Synthesis and characterization of piperidin-4-one derivatives using green solvent

Article abstract of DOI:10.14233/ajchem.2020.22589

A deep eutectic solvent of glucose-urea was found to be an inexpensive and effective reaction medium in the synthesis of piperidin-4-one derivatives. In this work, 3-methyl-2,6-diphenyl piperidin-4-one (4a), 3,5-dimethyl-2,6-diphenylpiperidin-4-one (4b), 2,6-diphenylpiperidin-4-one (4c), piperidin-4-one (4d), 3,5-dimethylpiperidin-4-one (4e), 3-methyl-2,6-di(2-hydroxyphenyl)piperidin-4-one (4f), 3,5-dimethyl 2,6-di(2-hydroxyphenyl)piperidin-4one (4g) were synthesized using a deep eutectic solvent (DES) of glucose and urea with the percentage composition of 60:40. The yields of these products were 82, 78, 75, 68, 72, 70 and 70 %, respectively. The products obtained were characterized by FT-IR and ¹H NMR spectroscopic techniques. A synthesis of piperidin-4-one derivatives by using this green solvent was considered to be new environmentally safe synthetic method.

Full text of DOI:10.14233/ajchem.2020.22589

Asian Journal of Chemistry; Vol. 32, No. 4 (2020), 981-984
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22589
Synthesis and Characterization of Piperidin-4-one Derivatives Using Green Solvent
1,
2,*,
K. HEMALATHA
and D. ILANGESWARAN
1Department of Chemistry, Justice Basheer Ahmed Sayeed College for Women (Autonomous), Teynampet, Chennai-600018, India
2Department of Chemistry, Rajah Serfoji Government College (Affiliated to Bharathidasan University), Thanjavur-613005, India
*Corresponding author: E-mail: dhailangeswaran@gmail.com
Received: 11 December 2019;
Accepted: 30 January 2020;
Published online: 25 February 2020;
AJC-19823
A deep eutectic solvent of glucose-urea was found to be an inexpensive and effective reaction medium in the synthesis of piperidin-4-one
derivatives. In this work, 3-methyl-2,6-diphenyl piperidin-4-one (4a), 3,5-dimethyl-2,6-diphenylpiperidin-4-one (4b), 2,6-diphenylpiperidin-
4-one (4c), piperidin-4-one (4d), 3,5-dimethylpiperidin-4-one (4e), 3-methyl-2,6-di(2-hydroxyphenyl)piperidin-4-one (4f), 3,5-dimethyl
2,6-di(2-hydroxyphenyl)piperidin-4one (4g) were synthesized using a deep eutectic solvent (DES) of glucose and urea with the percentage
composition of 60:40. The yields of these products were 82, 78, 75, 68, 72, 70 and 70 %, respectively. The products obtained were
characterized by FT-IR and 1H NMR spectroscopic techniques. A synthesis of piperidin-4-one derivatives by using this green solvent was
considered to be new environmentally safe synthetic method.
Keywords: Deep eutectic solvent, Piperidin-4-one derivatives, Glucose-urea.
of glucose-urea. In this work, glucose-urea DES used as a
reaction medium for the synthesis of some piperidin-4-one
derivatives.Among the wide variety of heterocyclic compounds
that have been explored for developing pharmaceutically
important molecules piperidin-4-ones exhibit various biological
activities like analgesic, antihypertensive, central nervous
system depressant, antiviral, bactericidal and fungicidal activities
[26-30]. Numerous pharmacological activities of substituted
piperidin-4-ones trigger to synthesis these products by using
DES. In traditional method, high toxic organic solvents are used
for the synthesis of piperidin-4-one derivatives [31,32] herein,
a new solvent (glucose + urea DES) is identified to synthesize
these compounds without producing harmful byproducts and
environmental friendly benign method.
