Synthesis and antimicrobial activities of N-chloroacetyl-2,6- diarylpiperidin-4-ones

Article abstract of DOI:10.1007/s00044-007-9023-x

An array of new N-chloroacetyl-2,6-diarylpiperidin-4-ones has been synthesised and their antibacterial activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Salmonella typhi, and antifungal activity against Cryptococcus neoformans, Candida albicans, Rhizopus sp., Aspergillus flavus, and Aspergillus niger examined. Compounds 14 against P. aeruginosa, 15 against S. typhi, 16 against S. aureus, and 19 against B. subtilis showed marked antibacterial activity. Similarly, compounds 15 and 19 against A. niger and 19 against A. flavus exerted significant antifungal activities. Birkhaeuser 2007.

Full text of DOI:10.1007/s00044-007-9023-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2007) 16:188–204
DOI 10.1007/s00044-007-9023-x
ORIGINAL RESEARCH
Synthesis and antimicrobial activities of N-chloroacetyl-
2,6-diarylpiperidin-4-ones
G. Aridoss Æ S. Balasubramanian Æ P. Parthiban Æ
R. Ramachandran Æ S. Kabilan
Received: 5 September 2006 / Accepted: 29 June 2007 / Published online: 4 October 2007
¨
ꢀ Birkhauser Boston 2007
Abstract An array of new N-chloroacetyl-2,6-diarylpiperidin-4-ones has been
synthesised and their antibacterial activity against Staphylococcus aureus, Escher-
ichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Salmonella typhi, and
antifungal activity against Cryptococcus neoformans, Candida albicans, Rhizopus
sp., Aspergillus flavus, and Aspergillus niger examined. Compounds 14 against P.
aeruginosa, 15 against S. typhi, 16 against S. aureus, and 19 against B. subtilis
showed marked antibacterial activity. Similarly, compounds 15 and 19 against A.
niger and 19 against A. flavus exerted significant antifungal activities.
Keywords Synthesis ꢀ Piperidin-4-ones ꢀ Chloroacetylation ꢀ
Antibacterial activity ꢀ Antifungal activity
Introduction
In recent years, there has been growing interest in the synthesis of bioactive
compounds in the field of heterocyclic chemistry. Among the family of heterocyclic
compounds, the nitrogen-containing heterocycles, especially piperidin-4-ones, have
gained considerable importance presumably because of their varied biological
properties such as antiviral, antitumour (El-Subbagh et al., 2000), analgesic (Jerom
and Spencer, 1988), local anaesthetic (Perumal et al., 2001; Hagenbach and Gysin,
1952)antimicrobial, bactericidal, fungicidal, herbicidal, insecticidal, antihistaminic,
anti-inflammatory, anticancer, and central nervous system (CNS) stimulant and
G. Aridoss ꢀ S. Balasubramanian ꢀ P. Parthiban ꢀ R. Ramachandran ꢀ S. Kabilan (&)
Department of Chemistry, Annamalai University, Annamalainagar 608 002 Tamil Nadu, India
e-mail: skabilan@rediffmail.com
S. Balasubramanian
Department of Chemistry, Bowman Oddy Laboratories, The University of Toledo, 2801, W.
Bancroft Street, MS 602, Toledo, OH 43606, USA

Med Chem Res (2007) 16:188–204
189
depressant activities (Mobio et al., 1989; Katritzky and Fan, 1968; Ganellin and
Spickett, 1965). Lijinsky and Taylor (1975) found that the blocking of a-positions to
that of nitrogen in piperidone using alkyl groups provided advantages over unblocked
ones in terms of biological activity. Furthermore, the significance of piperidin-4-one
as an intermediary in the synthesis of a variety of physiologically active compounds
have been reviewed by Prostakov and Gaivoronskaya (1978). The structure of the
piperidone nucleus can also be frequently recognised in the molecular framework of
most of the naturally occurring alkaloids and synthetic compounds, which are
endowed with interesting biological and pharmacological properties.
Similarly, amides are well known for their therapeutic values (Chauhan et al.,
2001; Chauhan et al., 1970) . The chemistry of amines with chloroacetyl groups is
also fascinating and has received significant attention over the years, resulting in
substantial advances both in synthetic and medicinal aspects. N-Benzyl-b-chloro-
propionamide is a well-proven (Cassel and Kushner, 1951; Kushneret al., 1951)
anticonvulsant agent marketed under the trade names Hibicon and Hydrane.
Chloroacetyl amides of some amines were found to exert diverse biological
properties such as antiepileptic (Kochetkov and Dudykina, 1951), antispasmodic
(Kochetkov and Dudykina, 1957), antitumor, anti multidrug resistance (MDR,
Eregowda et al., 2000), antimicrobial (Al-Haiza et al., 2003), herbicidal (Gan J
et al., 2002), and mild stimulant and depressant activities (Hasan et al., 1971).
Recently, our group has actively engaged in the synthesis (Ramalingan et al.,
2003a; 2004a; 2004b; Balasubramanian et al., 2002; 2003; Aridoss et al., 2006a) of
2,6-diarylpiperidin-4-ones with and without substituents at C-3, C-5, and at the
heterocyclic nitrogen, and has also explored the existence of a varied degree of
in vitro antibacterial and antifungal activities (Ramalingan et al., 2003b; 2003c;
2004c; Balasubramanian et al., 2004; 2005; 2006; Aridoss G et al., 2006b; Parthiban
P et al., 2006).
In light of the above observations, it was thought worthwhile to synthesise a
system that brings 2,6-diarylpiperidin-4-ones and chloroacetyl chloride together to
furnish the corresponding amides 11–20 with the hope of developing some
promising antimicrobial agents.
Results and Discussion
Chemistry
Chloroacetylation of 2,6-diarylpiperidin-4-ones was effected initially by using
Na2CO3/K2CO3 as a base and benzene as a solvent. Only poor yields were achieved.
Instead, when triethylamine was used as base the yield of the product improved
significantly (i.e., about 80–94%) in stirring mode at about 30–35ꢁC. Furthermore,
while using a more-basic catalyst such as NaOH, KOH, and pyridine individually to
effect chloroacetylation, undesired products were obtained along with the expected
product. This may be ascribed to the bifunctional nature of chloroacetyl chloride
and also due to the presence of active hydrogens at the C-3 and C-5 positions of
piperidin-4-one, which may undergo chloroacetylation besides the secondary

