Synthesis and stereochemistry of highly crowded N-benzylpiperidones

Article abstract of DOI:10.1016/j.molstruc.2011.10.037

A series of N-benzylated 3,5-diakyl-2,6-diarylpiperidin-4-ones 4-8 were conveniently synthesized in significant yields of 68-88% by N-benzylation of the corresponding 2,6-diaryl-3,5-dimethylpiperidin-4-ones 1-3 using different benzyl bromides. Initially,

Full text of DOI:10.1016/j.molstruc.2011.10.037

Journal of Molecular Structure 1007 (2012) 158–167
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and stereochemistry of highly crowded N-benzylpiperidones
Someshwar D. Dindulkar a, Paramasivam Parthiban b, Vedavati G. Puranik c, Yeon Tae Jeong a,
⇑
a Department of Image Science and Engineering, Pukyong National University, Busan 608 737, Republic of Korea
b Department of Biomedicinal Chemistry, Inje University, Gimhae 621-749, Gyeongnam, Republic of Korea
c Center for Materials Characterization, National Chemical Laboratory, Pune 400 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-benzylated 3,5-diakyl-2,6-diarylpiperidin-4-ones 4–8 were conveniently synthesized in sig-
nificant yields of 68–88% by N-benzylation of the corresponding 2,6-diaryl-3,5-dimethylpiperidin-4-ones
1–3 using different benzyl bromides. Initially, the new piperidone 2,6-bis(4-ethoxyphenyl)-3,5-dim-
ethylpiperidin-4-one 3 was synthesized by the condensation of 1:1:2 M ratio of 3-pentanone, ammonium
acetate and para-ethoxybenzaldehyde in ethanolic medium. All the synthesized new compounds 3–8
were characterized by their analytical and spectral (IR, 1H and 13C NMR) interpretations. The stereochem-
istry of the new piperidone 3 was elucidated as chair conformation with an equatorial orientation of all
substituents, suggested by its vicinal couplings from 1H NMR spectrum. To investigate the impact on pip-
eridone stereochemistry as well as NMR chemical shifts, all the N-benzylated products 4–8 were com-
pared with their corresponding precursors, and as a result, it is clearly established that all the
synthesized N-benzyl piperidones exist in the chair conformation with an equatorial orientation of all
the substituents at C-2, C-3, C-5, C-6 and N. Contrary to the probability all N-benzylated compounds
retain the same conformation and configuration as their precursors, however, a remarkable change on
the chemical shifts are observed. For the further unambiguous confirmation of stereochemistry, the 1-
benzyl-3,5-dimethyl-2,6-diphenylpiperidin-4-one 4 was examined by single-crystal X-ray diffraction.
The compound 4, C26H27NO, crystallized in a P-1 space group under triclinic system with unit cell dimen-
Received 21 September 2011
Received in revised form 18 October 2011
Accepted 18 October 2011
Available online 25 October 2011
Keywords:
Piperidin-4-one
N-benzylation
NMR
Crystal structure
Configuration
Chair conformation
sions a, b, c (Å) and
a, b,
c
(°) of 10.156(2), 11.002(2), 11.348(4) and 116.74(4), 100.81(3), 100.17(3),
respectively.
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
the stereochemistry of the synthesized molecules is a major crite-
rion for their biological activities, it is of immense help to establish
the stereochemistry of the newly synthesized molecules [12–14].
As a strong background of the reports [15–25] on the changes in
ring conformation and biological actions of 2,6-disubstituted pip-
eridones by the introduction of certain hetero-conjugate groups
such as Cl, OH, NO, CH3, CHO, COCH3, COC6H5, and COCH2Cl at
the ring nitrogen prompted to extend our N-benzylation on highly
crowded 3,5-dialkyl-2,6-diarylpiperidin-4-ones to exploit the con-
figurational and conformational changes.
The piperidin-4-one pharmacophore is present in a wide variety
of naturally occurring alkaloids and is responsible for a number of
biological actions such as antibacterial, antifungal, antituberculo-
stic, anticancer, antioxidant, antiinflammatory, neuronal nicotinic
antagonistic activity, CNS stimulant and depressant [1–7]. The di-
verse biological actions are continuously attracting the chemists
to synthesis new piperidone molecules with diversified substitu-
ents to enhance their activities. Thus the syntheses of new mole-
cules are in good practice and more desirable in pharmaceutical
aspects [8–10].
2. Experimental
The literatures of piperidin-4-ones [5–7] reveal that the
introduction an atom or group on the secondary amino group as
well as on both sides of the secondary amino group and active
methylene centers will enhance the biological activity, signifi-
cantly. Hence, in the biological perspectives, we have planned
N-benzylation on some highly crowded 2,6-diarly-3,5-dimethylpi-
peridin-4-ones as a continuation of our previous study [11]. Since
2.1. Materials and methods
The reagents used in the present study were procured from
Aldrich and Alfa Aesar and used directly without further purifica-
tion. Solvents used were of commercial grade and purified prior
to use. The progress of the reactions was monitored by thin layer
chromatography (TLC) on 250 lm silica plates using a mixture of
9:1 n-hexane and ethyl acetate as an eluent. Melting points were
taken in open capillaries and are uncorrected; Sturat melting point
⇑
Corresponding author.
