Spectral characterization of novel bis heterocycles comprising both piperidine and thiohydantoin nuclei

Article abstract of DOI:10.1007/s11164-010-0221-7

A series of bis heterocycles comprising both piperidine and thiohydantoin nuclei namely 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4- ones is synthesized and characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional

Full text of DOI:10.1007/s11164-010-0221-7

Res Chem Intermed (2010) 36:1073–1084
DOI 10.1007/s11164-010-0221-7
Spectral characterization of novel bis heterocycles
comprising both piperidine and thiohydantoin nuclei
•
J. Thanusu V. Kanagarajan M. Gopalakrishnan
•
Received: 15 June 2010 / Accepted: 1 November 2010 / Published online: 24 November 2010
ꢀ Springer Science+Business Media B.V. 2010
Abstract A series of bis heterocycles comprising both piperidine and thiohydantoin
nuclei namely 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones is
synthesized and characterized by melting point, elemental analysis, MS, FT–IR, one-
1
dimensional NMR (1H, D2O exchanged H and 13C), two-dimensional HOMOCOSY,
and NOESY spectroscopic data.
Keywords 3-alkyl-2 Á 6-diarylpiperin-4-ones Á 3-alkyl-2 Á 6-diarylpiperin-4-one
thiosemicarbazones Á 3-(3-alkyl-2, 6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-
4-ones Á HOMOCOSY Á NOESY
Introduction
Baliah et al. [1, 2] have reviewed the importance of piperidin-4-ones as
intermediates in the synthesis of several physiologically active compounds.
Similarly, Lijinsky and Taylor [3] have found that the presence of substituents at
both the a-positions to that of N in piperidin-4-one is important to exert marked
biological properties. Bioactive heterocyclic ring systems having 2,6-diaryl-
piperidine-4-one nucleus with different substituents at 3- and 5-positions of the
ring have aroused great interest due to their wide variety of biological properties
[4–11]. Thiohydantoins are sulfur analogs of hydantoins with one or both carbonyl
groups replaced by thiocarbonyl groups [12]. Among the known thiohydantoins,
2-thiohydantoins were most notably known due of their wide applications as
hypolipidemic [13], anticarcinogenic [14], antimutagenic [15], antithyroidal [16]
antiviral (e.g., against herpes simplex virus, HSV) [17], human immunodeficiency
J. Thanusu Á V. Kanagarajan Á M. Gopalakrishnan (&)
Department of Chemistry, Synthetic Organic Chemistry Laboratory, Annamalai University,
Annamalai Nagar 608 002, Tamil Nadu, India
e-mail: profmgk@yahoo.co.in
123

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J. Thanusu et al.
virus (HIV) [18], and tuberculosis [19]), antimicrobial (antifungal and antibacterial)
[20], anti-ulcer and anti-inflammatory agents [21], as well as pesticides [22].
Additionally, 2-thiohydantoins have been used as reference standards for the
development of C-terminal protein sequencing [23], as reagents for the development
of dyes [24] and in textile printing, metal cation complexation, and polymerization
catalysis [25]. In connection with our earlier work and as part of our ongoing
research programme on synthesis of structurally diverse potent biologically active
heterocycles [26–33], we planned to design a system that combines both bioactive
piperidine and thiohydantoin components together to give a new series of bis
heterocycles comprising both piperidine and thiohydantoin nuclei and their
structural elucidation using spectroscopic techniques were discussed.
Results and discussion
In the present work, a new series of potent antimicrobial agents [34], bis
heterocycles comprising both piperidine and thiohydantoin nuclei namely 3-(3-
alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones 46–60 was synthe-
sized by the treatment of the respective thiosemicarbazones 31–45 with chloroethyl
acetate and anhydrous sodium acetate in refluxing ethanol for 4 h. The synthetic
route for the formation of compounds 46–60 is given in Scheme 1. The physical
and analytical data are given in Table 1. The structures of all the synthesized
compounds 46–60 are discussed with the help of m.p.’s, elemental analysis, FT–IR,
MS, and one-dimensional NMR (1H, 13C) spectra.
O
O
O
R1
R1
R2
Aqu. NH3
Ice, 200C
R1
R2
EtOH
warm, 15 min.
