Synthesis, spectral, stereochemical and biological evaluation of (E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamide derivatives

Article abstract of DOI:10.1080/10426507.2017.1315580

A series of new (E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamides (1-6) were synthesized from the corresponding 3-pentyl-2,6-diarylpiperidine-4-ones condensation with phenyl thiosemicarbazide. Their chemical structures were confirmed by means of elemental analysis, FT-IR, ¹H, and ¹³C NMR spectral techniques and for compound 3, HOMOCOSY, HSQC, HMBC, NOESY, and DEPT NMR spectral techniques. From the NMR spectral data the compounds (1-6) are shown to exist in normal chair conformation with equatorial orientation of all the phenyl groups at C-2 and C-6 and pentyl group at C-3. The synthesized compounds were screened for their bacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, and Escherichia coli and fungal activity against Candida albicans, Rhizopus sp, Aspergillus niger, and Aspergillus flasvus.

Full text of DOI:10.1080/10426507.2017.1315580

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis, spectral, stereochemical and biological
evaluation of (E)-2-(3-pentyl-2,6-diarylpiperidin-4-
ylidene)-N-phenylhydrazinecarbothioamide
derivatives
Mariadoss Arockia doss, Sambandam Savithiri, Govindasamy Rajarajan &
Venugopal Thanikachalam
To cite this article: Mariadoss Arockia doss, Sambandam Savithiri, Govindasamy Rajarajan &
Venugopal Thanikachalam (2017): Synthesis, spectral, stereochemical and biological evaluation
of (E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamide derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1315580
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1315580
Accepted author version posted online: 10
Apr 2017.
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Synthesis, spectral, stereochemical and biological evaluation of (E)-2-(3-pentyl-2,6-
diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamide derivatives
*
Mariadoss Arockia doss, Sambandam Savithiri, Govindasamy Rajarajan , Venugopal
Thanikachalam
Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
*
Corresponding author: E-mail: rajarajang70@gmail.com
Abstract
A
series
of
new
(E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-
phenylhydrazinecarbothioamides (1-6) were synthesized from the corresponding 3-pentyl-2,6-
diarylpiperidine-4-ones condensation with phenyl thiosemicarbazide. Their chemical structures
1
13
were confirmed by means of elemental analysis, FT-IR, H and C NMR spectral techniques and
for compound 3, HOMOCOSY, HSQC, HMBC, NOESY and DEPT NMR spectral techniques.
From the NMR spectral data the compounds (1-6) are shown to exist in normal chair
conformation with equatorial orientation of all the phenyl groups at C-2 and C-6 and pentyl
group at C-3. The synthesized compounds were screened for their bacterial activity aganist
Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi and Escherichia coli and
fungal activity aganist Candida albicans, Rhizopus sp, Aspergillus niger and Aspergillus flasvus.
1
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Keywords
3
-pentylpiperidone; phenylthiosemicarbazone; NMR; antibacterial activity; antifungal activity.
2
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Introduction
1
13
H and C NMR techniques have been extensively applied in deriving stereodynamical
information about a wide variety of systems. It gives information about the influence of
1
,2
electronic and conformational effect on chemical shifts . Vicinal proton-proton coupling
constant can be used for conformational analysis since it depends on the torsional angle between
3
two protons on adjacent carbons . 2,6-diarylpiperidin-4-ones normally adopt a chair
4
-7
conformation with equatorial orientation of all the substituents . The conversion of the
8-16
carbonyl group into C=NOH, C=N-NH , C=N-N=CH , C=N-NHPh or C=N-NHCSNH
2
causes
2
2
an abrupt change in the chemical shift of the ring carbons and associated protons and also exhibit
a change in conformation of the compound and orientation of the substituents. In the family of
heterocyclic compounds, nitrogen containing heterocycles especially piperidones gain
17
considerable importance owing to their varied biological properties such as antitumour
,
1
8
19
analgesic local anaesthetic hypertensive, antimicrobial, bactericidal, fungicidal, herbicidal,
,
,
insecticidal, antihistaminic, anti-inflammatory, anticancer, CNS stimulant and depressant
2
0-22
activities
.
However, little is known about piperidine-4-ones substituted with a thiosemicarbazone
moiety possessing potential pharmacological activities such as antiviral, antimalarial and
23-26
antiprotozoal activities
. Thiosemicarbazones were reported to be associated with
2
7,28
antimicrobial activity . Several semicarbazones as well as their sulphur analogues and their
2
9
derivatives have proved their efficiency and efficacy in combating various diseases . In this
study,
a
new
series
of
(E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-
3
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phenylhydrazinecarbothioamides (1-6) were synthesized and characterized by elemental, FT-IR,
1
13
1
1
H, C NMR analyses. H- H COSY, HSQC, HMBC, NOESY and DEPT spectral techniques
were used for compound 3. The synthesized compounds were screened for their antibacterial and
antifungal activity.
Results and discussion
(E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamides (E3-
PPNPs)were synthesized according to the synthetic sequences of reactions illustrated in Scheme
1
.
IR spectral analysis of compounds 1-6
IR spectra of all the synthesized compounds (1-6) showed the absence of C=O stretching
-1
-1
frequency (1700 cm ) and new stretching frequencies appeared at 1594 and 1271 cm
confirming the condensation of 2,6-diarylpiperidin-4-one with phenylthiosemicarbazide.
