TiCl2·2H2O catalyzed one-pot synthesis of highly functionalized tetrahydropiperidines and evaluation of their antimicrobial activities

Article abstract of DOI:10.1515/hc-2015-0081

One-pot condensation reaction of ethyl acetoacetate, various substituted benzaldehydes and anilines in the presence of TiCl₂·2H₂O yields highly functionalized tetrahydropiperidines. Atom economy, efficiency, and short reaction times are the advantages of the method, which is carried out under mild conditions using easily accessible and inexpensive chemicals. The antimicrobial activity of the synthesized products was evaluated against three Gram-positive and three Gram-negative bacteria, a yeast and a fungus strain using disc diffusion and minimum inhibitory concentration methods.

Full text of DOI:10.1515/hc-2015-0081

Heterocycl. Commun. 2016; aop
Mohsen Abbasi, Seyed Mohammad Seyedi*, Hamid Sadeghian, Maryam Akhbari,
Mohammadreza Enayaty and Ali Shiri
TiCl2·2H2O catalyzed one-pot synthesis of
highly functionalized tetrahydropiperidines and
evaluation of their antimicrobial activities
DOI 10.1515/hc-2015-0081
biological properties such as antihypertensive [10],
antibacterial [11], anti-inflammatory [12], and antima-
larial activity [13]. Tetrahydropiperidines have also been
utilized as useful synthetic precursors for the prepara-
tion of other compounds. Various methods have been
developed for the synthesis of functionalized piperi-
dines in the presence of catalysts such as L-proline/TFA
[13], InCl3 [14], 1-methyl-2-oxopyrrolidinium hydrogen
sulfate ([Hpyro][HSO4]) [15], tetrabutylammonium tribro-
mide (TBATB) [7], ZrOCl2·8H2O [16], Bi(NO3)3·5H2O [17],
SPINOL-phosphoric acids [18], BF3·SiO2 [19], trityl chlo-
ride (Ph3CCl) [20], FeCl3/SiO2 nanoparticles [21], cerium
ammonium nitrate (CAN) [22], molecular iodine (I2) [23],
and picric acid [24]. Despite the large number of reported
Received June 22, 2015; accepted October 2, 2015
Abstract: One-pot condensation reaction of ethyl acetoac-
etate, various substituted benzaldehydes and anilines in
the presence of TiCl2·2H2O yields highly functionalized tet-
rahydropiperidines. Atom economy, efficiency, and short
reaction times are the advantages of the method, which
is carried out under mild conditions using easily accessi-
ble and inexpensive chemicals. The antimicrobial activity
of the synthesized products was evaluated against three
Gram-positive and three Gram-negative bacteria, a yeast
and a fungus strain using disc diffusion and minimum
inhibitory concentration methods.
Keywords: antibacterial activity; multicomponent reac- catalysts for the synthesis of functionalized piperidines,
tion; TiCl2·2H2O; tetrahydropiperidine.
many of the methods suffer from disadvantages such
as long reaction times, need for excess amounts of the
reagent, low yields, use of toxic or expensive reagents,
tedious work-up procedures, and high temperature con-
ditions. Therefore, there is a need for alternative methods
that avoids these problems. In continuation of our inter-
est in developing protocols for the synthesis of heterocy-
clic compounds [25, 26], herein we report TiCl2·2H2O as a
new catalyst for the fast, facile, and efficient synthesis of
highly functionalized piperidine derivatives by the direct
condensation of a variety of anilines with aryl aldehydes
and ethyl acetoacetate under mild reaction conditions
(Scheme 1).
Introduction
In multicomponent reactions (MCRs), three or more
different starting materials undergo a reaction to form
diverse complex molecules in a one-pot strategy with
reducing waste, good efficiency, high selectivity, time
saving, and high safety [1–3]. Tetrahydropiperidine and
their derivatives are an important class of heterocyclic
molecules found in numerous natural products and bio-
logically active compounds [4–9]. They have also shown
*Corresponding author: Seyed Mohammad Seyedi, Department
of Chemistry, Faculty of Science, Ferdowsi University of Mashhad,
91775-1436 Mashhad, Iran, e-mail: smseyedi@um.ac.ir
Mohsen Abbasi and Ali Shiri: Department of Chemistry, Faculty of
Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad,
Iran
Hamid Sadeghian: Department of Laboratory Sciences, School of
Paramedical Sciences, Mashhad University of Medical Sciences,
Mashhad, Iran
Results and discussion
Initially, in order to find an efficient catalyst, the model
reaction of benzaldehyde (2 mmol), aniline (2 mmol), and
ethyl acetoacetate (1 mmol) in the presence of various
potential catalysts in ethanol at ambient temperature was
studied. The results are summarized in Table 1. As can be
seen, the best result was obtained using TiCl2·2H2O.
