BF3·SiO2 is a simple and efficient Lewis acid catalyst for the one-pot synthesis of polyfunctionalized piperidin-4-ones

Article abstract of DOI:10.1007/s00706-011-0576-5

A range of Lewis acid catalysts were used for a series of one-pot multi-component reactions. Of them, silica-supported boron trifluoride (BF ₃·SiO₂) was found to be an effective catalyst for the promotion of the modified Mannich cond

Full text of DOI:10.1007/s00706-011-0576-5

Monatsh Chem (2012) 143:113–118
DOI 10.1007/s00706-011-0576-5
ORIGINAL PAPER
BF3ꢀSiO2 is a simple and efficient Lewis acid catalyst for the one-pot
synthesis of polyfunctionalized piperidin-4-ones
•
Someshwar D. Dindulkar Paramasivam Parthiban
•
Yeon Tae Jeong
Received: 15 March 2011 / Accepted: 12 July 2011 / Published online: 26 August 2011
Ó Springer-Verlag 2011
Abstract A range of Lewis acid catalysts were used for a
series of one-pot multi-component reactions. Of them,
silica-supported boron trifluoride (BF3ꢀSiO2) was found to
be an effective catalyst for the promotion of the modified
Mannich condensation of ketones, aldehydes, and ammo-
nium acetate in 1:2:1 molar ratio to afford 3,5-dialkyl-2,6-
diarylpiperidin-4-ones in high yields of 80–92%. Also this
simple, easily prepared, and reusable catalyst executed the
condensation very effectively in a significantly shorter
reaction duration (about 1–4 h) than the conventional
method, which requires 1 day or more and involves a
tedious work-up procedure. Further, this protocol ensures
the stereospecificity; accordingly, all the synthesized pip-
eridones adopted a chair conformation with an equatorial
orientation of all substituents at C-2, C-3, C-5, and C-6.
spectrum of biological activities, e.g., antibacterial, anti-
fungal, antitubercular, antitumor, antiinflammatory, CNS
stimulant/depressant, sedative, and neuronal nicotinic
antagonistic activity[1–8]. Although this moiety is presentin
countless alkaloids, the synthesis of new piperidones is also
very interesting in the field of medicinal chemistry because
of their potential use in drug development [9–12].
Multi-component reactions (MCRs) are of great impor-
tance in organic synthesis to generate products in a single
synthetic operation [13–15]. Development of new as well
as improvement of known MCRs is an area of considerable
current interest. One such reaction is the synthesis of
diversely substituted piperidones by a three-component
one-pot reaction using ketones, aromatic aldehydes, and
ammonium acetate in 1:2:1 molar ratio (a modified suc-
cessive double Mannich condensation, reported by Noller
and Baliah [16]). Although many authors reported the use
of Lewis acid catalysts for the typical Mannich condensa-
tion [17–21], to the best of our knowledge no catalyst has
been used up to now to improve the yield and reaction
conditions of the modified Mannich reaction, except a
recent report of L-proline-catalyzed synthesis of 2,6-diaryl-
3-methylpiperidin-4-ones using butan-2-one, benzalde-
hydes, and ammonia in 1:2:1 molar ratio with 1 mol of
L-proline as a homogeneous catalyst [22]. Thus, the impor-
tance of the biologically potent piperidone heterocycle urged
us to apply a suitable catalyst to increase the yield and at the
same time to improve the tedious work-up and reaction
conditions.
Keywords Heterogeneous catalysis ꢀ BF3ꢀSiO2 ꢀ
One-pot synthesis ꢀ Mannich bases ꢀ
Polyfunctionalized piperidin-4-ones
Introduction
Diversely substituted derivatives of the piperidin-4-one ring
system are of great importance because of their broad
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0576-5) contains supplementary
material, which is available to authorized users.