Besides, the target compounds were confirmed by the presence of 4-phenylsemicarbazone NH
-1
stretching frequency around 3308-3062 cm and aromatic stretching frequency in the region
-1
3
2
025-2950 cm and also the intense aliphatic stretching frequency observed in the region 2925-
-1
854 cm .
NMR spectral analysis of compounds 1-6
1
13
All the synthesized compounds were characterised by 1D NMR spectra ( H and C). For
compound 3, all the spectral signals are assigned unambiguously by 2D NMR spectra
4
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(HOMOCOSY, NOESY, HSQC and HMBC). The chemical shift values are given in Tables 1
and 2 and the correlations are given in Table 3.
1
H NMR spectral analysis
1
The H NMR spectral signals are assigned based on their position, multiplicity and integral
values comparing with the parent piperidones. In general, aromatic protons resonate in the
1
downfield region at around 7 ppm due to magnetic anisotropic effect (ring current effect). H
NMR spectrum of compound 3 showed two signals in the downfield region. The singlet at 9.35
ppm with one proton integral and singlet at 8.87 ppm with one proton integral are due to NH
proton of –NHCS and CSNHPh groups in the thiosemicarbazone, respectively. The multiplet in
the region7.23-7.66 ppm with thirteen proton integral value is obviously due to the phenyl ring
protons at C-2, C-6 and CSNHPh group.
The two doublets in the upfield region at 3.88 ppm with coupling constant of 10.8 Hz and at 3.64
ppm with coupling constant of 10.0 Hz with one proton integral each are due to the benzylic
protons H-6a and H-2a, respectively. The doublet at 2.94 ppm corresponding to one proton is
3
assigned to H-5e. There are three signals at relatively upfield region at 2.94 ppm (d, J = 13.6
3
3
Hz), 2.51 ppm (t, J = 9.6 Hz) and 2.22 ppm (t, J = 12.4 Hz). The coupling constant values and
multiplicity of the signals suggest that the doublet at 2.94 may couple with the triplet at 2.22, and
2
.51 ppm may couple with the methine proton at C-3. Further, the magnitude of geminal
coupling constant of the signals at 2.94 and 2.22 ppm shows that they should be present on the
same carbon. The signals are due to the methylene protons at C-5. Moreover, the methylene
protons on 2.94 and 2.22 ppm are assigned to H-5e and H-5a protons, respectively. Hence, the
5
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remaining signal at 2.51 ppm may be assigned to the methine proton at C-3. On the basis of their
vicinal coupling constant values, the signals in the region 1.19-1.66 ppm corresponding to eight
protons should be due to the methylene protons in the pentyl group. There is a triplet at 0.77 ppm
corresponding to three protons and this should be due to the methyl proton in pentyl group. The
1
H chemical shift values are summarized in Table 1. The assignments are further confirmed by
HOMOCOSY and NOESY correlation spectrum of compound 3.
Conformational analysis
5
Based on the previous study the compounds (1-6) should exist in chair conformation. In
the chair conformation the aryl groups alkyl group at C-3 are equatorial orientation. The
coupling constant values and position of the chemical shifts were used to predict the
3
conformation of the compound. The observation of large vicinal coupling constant values J
=
2a3a
3
1
0.0 and J
= 10.8 Hz and small value of the vicinal coupling constant are not resolved. For
6a5a
the protons of C-6 and C-2 in 1-6 indicate that the six member heterocyclic ring adopts normal
chair conformation (Fig. 1) with equatorial orientation of aryl groups at C-2 and C-6 and pentyl
group at C-3. In compounds (1-6) the heterocyclic ring may be flattened or distorted about the
(C-2)-(C-3) bond to decrease gauche interaction between the equatorial phenyl groups and the
equatorial pentyl group at C-2, C-6 and C-3, respectively.
The chemical shifts values of compounds (1-6) compared with parent ketones, H-5e proton is
deshielded by ~0.25 ppm and H-5a proton is shielded by ~1.29 ppm. Similarly, C-5 is shielded to
an extent of ~8.08 ppm whereas C-3 is shielded only to a small extent of ~0.30 ppm. These
30
observations are similar to those made in 3t-alkyl-2r,6c-diarylpiperidin-4-one oximes with E
6
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configuration about the C=N bond. Obviously, in compounds (1-6), the configuration about C=N
bond is E (Fig. 1). In all the thiosemicarbazones, H-5e has a higher chemical shift than H-5a and
C-5 has a lower chemical shift than C-3. Hence, in compounds (1-6), the configuration about the
C=N bond should be E and the six membered hetrocyclic ring adopts chair conformation with
the orientation of N-NH-CS-NHPh moiety syn to the C-5 carbon (Fig. 1).
1
3
C NMR spectral analysis
1
3
In the C NMR spectrum of compound 3, the aromatic carbons are distinguished from other
carbons by their characteristic absorptions at 123.6-133.9 ppm. Ipso carbons of phenyl groups
(C’, C’’ and C’’’) resonate at 138.0, 140.2 and 146.1 ppm. Thio carbonyl carbon (C=S) is
observed downfield at 176.3 ppm and the C-4 carbon (C=N) resonated at 152.6 ppm.
