Alum as an efficient catalyst for the multicomponent synthesis of functionalized piperidines

Article abstract of DOI:10.1007/s11164-017-2979-3

An effective approach to the synthesis of functionalized piperidines via a one-pot multicomponent reaction of aniline, β-ketoester and aldehyde in the presence of alum as an efficient catalyst has been reported. The present procedure offers advantages such as simple workup, short reaction time and offers rapid access to a variety of functionalized piperidines.

Full text of DOI:10.1007/s11164-017-2979-3

Res Chem Intermed
DOI 10.1007/s11164-017-2979-3
Alum as an efficient catalyst for the multicomponent
synthesis of functionalized piperidines
Ramneet Kaur1 Annah Gupta1 Kamal K. Kapoor1
•
•
Received: 10 January 2017 / Accepted: 3 May 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract An effective approach to the synthesis of functionalized piperidines via a
one-pot multicomponent reaction of aniline, b-ketoester and aldehyde in the pres-
ence of alum as an efficient catalyst has been reported. The present procedure offers
advantages such as simple workup, short reaction time and offers rapid access to a
variety of functionalized piperidines.
Keywords Alum Á Piperidine Á Multicomponent reaction Á b-ketoester
Introduction
The piperidine moiety is highly privileged, found in many bioactive alkaloids and
has widely been explored [1–5]. Several piperidines and their analogs are known to
possess anti-malarial, anti-bacterial, anti-hypertensive, anti-cancer, anti-inflamma-
tory and anti-convulsant activities [6–10]. They are present in organic fine
chemicals [11–13] and exhibit enzyme inhibitory activity against farnesyl
transferase or dihydroorotate dehydrogenase (DHODH) [14–16]. The piperidine
scaffold is present in many recognized drugs [17–20] such as, Palinavir is a potent
peptidomimetic-based HIV-protease inhibitor [21], Methylphenidate is used for the
treatment of Parkinson’s disease, nocturnal enuresis, and attention-deficit hyperac-
tivity disorder [22, 23], Methyprylon is a piperidine sedative-hypnotic drug [24] and
Donepezil is used for acetylcholinesterase (AChE) inhibition [25]. Furthermore,
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2979-3)
contains supplementary material, which is available to authorized users.
&
Kamal K. Kapoor
kamalkka@gmail.com
1
Department of Chemistry, University of Jammu, Jammu 180 006, India
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R. Kaur et al.
these scaffolds find useful applications as therapeutic agents in the treatment of
influenza infection and diabetes [26–28].
In view of the biological, pharmacological and synthetic importance of piperidines,
many protocols have been developed. Among the various decorums, the most widely
used are one-pot multicomponent condensation of aldehyde, aniline and b-ketoester in
the presence of catalysts such as InCl3 [29, 30], LaCl3.7H2O [31], bromodimethyl-
sulfonium bromide (BDMS) [32], iodine [33], BF3/SiO2 [34], SbI3 [35], ZrOCl2.7-
H2O [36], tetrabutylammonium tribromide (TBATB) [37], tartaric acid [38], cerium
ammonium nitrate [39], a-Fe2O3-BIMtribromide [40], amberlite IRA400-Cl Resin/I2/
KI [41], TiCl2.H2O [42], p-sulfonic acid calix[n]arenes [43] and Magnesium
hydrogen sulfate [44]. Some of these pathways suffer from one or more of the
drawbacks like poor yields, long reaction times, high loading of expensive catalyst,
use of the toxic catalyst and poor agreement with the green chemistry protocols.
Therefore, it is necessary to develop a simple and environmentally benevolent
synthetic procedure for the preparation of functionalized piperidines.
Alum (KAl(SO4)2Á12H2O) has received an extensive recognition in organic
synthesis due to its significant properties of being a readily available, inexpensive,
non-toxic catalyst with easy handling and workup procedure. Many organic
transformations such as the synthesis of tetrahydrobenzoxanthenones [45], 2-3
dihydroquinazolin-4(1H)-ones [46], spirooxindole [47, 48], coumarins [49] and 1,5-
benzodiazepines [50] have been achieved by using alum as catalyst.
In our ongoing efforts to explore the usage of alum as an eco- friendly Lewis acid
catalyst in organic synthesis, we contemplated employing it for the synthesis of
functionalized piperidines via Knoevenagel condensation followed by [4 ? 2] aza
Diels–Alder reaction between the anilines, b-ketoesters and aldehydes.
Result and discussion
To begin with, a mixture of aniline (2 mmol), ethylacetoacetate (1 mmol) and alum
(20 mol%) in ethanol (10 mL) was stirred at room temperature. After 15 min, TLC
revealed the complete disappearance of ethylacetoacetate with appearance of a new
spot and at this stage, p-chloro benzaldehyde (2 mmol) was added, and the reaction
mixture was stirred till the formation of product (8 h, TLC). The desired product
ethyl 2,6-bis (4-chloro phenyl)-1phenyl-4-(phenylamino)-1,2,5,6-tetrahydropy-
ridine-3-carboxylate was obtained as pale yellow solid in 82% yield. To improve
the yield and time of the product formation, the aforementioned reaction was
refluxed after the addition of p-chloro benzaldehyde. The reaction got completed in
four hours and a slight improvement in yield (86%) was also noticed.