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Med Chem Res (2007) 16:188–204
nitrogen. Generally, the attachment of an electron-withdrawing acyl group (-COR)
at the nitrogen site of the 2,6-diarylpiperidin-4-one ring is known to exert a major
change in the ring conformation and the chemical shifts of ring carbons and attached
protons (Krishnapillai et al., 2000; Krishnakumar and Krishnapillai 1996). These
conformational and chemical-shift changes are attributed to the involvement of the
lone pair of electrons on the ring nitrogen in conjugation with the -COR function
(Chow et al., 1968; Lunazzi et al., 1982; Lunazzi et al., 1980; Ravindran et al.,
1991; Senthilkumar et al., 1992; Krishnakumar and Krishnapillay, 1996; Krish-
nakumar and Krishnapillay, 1992; Krishnapillay et al., 2000; Gdaniec et al., 1995;
Rubiralta et al., 1989). Hence, this kind of conjugation creates partial double-bond
character about the N–CO bond in 11–20, which in turn leads to restricted rotation
about this bond as shown in Scheme 1. Existence of restricted rotation in the
molecule is also confirmed by the broadening of the signal of the benzylic protons
(H2 and H6) at room temperature. If rotation about the N–CO bond is slow (i.e.,
restricted rotation) on the nuclear magnetic resonance (NMR) time scale due to its
high energy barrier, two sets of signals can be expected for the corresponding two
rotomers A and B (Scheme 2) in its NMR spectrum. Despite the restricted rotation,
two separate spectra were not obtained for the compounds 11–20 pertaining to the
two rotomers A and B. Instead, we have only the average NMR spectra for these
compounds at room temperature. Hence, it can be assumed that these two rotomers
undergo interconversion at a faster rate than the NMR time scale.
O
O
R
R
1
R
R
1
2
2
N
Ar
N
Ar
Ar
Ar
O
O
Cl
Cl
Scheme 1
O
N
O
R
R
R
2
R
1
2
1
Ar
N
Ar
Ar
Ar
O
O
Cl
Cl
B
A
Scheme 2

Med Chem Res (2007) 16:188–204
191
O
O
R
R
1
2
R
R
1
2
EtOH
Heat
O
O
+
N
H
H
H
NH4OAC
R
R
R
R
1-10
NEt3
ClCH2COCl
6-8 h. stirring
°
30-35
C
O
N
R
2
R
1
R
O
R
Cl
11-20
Compound
R1
R2
H
H
H
H
H
R
H
1, 11
2, 12
3, 13
4, 14
5, 15
6, 16
7, 17
8, 18
9, 19
10, 20
H
H
CH3
H
CH(CH3)2
CH3
Cl
Cl
Cl
CH2CH3
CH3
CH3
H
CH3
OCH3
OCH3
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
Scheme 3
The schematic representation and analytical data for the synthesised
compounds 11–20 are furnished in Scheme 3 and Table 1, respectively.
Condensation of respective ketones, aldehyde, and ammonium acetate in the
ratio of 1:2:1 respectively afforded the formation of 2,6-diarylpiperidin-4-ones 1–
10. N-Chloroacetylation of the piperidin-4-ones was achieved by using trieth-
ylamine as catalyst.

