Stereoselective synthesis and spectral studies of some benzotriazolylacetyl hydrazones of 3–alkyl–2,6–diarylpiperidin–4–ones

Article abstract of DOI:10.1016/j.molstruc.2017.09.010

An effort to include biologically potent benzotriazole nucleus into piperidine ring is achieved through hydrazone formation. The characterization of the synthesized compounds was carried out using FT-IR, ¹H &¹³C NMR, ¹H–¹H COSY, ¹H–¹³C COSY, NOESY spectral techniques and GC-Mass spectrum. The spectral assignments were done without ambiguity using 2D-NMR techniques. The conformational preference of the piperidine ring deduced from the spectral studies is ‘chair’. The diastereotopic nature of the methylene protons/methyl groups present in the molecules is revealed clearly in their spectral pattern observed.

Full text of DOI:10.1016/j.molstruc.2017.09.010

Accepted Manuscript
Stereoselective synthesis and spectral studies of some benzotriazolylacetyl
hydrazones of 3–alkyl–2,6–diarylpiperidin–4–ones
M. Velayutham Pillai, K. Rajeswari, C. Udhaya Kumar, K. Gokula Krishnan, S.
Mahendran, C. Ramalingan, E.R. Nagarajan, T. Vidhyasagar
PII:
S0022-2860(17)31187-0
10.1016/j.molstruc.2017.09.010
MOLSTR 24259
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 29 June 2017
Revised Date: 1 September 2017
Accepted Date: 6 September 2017
Please cite this article as: M.V. Pillai, K. Rajeswari, C.U. Kumar, K.G. Krishnan, S. Mahendran, C.
Ramalingan, E.R. Nagarajan, T. Vidhyasagar, Stereoselective synthesis and spectral studies of some
benzotriazolylacetyl hydrazones of 3–alkyl–2,6–diarylpiperidin–4–ones, Journal of Molecular Structure
(2017), doi: 10.1016/j.molstruc.2017.09.010.
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ACCEPTED MANUSCRIPT
STEREOSELECTIVE SYNTHESIS AND SPECTRAL STUDIES OF SOME
BENZOTRIAZOLYLACETYL HYDRAZONES OF 3–ALKYL–2,6–
DIARYLPIPERIDIN–4–ONES
M. Velayutham Pillaia,b, K. Rajeswaria,c, C. Udhaya Kumarb, K. Gokula Krishnanb,
S. Mahendranb, C. Ramalinganb, E.R. Nagarajanb, T. Vidhyasagara*
* Corresponding author: E-mail id: tvschemau@gmail.com (T. Vidhyasagar)

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aDepartment of Chemistry, Annamalai University, Annamalai Nagar-608002, Tamil Nadu, India.
bDepartment of Chemistry, Kalasalingam University, Krishnankovil-626126, Tamil Nadu, India.
cDepartment of Chemistry, Government College for Women (Autonomous), Kumbakonam- 612001, Tamil Nadu,
India.
----------------------------------------------------------------------------------------------------------------
Graphical Abstract

