Synthesis of novel N-hydroxy heterocycles via intramolecular reductive cyclization of diketoximes by NaBH3CN

Article abstract of DOI:10.1039/c1ob05232b

A simple and efficient protocol for the construction of substituted piperazines, piperidines, thiomorpholines, decahydroquinolines, perhydrocyclopenta[b]pyridine, and pyrrolidines bearing N-hydroxy substituents through intramolecular reductive cyclization of diketoximes using sodium cyanoborohydride is described.

Full text of DOI:10.1039/c1ob05232b

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PAPER
Synthesis of novel N-hydroxy heterocycles via intramolecular reductive
cyclization of diketoximes by NaBH3CN†
Muthupandi Nagaraj,a Muthusamy Boominathan,a Shanmugam Muthusubramanian*a and
Nattamai Bhuvaneshb
Received 14th February 2011, Accepted 25th March 2011
DOI: 10.1039/c1ob05232b
A simple and efficient protocol for the construction of substituted piperazines, piperidines,
thiomorpholines, decahydroquinolines, perhydrocyclopenta[b]pyridine, and pyrrolidines bearing
N-hydroxy substituents through intramolecular reductive cyclization of diketoximes using sodium
cyanoborohydride is described.
ing nitrones which are useful for 1,3-dipolar cycloaddition.15 The
N-hydroxyl group could be deprotected by zinc dust in methanol
Introduction
and synthetic modifications can be achieved on the nitrogen.16
The thiomorpholine chemistry has been developed extensively
and thiomorpholine analogs are associated with a variety of phar-
macological activities including antimycobacterial, antimalarial,
analgesic, and anti-inflammatory activities.17 Thiomorpholines
serve as precursors for sulfur ylides useful in the asymmetric
epoxidation of aldehydes.18
Piperazine, piperidine, thiomorpholine, decahydroquinoline, and
pyrrolidine are important classes of nitrogen heterocycles having
outstanding biological properties and a wide range of applications
to pharmaceutical and synthetic intermediates. One of the privi-
leged scaffolds in medicinal chemistry is the piperazine unit, which
is found in many important drugs on the market. An examination
of 1000 orally administered drugs disclosed that 7% of them
contain a piperazine scaffold.1 Piperazine nuclei are found in a
range of biologically active compounds.2 The significant hurdle
in using piperazines as biological scaffolds is the difficulty in
introducing substituents on their carbon backbone, which restricts
SAR studies to substitution at the nitrogens.3 Syntheses of the
piperazine entity have been achieved by organometallic catalysis,4
reductive cyclization,5 and condensation reactions.6 Recently N-
Boc and N-OH protected piperazines have been prepared from
pyrazine N-oxides.7 Hulme’s UDC (Ugi/de-Boc/cyclize) sequence
leads to unsymmetrical diketopiperazines which can be reduced
to the corresponding piperazines.8 Recently chiral piperazine
scaffolds were obtained by ring opening of aziridines with amino
acids, followed by Fukuyama–Mitsunobu cyclization.9
About forty decahydroquinoline alkaloids have been isolated
from frog skin extracts. Decahydroquinolines were initially be-
lieved to be unique to amphibians until recently when two isomers
of this class were isolated in extracts of myrmicine ants.19 Recently
diverse synthetic strategies and methods have been developed to
access such motifs, and a variety of general, broadly applicable
approaches have emerged. Strategies that involve intramolecular
Diels–Alder reaction20 NIS promoted aminocyclization21 Beck-
mann rearrangements of tetrahydroindanones,22 [3,3]-sigmatropic
24
rearrangements,23 and biomimetic approaches have also been
put forward.
Cyanoborohydride25 is a versatile reducing agent for a variety
of organic functional groups, like carbonyls, oximes, enamines,
in addition to effecting reductive amination.26 NaBH3CN in
conjugation with Bu3SnCl effects radical reductive cyclisation
via demethoxylation,27 whilst the combination of NaBH3CN
and BF3 etherate reduces indole and acridine to their dihydro
derivatives.28 Very recently, primary amines have been synthesised
from aldehydes through reductive amination.29
The substituted piperidines are core structures of many
naturally occurring alkaloids10 and have attractive pharmaco-
logical activities.11 Thus, the synthesis of highly substituted
piperidines has gained considerable attention.12 Previously, N-
hydroxypiperidine and pyrrolidine13 were obtained by Michael
addition of bis a,b-unsaturated diesters with hydroxylamine. N-
Alkylhydroxylamine can be oxidized14 to furnish the correspond-
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj
Results and discussion
University, Madurai, 625 021, India. E-mail: muthumanian2001@yahoo.
com
A facile general synthetic protocol for the above mentioned
heterocycles bearing N-hydroxyl groups has been developed
and the results are described here. When substituted N-aryl-
N,N-diphenacylamine dioximes 1 were subjected to sodium
cyanoborohydride in the expectation of generating bis-N-
alkylhydroxylamines 2, interestingly, the reaction resulted in
bX-ray diffraction lab, Department of chemistry, A&M University, Texas,
TX, 77842, USA
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra. CCDC reference numbers 801741, 811676–811678. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05232b
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Scheme 1 Synthesis of 1-hydroxy-2,4,6-triarylpiperazine.
Table 1 Isolated yield and reaction time of 3 and 5
Entry
Product
R1
R2
Yield (%)
Time (min)
1
2
3
4
5
6
3a
3b
3c
3d
3e
5
H
H
H
OMe
Cl
H
86
82
87
86
81
78
20
15
20
25
30
25
OMe
CH3
OMe
OMe
—
—
intramolecular reductive cyclization furnishing a series of 1-
hydroxy-2,4,6-triarylpiperazines 3 (Scheme 1, Table 1) in excellent
yields (above 80%) and the reaction was completed within 15–
30 min. This reaction proceeds stereoselectively giving a single
isomer with all substituents oriented equatorially30 (Fig. 1). It is
pertinent to note that none of the existing strategies offers imme-
diate access to cis-2,6-disubstituted N-hydroxy-N¢-arylpiperazine.
Elsewhere, aldoximes were reduced under these conditions
to give dialkylhydroxylamine with primary alkyl substitution
adjacent to nitrogen, and normal ketoximes were reduced to N-
alkylhydroxylamines, as the major products.26a In the present case,
ketoximes yielded cyclic dialkylhydroxlamines with secondary
alkyl substitution adjacent to nitrogen, and these were given
exclusively. A plausible mechanism for the formation of 3 is shown
in Scheme 2, as proposed for the similar intermolecular reaction.26a
The scope of the above reaction was also investigated with
a tetraoxime of the type 4 (Scheme 3), which was obtained as
a single isomer by a reported procedure.31 The reaction of 4
with cyanoborohydride affords an interesting molecule with two
piperazyl units linked by a phenyl ring, 5. The 1H and 13C NMR
spectra of 5 confirm that the molecule is symmetrical (Scheme 3,
Table 1).
Fig. 1 Structure of 3a from X-ray analysis.
ethanone oxime 6. Further alkylation of 6 under these conditions
might have been blocked due to the monosubstituted derivative
preferring to exist in a cyclic form.