A set of signals in the upfield region of 50.3 and 36.6 ppm are assigned to C-3 and C-5 carbons,
respectively. Among these two carbons, C-5 is more shielded than C-3 due to γ-syn effect (C-H
bond is polarised and the carbon (C-5) acquired negative charge as shown (Fig 1). Similarly, C-2
and C-6 carbon resonances are observed at 67.7 and 61.0 ppm, respectively and the observed
shielding of C-6 is due to extended γ-syn effect. The signals observed around 22.7, 26.0, 27.0
and 32.4 ppm are assigned to methylene carbons of pentyl group and the upfield signal at 14.02
1
3
ppm is assigned to the methyl carbon of the pentyl group. The C chemical shift values are
summarized in Table 2.
By comparing the chemical shift of α-carbons (C-3 and C-5) of phenylthiosemicarbazone with
the corresponding piperidones, the α-effect was analysed. Due to the diminished
electronegativity of C=N compared with C=O, the α-carbons significantly shielded in
7
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phenylthiosemicarbazone compared to their parent piperidones. Though the shielding of α-
carbons to C=N is in accordance with the expected electronegativity effect, the syn α-carbon is
more shielded than the anti α-carbon. This is substantiated by the interaction of the CN-NH-bond
with the syn α C-H (e) bond (Fig. 1). This interaction induces a polarity in the syn α C-H (e)
bond, so that the syn α-equatorial proton (H-5e) acquires a slight positive charge and the C-5
carbon acquires a slight negative charge. And, as a consequence, the proton and carbon are
3
1
deshielded and shielded . The sum of shielding experienced on syn α-carbon is about ~ 11-18
ppm for all the compounds whereas the shielding experienced on anti α-carbon is only about ~ 4-
1
0 ppm. Particularly in 3-sustituted compounds, the shielding of anti α-carbon is about ~0.3-10.8
ppm while in the symmetric thiosemicarbazone the shielding magnitude increases to ~ 7.5-14.9
ppm. This variation is solely due to the effect of the alkyl substituents of the anti α-carbon (C-3).
1
3
C NMR spectral study supported that the proposed chair conformation of the synthesized
compounds with the equatorial orientation of the bulky aryl and alkyl groups.
Generally in thiosemicarbazone, the syn α-carbon is more shielded than the anti α-carbon,
probably the chemical shift difference between the α-carbons varying by 13-12 ppm depending
on the structure of the thiosemicarbazone (Table 4).
Antimicrobial activity of E3-PPNPs
Antibacterial and antifungal activities
The preliminary antimicrobial activity of the compounds (1-6) was examined using disc
3
3-35
diffusion and serial dilution methods
. The bacterial strains viz., Pseudomonas aeruginosa,
Staphylococcus aureus, Salmonella typhi and Escherichia coli and fungal strains viz., Candida
8
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albicans, Rhizopus sp, Aspergillus niger and Aspergillus flasvus were used for this study. DMSO
was used as a control while Ciprofloxacin and Amphotericin B were used as standard drugs for
bacterial and fungal strains, respectively.
The zone of inhibition (mm) and the minimum inhibitory concentration (MIC in μg/mL) of
compounds 1-6 against the bacterial and fungal strains are given in Tables S 1 and S 2
(Supplemental Materials), respectively. From the zone of inhibition, it is clear that compounds 2,
4
and 6 against Pseudomonas aeruginosa, 2 and 5 against Staphylococcus aureus, compound 2
against Salmonella typhi, 2, 5 and 6 against Escherichia coli are found to be potent antibacterial
agents. Similarly, compound 5 against Candida albicans, 2, 5 and 6 against Rhizopus sp, 2
against Aspergillus niger and compounds 2 and 5 against Aspergillus flavus are good antifungal
agents.
It is clear from Table S 1 that compound 2 against Pseudomonas aeruginosa and Staphylococcus
aureus, compounds 2, 4, 5 and 6 against Salmonella typhi, 6 against Escherichia coli exerted
better activity whereas against the rest of organisms the activity was not appreciable. In the case
of antifungal activity, compounds 2 and 6 against Candida albicans, 2, 5 and 6 against Rhizopus
sp and Aspergillus niger, compound 2 against Aspergillus flavus produced marked antifungal
activity. Among the compounds tested for the antibacterial and antifungal activity, compound 2
against Rhizopus sp, was shown to be superior with a minimum inhibitory concentration of 12.5
μg/mL and its activity was also two fold higher than the standard used.
From Table S 1, it is clear that compound 1, without any substitution at para position of the
phenyl group at C-2 and C-6 in piperidone moiety, exhibited poor activity against all the tested
9
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bacterial strains. Introduction of fluoro atom on the para position of the phenyl group at C-2 and
C-6 in compound 1, (compound 2) showed excellent activity against all the tested bacterial
strains except E. Coli. Substitution of chloro atom at the para position of the phenyl group at C-2
and C-6 in compound 1, (compound 3) exhibited poor activity against all the tested bacterial
strains. Replacement of chloro atom by bromo atom at C-2 and C-6 in compounds 3, (compound
4
) exhibited excellent activity against Escherichia coli and Salmonella typhi while poor activity
was noted against Pseudomonas aeruginosa and Staphylococcus aureus. Comparison of para
fluoro compound 2 with para chloro 3 and para bromo compound 4, compound 2 showed
excellent activity against all the tested bacterial strains. Since fluoro compound has higher
electronegativity, it behaves as good bactericide. Introduction of methoxy group at the para
position of the phenyl group at C-2 and C-6 in compound 5 exhibited activity against
Pseudomonas aeruginosa, while poor activity was noted against Staphylococcus aureus,
Salmonella typhi and Escherichia coli. Further introduction of another methoxy group in the
phenyl groups at C-2 and C-6 in 5 (compound 6) showed excellent activity against Escherichia
coli and Salmonella typhi whereas poor activity was observed against Pseudomonas aeruginosa
and Staphylococcus aureus.
