Synthesis, spectral and antimicrobial evaluation of some novel 1-methyl-3-alkyl-2,6-diphenylpiperidin-4-one oxime carbonates

Article abstract of DOI:10.1016/j.bmcl.2013.04.005

Synthesis of some novel biologically active piperidin-4-one oxime carbonates from 1-methyl-3alkyl-2,6-diphenylpiperidin-4-one oximes and substituted chloroformates was carried out in the presence of potassium carbonate as base and tetrabutylammonium bromide (TBAB) as catalyst. The newly synthesized compounds were characterized by IR, ¹H, ¹³C NMR and LC-mass spectra. Based on the ¹H NMR analysis, all the compounds were found to adopt normal chair conformation with equatorial orientation of all the substituents. For all the synthesized compounds (5a-5l) antimicrobial activity has been tested against bacterial and fungal strains using Streptomycin and Amphotericin B as standards.

Full text of DOI:10.1016/j.bmcl.2013.04.005

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3195–3199
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, spectral and antimicrobial evaluation of some novel
1-methyl-3-alkyl-2,6-diphenylpiperidin-4-one oxime carbonates
⇑
Rajamanickam Sivakumar, Kannan Gokula krishnan, Venugopal Thanikachalam
Department of Chemistry, Annamalai University, Annamalainagar, 608 002 Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of some novel biologically active piperidin-4-one oxime carbonates from 1-methyl-3alkyl-2,6-
diphenylpiperidin-4-one oximes and substituted chloroformates was carried out in the presence of
potassium carbonate as base and tetrabutylammonium bromide (TBAB) as catalyst. The newly synthe-
sized compounds were characterized by IR, 1H, 13C NMR and LC–mass spectra. Based on the 1H NMR anal-
ysis, all the compounds were found to adopt normal chair conformation with equatorial orientation of all
the substituents. For all the synthesized compounds (5a–5l) antimicrobial activity has been tested
against bacterial and fungal strains using Streptomycin and Amphotericin B as standards.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 6 December 2012
Revised 23 March 2013
Accepted 1 April 2013
Available online 13 April 2013
Keywords:
Oxime carbonates
Chloroformates
Tetrabutylammonium bromide
Carbonylation
Various strategies are currently being employed to develop no-
vel antibiotics and to improve the effectiveness of established
antimicrobial compounds. Heterocyclic compounds having very
good biological activity, specifically piperidine skeletons are
attractive targets of organic synthesis owing to their pharmaco-
logical activity and wide occurrence in nature.1,2 Piperidines are
known to have CNS depressant activity at low dosage levels but
stimulant activity with increased doses. In addition, the piperi-
dine skelton possesses analgesic, ganglionic blocking and anes-
thetic properties.3,4 The compounds with aryl substituents at
carbons 2 and 6 in the piperidine ring have been documented
as potent microbial agents.5–9
Generally organic carbonates are important precursors which
have unique applications in industry,10 biological/medicinal
fields11 and are useful synthetic intermediates.12 However, synthe-
sis of organic carbonates are limited since the established proce-
dure employs the use of toxic starting materials such as
phosgene13 and its derivatives.14 As an alternative approach,
substituted chloroformates,15,16 are the most frequently used re-
agents for the preparation of organic carbonates. This reagent has
gained much attention recently, because of easy handling, nontoxic
nature as well as good reactivity which led to a successful synthe-
sis of the title compounds. Some of the oxime carbonates have
bronchodilatory and anti-inflammatory activities17 and also act
as fungicides in crop protection.18 The cyanoacetamide-based
oxime carbonates are used to design active reagents in peptide
synthesis.19 The structures of the above mentioned oxime carbon-
ates are shown in Figure 1. In particular, piperidin-4-one oximes
and their derivatives like ethers,20–22 esters23 represent important
classes of organic molecules that attract the interest of both syn-
thetic and medicinal chemists. But it is envisaged from literature
that there is scarcity of reports on the synthesis and biological
study of piperidin-4-one oxime carbonates. Thus, in continuation
of our interest in searching for new biologically active piperidin-
4-one analogues, the title compounds viz., piperidin-4-one oxime
carbonates were synthesized.
