Synthesis of new analogues of diphenylpyraline

Article abstract of DOI:10.1016/S0040-4020(03)00072-3

1-Unsubstituted 4-dimethylamino-5,6-dihydropyridine-2(1H)-thiones were converted to isomeric piperidin-4-ols which were separated and N-methylated to 2-substituted 1-methylpiperidin-4-ols. Their 1-phenyl analogues were prepared from 4-dimethylamino-5,6-dihydro-1-phenylpyridine-2(1H)-thiones. After their conversion to dihydro-1-phenylpyridin-4(1H)-ones the hydrogenation gave isomeric 1-phenylpiperidin-4-ols which were separated. O-Alkylation of the 1-substituted piperidin-4-ols by various methods yielded 2-substituted analogues of diphenylpyraline. Their antimycobacterial activity was examined. The configurations and conformations of the piperidine derivatives were investigated by NMR spectroscopy.

Full text of DOI:10.1016/S0040-4020(03)00072-3

Tetrahedron 59 (2003) 1403–1411
Synthesis of new analogues of diphenylpyraline
*
Robert Weis, Andreas J. Kungl and Werner Seebacher
¨
Institute of Pharmaceutical Chemistry and Pharmaceutical Technology, University of Graz, Universitatsplatz 1, A-8010 Graz, Austria
Received 1 October 2002; revised 20 December 2002; accepted 10 January 2003
Abstract—1-Unsubstituted 4-dimethylamino-5,6-dihydropyridine-2(1H)-thiones were converted to isomeric piperidin-4-ols which were
separated and N-methylated to 2-substituted 1-methylpiperidin-4-ols. Their 1-phenyl analogues were prepared from 4-dimethylamino-5,6-
dihydro-1-phenylpyridine-2(1H)-thiones. After their conversion to dihydro-1-phenylpyridin-4(1H)-ones the hydrogenation gave isomeric
1-phenylpiperidin-4-ols which were separated. O-Alkylation of the 1-substituted piperidin-4-ols by various methods yielded 2-substituted
analogues of diphenylpyraline. Their antimycobacterial activity was examined. The configurations and conformations of the piperidine
derivatives were investigated by NMR spectroscopy. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
spectra are recorded in DMSO-d6 only signals of 3 are
visible which was deduced from the singlet of the olefinic
proton at 5.5 ppm in the 1H NMR spectrum. When
measured in CDCl3 exclusively resonances of 4 can be
observed: the Hs at C-5 of 4 resonate as two doublets in the
1H NMR spectrum at ,3.8 ppm. Their 2J coupling
constants were ca. 20 Hz establishing the 6-thioxopiperi-
din-4-one structure. The catalytic hydrogenation of 3, 4 with
Raney nickel W-730 yielded a mixture of the diastereo-
isomers 5a and 5b. Those were separated by LC affording
larger amounts of isomer 5a which is energetically favored
due to its equatorial substituent in ring position 4. The
piperidinols 5 were treated with formaldehyde and formic
acid to afford the 1-methyl-4-piperidinols 6a and 6b,
respectively, in a Leuckart–Wallach procedure (Scheme 1).
Diphenylpyraline 19 is an antihistaminic agent1 which is
mainly used against nausea, itching and hay fever in
medicinal therapy. Besides it possesses bronchospasmo-
lytic2 and antimycobacterial3 properties as well as activity
against parkinsonism.4 Some of its metal complexes were
reported to have antibacterial and antifungal potency.5,6
Many derivatives with different substitution on nitrogen or
at the aromatic ring system have been prepared.7–24 Some
of them were described to have less sedative side-
effects,22–26 additional antiinflammatory activity11,13 or
antagonistic activity against leukotriene production.9 Sub-
stitution of the piperidine ring was restricted to 3-methyl-,27
dimethyl-18,20,27 and trimethylderivatives.20 Monosubsti-
tution in position 2 of the piperidine ring of diphenyl-
pyraline analogues has not yet been reported. This paper
deals with the first syntheses of 2-substituted derivatives of
diphenylpyraline and its 1-phenyl analogue. The antimyco-
bacterial activity of the prepared compounds has been
investigated.
We were not able to prepare their 1-phenyl analogues by
reaction of 5a,b with halobenzenes due to the preferred
formation of 4-phenoxypiperidines. We did not examine
other methods or the protection of the 4-hydroxy group of
5a,b because the dihydro-1-phenylpyridine-2(1H)-thiones
9 and 10 were obtained in acceptable yields from
the 6-phenylimino-2H-thiopyran-4-amines 7 and 8 by a
Dimroth rearrangement.31 In comparison to their 1-unsub-
stituted analogue 2, compounds 9 and 10 are stable against
caustic soda. However, their methoiodides gave the
dihydropyridin-4(1H)-ones 11 and 12. When those were
stirred in an inert-gas atmosphere with Raney nickel W-232
the methylthio group was removed giving selectively
compounds 13 and 14.31 For the hydrogenation of 12 the
use of the more active Raney nickel catalysts W-433 and
W-7 was examined. The yielded isomeric 1-phenylpiperi-
din-4-ols 17a,b were accompanied by high amounts of
the pentanol 15. The latter was prepared in good yields
by shaking of 12 with Raney nickel W-7 under hydro-
gen pressure. The treatment of 11 or 12 with Raney nickel
W-2 under the same conditions gave mixtures of the
2. Results and discussion
The synthesis of the 1-methyl compounds is based on the
cyclization of an a,b-unsaturated ketone 1 with dimethyl-
ammonium rhodanide to a 6-substituted 4-dimethylamino-
pyridine-2-thione 2.28 When the latter is treated with
dilute caustic soda the dimethylamino group is replaced
by a hydroxy substituent.29 Compound 2 gives a mixture of
the 4-hydroxy derivative 3 and its tautomer 4. If NMR
Keywords: antibacterials; diphenylpyraline; hydrogenation; piperidines;
stereoisomerism.
*
Corresponding author. Tel.: þ43-316-380-5379; fax: þ43-316-380-9846;
e-mail: robert.weis@uni-graz.at
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00072-3

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R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
Scheme 1. Reagents and reaction conditions: (i) NH2(Me)2SCN, PhBr, 1708C, 8 h; (ii) NaOH, 608C, 72 h; (iii) Raney nickel W-7, ethanol, 45 psi (H2), room
temperature, 96 h; (iv) HCOOH, CH2O, 1008C.
corresponding 1-phenylpiperidin-4-ols 16a,b or 17a,b
(Scheme 2). The isomers were separated by LC yielding
larger amounts of compounds 16a and 17a, which have
equatorial substituents in ring position 2.
