Convenient synthesis and NMR spectral studies of variously substituted N-methylpiperidin-4-one-O-benzyloximes

Article abstract of DOI:10.1007/s00706-008-0021-6

A series of variously substituted N-methylpiperidin-4-one-O-benzyloximes were synthesized by three different methods. Among them, the direct conversion of 2,6-diarylpiperidin-4-ones into the corresponding oxime ethers (method A) was proved to be better than the other two methods in the sense of good yield, convenience, easy work-up and quick reaction time. All the synthesized compounds are characterized by IR, Mass and NMR (¹H NMR, ¹³C NMR, ¹H-¹H COSY, ¹H-¹³C COSY and HMBC) spectral studies. The conformational preference of the synthesized oxime ethers with/without alkyl and aryl substituents at C-3/C-5 and C-2/C-6 is discussed using the spectral data. The observed chemical shifts and coupling constants suggest that the synthesized oxime ethers adopt chair conformation with equatorial orientation of all the substituents, whereas 1-methyl-3-isopropyl-2, 6-diphenylpiperidin-4-one-O-benzyloxime also exists in boat conformation. Based on the NMR data, the effects of oximination on ring carbons and their associated protons and alkyl substituents are discussed. In addition, the effect of NMe group on the 2,6-diarylpiperidin-4-one-O-benzyloximes was also studied.

Full text of DOI:10.1007/s00706-008-0021-6

Monatsh Chem (2009) 140:287–301
DOI 10.1007/s00706-008-0021-6
ORIGINAL PAPER
Convenient synthesis and NMR spectral studies of variously
substituted N-methylpiperidin-4-one-O-benzyloximes
Paramasivam Parthiban Æ Mannangatty Rani Æ
Senthamaraikannan Kabilan
Received: 29 April 2008 / Accepted: 2 June 2008 / Published online: 25 September 2008
Ó Springer-Verlag 2008
Abstract A series of variously substituted N-methylpi-
peridin-4-one-O-benzyloximes were synthesized by three
different methods. Among them, the direct conversion of
2,6-diarylpiperidin-4-ones into the corresponding oxime
ethers (method A) was proved to be better than the other
two methods in the sense of good yield, convenience, easy
work-up and quick reaction time. All the synthesized
compounds are characterized by IR, Mass and NMR
(1H NMR, 13C NMR, H-1H COSY, H-13C COSY and
HMBC) spectral studies. The conformational preference of
the synthesized oxime ethers with/without alkyl and aryl
substituents at C-3/C-5 and C-2/C-6 is discussed using the
spectral data. The observed chemical shifts and coupling
constants suggest that the synthesized oxime ethers adopt
chair conformation with equatorial orientation of all
the substituents, whereas 1-methyl-3-isopropyl-2,6-diph-
enylpiperidin-4-one-O-benzyloxime also exists in boat
conformation. Based on the NMR data, the effects of ox-
imination on ring carbons and their associated protons and
alkyl substituents are discussed. In addition, the effect of
NMe group on the 2,6-diarylpiperidin-4-one-O-benzyloxi-
mes was also studied.
Introduction
The NMR technique is a versatile tool for the structural
elucidation of most of the organic compounds and useful for
the conformational analysis also. H NMR and 13C NMR
1
techniques have been extensively applied in deriving ste-
reodynamical information about a wide variety of systems.
They give information about the influence of electronic and
conformational effects on chemical shifts and coupling
constants. Vicinal coupling constant values have been used
for the conformational analysis which can give an indica-
tion of the orientation of the substituents [1, 2].
1
1
2,6-Diarylpiperidin-4-ones [3] have been subjected to
a variety of synthetic [4–8] and physico-chemical studies
[9–11]. 2,6-Diarylpiperidin-4-ones normally adopt chair
conformation with equatorial orientation of all the substit-
uents [12–15]. When certain heteroconjucate groups,
such as –NO, –CHO, –COMe, –COCH2Cl, –COPh, etc., are
introduced at the ring nitrogen of the 2,6-disubstituted
piperidone system they cause a major change in ring con-
formation [16–25]. Likewise, the conversion of the carbonyl
group into C=N–OH, C=N–OBn, C=N–NH2, C=N–N=CH2,
C=NNHCSNH2, C=N–NHPh, [26–37] exhibit an abrupt
change in the chemical shifts of the ring carbons and asso-
ciated protons, and also exhibit a change in conformation of
the compound and orientation of the substituents.
Keywords N-Methylpiperidin-4-ones ꢀ Oxime ether ꢀ
NMR ꢀ Effect of oximination ꢀ Effect of N-methylation
In general, the change in electronegativity of a particular
group or atom on the ring causes a major change in
chemical shifts on the ring carbons and their associated
protons [28, 35]. In continuation of our earlier work on the
spectral [28] and biological [38–41] studies of piperidone
oxime ethers, in the present study we report herein a
convenient synthesis and complete NMR spectral studies of
diversely substituted N-methylpiperidin-4-one-O-benzy-
loximes with a view to assign its proton and carbon signals
Present Address:
P. Parthiban
Department of Chemistry, Indian Institute of Technology
Madras, Chennai 600 036, India
P. Parthiban ꢀ M. Rani ꢀ S. Kabilan (&)
Department of Chemistry, Annamalai University,
Annamalainagar 608 002, India
e-mail: prskabilan@rediffmail.com
123