INTRODUCTION
In recent years, deep eutectic solvents (DES) are emerging
type of environment friendly green solvents. Deep eutectic
solvents have been made to eliminate the consumption of
volatile organic solvents as reaction media which contribute
to major source of environmental pollution. Even though the
problems associated with conventional volatile organic solvents
are well studied, the usage of green and biorenewable solvents
still remains an endless challenge [1]. In this sense, advantages
of using DES as reaction medium is highlighted from the fact
that they are biodegradable, non-toxic recyclable and could be
easily prepared using inexpensive raw materials [2-6]. Deep
eutectic solvents (DES) have been studied in a variety of appli-
cations including metal dispositions, metalloid dissolution,
purification of biodiesel, biotransformation, different synthetic
processes and metal catalyses organic reactions [7-15]. In
recent years, low melting mixtures and inorganic salts have
been introduced as new alternative sustainable solvents for
organic transformation [16-22]. Our focus is on glucose-urea
based DES, where urea acts as a hydrogenbond acceptor (HBA)
and is combined with hydrogen bond donor (HBD) like glucose
[23-25] in order to form a low melting point eutectic mixture
EXPERIMENTAL
The melting points were measured in open capillaries and
are uncorrected. IR spectra were recorded on AT-FT-IR spec-
1
trometer. H NMR spectra were recorded at BRUKER (500
MHz, 400 MHz) spectrometer using CDCl3 & DMSO as solvent
and TMS as standard.
Preparation of glucose-urea DES:The mixture of glucose
and urea (60:40) was heated up to 73 ºC until a homogenous
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982 Hemalatha et al.
Asian J. Chem.
transparent colourless liquid was formed. Thus glucose-urea
DES was prepared.
3396 ν(O-H), 3208 ν(N-H), 2920 ν(C-H), 1705-1659 ν(C=O),
1456-1403 ν(C=C), 756 ν(Ar-H). 1H NMR (400 MHz, DMSO):
δ 6.853-7.440 (m, 8H,Ar-H), 6.853-6.894 (m, 4H, ortho proton
to OH), 6.951-6.989 (m, 4H, para proton to OH), 7.193-7.440
(m, 4H, meta proton to OH), 5.460 (s, 1H, phenolic proton),
3.377 (s, 1H, NH), 2.207-2.310 (dd, 2H, H-2,6 position), 1.797-
1.972 (q, 1H, H-3 position), 1.50-1.579 (d, 2H, H-5 position),
0.6648-0.6808 (d, 3H, CH3).
General procedure for synthesis of piperidin-4-one
derivatives:A deep eutectic solvent of glucose-urea was found
to be an inexpensive and effective reaction medium in the
synthesis of piperidin-4-one derivatives. In this work piperidin-
4-one derivatives (4a-g) were synthesized using a deep eutectic
solvent (DES) of glucose and urea with the percentage compo-
sition of 60:40. In this synthesis various ketones (1) (acetone,
ethyl methyl ketone and diethyl ketone) (6 mL:0.1 mol), alde-
hydes (2) (0.1 mol) (benzaldehyde, formaldehyde, salicylal-
dehyde) (12 mL, 0.2 mol) and ammonia solution (3) (20 mL)
taken in round bottom flask containing glucose and urea DES.
The mixture is refluxed at 60-70 °C in a water bath with occa-
sional shaking until the colour changes into red orange. The
product formed was monitored by TLC. The solution is cooled
and then conc. HCl (10 mL) is added. A precipitate obtained
was dispersed in water and excess ammonia was added until a
clear solution formed. Then the clear solution was poured into
ice cold water and then precipitate was filtered. The product
formed was washed several times with water and dried. Then
the product 4 was recrystallized with alcohol (Scheme-I).
Synthesized compounds (4a-g) were characterized by FT-IR
and 1H NMR spectroscopic techniques.
3-Methyl-2,6-diphenylpiperidin-4-one (4a): Yield: 82
%; m.p.: 112 ºC; m.f.: C18H19NO; FT-IR (cm-1): 3316 ν(N-H),
3033-2801 ν(C-H), 1708 ν(C=O), 1452-1218 ν(C=C), 756
ν(Ar-H). 1H NMR (500 MHz, CDCl3): δ 7.243-7.465 (m, 10H,
Ar-H), 4.069-4.098 (dd, 2H, H-2,6 position), 3.607-3.628 (q,
1-H, H-3 position), 2.630-2753 (d, 2H, H-5 position), 2.113
(s, 1H, N-H), 0.840 (s, 3H, CH3).
3,5-Dimethyl 2,6-diphenylpiperidin-4-one (4b):Yield:
78 %; m.p.: 140 ºC; m.f.: C19H21NO; FT-IR (νmax, cm-1): 3209
ν(N-H), 3061-2981 ν(C-H in phenyl ring), 2638 ν(C-H in
aliphatic), 1692 ν(C=O), 1495-1451 ν(C=C), 760 ν(Ar-H).
