Synthesis of 3-arylidene-4-piperidone derivatives as potent antioxidant agents: A solvent free approach

Article abstract of DOI:10.14233/ajchem.2019.21538

A simple procedure using grinding method of condensation of N-acetyl-3-methyl-2,6-diarylpiperidin-4-one with aldehyde gave N-acetyl-3-arylidene-5-methyl-2,6-diarylpiperidin-4-one with good yield. The structure of the synthesized compounds was assigned on

Full text of DOI:10.14233/ajchem.2019.21538

Asian Journal of Chemistry; Vol. 31, No. 2 (2019), 469-471
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21538
Synthesis of 3-Arylidene-4-Piperidone Derivatives as
Potent Antioxidant Agents: A Solvent Free Approach
1
2
1,*
V. LALITHA , T. MARUTHAVANAN and P. VENKATESAN
1Department of Chemistry, Thiruvalluvar Government Arts College, Rasipuram-637401, India
2Department of Chemistry, Sona College of Technology, Salem-636005, India
*Corresponding author: E-mail : venkatesanps@yahoo.co.in
Received: 22 June 2018;
Accepted: 12 November 2018;
Published online: 31 December 2018;
AJC-19229
A simple procedure using grinding method of condensation of N-acetyl-3-methyl-2,6-diarylpiperidin-4-one with aldehyde gave N-acetyl-
3-arylidene-5-methyl-2,6-diarylpiperidin-4-one with good yield. The structure of the synthesized compounds was assigned on the basis
of IR, 1H NMR and mass spectral studies. The synthesized compounds showed remarkable in vitro antioxidant activity.
Keywords: Piperidin-4-one, Arylidene derivatives, Chalcone, Grinding method, Antioxidant activity.
range of 4000 to 400 cm-1. 1H NMR spectrum (500 MHz) was
recorded on BrukerAVANCE III 500 MHz NMR Spectrometer
INTRODUCTION
Usage of organic solvents in various synthetic processes
are hazardous to the environment as well as human health. Thus,
the various eco-friendly methods in Green Chemistry have drawn
attention in organic synthesis. Because of simple workup proce-
dure, time consumption, compatibility with various functional
groups and good yields, the grindstone method has recently drawn
attention [1] in many reactions like Reformatsky reaction [2],
Grignard reaction [3], Aldol condensation [4], Knoevenagel
reaction [5], Michael addition [6], Wittig reaction [7], Biginelli
reaction [8], etc.
In addition, piperidin-4-ones moiety have been reported
to show the considerable biological importance such as anti-
pyretic, antioxidant, antimicrobial, antitumor activities [9-13].
Because of their extensive importance, we opted the grindstone
method to synthesize N-acetyl-3-arylidene-5-methyl-2,6-diaryl-
piperidin-4-one. The synthesized compounds were evaluated
for free radical scavenging activity.
using CDCl3 as solvent and tetramethyl silane (TMS) as the
internal standard. The chemical shift of H NMR spectrum
1
was reported in ppm scale. Mass spectrum was carried out
using Finnegan Mat 8230 mass spectrometer and fragmen-
tations were given in m/z values. The elemental analysis was
carried out onVario EL-III elemental analyzer and their reports
were agreed within 0.4 % of theoretical values. The progress
of the reaction was monitored by thin layer chromatography
on silica gel 60 F254 (Merck). The isolation of pure compounds
was done by column chromatography with silica gel 60-120
mesh (Merck). The parent compounds (1 and 2) were synthe-
sized as reported work [14].
Synthesis of N-acetyl-3-arylidene-5-methyl-2,6-diaryl-
piperidin-4-one (5-10) by grinding method: A mixture of
N-acetyl-3-methyl-2,6-diarylpiperidin-4-one (3,4) (0.01 mol),
arylaldehyde (0.01 mol) and NaOH pellets (0.5 g) were grounded
well at room temperature for 25-40 min using mortar and pestle.
Completion of the reaction was ascertained by TLC. Then,
the reaction mixture was transferred to a beaker containing
100 mL of ice water and neutralized with acetic acid. The resul-
ting residue is filtered, dried and subjected to column chromato-
gram to isolate pure compound using benzene-chloroform
(3:1) eluent (Scheme-I).