N-Hydroxypiperidine
After the generation of piperazine units, our attention turned to
the construction of 1-hydroxy-2,4,6-triarylpiperidine derivatives
from 1,3,5-triphenylpentane-1,5-dione. These ketones, inciden-
32
tally, were prepared by a modified literature method
from
acetophenone and aryl aldehyde with a catalytic amount of
tetrabutylammonium bromide and potassium hydroxide under
solvent free conditions. The oximes of these ketones 7, when
treated with cyanoborohydride, gave two diastereomers, 8 and 9 in
a 1 : 1 ratio (Scheme 4, Table 2). The H-4 appears as a broadened
In an attempt to synthesise an ortho analogue of 5, we
tried to prepare the tetraoxime from o-phenylenediamine and 4-
methoxy-a-bromoacetophenone oxime. This, however, resulted in
the formation of 2-(2-aminophenylamino)-1-(4-methoxyphenyl)
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Scheme 2 Mechanism for the formation of 3.
Table 2 Isolated yield and reaction time of 8, 9 and 11
Entry
Product
R
Yield (%)
Time (min)
1
2
3
4
5
6
7
8
9
8a : 9a
8b : 9b
8c : 9c
8d : 9d
11a
Phenyl
2-Pyridyl
4-Chloro-phenyl
1-Naphthyl
H
Cl
Br
Me
OMe
40 : 42
41 : 43
38 : 40
38 : 36a
87
86
86
20
25
30
30
15
10
10
15
20
11b
Fig. 2 Structure of 8b from X-ray analysis.
N-Hydroxydecahydroquinoline
11c
11d
85
84
11e
a Inseparable diastereoisomers.
In a similar manner, N-hydroxy 2,4,6-trisubstituted decahydro-
quinolines have also been prepared from the oximes of 2-(3-
oxo-1,3-diarylpropyl)cyclohexanone 12 (Scheme 6). This ketone
is diastereomerically almost pure with a trace of another isomer
as evidenced from the NMR spectrum. Upon oximation, however,
more geometrical isomers were obtained, the mixture of which
was subjected to reductive cyclisation. Though 2,4,6-trisubstituted
decahydroquinoline derivatives possess five stereogenic centers,
only four diastereoisomers, 13, 14, 15 and 16, were obtained.
Among them, cis-decahydroquinolines (13, 14 and 15) were
obtained predominantly, even though trans-decahydroquinoline
is expected to be thermodynamically more stable (Table 3). This
can be explained by the facts that (i) the cyclic oxime is reduced
preferentially due to internal strain relief and (ii) the attack of
hydride is favoured from the less hindered side of the ring.
singlet at 3.20 ppm in 8a, while it appears as a triplet of triplets
(J = 12.0 Hz, 3.0 Hz) at 3.01 ppm in 9a. The structure of 8b has
also been confirmed by single crystal analysis (Fig. 2).33
N-Hydroxythiomorpholine
This strategy was then extended to the synthesis of thiomorpho-
lines by employing dioximes of substituted diphenacyl sulfides 10.
This afforded 4-hydroxy-3e,5e-diaryl thiomorpholines 11 diastere-
oselectively (Scheme 5). The ring closure is relatively quicker in
these cases (Table 2).
Scheme 3 Synthesis of 4,4¢-(1,4-phenylene)bis(2,6-diphenylpiperazin-1-ol).
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Scheme 4 Synthesis of 1-hydroxy-2,4,6-triarylpiperidine.
Scheme 5 Synthesis of 4-hydroxy-3,5-diarylthiomorpholine.
Scheme 6 Synthesis of 2,4,6-trisubstituted decahydroquinoline.
Table 3 Isolated yield of decahydroquinoline derivatives
Entry
R1
R2
R3
13
14
15
16
a
b
c
Ph
Ph
Ph
4-Me-Ph
Ph
H
H
t-Bu
t-Bu
35
35
—
9
26
30
trace
—
5
15
12
21
22
4-Cl-Ph
4-Cl-Ph
Ph
—
35
36
d
The conformations of 13–16 have been assigned readily as it
is possible to identify the hydrogens at the ring junctions, those
adjacent to nitrogen and the benzylic hydrogens from one and two
dimensional NMR spectra in all these cases.
The signal of H-4 of 13 has two diaxial and one axial–equatorial
couplings (ddd, 12.6, 12.6 and 4.5 Hz) suggesting that H-4 and
H-4a are likely to be trans to each other. H-4a occurs as a
broadened doublet implying a cis relationship between H-4a and
H-8a. Similarly, H-8a also appeared as a broadened doublet. The
structure of 13a has been confirmed by X-ray crystallographic
study of a single crystal (Fig. 3).34
Fig. 3 Structure of 13a from X-ray analysis.
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Scheme 7 Synthesis of 4-(4-chlorophenyl)-2-phenyloctahydro-1H-cyclopenta[b]pyridin-1-ol.
In 14, H-4 has one diaxial and two axial–equatorial couplings
(ddd, 13.2, 3.9 and 3.9 Hz) which reveals that C4–H and C4a–H
are cis to each other. C4a–H appears as a multiplet, while C8a–H
appears as an apparent quartet with negligible coupling, revealing
that C4a–H and C8a–H are cis to each other. The structure 14b
has been confirmed by X-ray crystallographic study of a single
crystal (Fig. 4).35
cyclopentanone to chalcone, was treated with cyanoborohydride
to yield three isomers (18, 19 and 20) in almost equal amounts.
The three diastereoisomers were successfully separated by column
chromatography. The nature of the ring fusion and the stereochem-
istry around C2 and C4 (Scheme 7) could be established by one
and two dimensional NMR experiments. Related compounds have
been recently reported via reductive cyclization of mono oximes
using NaBH4.36
N-Hydroxypyrrolidine
The above reactions employ 1,5-diketones as the precursors.
Next, we were prompted to extend the application of this
methodology for the creation of heterocycles using 1,4-diketones.
Thus, the 1,4-dioxime 21 of dibenzoyl ethane was subjected to
sodium cyanoborohydride treatment. As expected, the reductive
cyclisation of 21 afforded an excellent yield of 2,5-diphenyl-N-
hydroxypyrrolidine 22 (Scheme 8), with the two aryl groups cis
to each other, as evidenced by their chemical equivalence in the
NMR spectrum.
Fig. 4 Structure of 14b from X-ray analysis.
It is interesting to find that the presence of a tert-butyl group at
the 6th position leads to the formation of 15 as the major product.
The C4–H has only one weak coupling in 15, pointing to the axial
orientation of the aryl at C-4. As C4a–H has only one diaxial
type coupling, it is inferred to be cis to C8a–H, which occurs
as an apparent quartet with a very small coupling. As C8a–H
is not found to have any axial–axial relationship with any of its
neighbouring hydrogens, the ring fusion is deduced to be cis as in
14.
Scheme 8 Synthesis of 2,5-diphenylpyrrolidin-1-ol.
An attempted oximation of the aromatic dialdehyde o-
phthalaldehyde by the treatment of hydroxylamine hydrochloride
and anhydrous sodium acetate yielded only 2-cyanobenzamide 23
exclusively and not the dioxime (Scheme 9).
The remaining isomer 16 needs to be necessarily a trans-
decahydroquinoline system. Relief of steric strain in isomer
16, compared to the situation in isomers 13–15, has led to
deshielding of the carbon nuclei and shielding of the protons at
the ring junction and at the benzylic center. However, the relative
stereochemistry at C2 and C4, with reference to the ring junctions,
could not be deduced unequivocally.
Scheme 9 Reaction of o-phthalaldehyde with hydroxylamine.
N-Hydroxyperhydrocyclopenta[b]pyridine
Similarly, efforts to obtain the 1,3-dioxime also proved difficult,
as this reaction always led to the formation of isoxazole 24. It
is pertinent to note that a typical 1,6-dioxime 25 of the ketone
generated by Friedel–Crafts acylation of benzene with adipoyl
Another bicyclic system comprising a cyclopentyl system fused to
a piperidine moiety has also been synthesised using this protocol.