H3C
O
R2
HCl
H
O
H
N
H
(16-30)
N
H
.HCl
(1-15)
+
X
X
X
X
S
CH3
+
EtOH
reflux, 2h
NH4
-O
H2N
N
H
NH2
X
X
O
O
N
S
H2N
5
2
4
ClCH2CO2Et
Anhyd.CH3COONa
EtOH
1
HN
3 N
NH
N
reflux, 4 h
S
R1
R2
R1
R2
4
3
5
2
1
6
N
H
(31-45)
N
H
(46-60)
X
X
X
X
Scheme 1 Synthetic route for the formation of 3-(3-substituted-2,6-diaryl-piperidin-4-ylideneamino)-2-
thioxoimidazolidin-4-ones
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Spectral characterization of novel bis heterocycles
1075
Table 1 Physical and analytical characteristics of compounds 46-60
Compounds R1 R2
X
Yield m.p. Elemental analysis (%)
(%)
m/z (M?1)?•
Molecular
formula
(8C)
C Found
(calculated) (calculated) (calculated)
H Found
N Found
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
H
H
H
H
H
H
H
H
H
F
74
78
67
108 65.87
(65.91)
5.50
15.33
365
(5.53)
4.50
(15.37)
13.96
C20H20N4OS
H
103 59.97
(59.99)
400
(4.53)
4.15
(13.99)
12.91
C20H18F2N4OS
H
Cl
167 55.41
(55.43)
432
(4.19)
5.66
(12.93)
13.17
C20H18Cl2N4OS
H
OCH3 72
CH3 70
158 62.20
(62.24)
424
(5.70)
6.15
(13.20)
14.23
C22H24N4O3S
H
142 67.30
(67.32)
392
(6.16)
5.82
(14.27)
14.76
C22H24N4OS
CH3
CH3
CH3
CH3
CH3
H
F
75
78
75
171 66.60
(66.64)
378
(5.86)
4.82
(14.80)
13.48
C21H22N4OS
182 60.81
(60.85)
414
(4.86)
4.47
(13.52)
12.49
C21H20F2N4OS
446
Cl
187 56.35
(56.38)
(4.51)
5.95
(12.52)
12.68
C21H20Cl2N4OS
OCH3 72
CH3 70
182 62.95
(62.99)
438
(5.98)
6.41
(12.78)
13.75
C23H26N4O3S
136 67.92
(67.95)
406
(6.45)
6.14
(13.78)
14.21
C23H26N4OS
392
CH3 CH3
CH3 CH3
H
F
76
77
75
148 67.28
(67.32)
(6.16)
5.11
(14.27)
13.03
C
22H24N4OS
428
134 61.64
(61.67)
(5.17)
4.78
(13.08)
12.11
C22H22F2N4OS
CH3 CH3 Cl
176 57.21
(57.27)
460
(4.81)
6.52
(12.14)
12.33
C22H22Cl2N4OS
CH3 CH3 OCH3 72
CH3 CH3 CH3 71
132 63.65
(63.69)
452
(6.24)
6.68
(12.38)
13.28
C24H28N4O3S
124 68.52
(68.54)
420
(6.71)
(13.32)
C24H28N4OS
In order to investigate the spectral assignments, compound 46 was chosen as a
representative compound. IR spectrum of 3-(2,6-diphenylpiperidin-4-ylidenea-
mino)-2-thioxoimidazolidin-4-one 46 shows characteristic frequencies at 1,728,
1,215 cm-1 are due to the presence of the carbonyl group and the thiocarbonyl
group. Absorption frequencies are in the region of 3,300–3,426 cm-1, suggesting the
presence of –NH groups. In addition, the absorption frequency at 1,635 cm-1 was
due to C=N stretching vibration. Mass spectrum of compound 46 shows a molecular
123

1076
J. Thanusu et al.
ion peak at m/z 365.25 (M?•?1), which is consistent with the proposed molecular
formula of 46. The elemental analysis (Ccal 65.87, Cobs 65.91; Hcal 5.53, Hobs
5.50; Ncal 15.37, Nobs 15.33) are consistent with the proposed molecular formula
(C20H20N4OS) of 46.
The assignments of signals in the 1H NMR spectrum of compound 46 have been
done based on total widths and spin multiplicities. There are two double doublet
centered at 3.90 ppm and 4.17 ppm. Each signal corresponds to one proton. These
two signals are due to the benzylic protons H2a and H6a (3.90/H2a, 4.17/H6a). Two
coupling constants are extracted from the double doublet at 3.88–3.92 and the
values are 11.76 Hz and 3.08 Hz. The lower value is due to the vicinal coupling of
J
2a,3e and the higher value corresponds to trans coupling of J2a,3a. The two coupling
constants are calculated from the double doublet at 4.15–4.19 ppm and the values
are 11.88 Hz and 3.20 Hz. The lower value is due to the vicinal coupling of J6a,5e
and the higher value is due to the trans coupling of J6a,5a. The double doublets
observed at 2.41–2.37 ppm and 3.62–3.66 ppm are due to the equatorial methylenic
protons H3e and H5e, respectively. A double doublet is expected for axial methylenic
proton H5a, but a multiplet is obtained at 2.43–2.52 ppm corresponds to H5a proton.
A double doublet at 2.37–2.41 ppm has two coupling constants and the coupling
values are 2.96 Hz and 13.64 Hz. The lower value corresponds to vicinal coupling
of J3e,2a and the higher value corresponds to geminal coupling of J3e,3a. The two
coupling constant values are extracted from the double doublet at 3.62–3.66 ppm.
The lower value 2.96 Hz is due to vicinal coupling of J5e, 6a and the higher value
13.52 Hz is due to geminal coupling of J5e, 5a. A sharp singlet observed at 3.80 ppm
is due to the methylene protons of imidazolidine moiety. A double doublet is
expected for axial methylenic proton H3a, but a multiplet is obtained at
1.97–2.05 ppm corresponds to H3a proton. The NH proton of piperidone moiety
observed as a broad singlet at 2.83 ppm. The broad signal at 11.78 ppm is due to the
NH proton of imidazolidine moiety. A multiplet appeared in the range of
7.23–7.50 ppm is due to aromatic ring protons at C-2 and C-6 positions.