S. D. Dindulkar ꢀ Y. T. Jeong (&)
Department of Image Science and Engineering,
Pukyong National University, Busan 608-737, Korea
e-mail: ytjeong@pknu.ac.kr
Results and discussion
P. Parthiban
Department of Biomedicinal Chemistry, Inje University,
Gyeongnam, Gimhae 621-749, Korea
The reaction of butan-2-one (5 mmol), benzaldehyde
(10 mmol), and ammonium acetate (5 mmol) in ethanol
123

114
S. D. Dindulkar et al.
Table 1 Effect of various catalysts on the synthesis of 3-methyl-2,6-diphenylpiperidin-4-one (1)
Entrya
Catalyst (10 mol%)
Temp/°C
Yield/%b
Time/h
1
No catalyst
60
60
60
60
60
60
40
50
60
70
60
60
60
60
42
45
70
43
65
85
47
76
92
90
50
93
87
81
24
1
2
I2
3
HBF4
1
4
H3BO3
1
5
H2SO4ꢀSiO2
1
6
BF3ꢀEt2O
1
7
BF3ꢀSiO2
1
8
BF3ꢀSiO2
1
9
BF3ꢀSiO2
1
10
11
12
13
14
a
BF3ꢀSiO2
1
BF3ꢀSiO2 solvent free
BF3ꢀSiO2 (20 mol%)
BF3ꢀSiO2 (10 mol%), 2nd run
BF3ꢀSiO2 (10 mol%), 3rd run
12
1
1
1
Reaction conditions: benzaldehyde (10 mmol), butan-2-one (5 mmol), ammonium acetate (5 mmol), catalyst (10 mol%) in 15 cm3 of distilled
ethanol
b
Isolated yield
was considered as the model reaction. This afforded
(2a,3b,6a)-2,6-diaryl-3-methylpiperidin-4-one in only 42%
yield after 24 h (Table 1, entry 1) and involved a tedious
work-up procedure, including the conversion of the product
to its hydrochloride salt, performed according to the litera-
ture [16, 23]. Hence, we used a range of Lewis acid catalysts,
viz., molecular iodine, HBF4, H3BO3, H2SO4ꢀSiO2, and
BF3ꢀEt2O, to find an effective catalyst to promote this multi-
component one-pot Mannich condensation (Table 1).
of the reactants to the catalyst’s active sites is probably the
main reason for the improvement in the yield compared to
BF3ꢀEt2O. Moreover, BF3ꢀSiO2 does not require special
precautions for the preparation or handling and it can be
stored at ambient temperature for months without losing its
catalytic efficiency [24].
We aimed to further optimize the reaction by changing
the temperature; accordingly, the model reaction was also
performed at 40, 50, and 70 °C with constant stirring in
ethanolic medium, but no improvement in the yield was
observed above 60 °C. Furthermore, in an attempt to
optimize the catalyst, we used 20 mol% of BF3ꢀSiO2 at
60 °C for 1 h, which afforded 93%; however, this
improvement was not significant given that double the
quantity of catalyst was used.
Table 1 shows that the reaction afforded piperidin-4-one
1 in only 43–70% yield in the presence of Lewis acid
catalysts such as molecular iodine, HBF4, H3BO3, and
H2SO4ꢀSiO2 at 60 °C. However, the use of BF3ꢀEt2O
afforded piperidin-4-one 1 in 85% yield at 60 °C in 1 h, but
the product was sticky in nature. To get rid of the unnec-
essary purification process of this sticky product and also
with the expectation of further improving the yield, we
performed the model reaction with BF3ꢀSiO2 as a hetero-
geneous catalyst. As a result, 10 mol% of BF3ꢀSiO2 at
60 °C afforded a high yield of 92% in just 1 h, but no
improvement beyond this. The more efficient accessibility
A complete analysis of Table 1 suggests that 10 mol%
of BF3ꢀSiO2 (37% w/w) at 60 °C (entry 9) is an excellent
protocol for this modified Mannich condensation to afford
the polyfunctionalized piperidin-4-ones.