Maryam Akhbari and Mohammadreza Enayaty: Department of
Phytochemistry, Essential Oil Research Institute, University of
Kashan, Kashan, Iran
Then, the model reaction was optimized by using
several solvents. The results presented in Table 2 show
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ꢀꢀꢀꢁ
2ꢀ
ꢀM. Abbasi et al.: Highly functionalized tetrahydropiperidines
R2
CHO
NH2
NH
N
O
O
O
TiCl2 2H
2O (15 mol%)
OEt
OEt
EtOH, rt
R1
R2
1
2
3
R1
R1
R2
4a–w
Scheme 1ꢀSynthesis of compounds 4a–w. For definition of the substituents R1 and R2, see Table 3.
a
Table 1ꢀSynthesis of piperidine 4a in the presence of various
To explore the scope and substrate limitations of
catalysts.
the reaction, various substituted benzaldehydes and
anilines were allowed to react with ethyl acetoacetate
under the optimized conditions. The results are summa-
rized in Table 3. The method is efficient and superior in
comparison with the reported literature preparations.
Various derivatives were obtained in relatively high
yields. The electron withdrawing or electron donating
nature of the aryl group affects the reaction rate, but no
clear substitution effect on the yield is observed. The
structures of the synthesized products were identified
by comparison of their spectroscopic data and melting
points with those of literature reports. The structures
of new compounds 4j and 4s were confirmed by IR,
1H NMR, 13C NMR, mass spectrometry, and elemental
analysis data.
Entryꢁ
Catalyst (10 mol%)
ꢁ
Time (h)
ꢁ Yield (%)
1
2
3
4
5
6
7
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
Sr(NO3).6H2O
NaH2PO4
Al(NO3)3.9H2O
(NH4)3PMo12O40. 6H2Oꢂ
ꢂ
ꢂ
ꢂ
24
24
20
20
18
12
7
ꢂ 10
ꢂ Trace
ꢂ 25
ꢂ 40
Co(NO3)3.6H2O
IrCl3.3H2O
ꢂ
ꢂ
ꢂ
ꢂ 45
ꢂ 62
.
TiCl2 2H2O
ꢂ 73
aExperimental conditions: benzaldehyde (2 mmol), aniline
(2 mmol), and ethyl acetoacetate (1 mmol) in ethanol (5 mL) at room
temperature.
Table 2ꢀThe effect of different solvents and different amounts of
TiCl2·2H2O on the yield of 4a at room temperature.
A plausible mechanism for the discussed synthesis is
shown in Scheme 2. Initially, the reaction of arylamine 1
and ethyl acetoacetate 2 gives the β-enaminone 5 in the
presence of TiCl2·2H2O [27]. In a similar way, condensa-
tion of arylamine 1 with arylaldehyde 3 generates the cor-
responding imine 6. Then, the intermolecular Mannich
reaction of β-enaminone 5 with the imine 6 activated by
TiCl2·2H2O affords the intermediate product 7 [27]. The
reaction of 7 with the second activated molecule of ary-
laldehyde produces the intermediate compound 8. Then,
8 undergoes tautomerization to 9 which is stabilized by
intramolecular hydrogen bond. Finally, the intramolecu-
lar Mannich-type reaction of 9 generates the intermediate
product 10 which is a direct precursor to the final product
Entryꢁ
Solventꢁ
Neat
MeOH ꢂ
CH3CN ꢂ
Catalyst (mol%)
ꢁ Time (h)
ꢁ Yield (%)
1
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
15
15
15
15
15
15
15
–
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
4
4
ꢂ 47
ꢂ 85
ꢂ 76
ꢂ 40
ꢂ –
ꢂ Trace
ꢂ 90
ꢂ –
2
3
8
4
EtOAc
H2O
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
12
20
20
4
5
6
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
7
8
18
10
7
9
5
10
20
ꢂ 55
ꢂ 73
ꢂ 88
10
11
4
that EtOH is the solvent of choice. Running the synthesis 4a–w [17].
of model compound 4a in the absence of solvent leads to a
The antimicrobial activity evaluations of selected
compounds 4 against three Gram-positive containing
47% yield at room temperature (Table 2, entry 1).
