Chemoselective synthesis and spectral studies of N-thiocyanatoacetyl derivatives of 3-alkyl-2,6-diarylpiperidin-4-ones

Article abstract of DOI:10.1080/10426507.2016.1149852

A series of N–thiocyanatoacetyl derivatives of 3–alkyl–2,6–diarylpiperidin–4–ones has been synthesized by the reaction between the N–chloroacetyl derivatives of the respective piperidin–4–ones and the ambident thiocyanate nucleophile. The synthesized compounds have been characterized through FT–IR,¹H,¹³C,¹H–¹H COSY,¹H–¹³C COSY and NOESY spectra. The spectral data reveal the conformational priority of the six-membered heterocyclic ring.

Full text of DOI:10.1080/10426507.2016.1149852

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Chemoselective Synthesis and Spectral
Studies of N–Thiocyanatoacetyl Derivatives of
3–Alkyl–2,6–Diarylpiperidin–4–Ones
M. Velayutham Pillai, K. Rajeswari, C. Udhaya Kumar, C. Ramalingan, A.
Manohar & T. Vidhyasagar
To cite this article: M. Velayutham Pillai, K. Rajeswari, C. Udhaya Kumar, C. Ramalingan,
A. Manohar & T. Vidhyasagar (2016): Chemoselective Synthesis and Spectral Studies of
N–Thiocyanatoacetyl Derivatives of 3–Alkyl–2,6–Diarylpiperidin–4–Ones, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2016.1149852
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1149852
Accepted author version posted online: 18
Feb 2016.
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Date: 21 February 2016, At: 18:00

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CHEMOSELECTIVE SYNTHESIS AND SPECTRAL STUDIES OF N--
THIOCYANATOACETYL DERIVATIVES OF 3--ALKYL--2,6--
DIARYLPIPERIDIN--4--ONES
M. Velayutham Pillaia,b, K. Rajeswaria, C. Udhaya Kumar a,b, C. Ramalinganb, A.
Manoharb, T. Vidhyasagara,*
aDepartment of Chemistry, Annamalai University, Annamalai Nagar--608 002, Tamil Nadu,
India.
bDepartment of Chemistry, Kalasalingam University, Krishnan Kovil--626 126, Tamil Nadu,
India.
*Corresponding author: E--mail: tvschemau@gmail.com; Tel.: +91 98944 45979
Abstract
A series of N--thiocyanatoacetyl derivatives of 3--alkyl--2,6--diarylpiperidin--4--ones has been
synthesized by the reaction between the N--chloroacetyl derivatives of the respective piperidin--
4--ones and the ambident thiocyanate nucleophile. The synthesized compounds have been
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characterized through FT--IR, H, C, H--1H COSY, H--13C COSY and NOESY spectra. The
spectral data reveal the conformational priority of the six membered heterocyclic ring.
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Key words
Chemoselective, piperidin--4--ones, thiocyanatoacetyl, NMR spectra, stereochemistry
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Introduction
The thiocyanate group is present in various anticancer natural products formed by the
deglycosylation of glucosinolates derived from cruciferous vegetables [1]. Further, this
functional group could be used as a masked mercapto group and as a precursor for sulphur
containing heterocycles whose role as pesticides [2,3] in agriculture is also significant
industrially. Other important applications of alkyl thiocyanates are biocidal [4], antiasthmatic [5],
vulcanization accelerators [6]. The synthetic applications of organic thiocyanates are exemplified
by their use in the synthesis of sulphur--containing compounds such as sulfides [7], cyano--
thiolated compounds [8], and nitriles (through desulphuration) [9]. Despite the above facts, it is
pertinent to note that thiocyanate moiety is present in some biologically active natural products
[10].
2--Chloroacetamides derived from a primary amine are widely used intermediates in
organic synthesis because they could be transformed to thiazoles by cyclization reaction with
ammonium or potassium thiocyanate. In the case of chloroacetamides derived from secondary
amines, no cyclization is possible upon reaction with thiocyanate salts; instead alkyl thiocyanates
are formed which are also functionally significant molecules with biological value.