The dioxime 17 of the ketone prepared by Michael addition of
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chloride failed to undergo reductive cyclisation even after 24 h
(Scheme 10).
Typical experimental procedure for the reductive cyclization of
diketoxime with sodium cyanoborohydride26a
To a suspension of diketoxime (2.7 mmol) in 5 ml of methanol
was added sodium cyanoborohydride (11.8 mmol) and glacial
acetic acid (20 mL) in four portions with three minute intervals,
each time adjusting the pH to 4 by adding glacial acetic acid
with 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 addition of 6 N potassium hydroxide solution.
The reaction mixture was then extracted with chloroform. The
combined extracts were dried (anhydrous sodium sulfate) and
evaporated in vacuo. The individual compounds were isolated by
column chromatography using 1% ethyl acetate and petroleum
ether.
Scheme 10 Other attempted reactions.
2,4,6-Triphenylpiperazin-1-ol (3a)
Colorless solid; mp 140–142 ◦C; IR (KBr) 3535, 3056, 3028, 2869,
2840, 1595, 1502, 1452, 1197, 743, 698 cm-1; 1H NMR (300 MHz,
CDCl3): d = 3.06 (dd, J = 12.0 Hz, 11.4 Hz, 2H), 3.75 (dd, J =
12.0 Hz, 3.0 Hz, 2H), 4.10 (dd, J = 11.4 Hz, 3.0 Hz, 2H), 4.59 (s,
1H), 6.86 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 7.2 Hz, 2H), 7.28 (t, J =
7.2 Hz, 2H), 7.32 (bt, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 4H),
7.56 (dd, J = 7.5 Hz, 1.2 Hz, 4H); 13C NMR (75 MHz, CDCl3): d =
56.6, 70.1, 116.0, 119.9, 127.6, 127.7, 128.6, 129.2, 140.4, 149.5;
Anal. Calcd. for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C,
79.83; H, 6.63; N, 8.38%.
All the above reactions, when carried out with sodium boro-
hydride instead of sodium cyanoborohydride, were found to
be ineffective giving only poor yields of the cyclised products,
despite prolonged reaction times. It should be mentioned that
Pradhan et al. have reported unusual reactions of steroidal and
non steroidal 1,5-dioximes with NaBH4.37 During the synthesis of
polyhydroxylated aza-heterocycles by double reductive amination
using NaBH3CN, in situ formation of oxime and subsequent
cyclization has been effected in a 1,4-dicarbonyl unit.38
Conclusions
4-(4-Methoxyphenyl)-2,6-diphenylpiperazin-1-ol (3b)
Colourless solid; mp 123–125 ◦C; IR (KBr) 3235, 3056, 1495,
1482, 1412, 1386, 1232, 1192, 740, 672 cm-1; Theoretical mass:
361.4; measured mass: 361.5 and 402.6 (acetonitrile adduct); H
NMR (300 MHz, CDCl3): d = 2.96 (dd, J = 12.1 Hz, 11.4 Hz, 2H),
3.56 (bd, J = 12.1 Hz, 2H), 3.72 (s, 3H), 4.10 (dd, J = 11.4 Hz,
3.0 Hz, 2H), 4.58 (s, 1H), 6.77 (d, J = 9.0 Hz, 2H), 6.84 (d, J =
9.0 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 4H),
7.53 (d, J = 7.2 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 55.5,
58.2, 70.33, 114.4, 118.2, 127.6, 127.7, 128.5, 140.5, 143.9, 153.9;
Anal. Calcd. for C23H24N2O2: C, 76.64; H, 6.71; N, 7.77. Found:
C, 76.53; H, 6.68; N, 7.69%.
A simple methodology for the synthesising N-hydroxy heterocy-
cles through intramolecular reductive cyclization of diketoximes
using sodium cyanoborohydride has been developed. The pro-
posed strategy of preparing heterocycles has advantages over other
methods, through the readily availability of the reagents and their
lowcost, itsprogressundertransitionmetal-freeconditions, andits
facile and expedient experimental procedure. Work is in progress
in our research group in expanding the substrate range to obtain
novel heterocycles with asymmetric induction.
1
Experimental section
Nuclear Magnetic Resonance (1H and 13C NMR) spectra were
recorded on a Bruker 300 MHz spectrometer in CDCl3 using
TMS as internal standard. Chemical shifts are reported in parts
per million (d), coupling constants (J values) are reported in
hertz (Hz). 13C NMR spectra were routinely run with broadband
decoupling. Infrared spectra were recorded on a Shimadzu FT-
IR instrument (in KBr pellets). Band positions are reported in
reciprocal centimetres (cm-1). Melting points were determined on
a melting point apparatus (Inlab Pvt Ltd, India) equipped with a
thermometer and were uncorrected. Column chromatography was
carried out on silica gel (60–120 mesh) using petroleum ether–ethyl
acetate as eluent. Elemental analyses were performed on a Perkin
Elmer 2400 series II Elemental CHNS analyzer.
2,6-Diphenyl-4-(4-methylphenyl)-piperazin-1-ol (3c)
Viscous liquid; IR (KBr) 3432, 2869, 2840, 1502, 1238, 1197, 722,
678 cm-1; 1H NMR (300 MHz, CDCl3): d = 2.25 (s, 3H), 2.96 (dd,
J = 12.3 Hz, 11.7 Hz, 2H), 3.64 (bd, J = 12.3 Hz, 2H), 4.05 (dd, J =
11.7 Hz, 2.8 Hz, 2H), 4.65 (bs, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.02
(d, J = 8.4 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 4H),
7.51 (d, J = 7.5 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 20.3,
57.1, 70.1, 116.3, 127.6, 128.1, 128.5, 129.4, 129.7, 140.5, 147.4;
Anal. Calcd. for C23H24N2O: C, 80.20; H, 7.02; N, 8.13. Found: C,
80.06; H, 7.14; N, 8.19%.
2,4,6-Tris-(4-methoxyphenyl)piperazin-1-ol (3d)
Substituted N-aryl-N,N-diphenacylamine dioximes 1a and 4
have been synthesized by a reported procedure while all other
Viscous liquid; IR (KBr) 3325, 3056, 2869, 2840, 1585, 1495, 1238,
31
1
1197, 722, 681 cm-1; H NMR (300 MHz, CDCl3): d = 2.94 (dd,
dioximes have been prepared by oximation of the corresponding
ketones.39
J = 12.0 Hz, 11.4 Hz, 2H), 3.54 (bd, J = 12.0 Hz, 2H), 3.74 (s, 3H),
3.86 (s, 6H), 4.05 (dd, J = 11.4 Hz, 2.4 Hz, 2H), 4.56 (s, 1H) 6.78
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(d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.4 Hz,
4H), 7.44 (d, J = 8.4 Hz, 4H); 13C NMR (75 MHz, CDCl3): d =
159.2, 154.0, 144.1, 132.7, 128.7, 118.2, 114.5, 113.9, 69.8, 58.2,
55.5, 55.3; Anal. Calcd. for C25H28N2O4: C, 71.41; H, 6.71; N, 6.66.
Found: C, 71.28; H, 6.59; N, 6.53%.