The substituted piperdin-4-one oxime carbonates (5a–5l) were
synthesized by a four step procedure as shown in Scheme 1.
Mannich condensation was applied to prepare the 3-methyl-
2,6-diphenylpiperidin-4-one 2a24,25 followed by methylation using
methyl iodide in the presence of anhydrous potassium carbonate
and acetone as solvent to get 1,3-dimethyl-2,6-diphenylpiperi-
din-4-one 3a.26 Oximation of 3a using hydroxylamine hydrochlo-
ride in the presence of sodium acetate trihydrate in absolute
ethanol at reflux condition gave 1,3-dimethyl-2,6-diphenylpiperi-
din-4-one oxime 4a in good yield.27 Similarly, the other piperi-
dones 2b and 2c were prepared by the same Mannich
condensation using methyl propyl ketone 1b and methyl isobutyl
ketone 1c, respectively. Methylation followed by oximation of 2b
and 2c, resulted in the corresponding oximes 4b and 4c,
respectively.
As a pilot study for feasibility, we set out to access the scope and
limitations of the reaction conditions beginning with the carbonyl-
ation of oxime 4a as a model substrate utilizing various bases. As
shown in Table 1, different bases, including organic bases and alka-
li metal carbonates were used in stoichiometric amounts.
⇑
Corresponding author. Tel.: +91 9488476098.
E-mail address: profvt.chemau@gmail.com (V. Thanikachalam).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.04.005

3196
R. Sivakumar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3195–3199
Table 2
Formation of oxime carbonate (5a) from oxime (4a) utilizing various solvents
S. No.
Solvent
Time (h)
Yield of 5a (%)
1
2
3
4
5
THF
DMF
CH2Cl2
CH3CN
1,4-Dioxane
2
10
18
18
18
92
30
20
No reaction
No reaction
Five solvents were screened and of these anhydrous tetrahydro-
furan was found to be a good solvent for oxime carbonate forma-
tion. Reaction in other dry solvents including dimethyl
formamide and methylene dichloride gave low yields whereas,
no product was formed in acetonitrile or 1,4-dioxane and the start-
ing oxime 4a was fully recovered. Based on these results, we have
decided to introduce the oxime carbonates functionality in to a
wide spectrum of oximes, using potassium carbonate in tetrahy-
drofuran (THF) in the presence of tetrabutylammonium bromide
(TBAB) as catalyst. The results obtained were also in agreement
with our expectation for all the kind of alkyl or aryl chloroformates.
The structures of all the synthesized oxime carbonates were
established based on nuclear magnetic spectroscopy (1H and 13C),
infrared spectrometry (IR), and liquid chromatography–mass
spectrometry (LC–MS). (The physical and analytical data of all
the synthesized compounds 5a–5l are given in Supplementary
data.)
For the determination of stereochemistry of the oxime carbon-
ates, the 1H NMR spectrum of 5a is used as a representative case.
The heterocyclic ring of 5a has three stereogenic centres and four
enantiomeric pairs of diastereomers are expected for the oxime
carbonate 5a. However, 1H and 13C NMR spectra of 5a did not sup-
port the formation of enantiomers as evidenced by the signals and
confirmed by the presence of only one of the isomers exclusively in
each case.
Aromatic proton peaks of two phenyl rings of the oxime car-
bonate 5a, appear in the region of 7.44–7.27 ppm as multiplets.
The methyl protons attached to the carbonate oxygen are ob-
served as a singlet at 3.86 ppm. The methyl protons attached
to the piperidine nitrogen of 5a resonate at 1.71 ppm as a singlet
with three protons integral. The equatorial proton peak of carbon
5 is observed at 3.45 ppm as a doublet of doublet and the axial
proton peak of carbon 5 is observed at 2.33 ppm as a triplet. One
proton peak on carbon 6 appears at 3.26 ppm as a doublet of
doublet with coupling constant value of 12 and 3.2 Hz, respec-
tively, due to two protons of carbon 5. One proton peak of car-
bon 2 appears at 2.98 ppm as a doublet with the coupling
constant value of 10 Hz due to one proton of carbon 3. The sig-
nal observed at 2.77 ppm as a multiplet with one proton integral
corresponds to carbon 3. Moreover, the protons of the methyl
group attached to the carbon 3 of 5a resonate as a doublet at
0.92 ppm.