E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.10.037

S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
159
Table 2
apparatus (Barloworld Scientific, UK) was used to determine the
Crystal data and structure refinement of compound 4.
melting points of the synthesized compounds. FT-IR spectra were
recorded on a Varian 1000 FT-IR Scimitar Series spectrophotome-
ter. Analytical data of all the synthesized new compounds are pro-
vided in Table 1.
Parameters
4 (CCDC No. 844629)
C26H27NO
Empirical formula
Molecular weight
Crystal color
Crystal system
Space group
369.49
Colorless
Triclinic
P-1
2.2. Recording of one-dimensional NMR spectra
Temperature (K)
Wavelength k (Å)
Unit cell dimensions (Å, °)
296(2)
0.71073
a = 10.156(2),
1D NMR spectra of all the synthesized compounds were re-
corded on JEOL JNM ECP 400 NMR spectrometer at 294 K. The 1H
and 13C NMR spectra were measured on 0.03 M and 0.05 M solu-
tions, respectively, in CDCl3 with TMS as internal reference in
5 mm NMR tubes. The pulse conditions were as follows: 1H NMR
spectra: SF 399.78 MHz, AQ 2.73 s, NS 32, DS 0, SW 5998.8 Hz,
a
= 116.74(4)
b = 11.002(2), b = 100.81(3)
c = 11.3478(4),
1061.85(12)
c = 100.17(3)
Volume (A3)
Cell formula units Z
2
Calculated density (mg mÀ3
)
1156
0.069
396
Absorption coefficient (mmÀ1
F(000)
)
pulse 4.65 ls, angle 45°, width 9.3 ls, DR 0.366 Hz, RD 5 s, RG
13, data points 16,384, pre scan delay 1 s; 13C NMR spectra: SF
100.52 MHz, AQ 1.25 s, NS 250, DS 4, SW 26178.01 Hz, Pulse
Crystal size (mm)
Theta ranges for data collection
0.38 Â 0.24 Â 0.29
2.11–25.00
(°)
3.13 ls, angle 30°, width 9.4 ls, DR 0.798 Hz, RD 1 s, RG 25, data
points 32,768, pre scan delay 1 s.
Index ranges
À12 6 h 6 11, À13 6 k 6 13,
À13 6 l 6 13
The 1H and 13C chemical shift values are given in d scale (ppm)
and referred to TMS, (13C, via the solvent signal of CHCl3 at
77.16 ppm). Coupling constants ‘‘J’’ are reported in Hz. The expan-
sions 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, qn:
quintet, m: multiplet, unr m: unresolved multiplet, SF: spectrome-
ter frequency, AQ: acquisition time, NS: number of transients, DS:
dummy scans, SW: spectral width, DR: digital resolution, RD:
relaxation delay, RG: receiver gain.
Reflections collected
Independent reflections
Completeness to theta = 25.00°
(%)
9763
3721 [R(int) = 0.0275]
99.7
Max. and min. transmission
Refinement method
Data/restrains/parameters
Goodness of fit on F2
0.9938 and 0.9743
Full-matrix least-squares on F2
3721/0/255
1.046
Final R indices [I > 2
r
(I) ]
R1 = 0.0413, wR2 = 0.1110
R1 = 0.0567, wR2 = 0.1222
0.141 and À0.137
R indices (all data)
Largest diff. peak and hole (e ÅÀ3
)
2.4. Synthesis of 3,5-dialkyl-2,6-diarylpiperidin-4-ones (1–3)
2.3. Recording of single-crystal XRD
All the parent 2,6-diarylpiperidin-4-ones were synthesized by
adopting the literature precedent Noller and Baliah [28] by the
condensation of respective ketones, aldehydes and ammonium
acetate in 1:2:1 M ratio.
The X-ray diffraction quality crystals of 1-benzyl-3,5-di-
methyl-2,6-diphenylpiperidin-4-one
4 were obtained by slow
evaporation from ethanol and the crystal structure was deter-
mined by X-ray diffraction data, which collected on a Bruker
SMART APEX CCD diffractometer [26] using Mo Ka radiation with
fine focus tube with 50 KV and 30 mA. Crystal to detector dis-
tance 6.05 cm, 512 Â 512 pixels/frame, oscillation/frame À0.3°,
maximum detector swing angle = À30.0°, beam center = 260.2
and 252.5, in plane spot width = 1.24, SAINT integration, Quad-
rant data acquisition, total scans = 4, total frames = 2424. All the
data were corrected for Lorentzian, polarization and absorption
effects. SADABS correction applied, SHELX-97 (ShelxTL) [27] was
used for structure solution and full matrix least squares refine-
ment on F2. Hydrogen atoms were included in the refinement
as per the riding model. All the remaining crystal parameters
are represented in Table 2.