Results and Discussion
Chemistry
N--chloroacetyl piperidin--4--ones subjected to thiocyanation using potassium
thiocyanate in acetonitrile as the solvent, in reflux conditions, yielded the title compounds. Here,
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there are two possibilities of attack by the triatomic fragment --SCN upon the substrate. The first
one is the displacement of chlorine atom by thiocyanate to give thiocyanato acetyl derivatives
and the second possibility is the reaction between enolizable ketone part of the substrate with the
thiocyanogen [(SCN)2] that could be formed from the thiocyanate salt to yield α--
ketothiocyantes. In this case, the second possibility is ruled out and chemoselectivity is achieved
due to the reactivity of the chloroacetyl moiety.
Among the solvents reported in the literature for thiocyanation viz. acetone, N,N'--
dimethylformamide and acetonitrile, the reaction was found to be smooth and better with
acetonitrile when heated under reflux for 3--6 h. The solid formed upon cooling to room
temperature was separated by filtration and recrystallization in ethanol--ethyl acetate mixture
(2:1 ratio) gave pure compound. The Scheme 1 illustrates the procedure for the synthesis of N--
thiocyanato acetyl piperidin--4--ones, 23--33.
Spectral Characterization and Analysis
Analysis of IR and Mass spectra
Infrared spectra of the synthesized compounds exhibited significant absorptions
pertaining to the functional groups present such as thiocyanate (SCN), ketone carbonyl (C = O),
amido carbonyl (CONH) and the absorption frequencies (cm--1) are presented in the experimental
section along with mass spectral data. FT--IR and GC--Mass spectra of the synthesized
compounds are available in the Supplemental materials (Figures S 1 -- S 12).
Analysis of 1H NMR spectra
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Among the different N--thiocyanatoacetyl derivatives of 3--alkyl--2,6--diarylpiperidin--4--one
(23--33) synthesized, compound 23 is taken as a representative to discuss the spectral features of
the compounds. The numbering scheme followed for discussion is shown through Figure 1. The
1H NMR and the 2--D correlation spectra of the synthesized compounds are given in the
1
supplemental materials (Figures S 13 -- S23 and Figure S35 -- S37) and the H chemical shift
values, splitting pattern and coupling constant values are listed in the experimental section.
In the 1H NMR spectrum of compound 23 (Figure 2), all the aromatic protons resonate in
between 7.03 ppm and 7.38 ppm. The protons of the C3--Me group are observable as a singlet at
1
0.98 ppm. The H--1H COSY spectrum reveals the correlation (Table 1) between the C3--Me
protons and H3 proton resonating at 3.02 ppm as a singlet. The methylene protons attached to C-
-5 carbon atom resonate separately at 3.76 (bs) and 3.96 ppm (d, 2J = 13.2 Hz) respectively. This
identification is based on the observation of cross peaks between these two protons in the 1H--1H
COSY spectrum. Further, it is known from the literatures [11] that in cyclohexane and related
saturated six membered cyclic systems, the equatorial protons are deshielded than axial protons
due to ring current effect. Therefore, the former signal is assigned for H5e proton and the latter
for H5a proton.
A doublet of doublets encompassing H3 proton observed around 3 ppm is identified as
the signal due to the diastereotopic protons H8A and H8B from the correlations between these two
in the 1H--1H COSY spectrum as well as their large coupling constant values (J >15 Hz) typical
for geminal coupling pattern. The remaining two broad singlets at 5.10 and 5.98 ppm
corresponding to one proton each are assigned to H2 and H6 protons based on the literature
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reports [12] available for similar compounds as there are no correlations exhibited by these
protons with their neighbours. The broadening of these signals is accounted by the ring flattening
caused due to the involvement of lone pair of electrons available on the nitrogen atom [13]. The
change in hybridization state of nitrogen atom from sp3 to sp2 is pronounced in the extent of
deshielding, broadening and weakening of the signals of the adjacent protons [14].