The observation of one large (12 Hz) and one small coupling
constant (3.2 Hz) about C5–C6 bond in 5a reveals that the phenyl
ring at carbon 6 adopts equatorial orientation. The large coupling
(10 Hz) about C2–C3 bond also reveals the equatorial orientations
of phenyl ring at carbon 2 and methyl group at carbon 3. So the
six-membered heterocyclic ring of 5a adopts a normal chair con-
formation with equatorial orientation of all the substituent’s. Fur-
thermore, equatorial disposition of phenyl groups at carbon 2 and
6 makes the chair conformation more rigid thereby preventing
interconversion from one into another. Thus, the relative stereo-
chemistry of one of the enantiomeric pair of 5a is shown in
Figure 2.
Figure 1. Structures of some oxime carbonates used in various applications.
Table 1 shows that no product was formed in the presence of
lithium carbonate and poor yield was obtained with organic bases.
Finally potassium carbonate alone gave a good yield while with the
same in the presence of tetrabutylammonium bromide (TBAB) the
product was formed in short reaction time with excellent yield
(92%).
Next, we focused our attention towards the effect of solvents for
oxime carbonate (5a) formation and the observed results were
shown in Table 2.
Table 1
Formation of oxime carbonate (5a) from oxime (4a) utilizing various bases in THF
S. No.
Base
Time (h)
Yield of 5a (%)
1
2
3
4
5
6
Pyridine
Et3N
DIPA
Li2CO3
K2CO3
K2CO3
48
48
48
24
10
2
30
20
20
No reaction
80
92 (in the presence of TBAB)
The oxime carbonates contain C@N double bond in 5a and a
free rotation of the imino double bond is restricted. Hence, the

R. Sivakumar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3195–3199
3197
Scheme 1. Reaction protocol for the synthesis of substituted piperidin-4-one oxime carbonates (5a–5l).
Fig. 3), the unusual deshielding absorption of one proton signal
(3.45 ppm) should not be observed for the proton on -carbon
a
to the C@N moiety in the case of 5a. Hence, the N–O bond of
the oxime carbonate moiety takes syn configuration to carbon
5 (Fig. 3) rather than syn to carbon 3. This is because of a severe
interaction between N–O bond and syn
this interaction, the syn -(C–H) bond is said to be polarized
and the syn -equatorial hydrogen acquires a slight positive
charge and the syn -carbon acquires a slight negative charge.
The negative charge on the syn -carbon C5 is transmitted to
syn -axial hydrogen that is, H5ax to some extent. Therefore,
a-(C–H) bond. Due to
a
a
a
a
a
equatorial hydrogen of C5 that is, H5eq is more deshielded than
axial hydrogen of C5 that is, H5ax. Based on this it could be con-
cluded that the N–O bond is syn (E-isomer) to carbon 5.
The 13C NMR spectrum of 5a is chosen as an example for discus-
sion. The aromatic carbons absorb at 127.19–128.76 ppm and
ipso carbons of the two phenyl groups absorb at 143.45 and
142.20 ppm, respectively. The carbon of imino group of 5a ab-
sorbs at a downfield of 154.77 ppm, due to the electronegativity
of nitrogen and anisotropic effect. The piperidine ring carbons of
5a, carbons 2 and 6 are observed in the downfield region of
76.73 and 69.23 ppm, respectively. The carbons 3 and 5 are ob-
served in the upfield region of 43.73 and 36.33 ppm, respec-
tively. The carbonyl (C@O) group resonates at 167.36 ppm and
N–Me absorb at 41.35 ppm. The methyl group at carbon 3 is ob-
served at 12.45 ppm and OMe group of carbonate functionality
resonates at 55.15 ppm.
Figure 2. Conformation of compound 5a.
Figure 3. Configuration about N–O bond with respect to carbon 5.