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Med Chem Res (2007) 16:188–204
Elemental analysis (observed)*
Table 1 Analytical data of compounds 11–20
Entry
Yield (%)
Melting point (ꢁC)
Molecular formula
C (%)
H (%)
N (%)
11
12
13
14
15
16
17
18
19
20
*
84
94
89
82
80
84
83
80
81
88
120–122
131
C
C
C
C
C
C
19H18NO2Cl
20H20NO2Cl
22H24NO2Cl
20H18NO2 Cl3
21H20NO2Cl3
21H20NO2Cl3
69.57
70.28
71.40
58.45
59.35
59.31
65.73
66.40
71.43
71.91
5.53
5.91
6.52
4.41
4.75
4.74
6.03
6.31
6.55
6.82
4.28
4.10
3.78
3.40
3.29
3.29
3.48
3.36
3.78
3.65
102
159
Semisolid
128
108–110
162–164
118–120
158–160
C22H24NO4Cl
C23H26NO4Cl
C22H24NO2Cl
C23H26NO2Cl
The observed microanalysis values for C, H, and N were within 0.4% of the theoretical values
Fig. 1 Target compound
numbering
O
R
R
2
1
4
5
6
3
2
1
N
6'
2'
2''''
O
R
R
Cl
To get a clear idea about the structure–activity relationship results for the
synthesised compounds, numberings of the target compound are done as shown in
Fig. 1.
Pharmacology
In vitro antibacterial and antifungal activity
The in vitro antimicrobial activities of the compounds were tested in Sabouraud’s
dextrose broth (SDB, Hi-media, Mumbai) for fungi and nutrient broth (NB, Hi-
media, Mumbai) for bacteria by the twofold serial dilution method (Dhar et al.,
1968). The test compounds were dissolved in dimethylsulphoxide (DMSO) to
obtain 1 mg/mL stock solutions. Seeded broth (broth containing microbial spores)
was prepared in NB from 24-hour-old bacterial cultures on nutrient agar (Hi-media,
Mumbai) at 37 1ꢁC while fungal spores from 24-hour- to 7-day-old Sabouraud’s
agar slant cultures were suspended in SDB. The colony-forming units (cfu) of the
seeded broth were determined by the plating technique and adjusted in the range

Med Chem Res (2007) 16:188–204
193
104–105 cfu/mL. The final inoculum size was 106 cfu/mL for the antibacterial assay
and 1.1–1.5 · 102 cfu/mL for the antifungal assay. Testing was performed at pH 7.4
0.2. Exactly 0.2 mL of the solution of test compound was added to 1.8 mL of
seeded broth to form the first dilution. One mL of this was diluted with a further 1
mL of the seeded broth to give the second dilution and so on until six such dilutions
were obtained. A set of assay tubes containing only seeded broth was kept as control
and likewise solvent controls were also run simultaneously. The tubes were
incubated in BOD incubators at 37 1ꢁC for bacteria and 28 1ꢁC for fungi. The
minimum inhibitory concentrations (MICs) were recorded by visual observations
after 24 hours (for bacteria) and 72–96 hours (for fungi) of incubation. Streptomycin
and ciprofloxacin were used as standards for bacterial study while amphotericin B
was used as a standard for the fungal study.
Structure–activity relationship results
Antibacterial activity
All the synthesised novel N-chloroacetyl-2,6-diarylpiperidin-4-ones (11–20) were
assessed to elicit their antibacterial activity in vitro against Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and
Salmonella typhi. Against Mycobacterium tuberculosis, streptomycin was the
first antibiotic used and also found importance for years in monotherapy
regimens, leading to the emergence of resistance. Apart from its other antibiotic
properties, it is one of the most widely used agents for dermatological reasons
(Le Gall et al., 2005; Ruiz et al., 2002). Therefore, the antibacterial potency of
the synthesised compounds was compared with broad-spectrum antibiotics,
namely streptomycin and ciprofloxacin, and their minimum inhibitory concen-
tration values are summarised in Table 2.
A close survey of the MIC values indicates that all the compounds exhibited a
varied range (12.5–200 lg/mL) of antibacterial activity against all the tested
bacterial strains except 11, which did not show activity against B. subtilis and E. coli
even at a maximum concentration of 200 lg/mL. The compounds without any
substituent at the para position of the phenyl groups at the C-2 and C-6 positions of
the heterocyclic ring (11–20) showed antibacterial activity in the range of 50–200
lg/mL.
Compound 11, which was inactive against B. subtilis and E. coli, became active
with the introduction of a methyl (compound 12) or isopropyl (compound 13) group
at the C-3 position and showed MICs, respectively, of 100 and 200 lg/mL.
Likewise, against S. aureus, this substitution improved the activity by about 50%
compared to 11. But, against P. aeruginosa, 50% decreased activity was noted in 12
and 13 compared to the unsubstituted one (compound 11).
Replacement of phenyl groups present at the C-2 and C-6 positions of compound
12 by p-chlorophenyl groups (compound 14) registered a two- to fourfold increase
in activity against all the tested organisms but S. typhi, for which a onefold
decreased activity was noted while the same activity was retained towards B.

