Synthesis of highly substituted n-hydroxy piperidine via intramolecular reductive cyclization of 1-keto-5-ketoxime

Article abstract of DOI:10.1080/00397911.2011.614715

Diasteroselective synthesis of highly substituted N-hydroxypiperidine was achieved by an intramolecular reductive cyclization of monoxime (2) of the 1,5-diketone (1), generated from 2-(cyclohexylthio)-1-phenylethanone and arylaldehyde, using NaBH3 CN. The major product N-hydroxypiperidine (3) has been found to be racemate of a single diastereomer.

Full text of DOI:10.1080/00397911.2011.614715

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Synthesis of Highly Substituted N-
Hydroxy Piperidine via Intramolecular
Reductive Cyclization of 1-Keto-5-
ketoxime
Muthupandi Nagaraj a , Muthusamy Boominathan a , Ramaiyan
Manikannan a , Shanmugam Muthusubramanian a & Nattamai
Bhuvanesh b
a Department of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University, Madurai, India
b X-Ray Diffraction Laboratory, Department of Chemistry, A & M
University, College Station, Texas, USA
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Muthupandi Nagaraj , Muthusamy Boominathan , Ramaiyan Manikannan ,
Shanmugam Muthusubramanian & Nattamai Bhuvanesh (2013): Synthesis of Highly Substituted
N-Hydroxy Piperidine via Intramolecular Reductive Cyclization of 1-Keto-5-ketoxime, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:7, 930-940
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Synthetic Communications1, 43: 930–940, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.614715
SYNTHESIS OF HIGHLY SUBSTITUTED N-HYDROXY
PIPERIDINE VIA INTRAMOLECULAR REDUCTIVE
CYCLIZATION OF 1-KETO-5-KETOXIME
Muthupandi Nagaraj,1 Muthusamy Boominathan,1
Ramaiyan Manikannan,1 Shanmugam Muthusubramanian,1
and Nattamai Bhuvanesh2
1Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai, India
2X-Ray Diffraction Laboratory, Department of Chemistry, A & M University,
College Station, Texas, USA
GRAPHICAL ABSTRACT
Abstract Diasteroselective synthesis of highly substituted N-hydroxypiperidine was
achieved by an intramolecular reductive cyclization of monoxime (2) of the 1,5-diketone
(1), generated from 2-(cyclohexylthio)-1-phenylethanone and arylaldehyde, using
NaBH3CN. The major product N-hydroxypiperidine (3) has been found to be racemate
of a single diastereomer.
Keywords Intramolecular reductive cyclization; N-hydroxypiperidine; sodium
cyanoborohydride
INTRODUCTION
The substituted piperidines are core structures of many naturally occurring
alkaloids[1] and have attractive pharmacological activities such as antihypertensive,[2]
antibacterial,[3] antimalarial,[4] anticonvulsant, and anti-inflammatory activities.[5] For
example, over the past 10 years, thousands of piperidine-containing compounds have
been entered into preclinical and clinical trials.[6] Consequently, a huge amount of
effort has been directed toward developing ever more efficient methods to synthesize
them.[7] However, expensive and excess amounts of catalysts are some of the
Received July 11, 2011.
Address correspondence to Shanmugam Muthusubramanian, Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India. E-mail: muthumanian2001
@yahoo.com
930

HIGHLY SUBSTITUTED N-HYDROXY PIPERIDINE
931
disadvantages of these methods. Therefore, there is a need for an efficient diastero-
selective synthetic protocol to obtain these valuable compounds in good yields.
RESULTS AND DISCUSSION
We have recently reported the synthesis of various 2,4,6-triaryl-N-hydroxypiper-
idines and other related heterocycles via intramolecular reductive cyclization of dike-
toximes.[8] Such ring closure has been effected earlier also.[9] This approach is now
extended to the diasteroselective synthesis of highly substituted piperidine systems
from 1-keto-5-ketoximes originated from more branched ketones. 2-(Cyclohexylthio)
-1-arylethanone reacts with arylaldehyde in presence of alkali base and a phase
transfer catalyst to give the corresponding 1,5-diketone 1 (Scheme 1) following the pro-
cedure described earlier for a similar system.[8] The reaction yielded a single product
quantitatively and obviously the reaction is stereoselective.