Unsubstituted 2-phenyl-4-piperidinols were obtained
enantiomerically pure from a 3-hydroxy-5-oxopentane-
nitrile35 as well as by stepwise hydrogenation of 6-phenyl-
piperidine-2,4-dione.36 Besides, the 4-piperidinols might as
well be prepared via the corresponding 2-substituted
4-piperidones. The latter are accessible by acid-catalyzed
Mannich reaction of an aldehyde, an amine and an a,b-
unsaturated ketone37 – 39 or by intermolecular double
Michael reaction of a,b-unsaturated g-ketosulfones with
benzylamine.40–42 Furthermore, cyclizations of appropriate
2-Substituted 4-piperidinols have already been prepared by
other methods. Hydroboration of tetrahydro-2-isopropyl-1-
methylpyridine gave a mixture of 3 isomeric isopropyl-1-
methylpiperidinols from which small amounts of com-
pounds 6a and 6b were separated by means of GLC.34
Scheme 2. Reagents and reaction conditions: (i) DMF, 1608C, 16 h; (ii) CH3I, CHCl3, room temperature, 18 h; NaOH, 1108C, 2 h; (iii) Raney nickel W-2,
ethanol, room temperature; (iv) Raney nickel W-7, ethanol, 45 psi (H2), room temperature, 8 h; (v) Raney nickel W-2, ethanol, 30 psi (H2), room temperature,
6 h.

R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
1405
Scheme 3. Reagents and reaction conditions: method A: (Ph)2CHBr, K2CO3, 1408C, 5 h; method B: (Ph)2CHBr, NaH, DMF, room temperature, 3 h; method
C: (Ph)2CN2, PhMe, 1308C, 18 h; method D: (Ph)2CHOH, toluene-4-sulfonic acid, PhMe, 1308C, 6 h.
imino acetales43 – 45 or of pent-1,4-diene-3-ones with
amines46–49 have been reported. The flash vacuum thermo-
lysis of 4-oxa-5-azaspiro[2.4]heptanes gave mixtures con-
taining 1,2-disubstituted 4-piperidones.50–52
high amounts of the alkoxypiperidines 21a,b and 22a,b
(Scheme 3).
1
The resonances in H and 13C NMR spectra of all new
compounds were assigned by means of 2D NMR spectra
(gCOSY, gHSQC, gHMQC optimized for long-range
couplings of 10 Hz). O-Alkylation of the piperidinols 6,
16 and 17 to compounds 20, 21 and 22 was established
by a long-range coupling from the methine proton of the
diphenylmethyl group to the C-4. The OCH carbons of
compounds 20, 21 and 22 typically resonate at 80 ppm in
13C NMR spectra. Due to the introduction of the benzhydryl
group the signals for the C-4 in the 13C NMR spectra of
compounds 20, 21 and 22 were shifted ca. 5 ppm to lower
field whereas those for the C-3 and the C-5 were shifted
3 ppm upfield in comparison to compounds 6, 16 and 17.
The shifts of the resonances for the C-2 and C-6 were altered
less than 1.5 ppm. Only the signals for the C-5 and the C-6
of compound 21a were unusually shifted ca. 4 ppm upfield
which should be due to its different average conformation as
stated below.
Diphenylpyraline 19 has been synthesized from 1-methyl-
piperidin-4-ol 18 and halodiphenylmethanes18,21 or diphenyl-
diazomethanes.53 The 2-substituted piperidin-4-ols 6, 16 or
17 were fused together with bromodiphenylmethane and
potassium carbonate (method A) yielding the title com-
pounds 20a,b in good and 21a,b and 22a,b in poor yields.
The disadvantage of this method is the undesired formation
of N-substituted side products which is the main reaction of
the 1-phenyl compounds 16 and 17. Attempts to favor the
formation of ethers by deprotonation of the piperidinols
6a,b and 16a with sodium hydride and subsequent
etherification with bromodiphenylmethane (method B)
went wrong and only small quantities of 20a,b and 21a
were afforded. Therefore the reactions of 16b and 17a,b
were not examined by this method. Piperidinol 16a was
etherified with diphenyldiazomethane (method C) giving
21a in acceptable yields. However, the etherification of
compounds 16a,b and 17a,b by the reaction with diphenyl-
methanol in the presence of toluene-4-sulfonic acid (method
D) was established as the superior method affording
The relative configurations of the piperidine derivatives 5, 6,
3
16, 17, 20, 21 and 22 were deduced from the J coupling
constants in their 1H NMR spectra. 3J(2-H, 3-Hax) and 3J(3-Hax,
4-H) coupling constants of ca. 11 Hz indicate axial positions
of the involved protons of the piperidine derivatives. Their
average conformations were investigated by NOE experi-
ments. Furthermore w-couplings54 were removed by
homodecoupling experiments and detected in this way,
but we did not measure their exact values.
The coupling constants of the axial and equatorial protons of
compounds 16a and 17b make their unambiguous assign-
ment feasible. Instead of the expected 11–12 Hz couplings
their diaxial 3J coupling constants were only ca. 9 Hz
revealing a slight deviation from the chair conformation.
But their diphenylmethyl ethers 21a and 22b do not
prefer chair conformations which is indicated by similar
coupling constants of the geminal protons in their 1H NMR
spectra.
However, all below-mentioned piperidine derivatives prefer
chair conformations as was demonstrated by the following
NMR investigations.
Figure 1. NOEs (arrows) and w-couplings (bold) in 1H NMR spectra of 5a,
6a, 17a, 20a, 22a.

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R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
been investigated by NMR spectroscopy. The prepared title
compounds have antimycobacterial activity.
3. Experimental
3.1. General
Melting points were obtained on a digital melting point
apparatus Electrothermal IA 9200 and are uncorrected. IR
spectra: infrared spectrometer system 2000 FT (Perkin–
Elmer). NMR spectra: Varian Inova 400 (297 K) 5 mm
1
tubes, TMS as internal standard. H- and 13C-resonances
were assigned using 1H,1H- and 1H,13C-correlation spectra.
Microanalyses: EA 1108 CHNS-O apparatus (Carlo Erba) at
the Microanalytical Laboratory at the Institute of Physical
Chemistry, University of Vienna. Hydrogenations were
performed in a Parr hydrogenation apparatus shaker type
3911. Chromatography: column chromatography (CC):
pump: Labomatic MD-80, silica gel 60 (Merck), 0.015–
Figure 2. NOEs (arrows) and w-couplings (bold) in 1H NMR spectra of
16b, 21b and of 5b, 6b, 20b.
The protons in positions 2 and 4 of compounds 5a, 6a, 17a,
and 20a and 22a were revealed as axial. NOEs from the
axial Hs at C-3 to the axial Hs at C-5 as well as from the Hs
at C-4 to the axial Hs at C-2 and C-6 were detected. W-
couplings were observed between the equatorial Hs at C-3
and C-5 (Fig. 1) with the exception of 5a due to the
superposition of peaks.
