Synthesis, spectral and biological evaluation of some new thiazolidinones and thiazoles based on t-3-alkyl-r-2,c-6-diarylpiperidin-4-ones

Article abstract of DOI:10.1016/j.ejmech.2009.05.015

A stereospecific synthesis of some thiazolidinones and thiazoles was achieved conveniently through certain α-halo keto agents and reactivity of chloroacetyl chloride was successfully enhanced by CsF-Celite + CH₃COONa. NMR studies revealed that the configuration of N-N bond is found to be anti with respect to C-3 alkyl group while C{double bond, long}N bond in thiazolidinone is trans with respect to N-N bond. Antimycobacterial activity tested against Mycobacterium tuberculosis indicated that compounds 19, 20, 24, 29, 30 and 32 exhibited twofold enhanced potency than Rifampicin. Similarly, antimicrobial screening studies pointed out that compounds 21 and 28 exceptionally noticed promising activities and particularly, 21 against Staphylococcus aureus and, 24 and 32 against Rhizopus sp. exhibited onefold elevated inhibition potency whereas 21 against Klebsiella pneumoniae showed twofold improved potency than Ciprofloxacin and Amphotericin B.

Full text of DOI:10.1016/j.ejmech.2009.05.015

European Journal of Medicinal Chemistry 44 (2009) 4199–4210
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, spectral and biological evaluation of some new thiazolidinones
and thiazoles based on t-3-alkyl-r-2,c-6-diarylpiperidin-4-ones
*
G. Aridoss, S. Amirthaganesan, M.S. Kim, J.T. Kim, Yeon Tae Jeong
Division of Image Science and Information Engineering, Pukyong National University, San 100, Yongdang-Dong, Nam-Gu, Busan 608 739, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereospecific synthesis of some thiazolidinones and thiazoles was achieved conveniently through
Received 3 March 2009
Received in revised form
9 May 2009
Accepted 15 May 2009
Available online 23 May 2009
certain a-halo keto agents and reactivity of chloroacetyl chloride was successfully enhanced by CsF–
Celite þ CH3COONa. NMR studies revealed that the configuration of N–N bond is found to be anti with
respect to C-3 alkyl group while C]N bond in thiazolidinone is trans with respect to N–N bond. Anti-
mycobacterial activity tested against Mycobacterium tuberculosis indicated that compounds 19, 20, 24, 29,
30 and 32 exhibited twofold enhanced potency than Rifampicin. Similarly, antimicrobial screening
studies pointed out that compounds 21 and 28 exceptionally noticed promising activities and particu-
larly, 21 against Staphylococcus aureus and, 24 and 32 against Rhizopus sp. exhibited onefold elevated
inhibition potency whereas 21 against Klebsiella pneumoniae showed twofold improved potency than
Ciprofloxacin and Amphotericin B.
Keywords:
2,6-Diarylpiperidin-4-one
Thiazolidinone
Thiazole
Antimycobacterial activity
Antimicrobial activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
Though a number of drugs are available for the initial treatment
of tuberculosis, the current anti-TB regimen is rather complex and
Tuberculosis (TB) is a chronic life threatening disease caused by
slow-growing single infectious agent Mycobacterium tuberculosis
and kills approximately two million people annually. According to
World Health Organization (WHO), one-third of the number of new
TB cases (new TB infection develops at a rate of one per second)
occurs in Southeast Asia, but the estimated incidence per capita is
highest in Africa [1]. The rise in the incidence of tuberculosis
worldwide is partly due to poverty and inequity and partly to the
HIV/AIDS pandemic, which greatly increase the risk of infectious
proceeding to overt disease. Currently, the reemergence of TB
infection is further complex by an increase of M. tuberculosis strains
resistant to first line drugs (MDR-TB) used in conventional antitu-
bercular therapy and is becoming a threat to public health world-
wide. Another serious concern, in the context of MDR-TB, is the
XDR-TB (extensively drug-resistant tuberculosis), which are strains
resistant to first and second line anti-TB drugs. Numerous synthetic
molecules with antimycobacterial activity have been reported with
known or suspected modes of action right from late 1990s [2–4].
Most of them were identified on the basis of their activity against
whole cells.
requires longer treatment time. Therefore, a novel class of anti-
mycobacterial is urgently needed with modes of action divergent
from those drugs used in current therapy and to shorten the
duration for anti-TB therapy.
Thiazolidin-4-ones are an important group of heterocyclic
compounds, having valuable biological activities in the areas of
medicine. Recently, antimicrobial and antimycobacterial activities
[5–7] of this framework containing compounds were explored well
whereas their 2,3-disubstituted analogues have proved to be
predominantly effective non-nucleoside HIV reverse transcriptase
inhibitors [8]. Likewise, thiazole and their 2-substituted derivatives
were also reported to exhibit diverse biological properties such as
antituberculous and antimicrobial activities [9]. Moreover, it has
been found in the drug development program for the treatment of
inflammation [10] and HIV [11].
In corollary of the interesting biological and pharmaceutical
properties and synthetic utility, substantial interest has been
demonstrated towards piperidin-4-ones; this substructure con-
taining compounds is widely prevalent in numerous alkaloids and
synthetically derived compounds of biological importance [12]. In
recent times, our interest has been focused on exploring the reac-
tivity of variously substituted 2,6-diarylpiperidin-4-ones [13] and
the generated diverse heterocycles by employing the said synthon
were eventually evaluated for their antibacterial, antifungal, anal-
gesic, antipyretic and antimycobacterial profiles [14]. Moreover,
* Corresponding author. Tel.: þ82 51 629 6411; fax: þ82 51 629 6408.
E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.05.015

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G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
thiosemicarbazones, oximes, oxime ethers or by sulphur and
nitrogen containing heterocycles obtained via exploring the reac-
tivity of keto group at the 4th position have proved to exert better
microbiological activities than their corresponding ketones [15,16].
In view of the continued interest in the development of simpler
and more convenient synthetic routes for achieving the biologically
challenging heterocyclic systems, a simple method is reported
herein to synthesize some new piperidone based 1,3-thiazolidin-4-
ones and 1,3-thiazoles with good yield in a stereospecific manner
by the condensation of easily accessible 3-alkyl-2,6-diary-
forms (9–16a and b) as outlined in Scheme 1 (steps C1 and C2) and
may expect to be stable in solvent. However, the existence of these
two forms was confirmed by the reaction of thiosemicarbazones
with few cyclizing agents (a-halo keto compounds) such as
ClCH2COCl (CAC), BrCH2COCl (BAC), BrCH2COOEt (EBA) and
ClCH2COCH2COOEt (ECAA) in boiling ethanol. All the synthesized
compounds were characterized without ambiguity by analytical
and spectral (1H NMR, 13C NMR, NOESY, HSQC, HMBC, Mass and IR)
studies. These studies proved that when cyclization was effected by
CAC, BAC and EBA in ethanol, 1,3-thiazolidin-4-ones (17–24) were
formed exclusively in a stereospecific manner with moderate to
good yields (66–85%) without the formation of 17a–24a. This
suggests that enolization (i.e., formation of thioenols 9a–16a via the
migration of secondary amino proton) along the path C1 favors
thiozolidinone formation through nucleophilic substitution of
halogen by thiolate group which in turn cyclizes by dehy-
drohalogenation (while using CAC and BAC as reagent) or by loss of
a molecule of ethanol (in EBA).
Upon cyclization of 9–16 with ECAA in ethanol, 4-carbethox-
ymethyl-1,3-thiazoles 25–32 were resulted along the Hantzsch
thiazole synthesis and not 25a–32a. This indicates that the tauto-
meric form 9b–16b (through path C2) favors thiazole synthesis. The
aforesaid methods clearly demonstrate that existence of two
different tautomeric forms about thioamide group depends upon
the nature of cyclizing agent used.
lpiperidin-4-thiosemicarbazones with some
compounds as cyclizing reagents. Further, we have found out
a suitable -halocarbonyl compound as a cyclizing reagent for
thiazolidinone formation and improved the reactivity of one of the
-halocarbonyl compounds viz., chloroacetyl chloride through
a-halocarbonyl
a
a
CeF–Celite þ sodium acetate solid base catalyst using freshly
distilled ethanol as solvent. The synthesized compounds are
heavily expected to have better biological profiles as thiazolidinone,
thiazole and 2,6-diarylpiperidin-4-one bio-labile components are
linked together to achieve the target compounds.
2. Chemistry
The synthetic strategy leading to the key intermediate and the
target compounds are illustrated in Scheme 1. The key thio-
semicarbazone intermediates 9–16 were prepared in excellent
yield through two consecutive steps start by condensing suitably
substituted benzaldehyde, ketone and ammonium acetate in one
pot (afforded piperidones) followed by treatment with thio-
semicarbazide in acidic methanol under refluxed condition. The
formed thiosemicarbazone can take up two different tautomeric
We have investigated in detail about the reactivity of chlor-
oacetyl chloride (CAC), bromoacetyl chloride (BAC) and ethyl
bromoacetate (EBA) towards thiosemicarbazone of 2,6-diary-
lpiperidin-4-ones in ethanol at different catalytic conditions
(Method 1: cyclizing agent only; Method 2: cyclizing agent þ acetic
acid; Method 3: cyclizing agent þ acetic acid þ sodium acetate;
O
O
O
N
R1
R1
R1
H3C
O
O
B
A
N
H
H
H
R2
NH4OAc
R
R
R
R
R
R
1-8
S
NH2
HS
NH2
HS
NH
C
HN
N
HN
N
N
N
C1
C2
R1
R1
R1
N
N
N
R2
R2
9a-16a
R2
R
R
R
R
R
R
9-16
9b-16b
R = H, Cl, Br, F, OCH3, CH3
R1= CH3, CH2CH3
R2= H, CH3
g
COOCH2CH3
h
O
O
f
X-CH2-COY
COOCH2CH3
X-CH2-COY
e
e
a
X = Cl, Br
Y = Cl, OE,
d
c
X = Cl, Br
Y = Cl, OE,
d
S
N
S
NH
N
S
NH
a
c
S
N
b
CH2COOEt
CH2COOEt
b
D
E
E
D
HN
N
N
HN
N
N
4
N
4
R1
R1
R1
2'
R1
3
2
5
6
3
2
5
6
6'
1
1
2'
6'
N
N
N
N
2''"
6""
2''"
R2
6""
R2
R2
R2
R
R
R
R
R
R
R
R
25-32
17a-24a
17-24
25a-32a
; (C) NH2NHCSNH2, Hþ, MeOH/
D;
Scheme 1. Synthesis of compounds 17–32. Reagents and conditions: (A) i. EtOH/Heat/HCl, ii. NH3; (B) CH3I, anhyd. K2CO3, dry acetone/
D
(D) ClCH2COCl, CsF–Celite/NaOAc, EtOH/ or BrCH2COCl, EtOH/ or BrCH2COOEt, EtOH/ ; (E) ClCH2COCH2COOEt [or] ClCH=C(OH)CH2COOEt EtOH/D.
D
D
D

