One-pot multicomponent synthesis of highly substituted piperidines using p-toluenesulfonic acid monohydrate as catalyst

Article abstract of DOI:10.1007/s00706-011-0671-7

β-Toluenesulfonic acid monohydrate (p-TsOH-H₂O) is a highly effective and efficient catalyst for the one-pot multicomponent coupling of aldehydes, amines, and β-ketoesters in EtOH at ambient temperature to give highly functionalized piperidines in high yields. This one-pot reaction has some important advantages such as the easy workup procedure, simple and readily available precursors, nontoxic and inexpensive catalyst, and good to high yields. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0671-7

Monatsh Chem (2012) 143:939–945
DOI 10.1007/s00706-011-0671-7
ORIGINAL PAPER
One-pot multicomponent synthesis of highly substituted
piperidines using p-toluenesulfonic acid monohydrate as catalyst
•
Seyed Sajad Sajadikhah Malek Taher Maghsoodlou
•
•
•
Nourallah Hazeri Sayyed Mostafa Habibi-Khorassani
Sayyed Jalal Shams-Najafi
Received: 24 June 2011 / Accepted: 4 October 2011 / Published online: 18 November 2011
Ó Springer-Verlag 2011
Abstract p-Toluenesulfonic acid monohydrate (p-TsOHꢀ
H2O) is a highly effective and efficient catalyst for the one-
pot multicomponent coupling of aldehydes, amines, and
b-ketoesters in EtOH at ambient temperature to give highly
functionalized piperidines in high yields. This one-pot
reaction has some important advantages such as the easy
workup procedure, simple and readily available precursors,
nontoxic and inexpensive catalyst, and good to high yields.
synthetic organic chemistry [5–7]. Polyfunctionalized het-
erocyclic compounds play important roles in the drug
discovery process and analysis of drugs in late develop-
ment. Piperidines and their analogues have received
attention owing to their biological activities [8, 9], e.g., they
act as antimalarial [10], antihypertensive [11], antibacterial
[12], anticonvulsant, and anti-inflammatory agents [13]. As
a result, various synthetic approaches have been developed
for the synthesis of piperidines based on intramolecular
Mannich reaction onto iminium ions [14], imino Diels–
Alder reaction [15, 16], aza-Prins cyclizations [17, 18],
intramolecular Michael reaction [19], and cyclopropane
ring-opening/Conia-ene cyclization [20]. Recently, the
syntheses of functionalized piperidines have been reported
using MCRs in the presence of L-proline/tetrahydrofuran
(THF) [10], InCl3 [21, 22], bromodimethylsulfonium bro-
mide (BDMS) [23], tetrabutylammonium tribromide
(TBATB) [24], iodine [25], cerium ammonium nitrate
(CAN) [26], and ZrOCl2ꢀ8H2O [27] as a catalyst. However,
some of these methods have drawbacks, such as long
reaction times, unsatisfactory yields, or use of expensive
catalysts. Therefore, it is necessary to further develop a
simple and greener synthesis of piperidines without these
problems.
Keywords Heterocycle ꢀ Piperidine ꢀ
Multicomponent reaction ꢀ Homogeneous catalyst ꢀ
p-TsOHꢀH2O
Introduction
Multicomponent reactions (MCRs) are a special type of
synthetically useful organic reaction in which three or more
different starting materials react to generate a product in a
one-pot procedure [1]. MCRs are also powerful tools in
medicinal chemistry and allow fast, automated, and high-
throughput generation of organic compounds [2].
Nitrogen-containing heterocyclic compounds are wide-
spread in nature, and their applications to biologically
active pharmaceuticals, agrochemicals, and functional
materials are becoming more and more important [3, 4].
Therefore, the development of new efficient methods for
synthesis of N-heterocycles is one major interest of modern
The use of organic catalysts has received considerable
attention in organic synthesis owing to their important
advantages such as the possibility of performing reactions
with acid-sensitive substrates, milder reaction conditions,
and selectivity [28–30]. p-Toluenesulfonic acid monohy-
drate (p-TsOHꢀH2O) has received considerable attention in
organic synthesis owing to its advantages such as low cost
and ease of handling and isolation [31–33]. In continuation
of our work on MCRs [34–38], in this work we report a
simple and efficient procedure for the one-pot multicom-
ponent synthesis of highly substituted piperidine derivatives
S. S. Sajadikhah ꢀ M. T. Maghsoodlou (&) ꢀ N. Hazeri ꢀ
S. M. Habibi-Khorassani ꢀ S. J. Shams-Najafi
Department of Chemistry, Faculty of Science,
University of Sistan and Baluchestan,
P. O. Box 98135-674 Zahedan, Iran
e-mail: mt_maghsoodlou@yahoo.com
123

940
S. S. Sajadikhah et al.
Scheme 1
R2
CHO
NH
O
2
2
4
O
O
3
OR3
R1
p-TsOH·H2O
5
6
OR3
1
+
2
EtOH, r.t.