˚
0.025 mm, pore-diameter 60 A; column diameter 40 mm,
layer thickness 410 mm, rate of flow: 15 ml/min, detection:
Wellchrom K-2400 RI detector (Knauer), thin-layer
chromatography (TLC): TLC plates (Merck) silica gel 60
F254
.
Compounds 16b and 21b have equatorial Hs at C-2 and
axial Hs at C-4. NOEs were detected from the Hs at C-4 to
the axial Hs at C-6 and from the axial H at C-3 of 21b to its
axial H at C-5. The latter NOE was invisible for 16b because
of the superposition of peaks. However, w-couplings
between the equatorial protons in positions 2 and 6 and in
positions 3 and 5 of 16b and 21b were successfully removed
by homodecoupling experiments (Fig. 2). Compounds 5b,
6b and 20b have axial protons in position 2 and equatorial
protons in position 4. Accordingly, NOEs were determined
from the axial Hs at C-2 to the axial Hs at C-6 and from the
axial Hs at C-3 to the axial Hs at C-5. The latter was not
distinguishable beyond all doubt for compound 20b due to
overlap of the signals of the equatorial proton at C-3 and the
axial proton at C-5. W-couplings between the equatorial Hs
at C-3 and C-5 were invisible as a result of the superposition
of the involved protons, but we could detect them between
the equatorial Hs at C-4 and C-6 (Fig. 2).
3.2. (RS)-(6)-4-Dimethylamino-5,6-dihydro-6-isopropyl-
pyridine-2(1H)-thione (2)
Ketone 1 (0.2 mol) and dimethylammonium rhodanide
(0.1 mol) were suspended in 100 ml of bromobenzene.
The mixture was refluxed for 8 h at a water separator and the
solvent removed in vacuo. The residue was triturated with
propan-2-ol, filtered with suction and recrystallized. Yield:
13.52 g (68.2%); mp 1428C (propan-2-ol); IR (KBr):
n¼3169 (s), 2952 (m), 1571 (s), 1525 (s), 1400 (s), 1121
˜
(s), 1057 (s), 976 (s) cm21
;
1H NMR (DMSO-d6, d,
400 MHz): 0.88, 0.90 (2d, J¼6.8 Hz, 6H, CH(CH3)2),
1.89–2.02 (m, 1H, CH(CH3)2), 2.24 (dd, J¼16.4, 11.6 Hz,
1H, 5-H), 2.43 (dd, J¼16.4, 5.6 Hz, 1H, 5-H), 2.91 (s, 6H,
N(CH3)2), 3.20–3.26 (m, 1H, 6-H), 5.16 (s, 1H, 3-H), 8.06
(s, 1H, NH) ppm. 13C NMR (DMSO-d6, d, 100 MHz):
17.50, 18.41 (CH(CH3)2), 25.70 (C-5), 29.80 (CH(CH3)2),
38.95 (N(CH3)2), 56.67 (C-6), 97.32 (C-3), 154.42 (C-4),
189.78 (C-2) ppm. Anal. calcd for C10H18N2S (198.33): C,
60.56; H, 9.15; N, 14.12; S, 16.17%. Found: C, 60.62; H,
9.18; N, 14.14; S, 15.91%.
The antimycobacterial activities of compounds 20–22 were
preliminarily tested in liquid media by incubating 1:1000
diluted overnight cultures of M. smegmatis with increasing
concentrations of compounds at 378C under constant
shaking. After 5 h incubation, the growth inhibitory activity
was determined from the absorption of the compound-
containing media at 600 nm using diphenylpyraline as
reference compound. All compounds tested within this
set-up showed antimycobacterial activity which will be
further investigated against M. tuberculosis H37Rv by the
Tuberculosis Antimicrobial Acquisition and Coordinating
Facility (TAACF, Southern Research Institute, America).
3.3. (RS)-(6)-5,6-Dihydro-4-hydroxy-6-isopropyl-
pyridine-2(1H)-thione (3) resp. (RS)-(6)-2-(1-Methyl-
ethyl)-6-thioxopiperidin-4-one (4)
Compound 2 (0.050 mol) was suspended in a 2 M solution
of sodium hydroxide (0.5 mol) and stirred at 608C for 72 h.
The mixture was cooled and filtered. The ice-cooled
solution was acidified with HClconc. The separated oil was
dissolved in dichloromethane. The organic layer was
washed with H2O, dried over Na2SO4 and the solvent was
removed in vacuo. The product may be recrystallized, but
smells bad and is readily decomposing. Therefore the oily
residue was used for the synthesis of the piperidin-4-oles 5a
and 5b without further purification. Yield: 6.10 g (71.2%);
Isomeric 2-substituted piperidin-4-ols have been prepared
via new pathways and separated by CC. Their etherification
to new analogues of diphenylpyraline was managed by
various methods. The configurations and the preferred
conformations of all synthesized piperidine derivatives have

R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
1407
mp 568C (benzene); IR (KBr): n¼3403 (m), 3197 (m), 2963
1.50–1.76 (m, 4H, CH(CH3)2, 3-Hequ, 5-Hax, 5-Hequ), 2.27
(br, 2H, NH, OH), 2.67 (ddd, J¼11.4, 6.3, 2.6 Hz, 1H, 2-
Hax), 2.88 (ddd, J¼ 12.0, 4.5, 2.7 Hz, 1H, 6-Hequ), 3.03
(ddd, J¼12.0, 12.0, 3.6 Hz, 1H, 6-Hax), 4.14–4.19 (m, 1H,
4-Hequ) ppm. 13C NMR (CDCl3, d, 100 MHz): 18.71, 18.80
(CH(CH3)2), 32.57 (CH(CH3)2), 33.15 (C-5), 36.07 (C-3),
40.95 (C-6), 56.13 (C-2), 64.90 (C-4) ppm. Anal. calcd for
C8H18ClNO (179.69): C, 53.47; H, 10.10; Cl, 19.73; N,
7.79%. Found: C, 53.54; H, 10.00; Cl, 19.72; N, 7.72%.
˜
(m), 1723 (s), 1612 (s), 1339 (m), 1105 (m) cm21
.
Compound 3. 1H NMR (DMSO-d6, d, 400 MHz): 0.86, 0.88
(2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.92–2.02 (m, 1H,
CH(CH3)2), 2.23–2.27 (m, 2H, 5-H), 3.33–3.40 (m, 1H,
6-H), 5.50 (s, 1H, 3-H), 8.89 (s, 1H, NH), 10.60 (br, 1H,
OH) ppm. 13C NMR (CDCl3, d, 100 MHz): 17.35, 18.48
(CH(CH3)2), 27.47 (C-5), 30.09 (CH(CH3)2), 57.08 (C-6),
103.58 (C-3), 163.86 (C-4), 192.70 (C-2) ppm.
