–C5–C20] and 179.43(14)° [C7–C1–C6–C26],
whereas the torsion angles of the phenyl rings C8–C9–C10–C11–
C12–C13 and C14–C15–C16–C17–C18–C19 in the boat form are
120.27(16) [C7–C1–C2–C8] and ꢁ122.85(16)° [C7–C4–C3–C14],
respectively. The phenyl groups in the chair form are orientated
at an angle of 19.36(3)° with respect to one another whereas in
the boat form, they are oriented at an angle of 40.09(5)°.
a
a
c
a
c
bons. According to A1,3-interaction, the H-5 and C-5 are acquired
the positive and negative charges, respectively. Thus in 26, C-5 is
shielded by 6.67 ppm by the acquired negative charge besides
the shielding of 10.43 ppm exerted by the electronegativity effect
on the syn carbons. Then the excess of negative charge on the
syn-
the syn-
a
carbon transmitted to the syn-b carbon and some extent to
carbon also. Hence, the expected deshielding by the elec-
c
tronegativity effect is overturned on the syn-b carbons C-4 and C-6
by the shielding of 1.24 and 1.19 ppm, respectively. This result
R
R
R = H/CH3
O
O
'W' correlation
1,3-allylic
N
N
by H,H-COSY
interaction
9
9
δ
H
H
H
Ar
H
Ar
δ
5
1
5
1
syn
HN
HN
7
H
H
7
4
4
Ar
6
Ar
2
8
2
8
6
All the synthesized oximes and O-methyloximes were tested
for their in vitro antimicrobial activity against a panel of patho-
genic bacteria (Bacillus subtilis, Staphylococcus aureus, Klebsiella
pneumoniae and Pseudomonas aeruginosa) and fungi (Candida
albicans, Candida parapsilosis, Aspergillus niger and Cryptococcus
neoformans) by standard broth micro-dilution technique by NCCLS
3
3
Ar
H
Ar
H
Ar
anti
Ar
N
H
N
H
(a)
(b)
Figure 3. (a) Non-bonded A1,3-interaction between the N–O and C(5)–H bonds in
26–75; (b) Long-range coupling between the bridge-head protons H-1 and H-5 by
‘W’ arrangement, from the H,H-COSY spectrum of 51, 52 and 53.
Parthiban, Paramasivam