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STEREOSELECTIVE SYNTHESIS AND SPECTRAL STUDIES OF SOME
BENZOTRIAZOLYLACETYL HYDRAZONES OF 3–ALKYL–2,6–
DIARYLPIPERIDIN–4–ONES
M. Velayutham Pillaia,b, K. Rajeswaria,c, C. Udhaya Kumarb, K. Gokula Krishnanb,
S. Mahendranb, C. Ramalinganb, E.R. Nagarajanb, , T. Vidhyasagara*
aDepartment of Chemistry, Annamalai University, Annamalai Nagar-608002, Tamil Nadu, India.
bDepartment of Chemistry, Kalasalingam University, Krishnankovil-626126, Tamil Nadu, India.
cDepartment of Chemistry, Government College for Women (Autonomous), Kumbakonam-
612001, Tamil Nadu, India.
Abstract
An effort to include biologically potent benzotriazole nucleus into piperidine ring is
achieved through hydrazone formation. The characterization of the synthesized compounds was
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carried out using FT-IR, H &13C NMR, H-1H COSY, H-13C COSY, NOESY spectral
techniques and GC-Mass spectrum. The spectral assignments were done without ambiguity using
2D-NMR techniques. The conformational preference of the piperidine ring deduced from the
spectral studies is ‘chair’. The diastereotopic nature of the methylene protons/methyl groups
present in the molecules is revealed clearly in their spectral pattern observed.
Key Words: Piperidin-4-one, benzotriazolyl acetichyrazide, 1D & 2D NMR spectra.
* Corresponding author: E-mail id: tvschemau@gmail.com (T. Vidhyasagar)
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1. Introduction
Functionalized piperidines and their derivatives are important pharmacophores which are
present in many pharmaceuticals [1]. Substituted piperidines particularly 2– and/or 2,6–
disubstituted piperidines are synthetically important [2-20] as they exhibit wide spectrum of
biological activities [6]. Likewise 3,5–disubstituted piperidines are important fundamentally as
backbones for alkaloids, [21] high affinity agonists of human GABA–A receptors,[4b] farnesyl–
protein transferase inhibitors [23] and continue to be basic moieties in pharmaceutical research
and have been target molecules in organic synthesis [24–40].
4–Piperidone is an important derivative as well as an intermediate in the manufacture of
certain chemicals and pharmaceutical drugs [41-43] such as fentanyl, carfentanyl and
ramifentanyl. Further, compounds with 4–piperidone nucleus show desirable biological
properties viz. antiviral [44], antitumor [45], central nervous system stimulant [46], analgesic
[47], anticancer [48] and antimicrobial activity [49].
Hydrazones are having remarkable physiological and biological activities and also found
application as insecticides, anticoagulants, antitumor agents, antioxidants and plant growth
regulators [50-55]. Metal complexes formed from hydrazone ligands are having application in
non–liner optics, sensors, medicine etc [56]. Several anti–inflammatory, antinociceptive, and
antiplatelet active drugs contain hydrazone and acylhydrazone moieties as core pharmacophore
units in their structure [57].
Azoles are forming a crucial part in the history of heterocyclic chemistry and also been
used as synthons in synthetic organic chemistry. The growing interest in the research of azole
chemistry is pertaining to the versatility of azole groups in chemotherapeutical activity. Reports
are available about the benzotriazole derivatives which are potent in biological activity [58,59].
The role of benzotriazole derivatives as a precursor in organic syntheses [60,61],antiprotozoal
[62], antimicrobial [63], anticonvulsant, anti–inflammatory [64] and anti–tumor [65] agents has
been proven by several researchers. Having these facts in mind, we have designed and
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synthesized a new series of biologically significant compounds with piperidine and benzotriazole
moieties connected through potent hydrazone functionality. The structural elucidation of these
compounds has been done by 1-D and 2-D NMR spectral techniques and the data are interpreted.
2. Experimental
2.1 General
All the solvents used for recrystallization and thin layer chromatography were of
analytical grade and used without further purification. All reactions were monitored by thin layer
chromatography on silica gel precoated aluminum sheets (Type 60 GF254, Merck). All the final
compounds were purified by column chromatography with silica gel (100-200 mesh) and pet
ether: ethyl acetate eluent system in 95:5 % (v/v) ratio. The melting points were recorded in open
capillaries and are uncorrected. Elemental analysis of compounds have been carried out on a C,
H, N analyzer type 1180(Carlo-Erba) and the report is shown in Table S1. FT-IR spectra were
recorded on an AVATAR-330 FT-IR spectrometer (Thermo Nicolet) using KBr (pellet form).
Mass spectra were recorded on a Varian Saturn 2000 GC-MS/MS spectrometer using electron
impact technique. Samples were prepared by dissolving about 1 mg of compound in 5 mL of
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spectral grade methanol/acetone. H and C NMR spectra for all the compounds were recorded
at 400 MHz and 100 MHz, in a Bruker ULTRASHIELD 400 PLUS instrument, using deuterated
chloroform/deuterated DMSO as the solvent by taking about 10 mg and 50 mg of compound
1
respectively for recording H NMR and 13C NMR spectra. Tetramethylsilane (TMS) was used as
an internal reference for all NMR spectra, with chemical shifts reported in δ units (parts per
1
million) relative to the standard. H NMR splitting patterns are designated as singlet (s), broad
singlet (bs), doublet (d), doublet of doublet (dd), triplet (t) and multiplet (m). Coupling constants
are expressed in Hertz (Hz).
2.2 Synthesis of Benzotriazolyl hydrazones of 3–alkyl–2,6–diaryl piperidin–4–ones (25–38)
The parent compounds (1-11) were synthesized by Mannich condensation of aromatic
aldehydes, ketones and ammonium acetate in ethanol [66]. The benzotriazolyl acetic hydrazide
was prepared by following the procedure reported in the literature [67]. Further, compounds 1–3
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were methylated by methyl iodide in the presence of K2CO3 and acetone at refluxing conditions
(12-14).
The title compounds 15–28 were prepared as follows: A mixture of 3–alkyl–2,6–
diarylpiperidin–4–ones (2 mmol) and benzotriazolylacetic hydrazide (2mmol) in ethanol (10 mL)
was heated to reflux for 3–6 h. The progress of the reaction was monitored by TLC. After
completion of the reaction, the solid product separated on cooling was collected by filtration and
washed well with water (Scheme 1). Pure sample was obtained by recrystallization from 1:1
mixture of ethanol and ethyl acetate. Yield: 72 -87 %
3. Results and Discussion
A series of new benzotriazolylacetyl hydrazones of 3–alkyl–2,6–diarylpiperidin–4–ones
has been prepared (Scheme 1) in good to excellent yields by the condensation of
benzotriazolylacetic hydrazide with piperidin–4–ones. A higher degree of diastereoselectivity
(selective formation of E isomer) was achieved owing to the presence of alkyl substituent
adjacent to the carbonyl group which decides the orientation of the hydrazone moiety (–NH–N=)
as anti with respect to it. Therefore the diastereoselectivity of the reaction is ascertained as
substrate controlled. The numbering of carbon atoms in the compounds is shown in Fig.1 and the
protons are numbered accordingly. The newly synthesized hydrazones were characterized by IR,
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Mass, H NMR, C NMR, H–1H COSY, H–13C COSY and NOESY spectral techniques. The
signals in the 1H NMR spectra are assigned based on their chemical shift values, splitting pattern,