Compound 1 showed excellent activity against Aspergillus niger whereas poor activity was noted
against all the remaining tested fungal strains. Introduction of fluoro atom in the para position of
the
phenyl
group
at
C-2
and
C-6
of
piperidone
moiety
in
1,
(compound 2) showed excellent activity against all the tested fungal strains. The addition of
chloro atom in the para position of the phenyl group at C-2 and C-6 in 1, (compound 3) showed
excellent activity against Aspergillus niger but poor activity was noted against all the remaining
10
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tested fungal strains. Substitution of bromo substituent in the para position of the phenyl group
at C-2 and C-6 in 1 (compound 4) has improved the activity against Candida albicans but did not
cause any change in activity against all the remaining fungal strains. Introduction of methoxy
group in the para position of the phenyl ring at C-2 and C-6 in 1, (compound 5) exhibited
excellent activity against all the tested fungal strains. Further, addition of another methoxy group
on phenyl ring at C-2 and C-6 in 5, (compound 6) has excellent improvement on their activity
against all the fungal strains.
We conclude based on the above observations that fluoro and methoxy substituted compounds
have excellent activities against all the tested bacterial and fungal strains Comparison of (E)-2-
(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamide and 3-pentyl-2,6-
3
6
diarylpiperidin-4-one thiosemicarbzone , show that the title compounds have excellent activities
against all the tested bacterial and fungal strains. This is due to delocalisation of π electrons in
phenyl groups at thiosemicarbazone group.
The potency of synthesized compounds 1-6 against the tested bacterial and fungal strains was
calculated in comparison with the reference standard by using the following equation.
MIC

μg/ mL

of refernce compound
Potency %
100
MIC μg/ mL of tested compound


The results obtained from the above equation are presented in Figs. S1 and S2. On comparison
with Ciprofloxacin, compound 2 against Staphylococcus aureus exhibited double the potency
(200 %) while compound 2 against Pseudomonas aeruginisa, 6 against Escherichia coli and
compounds 2, 4, 5 and 6 against Salmonella typhi showed equal potency. But the remaining
11
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compounds were found to be lesser potency in the range 6.25-50 % than the standard drug. With
reference to Amphotericin B an equal potency was noted in compounds 2 and 6 against Candida
albicans , 5 against Rhizopus sp, compounds 1 and 3 against A.niger and A.flavus while
compound 2 and 6 against Rhizopus sp, 5 and 6 against Aspergillus nniger compounds 2 and 6
against Aspergillus flavus are doubly effective. But 12.5-50 % was noted with rest of the
compounds when compare to standard drug.
Conclusions
A series of (E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamides
have been synthesized successfully in appreciable yields and were characterised by elemental
1
13
analysis, FT-IR, Mass, 1D ( H and C) and 2D (HOMOCOSY, HSQC, HMBC, NOESY and
DEPT) NMR spectral techniques. The observed vicinal proton-proton coupling constants suggest
that in N-phenylhydrazinecarbothioamides 1-6, the piperidine ring adopts chair conformation
with equatorial orientation of alkyl group at C-3 and aryl groups at C-2 and C-6 positions. The
results of the biological studies suggested that compound 2 (against bacteria and fungai)
displayed better activity than the standards Ciprofloxacin and Amphotericin B, respectively
against all the tested strains. The other compounds showed moderate to good inhibition against
tested bacterial and fungal strains.
Experimental
Materials and methods
All the solvents used were of spectral grade. The melting points of the compounds were
measured in open capillaries and are uncorrected. IR spectra were recorded on an AVATAR-330
12
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1
FT-IR spectrometer (Thermo Nicolet) using KBr (pellet form). H NMR spectra were recorded at
1
3
4
00 MHz and C NMR spectra at 100 MHz on BRUKER model using CDCl as solvent for all
3
the compounds. Mass spectra were recorded on a JEOL GCMATE II GC-MS. Microanalyses
were performed on a VarioMicro V2.2.0 CHN analyser.
General procedure for (E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-phenylhydrazine
carbothioamide (1-6)
32
A
mixture
of
3-pentyl-2,6-diarylpiperidin-4-one
(0.1
mol)
and
4
-phenylthiosemicarbazide (0.1 mol) in the presence of few drops of conc. hydrochloric acid in
methanol was refluxed for about 1 to 2 h. After the completion of reaction, the reaction mixture
was cooled and poured into crushed ice and kept at room temperature. The solid product was
1
13
separated by filtration and washed with water and recrystallized from methanol. H and C
NMR spectra of compounds 1-6 are given in Figures S 3-S 14 and HOMOCOSY, NOESY,
HSQC, HMBC, and DEPT NMR spectra of compound 3 are given Figures S 15-S 19
(Supplemental Materials).