2.5. Synthesis of 1-benzyl-3,5-dialkyl-2,6-diarylpiperidin-4-ones
(4–8)
A mixture of respective 3,5-dialkyl-2,6-diarylpiperidin-4-ones
(1–3) (0.01 mol), anhydrous potassium carbonate (0.02 mol,
2.76 g) and benzyl bromide (0.015 mol, 1.78 ml)/para-F benzyl bro-
mide/para-CF3 benzyl bromide in DMF (20 ml) was stirred at room
temperature for 36–48 h. Progress and completion of the reactions
were monitored by TLC. After the completion, an excess of ice-cold
water was added and extracted using dichloromethane. The
organic layer, thus separated was thrice washed with brine
Table 1
Analytical data of compounds 3–8.
Compound Physical appearance
Yield
(%)
M.p
(°C)
IR (cmÀ1
)
3
4
5
6
7
8
White amorphous
powder
Yellow amorphous
powder
53
68
88
85
80
72
106–
108
129–
131
118–
120
140–
142
121–
123
128–
130
3310, 2976, 2930, 2874, 2810, 1701, 1612, 1510, 1452, 1393, 1300, 1240, 1173, 1048, 982, 921, 646, 537
3064, 3023, 2973, 2940, 2889, 2829, 1717, 1606, 1492, 1453, 1354, 1208, 1146, 910, 862, 751, 697, 550
Off-white crystals
3063, 3024, 2951, 2880, 2872, 2805, 1717, 1643, 1497, 1452, 1350, 1261, 1204, 1139, 1090, 1058, 1017, 985,
838, 741, 706, 573
3025, 2976, 2925, 2881, 2814, 1709, 1609, 1511, 1238, 1174, 1115, 1045, 988, 956, 919, 843, 807, 732, 689, 553
Off-white crystals
Off-white crystalline
powder
White crystalline
powder
3025, 2975, 2928, 2884, 2822, 1709, 1609, 1511, 1449. 1389, 1355, 1303, 1238, 1175, 1148, 1115, 1045, 958,
919, 843, 810, 731, 691, 613, 553
3026, 2977, 2935, 2886, 2921, 1709, 1611, 1511, 1477, 1452, 1393, 1330, 1242, 1160, 1101, 1066, 1017, 988,
956, 921, 812, 756, 689, 652, 594, 550

160
S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
O
O
H3C
CH3
H3C
CH3
H
O
O
H
Ethanol
N
H
Warm
R
R
1 - 3
An hyd. K2CO3
DMF
R
R
Br
Stirring / rt
CH3COONH4
O
H3C
CH3
4
R1
5
6
3
2
o
o
1
i
i
m
m
N
o
Compound
R
R1
p
o
p
i
R
m
R
m
1, 4
2, 5
3, 6
7
H
H
H
H
F
CH(CH3)2
o
p
4-OCH2CH3
4-OCH2CH3
m
R1
8
4-OCH2CH3 CF3
4 - 8
Scheme 1. Synthesis of 1-benzyl-2,6-diaryl-3,5-dimethylpiperidin-4-ones 4–8 and their precursors 1–3.
Table 3
The proton chemical shift values of compounds 1–8 (d, ppm) and the coupling constants ‘‘J’’ are given between brackets in Hz.
Compound H-2/H-6
(dd)
H-3/H-5
(sextet)
CH3 at C-3/ NH/ACH2A of Substituent on the phenyl
Aromatic protons
C-5 (d)
N-Bn (s)
1a
2a
3
3.61 [10.24] 2.81–2.74
3.59 [10.24] 2.94–2.85
3.54 [10.24] 2.77–2.69
3.51 [10.24] 2.91–2.84
0.82
2.05 br s (NH)
–
7.43, d [7.3], 4H, o-H of the Ph at C-2/C-6; 7.34–7.22, m, 6H, m/
p-H of the Ph at C-2/C-6
7.35, d [7.8], 4H, o-H of the Ph at C-2/C-6; 7.18, d [8.2], 4H, m-
H of the Ph at C-2/C-6
7.33, d [8.44], 4H, o-H of the Ph at C-2/C-6; 6.85, d [8.80], 4H,
m-H of the Ph at C-2/C-6
7.49, d [7.72], 4H, o-H of the Ph at C-2/C-6; 7.34, t [7.72], 4H,
m-H of the Ph at C-2/C-6; 7.25, m, 2H, p-H of the Ph at C-2/C-
6; 7.08, t [7.08], 3H, m/p-H of N-Bn; 6.80, m, 2H, o-H of N-Bn
7.35, d, [8.08], 4H, o-H of the Ph at C-2/C-6; 7.14, d, [8.04], 4H,
m-H of the Ph at C-2/C-6; 7.04, m, 3H, m/p-H of N-Bn; 6.78, m,
2H, o-H of N-Bn
7.34, d [8.44], 4H, o-H of the Ph at C-2/C-6; 7.07, m, 3H, m/p-H
of N-Bn; 6.84, d [8.80], 4H, m-H of the Ph at C-2/C-6; 6.78, m,
2H, o-H of N-Bn
i
0.84 [6.48] 2.01 br s (NH) 1.23, d [6.84], CH3 of Pr;