288
P. Parthiban et al.
unambiguously and compare its stereochemical aspects
with that of its non-NMe analog. In addition, the effects of
oximino group at C-4 and Me at N-1 have been studied.
those of some of the analogs piperidones. In general, the
aromatic protons resonate in the downfield region at around
7 ppm due to the magnetic anisotropic effect (ring current
effect). Hence, the multiplet appearing in the aromatic
region of about 7.23–7.16 ppm (5H) is unambiguously
assigned to the Ph-H of the OBn moiety.
Results and discussion
In the aliphatic region, two sharp singlets and four
triplets are observed. Of the two singlets at 4.97 (2H) and
2.18 ppm (3H), the downfield singlet is ascribed to the
methylene protons of the OBn group. Another singlet at
2.18 ppm is assigned to the NMe protons. There are four
triplets appearing at 2.55, 2.38, 2.32 and 2.25 ppm (each
2H). Each triplet is raised owing to the splitting of each
methylene group protons by the neighboring methylene
protons. Actually, an individual signal for each protons of
every methylene group is expected, but due to the fast
rotation of N–O on the NMR time scale, every two protons
of the same methylene groups acquire a similar electronic
environment and, thus, an average triplet is observed for
each methylene group. Moreover, all the triplets have an
average coupling constant in the range between 5.0 and
5.4 Hz. By considering the oximination effect, the triplets
at 2.38 and 2.32 ppm are assigned, respectively, to H-2 and
H-6 protons. The other two are attributed to the a-protons.
Of the two, the 2.55 ppm is unambiguously assigned to
the H-5 protons due to the 1,3-spatial proximity effect with
N–O bond. And, as a consequence, the most downfield
triplet is assigned to H-3 protons. Based on the chemical
shifts and coupling constants (Table 1), the conformation
of the piperidone heterocycle is proposed as chair (Fig. 1).
Synthesis
Treatment of ketones with hydroxylamine hydrochloride
and sodium acetate in boiling ethanol afforded the corre-
sponding oximes in good yields [42]. Treatment of ketones
with hydroxylamine hydrochloride and an ion-exchange
resin (Amberlyst A-21) as catalyst in ethanol leads to
oxime in 70–100% yield at room temperature and with a
simple work-up procedure [43]. In the present study, a
series of new piperidone oxime ethers were synthesized.
Synthesis of the target compounds was achieved by
adopting the following three synthetic strategies as shown
in Scheme 1. They are, method A: N-methylpiperidin-4-
ones are directly refluxed with O-benzylhydroxylamine
hydrochloride and sodium acetate trihydrate in methanol;
method B: the oximes of N-methylpiperidin-4-ones are
converted into oxime ethers by treating with benzyl bro-
mide in the presence of NaH/DMF; and method C:
piperidin-4-ones are treated with O-benzyl hydroxylamine
hydrochloride followed by N-methylation.
Condensation of respective ketone, aromatic aldehyde
and ammonium acetate in 1:2:1 ratio afforded the formation
of 2,6-diarylpiperidin-4-ones [3] 1–7. N-Alkylation [44] of
1–7 using MeI (methyl iodide) in the presence of anhydrous
K2CO3 afforded 9–15. Use of MeI over DMS (dimethyl
sulphate) is found to be superior in terms of good yield as a
single product, convenience and easy work-up procedure.
1H and 13C NMR spectra were recorded for all the syn-
thesized compounds. In addition, for compound 30, HSQC,
and for 32, HOMOCOSY, HSQC and HMBC, were also
recorded. Mass spectra and elemental analyses were recorded
for all compounds and are in agreement with their respective
proposed molecular formulae. The analytical data are pro-
vided as supplementary material. IR spectra of all the
synthesized compounds support the formation of oxime ether
1H NMR spectral study of 1-methyl-2,6-
diphenylpiperidin-4-one-O-benzyl oxime (31)
The multiplet appears in the range 7.37–7.17 ppm (15H) is
obviously assigned to the Ph-H at C-2, C-6 and OBn group.
A sharp singlet with two protons integral at 5.01 ppm is
conveniently assigned to the OBn methylene protons by
comparing with the corresponding signal in compound 30.
In 31, the singlet for NMe appears at 0.49 ppm upfield
compared with 30, due to the pavement of the equatorial
Ph substituents on either side of the NMe.
by the appearance of a band at about 1,639–1,649 cm-1
,
In 1, the resonances of benzylic protons (H-2a, H-6a) and
methylene protons (H-3, H-5) were reported to observe,
respectively, at 4.01 and 2.45 ppm [46] whereas the same of
its NMe analog observed at 3.30 and 2.60 ppm. Hence, the
introduction of a Me at NH shields H-2a,6a by 0.71 ppm and
deshields H-3,5 by 0.15 ppm. The similar effect is also
observed in 2,6-diphenylpiperidine [48]. In 31, the doublet of
doublets appears at 3.17 (3J2a,3a = 9.3 Hz, 3J2a,3e = 5.4 Hz)
which is a characteristic stretching band region for the C=N
group [28]. Moreover, the formation of the NMe group is also
confirmed by the disappearance of the characteristic stretch-
ing frequency of the piperidone NH at around 3,310 cm-1
.
1H NMR spectral study of 1-methylpiperidin-4-one-O-
benzyloxime (30)
3
and 3.09 ppm (3J5a,6a = 11.5 Hz, J5e,6a = 2.2 Hz). Both
The 1H NMR signals are assigned based on their positions,
multiplicity and integral values, and by comparing with
are 0.76 ppm shielded compared with the benzylic protons
H-2a (3.93 ppm, dd) and H-6a (3.85 ppm, dd) of 23. Hence,
123

Convenient synthesis and NMR spectral studies
289
Scheme 1
O
O
R1
R1
NH4OAc/EtOH
O
O
N
H
Warm
H
H
R
R
1-7
R
R
MeI
Anhyd. K2CO3
Method A
Acetone/Reflux
O
N
O
ONH2.HCl
R1
N
N
R1
NaOAc.3H2O/MeOH
Me
Reflux
R
R
Me
8-15
R
R
30-37
NH2OH.HCl
NaOAc.3H2O
EtOH/Reflux
Method B
HO
N
N
Br
R1
NaH/DMF/Stirring
0oC- r.t.
Me
R
R
16-22
Method C
O
O
N
N
R1
R1
MeI/Anhyd. K2CO3
4
3
2
5
Acetone/Reflux
2''
6''
6
1
2'
6'
6'''
2'''
N
N
H
2''''
6''''
Me
R
R
R
R
23-29
31-37
Compounds
R
R1
H
-
H
8
30
H
1, 9, 16, 23, 31
2, 10, 17, 24, 32
3, 11, 18, 25, 33
4, 12, 19, 26, 34
5, 13, 20, 27, 35
6, 14, 21, 28, 36
7, 15, 22, 29, 37
H
Me
Me
Me
Me
Et
Cl
Me
OMe
H
H
iPr
123

290
P. Parthiban et al.
Obviously, another signal at 2.40 ppm is designated to the
methylene protons at C-3.
Table 1 Coupling constant values of compounds 30–37, 15, 22 and
29 (J, Hz)
3
3
3
2
3
Compound J2a,3a J2a,3e J5a,6a J5a,5e J5e,6a 3J3a,Me/3J3a,7
Eventhough the chemical shifts are in favor for chair
conformation, the coupling constants are considerably
varied from the expected/literature values. Particularly,
30
31
32
33
34
35
36
37
15
22
29
a
5.3 (J2,3
)
5.4 (J5,6
)
–
3
3
9.3
5.4
11.5
14.1
2.2
2.9
3.2
3.0
3.2
2.7
3.5
3.6
4.4
3.6
–
the J2a,3a and J2a,3e deviate considerably from the
3
3
10.3
10.3
10.1
10.2
10.1
7.2
–
–
–
–
–
–
–
–
–
11.9
13.8
13.9
13.8
13.8
13.7
11.7
13.4
11.0
14.6
6.4
6.5
6.5
6.5
–
expected range. In 23, the J2a,3a and J2a,3e are 11.5 and
2.9 Hz whereas in 31 they are 9.3 and 5.4 Hz, respec-
tively. There is a significant decrease (2.2 Hz) in vicinal
diaxial coupling and increase (2.2 Hz) in vicinal axial-
equatorial coupling. At the same time, there is no notable
variation in syn side vicinal and geminal couplings except
3J5e,6a (3J5e,6a of 31 and 23 are 2.2 and 2.8 Hz, respec-
tively). Based on the chemical shifts and the rest of the
coupling constants, we can suggest that the compound is
in chair conformation with puckering about the C(2)–C(3)
bond.
12.0
a
–
11.9
11.7
10.7
11.7
11.0
11.3
7.1
2.8
6.0
3.9
10.6
7.6
8.9
Could not be determined due to overlapped signals
OBn
1H NMR spectral study of 1,3-dimethyl-2,6-
diphenylpiperidin-4-one-O-benzyloxime (32)
H
δ
H
N
In Fig. 2, a multiplet appears in the range 7.31–7.09 ppm
with 15 protons. Hence, it is assigned to the Ph-H at C-2,
C-6 and OBn moiety. The sharp singlets at 5.00 (2H) and
1.58 ppm (3H) are respectively assigned to the OBn
methylene and NMe protons by comparing with these
protons resonance in 31.
H
6
Ar
δ
4
5
2
1
R1
3
N
H
The doublet at 0.71 ppm (3H, J = 6.4 Hz) is designated
to the Me substituent at C-3 by comparing with 2. Due to
the introduction of a Me group at C-3, the nature of split-
ting of piperidone ring protons of 32 is drastically varied
from the previous compound 31. In this spectrum, there are
five signals between 3.41 and 2.02 ppm (each 1H), which
shows that every proton in the piperidone ring gives indi-
vidual signals unlike 31. In 32, the doublet at 2.70 ppm
with (diaxial) coupling constant of 10.2 Hz may be
assigned to the H-2a proton, which is shielded by 0.47 ppm
compared with the H-2a resonance in 31 [49].
Me
Ar
H
Fig. 1 Chair conformation
the doublet of doublets at 3.17 and 3.09 ppm are respectively
assigned to the H-2a and H-6a of 31.
The vicinal and geminal coupling constants of benzylic
protons are significantly varied from the corresponding
non-NMe oxime ether 23. The vicinal diaxial coupling
constant is decreased on the anti side (3J2a,3a = 9.3 Hz)
rather than the syn side (3J5a,6a = 11.5 Hz), whereas
There are two doublets of doublets appearing in the
higher frequency region at 3.41 and 3.05 ppm. In 2,6-di-
arylpiperidin-4-one systems, the diaxial and axial-
equatorial coupling constants are observed at about 12 and
3 Hz, respectively. Hence, the doublet of doublet at
3.05 ppm may be designated to H-6a and this is raised due
to the coupling of H-6a with H-5a (3J5a,6a = 11.9 Hz) and
H-5e (3J5e,6a = 2.9 Hz). Therefore, the doublets of doublet
the vicinal axial-equatorial coupling constant (3J2a,3e
=
5.4 Hz) of anti side is greater than the syn side
3
(3J5e,6a = 2.2 Hz). The decrease in J2a,3a is about 2.2 Hz
compared with 3J5a,6a and this may be due to the puckering
about the C(2)–C(3) bond by means of the introduction of a
Me group at NH. By comparing compound 23 and con-
sidering the effect of NMe group, the higher frequency
doublet at 3.36 ppm (2J5a,5e = 14.1 Hz) is designated to
the syn a-equatorial proton H-5e. The higher d value for H-
5e is due to the interaction of the N–O bond with the C–
H(5e) bond (Fig. 1). Hence, H-5e appears in the downfield
region and, as a consequence, the upfield signal at
2.09 ppm is attributed to the syn a-axial proton H-5a.
3
at 3.41 ppm (2J5e,5a = 13.8 Hz, J5e,6a = 2.9 Hz) can be
assigned to the H-5e proton by considering the 1,3-spatial
proximity effect. Of the two signals between 2 and
2.5 ppm, the triplet at 2.02 ppm (Jave = 12.9 Hz) may be
assigned to H-5a owing to the induced polarity on C(5)–
H(e) bond (Fig. 1). The sextet at 2.48 ppm is attributed to
the methinic proton H-3a.
123