(E)-2-(3-pentyl-2,6-diphenylpiperidin-4-ylidene)-N-phenylhydrazinecarbothioamide (1)
Yield 75 %; m.p.: 190-192 ºC; MF: C H N S; Elemental analysis (%):Calcd :C, 73.95; H, 7.18;
29
34
4
-1
N, 11.87; S, 6.73; found:C, 74.00; H, 7.28; N, 11.90; S, 6.81; IR (KBr) (cm ): 3424 (NH-
piperidine ring), 3308-3084 (NH- phenylthiosemicarbazide), 3057-3027 (aromatic CH
stretching), 2924-2855 (aliphatic CH stretching), 1594 (C=N stretching), 1534 (C=C stretching),
1
1
268 (C=S), 1109 (C-N stretching), 753-698 (aromatic C-H out of plane bending vibration); H
NMR (400 MHz, CDCl , δ, ppm): 9.38 (s,1H, NH ), 8.73 (s,1H, NH), 7.22-7.68 (m, Ar-H), 3.91
3
13
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(d, J6a5a= 11.2 Hz,1H, H-6) , 3.67 (d, J2a3a= 9.6 Hz, 1H, H-2,), 2.59 (t, 1H, H-3a), 2.29 (t, J5a5e=
13
1
3.6 Hz, 1H, H-5ax ), 2.95 (d, 1H, H-5eq), 1.16 (m, 8H, CH ), 0.77 (t, 3H, CH ); C NMR (100
,
2
3
MHz,
CDCl3,
δ,
ppm):
176.4
(C=S),
153.4
(C-4),
123.6,
1
3
25.9,126.7,127.5,128.0,128.2,128.6,128.8,138.0,142.6 (Ar-C), 67.7 (C-2), 61.0 (C-6), 50.3 (C-
), 36.6 (C-5), 22.7,26.1,27.0, 32.4 (CH ), 14.0 (CH ).
2
3
(E)-2-(3-pentyl-2,6-di(4-fluorophenyl) piperidin-4-ylidene)-N-phenylhydrazinecarbothioamide (2)
Yield 70 %; m.p.: 180-182 ºC; MF: C H F N S; Elemental analysis (%):Calcd :C,
2
9
32
2
4
-
1
6
3
8.63; H, 6.30; N, 10.85; S, 6.16; found: C, 68.75; H, 6.37; N, 11.06; S, 6.33; IR (KBr) (cm ):
430 (NH- piperidine ring), 3066 (NH- phenylthiosemicarbazide), 2956-2927 (aromatic CH
stretching), 2859-2810 (aliphatic CH stretching), 1600 (C=N stretching), 1547 (C=C stretching),
1
1
224 (C=S), 1094 (C-N stretching), 752-692 (aromatic C-H out of plane bending vibration); H
NMR (400 MHz, CDCl , δ, ppm): 9.36 (s,1H, NH ), 8.78 (s,1H, NH ), 7.03-7.67 (m, Ar-H), 3.90
3
(d, J6a5a= 11.6 Hz,1H, H-6) , 3.66 (d, J2a3a= 9.6 Hz, 1H, H-2,), 2.53 (s, 1H, H-3a), 2.25 (d, J5a5e=
13
1
4.4 Hz, 1H, H-5ax ), 2.93 (d, 1H, H-5eq), 1.18-1.66 (m, 8H, CH ), 0.78 (t, 3H, CH ); C NMR (100
, 2 3
MHz, CDCl , δ, ppm): 176.4 (C=S), 151.3 (C-4), 115.4,115.6,115.8,123.6,126.0,128.4,128.2,129.6,137.9
3
(
Ar-C), 66.9 (C-2), 60.2 (C-6), 50.3 (C-3), 36.8 (C-5), 22.6, 26.0,32.4 (CH ), 14.0 (CH ).
2 3
(E)-2-(3-pentyl-2,6-di(4-chlorophenyl) piperidin-4-ylidene)-N-phenylhydrazinecarbothioamide (3)
Yield 78 %; m.p.: 195-197 ºC; MF: C H Cl N S; Elemental analysis (%): Calcd :C,
2
9
32
2
4
-
1
6
3
4.47; H, 5.96; N, 10.29; S, 5.85; found: C, 64.55; H, 5.98; N, 10.38; S, 5.94; IR (KBr) (cm ):
430 (NH- piperidine ring), 3308-3062 (NH- phenylthiosemicarbazide), 3025-2950 (aromatic
CH stretching), 2925-2854 (aliphatic CH stretching), 1594 (C=N stretching), 1529 (C=C
stretching), 1271 (C=S), 1089 (C-N stretching), 752-692 (aromatic C-H out of plane bending
14
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1
vibration); H NMR (400 MHz, CDCl , δ, ppm): 9.35 (s,1H, NH ), 8.87 (s,1H, NH ), 7.23-7.66
3
(m, Ar-H), 3.88 (d, J6a5a= 10.8 Hz, 1H, H-6) , 3.64 (d, J2a3a= 10.0 Hz, 1H, H-2,), 2.51 (t, 1H, H-
3
a), 2.22 (t, J5a5e= 13.6 Hz, 1H, H-5ax), 2.94 (d, 1H, H-5eq), 1.19-1.66 (m, 8H, CH ), 0.77 (t, 3H,
2
13
CH3);
C
NMR (100 MHz, CDCl3, δ, ppm): 176.3 (C=S), 152.6 (C-
4
5
),123.6,124.1,126.0,128.1,129.0,129.3,133.8,133.9,137.9,146.1 (Ar-C), 66.9 (C-2), 60.2 (C-6),
0.2 (C-3), 36.6 (C-5), 22.7,26.0,27.0,32.4 (CH ), 14.0 (CH ).