Changing the amount of catalyst (0, 10, 20, 30 mol%) as well as solvent
(methanol, acetonitrile, ethyl-acetate, THF) did not prove beneficial in term of yield
and time (Table 1).
To further explore the scope of methodology, commercially available substituted
anilines, b- ketoesters, and substituted aldehydes were submitted to optimized
reaction conditions, and the results are listed in Table 2. Single crystal X-ray
analysis of the product 4j [51, 56] confirmed their identity.
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Alum as an efficient catalyst for the multicomponent…
Table 1 Optimization of reaction conditions
Entry
Solvent
Amount of catalyst
(w.r.t b-ketoester)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
MeOH
CH3CN
EtOAc
THF
20 mol%
10 mol%
30 mol%
0
4
9
86
63
4
83
12
7
No reaction
20 mol%
20 mol%
20 mol%
20 mol%
57
66
35
52
10
9
8
Reaction conditions: aniline (2 mmol), ethylacetoacetate (1 mmol), p-chloro benzaldehyde (2 mmol) and
alum (20 mol%, 0.2 mmol) under refluxing conditions
a
Isolated yields
Keeping in view the earlier literature reports [6, 31, 32, 35, 36, 38], the following
mechanism involving Knoevenagel and aza Diels–Alder reaction is proposed as
Scheme 1. In the presence of alum, one molecule of aromatic amine (1) reacts with
b-ketoester (3) to give b-enaminone (I) which further reacts with one molecule of
aldehyde via Knoevenagel condensations to form an intermediate (III) that
tautomerizes to intermediate (IV). Additionally, imine (II) was formed by the
condensation of aromatic amine with aldehyde. The intermediate (IV) and imine
(II) undergo intramolecular [4 ? 2] aza Diels–Alder reaction to afford the desired
functionalized piperidines.
To support the integrity of the above proposed mechanism, a mixture of one
equivalent each of aniline and ethyl acetocetate in ethanol (10 ml) was stirred in a
round bottom flask in the presence of alum (20 mol%) for 15 min, and the product
obtained was isolated by column chromatography and found to be b-enaminone (1)
with spectral data (1H, 13C NMR) comparable to that reported earlier [52, 53].
However, bids to isolate the intermediate (IV) proved futile owing to its
unstable nature13 (1H and 13C NMR spectra of enamine 1 are also included in the
Supplementary information).
The efficiency of our method with earlier reported methods is compared by the
amount of catalyst, reaction conditions, yield and time. It is clear from the table (Table 3,
Entry 1), that 20 mol% alum is most effective with respect to reaction time and yield of
products and thus corroborating the efficiency of the present method.
Experimental
General
All the commercially available reagents were purchased from Aldrich and were
used without further purification. Melting points (°C) were measured in open glass
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Alum as an efficient catalyst for the multicomponent…
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Alum as an efficient catalyst for the multicomponent…
Scheme 1 Proposed mechanism for the synthesis of highly functionalized piperidines
Table 3 Comparison of the catalytic activity of alum with reported methods for the one-pot multi-
component synthesis of functionalized piperidines
S. no
Catalyst
Reaction conditions
Yield (%)
Time
1
2
3
4
5
6
7
Alum (20 mol%)
11
EtOH, Reflux
MeCN, R.T
MeOH, R.T
MeOH, RT
85
60
80
81
78
82
80
3 h 25 min
48 h
InCl3 (33 mol%)
12
LaCl3.7H2O (20 mol%)
14
3 h 30 min
8 h
I2 (10 mol%)
15
BF3.SiO2 (15 mol%)
16
MeOH, 65 °C
EtOH, 50 °C
EtOH, Reflux
9 h
SbI3 (15 mol%)
17
ZrOCl2.8H2O (20 mol%)
6 h
3 h 30 min
Reaction conditions: aniline (2 mmol), methyl acetoacetate (1 mmol), benzaldehyde (2 mmol) and
catalyst
capillaries using Perfit melting point apparatus and are uncorrected. The progress of
the reaction was monitored by thin layer chromatography (TLC) using silica gel pre-
coated aluminium sheets (60 F254, Merck). Visualization of spots was effected by
exposure to ultraviolet light (UV) at 254 nm, iodine vapours, 2% 2,4-
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R. Kaur et al.
dinitrophenylhydrazine in methanol containing few drops of H2SO4 and draggen-
1
droff reagent. H NMR and 13C NMR spectra in CDCl3 as solvents were recorded
on Bruker.
1
An AC-400 spectrometer operating at 400 MHz for H and 100 MHz for 13C,
with tetramethylsilane (TMS) was the internal standard. Electron impact mass
spectra (EIMS) were recorded on a Micro Mass VG-7070 H mass spectrometer at
70 eV. Elemental analysis was performed on a Leco CHNS-932 analyzer.