Convenient synthesis and NMR spectral studies
291
Fig. 2 1H NMR spectrum
of compound 32
N-CH3
H-5a
H-2a
CH3 at C-3
Ph-H
H-5e
O-CH2-Ph
H-6a
H-3a
/ppm
Fig. 3 HOMOCOSY spectrum
of compound 32
N-CH3
H-2a
CH3 at C-3
H-6a
Ph-H
O-CH2-Ph
H-5a
H-3a
H-5e
CH3 at C-3
N-CH3
H-5a
H-3a
H-2a
H-6a
H-5e
O-CH2-Ph
Ph-H
/ppm
The HOMO correlations (Fig. 3; Table 2) between the
sextet at 2.48 ppm and the doublets at 2.70 (H-2a) and
0.71 ppm (Me at C-3) clearly shows that the resonance at
2.48 ppm is only due to the H-3a proton. The benzylic
proton H-6a has strong and weak correlations with 2.02 and
3.41 ppm, which unambiguously confirm the assignment of
2.02 and 3.41 ppm, respectively, for H-5a and H-5e. The
strong correlation between the doublet of doublet at
123

292
P. Parthiban et al.
H
H
H
Table 2 Correlations in the HOMOCOSY spectrum of compound 32
(d, ppm)
H
Me
H
H
MeN
MeN
Signal
Correlations
C=N-OBn
C=N-OBn
Ph
Ph
7.31–7.09 (Ph-H)
3.41 (dd, 1H, H-5e)
3.05 (dd, 1H, H-6a)
2.70 (d, 1H, H-2a)
2.48 (sextet, 1H, H-3a)
2.02 (t, 1H, H-5a)
1.58 (N–CH3)
–
Me
H
H
2.70, 3.05
2.02, 3.41
2.48
Fig. 5 Ethyl group conformation of compound 36
2.70, 0.71
3.41, 3.05
–
In 34 and 35, the upfield doublet of doublets with four
protons integral are assigned to the protons ortho to the Me/
OMe substituents (i.e., H-2000/H-6000). However, more
shielding (about 0.31 ppm) for 35 is akin to the ortho effect
of the OMe group. Due to the effect of oximination, in 34
and 35, the Me/OMe groups at C-20000/C-60000 appear as
separate signals.
0.71 (CH3 at C-3)
2.48
H
1H NMR spectral study of 1-methyl-3-ethyl-2,
6-diphenylpiperidin-4-one-O-benzyloxime (36)
C=N-OBn
Me
The protons assignment of 36 is carried out with reference
to 32. Except H-2a and H-3a, all other protons are reso-
nated in the same region as in 32. The anti b-axial benzylic
proton H-2a and anti a-axial methine proton H-3a
are respectively deshielded and shielded by 0.21 and
0.11 ppm, due to the replacement of the equatorial Me by
Et group at C-3. Moreover, the syn b-axial benzylic proton
H-6a also been deshielded by 0.06 ppm. The upfield triplet
at 0.68 ppm (3H) and multiplets centered at 1.06 and
1.44 ppm (each 1H) are corresponding to Et protons.
Among the signals, the triplet is due to the Me protons
whereas the multiplets are caused by the methylene protons
of the Et; both the multiplets are interchangeable. Since the
observed coupling constants are similar to 32, compound
36 is also suggested as adopting chair conformation with
equatorial orientation of the Ph and Et groups, respectively,
at C-2, C-6 and C-3 as in Fig. 1. The conformation of the
Et group is depicted in Fig. 5.
Ph
NMe
H
Fig. 4 Flattening about the C(2)–C(3) bond
3.41 ppm (H-5e) and the triplet at 2.02 ppm also explain
that the triplet is ascribed to the H-5a proton. The absence
of correlation for the sharp singlet at 1.58 ppm with any of
the proton signals clearly shows that the signal at 1.58 ppm
is due to the NMe protons.
The observed splitting pattern, chemical shifts and
coupling constants clearly suggest that the compound
adopts chair conformation with equatorial orientation of all
the substituents (Fig. 1). The chemical shift difference
3
3
(1.6 Hz) between J2a,3a and J5a,6a is obviously due to the
introduction of a Me group at C-3, which leads to flattening
of the ring about the C(2)–C(3) bond to decrease the Ph-Me
gauche interaction (Fig. 4).
1H NMR spectral study of 1-methyl-3-isopropyl-2,
6-diphenylpiperidin-4-one-O-benzyloxime (37)
In 37, other than piperidone ring protons, all appear in the
expected chemical shift region. The doublets at 1.07 (3H,
J = 6.5 Hz) and 1.23 (3H, J = 6.5 Hz) are conveniently
1H NMR spectral study of 1,3-dimethyl-2,
6-diarylpiperidin-4-one-O-benzyloximes (33–35)
i
assigned to the Me protons of the Pr group by comparing
Notwithstanding the substitution in phenyl rings, all the
proton resonance of compounds 33, 34 and 35 are assigned
in a similar manner of 32. The Ph protons are assigned by
considering the nature of the substituent. Generally, in para
substituted phenyl rings, protons ortho to the substituents
are chemically equivalent. Similarly, protons meta to the
substituents are also chemically equivalent. Hence, two
sets of signals are quite obvious for that kind of Ph.
22 and 29. Owing to the diastereotopic nature, both the Me
signals are interchangeable. The expected sharp singlet for
the NMe is overlapped with the multiplet of H-7 centered at
1.73 ppm.
There are two signals at 3.44 and 3.46 ppm corre-
sponding to one proton each. Of the two, the downfield
signal is
3J5e,6a = 3.5 Hz), which suggests that the signal is due to
a
doublet of doublet (3J5a,6a = 10.7 Hz;
123