194
Med Chem Res (2007) 16:188–204
Table 2 In vitro antibacterial activity of compounds 11–20
Entry
Minimum inhibitory concentration (MIC) in lg/mL
S. aureus
B. subtilis
E. coli
P. aeruginosa
S. typhi
11
200
100
100
50
-
100
200
100
25
-
100
200
25
100
200
200
12.5
50
50
50
12
13
100
100
12.5
25
14
15
25
50
16
12.5
25
100
200
50
50
100
50
17
100
100
25
100
25
18
50
100
100
200
50
19
100
200
25
12.5
100
12.5
50
50
20
50
100
25
Streptomycin
Ciprofloxacin
50
25
25
12.5
50
-, no inhibition even at a higher concentration of 200 lg/mL
subtilis. This phenyl group modification (i.e., in compound 14) was found to be
remarkable against P. aeruginosa as it showed a fourfold increased activity while
against E. coli the activity was enhanced by only twofold compared to 12.
Moreover, the introduction of an ethyl group in place of methyl function in 14
(compound 15) exhibited appreciable inhibition potency towards the tested bacteria
at a minimum concentration between 12.5 and 50 lg/mL. A well-pronounced effect
(i.e., two- to threefold increased activity) was noted against B. subtilis and S. typhi.
However, owing to the introduction of another methyl group at the C-5 position in
14 (compound 16), twofold improvement in the antibacterial potency was found
against S. aureus and S. typhi, while against the rest of the organisms, an appreciable
decrease in activity was noted compared to 14.
Substitution of the p-methoxyphenyl group in place of p-chlorophenyl function
of 14 and 16 (compounds 17 and 18) suppressed the activity against all the tested
organisms except S. aureus and B. subtilis against which compounds 17 and 18,
respectively registered 50% improved activity. However, these compounds (17 and
18) exhibited greater activity than the compounds 11–13 in which the N-
chloroacetamide is flanked by a phenyl group only (having no substitution at the
para position).
Introduction of p-methylphenyl groups instead of p-methoxyphenyl moieties in
17 and 18 (compounds 19 and 20) exhibited an elevated antibacterial potency
against B. subtilis and E. coli while against the rest of the strains a decreased activity
was observed. Besides, the activity of 19 against B. subtilis, E.coli and S. typhi
respectively exerted four-, two- and onefold improved activity compared to 17
whereas against E. coli, compound 20 produced a 50% increased activity compared
to 18. Moreover, the observed potencies of 19 and 20 were also found to be better
than 11–13.

Med Chem Res (2007) 16:188–204
195
Table 3 In vitro antifungal activity of compounds 11–20
Entry
Minimum inhibitory concentration (MIC) in lg/mL
C. neoformans
C. albicans
Rhizopus sp.
A. niger
A. flavus
11
-
100
200
100
50
200
200
50
-
100
100
25
-
200
100
50
100
200
-
12
13
14
100
100
200
100
100
50
25
15
50
12.5
50
25
16
50
100
25
100
50
17
100
100
25
50
18
100
50
25
50
19
12.5
100
50
12.5
50
20
50
50
25
Amphotericin B
25
25
25
50
-, no inhibition even at a higher concentration of 200 lg/mL
Antifungal activities
The in vitro antifungal activities of the novel compounds 11–20 were examined
against the five fungal strains Cryptococcus neoformans, Candida albicans,
Rhizopus sp., Aspergillus niger, and Aspergillus flavus. Here, amphotericin B was
used as standard drug. The MIC values of the tested compounds and the standard are
illustrated in Table 3.
The compounds 11–13 without any substituents at the para position of phenyl
groups present at the carbon atoms adjacent to the heterocyclic nitrogen exhibited
antifungal activity in the region 50–200 lg/mL. However, compound 11 against C.
neoformans, Rhizopus sp., and A. niger and 13 against A. flavus did not show
antifungal activity even at a maximum concentration of 200 lg/mL. Moreover,
methyl group incorporation at the C-3 position in 11 (compound 10) improved the
activity considerably against C. neoformans, Rhizopus sp., and A. niger and
recorded MIC values in the range 100–200 lg/mL for the respective organisms.
Likewise, 50% improved activity was noted in compound 12 against A. flavus
compared to 11.
Replacement of the methyl group in 12 by an isopropyl group (compound 13)
registered two- and onefold improved activites against C. albicans and A. niger,
respectively, while against Rhizopus sp. the activity was retained as such. However,
this modification decreased the activity against C. neoformans by 50% and became
inactive against A. flavus.
If the heterocyclic nitrogen of compound 12 was flanked by p-chlorophenyl
groups (compound 14) instead of phenyl groups, a marked improvement in activity
was noted. The increased activity was significant against Rhizopus sp. and A. niger
(i.e., twofold increased activity) while against C. albicans and A. flavus, the activity
was improved by 50%. However, substitution of the ethyl group in place of methyl

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Med Chem Res (2007) 16:188–204
function in compound 14 (compound 15) registered further improvement in
inhibitory activity against C. neoformans and A. niger while against C. albicans and
A. flavus the activity was retained. Introduction of another methyl group at C-5
position in 14 resulted in a notable decrease in activity against all the tested
organisms except against A. niger, which retained the activity at the same MIC.
Due to the introduction of a methoxy group in place of the chloro function
present at the para position of the phenyl groups (i.e., compound 17), there is no
improvement in antifungal potency against the tested organisms except against A.
flavus for which a 50% decrease in activity was noted. Even after the incorporation
of another methyl group at the C-5 position in 17 (compound 18), there was no
indication of enhancement of activity against C. neoformans, C. albicans, and A.
flavus whereas against A. niger, the activity was improved by 50%. Furthermore,
against Rhizopus sp. a twofold decreased activity was achieved.
Replacement of p-methoxyphenyl groups in 17 and 18 (compounds 19 and 20)
had a marked impact over the antifungal activity against the panel of organisms
under study. Compound 19 showed a twofold increased activity against C.
neoformans and A. flavus while against the rest of the strains a 50% improved
activity was noted. However, introduction of another methyl group at the C-5
position in 19 (compound 20) was found to decrease the activity against all the
organisms except C. albicans for which the same activity was retained at the same
MIC.
However, it is very clear from Table 3 that compounds 17 and 20 registered
better activity than compounds 11–13, which bear phenyl groups at the C-2 and C-6
positions of heterocyclic ring (i.e., without any substituents at the para position).
Conclusion
A comparison of potency of the compounds 11–20 is given in the form of Figs. 2–4
by employing the following the equation.
MIC ðlg=mlÞ of reference compound
Potency ð%Þ ¼
ꢁ 100
MIC ðlg=mlÞ of tested compound
A close survey of the in vitro antibacterial and antifungal activity profile of the new
N-chloroacetyl-2,6-diarylpiperidin-4-ones against the tested bacterial and fungal
organisms gives a clear picture about the structure–activity correlations among
compounds 11–20 under study. Compounds 14–20 with chloro, methoxy, or methyl
functions at the para positions of the aryl groups present at the C-2 and C-6
positions of the piperidone moiety along with and without alkyl substituent at the C-
3 and C-5 positions exerted a varied range of biological activities, while the activity
was not significant for compounds 11–13 without any substituent at the para
position of phenyl groups.
Among compounds 14–20, 15–17 against S. aureus, 15 and 19 against B. subtilis,
14 and 19 against E. coli, 14 against P. aeruginosa, and 15, 16, and 18 against S.
typhi were shown to be significant in their antibacterial potency at 12.5 and 25 lg/
mL. Furthermore, their activity was also on a par with the standard drugs used and