General procedure
A mixture of aryl-amine (2 mmol), b-keto ester (1 mmol) and alum (20 mol%) was
stirred at room temperature in ethanol (10 mL) for 15 min (TLC) followed by the
addition of aldehyde (2 mmol). The reaction mixture was refluxed till the
completion of reaction (TLC). The catalyst was filtered off and solvent was
concentrated in vacuo. and the residue was dissolved in ethylacetate (30 ml),
washed with water (5 9 10 ml), and brine (2 9 10 ml) and dried over anhydrous
Na2SO4. Ethylacetate was concentrated in vacuo to yield the desired product.
Spectral data of the synthesized compounds
Compound 4a: Ethyl-1-phenyl-4-(phenylamino)-2,6-di-p-tolyl-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.34 (s, 1H,
D2O exchangeable), 7.32–7.23 (m, 3H), 7.16–7.06 (m, 10H), 6.64 (t, J = 7.2 Hz,
1H), 6.57 (d, J = 8.3 Hz, 2H), 6.46 (s, 1H), 6.34 (d, J = 6.4 Hz, 2H), 5.16 (d,
J = 4 Hz, 1H), 4.55–4.44 (m, 1H), 4.41–4.32 (m, 1H), 2.95–2.77 (m, 2H), 2.37 (d,
J = 6.0 Hz, 6H), 1.50 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 168.3,
156.1, 147.1, 141.0, 139.7, 138.0, 136.6, 135.7, 129.2, 128.9, 128.8, 128.8, 126.5,
126.3, 125.7, 125.5, 115.9, 112.9, 98.3, 59.6, 57.9, 54.8, 33.6, 21.1, 21.0, 14.8.
Anal. Calcd for C34H34N2O2: C, 81.24; H, 6.82; N, 5.57%. Found: C, 81.19; H,
6.79; N, 5.51%. MS(ESI) (m/z): 503 [M ? H]?.
Compound 4b: Ethyl-2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.36 (s, 1H,
D2O exchangeable), 7.29 (s, 2H), 7.21–7.07 (m, 7H), 6.85 (d, J = 6.4 Hz, 4H), 6.61
(dd, J = 21.5, 5.1 Hz, 3H), 6.41 (s, 3H), 5.13 (s, 1H), 4.48 (dd, J = 10.7, 6.8 Hz,
1H), 4.35 (dd, J = 10.7, 6.8 Hz, 1H), 3.82 (d, J = 3.8 Hz, 6H), 2.85 (dd, J = 38.7,
14.7 Hz, 2H), 1.50 (t, J = 4 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 168.2,
158.6, 158, 156.1, 147.0, 137.9, 135.9, 134.6, 128.8, 127.6, 127.4, 125.7, 125.5,
116.0, 113.9, 113.5, 112.9, 98.3, 59.6, 57.5, 55.3, 55.2, 54.5, 33.7, 14.8. Anal.
Calcd for C34H34N2O4: C, 76.38; H, 6.41; N, 5.24%. Found: C, 76.29; H, 6.35; N,
5.20%. MS(ESI) (m/z): 535 [M ? H]?.
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Alum as an efficient catalyst for the multicomponent…
Compound 4c: Ethyl-2,6-bis(4-chlorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3 carboxylate
Physical appearance Pale yellow solid. 1H NMR (400 MHz, CDCl3): d 10.00 (s,
1H, D2O exchangeable), 7.40–6.99 (m, 14H), 6.72 (t, J = 7.5 Hz, 1H), 6.65–6.40
(m, 4H), 5.15 (s, 1H), 4.76–4.34 (m, 2H), 3.17–2.52 (m, 2H), 1.52 (t, J = 7.3 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 168.0, 155.8, 146.5, 142.5, 140.9, 137.6,
132.8, 132.1, 129.1, 129.0, 128.8, 128.4, 128.0, 127.8, 125.9, 125.7, 116.7, 113.0,
97.8, 59.9, 57.4, 54.7, 33.7, 14.8. Anal. Calcd for C32H28Cl2N2O2: C, 70.72; H,
5.19; N, 5.15; %. Found: C, 70.65; H, 5.23; N, 5.09%. MS(ESI) (m/z): 544, 546
[M ? H]?.
Compound 4d: Ethyl-2,6-bis(4-bromophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.36 (s, 1H,
D2O exchangeable), 7.44 (d, J = 7.9 Hz, 4H), 7.29–7.03 (m, 10H), 6.70 (t,
J = 7.2 Hz, 1H), 6.52 (d, J = 8.1 Hz, 2H), 6.46 (d, J = 7.4 Hz, 1H), 6.41 (s, 1H),
5.14 (s, 1H), 4.51–4.49 (m,1H), 4.39 (dd, J = 15.8, 8.7 Hz, 1H), 2.96–2.65 (m, 2H),
1.51 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 167.9, 155.8, 146.4,
143.0, 141.5, 137.6, 131.7, 131.4, 129.1, 129.0, 128.4, 128.2, 125.7, 120.9, 120.2,
116.8, 113.0, 97.7, 59.9, 57.4, 54.8, 33.6, 14.8. Anal. Calcd for C32H28Br2N2O2:
C, 60.78; H, 4.46; N, 4.43%. Found: C, 60.65; H, 4.52; N, 4.39%. MS(ESI) (m/z):
633, 635 [M ? H]?.
