Environmentally benign one-pot synthesis and antimicrobial activity of 1-methyl-2,6-diarylpiperidin-4-ones

Article abstract of DOI:10.2478/s11696-011-0046-x

An efficient and environmentally benign one-pot method for the synthesis of 1-methyl-2,6- diarylpiperidin-4-ones using montmorillonite K-10 as a catalyst has been developed. Antimicrobial activity of the compounds has been tested against selected represen

Full text of DOI:10.2478/s11696-011-0046-x

Chemical Papers 65 (5) 743–746 (2011)
DOI: 10.2478/s11696-011-0046-x
SHORT COMMUNICATION
Environmentally benign one-pot synthesis and antimicrobial
activity of 1-methyl-2,6-diarylpiperidin-4-ones
a
aPattusamy Nithya, a,cFazlur-Rahman Nawaz Khan*, Selvaraj Mohana Roopan,
c
bUma Shankar, Jong Sung Jin
aOrganic Chemistry Division, School of Advanced Sciences, bSchool of Bio Sciences & Technology, VIT University,
Vellore, Tamil Nadu 632 014, India
cDivision of High Technology Materials Research, Busan Center, Korea Basic Science Institute (KBSI),
Busan 618-230, Republic of Korea
Received 6 December 2010; Revised 29 March 2011; Accepted 5 April 2011
An efficient and environmentally benign one-pot method for the synthesis of 1-methyl-2,6-
diarylpiperidin-4-ones using montmorillonite K-10 as a catalyst has been developed. Antimicrobial
activity of the compounds has been tested against selected representatives of Gram-positive and
Gram-negative bacteria and fungi.
c
ꢀ 2011 Institute of Chemistry, Slovak Academy of Sciences
Keywords: montmorillonite K-10, catalyst reusability, mild conditions, antimicrobial activity
One-pot reaction strategy (Zeng et al., 2009; Ma et
al., 2000; Juang et al., 2005; Menche et al., 2007; Gu et
al., 2004) improves the efficacy of a chemical reaction,
significantly reduces the time needed for some reac-
tion steps to proceed, avoids lengthy separation and
purification of the reaction products, with resultant
important commercial implications.
O
N
R1
R2
Ar
R1
R
O
i
R
Ar
+ ArCHO + CH3NH2
II III
R2
I
CH3
IV
The piperidone moiety (Noller & Baliah, 1948; Bal-
asubramanian & Padma, 1963a, 1963b), an interest-
ing component of natural alkaloids (Katritzky & Fan,
1990; Edwards et al., 1988) possesses antibacterial
(Rameshkumar et al., 2003; Srinivasan, et al. 2006),
antipyretic (Aridoss et al., 2009), anti-inflammatory
(Ganellin & Spickett, 1965; Venkatesa Perumal et al.,
2001), and anti-cancer (Pati et al., 2009; Dimmock et
al., 1994; Mobio et al., 1989) activities.
Although there are a number of reports on
the synthesis of 1,3-dimethyl-2,6-diarylpiperidin-4-
ones (Noller & Baliah, 1948; Balasubramanian &
Padma, 1963a, 1963b, 1968; Balasubramanian &
D’Souza, 1963; Jeyaraman et al., 1995; Eliel et al.,
1982; Vijayalakshmi et al., 2006; Baliah et al., 1983;
Weintraub et al., 2003; Srinivasan et al., 2005; Nithya
Fig. 1. One-pot synthesis of 1-methyl-2,6-diarylpiperidin-4-
ones. Reaction conditions: i) montmorillonite K-10, 45–
50◦C.
et al., 2009; Roopan & Khan, 2010), there remains a
need for the introduction of safer and more efficient
methods of synthesis. It has been reported (Nikalje et
al., 2000; Varma, 2002; Polshettiwar & Varma, 2008;
Dasgupta & T¨oro¨k, 2008) that montmorillonite K-10
is a reusable heterogeneous solid clay used as an acidic
catalyst to enhance the yield of the Mannich reaction.
In this paper, we report on a one-pot synthesis
of 1-methyl-2,6-diarylpiperidin-4-one derivatives us-
ing montmorillonite K-10 as a catalyst (Fig. 1). It
was found that the established method is effective for
*Corresponding author, e-mail: nawaz f@yahoo.co.in