In the 13C NMR spectrum of 46, resonances in the aliphatic range of 29.62,
37.30, 60.23, 61.12, and 43.64 ppm have been observed. The signals appearing at
29.62 and 37.30 ppm are due to C-3 and C-5 carbons, respectively. Among the
signals at 60.23 ppm and 61.12 ppm for the benzylic carbons, the one at 60.23 ppm
is due to C-2 and the signal at 61.12 ppm is due to C-6 carbon. 13C resonance at
43.64 ppm must be due to the methylene carbon of imidazolidine moiety (at C-5).
The signal at 163.19 ppm is conveniently assigned to C=N carbon of piperidone
moiety. The 13C resonance of carbonyl carbon and thiocarbonyl carbon at C-4 and
C-2 of imidazolidine moiety appeared at 167.63 and 173.87 ppm (C=S/173.87;
C=O/167.63), respectively. The ipso carbons appeared at 144.01 and 144.16 ppm.
The signals appearing in the region of 126.51–128.15 are due to the aromatic
carbons in two phenyl rings at C-2 and C-6 positions. All the above-mentioned
assignments are further confirmed by HOMOCOSY and NOESY spectra.
In the HOMOCOSY spectrum of 46, the signal at 3.90 ppm shows cross peaks
with the signals at 2.01 ppm and 2.39 ppm. The signal at 4.17 ppm shows cross
peaks with the signals at 2.48 and 3.64 ppm. Consequently, the signal at 3.90 ppm
must be due to the benzylic proton H2a. Since this can have coupling only with the
123

Spectral characterization of novel bis heterocycles
1077
Fig. 1 3-(2,6-
diphenylpiperidin-4-
ylideneamino)-2-
thioxoimidazolidin-4-one 46
(Chair conformation)
H
O
N
H
H
N
H
S
H
N
H
N
H
H
H3e and H3a protons, the two signals at 2.01 ppm and 2.39 ppm are assigned to H3a
and H3e proton, respectively. The signal at 4.17 ppm must be due to the benzylic
proton H6a, since this can have coupling with H5a and H3e protons. The two signals
at 2.48 and 3.64 ppm are assigned to H5a and H5e protons, respectively. The
individual assignments can be made by using its NOESY spectrum.
In the NOESY spectrum of 46, the signals of benzylic proton (H2a,H6a) have
strong nOe with signals of methylene protons (H3e and H5a proton). Hence the
signal at 3.90 ppm has strong nOe with the signal at 2.39 ppm. The signal at
4.17 ppm has strong nOe with the signal 2.48 ppm. From this, it is concluded that
the signal at 3.90 ppm must be due to the benzylic proton H2a. The signal at
4.17 ppm must be due to the benzylic proton H6a. The signals at 2.39 ppm and
2.48 ppm must be due to H3e and H5a proton, respectively. Moreover, an interesting
observation from the NOESY spectrum of compound 46 is that signal at 11.78 ppm
has strong nOe with the signal at 2.01 ppm. Hence, the signal at 11.78 must be due
to NH proton of imidazolidine moiety and the signal at 2.01 ppm must be due to H3a
proton. The signal at 3.80 ppm has strong nOe with the signal at 2.01 ppm and
2.39 ppm. The signal at 3.80 ppm must be due to methylene proton of imidazolidine
moiety. The signal at 2.39 ppm is due to H3e proton. From the NOESY spectrum,
we concluded that imidazolidine moiety of 46 present towards the H3a and H3e
protons of piperidone moiety of 46. From the view of nOes of –NH and CH2 protons
of imidazolidine moiety, the –NH signal (11.78 ppm) and CH2 signal (3.80 ppm)
must be very close to methylene protons of piperidone moiety at C-3 position.
Therefore, with reference to HOMOCOSY and NOESY correlations in compound
46, the tentative assignments made for its ring and substituent protons are
confirmed. It has been well proven that mostly and favorably 2,6-diarylpiperidin-4-
one ring adopts chair conformation with all its substituents at equatorial disposition
[1]. Moreover, equatorial disposition of the phenyl group at C-2 and C-6 makes the
chair conformation more rigid, thereby preventing interconversion of one chair into
another. Hence, based on the obtained chemical shifts and coupling constant values,
normal chair conformation (Fig. 1) is proposed for compound 46.
Two-dimensional HOMOCOSY and NOESY NMR spectral assignments
for the synthesized 3-(3,3-dimethyl-2,6-diphenylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 56
Two singlets of two methyl protons at 0.97 and 1.19 ppm had a cross peak with the
signal at 3.72 ppm. Hence, the signal at 3.72 ppm must be due to the H2a proton.