coupling constants and correlations in the 2–D NMR spectra for compound 16 and for other
compounds the signals were assigned by comparing chemical shift values of them with the
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1
former. The H–1H COSY and H–13C COSY unraveled the problems during assignment of the
signals in 1H and 13C NMR spectra.
3.1 Spectral Characterization and Analysis
3.1.1 Analysis of IR and Mass spectra
Infrared spectra of the synthesized compounds exhibited significant absorptions
pertaining to the functional groups present such as imino (C=N), carbonyl (C=O), and the
absorption frequencies (in cm–1) are presented in Table 1. Mass spectrum of compound 25 has
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shown (M+H)+ value = 439.40. FT–IR and LC–Mass spectra of the synthesized compounds are
shown through Fig. S1 - S15.
3.1.2 Analysis of 1H NMR spectra
The 1H NMR spectra of compounds 15–28 are shown through Fig. S16 - S29. Among the
fourteen benzotriazolyl hydrazones synthesized, compound 16 is chosen as a representative to
discuss about the spectral features. The numbering scheme given to compound 16 and its
1
analogues is shown in Fig. 1. The H NMR spectral data of compounds 15 to 28 are listed in
Table 2.
1
In the H NMR spectrum of compound 16 (Fig. 2), the methyl protons of the C3–Et
group, NH proton of the piperidine ring, proton of the –CONH–moiety (H8) and aromatic
protons are observed at 0.89 (s), 1.85 (bs), 9.28 (s) and 7.32–7.47ppm(m). The methylene
protons of the C3–Et group are observed as separate signals at 1.31 (m) and 1.66 ppm (m) due to
their diastereotopic nature which is also evidenced from the cross peaks displayed between Me
protons and the methylene protons in the 1H–1H COSY spectrum (Fig. S30, Fig. 3 and Table 4).
Likewise, the resonance of H3a proton at 2.48ppm (m) is ascertained by the correlations among
this proton and the methylene protons previously described. Further, another cross peak
exhibited by H3 proton with the doublet at 3.65ppm (J =9.6 Hz) revealed that the latter one is
due to H2a proton.
The three protons H5a, H5e and H6a, forming an AMX spin system of coupling are
detectable at 2.12ppm (t, J =12.4 Hz), 2.84ppm (d, J =13.6 Hz) and 3.76ppm (d, J =12 Hz). The
diastereotopic methylene protons H10A and H10B, constituting an AB system of spin coupling
with second order spectral characteristics are observed in the deshielded portion of the spectrum
at 5.91 ppm (d, J =17.6 Hz) and 5.75 ppm (d, J =18.4 Hz) respectively. An isolated doublet
found in the aromatic region of the spectra at 8.05ppm (J =7.2 Hz) is identified as that belongs to
one of the proton of the benzotriazole nucleus (H4’) from the literature reports [68-70] available
for similar molecules.
3.1.3 Analysis of 13C NMR spectrum
The 13C NMR spectra of compounds 15–28 are displayed in Fig. S31 – S44 and Table 3
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enlists the C chemical shifts of the same. In the C NMR spectrum of compound 16 (Fig. 4),
the resonance of amido carbonyl carbon (C9) is observed at 167.6 ppm and the ipso carbons of
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the phenyl rings have shown their resonance at 142.2 ppm and 142.6 ppm respectively while the
resonance of imino carbon (C4) is observed at 156.2 ppm.
1
From the H–13C COSY spectrum of compound 16 (Fig. S45, Table 4 and Fig. 5), the
signal of methyl carbon of the C3–Et group is assigned based on its correlation with
corresponding protons at 12.0 ppm. Similarly, the methylene carbon atoms bearing
diastereotopic hydrogens at 3rd, 5th and 10th positions of the molecule are found to show cross
peaks with respective protons at 19.0, 36.0 and 49.2 ppm and thereby those signals are assigned
to them unambiguously. The C3, C6 and C2 carbons are also exhibited cross peaks at 52.0, 60.7
and 67.5 ppm respectively. In the aromatic region of the spectrum, the resonances observed at
109.7, 120.6, 123.9, 127.9, 133.9 and 146.0 are assigned to C7', C4', C5', C6', C7a' and C3a'
respectively based on the spectra data reported for similar compounds in the literature [68-70]
and correlations observed in the 1H–13C spectrum. All the aromatic carbons belong to aryl groups
at C2 and C6 carbons shown their signals between 126.5–155.9 ppm collectively.
3.1.4 Stereochemistry
In substituted piperidine derivatives, the relative stereochemistry of the
protons/substituents is determined conveniently by extracting coupling constants of the coupled
protons. The relationship between the magnitude of coupling constant and the dihedral angle is
given by Karplus equation and it applies well to these six membered cyclic systems. From that
relation we know that the magnitude of vicinal coupling constant exceeding 10 Hz indicates the
trans axial orientation of the coupled protons and thereby the equatorial orientation of the
substituents. The values less than 10 Hz represent axial–axial or axial–equatorial or equatorial–
equatorial relationship between the coupled protons.
In this case, the coupling between H2–H3 protons and H5–H6 protons are respectively
9.6 Hz (3J2a,3a) and 12 Hz (3J5a,6a). This observation supports a chair conformation for the
piperidine ring in which all the substituents i.e. phenyl and methyl groups are equatorially
oriented. Equatorial orientation of the bulky groups like phenyl provide stability to the molecule
than at axial positions because it avoids the 1,3–diaxial interaction among the axial groups.
As the molecule of study contains a double bond at C4 carbon, there arises the possibility
of existence of geometrical isomerism. The configuration about the C=N bond could be either Z
or E depending upon the relative orientation of the hydrazone moiety with respect to the C3–
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alkyl substituent. 13C NMR spectroscopy provides sufficient light regarding this matter in such a
way that the increased shielding of the carbon which lies syn to the hydrazone moiety reveals the
configuration. For compound 26, the chemical shift values of C5 and C3 carbons differ by about
16 ppm (δC5=52.0 ppm and δC3=36.0 ppm) indicating that the configuration as E with respect to
the C3–Et group.
The NOESY spectrum of compound 16 (Fig. S46, Table 4 and Fig.6), exhibits
correlation between methyl, methylene protons of the C3–Et group, H6a, piperidine NH and H2a
protons which are lying in the same side of the piperidine ring. The H10A and H10B protons
show cross peaks with methyl protons of the C3–Et group in the NOESY indicate their spatial
proximity with the C3–Et group. The H8 (CONH) proton is also found to be close with H5a and
H5e protons which reiterate the previous conclusion about the configuration.
4. Conclusion
A series of novel benzotriazolylacetyl hydrazones of 3–alkyl–2,6–diarylpiperidin–4–ones
1
1
were synthesized stereoselectively and characterized by IR, Mass, H NMR, 13C NMR, H–1H
COSY, 1H–13C COSY and NOESY spectra. The configuration of the molecules about the newly
formed imino bond and the preferred conformation of the heterocyclic ring were established
through 1H, 13C NMR NOESY and spectra.
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[65] A. Al Soud, N. A. Al Masoudi, A. R. S. Ferwanah, Bioorg. Med. Chem. 11 (2003) 1701.
[66] C.R. Noller, V. Baliah, J. Am. Chem. Soc., 70 (1948) 3853.
[67] K. C. Asati, S. K. Srivastava, S. D. Srivastava Indian J. Chem. 45B, (2006) 526.
[68] A. R. Katritzky, J. Wu, L. Wrobel, S. Rachwal, P. J. Steel, Acta Chem. Scand. 47 (1993)
167.
[69] A. R. Katrizky, N. G. Akhmedov, S. N. Denisenko, S. Perumal, Can. J. Chem. 79 (2001)
1655.
10