Compound 4e: Ehyl-1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.37 (s, 1H,
D2O exchangeable), 7.43–7.11 (m, 15H), 6.72–6.50 (m, 4H), 6.34 (d, J = 5.2 Hz,
2H), 5.21 (s, 1H), 4.58–4.48 (m, 1H), 4.40–4.37 (m, 1H), 2.95 (dd, J = 15.1,
5.6 Hz, 1H), 2.89–2.76 (m, 1H), 1.54 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 168.2, 156.1, 147.0, 144.0, 142.8, 137.9, 128.9, 128.8, 128.6, 128.2,
127.1, 126.6, 126.4, 126.3, 125.8, 125.7, 116.1, 112.9, 98.2, 59.7, 58.2, 55.1, 33.6,
14.8. Anal. Calcd for C32H30N2O2: C, 80.98; H, 6.37; N, 5.90%. Found: C, 80.87;
H, 6.41; N, 5.95%. MS(ESI) (m/z): 475 [M ? H]?.
Compound 4f: Ethyl-2,6-bis(4-nitrophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance Yellow solid. H NMR (400 MHz, CDCl3): d 10.75 (s, 1H,
D2O exchangeable), 8.28 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.7 Hz, 2H), 7.76 (d,
J = 8.5 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 7.26–7.14 (m,
3H), 7.03 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 8.2 Hz, 3H), 6.04 (s, 1H), 4.74–4.68 (m,
1H), 4.30 -4.14 (m, 2H), 2.85 (dd, J = 15.7, 3.4 Hz, 1H), 2.48 (dd, J = 15.7,
12.1 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 168.0,
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R. Kaur et al.
156.3, 153.9, 150.1, 149.6, 147.1, 147.0, 138.0, 129.5, 129.1, 128.1, 127.7, 125.5,
124.1, 123.7, 120.9, 120.8, 117.8, 96.4, 62.0, 61.0, 60.0, 36.1, 14.4. Anal. Calcd for
C32H28N4O6: C, 68.07; H, 5.00; N, 9.92%. Found: C, 68.00; H, 5.08; N, 9.87%.
MS(ESI) (m/z): 565 [M ? H]?.
Compound 4g: Ethyl-2,6-bis(3-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.35 (s, 1H,
D2O exchangeable), 7.29 (s, 1H), 7.22 (t, J = 7.8, Hz, 2H), 7.18–7.05 (m, 4H), 7.0
4–6.91 (m, 2H), 6.86–6.71 (m, 4H), 6.67–6.53 (m, 3H), 6.45 (s, 1H), 6.36 (d,
J = 6.6, Hz, 2H), 5.14 (s, 1H), 4.54–4.30 (m, 2H), 3.81 (d, J = 3.9 Hz, 6H), 2.97
(dd, J = 15.1, 5.7 Hz, 1H), 2.81 (dd, J = 15.1, 2.3 Hz, 1H), 1.50 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 168.1, 159.8, 159.6, 156.2, 146.9, 145.9,
144.6, 137.8, 129.6, 129.1, 128.8, 128.8, 125.9, 125.7, 119.0, 118.8, 116.2, 112.9,
112.8, 112.8, 111.6, 111.1, 97.8, 59.6, 58.2, 55.1, 55.1, 55.0, 33.5, 14.8. Anal.
Calcd for C34H34N2O4: C, 76.38; H, 6.41; N, 5.24%. Found: C, 76.24; H, 6.35; N,
5.20%. MS(ESI) (m/z): 535 [M ? H]?.
Compound 4h: Ethyl-2,6-bis(3-chlorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.28 (s, 1H,
D2O exchangeable), 7.23–6.95 (m, 11H), 6.75–6.34 (m, 6H), 6.20 (d, J = 8.3 Hz,
2H), 5.14 (d, J = 5.6 Hz, 1H), 4.62–4.28 (m, 2H), 2.89 (dd, J = 15.2, 5.7 Hz, 1H),
2.73 (d, J = 15.0 Hz, 1H), 1.51 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 168.1, 160.7, 155.4, 145.5, 143.2, 142.2, 136.4, 135.9, 131.6, 131.3,
128.3, 127.4, 127.0, 126.5, 126.5, 126.3, 125.5, 122.2, 121.2, 116.2, 114.0, 98.6,
59.9, 58.3, 55.2, 33.4, 14.8. Anal. Calcd for C32H28Cl2N2O2: C, 70.72; H, 5.19; N,
5.15%. Found: C, 70.62; H, 5.26; N, 5.16%. MS(ESI) (m/z): 544, 546 [M ? H]?.