3
N1
NH2
R1
R1
R2
2
R2
R1, R2: Me, OMe, NO2, F, Cl, Br
R3: Me, Et
4
from reaction between aromatic aldehydes, anilines, and
b-ketoesters in the presence of p-TsOHꢀH2O as a catalyst
under mild reaction conditions at ambient temperature
(Scheme 1).
at ambient temperature (Table 1, entry 5). When the
reaction was carried out under solvent-free conditions, the
product was obtained in a moderate yield (42%) that may
be due to the lack of effective interaction of reactants with
the catalyst. To illustrate the need for catalytic amounts of
p-TsOHꢀH2O in these reactions, the reaction of 4-methyl-
benzaldehyde, aniline, and methyl acetoacetate was studied
in the absence of the catalyst in ethanol. No product
was obtained at room temperature after 24 h (Table 1,
entry 11).
Results and discussion
First, 4-methylbenzaldehyde (2 mmol) was treated with
aniline (2 mmol) and methyl acetoacetate (1 mmol) in the
presence of p-toluenesulfonic acid monohydrate (0.03 g) in
ethanol at ambient temperature. The reaction proceeded
smoothly to give the corresponding highly functionalized
piperidine 4a in 49% yield after 12 h (Table 1, entry 1). To
determine the best experimental conditions, the reaction of
4-methylbenzaldehyde, aniline, and methyl acetoacetate
was considered as the model (Table 1). The best result was
obtained in the presence 0.11 g of p-TsOHꢀH2O in ethanol
Several reactions between substituted benzaldehydes,
anilines, and methyl or ethyl acetoacetate were examined
under the optimized conditions, and the results are
summarized in Table 2. Benzaldehydes with electron-
withdrawing as well as electron-releasing groups reacted
efficiently with anilines to give the corresponding piperi-
dines in good to high yields. Various substituents on the
benzene ring such as OMe, Me, NO2, F, Cl, and Br were
tolerated during the reaction. In all cases, the reaction
proceeded to afford piperidine derivatives in good yields.
However, the reaction of 4-methoxy- or 4-(dimethyl-
amino)benzaldehyde, p-anisidine, and methyl acetoacetate
did not form any piperidine (Table 2, entries 24, 25).
The structures of new compounds 4s–4w were deduced
Table 1 Optimization of the reaction conditions for the synthesis of
highly substituted piperidine 4a from the reaction between 4-meth-
ylbenzaldehyde, aniline, and methyl acetoacetate at ambient
temperature
Entry
Solvent
Catalyst/g
Time/h
Yield/%a
1
on the basis of IR, H, and 13C NMR spectroscopy, mass
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
CH3CN
H2O
0.03
12
12
8
49
58
79
85
89
89
89
84
72
37
42
–
spectrometry, and elemental analysis. The mass spectrum
of 4s displayed the molecular ion peak (M?) at m/z = 538,
1
which is consistent with the proposed structure. The H
2
0.05
3
0.07
4
0.09
8
NMR spectrum of 4s exhibited a triplet at d = 1.49 ppm
(J = 7.2 Hz) for methyl protons of the carbethoxy group
and two sharp singlets arising from two methyl groups at
d = 2.36 and 2.39 ppm. Two doublets of doublets were
shown at d = 2.67 (J = 15.2, 2.4 Hz) and 2.86 ppm
(J = 15.2, 5.8 Hz) for methylene protons of the piperidine
ring (H0-5, H00-5). The methylene protons of the carbethoxy
group, being distereotopic protons, were observed as two
doublets of quartets at d = 4.36 (J = 10.4, 7.2 Hz) and
4.49 ppm (J = 10.4, 6.8 Hz). One of the methine protons
5
0.11
7
6
0.13
7
7
0.15
7
7
0.11
7
8
0.11
7
9
0.11
12
12
24
10
11
a
Neat
0.11
EtOH
No catalyst
Isolated yield
123

One-pot multicomponent synthesis of highly substituted piperidines
941
Table 2 Synthesis of highly substituted piperidines 4a–4w
Entry
R1
R2
R3
Product
Time/h
Yield/%a
M.p./°C
Lit. m.p./°Cb [Ref.]