The double doublet at 4.15 ppm had cross peaks with the signal at 2.54 ppm and
123

1078
J. Thanusu et al.
Fig. 2 Chair conformation
Compound 56
O
5
HN
S
4
3
N
1
2
H
N
H
6
H
4
5
H
2
1
3
CH3
N
H
H3C
vice versa. This mutual correlation clearly showed that the signal at 4.15 ppm was
due to the H6a proton and the signal at 2.54 ppm must be due to the H5e proton. The
individual assignments can be made using its NOESY spectrum.
From the NOESY spectrum of compound 56, it was interesting to note that the
two methyl protons at 0.97 ppm and 1.19 ppm had nOe with protons at 3.72 ppm.
This shows that the signal at 3.72 ppm should be due to the H2a proton. The double
doublet at 4.15 ppm had strong nOe with the proton at 2.54 ppm. This revealed that
the signal at 2.54 ppm must be due to the H5e proton. In addition, the signal at
3.91 ppm had strong nOe with the proton signal at 2.54 ppm and weak nOe with the
proton signal at 3.21 ppm. Hence, the signal at 3.91 ppm must be due to methylene
proton of imidazolidine moiety. The signal at 3.21 ppm must be due to the H5a
proton. NH proton signal (11.80 ppm) of imidazolidine moiety had strong nOe with
methine proton signals at 2.54 and 3.21 ppm. This showed clearly that the NH and
CH2 protons of imidazolidine moiety must be very close to the methylene protons at
C-5 position of piperidone moiety. Therefore, with reference to HOMOCOSY and
NOESY correlations in compound 46, the assignments made for its ring and
substituent protons were confirmed. Hence, based on the obtained chemical shifts
and coupling constant values, normal chair conformation (Fig. 2) was proposed for
compound 56.
Experimental
General remarks
We used TLC to assess the reactions and the purity of the products. All the reported
melting points were taken in open capillaries and were uncorrected. IR spectra were
recorded in KBr (pellet forms) on a Thermo Nicolet-Avatar–330 FT-IR spectro-
photometer and noteworthy absorption values (cm-1) alone are listed. One-
dimensional 1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, on a Bruker AMX 400 NMR spectrometer using DMSO-d as solvent.
Two-dimensional HOMOCOSY and NOESY spectra were recorded at 500 MHz on
a Bruker DRX 500 NMR spectrometer using DMSO-d as solvent. The electron
123

Spectral characterization of novel bis heterocycles
1079
spray impact (ESI) positive (?ve) mass (MS) spectra were recorded on a Bruker
Daltonics LC–MS spectrometer. Satisfactory microanalysis was obtained on a Carlo
Erba 1106 CHN analyzer.
By adopting the literature precedent [2], 3-alkyl-2,6-diarylpiperidin-4-ones
16–30 and their thiosemicarbazones 31–45 were prepared.
Typical procedure for the synthesis of 3-(2,6-diphenylpiperidin-4-
ylideneamino)-2-thioxoimidazolidin-4-one 46
To a well-stirred solution of 2,6-diphenylpiperidin-4-one thiosemicarbazone 31
(5 mmol) and anhydrous sodium acetate (5 mmol) in 30 ml of ethanol, chloroethyl
acetate (5 mmol) in 15 ml of ethanol was added drop-wise through the addition funnel
for about 10 min. The reaction mixture was then refluxed further for 4 h. After
completion of the reaction, the reaction mixture was poured into ice cold water and the
solid mass was collected and recrystallized twice from ethanol to yield compound 46.
IR (KBr) (cm-1): 3400, 3306, 3060, 3029, 2980, 2896, 2797, 1728, 1635, 1598, 1215,
701, 758, 1041; 1H NMR (d ppm): 1.97–2.05 (m, 1H, H3a), 2.37–2.41 (dd, 1H, H3e,
J3e,3a = 13.64 Hz, J3e,2a = 2.96 Hz); 2.43–2.52 (m, 1H, H5a), 2.83 (s, 1H, NH of
piperidine), 3.62–3.66 (dd, H5e, J5e,5a = 2.96 Hz, J5e,6a = 13.52 Hz), 3.80 (s, 2H, CH2
of imidazolidine), 3.88–3.92 (dd, 1H, H2a, J2a,3e = 3.08 Hz, J2a,3a = 11.76 Hz),
4.15–4.19 (dd, 1H, H6a, J6a,5e = 3.20 Hz, J6a,5a = 11.88 Hz), 7.23–7.50 (m, 10H, Ar–
H’s), 11.78 (s, NH of imidazolidine); in the D2O exchanged 1H NMR spectrum, two
peaks at 2.83 ppm and 11.78 ppm, which resonances are due to NH of piperidine and
imidazolidine, respectively, disappeared; 13C NMR (d ppm): 29.6 C-3, 37.3 C-5, 43.6
CH2 of imidazolidine, 60.2 C-2, 61.1 C-6, 126.5–128.1 Ar–C’s, 144.0, 144.1 ipso-C,
163.1 C=N, 167.6 C=O, 173.8 C=S.
Compounds 47–60 were synthesized in a similar fashion.