Analysis of 13C NMR spectra
The 13C NMR spectra of the synthesized compounds are given in the Supplemental Materials
(Figured S 24 -- S 34) and the spectral data of the same are shown in the experimental section.
13
In the C NMR spectrum of compound 23 (Figure 3), the resonance due to C4, C7, and C10
carbons are observed at 207.8, 167.9 and 112.2 ppm respectively. The ipso carbons of the phenyl
ring attached at C2 and C6 carbons showed their signals at 140.2 and 139.8 ppm while the
signals of remaining aromatic carbons are observed between 126.7 and 129.3 ppm.
1
From the observed correlations in the H--13C COSY spectrum (Figure 5 and Table 1) between
13
proton signals of C3--Me group and the C signal at 13.1 ppm, the latter is assigned to that of
13
1
methyl carbon at C3 carbon. The cross peaks correlating C signal at 40.1 ppm with H signals
at 3.76 and 3.96 ppm (due to H5a and H5e protons) provide sufficient support to assign the
signal to the former. Likewise, the 13C signal at 42.6 ppm correlating with the signals of
diastereotopic hydrogens of C8 (at 2.86 and 3.23 ppm) is assigned to C8 carbon. The resonance
of C3 carbon is ascertained as that one present at 46.3 ppm by the correlation observed in the 1H-
-13C COSY spectrum.
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The signals of C2 and C6 carbons of the piperidine ring are observed as broad and less intense at
63.2 and 54.7 ppm respectively. These carbons didn’t shown correlations with respective protons
1
in the H--13C COSY spectrum and the assignment is carried out with the help of previous
literature reports available for similar compounds [12, 13].
Stereochemistry
The compounds 23--33 contain a piperidine ring system with vicinal protons at C2--C3 and C5--
C6 part of the ring. It is generally possible to deduce the relative stereochemistry of the vicinally
coupled protons in conformationally rigid molecules like piperidines substituted with relatively
bulky groups. However, in this case the expected signal patterns of the H2 and H6 protons are
lost due to the puckering of piperidine ring due to amide formation. The signals of H2 and H6
protons are found as broad singlets against the expected doublet and doublet of doublet pattern.
In 1H--1H COSY and 1H--13C COSY spectra, no correlations were observed between H2 and H6
with their neighbours and attached carbons. So, deciding stereochemistry is only partial using
these spectral results and NOESY correlations observed helped in this regard for compound 23.
The NOESY correlations observed in compound 23 are shown in Figure 6 and Table 1. There are
significant correlations among C3--Me protons H3, H2, H6, H5e and also with one of the
diastereotopic protons at C8 carbon. Similarly correlation between H6 and H5a proton and
correlation between the latter one with H5e proton are observed. The correlation between the
H8A/H8B proton(s) and H6, H5a and H5e protons reveals the fact that the N--acyl moiety is
oriented in such a way that both C3--Me and N--C = O groups are lying in the same side of the
piperidine ring. The conformational preference of the molecule from the NOESY correlations
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could be deduced as twist boat as the flattening of the ring about the plane containing C2, C6 and
N atoms doesn’t allow the molecule to take a chair or boat form. The puckering caused due to
flattening prevents the coupling between H2 & H3 and H6 & H5 protons. The preferential
conformation of compounds 23--33 is as shown in Figure 6.
Experimental
Materials and methods
Procedure for recording FT--IR, 1H, 13C NMR and 2D--NMR spectra
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). FT--IR
spectra were recorded on an AVATAR--330 FT--IR spectrometer (Thermo Nicolet) using KBr
(pellet form). 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 the experimental section. Mass spectrum was recorded on a
Varian Saturn 2000 GC--MS/MS spectrometer using electron impact technique. Sample was
prepared by dissolving about 1 mg of compound in 5 mL of spectral grade methanol. 1H and 13C
NMR spectra for all the compounds were recorded at 400 MHz and 100 MHz, in a Bruker
ULTRASHIELD 400 PLUS instrument, using deuterated chloroform as the solvent by taking
about 10 mg and 50 mg of compound respectively for recording 1H NMR and 13C NMR spectra.