3.5. 1-Methylpiperidin-4-ols (6)
1
Compound 4. H NMR (CDCl3, d, 400 MHz): 1.02, 1.06
(2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.93–2.06 (m, 1H,
CH(CH3)2), 2.45 (dd, J¼16.8, 9.2 Hz, 1H, 3-H), 2.65 (dd,
J¼16.8, 4.8 Hz, 1H, 3-H), 3.63–3.69 (m, 1H, 2-H), 3.71,
3.84 (2d, J¼20.4 Hz, 2H, 5-H), 9.02 (s, 1H, NH) ppm. 13C
NMR (CDCl3, d, 100 MHz): 17.79, 18.44 (CH(CH3)2),
31.74 (CH(CH3)2), 39.76 (C-3), 54.71 (C-5), 58.98 (C-2),
198.47 (C-6), 201.93 (C-4) ppm.
General procedure. Formic acid (0.05 mol) was added to
compounds 5a or 5b (0.01 mol) at 08C. The mixture was
slowly warmed until solution occurred. A 37% aqueous
solution of formaldehyde (0.02 mol) was subsequently
added at room temperature. The solution was heated on a
steam bath until the generation of carbon dioxide ceased.
The solution was cooled, acidified with concentrated
hydrochloric acid and the solvent removed in vacuo. The
oily residue was dissolved in 2 ml of H2O, made alkaline
with a 25% solution of caustic soda and extracted three
times with ether. The combined organic layers were dried
over sodium sulfate and the solvent was evaporated. The
hydrochlorides of 6a and 6b were afforded by treatment
with equivalent amounts of a 1 M solution of hydrogen
chloride in diethylether. The solvent was evaporated and the
residues were recrystallized.
3.4. 2-Isopropylpiperidin-4-ols (5a,b)
15 g of freshly prepared Raney nickel W-730 were added to a
solution of 3a, 4a (0.02 mol) in 200 ml of ethanol. The
mixture was shaken at room temperature at 45 psi for 96 h.
The reaction mixture was sucked off. The residue was
washed with ethanol. The filtrate was concentrated in vacuo.
The residue was dissolved in dichloromethane and H2O. The
layers were separated and the aqueous layer was extracted
once with dichloromethane. The combined organic layers
were dried over sodium sulfate. The solvent was evaporated
and the diastereomeric piperidinols were separated by CC
over silica gel eluting with methanol/ethyl acetate (4:1). The
hydrochlorides of 5a and 5b were afforded by treatment
with equivalent amounts of a 1 M solution of hydrogen
chloride in diethylether. The solvent was evaporated and the
residues were recrystallized.
3.5.1. (2RS,4SR)-(6)-2-Isopropyl-1-methylpiperidin-4-ol
(6a). Yield: 1.72 g (88.8%); mp (HCl): 2018C (acetone); IR
(base, KBr): n¼3417 (s), 2959 (s), 2933 (s), 1631 (s), 1602
˜
(m), 1461 (m), 1377 (m), 1072 (m) cm21; NMR (base): 1H
NMR (CDCl3, d, 400 MHz): 0.87, 0.90 (2d, J¼6.8 Hz, 6H,
CH(CH3)2), 1.22 (ddd, J¼11.4, 11.4, 11.4 Hz, 1H, 3-Hax),
1.58 (dddd, J¼12.3, 12.3, 12.3, 4.2 Hz, 1H, 5-Hax), 1.78
(ddd, J¼11.4, 4.0, 2.2 Hz, 1H, 2-Hax), 1.82–1.92 (m, 2H, 3-
Hequ, 5-Hequ), 2.02–2.10 (m, 1H, CH(CH3)2), 2.16 (ddd,
J¼12.3, 12.3, 2.4 Hz, 1H, 6-Hax), 2.23 (s, 3H, NCH3), 2.55
(br, 1H, OH), 2.93 (ddd, J¼12.3, 3.4, 3.4 Hz, 1H, 6-Hequ),
3.54–3.63 (m, 1H, 4-Hax) ppm. 13C NMR (CDCl3, d,
100 MHz): 14.89, 19.99 (CH(CH3)2), 27.60 (CH(CH3)2),
33.02 (C-3), 34.85 (C-5), 41.48 (NCH3), 55.71 (C-6), 67.09
(C-2), 69.59 (C-4) ppm. Anal. calcd for C9H20ClNO
(193.72): C, 55.80; H, 10.41; Cl, 18.30; N, 7.23%. Found:
C, 55.95; H, 10.46; Cl, 18.30; N, 7.22%.
3.4.1. (2RS,4SR)-(6)-2-Isopropylpiperidin-4-ol (5a).
Yield: 2.24 g (62.3%); mp (HCl): 2118C (acetone); Rf
(base)¼ 0.20 (methanol/ethyl acetate¼4:1); IR (base, KBr):
n¼3269 (m), 2936 (s), 2858 (s), 1468 (m), 1449 (m), 1366
˜
(m), 1055 (s), 857 (s) cm21; NMR (base): 1H NMR (CDCl3,
d, 400 MHz): 0.92, 0.94 (2d, J¼6.8 Hz, 6H, CH(CH3)2),
1.04 (ddd, J¼11.4, 11.4, 11.4 Hz, 1H, 3-Hax), 1.33 (dddd,
J¼ 12.1, 12.1, 12.1, 4.3 Hz, 1H, 5-Hax), 1.57–1.65 (m, 1H,
CH(CH3)2), 1.80 (br, 2H, NH, OH), 1.91–2.02 (m, 2H,
3-Hequ, 5-Hequ), 2.28 (ddd, J¼11.2, 5.8, 2.3 Hz, 1H, 2-Hax),
2.60 (ddd, J¼12.5, 12.5, 2.5 Hz, 1H, 6-Hax), 3.14 (ddd,
J¼12.5, 4.3, 2.5 Hz, 1H, 6-Hequ), 3.58–3.66 (m, 1H,
4-Hax) ppm. 13C NMR (CDCl3, d, 100 MHz): 18.68, 19.00
(CH(CH3)2), 32.87 (CH(CH3)2), 36.14 (C-5), 38.92 (C-3),
44.76 (C-6), 61.12 (C-2), 69.71 (C-4) ppm. Anal. calcd for
C8H18ClNO (179.69): C, 53.47; H, 10.10; Cl, 19.73; N,
7.79%. Found: C, 53.51; H, 9.98; Cl, 19.90; N, 7.68%.