2
3
(E)-2-(3-pentyl-2,6-di(4-bromophenyl) piperidin-4-ylidene)-N-phenylhydrazinecarbothioamide (4)
Yield 68 %; m.p.: 189-191 ºC; MF: C H Br N S; Elemental analysis (%):Calcd :C,
2
9
32
2
4
-
1
7
3
0.10; H, 7.18; N, 10.44; S, 5.99; found:C, 70.16; H, 7.22; N, 10.56; S, 6.04; IR (KBr) (cm ):
414 (NH- piperidine ring), 3063 (NH- phenylthiosemicarbazide), 3002-2958 (aromatic CH
stretching), 2928-2855 (aliphatic CH stretching), 1597 (C=N stretching), 1514 (C=C stretching),
1
1
263 (C=S), 1026 (C-N stretching), 759-697 (aromatic C-H out of plane bending vibration); H
NMR (400 MHz, CDCl , δ, ppm): 10.16 (s,1H, NH ), 8.35 (s,1H, NH ), 7.26-7.53 (m, Ar-H),
3
4
.81 (d, J6a5a= 10.4 Hz, 1H, H-6) , 4.60 (d, J2a3a= 10.0 Hz, 1H, H-2,), 3.66 (d, 1H, H-3a), 2.65 (q,
13
J5a5e= 11.2 Hz, 1H, H-5ax), 4.01 (dd, 1H, H-5eq), 0.95-1.30 (m, 8H, CH ), 0.67 (t, 3H, CH ); C
2
3
NMR
(100
MHz,
CDCl3,
δ,
ppm):
178.4
(C=S),
158.3
(C-4),
1
14.7,127.6,128.3,128.8,129.6,129.7,129.9,130.5,131.9,132.2,132.4 (Ar-C), 65.1 (C-2), 61.2 (C-6),
8.2 (C-3), 42.6 (C-5), 22.7,25.4,27.4,32.0(CH ), 14.2 (CH ).
4
2
3
(E)-2-(3-pentyl-2,6-di(4-methoxyphenyl) piperidin-4-ylidene)-N-phenylhydrazinecarbothioamide (5)
Yield 60 %; m.p.: 203-205 ºC; MF: C H N O S; Elemental analysis (%):Calcd :C,
31
38
4
2
-
1
6
3
6.01; H, 7.15; N, 9.37; S, 5.37; found: C, 67.09; H, 7.15; N, 9.48; S, 5.43; IR (KBr) (cm ):
414 (NH- piperidine ring), 3063 (NH- phenylthiosemicarbazide), 3002-2958 (aromatic CH
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stretching), 2928-2855 (aliphatic CH stretching), 1597 (C=N stretching), 1514 (C=C stretching),
1
1
263 (C=S), 1026 (C-N stretching), 759-697 (aromatic C-H out of plane bending vibration); H
NMR (400 MHz, CDCl , δ, ppm): 9.41 (s,1H, NH ), 8.82 (s,1H, NH ), 6.84-7.71 (m, Ar-H), 4.81
3
(d, J6a5a= 10.8 Hz,1H, H-6) , 4.78 (d, J2a3a= 9.6 Hz, 1H, H-2,), 2.63 (t, 1H, H-3a), 2.18 (t, J5a5e=
13
8
.4 Hz, 1H, H-5ax), 3.82 (s, 1H, H-5eq), 1.09-1.45 (m, 8H, CH ), 0.66 (t, 3H, CH ); C NMR
2 3
(
100 MHz, CDCl , δ, ppm): 188.8 (C=S), 159.6 (C-4), 113.9,114.0,114.1, 114.4,
3
1
15.5,127.7,129.0,129.8,130.0,130.3,135.0,142.2 (Ar-C), 65.3 (C-2), 58.0 (C-6), 55.3 (OCH ), 48.5 (C-
3
3
), 40.9 (C-5), 22.7,25.6,27.8, 32.0(CH ), 14.2 (CH ).
2 3
(E)-2-(3-pentyl-2,6-di(3,4-dimethoxyphenyl)piperidin-4-ylidene)-N-phenylhydrazinecarbothioamide(6)
Yield 68 %; m.p.: 225-227 ºC; MF: C H N O S; Elemental analysis (%):Calcd :C, 74.55; H,
33
42
4
4
-1
7
.50; N, 11.16; S, 6.38; found: C, 74.66; H, 7.68; N, 11.23; S, 6.43; IR (KBr) (cm ): 3414 (NH-
piperidine ring), 3063 (NH- phenylthiosemicarbazide), 3002-2958 (aromatic CH stretching),
2
928-2855 (aliphatic CH stretching), 1597 (C=N stretching), 1514 (C=C stretching), 1263
1
(
C=S), 1026 (C-N stretching), 759-697 (aromatic C-H out of plane bending vibration); H NMR
(
400 MHz, CDCl , δ, ppm): 10.20 (s,1H, NH ), 9.12 (s,1H, NH ), 6.82-7.69 (m, Ar-H), 4.79 (d,
3
J6a5a= 10.8 Hz,1H, H-6) , 4.57 (d, J2a3a= 9.6 Hz, 1H, H-2,), 2.58 (d, 1H, H-3a), 1.90 (t, J5a5e= 10.8
13
Hz, 1H, H-5ax), 3.91 (d, 1H, H-5eq), 0.81-1.25 (m, 8H, CH ), 0.62 (t, 3H, CH ); C NMR (100
2
3
MHz,
CDCl3,
δ,
ppm):
173.9
(C=S),
151.3
(C-4),
1
11.1,111.2,127.7,128.9,129.9,130.4,135.0,138.2,141.1,143.2,149.1 (Ar-C), 65.9 (C-2), 58.6 (C-6),
5.9,56.2 (OCH ), 49.0 (C-3), 36.6 (C-5), 22.0,25.6,27.8,32.2 (CH ), 13.8 (CH ).