Tetramethylsilane (TMS) was used as an internal reference for all NMR spectra, with chemical
1
shifts reported in δ units (parts per million) relative to the standard. H NMR splitting patterns
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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).
Synthesis of N--thiocyanatoacetyl derivatives of 3--alkyl--2,6--diarylpiperidin--4--ones (23--33)
The parent compounds 3--alkyl--2,6--diarylpiperidin--4--ones, (1--11) were synthesized by the
Mannich condensation of aromatic aldehydes, ketones and ammonium acetate in ethanol. The
typical procedure involves the steps as given below: An ethanolic solution of ketone (0.1 mole),
aromatic aldehyde (0.2 mole) and ammonium acetate (0.1 mole) was heated to boiling and kept
aside for cooling. After cooling to the room temperature, an equal quantity of diethyl ether was
added followed by the addition of concentrated hydrochloric acid in drop wise to precipitate the
hydrochloride salt of the piperidin--4--ones. The solid thus formed was filtered and washed with
ethanol:ether mixture (2:1) to remove any impurities present. Hydrochloride salt of the piperidin-
-4--ones was made into a paste with acetone and aqueous ammonia added in drops to get the free
base in pure form as solid after diluting the solution with water.
The piperidin--4--ones (1--11) were further chloroacetylated with chloroacetyl chloride in
benzene medium using Et3N as the base following the literature report [15] to get N--
chloroacetyl derivatives of 3--alkyl--2,6--diarylpiperidin--4--ones, 12--22. The title compounds
3--alkyl--2,6--diaryl--1--(2--thiocyanatoacetyl)piperidin--4--ones, (23--33) were prepared as
follows: An equimolar mixture of N--chloroacetyl piperidin--4--one and potassium thiocyanate
in acetonitrile was heated to reflux for 3--6 h. The progress of the reaction was monitored by
TLC. After completion of the reaction, a solid formed after cooling of the reaction mixture to the
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room temperature was collected. This solid was washed with water and recrystallized from
ethanol--chloroform mixture to get the pure product.
The spectral and other physical data of the newly synthesized compounds are given below.
3--Methyl--2,6--diphenyl--1--(2--thiocyanatoacetyl)piperidin--4--one (23): Yellow solid;
Yield 79%; m. p.: 166°C; (KBr, cm1): 2154 (SCN), 1718 (C = O, Ketone), 1611 (C = O,
Amide); 1H NMR (400 MHz, CDCl3) δ: 5.10 (bs, H2), 3.02 (s, H3), 3.76 (bs, H5a), 3.96 (d, J =
13.2 Hz, H5e), 5.98 (bs, H6), 3.23 (d, J = 17.2 Hz, H8A), 2.86 (d, J = 16 Hz, H8B), 0.98 (s, C3--
Me), (7.03 (s), 7.30 (s), 7.37 (d, J = 7.2 Hz), (Aromatic)); 13C NMR (100 MHz, CDCl3) δ: 63.2
(C2), 46.3 (C3), 207.8 (C4), 42.6 (C5), 54.7 (C6), 167.9 (C7), 40.1 (C8), 112.2 (C9/C10), 139.8
& 140.2 (ipso), 126.7--129.3 (Aromatic), 13.1 (C3--Me); C, H, N Analysis: C = 69.20, H =
5.53, N = 7.69; Found: C = 69.19, H = 5.54, N = 7.67.