We also studied the reusability of the BF3ꢀSiO2 catalyst
for at least two more cycles. Accordingly, after the first run
123

BF3ꢀSiO2 is a simple and efficient catalyst
115
Scheme 1
O
+
R2
O
R1
O
O
H
R
H
R2
R1
BF3.SiO2 (10 mol%)
Ethanol, 60 °C
4
5
6
3
2
2'a
2'd
6'a
6'd
1
6'
2'
6'b
6'c
2'b
2'c
N
H
6'e
2'e
R
+
R
R
NH4OAc
1-15
R = H, Me, OMe, Br, Cl, i-Pr, OEt
R1 = Me, Et, i-Pr
R2 = H, Me
with 92% yield, the recovered catalyst was washed, dried,
and used for a second and third time. Yields of 87 and 81%,
respectively, were obtained, thus proving the catalyst’s
reusability.
(Scheme 1). The yields obtained by this protocol along
with the relevant literature are summarized in Table 2. The
physical appearance, melting point, 1H NMR, and 13C
NMR data of the known compounds were in good agree-
ment with those in the literature. All new compounds were
completely characterized by their analytical and spectral
data. On the basis of their NMR analysis, all fifteen com-
pounds exist in a chair conformation with an equatorial
orientation of the substituents at C-2, C-3, C-5, and C-6.
To generalize the above protocol, we extended the
synthesis to a variety of five known piperidones (1, 2, 6, 12,
and 14) and ten new piperidones using electron-donating
methoxy, ethoxy, and isopropyl as well as electron-with-
drawing bromo- and chloro-substituted benzaldehydes
Table 2 BF3ꢀSiO2-catalyzed synthesis of 3,5-dialkyl-2,6-diarylpiperidin-4-ones 1–15
Comp.
R
R1
R2
Yield/%
Yieldc/%
Yieldd/%
Yielde/%
Timef/h
M.p./°C (Lit. m.p.)
1
H
CH3
H
40a, 30b
75
66
–
42
40
27
15
–
92
91
88
89
82
91
87
89
92
84
85
90
88
81
80
1
3
4
2
3
1
2
3
1
2
4
2
3
1
2
86–88 (86–87 [16])
138–140 (137 [22])
96–98
2
4-OCH3
3-OCH3
4-CH(CH3)2
4-Br
CH3
H
–
3
CH3
H
–
4
CH3
H
–
–
103–105
5
CH3
H
–
–
114–116
6
H
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH(CH3)2
CH(CH3)2
CH3
H
–
–
41
14
12
45
–
109–111
7
4-CH(CH3)2
4-OCH2CH3
4-Cl
H
–
–
52–54
8
H
–
–
Semi-solid
112–114
9
H
–
–
10
11
12
13
14
15
a
4-Br
H
–
–
99–101
3-OCH3
H
H
–
20a
–
–
78–80
H
78
–
–
126–128 (125–126 [16])
102–104
4-Br
H
–
–
H
CH3
CH3
75a, 44b
–
–
133–135 (131–133 [16])
78–80
4-CH(CH3)2
CH3
–
–
30
Literature yield by conventional method [16]
Literature yield by conventional method [25]
Literature yield using L-proline (30 mol%) [22]
Isolated yield by conventional method [23]
b
c
d
e
f
Isolated yield using BF3ꢀSiO2 (10 mol%) according to this study
Reaction duration of the present study
123

116
S. D. Dindulkar et al.
General procedure for the synthesis of 3,5-dialkyl-2,6-
diarylpiperidin-4-ones 1–15
Conclusion
A range of Lewis acid catalysts, viz., I2, HBF4, H3BO3,
H2SO4ꢀSiO2, BF3ꢀEt2O, and BF3ꢀSiO2, were applied for
the multi-component one-pot synthesis of Mannich bases
by a modified Mannich condensation. The use of
10 mol% BF3ꢀSiO2 (37% w/w) at 60 °C was found to be
a simple and straightforward protocol for the synthesis of
polyfunctionalized piperidin-4-ones using three compo-
nents, viz., benzaldehydes substituted with electron-
withdrawing/donating groups, butan-2-one/pentan-2-one/
pentan-3-one/4-methylpentan-2-one, and ammonium ace-
tate in 2:1:1 molar ratio. Higher yields, very short
reaction duration, avoidance of tedious work-up proce-
dures, operational simplicity, and effective reusability of
the catalyst are some of the advantages of this protocol.