1H NMR (400 MHz, DMSO): δ 6.556-7.961 (m, 10H, Ar-H),
4.121-4.234 (d, 2H, H-2,6 position), 3.375 (s, 1H, NH), 2.018-
2.178 (dq, 2H, H-3,5 position), 0.656-0.711 (dd, 6H, CH3).
2,6-Diphenylpiperidin-4-one (4c):Yield: 75 %; m.p.: 96
ºC; m.f.: C17H17NO; FT-IR (νmax, cm-1): 3053 ν(N-H), 3023-
2854 ν(C-H), 1701 ν(C=O), 1495-1447 ν(C=C), 755 ν(Ar- H).
1H NMR (500 MHz, CDCl3): δ 6.686- 8.194 (m, 10H, Ar-H),
4.362-5.249 (m, 2H, H-2,6 position), 3.830-3.852 (d, 2H, H-
3,5 position), 2.871 (s, N-H).
3,5-Dimethyl-2,6-di(2-hydroxyphenyl)piperidin-4-one
(4g):Yield: 70 %; m.p.: 242 °C; m.f.: C19H21NO3; FT-IR (νmax
,
cm-1): 3208 ν(O-H), 3076 ν(N-H), 2974-2936 ν(C-H), 1695-
1622 ν(C=O), 1486-1455 ν(C=C), 758 ν(Ar-H). 1H NMR (400
MHz, DMSO): δ 6.803-7.313 (m, 8H,Ar-H), 6.803-6.883 (m,
4H, ortho proton to OH), 6.974-6.995 (m, 4H, para proton to
OH), 7.048-7.313 (m, 4H, meta proton to OH), 4.980 (s, 1H,
phenolic proton), 3.939-3.957 (dd, 2H, H-2,6 position), 3.364
(s, 1H, NH), 1.880-1.894 (dq, 1H, H-3,5 position), 0.666-1.064
(d, 6H, CH3).
RESULTS AND DISCUSSION
In this work, piperidin-4-one derivatives (4a-g) were synth-
esized by glucose-urea DES as a green solvent. The synthesized
3-methyl-2,6-diphenylpiperidin-4one (4a) showed strong
absorption at 3316 cm-1 for N-H, 1708 cm-1 for carbonyl group
and 756 cm-1 for aromatic group in FT-IR spectrum. 1H NMR
in CDCl3 spectrum in showed the multiplet at δ 7.243-7.465
for aromatic proton, singlet in δ 2.113 for N-proton and singlet
in δ 0.840 for methyl proton. These spectral data very much
agree with the structure of compound 4a. The FT-IR spectrum
of 3,5-dimethyl-2,6-diphenylpiperidin-4-one (4b) showed
strong absorption at 3209 cm-1 for N-H, 1692cm-1 for carbonyl
group and 760 cm-1 for aromatic group. 1H NMR in DMSO
spectrum showed the multiplet at δ 6.556-7.961 for aromatic
proton, singlet in δ 3.375 for N-proton and doublet in δ 0.656-
0.711 for methyl proton in 3,5-position. These spectral data
supported the structure of compound 4b. 2,6-Diphenylpipe-
ridin-4-one (4c) showed strong absorption at 3053 cm-1 for
N-H, 1701 cm-1 for carbonyl group and 755 cm-1 for aromatic
group in FT-IR spectrum. 1H NMR in CDCl3 spectrum showed
the multiplet at δ 6.686- 8.194 for aromatic proton, singlet in
δ 2.871 for N-proton revealed the structure of compound 4c.
The FT-IR spectrum of piperidin-4-one (4d) showed absorption
at 3351 cm-1 for N-H, 1649 cm-1 for carbonyl group. 1H NMR in
CDCl3 spectrum showed the absence of multiplet for aromatic
substituent 2,6-position, singlet in δ 2.185 for N-proton con-
firmed the structure of compound 4d. The structure of 3,5-
dimethylpiperidin-4-one (4e) confirmed by the FT-IR absor-
ption at 3332 cm-1 for N-H, 1658 cm-1 for carbonyl group and
1H NMR spectrum in DMSO showed the absence multiplet
for aromatic substituent, singlet in δ 3.726 for N-proton and
double quintet at δ 2.245-2.2841 for methyl proton 3,5-position.