Convenient synthesis and NMR spectral studies
293
Table 3 Correlations in the HSQC spectrum of compound 30 (d,
ppm)
OBn
Signal
Correlations
N
Me
Ph
7.23–7.16 (m, 5H, Ph-H)
127.82 (meta), 127.45 (para), 127.14
(ortho)
4.97 (s, 2H, –O–CH2-Ph)
2.55 (t, 2H, H-5)
2.38 (t, 2H, H-2)
2.32 (t, 2H, H-6)
2.25 (t, 2H, H-3)
2.18 (N–CH3)
74.83
55.41
31.01
24.96
54.09
45.41
N
Ph
H
Me
H
H
Me
H
H
H
again proves that the compound is largely populated in boat
form.
Fig. 6 Boat conformation
3
The J3a,7 of 15 is only 2.8 Hz whereas it is 7.1 Hz for
37. This coupling constant is also very significantly an
added support for the existence of boat form. From this
coupling constant, we can get one more interesting fact i.e.,
in 15 (which was reported to adopt chair conformation),
according to the gauche proton coupling (J = 2–4 Hz), the
the benzylic proton H-6. Obviously the doublet at
3.44 ppm (3J2a,3a = 7.2 Hz) is postulated to another ben-
zylic proton H-2. The decrease in vicinal coupling
constants compared with other 3-substititued analogs and
the downfield signal of H-6 over H-2 clearly suggest that
the compound is significantly populated in boat form.
While comparing the vicinal coupling constant (3J2a,3a) for
the doublets of 15, 22, 29 and 37, compound 37 shows a
i
conformation of the Pr was depicted as in Fig. 7a, but in
3
i
37, J3a,7 clearly suggests that the Pr exists in both the
conformations shown in Fig. 7a and b. This can be
explained as follows. In boat conformation, the H-7 is anti
to H-3 and hence the anti proton coupling is experienced
3
significant decrease in J2a,3a and also an appreciable
3
decrease in J5a,6a, which strongly indicate that the com-
pound is, to a considerable extent, in boat form.
i
by this Pr group; it should be around 10–12 Hz (charac-
teristic coupling constant value for anti protons). Due to
the significant population of boat form, a drastic increase is
observed in 3J3a,7 when compared to 15, 22 and 29. Owing
to the presence of both chair and boat conformation in
Among the three doublets of doublets at 3.23, 2.63 and
2.44 ppm (each 1H), the 2.44 ppm is assigned to the H-3a
proton by its coupling constants. Of the remaining two
doublets of doublets, the downfield and upfield signals are
respectively designated to H-5e and H-5a. In chair form,
the H-5e and H-5a experiences a pronounced deshielding
and shielding, respectively, but in boat conformation
(Fig. 6), the syn a-axial proton H-5a would not be perfectly
in axial position and seems to occupy an equatorial position
and, as a consequence, this proton is involved in interaction
with the N–O bond. Hence, the H-5a in boat form is de-
shielded compared with H-5e. As a sum of boat and chair
conformations, this deviation is observed in 37. This also
i
solution, Pr group adopts the conformation of Fig. 7a and
b in chair and boat forms, respectively.
13C NMR spectral study of 1-methylpiperidin-4-one-O-
benzyloxime (30)
The Ph and quaternary carbons are unambiguously
assigned by their HSQC correlations (Table 3). In its
HSQC spectrum, the carbon resonance at 74.83 ppm has a
cross peak with the singlet at 4.97 ppm, which indicates
that the signal at 74.83 ppm is due to the OBn methylene
carbon. There are five intense signals in the aliphatic region
at 55.41, 54.09, 45.41, 31.01 and 24.96 ppm. Among the
signals, one at 45.41 ppm is assigned to the NMe carbon,
which only correlates with the singlet at 2.18 ppm.
H
H
H
Me'
Me
Me'
MeN
MeN
C=N-OBn
C=N-OBn
The signals at 55.41 and 54.09 ppm are respectively
assigned to C-2 and C-6 carbons by comparing parent
ketone. According to the expected electronegativity effect,
the anti and syn b-carbons are respectively deshielded
(0.90 ppm) and shielded (1.33 ppm). Similarly, the anti
and syn a-carbons are also assigned by considering the
Ph
Ph
Me
H
H
H
(a)
(b)
Fig. 7 Isopropyl group conformation of compound 37; a in chair
form, b in boat form
123

294
P. Parthiban et al.
decrease in electronegativity on C-4. The assignments are
done by comparing with similar type of compounds and
cyclohexanone oximes [50], which are further, unambigu-
group is flanked either side by the Ph rings at C-2 and C-6;
hence, the Me carbon is shielded by about 4 ppm.
ously confirmed by H-13C correlations (Table 3).
13C NMR spectral study of 1,3-dimethyl-2,
6-diphenylpiperidin-4-one-O-benzyloxime (32)
1
13C NMR spectral study of 1-methyl-2,
6-diphenylpiperidin-4-one-O-benzyloxime (31)
In the 13C NMR spectrum of 32, the most upfield resonance
at 12.62 ppm is assigned to the Me group at C-3. In
addition, there are six signals observed in the aliphatic
region at 77.66, 75.47, 69.31, 43.13, 41.44 and 35.22 ppm.
In its HSQC spectrum (Fig. 8), the carbon signals at 77.66
and 69.31 ppm have cross peaks with the proton reso-
nances at 2.70 (H-2a) and 3.05 ppm (H-6a), respectively.
Hence, they are conveniently assigned to the C-2 and C-6
carbons, respectively. Since the carbon resonance at
75.47 ppm has a cross peak with the singlet at 5.00 ppm, it
is conveniently assigned to the OBn methylene carbon. The
sextet at 2.48 (H-3a) and a sharp singlet at 1.58 ppm (NMe)
have correlations with 43.13 and 41.44 ppm, respectively.
Hence, the carbon resonances at 43.13 and 41.44 ppm are
respectively assigned to C-3 and NMe carbons.
The carbon resonances beyond 127 ppm are due to the
phenyl rings at C-2, C-6 and OBn moiety. The less intense
signals at 156.78, 144.20 and 143.99 ppm are respectively
assigned to the quaternary carbons C-4, C-20 and C-60. The
still less intense signal at 138.15 ppm is conveniently
assigned to the OBn ipso carbon by comparing with 30.
Similarly, the intense signal at 75.48 ppm is assigned to the
OBn methylene carbon.
By comparing with 23, the higher frequency aliphatic
region signals at 70.71 and 69.34 ppm are assigned to the
benzylic carbons C-2 and C-6, respectively. The signals at
41.27 and 35.36 ppm are respectively assigned to the
methylenic carbons C-3 and C-5. The benzylic (C-2, C-6)
and methylenic (C-3, C-5) carbons are deshielded by 8.73,
8.67 and 0.86, 1.16 ppm, respectively. This is obviously
due to the introduction of a Me group in the ring nitrogen
of compound 23. Generally, the NMe carbon resonates at
about 41 ppm in 1-methyl-2,6-diphenylpiperidin-4-one
[51] whereas the same is reported to be observed at about
45 ppm in 1-methylpiperidin-4-one [44]. Here, the Me
The signals from 128.48 to 127.02 ppm have correla-
tions with the Ph protons multiplet. However, the signals
beyond 128.48 ppm have no correlation with any of the
proton signals. Hence, they are identified as quaternary
carbons. In order to carry out unambiguous assignment of
the quaternary carbon signals, the HMBC spectrum (Fig. 9)
has been recorded.
Fig. 8 HSQC spectrum
of compound 32
H-2a
O-CH2-Ph
N-CH3
CH3 at C-3
H-6a
H-5e
Ph-H
H-5a
H-3a
CH3 at C-3
C-5
N-CH3
C-3
C-6
O-CH2-Ph
C-2
Ph carbons
Bn ipso carbon
C-2'
C=N
C-6'
/ppm
123