5
3
2
3
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Acknowledgments
The authors would like to acknowledge University Grant Commission of India for
providing Major research project No: 42-343/2013(SR) and Annamalai University for providing
necessary facilities.
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2
3
4
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78-879.
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0. Pandiarajan, K.; Tamilselvi, P.; Gurumani, V. Indian J. Chem. 1994, 33B, 971-977.
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1. Gurumani, V.; Pandiarajan, K.; Swaminathan, M. Bull. Chem. Soc. Jpn. 1997, 70, 29-35.
2. Bhaskar reddy, D.; Somasekar reddy, A.; Padmavathy, V. Indian J. Chem. 1999, 38B,
41-147.
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3. Subbagh, E.I.; Abu-Zaid, S.M.; Mahran, M.A.; Badria, F.A.; Ai-obaid, A.M. J. Med.
Chem. 2000, 43, 2915-2921.
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S.K. Biol. Pharm. Bull. 2003, 26, 188-193.
5. Manimekalai, A.; Jayabharathi, J.; Rufina, L.; Mahendhiran, R. Indian J. Chem. 2003,
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2B, 2074-2079.
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6. Manimekalai, A.; Senthilsivakumar, B.; Maruthavanan, T. Indian J. Chem. 2004, 43B,
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7. Jerom, B.R.; Spencer, K.H. Eur. Pat. Appl. EP 1988, 277794.
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0. Mobio, I.G.; Soldatenkov, A.T.; Federov, V.O.; Ageev, E.A.; Sergeeva, N.D.; Lin. S.;
Stashenku, E.E.; Prostakov, N.S.; Andreeva, E.L. Khim. Farm. Zh. 1989, 23,421-.
1. Katritzky, A.R.; Fan, W.Q. J. Org. Chem. 1990, 55, 3205-3209.
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2. Ganellin, C.R.; Spicket,t R.G.W. J. Med. Chem. 1965, 8, 619-625.
3. Klayman, D.L.; Bartosevich, J.F.; Griffin, T.S.; Mason, C.J.; Scovill, J.P. J. Med. Chem.
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979, 22, 855-862.
4. Pandeya, S.N.; Ponnilavarasan, I.; Pandey, A.; Lahan, R.; Stables, J.P. Pharmazie
999,54, 923-925.
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5. Pandeya, S.N.; Manjula, H.; Stables, J.P.; Pharmazie 2001, 56, 121-124.
6. Bharti, N.; Husain, K.; Garza, M.T.G.; Cruz-Vega, D.E.; Castro-Garza, J.; Mata-
Cardenas, B.D; Naqvia, F.; Azama, A. Bioorg. Med. Chem. Lett. 2002, 12, 3475-3478.
7. Srivastava, A. K.; Suresh, C.B. J. Indian Chem. Soc. 1976, 53,841-845.
8. Manowitz, M.; Walter, G. Pharm. Sci. 1965, 54, 650-655.
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1. Sylvestre, S.; Pandiarajan, K. Spectrochim. Acta Part A 2011, 78, 153-159.
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3
3
3
3
2. Savithiri, S.; Rajarajan, G.; Srividhya, V.; Jijesh, J.; Thanikachalam, V.; Jayabharathi, J.;
Arockia doss, M. Can. Chem. Trans. 2014, 2, 201-220.
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014, 2, 403-417.