EXPERIMENTAL
All common chemicals and solvents were purchased from
Nice and Spectra Chemicals, India. IR spectrum was recorded
on Perkin-Elmer 577 IR spectrometer with KBr pellets in the
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470 Lalitha et al.
Asian J. Chem.
8H, ArH), 4.47 (d, 3J6a,5a = 11 Hz, 1H, 6-Ha), 4.95 (s, 1H, 2-Ha),
3.04 (m, 1H, 5-Ha), 0.87 (d, 3H, 5-CH3), 1.92 (s, 3H, N-COCH3),
7.91 (s, 1H, 3-methylene), 3.77 and 3.85 (s, 6H, Ar-OCH3); MS:
m/z 445.26 (M+). Elemental anal. calc (found) % for C27H27NO5:
C, 72.79 (72.86); H, 6.11 (6.08); N, 3.14 (3.13).
N-acetyl-3-(4-methoxybenzylidene)-5-methyl-2,6-di(4-
methoxyphenyl)piperidin-4-one (10): Pale yellow solid; m.p.
164 ºC; IR (KBr, νmax, cm-1): 3012 (ArCH), 1677 and 1704
(C=O str.), 1380 (CH3 bend.), 1902 (CH3 overtone); 1H NMR
(500 MHz, CDCl3): δ 6.62-7.68 (m, 12H, ArH), 4.43 (d, 3J6a,5a
= 11 Hz, 1H, 6-Ha), 4.97 (s, 1H, 2-Ha), 3.05-3.09 (m, 1H, 5-Ha),
0.87 (d, 3H, 5-CH3), 1.90 (s, 3H, N-COCH3), 7.96 (s, 1H, 3-meth-
ylene), 3.78, 3.80 and 3.89 (s, 9H,Ar-OCH3); MS: m/z 485.08
(M+). Elemental anal. calc (found) % for C30H31NO5: C, 74.21
(74.14); H, 6.43 (6.41); N, 2.88 (2.89).
Synthesis of N-acetyl-3-arylidene-5-methyl-2,6-diaryl-
piperidin-4-one (5-10) by conventional method [15]: The
appropriate N-acetyl-3-methyl-2,6-diarylpiperidin-4-one (3,
4) (0.01 mol) and appropriate arylaldehyde (0.01 mol) was
added to 100 mL ethanol. To the reaction mixture, 0.002 mol
of NaOH was added and refluxed till completion of the
reaction. Then, it was transferred into a beaker containing 100
mL of ice water. The resulting residue is filtered, dried and
subjected to column chromatogram to isolate pure compound
using chloroform-benzene (1:3) eluent.
O
N
R'
R'CHO / NaOH
(grinding)
R
R
O
O
N
O
Ac2O
Et3N / Benzene
(5-10)
N
H
(1-2)
R
R
R
R
R'CHO
NaOH
O
O
(3-4)
1, 3, 5, 6, 7 : R=C6H5-
2, 4, 8, 9, 10: R= (p-OCH3)C6H4-
5, 8 : R'=C6H5-
6, 9 : R'=furfuryl-
7, 10: R'=(p-OCH3)C6H4-
R
N
R
O
R'
(11)
Scheme-I: Synthetic pathway of target compounds
N-acetyl-3-benzylidene-5-methyl-2,6-diphenylpiperidin-
4-one (5): Pale yellow solid; m.p. 168 ºC; IR (KBr, νmax, cm-1):
2982 (ArCH), 1679 and 1708 (C=O str.), 1374 (CH3 bend),
1880 (CH3 overtone); 1H NMR (500 MHz, CDCl3): δ 6.85-7.74
(m, 15H, ArH), 4.51 (d, 3J6a,5a = 11.5 Hz, 1H, 6-Ha), 5.00 (s,
1H, 2-Ha), 3.07 (m, 1H, 5-Ha), 0.89 (d, 3H, 5-CH3), 1.89 (s,
3H, N-COCH3), 8.19 (s, 1H, 3-methylene); MS: m/z 395.32
(M+). Elemental anal. calc (found) % for C27H25NO2: C, 82.00
(81.78); H, 6.37 (6.38); N, 3.54 (3.55).