Med Chem Res (2007) 16:188–204
197
450
400
350
300
250
200
150
100
50
Staphylococcus aureus
Escherichia coli
Bacillus subtilis
Pseudomonas aeruginosa
Salmonella typhi
0
11
12
13
14
15
16
17
18
19
20
Compound
Fig. 2 Comparison of potency of compounds 11–20 with streptomycin (as standard) against bacterial
strains from serial dilution method
450
400
350
300
250
200
150
100
50
Staphylococcus aureus
Escherichia coli
Salmonella typhi
Bacillus subtilis
Pseudomonas aeruginosa
0
11
12
13
14
15
16
17
18
19
20
Compound
Fig. 3 Comparison of potency of compounds 11–20 with ciprofloxacin (as standard) against bacterial
strains from serial dilution method
450
Cryptococcus neoformans
400
Rhizopus sp.
350
300
250
200
150
100
50
Aspergillus flavus
Candida albicans
Aspergillus niger
0
11
12
13
14
15
16
17
18
19
20
Compound
Fig. 4 Comparison of potency of compounds 11–20 with streptomycin B (as standard) against fungal
strains from serial dilution method

198
Med Chem Res (2007) 16:188–204
for some compounds was even higher than the activity of the standard drugs.
Though most of the compounds studied exhibited moderate to significant
antibacterial activity, compound 15 (with an ethyl group at C-3 and a p-
chlorophenyl group at the C-2 and C-6 positions) was found to exert a pronounced
effect against all the tested organisms.
Similarly, against the tested fungal strains, compound 19 against C. neoformans,
14 and 17 against Rhizopus sp., 15, 18, and 19 against A. niger, and 14, 15, and 19
against A. flavus recorded enhanced activity at 12.5 and 25 lg/mL. However, the
activity of compound 19 against all the tested organisms was found to be superior to
the other compounds and with an even higher activity than the standard against A.
niger and A. flavus.
From this study, it is clear that presence of an alkyl group at the C-3 or C-3/C-5
positions of the piperidone ring is considered to be advantageous as well as the
presence of either chloro or methoxy functions at the para positions of phenyl
groups present at C-2 and C-6 positions for elevated antimicrobial activity.
Furthermore, the observed marked antibacterial and antifungal activities may be
considered as key steps for the building of novel chemical entities with comparable
pharmacological profiles to that of the standard drugs after considering results from
toxicology studies.
Experimental
Thin-layer chromatography (TLC) was carried out to monitor the course of the
reaction and the purity of the product. Melting points were recorded in open
capillaries and are uncorrected. Infrared (IR) spectra were recorded in an
AVATAR-330 Fourier-transform (FT)-IR spectrophotometer (Thermo Nicolet)
and only noteworthy absorption levels (reciprocal centimeters) are listed. 1H-
NMR spectra were recorded at 400 MHz on a BRUKER AMX 400 MHz
spectrometer using CDCl3 as the solvent and trimethyl silane (TMS) as an
internal standard. 13C-NMR spectra were recorded at 100 MHz on a BRUKER
AMX 400 MHz spectrometer in CDCl3. Mass spectra were recorded on a Jeol
SX-102 (EI) and microanalyses were performed on an Heraeus Carlo Erba 1108
CHN analyser. Unless otherwise stated, all the reagents and solvents used were
of high grade and purchased from Fluka and Merck. All solvents were distilled
prior to use.
By employing the literature precedent of Noller and Baliah (1948), all the parent
2,6-diarylpiperidin-4-ones were prepared by the condensation of appropriate
ketones, aldehydes, and ammonium acetate in a 1:2:1 ratio using ethanol as a
solvent.
Synthesis of N-chloroacetyl-2,6-diphenylpiperidin-4-one (11)
To a well-stirred solution of 2,6-diphenylpiperidin-4-one 1 (0.005 mol) and
triethylamine (0.005 mol) in benzene, chloroacetyl chloride (0.005 mol) in benzene