G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
4201
Method 4: cyclizing agent þ sodium acetate; Method 5: cyclzing
agent þ CeF–Celite þ sodium acetate) and also reported the supe-
riority of one over the other on the basis of yield and reaction time.
When cyclization was effected by CAC through Methods 1 to 3,
we have achieved the desired products in low yield (24–34%)
besides the formation of appreciable quantity of the parent 2,6-
diarylpiperidin-4-one (Scheme 2) by C(4)]N cleavage. However,
while using sodium acetate as base (Method 4), yield was increased
(45–50%) without the formation of parent piperidone. This indi-
cates that the problem seemed to stem from the liberated HCl in
situ in the reaction that might cause the decomposition of C(4)]N
function in products (and not in the thiosemicarbazone function
because, its formation from ketone was catalyzed by few drops of
con. HCl). Since the CsF adsorbed over Celite was used successfully
for the chemoselective esterification of carboxylic acid with alkyl
halides [17] and for N-alkylation of different amino compounds
[18], we employed CsF–Celite in combination with sodium acetate
as catalyst (Method 5) for cyclization. This not only enhanced the
yield (66–72%) but also impedes or completely prevents the
formation of parent piperidones.
While using EBA as a cyclizing agent, surprisingly the preferred
products only yielded (73–80%, Table 1) in all the four methods
without the decomposition of formed products (i.e., no piperidone
formation). This indicates that C(4)]N function in products may
perhaps be stable towards HBr produced in situ in the reaction.
In order to recheck this scenario, we have used BAC (contains
both chloro and bromo functionalities) in place of EBA but results
are different i.e., Methods 2 and 3 end with piperidone formation
along with the desired products whereas Methods 1 and 4 exclu-
sively afforded products in good yield (80–85%, Table 1). The
aforementioned findings were further confirmed by refluxing the
representative compound 17 in ethanol along with few drops of con.
HCl or con. HCl/glacial acetic acid mixture as shown in Scheme 2,
which afforded the corresponding, piperidone in 21% and 25%
respectively.
From the obtained results, it is very transparent that use of the
reagent without any catalyst (Method 1) is found to be superior
over rest of the methods except in using CAC where CsF–Cel-
ite þ NaOAc was proved to be excellent. Further, on the basis of
yield and reaction time, BAC can be used as a surrogate for CAC and
EBA in thiazolidinone formation in this series of compounds. The
results are reproduced in Table 1.
3. Pharmacology
Antimycobacterial activity of the synthesized compounds 17–32
was evaluated against M. tuberculosis-H37Rv by radiometric
respiratory technique using the BACTEC system [19]. Antibacterial
and antifungal activities of the said compounds 17–32 were
assessed in vitro against each three-representative bacterial species
viz., Staphylococcus aureus, [Gram-positive], Escherichia coli and
Klebsiella pneumoniae [Gram-negative] and fungal species viz.,
Candida albicans, Aspergillus flavus and Rhizopus sp. by broth
microdilution technique as per the guidelines of National
Committee for Clinical Laboratory Standards (NCCLS) [20]. The
solvent, DMSO used for the preparation of compounds did not
show inhibition against the tested organisms.
4. Results and discussion
1H and 13C NMR spectra were recorded for all the target
compounds whereas for 17 and 27, IR and mass spectra were also
recorded. For comparison, NMR spectra were recorded for the
representative key intermediates 9, 10 and 16.
4.1. 1H NMR analysis of thiazolidinone derivatives 17–24
It has been reported earlier that azine formed by 3-methyl-2,6-
diphenylpiperidin-4-one [21] exists in a pair of isomers. However,
we have achieved exclusively one isomer (evidenced by 1H NMR) in
17–24 and exists in s-trans (Fig. 1a) form rather than s-cis (Fig. 1b)
because the latter one is improbable due to the prevailing severe
electronic interactions and steric repulsions.
In 9, 10 and 16, NH/NH2 signals of thiosemicarbazone moiety
appear at 9.19(s)/6.87(d), 8.82(s)/6.48(d) and 8.91(s)/6.69(d) ppm
respectively. The position and presence or absence of NH and NH2
Therefore, these observations clearly suggest that C(4)]N
(in 17–24) issensitive to HClor HCl/aceticacid only whereas itis stable
in systems containing both HCl and HBr because of the presumed
counter ion effect. However, in the case of ECAA, the preferred prod-
ucts only achieved in all the four Methods (1–4) without any degra-
dation. This signifies that loss of conjugation may makes C(4)]N bond
more stable in 25–32 though HCl is generated in situ in the system.
O
O
S
NH2
N
Reagent only
S
NH
N
R1
(if X = Y = Cl)
HN
N
+
N
With AcOH
X-CH2-COY
R1
R1
R2
1-8
R
R
N
With AcOH /
NaOAc
N
R2
R
R
R2
9-16
R
R
17-24
Where X = Cl, Br and Y = Cl
Con.HCl/ Ethanol/ Reflux (or)
Con.HCl/ AcOH/ Ethanol/ Reflux
From 17 to 1
Scheme 2. Decomposition of thiazolidinones by different reagents.

4202
G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
Table 1
Synthesis of thiazolidinones (17–24) and thiazoles (25–32) using a-halocarbonyl compounds from 3-alkyl-2,6-diarylpiperidin-4-thiosemicarbazones.
Entry
CAC
BAC
EBA
ECAA
Mp (ꢁC)
Molecular formula (Mol. wt.)
By Method 5
RTa (h)
By Method 1
RT (h)
By Method 1
RT (h)
By Method 1
RT (h)
Yieldb (%)
Yield (%)
Yield (%)
Yield (%)
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
6
72
71
69
66
66
72
70
72
–
–
–
–
–
45 min
1
1.5
1.5
1.5
45 min
1
85
82
83
81
80
84
84
85
–
–
–
–
–
30 min
1
1.5
2.0
2.0
1.5
1.0
30 min
–
–
–
–
–
–
–
–
80
75
73
76
73
77
79
80
–
–
–
–
–
–
–
–
–
–
–
–
–
2.0
2.5
2.0
2.5
2.5
2.0
2.0
2.0
–
–
–
–
–
–
–
–
90
87
84
88
85
87
88
90
188–190
84–86
160
210–211
98–100
184
187–188
178–180
99–101
92–93
84–86
106
98–100
96–98
88–89
78–80
C
21H22N4OS (378.49)
C22H24N4OS (392.52)
C21H20Cl2N4OS (447.38)
6.5
6.5
7.0
7.0
6.0
5.5
6.0
–
–
–
–
–
C21H20Br2N4OS (536.28)
C21H20F2N4OS (414.47)
C23H26N4O3S (438.54)
C23H26N4OS (406.54)
C22H24N4OS (392.52)
C25H28N4O2S (448.58)
C26H30N4O2S (462.61)
45 min
–
–
–
–
–
–
–
–
C25H26Cl2N4O2S (517.47)
C25H26Br2N4O2S (606.37)
C25H26F2N4O2S (484.56)
C27H32N4O4S (508.63)
C27H32N4O2S (476.63)
C26H30N4O2S (462.61)
–
–
–
–
–
–
–
–
–
–
–
–
CAC: chloroacetyl chloride; BAC: bromoacetyl chloride; EBA: ethyl bromoacetate; ECAA: ethyl 4-chloroacetoacetate.
a
RT: reaction time.
After column chromatography.
b
signals in the 1H NMR spectrum of final compounds determine the
mode of cyclization.
thiosemicarbazone derivatives. As well, a broad singlet observed at
8.52, 8.48 and 8.61 ppm respectively for 27, 29 and 32 (in rest of the
compounds, absorption due to NH proton could not be identified
when recorded in CDCl3) could be assignable to NH proton as it
exchanged with D2O. This clearly envisages that NH of thio-
semicarbazone moiety did not involve in thioenol formation
through tautomerism, instead amino proton of the same took part
in exchange process (as shown in Scheme 1 [9b–16b]). This is also
supported by IR spectra of the representative compound 27 by
showing two intense bands at 1732 and 1553 cmꢀ1 for ester
carbonyl and C(4)]N stretching vibrations respectively. Hence, the
final products were obtained through Hantzsch thiazole synthesis
upon condensing 9b–16b with ethyl 4-chloroacetoacetate.
However, noticeable deshielding effect on H-5eq protons
compared to their corresponding parent ketones [19] suggests that
N–NH bond in 25–32 also anti to the alkyl group at C-3 like N–N
bond in 17–24.
Besides the piperidone ring proton signals, the noticed two
singlets in the region 6.42–6.47 ppm (for 1H) and 3.56–3.59 ppm
(for 2H) of their 1H NMR spectrum (of compounds 25–32) are
pertinent to H-e and H-f protons whereas a quartet (for 2H) and
triplet (for 3H) in the regions 4.16–4.18 and 1.25–1.27 ppm are
respectively due to H-g [CH2] and H-h [CH3] protons of ester in
thiazole ring system.
There is a broad and low intense signal with one proton integral
at 8.13 ppm for 20 in CDCl3. The same signal is shifted downfield by
about 3.65 ppm when recorded in DMSO-d6 (17 also shows a broad
signal at 11.74 ppm in DMSO-d6). Therefore it is assigned to amide
NH proton (D2O exchangeable) in thiozolidinone moiety. Further, IR
spectra recorded for the representative compound 17 also confirms
this by exhibiting three sharp intense bands at 1714, 1632 and
1598 cmꢀ1 characteristic for amide carbonyl, C(4)]N and C(b)]N
respectively whereas NH of amide and piperidone moiety showed
weak broad bands at 3423 and 3161 cmꢀ1 respectively.
In all the compounds, the chemical shift value of H-5eq appears
significantly in the low field compared to H-5ax (difference is
z1.3 ppm). Moreover, comparison of piperidine ring protons
absorption in thiazolidinone derivatives with their corresponding
thiosemicarbazone and parent ketone [22] counter parts indicates
that a significant difference is noted only in H-5eq protons (about
0.6/0.8 ppm) while in rest of the protons, the observed difference is
minimum. It is apparent from this observation that the configuration
of N–N bond in 17–24 should be syn with respect to C-5 carbon (or
anti with respect to alkyl group at C-3 position). Further, the
magnitude of deshielding in H-5eq confirms that NH proton in thi-
osemicarbazone should involve in tautomerization to form thioenol
isomer as in 9a–16a which upon cyclization, furnished 17–24 (where
the electron density of the nitrogen adjacent to thiazolidinone ring
(Cb]N) is increased due to the existing conjugation). As a result of
The observed magnitude of coupling constants clearly demon-
strates that the piperidone ring in both sets of compounds adopts
the suggested configuration, syn
a C–H bond (C-H5eq) is polarized
greatly through the electron pool of N thereby acquires fractional
positive charge on the proton (and negative charge on C-5-refer
Fig. 2) and in turn deshields remarkably.
a
b
Besides, the sharp intense singlet with two protons integral in
the region 3.64–3.76 ppm is pertinent to methylene protons of
thiazolidinone moiety.
All these observed facts clearly demonstrate that piperidone and
thiazolidinone ring systems are linked through azine N–N bond as
indicated in Scheme 1 and confirms the proposed structure (17–24).
S
N
N
N
C
N
S
N
N
4.2. 1H NMR analysis of thiazole derivatives 25–32
s-cis form
s-trans from
It is obvious that chemical shift values of piperidone ring
protons in 25–32 do not vary appreciably from their corresponding
Fig. 1. Two different isomeric forms of 17–32 about azine function.