The compound 1d exhibits three one-hydrogen signals at 4.10 (dd, 11.0 Hz &
5.4 Hz), 5.20 (d, 5.4 Hz), and 4.8 (d, 11.0 Hz) ppm. The 13C NMR spectrum has three
methine carbon signals at 47.0, 52.0, and 52.4 ppm and two carbonyl carbon signals
at 194.0 and 194.8 ppm. The stereochemistry of compound 1 obtained can be ascer-
tained as follows: Both A and B forms of 1 (Fig. 1) have internal mirror planes of
symmetry, and hence the hydrogens=cyclohexylthio groups attached to C-2 and
C-4 are enantiotopic and are expected to have identical chemical shifts in the
NMR spectrum. In the pair of enantiomers C and D, the hydrogens attached C-2
and C-4 are diasterotropic and hence become chemically nonequivalent. Thus com-
pound 1 obtained is the racemate C/D and not the meso forms A or B. Thus it is clear
that this reaction is stereoselective, giving only the racemate and not either of the
meso forms. The reason for the preferential formation of the racemate form of this
ketone over the meso forms is not clear. The ultimate evidence for the assigned struc-
ture for 1 comes from the crystal structure, and the single crystal X-ray analysis of
the ketone 1b (Fig. 2) has unambiguously revealed the correct stereochemistry.[10]
Recently a similar structural study on benzamarones has been reported.[11] It
must be mentioned that the formation of 1,5-diketones related to 1 from x-arylthio
substituted acetophenones, generated from aromatic thiols such as thiophenol,
Scheme 1. Preparation of 1,5-diketone 1 (a–d).

932
M. NAGARAJ ET AL.
Figure 1. Possible stereoisomers of 1.
2-mercacptobenzimidazole, and 2-mercaptobenzooxazole, is very difficult, the rea-
son for which is not clear. The ketone 1 (0.50 g, 9.0 mmol) was refluxed with excess
hydroxylamine hydrochloride (0.37 g, 54.0 mmol) and anhydrous sodium acetate
(0.44 g, 54.0 mmol) in ethanol for 2 h, but only a monooxime 2, as a single geometri-
cal isomer, was formed exclusively, probably due to steric hindrance. This monoxime
2 on treatment with sodium cyanoborohydride yields polysubstituted N-hydroxy
piperidine 3 (Scheme 2).
All the monoxime derivatives 2 give excellent yield of the product 3 and the
1
reactions were completed within 10–20 min (Table 1). The H NMR spectrum of
Figure 2. X-ray structure of 1b. (Figure is provided in color online.)

HIGHLY SUBSTITUTED N-HYDROXY PIPERIDINE
933
Scheme 2. Intramolecular reductive cyclization of 2a–d. (Figure is provided in color online.)
3d has all its heterocyclic ring hydrogens distinctly separated (a doublet at 4.26 ppm,
2.1 Hz; a doublet at 3.76 ppm, 10.2 Hz; a triplet at 3.42 ppm, 10.2 Hz; a doublet of
doublet at 3.24 ppm, 12.3 and 3.0 Hz; and a triplet at 2.76 ppm, 3.0 Hz). It is clear
that all the substitutents except one cyclohexylthio group occupy the equatorial posi-
tions in the resultant piperidine derivative. This is expected from the conformation of
the starting material, where the cyclohexylthio groups are to be trans to each other
and the reaction cannot bring out any change in the configurations of the carbons
bearing these groups and the intervening carbon. The structure of 3d was confirmed
by single-crystal X-ray analysis (Figs. 3 and 4).[12]
A trace amount of another compound 4, an isomer of 3, has also been noticed
in the crude NMR spectra of all the compunds, before purification to get 3. In one
case, 4d has been suceesfully separated. Compound 4d exhibits two sets of triplets
(2H, 2.85 ppm, J ¼ 10.5 Hz; 1H, 2.62 ppm, J ¼ 10.5 Hz) and a doublet (2H,
Table 1. Isolated yield and reaction time for the formation of 3
Entry
R1
R2
Yield (%)
Time (min)
3a
3b
3c
3d
H
H
H
Cl
H
88
83
80
86
15
15
20
10
Cl
Cl
Cl