Med Chem Res (2007) 16:188–204
199
was added dropwise for about half an hour. Stirring was continued with mild heating
(30–35ꢁC) using a magnetic stirrer. After the completion of the reaction, it was
poured into water and extracted with ether. The collected ether extracts were then
washed well with 3% sodium bicarbonate solution and dried over anhydrous sodium
sulfate. This upon evaporation afforded the compound 11 in good yield.
IR (KBr) (cm–1): 3059, 3029, 2953, 2912 (C–H stretching), 1723 (C=O
stretching), 1633 (N–C=O stretching), 1495, 1449, 1391, 1358, 1241, 1146, 1083,
1023, 947, 844, 781, 701, 596, 544, 482, 427. 1H NMR (d ppm): 3.08 (dd, 2J3a,3e
=
=
3
3
2
2J5a,5e =17.44 Hz; J2a,3a= J5a,6a = 6.24 Hz, 2H, H3a and H5a), 2.78 (dd, J3a,3e
2J5a,5e = 17.64 Hz; 3J2a,3e = 3J5e,6a = 5.52 Hz, 2H, H3e and H5e), 3.93 (s, 2H, CH2Cl),
5.88 (bs, 2H, H2 and H6), 7.19–7.30 (m, 10H, aryl protons). 13C NMR (d ppm):
55.360 (C-2 and C-6), 44.062 (C-3 and C-5), 206.331 (C=O at C-4), 168.656 (N–
C=O), 140.796 (C-20 and C-60 ipso), 129.110, 128.046, 126.569 (other aryl carbons),
42.676 (CH2Cl).
The compounds 12–20 were prepared similarly.
N-Chloroacetyl-3-methyl-2,6-diphenylpiperidin-4-one (12)
IR (KBr) (cm–1): 3077, 3057, 3028, 2971, 2937, 2886 (C–H stretching), 1721 (C=O
stretching), 1651 (N–C=O stretching), 1495, 1453, 1386, 1323, 1253, 1199, 1116,
1079, 1027, 931, 855, 784, 744, 704, 607, 529, 405. Mass (m/z): 342 (M)+ (100%,
molecular formula: C20H20NO2Cl), 316, 301, 288, 249, 238, 224, 182, 149, 131,
119, 105, 91, 77. 1H NMR (d ppm): 3.17 (dd, 2J5a,5e = 18.22 Hz; 3J5a,6a = 6.10 Hz,
1H, H5a), 2.83 (dd, 2J5a,5e = 18.22 Hz; 3J5e,6a = 5.91 Hz, 1H, H5e), 3.06 (t, 1H, H3a),
3.88, 3.93 (two d, 2H, CH2Cl), 5.39 (bs, 1H, H2), 5.92 (bs, 1H, H6), 7.11–7.36 (m,
10H, aryl protons), 1.06 (d, J = 6.62 Hz, 3H, CH3 at C-3). 13C NMR (d ppm):
61.846 (C-2), 54.730 (C-6), 46.141 (C-3), 42.975 (C-5), 208.610 (C=O at C-4),
168.942 (N–C=O), 140.920 (C-60 ipso), 140.653 (C-20 ipso), 129.208, 128.932,
128.133, 127.528, 126.662 (other aryl carbons), 42.730 (CH2Cl), 13.628 (CH3 at C-
3).
N-Chloroacetyl-3-isopropyl-2,6-diphenylpiperidin-4-one (13)
IR (KBr) (cm–1): 3082, 3044, 3028, 2984, 2962, 2924, 2897, 2869 (C–H
stretching), 1718 (C=O stretching), 1648 (N–C=O stretching), 1494, 1454, 1383,
1
1263, 1216, 1137, 1105, 1031, 993, 931, 764, 701, 627, 518. H NMR (d ppm):
2
2.82 [dd, J =18.51 Hz; J = 8.91 Hz, 2H(merged), H5a and H3a], 2.72 (dd, J5a,5e
=17.03 Hz; 3J5e,6a = 6.02 Hz, 1H, H5e), 3.91, 4.04 (two d, 2H, CH2Cl), 6.45 (bs, 1H,
H2), 5.43 (bs, 1H, H6), 6.98–7.30 (m, 10H, aryl protons), 2.08–2.16 (m, 1H, H7 at C-
3), 1.13 (d, J = 6.53 Hz, 3H, CH3), 1.07 (d, J = 6.68 Hz, 3H, CH3). 13C NMR (d
ppm): 57.772 (C-2), 57.189 (C-6), 54.942 (C-3), 44.639 (C-5), 208.374 (C=O at C-
4), 168.635 (N-C=O), 140.888 (C-20 and C-60 ipso), 128.988, 128.496, 128.281,
127.775, 127.549, 127.448, 125.894 (other aryl carbons), 42.406 (CH2Cl), 28.562
(C-7), 21.282 (CH3), 20.402 (CH3).