N-acetyl-3-(furan-2-ylmethylene)-5-methyl-2,6-di-
phenylpiperidin-4-one (6): Dull white solid; m.p. 212 ºC; IR
(KBr, νmax, cm-1): 3102 (ArCH), 1682 and 1703 (C=O str.),
1392 (CH3 bend.), 1880 (CH3 overtone). 1H NMR (500 MHz,
CDCl3): δ 6.44-6.94 (m, 3H, furyl-H), 7.14-7.78 (m, 10H,ArH),
4.53 (d, 3J6a,5a = 11.5 Hz, 1H, 6-Ha), 4.98 (s, 1H, 2-Ha), 3.03-
3.06 (m, 1H, 5-Ha), 0.88 (d, 3H, 5-CH3), 1.93 (s, 3H, N-COCH3),
8.14 (s, 1H, 3-methylene); MS: m/z 385.29 (M+). Elemental
anal. calc (found) % for C25H23NO3: C, 77.90 (77.68); H, 6.01
(6.02); N, 3.63 (3.62).
N-acetyl-3-(4-methoxybenzylidene)-5-methyl-2,6-di-
phenylpiperidin-4-one (7): Dull white solid; m.p. 128 ºC; IR
(KBr, νmax, cm-1): 2996 (ArCH), 1676 and 1705 (C=O str.),
1388 (CH3 bend), 1912 (CH3 overtone); 1H NMR (500 MHz,
CDCl3): δ 6.84-7.92 (m, 14H, ArH), 4.49 (d, 3J6a,5a = 11.5 Hz,
1H, 6-Ha), 4.99 (s, 1H, 2-Ha), 3.08-3.12 (m, 1H, 5-Ha), 0.87
(d, 3H, 5-CH3), 2.03 (s, 3H, N-COCH3), 8.14 (s, 1H, 3-methylene),
3.81 (s, 3H, Ar-OCH3); MS: m/z 425.41 (M+). Elemental anal.
calc (found) % for C28H27NO3: C, 79.03 (78.91); H, 6.40 (6.38);
N, 3.29 (3.30).
RESULTS AND DISCUSSION
An attempt was made to synthesize 3-methyl-2,6-diaryl-
1-(2-arylacetyl)-piperidin-4-one (11) by condensation of N-
acetyl-3-methyl-2,6-diarylpiperidin-4-one (3,4) and aryl aldehyde
as given in Scheme-I. The reaction mixture was taken in pestle
and ground well using a mortar with catalytic amount of NaOH.
We observed that the reaction mixture was in semi-liquid state
while grinding and gradually solidified. The progress of reaction
was monitored by TLC and the resulted products were separ-
ated by column chromatography with benzene-chloroform eluent
to get pure compounds. On careful investigation based on spectral
data, it was found that a formation of new series of compounds,
N-acetyl-3-arylidene-5-methyl-2,6-diphenylpiperidin-4-one
(5-10) instead of an expected compound, 3-methyl-2,6-diaryl-
1-(2-arylacetyl)-piperidin-4-one (11).
The IR spectrum of N-acetyl-3-benzylidene-5-methyl-2,6-
diphenylpiperidin-4-one (5) showed the stretching absorption
for -C=O at 1679 cm-1 and 1708 cm-1 due to carbonyl group at
C-4 position and acetyl group, respectively. The 1H NMR spec-
trum of N-acetyl-3-benzylidene-5-methyl-2,6-diphenylpiperidin-
4-one (5) revealed that the aromatic protons were resonated at
6.85-7.74 ppm. The H(2) proton was appeared as singlet at
5.00 ppm. The doublet at 4.5 ppm was assigned to H(6) proton.