934
M. NAGARAJ ET AL.
Figure 3. X-ray structure of 3d. (Figure is provided in color online.)
Figure 4. Configuration of the racemate 3. (Figure is provided in color online.)
3.73 ppm, J ¼ 10.5 Hz). It is unarguably assigned to the all equatorially substituted
N-hydroxypiperidine. The formation can be accounted for by the initial equili-
bration of the ketooxime by the base at the a -carbon, before getting cyclized. The
mechanism of formation of 3 and 4 from 2 is outlined in Scheme 3.

HIGHLY SUBSTITUTED N-HYDROXY PIPERIDINE
935
Scheme 3. Mechanism of formation of 3 and 4. (Figure is provided in color online.)
CONCLUSION
A simple methodology for diastereoselectively synthesizing, N-hydroxy
polysubstituted piperidine via intramolecular reductive cyclization of monooxime
of 1,5-diketones using sodium cyanoborohydride has been described. The correct
stereochemistry of the racemate 1 and that of the racemate 3 have been assigned
by NMR spectra and single-crystal X-ray data.
EXPERIMENTAL
Melting points were measured in open capillary tubes and are uncorrected. The
1H, 13C, and 2D NMR spectra were recorded on a Bruker (Avance) 300 MHz NMR
instrument using tetramethylsilane (TMS) as internal standard and CDCl3 as sol-
vent. Standard Bruker software was used throughout. Chemical shifts are given in
parts per million (d scale), and the coupling constants are given in hertz (Hz). Silica
gel G plates (Merck) were used for thin layer chromatographic (TLC) analysis with a
mixture of petroleum ether (60–80 ꢀC) and ethyl acetate as eluent. Elemental analyses
were performed on a Perkin-Elmer 2400 series II elemental CHNS analyzer. The
diketones 1a–d were prepared by grinding the corresponding aldehydes and
2-(cyclohexylthio)-1-phenylethanone in the presence of potassium hydroxide
(10 mol %) and tetrabutylammonium bromide (10 mol%) under solvent-free con-
ditions at room temperature.[8]

936
M. NAGARAJ ET AL.
Typical Experimental Procedure for the Reductive Cyclization of
Diketoxime with Sodium Cyanoborohydride[13]
Sodium cyanoborohydride (0.27 g, 43.7 mmole) and glacial acetic acid
(20.0 mL) in four portions were added to a suspension of ketooxime 2 (0.50 g,
8.75 mmol) in 5.0 mL of methanol with 3-min intervals, each time adjusting the
pH to 4 by adding glacial acetic acid with a trace of bromocresol green as indicator.
The reaction was monitored by TLC. After the completion of the reaction, the pH
was brought to 9 by 6 N potassium hydroxide solution. The reaction mixture was
then extracted with chloroform. The combined extracts were dried (anhydrous
sodium sulfate) and evaporated in vacuum. The individual compounds were isolated
by column chromatography using 1% ethyl acetate and petroleum ether.