In particular, all reactions carried out by this protocol
afforded piperidones in 80–92% yield as a single isomer
with an equatorial orientation of all substituents in the
chair conformation.
Benzaldehyde (4 mmol), ammonium acetate (2 mmol),
ketone (2 mmol), and 10 mol% of BF3ꢀSiO2 (37% w/w) in
15 cm3 of distilled ethanol were mixed in a round-bottom
flask and heated to 60 °C for 1–4 h (Table 1). The progress
of the reaction was monitored by TLC. After completion of
the reaction, the mixture was cooled to room temperature,
and the catalyst was removed by filtration. After evapora-
tion of the solvent, the oily residue or impure solid
obtained was washed with excess water. The solid was then
1
crystallized from ethanol. The complete H and 13C spec-
troscopic data of all new compounds are reported here; the
data of the known compounds 1, 2, 6, 12, and 14 are
provided in the Electronic Supplementary Material.
(2a,3b,6a)-2,6-Bis(3-methoxyphenyl)-3-methylpiperidin-4-
one (3, C20H23NO3)
White solid, m.p.: 96–98 °C; 1H NMR (400 MHz, CDCl3):
d = 7.21–7.15 (m, 2H, H-20d/60d), 6.97–6.94 (m, 4H,
H-20a/60a, H-20e/60e), 6.78–6.72 (m, 2H, H-20c/60c), 3.98
(dd, J = 3.1, 11.5 Hz, H-6a), 3.75 (s, OCH3), 3.73 (s,
OCH3), 3.50 (d, J = 10.2 Hz, H-2a), 2.66–2.51 (m, H-3a,
H-5a, H-5e), 2.03 (br s, NH), 0.76 (d, J = 6.5 Hz, CH3 at
C-3) ppm; 13C NMR (100.52 MHz, CDCl3): d = 209.69
(C-4), 159.86, 159.79 (C-20b/60b), 144.53, 143.58 (C-20/60),
129.76, 129.56, 129.56 (C-20d/60d), 120.27, 118.87 (C-20e/
60e), 113.45, 113.11, 112.96, 112.30 (C-20a/60a), 68.39
(C-2), 61.53 (C-6), 55.32 (OCH3), 51.77 (C-3), 51.02
(C-5), 10.29 (CH3 at C-3) ppm.
Experimental
All reagents were obtained from Aldrich and Alfa Aesar
and were used directly without further purification. The
progress of the reactions was monitored by thin-layer
chromatography (TLC) on 250-lm silica plates using a 9:1
1
n-hexane/ethyl acetate mixture as the eluent. All H and
13C NMR spectra of the synthesized compounds were
recorded on a Jeol JNM ECP 400 NMR spectrometer at
294 K. The 1H and 13C NMR spectra were measured using
0.03 and 0.05 M solutions, respectively, in CDCl3 with
(2a,3b,6a)-2,6-Bis(4-isopropylphenyl)-3-methylpiperidin-
4-one (4, C24H31NO)
White crystalline solid, m.p.: 103–105 °C; 1H NMR
(400 MHz, CDCl3): d = 7.36 (dd, J = 2.5, 8 Hz, 4H,
H-20a/20e, H-60a/60e), 7.19 (dd, J = 4.2, 8.2 Hz, 4H, H-20b/
20d, H-60b/60d), 4.05 (dd, J = 2.9, 11.7 Hz, H-6a), 3.58 (d,
J = 10.6 Hz, H-2a), 2.94–2.84 (m, CH of i-Pr), 2.77–2.59
(m, H-3a, H-5a, H-5e), 2.06 (br s, NH), 1.24 (d,
J = 5.6 Hz, CH3 of i-Pr), 1.22 (d, J = 5.6 Hz, CH3 of
i-Pr), 0.83 (d, J = 6.6 Hz, CH3 at C-3) ppm; 13C NMR
(100.52 MHz, CDCl3): d = 210.21 (C-4), 148.70, 148.56
(C-20c/60c), 140.29, 139.42 (C-20/60), 127.75 (C-20a/20e,
C-60a/60e), 126.74, 126.62 (C-20b/20d, C-60b/60d), 68.36
(C-2), 61.46 (C-6), 51.78 (C-3), 50.94 (C-5), 33.91 (CH of
i-Pr), 24.12, 24.08 (CH3 of i-Pr), 10.38 (CH3 at C-3) ppm.