Different molar ratios of the catalyst were also inves- (Staphylococcus aureus, Staphylococcus epidermidis, and
tigated. The best result was obtained in the presence of Bacillus subtilis) and three Gram-negative (Klebsiella
15 mol% TiCl2·2H2O in EtOH at room temperature (Table 2, pneumonia, Escherichia coli, and Salmonella enterica) bac-
entry 7). An increase in the amount of catalyst does not teria, a yeast (Candida albicans), and a fungus (Aspergillus
improve the yield and in its absence no product is obtained niger) strain are presented in Table 4. As can be seen, only
even after 18 h (Table 2, entries 8–11).
a few compounds show antibacterial activity against the
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ꢁꢀꢀꢀ
M. Abbasi et al.: Highly functionalized tetrahydropiperidinesꢃ ꢃ3
Table 3ꢀSynthesis of tetrahydropiperidines 4a–w in the presence of TiCl2·2H2O at room temperature.
Entryꢁ
R1
ꢁ
R2
ꢁ
Time (h)
ꢁ Lit. time (h)
ꢁ Yielda (%)
ꢁ Lit. yield (%)
ꢁ
Mp (°C)
ꢁ Lit. mp (°C)
ꢁ [Ref]
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
H
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
H
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
8
3.5
4
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
20
14
22
20
24
24
23
20
23
–
18
28
14
16
20
17
21
18
–
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
84
89
91
89
90
91
87
89
84
86
87
89
88
85
89
91
92
89
87
90
90
88
75
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
81
85
81
75
86
74
68
83
74
–
80
88
79
80
74
65
70
84
–
ꢂ 169–171
ꢂ 196–198
ꢂ 197–198
ꢂ 170–172
ꢂ 197–198
ꢂ 174–176
ꢂ 229–231
ꢂ 205–207
ꢂ 153–154
ꢂ 181–182
ꢂ 249–251
ꢂ 237–239
ꢂ 217–219
ꢂ 186–187
ꢂ 205–207
ꢂ 219–220
ꢂ 227–228
ꢂ 223–224
ꢂ 189–190
ꢂ 226–227
ꢂ 183–185
ꢂ 184–186
ꢂ 139–141
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
175–176
201–202
197–199
170–172
196–198
172–173
230–231
204–208
155–157
–
247–250
234–236
218–220
183–185
205–207
221–224
227–229
219–222
–
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
[22]
[14]
[22]
[17]
[17]
[17]
[22]
[22]
[22]
H
4-Cl
4-Br
3-I
H
H
5
H
4-Me
4
H
4-OMeꢂ
6
4-Me
4-F
H
ꢂ
ꢂ
ꢂ
ꢂ
5
H
5
3-Me
3-Me
4-NO2
4-Me
4-Me
4-Me
4-Me
4-Me
4-Cl
4-Cl
4-Cl
3-Cl
H
6
4-Me
H
8
ꢂ
6
[22]
[22]
[14]
[14]
[17]
[22]
[14]
[14]
4-Br
4-Cl
4-F
3-I
4-OMeꢂ
4-Me
4-F
3-I
4-OMeꢂ
4-Cl
4-Br
3-I
ꢂ
ꢂ
ꢂ
ꢂ
5.5
5
7
6
4
ꢂ
ꢂ
ꢂ
4.5
4
4s
4t
4u
4v
4w
5
4
4.5
7
5
17
21
21
14
73
84
76
77
167–169
180–181
184–186
140–142
[22]
[22]
[22]
[14]
4-OMeꢂ
4-OMeꢂ
4-NO2
ꢂ
ꢂ
ꢂ
ꢂ
aIsolated yields.