1
4-Me
4-Me
4-OMe
3-Cl
H
Me
Et
4a
4b
4c
4d
4e
4f
7
7
89
87
84
85
86
88
47
44
78
84
88
87
87
85
77
80
89
85
89
78
84
80
86
211–213
226–228
184–186
218–220
188–190
178–181
178–181
234–236
172–173
170–172
198–201
187–188
160–161
202–203
193–195
228–231
222–224
204–205
183–185
173–175
200–202
166–168
179–181
–
212–214 [23]
228–231 [25]
187–188 [23]
220–221 [26]
189–191 [23]
180 [10]
182–183 [25]
239–241 [25]
169–171 [23]
173 [10]
202 [10]
190 [10]
162–163 [26]
204–205 [26]
194–195 [26]
229–230 [23]
225–226 [23]
206–208 [25]
–
2
H
3
H
Me
Me
Me
Me
Me
Me
Me
Et
10
7
4
H
5
4-Cl
H
7
6
4-F
H
7
7
3-NO2
4-NO2
H
H
4g
4h
4i
16
16
10
10
12
9
8
H
9
H
10
11
12
13
14
15
16
17
18
19
20
21
21
23
24
25
a
H
4-OMe
4-Cl
4-Cl
4-OMe
4-OMe
4-Cl
4-Br
4-OMe
4-Me
4-F
4j
H
Et
4k
4l
3-Cl
Et
3-Cl
Me
Me
Me
Me
Me
Me
Et
4m
4n
4o
4p
4q
4r
4s
4t
10
10
15
9
4-F
4-OMe
4-Me
4-Me
4-Me
4-Me
4-Me
4-F
7
7
8
3,4-di-Cl
4-Me
H
Et
12
7
–
Me
Et
4u
4v
4w
–
–
4-OMe
H
14
9
–
4-OMe
4-OMe
4-OMe
Et
–
c
–
4-OMe
4-NMe2
Me
Me
24
24
–
c
–
–
–
–
Isolated yield
b
All known products reported previously in the literature were characterized by comparison of IR and NMR spectra with those of authentic
samples
c
No reaction
of the piperidine ring (H-6) was observed as a doublet at
d = 5.08 ppm (J = 3.6 Hz), and another methine pro-
ton (H-2) appeared as a singlet at d = 6.35 ppm. The
aromatic protons were observed as mixture of multiplets
at d = 6.25–7.23 ppm. A singlet for the NH group at
d = 10.22 ppm indicated intramolecular hydrogen bond
formation with the vicinal carbonyl group. The 13C NMR
spectrum of 4s showed 25 distinct resonances in agreement
with the proposed structure. Partial assignments of these
resonances are given in the ‘‘Experimental’’ section. The
relative stereochemistry of this class of compounds has
been confirmed by single X-ray crystallographic analysis
[21–27], and the stereochemistry of our products was
proved by comparison of spectroscopic data of some
products with those of authentic samples (Table 3).
give enamine 5 and imine 6 (Scheme 2). Next, enamine 5
reacts with imine 6 to produce intermediate 7 through
intermolecular Mannich-type reaction. The reaction between
intermediate 7 and aldehyde gives intermediate 8 by the
elimination of H2O. Then, tautomerization of 8 generates
intermediate 9, which immediately undergoes intramolecular
Mannich-type reaction to give intermediate 10. Finally, the
intermediate 10 tautomerizes to generate the desired piperi-
dine derivative 4 owing to conjugation with the ester group.
To show the merit of the present work in comparison
with reported results in the literature, we compared the
performance of p-TsOHꢀH2O with that of L-proline/THF
[10], InCl3 [21], BDMS [23], TBATB [24], iodine [25],
CAN [26], and ZrOCl2ꢀ8H2O [27] in the synthesis of
highly functionalized piperidine derivatives. As shown in
Table 4, p-TsOHꢀH2O can act as effective catalyst with
respect to reaction times and yields of products.
On the basis of the proposed mechanism in the literature
[10, 21–27], it is reasonable to assume that piperidine 4
results from initial condensation of aromatic aldehyde and
b-ketoester 3 with aniline in the presence of p-TsOHꢀH2O to
In conclusion, we have developed a simple and efficient
method for the synthesis of highly substituted piperidines
123

942
S. S. Sajadikhah et al.
Table 3 Comparison of spectroscopic data of some products with those of authentic samples
R2
NH
O
4
3
OR3
5
6
2
N
1
R1
R1
R2
4
Entry
1
Compound
H shift (found)
H-2: 6.38 (s)
H shift (lit.)