3-(2,6-bis(4-fluorophenyl)piperidin-4-ylideneamino)-2-thioxoimidazolidin-
4-one 47
IR (KBr) (cm-1): 3430, 3317, 3076, 3030, 2956, 2924, 2854, 1717, 1641, 1604,
1092, 835, 733, 519; 1H NMR (d ppm): 1.98–2.05 (m, 1H, H3a), 2.39–2.44 (dd, 1H,
H3e, J3e,3a = 13.52 Hz, J3e,2a =2.96 Hz); 2.44–2.49 (m, 1H, H5a), 2.86 (s, 1H, NH of
piperidine), 3.51–3.55 (dd, 1H, H5e, J5e,5a = 2.96 Hz, J5e,6a =13.40 Hz), 3.77 (s, 2H,
CH2 of imidazolidine), 3.85–3.89 (dd, 1H, H2a, J2a,3e = 2.96 Hz, J2a,3a = 11.76 Hz),
4.16–4.20 (dd, 1H, H6a, J6a,5e = 3.32 Hz, J6a,5a = 11.96 Hz), 7.18–7.37 (m, 8H, Ar–
H’s), 11.81 (s, 1H, NH of imidazolidine); 13C NMR (d ppm): 30.1 C-3, 38.2 C-5,
43.4 CH2 of imidazolidine, 61.8 C-2, 62.9 C-6, 114.3–142.6 Ar–C’s, 142.9, 159.6
ipso-C, 162.0 C=N, 166.7 C=O, 173.7 C=S.
3-(2,6-bis(4-chlorophenyl)piperidin-4-ylideneamino)-2-thioxoimidazolidin-
4-one 48
IR (KBr) (cm-1): 3400, 3309, 3065, 3032, 2978, 2923, 2852, 1724, 1628, 1595,
1195, 1014, 826, 722, 676, 634; 1H NMR (d ppm): 1.98–2.05 (m, 1H, H3a),
123

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J. Thanusu et al.
2.38–2.42 (dd, 1H, H3e, J3e,3a =13.52 Hz, J3e,2a = 2.98 Hz); 2.43–2.48 (m, 1H, H5a),
2.79 (s, 1H, NH of piperidine), 3.52–3.56 (dd, 1H, H5e, J5e,5a = 3.08 Hz, J5e,6a
13.42 Hz), 3.78 (s, 2H, CH2 of imidazolidine), 3.87–3.91 (dd, 1H, H2a, J2a,3e = 3.08 Hz,
=
J
2a,3a = 11.76 Hz), 4.15–4.19 (dd, 1H, H6a, J6a,5e = 3.14 Hz, J6a,5a = 11.70 Hz), 7.30–7.58
(m, 8H, Ar–H’s), 11.79 (s, 1H, NH of imidazolidine); 13C NMR (d ppm): 30.0 C-3, 38.8
C-5, 43.5 CH2 of imidazolidine, 60.9 C-2, 61.2 C-6, 126.7–140.4 Ar–C’s, 144.7, 145.3
ipso-C, 163.1 C=N, 166.8 C=O, 173.5 C=S.
3-(2,6-bis(4-methoxyphenyl)piperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 49
IR (KBr) (cm-1): 3400, 3306, 3065, 3020, 2962, 2924, 2853, 1728, 1630, 1601,
1
1251, 1031, 830, 749, 527; H NMR (d ppm): 1.97–2.04 (m, 1H, H3a), 2.35–2.39
(dd, 1H, H3e, J3e,3a = 13.52 Hz, J3e,2a = 2.96 Hz); 2.43–2.50 (m, 1H, H5a), 2.89 (s,
1H, NH of piperidine), 3.48–3.53 (dd, 1H, H5e, J5e,5a = 3.16 Hz, J5e,6a = 13.40 Hz),
3.59 (s, 6H, OCH3 at the phenyl rings), 3.72 (s, 2H, CH2 of imidazolidine),
3.87–3.91 (dd, 1H, H2a, J2a,3e = 3.16 Hz, J2a,3a = 11.68 Hz), 4.13–4.17 (dd, 1H, H6a,
J
6a,5e = 3.08 Hz, J6a,5a = 11.68 Hz), 7.19–7.42 (m, 8H, Ar–H’s), 11.78 (s, 1H, NH of
imidazolidine); 13C NMR (d ppm): 30.1 C-3, 37.0 C-5, 43.1 CH2 of imidazolidine,
54.2 –OCH3 at the phenyl rings, 60.2 C-2, 61.1 C-6, 127.3–144.0 Ar–C’s, 144.1,
159.9, ipso-C, 162.3 C=N, 167.7 C=O, 173.8 C=S.