Cl
Cl
Ti
O
O
OEt
Cl
Ar
N
O
2
Ar
OEt
N
O
5
Intermolecular
Mannich reaction
Cl
Ti
OEt
Ar NH2
O
Ar
N
H
Ar'
1
Ar'
H
N
Ar'
3
7
Ar
Cl Cl
Ti
H
6
O
Ar'
3
Ar
Ar
Ar
Ar
NH
N
O
O
NH
N
O
O
Intramolecular
Mannich reaction
OEt
OEt
OEt
OEt
Ar'
Ar'
N
Ar'
N
Ar'
N
Ar'
Ar'
N
Ar'
Ar'
Ar
Ar
Ar
Ar
4a–w
10
9
8
Scheme 2ꢀA plausible mechanism for the synthesis of piperidines 4a–w.
mentioned bacteria strains. Compound 4w with nitro and
iodo substituents displays the highest activity, while com-
Conclusions
pounds separately substituted with either a nitro group or A facile and efficient method for the synthesis of highly
an iodine atom are devoid of activity. substituted piperidines was developed. Some of the
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ꢀꢀꢀꢁ
4ꢀ ꢀM. Abbasi et al.: Highly functionalized tetrahydropiperidines
NH); 13C NMR (100 MHz, CDCl3): δ 14.4, 20.5, 21.2, 21.7, 34.4, 56.2, 58.2,
60.1, 95.1, 113.5, 125.2, 125.5, 127.3, 127.6, 127.8, 128.7, 126.5, 127.2, 128.8,
129.3, 130.1, 135.2, 138.9, 139.4, 146.3, 154.4, 169.6; MS (EI, 70 eV): m/z
Table 4ꢀAntibacterial activity of the synthesized piperidine
derivatives and reference drugs.
+
530 [M ]. Anal. Calcd for C36H38N2O2: C, 81.47; H, 7.22; N, 5.28. Found:
Compound
ꢁ
ꢁ
S. enterica
ꢁ
ꢁ
E. coli
C, 81.40; H, 7.43; N, 5.34.
DDa
ꢁ MICb
DD
ꢁ MIC
Ethyl 2,6-bis(4-chlorophenyl)-1-(3-iodophenyl)-4-((3-iodophenyl)
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4s)ꢁWhite solid;
mp 189–190°C; IR (KBr): 3234, 3069, 2956, 2875,1657, 1604, 1459, 1375,
1249, 1075 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.47 (3H, t, J ꢀ=ꢀ 7.5 Hz, CH3),
2.69 (1H, dd, J ꢀ=ꢀ 14.6, 2.7 Hz, C5-H′), 2.82 (1H, dd, J ꢀ=ꢀ 14.6, 5.4 Hz, C5-H″),
4.35 (1H, m, OCH2), 4.47 (1H, m, OCH2), 5.06 (1H, m, C6-H), 6.26 (1H,
s, C2-H), 6.37–6.46 (4H, m, ArH), 6.55 (1H, s, ArH), 6.74 (2H, d, J ꢀ=ꢀ 7.6
Hz, ArH), 6.93–7.24 (9H, m, ArH), 10.29 (1H, s, NH); 13C NMR (100 MHz,
CDCl3): δ 16.4, 33.9, 55.4, 59.1, 61.9, 99.2, 113.4, 117.4, 121.7, 123.8, 124.2,
125.4, 128.4, 128.8, 129.2, 129.6, 129.9, 130.2, 131.4, 131.7, 133.9, 134.7,
4q
4s
4t
ꢂ
ꢂ
ꢂ
ꢂ
11
10
9
12
10
10
ꢂ 750
ꢂ ꢂ>ꢂ1000
ꢂ NA
ꢂ 750
ꢂ 125
ꢂ 150
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
–
–
ꢂ
ꢂ
ꢂ
–
–
–
–
4w
13
15
12
ꢂ 500
ꢂ 100
ꢂ 125
Streptomycin (standard)ꢂ
Rifampicin (standard)
ꢂ
Compounds with no sensitivity are not reported.
aDiffusion diameter (mm).
bMinimum inhibitory concentration (μg/mL).
+
141.4, 142.5, 142.8, 147.9, 155.8, 168.9; MS (EI, 70 eV): m/z 793 [M ]. Anal.