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Med Chem Res (2007) 16:188–204
N-Chloroacetyl-3-methyl-2,6-bis(p-chlorophenyl)piperidin-4-one (14)
IR (KBr) (cm–1): 3071, 3044, 2981, 2929, 2869 (C–H stretching); 1723 (C=O
stretching); 1658 (N–C=O stretching); 1492, 1433, 1401, 1342, 1302, 1263, 1130,
1
1093, 1013, 942, 834, 735, 670, 585, 543, 499, 448; H NMR (d,ppm): 3.11 (dd,
2J5a,5e = 18.13 Hz; 3J5a,6a = 5.46 Hz, 1H, H5a); 2.87 (dd, 2J5a,5e = 18.17 Hz; 3J5e,6a
=
6.02 Hz, 1H, H5e); 2.96 (t, 1H, H3a); 3.94 (t, 2H, CH2Cl); 5.35 (bs, 1H, H2); 5.86 (bs,
1H, H6); 7.03, 7.15 (two d, 4H, aryl protons meta to chlorine); 7.25, 7.32 (two d, 4H,
aryl protons ortho to chlorine); 1.06 (d, J = 6.63 Hz, 3H, CH3 at C-3); 13C NMR (d,
ppm): 61.256 (C-2); 54.343 (C-6); 46.117 (C-3); 42.477 (C-5); 207.687 (C=O at C-
4); 168.711 (N–C=O); 138.996 (C-60 ipso); 138.818 (C-20 ipso); 134.310 (C-60000
ipso); 134.186 (C-20000 ipso); 129.403, 129.114, 128.892, 128.047 (other aryl
carbons); 42.330 (CH2Cl); 13.753 (CH3 at C-3).
N-Chloroacetyl-3-ethyl-2,6-bis(p-chlorophenyl)piperidin-4-one (15)
IR (KBr) (cm–1): 3094, 3066, 3035, 2967, 2934, 2876 (C–H stretching); 1720
(C=O stretching); 1655 (N–C=O stretching); 1595, 1492, 1407, 1341, 1254, 1220,
1
1092, 1143, 1013, 963, 827, 680, 548,498; H NMR (d, ppm): 2.65–2.88 (m, 3H,
H5a, H5e and H3a); 3.96, 4.0 (two d, 2H, CH2Cl); 5.90 (bs, 1H, H2); 5.50 (bs, 1H,
H6); 6.89–7.1 (m, 8H, aryl protons); 1.59 (m, 2H, CH2CH3 at C-3); 0.89 (t, 3H,
CH2CH3 at C-3); 13C NMR (d, ppm): 56.693 (C-2); 55.871 (C-6); 52.585 (C-3);
43.492 (C-5); 208.047 (C=O at C-4); 168.851 (N–C=O); 139.024 (C-60 ipso);
138.862 (C-20 ipso); 134.185 (C-60000 ipso); 133.980 (C-20000 ipso); 129.353, 128.974,
128.911, 127.696 (other aryl carbons); 42.183 (CH2Cl); 23.382 (CH2CH3 at C-3);
11.728 (CH2CH3 at C-3).
N-Chloroacetyl-3,5-dimethyl-2,6-bis(p-chlorophenyl)piperidin-4-one (16)
IR (KBr) (cm–1): 3010, 2983, 2938, 2872 (C–H stretching); 1717 (C=O stretching);
1652 (N–C=O stretching); 1492, 1386, 1335, 1258, 1206, 1091, 1014, 836, 788, 652;
1H NMR (d, ppm): 3.03–3.09 (m, 2H, H3a and H5a); 3.89 (s, 2H, CH2Cl); 5.42 (bs, 2H,
H2 and H6); 7.12 (d, 4H, aryl protons meta to chlorine); 7.33 (d, 4H, aryl protons ortho
to chlorine); 1.09 (d, J = 6.91 Hz, 6H, CH3 at C-3 and C-5); 13C NMR (d, ppm): 60.731
(C-2 and C-6); 45.509 (C-3 and C-5); 209.762 (C=O at C-4); 169.301 (N–C=O);
139.204 (C-20 and C-60 ipso); 134.348 (C-20000 and C-60000 ipso); 129.321, 128.812
(other aryl carbons); 42.381 (CH2Cl); 14.137 (CH3 at C-3 and C-5).
N-Chloroacetyl-3-methyl-2,6-bis(p-methoxyphenyl)piperidin-4-one (17)
IR (KBr) (cm–1): 3060, 3006, 2968, 2831 (C–H stretching); 1714 (C=O stretching);
1646 (N–C=O stretching); 1610, 1512, 1463, 1389, 1306, 1252, 1179, 1116, 1029,
930, 870, 848, 787, 662, 553, 411; 1H NMR (d, ppm): 3.15 (dd, 2J5a,5e = 18.32 Hz;