The H(5) proton was resonated at 3.07 ppm as multiplet and
the doublet in the region at 0.89 ppm was observed for H(5)-
methyl group. The appearance of singlet at 1.89 ppm for N-acetyl
group and another singlet at 8.19 ppm for 3-methylene group
confirm the formation N-acetyl-3-benzylidene-5-methyl-2,6-
diphenylpiperidin-4-one (5).Akin to compound 5, the structure
of rest of the synthesized compounds (6-10) was assigned. In
addition, the mass spectrum of compounds (5-10) revealed that
the observed molecular ion peak was in good agreement with
N-acetyl-3-benzylidene-5-methyl-2,6-di(4-methoxy-
phenyl)piperidin-4-one (8):White solid; m.p. 172 ºC; IR(KBr,
ν
max, cm-1): 3001 (ArCH), 1674 and 1702 (C=O str.), 1372 (CH3
bend.), 1896 (CH3 overtone); 1H NMR (500 MHz, CDCl3): δ
6.68-7.68 (m, 13H, ArH), 4.48 (d, 3J6a,5a = 12 Hz, 1H, 6-Ha),
4.96 (s, 1H, 2-Ha), 3.07 (m, 1H, 5-Ha), 0.84 (d, 3H, 5-CH3),
1.88 (s, 3H, N-COCH3), 8.01 (s, 1H, 3-methylene), 3.77 and
3.86 (s, 6H, Ar-OCH3); MS: m/z 455.28 (M+). Elemental anal.
calc (found) % for C29H29NO4: C, 76.46 (76.54); H, 6.42 (6.41);
N, 3.07 (3.07).
N-acetyl-3-(furan-2-ylmethylene)-5-methyl-2,6-di(4-
methoxyphenyl)piperidin-4-one (9): Dull white solid; m.p.
68 ºC; IR (KBr, νmax, cm-1): 3112 (ArCH), 1680 and 1707 (C=O
str.), 1392 (CH3 bend.), 1899 (CH3 overtone); 1H NMR (500
MHz, CDCl3): δ 6.31-6.78 (m, 3H, furyl-H), 6.86-7.84 (m,

Vol. 31, No. 2 (2019)
Compounds
Synthesis of 3-Arylidene-4-Piperidone Derivatives as Potent Antioxidant Agents 471
TABLE-1
PHYSICAL DATA AND in vitro ANTIOXIDANT ACTIVITY OF COMPOUNDS 5-10
Reaction time Yield (%)
Antioxidant
activity (%)
Grind (min)
Reflux (h)
Grind
86
82
84
82
81
81
–
Reflux
66
68
62
64
72
68
–
35
30
25
25
40
35
–
11
8
10
10
9
10.22
64.24
28.48
7.04
51.62
32.54
76.31
5
6
7
8
9
10
7
–
Ascorbic acid
3. R.A. Sheldon, Green Chem., 7, 267 (2005);
the calculated mass and their purity was confirmed by elemental
analysis.
The physical data of synthesized compounds are given in
Table-1. The data showed that solvent free grinding technique
gave more yield than conventional reflux method with short
reaction time.
The in vitro antioxidant activity of synthesized compounds
was studied based on the radical scavenging effect of stable
DPPH free radical using ascorbic acid as a standard [16]. The
results (Table-1) showed that N-acetyl-3-(furan-2-ylmethyl-
ene)-5-methyl-2,6-diphenylpiperidin-4-one (6) and N-acetyl-
3-(furan-2-yl-methylene)-5-methyl-2,6-di(4-methoxyphenyl)-
piperidin-4-one (9), which possess furfuryl moiety were showed
good antioxidant activity. However, N-acetyl-3-benzylidene-
5-methyl-2,6-diphenylpiperidin-4-one (5) and N-acetyl-3-benzy-
lidene-5-methyl-2,6-di(4-methoxyphenyl)piperidin-4-one (8)
showed very less antioxidant activity.
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Conclusion
The 1H NMR spectrum and other spectral studies confirm
the formation of N-acetyl-3-arylidene-5-methyl-2,6-diarylpip-
eridin-4-one (5-10) under solvent free grinding technique with
short reaction rime and simple work up procedure. The synthe-
sized compounds showed considerable antioxidant activity.
CONFLICT OF INTEREST
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The authors declare that there is no conflict of interests
regarding the publication of this article.
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