i
2.83–2.77, m CH of Pr
0.82 [6.60] 2.60 br s (NH) 4.02, q, CH2 of OEt; 1.40, t
[6.96] CH3 of OEt
4
0.73 [6.56] 3.49
0.72 [6.60] 3.47
0.71 [6.60] 3.48
–
i
5
6
3.43 [10.28] 2.94–2.84
3.41 [10.24] 2.87–2.80
1.23, d, [6.96] CH3 of Pr;
2.92–2.82, m, CH of Pr
i
4.02, q, CH2 of OEt; 1.41, t
[6.96] CH3 of OEt
7
8
3.35 [10.64] 2.89–2.81
3.32 [10.64] 2.97–2.89
0.72 [6.56] 3.45
0.73 [6.60] 3.47
4.02, q, CH2 of OEt; 1.41, t
[6.96] CH3 of OEt
3.96, q, CH2 of OEt; 1.38, t
[6.96] CH3 of OEt
7.31, d [8.40], 4H, o-H of the Ph at C-2/C-6; 6.83, d [8.44], 4H,
m-H of the Ph at C-2/C-6; 6.73, d [6.96], 4H, o/m-H of N-Bn
7.23, t [8.44, 8.80], 6H, o-H of the Ph at C-2/C-6 and m-H of N-
Bn; 6.84, t [8.80, 9.16], 4H, m-H of the Ph at C-2/C-6; 6.74, d
[8.80], 2H, o-H of N-Bn
a
Values are taken from Ref. [34], recorded at 400 MHz in CDCl3.
solution (3 Â 10 mL) and dried over anhydrous Na2SO4. The organ-
ic layer was then concentrated in rota to obtain the crude product,
followed by purification on silica-gel (Merck, 230–400 mesh) using
a mixture of n-hexane and ethyl acetate, afforded the pure
1-benzyl-3,5-dialkyl-2,6-diarylpiperidin-4-ones 4–8 in good yields
68–88%.

S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
161
Table 4
The 13C chemical shift values of compounds 1–8 (d, ppm).
Compound C-2/ C-3/ C-4
C-6 C-5
ACH3 at
C-3/C-5
ACH2A
of N-Bn
Substituents on the phenyl
–
ipso carbons
at C-2/C-6
ipso carbon iPr/OEt bearing
Other phenyl carbons
of N-Bn
ipso carbons
1a
2a
68.87 52.05 211.14 10.57
68.71 52.03 211.65 10.69
–
–
142.04
–
–
–
128.50, 127.94, 127.75
127.71, 126.51,
24.14, CH3 of iPr; 33.89, CH of 139.50
148.55
iPr
3
4
5
6
7
8
68.24 52.07 211.47 10.56
73.49 53.63 210.53 11.48
73.98 54.26 210.95 11.56
73.13 53.63 210.82 11.47
73.71 53.40 210.78 11.48
75.40 55.49 210.60 11.45
–
63.43, CH2 of OEt;
14.87, CH3 of OEt
–
134.07
142.10
139.38
–
158.60
–
128.73, 114.37
51.60
51.28
51.74
51.70
51.38
137.05
137.97
137.67
130.74
143.47
129.69, 128.84, 128.50,
127.71, 127.57, 126.55
129.51, 128.78, 127.45,
126.40, 126.20
129.76, 129.51, 127.47,
126.31, 114. 32
162.57 (F bearing ipso
carbon), 129.79, 114.39
129.92, 128.81 (CF3 bearing
i
24.18, 24.09, CH3 of Pr;
148.22
158.37
158.48
158.60
i
33.87, CH of Pr
63.46, CH2 of OEt; 14.97, CH3 134.06
of OEt
63.55, CH2 of OEt; 14.99, CH3 133.89
of OEt
63.50, CH2 of OEt; 14.93, CH3 133.36
of OEt; 124.10, CF3
ipso carbon), 114.32
a
Values are taken from Ref. [34], recorded at 100.5 MHz in CDCl3.
The 1H and 13C NMR chemical shifts of all the synthesized
N-benzylpiperidones and their precursors are provided in
Tables 3 and 4.
3. Result and discussion
3.1. Synthesis of compounds
The synthetic pathway of piperidones and their N-benzyl deriv-
atives are provided as Scheme 1. The versatility of nuclear
magnetic resonance (NMR) spectroscopy towards the structural
elucidation of organic compounds prompted to utilize for this
study, and particularly, the vicinal coupling constants derived from
the proton NMR are of immense helpful for the conformational and
stereochemical diagnosis [29–32]. Along with the NMR spectral
studies in solution state, the single-crystal XRD analysis was also
performed for the compound 4 to unambiguously establish the
stereochemistry in solid state.