Convenient synthesis and NMR spectral studies
295
H-2a
Fig. 9 HMBC spectrum
of compound 32
N-CH3
CH3 at C-3
H-6a
H-5e
O-CH2-Ph
Ph-H
H-5a
H-3a
CH3 at C-3
C-5
N-CH3
C-3
C-6
O-CH2-Ph
C-2
Ph carbons
OBn ipso carbon
C-2'
C-6'
C=N
/ppm
Table 4 Correlations in
the HSQC and HMBC spectra
of compound 32 (d, ppm)
Signal
Correlations in HSQC Correlations in HMBC
7.31–7.09 (Ph-H)
128.48–127.02
144.23(a), 142.85(a), 138.28(a,b), 77.66(b), 75.47(b),
69.31(b)
5.01 (–O–CH2-Ph)
3.41 (dd, 1H, H-5e)
3.05 (dd, 1H, H-6a)
2.70 (d, 1H, H-2a)
75.47
35.13
69.31
77.66
138.28(a), 128.48–127.02(b)
158.78(a), 43.13(b)
144.23(a), 128.48–127.02(b)
158.78(b), 142.85(a), 128.48–127.02(b), 69.31(b),
41.44(b), 12.62(b)
2.48 (sextet, 1H, H-3a)
2.02 (t, 1H, H-5a)
1.58 (N–CH3)
43.13
35.13
41.44
12.62
158.78(a), 142.85(b), 77.66(a), 12.62(a)
158.78(a), 144.23(b), 69.31(a)
77.66(b), 69.31(b)
a a-Correlation
b b-Correlation
c c-Correlation
0.71 (CH3 at C-3)
158.78(b), 77.66(b), 43.13(a)
13C NMR spectral study of 1,3-dimethyl-2,
6-diarylpiperidin-4-one-O-benzyloximes (33–35)
The lower frequency resonance at 138.28 ppm has good
correlation with the OBn methylene protons signal (a-cor-
relation) and with the Ph protons signal (a-correlation); this
clearly indicates that the signal is ascribed to the OBn ipso
carbon. The higher frequency resonance at 158.78 ppm has
a-correlations with H-3a (2.48 ppm), H-5a (2.01 ppm) and
H-5e (3.41 ppm), and also a strong and weak b-correlation,
respectively, with Me at C-3 (0.71 ppm) and H-2a
(2.70 ppm). Thus, the above correlations clearly explain
that the signal at 158.78 ppm is obviously due to the C=N
carbon. From the multiple bond correlations, the resonances
at 142.85 and 144.23 ppm are respectively designated to the
ipso carbons C-20 and C-60. All the HSQC and HMBC
correlations are listed in Table 4.
All the carbon signals are assigned with respect to 32.
Owing to the introduction of Cl/Me/OMe substituents at C-
20000/C-60000, aryl carbons resonances vary from 32. All the
assignments are summarized in the respective compounds
experimental section.
13C NMR spectral study of 1-methyl-3-ethyl-2,6-
diphenylpiperidin-4-one-O-benzyloxime (36)
The carbon signals are assigned by comparing the corre-
sponding carbon signals in compound 28 with the impact
123

296
P. Parthiban et al.
Effect of oximination
of Me at N-1 and Et at C-3. The replacement of Me by Et
group at C-3 in 24 (i.e., compound 28) deshields the anti a-
carbon C-3 by 6.08 ppm whereas it shields the anti b-
carbon C-5 by 1.74 ppm. In 36, also, due to the decrease in
the electropositive nature of the Et substituent compared
with Me, the C-3 (a-carbon) is deshielded by 7.06 ppm
while the C-2 (b-carbon) is shielded by 1.74 ppm. Hence,
the signals at 67.35, 60.73, 49.45 and 34.36 ppm are
respectively assigned to the C-2, C-6, C-3 and C-5 carbons.
Decrease in electronegativity of a particular group in the
six-membered heterocyclic ring skeleton shields the a-
carbons and deshields the b- and c-carbons [52]. According
to the less polar nature of the C=N than the C=O bond, the
electronegativity of the C=N–OBn group must be less than
that of the C=O group. All the Dd (dN-methylpiperidone
-
d
oxime ether) values for the piperidone ring carbons of the
synthesized compounds 30–32 and 36 are represented in
Table 5. (Due to lack of all the data for parent ketones, we
did not compare the effect for 33–35. However, as the
piperidone carbons chemical shifts of 33–35 are similar to
32, the oximination effect should also be same as 32.)
The a-carbons are shielded and c-carbons are deshielded
according to the expected electronegativity effect on C-4
carbon (electronegativity on C-4 carbon is reduced by
oximination). Not withstanding the decrease in electro-
negativity on C-4, the syn b-carbon is shielded by the
polarization of the C–H(5e) bond. Moreover, the then
polarized C–H(5e) bond causes severe impact on syn a-
carbon over syn b-carbon. Oximination effects on the N-
methylpiperidone oxime ether ring carbons (a and b),
substituent at C-3 (b and c) and ipso carbons (c) are
reported in Table 5.
13C NMR spectral study of 1-methyl-3-isopropyl-2,
6-diphenylpiperidin-4-one-O-benzyloxime (37)
The carbon resonances beyond 126 ppm are assigned by
comparing its analogs 3-Me (32) and 3-Et oxime ethers
(36). There are three signals in the upfield region at 29.08,
21.44 and 18.44 ppm. Of the three signals, the one at
i
29.08 ppm is assigned to the Pr methine carbon as in the
case of its non-NMe analog 29. Similarly, the resonances at
21.44 and 18.44 ppm are designated to Me and Me0 of the
iPr side chain at C-3; both the Me signals are
interchangeable.
Among the signals at 72.64, 67.08, 54.06, 41.93 and
35.27 ppm, the 41.93 ppm carbon resonance is unambig-
uously assigned to the NMe carbon. The remaining four
signals are attributed to the piperidone ring carbons. The
i
a-Effect
effect of the Pr group in place of Me in 32 and also the
effect of N-methylation on the piperidone ring carbons
in 29 have been taken into account for the assignment of
the ring carbons signal in addition to the oximination
effect.
By comparing the chemical shifts of a-carbons (C-3 and
C-5) of the oxime ether with the corresponding piperidones,
the a-effect was analyzed. Due to the diminished electro-
negativity of C=N compared with C=O, the a-carbons are
significantly shielded in oxime ether compared with their
respective N-methyl piperidones. Though the shielding of
a-carbons is in accord with the expected electronegativity
effect, the syn a-carbon is more pronounced than that of
anti a-carbon. This is substantiated by the interaction of the
N–O bond with the syn a C–H(e) bond (Fig. 5). This
interaction induces a polarity in the syn a C–H(e) bond so
that the syn a-equatorial proton (H-5e) acquires a slight
positive charge and the C-5 carbon acquires a slight neg-
ative charge. And, as a consequence, the proton and carbon
are respectively deshielded and shielded.
Introduction of a Me at N-1 in compound 7 (i.e., com-
pound 15) deshields the C-2 and C-6 by 8.16 and
8.37 ppm, respectively. Similarly in 29, the introduction of
a Me at ring nitrogen, respectively deshields the benzylic
carbons C-2 and C-6 by 7.48 and 7.34 ppm. Therefore, the
signals at 72.64 and 67.08 ppm are conveniently assigned
to C-2 and C-6 carbons, respectively. According to N-
methylation, shielding is observed on C-5 and C-3. In 32,
i
due to the replacement of Me by Pr at C-3, the C-3 and
C-5 are shielded by 0.76 and 0.58 ppm when compared to
29. Hence, the signals at 54.06 and 35.27 ppm are
respectively assigned to C-3 and C-5.
Table 5 13C Chemical shift difference between N-methylpiperidone and corresponding oxime ether (dN-methylpiperidone - doxime ether) [Dd, ppm]
Compound
C-2
C-3
C-4
C-5
C-6
C-20
C-60
Me at C-3
30
31
32
36
-0.09
-0.82
-0.48
-0.44
10.04
9.21
7.75
7.50
50.86
49.03
48.70
49.42
16.09
15.12
15.41
15.62
1.23
0.55
1.10
1.30
–
–
–
-1.36
-0.80
-1.16
-1.16
-1.13
-2.38
-
-1.62
-1.24 (–CH2)
Negative sign denotes deshielding
123