1
TMS as internal reference in 5-mm NMR tubes. The H
and 13C chemical shift values are given in d (ppm) and
referenced to TMS (in the 13C spectra via the solvent signal
of CHCl3 at 77.16 ppm). Coupling constants J are reported
in hertz. IR and HR-MS were recorded on Perkin-Elmer
Spectrum GX FT-IR spectrometer and Jeol JMS-700 mass
spectrometer, respectively. All melting points were deter-
mined using open capillaries on an Electrothermal-9100
(Japan) instrument.
Preparation of silica-supported BF3
A mixture of 5 cm3 methanol containing 0.6 g (4.2 mmol)
BF3ꢀOEt2 and 0.4 g of non-preheated silica gel was stirred
for about 1 h at room temperature. The slurry was then
dried slowly on a rotary evaporator at 40 °C. The obtained
solid was dried at ambient temperature for 2 h and then
used for this study.
(2a,3b,6a)-2,6-Bis(4-bromophenyl)-3-methylpiperidin-4-
one (5, C18H17Br2NO)
White solid, m.p.: 114–116 °C; 1H NMR (400 MHz,
CDCl3): d = 7.47 (t, J = 8.8 Hz, 4H, H-20a/20e, H-60a/
123

BF3ꢀSiO2 is a simple and efficient catalyst
117
60e), 7.33 (dd, J = 6.7, 8.4 Hz, 4H, H-20b/20d, H-60b/60d),
4.04 (dd, J = 3.2, 11.3 Hz, H-6a), 3.58 (d, J = 10.2 Hz,
H-2a), 2.68–2.55 (m, H-3a, H-5a, H-5e), 2.08 (br s, NH),
0.81 (d, J = 6.9 Hz, CH3 at C-3) ppm; 13C NMR
(100.52 MHz, CDCl3): d = 208.53 (C-4), 141.60, 140.73
(C-20/60), 132.35, 131.74, 131.66 (C-20b/20d, C-60b/60d),
130.93, 129.39, 128.23 (C-20a/20e, C-60a/60e), 67.55 (C-2),
60.78 (C-6), 51.46 (C-3), 50.64 (C-5), 10.09 (CH3 at C-3)
(100.52 MHz, CDCl3): d = 208.32 (C-4), 141.22, 140.33
(C-20/60), 133.79, 133.56 (C-20c/60c), 129.26, 128.92,
128.87, 127.96 (remaining phenyl carbons), 66.00 (C-2),
61.10 (C-6), 58.45 (C-3), 51.52 (C-5), 17.90 (CH2 of Et at
C-3), 12.31 (CH3 of Et at C-3) ppm.