3.2. Analysis of the IR spectrum of compounds 1–8
The strong absorption band around 3300 cmÀ1 in the IR
spectrum is normally assigned to NAH stretching mode of the
secondary amines [32]. For the parent compounds, the band at
3313 cmÀ1 corresponds to the NAH stretching of compound 1
and which appeared at 3310 cmÀ1 for compounds 2 and 3. The ab-
sence of NAH stretching frequency at 3313 cmÀ1 in compound 4,
3310 cmÀ1 in compounds 5–8 clearly confirms the N-benzylation.
Fig. 1. 1H NMR spectrum of 2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one 3.

162
S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
Fig. 2. 13C NMR spectrum of 2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one 3.
Fig. 3. 1H NMR spectrum of 1-benzyl-2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one 6.

S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
163
H
H
H
H
O
H
H
6
H
4
5
H
2
1
3
N
H
R
H
H
H
R
Fig. 4. Stereochemical representation of the N-benzylated piperidin-4-ones and
their precursors.
Fig. 6. Anisotropic displacement representation of the molecule 4 with atoms
represented with 50% probability ellipsoids.
The characteristic vibrational band in the region 1725–
1675 cmÀ1 was reported for the carbonyl functionality [32]. For
all the synthesized compounds, the sharp band in the region
1717–1709 cmÀ1 (for C@O group) supports the piperidin-4-ones
4–8. By the N-benzylation, the carbonyl stretching frequency
shifted about 8–10 cmÀ1 from their non-N-benzyl analogs 1–3;
the C@O of compound 3 is appeared at 1701 cmÀ1 while com-
pounds 1 and 2 appeared at 1710 and 1711 cmÀ1, respectively.
Absorption arising from the aromatic and aliphatic CAH
stretching occurs generally in the region of 3075–2775 cmÀ1. In
compounds 3–8, the bands between 3064 and 2805 cmÀ1 are due
to the aromatic and aliphatic CAH stretchings. The band about
2880 cmÀ1 is assigned to the ACH3 symmetric stretching vibration.
Similarly, the band about 1600 cmÀ1 can be easily assigned to C@C
stretching mode of the phenyl rings. In addition, several other
characteristic bands of 1–8 are also furnished in the Table 1.
3.3. Proton and 13C NMR spectral analysis of compound 3
The 1H NMR spectral signals are assigned based on their posi-
tion, multiplicity and integral values. In general, the aromatic pro-
tons resonate in the downfield region of around 7 ppm due to
magnetic anisotropic effect (ring current effect).
In the 1H NMR spectrum (Fig. 1) of 3,5-dimethyl-2,6-bis(4-eth-
oxyphenyl)piperidin-4-one 3, two doublets are observed around
7 ppm. Of the two doublets, one at 7.33 (4H, d, J = 8.44 Hz) is due
to the ortho protons, they are deshielded by the lone pair of
Fig. 5. 13C NMR spectrum of 1-benzyl-2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one 6.

164
S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
electrons on the nitrogen while the meta protons (ortho to ethoxy
substituents) are shielded by the ortho effect of the ethoxy group
and thus appear in the upfield region of 6.85 ppm (4H, d,
J = 8.80 Hz). The quartet at 4.02 ppm (4H) and the triplet at
1.40 ppm (6H, d, J = 6.96 Hz) are assigned to the ACH2 and ACH3
protons of the ethyl on the para positions of the phenyls at C-2
and C-6 by comparing the resonances of analogous compound [33].
The doublet at 3.54 (2H) and a sextet at 2.77–2.69 ppm (2H) are
assigned to the protons at C-2/C-6 and C-3/C-5, respectively, by
considering analogous piperidones [34]. The vicinal coupling of
the doublet (3J = 10.24 Hz) clearly insist that the coupling occurred
by the axial protons (3Ja,a) and hence suggest the chair conforma-
tion with equatorial orientations of the phenyl and methyl groups.
The 13C NMR spectrum of compound 3 is displayed in Fig. 2. The
signals at 68.24 and 52.03 are assigned to C-2/C-6 and C-3/C-5
carbons, respectively, by comparing analogous piperidones [34].
The upfield signals at 63.43 and 14.87 are designated to the
ACH2 and ACH3 protons of the ethyl on the para positions of the
phenyls at C-2 and C-6 while the downfield signals, 158.60 and
134.07 ppm are assigned to the ipso carbons, and the resonances
at 128.73 and 114.37 ppm are consigned to the carbons meta and
ortho to the ethoxy substituents; the latter are shielded by
15 ppm due the ortho effect of the ethoxy group and thus appear
in the upfield region at 114.37 ppm [33]. Well downfield and up-
field signals 211.47 and 10.56 are allotted to the carbonyl carbon
C-4 and ACH3 at C-3/C-5, respectively.
3.4. Proton and 13C NMR spectral analysis of compounds 4–8
The proton NMR chemical shifts of the N-benzylpiperidones 4–
8 are allocated with the use of their corresponding precursors 1–3.