G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
4203
.
distinctive signals in the low field region and three reasonably
intense signals in the high field region characteristic for thiazole
moiety. The two closely spaced low intense signals in the region
170.45–170.93 and 169.84–170.23 ppm are respectively due to ester
carbonyl and C-b ipso carbons. This assignment is also in accordance
with the observations of Sarodnick et al. [25] in the substituted
thiazole ring system. Similarly, other two low intense signals at
z144 (143.61–144.49 ppm) and z106 ppm (105.69–106.39 ppm)
are attributed to other ipso carbon C-d and methine carbon C-e
respectively. Likewise, the chemical shift values in the high field
regions at about 36.99–37.46, 60.89–60.98 and 14.09–14.20 ppm
correspond to side chain carbons i.e., C-f, C-g and C-h respectively.
N
N
H
6
H
syn side
4
H
5
Ar
R2
R1
4.5. Two dimensional NMR analysis of compounds 17 and 32
2
H
3
In order to support the assignments made through one
dimensional NMR, two dimensional NMR viz., NOESY, HSQC and
HMBC spectra were recorded for the representative compounds 17
and 32 and are displayed in the supplementary files (along with
their respective 1H and 13C NMR) while the noticed correlations are
given in Tables 2 and 3. The correlations such as C-b/thiazolidinone
protons, C-d/thiazolidinone protons and C-4/(3-CH3/H-5eq) in
HMBC spectrum of 17 confirm the respective carbon signals.
Similarly, C-d, C-b and COOEt carbonyl signals in 32 were ascer-
tained undoubtedly due to their correlations with H-f/H-e, H-e and
H-f/H-g/H-e protons respectively in its HMBC. On the basis of these
correlations, the said signals in rest of the compounds were also
assigned directly.
N1
anti side
Ar
H
Fig. 2. Electronic interaction in 17–32.
a rigid chair conformation with equatorial orientation of aryl
groups at C-2/C-6 and alkyl group at C-3.
4.3. 13C NMR analysis of thiazolidinone derivatives 17–24
Though C-5 and C-3 carbons in piperidone ring system are
shielded well, the magnitude of shielding is significant at C-5
compared to C-3 carbon. This extent of upfield shift in 17–24 is
primarily due to the decreased electronegativity of the C]N system
compared to the corresponding C]O function in 1–8. Lambert et al.
[23] also found the similar trend in six-membered heterocyclic
system due to changes in the electronegativity of a function in the
ring skeleton. Further, 1H NMR studies revealed that configuration
of N–N bond in 17–24 is syn with respect to C-5 carbon (or anti to
alkyl group at C-3) and hence polarizes syn C-H5e bond as shown in
Fig. 2 through electronic interaction. Therefore, C-5 carbon is
shielded well compared to C-3.
In addition to the above said resonances, there were also signals
in the low field regions 166.9–169.86 and 162.34–162.73 ppm.
Earlier reports [21,24] reveal that imine carbon (C-4) showed
resonance around 160–163 ppm. Further, our previous studies [13]
demonstrate that chemical shift values of C-4 carbon in piperidone
system is influenced by the alkyl group at C-3 and/or N-1 and
different substituents at 4th position of phenyl groups (i.e., at C-2&/
C-6&) through electronic and mesomeric effects. On the basis of
this, the resonance of C-4 carbon in each of the compounds 17–24 is
expected to differ by about 1–2 ppm, since they differ by the nature
of substituents in the piperidone ring system. Therefore, the
absorption frequency in the region 166.9–169.86 ppm only holds
good these difference whereas the resonances in the region
162.34–162.73 fail in this respect. Thus, the former and later
regions are assigned without ambiguity to C-4 and C-b carbons
respectively. Further, two signals in the region 173.5–173.79 and
32.6-32.93 ppm are distinctive for carbonyl (C-d) and methylene
carbons (C-e) of thiazolidinone skeleton.
4.6. Antimycobacterial activity
Antimycobacterial activity of the compounds was evaluated
against M. tuberculosis-H37Rv and the observed MICs are presented
in Table 4. Isoniazid and Rifampicin were used as standard drugs. It
is apparent from the results that none of the compounds showed
MIC less than 16 mg/ml. As well, few of the compounds showed
comparable activity with Rifampicin but all the compounds were
less active than Isoniazid drug. From the obtained results the
following SAR has been made. In both series, compounds 17 and 25
with methyl group at C-3 of piperidone system registered the MIC
at 64
completely eliminated the antimycobacterial activity up to a high-
est concentration (i.e., 256 g/ml) tested in this study. As is evident
mg/ml whereas the replacement of methyl by ethyl group
m
from the data (Table 4) that introduction of halogens such as
chlorine (19) or bromine (20) at the para position of phenyl groups
in thiazolidinone derivative 17 was noteworthy and registered
twofold elevated inhibition potency with a lowest MIC of 16 mg/ml
whereas the substitution by fluorine (21) registered onefold
decreased activity than 17. The above said observations are
completely reversed in the case of thiazole series with respect to
the said halogens incorporation, i.e., compounds 27 and 28 bearing
chlorine and bromine respectively did not show activity even at
a
maximum concentration of 256
substituted analogue 29 displayed excellent activity at lowest
concentration of 16 g/ml. Instead of electron withdrawing halo-
mg/ml whereas fluorine
m
gens, substitution of electron donating methoxy functionality in 17
and 25 (i.e., compounds 22 and 30 respectively) was also significant
in exhibiting moderate to good antimycobacterial activity at MIC 32
4.4. 13C NMR analysis of thiazole derivatives 25–32
and 16 mg/ml respectively. However in both derivatives, methyl
group modification (compounds 23 and 31) in place of methoxy
group was not significant as it is evident from the appreciable
decrease in activity. A striking observation from this study is that
compounds 24 and 32 resulted by methyl group incorporation at
the piperidone nitrogen of 17 and 25 respectively displayed
Here also the same trend in resonance frequency was noticed for
the piperidone ring system. However, the marked upfield shift of C-
4 carbon (151.7–153.9) in 25–32 compared to 17–24 is due to the
decreased electronegativity of C(4)]N group by the loss of conju-
gation. Apart from the piperidone signals, there were four
promising improvement (MIC at 16 mg/ml i.e., about twofold