3.5.2. (2RS,4RS)-(6)-2-Isopropyl-1-methylpiperidin-4-ol
(6b). Yield: 1.47 g (75.9%); mp (HCl): 1598C (aceto-
ne/ether); IR (base, KBr): n¼3339 (m), 2958 (s), 2780 (m),
˜
1460 (m), 1375 (m), 1270 (m), 1074 (s) cm21; NMR (base):
1H NMR (CDCl3, d, 400 MHz): 0.85, 0.88 (2d, J¼6.7 Hz,
6H, CH(CH3)2), 1.49 (ddd, J¼13.8, 11.4, 2.7 Hz, 1H,
3-Hax), 1.57–1.69 (m, 2H, 3-Hequ, 5-Hequ), 1.82–1.92 (m,
1H, 5-Hax), 1.94 (br, 1H, OH), 2.08–2.21 (m, 2H, 2-Hax,
CH(CH3)2), 2.27 (s, 3H, NCH3), 2.53 (ddd, J¼12.2, 12.2,
2.8 Hz, 1H, 6-Hax), 2.70 (ddd, J¼12.2, 4.7, 2.7 Hz, 1H,
6-Hequ), 4.13–4.18 (m, 1H, 4-Hequ) ppm. 13C NMR (CDCl3,
d, 100 MHz): 14.88, 19.89 (CH(CH3)2), 27.16 (CH(CH3)2),
30.48 (C-3), 32.29 (C-5), 42.41 (NCH3), 51.38 (C-6), 62.43
(C-2), 64.78 (C-4) ppm. Anal. calcd for C9H20ClNO
(193.72): C, 55.80; H, 10.41; Cl, 18.30; N, 7.23%. Found:
C, 55.99; H, 10.17; Cl, 18.16; N, 7.22%.
3.4.2. (2RS,4RS)-(6)-2-Isopropylpiperidin-4-ol (5b).
Yield: 0.47 g (13.1%); mp (HCl): 1738C (acetone); Rf
(base)¼ 0.15 (methanol/ethyl acetate¼4:1); IR (KBr):
n¼3267 (m), 2944 (m), 2889 (m), 1476 (m), 1371 (m),
˜
1
1271 (s), 1078 (s), 996 (s), 887 (s) cm21; NMR (base): H
NMR (CDCl3, d, 400 MHz): 0.89, 0.91 (2d, J¼6.8 Hz, 6H,
CH(CH3)2), 1.41 (ddd, J¼13.7, 11.4, 2.8 Hz, 1H, 3-Hax),

1408
R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
3.6. (RS)-(6)-1-Anilino-5-phenylpentan-3-ol (15)
3.7.2. (2RS,4RS)-(6)-2-Isopropyl-1-phenylpiperidin-4-ol
(16b). Yield: 0.54 g (21.1%); mp (HCl): 1658C (ethanol/
ethyl acetate); Rf (base)¼0.27 (toluene/ethyl acetate¼6:3);
10 g of freshly prepared Raney nickel W-730 were added to a
solution of 12 (0.005 mol) in 70 ml of ethanol. The mixture
was shaken at room temperature at 45 psi for 8 h. The
reaction mixture was sucked off. The residue was washed
with ethanol and the filtrate was concentrated in vacuo. The
residue was dissolved in dichloromethane and H2O. The
layers were separated and the aqueous layer was extracted
once with dichloromethane. The combined organic layers
were dried over sodium sulfate. The solvent was evaporated
and the pentanol 15 was separated from small amounts of
17a and 17b by CC over silica gel eluting with toluene/ethyl
acetate (9:1). The solvent was evaporated and the oily
residue was recrystallized. Yield: 1.02 g (79.9%); mp 908C
(ethanol/water); Rf¼0.12 (toluene/ethyl acetate¼9:1); IR
IR (KBr): n¼3345 (s), 2966 (m), 2612 (m), 1495 (m), 1427
˜
(m), 1393 (s), 1374 (s), 981 (s), 776 (m), 757 (m), 698
1
(m) cm21; NMR (base): H NMR (CDCl3, d, 400 MHz):
0.88, 0.99 (2d, J¼6.6 Hz, 6H, CH(CH3)2), 1.41 (ddd, J¼
13.6, 11.3, 5.1 Hz, 1H, 3-Hax), 1.44 (br, 1H, OH), 1.49
(dddd, J¼11.8, 11.8, 11.8, 4.4 Hz, 1H, 5-Hax), 1.86–1.93
(m, 1H, 5-Hequ), 2.02–2.12 (m, 2H, 3-Hequ, CH(CH3)2),
3.07 (ddd, J¼14.4, 12.0, 2.7 Hz, 1H, 6-Hax), 3.49–3.55 (m,
1H, 2-Hequ), 3.62–3.69 (m, 1H, 6-Hequ), 3.93–4.02 (m, 1H,
4-Hax), 6.68–7.22 (m, 5H, aromatic H) ppm. 13C NMR
(CDCl3, d, 100 MHz): 20.27, 20.53 (CH(CH3)2), 27.89
(CH(CH3)2), 33.58 (C-5), 34.24 (C-3), 40.86 (C-6), 62.47
(C-2), 65.79 (C-4), 115.11, 117.28, 129.16, 150.71 (aro-
matic C) ppm. Anal. calcd for C14H22ClNO (255.79): C,
65.74; H, 8.67; Cl, 13.86; N, 5.48%. Found: C, 65.71; H,
8.78; Cl, 13.84; N, 5.46%.
(KBr): n¼3272 (s), 2946 (m), 2918 (m), 1604 (s), 1507 (s),
˜
1052 (s), 931 (m), 755 (s), 737 (m), 691 (s) cm21; 1H NMR
(DMSO-d6, d, 400 MHz): 1.54–1.73 (m, 4H, 2-H, 4-H),
2.54–2.62 (m, 1H, 5-H), 2.68–2.75 (m, 1H, 5-H), 3.00–
3.14 (m, 2H, 1-H), 3.53–3.61 (m, 2H, 3-H), 4.58 (d, J¼
5.6 Hz, 1H, OH), 5.45 (d, J¼5.4 Hz, 1H, NH), 6.47–7.28
(m, 10H, aromatic H) ppm. 13C NMR (DMSO-d6, d,
100 MHz): 31.54 (C-5), 36.47 (C-2), 39.41 (C-4), 39.85
(C-1), 67.46 (C-3), 111.87, 115.27, 125.52, 128.23, 128.26,
128.82, 142.46, 149.07 (aromatic C) ppm. Anal. calcd for
C17H21NO (255.36): C, 79.96; H, 8.29; N, 5.49%. Found: C,
79.70; H, 8.11; N, 5.37%.