Convenient synthesis and NMR spectral studies
297
on the syn b-carbon by the transmittance of the negative
charge outweighs the deshielding produced by the elec-
tronegativity effect. Table 6 sets out the chemical shift
difference between the benzylic protons.
Table 6 Chemical shift differences between piperidone ring protons
of oxime ethers 31–37 (Dd, ppm)
Compound
Dd5e,5a
Dd3a,5a
Dd2a,6a
31
32
33
34
35
36
37
1.27
1.39
1.40
1.37
1.37
1.37
0.60
0.31
0.46
0.08
-0.35
-0.30
-0.31
-0.30
-0.20
-0.02
c-Effect
0.47
0.47
The c-effect is studied by comparing the chemical shifts of
the ipso carbons C-20 and C-60 in N-methylpiperidones with
corresponding oxime ethers. The ipso carbons are de-
shielded in all oxime ethers, with the expected
electronegativity effect. The c-effect magnitude is about
1 ppm for all compounds and the values are reported in
Table 5.
0.45
0.32
-0.19
Negative sign denotes deshielding
The sum of shielding experienced on syn a-carbon is
about 15–16 ppm for all compounds whereas the shielding
experienced on anti a-carbon is only about 7.5–10 ppm.
Particularly in 3-substituted compounds, the shielding of
anti a-carbon is about 7.5 ppm while in the symmetric
ketoximes the shielding magnitude increased to 9–10 ppm.
This variation is solely due to the effect of the alkyl sub-
stituents at the anti a-carbon (C-3).
Owing to the interaction of N–O bond with the syn a C–
H(e) bond, the syn a-equatorial proton (H-5e) gets a slight
positive charge and the C-5 carbon gets a slight negative
charge. Akin to this, H-5e deshielded about 1 ppm and
appeared at around 3.5 ppm in all compounds while the syn
a-axial proton (H-5a) is shielded by the negative charge on
the syn a carbon. The difference between the H-5e and H-
5a is about 1.3 ppm in 31–36 while the difference is con-
siderably decreased in 37. This indicates that the
conformation of the compound deviates from predominant
chair form. The differences between all the a-protons are
represented in Table 6. The differences between the axial
a-protons are about 0.4 ppm, which is in good agreement
with our earlier report on non-NMe analogs [28].
Oximino group effect on alkyl group
According to the electronegativity effect, the observed b-
effect (deshielding) on methyl carbon of 32 (Me at C-3) is
about 1.62 ppm and on methylene carbon (CH2 of Et at C-
3) of 36 is 1.24 ppm. Due to the decrease in electronega-
tivity, the c-effect is also observed on the alkyl group. In
36, the Me carbon of the Et substituent at C-3 is deshielded
by 0.13 ppm.
Effect of N-methyl group on piperidone ring
The introduction of a Me at ring nitrogen of compounds
31–37 causes a significant effect on the benzylic and
methylenic/methinic carbons and their associated protons.
The NMe group gives a better deshielding on the C-2, C-6
carbons and a poor deshielding on the C-3, C-5 carbons
while a little shielding is exerted on the C-4 carbon. As a
consequence, H-2a and H-6a are shielded whereas H-3a
and H-5a are deshielded.
The effect of the introduction of a Me at N-1 of com-
pounds 23–29 (i.e., compounds 31–37) is reported in
Tables 7 and 8, respectively, for the ring carbons of the
piperidone moiety and their associated protons. The
b-Effect
The b-effect can be studied by comparing the chemical
shifts of the b-carbons C-2 and C-6 of the piperidone
oxime ether with corresponding piperidones. In six-mem-
ber heterocycles, a decrease in electronegativity of a group
in the ring deshields b-carbons and shields b-protons [26,
27]. The deshielding of anti b-carbon is in accordance with
the expected electronegativity effect, and the magnitude of
deshielding is less than 1 ppm. The syn b-carbons are
shielded and the shielding magnitude is about 1 ppm for
compounds 30, 32 and 36, but 31 is deshielded by only
0.55 ppm, probably due to the puckering in its conforma-
tion. The reason for the shielding is due to the negative
charge on the syn a-carbon, which is transmitted to a small
extent on the syn b-carbon. Thus, the shielding produced
Table 7 The effect of N-methylation on ring carbons of oxime ethers
31–37 (d, ppm)
Compound C-2
C-3
C-4 C-5
C-6
Me at C-3
31
32
33
34
35
36
37
-8.73 -0.86 1.00 -1.16 -8.67
-8.16
–
0.24 1.37 -0.43 -8.37 -0.71
-8.74 -0.18 0.31 -0.74 -8.82 -0.94
-8.46 -0.02 0.60 -0.63 -8.66 -0.79
-8.53 -0.07 0.57 -0.74 -8.67 -0.93
-8.57 -0.74 0.12 -1.26 -8.62 -0.90 (–CH2)
-7.48 -0.76 0.61 -0.58 -7.34 -1.07 (–CH)
Negative sign denotes deshielding
123