4204
G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
Table 2
Correlations in NOESY, HSQC and HMBC spectra of compound 17 [
Entry 1H NMR signal
Correlations in NOESY Correlations in HSQC
17 0.93 (d, 3H, CH3 at C-3)
d (ppm)].
Correlations in HMBC
2.62 (st),a 3.55
(m),a 7.45 (w)a
3.61 (m)
11.94 (CH3 at C-3)
45.51 (C-3), 69.24 (C-2), 169.74 (C-4)
2.22 (bt, 1H, H-5ax)
2.62 (m, 1H, H-3ax)
3.55 (d, 1H, H-2ax)
37.79 (C-5)
45.51 (C-3)
69.24 (C-2)
No correlations
No correlations
0.93 (m)
0.93 (m), 3.89 (m),
7.45 (st)
11.94 (CH3 at C-3), 61.05 (C-6), 127.87 (ortho phenyl carbon), 142.61
(phenyl ipso carbon)
3.61 (dd, 1H, H-5eq)
3.74 (s, 2H, thiazolidinone H)
2.22 (st)
No correlations
37.79 (C-5)
32.89
169.74 (C-4)
162.36 (C-b of thaizolidinone imine), 173.42
(C-e, i.e., thaizolidinone CH2) (C-d of thaizolidinone amide)
3.89 (dd, 1H, H-6ax)
7.25 (m, 2H, phenyl para protons)
3.55 (m), 7.43 (m)
No correlations
61.05 (C-6)
127.54, 127.68
126.70 (ortho phenyl carbon)
126.70 (phenyl ortho carbon)
(phenyl para carbons)
128.34, 128.45
7.33 (m, 4H, phenyl meta protons)
No correlations
127.54, 127.68 (phenyl para carbons), 127.89
(phenyl meta carbons)
126.70, 127.87
(phenyl ortho carbon), 142.61, 143.56 (phenyl ipso carbons)
69.24 (C-2), 61.05 (C-6), 127.54, 127.68 (phenyl para carbons)
7.43, 7.45 (2s, 4H, phenyl ortho protons) 3.55 (m), 3.89 (m)
(phenyl ortho carbons)
a
st – strong, w – weak, m – medium.
enhancement) in their inhibitory potency. Therefore, the higher
inhibitory activity of compounds 24 and 32 compared to that of
corresponding precedents 17 and 25 respectively can be possibly
attributed to the lower electronegativity of tertiary nitrogen by the
introduced electron releasing methyl group than secondary NH. A
comparison of antimycobacterial potency of compounds 17–32
calculated against the MIC of Rifampicin is displayed as bar graph in
Fig. 3. It is comprehensible from Fig. 3 that compounds 19, 20, 24
(in thiazolidinone series), 29, 30 and 32 (in thiazole series) regis-
tered 200% higher antimycobacterial potency while compound 22
(in thiazolidinone series) produced equivalent potency to that of
the standard drug, Rifampicin.
tested microbial species. The extent of antimicrobial activity
depended both on the species of microorganism and on the type of
functional groups present in the molecule. As the compounds with
3-ethyl group in the piperidone moiety of both thiazolidinone (18)
and thiazole (26) derivatives were almost inactive compared to 3-
methyl analogues, we have synthesized the later derivatives only
which differs in the substituents at the para position of phenyl
groups in piperidone nucleus.
4.7.1. Antibacterial activity
From the obtained results (Table 5), it has been noticed that all
the tested compounds exhibited moderate to good antibacterial
properties against the tested two Gram-negative and one Gram-
positive bacteria except 25, 31 against S. aureus, 18, 26 against E. coli
and 18, 25 and 26 against K. pneumoniae. Most of the compounds
exhibited significant activity against S. aureus as exemplified by
compounds 19–21, 28 and 29 with electron withdrawing halogens
at the 4th position in phenyl group. Among them, compounds 19/20
(with para chloro/bromo substituted analogues of 17) and 21 (with
para fluoro analogue) produced respectively equivalent and onefold
elevated inhibition potency than the reference drug, Ciprofloxacin.
Conversely, substitution of electron donating methoxy or methyl
functionalities in place of halogens decreased the activity against S.
aureus appreciably. However, removal of substitution from the
4.7. Antimicrobial activity
Antibacterial and antifungal activities of the synthesized
compounds (17–32) were assessed in vitro against each three-
representative bacterial species viz., S. aureus, [Gram-positive],
E. coli and K. pneumoniae [Gram-negative] and fungal species viz.,
C. albicans, A. flavus and Rhizopus sp. Table 5 displays activity of
compounds in terms of minimum inhibitory concentrations (MIC in
mg/ml) along with reference drugs, Ciprofloxacin and Amphotericin
B respectively for bacteria and fungi. The investigated compounds
showed different degrees of antimicrobial activity in relation to the
Table 3
Correlations in NOESY, HSQC and HMBC spectra of compound 32 [d (ppm)].
Entry 1H NMR signal
Correlations in NOESY
Correlations in HSQC
Correlations in HMBC
32 0.87 (d, 3H, CH3 at C-3)
2.67 (st), 2.89 (m)
4.16 (st)
2.89 (st), 3.19 (st), 7.43 (m)
No correlations
2.89 (m)
No correlations
0.87 (w), 1.72 (m), 2.67
(m), 3.19 (w), 7.41, 7.43 (m)
2.89 (m), 7.41, 7.43 (m)
6.43 (s), 8.61 (w)
1.25 (st)
12.76 (CH3 at C-3)
14.13 (C-h)
41.47 (N–CH3)
36.51 (C-5)
44.82 (C-3)
–
44.82 (C-3), 77.79 (C-2), 152.49 (C-4)
60.89 (C-g)
69.15 (C-6), 77.79 (C-2)
No correlations
No correlations
1.25 (t, 3H, H-h)
1.72 (s, 3H, CH3 at N1)
2.34 (bt, 1H, H-5ax)
2.67 (m, 1H, H-3ax)
2.75 (dd, 1H, H-5eq)
2.89 (dd, 1H, H-2ax)
No correlations
77.79 (C-2)
12.76 (CH3 at C-3), 41.47 (N–CH3), 128.08 (phenyl carbon), 142.89
(C-20 ipso carbon)
No correlations
106.18 (C-e), 143.74 (C-d), 170.46 (C]O)
14.13 (C-h), 170.46 (C]O)
37.38 (C-f), 143.74 (C-d), 169.93 (C-b), 170.46 (C]O)
126.91 (phenyl ortho carbon)
3.19 (dd, 1H, H-6ax)
3.56 (s, 2H, H-f)
4.16 (q, 2H, H-g)
6.43 (s, 1H, Thiazole H)
7.28 (m, 2H, phenyl para protons)
69.15 (C-6)
37.38 (C-f)
60.89 (C-g)
3.56 (st)
No correlations
106.18 (Thiazole CH)
127.58, 127.61
(phenyl para carbons)
128.37, 128.74
(phenyl meta carbons)
126.91, 128.08
(phenyl ortho carbons)
–
7.35 (t, 4H, phenyl meta protons)
No correlations
126.91, 128.01 (phenyl ortho carbons), 142.89 (C-20 ipso carbon)
69.15 (C-6), 77.79 (C-2), 127.58, 127.61 (phenyl para carbons),
No correlations
7.41, 7.43 (2s, 4H, phenyl ortho protons) 2.89 (m), 3.19 (m), 1.72 (w)
8.61 (bs, 1H, NH)
ast – strong, w – weak, m – medium.
3.56 (w)

G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
4205
Table 4
Antimycobacterial activity of compounds 17–32 against M. tuberculosis-H37Rv (ATCC 27294).
R3
N
R1
N
R2
R
R
Entry
R1
R2
R
R3
MICa [APb]
COOEt
S
S
O
N
N
H
NH
N
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Me
Et
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
H
H
Cl
Br
F
OMe
Me
H
H
H
Cl
Br
F
OMe
Me
H
-do-
-do-
-do-
-do-
-do-
-do-
-do-
-do-
–
–
–
–
–
–
–
–
–
–
–
–
–
-do-
-do-
-do-
-do-
-do-
-do-
-do-
-do-
–
64 [0.39S1/50S2
]
>256
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
16 [1.56S1/200S2
16 [1.56S1/200S2
]
]
]
128 [0.19S1/25S2
32 [0.78S1/100S2
]
64 [0.39S1/50S2
]
16 [1.56S1/200S2
]
64 [0.39S1/50S2
>256
]
>256
>256
16 [1.56S1/200S2
16 [1.56S1/200S2
>256
]
]
–
–
–
–
16 [1.56S1/200S2
0.25
]
Isoniazid
Rifampicin
–
–
32
S1
S2
and – AP compared to Isoniazid and Rifampicin standards respectively.
a
MIC: minimum inhibitory concentration represented in
Antimycobacterial potency (AP) ¼ MIC of Rifampicin/MIC of test compound ꢂ 100.
m
g/mL.
b
phenyl groups and inclusion of methyl group at the piperidone
nitrogen (compounds 24 and 32) produced moderate activity
against S. aureus with a MIC of 16 mg/ml. Against E. coli, irrespective
of the type of halogens present in the phenyl groups, none of the
compounds produced better activity in both series with the
exception of 28 (bearing 4-bromo phenyl), which recorded the same
phenyl ring is important, which is corroborated by elevated activity
of compounds with chloro or bromo or fluoro group and decreased
activity of compounds with either methyl or methoxy group in the
4-position of phenyl ring. However in thiazole derivatives, only
bromine bearing compound seems better than chlorine and fluo-
rine analogues.
MIC (4 mg/ml) with that of the reference standard.
To our surprise, the inhibitory activity of compound 21 against
K. pneumoniae was especially interesting, exhibiting MIC value
about twofold times lower than the reference Ciprofloxacin. Simi-
larly, compounds 20 and 28 exerted onefold lower MIC values than
the reference while the remaining compounds produced moderate
to no activity against K. pneumoniae. The noticed results suggest
that the electro-withdrawing property of the 4-substituent in the
4.7.2. Antifungal activity
The investigated in vitro antifungal screening data has shown
that few of the compounds in both the series produced consider-
able and varied results. It is apparent from Table 5 that compounds
with methyl (17/25) or ethyl (18/26) group at C-3 failed to exert
activity against all the three pathogenic strains at MIC less than
256
64
m
g/ml except 17 against A. flavus (for which MIC was noticed at
mg/ml). Likewise, incorporation of methoxy (22 or 30) or methyl
(23 or 31) group at the 4th position in phenyl groups of either 17 or
25 also did not show appreciable antifungal activity against the
tested organisms. But, instead of methyl or methoxy groups,
halogen (particularly, bromine or fluorine) substituted analogues
20, 21, 28, 29 and compounds 24 and 32 obtained by substitution of
methyl group at N(1) in 17 or 25 respectively seem better in dis-
playing pronounced inhibitory power. Thus against C. albicans and
A. flavus, compounds 28 and 21 respectively showed equivalent
potency in comparison with reference Amphotericin B whilst all
250
200
150
100
50
0
other compounds exhibited MIC between 16 and 256
Although compounds 17, 18 and 25 did not exert antifungal activity
against Rhizopus sp. up to 256 g/ml, interestingly, compounds 20,
21 and 29 exhibited the same potency (MIC: 16 g/ml) whereas
compounds 24 in thiazolidinones and 32 in thiazoles registered
mg/ml.
17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
Compound
m
m
Fig. 3. Comparison of antimycobacterial potency of compounds 17–32 with Rifampicin
against M. tuberculosis-H37Rv.