Spectral and Analytical Data
2,4-Bis(cyclohexylthio)-1,3,5-triphenylpentane-1,5-dione (1a). Colorless
solid (82%); mp 156–158 ꢀC; IR (KBr) (c max=cmꢁ1): 1694 (C O), 790 (C-S);. H
1
=
NMR (300 MHz, CDCl3) dH: 0.97–1.26 (m, 12H, cyclohexyl H), 1.50–1.72 (m, 8H,
cyclohexyl H), 2.46 (bs, 1H, cyclohexyl CH), 2.72 (bs, 1H, cyclohexyl CH), 4.07
(dd, 1H, J ¼ 10.5 Hz, J ¼ 5.7 Hz, CH), 4.82 (d, 1H, J ¼ 10.5 Hz, CH), 5.17 (d, 1H,
J ¼ 5.7 Hz, CH), 7.12–7.26 (m, 6H, Ar-H), 7.32–7.36 (m, 5H, Ar-H), 7.63 (d, 2H,
J ¼ 8.7 Hz, Ar-H), 7.82 (d, 2H, J ¼ 8.4 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC:
25.2, 25.6, 26.0, 26.2, 33.7, 34.0, 34.5, 44.1, 46.9, 51.8, 52.1, 128.2, 128.8, 129.0
(2C), 129.2, 129.4, 129.7, 130.0, 130.4, 134.5, 136.5, 137.5, 194.0, 194.8.
3-(4-Chlorophenyl)-2,4-bis(cyclohexylthio)-1,5-diphenylpentane-1,5-
dione (1b). Colorless solid (78%); mp 173–175 ꢀC; IR (KBr) (c max=cmꢁ1): 1698
1
=
(C O), 782 (C-S); H NMR (300 MHz, CDCl3) dH: 1.02–1.27 (m, 12H, cyclohexyl
H), 1.53–1.76 (m, 8H, cyclohexyl H), 2.36 (bs, 1H, cyclohexyl CH), 2.62 (bs, 1H,
cyclohexyl CH), 4.13 (dd, 1H, J ¼ 10.8 Hz, J ¼ 5.2 Hz, CH), 4.80 (d, 1H, J ¼ 10.8 Hz,
Hz, CH), 5.22 (d, 1H, J ¼ 5.2 Hz, CH), 7.12–7.18 (m, 4H, Ar-H), 7.35 (d, 2H,
J ¼ 8.7 Hz, Ar-H), 7.37–7.39 (m, 2H, Ar-H), 7.47 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.76
(d, 2H, J ¼ 8.1 Hz, Ar-H), 7.94 (d, 2H, J ¼ 8.4 Hz, Ar-H); 13C NMR (75 MHz,
CDCl3) dC: 25.4, 25.9, 26.1, 26.3, 33.7, 34.2, 34.3, 44.2, 46.9, 51.9, 52.3, 128.2,
128.8, 129.0, 129.2, 129.4, 129.7, 130.0, 130.4, 134.5, 136.5, 138.2, 138.5, 194.2, 194.9.
1,5-Bis(4-chlorophenyl)-2,4-bis(cyclohexylthio)-3-phenylpentane-1,5-
dione (1c). Colorless solid (84%); mp 142–146 ꢀC; IR (KBr) (c max=cmꢁ1): 1697
1
=
(C O), 787 (C-S); H NMR (300 MHz, CDCl3) dH: 0.99–1.28 (m, 12H, cyclohexyl
H), 1.43–1.71 (m, 8H, cyclohexyl H), 2.42 (bs, 1H, cyclohexyl CH), 2.69 (bs, 1H,
cyclohexyl CH), 4.09 (dd, 1H, J ¼ 10.5 Hz, J ¼ 5.4 Hz, CH), 4.86 (d, 1H, J ¼ 10.5 Hz,
Hz, CH), 5.20 (d, 1H, J ¼ 5.4 Hz, CH), 7.09–7.21 (m, 5H, Ar-H), 7.35 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 7.47 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.76 (d, 2H, J ¼ 8.4 Hz, Ar-H),
7.94 (d, 2H, J ¼ 8.1 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 24.9, 25.1, 26.2
(2C), 33.4, 34.3, 34.5, 44.0, 46.7, 51.6, 52.1, 128.1, 128.7, 129.0, 129.1, 129.3,
129.9, 130.1, 130.2, 132.4, 134.2, 136.3, 139.5, 194.0, 194.3.