744
P. Nithya et al./Chemical Papers 65 (5) 743–746 (2011)
Table 1. Characterisation data of prepared piperidin-4-one derivatives
Compound
R
R1
R2
Ar
M.p./◦C
Yielda/%
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
CH3
H
H
H
H
H
H
CH3
H
H
C6H5
3-MeO-C6H4
4-HO-C6H4
4-Cl-C6H4
C6H5
C6H5
C6H5
4-MeO-C6H4
3,4-(MeO)2-C6H3
130–131b
132–133
139–140
143–144
131–132c
90–92d
108–110e
132–133g
147–148f
78
72
75
66
70
67
68
71
69
CH(CH3)2
CH3
CH3
H
H
CH3
a) Isolated yields after column chromatography; b) 130–131◦C reported by Balasubramanian and Padma (1963b); c) 131–132◦C; d)
91–92◦C; e) 109–110◦C; f ) 148–149◦C reported by Noller and Baliah (1948); g) 104–105◦C reported by Baliah and Gopalakrishnan
(1954).
Table 2. Spectral data of newly synthesised compounds
Compound
Spectral data
IVb
IR, ν˜/cm−1: 1703, 702
1H NMR (CDCl3), δ: 0.9 (s, 3H), 2.25 (s, 3H, CH3), 2.55–2.79 (m, 3H, H-3, H-5), 3.67 (dt, 1H, J = 6.8 Hz, J = 7.1
Hz, H-2), 3.79 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.15 (dd, 1H, J = 7.2 Hz, J = 7.6 Hz, H-6), 6.69 (d, J = 6.3 Hz,
Haryl), 7.45 (d, J = 6.8 Hz, Haryl
)
13C NMR (CDCl3), δ: 10.1, 35.8, 51.2, 51.5, 54.9, 55.3, 61.5, 68.1, 113.2, 113.5, 127.5, 129.6, 143.4, 144.3, 159.8,
159.9, 209.5
LCMS, m/z: 339 (M+
)
IVc
IVd
IR, ν˜/cm−1: 3426, 1702, 700
1H NMR (CDCl3), δ: 0.95 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.74–2.86 (dt, 2H, J = 7.2 Hz, J = 7.6 Hz, H-5), 3.65
(dt, 1H, J = 6.8 Hz, H-2), 3.74 (dt, 1H, J = 7.0 Hz, J = 7.3 Hz, H-3), 4.19 (dd, 1H, J = 7.3 Hz, J = 7.7 Hz, H-6),
6.86 (d, J = 6.7 Hz, Haryl), 7.88 (d, J = 6.9 Hz, Haryl), 8.91 (bs, 1H, OH)
13C NMR (CDCl3), δ: 10.5, 38.5, 51.5, 51.7, 61.9, 68.2, 126.2, 127.6, 127.9, 128.3, 128.5, 128.7, 141.7, 142.6, 209.7
LCMS, m/z: 309 (M+
)
IR, ν˜/cm−1: 1705, 689
1H NMR (CDCl3), δ: 0.98 (s, 3H, CH3), 2.23 (s, 3H, CH3), 2.64–2.71 (dt, 2H, J = 7.2 Hz, J = 7.6 Hz, H-5), 3.65
(dt, 1H, J = 6.8 Hz, J = 7.1 Hz, H-2), 3.77 (dt, 1H, J = 6.85 Hz, J = 7.2 Hz, H-3), 4.17 (dd, 1H, J = 7.2 Hz, J =
7.5 Hz, H-6), 6.89 (d, J = 6.8 Hz, Haryl), 8.05 (d, J = 7.1 Hz, Haryl
13C NMR (CDCl3), δ: 10.8, 37.8, 51.6, 51.7, 61.8, 68.7, 127.5, 127.8, 128.6, 128.7, 129.5, 141.3, 142.8, 209.8
LCMS, m/z: 347 (M+
)
)
the preparation of tetrasubstituted piperidin-4-ones
(IVa–IVi) from various aromatic aldehydes (II ) in
good yields without the formation of any by-products.
To optimise the efficiency of the catalyst, 10 mg to
100 mg of montmorillonite K-10 was used. The best
catalytic effect was found to be with 100 mg. After
completion of the reaction, the catalyst can be read-
ily recovered by diluting the reaction mixture with
dichloromethane, followed by filtration and washing
with diethyl ether (93–96 % average recovery yields).
The recovered catalyst was reused in five subsequent
runs without significant decrease in activity.
All chemicals were purchased from Sigma–Aldrich
(India) and Merck (India). Melting points were mea-
sured on an Elchem microprocessor-based DT appa-
ratus (India) in open capillary tubes and are uncor-
rected. Column chromatography was performed us-
ing silica gel (230–400 mesh). FTIR spectra (in KBr
pellets) were recorded on a Nucon infrared spec-
trophotometer (India). Mass spectra (LCMS, 70 eV)
were recorded using an Agilent 1100 Series LC-MSD
Ion Trap system (India) in EI mode. 1H (500 MHz)
and 13C (125 MHz) NMR spectra (in CDCl3) were
recorded on a Bruker AVIII-500 spectrometer (India).
1-Methyl-2,6-diarylpiperidin-4-ones (IVa–IVi) we-
re synthesised in accordance with the general method
as follows: a mixture of methylamine (40 % solution
in water, 2.5 mmol), montmorillonite K-10 (100 mg),
ketone I (1 mmol), and freshly distilled aromatic alde-
hyde II (2 mmol) was heated in a water bath at 45–
50◦C until the solution turned yellow and was then
set aside at room temperature overnight. After com-
pletion of the reaction (monitored by TLC), the re-
action mixture was poured into ether (10 mL) and
treated with aqueous hydrochloric acid (20 mL). The
hydrochloride salt of the piperidin-4-one was filtered
off, washed with ether and dissolved in ethanol (10
mL) followed by the addition of a slight excess of
aqueous ammonia and finally diluted with water (200
mL) at 0◦C. The precipitated piperidin-4-one deriva-