3--Ethyl--2,6--diphenyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 24: Pale yellow solid;
Yield 81%; m. p.: 159°C; (KBr, cm1): 2156 (SCN), 1713 (C = O, Ketone), 1608 (C = O,
1
Amide); H NMR (400 MHz, CDCl3) δ: 6.06 (bs, H2), 2.94 (s, H3), 3.76 (d, J = 8.8 Hz, H5a),
4.01 (d, J = 13.2 Hz, H5e), 5.35 (bs, H6), 3.03 (s, H8A), 2.70 (d, J = 14.8 Hz, H8B), 1.03 (s, C3--
Me), 1.64 (m, C3--CH2), (7.04 (s), 7.27 (s), 7.31 (s) (Aromatic)); 13C NMR (100 MHz, CDCl3)
δ: 57.3 (C2), 51.9 (C3), 207.9 (C4), 44.7 (C5), 168.0 (C7), 39.8 (C8), 112.1 (C9/C10), 140.0 &
140.4 (ipso), 126.2--129.5 (Aromatic), 22.8 (C3--CH2), 11.6 (C3--Me); C, H, N Analysis: C =
69.81, H = 5.86, N = 7.40; Found: C = 69.79, H = 5.87, N = 7.41.
3,5--Dimethyl--2,6--diphenyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 25: Pale yellow
solid; Yield 73%; m. p.: 157°C; (KBr, cm1): 2153 (SCN), 1714 (C = O, Ketone), 1613 (C = O,
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1
Amide); H NMR (400 MHz, CDCl3) δ: 5.33 (bs, H2, Merged with H3 signal), 3.88 (s, H3,
Merged with H2 signal), 3.88 (s, H5e, Merged with H3 signal), 5.33 (bs, H6, Merged with H2
signal), 3.17 (s, H8A), 3.17 (s, H8B), 1.08 (s, C3--Me), 1.09 (s, C5--Me) (7.12 (s), 7.34 (s),
(Aromatic)); 13C NMR (100 MHz, CDCl3) δ: 61.8 (C2), 45.3 (C3), 210.1 (C4), 40.1 (C5), 45.3
(C6), 168.1 (C7), 40.1 (C8), 112.2 (C9/C10), 140.0 & 140.6 (ipso), 127.0--129.3 (Aromatic),
14.3 (C3--Me & C5--Me); C, H, N Analysis: C = 69.81, H = 5.86, N = 7.40; Found: C = 69.82,
H = 5.84, N = 7.39.
3--Isopropyl--5--methyl--2,6--diphenyl--1--(2--thiocyanatoacetyl)piperidin--4--one,
26:
Yellow solid; Yield 77%; m. p.: 155°C; (KBr, cm1): 2152 (SCN), 1722 (C = O, Ketone), 1617
1
(C = O, Amide); H NMR (400 MHz, CDCl3) δ: 6.48 (bs, H2), 2.89 (dd, J = 8.4 Hz & 1.6 Hz
H3), 3.64 (bs, H5a), 4.09 (d, J = 14.4 Hz, H5e), 6.48 (bs, H6), 2.87 (dd, J = 17.2 Hz & 10.4 Hz
H8A), 2.68 (dd, J = 17.2 Hz & 4.8 Hz H8B), 2.07 (CH, m, C3--i Pr) 1.10 (s, CH3), (6.93 (s), 7.21
13
(s), 7.31 (m) (Aromatic)); C NMR (100 MHz, CDCl3) δ: 58.2 (C2), 54.6 (C3), 207.8 (C4),
45.5 (C5), 57.0 (C6), 167.8 (C7), 39.8 (C8), 112.1 (C9/C10), 140.3 (ipso), 125.9--129.5
(Aromatic), 28.9 (CH, C3--i Pr) 20.5 C3--i Pr--Me) 21.1 (C3 i Pr--Me'); C, H, N Analysis: C
= 70.38, H = 6.16, N = 7.14; Found: C = 70.37, H = 6.17, N = 7.13.