3.7.3. (2RS,4SR)-(6)-1,2-Diphenylpiperidin-4-ol (17a).
Yield: 1.70 g (56.0%); mp (HCl): 2278C (ethanol/ethyl
acetate); Rf (base)¼0.06 (toluene/ethyl acetate¼9:1); IR
(KBr): n¼ 3359 (s), 2520 (s), 1494 (m), 1242 (m), 1081 (s),
˜
1
762 (s), 699 (s) cm21; NMR (base): H NMR (CDCl3, d,
400 MHz): 1.57 (br, 1H, OH), 1.77 (ddd, J¼11.6, 11.6,
10.5 Hz, 1H, 3-Hax), 1.85 (dddd, J¼11.9, 11.1, 11.1, 4.0 Hz,
1H, 5-Hax), 2.05–2.12 (m, 1H, 5-Hequ), 2.18–2.24 (m, 1H,
3-Hequ), 2.93 (ddd, J¼12.5, 11.9, 2.7 Hz, 1H, 6-Hax), 3.54
(ddd, J¼12.5, 4.0, 4.0 Hz, 1H, 6-Hequ), 3.83–3.91 (m, 1H,
4-Hax), 4.11 (dd, J¼10.5, 3.3 Hz, 1H, 2-Hax), 6.80–7.25 (m,
10H, aromatic H) ppm. 13C NMR (CDCl3, d, 100 MHz):
35.45 (C-5), 45.18 (C-3), 54.16 (C-6), 62.18 (C-2), 68.89
(C-4), 122.31, 123.10, 126.51, 127.11, 128.23, 128.44,
143.66, 151.74 (aromatic C) ppm. Anal. calcd for C17H20-
ClNOþ0.3C2H5OH (303.63): C, 69.62; H, 7.24; Cl, 11.68;
N, 4.61%. Found: C, 69.68; H, 7.17; Cl, 11.54; N, 4.50%.
3.7. 1-Phenylpiperidin-4-ols (16, 17)
General procedure. 10 g of freshly prepared Raney
nickel W-232 were added to a solution of compounds
11 or 12 (0.01 mol) in 50 ml of ethanol. The mixture was
shaken at room temperature at 30 psi for 6 h. The
reaction mixture was sucked off. The residue was
washed repeatedly with ethanol. The filtrate was con-
centrated in vacuo. The isomers were separated by CC
over silica gel eluting with toluene/ethyl acetate (6:3) or
toluene/ethyl acetate (9:1), respectively. The hydrochlorides
of 16, 17 were afforded by treatment with equivalent
amounts of a 1 M solution of hydrogen chloride in
diethylether. The solvent was evaporated and the residues
recrystallized.
3.7.4. (2RS,4RS)-(6)-1,2-Diphenylpiperidin-4-ol (17b).
Yield: 0.60 g (20.7%); mp (HCl): 1698C (ethanol/ethyl
acetate); Rf (base)¼0.10 (toluene/ethyl acetate¼9:1); IR
(KBr): n¼ 3447 (m), 2930 (m), 2560 (s), 2315 (s), 1491 (s),
˜
1
1413 (s), 982 (s), 765 (s), 700 (s) cm21; NMR (base): H
NMR (CDCl3, d, 400 MHz): 1.68 (dddd, J¼12.7, 8.8, 8.8,
4.0 Hz, 1H, 5-Hax), 1.81 (br, 1H, OH), 1.93 (ddd, J¼13.6,
8.8, 4.9 Hz, 1H, 3-Hax), 1.96–2.03 (m, 1H, 5-Hequ), 2.33–
2.40 (m, 1H, 3-Hequ), 3.23 (ddd, J¼13.2, 9.6, 3.6 Hz, 1H,
6-Hax), 3.65 (ddd, J¼13.2, 4.9, 4.9 Hz, 1H, 6-Hequ), 3.87–
3.93 (m, 1H, 4-Hax), 4.98 (dd, J¼4.9, 4.9 Hz, 1H, 2-Hequ),
6.72–7.30 (m, 10H, aromatic H) ppm. 13C NMR (CDCl3, d,
100 MHz): 33.87 (C-5), 39.41 (C-3), 44.37 (C-6), 57.52
(C-2), 64.97 (C-4), 116.80, 118.90, 126.43, 126.91, 128.41,
129.02, 141.88, 150.58 (aromatic C) ppm. Anal. calcd for
C17H20ClNO (289.81): C, 70.46; H, 6.96; Cl, 12.23; N,
4.83%. Found: C, 70.37; H, 7.09; Cl, 12.12; N, 4.79%.
3.7.1. (2RS,4SR)-(6)-2-Isopropyl-1-phenylpiperidin-4-ol
(16a). Yield: 1.54 g (60.2%); mp (HCl): 2308C (ethanol/
ethyl acetate); Rf (base)¼0.22 (toluene/ethyl acetate¼6:3);
IR (KBr): n¼3337 (s), 2972 (m), 2538 (s), 1495 (m), 1090
˜
(s) 1030 (m), 756 (m), 694 (m) cm21; NMR (base): H
1
NMR (CDCl3, d, 400 MHz): 0.83 (d, J¼6.7 Hz, 6H,
CH(CH3)2), 1.53 (ddd, J¼12.7, 9.1, 9.1 Hz, 1H, 3-Hax),
1.63 (dddd, J¼ 12.7, 9.0, 9.0, 4.0 Hz, 1H, 5-Hax), 1.79 (br,
1H, OH), 1.86–2.00 (m, 3H, 3-Hequ, 5-Hequ, CH(CH3)2),
2.93 (ddd, J¼12.7, 9.0, 3.4 Hz, 1H, 6-Hax), 2.94–3.00 (m,
1H, 2-Hax), 3.23 (ddd, J¼12.7, 5.7, 4.0 Hz, 1H, 6-Hequ),
3.80–3.88 (m, 1H, 4-Hax), 6.96–7.29 (m, 5H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 16.55, 19.30
(CH(CH3)2), 28.41 (CH(CH3)2), 32.96 (C-3), 34.32 (C-5),
50.38 (C-6), 62.22 (C-2), 68.69 (C-4), 122.15, 128.98,
151.78 (aromatic C) ppm. Anal. calcd for C14H22ClNO
(255.79): C, 65.74; H, 8.67; Cl, 13.86; N, 5.48%. Found: C,
65.76; H, 8.66; Cl, 13.88; N, 5.35%.
3.8. 4-Benzhydryloxy-1-methylpiperidines (20–22)
General procedures. After their preparation according to
methods A–D compounds 20–22 were purified by CC over
silica gel eluting with the solvent mentioned under their Rf
values. Their hydrochlorides were afforded by treatment
with equivalent amounts of a 1 M solution of hydrogen

R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
1409
chloride in diethylether. The solvent was evaporated and the
residues recrystallized.