298
P. Parthiban et al.
Table 8 The effect of N-
methylation on ring protons of
oxime ethers 31–37 (d, ppm)
Compound
H-2a
H-3a
H-3e
H-5a
H-5e
0.16
H-6a
Me at C-3
31
32
33
34
35
36
37
0.76
0.71
0.50
0.50
0.56
0.68
0.38
-0.06
-0.08
-0.23
-0.17
-0.21
0.01
0.18
–
-0.08
-0.09
-0.24
-0.27
-0.20
-0.04
-0.45
0.76
0.69
0.52
0.52
0.59
0.67
0.35
–
0.10
-0.02
-0.10
0
0.09
–
-0.04
–
-0.07
–
-0.01
–
0.08
0.11 (–CH2)
-0.05 (–CH)
Negative sign denotes
deshielding
-0.04
–
0.05
oximino carbon (c-position to the NMe) is also shielded
about 0.12 to 1.37 ppm due to N-methylation; the magni-
tude of shielding depends on the substitution at C-3.
NMR spectra are of 5 mm diameter. Electro Spray Mass
Spectra (ESMS) were recorded on an API 3000 series mass
spectrometer while Electron Impact Mass Spectra (EIMS)
were recorded on a mass engine HP 5989 series. Microa-
nalyses were performed on a Heraeus Carlo Erba 1108
CHN analyzer.
Conclusion
All the synthesized oxime ethers (30–37) were charac-
terized by their IR, Mass and NMR studies. All the
spectral studies and elemental analysis reports strongly
confirm the formation of the target compounds. Based on
the observed chemical shifts and coupling constants, the
conformation of the six-member heterocycle and alkyl
substituent at C-3 are proposed. The compounds 30–36
adopt normal chair conformation (31 is not in perfect
chair form; there is a slight puckering observed about the
C(2)–C(3)bond) with equatorial orientation of the sub-
stituents at C-2, C-3 and C-6, whereas 37 contributes a
significant boat conformation along with the chair con-
formation in solution and its population in boat form is
significantly higher than its non-NMe analog 29 [28].
Moreover, the NMR spectral studies clearly reveal that
the unsymmetrical oxime ethers 32–37 are exclusively in
E form. The oximination effect on the piperidone ring
carbons, their attached protons and alkyl substituents are
recorded and are also found to be significant beyond the
c-position. In addition, the effect of N-methylation on the
above is also very significant.
Preparation of 2,6-diarylpiperidin-4-ones (1–7)
All the parent 2,6-diarylpiperidin-4-ones were prepared by
the condensation of respective ketones, aldehydes and
ammonium acetate in warm ethanol in the ratio of 1:2:1.
Preparation of 1-methyl-2,6-diarylpiperidin-4-ones
(8–15)
A mixture of respective 2,6-diarylpiperidin-4-ones 1–7
(0.01 mol), anhydrous potassium carbonate (2 g) and MeI
(0.01 mol) in acetone (30 ml) was refluxed for 3 h.
Removal of acetone by distillation, dilution with water
and treatment with aqueous ammonia afforded corre-
sponding 1-methyl-2,6-diarylpiperidin-4-ones 9–15. 1-
Methyl piperidin-4-one 8 was procured from Fluka and
used as such.
Preparation of 1-methyl-2,6-diarylpiperidin-4-one
oximes (16–22)
1-Methyl-2,6-diarylpiperidin-4-one (1 equiv), sodium ace-
tate trihydrate (3 equiv) and hydroxylamine hydrochloride
(1.2 equiv) were refluxed for minimum 30 min in ethanol.
After completion of the reaction, the mixture was poured
into water and the solid thus obtained was filtered and
recrystallized from ethanol to afford 1-methyl-2,6-diph-
enylpiperidin-4-one oximes.
Experimental
All the reported melting points were taken in open capil-
laries. IR spectra were recorded in a Thermo Nicolet
AVATAR-330 FT-IR spectrophotometer by KBr pellet
technique and only noteworthy absorption levels are listed
in reciprocal centimeters. H and 13C NMR spectra were
1
recorded respectively at 400 and 100.6 MHz on a BRU-
KER AMX 400 spectrometer using CDCl3 as solvent and
Synthesis of 2,6-diarylpiperidin-4-one-O-benzyloximes
(23–29)
1
TMS as internal standard. H-1H COSY, HSQC and HMBC
were recorded on a BRUKER DRX 500 NMR spectrom-
eter with standard parameters using 0.05 M solutions of the
samples prepared in CDCl3. The tubes used for recording
A mixture of 2,6-diarylpiperidin-4-one (1 equiv), O-ben-
zylhydroxylamine hydrochloride (1 equiv) and sodium
acetate trihydrate (3 equiv) in methanol was refluxed until
123

Convenient synthesis and NMR spectral studies
299
(Ph carbons), 74.83 (OCH2), 55.41 (C-2), 54.09 (C-6),
45.41 (N–CH3), 31.01 (C-3), 24.96 (C-5) ppm; MS (ES):
m/z = 219.0 (M ? 1).
completion of the reaction. After completion, water was
added and extracted with ether, dried with anhydrous
sodium sulphate and evaporated.
1-Methyl-2,6-diphenylpiperidin-4-one-O-benzyloxime
(31, C25H26N2O)
Synthesis of 1-methyl-2,6-diarylpiperidin-4-one-O-
benzyloximes (30–37)
Yield: 95%; M.p.: 80 °C; IR (KBr): vꢀ ¼ 3; 061; 3,029,
2,963, 2,912, 2,850, 2,785 (C–H stretching); 1644 (C=N
stretching); 1,601 (C=C stretching-Ph); 1,493, 1,453,
1,423, 1,361, 1,304, 1,262, 1,201, 1,036, 931, 802; 754
(N–O stretching); 698, 618, 509, 466; 1H NMR (400 MHz,
CDCl3): d = 7.37–7.17 (m, Ph-H), 5.01 (s, OCH2), 3.36
(d, H-5e), 3.17 (dd, H-2a), 3.09 (dd, H-6a), 2.40 (m, H-3),
2.09 (t, H-5a), 1.69 (N–CH3) ppm; 13C NMR (100.6 MHz,
CDCl3): d = 156.78 (C-4), 144.20 (C-20), 143.99 (C-60),
138.15 (OBn ipso carbon), 128.67, 128.36, 128.03, 127.70,
127.40, 127.34 (Ph carbons), 75.48 (OCH2), 70.71 (C-2),
69.34 (C-6), 41.27 (C-3, N–CH3), 35.36 (C-5) ppm; MS
(ES): m/z = 371.2 (M ? 1).
Method A: A mixture of ketone (1 equiv), O-benzylhydr-
oxylamine hydrochloride (1 equiv) and sodium acetate
trihydrate (3 equiv) in methanol was refluxed for about 7–
20 h (depending upon the nature of substituents at C-3).
After the completion of reaction, excess of solvent was
removed under reduced pressure then water was added and
extracted with chloroform. The organic layer was dried
over anhydrous sodium sulphate and concentrated in vac-
uum. The residue thus obtained was triturated with diethyl
ether to afford the solid product.
Method B: One equivalent of the respective oxime (16–
22) in DMF was added slowly to a suspension of NaH (1
equiv) in DMF at 0 °C. Then the reaction mixture was
stirred for about half an hour and a solution of benzyl
bromide (1 equiv) in DMF was added. The reaction mix-
ture was stirred at room temperature for about 1–2 days
(depending upon the nature of substituent at C-3). Later,
the reaction mixture was poured into water and extracted
with chloroform. The organic phase was washed with
brine, dried over anhydrous sodium sulphate and concen-
trated in vacuum. The obtained product was purified over
neutral alumina using 5:1 mixture of n-hexane–ethyl ace-
tate as eluent.
1,3-Dimethyl-2,6-diphenylpiperidin-4-one-O-benzyloxime
(32, C26H28N2O)
Yield: 93%; M.p.: 76–77 °C; IR (KBr): vꢀ ¼ 3; 061; 3,029,
2,971, 2,928, 2,871, 2,781 (C–H stretching); 1,639 (C=N
stretching); 1,601 (C=C stretching-Ph); 1,493, 1,453,
1,423, 1,362, 1,308, 1,234, 1,125, 1,045, 1,017, 922,
1
875; 753 (N–O stretching); 699, 619, 554, 508; H NMR
(400 MHz, CDCl3): d = 7.31–7.09 (m, Ph-H), 5.00 (s,
OCH2), 3.41 (dd, H-5e), 3.05 (dd, H-6a), 2.70 (d, H-2a),
2.48 (m, H-3a), 2.02 (t, H-5a), 1.58 (N–CH3), 0.71 (d,
CH3 at C-3) ppm; 13C NMR (100.6 MHz, CDCl3):
d = 158.78 (C-4), 144.23 (C-60), 142.85 (C-20), 138.28
(OBn ipso carbon), 128.48, 128.29, 128.10, 128.04,
127.43, 127.27, 127.15, 127.02 (Ph carbons), 77.66 (C-
2), 75.47 (OCH2), 69.31 (C-6), 43.13 (C-3), 41.44 (N–
CH3), 35.20 (C-5), 12.62 (CH3 at C-3) ppm; MS (EI): m/
z = 384 (M?).
Method C: A mixture of 2,6-diarylpiperidin-4-one-O-
benzyloxime (23–29) (0.001 mol), anhydrous potassium
carbonate (0.2 g) and methyl iodide (0.001 mol) in acetone
(10 ml) was refluxed until the completion of N-methyla-
tion. Then, the excess of solvent was removed and the
residue was washed with water, aqueous ammonia and
again by water. After that, the reaction mass was extracted
with dichloromethane (DCM), dried with anhydrous
sodium sulphate and concentrated. Thus, the obtained N-
methylpiperidone oxime ether was purified by column
chromatography using neutral alumina as adsorbent and n-
hexane–ethyl acetate (2:1) as eluent.
1,3-Dimethyl-2,6-bis(4-chlorophenyl)piperidin-4-one-O-
benzyloxime (33, C26H26N2OCl2)
Yield: 89%; M.p.: 136 °C; IR (KBr): vꢀ ¼ 3; 030; 2,970,
2,930, 2,871, 2,787 (C–H stretching); 1,639 (C=N stretch-
ing); 1,599 (C=C stretching-Ph); 1,485, 1,447, 1,372,
1,299, 1,259, 1,016, 921, 830; 750 (N–O stretching); 699;
1
580 (C–Cl stretching); 509; H NMR (400 MHz, CDCl3):
1-Methylpiperidin-4-one-O-benzyloxime (30, C13H18N2O)
Yield: 96%; Semi-solid; IR (KBr):vꢀ ¼ 3; 062; 3,031, 2,941,
2,847, 2,787, 2,753 (C–H stretching); 1646 (C=N stretch-
ing); 1563 (C=C stretching-Ph); 1,497, 1,456, 1,427, 1,371,
1,328, 1,279, 1,214, 1,134, 1,042, 909, 872, 804; 740 (N–O
stretching); 700, 614, 540, 472; 1H NMR (400 MHz,
CDCl3): d = 7.23–7.16 (m, Ph-H), 4.97 (s, OCH2), 2.55 (t,
H-5), 2.38 (t, H-2), 2.32 (t, H-6), 2.25 (t, H-3), 2.18 (N–
CH3) ppm; 13C NMR (100.6 MHz, CDCl3): d = 156.24
(C-4), 137.73 (OBn ipso carbon), 127.82, 127.45, 127.14
d = 7.35–7.20 (m, Ar–H), 5.09 (s, OCH2), 3.45 (dd, H-5e),
3.13 (dd, H-6a), 2.83 (d, H-2a), 2.51 (m, H-3a), 2.04 (dd,
H-5a), 1.66 (N–CH3), 0.79 (d, CH3 at C-3) ppm; 13C NMR
(100.6 MHz, CDCl3): d = 158.48 (C-4), 142.77 (C-60),
141.45 (C-20), 138.22 (OBn ipso carbon), 133.11 (C-60000),
132.97 (C-20000), 129.51, 128.86, 128.72, 128.55, 128.30,
127.72 (Ar carbons), 76.98 (C-2), 75.70 (OCH2), 68.63 (C-
6), 43.22 (C-3), 41.54 (N–CH3), 35.17 (C-5), 12.57 (CH3 at
C-3) ppm; MS (ES): m/z = 453.2 (M ? 1).
123