4206
G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
Table 5
24 and 32 against Rhizopus sp. were remarkably inhibited the growth
In vitro antimicrobial activities (MIC in
bacterial and fungal strains.
mg/mL) of compounds 17–32 against selected
of the tested organisms at lowest MIC and hence were considered as
potent candidates. The structural requirements for the active
compound in both series against each strain are represented as
schematic diagram in Fig. 4. It is concluded that thaizolidinone
derivatives are better than thiazoles in their biological properties.
Entry
Thiazolidinone series
Minimum inhibitory concentration (MICa in
Bacterial strains Fungal strains
S. aureus E. coli K. pneumoniae C. albicans A. flavus Rhizopus sp.
mg/mL)
6. Experimental protocols
17
18
19
20
21
22
23
24
64
128
8
8
4
32
64
16
256
>256 >256
128
16
32
32
128
128
64
>256
256
128
64
64
>256
128
32
>256b
>256
256
16
6.1. General
128
8
4
64
256
64
The course of the reactions and purity of the products were
assessed by performing TLC. Melting points were determined in
Electrothermal-9100 (Japan) instrument and are uncorrected. IR
spectra were recorded in FT-IR Perkin–Elmer Spectrum GX spec-
trophotometer and only noteworthy absorption levels (reciprocal
centimeters) are listed. All the NMR spectra were recorded on JEOL
(Japan) JNM ECP-400 instrument operating at 400 MHz for 1H and
100.6 MHz for completely proton decoupled 13C. CDCl3 and DMSO-
d6 were used as solvent and TMS as internal standard. The chemical
shift values were reported in ppm (parts per million) relative to
TMS and the spin multiplicities are indicated as follows: s (singlet),
bs (broad singlet), d (doublet), dd (double doublet), bt (broad
triplet), q (quartet) and m (multiplet) while axial and equatorial are
mentioned as ‘ax’ and ‘eq’ respectively. Coupling constant (J) values
are represented in Hertz (Hz). The tubes used for recording NMR
spectra are of 5 mm in diameter. Mass spectra were recorded in
JEOL, JMS-700 while microanalyses in Heraeus Carlo Erba 1108 CHN
analyzer. Purification of the final compounds was done using silica
gel (200–400 mesh-60 Å). Unless otherwise stated, all the reagents
and solvents used were of high grade and purchased from Fluka
and Merck. They were used as received without any further
purification.
16
8
16
64
>256
64
128
128
64
128
256
8
Thiazole series
25
26
27
28
29
30
31
>256
128
32
16
16
64
>256
16
128 >256
>256 >256
64
4
32
128
128
128
4
>256
>256
>256
8
128
>256
>256
256
–
256
>256
64
32
32
>256
>256
64
>256
256
128
256
16
256
128
8
128
8
64
256
256
32
32
Cfnc
Am Bd
8
16
–
–
–
–
–
8
8
16
a
MIC is the lowest concentration of an antimicrobial agent that will significantly
inhibit the visible growth of microorganism after a period of incubation.
b
No inhibition up to a highest concentration of 256
Cfn: Ciprofloxacin.
Am B: Amphotericin B.
mg/ml.
c
d
onefold enhanced potency (MIC: 8 mg/ml) compared to the refer-
ence drug. The antifungal screening studies revealed that N(1)-
methyl substituted compounds 24 and 32 emerged as potent
compounds against Rhizopus sp. though they were not effectively
inhibited the growth of other two tested fungal strains.
Among the set of series examined for their biological effec-
tiveness, the thiazolidinone bearing compounds elicited better
biological response than the corresponding thiazole analogues and
particularly the antibacterial potency of the former one is more
prominent as revealed from the observed results. It is recognized
that the presence of azine function (–C]N–N]C–) is expected to
be the key factor in exhibiting better biological activity in thiazo-
lidinone than thiazole because the latter does not have conjugation
about the azine function. Moreover, thiazolidin-4-ones were
reportedly interfering with the biosynthesis of peptidoglycan (an
essential component of the cell wall of both Gram-positive and
Gram-negative bacteria) by inhibiting the bacterial enzyme Mur B
[26] and hence expressed marked potency.
6.2. Chemistry general procedures
2,6-Diarylpiperidin-4-ones 1–7 [27a] were prepared according
to the literature procedures.
6.3. Preparation of 1,3-dimethyl-2,6-diphenylpiperidin-4-one (8)
A mixture of 3-methyl-2,6-diphenylpiperidin-4-one 1 (1 g,
3.77 mmol), anhydrous potassium carbonate (1 g, 7.5 mmol) and
methyl iodide (0.8 g, 5.65 mmol) in acetone (20 ml) was refluxed
for 3 h on a water bath. Removal of acetone along with excess of
methyl iodide under reduced pressure followed by dilution with
water and treatment with aqueous ammonia afforded the corre-
sponding 1,3-dimethyl-2,6-diphenylpiperidin-4-one 8. This upon
recrystallization in hot ethanol gave 0.98 g (93%) of pure
compound. Melting point of the pure compound was in good
agreement with the literature [27b].
5. Conclusion
In conclusion, we have reported herewith a stereospecific
synthesis of the target compounds 17–32 in good yields and are
known to exist exclusively in s-trans form. As well, reactivity of
chloroacetyl chloride towards achieving the desired thiazolidinones
was successfully promoted by employing CsF–Celite þ sodium
acetate combination as catalyst besides finding bromoacetyl chloride
6.4. Preparation of 3-methyl-2,6-diphenylpiperidin-4-
thiosemicarbazone (9)
3-Methyl-2,6-diphenylpiperidin-4-one 1 (1 g, 3.77 mmol) was
completely dissolved in boiling methanol (20 ml). To this, 2–3 drops
of con. HCl was added (excess of acid is fatal to the reaction) followed
by thiosemicarbazide (0.34 g, 3.77 mmol) and refluxed the contents
for 3 h on a water bath. The progress of reaction was monitored by
TLC. After the completion of reaction, the contents were brought to
room temperature and the separated solids were filtered. Recrys-
tallization of the compound in hot methanol furnished 1.15 g (90%)
of pure 3-methyl-2,6-diphenylpiperidin-4-thiosemicarbazone in
white crystalline form. Melting point of the pure compound was in
as one of the effective choice of cyclizing agents among the three a-
halo keto reagents used for thiazolidinone formation. NMR studies
proved that the piperidone ring adopts rigid chair conformationwith
equatorial orientation of alkyl and aryl groups whereas the confor-
mation of N–N bond is found to be anti with respect to alkyl group at