H-2: 6.37 (s)
[Ref.]a
[23]
4a
H0-5, H00-5: 2.70 (dd, J = 15.2, 2.4 Hz),
2.83 (dd, J = 15.2, 5.6 Hz)
H0-5, H00-5: 2.74 (dd, J = 15.2, 2.4 Hz),
2.84 (dd, J = 15.2, 5.6 Hz)
H-6: 5.10 (d, J = 2.8 Hz)
H-6: 5.08–5.09 (m)
2
3
4
5
6
7
8
9
10
a
4b
4e
4i
H-2: 6.42 (s)
H0-5, H00-5: 2.80 (dd, J = 15.2, 2.4 Hz),
2.89 (dd, J = 15.2, 5.6 Hz)
H-2: 6.40 (s)
H0-5, H00-5: 2.76 (dd, J = 15.2, 2.4 Hz),
2.86 (dd, J = 15.2, 5.6 Hz)
[25]
H-6: 5.13 (d, J = 2.6 Hz)
H-6: 5.11 (d J = 2.4 Hz)
H-2: 6.41 (s)
H0-5, H00-5: 2.74 (dd, J = 15.2, 2.4 Hz),
2.82 (dd, J = 15.2, 5.6 Hz)
H-2: 6.35 (s)
H0-5, H00-5: 2.74 (dd, J = 15.2, 2.4 Hz),
2.82 (dd, J = 15.2, 5.6 Hz)
[23]
H-6: 5.10 (br s)
H-6: 5.09–5.10 (m)
H-2: 6.38 (s)
H0-5, H00-5: 2.69 (dd, J = 15.1, 2.4 Hz),
2.84 (dd, J = 15.1, 5.6 Hz)
H-2: 6.46 (s)
H0-5, H00-5: 2.77 (dd, J = 15.3, 2.3 Hz),
2.88 (dd, J = 15.3, 5.8 Hz)
[21]
H-6: 5.13 (br s)
H-6: 5.15 (m)
4p
4s
H-2: 6.41 (s)
H0-5, H00-5: 2.74 (d, J = 15.2 Hz), 2.89
(dd, J = 15.2, 5.8 Hz)
H-2: 6.29 (s)
H0-5, H00-5: 2.67 (dd, J = 15.2, 2.4 Hz),
2.82 (dd, J = 15.2, 5.6 Hz)
[23]
H-6: 5.10 (d, J = 3.6 Hz)
H-6: 5.03–5.04 (m)
H-2: 6.35 (s)
H0-5, H00-5: 2.67 (dd, J = 15.2, 2.4 Hz),
2.86 (dd, J = 15.2, 5.8 Hz)
-
This work
This work
This work
This work
This work
H-6: 5.08 (d, J = 3.6 Hz)
4t
H-2: 6.36 (s)
H0-5, H00-5: 2.73 (d, J = 15.2 Hz), 2.90
(dd, J = 15.2, 5.6 Hz)
-
-
-
-
H-6: 5.08 (br s)
4u
4v
4w
H-2: 6.37 (s)
H0-5, H00-5: 2.75 (dd, J = 15.1, 2.4 Hz),
2.83 (dd, J = 15.1, 5.6 Hz)
H-6: 5.11 (br s)
H-2: 6.42 (s)
H0-5, H00-5: 2.80 (dd, J = 15.2, 2.4 Hz),
2.90 (dd, J = 15.2, 5.6 Hz)
H-6: 5.13 (d, J = 2.8 Hz)
H-2: 6.38 (s)
H0-5, H00-5: 2.68 (dd, J = 15.1, 2.4 Hz),
2.83 (dd, J = 15.2, 5.6 Hz)
H-6: 5.09 (d, J = 3.2 Hz)
In these references, the relative stereochemistry of this class of compounds has been confirmed by single X-ray crystallographic analysis
123

One-pot multicomponent synthesis of highly substituted piperidines
943
Scheme 2
O
O
R2
OR3
3
NH
O
OR3
5
NH2
·
p-TsOH H2O
CHO
R1
R2
R1
2
1
N
R2
6
R2
R2
CHO
N
O
N
N
O
Inter-molecular
Mannich reaction
R1
OR3
OR3
1
5 + 6
HN
R1
R1
R1
R2
R2
7
8
p-TsOH·H2O
R2
R2
H
N
O
N
O
Intra-molecular
Mannich reaction
OR3
OR3
p-TsOH·H2O
4
N
N
R1
R1
R1
R1
R2
R2
10
9
by one-pot MCR under mild conditions using p-toluene-
sulfonic acid monohydrate as the catalyst in ethanol. This
reaction can be regarded as an efficient approach for the
preparation of synthetically and pharmaceutically impor-
tant piperidine systems. This one-pot reaction has some
important advantages such as the easy workup procedure,
simple and readily available precursors, nontoxic and
inexpensive catalyst, and good to high yields.
recorded on an Agilent Technology (HP) mass spectro-
meter, operating at an ionization potential of 70 eV. The
aromatic aldehydes, anilines, b-ketoesters, and p-TsOHꢀH2O
were obtained from Merck (Darmstadt, Germany), Acros
(Geel, Belgium), and Fluka (Buchs, Switzerland), and used
without further purification.