3.8.2. (2RS,4RS)-(6)-4-Benzhydryloxy-2-isopropyl-1-
methylpiperidine (20b). Yield (A): 1.43 g (65.2%), (B):
1.15 g (52.5%); mp (HCl): 2158C (acetone/ether); Rf
(base)¼0.10 (toluene/methanol¼9:1); IR (base, KBr):
General method A. The piperidinols 6, 16 or 17 (0.006 mol),
bromodiphenylmethane (0.006 mol) and potassium carbo-
nate (0.003 mol) were stirred on an oil bath at 1408C for 5 h.
The mixture was cooled and benzene (30 ml) was added.
The inorganic salts were dissolved in water (5 ml). The
layers were separated in a separatory funnel. The aqueous
layer was extracted once with benzene (10 ml). The com-
bined organic layers were washed twice with water, dried
and evaporated.
n¼3029 (w), 2957 (s), 2932 (m), 2796 (m), 1492 (m),
˜
1456 (s), 1266 (m), 1065 (s), 746 (m), 701 (s) cm21; NMR
(base): 1H NMR (CDCl3, d, 400 MHz): 0.82, 0.84 (2d,
J¼7.0 Hz, 6H, CH(CH3)2), 1.32 (ddd, J¼14.0, 11.3, 2.7 Hz,
1H, 3-Hax), 1.67–1.87 (m, 3H, 3-Hequ, 5-Hax, 5-Hequ),
2.06–2.17 (m, 1H, CH(CH3)2), 2.27 (s, 3H, NCH3), 2.23–
2.33 (m, 1H, 2-Hax), 2.64 (ddd, J¼11.8, 11.8, 2.8 Hz, 1H,
6-Hax), 2.66–2.74 (m, 1H, 6-Hequ), 3.75–3.78 (m, 1H,
4-Hequ), 5.45 (s, 1H, OCH), 7.23–7.37 (m, 10H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 14.95, 19.82
(CH(CH3)2), 27.02 (CH(CH3)2), 27.41 (C-3), 29.34 (C-5),
41.92 (NCH3), 52.45 (C-6), 63.40 (C-2), 69.40 (C-4), 80.47
(OCH), 126.90, 127.10, 127.30, 127.36, 128.28, 128.31,
142.70, 142.80 (aromatic C) ppm. Anal. calcd for C22H30-
ClNOþ0.3H2O (365.34): C, 72.33; H, 8.44; Cl, 9.70; N,
3.83%. Found: C, 72.32; H, 8.43; Cl, 9.77; N, 3.84%.
General method B. To an ice-cooled solution of compounds
6, 16 or 17 (0.006 mol) in 50 ml of freshly distilled
N,N-dimethylformamide (DMF) was added sodium hydride
(0.007 mol of a 60% dispersion in mineral oil). Bromo-
diphenylmethane (0.007 mol) was dissolved in DMF and
added dropwise to the reaction mixture, which was stirred at
room temperature for 3 h (longer reaction periods did not
cause increase in yield). After addition of ethanol (10 ml),
the mixture was poured into ice-water (200 ml). The product
was extracted three times with benzene. The workup was
identical with method A.
3.8.3. (2RS,4SR)-(6)-4-Benzhydryloxy-2-isopropyl-1-
phenylpiperidine (21a). Yield (A): 1.08 g (42.7%), (B):
0.77 g (30.4%), (C): 0.55 g (65.2%), (D): 0.75 g (88.9%);
mp (HCl): 2198C (ethanol/ethyl acetate); Rf (base)¼0.25
General method C. To a solution of the piperidinols 6, 16 or
17 (0.002 mol) in 20 ml of dry toluene diphenyldiazo-
methane (0.0024 mol) was added. The mixture was heated
under reflux for 18 h. After cooling to room temperature the
organic layer was repeatedly extracted with a 2 M solution
of HCl in water. The aqueous phase was made alkaline with
dilute caustic soda and extracted with toluene. The organic
layer was concentrated in vacuo.
(cyclohexane/ethyl acetate¼19:1); IR (KBr): n¼2969 (m),
˜
2271 (s), 1599 (m), 1492 (s), 1485 (s), 1411 (s), 1092 (s),
709 (s) cm21; NMR (base): 1H NMR (CDCl3, d, 400 MHz):
0.83, 0.89 (2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.67–1.94 (m,
4H, 3-H, 5-H), 2.11–2.23 (m, 1H, CH(CH3)2), 3.00 (ddd,
J¼13.0, 8.6, 4.3 Hz, 1H, 6-H), 3.08–3.14 (m, 1H, 2-H),
3.29 (ddd, J¼13.0, 7.8, 3.6 Hz, 1H, 6-H), 3.57–3.63 (m, 1H,
4-H), 5.53 (s, 1H, OCH), 6.82–7.38 (m, 15H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 17.65, 20.23
(CH(CH3)2), 28.72 (CH(CH3)2), 29.84 (C-3), 30.03 (C-5),
46.86 (C-6), 62.03 (C-2), 72.92 (C-4), 80.63 (OCH), 119.85,
120.40, 126.78, 126.95, 127.19, 127.29, 128.28, 128.31,
128.99, 142.80, 143.13, 151.49 (aromatic C) ppm. Anal.
calcd for C27H32ClNO (422.01): C, 76.85; H, 7.64; Cl,
8.40; N, 3.32%. Found: C, 76.91; H, 7.77; Cl, 8.30; N,
3.33%.
General method D. A solution of the piperidinols 6, 16 or 17
(0.002 mol), diphenylmethanol (0.0025 mol) and toluene-4-
sulfonic acid monohydrate (0.0025 mol) in 100 ml of
toluene was refluxed at a water separator for 6 h. After
cooling to room temperature the mixture was washed once
with a 1 M aqueous solution of caustic soda and twice with
water. The organic layer was dried over Na2SO4 and the
solvent removed in vacuo.