2e,4a,6e-Triphenylpiperidin-1-ol (8a)
Colorless solid; mp 183–185 ◦C; IR (KBr) 3221, 1498, 1427, 1089,
1047, 762, 701, 587 cm-1; 1H NMR (300 MHz, CDCl3): d = 2.28
(td, J = 12.0 Hz, 4.8 Hz, 2H), 2.42 (bd, J = 12.0 Hz, 2H), 3.20
(bs, 1H), 3.92 (bd, J = 12.0 Hz, 2H), 4.43 (s, 1H), 7.25 (d, J =
7.5 Hz, 2H), 7.33–7.40 (m, 9H), 7.46 (d, J = 6.9 Hz, 4H); 13C
NMR (75 MHz, CDCl3): d = 34.8, 39.3, 67.2, 126.9, 127.2, 128.5,
128.7, 128.9, 131.8, 140.8, 143.7; Anal. Calcd. for C23H23NO: C,
83.85; H, 7.04; N, 4.25. Found: C, 83.71; H, 7.11; N, 4.12%.
2,6-Bis(4-chlorophenyl)-4-(4-methoxyphenyl)piperazin-1-ol (3e)
Colorless solid; mp 154–156 ◦C; IR (KBr) 3335, 3056, 2859, 2820,
1498, 1228, 1187, 740, 698 cm-1; 1H NMR (300 MHz, CDCl3): d =
2.91 (dd, J = 12.3 Hz, 11.1 Hz, 2H), 3.53 (bd, J = 12.3 Hz, 2H),
3.77 (s, 3H), 4.08 (dd, J = 11.1 Hz, 2.7 Hz, 2H), 4.59 (bs, 1H), 6.78
(d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 7.2 Hz,
4H), 7.50 (d, J = 7.2 Hz, 4H); 13C NMR (75 MHz, CDCl3): d =
154.3, 143.7, 138.8, 133.4, 128.9, 128.7, 118.5, 114.6, 69.8, 58.1,
55.5; Anal. Calcd. for C23H22Cl2N2O2: C, 64.34; H, 5.16; N, 6.52.
Found: C, 64.19; H, 5.22; N, 6.48%.
2e,4e,6e-Triphenylpiperidin-1-ol (9a)
Colorless solid; mp 162–164 ◦C; IR (KBr) 3201, 1547, 1463, 1095,
756, 721, 621 cm-1; 1H NMR (300 MHz, CDCl3): d = 1.96 (q, J =
12.0 Hz, 2H), 2.13 (dd, J = 12.0 Hz, 3.0 Hz, 2H), 3.01 (tt, J =
12.0 Hz, 3.0 Hz, 1H), 3.93 (dd, J = 12.0 Hz, 3.0 Hz, 2H), 4.63 (s,
1H), 7.22 (dd, J = 7.2 Hz, 2.4 Hz, 2H), 7.26–7.28 (m, 5H), 7.36
(t, J = 8.1 Hz, 4H), 7.52 (dd, J = 8.1 Hz, 1.5 Hz, 4H); 13C NMR
(75 MHz, CDCl3): d = 41.9, 43.0, 72.1, 126.3, 126.6, 127.0, 127.1,
128.4, 128.5, 143.6, 144.2; Anal. Calcd. for C23H23NO: C, 83.85;
H, 7.04; N, 4.25. Found: C, 83.71; H, 7.12; N, 4.14%.
2-((4-(Bis(2-(hydroxyimino)-2-phenylethyl)amino)phenyl)(2-
(hydroxyimino)-2-phenylethyl)amino)-1-phenylethanone oxime (4)
Colorless solid; mp 162 ◦C; IR (KBr) 3335, 3215, 2859, 2820,
1625, 1567, 1366, 1228, 1187, 740, 698 cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 4.09 (s, 4H), 4.40 (s, 4H), 6.58 (s, 4H), 7.19 (d,
J = 7.5 Hz, 4H), 7.31 (m, 16H), 10.71 (s, 2H), 11.32 (s, 2H); 13C
NMR (75 MHz, DMSO-d6): d = 156.9; 153.3, 141.3, 140.6, 136.0,
133.6, 128.6, 128.4, 128.1,* 127.3 115.4, 55.4, 46.6; Anal. Calcd.
for C38H36N6O4: C, 71.23; H, 5.66; N, 13.12; Found: C, 71.09; H,
5.78; N, 13.03%. *Two carbons merged here.
2e,6e-Diphenyl-4a-(pyridin-2-yl)piperidin-1-ol (8b)
Colorless solid; mp 171–173 ◦C; IR (KBr) 3191, 1581, 1463, 1081,
1037, 763, 700, 549 cm-1; Theoretical mass: 331.4; measured mass:
1
331.25; H NMR (300 MHz, CDCl3): d = 2.24 (td, J = 12.6 Hz,
3.0 Hz, 2H), 2.61 (bd, J = 12.6 Hz, 2H), 3.25 (bs, 1H), 4.01 (dd,
J = 12.6 Hz, 3.0 Hz, 2H), 4.48 (s, 1H), 7.24 (td, J = 7.5 Hz, 2.4 Hz,
1H), 7.26 (bt, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hz, 4H), 7.41 (d, J =
7.5 Hz, 1H), 7.47 (dd, J = 8.4 Hz, 1.2 Hz, 4H), 7.70 (td, J = 7.5 Hz,
1.8 Hz, 1H), 8.65 (d, J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d = 38.1, 38.7, 67.5, 120.9, 121.8, 126.9, 127.1, 128.4, 136.2, 144.3,
149.3, 162.4; Anal. Calcd. for C22H22N2O: C, 79.97; H, 6.71; N,
8.48. Found: C, 79.84; H, 6.59; N, 8.35%.
4,4¢-(1,4-Phenylene)bis(2,6-diphenylpiperazin-1-ol) (5)
Colorless solid; mp 190–192 ◦C; IR (KBr) 3525, 3026, 3018, 2861,
2838, 1590, 1498, 1452, 1376, 1231, 1192, 741, 690 cm-1; Theo-
1
retical mass: 583.3; measured mass: 583.2; H NMR (300 MHz,
CDCl3): d = 2.95 (dd, J = 11.7 Hz, 11.4 Hz, 4H), 3.56 (bd, J =
11.7 Hz, 4H), 4.08 (dd, J = 11.4 Hz, 3.0 Hz, 4H), 4.53 (s, 2H), 6.81
(s, 4H), 7.28 (t, J = 7.2 Hz, 4H), 7.38 (t, J = 7.2 Hz, 8H), 7.53 (d,
J = 7.2 Hz, 8H); 13C NMR (75 MHz, CDCl3): d = 57.7, 70.3, 117.7,
127.6, 127.7, 128.6, 140.6, 143.8; Anal. Calcd. for C38H38N4O2: C,
78.32; H, 6.57; N, 9.61. Found: C, 78.18; H, 6.46; N, 9.57%.
2e,6e-Diphenyl-4e-(pyridin-2-yl)piperidin-1-ol (9b)
Colorless solid; mp 168–170 ◦C; IR (KBr) 3255, 1557, 1425, 1092,
758, 703, 563 cm-1; 1H NMR (300 MHz, CDCl3): d = 2.10 (q, J =
12.0 Hz, 2H), 2.21 (bd, J = 12.0 Hz, 2H), 3.15 (tt, J = 12.0 Hz,
3.0 Hz, 1H), 3.93 (dd, J = 12.0 Hz, 3.0 Hz, 2H), 4.56 (s, 1H), 7.16
(td, J = 7.2 Hz, 2.4 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.23 (bt,
J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 4H), 7.52 (dd, J = 7.5 Hz,
1.2 Hz, 4H), 7.63 (td, J = 7.2 Hz, 1.8 Hz, 1H), 8.45 (dd, J = 7.2 Hz,
1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 41.5, 43.9, 71.9,
120.9, 121.5, 127.0, 127.1, 128.4, 136.5, 143.6, 149.2, 163.1; Anal.