General procedure for synthesis of highly
functionalized piperidines 4
Experimental
A solution of aromatic amine 2 (2 mmol) and b-ketoester 3
(1 mmol) in 5 cm3 EtOH was stirred for 20 min in the
presence of 0.11 g p-TsOHꢀH2O at ambient temperature.
Next, the aromatic aldehyde 1 (2 mmol) was added and the
reaction mixture was stirred for the time indicated in
Table 2. The progress of the reaction was monitored by
thin-layer chromatography (TLC). After completion of the
reaction, the thick precipitate was filtered off and washed
with ethanol (3 9 2 cm3) to give the pure product 4.
Melting points and IR spectra were measured on an Elec-
trothermal 9100 apparatus and a JASCO FT/IR-460 plus
spectrometer, respectively. The H and 13C NMR spectra
1
were recorded on a Bruker DRX-400 Avance instrument
with CDCl3 as solvent at 400 and 100 MHz, respectively.
Elemental analyses for C, H, and N were performed using a
Heraeus CHN-O-Rapid analyzer. The mass spectra were
123

944
S. S. Sajadikhah et al.
5.08 (d, J = 3.6 Hz, 1H, H-6), 6.25–6.29 (m, 2H, ArH),
6.35 (s, 1H, H-2), 6.44–6.48 (m, 2H, ArH), 6.77–6.84 (m,
4H, ArH), 7.06–7.23 (m, 8H, ArH), 10.22 (s, 1H, NH)
ppm; 13C NMR (100 MHz, CDCl3): d = 14.8 (OCH2CH3),
21.0 (CH3), 21.1 (CH3), 33.6 (C-5), 55.4 (C-2), 58.1 (C-6),
59.7 (OCH2CH3), 98.3 (C-3), 113.6 (d, J = 7.0 Hz), 115.2
(d, J = 22.0 Hz), 115.6 (d, J = 23.0 Hz), 126.9 (d,
J = 23.0 Hz), 127.9 (d, J = 9.0 Hz), 129.0, 129.4, 134.0
(d, J = 3.0 Hz), 135.9, 136.9, 139.7, 140.7, 143.6, 155.0
Table 4 Comparison of p-TsOHꢀH2O with L-proline/THF [10], InCl3
[21], BDMS [23], TBATB [24], iodine [25], CAN [26], and
ZrOCl2ꢀ8H2O [27] in the synthesis highly functionalized piperidine
derivatives
Entry Compound Catalyst/conditions
Time/h Yield/%
1
2
3
4
4a
4c
4e
4i
L-Proline/THF/CH3CN,
20–30 °C
InCl3/CH3CN, r.t.
–
–
24
3
50
80
78
84
85
–
BDMS/CH3CN, r.t.
TBATB/EtOH, r.t.
I2/MeOH, r.t.
1
1
(d, JCF = 234.0 Hz), 156.0 (C-4), 160.7 (d, JCF
=
10
8
245.0 Hz), 168.2 (C=O) ppm; MS (EI, 70 eV): m/z (%) =
538 (M?, 2), 465 (2), 447 (12), 324 (45), 296 (21), 252
(19), 213 (100), 111 (7), 95 (23), 91 (18).
CAN/CH3CN, r.t.
22
–
ZrOCl2ꢀ8H2O/EtOH, reflux
p-TsOHꢀH2O/EtOH, r.t.
L-Proline/THF/CH3CN,
20–30 °C
InCl3/CH3CN, r.t.
7
89
70
Ethyl 1-(3,4-dichlorophenyl)-4-(3,4-dichlorophenylamino)-
1,2,5,6-tetrahydro-2,6-bis(4-methylphenyl)pyridine-3-car-
boxylate (4t, C34H30Cl4N2O2)
18
24
3
52
77
80
74
83
80
84
–
White solid; m.p.: 173–175 °C; IR (KBr): v = 3,301 (NH),
1,660 (C=O) cm-1; 1H NMR (400 MHz, CDCl3): d = 1.50
(t, J = 6.4 Hz, 3H, OCH2CH3), 2.34 (s, 3H, CH3), 2.35 (s,
3H, CH3), 2.73 (d, J = 15.2 Hz, 1H, H0-5), 2.90 (dd, J =
15.2, 5.6 Hz, 1H, H00-5), 4.31–4.40 (m, 1H, OCHaHb),
4.46–4.54 (m, 1H, OCHaHb), 5.08 (br s, 1H, H-6), 6.15 (d,
J = 7.2 Hz, 2H, ArH), 6.36 (s, 1H, H-2), 6.42 (d, J =
7.6 Hz, 2H, ArH), 6.95–7.25 (m, 10H, ArH), 10.24 (s, 1H,
NH) ppm; 13C NMR (100 MHz, CDCl3): d = 14.8
(OCH2CH3), 21.6 (CH3), 21.8 (CH3), 33.4 (C-5), 55.3
(C-2), 58.3 (C-6), 59.8 (OCH2CH3), 98.9 (C-3), 108.3,
114.6, 119.1, 123.5, 123.5, 126.9, 127.2, 127.4, 127.4,
128.2, 128.2, 128.7, 131.5, 131.9, 137.0, 138.0, 138.4,
142.2, 143.3, 146.0, 155.3 (C-4), 168.1 (C=O) ppm; MS
(EI, 70 eV): m/z (%) = 641 ([M ? 1]?, 1), 640 (M?, 3),
569 (100), 488 (50), 386 (65), 312 (31), 272 (35), 115 (32),
91 (42), 65 (13).