HIGHLY SUBSTITUTED N-HYDROXY PIPERIDINE
937
1,3,5-Tris(4-chlorophenyl)-2,4-bis(cyclohexylthio)pentane-1,5-dione (1d).
Colorless solid (76%); mp 152–156 ꢀC; IR (KBr) (c max=cmꢁ1): 1692 (C O), 778
=
(C-S);1H NMR (300 MHz, CDCl3) dH: 1.00–1.30 (m, 12H, cyclohexyl H),
1.53–1.80 (m, 8H, cyclohexyl H), 2.47 (bs, 1H, cyclohexyl CH), 2.74 (bs, 1H, cyclo-
hexyl CH), 4.10 (dd, 1H, J ¼ 10.8 Hz, J ¼ 5.7 Hz, CH), 4.86 (d, 1H, J ¼ 10.8 Hz, CH),
5.20 (d, 1H, J ¼ 5.7 Hz, CH), 7.12 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.15 (d, 2H, J ¼ 8.7 Hz,
Ar-H), 7.35 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.47 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.76 (d, 2H,
J ¼ 8.7 Hz, Ar-H), 7.94 (d, 2H, J ¼ 8.7 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC:
25.4, 25.9, 26.1 (2C), 33.7, 34.2, 34.3, 44.2, 46.9, 51.9, 52.3, 128.2, 128.8, 129.0,
129.2, 129.4 (2C), 129.7, 130.0, 130.4, 134.5, 136.5, 139.5, 194.0, 194.8.
2,4-Bis(cyclohexylthio)-5-(hydroxyimino)-1,3,5-triphenylpentan-1-one
(2a). Colorless solid (86%); mp 163–165 ꢀC; IR (KBr) (c max=cmꢁ1): 3298 (NOH),
1
=
=
1692 (C O), 1683 (C N), 933 (N-O), 790 (C-S); H NMR (300 MHz, CDCl3) dH:
0.96–1.15 (m, 6H, cyclohexyl H), 1.26–1.72 (m, 12H, cyclohexyl H), 1.86–2.12 (m,
2H, cyclohexyl H), 2.15 (bs, 1H, cyclohexyl CH), 2.56 (bs, 1H, cyclohexyl CH),
3.36 (dd, 1H, J ¼ 11.4 Hz, J ¼ 4.5 Hz, CH), 4.52 (d, 1H, J ¼ 11.4 Hz, CH), 5.14 (d,
1H, J ¼ 4.5 Hz, CH), 7.12–7.26 (m, 6H, Ar-H), 7.32–7.36 (m, 5H, Ar-H), 7.42 (d,
2H, J ¼ 8.7 Hz, Ar-H), 7.82 (d, 2H, J ¼ 8.4 Hz, Ar-H); 13C NMR (75 MHz, CDCl3)
dC: 25.0, 25.3, 26.2, 26.4, 33.9, 34.1, 34.5, 44.2, 46.2, 51.9, 52.2, 127.9, 128.6, 129.2,
129.5 (2C), 129.7, 129.9, 130.1, 130.3, 134.2, 136.0, 136.5, 154.3, 194.6.