Calcd for C32H26Cl2I2N2O2: C, 48.33; H, 3.30; N, 3.52. Found: C, 48.39; H,
3.21; N, 3.69.
synthesized products exhibit noticeable antibacterial
activity.
Antimicrobial activity assays
Experimental
Antimicrobial activity was determined against three
Gram-positive bacteria (S. epidermidis ATCC 12228, S.
aureus ATCC 29737, and B. subtilis ATCC 6633) and three
Gram-negative bacteria (S. enteriae PTCC 1188, E. coli
ATCC 10536, and K. pneumonia ATCC 10031), an yeast (C.
albicans ATCC 10231), and a fungus (A. niger ATCC 16404).
Antimicrobial activities of the samples were determined
by disc diffusion method through determination of a
diameter of inhibition zones [28]. Bacterial strains which
were sensitive to the samples in the disc diffusion assay
were chosen to study minimal inhibition concentration
(MIC) using a micro-well dilution assay method [29].
Streptomycin and rifampicin for bacteria and nystatin for
yeast were used as standard reference drugs under con-
centration conditions identical to that of test compounds.
All reagents were purchased from Merck and Aldrich and used with-
out further purification. Melting points were recorded on an Electro-
thermal type 9300 apparatus. FT-IR spectra were recorded using KBr
1
disks on an Avatar 370 FT-IR Thermo Nicolet spectrometer. H NMR
and 13C NMR spectra were collected on a Bruker Avance 400 spec-
trometer. Mass spectra were obtained on a Varian Mat CH-7 spectrom-
eter. Elemental analysis was performed on a Thermo Finnigan Flash
EA microanalyzer.
General procedure for the preparation of piperidines
4a–w
A solution of aniline or substituted aniline (2 mmol), ethyl acetoac-
etate (1 mmol), TiCl2·2H2O (15 mol%) in 96% EtOH (5 mL) was stirred
at room temperature. After 20 min, benzaldehyde or substituted
benzaldehyde (2 mmol) was added and the mixture was stirred for
the time indicated in Table 3. After the completion of the reaction
as monitored by TLC using CHCl3/MeOH (9:1) as eluent, the resulting
solid was filtered off, washed with EtOH (2ꢀ×ꢀ20 mL) and crystallized
from EtOH. The crude product found in the mother liquor was further
purified by column chromatography using CHCl3/MeOH (20:1) as elu-
ent and then crystallized from EtOH. Products prepared previously
are listed in Table 3.
References
[1] Brauch, S.; Van Berkel, S. S.; Westermann, B. Higher-order mul-
ticomponent reactions: beyond four reactants. Chem. Soc. Rev.
2013, 42, 4948–4962.
[2] Gu,Y. Multicomponent reactions in unconventional solvents:
state of the art. Green Chem. 2012, 14, 2091–2128.
[3] Shaabani, S.; Shaabani, A.; Ng, S. W. One-pot synthesis of
coumarin-3-carboxamides containing a triazole ring via an
isocyanide-based six-component reaction. ACS. Comb. Sci.
2014, 16, 176–183.
[4] Marcus, B.; Pankaj, C.; Robert, H.; Gerhard, R.; Dieter, E.
Asymmetric synthesis of tetrahydropyridines via an organocata-
lytic one-pot multicomponent michael/aza-Henry/cyclization
triple domino reaction. Org. Lett. 2014, 16, 6012–6015.
Ethyl 2,6-di-m-tolyl-1-(p-tolyl)-4-(p-tolylamino)-1,2,5,6-tetrahy-
dropyridine-3-carboxylate (4j)ꢁWhite solid; mp 181–182°C; IR
(KBr): 3249, 3068, 2956, 2869, 1649, 1585, 1452, 1372, 1249, 1075 cm-1; 1H
NMR (400 MHz, CDCl3): δ 1.46 (3H, t, J ꢀ=ꢀ 7.2 Hz, CH3), 2.17 (3H, s, CH3,
at phenyl), 2.27 (3H, s, CH3, at phenyl), 2.32 (6H, m, CH3, at phenyl),
2.70 (1H, dd, J ꢀ=ꢀ 15.2, 2.2 Hz, C5-H′), 2.83 (1H, dd, J ꢀ=ꢀ 15.2, 5.4 Hz, C5-
H″), 4.33 (1H, m, OCH2), 4.47 (1H, m, OCH2), 5.08 (1H, m, C6-H), 6.15
(2H, m, ArH), 6.37 (1H, s, C2-H), 6.45 (2H, m, ArH), 6.89 (3H, d, J ꢀ=ꢀ
10.5 Hz), 6.95 (2H, d, J ꢀ=ꢀ 7.6 Hz), 7.03–7.26 (7H, m, ArH), 10.19 (1H, s,
Unauthenticated
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ꢁꢀꢀꢀ
M. Abbasi et al.: Highly functionalized tetrahydropiperidinesꢃ ꢃ5
[5] Mateeva, N. N.; Winfield, L. L.; Redda, K. K. The chemistry and
pharmacology of tetrahydropyridines. Curr. Med. Chem. 2005,
12, 551–571.