BDMS/CH3CN, r.t.
TBATB/EtOH, r.t.
I2/MeOH, r.t.
8
8
CAN/CH3CN, r.t.
10
4
ZrOCl2ꢀ8H2O/EtOH, reflux
p-TsOHꢀH2O/EtOH, r.t.
L-Proline/THF/CH3CN,
20–30 °C
InCl3/CH3CN, r.t.
10
–
–
–
BDMS/CH3CN, r.t.
TBATB/EtOH, r.t.
I2/MeOH, 55 °C
3
76
82
85
86
80
86
70
10
6
CAN/CH3CN, r.t.
15
4
ZrOCl2ꢀ8H2O/EtOH, reflux
p-TsOHꢀH2O/EtOH, r.t.
L-Proline/THF/CH3CN,
7
17
20–30 °C
InCl3/CH3CN, r.t.
BDMS/CH3CN, r.t.
TBATB/EtOH, r.t.
I2/MeOH, 55 °C
CAN/CH3CN, r.t.
24
3
60
75
74
81
82
80
78
Methyl 2,6-bis(4-fluorophenyl)-1,2,5,6-tetrahydro-
1-(4-methylphenyl)-4-(4-methylphenylamino)pyridine-
3-carboxylate (4u, C33H30F2N2O2)
24
8
White solid; m.p.: 200–202 °C; IR (KBr): v = 3,264 (NH),
1,658 (C=O) cm-1; 1H NMR (400 MHz, CDCl3): d = 2.20
(s, 3H, CH3), 2.31 (s, 3H, CH3), 2.75 (dd, J = 15.1, 2.4 Hz,
1H, H0-5), 2.83 (dd, J = 15.1, 5.6 Hz, 1H, H00-5), 3.95 (s,
3H, OCH3), 5.11 (br s, 1H, H-6), 6.31 (d, J = 8.4 Hz, 2H,
ArH), 6.37 (s, 1H, H-2), 6.42 (d, 2H, J = 8.8 Hz, ArH),
6.92 (d, J = 8.4 Hz, 2H, ArH), 6.97–7.02 (m, 6H, ArH),
7.12–7.15 (m, 2H, ArH), 7.27–7.31 (m, 2H, ArH), 10.22 (s,
1H, NH) ppm; 13C NMR (100 MHz, CDCl3): d = 20.1
(CH3), 20.9 (CH3), 33.7 (C-5), 51.0 (OCH3), 54.7 (C-2),
57.3 (C-6), 97.2 (C-3), 113.0, 114.9 (d, J = 21.0 Hz), 115.4
(d, J = 21.0 Hz), 125.6, 125.8, 127.9 (d, J = 8.0 Hz), 128.2
(d, J = 7.0 Hz), 129.6, 135.0, 135.9, 138.4, 139.7, 144.5,
20
ZrOCl2ꢀ8H2O/EtOH, reflux 3.5
p-TsOHꢀH2O/EtOH, r.t. 10
Ethyl 1-(4-fluorophenyl)-4-(4-fluorophenylamino)-1,2,5,6-
tetrahydro-2,6-bis(4-methylphenyl)pyridine-3-carboxylate
(4s, C34H32F2N2O2)
White solid; m.p.: 183–185 °C; IR (KBr): v = 3,295 (NH),
1,655 (C=O) cm-1; 1H NMR (400 MHz, CDCl3): d = 1.49
(t, J = 7.2 Hz, 3H, OCH2CH3), 2.36 (s, 3H, CH3), 2.39 (s,
3H, CH3), 2.67 (dd, J = 15.2, 2.4 Hz, 1H, H0-5), 2.86 (dd,
J = 15.2, 5.8 Hz, 1H, H00-5), 4.36 (dq, J = 10.5, 7.2 Hz,
1H, OCHaHb), 4.49 (dq, J = 10.5, 6.8 Hz, 1H, OCHaHb),
1
1
156.4 (C-4), 161.5 (d, JCF = 243.0 Hz), 161.9 (d, JCF
244.0 Hz), 168.4 (C=O) ppm; MS (EI, 70 eV): m/z (%) =
=
123

One-pot multicomponent synthesis of highly substituted piperidines
945
524 (M?, 23), 465 (9), 429 (87), 397 (21), 310 (100), 296
(9), 278 (54), 252 (47), 106 (13), 91 (77), 65 (25).