The representative 1H NMR spectrum of compound 6 (1-benzyl-
2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one) is repro-
duced in Fig. 3.
There is no variation in the resonances of phenyl protons and
the ethoxy substituents on the phenyl by N-benzylation. However,
Fig. 7. The angles between the various phenyl groups of compound 4 is calculated from the mean planes of the phenyl groups: (a) between C1 and C-5 is 42.70°; (b) between
C5 and C20 is 19.00°; (c) between C1 and C20 is 45.71°.

S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
165
a significant variation is observed on H-2/H-6, H-3/H-5 and ACH3
at C-3/C-5 with no variation in the splitting pattern. The doublet
at 3.41 ppm with a vicinal coupling of 10.24 Hz clearly insists that
the N-benzylpiperidone does not alter the conformation as well as
configuration from their non-N-benzyl precursor 3. The singlet at
3.48 ppm (2H) is unambiguously designated the ACH2 of N-Bn
group and the ortho and meta/para protons of its phenyl appear
as unresolved doublets of doublets at 6.78 (2H) and 7.07 ppm
(3H), respectively.
information about the puckering of the piperidone ring
C1AC2AC3AC4AC5AN has been acquired. According to Cremer
and Pople [35], for an ideal chair, the ring puckering parameters
such as total puckering amplitude ‘QT’ and phase angle ‘h’ should
be 0.63 Å and either 0° or 180°. The ‘QT’ and ‘h’ values of compound
4 are 0.5480 Å and 6.53°. Thus the molecule exists in the chair con-
formation with a slight deviation from the ideal chair as witnessed
by the puckering parameters. ORTEP of the compound 4 is shown
in Fig. 6.
Analogous para-F and para-CF3 substituted N-Bn compounds 7
and 8 are assigned according to 6, and compounds 4 and 5 are ana-
lyzed along with their precursors 1 and 2, respectively. The vicinal
coupling constants, chemical shifts and splitting pattern of all the
synthesized new compounds 3–8 suggest that they are exist in
the chair conformation with an equatorial orientation of the sub-
stituents as shown in Fig. 4.
The stereochemistries of the substituents on the heterocycle are
elucidated as follows. The equatorial orientation of the methyl
groups on both the active methylene centers are witnessed by their
torsion angles À175.84(14)° [C18AC2AC3AC-4]/À178.13(13)°
[NAC1AC-2AC18]
and
176.66(13)°
[C2AC3AC-4AC19]/
177.19(12)° [NAC4AC-5AC19]. Similarly, the equatorial orienta-
tions of the phenyl groups on both sides of the tertiary amino
group are established by their torsion angles; they are
The 13C NMR spectrum of compound 6 is reproduced in Fig. 5.
The carbon chemical shifts assignments are made by the compari-
son with its precursor 3 and analogous compounds along with the
effects of methyl and benzyl groups at ring nitrogen. Similarly
other compounds also analyzed and all the piperidone ring carbons
and all substituents carbons are unambiguously characterized and
reproduced in Table 4. Of the para-ethoxypehenyl compounds 6–8,
the carbon chemical shifts of compounds 6 (N-Bn) and 7 (para-F N-
Bn) are very similar, whereas the C-2/C-6 and C-3/C-5 of 8 (para-
CF3 N-Bn) are deshielded about 2 ppm, and a downfield signal of
143.47 ppm is ascribed to the CF3.
3.5. Single-crystal XRD analysis of 1-benzyl-3,5-dimethyl-2,6-
diphenylpiperidin-4-one 4
For further unambiguous witness to the stereochemistry of the
N-benzylated product, a single-crystal X-ray diffraction analysis
has been performed on compound 4, and as a result, the following
Fig. 9. The zigzag chain arrangement of molecules along the c axis is extended by
the weak intermolecular interactions between the H-13 of adjacent molecules. This
short contact distance (2.310 Å) is lesser than the sum of the van der Waals radii.
Fig. 8. The crystal packing is stabilized by
interaction between the C7AH7Á Á ÁO of 2.571 Å.
a
weak intermolecular CAHÁ Á ÁO

166
S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
À174.80(12) [C3AC2AC1AC12] and 174.10(11)° [C3AC4AC5AC6].
The N atom of the piperidone molecule shows the sp3 hybridiza-
tion, which can be evidenced by the angles around that nitrogen
atom. The benzyl group on the nitrogen also adopts an equatorial
disposition to the best plane of the piperidone ring, which is evi-
denced from the torsion angles C20ANAC1AC2 = À179.45(11)°
and C20ANAC5AC4 = À179.39(11)°. Compare to its 3-alkyl analog,
all torsion angles are very closer to 180°. Some other important
torsion angles, bond angles and bond length are listed in the Sup-
plementary material.