3,3--Dimethyl--2,6--diphenyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 27: Beige solid;
Yield 78%; m. p.: 160°C; (KBr, cm1): 2157 (SCN), 1715 (C = O, Ketone), 1636 (C = O,
Amide); 1H NMR (400 MHz, CDCl3) δ: 6.11 (s, H2), 3.50 (s, H5a), 4.06 (d, J = 14.4 Hz, H5e),
5.18 (s, H6), 3.05 (dd, J = 18 Hz & 11.2 Hz, H8A), 2.94 (dd, J = 18 Hz & 5.2 Hz, H8B), 1.35 (s,
C3--Me), 1.36 (s, C3--Me'), (6.64 (d, J = 4.8 Hz), 7.18 (s), 7.33 (s) (Aromatic)); 13C NMR (100
MHz, CDCl3) δ: 69.5 (C2), 47.3 (C3), 209.8 (C4), 47.2 (C5), 58.2 (C6), 167.4 (C7), 39.5 (C8),
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112.1 (C9/C10), 138.2 & 141.3 (ipso), 125.2--129.7 (Aromatic), 21.4 (C3--Me), 26.0 (C3--
Me'); C, H, N Analysis: C = 69.81, H = 5.86, N = 7.40; Found: C = 69.80, H = 5.85, N = 7.41.
3--Methyl--1--(2--thiocyanatoacetyl)--2,6--di--p--tolylpiperidin--4--one, 28: Beige solid;
Yield 73%; m. p.: 154°C; (KBr, cm1): 2156 (SCN), 1718 (C = O, Ketone), 1619 (C = O,
Amide); 1H NMR (400 MHz, CDCl3) δ: 5.98 (bs, H2), 3.00 (s, H3), 3.76 (bs, H5a), 3.94 (d, J =
13.6 Hz, H5e), 5.03 (bs, H6), 3.21 (d, J = 16.4 Hz, H8A), 2.82 (d, J = 16.8 Hz, H8B), 0.96 (s, C3-
-Me), (6.91 (s), 7.10 (d, J = 6.8 Hz), 7.17 (s), (Aromatic)), 2.32 (s, Ar--CH3), 2.36 (s, Ar--CH3);
13C NMR (100 MHz, CDCl3) δ: 63.1 (C2), 46.5 (C3), 208.1 (C4), 42.7 (C5), 53.9 (C6), 167.9
(C7), 40.3 (C8), 112.4 (C9/C10), 138.2 & 138.3 (ipso), 125.1--129.9 (Aromatic), 12.6 (C3--
'
Me), 21.0 (Ar--CH3), 21.1 (Ar--CH3 ); C, H, N Analysis: C = 70.38, H = 6.16, N = 7.14;
Found: C = 70.38, H = 6.17, N = 6.17.
2,6--Bis(4--methoxyphenyl)--3--methyl--1--(2--thiocyanatoacetyl)piperidin--4--one,
29:
Brown solid; Yield 70%; m. p.: 170°C; (KBr, cm1): 2155 (SCN), 1713 (C = O, Ketone), 1610
1
(C = O, Amide), 1181 (C--O); H NMR (400 MHz, CDCl3) δ: 6.03 (bs, H2), 2.99 (s, H3), 3.80
(d, J = 13.2 Hz, H5a), 3.98 (d, J = 12 Hz, H5e), 4.96 (bs, H6), 3.20 (d, J = 16.4 Hz, H8A), 2.84
(d, J = 14.4 Hz, H8B), 0.96 (s, C3--Me), (6.81 (d) J = 7.2 Hz), 6.89 d) J = 8 Hz), 7.16 (s),
'
13
(Aromatic)), 3.79 (Ar--OCH3), 3.82 (Ar--OCH3 ); C NMR (100 MHz, CDCl3) δ: 62.8 (C2),
46.6 (C3), 208.2 (C4), 42.6 (C5), 53.6 (C6), 167.8 (C7), 40.3 (C8), 112.5 (C9/C10), 131.9,
132.2, 159.3 & 159.4 (ipso), 113.9--129.9 (Aromatic), 12.9 (C3--Me), 55.3 (Ar--OCH3), 55.6
'
(Ar--OCH3 ); C, H, N Analysis: C = 65.07, H = 5.70, N = 6.60; Found: C = 65.08, H = 5.69, N
= 6.61.