3. Lichtenthaler FW (2002) Acc Chem Res 35:728
4. Litvinov VP (2003) Russ Chem Rev 72:69
5. Padwa A, Waterson AG (2000) Curr Org Chem 4:175
6. Orru RVA, de Greef M (2003) Synthesis 1471
7. Kirsch G, Hesse S, Comel A (2004) Curr Org Synth 1:47
8. O’Hagan D (2000) Nat Prod Rep 17:435
9. Daly JW, Spande TF, Garraffo HM (2005) J Nat Prod 68:1556
10. Misra M, Pandey SK, Pandey VP, Pandey J, Tripathi R, Tripathi
RP (2009) Bioorg Med Chem 17:625
11. Petit S, Nallet JP, Guillard M, Dreux J, Chermat R, Poncelet M,
Bulach C, Simon P, Fontaine C, Barthelmebs M, Imbs JL (1991)
Eur J Med Chem 26:19
12. Zhou Y, Gregor VE, Ayida BK, Winters GC, Sun Z, Murphy D,
Haley G, Bailey D, Froelich JM, Fish S, Webber SE, Hermann T,
Wall D (2007) Bioorg Med Chem Lett 17:1206
13. Bin H, Grider AM, Stables JP (2001) Eur J Med Chem 36:265
14. Davis FA, Chao B, Rao A (2001) Org Lett 3:3169
15. Takasu K, Shindoh N, Tokuyama H, Ihara M (2006) Tetrahedron
62:11900
16. Sales M, Charette AB (2005) Org Lett 7:5773
17. Murty MSR, Ram R, Yadav JS (2008) Tetrahedron Lett 49:1141
18. Carballo RM, Ramirez MA, Rodriguez ML, Martin VS, Padron JI
(2006) Org Lett 8:3837
19. Fustero S, Jimenez D, Moscardo J, Catalan S, del Pozo C (2007)
Org Lett 9:5283
20. Lebold TP, Leduc AB, Kerr MA (2009) Org Lett 11:3770
21. Clark PA, Zaytzev AV, Whitwood AC (2007) Tetrahedron Lett
48:5209
Ethyl 1,2,5,6-tetrahydro-2,6-bis(4-methoxyphenyl)-
1-phenyl-4-(phenylamino)pyridine-3-carboxylate
(4v, C34H34N2O4)
White solid; m.p.: 166–168 °C; IR (KBr): v = 3,255 (NH),
1,656 (C=O) cm-1; 1H NMR (400 MHz, CDCl3): d = 1.50
(t, J = 7.2 Hz, 3H, OCH2CH3), 2.80 (dd, J = 15.2, 2.4 Hz,
1H, H0-5), 2.90 (dd, J = 15.2, 5.6 Hz, 1H, H00-5), 3.82 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 4.38 (dq, J = 10.8, 7.2 Hz,
1H, OCHaHb), 4.50 (dq, J = 10.8, 7.0 Hz, 1H, OCHaHb),
5.13 (d, J = 2.8 Hz, 1H, H-6), 6.41 (d, J = 6.8 Hz, 2H,
ArH), 6.42 (s, 1H, H-2), 6.58 (d, J = 8.4 Hz, 2H, ArH),
6.65 (t, J = 7.2 Hz, 1H, ArH), 6.84–6.87 (m, 4H, ArH),
7.09–7.29 (m, 9H, ArH), 10.36 (s, 1H, NH) ppm; 13C NMR
(100 MHz, CDCl3): d = 14.6 (OCH2CH3), 33.8 (C-5), 54.5
(C-2), 55.2 (OCH3), 55.3 (OCH3), 57.5 (C-6), 59.6
(OCH2CH3), 98.4 (C-3), 113.0, 113.6, 114.0, 116.0,
125.6, 125.7, 127.5, 127.7, 128.9, 134.7, 136.0, 138.0,
147.1, 156.2 (C-4), 158.1, 158.7, 168.3 (C=O) ppm; MS
(EI, 70 eV): m/z (%) = 534 (M?, 13), 461 (4), 427 (41),
322 (80), 211 (79), 210 (100), 134 (5), 104 (5), 77 (41).