ACCEPTED MANUSCRIPT
[70] A. R. Katrizky, N. G. Akhmedov, I. Ghiviriga, O. V. Denisko, P. J. Steel, J. Phys. Org.
Chem. 16 (2003) 158.
11

ACCEPTED MANUSCRIPT
STEREOSELECTIVE SYNTHESIS AND SPECTRAL STUDIES OF SOME
BENZOTRIAZOLYLACETYL HYDRAZONES OF 3–ALKYL–2,6–
DIARYLPIPERIDIN–4–ONES
M. Velayutham Pillaia,b, K. Rajeswaria,c, C. Udhaya Kumarb, K. Gokula Krishnanb,
S. Mahendranb, C. Ramalinganb, E.R. Nagarajanb, T. Vidhyasagara*
a Department of Chemistry, Annamalai University, Annamalai Nagar-608002, Tamil Nadu, India.
b Department of Chemistry, Kalasalingam University, Krishnankovil-626126, Tamil Nadu, India.
c Department of Chemistry, Government College for Women (Autonomous), Kumbakonam- 612001,
Tamil Nadu, India.
----------------------------------------------------------------------------------------------------------------
Table Captions
Table 1 Significant IR absorption frequencies (cm–1) and (M+H)+ values of
compounds 15–28
1
Table 2 H chemical shifts, splitting pattern and coupling constant values of
compounds 15–28
Table 3 13C chemical shift values of compounds 15–28
Table 4 1H–1H COSY, 1H–13C COSY and NOESY correlations of compound 16
* Corresponding author: E-mail id: tvschemau@gmail.com (T. Vidhyasagar)
1