All the synthesized compounds 5a–5l were tested for their anti-
bacterial activity in vitro against Streptococcus faecalis, Bacillus sub-
tilis, Escherichia coli, Pseudomonas aeruginosa and Klebsiella
pneumoniae. Streptomycin was used as the standard drug whose
minimum inhibitory concentration values are furnished in Table 3.
existence of geometrical isomerism is possible (E- or Z-isomer)
and it is evidenced by a single set of signals in 1H NMR spec-
trum. If the N–O is anti to carbon 5 (or syn to carbon 3,

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R. Sivakumar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3195–3199
Table 3
In vitro antibacterial activity of compounds 5a–5l
Compound
S. faecalis
g/mL) Zone (mm)
B. subtilis
g/mL) Zone (mm)
E. coli
g/mL) Zone (mm)
P. aeruginosa
g/mL) Zone (mm)
K. pneumoniae
MIC (lg/mL) Zone (mm)
MIC (l
MIC (l
MIC (l
MIC (l
4a
4b
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
200
200
50
200
100
50
200
100
50
25
25
25
12.5
12.5
À
100
50
25
50
25
12.5
50
25
12.5
25
25
25
50
25
6.25
12.5
+
+
+
+
+
+
+
+
100
50
50
50
25
12.5
50
25
12.5
12.5
25
+
+
++
+
+
++
+
+
++
++
+
++
+++
+++
+++
28
200
200
200
200
200
200
200
200
200
25
À
200
200
200
200
200
200
200
200
200
12.5
6.25
6.25
12.5
6.25
6.25
À
+
À
À
+
+
À
À
À
À
+
À
À
+
À
À
À
À
À
+
À
À
+
+
+
À
À
++
++
++
+++
+++
++++
22
+
++
+++
+++
+++
++++
++++
26
++
++
++
++
++++
28
12.5
++
+++
+++
+++
++++
26
25
6.25
25
12.5
6.25
25
12.5
12.5
12.5
12.5
6.25
50
Streptomycin
25
MIC = minimum inhibition concentration, zone = zone of inhibition.
‘À’ = Inactive, ‘+’ = weakly active (12–16 mm), ‘++’ = moderately active (17–21 mm), ‘+++’ = strongly active (22–29 mm), ‘++++’ = highly active (32–34 mm).
Table 4
In vitro antifungal activity of compounds 5a–5l
Compound
Penicillium
Rhizopus
Fusarium
A. niger
A. flavus
MIC (
l
g/mL) Zone (mm) MIC (
l
g/mL) Zone (mm) MIC (
l
g/mL) Zone (mm) MIC (
l
g/mL) Zone (mm) MIC (
l
g/mL) Zone (mm)
4a
4b
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
200
200
100
200
200
200
200
200
200
50
25
25
25
25
12.5
25
À
100
100
50
200
100
200
200
100
200
50
25
25
25
25
25
25
+
+
+
200
200
200
200
200
200
200
200
200
25
50
25
25
12.5
12.5
25
À
200
200
200
200
200
200
200
200
200
100
50
À
À
200
200
200
100
200
100
100
200
100
50
50
50
50
25
25
50
À
À
À
À
+
À
À
À
À
À
À
À
+
À
+
À
À
À
À
À
À
À
+
À
À
À
À
+
À
+
À
À
À
À
À
À
À
+
+
+
+
+
+
++
++
++
++
++++
22
++
++
++
++
+++
21
++
++
++
+++
++++
22
++
+
++
++
++
21
++
++
++
++
+++
22
50
50
25
25
Amphotericin B
50
MIC = minimum inhibition concentration, zone = zone of inhibition.
‘À’ = Inactive, ‘+’ = weakly active (12–16 mm), ‘++’ = moderately active (17–21 mm), ‘+++’ = strongly active (22–29 mm), ‘++++’ = highly active (32–34 mm).