C-3. Antimycobacterial activity tested against M. tuberculosis indi-
cates that compounds 19, 20, 24, 29, 30 and 32 displayed excellent
activity. Likewise, antimicrobial assessment suggested that
compounds 21 against S. aureus, 20, 21, 28 against K. pneumoniae and

G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
4207
COOEt
O
p-(Cl, Br)-phenyl, NH; Phenyl, N-Me
p-(Cl, Br, F)-phenyl, NH
p-(F, OMe)-phenyl, NH; Phenyl, N-Me
M. tuberculosis
S. aureus
S
N
N
S
NH
---
p-Br-phenyl, NH
---
HN
E. coli
N
N
p-(Br, F)-phenyl, NH
p-Br-phenyl, NH
p-Br-phenyl, NH
K. pneumoniae
C. albicans
CH3
Ar
CH3
Ar
---
p-F-phenyl, NH
Ar
N
R
Ar
N
R
---
A. flavus
p-(Br, F)-phenyl, NH; Phenyl, N-Me
p-F-phenyl, NH; phenyl, N-Me
Rhizopus sp.
25-32
17-24
Ar = Phenyl, p-(F/ Cl/ Br/ OMe/ Me)-phenyl; R = H, Me
Fig. 4. Comparison of structural requirements for thiazolidinone and thiazole derivatives 17–32 towards their antimycobacterial and antimicrobial potencies.
good agreement with the literature [16b]. The rest of the compounds
[C(b)]N] (intense bands), 1494, 1455, 1425, 1400, 1376, 1331, 1277,
10–16 were prepared in a similar manner.
1259, 1233, 1203, 1101, 1029, 991 (weak bands), 752, 701 (medium
intense bands), 529 cmꢀ1 1H NMR in CDCl3
. (d ppm): 7.44 (d, 4H,
phenyl ortho protons), 7.33 (m, 4H, phenyl meta protons), 7.25 (m,
2H, phenyl para protons), 3.89 (dd, 1H, J6a,5e ¼ 2.75, J6a,5a ¼ 11.53, H-
6ax), 3.74 (s, 2H, thiazolidinone H), 3.61 (dd, 1H, J5a,5e ¼ 13.55, H-
5eq), 3.55 (d, 1H, J2a,3a ¼ 10.25, H-2ax), 2.62 (m, 1H, H-3ax), 2.22 (bt,
1H, H-5ax), 0.93 (d, 3H, JH,Me ¼ 6.59, CH3 at 3); 1H NMR in DMSO-d6
6.5. Typical procedure for the synthesis of 2-[3-methyl-2,6-
diphenylpiperidin-4-hydrazono]-1,3-thiazolidin-4-one (17)
by Methods 1–4
To a boiling solution of 3-methyl-2,6-diphenylpiperidin-4-thi-
osemicarbazone 9a (0.4 g, 1.18 mmol) in ethanol (20 ml) along
with acetic acid (1 ml – Method 2) or sodium acetate (0.29 g,
3.54 mmol – Method 3) or acetic acid–sodium acetate buffer (1 ml
AcOH/0.29 g NaOAc – Method 4) as catalyst or without any catalyst
(Method 1), either of the cyclizing agent {ClCH2COCl [0.13 g
(0.1 ml), 1.18 mmol] or BrCH2COCl [0.19 g (0.1 ml), 1.18 mmol)] or
BrCH2COOEt [0.2 g (0.13 ml) 1.18 mmol]} was added dropwise and
refluxed at about 80 ꢁC. Completion of the reaction was ascer-
tained by the pale or intense orange yellow coloration. The
contents were then brought to room temperature, poured into
water (75 ml) containing sodium bicarbonate and extracted with
ethyl acetate (3 ꢂ 25 ml). The combined organic layers were
washed with distilled water, brine and dried over sodium sulphate.
Evaporation of the solvent under reduced pressure gave the crude
mass. Purification of the compound over silica gel using
EtOAc:CHCl3 (1:10) or EtOAc:n-hexane (3:10) as eluting solvent
afforded the title compound 17 as pale yellow colored resinous
mass. Free flowing pale yellow solid (0.38 g, 85% yield while using
BrCH2COCl) was obtained upon triturating the residue with n-
hexane followed by ether.
(d ppm): 11.74 (s, 1H, amide NH), 2.50 (s, 1H, NH-merged with
solvent signal); 13C NMR (
d ppm): 173.50 (C-d), 169.69 (C-4), 162.47
(C-b), 143.53 (C-60), 142.59 (C-20), 128.34, 128.45 (phenyl meta
carbons), 127.54, 127.68 (phenyl para carbons), 126.70, 127.87
(phenyl ortho carbons), 69.24 (C-2), 61.05 (C-6), 45.49 (C-3), 37.78
(C-5), 32.91 (C-e), 11.94 (CH3 at C-3); EI-MS m/z 378 (26%, Mþ), 263
(100%), 194 (90%), 167 (13%), 156 (45%), 144 (25%), 128 (36%), 115
(51%), 91 (60%), 77 (40%). Anal. Calcd for C21H22N4OS (%): C, 66.64; H,
5.86; N, 14.80; Found (%): C, 66.22; H, 5.70; N, 14.69.
Similar procedure was adopted for the synthesis of rest of the
compounds 18–24 in this series with the same equivalents of
respective thiosemicarbazone derivatives and cyclizing agent. NMR
spectra of these compounds also recorded using the same solvent
system. The given yields of products correspond to bromoacetyl
chloride as cyclizing agent because of its superiority over others.
6.6.1. 2-[3-Ethyl-2,6-diphenylpiperidin-4-hydrazono]-1,3-
thiazolidin-4-one (18)
Compound 18 was obtained as yellow color solid from 10a
(0.37 g, 82% yield), mp 84–86 ꢁC (dec.); 1H NMR (
d ppm): 7.41–7.19
(m, 10H, phenyl protons), 3.89 (dd, 1H, J6a,5e ¼ 2.56, J6a,5a ¼ 11.72, H-
6ax), 3.69 (d [with very small splitting at the peak], 2H, J ¼ 1.09,
thiazolidinone H), 3.65 (d, 1H, J2a,3a ¼ 10.25, H-2ax), 3.57 (dd, 1H,
J5a,5e ¼ 13.36, H-5eq), 2.48 (m, 1H, H-3ax), 2.21 (bt, 1H, H-5ax), 2.04
(NH at 1), 1.67 (m, 1H, CH2CH3 at 3), 1.25 (m, 1H, CH2CH3 at 3), 0.88
6.6. Typical procedure for the synthesis of 2-[3-methyl-2,6-
diphenylpiperidin-4-hydrazono]-1,3-thiazolidin-4-one (17)
by Method 5
(t, 3H, J ¼ 7.32, CH2CH3 at 3); 13C NMR (
d ppm): 173.65 (C-d), 168.24
The solid catalyst CsF–Celite was prepared by stirring an aqueous
solution of CsF (Aldrich) and Celite 521 (Fluka) at room temperature
for 20 min as reported elsewhere [17,18]. To a well stirred boiling
solution of 3-methyl-2,6-diphenylpiperidin-4-thiosemicarbazone
9a (0.4 g, 1.18 mmol), CsF–Celite (0.27 g, 1.77 mmol) and sodium
acetate (0.20 g, 2.36 mmol) in freshly distilled ethanol, chloroacetyl
chloride [0.13 g (0.1 ml), 1.18 mmol] was added dropwise. After the
completion of reaction, the catalyst was filtered off, washed with
ethyl acetate (15 ml). 0.32 g (72% yield) of the title compound 17 was
obtained as pale yellow color solid by adopting the above mentioned
work-up and purification process: mp 188–190 ꢁC (dec.); IR (KBr)
3423 (amide NH), 3161 (ring NH), 3063, 3030, 2981, 2935, 2796
(weak bands), 1714 (thiazolidinone C]O), 1632 [C(4)]N], 1598
(C-4), 162.34 (C-b), 143.49 (C-60), 142.49 (C-20), 128.74–126.65
(phenyl carbons), 67.49 (C-2), 61.06 (C-6), 52.03 (C-3), 38.12 (C-5),
32.93 (C-e), 19.01 (CH2CH3 at C-3), 12.00 (CH2CH3 at C-3). Anal.
Calcd for C22H24N4OS (%): C, 67.32; H, 6.16; N, 14.27; Found (%): C,
67.13; H, 6.05; N, 14.18.
6.6.2. 2-[3-Methyl-2,6-bis(p-chlorophenyl)piperidin-4-
hydrazono]-1,3-thiazolidin-4-one (19)
Compound 19 was obtained as pale yellow color solid from 11a
(0.37 g, 83% yield), mp 160 ꢁC (dec.); 1H NMR (
d ppm): 7.39–7.28
(m, 8H, aromatic protons), 3.86 (d, 1H, J6a,5e ¼ 2.56, H-6ax), 3.74 (s,
2H, thiazolidinone H), 3.57 (dd, 1H, J5a,5e ¼ 13.36, H-5eq), 3.52 (d,