ACCEPTED MANUSCRIPT
Table 1 Significant IR absorption frequencies (cm–1) and (M+H)+ values of compounds 25–
38
Mass(Observed)
Compound
–NH– >C=O >C=N–
Others
––
(M+H)+
3199
3199
3207
3088
––
1694
1687
1682
1683
1684
1697
1688
1684
1683
1694
1690
1685
1687
1687
1599
––
439.40
15
16
17
18
19
20
21
22
23
24
25
26
27
28
––
––
––
––
––
––
––
––
––
–
1603
1613
1611
1615
1616
1618
1603
1615
––
–
––
1173 (C–O)
748 (C–Cl)
1354 (NO2)
738 (C–Cl)
1490 (C–F)
746 (C–Br)
1126 (C–O)
––
3199
3098
3108
3218
3201
––
––
––
––
––
3203
3208
1687
1599
1637
1627
––
––
2

ACCEPTED MANUSCRIPT
Table 2 1H chemical shifts, splitting pattern and coupling constant values of compounds 15–28
H10A &
Compound CONH
H6a
H2a
H5e
H3a
H5a
NH/NCH3
Others
H10B
5.84 (d)
J =17.6
Hz 5.75
(d)
2.17 (t)
J =13.6
Hz,
Signal
Merged
With HOD
signal
2.77 (d)
J =13.2 2.57 (m)
C3–Me 0.89 (d) J =5.2 Hz
Aromatic 8.01 (d) J =8 Hz,
7.19–7.44 (m)
8.74
3.82 (d)
J =11.2 Hz
3.50 (d)
J =10 Hz
15
(s)
Hz
J =17.2
Hz
12.4 Hz
5.91 (d)
J =17.6
Hz
5.75
(d)J
=18.4
Hz
5.80 (d)
J =17.2
Hz
5.88 (d)
J =18
Hz
C3–Me 0.89 (s)CHH 1.31
(m)CHH 1.66
(m)Aromatic7.32 (s)7.36
(d)J = 4.8 Hz7.47 (s)8.05
(d)J =7.2 Hz
2.12 (t)
J =12.4
Hz
3.65 (d)
J =9.6
Hz
2.84 (d)
J = 13.6 2.48 (m)
9.28
(s)
3.76 (d)
J =12 Hz
1.85 (bs)
1.82 (bs0
16
Hz
12 Hz
C3–Me 1.09 (s)C3–Me’
1.21 (s)Aromatic6.69 (d)J
=4 Hz7.04 (s)7.32–7.49
(m)7.58 (d)J =6.4 Hz8.06
(d)J =6.8 Hz
9.05
(s)
3.75 (s)
3.75 (s)
2.68 (d)
–––
2.31 (d)
17
C3–Me 0.94 (d)J =4.8 Hz
Aromatic ArCH3 2.33
(s)ArCH3’ 2.35 (s)7.13 (d)J
=7.2 Hz7.17 (d)J =6.8
Hz7.27 (d)J =9.2 Hz7.35
(d)J =7.2 Hz7.49 (s)8.07
(d)J =8 Hz
5.89 (d)
J =17.6
Hz
5.80 (d)
J =18
Hz
2.16 (t)
J =12.8
Hz J
3.50 (d)
J =10 Hz
2.79 (d)
J =14
Hz
8.94
(s)
3.79 (d)
J =11.6 Hz
2.58 (m)
1.97 (bs)
1.89 (bs)
18
=12.4 Hz
9.20
5.87 (d)
3.70 (d)
3.45 (d)
2.78 (d) 2.52 (m)
3
2.08 (t)
C3–Me 0.92 (d) J =5.2 Hz
19