Calcd. for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.89;
H, 6.62; N, 8.40%.
2-(2-Aminophenylamino)-1-(4-methoxyphenyl)ethanone oxime (6)
To a solution of o-phenylenediamine (0.37 g, 3.4 mmol) in 20 mL of
50% aqueous ethanol, a-bromo-4-methoxyacetophenone oxime
(1.12 g, 4.6 mmol) was added in portions within 5 min. The
reaction mixture was stirred at room temperature for an hour. The
precipitate formed was filtered and recrystallized from ethanol.
Yellow solid; yield = 72%; mp 76–78 ◦C; IR (KBr) 3535, 3356,
2059, 2820, 1625, 1516, 1366, 1228, 1187, 740, 698 cm-1;1H NMR
(300 MHz, CDCl3): d = 3.83 (s, 3H), 4.06 (s, 2H), 4.41 (s, 2H), 6.52
(d, J = 7.5 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.7 Hz,
2H), 7.69 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.85 (d, J =
8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): d = 41.7, 55.3, 113.1,
113.8, 119.0, 127.7, 127.8, 128.0, 129.5, 133.6, 137.0, 156.9, 161.5;
Anal. Calcd. for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49; Found:
C, 66.35; H, 6.29; N, 15.44%.
4a-(4-Chlorophenyl)-2e,6e-diphenylpiperidin-1-ol (8c)
Colorless solid; mp 153–155 ◦C; IR (KBr) 3232, 1581, 1463, 1087,
1039, 786, 725, 624 cm-1; 1H NMR (300 MHz, CDCl3): d = 2.25
(td, J = 12.0 Hz, 4.8 Hz, 2H), 2.40 (bd, J = 12.0 Hz, 2H), 3.19 (bs,
1H), 3.96 (bd, J = 12.0 Hz, 2H), 4.40 (s, 1H) 7.24–7.47 (m, 10H),
7.68 (d, J = 7.5 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 34.8,
39.3, 67.3, 126.9, 127.1, 128.2, 128.4, 128.7, 131.8, 140.1, 143.7;
Anal. Calcd. for C23H22ClNO: C, 75.92; H, 6.09; N, 3.85. Found:
C, 75.83; H, 6.01; N, 3.78%.
4648 | Org. Biomol. Chem., 2011, 9, 4642–4652
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4e-(4-Chlorophenyl)-2e,6e-diphenylpiperidin-1-ol (9c)
cis-3e,5e-Bis(4-methylphenyl)thiomorpholin-4-ol (11d)
Colorless solid; mp 171–173 ◦C; IR (KBr) 3191, 1621, 1463, 1095,
1042, 772, 731, 641 cm-1; 1H NMR (300 MHz, CDCl3): d = 1.95
(q, J = 12.0 Hz, 2H), 2.17 (bd, J = 12.0 Hz, 2H), 2.96 (tt, J =
12.0 Hz, 3.3 Hz, 1H), 3.90 (bd, J = 12.0 Hz, 2H), 4.44 (s, 1H),
7.12–7.28 (m, 6H), 7.34 (t, J = 8.4 Hz, 4H), 7.48 (dd, J = 8.4 Hz,
1.5 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 41.4, 42.9, 72.0,
127.0, 127.2, 128.0, 128.5,* 132.0, 142.7, 143.4; Anal. Calcd. for
C23H22ClNO: C, 75.92; H, 6.09; N, 3.85. Found: C, 75.84; H, 6.01;
N, 3.78. * One carbon merged here%.
Colorless solid; mp 138–140 ◦C; IR (KBr) 3517, 2835, 2751, 1489,
1411, 1358, 1311, 1091, 1063, 1031, 831, 769, 746, 557, 523 cm-1; 1H
NMR (300 MHz, CDCl3): d = 2.34 (s, 6H), 2.64 (dd, J = 13.2 Hz,
2.1 Hz, 2H), 3.04 (dd, J = 13.2 Hz, 11.1 Hz, 2H), 4.00 (dd, J =
11.1 Hz, 2.1 Hz, 2H), 4.40 (s, 1H), 7.16 (d, J = 8.1 Hz, 4H), 7.34
(d, J = 8.1 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 21.1, 36.5,
73.0, 126.7, 129.3, 137.2, 139.7; Anal. Calcd. for C18H21NOS: C,
72.20; H, 7.07; N, 4.68; S, 10.71. Found: C, 72.15; H, 7.11; N, 4.73;
S, 10.68%.
cis-3e,5e-bis(4-methoxyphenyl)thiomorpholin-4-ol (11e)
4-(Naphthalen-1-yl)-2,6-diphenylpiperidin-1-ol (mixture of
diastereoisomers, 8d and 9d)
Colorless solid; mp 183 ◦C; IR (KBr) 3516, 2939, 2851, 1469,
1421, 1358, 1311, 1091, 1063, 1011, 821, 789, 746, 567, 543 cm-1;
1H NMR (300 MHz, CDCl3): d = 2.61 (bd, J = 13.8 Hz, 2H), 3.03
(dd, J = 13.8 Hz, 11.1 Hz, 2H), 3.78 (s, 6H), 3.98 (dd, J = 11.1 Hz,
1.8 Hz, 2H), 4.44 (s, 1H), 6.86 (d, J = 8.1 Hz, 4H), 7.36 (d, J =
8.1 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 36.5, 55.2, 72.8,
113.9 127.9, 134.8, 158.8; Anal. Calcd. for C18H21NO3S: C, 65.23;
H, 6.39; N, 4.23; S, 9.67. Found: C, 65.18; H, 6.31; N, 4.19; S,
9.61%.
It is difficult to separate the diastereomers by column chromatog-
raphy as they have close Rf values. The spectrum of the crude
reaction mixture reveals the presence of both isomers in nearly
equal amounts.
Preparation of 3, 5-disustituted 1-hydroxythiomorpholine
All the diketo sulfide precursors were prepared from phenacyl
bromide and sodium sulfide in ethanol at 25–30 C◦. Oximation
followed by ring closure was carried out as described above.
Preparation of substituted N-hydroxy decahydroquinoline (13–16;
a–d)
The required ketones were prepared from the respective chalcone
and cyclohexanone in ethanol medium with a catalytic amount
of potassium hydroxide. Oximation of 12 and the subsequent
cyanoborohydride treatment were carried out as described above.
The diastereoisomers were isolated by column chromatography
with petroleum ether : ethyl acetate (99 : 1).
cis-3e,5e-Diphenylthiomorpholin-4-ol (11a)
Colorless solid; mp 182–184 ◦C; IR (KBr) 3525, 2935, 2851, 1469,
1421, 1358, 1311, 1091, 1063, 1011, 821, 789, 746, 557, 513 cm-1;
1H NMR (300 MHz, CDCl3): d = 2.65 (bd, J = 13.8 Hz, 2H), 3.04
(dd, J = 13.8 Hz, 11.1 Hz, 2H), 4.04 (bd, J = 11.1 Hz, 2H), 4.50
(s, 1H) 7.25–7.30 (m, 6H), 7.45 (d, J = 8.1 Hz, 4H); 13C NMR
(75 MHz, CDCl3): d = 36.4, 73.2, 126.8, 127.4, 128.5, 142.5; Anal.