3-(2,6-dip-tolylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one 50
IR (KBr) (cm-1): 3403, 3308, 3063, 3018, 2960, 2921, 2850, 1727, 1631, 1600,
1249, 1023, 828, 742, 524; 1H NMR (d ppm): 1.97–2.05 (m, 1H, H3a), 2.18 (s, 6H,
CH3 at the phenyl rings), 2.34–2.38 (dd, 1H, H3e, J3e,3a = 13.50 Hz, J3e,2a
=
2.97 Hz); 2.45–2.52 (m, 1H, H5a), 2.84 (s, 1H, NH of piperidine), 3.49–3.52 (dd,
1H, H5e, J5e,5a = 3.14 Hz, J5e,6a = 13.42 Hz), 3.76 (s, 2H, CH2 of imidazolidine),
3.88–3.90 (dd, 1H, H2a, J2a,3e = 3.14 Hz, J2a,3a = 11.66 Hz), 4.14–4.18 (dd, 1H, H6a,
J
6a,5e = 3.07 Hz, J6a,5a = 11.66 Hz), 7.17–7.39 (m, 8H, Ar–H’s), 11.76 (s, 1H, NH of
imidazolidine); 13C NMR (d ppm): 22.2 –CH3 at the phenyl rings, 30.3 C-3, 37.2
C-5, 43.3 CH2 of imidazolidine, 60.1 C-2, 61.0 C-6, 127.1–143.9 Ar–C’s, 144.1,
147.2, ipso-C, 162.8 C=N, 167.5 C=O, 173.5 C=S.
3-(3-methyl-2,6-diphenylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one 51
IR (KBr) (cm-1): 3420, 3311, 3063, 3031, 2978, 2933, 1713, 1634, 1600, 1232,
1
755, 702; H NMR (d ppm): 0.77–0.79 (d, 3H, CH3 at C-3, JCH3,3a = 6.45 Hz),
2.05–2.11 (m, 1H, H5a), 2.55–2.59 (m, 1H, H3a), the signal for 1H, NH of
piperidine merged with water peak, 2.69–2.79 (m, 1H, H5e), 3.45–3.48 (d, 1H, H2a,
J2a,3a = 9.98 Hz), 3.54–3.58 (dd, 1H, H6a, J6a,5e = 2.50 Hz, J6a,5a = 12.95 Hz), 3.76
(s, 2H, CH2 of imidazolidine), 7.24–7.47 (m, 10H, Ar–H’s), 11.71 (s, NH
of imidazolidine); 13C NMR (d ppm): 11.9 –CH3 at C-3, 32.5 C-5, 37.3 C-3,
44.4 CH2 of imidazolidine, 60.4 C-6, 68.7 C-2, 126.5–128.1 Ar–C’s, 144.9, 144.0,
ipso-C, 163.1 C=N, 167.5 C=O, 173.8 C=S.
123

Spectral characterization of novel bis heterocycles
1081
3-(2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 52
IR (KBr) (cm-1): 3412, 3304, 3071, 3030, 2985, 2931, 2869, 1717, 1635, 1597,
1221, 1030, 535, 836, 766; 1H NMR (d ppm): 0.78–0.80 (d, 3H, CH3 at C-3, JCH3,3a
6.58 Hz), 2.07–2.09 (m, 1H, H5a), 2.54–2.59 (m, 1H, H3a), the signal for 1H, NH of
=
piperidine merged with water peak, 2.67–2.79 (m, 1H, H5e), 3.46–3.48 (d, 1H, H2a,
J
2a,3a = 10.61 Hz), 3.54–3.58 (dd, 1H, H6a, J6a,5e = 2.46 Hz, J6a,5a = 12.46 Hz), 3.78
(s, 2H, CH2 of imidazolidine), 7.12–7.51 (m, 8H, Ar–H’s), 11.72 (s, NH of
imidazolidine); 13C NMR (d ppm): 11.8 –CH3 at C-3, 32.5 C-5, 37.2 C-3, 44.5 CH2
of imidazolidine, 61.0 C-6, 67.7 C-2, 114.6–160.7 Ar–C’s, 162.4, 162.5, ipso-C,
163.4 C=N, 169.2 C=O, 173.9 C=S.
3-(2,6-bis(4-chlorophenyl)-3-methylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 53
IR (KBr) (cm-1): 3429, 3282, 3070, 3032, 2985, 2931, 1718, 1625, 1592, 1210,
1017, 897, 823; 1H NMR (d ppm): 0.77–0.79 (d, 3H, CH3 at C-3, JCH3,3a = 6.57 Hz),
2.01–2.07 (m, 1H, H5a), 2.53–2.57 (m, 1H, H3a), the signal for 1H, NH of piperidine