ACCEPTED MANUSCRIPT
H10A &
H10B
Compound CONH
H6a
H2a
H5e
H3a
H5a
NH/NCH3
Others
(s)
J =17.6
Hz
5.77 (d)
J =17.6
Hz
J =11.6 Hz
J =10 Hz J =13.2
J =12.8
Hz
12.4 Hz
Aromatic
ArOCH3 3.79 (s) ArOCH3'
3.81 (s)
6.82 (d)J =7.2 Hz 6.89 (d) J
=7.2 Hz 7.25 (d) J =7.6 Hz
7.37 (d) J =6.8 Hz
Hz
7.47 (s) 8.05 (d) J =7.6 Hz
2.59 (m)
Merged
with
solvent
signal
2.03 (bs)
Merged
with NH
signal
2.03 (bs)
Merged
with H5a
signal
C3–Me 0.96 (s)
Aromatic
7.28 (s) 7.47 (s) 7.73 (s)
7.99 (s)
4.30 (bs)
Merged with
H2a
4.30 (bs)
Merged
with H6a
9.97
(s)
5.80 (s)
3.21 (s)
2.99 (d)
20
C3–Me 0.93 (d) J =5.6 Hz
Aromatic
7.30 (s) 7.41 (d) J =8.4 Hz
7.52 J =6.4 Hz 7.59 (d) J
=7.2 Hz
7.75 (s) 7.85 (d) J =6.4 Hz
7.92 (d)
J =8 Hz 8.09 (d) 7.6 Hz
8.38 (s)
5.92 (d)
J =17.6
Hz
5.75 (d)
J =18
Hz
3.64 (d)
J =9.6
Hz
2.00 (t)
J =12.8
Hz
9.98
(s)
3.74 (d)
J =11.6 Hz
J =13.6 2.59 (m)
1.78 (bs)
21
Hz
12.4 Hz
C3–Me 0.93 (d) J =5.6 Hz
Aromatic
7.31 (d) J =8.4 Hz 7.35 (s)
7.39 (d)
J =6.8 Hz 7.45 (s) 7.49 (d) J
=7.6 Hz
7.58 (d) J =8 Hz 7.67 (s)
8.08 (d)
5.86 (d)
J =18.8
Hz
5.80 (d)
J =18
Hz
2.54 (m)
Merged
with
solvent
signal
2.06 (t)
J =13.2
Hz
10.9
(s)
3.91 (d)
J =11.2 Hz
3.56 (d)
J =10 Hz J =14 Hz
3.38 (d)
2.17 (bs)
22
12. 4 Hz
4

ACCEPTED MANUSCRIPT
H10A &
H10B
Compound CONH
H6a
H2a
H5e
H3a
H5a
NH/NCH3
Others
J =8 Hz
C3–Me 0.93 (d)J =4.8 Hz
Aromatic
6.99 (t) J =7.6 Hz 7.06 (t) J
=7.6 Hz
7.33 (s) 7.37 (s 7.44 (s) 7.49
(s)
5.89 (d)
J =18
Hz
5.789d)
J =17.2
Hz
2.81 (d)
J =13.6 2.53 (m) J =12.8
2.10 (t)
9.15
(s)
3.77 (d)
J =10.8 Hz
3.52 (d)
J =9.6 Hz
2.00 (bs)
23
Hz
Hz
8.06 (d) J =8 Hz
5.86 (d)
J =16.8
Hz
5.81 (d)
J =18
Hz
5.91 (s)
J =17.6
Hz
5.80 (d)
J =17.6
Hz
C3–Me 0.94 (d) J =4.8 Hz
Aromatic 7.41 (t) J =7.6 Hz
7 .46 (s )7.50 (d)
J =8 Hz 7.61 (d) J =8 Hz
7.85 (s)
2.53 (m)
Merged
with
solvent
signal
2.04 (t)
J =12.4
Hz
3.41 (d)
J =13.6
Hz
11.06
(s)
3.90 (d)
J =11.2 Hz
3.55 (d)
J =10 Hz
2.35 (bs)
1.90 (bs)
24
12 Hz
8.02 (d) J =7.2 Hz
C3–Me 0.98 (d)J =4.8 Hz
Aromatic
6.64 (s) 6.70 (s) 7.37 (s)
7.50 (s) 7.86 (s) 8.06 (d) J
=8 Hz
2.16 (t)
J =12.4
Hz
3.44 (d)
J =10.4
Hz
2.85 (d)
9.10
(s)
3.72
(bs)
J =13.2 2.57 (m)
25
Hz
12 Hz
5.82 (d)
J = 14.8
Hz
5.65 (d)
J =14.8
Hz
2.73 (bs) 2.66 (bs)
C3–Me 0.84 (s) Aromatic
7.27 (s)
7.39 (d) J =7.6 Hz 8.07 (d)
J =6.8 Hz
9.21
(s)
Merged
with H3a with H5e
signal signal
Merged
2.97 (bs)
2.81 (bs)
2.18 (bs)
1.68 (s)
26
5