Med Chem Res (2007) 16:188–204
201
3J5a,6a = 5.59 Hz, 1H, H5a); 2.80 (dd, 2J5a,5e = 18.38 Hz; 3J5e,6a = 6.01 Hz, 1H, H5e);
3.03 (t, 1H, H3a); 3.89, 3.94 (two d, 2H, CH2Cl); 5.30 (bs,1H, H2); 5.86 (bs, 1H, H6);
6.79, 6.86 (two d, 4H, aryl protons ortho to methoxy group); 7.01, 7.15 (two d, 4H,
aryl protons meta to methoxy group); 3.81, 3.78 (two s, 6H, OCH3 at C-20000 and C-
60000 ), 1.03 (d, J = 5.17 Hz, 3H, CH3 at C-3); 13C NMR (d, ppm): 61.443 (C-2);
54.197 (C-6); 46.351 (C-3); 43.058 (C-5); 208.771(C=O at C-4); 168.755 (N–C=O);
159.351 (C-60000 ipso); 159.277 (C-20000 ipso); 132.983 (C-60 ipso); 132.776 (C-20
ipso); 128.731, 127.939, 114.510, 114.248 (other aryl carbons); 55.325, 55.274
(OCH3 at C-20000 and C-60000); 42.672 (CH2Cl); 13.588 (CH3 at C-3).
N-Chloroacetyl-3,5-dimethyl-2,6-bis(p-methoxyphenyl)piperidin-4-one (18)
IR (KBr) (cm–1): 3021, 3015, 3000, 2973, 2962, 2935, 2902, 2836 (C–H
stretching); 1713 (C=O stretching); 1658 (N–C=O stretching); 1609, 1513, 1458,
1
1388, 1289, 1252, 1180, 1110, 1029, 974, 886, 838, 809, 722, 586, 542; H NMR
(d, ppm): 3.12 (t, 2H, H3a and H5a); 3.90 (s, 2H, CH2Cl); 5.39 (bs, 2H, H2 and H6);
6.85 (d, 4H, aryl protons ortho to methoxy group); 7.09 (d, 4H, aryl protons meta to
methoxy group); 3.81 (s, 6H, OCH3 at C-20000 and C-60000); 1.08 (d, J = 6.66 Hz, 6H,
CH3 at C-3 and C-5); 13C NMR (d, ppm): 60.679 (C-2 and C-6); 45.638 (C-3 and
C-5); 210.813 (C=O at C-4); 169.174 (N–C=O); 159.241 (C-20000 and C-60000 ipso);
132.920 (C-20 and C-60 ipso); 128.594, 114.238 (other aryl carbons); 42.585
(CH2Cl); 55.198 (OCH3 at C-20000 and C-60000), 14.030 (CH3 at C-3 and C-5)
N-Chloroacetyl-3-methyl-2,6-bis(p-methylphenyl)piperidin-4-one (19)
IR (KBr) (cm–1): 3066, 3000, 2967, 2934, 2835 (C–H stretching); 1713 (C=O
stretching); 1646 (N–C=O stretching); 1611, 1512, 1461, 1388, 1305, 1252, 1179,
1
2
1117, 1030, 929, 837, 785, 549; H NMR (d, ppm): 3.15 (dd, J5a,5e = 18.03 Hz;
3J5a,6a = 5.59 Hz, 1H, H5a); 2.79 (dd, 2J5a,5e = 18.25 Hz; 3J5e,6a = 5.62 Hz, 1H, H5e);
3.03 (t, 1H, H3a); 3.85–3.96 (m, 2H, CH2Cl); 5.34 (bs,1H, H2); 5.87 (bs, 1H, H6);
7.00–7.35 (m, 8H, aryl protons); 2.34, 2.31 (two s, 6H, CH3 at C-20000 and C-60000 ),
1.03 (d, 3H, CH3 at C-3); 13C NMR (d, ppm): 61.611 (C-2); 54.449 (C-6); 46.099
(C-3); 43.027 (C-5); 208.595 (C=O at C-4); 168.743 (N–C=O); 137.708, 137.981
and 137.488 (C-20000, C-60000 and C-20, C-60 ipso carbons); 129.654, 129.400,
127.364, 126.509 (other aryl carbons); 20.845 (CH3 at C-20000 and C-60000); 42.634
(CH2Cl); 13.462 (CH3 at C-3).
N-Chloroacetyl-3,5-dimethyl-2,6-bis(p-methylphenyl)piperidin-4-one (20)
IR (KBr) (cm–1): 3028, 2983, 2941, 2875 (C–H stretching), 1718 (C=O stretching),
1649 (C=O stretching), 1514, 1454, 1383, 1256, 1185, 1120, 1026, 972, 926, 881,
1
823, 793, 719, 658, 585, 521, 423. H NMR (d ppm): 3.12 (t, 2H, H3a and H5a),
3.89 (s, 2H, -CH2Cl), 5.41 (broad s, 2H, H2 and H6 benzylic protons), 7.06 (d, 4H,

202
Med Chem Res (2007) 16:188–204
aryl protons ortho to methoxy group), 7.3 (d, 4H, aryl protons meta to methoxy
group), 2.33 (s, 6H, at C-20000 and C-60000), 1.07 (d, J= 6.47 Hz, 6H, CH3 at C-3 and
C-5). 13C NMR (d ppm): 60.947 (C-2 and C-6), 45.507 (C-3 and C-5), 210.851
(C=O at C-4), 169.244 (N–C=O), 137.768 (C-20 and C-60 ipso), 137.919 (C-20000 and
C-60000 ipso), 127.345, 129.505 (aryl carbons), 42.652 (–CH2–Cl), 20.881 (CH3 at C-
20000 and C-60000), 14.035 (CH3 at C-3 and C-5).
Acknowledgement We are thankful to Prof. K. Pandiarajan, Head, Department of Chemistry,
Annamalai University for the facilities provided. SK is grateful to University Grants Commission and
Council of Scientific and Industrial Research, New Delhi, India for financial support in the form of the
Major Research Projects. SB is grateful to Council of Scientific and Industrial Research, New Delhi, India
for a Senior Research Fellowship. We also thank the NMR Research Centre, IISc, Bangalore for
providing the facilities to record the NMR spectra.
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