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2,6--Bis(4--fluorophenyl)--3--methyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 30: Yellow
solid; Yield 76%; m. p.: 172°C; (KBr, cm1): 2157 (SCN), 1713 (C = O, Ketone), 1611 (C = O,
Amide), 1227 (C--F); 1H NMR (400 MHz, CDCl3) δ: 5.96 (bs, H2), 2.96 (s, H3), 3.82 (bs, H5a),
3.99 (d, J = 12.4 Hz, H5e), 5.12 (bs, H6), 3.18 (d, J = 16.8 Hz, H8A), 2.90 (d, J = 18.4 Hz, H8B),
1.01 (s, C3--Me), (7.00 (s), 7.07 (s), 7.21 (s), (Aromatic)); 13C NMR (100 MHz, CDCl3) δ: 62.5
(C2), 46.5 (C3), 207.2 (C4), 42.5 (C5), 53.6 (C6), 167.7 (C7), 39.9 (C8), 112.0 (C9/C10),
135.6, 135.9, 161.1 & 163.6 (ipso), 116.2--129.2 (Aromatic), 13.2 (C3--Me); C, H, N Analysis:
C = 62.99, H = 4.53, N = 7.00; Found: C = 63.01, H = 4.54, N = 7.01.
2,6--Bis(4--bromophenyl)--3--methyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 31: Brown
solid; Yield 80%; m. p.: 168°C; (KBr, cm1): 2156 (SCN), 1720 (C = O, Ketone), 1638 (C = O,
1
Amide); H NMR (400 MHz, CDCl3) δ: 5.92 (bs, H2), 2.89 (d) Merged with H8 signal, H3),
3.83 (bs, H5a), 3.99 (d, J = 13.2 Hz, H5e), 5.08 (bs, H6), 3.16 (d, J = 18 Hz, H8A), 2.89 (d, J =
16.4 Hz, H8B), 0.99 (s, C3--Me), (6.90 (bs), 7.11 (bs), 7.44 (d, J = 7.2 Hz), 7.51 (d, J = 7.2 Hz),
(Aromatic)); 13C NMR (100 MHz, CDCl3) δ: 62.7 (C2), 46.3 (C3), 206.9 (C4), 42.0 (C5), 54.3
(C6), 167.8 (C7), 39.7 (C8), 112.1 (C9/C10), 138.7 & 138.9 (ipso), 122.6--132.5 (Aromatic),
13.1 (C3--Me); C, H, N Analysis: C = 48.30, H = 3.47, N = 5.36; Found: C = 48.28, H = 3.46,
N = 5.38.
2,6--Bis(2--chlorophenyl)--3--methyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 32: Brown
solid; Yield 78%; m. p.: 171°C; (KBr, cm1): 2151 (SCN), 1720 (C = O, Ketone), 1643 (C = O,
1
Amide), 755 (C--Cl); H NMR (400 MHz, CDCl3) δ: 6.03 (bs, H2), 3.06 (s, H3), 3.93 (d, J =
15.2 Hz, H5a), 4.09 (d, J = 15.2 Hz, H5e), 5.72 (s, H6), 3.12 (s, H8A), 3.01 (s, H8B), 1.17 (d, J =
4.8 Hz, C3--Me), (6.93 (d, J = 6.8 Hz), 7.18 (s), 7.28 (t, J = 7.2 Hz, 8.4 Hz), 7.46 (s),
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(Aromatic)); 13C NMR (100 MHz, CDCl3) δ: 59.0 (C2), 47.7 (C3), 207.6 (C4), 42.5 (C5), 53.1
(C6), 167.6 (C7), 39.0 (C8), 112.0 (C9/C10), 137.2 & 137.3 (ipso), 127.5--134.1 (Aromatic),
13.5 (C3--Me); C, H, N Analysis: C = 58.20, H = 4.19, N = 6.46; Found: C = 58.22, H = 4.18,
N = 6.44; Mass (M+H+) 433.07.