The angles between all phenyl groups are schematically repre-
sented in Fig. 7. The phenyl groups at C-2 and C-6 (i.e., on both
sides of the tertiary amino group) are oriented at an angle of
42.70° and the phenyl groups at C-6 and N-Bn also oriented at an
angle of 42.70° as well, whereas the phenyl groups at C-2 and N-
Bn is only 19.00°. Hence, it can be concluded that the N-Bn is ori-
ented towards the phenyl at C-2. For the 3-alkyl analog [11], a sim-
ilar angle of 49.04° was noticed between the phenyls at C-2 and C-
6; but, the benzyl group was oriented towards the C-6 as observed
by the closer angle of 27.35° than 74.63° with the phenyl at C-2.
There are no classical hydrogen bonds observed in this mole-
cule, however it is stabilized by weak intermolecular hydrogen
bonds as shown in Fig. 8 (C7AH7Á Á ÁO = 2.571 Å). In 3-alkyl analog,
the packing was stabilized by C1AH1Á Á ÁO = 2.525 Å, where the H1
is one of the piperidone ring protons cis to the alkyl substituent and
adjacent to the amino group. In this 3,5-dimethyl molecule 4, the
H7 is one of the ortho protons of the phenyl ring, closer to benzyl.
Further, the zigzag crystal packing is observed along the c axis and
is reproduced in Fig. 9.
groups at C-2, C-6 and N-benzyl, all of them retained their precur-
sors’ stereochemistry. The observed vicinal couplings 4–8 are in
good agreement with their precursors; however a slight excess of
‘‘J’’ on compounds 7 and 8 suggest that they are slightly more puck-
ered than other compounds.
The above stereochemistry disclosed by NMR is further sup-
ported by the single-crystal XRD results of compound 4. As evi-
denced by the ring puckering parameters (QT = 0.5480 Å and
h = 6.53°) the compound exists in the chair conformation but devi-
ates from the ideal chair. The stereochemistry of C-2, C-3, C-5 and
C-6 are identified as S, R, S and R, respectively and the molecule is
stabilized by weak intermolecular CHÁ Á ÁO interactions. The com-
plete crystallographic analysis such as asymmetric parameters,
ring puckering parameters, torsion angles, dihedral angles of the
substituents and the angles between the various substituents of
the molecule clearly witnessed its stereochemistry in the solid
state as in solution.
Acknowledgements
This research work was supported by the Industrial Technology
Development Program, which was conducted by the Ministry of
Knowledge Economy of the Korean Government.
Appendix A. Supplementary data
Some important crystallographic data of 4 and the effects on the
chemical shifts by N-benzylation are tabulated for all compounds.
The complete set of structural parameters for 4 (CCDC No. 844629)
in CIF format is available as an Electronic Supplementary Publica-
tion from the Cambridge Crystallographic Data Centre www.ccdc.
cam.ac.uk/conts/retrieving.html.
3.6. The effect of N-benzylation on proton and carbon chemical shifts
The effects on the piperidone ring carbons (C-2, C-3, C-4, C-5
and C-6) and their attached protons (H-2, H-3, H-5 and H-6) as well
as on the methyl substituents at C-3 and C-5 are studied by com-
paring the chemical shifts of N-benzylpiperidones 4–8 with their
non-N-benzyl counterparts 1–3. The effects on proton and carbon
chemical shifts are summarized as Tables and provided in Supple-
mentary material.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2011.10.037.
References
[1] W. Lijinsky, H.W. Taylor, Int. J. Cancer 16 (1975) 318.
[2] N.S. Prostakov, L.A. Gaivoronskaya, Russ. Chem. Rev. 47 (1978) 447.
[3] B.R. Jerom, K.H. Spencer, Eur. Pat. Appl. EP 277794 (1988).
[4] M.J. Schneider, in: S.W. Pelletier (Ed.), Alkaloids: Chemical and Biological
Perspectives, vol. 10, Wiley, New York, 1996, p. 155.
[5] H.I. El-Subbagh, S.M. Abu-Zaid, M.A. Mahran, F.A. Badria, A.M. Alobaid, J. Med.
Chem. 43 (2000) 2915 (and references cited therein).
[6] P. Parthiban, S. Balasubramanian, G. Aridoss, S. Kabilan, Med. Chem. Res. 14
(2005) 523.
The effects on the proton chemical shifts are not remarkable by
N-benzylation. The
a-protons H-2/H-6 are shielded by 0.1–
0.16 ppm, but the 0.13 ppm shielding of 3 is increased to 0.19
and 0.22 by para-F and para-CF3 substituted N-benzyl moieties,
respectively. The b-protons H-3/H-5 are deshielded to a maximum
of 0.12 ppm by para-F N-benzyl group 7 whereas the
(CH3 at C-3 and C-5) are shielded between 0.09 and 0.12 ppm.
c
-protons
[7] P. Parthiban, G. Aridoss, P. Rathika, V. Ramkumar, S. Kabilan, Bioorg. Med.
Chem. Lett. 19 (2009) 2981.
[8] T. Honda, M. Kimura, Org. Lett. 2 (2000) 3925.
[9] H. Takahata, H. Ouchi, M. Ichionose, H. Nemoto, Org. Lett. 4 (2002) 3459.