(2a,3b,6a)-2,6-Bis(4-bromophenyl)-3-ethylpiperidin-4-one
(10, C19H19Br2NO)
Pale yellow powder, m.p.: 99–101 °C; 1H NMR
(400 MHz, CDCl3): d = 7.49 (d, J = 8.4 Hz, 2H, H-60a/
60e), 7.46 (d, J = 8.4 Hz, 2H, H-20a/20e), 7.34 (d,
J = 8.4 Hz, 2H, H-60b/60d), 7.31 (d, J = 8.4 Hz, 2H, H-
20b/20d), 4.03 (dd, J = 4.2, 10.8 Hz, H-6a), 3.69 (d,
J = 9.8 Hz, H-2a), 2.65–2.41 (m, H-3a, H-5a, H-5e),
2.01 (br s, NH), 1.62–1.49 (m, CH of Et at C-3), 1.16–1.07
(m, CH0 of Et at C-3), 0.76 (t, J = 7.5 Hz, CH3 of Et at C-
3) ppm; 13C NMR (100.52 MHz, CDCl3): d = 208.01 (C-
4), 141.56, 140.67 (C-20/60), 134.86, 132.25, 131.63,
131.59 (C-20b/20d, C-60b/60d), 130.83, 129.58, 128.17 (C-
20a/20e, C-60a/60e), 67.76 (C-2), 60.87 (C-6), 58.08 (C-3),
51.17 (C-5), 17.73 (CH2 of Et at C-3), 12.15 (CH3 of Et at
ꢀ
ppm; IR (KBr): m = 3,323 (N–H stretching), 3,048, 3,029,
2,994, 2,971, 2,962, 2,935, 2,905, 2,875, 2,825, 2,808 (C–H
stretching), 1,708 (C=O stretching), 1,590 (C=C stretching-
Ph) cm-1; HRMS: m/z calcd 420.97, found 420.96.
(2a,3b,6a)-3-Ethyl-2,6-bis(4-isopropylphenyl) piperidin-4-
one (7, C25H33NO)
White solid, m.p.: 52–54 °C; 1H NMR (400 MHz, CDCl3):
d = 7.35 (t, J = 7.0 Hz, 4H, H-20a/20e, H-60a/60e), 7.19 (t,
J = 7.1 Hz, 4H, H-20b/20d, H-60b/60d), 4.03 (dd, J = 2.4,
11.6 Hz, H-6a), 3.72 (d, J = 9.9 Hz, H-2a), 2.95–2.84 (m,
CH of i-Pr), 2.74 (t, J = 12.4 Hz, H-3a), 2.61–2.57 (m, H-
5a, H-5e), 1.92 (br s, NH), 1.60–1.49 (m, CH of Et at C-3),
1.23 (t, J = 7.1 Hz, CH3 of i-Pr), 1.18–1.12 (m, CH0 of Et
at C-3), 0.79 (t, J = 7.1 Hz, CH3 of Et at C-3) ppm; 13C
NMR (100.52 MHz, CDCl3): d = 209.99 (C-4), 148.63,
148.50 (C-20c/60c), 140.18, 139.27 (C-20/60), 127.79 (C-20a/
20e, C-60a/60e), 126.68, 126.59 (C-20b/20d, C-60b/60d), 66.60
(C-2), 61.63 (C-6), 58.46 (C-3), 51.51 (C-5), 33.86 (CH of
i-Pr), 24.09 (CH3 of i-Pr), 18.03 (CH2 of Et at C-3), 12.32
(CH3 of Et at C-3) ppm.
ꢀ
C-3) ppm; IR (KBr): m = 3,322 (N–H stretching), 3,058,
2,963, 2,930, 2,859, 2,805, 2,778 (C–H stretching), 1,706
(C=O stretching), 1,588, 1,573 (C=C stretching-Ph) cm-1
;
HRMS: m/z calcd 437.98, found 437.98.