Compound 4i: Ethyl-2,6-bis(2-nitrophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
Physical appearance Yellow solid. 1H NMR (400 MHz, CDCl3): d 10.51 (s, 1H,,
D2O exchangeable), 7.92 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55–7.02
(m, 12H), 6.87 (s, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.70–6.50 (m, 3H), 5.89 (t,
J = 5.0 Hz, 1H), 4.44–4.10 (m, 2H), 3.05–2.85 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 167.9, 155.6, 150.1, 148.4, 145.9, 137.5, 137.3,
137.0, 133.3, 131.4, 129.5, 129.2, 129.1, 128.4, 127.8, 126.2, 125.6, 125.0, 124.5,
119.4, 116.3, 95.1, 60.2, 54.0, 52.6, 31.4, 14.3. Anal. Calcd for C32H28N4O6: C,
68.07; H, 5.00; N, 9.92; O, 17.00%. Found: C, 67.97; H, 5.11; N, 9.95%. MS(ESI)
(m/z): 565 [M ? H]?.
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Alum as an efficient catalyst for the multicomponent…
Compound 4j: Ethyl-1-phenyl-4-(phenylamino)-2,6-bis(3,4,5-trimethoxyphenyl)-
1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.35 (s, 1H,
D2O exchangeable), 7.19–7.07 (m, 5H), 6.69–6.55 (m, 5H), 6.40 (d, J = 5.7 Hz,
5H), 5.07 (s, 1H), 4.54–4.44 (m, 1H), 4.32 (dd, J = 15.9, 8.7 Hz, 1H), 3.86 (d,
J = 3.1 Hz, 6H), 3.74 (d, J = 14.9 Hz, 12H), 2.99 (dd, J = 14.8, 5.0 Hz, 1H), 2.79
(d, J = 14.8 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
168.0, 156.7, 153.3, 152.9, 146.9, 139.7, 138.5, 137.8, 136.9, 136.3, 128.8, 126.1,
125.9, 116.4, 112.9, 103.7, 103.0, 97.4, 60.9, 60.8, 59.5, 58.3, 56.0, 56.0, 55.9, 55.4,
33.7, 15.0. Anal. Calcd for C38H42N2O8: C, 69.71; H, 6.47; N, 4.28%. Found: C,
69.66; H, 6.52; N, 4.26%. MS(ESI) (m/z): 655 [M ? H]?.
Compound 4k: Ethyl-2,6-bis(benzo[d] [1, 3] dioxol-5-yl)-1-phenyl-4-
(phenylamino)piperidine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.38 (s, 1H,
D2O exchangeable), 7.20–7.06 (m, 5H), 6.88 (s, 1H), 6.77–6.70 (m, 2H),
6.82–6.61(m, 4H), 6.55 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 7.6 Hz, 2H), 6.34 (s,
1H), 6.08–5.81 (m, 4H), 5.05 (s, 1H), 4.29–4.28 (m, 2H), 2.93 (dd, J = 15.2,
5.7 Hz, 1H), 2.79 (d, J = 15.8 Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 167.4, 149.3, 148.6, 148.2, 147.6, 147.0, 146.5, 139.4, 137.9,
136.8, 128.8, 128.8, 125.6, 125.6, 119.4, 119.4, 116.3, 116.0, 113.0, 113.0, 108.3,
107.7, 107.3, 107.1, 100.9, 100.9, 95.9, 59.7, 57.7, 56.1, 33.7, 14.7. Anal. Calcd for
C34H30N2O6: C, 72.58; H, 5.37; N, 4.98%. Found: C, 72.49; H, 5.35; N, 5.02%.
MS(ESI) (m/z): 563 [M ? H]?.
Compound 4l: Ethyl-1-phenyl-4-(phenylamino)-2,6-di(thiophen-2-yl)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance Brown solid. H NMR (400 MHz, CDCl3): d 10.67 (s, 1H,
D2O exchangeable), d 7.34 (t, J = 7.8 Hz, 2H), 7.27 (dd, J = 6.9, 3.4 Hz, 2H),
7.23–7.15 (m, 3H), 7.12–7.06 (m, 2H), 7.01 (t, J = 8.3 Hz, 5H), 6.96–6.76 (m, 2H),
6.21 (s, 1H), 4.94 (dd, J = 11.4, 4.3 Hz, 1H), 4.47–4.04 (m, 2H), 3.08–2.84 (m,
2H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 167.8, 157.0,
152.7, 149.9, 148.4, 138.3, 129.3, 128.7, 127.0, 126.4, 125.0, 124.6, 124.1, 123.9,
123.9, 123.9, 119.2, 116.3, 98.8, 59.8, 59.5, 56.0, 37.0, 14.5. Anal. Calcd for
C28H26N2O2S2: C, 69.11; H, 5.39; N, 5.76; S, 13.18%. Found: C, 69.14; H, 5.32;
N, 5.80; S, 13.20%. MS(ESI) (m/z): 487 [M ? H]?.