[10] A.R. Katritzky, W.J. Fan, J. Org. Chem. 55 (1990) 3205 (and references cited
therein).
[11] S.D. Dindulkar, P. Parthiban, V.G. Puranik, Y.T. Jeong, J. Mol. Struct. 990 (2011)
44.
[12] P. Parthiban, V. Subalakshmi, K. Balasubramanian, N. Islam, J.S. Choi, Y.T. Jeong,
Bioorg. Med. Chem. Lett. 21 (2011) 2287.
The effects on the carbon chemical shifts are noteworthy by N-
benzylation, most of
experienced deshielding. Of them, specifically, the
a
, b and
c
carbons to the ring nitrogen are
-carbons C-2/
a
C-6 deshielded to the maximum of 7.16 ppm. Compare to 6
(4.89 ppm), compounds 7 and 8 (5.47 and7.16 ppm) are about 1
and 2 ppm further deshielded by increasing electronegativity of
the F and -CF3 groups, respectively.
[13] P. Parthiban, S. Kabilan, V. Ramkumar, Y.T. Jeong, Bioorg. Med. Chem. Lett. 20
(2010) 6452.
[14] P. Parthiban, P. Rathika, V. Ramkumar, S.M. Son, Y.T. Jeong, Bioorg. Med. Chem.
Lett. 20 (2010) 1642.
[15] P. Parthiban, M. Rani, S. Kabilan, Monatsh. Chem. 140 (2009) 287.
[16] K.D. Berlin, K. Ramalingam, N. Satyamurthy, R. Sivakumar, J. Org. Chem. 44
(1979) 471.
4. Conclusions
The new piperidone 3 and the series of new N-benzylpiperi-
dones 4–8 were unambiguously characterized by their NMR spec-
tra. Accordingly, all N-benzylpiperidones are exist in the chair
conformation with an equatorial orientation of all substituents at
C-2, C-3, C-5 and C-6 as their non-N-benzylated precursors along
with an equatorial disposition of the benzyl/substituted benzyl
group at ring nitrogen. In fact, a significant change in the confor-
mation is not occurred as expected by the N-benzylation of highly
crowded piperidones. Regardless of the substituents on the phenyl
[17] L. Lunazzi, D. Macciantelli, G. Cerioni, J. Org. Chem. 47 (1982) 4579.
[18] T. Ravindran, R. Jeyaraman, R.W. Murray, M.J. Singh, J. Org. Chem. 56 (1991)
4833.
[19] U.P. Senthilkumar, R. Jeyaraman, R.W. Murray, M.J. Singh, J. Org. Chem. 57
(1992) 6006.
[20] K. Pandiarajan, R. Sekar, R. Anantharaman, V. Ramalingam, D. Marko, Indian J.
Chem. 30B (1991) 490.
[21] J. Chakkaravarthy, G. Muthukumaran, K. Pandiarajan, J. Mol. Struct. 889 (2008)
297.
[22] M. Krishnapillay, R. Krishnakumar, A. Nagarajan, G. Jeyaraman, Indian J. Chem.
39B (2000) 419.

S.D. Dindulkar et al. / Journal of Molecular Structure 1007 (2012) 158–167
167
[23] G. Aridoss, S. Balasubramanian, P. Parthiban, S. Kabilan, Spectrochim. Acta Part
A 68 (2007) 1153.
[30] P. Parthiban, S. Balasubramanian, G. Aridoss, S. Kabilan, Spectrochim. Acta Part
A 70 (2008) 11.
[24] R. Ramachandran, P. Parthiban, M. Rani, S. Kabilan, Y.T. Jeong, Acta Crystallogr.
66E (2010) o2284.
[31] E. Breitmaier, Structure Elucidation by NMR in Organic Chemistry: A Practical
Guide, third ed., John Wiley, New York, 2002.
[25] P. Parthiban, R. Pallela, S.-K. Kim, D.H. Park, Y.T. Jeong, Bioorg. Med. Chem. Lett.
21 (2011) 6678.
[32] R.M. Silverstein, F.X. Webster, D.J. Kiemle, Spectrometric Identification of
Organic Compounds, seventh ed., John Wiley, New York, 2005.
[33] D.H. Park, Y.T. Jeong, P. Parthiban, J. Mol. Struct., in press, doi:10.1016/
j.molstruc.2011.08.006.
[34] S.D. Dindulkar, P. Parthiban, Y.T. Jeong, Monatsh. Chem., in press, doi:10.1007/
s00706-011-0576-5.
[26] Bruker, SMART, SAINT, Bruker AXS, Inc., Madison, Wisconsin, USA, 1998.
[27] G.M. Sheldrick, Acta Crystallogr. A64 (2008) 112.
[28] C.R. Noller, V. Baliah, J. Am. Chem. Soc. 70 (1948) 3853.
[29] C.W. Caldwell, A.D. Gauthier, M.N. Grew, Magn. Reson. Chem. 31 (1993)
309.
[35] D. Cremer, J.A. Pople, J. Am. Chem. Soc. 97 (1975) 1354.