(2a,3b,6a)-3-Ethyl-2,6-bis(4-methoxyphenyl)piperidin-4-
one (11, C21H25NO3)
White solid, m.p.: 78–80 °C; 1H NMR (400 MHz, CDCl3):
d = 7.24–7.23 (m, 2H, H-20d/60d), 7.04–7.01 (m, 4H,
H-20a/60a, H-20e/60e), 6.82–6.81 (m, 2H, H-20c/60c), 4.02
(dd, J = 3.0, 11.6 Hz, H-6a), 3.82 (s, OCH3), 3.79 (s,
OCH3), 3.67 (d, J = 10.2 Hz, H-2a), 2.69 (t, J = 12.1 Hz,
H-3a), 2.60–2.53 (m, H-5a, H-5e), 2.03 (br s, NH),
1.61–1.50 (m, CH of Et at C-3), 1.18–1.11 (m, CH0 of Et
at C-3), 0.77 (t, J = 7.3 Hz, CH3 of Et at C-3) ppm; 13C
NMR (100.52 MHz, CDCl3): d = 208.94 (C-4), 159.72,
159.66 (C-20b/60b), 144.65, 144.42 (C-20/60), 129.56,
129.40 (C-20d/60d), 120.21, 118.71 (C-20e/60e), 112.93,
112.80, 112.81 (C-20a/60a), 66.56 (C-2), 61.57 (C-6), 58.34
(C-3), 51.46 (C-5), 17.86 (CH2 of Et at C-3), 12.23 (CH3 of
(2a,3b,6a)-2,6-Bis(4-ethoxyphenyl)-3-ethylpiperidin-4-one
(8, C23H29NO3)
1
White semi-solid; H NMR (400 MHz, CDCl3): d = 7.34
(t, J = 7.8 Hz, 4H, H-20a/20e, H-60a/60e), 6.86 (t,
J = 8.4 Hz, 4H, H-20b/20d, H-60b/60d), 4.03–3.97 (m, H-
6a and CH2 of OEt), 3.64 (d, J = 10.2 Hz, H-2a), 2.69 (t,
J = 12.1 Hz, H-3a), 2.57–2.51 (m, H-5a, H-5e), 1.98 (br s,
NH), 1.60–1.49 (m, CH of Et), 1.40 (q, J = 6.7 Hz, CH3 of
OEt), 1.17–1.09 (m, CH0 of Et), 0.77 (t, J = 7.3 Hz, CH3
of Et at C-3) ppm; 13C NMR (100.52 MHz, CDCl3):
d = 209.80 (C-4), 158.66, 158.53 (C-20c/60c), 135.03,
134.09 (C-20/60), 128.92, 127.71 (C-20a/20e, C-60a/60e),
114.54 (C-20b/20d, C-60b/60d), 66.28 (C-2), 63.49 (CH2 of
OEt), 61.28 (C-6), 58.77 (C-3), 51.84 (C-5), 18.00 (CH2 of
Et), 14.95 (CH3 of OEt), 12.42 (CH3 of Et at C-3) ppm.
ꢀ
Et at C-3) ppm; IR (KBr): m = 3,310 (N–H stretching),
3,053, 2,962, 2,937, 2,876, 2,836 (C–H stretching), 1,709
(C=O stretching), 1,601, 1,587 (C=C stretching-Ph) cm-1
;
HRMS: m/z calcd 339.18, found 339.18.
(2a,3b,6a)-2,6-Bis(4-chlorophenyl)-3-ethylpiperidin-4-one
(9, C19H19Cl2NO)
(2a,3b,6a)-2,6-Bis(4-bromophenyl)-3-isopropylpiperidin-
4-one (13, C20H21Br2NO)
White solid, m.p.: 112–114 °C; 1H NMR (400 MHz,
CDCl3): d = 7.41–7.29 (m, 8H, Ph), 4.04 (dd, J = 3.1,
11.5 Hz, H-6a), 3.70 (d, J = 10.6 Hz, H-2a), 2.66 (t,
J = 12.0 Hz, H-3a), 2.58–2.48 (m, H-5a, H-5e), 2.01 (br s,
NH), 1.60–1.49 (m, CH of Et), 1.14–1.08 (m, CH0 of Et),
0.77 (t, J = 7.5 Hz, CH3 of Et at C-3) ppm; 13C NMR
White powder, m.p.: 102–104 °C; 1H NMR (400 MHz,
CDCl3): d = 7.56–7.30 (m, 8H, Ph), 4.08 (dd, J = 3.2,
11.1 Hz, H-6a), 3.99 (d, J = 10.7 Hz, H-2a), 2.65–2.52
(m, H-3a, H-5a, H-5e), 1.99 (br s, NH), 1.68–1.63 (m, CH
of i-Pr at C-3), 1.01 (d, J = 6.4 Hz, CH3 of i-Pr at C-3),
0.91 (d, J = 7.2 Hz, CH3 of i-Pr at C-3) ppm; 13C NMR
0
123