ACCEPTED MANUSCRIPT
H10A &
H10B
Compound CONH
H6a
H2a
H5e
H3a
H5a
NH/NCH3
Others
CHH 1.20 (m) CHH 1.54
(m)
C3–Me 0.84 (s)
Aromatic7.2 (s)
7.30 (s) 7.38 (s) 7.40 (s)
7.49 (s)
5.84 (d)
J =16.4
Hz
2.89(m)
Merged
9.49
(s)
2.89(m)Merged
2.70 (d) 2.49 (m) 2.06 (bs)
1.62 (s)
27
5.58 (d) with H2a signal with H6a
J =17.6
signal
Hz
8.06 (d)J =7.6 Hz
5.90 (d)
J =18
Hz
5.81 (d)
J =18
Hz
3.09 (s)
Merged
with
H6a
signal
C3–Me 1.00 (s) C3–Me'
1.30 (s)
Aromatic 7.264–7.37 (m)
7.51 (s)
3.09 (s)
Merged with
H2a signal
8.85
(s)
2.63 (d)
J =14 Hz
2.50 (t)
J =10 Hz
–––
1.76 (s)
28
8.08 (d) J =6 Hz
6

ACCEPTED MANUSCRIPT
Table 3 13C chemical shift values of compounds 15–28
Compound
C2
C3
C4
C5
C6
C9
C10
Aromatic
Others
ipso 142.4,143.2
Others 109.9–133.9,145.7
ipso 142.2, 142.6
Others 109.7–133.9,146.0
ipso 140.0, 143.1
69.1
67.5
70.4
45.1
52.0
43.5
156.8
155.9
161.1
36.1
36.0
31.9
60.5
60.7
60.8
167.7
167.6
168.1
49.3
49.2
49.3
C3–Me 12.2
15
16
17
C3–Me 12.0
CH2 19.0
C3–Me 21.0
C3–Me’ 22.7
Others 109.8–133.9,146.0
ipso 139.3, 139.8
Others 109.7–137.6,
144.8, 146.0
C3–Me 21.1
Ar–Me 21.1
68.9
68.5
45.3
45.4
157.2
157.8
35.7
35.7
60.5
59.8
167.5
168.0
49.3
49.2
18
19
ipso 134.7, 135.1,
30 159.1, 159.2
Others 109.9–133.9,
144.8, 145.9
C3–Me 12.2
Ar–OCH3 55.2,
Ar–OCH3’ 55.3
ipso 139.3, 139.7
62.3
68.1
67.9
44.8
45.1
44.7
155.0
156.2
155.7
33.7
35.6
35.7
56.0
59.2
59.3
167.4
168.7
167.4
49.0
49.1
48.9
C3–Me 11.2
C3–Me 12.0
C3–Me 11.7
20
21
22
Others 109.7–133.2,145.2
ipso 148.2, 148.4,144.4, 144.6
Others 109.6–144.3,145.7
ipso 141.2, 141.4
Others 109.6–133.5
ipso 138.0, 138.4,
68.3
45.4
156.9
35.8
59.8
168.0
49.2
161.0, 161.2, 163.6
Others109.6–133.9, 146.0
ipso 141.6, 142.4
C3–Me 12.1
C3–Me 11.9
23
67.9
69.5
44.5
45.3
155.6
156.7
35.8
35.7
59.2
60.8
167.5
167.8
48.9
49.2
7
24
25
Others 110.1–133.6, 144.0, 145.1
ipso 153.2, 153.3, 137.4,
137.6,137.8, 138.4
C3–Me 12.2
ArOCH3 56.1,