merged with water peak, 2.68–2.80 (m, 1H, H5e), 3.46–3.48 (d, 1H, H2a, J2a,3a
=
10.82 Hz), 3.54–3.58 (dd, 1H, H6a, J6a,5e =2.44 Hz, J6a,5a = 12.45 Hz), 3.90
(s, 2H, CH2 of imidazolidine), 7.37–7.49 (m, 8H, Ar–H’s), 11.74 (s, NH of
imidazolidine); 13C NMR (d ppm): 11.8 –CH3 at C-3, 31.8 C-5, 36.8 C-3, 44.3 CH2
of imidazolidine, 61.0 C-6, 67.7 C-2, 128.0–131.7 Ar–C’s, 141.8, 142.8 ipso-C,
160.8 C=N, 166.9 C=O, 171.5 C=S.
3-(2,6-bis(4-methoxyphenyl)-3-methylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 54
IR (KBr) (cm-1): 3426, 3286, 3080, 2981, 2927, 1722, 1627, 1594, 1200, 1025, 897,
812, 744, 527; 1H NMR (d ppm): 0.78–0.80 (d, 3H, CH3 at C-3, JCH3,3a = 6.45 Hz),
2.04–2.08 (m, 1H, H5a), 2.55–2.59 (m, 1H, H3a), the signal for 1H, NH of piperidine
merged with water peak, 2.69–2.79 (m, 1H, H5e), 3.46–3.48 (d, 1H, H2a, J2a,3a
=
10.72 Hz), 3.54–3.58 (dd, 1H, H6a, J6a,5e = 2.56 Hz, J6a,5a = 12.87 Hz), 3.28 (s, 6H,
OCH3 at the phenyl rings), 3.78 (s, 2H, CH2 of imidazolidine), 6.86–7.36 (m, 8H, Ar–
H’s), 11.82 (s, NH of imidazolidine); 13C NMR (d ppm): 11.9 –CH3 at C-3, 32.5 C-5,
37.3C-3,44.6CH2 ofimidazolidine, 54.9–OCH3 atthephenylrings, 60.5C-6,68.1C-2,
127.6–158.4 Ar–C’s, 160.5, 163.1 ipso-C, 166.9 C=N, 169.7 C=O, 173.9 C=S.
3-(3-methyl-2,6-dip-tolylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one 55
IR (KBr) (cm-1): 3441, 3312, 3229, 3060, 2971, 2931, 1727, 1634, 1607, 1247, 1031,
542, 833, 753; 1H NMR (d ppm): 0.78–0.80 (d, 3H, CH3 at C-3, JCH3,3a = 6.38 Hz),
2.01–2.07(m, 1H, H5a), 2.19(s, 6H, CH3 atthe phenylrings), 2.54–2.58(m, 1H, H3a), the
signal for 1H, NH of piperidine merged with water peak, 2.69–2.79 (m, 1H, H5e),
3.44–3.47 (d, 1H, H2a, J2a,3a = 10.85 Hz), 3.54–3.58 (dd, 1H, H6a, J6a,5e = 2.55 Hz,
123

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J. Thanusu et al.
J6a,5a = 12.89 Hz), 3.89 (s, 2H, CH2 of imidazolidine), 7.10–7.33 (m, 8H, Ar–H’s),
11.75 (s, NH of imidazolidine); 13C NMR (d ppm): 11.9 –CH3 at C-3, 20.6 –CH3 at the
phenyl rings, 32.5 C-5, 37.0 C-3, 44.5 CH2 of imidazolidine, 60.2 C-6, 68.4 C-2,
126.3–136.2 Ar–C’s, 139.9, 140.9 ipso-C, 166.8 C=N, 169.6 C=O, 171.5 C=S.
3-(3,3-dimethyl-2,6-diphenylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-
4-one 56
IR (KBr) (cm-1): 3496, 3307, 3060, 3027, 2973, 2926, 2852, 1719, 1625, 1206,
1
1028, 758, 703; H NMR (d ppm): 0.97 (s, 3H, CH3 at C-4), 1.19 (s, 3H, CH3 at
C-4), 2.52–2.56 (dd, 1H, H5e, J5e,5a = 13.96 Hz, J5e,6a = 3.64 Hz), 2.75 (s, 1H, H1);
3.18–3.25 (m, 1H, H5a), 3.72 (s, 1H, H2a), 3.91 (s, 2H, CH2 of imidazolidine),
4.13–4.18 (dd, 1H, H6a, J6a,5e = 3.64 Hz, J6a,5a = 14.44 Hz), 7.21–7.53 (m, 10H,
H
at C-4, 43.5 CH2 of imidazolidine, 46.4 C-5, 48.8 C-3, 61.0 C-6, 69.8 C-2,
126.5–140.3 Arom-C’s, 143.5, 144.2 ipso C’s, 163.1 C=N, 167.3 C=O, 173.8 C=S.
arom), 11.80 (s, 1H, NH of imidazolidine); 13C NMR (d ppm): 20.4, 20.8 two CH3
3-(2,6-bis(4-fluorophenyl)-3,3-dimethylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 57
IR (KBr) (cm-1): 3480, 3309, 3147, 3072, 2975, 2923, 1719, 1628, 1222, 836, 702,
1
656, 525; H NMR (d ppm): 0.96 (s, 3H, CH3 at C-4), 1.18 (s, 3H, CH3 at C-4),
2.53–2.58 (dd, 1H, H5e, J5e,5a = 13.80 Hz, J5e,6a = 3.60 Hz), 2.80 (s, 1H, H1);
3.19–3.27 (m, 1H, H5a), 3.78 (s, 1H, H2a), 3.92 (s, 2H, CH2 of imidazolidine),
4.15–4.19 (dd, 1H, H6a, J6a,5e = 3.60 Hz, J6a,5a = 14.44 Hz), 7.30–7.59 (m, 8H,
H
at C-4, 43.5 CH2 of imidazolidine, 46.4 C-5, 48.8 C-3, 61.0 C-6, 69.9 C-2,
113.9–140.4 Arom-C’s, 160.4, 160.6 ipso C’s, 163.3 C=N, 166.9 C=O, 173.8 C=S.