2,6--Bis(4--chlorophenyl)--3--methyl--1--(2--thiocyanatoacetyl)piperidin--4--one, 33: Brown
solid; Yield 78%; m. p.: 167°C; (KBr, cm1): 2155 (SCN), 1720 (C = O, Ketone), 1641 (C = O,
Amide); 1H NMR (400 MHz, CDCl3) δ: 5.93 (bs, H2), 2.89 (d, Merged with H8 signal H3), 3.81
(s, H5a), 3.98 (d, J = 14 Hz, H5e), 5.07 (bs, H6), 3.17 (d, J = 16.8 Hz, H8A), 2.89 (d, J = 18 Hz,
H8B), 1.00 (s, C3--Me), (6.97 (s), 7.17 (s), 7.29 (d, J = 6.8 Hz) 7.36 (d, J = 6.8 Hz) (Aromatic));
13C NMR (100 MHz, CDCl3) δ: 62.6 (C2), 46.3 (C3), 206.8 (C4), 42.1 (C5), 53.9 (C6), 167.7
(C7), 39.7 (C8), 111.9 (C9/C10), 138.1 & 138.4 (ipso), 128.1--134.7 (Aromatic), 13.1 (C3--
Me); C, H, N Analysis: C = 58.20, H = 4.19, N = 6.46; Found: C = 58.21, H = 4.20, N = 6.48.
Conclusion
A series of N--thiocyanatoacetyl derivatives of 3--alkyl--2,6--diarylpiperidin--4--ones were
synthesized by the reaction between N--chloroacetyl piperidones and potassium thiocyanate.
Replacement of the chlorine atom of the chloroacetyl moiety by the thiocyanate nucleophile took
place in a facile manner while using acetonitrile as the solvent. The synthesized compounds were
characterized by FT--IR, 1D and 2D NMR techniques and all the signals in the 1H and 13C NMR
spectra were unambiguously assigned. The stereochemistry of the substituents present in the
piperidone ring was found out and the conformational preference of the molecules in the solution
state is twist boat as evidenced from the 1H NMR and NOESY spectral analyses.
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1
1
Table 1 H--1H COSY, H--13C COSY and NOESY spectral correlations of compound
23
Correlations in the 1H-- Correlations in the 1H--
Correlations in the
NOESY (1H chemical
shifts in ppm)
1H chemical
shifts (ppm)
1H COSY (1H chemical
shifts in ppm)
13C COSY (13C
chemical shifts in ppm)
7.03, 7.30--
7.38
(Aromatic
Hydrogens)
0.98, 3.02, 3.23, 3.96,
5.10, 5.96
7.30--7.38, 7.03
126.7--129.3
5.98 (H6)
5.10 (H2)
----
----
----
----
2.86. 7.30--7.38
0.93, 3.96, 7.03
3.02, 3.76,5.10,
5.98,7.03, 7.30--7.38
3.96 (H5e)
3.76 (H5a)
3.76
40.1
3.96
2.86, 3.23
0.98
40.1
42.6
46.3
13.1
3.02, 3.96, 7.03
3.23 & 2.86
(H8A & H8B)
2.86, 3.23, 3.76,7.03--
7.38,5.98
3.02 (H3)
0.98, 7.03, 7.30--7.38
3.02, 3.96, 5.10,
5.98,7.03, 7.30--7.38
0.98 (C3--Me)
3.02
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Figure 1 Numbering pattern followed for compounds 23--33 to explain NMR spectra
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Figure 2 1H NMR spectrum of compound 23
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Figure 3 13C NMR spectrum of compound 23
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Figure 4 Selected 1H--1H COSY correlations of compound 23
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Figure 5 Selected 1H--13C COSY correlations of compound 23
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Figure 6 Selected NOESY spectral correlations and the preferred conformation of compound 23
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