Calcd. for C16H17NOS: C, 70.81; H, 6.31; N, 5.16; S, 11.82. Found:
C, 70.75; H, 6.27; N, 5.11; S, 11.77%.
2e,4e-Diphenyl-cis-decahydroquinoline-1-ol (aryls cis to ring
junction hydrogens) (13a)
Colorless solid; mp 196–198 ◦C; IR (KBr) 3207, 1596, 1497, 1447,
718, 651, 567, 509 cm-1; 1H NMR (300 MHz, CDCl3): d = 1.09–
1.42 (m, 5H), 1.70–1.92 (m, 4H), 2.22 (bd, J = 12.0 Hz, 1H), 2.27
(bd, J = 11.1 Hz, 1H), 3.06 (ddd, J = 12.0 Hz, 12.0 Hz, 4.5 Hz, 1H),
3.14 (bd, J = 12.0 Hz, 1H), 4.06 (dd, J = 11.4 Hz, 2.0 Hz, 1H),
6.0 (bs, 1H), 7.15–7.42 (m, 10H); 13C NMR (75 MHz, CDCl3):
d = 18.2, 21.0, 25.3, 27.8, 39.0, 41.2, 43.4, 64.5, 65.2, 126.6, 127.1,
127.4, 127.6, 128.3, 128.4, 143.0, 143.7; Anal. calcd. for C21H25NO:
C, 82.04; H, 8.20; N, 4.56; Found: C, 82.11; H, 8.09; N, 4.45%.
cis-3e,5e-Bis(4-chlorophenyl)thiomorpholin-4-ol (11b)
Colorless solid; mp 128–130 ◦C; IR (KBr) 3552, 2935, 2877, 1488,
1411, 1367, 1311, 1098, 1066, 1006, 825, 792, 748, 569, 523 cm-1;
1H NMR (300 MHz, CDCl3): d = 2.62 (bd, J = 14.1 Hz, 2H), 2.99
(dd, J = 14.1 Hz, 11.1 Hz, 2H), 3.99 (dd, J = 11.1 Hz, 2.1 Hz, 2H),
4.46 (s, 1H), 7.32 (d, J = 8.4 Hz, 4H), 7.37 (d, J = 8.4 Hz, 4H);
13C NMR (75 MHz, CDCl3): d = 36.3, 72.7, 128.2, 128.9, 133.2,
140.8; Anal. Calcd. for C16H15Cl2NOS: C, 56.48; H, 4.44; N, 4.12;
S, 9.42. Found: C, 56.43; H, 4.48; N, 4.18; S, 9.38%.
4e-(4-Chlorophenyl)-2e-phenyl-cis-decahydroquinoline-1-ol (aryls
cis to ring junction hydrogens) (13b)
Colorless solid; mp 173–175 ◦C; IR (KBr) 3207, 1596, 1497, 1447,
718, 651, 567, 509 cm-1; Theoretical mass: 342.8; measured mass:
342.5; 1H NMR (300 MHz, CDCl3): d = 1.30–1.35 (m, 6H), 1.72–
1.90 (m, 3H), 2.14 (d, J = 12.6 Hz, 1H), 2.25 (bd, J = 12.3 Hz, 1H),
3.06 (ddd, J = 12.6 Hz, 12.6 Hz, 4.5 Hz, 1H), 3.40 (bd, J = 12.0 Hz,
1H), 4.06 (dd, J = 11.7 Hz, 2.1 Hz, 1H), 4.98 (bs, 1H), 7.11 (d, J =
8.1 Hz, 2H), 7.25 (dd, J = 7.5 Hz, 1.8 Hz, 2H), 7.32 (t, J = 7.5 Hz,
3H), 7.40 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 18.2,
20.9, 25.2, 27.7, 38.6, 41.3, 43.5, 64.5, 65.2, 127.2, 128.4, 128.6,
128.7, 129.1, 131.9, 142.2, 143.1. Anal. calcd. for C21H24ClNO: C,
73.78; H, 7.08; N, 4.10; Found: C, 73.64; H, 7.01; N, 4.18%.
cis-3e,5e-Bis(4-bromophenyl)thiomorpholin-4-ol (11c)
Colorless solid; mp 168–170 ◦C; IR (KBr) 3544, 2925, 2867, 1481,
1419, 1363, 1309, 1093, 1066, 1006, 825, 792, 748, 557, 503 cm-1;
Theoretical mass: 428.2; measured mass: 487.3, 488.3, 489.2, and
1
502.2 (acetate adduct); H NMR (300 MHz, CDCl3) d 2.62 (bd,
J = 14.1 Hz, 2H), 2.97 (dd, J = 14.1 Hz, 11.1 Hz, 2H), 3.95 (dd, J =
11.1 Hz, 1.8 Hz, 2H), 4.48 (s, 1H), 7.29 (d, J = 8.4 Hz, 4H), 7.46 (d,
J = 8.4 Hz, 4H); 13C NMR (75 MHz, CDCl3) d 36.2, 72.6, 121.3
128.5, 131.8, 141.3; Anal. Calcd. for C16H15Br2NOS: C, 44.78; H,
3.52; N, 3.26; S, 7.47. Found: C, 44.73; H, 3.58; N, 3.23; S, 7.42%.
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6e-tert-Butyl-4e-phenyl-2e-(4-methylphenyl)-cis-
decahydroquinoline-1-ol (aryls cis to ring junction hydrogens)
(13d)
6e-tert-Butyl-4e-(4-chlorophenyl)-2a-phenyl
cis-decahydroquinoline-1-ol (15c)
Viscous liquid; IR (KBr): 3365, 2854, 1527, 1415, 1193, 756, 722,
1
Viscous liquid; IR (KBr) 3207, 1596, 1497, 1447, 718, 651, 567,
509 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.71 (s, 9H), 0.86–1.04
(m, 2H), 1.20–1.41 (m, 3H), 1.70–1.92 (m, 3H), 2.14–2.27 (m, 2H),
2.30 (s, 3H), 2.98 (ddd, J = 12.0 Hz, 12.0 Hz, 3.6 Hz, 1H), 3.14
(bd, J = 7.2 Hz, 1H), 4.03 (dd, J = 11.4 Hz, 2.0 Hz, 1H), 5.28 (bs,
1H), 7.04 (m, 3H), 7.23 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.2 Hz,
2H), 7.40 (d, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d =
18.5, 20.9, 26.1, 27.4, 28.8, 32.2, 39.2, 41.8, 43.3, 43.0, 64.6, 65.4,
127.1, 127.3, 127.5, 128.4, 129.0, 135.7, 140.4, 143.2. Anal. Calcd.
for C26H35NO: C, 82.71; H, 9.34; N, 3.71. Found: C, 82.61; H, 9.39;
N, 3.77%.
565 cm-1; H NMR (300 MHz, CDCl3): d = 0.92 (s, 9H), 1.22–
1.25 (m, 2H), 1.40–1.42 (m, 1H), 1.51–1.53 (m, 2H), 1.91 (q, J =
12.3 Hz, 1H), 2.10 (bd, J = 12.6 Hz, 1H), 2.29–2.30 (m, 1H), 2.35
(td, J = 7.2 Hz, 1.5 Hz, 1H), 2.38–2.40 (m, 1H), 2.74 (bd, J =
5.1 Hz, 1H), 2.86 (bd, J = 2.7 Hz, 1H), 3.74 (dd, J = 12.6 Hz,
3.0 Hz, 1H), 4.40 (s, 1H), 7.21–7.39 (m, 9H); 13C NMR (75 MHz,
CDCl3): d = 20.9, 27.6, 29.0, 30.1, 32.6, 36.1, 41.8, 43.7, 48.0,
59.6, 68.8, 126.9, 127.0, 128.3, 128.5, 129.0, 131.4, 142.6, 144.5.