[18] Li, X.; Zhao, Y.; Qu, H.; Mao, Z.; Lin, X. Organocatalytic asym-
metric multicomponent reactions of aromatic aldehydes and
anilines with β-ketoesters: facile and atom-economical access
to chiral tetrahydropyridines. Chem. Commun. 2013, 49, 1401.
[19] Ramachandran, R.; Jayanthi, S.; Jeong, Y. T. One-pot synthesis
of highly diversified tetrahydropyridines by tandem conden-
sation of aldehydes, amines, and β-ketoesters. Tetrahedron
2012, 68, 363–369.
[20] Sajadikhah, S. S.; Hazeri, N.; Maghsoodlou, M. T.; Habibi-
Khorassani, S. M.; Willis, A. C. Trityl chloride as an efficient
organic catalyst for one-pot, five-component and diastereose-
lective synthesis of highly substituted piperidines. Res. Chem.
Intermed. 2014, 40, 723–736.
[21] Safaei-Ghomi, J.; Ziarati, A. An efficient FeCl3/SiO2 NPs as a
reusable heterogeneous catalyzed five-component reactions of
tetrahydropyridines under mild conditions. J. Iran. Chem. Soc.
2013, 10, 135–139.
[22] Wang, H. J.; Mo, L. P.; Zhang, Z. H. Cerium ammonium nitrate-
catalyzed multicomponent reaction for efficient synthesis of
functionalized tetrahydropyridines. ACS. Comb. Sci. 2011, 13,
181–185.
[23] Khan, A. T.; Khan, M. M.; Bannura, K. K. Iodine catalyzed
one-pot five-component reactions for direct synthesis of
densely functionalized piperidines. Tetrahedron 2010, 66,
7762–7772.
[24] Mukhopadhyay, C.; Rana, S.; Butcher, R. J.; Schmiedekamp, A.
M. First report of syn isomers in the diastereoselective synthe-
sis of highly functionalized piperidines catalysed by wet picric
acid: factors influencing the syn-anti ratios. Tetrahedron Lett.
2011, 52, 5835–5840.
[25] Eshghi, H.; Khojastehnezhad, A.; Moeinpour, F.;
Bakavoli, M.; Seyedi, S. M.; Abbasi, M. Synthesis, characteri-
zation and first application of keggin-type heteropoly acids
supported on silica coated NiFe2O4 as novel magnetically
catalysts for the synthesis of tetrahydropyridines. RSC Adv.
2014, 4, 39782–39789.
[6] Duttwyler, S.; Lu, C.; Mercado, B. Q.; Bergman, R. G.; Ellman, J.
A. Regio- and stereoselective 1,2-dihydropyridine alkylation/
addition sequence for the synthesis of piperidines with quater-
nary centers. Angew. Chem. Int. Ed. 2014, 53, 3877–3880.
[7] Khan, A. T.; Lal, M.; Khan, M. M. Synthesis of highly functional-
ized piperidines by one-pot multicomponent reaction using
tetrabutylammonium tribromide (TBATB). Tetrahedron Lett.
2010, 51, 4419–4424.
[8] Mohite, A. R.; Sultane, P. R.; Bhat, R. G. BF3·Et2O and trifluoro-
acetic acid/triethyl amine-mediated synthesis of functionalized
piperidines. Tetrahedron Lett. 2012, 53, 30–35.
[9] Viegas, C.; Bolzani, J. V. S.; Furlan, M.; Barreiro, E. J.; Young, M.