All the synthesized compounds were tested from higher con-
centration (200 g/mL) to lower concentration (6.25 g/mL)
moniae registered excellent antibacterial activity (MIC at 6.25–
12.5 g/mL). The chloro substituted piperidin-4-one oxime car-
l
l
l
against the above mentioned organisms. From Table 3, it is clear
that the parent compounds 4a–4c did not show significant activity
against all the tested organisms and the compounds 5a–5c are
weakly active against S. faecalis, B. subtilis, and E. coli. However,
compound 5a did not have activity against S. faecalis, P. aeruginosa,
and K. pneumoniae and the compound 5c is also inactive against K.
bonates 5j–5l showed maximum inhibition activity against all
the strains, the presence of ethyl group at C(3) position in com-
pound 5k shows improved activity when compared with the com-
pound 5j against B. subtilis, P. aeruginosa and K. pneumoniae. The
presence of isopropyl group at C(3) position in compound 5l
showed further improvement when compared to 5j–5k against
all the strains except E. coli. Based on the results, the compounds
5j–5l registered excellent antibacterial activity (MIC at 6.25–
pneumoniae even at higher concentrations (200 lg/mL). Of these
methyl substituted piperidin-4-one oxime carbonates 5a–5c, the
compound 5c exhibit improved activity against S. faecalis, B. subtilis
and E. coli when compared with the compounds 5a–5b. The com-
pounds 5d–5f showed no appreciable change in activity against
all the tested organisms compared to the compounds 5a–5c.
Among the various substituted compounds 5a–5f, compounds 5a
and 5d against S. faecalis, compound 5a–5f against P. aeruginosa
and K. pneumoniae did not show any activity even at higher con-
12.5 lg/mL) against all the strains except 5j against B. subtilis. In
an overall view, the inhibitory potencies of compounds 5a–5f are
very less than that of compounds 5j–5l and for the chloro substi-
tuted compounds the inhibitory potency falls in the order
5l > 5k > 5j.
In order to extend the antimicrobial evaluation, the synthesized
compounds were also screened for in vitro antifungal activity with
five fungal strains viz., Penicillin, Rhizopus sp., Fusarium, Aspergillus
niger and Aspergillus flavus. Amphotericin B was used as the stan-
dard drug whose minimum inhibitory concentration values are
furnished in Table 4.
centrations (200 lg/mL). The phenyl substituted piperidin-4-one
oxime carbonates 5g–5i showed maximum inhibition activity
against all the strains but 5g showed better activity against
E. coli and K. pneumoniae, 5h–5i against P. aeruginosa and K. pneu-

R. Sivakumar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3195–3199
3199
The parent compounds 4a–4c did not show significant activity
References and notes
against all the tested organisms. The compounds 5a–5f did not
show in vitro antifungal activity even at the maximum concentra-
tion of 200 lg/mL against all the tested organisms except 5a, 5c, 5d
and 5f against A. flavus, 5b and 5e against Rhizopus. The phenyl
substituted piperidin-4-one oxime carbonates 5g–5i showed
improvement in the activity when compared to the compounds
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5a–5f and they showed MIC ranging from 25 to 100 lg/mL against
all the tested organisms. Introduction of ethyl group at C(3) posi-
tion in compound 5h showed increase in activity against all the
tested strains when compared to the compound 5g except for
Fusarium and A. flavus. Against Fusarium, activity was reduced
but activity against A. flavus was unchanged. The presence of iso-
propyl group at C(3) position in compound 5i, did not show appre-
ciable change in activity compared with the compound 5h except
for Fusarium. The chloro substituted piperidin-4-one oxime car-
bonates 5j–5l showed maximum inhibition activity against all
the strains (Table 4). Based on the results, compounds 5j–5l have
excellent antifungal activity compared to 5a–5f.
In conclusion, several substituted piperidin-4-one oxime car-
bonates were synthesized through Mannich reaction followed by
methylation, oximation and finally carbonylation with substituted
chloroformates. The final carbonylation step using, potassium car-
bonate in the presence of tetrabutylammonium bromide gave
excellent yields with shortest reaction time. The nuclear magnetic
resonance studies showed that all the synthesized oxime carbon-
ates exist in normal chair conformation and the orientation of N–
O bond is syn to carbon 5. The chloro substituted oxime carbonates
5j–5l showed excellent antibacterial activity as well as antifungal
activity when compared to all the other oxime carbonates. Based
on the antimicrobial studies, it is believed that the oxime carbon-
ates may lead to chemical entities with better pharmacological
profile than standard drugs. Thus, in future this class of oxime car-
bonates may be used as templates for the design of better drugs to
combat bacterial and fungal infections.
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The authors are thankful to RMMCH, Annamalai University for
the evaluation of antimicrobial activity.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
04.005.