In 3-methyl 2,6-di(2-hydroxyphenyl)piperidin-4-one (4f) FT-
IR spectrum absorptions were observed at 3396 cm-1 for O-H,
3208 cm-1 for N-H, 1659-1705 cm-1 for carbonyl group & 756
Piperidin-4-one (4d): Yield: 68 %; m.p.: 79 ºC; m.f.:
C5H9NO; FT-IR (νmax, cm-1): 3351 ν(N-H), 3027 ν(C-H), 1649
ν(C=O), 1247-1130 ν(C-C). 1H NMR (500 MHz, CDCl3): δ
1.603 (dd, 4H, H-2,6 position), 1.257 (dd, 4H, H-3,5 position),
2.185 (s, 1H, NH).
3,5-Dimethyl piperidin-4-one (4e): Yield: 72 %; m.p.:
86 ºC; m.f.: C7H13NO; FT-IR (νmax, cm-1): 3332 ν(N-H), 3136
ν(C-H), 1658 ν(C=O), 1519-1394 ν(C-C). 1H NMR (400 MHz,
DMSO): δ 4.440-4.727 (dd, 2H, H-2,6 equatorial proton),
3.222-3.468 (dd, 2H, H-2,6 axial position), 2.245-2.2841 (dq,
2H, H-3,5 position), 3.726 (s, 1H, NH), 1.091-1.971 (d, 6H,
CH3).
1
cm-1 for aromatic group and H NMR spectrum in DMSO
showed multiplet at δ 6.853-7.440 for aromatic proton, δ 5.460
for phenolic proton δ 3.377 for N-proton and double quintet
at ä 2.245-2.2841 for methyl proton in 3-position. The structure
3-Methyl-2,6-di(2-hydroxyphenyl)piperidin-4-one (4f):
Yield: 70 %; m.p.: 220 ºC; m.f.: C18H19NO3; FT-IR (νmax, cm-1):

Vol. 32, No. 4 (2020)
Synthesis and Characterization of Piperidin-4-one Derivatives Using Green Solvent 983
O
O
CH3
O
DES
Glucose + Urea
CH3
H
H
1
O
+
-2H2O
2
2
H
H
C6H5
C6H5
C6H5
C6H5
N
H
N
H
O
3-Methyl-2,6-diphenylpiperidin-4-one (4a)
3
O
H3C
CH3
DES
Glucose + Urea
H
H3C
CH3
H
1
O
O
H
+
2
-2H2O
2
H
C6H5
C6H5
C6H5
N
H
C6H5
N
H
3
3,5-Dimethyl-2,6-diphenylpiperidin-4-one (4b)
O
O
H
H
DES
Glucose + Urea
H3C
O
CH3
1
O
+
2
-2H2O
2
H
H
C6H5
C6H5
C6H5
N
H
C6H5
N
H
3
2,6-Diphenylpiperidin-4-one (4c)
O
O
H
H
DES
Glucose + Urea
H
H
H3C
O
CH3
1
O
+
-2H2O
2
2
H
H
N
N
H
H
3
Piperidin-4-one (4d)
O
O
H3C
CH3
H3C
CH3
DES
1
H
Glucose + Urea
H
O
+
-2H2O
O
2
N
H
2
H
H
H
H
N
H
3,5-Dimethylpiperidin-4-one (4e)
3
O
OH
H3C
H3C
CHO
DES
Glucose + Urea
1
CH3
N
H
+
OHC
-2H2O
H
H
N
OH HO
2
2
OH
HO
3-Methyl-2,6-di(2-hydroxyphenyl)piperidin-4-one (4f )
H
3
O
O
CH3
H3C
CH3
H3C
CHO
DES
Glucose + Urea
1
N
H
+
-2H2O
OHC
H
H
N
OH HO
2
2
OH
HO
3,5-Dimethyl-2,6-di(2-hydroxyphenyl)piperidin-4-one (4g)
H
3
Scheme-I: Synthetic route of piperidin-4-one derivatives (4a-g) using glucose-urea as green solvent

984 Hemalatha et al.
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Conclusion
In this study, newer green solvent of glucose-urea DES
was used for the synthesis of piperidin-4-one derivatives. The
products were synthesized in good yields and excellent purities.
When compared to the conventional synthetic method, deep
eutectic solvent synthesis is environmental friendly and volatile
chemical usage is minimized with good yields. Pharmaceuti-
cally important piperidin-4-one derivatives were synthesized
by using glucose-urea DES method is benign for green synthetic
method against the volatile organic solvents.
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CONFLICT OF INTEREST
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