P. Nithya et al./Chemical Papers 65 (5) 743–746 (2011)
745
tive was re-crystallised from ethanol or ethanol/ethyl
acetate mixture.
The structure of all new compounds was confirmed
by spectral data. The spectral and physical and chem-
ical data of known compounds were in agreement with
the published data (Tables 1 and 2).
Synthesised piperidin-4-ones VIa–IVi were scree-
ned for antibacterial activity against Staphylococcus
aureus (ATCC 25923), Staphylococcus epidermidis
(ATCC 3583), Bacillus subtilis (ATCC 2063) (Gram-
positive bacteria) and Escherichia coli (ATCC 25922),
Klebsiella pneumonia (ATCC 13883), and Pseu-
domonas aeruginosa (ATCC 27853) (Gram-negative
bacteria) by a well-diffusion method (Barry, 1976;
Dhar et al., 1968). Ampicillin was used as a standard
drug. The antifungal activity was screened against As-
pergillus niger, Aspergillus flavus, Aspergillus fumiga-
tus, and Candida albicans. Ciproflaxin (25 µg mL−1
)
was used as a standard drug. For the bioassay, the
compounds were dissolved in DMSO. The two-fold di-
lution of the compounds was prepared (2.0 mg mL−1
,
1.0 mg mL−1, 0.5 mg mL−1, 0.25 mg mL−1, 0.125
mg mL−1, 0.062 mg mL−1, 0.031 mg mL−1, 0.015 mg
mL−1, 0.0078 mg mL−1, 0.0039 mg mL−1). No antimi-
crobial activity was observed in the solvent employed.
The results of antimicrobial testing are presented in
Table 3.
It was found that compounds with unsubstituted
phenyls (IVa, IVe–IVg) exhibited moderate activity
against most of the tested microorganisms. Similarly,
a compound with methyl groups at C-3 and C-5 (IVi)
showed better activity against all strains in compari-
son with compounds having H and isopropyl groups at
C-3 position. As to antifungal activity, the compounds
with the methyl group at C-3 position exhibited a
good zone of inhibition against all the strains tested.
Replacement of the methyl group with isopropyl (com-
pound IVg) resulted in a positive response towards A.
niger (100 mg mL−1). It is worth mentioning that the
compounds with unsubstituted phenyls at C-2 and C-
6 (IVe–IVg) showed better activity against A. niger.
Acknowledgements. The authors wish to express their
thanks to the Technology Business Incubator, VIT University
and the SAIF, Indian Institute of Technology, Madras, for pro-
viding analytical facilities.
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