arom), 11.79 (s, 1H, NH of imidazolidine); 13C NMR (d ppm): 20.3, 20.7 two CH3
3-(2,6-bis(4-chlorophenyl)-3,3-dimethylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 58
IR (KBr) (cm-1): 3400, 3306, 3093, 3030, 2974, 2928, 2852, 1722, 1630, 1203,
1015, 827, 766, 523; 1H NMR (d ppm): 0.98 (s, 3H, CH3 at C-4), 1.28 (s, 3H, CH3 at
C-4), 2.54-2.58 (dd, 1H, H5e, J5e,5a = 13.92 Hz, J5e,6a = 3.64 Hz), 2.81 (s, 1H, H1);
3.18–3.25 (m, 1H, H5a), 3.77 (s, 1H, H2a), 3.94 (s, 2H, CH2 of imidazolidine),
4.16–4.21 (dd, 1H, H6a, J6a,5e = 3.64 Hz, J6a,5a = 14.48 Hz), 7.37–7.89 (m, 8H,
H
at C-4, 43.4 CH2 of imidazolidine, 46.0 C-5, 48.5 C-3, 61.4 C-6, 68.6 C-2,
113.4–139.2 Arom-C’s, 158.8, 159.2 ipso C’s, 163.2 C=N, 165.9 C=O, 173.5 C=S.
arom), 11.85 (s, 1H, NH of imidazolidine); 13C NMR (d ppm): 20.2, 20.8 two CH3
3-(2,6-bis(4-methoxyphenyl)-3,3-dimethylpiperidin-4-ylideneamino)-
2-thioxoimidazolidin-4-one 59
IR (KBr) (cm-1): 3448, 3317, 3098, 3027, 2976, 2924, 2861, 1702, 1626, 1211,
1028, 818, 747, 519; 1H NMR (d ppm): 0.98 (s, 3H, CH3 at C-4), 1.16 (s, 3H, CH3 at
123

Spectral characterization of novel bis heterocycles
1083
C-4), 2.54–2.58 (dd, 1H, H5e, J5e,5a = 13.94 Hz, J5e,6a = 3.66 Hz), 2.76 (s, 1H, H1);
3.19-3.25 (m, 1H, H5a), 3.56 (s, 6H, OCH3 at the phenyl rings),3.79 (s, 1H, H2a),
3.91 (s, 2H, CH2 of imidazolidine), 4.17–4.22 (dd, 1H, H6a, J6a,5e = 3.66 Hz, J6a,5a
=
14.50 Hz), 7.19–7.76 (m, 8H, Harom), 11.79 (s, 1H, NH of imidazolidine); 13C NMR
(d ppm): 20.3, 20.7 two CH3 at C-4, 43.5 CH2 of imidazolidine, 46.5 C-5, 48.9 C-3,
54.0 –OCH3 at the phenyl rings, 61.0 C-6, 68.2 C-2, 126.4–141.1 Arom-C’s, 141.3,
142.2 ipso C’s, 163.1 C=N, 166.8 C=O, 173.8 C=S.
3-(3,3-dimethyl-2,6-dip-tolylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-
4-one 60
IR (KBr) (cm-1): 3450, 3318, 3093, 3022, 2974, 2925, 2864, 1705, 1628, 1209,
1023, 817, 749, 516; 1H NMR (d ppm): 0.99 (s, 3H, CH3 at C-4), 1.18 (s, 3H, CH3 at
C-4), 2.24 (s, 6H, CH3 of phenyl rings), 2.55–2.59 (dd, 1H, H5e, J5e,5a = 13.96 Hz,
J5e,6a = 3.68 Hz), 2.77 (s, 1H, H1); 3.19–3.26 (m, 1H, H5a), 3.80 (s, 1H, H2a), 3.92
(s, 2H, CH2 of imidazolidine), 4.18–4.23 (dd, 1H, H6a, J6a,5e = 3.68 Hz, J6a,5a
=
14.52 Hz), 7.21–7.80 (m, 8H, Harom), 11.80 (s, 1H, NH of imidazolidine); 13C NMR
(d ppm): 20.3, 20.7 two CH3 at C-4, 22.7 (–CH3 of phenyl rings), 43.5 CH2 of
imidazolidine, 46.5 C-5, 48.9 C-3, 61.0 C-6, 68.2 C-2, 126.4–141.1 Arom-C’s,
141.3, 142.2 ipso C’s, 163.1 C=N, 166.8 C=O, 173.8 C=S.
Acknowledgments The authors are thankful to NMR Research Centre, Indian Institute of Science,
Bangalore, for recording spectra. One of the authors, V. Kanagarajan, is grateful to the Council of
Scientific and Industrial Research (CSIR), New Delhi, India, for providing financial support in the form of
a CSIR-Senior Research Fellowship (SRF) in Organic Chemistry. Another author, J. Thanusu, is highly
thankful to Annamalai University authorities for providing a University Fellowship.
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