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1
Table 1 H Chemical shift (ppm) of compounds 1-6 and their parent piperidine-4-ones
Compound
1
H-6
H-2
H-5e
2.94
H-3a
2.59
H-5a
2.29
NH
NH
CH2
CH3
0.77
OCH3
-
Aromatic Protons
7.22-7.68
3
.91
4.06)
.90
4.95)
.88
4.93)
.81
3.94)
.78
4.00)
.79
4.02)
3.67
8.73 9.38
1.16-
(
(
(
(
(3.70) (2.65) (2.65) (2.73)
3.66 2.93 2.53 2.25
(4.73) (2.51) (2.70) (3.65)
3.64 2.94 2.51 2.22
(4.70) (2.69) (3.38) (3.51)
4.60 4.01 3.66 2.65
(3.58) (2.57) (2.47) (1.95)
4.57 3.82 2.63 2.18
(3.63) (2.57) (2.57) (2.70)
4.57 3.91 2.58 1.90
(3.65) (3.57) (2.65) (2.13)
(0.78)
0.78
3
2
3
4
8.78 9.36
8.87 9.35
1.18-1.66
1.19-1.66
-
-
-
7.03-7.67
7.23-7.66
7.26-7.53
(0.76)
0.77
3
(0.62)
0.67
4
8.35 10.16 0.95-1.30
8.82 9.41 1.09-1.45
9.12 10.20 0.81-1.25
(0.71)
0.66
4
5
3.79
3.87
6.84-7.71
6.82-7.69
(
(
(0.79)
4
0.62
6
(0.79)
Values in the parentheses correspond to parent piperidones
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13
a
Table 2 C Chemical shifts (ppm) of compounds 1-6 and their parent piperidine-4-ones
Compoun
d
Aromatic
Carbons
C-2
C-3
C-4
C-5
C-6
-CH2-
CH3
C=S
OCH3
-
6
7.7
50.3
153.4
36.6
61.0
14.0
1
22.7-32.4
176.4
123.6-142.6
(
67.2)
(57.1)
(209.3)
(51.6)
(61.9)
(14.0)
6
6.9
62.5)
6.9
62.6)
5.1
66.4)
5.3
66.6)
5.9
67.0)
50.3
(44.8)
50.2
151.3
(203.3)
152.6
36.8
(31.1)
36.6
60.2
(58.4)
60.2
14.0
(13.6)
14.0
2
3
4
22.6-32.4
22.7-32.4
22.7-32.0
176.4
176.3
178.4
-
-
-
115.4-137.9
123.6-146.1
114.7-132.4
(
(
(
6
(50.5)
48.2
(203.1)
158.3
(44.7)
42.6
(58.5)
61.2
(13.6)
14.2
6
(57.0)
48.5
(208.3)
159.6
(51.4)
40.9
(61.2)
58.0
(14.0)
14.2
6
5
6
22.7-32.0
22.0-32.2
176.6
176.9
55.3
113.9-142.2
(
(57.3)
(209.7)
(51.8)
(61.3)
(14.0)
6
49.0
155.8
36.6
58.6
13.8
55.93-56.20 111.1-149.2
(
(56.0)
(208.7)
(51.5)
(61.6)
(14.0)
Values in the parentheses correspond to parent piperidones
a
Taken from Ref. 32.
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Table 3 Correlation in HOMOCOSY, NOESY, HSQC and HMBC spectra of compound 3 (δ, ppm)
1
Correlation in
HOMOCOSY
Correlation in
HSQC
H NMR signal
Correlation in NOESY
Correlation in HMBC
2
.22 (H-5a), 2.94
2.22 (H-5a), 2.94 (H-5e),
7.23-7.66 (Aromatic Proton)
3
3
.88 (H-6)
.64 (H-2)
60.2 (C-6)
123.6-146.1 (Aromatic Carbon, α)
(H-5e)
2
.51 (H-3a), 1.19-1.66
6
1
0.2 (C-6, β), 50.2 (C-3, α), 152.6 (C-4, β), 123.6-
46.1 (Aromatic Carbon, α)
2.51 (H-3a)
(CH ), 7.23-7.66 (Aromatic
66.9 (C-2)
2
Proton)
2
.94 (H-5e), 3.88
2
2
2
.22 (H-5a)
.51 (H-3a)
.94 (H-5e)
2.94 (H-5e)
36.6 (C-5)
50.2 (C-3)
60.2 (C-6, α), 152.6 (C-4, α)
(
H-6)
.61 (H-2), 1.19-1.66
CH2)
.22 (H-5a), 3.88
H-6)
1.19-1.66 (CH2)
.19-1.66 (CH ), 0.77
3
1.19-1.66 (CH ), 7.23-7.66
2
66.9 (C-2, α), 22.6-32.4(CH , α), 152.6 (C-4, α)
2
(
(Aromatic Proton)
2.22 (H-5a), 3.88 (H-6)
1.19-1.66 (CH2)
2
36.6 (C-5)
14.0(CH3)
60.2 (C-6, α), 50.2 (C , β), 152.6 (C-4, α)
3
(
0
.77 (CH3)
22.6-32.4 (CH , Bonded)
2
1
22.6-32.4
(CH2)
2
1
.19-1.66 (CH2)
1.19-1.66 (CH ), 2.51 (H-3a)
14.0 (CH , Bonded)
2
3
(CH ), 2.51 (H-3a)
3
8
9
.73 (NH)
.38 (NH)
-
2.22 (H-5a), 2.94 (H-5e)
-
152.6 (C-4, β), 176.3 (C=S, α)
1
.19-1.66 (CH ), 7.23-7.66
2
-
-
123.6-146.1 (Aromatic Carbon, β)
(
Aromatic Proton)
.22 (H-5a), 2.51 (H-3a),
.88 (H-6), 3.64 (H-2), 9.38
NH)
2
123.6-146.1
(Aromatic
Carbon)
7
.23-7.66
7.01-7.45
(Aromatic Proton)
3
123.6-146.1 (Aromatic Carbon, Bonded)
(
Aromatic Proton)
(
23
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a

Table 4 Chemical shift differences between the α-carbons ( δα) in E3-PPNPs and piperidones
1
a-6a
δanti – δsyn (ppm)
E3-PPNPs
piperidone
E3-PPNPs -
piperidone
E3-PPNPs
piperidone
1
2
3
4
5
6
1a
2a
3a
4a
5a
6a
13.6
13.6
13.6
6.2
5.5
13.7
5.9
5.5
5.5
5.5
8.1
-0.1
7.7
0.7
7.6
2.1
4.5
-1.0
b- Taken from Ref. 32.
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Figure 1 Conformation of E3-PPNPs
25
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Scheme 1 Synthetic route for (E)-2-(3-pentyl-2,6-diarylpiperidin-4-ylidene)-N-
phenylhydrazinecarbothioamides
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