C. M.; Tomazela, D.; Eberlin, M. N. Further bioactive piperidine
alkaloids from the flowers and green fruits of Cassia spectabi-
lis. J. Nat. Prod. 2004, 67, 908–910.
[10] Petit, S.; Nallet, J. P.; Guillard, M.; Dreux, J.; Chermat, R.; Poncelet,
M.; Bulach, C.; Simon, P.; Fontaine, C.; Barthelmebs, M.; et al.
Synthèses et activités psychotropes de 3,4-diarylpipéridines. Cor-
rélation structure-activité et recherche d’une activité antihyper-
tensive. Eur. J. Med. Chem. 1991, 26, 19–32.
[11] Zhou, Y.; Gregor, V. E.; Ayida, B. K.; Winters, G. C.; Sun, Z.;
Murphy, D.; Haley, G.; Bailey, D.; Froelich, J. M.; Fish, S. Synthe-
sis and antitumor activity of indolylpyrimidines: Marine natural
product meridianin D analogues. Bioorg. Med. Chem. 2007,
15, 1206–1211.
[12] Ho, B.; Crider, A. M.; Stables, J. P. Synthesis and structure–
activity relationships of potential anticonvulsants based on
2-piperidinecarboxylic acid and related pharmacophores. Eur.
J. Med. Chem. 2001, 36, 265–286.
[13] Misra, M.; Pandey, S. K.; Pandey, V. P.; Pandey, J.; Tripathi, R.;
Tripathi, R. P. Organocatalyzed highly atom economic one pot
synthesis of tetrahydropyridines as antimalarials. Bioorg. Med.
Chem. 2009, 17, 625–633.
[14] Clarke, P. A.; Zaytzev, A. V.; Whitwood, A. C. Pot, atom and step
economic (PASE) synthesis of highly functionalized piperi-
dines: a five-component condensation. Tetrahedron Lett. 2007,
48, 5209–5212.
[15] Sajadikhah, S. S.; Hazeri, N.; Maghsoodlou, M. T.; Habibi-
Khorassani, S. M.; Beigbabaei, A.; Lashkari, M. A one-pot
multi-component synthesis of N-aryl-3-aminodihydropyrrol-
2-one-4-carboxylates catalysed by oxalic acid dihydrate.
J. Chem. Res. 2013, 37, 40–42.
[26] Rahimizadeh, M.; Seyedi, S. M.; Abbasi, M.; Eshghi, H.; Kho-
jastehnezhad, A.; Moeinpour, F.; Bakavoli, M. Nanomagnetically
modified ferric hydrogen sulfate (NiFe2O4@SiO2-FHS): a reus-
able green catalyst for the synthesis of highly functionalized
piperidine derivatives. J. Iran. Chem. Soc. 2015, 12, 839–844.
[27] Shaterian, H. R.; Azizi, K. Acidic ionic liquids catalyzed one-
pot, pseudo five-component, and diastereoselective synthesis
of highly functionalized piperidine derivatives. J. Mol. Liqiuds
2013, 180, 187–191.
[16] Mishra, S.; Ghosh, R. Efficient one-pot synthesis of functional-
ized piperidine scaffolds via ZrOCl2·8H2O catalyzed tandem
reactions of aromatic aldehydes with amines and acetoacetic
esters. Tetrahedron Lett. 2011, 52, 2857–2861.
[17] Brahmachari, G.; Das, S. Bismuth nitrate-catalyzed multicom-
ponent reaction for efficient and one-pot synthesis of densely
functionalized piperidine scaffolds at room temperature.
Tetrahedron Lett. 2012, 53, 1479–1484.
[28] Manjula, M. K.; Rai, K. M. L.; Gaonkar, S. L.; Raveesha, K. A.;
Satish, S. Synthesis of new series of 5,6-dihydro-4 H-1,2-oxa-
zines via hetero Diels-Alder reaction and evaluation of antimi-
crobial activity. Eur. J. Med. Chem. 2009, 44, 280–288.
[29] Oroojalian, F.; Kasra-Kermanshahi, R.; Azizi, M.; Bassami, M.
R. Phytochemical composition of the essential oils from three
Apiaceae species and their antibacterial effects on food-borne
pathogens. Food Chem. 2010, 120, 765–770.
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