3-(4-Chlorophenyl)-2,4-bis(cyclohexylthio)-5-(hydroxyimino)-1,5-
diphenylpentan-1-one (2b). Colorless solid (88%), mp 152–154 ꢀC, IR (KBr)
1
(c max=cmꢁ1): 3288 (NOH), 1696 (C O), 1680 (C N), 935 (N-O), 788 (C-S); H
NMR (300 MHz, CDCl3) dH: 0.95–1.12 (m, 6H, cyclohexyl H), 1.23–1.76 (m, 12H,
cyclohexyl H), 1.82–2.10 (m, 2H, cyclohexyl H), 2.16 (bs, 1H, cyclohexyl CH),
2.49 (bs, 1H, cyclohexyl CH), 3.42 (dd, 1H, J ¼ 10.8 Hz, J ¼ 4.2 Hz, CH), 4.48 (d,
1H, J ¼ 10.8 Hz, CH), 5.12 (d, 1H, J ¼ 4.2 Hz, CH), 7.09–7.16 (m, 4H, Ar-H), 7.25
(d, 2H, J ¼ 8.1 Hz, Ar-H), 7.29–7.32 (m, 2H, Ar-H), 7.41 (d, 2H, J ¼ 8.1 Hz,
Ar-H), 7.46 (d, 2H, J ¼ 7.2 Hz, Ar-H), 7.79 (d, 2H, J ¼ 7.5 Hz, Ar-H); 13C NMR
(75 MHz, CDCl3) dC: 25.2, 25.7, 26.2, 26.3, 33.7, 34.2, 34.4, 44.2, 46.9, 51.9, 52.1,
128.2, 128.8, 129.0, 129.2, 129.4, 129.7, 130.0, 130.4, 134.5, 136.5, 138.2, 138.5,
155.0, 194.9.
=
=
1,5-Bis(4-chlorophenyl)-2,4-bis(cyclohexylthio)-5-(hydroxyimino)-3-
phenylpentan-1-one (2c). Colorless solid (84%); mp 147–149 ꢀC; IR (KBr) (c
=
max
cmꢁ1): 3193 (NOH), 1699 (C O), 1678 (C N), 930 (N-O), 795 (C-S); H NMR
(300MHz, CDCl3) dH: 0.97–1.08 (m, 6H, cyclohexyl H), 1.23–1.71 (m, 12H, cyclohexyl
H), 1.78–2.03 (m, 2H, cyclohexyl H), 2.22 (bs, 1H, cyclohexyl CH), 2.42 (bs, 1H, cyclo-
hexyl CH), 3.52 (dd, 1H, J ¼ 10.5 Hz, J ¼ 5.4 Hz, CH), 4.46 (d, 1H, J ¼ 10.5 Hz, CH),
5.08 (d, 1H, J ¼ 5.4 Hz, CH), 7.10–7.18 (m, 5H, Ar-H), 7.28 (d, 2H, J ¼ 7.8 Hz,
Ar-H), 7.37 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.42 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.76 (d, 2H,
J ¼ 8.1 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 24.9, 25.2, 26.2, 26.7, 33.6, 34.1,
34.3, 44.2, 46.5, 51.4, 51.9, 128.1, 128.7, 129.0, 129.1, 129.3, 129.9, 130.1, 130.2,
132.4, 134.2, 136.3, 139.5, 154.9, 194.3.
1
=
=
1,3,5-Tris(4-chlorophenyl)-2,4-bis(cyclohexylthio)-5-(hydroxyimino)-
pentan-1-one (2d). Colorless solid; mp 138–140 ꢀC; IR (KBr) (c max=cmꢁ1): 3298

938
M. NAGARAJ ET AL.
=
=
(NOH), 1692 (C O), 1683 (C N), 933 (N-O), 790 (C-S). Calculated mass: 675.1;
found mass: 676.0.1H NMR (300 MHz, CDCl3) dH: 1.09–1.15 (m, 6H, cyclohexyl
H), 1.30–1.75 (m, 12H, cyclohexyl H), 1.95 (bs, 1H, cyclohexyl CH), 2.14 (bs, 1H,
cyclohexyl CH), 2.91–2.94 (m, 1H), 3.32 (dd, 1H, J ¼ 11.4 Hz, J ¼ 4.5 Hz, CH),
4.53 (d, 1H, J ¼ 11.4 Hz, CH), 5.17 (d, 1H, J ¼ 4.5 Hz, CH), 6.79 (d, 2H, J ¼ 7.8 Hz,
Hz, Ar-H), 6.91 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.15–7.19 (m, 4H, Ar-H), 7.44 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 7.89 (d, 2H, J ¼ 8.7 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC:
25.4, 25.8, 26.1, 33.4, 33.6, 34.2, 44.3, 44.7, 47.6, 51.9, 52.1, 127.8, 129.0, 129.4
(2C), 130.0, 131.4, 133.5 (2C), 134.2, 135.0, 135.2, 139.5, 155.8, 194.7.