22. Clark PA, Zaytzev AV, Whitwood AC (2008) Synthesis 3530
23. Khan AT, Parvin T, Choudhury LH (2008) J Org Chem 73:8393
24. Khan AT, Lal M, MdM Khan, Bannuru KKR (2010) Tetrahedron
Lett 51:4419
25. Khan AT, MdM Khan, Bannuru KKR (2010) Tetrahedron
66:7762
26. Wang H-J, Mo L-P, Zhang Z-H (2011) ACS Comb Sci 13:181
27. Mishra S, Rina G (2011) Tetrahedron Lett 52:2857
28. Khalafi-Nezhad A, Parhami A, Zare A, Moosavi-Zare AR,
Hasaninejad A, Panahi F (2008) Synthesis 617
29. Chandrasekhar S, Johny K, Reddy CR (2009) Tetrahedron
Asymmetr 20:1742
30. Dekamin MG, Sagheb-Asl S, Naimi-Jamal MR (2009) Tetrahe-
dron Lett 50:4063
31. Shaabani A, Maleki A, Mofakham H, Moghimi-Rad J (2008) J
Org Chem 73:3925
32. Shaabani A, Maleki A, Moghimi-Rad J (2007) J Org Chem
72:6309
33. Shaabani A, Seyyedhamzeh M, Maleki A, Bahnam M (2009)
Tetrahedron Lett 50:6355
Ethyl 1,2,5,6-tetrahydro-1-(4-methoxyphenyl)-
4-(4-methoxyphenylamino)-2,6-diphenylpyridine-
3-carboxylate (4w, C34H34N2O4)
White solid; m.p.: 179–181 °C; IR (KBr): v = 3,295 (NH),
1,648 (C=O) cm-1; 1H NMR (400 MHz, CDCl3): d = 1.48
(t, J = 7.0 Hz, 3H, OCH2 CH3), 2.68 (dd, J = 15.1, 2.4 Hz,
1H, H0-5), 2.83 (dd, J = 15.1, 5.6 Hz, 1H, H00-5), 3.69 (s,
3H, OCH3), 3.78 (s, 3H, OCH3), 4.32–4.38 (m, 1H,
OCHaHb), 4.43–4.49 (m, 1H, OCHaHb), 5.09 (d, J =
3.2 Hz, 1H, H-6), 6.24 (d, J = 8.8 Hz, 2H, ArH), 6.38 (s,
1H, H-2), 6.48 (d, J = 9.2 Hz, 2H, ArH), 6.64 (d, J =
8.4 Hz, 2H, ArH), 6.70 (d, J = 9.2 Hz, 2H, ArH), 7.20–7.37
(m, 10H, ArH), 10.18 (s, 1H, NH) ppm; 13C NMR
(100 MHz, CDCl3): d = 14.8 (OCH2CH3), 33.6 (C-5), 55.4
(OCH3), 55.6 (OCH3), 55.7 (C-2), 58.3 (C-6), 59.5
(OCH2CH3), 97.3 (C-3), 113.9, 114.1, 114.5, 126.2,
126.5, 126.8, 127.1, 127.8, 128.1, 128.6, 130.7, 141.4,
143.3, 144.4, 150.9, 156.8 (C-4), 157.8, 168.3 (C=O) ppm;
MS (EI, 70 eV): m/z (%) = 534 (M?, 7), 457 (18), 412 (8),
384 (2), 322 (27), 250 (12), 226 (39), 211 (28), 155 (100),
115 (21), 104 (14), 91 (11), 77 (35), 57 (78).
34. Maghsoodlou MT, Yavari I, Nassiri F, Dajahanian H, Razmjoo Z
(2003) Monatsh Chem 134:1585
35. Maghsoodlou MT, Hazeri N, Habibi-Khorassani SM, Heydari R,
Marandi G, Lashkari M, Bagherpour K, Gharechaei Z (2010)
Monatsh Chem 141:351
36. Marandi G, Maghsoodlou MT, Hazeri N, Habibi-Khorassani SM,
Akbarzadeh-Torbati N, Rostami-Charati F, Skelton BW, Makha
M (2011) Mol Divers 15:197
37. Maghsoodlou MT, Habibi-Khorassani SM, Heydari R, Hazeri N,
Sajadikhah SS, Rostamizadeh M (2010) Chin J Chem 28:285
38. Maghsoodlou MT, Habibi-Khorasani SM, Heydari R, Hazeri N,
Sajadikhah SS, Rostamizadeh M, Keishams L (2010) Turk J
Chem 34:565
Acknowledgments We gratefully acknowledge financial support
from the Research Council of the University of Sistan and
Baluchestan.
References
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