118
S. D. Dindulkar et al.
2. Parthiban P, Balasubramanian S, Aridoss G, Kabilan S (2005)
Med Chem Res 14:523
3. Aridoss G, Parthiban P, Ramachandran R, Prakash M, Kabilan S,
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83:379
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4:3459
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(100.52 MHz, CDCl3): d = 207.75 (C-4), 141.73, 141.03
(C-20/60), 131.13, 129.63, 129.56, 128.23 (remaining
phenyl carbons), 63.87 (C-2), 60.94 (C-6), 60.43 (C-3),
51.75 (C-5), 25.88 (CH of i-Pr at C-3), 20.97 (CH3 of i-Pr
0
at C-3), 17.67 (CH3 of i-Pr at C-3) ppm; IR (KBr):
ꢀ
m = 3,310 (N–H stretching), 3,044, 2,992, 2,958, 2,873
(C–H stretching), 1,712 (C=O stretching), 1,610 (C=C
stretching-Ph) cm-1; HRMS: m/z calcd 449.00, found 448.99.
(2a,3b,5b,6a)-2,6-Bis(4-isopropylphenyl)-3,5-dimethyl-
piperidin-4-one (15, C25H33NO)
White amorphous powder, m.p.: 78–80 °C; 1H NMR
(400 MHz,CDCl3): d = 7.35 (d, J = 7.8 Hz, 4H, H-20a/
60a, H-20e/60e), 7.18 (d, J = 8.2, Hz, 4H, H-20b/60b, H-20d/
60d), 3.59 (d, J = 10.2 Hz, H-2a, H-6a), 2.94–2.85 (m, H-
3a, H-5a), 2.83–2.77 (m, CH of i-Pr), 2.01 (br s, NH), 1.23
(d, J = 6.8 Hz, CH3 of i-Pr), 0.84 (d, J = 6.4 Hz, CH3 at
C-3 and C-5) ppm; 13C NMR (100.52 MHz, CDCl3):
d = 211.65 (C-4), 148.55 (C-20c/60c), 139.50 (C-20/60),
127.71 (C-20a/20e, C-60a/60e), 126.51 (C-20b/20d, C-60b/60d),
68.71 (C-2, C-6), 52.03 (C-3, C-5), 33.89 (CH of i-Pr),
24.14 (CH3 of i-Pr), 10.69 (CH3 at C-3 and C-5) ppm; IR
15. Bora U, Saikia A, Boruah RC (2003) Org Lett 5:435
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Org Chem 1397
18. Xu Q, Yang Z, Yin D, Wang J (2006) Front Chem Eng China
3:201
ꢀ
(KBr): m = 3,310 (N–H stretching), 3,053, 3,017, 2,964,
19. Wang M, Song Z-G, Wan X, Zhao S (2009) Monatsh Chem
140:1205
20. Bigdeli MA, Nemati F, Mahdavinia GH (2007) Tetrahedron Lett
48:6801
2,932, 2,893, 2,871, 2,812 (C–H stretching), 1,711 (C=O
stretching), 1,671 (C=C stretching-Ph) cm-1; HRMS: m/
z calcd 363.26, found 363.25.
21. Yadav JS, Reddy BVS, Shankar KS, Premalatha K, Swamy T
(2008) Lett Org Chem 5:353
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Struct 990:44
Acknowledgments This research work was supported by the
Industrial Technology Development Program, which was conducted
by the Ministry of Knowledge Economy of the Korean Government.
24. Klapotke TM, McMonagle F, Spence RR, Winfield JM (2006)
J Fluorine Chem 127:1446
25. Vatsadze SZ, Karinova Yu V, Kovalkina MA, Zyk NV (2000)
Chem Heterocycl Comp 36:1185
References
1. Parthiban P, Aridoss G, Rathika P, Ramkumar V, Kabilan S
(2009) Bioorg Med Chem Lett 19:2981
123