3,5-Bis(cyclohexylthio)-2,4,6-triphenylpiperidin-1-ol (3a). Colorless solid;
¼ cmꢁ1): 3438 (NOH), 799 (C-S). Anal. calcd. for
mp 163–165 ꢀC; IR (KBr) (c
C35H43NOS2: C, 75.36; H, 7.77; N, 2.51; S, 11.50%. Found: C, 75.22; H, 7.59; N,
max
1
2.48; S, 11.42%. H NMR (300 MHz, CDCl3) dH: 0.35–0.38 (m, 1H, cyclohexyl
H), 0.62–0.95 (m, 9H, cyclohexyl H), 1.20–1.99 (m, 12H, cyclohexyl H), 2.74 (t,
1H, J ¼ 2.7 Hz, CH), 3.22 (dd, 1H, J ¼ 11.7 Hz, J ¼ 2.7 Hz, CH), 3.45 (td, 1H,
J ¼ 11.7 Hz, J ¼ 2.7 Hz, CH), 3.76 (d, 1H, J ¼ 11.7 Hz, CH), 4.32 (d, 1H, J ¼ 2.7 Hz,
Hz, CH), 4.54 (s, 1H, NOH), 7.21–7.27 (m, 6H, Ar-H), 7.35–7.41 (m, 5H, Ar-H),
7.48–7.51 (m, 4H, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 25.1, 25.3, 26.4, 32.5,
32.6, 33.7, 44.3, 46.2, 47.1, 53.4, 58.2, 74.7, 79.4, 127.7, 128.0, 129.7 (2C), 130.8,
132.4, 132.6, 133.3 (2C), 138.6, 138.8, 140.1.
4-(4-Chlorophenyl)-3,5-bis(cyclohexylthio)-2,6-diphenylpiperidin-1-ol
(3b). Colorless solid; mp 145–147 ꢀC; IR (KBr) (c
¼ cmꢁ1): 3442 (NOH), 787
max
(C-S). Anal. calcd. for C35H42ClNOS2: C, 70.97; H, 7.15; N, 2.36; S, 10.83%. Found:
C, 70.83; H, 7.23; N, 2.24; S, 10.72%. 1H NMR (300 MHz, CDCl3) dH: 0.36–0.39 (m,
1H, cyclohexyl H), 0.64–0.97 (m, 9H, cyclohexyl H), 1.22–2.01 (m, 12H, cyclohexyl
H), 2.76 (t, 1H, J ¼ 3.0 Hz, CH), 3.24 (dd, 1H, J ¼ 12.0 Hz, J ¼ 3.0 Hz, CH), 3.42 (td,
1H, J ¼ 12.0 Hz, J ¼ 3.0 Hz, CH), 3.76 (d, 1H, J ¼ 12.0 Hz, CH), 4.26 (d, 1H,
J ¼ 3.0 Hz, CH), 4.52 (s, 1H, NOH), 7.23–7.30 (m, 7H, Ar-H), 7.35 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 7.43 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.51–7.53 (m, 3H, Ar-H); 13C
NMR (75 MHz, CDCl3) dC: 25.0, 25.4, 26.1, 32.3, 32.4, 33.8, 44.1, 46.3, 47.3, 53.2,
58.0, 74.8, 79.2, 127.5, 128.2, 129.9 (2C), 130.9, 132.6, 132.8 (2C), 133.3, 138.5,
138.6, 140.2.