Compound 4m: Ethyl-2,6-diphenyl-1-(p-tolyl)-4-(p-tolylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.35 (s, 1H,
D2O exchangeable), 7.55–7.26 (m, 10H), 6.99 (d, J = 7.9 Hz, 4H), 6.64–6.48 (m,
3H), 6.26 (d, J = 7.6 Hz, 2H), 5.23 (d, J = 5.5 Hz, 1H), 4.60–4.46 (m, 2H),
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R. Kaur et al.
3.05–2.75 (m, 2H), 2.30 (dd, J = 35.8, 6.1 Hz, 6H), 1.57 (t, J = 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 168.3, 156.5, 144.9, 144.4, 143.1, 135.6, 135.3, 129.5,
129.5, 128.7, 128.3, 126.7, 126.5, 126.0, 112.9, 97.7, 59.6, 58.3, 55.2, 33.6, 20.9,
20.2, 14.9. Anal. Calcd for C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; O, 6.37%.
Found: C, 81.20; H, 6.84; N, 5.59%. MS(ESI) (m/z): 503 [M ? H]?.
Compound 4n: Ethyl-1-(4-fluorophenyl)-4-((4-fluorophenyl)amino)-2,6-diphenyl-
1,2,5,6 tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.21 (s, 1H,
D2O exchangeable), 7.35–7.13 (m, 10H), 6.80 (m, 4H), 6.43 (dd, J = 15.3, 10.4 Hz,
3H), 6.30–6.13 (m, 2H), 5.11 (s, 1H), 4.54–4.44 (m, 1H), 4.40–4.31 (m, 1H), 2.85
(dd, J = 15.0, 5.4 Hz, 1H), 2.65 (d, J = 15.2 Hz, 1H), 1.49 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 168.2, 162.0, 159.5, 156.1, 156.0, 153.8, 143.6,
143.4, 142.7, 128.7, 128.2, 128.0, 128.0, 126.6, 126.3, 115.7, 115.5, 115.4, 115.1,
113.6, 113.6 98.0, 59.7, 58.4, 55.5, 33.5, 14.7. Anal. Calcd for C32H28F2N2O2: C,
75.28; H, 5.53; N, 5.49%. Found: C, 75.24; H, 5.55; N, 5.43%. MS(ESI) (m/z): 511
[M ? H]?.
Compound 4o: Ethyl-1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-diphenyl-
1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.28 (s, 1H,
D2O exchangeable), 7.37–7.25 (m, 8H), 7.19 (d, J = 6.9 Hz, 2H), 7.06 (dd,
J = 21.7, 8.5 Hz, 4H), 6.51–6.41 (m, 3H), 6.20 (d, J = 8.2 Hz, 2H), 5.14 (d,
J = 4.6 Hz, 1H), 4.51 (dd, J = 10.6, 7.1 Hz, 1H), 4.37 (dd, J = 10.6, 7.1 Hz, 1H),
2.89 (dd, J = 15.1, 5.7 Hz, 1H), 2.73 (d, J = 15.0 Hz, 1H), 1.51 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 168.6, 156.3, 146.9, 143.9, 142.7, 137.8,
128.9, 128.9, 128.7, 128.3, 127.2, 126.6, 126.4, 126.3, 125.9, 125.8, 116.2, 112.9,
97.9, 58.2, 55.1, 51.1, 33.6. Anal. Calcd for C32H28Cl2N2O2: C, 70.72; H, 5.19; N,
5.15%. Found: C, 70.67; H, 5.24; N, 5.21%. MS(ESI) (m/z): 544, 546 [M ? H]?.
Compound 4p: Ethyl-1-(3-chlorophenyl)-4-((3-chlorophenyl)amino)-2,6-diphenyl-
1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.27 (s, 1H,
D2O exchangeable), 7.45–7.23 (m, 8H), 7.19 (d, J = 7.0 Hz, 2H), 7.05 (dd,
J = 21.7, 8.2 Hz, 4H), 6.53–6.37 (m, 3H), 6.20 (d, J = 8.4 Hz, 2H), 5.15 (s, 1H),
4.60–4.30 (m, 2H), 2.88 (dd, J = 15, 5.2 Hz, 1H), 2.73 (d, J = 15.1 Hz, 1H), 1.51
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 168.1, 155.4, 145.4, 143.2,
142.2, 136.4, 131.3, 129, 128.8, 128.7, 128.3, 127.4, 127.0, 126.5, 126.5, 126.2,
121.2, 114.0, 98.6, 59.9, 58.3, 55.2, 33.4, 14.7. Anal. Calcd for C32H28Cl2N2O2: C,
70.72; H, 5.19; N, 5.15%. Found: C, 70.68; H, 5.12; N, 5.11%. MS(ESI) (m/z):
544, 546 [M ? H]?.