300
P. Parthiban et al.
1,3-Dimethyl-2,6-bis(4-methylphenyl)piperidin-4-one-O-
benzyloxime (34, C28H32N2O)
1-Methyl-3-isopropyl-2,6-diphenylpiperidin-4-one-O-ben-
zyloxime (37, C28H32N2O)
Yield: 91%; M.p.: 124 °C; IR (KBr): vꢀ ¼ 3; 027; 2,970,
2,922, 2,868, 2,789 (C–H stretching); 1,646 (C=N stretch-
ing); 1,599 (C=C stretching-Ph); 1,509, 1,457, 1,370,
1,306, 1,259, 1,211, 1,025, 919, 870, 805; 746 (N–O
Yield: 87%; M.p.: 116 °C; IR (KBr): vꢀ ¼ 3; 061; 3,030,
2,959, 2,925, 2,869, 2,786 (C–H stretching); 1,649 (C=N
stretching); 1,559 (C=C stretching-Ph); 1,495, 1,454,
1,364, 1,261, 1,208, 1,021, 946, 916, 803; 752 (N–O
1
1
stretching); 698, 660, 515; H NMR (400 MHz, CDCl3):
stretching); 696, 606, 459; H NMR (400 MHz, CDCl3):
d = 7.39–7.31 (m, Ar–H), 7.19–7.17 (dd, H-20000, H-60000),
5.14 (s, OCH2), 3.53 (dd, H-5e), 3.16 (dd, H-6a), 2.85 (d,
H-2a), 2.63 (m, H-3a), 2.39, 2.37 (p-CH3), 2.16 (t, H-5a),
1.74 (N–CH3), 0.86 (d, CH3 at C-3) ppm; 13C NMR
(100.6 MHz, CDCl3): d = 159.56 (C-4), 141.49 (C-60),
d = 7.51–7.32 (m, Ph-H), 5.17 (s, OCH2), 3.46 (dd, H-6a),
3.44 (d, H-2a), 3.23 (dd, H-5e), 2.63 (dd, H-5a), 2.44 (dd,
H-3a), 1.73 (m, CH of iPr, N–CH3), 1.23 (d, CH3), 1.07 (d,
CH3 ) ppm; 13C NMR (100.6 MHz, CDCl3): d = 157.37
0
(C-4), 144.68 (C-60), 144.31 (C-20), 138.81 (OBn ipso
carbon), 128.67, 128.57, 128.41, 128.22, 127.96, 127.49,
127.14, 126.84 (Ph carbons), 76.45 (OCH2), 72.64 (C-2),
67.08 (C-6), 54.06 (C-3), 41.44 (N–CH3), 35.27 (C-5),
140.03 (C-20), 138.30 (OBn ipso carbon), 136.75 (C-20000
,
C-60000), 129.19, 129.02, 128.12, 128.06, 127.68, 127.50,
113.82 (Ar carbons), 77.48 (C-2), 75.45 (OCH2), 69.13 (C-
6), 43.18 (C-3), 41.43 (N–CH3), 35.31 (C-5), 21.07 (p-
CH3), 12.64 (CH3 at C-3) ppm; MS (ES): m/z = 413.3
(M ? 1).
0
29.08 (CH), 21.44 (CH3), 18.44 (CH3 ) ppm; MS (ES):
m/z = 413.2 (M ? 1).
Compounds 31–37 were synthesized by adopting all the
above three methods while 30 was synthesized by method
A only. The summarized data of all the compounds are
obtained by Method A.
1,3-Dimethyl-2,6-bis(4-methoxyphenyl)piperidin-4-one-O-
benzyloxime (35, C28H32N2O3)
Yield: 90%; M.p.: 112 °C; IR (KBr): vꢀ ¼ 3; 065; 3,000,
2,965, 2,932, 2,835, 2,781 (C–H stretching); 1,645 (C=N
stretching); 1,610 (C=C stretching-Ph); 1,511, 1,456,
1,363, 1,302, 1,248, 1,174, 1,087, 1,035, 923; 751 (N–O
stretching); 694, 619, 544, 461; 1H NMR (400 MHz,
CDCl3): d = 7.36–7.28 (m, Ar–H), 6.89–6.85 (dd, H-2000,
H-6000), 5.09 (s, OCH2), 3.83, 3.79 (p-OCH3), 3.46 (dd, H-
5e), 3.08 (dd, H-6a), 2.78 (d, H-2a), 2.54 (m, H-3a), 2.09
(t, H-5a), 1.67 (N–CH3), 0.79 (d, CH3 at C-3) ppm; 13C
NMR (100.6 MHz, CDCl3): d = 159.62 (C-4), 158.85 (C-
20000, C-60000), 138.38 (OBn ipso carbon), 136.66 (C-60),
135.25 (C-20), 129.96, 129.12, 128.25, 127.61, 113.96,
113.78 (Ar carbons), 77.14 (C-2), 75.54 (OCH2), 68.77
(C-6), 55.24 (p-OCH3), 43.36 (C-3), 41.41 (N–CH3),
35.41 (C-5), 12.72 (CH3 at C-3) ppm; MS (ES): m/
z = 445.3 (M ? 1).
Acknowledgment We are grateful to NMR Research Center, IISc,
Bangalore, for providing all the NMR facilities.
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