Anal. Calcd. for C25H32ClNO: C, 75.45; H, 8.10; N, 3.52. Found:
C, 75.37; H, 8.02; N, 3.56%.
6-tert-Butyl-4a-phenyl-2e-(4-methylphenyl)-cis-
decahydroquinoline-1-ol (15d)
2e,4e-Diphenyl-cis-decahydroquinoline-1-ol (aryls trans to ring
junction hydrogens) (14a)
Viscous liquid; IR (KBr): 3343, 2842, 1521, 1435, 1186, 751, 731,
595 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.91 (s, 9H), 1.22–1.33
(m, 3H), 1.42–1.59 (m, 3H), 1.93 (q, J = 12.3 Hz, 1H), 2.18–2.29
(m, 2H), 2.35 (s, 3H), 2.41 (m, 1H), 2.75 (d, J = 5.7 Hz, 1H), 2.91
(bd, J = 3.0 Hz, 1H), 3.82 (dd, J = 12.3 Hz, 3.6 Hz, 1H), 4.31 (s,
1H), 7.16 (d, J = 7.5 Hz, 2H), 7.22–7.37 (m, 5H), 7.41 (d, J = 7.5 Hz,
2H), 13C NMR (75 MHz, CDCl3): d = 20.8, 21.0, 27.6, 29.1, 30.2,
32.6, 36.3, 41.9, 43.9, 48.8, 59.7, 69.0, 126.9, 127.0, 127.5, 128.5,
129.0, 135.1, 141.1, 144.9. Anal. Calcd. for C26H35NO: C, 82.71;
H, 9.34; N, 3.71. Found: C, 82.62; H, 9.28; N, 3.65%.
Colorless solid; mp 201–203 ◦C; IR (KBr) 3207, 1596, 1497, 1447,
718, 651, 567, 509 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.90–
0.94 (m, 1H), 1.15 (qt, J = 9.3 Hz, 3.6 Hz, 1H), 1.28–1.46 (m, 2H),
1.66–1.79 (m, 3H), 1.84 (dp, J = 10.7 Hz, 3.0 Hz, 1H), 2.04–2.10
(m, 1H), 2.23 (q, J = 11.7 Hz, 1H), 2.33 (bd, J = 12.6 Hz, 1H),
3.04–3.05 (m, 1H), 3.11 (ddd, J = 12.6 Hz, 3.0 Hz, 3.0 Hz, 1H),
3.73 (dd, J = 11.7 Hz, 3.6 Hz, 1H), 4.44 (s, 1H), 7.05 (dd, J =
7.5 Hz, 1.2 Hz, 2H), 7.23 (t, J = 7.2 Hz, 2H), 7.24–7.32 (m, 4H),
7.40 (d, J = 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d = 20.6,
21.3, 26.5, 29.4, 35.2, 44.6, 45.3, 65.6, 73.3, 126.7, 127.3, 128.2,
128.5, 128.7, 131.7, 142.5, 143.6. Anal. Calcd. for C21H25NO: C,
82.04; H, 8.20; N, 4.56; Found: C, 81.95; H, 8.26; N, 4.64%.
2,4-Diphenyl-trans-decahydroquinoline-1-ol (16a)
Viscous liquid; IR (KBr) 3255, 1557, 1425, 1092, 758, 703,
563 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.91 (qd, J = 12.3 Hz,
3.3 Hz, 1H), 1.13 (qt, J = 12.0 Hz, 4.5 Hz, 1H)1.26–1.29 (m, 2H),
1.43 (dt, J = 12.9 Hz, 1.8 Hz, 1H), 1.59–1.84 (m, 3H), 1.93 (td, J =
9.3 Hz, 2.1 Hz, 2H), 2.37–2.57 (m, 3H), 3.66–3.69 (m, 1H), 4.53
(s, 1H), 7.13 (dd, J = 8.4 Hz, 1.5 Hz, 2H), 7.25–7.32 (m, 6H), 7.40
(d, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d = 24.7, 25.5,
30.3, 30.5, 43.0, 46.2, 48.6, 71.2, 72.7, 126.1, 127.2, 127.1, 127.3,
128.2, 128.3, 141.5, 142.8. Anal. Calcd. for C21H25NO: C, 82.04;
H, 8.20; N, 4.56; Found: C, 82.11; H, 8.14; N, 4.48%.
4e-(4-Chlorophenyl)-2e-phenyl cis-decahydroquinoline-1-ol (aryls
trans to ring junction hydrogens) (14b)
Colorless solid; mp 201–203 ◦C; IR (KBr) 3207, 1596, 1497, 1447,
718, 651, 567, 509 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.92–
0.97 (m, 1H), 1.13 (qt, J = 9.3 Hz, 3.6 Hz, 1H), 1.28–1.39 (m, 2H),
1.63–1.84 (m, 3H), 1.84 (dp, J = 11.7 Hz, 3.3 Hz, 1H), 1.89–2.08
(m, 1H), 2.25 (q, J = 12.3 Hz, 1H), 2.42 (bd, J = 12.3 Hz, 1H),
3.01 (m, 1H), 3.09 (ddd, J = 13.2 Hz, 3.9 Hz, 3.9 Hz, 1H), 3.71
(dd, J = 12.6 Hz, 3.6 Hz, 1H), 4.44 (s, 1H), 7.05 (d, J = 8.1 Hz,
2H), 7.21 (d, J = 6.9 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.32–7.40
(m, 3H); 13C NMR (75 MHz, CDCl3): d = 20.5, 21.2, 26.5, 29.3,
35.4, 44.6, 44.7, 65.7, 73.0, 126.9, 127.1, 128.1, 128.5, 128.7, 131.7,
141.3, 144.4. Anal. Calcd. for C21H24ClNO: C, 73.78; H, 7.08; N,
4.10; Found: C, 73.69; H, 7.13; N, 4.03%.
4-(4-Chlorophenyl)-2-phenyl-trans-decahydroquinoline-1-ol (16b)
Viscous liquid; IR (KBr) 3255, 1557, 1425, 1092, 758, 703,
563 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.92 (qd, J = 12.6 Hz,
3.9 Hz, 1H), 1.13 (qt, J = 12.6 Hz, 4.5 Hz, 1H), 1.22–1.25 (m, 2H),
1.41 (dt, J = 13.2 Hz, 1.8 Hz, 1H), 1.59–1.86 (m, 3H), 1.94 (td, J =
9.0 Hz, 2.4 Hz, 2H), 2.39–2.47 (m, 3H), 3.68–3.70 (m, 1H), 4.51
(s, 1H), 7.13 (dd, J = 7.2 Hz, 1.5 Hz, 2H), 7.25 (d, J = 7.5 Hz, 2H),
7.30–7.32 (m, 3H), 7.40 (d, J = 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d = 24.9, 25.7, 30.1, 30.4, 43.1, 46.4, 48.8, 71.4, 72.8,
126.3, 127.0, 127.2, 127.5, 128.1, 128.4, 141.6, 143.8. Anal. Calcd.
for C21H24ClNO: C, 73.78; H, 7.08; N, 4.10; Found: C, 73.69; H,
7.01; N, 4.02%.