ACCEPTED MANUSCRIPT
Others 103.4–133.9, 144.8, 146.0
ArOCH3' 56.2
C3–Me 12.4
N–Me 40.6
C3–Et Me 12.0
CH2 19.7
ipso 142.1, 143.2
Others 109.4–133.2, 145.0
77.1
75.6
44.3
51.8
155.5
155.4
36.0
36.3
68.5
68.7
167.1
167.9
48.6
49.1
26
27
ipso 142.2, 143.4
Others 110.0–133.9
N–Me 41.3
C3–Me 22.3
C3–Me' 23.6
N–Me 42.5
ipso 139.2, 143.8
Others 109.8–133.9,144.8,146.0
79.2
43.2
160.2
32.4
69.5
167.7
49.3
28
8

ACCEPTED MANUSCRIPT
Table 4 1H–1H COSY, 1H–13C COSY and NOESY correlations of compound 16
Correlations in the 1H– Correlations in the 1H–
1H chemical shifts
NOESY
correlations
1H COSY (1H chemical 13C COSY(13C chemical
in ppm
shifts in ppm)
shifts in ppm)
9.28 (CONH)
8.05 (H7')
––
––
1.85, 2.84
7.32–7.37
7.32–7.47
109.7
7.32–7.47
(Aromatic
8.05
120.1, 128.7
hydrogens)
5.91 & 5.75
(H10A & H10B)
5.75, 5.91
2.12, 2.84
2.48
49.2
60.7
67.4
36.0
52.0
36.0
––
0.89, 7.47
1.85, 2.12,
2.84,7.32–7.37
0.89, 1.31, 1.66,
1.85
2.12, 3.76, 7.32–
7.37, 9.28
0.89, 1.31, 1.66,
2.12, 3.65,7.47
2.48, 2.84, 3.76,
7.32–7.37
3.76, 7.32–7.37,
9.28
3.76 (H6a)
3.65 (H2a)
2.84 (H5e)
2.12, 3.76
1.31, 1.66, 3.65
2.84, 3.76
––
2.48 (H3a)
2.12 (H5a)
1.85 (NH)
0.89, 1.31, 2.48,
3.65
0.89, 1.66, 2.48,
3.65, 7.47
1.66 CHH (C3–Et)
1.31 CHH (C3–Et)
0.89, 1.31, 2.48
0.89, 1.66, 2.48
19.0
19.0
1.31, 1.66, 2.48,
3.65, 5.75, 5.91,
7.47
0.89 CH3 (C3–Et)
1.31, 1.66
12.0
9

ACCEPTED MANUSCRIPT
STEREOSELECTIVE SYNTHESIS AND SPECTRAL STUDIES OF SOME
BENZOTRIAZOLYLACETYL HYDRAZONES OF 3–ALKYL–2,6–
DIARYLPIPERIDIN–4–ONES
M. Velayutham Pillaia,b, K. Rajeswaria,c, C. Udhaya Kumarb, K. Gokula Krishnanb,
S. Mahendranb, C. Ramalinganb, E.R. Nagarajanb, T. Vidhyasagar*a
aDepartment of Chemistry, Annamalai University, Annamalai Nagar-608002, Tamil Nadu, India
bDepartment of Chemistry, Kalasalingam University, Krishnankovil-626126, Tamil Nadu, India.
cDepartment of Chemistry, Government College for Women (Autonomous), Kumbakonam- 612001,
Tamil Nadu, India.
--------------------------------------------------------------------------------------------------------
Figures and Scheme Captions
Fig.1 Numbering pattern followed for compounds 15–28 to explain NMR spectra
Fig. 2 1H NMR spectrum of compound 16
Fig. 3 1H-1H COSY spectral correlations of compound 16
Fig. 4 13C NMR spectrum of compound 16
Fig. 5 1H-13C COSY spectral correlations of compound 16
Fig. 6 NOESY spectral correlations of compound 16
Scheme 1 Synthetic scheme of benzotriazolylacetyl hydrazones 15–28
* Corresponding author: E-mail id: tvschemau@gmail.com (T. Vidhyasagar)

ACCEPTED MANUSCRIPT
Fig.1 Numbering pattern followed for compounds 15–28 to explain NMR spectra

ACCEPTED MANUSCRIPT
Fig. 2 1H NMR spectrum of compound 16

ACCEPTED MANUSCRIPT
Fig. 3 1H-1H COSY spectral correlations of compound 16

ACCEPTED MANUSCRIPT
Fig. 4 13C NMR spectrum of compound 16

ACCEPTED MANUSCRIPT
Fig. 5 1H-13C COSY spectral correlations of compound 16

ACCEPTED MANUSCRIPT
Fig. 6 NOESY spectral correlations of compound 16