123

Alum as an efficient catalyst for the multicomponent…
Compound 4q: Ethyl-1-(2-chlorophenyl)-4-((2-chlorophenyl)amino)-2,6-diphenyl-
1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.28 (s, 1H,
D2O exchangeable), 7.37–7.24 (m, 8H), 7.19 (d, J = 6.9 Hz, 2H), 7.06 (dd,
J = 21.7, 8.0 Hz, 4H), 6.50–6.41 (m, 3H), 6.20 (d, J = 7.9 Hz, 2H), 5.15 (d,
J = 4.4 Hz, 1H), 4.56–4.47 (m, 1H), 4.38–4.34 (m, 1H), 2.90 (dd, J = 15.1,
5.6 Hz, 1H), 2.74 (d, J = 15.1 Hz, 1H), 1.51 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 168.1, 155.4, 145.5, 143.2, 142.2, 136.4, 131.3, 129.0, 128.8,
128.7, 128.4, 127.4, 127.0, 126.5, 126.5, 126.3, 121.2, 114.0, 98.7, 59.9, 58.3, 55.2,
33.5, 14.8. Anal. Calcd for C32H28Cl2N2O2: C, 70.72; H, 5.19; N, 5.15%. Found:
C, 70.70; H, 5.20; N, 5.14%. MS(ESI) (m/z): 544, 546 [M ? H]?.
Compound 4r: Ethyl-2,6-bis(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-1-(p-
tolyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.28 (s, 1H,
D2O exchangeable), 7.30–6.85 (m, 13H), 6.65–6.13 (m, 4H), 5.10 (s, 1H), 4.41 (d,
J = 44.4 Hz, 2H), 3.83 (s, 6H), 2.80 (d, J = 20.6 Hz, 2H), 2.25 (d, J = 41.5 Hz,
6H), 1.70–1.30 (m, 3H). 13C NMR (100 MHz, CDCl3): d 168.3, 158.6, 157.9,
156.5, 144.9, 136.3, 135.4, 135.3, 129.4, 127.7, 127.5, 125.8, 124.9, 113.9, 113.5,
112.9, 97.8, 59.5, 57.5, 55.3, 55.2, 54.6, 33.7, 20.9, 20.1, 14.8. Anal. Calcd for
C36H38N2O4: C, 76.84; H, 6.81; N, 4.98; O, 11.37%. Found: C, 76.78; H, 6.79; N,
5.02%. MS(ESI) (m/z): 563 [M ? H]?.
Compound 4s: Methyl-1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-
3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.34 (s, 1H,
D2O exchangeable), 7.43–7.21 (m, 11H), 7.18–7.09 (m, 5H), 6.71–6.53 (m, 4H),
6.35 (d, J = 6.8 Hz, 2H), 5.22 (d, J = 3.8 Hz, 1H), 4.00 (s, 3H), 3.01–2.80 (m, 2H).
13C NMR (100 MHz, CDCl3): d 168.6, 156.3, 146.9, 143.9, 142.7, 137.8, 128.9,
128.9, 128.7, 128.3, 127.2, 126.6, 126.4, 126.3, 125.9, 125.8, 116.2, 112.9, 97.9,
58.2, 55.1, 51.1, 33.6. Anal. Calcd for C31H28N2O2: C, 80.84; H, 6.13; N, 6.08%.
Found: C, 80.78; H, 6.15; N, 6.11%. MS (ESI) (m/z): 461 [M ? H]?.
Compound 4t: Methyl-2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.30 (s, 1H,
D2O exchangeable), d 7.25 (d, J = 8.2 Hz, 2H), 7.17–7.06 (m, 7H), 6.84 (d,
J = 8.2 Hz, 4H), 6.63 (t, J = 7.4 Hz, 1H), 6.56 (d, J = 8.2 Hz, 2H), 6.39 (d,
J = 6.5 Hz, 3H), 5.12 (s, 1H), 3.95 (s, 3H), 3.81 (d, J = 4.9 Hz, 6H), 2.88 (dd,
J = 15.1, 5.3 Hz, 1H), 2.78 (d, J = 15.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d
168.6, 158.6, 158.0, 156.3, 147.0, 137.9, 135.8, 134.6, 128.8, 128.8, 127.7, 127.4,
125.7, 125.6, 116.0, 113.9, 113.5, 112.9, 98.1, 57.5, 55.3, 55.2, 54.5, 51.0, 33.7.
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R. Kaur et al.
Anal. Calcd for C33H32N2O4: C, 76.13; H, 6.20; N, 5.38%. Found: C, 76.10; H,
6.14; N, 5.33%. MS (ESI) (m/z): 521 [M ? H]?.