6e-tert-Butyl-4e-(4-chlorophenyl)-2e-cis-decahydroquinoline-1-ol
(aryls trans to ring junction hydrogens) (14c)
Trace. 1H NMR splitting pattern is similar to isomer 14a and 14b.
6e-tert-Butyl-4-(4-chlorophenyl)-2-phenyl-trans-
2e,4a-Diphenyl-cis-decahydroquinoline-1-ol (15a)
decahydroquinoline-1-ol (16c)
Obtained in traces contaminated with 14a. 1H and 13C NMR
spectral patterns are similar to 15c and 15d.
Viscous liquid; IR (KBr) 3255, 1557, 1425, 1092, 758, 703,
563 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.77 (s, 9H),
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0.88–1.45 (m, 5H), 1.63 (qt, J = 9.0 Hz, 2.1 Hz, 1H), 1.86–1.94
(m, 3H), 2.31–2.50 (m, 3H), 3.65–3.68 (m, 1H), 4.62 (bs, 1H), 7.13
(dd, J = 7.2 Hz, 1.5 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.32 (t, J =
7.2 Hz, 3H), 7.40 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d = 25.5, 25.7, 27.4, 30.1, 30.4, 32.2, 46.0, 47.1, 48.2, 71.2, 72.7,
127.1, 127.2, 128.4, 128.5, 128.7, 131.8, 141.2, 143.2. Anal. Calcd.
for C25H32ClNO: C, 75.45; H, 8.10; N, 3.52; Found: C, 75.38; H,
8.04; N, 3.46%.
128.5, 128.6, 131.9, 142.3, 142.7. Anal. Calcd. for C20H22ClNO: C,
73.27; H, 6.76; N, 4.27. Found: C, 73.15; H, 6.64; N, 4.16%.
4e-(4-Chlorophenyl)-2e-phenyloctahydro-1H-cyclopenta[b]pyridin-
1-ol (The ring junction hydrogens are trans to the aryl groups) (20)
Viscous liquid; yield 21%; IR (KBr) 3449, 2853, 2827, 1621, 1522,
1
1452, 1362, 1241, 1191, 1039, 824 cm-1; H NMR (300 MHz,
CDCl3): d = 0.83–0.97 (m, 1H), 1.25–1.37 (m, 2H), 1.60–1.71 (m,
2H), 1.81–2.07 (m, 3H), 2.32 (q, J = 5.7 Hz, 1H), 2.54 (td, J =
12.0 Hz, 3.6 Hz, 1H), 3.69–3.71 (m, 1H), 4.05 (dd, J = 11.4 Hz,
2.7 Hz, 1H), 5.50 (bs, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.23–7.32
(m, 5H), 7.41 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d = 19.6, 26.9, 27.0, 41.9,* 43.0, 64.2, 68.5, 127.3, 127.7, 128.4,
128.5, 129.0, 132.0, 142.3, 142.6. Anal. Calcd. for C20H22ClNO: C,
73.27; H, 6.76; N, 4.27. Found: C, 73.14; H, 6.64; N, 4.15%. *Two
carbons merged here.
6e-tert-Butyl-4-phenyl-2-(4-methylphenyl)-trans-
decahydroquinoline-1-ol (16d)
Colorless solid; mp 162–164 ◦C; IR (KBr) 3255, 1557, 1425, 1092,
758, 703, 563 cm-1; 1H NMR (300 MHz, CDCl3): d = 0.86 (s, 9H),
0.92–1.94 (m, 9H)2.33 (s, 3H), 2.36–2.55 (m, 3H), 3.64–3.68 (m,
1H), 4.63 (bs, 1H), 7.02–7.18 (m, 5H), 7.27 (t, J = 6.9 Hz, 2H),
7.40 (d, J = 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d = 24.9,
25.7, 26.8, 29.9, 30.1, 30.4, 33.5, 43.1, 46.4, 48.8, 71.4, 72.8, 126.9,
127.2, 128.0, 128.3, 129.0, 135.6, 140.7, 143.6. Anal. Calcd. for
C26H35NO: C, 82.71; H, 9.34; N, 3.71. Found: C, 82.64; H, 9.23;
N, 3.63%.
Synthesis of 2,5 diphenyl-N-hydroxypyrrolidine (22)
1,2-Dibenzoylethane, prepared through Friedel–Crafts acylation
of benzene with succinoyl chloride, was converted to the corre-
sponding oxime. After cyanoborohydride treatment, 2,5-diphenyl-
N-hydroxypyrrolidine was obtained in excellent yield. Viscous
liquid; yield 87%; IR (KBr) 3535, 3056, 3028, 2869, 2840, 1595,
1502, 1238, 1197, 743, 698 cm-1; Theoretical mass: 240.3; measured
mass: 240.1; 1H NMR (300 MHz, CDCl3): d = 1.83 (m, 2H), 2.26
(m, 2H), 3.98 (m, 2H), 4.59 (bs, 1H), 7.25–7.35 (m, 6H), 7.48 (d,
J = 7.8 Hz, 4H); 13C NMR (75 MHz, CDCl3): d = 29.8, 71.0, 127.2,
127.4, 128.4, 142.5; Anal. Calcd. for C16H17NO: C, 80.30; H, 7.16;
N, 5.85. Found: C, 80.17; H, 7.04; N, 5.73%.
Preparation of 2-(3-(4-chlorophenyl)-3-(hydroxyimino)-1-
phenylpropyl) cyclopentanone oxime (17)
The ketone for the preparation of 17 was obtained from the
respective chalcone and cyclopentanone using catalytic amount
of potassium hydroxide in ethanol. Oximation followed by
cyanoborohydride treatment of 17 has yielded three diastereoiso-
mers, which have been isolated by column chromatography with
petroleum ether : ethyl acetate (99 : 1)
Acknowledgements
4e-(4-Chlorophenyl)-2e-phenyloctahydro-1H-cyclopenta[b]pyridin-
1-ol (Ring junction hydrogens and the aryl groups are all cis to each
other) (18)
The authors thank DST, New Delhi for assistance under the
IRHPA program for providing funds for creating an NMR facility.
Financial support from UGC, New Delhi and CSIR-JRF, New
Delhi is gratefully acknowledged.
Viscous liquid; yield 30%; IR (KBr) 3465, 2854, 2816, 1612, 1526,
1456, 1352, 1236, 1191, 1032, 826 cm-1; Theoretical mass: 328.8;
1
measured mass: 328.1; H NMR (300 MHz, CDCl3) d 1.16 (qd,
J = 8.1 Hz, 3.0 Hz, 1H), 1.43–1.69 (m, 2H), 1.74–1.91 (m, 3H),
2.12–2.40 (m, 3H), 3.16 (t, J = 4.5 Hz, 1H), 3.27 (dt, J = 13.5 Hz,
4.5 Hz, 1H), 3.68 (dd, J = 11.4 Hz, 2.4 Hz, 1H), 4.52 (bs, 1H), 7.09
(d, J = 8.4 Hz, 2H), 7.24–7.35 (m, 5H), 7.44 (d, J = 8.4 Hz, 2H);
13C NMR (75 MHz, CDCl3) d 21.6, 23.5, 30.5, 35.4, 40.8, 48.1,
70.3, 72.2, 127.1, 127.2, 128.3, 128.5, 128.6, 129.1, 142.7, 143.7.
Anal. Calcd. For C20H22ClNO: C, 73.27; H, 6.76; N, 4.27. Found:
C, 73.14; H, 6.64; N, 4.15%.
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