4208
G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
1H, J2a,3a ¼ 10.25, H-2ax), 2.54 (m, 1H, H-3ax), 2.12 (two d [over-
lapped], 1H, J5a,6a ¼ 12.08, J5a,5e ¼ 13.18, H-5ax], 2.05 (NH at 1), 0.91
JH,Me ¼ 6.22, CH3 at 3); 13C NMR (
d ppm): 173.79 (C-d), 169.66 (C-4),
162.70 (C-b), 140.53 (C-60), 139.61 (C-20), 137.11 (C-6&), 136.94 (C-
2&), 128.99–126.48 (aromatic carbons), 68.87 (C-2), 60.65 (C-6),
45.36 (C-3), 37.68 (C-5), 32.89 (C-e), 21.04, 20.98 (CH3 at C-2&/C-
6&), 11.91 (CH3 at C-3). Anal. Calcd for C23H26N4OS (%): C, 67.95; H,
6.45; N, 13.78; Found (%): C, 67.66; H, 6.32; N, 13.64.
(d, 3H, JH,Me ¼ 6.59, CH3 at 3); 13C NMR (
d ppm): 173.50 (C-d),166.97
(C-4), 162.73 (C-b), 141.79 (C-60), 140.79 (C-20), 132.79 (C-6&),
132.58 (C-2&), 128.84–127.67 (aromatic carbons), 67.98 (C-2),
59.98 (C-6), 44.89 (C-3), 37.20 (C-5), 32.62 (C-e), 11.42 (CH3 at C-3).
Anal. Calcd for C21H20Cl2N4OS (%): C, 56.38; H, 4.51; N, 12.52; Found
(%): C, 56.02; H, 4.42; N, 12.31.
6.6.7. 2-[1,3-Dimethyl-2,6-diphenylpiperidin-4-hydrazono]-1,3-
thiazolidin-4-one (24)
6.6.3. 2-[3-Methyl-2,6-bis(p-bromophenyl)piperidin-4-
hydrazono]-1,3-thiazolidin-4-one (20)
Compound 24 was obtained as pale yellow color solid from 16a
(0.38 g, 85% yield), mp 178–180 ꢁC (dec.); 1H NMR (
d ppm): 7.43–
Compound 20 was obtained as pale yellow color solid from 12a
7.22 (m, 10H, phenyl protons), 3.71 (d [with mild splitting at the
peak], 2H, J ¼ 1.47, thiazolidinone H), 3.46 (dd, 1H, J5a,5e ¼ 13.73, H-
5eq), 3.22 (dd, 1H, J6a,5e ¼ 2.93, J6a,5a ¼ 11.72, H-6ax), 2.72 (m, 1H, H-
3ax), 2.33 (bt, 1H, H-5ax), 1.69 (s, 3H, N–Me), 0.84 (d, 3H,
(0.35 g, 81% yield), mp 210–211 ꢁC (dec.); 1H NMR in CDCl3 (
d ppm):
8.13 (bs, amide NH), 7.49–7.32 (m, 8H, aromatic protons), 3.84 (d,
1H, J6a,5e ¼ 2.56, H-6ax), 3.76 (s, 2H, thiazolidinone H), 3.61 (dd, 1H,
J5a,5e ¼ 13.55, H-5eq), 3.52 (d, 1H, J2a,3a ¼ 9.89, H-2ax), 2.54 (m, 1H,
H-3ax), 2.09 (two d [overlapped]), 1H, J5a,6a ¼ 11.72, J5a,5e ¼ 13.18, H-
5ax), 1.99 (bs, NH at 1), 0.91 (d, 3H, JH,Me ¼ 6.59, CH3 at 3); 1H NMR
JH,Me ¼ 6.59, CH3 at 3); 13C NMR (
d ppm): 173.38 (C-d), 168.85 (C-4),
162.27 (C-b), 144.23 (C-60), 142.98 (C-20), 128.76–127.17 (phenyl
carbons), 77.75 (C-2), 69.71 (C-6), 45.31 (C-3), 41.42 (N–Me), 38.37
(C-5), 32.89 (C-e), 12.71 (CH3 at C-3). Anal. Calcd for C22H24N4OS
(%): C, 67.32; H, 6.16; N, 14.27; Found (%): C, 67.01; H, 6.02; N, 14.11.
in DMSO-d6 (d d ppm):
ppm): 11.78 (s, 1H, amide NH); 13C NMR (
173.62 (C-d), 167.34 (C-4), 162.82 (C-b), 142.47 (C-60), 141.41 (C-20),
131.28–128.21 (aromatic carbons), 121.21 (C-6&), 120.96 (C-2&),
68.28 (C-2), 60.22 (C-6), 45.11 (C-3), 37.38 (C-5), 32.81 (C-e), 11.62
(CH3 at C-3). Anal. Calcd for C21H20Br2N4OS (%): C, 47.03; H, 3.76; N,
10.45; Found (%): C, 47.39; H, 3.89; N, 10.32.
6.7. Typical procedure for the synthesis of ethyl 2-[3-methyl-2,6-
diphenylpiperidin-4-hydrazino]-1,3-thiazol-4-acetate (25)
6.6.4. 2-[3-Methyl-2,6-bis(p-fluorophenyl)piperidin-4-hydrazono]-
1,3-thiazolidin-4-one (21)
The procedure adopted for the synthesis of thiazolidinones was
followed here also with the use of ethyl 4-chloroacetoacetate
[0.19 g (0.16 ml), 1.18 mmol] as cyclizing agent. Commencement of
the reaction was revealed by change in color of the reaction mixture
from colorless to red upon addition of the cyclizing agent. Purifi-
cation of the compound over silica gel using EtOAc:CHCl3 (0.5:10)
or EtOAc:n-hexane (2:10) as eluting solvent afforded the title
compound 25 (0.48 g, 90% yield) as dark red color semi-solid from
9b. Trituration of the residue with ether gave free flowing red color
Compound 21 was obtained as spongy pale yellow color solid
from 13a (0.35 g, 80% yield), mp 98–100 ꢁC (dec.); 1H NMR (
d
ppm): 7.39–6.96 (m, 8H, aromatic protons), 3.86 (dd, 1H,
J6a,5e ¼ 2.56, J6a,5a ¼ 11.72, H-6ax), 3.72 (s, 2H, thiazolidinone H),
3.53 (signal was not resolved, 1H, H-5eq), 3.51 (d, 1H, J2a,3a ¼ 09.89,
H-2ax), 2.53 (m, 1H, H-3ax), 2.16 (two d [overlapped], 1H,
J5a,6a ¼ 12.08, J5a,5e ¼ 13.18, H-5ax), 0.89 (d, 3H, JH,Me ¼ 6.59, CH3 at
3); 13C NMR (
d
ppm): 173.42 (C-d), 169.07 (C-4), 162.76 (C-b),
solid: mp 99–101 ꢁC; 1H NMR (
d ppm): 7.48–7.25 (m, 10H, phenyl
163.49/163.34 (C-6&), 161.05/160.89 (C-6&), 139.27 (C-60), 138.26
(C-20), 129.24–115.16 (aromatic carbons), 68.38 (C-2), 60.29 (C-6),
45.66 (C-3), 37.89 (C-5), 32.89 (C-e), 11.85 (CH3 at C-3). Anal. Calcd
for C21H20F2N4OS (%): C, 60.85; H, 4.86; N, 13.52; Found (%): C,
60.61; H, 4.94; N, 13.61.
protons), 6.42 (s, 1H, thiazole H), 4.17 (q, 2H, J ¼ 7.32, H-g), 3.89 (dd,
1H, J6a,5e ¼ 2.38, J6a,5a ¼ 11.53, H-6ax), 3.56 (s, 2H, H-f), 3.52 (d, 1H,
J2a,3a ¼ 10.25, H-2ax), 2.99 (dd, 1H, J5a,5e ¼ 13.73, H-5eq), 2.57 (m,
1H, H-3ax), 2.19 (two
d
(overlapped), 1H, J5a,6a ¼ 12.08,
J5a,5e ¼ 13.55, H-5ax), 2.02 (s, NH at 1), 1.26 (t, 3H, J ¼ 7.14, H-h), 0.94
(d, 3H, JH,Me ¼ 6.59, CH3 at 3); 13C NMR (
d ppm): 170.93 (ester
6.6.5. 2-[3-Methyl-2,6-bis(p-methoxyphenyl)piperidin-4-
hydrazono]-1,3-thiazolidin-4-one (22)
carbonyl),170.23 (C-b ipso),153.90 (C-4), 143.61 (C-d), 143.22 (C-60),
142.60 (C-20), 128.72–126.45 (phenyl carbons), 105.69 (C-e), 69.33
(C-2), 60.91 (C-g), 60.63 (C-6), 44.89 (C-3), 36.99 (C-f), 36.23 (C-5),
14.09 (C-h), 11.99 (CH3 at C-3). Anal. Calcd for C25H28N4O2S (%): C,
66.94; H, 6.29; N, 12.49; Found (%): C, 67.26; H, 6.11; N, 12.24.
The remaining compounds 26–32 were also synthesized in
a similar fashion.
Compound 22 was obtained as pale yellow color solid from 14a
(0.37 g, 84% yield), mp 184 ꢁC (dec.); 1H NMR in CDCl3
(d ppm):
7.33–6.81 (m, 8H, aromatic protons), 3.84 (1H, merged with p-OMe
signal, H-6ax), 3.80, 3.75 (s, 6H, OCH3 at C-2&/C-6&), 3.69 (s, 2H,
thiazolidinone H), 3.51 (dd, 1H, J5a,5e ¼ 13.55, H-5eq), 3.46 (d, 1H,
J2a,3a ¼ 10.25, H-2ax), 2.55 (m, 1H, H-3ax), 2.20 (bt, 1H, H-5ax), 0.89
(d, 3H, JH,Me ¼ 6.59, CH3 at 3). 1H NMR in DMSO-d6 (
d
ppm): 11.82 (s,
6.7.1. Ethyl 2-[3-ethyl-2,6-diphenylpiperidin-4-hydrazino]-1,3-
thiazol-4-acetate (26)
amide NH); 13C NMR (
d ppm): 173.53 (C-d), 169.86 (C-4), 162.39 (C-
b), 158.98 (C-6&), 158.85 (C-2&), 135.83 (C-60), 134.90 (C-20),
128.79–113.63 (aromatic carbons), 68.58 (C-2), 60.41 (C-6), 55.18
(OCH3 at C-2&/C-6&), 45.60 (C-3), 37.83 (C-5), 32.90 (C-e), 11.93
(CH3 at C-3). Anal. Calcd for C23H26N4O3S (%): C, 62.99; H, 5.98; N,
12.78; Found (%): C, 63.21; H, 6.11; N, 12.98.
Compound 26 was obtained as brown color solid from 10b
(0.46 g, 87% yield), mp 92–93 ꢁC (dec.); 1H NMR (
d ppm): 7.47–7.23
(m, 10H, phenyl protons), 6.45 (s, 1H, thiazole H), 4.18 (q, 2H,
J ¼ 6.96, H-g), 3.88 (dd, 1H, J6a,5e ¼ 2.75, J6a,5a ¼ 11.49, H-6ax), 3.66
(d, 1H, J2a,3a ¼ 10.25, H-2ax), 3.59 (s, 2H, H-f), 2.83 (dd, 1H,
J5a,5e ¼ 13.73, H-5eq), 2.46 (m, 1H, H-3ax), 2.19 (bt, 1H, H-5ax), 1.68
(m, 1H, CH2CH3 at 3), 1.28 (m, 1H, CH2CH3 at 3), 1.27 (t, 3H, J ¼ 7.14,
6.6.6. 2-[3-Methyl-2,6-bis(p-methylyphenyl)piperidin-4-
hydrazono]-1,3-thiazolidin-4-one (23)
H-h), 0.91 (t, 3H, J ¼ 7.14, CH2CH3 at 3); 13C NMR (
d ppm): 170.52
Compound 23 was obtained as yellow color solid from 15a
(ester carbonyl), 170.10 (C-b ipso), 151.71 (C-4), 144.49 (C-d), 143.11
(C-60), 142.50 (C-20), 128.63–126.46 (phenyl carbons), 106.19 (C-e),
67.55 (C-2), 60.94 (C-g), 60.78 (C-6), 51.49 (C-3), 37.43 (C-f), 36.34
(C-5), 19.09 (CH2CH3 at 3), 14.16 (C-h), 11.84 (CH2CH3 at 3). Anal.
Calcd for C26H30N4O2S (%): C, 67.50; H, 6.54; N, 12.11; Found (%): C,
67.91; H, 6.32; N, 12.28.
(0.37 g, 84% yield), mp 187–188 ꢁC (dec.); 1H NMR (
d ppm): 7.29–
7.06 (m, 8H, aromatic protons), 3.84 (signal was not resolved,1H, H-
6ax), 3.65 (s, 2H, thiazolidinone H), 3.51 (dd, 1H, J5a,5e ¼ 13.55,
H-5eq), 3.47 (d, 1H, J2a,3a ¼ 10.25, H-2ax), 2.57 (m, 1H, H-3ax), 2.33,
2.28 (s, 6H, CH3 at C-2&/C-6&), 2.21 (bt, 1H, H-5ax), 0.90 (d, 3H,