2,6-Bis(4-chlorophenyl)-3,5-bis(cyclohexylthio)-4-phenylpiperidin-1-ol
¼ cmꢁ1): 3427 (NOH), 789
(3c). Colorless solid; mp 138–140 ꢀC; IR (KBr) (c
(C-S). Anal. calcd. for C35H41Cl2NOS2: C, 67.07; H, 6.59; N, 2.23; S, 10.23%.
max
1
Found: C, 66.96; H, 6.48; N, 2.28; S, 10.12%. H NMR (300 MHz, CDCl3) dH:
0.34–0.41 (m, 1H, cyclohexyl H), 0.62–0.99 (m, 9H, cyclohexyl H), 1.19–1.94 (m,
12H, cyclohexyl H), 2.72 (t, 1H, J ¼ 3.3 Hz, CH), 3.27 (d, 1H, J ¼ 12.0 Hz, CH),
3.38 (t, 1H, J ¼ 12.0 Hz, CH), 3.82 (d, 1H, J ¼ 12.0 Hz, CH), 4.26 (d, 1H, J ¼ 3.3 Hz,
Hz, CH), 4.57 (s, 1H, NOH), 7.23–7.30 (m, 5H, Ar-H), 7.35 (d, 2H, J ¼ 7.8 Hz,
Ar-H), 7.43 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.51–7.53 (m, 4H, Ar-H); 13C NMR
(75 MHz, CDCl3) dC: 25.1, 25.3, 26.4, 32.4, 32.6, 33.9, 44.3, 46.2, 47.4, 53.3, 58.2,
74.9, 79.1, 127.2, 128.0, 129.7 (2C), 130.6, 132.5, 132.8, 133.3, 138.5 (2C), 139.6,
140.8.

HIGHLY SUBSTITUTED N-HYDROXY PIPERIDINE
939
2,4,6-Tris(4-chlorophenyl)-3,5-bis(cyclohexylthio)piperidin-1-ol
(3d).
Colorless solid; mp 176–178 ꢀC; IR (KBr) (c
Anal. calcd. for C35H40Cl3NOS2: C, 63.58; H, 6.10; N, 2.12; S, 9.70%. Found: C,
¼ cmꢁ1): 3427 (NOH), 782 (C-S).
max
1
63.42; H, 6.18; N, 2.16; S, 9.62%. Calculated mass: 661.2; found mass: 662.1. H
NMR (300 MHz, CDCl3) dH: 0.33–0.37 (m, 1H, cyclohexyl H), 0.61–0.92 (m, 13H,
cyclohexyl H), 0.96–1.24 (m, 6H, cyclohexyl H), 1.53–1.55 (m, 2H, cyclohexyl H),
2.80 (bs, 1H, CH), 3.27 (dd, 1H, J ¼ 12.0 Hz, J ¼ 2.7 Hz, CH), 3.50 (t, 1H,
J ¼ 12.0 Hz, CH), 3.81 (d, 1H, J ¼ 12.0 Hz, CH), 4.30 (bs, 1H, CH), 4.60 (s, 1H,
NOH), 7.19–7.33 (m, 8H, Ar-H), 7.50 (d, 2H, J ¼ 7.2 Hz, Ar-H), 7.61–7.63 (m,
2H, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 25.1, 25.5, 26.0, 32.4, 32.7, 33.8, 43.7,
46.2, 47.1, 53.1, 58.5, 75.4, 80.0, 127.0, 127.3, 127.4 (2C), 127.6, 128.1, 128.6,
131.0, 132.3, 138.9, 140.1, 141.8.
ACKNOWLEDGMENTS
The authors thank the Department of Science and Technology, New Delhi, for
assistance under the IRHPA program for providing funds for creating an NMR
facility. Financial support from the University Grants Commission, New Delhi,
and the council of Scientific and Industrial Research, New Delhi, is gratefully
acknowledged.
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