Compound 4u: Methyl-2,6-bis(4-bromophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.26 (s, 1H,
D2O exchangeable), 7.41 (d, J = 7.6 Hz, 4H), 7.28 (s, 2H), 7.22–6.97 (m, 8H), 6.67
(t, J = 7.3 Hz, 1H), 6.45 (dd, J = 17.7, 7.7 Hz, 3H), 6.35 (s, 1H), 5.10 (s, 1H), 3.94
(s, 3H), 2.89–2.72 (m, 3H). 13C NMR (100 MHz, CDCl3): d 168.35, 156.10,
146.40, 142.86, 141.43, 137.52, 131.71, 131.40, 131.35, 129.06, 129.04, 128.81,
128.71, 128.43, 128.36, 128.13, 126.10, 125.77, 120.93, 120.25, 116.77, 112.90,
97.38, 57.37, 54.75, 51.22, 33.64. Anal. Calcd for C31H26Br2N2O2: C, 60.21; H,
4.24; N, 4.53%. Found: C, 60.24; H, 4.20; N, 4.48%. MS(ESI) (m/z): 619, 621
[M ? H]?.
Compound 4v: Methyl-1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-diphenyl-
1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance White solid. H NMR (400 MHz, CDCl3): d 10.25 (s, 1H,
D2O exchangeable), 7.33 (s, 8H), 7.20 (d, J = 7.1 Hz, 2H), 7.10 (d, J = 7.5 Hz,
2H), 7.03 (d, J = 8.1 Hz, 2H), 6.52–6.42 (m, 3H), 6.21 (d, J = 7.7 Hz, 2H), 5.16
(d, J = 4.4 Hz, 1H), 3.99 (s, 3H), 2.91 (dd, J = 15.1, 5.4 Hz, 1H), 2.74 (d,
J = 15.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 168.53, 155.68, 145.50,
143.17, 142.25, 136.36, 131.49, 129.07, 128.87, 128.75, 128.44, 127.13, 126.54,
126.32, 114.06, 98.44, 58.32, 55.31, 51.27, 33.52. Anal. Calcd for C31H26Cl2N2-
O2: C, 70.32; H, 4.95; N, 5.29%. Found: C, 70.29; H, 4.90; N, 5.23%. MS (ESI)
(m/z): 530, 532 [M ? H]?.
Compound 4w: methyl 2,6-bis(benzo[d] [1, 3] dioxol-5-yl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate
1
Physical appearance Yellow solid. H NMR (400 MHz, CDCl3): d 10.38 (s, 1H,
D2O exchangeable), 7.25–7.07 (m, 5H), 6.89 (s, 1H), 6.80–6.63 (m, 6H), 6.58 (d,
J = 8.1 Hz, 2H), 6.49 (d, J = 7.6 Hz, 2H), 6.36 (s, 1H), 5.96 (d, J = 5.5 Hz, 4H),
5.08 (d, J = 3.7 Hz, 1H), 3.95 (s, 3H), 2.96 (dd, J = 15.1, 5.4 Hz, 1H), 2.81 (d,
J = 15.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 168.4, 156.1, 147.8, 147.7,
146.7, 146.6, 146.0, 137.9, 137.8, 136.8, 128.9, 128.9, 125.8, 125.7, 119.5, 119.4,
116.3, 113.0, 108.4, 107.8, 107.3, 107.1, 100.9, 100.9, 97.8, 57.7, 54.8, 51.1, 33.7.
Anal. Calcd for C33H28N2O6: C, 72.25; H, 5.14; N, 5.11%. Found: C, 72.32; H,
5.10; N, 5.05%. MS (ESI) (m/z): 549 [M ? H]?.
Intermediate (I): Ethyl 3-(Phenylamino)but-2-enoate
1
Physical appearance Yellow Oil, H NMR (400 MHz, CDCl3): d 10.40 (s, 1H),
7.33 (d, J = 7.8 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 7.9 Hz, 2H), 4.71
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Alum as an efficient catalyst for the multicomponent…
(s, 1H), 4.17 (dd, J = 14.2, 7.1 Hz, 2H), 2.02 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 170.4, 158.9, 139.3, 129.0, 124.9, 124.4, 120.1, 86.0,
58.7, 20.3, 14.5. MS (ESI) (m/z): 206 [M ? H]?.
Conclusion
In conclusion, alum has been found to be an efficient catalyst for the synthesis of
functionalized piperidines from substituted amines, b-ketoesters and substituted
aldehyde. The procedure offers several advantages such as good yields, reduced
reaction time, easy work-up and no column chromatography. The catalyst is mild
and environmentally benign in nature.
Acknowledgements The authors are thankful to Department of Chemistry, University of Jammu for
providing all necessary facilities and Department of Science and Technology, Government of India, New
Delhi for NMR facility under PURSE and for an INSPIRE fellowship (A.G). Authors are thankful to Dr.
Puneet Sood, IIT Mandi for X-ray crystallography.
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56. Crystal data of product 4j: C38H42N2O8, Formula weight = 654., Wavelength = 0.71073 A,
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Monoclinic, P21/c, a = 17.8058 (14) A, b = 10.7940 (7) A, c = 19.6612 (15) A, a = 90°,
b = 112.962°(9), c = 90°, V = 3479 (4) A , Z = 4, DCalcd = 1.248 Mg/m3, CCDC No: 1469233
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