G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
4209
6.7.2. Ethyl 2-[3-methyl-2,6-bis(p-chlorophenylpiperidin-4-
hydrazino]-1,3-thiazol-4-acetate (27)
resolved, 1H, H-5eq), 2.51 (m, 1H, H-3ax), 2.16 (bt, 1H, H-5ax), 1.25
(t, 3H, J ¼ 6.77, H-h), 0.93 (d, 3H, JH,Me ¼ 6.22, CH3 at 3); 13C NMR (
d
Compound 27 was obtained as shiny and spongy red color
solid from 11b (0.43 g, 84% yield), mp 84–86 ꢁC (dec.); IR (KBr)
3305 (NH), 2976, 2931, 2873, 2815 (weak bands), 1732 (ester
C]O), 1553 {C(4)]N} [intense bands], 1489, 1442, 1408, 1369,
1336, 1312, 1260, 1226, 1200, 1152 (weak bands), 1088, 1030, 1013,
829 (medium intense bands), 715, 691, 600, 578 cmꢀ1 (weak
ppm): 170.47 (ester carbonyl), 170.12 (C-b ipso), 159.04 (C-6&/C-
2&), 153.55 (C-4), 144.37 (C-d), 135.37 (C-60), 134.86 (C-20), 128.78–
113.64 (aromatic carbons), 106.15 (C-e), 68.62 (C-2), 60.89 (C-g),
60.08 (C-6), 55.19 (OCH3 at C-2&/C-6&), 44.95 (C-3), 37.37 (C-f),
36.03 (C-5), 14.12 (C-h), 11.98 (CH3 at 3). Anal. Calcd for
C27H32N4O4S (%): C, 63.76; H, 6.34; N, 11.02; Found (%): C, 63.42; H,
6.11; N, 10.78.
bands); 1H NMR (
d ppm): 8.50 (bs, 1H, NH), 7.41–7.26 (m, 8H,
aromatic protons), 6.46 (s, 1H, thiazole H), 4.17 (q, 2H, J ¼ 6.96, H-
g), 3.85 (dd, 1H, J6a,5e ¼ 2.56, J6a,5a ¼ 11.72, H-6ax), 3.58 (s, 2H, H-f),
3.50 (d, 1H, J2a,3a ¼ 10.25, H-2ax), 2.78 (dd, 1H, J5a,5e ¼ 13.91, H-
6.7.6. Ethyl 2-[3-methyl-2,6-bis(p-methylphenylpiperidin-4-
hydrazino]-1,3-thiazol-4-acetate (31)
5eq), 2.49 (m, 1H, H-3ax), 2.13 [two
d
(overlapped), 1H,
Compound 31 was obtained as red color solid from 15b (0.46 g,
J5a,6a ¼ 11.70, J5a,5e ¼ 13.55, H-5ax], 1.97 (s, 1H, NH at 1), 1.26 (t, 3H,
88% yield), mp 88–89 ꢁC (dec.); 1H NMR (
d ppm): 7.35–7.13 (m, 8H,
J ¼ 7.14, H-h), 0.93 (d, 3H, JH,Me ¼ 6.22, CH3 at 3); 13C NMR (
d
ppm):
aromatic protons), 6.46 (s, 1H, thiazole H), 4.17 (q, 2H, J ¼ 6.96, H-g),
3.84 (d, 1H, J6a,5a ¼ 11.35, H-6ax), 3.59 (s, 2H, H-f), 3.48 (d, 1H,
J2a,3a ¼ 9.89, H-2ax), 2.79 (d, 1H, J6a,5a ¼ 13.69, H-5eq), 2.54 (m, 1H,
H-3ax), 2.34/2.33 (s, 6H, CH3 at C-2&/C-6&), 2.18 (bt, 1H, H-5ax),
1.26 (t, 3H, J ¼ 6.96, H-h), 0.93 (d, 3H, JH,Me ¼ 6.59, CH3 at 3); 13C
170.47 (ester carbonyl), 169.85 (C-b ipso), 152.21 (C-4), 144.45 (C-
d), 141.49 (C-60), 140.93 (C-20), 133.51 (C-2&/C-6&), 129.17–127.83
(aromatic carbons), 106.39 (C-e), 68.49 (C-2), 60.97 (C-g), 60.03
(C-6), 44.87 (C-3), 37.39 (C-f), 35.89 (C-5), 14.17 (C-h), 11.91 (CH3 at
3); EI-MS m/z 516 (7%, Mþ), 377 (9%), 331 (67%), 322 (37%), 262
(100%), 254 (72%), 192 (32%), 185 (46%), 165 (30%), 152 (34%), 140
(60%), 115 (36%), 98 (23%), 89 (29%), 71 (29%), 54 (15%). Anal. Calcd
for C25H26Cl2N4O2S (%): C, 58.03; H, 5.06; N, 10.83; Found (%): C,
58.31; H, 5.19; N, 10.96.
NMR (d ppm): 170.54 (ester carbonyl), 170.07 (C-b ipso), 153.58 (C-
4), 140.28 (C-60), 139.74 (C-20), 137.39 (C-2&/C-6&), 129.32–126.34
(aromatic carbons), 106.29 (C-e), 69.06 (C-2), 60.98 (C-g), 60.49 (C-
6), 44.91 (C-3), 37.46 (C-f), 36.06 (C-5), 21.16/21.12 (CH3 at C-2&/C-
6&), 14.20 (C-h), 12.06 (CH3 at 3). Anal. Calcd for C27H32N4O2S (%):
C, 68.04; H, 6.77; N, 11.75; Found (%): C, 67.65; H, 6.58; N, 11.87.
6.7.3. Ethyl 2-[3-methyl-2,6-bis(p-bromophenylpiperidin-4-
hydrazino]-1,3-thiazol-4-acetate (28)
6.7.7. Ethyl 2-[1,3-dimethyl-2,6-diphenylpiperidin-4-hydrazino]-
1,3-thiazol-4-acetate (32)
Compound 28 was obtained as shiny and spongy red color solid
from 12b (0.43 g, 88% yield), mp 106 ꢁC (dec.); 1H NMR (
d
ppm):
Compound 32 was obtained as shiny dark red color solid from
7.49–7.30 (m, 8H, aromatic protons), 6.46 (s, 1H, thiazole H), 4.17
(q, 2H, J ¼ 7.14, H-g), 3.83 (dd, 1H, J6a,5e ¼ 2.56, J6a,5a ¼ 11.72, H-
6ax), 3.58 (s, 2H, H-f), 3.49 (d, 1H, J2a,3a ¼ 10.25, H-2ax), 2.79
(dd, 1H, J5a,5e ¼ 13.91, H-5eq), 2.49 (m, 1H, H-3ax), 2.12 (bt, 1H, H-
5ax), 1.26 (t, 3H, J ¼ 7.14, H-h), 0.93 (d, 3H, JH,Me ¼ 6.59, CH3 at 3);
16b (0.47 g, 90% yield), mp 78–80 ꢁC (dec.); 1H NMR (
d ppm): d 8.61
(bs, 1H, NH), 7.41, 7.43 (2s, 4H, phenyl ortho protons), 7.41, 7.43 (2s,
4H, phenyl ortho protons), 7.35 (t, 4H, phenyl meta protons), 6.43 (s,
1H, thiazole H), 4.16 (q, 2H, J ¼ 6.56, H-g), 3.56 (s, 2H, H-f), 3.19 (dd,
1H, J6a,5e ¼ 2.75, J6a,5a ¼ 11.89, H-6ax), 2.89 (d, 1H, J2a,3a ¼ 10.25, H-
2ax), 2.75 (dd, 1H, J6a,5a ¼ 13.91, H-5eq), 2.67 (m, 1H, H-3ax), 2.34
(bt, 1H, H-5ax), 1.72 (s, 3H, N-Me), 1.25 (t, 3H, J ¼ 7.14, H-h), 0.87 (d,
13C NMR (
d ppm): 170.45 (ester carbonyl), 169.87 (C-b ipso), 152.16
(C-4), 144.38 (C-d), 141.98 (C-60), 141.41 (C-20), 131.81–128.17
(aromatic carbons), 121.63 (C-2&/C-6&), 106.37 (C-e), 68.51 (C-2),
60.96 (C-g), 60.04 (C-6), 44.79 (C-3), 37.37 (C-f), 35.85 (C-5), 14.16
(C-h), 11.91 (CH3 at 3). Anal. Calcd for C25H26Br2N4O2S (%): C, 49.52;
H, 4.32; N, 9.24; Found: C, 49.38; H, 4.17; N, 9.16.
3H, JH,Me ¼ 6.22, CH3 at 3); 13C NMR (
d ppm): 170.46 (ester
carbonyl),169.93 (C-b ipso),152.49 (C-4),143.74 (C-d),144.42 (C-60),
142.89 (C-20), 128.37, 128.74 (phenyl meta carbons), 127.58, 127.61
(phenyl para carbons), 126.91, 128.08 (phenyl ortho carbons), 106.18
(C-e), 77.79 (C-2), 69.15 (C-6), 60.89 (C-g), 44.82 (C-3), 41.47 (N–
CH3), 37.38 (C-f), 36.51 (C-5), 14.13 (C-h), 12.76 (CH3 at 3). Anal.
Calcd for C26H30N4O2S (%): C, 67.50; H, 6.54; N, 12.11; Found (%): C,
67.71; H, 6.71; N, 11.88.
6.7.4. Ethyl 2-[3-methyl-2,6-bis(p-fluorophenylpiperidin-4-
hydrazino]-1,3-thiazol-4-acetate (29)
Compound 29 was obtained as shiny and spongy red color solid
from 13b (0.44 g, 85% yield), mp 98–100 ꢁC (dec.); 1H NMR (
d ppm):
8.48 (s, 1H, NH), 7.44–7.02 (m, 8H, aromatic protons), 6.47 (s, 1H,
thiazole H), 4.18 (q, 2H, J ¼ 6.96, H-g), 3.87 (dd, 1H, J6a,5e ¼ 2.75,
J6a,5a ¼ 11.53, H-6ax), 3.59 (s, 2H, H-f), 3.51 (d, 1H, J2a,3a ¼ 9.89, H-
2ax), 2.79 (dd, 1H, J5a,5e ¼ 13.73, H-5eq), 2.51 (m, 1H, H-3ax), 2.16
(bt,1H, H-5ax), 2.01 (s,1H, NH at 1), 1.27 (t, 3H, J ¼ 7.14, H-h), 0.93 (d,
6.8. Decomposition of thiazolidinone (17) with con. HCl or con.
HCl þ acetic acid
To the boiling solution of 2-[3-methyl-2,6-diphenylpiperidin-4-
hydrazono]-1,3-thiazolidin-4-one 17 (0.15 g, 0.39 mmol) in ethanol,
con. HCl (0.3 ml or 5 drops because excess of HCl will salt out the
product) or con. HCl (0.3 ml or 5 drops) and acetic acid (0.4 ml)
were added. The contents were stirred well with reflux. TLC
confirmed the decomposition of products into the corresponding 3-
methyl-2,6-diphenylpiperidin-4-one (1). The reaction mixture was
cooled, quenched with aqueous sodium bicarbonate after 13 h
because further increase of reaction time had no significance. The
reaction mixture was extracted twice with ethyl acetate (2 ꢂ 15 ml),
washed with water (2 ꢂ 15 ml), brine and dried over sodium
sulphate. Evaporation of the solvent under reduced pressure gave
the crude mass. Purification of the crude product over silica gel
using EtOAc:n-hexane (2:10) as eluting solvent afforded compound
1 (0.021 g, 21% while using con. HCl and 0.025 g, 25% while using
con. HCl/AcOH) as white crystals. Melting point and NMR spectral
data were in good agreement with the reported results [22].
3H, JH,Me ¼ 6.59, CH3 at 3); 13C NMR (
d ppm): 170.49 (ester carbonyl),
169.84 (C-b ipso), 163.53 (C-6&), 161.11 (C-2&), 152.55 (C-4), 144.46
(C-d), 138.81 (C-60), 138.27 (C-20), 129.36–115.16 (aromatic carbons),
106.39 (C-e), 68.49 (C-2), 60.98 (C-g), 60.05 (C-6), 45.02 (C-3), 37.41
(C-f), 36.05 (C-5), 14.18 (C-h), 11.92 (CH3 at 3). Anal. Calcd for
C25H26F2N4O2S (%): C, 61.97; H, 5.41; N, 11.56; Found (%): C, 61.78; H,
5.32; N, 11.38.
6.7.5. Ethyl 2-[3-methyl-2,6-bis(p-methoxyphenylpiperidin-4-
hydrazino]-1,3-thiazol-4-acetate (30)
Compound 30 was obtained as brown color solid from 14b
(0.44 g, 87% yield), mp 96–98 ꢁC (dec.); 1H NMR (
d ppm): 7.37–6.87
(m, 8H, aromatic protons), 6.44 (s, 1H, thiazole H), 4.17 (q, 2H,
J ¼ 6.59, H-g), 3.79 (s, 7H, H-6ax and OCH3 at C-2&/C-6&), 3.57
(s, 2H, H-f), 3.46 (d, 1H, J2a,3a ¼ 9.52, H-2ax), 2.78 (signal was not

4210
G. Aridoss et al. / European Journal of Medicinal Chemistry 44 (2009) 4199–4210
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(e) G. Aridoss, S. Amirthaganesan, N. Ashok Kumar, J.T. Kim, K.T. Lim,
S. Kabilan, Y.T. Jeong, Bioorg. Med. Chem. Lett. 18 (2008) 6542.
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This research work was supported by the second stage of BK21
program.
Appendix. Supplementary data
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The proposed mechanistic pathways for the formation of frag-
ments encountered in the respective mass spectra of the
compounds and their discussion are made. Substituent parameters
for hydrazonothiazolidinone and hydrazinothiazole groups on the
ring carbon chemical shifts of piperidone framework in 17–32 were
calculated and discussed. 1H, 13C, NOESY, HSQC and HMBC spectra
for the representative compounds 17 and 32 are furnished.
Supplementary data associated with this article can be found in the
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