3.8.4. (2RS,4RS)-(6)-4-Benzhydryloxy-2-isopropyl-1-
phenylpiperidine (21b). Yield (A): 0.92 g (35.6%), (D):
0.67 g (77.7%); mp (HCl): 1828C (ethanol/ethyl acetate); Rf
(base)¼0.26 (cyclohexane/ethyl acetate¼19:1); IR (KBr):
3.8.1. (2RS,4SR)-(6)-4-Benzhydryloxy-2-isopropyl-1-
methylpiperidine (20a). Yield (A): 1.65 g (76.4%), (B):
1.11 g (51.4%); mp (HCl): 2298C (acetone/ether); Rf
(base)¼0.20 (toluene/methanol¼9:1); IR (base, KBr):
n¼2969 (m), 2490 (s), 1596 (m), 1492 (s), 1069 (s), 1048
˜
n¼3029 (w), 2957 (s), 2780 (m), 1492 (m), 1455 (s), 1274
(s), 760 (m), 700 (s) cm21; NMR (base): 1H NMR (CDCl3,
d, 400 MHz): 0.82, 0.84 (2d, J¼7.0 Hz, 6H, CH(CH3)2),
1.56 (ddd, J¼11.7, 11.1, 5.0 Hz, 1H, 3-Hax), 1.66 (dddd,
J¼12.3, 12.3, 10.5, 4.5 Hz, 1H, 5-Hax), 1.86–1.95 (m, 2H,
5-Hequ, CH(CH3)2), 2.07–2.13 (m, 1H, 3-Hequ), 2.99 (ddd,
J¼14.3, 12.3, 2.7 Hz, 1H, 6-Hax), 3.46–3.52 (m, 1H,
2-Hequ), 3.59–3.66 (m, 1H, 6-Hequ), 3.69–3.78 (m, 1H,
4-Hax), 5.55 (s, 1H, OCH), 6.67–7.34 (m, 15H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 19.95, 20.55
(CH(CH3)2), 27.73 (CH(CH3)2), 30.72 (C-5), 31.28 (C-3),
41.23 (C-6), 62.54 (C-2), 70.87 (C-4), 80.19 (OCH), 115.38,
117.33, 127.02, 127.09, 127.34, 128.30, 128.32, 129.10,
142.74, 142.77, 150.91 (aromatic C) ppm. Anal. calcd for
C27H32ClNOþ0.2 C2H5OH (431.22): C, 76.32; H, 7.76; Cl,
8.22; N, 3.25%. Found: C, 76.18; H, 7.78; Cl, 8.20; N,
3.28%.
˜
(m), 1075 (s), 744 (m), 701 (s) cm21; NMR (base): 1H NMR
(CDCl3, d, 400 MHz): 0.84, 0.86 (2d, J¼6.8 Hz, 6H,
CH(CH3)2), 1.31 (ddd, J¼11.7, 11.7, 11.7 Hz, 1H, 3-Hax),
1.58–1.68 (m, 2H, 2-Hax, 5-Hax), 1.85–1.92 (m, 1H,
3-Hequ), 1.93–2.05 (m, 3H, 5-Hequ, 6-Hax, CH(CH3)2),
2.16 (s, 3H, NCH3), 2.87 (ddd, J¼12.0, 3.5, 3.5 Hz, 1H,
6-Hequ), 3.29–3.37 (m, 1H, 4-Hax), 5.56 (s, 1H, OCH),
7.20–7.37 (m, 10H, aromatic H) ppm. 13C NMR (CDCl3, d,
100 MHz): 14.89, 19.71 (CH(CH3)2), 27.77 (CH(CH3)2),
30.21 (C-3), 31.98 (C-5), 41.70 (NCH3), 55.73 (C-6), 67.04
(C-2), 74.90 (C-4), 80.08 (OCH), 127.06, 127.08, 127.25,
127.31, 128.28, 128.32, 142.71, 142.91 (aromatic C) ppm.
Anal. calcd for C22H30ClNO (359.94): C, 73.41; H, 8.40; Cl,
9.85; N, 3.89%. Found: C, 73.22; H, 8.18; Cl, 9.83; N,
3.91%.

1410
R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
11. Sugiyama, N.; Akahoshi, F.; Kuwahara, S.; Kajii, M.; Sakaue,
Y.; Yakumaru, H.; Sugiura, M.; Fukaya, C. J. Med. Chem.
1994, 37, 1977–1982.
3.8.5. (2RS,4SR)-(6)-4-Benzhydryloxy-1,2-diphenyl-
piperidine (22a). Yield (A): 0.77 g (28.1%), (D): 0.78 g
(85.5%); mp (HCl): 1958C (ethanol/ethyl acetate); Rf
12. Falch, E.; Krogsgaard-Larsen, P. Eur. J. Med. Chem. Chim.
Ther. 1991, 26, 69–77.
(base)¼0.30 (toluene); IR (KBr): n¼3050 (m), 2358 (s),
˜
1599 (m), 1493 (s), 1449 (m), 1081 (s), 755 (s), 699
1
(s) cm21; NMR (base): H NMR (CDCl3, d, 400 MHz):
13. Regnier, G.; Dhainaut, A.; Duhault, J.; Lonchampt, M. (ADIR
et Cie.). EP 356323, 1990; Chem. Abstr. 1990, 113, 58932y.
14. Nishikawa, Y.; Shindo, T.; Ishii, K.; Nakamura, H.; Kon, T.;
Uno, H. J. Med. Chem. 1989, 32, 583–593.
1.92 (ddd, J¼12.7, 10.5, 10.5 Hz, 1H, 3-Hax), 1.97 (dddd,
J¼11.9, 11.1, 11.1, 4.1 Hz, 1H, 5-Hax), 2.10–2.18 (m, 1H,
5-Hequ), 2.27–2.35 (m, 1H, 3-Hequ), 2.87 (ddd, J¼11.9,
11.9, 2.8 Hz, 1H, 6-Hax), 3.54 (ddd, J¼11.9, 4.1, 4.1 Hz,
1H, 6-Hequ), 3.58–3.66 (m, 1H, 4-Hax), 4.05 (dd, J¼10.5,
3.3 Hz, 1H, 2-Hax), 5.56 (s, 1H, OCH), 6.78–7.33 (m, 20H,
aromatic H) ppm. 13C NMR (CDCl3, d, 100 MHz): 32.55
(C-5), 41.93 (C-3), 53.86 (C-6), 62.16 (C-2), 73.32 (C-4),
80.13 (OCH), 122.05, 122.84, 126.42, 126.99, 127.04,
127.15, 127.33, 127.34, 128.18, 128.31, 128.34, 128.41,
142.66, 143.90, 151.81 (aromatic C) ppm. Anal. calcd for
C30H30ClNO (456.03): C, 79.01; H, 6.63; Cl, 7.77; N,
3.07%. Found: C, 78.73; H, 6.75; Cl, 7.48; N, 3.00%.
15. Regnier, G. L.; Guillonneau, C. G.; Duhault, J. L.; Tisserand,
F. P.; Saint-Romas, G.; Holstorp, S. M. Eur. J. Med. Chem.
1987, 22, 243–250.
16. Takai, M.; Omori, K.; Hattori, S.; Ozawa, S.; Wakabayashi, T.
(Terumo Corp.). EP 226516, 1987; Chem. Abstr. 1987, 107,
154084v.
17. Cross, P. E.; Dickinson, R. P. (Pfizer Corp.). DE 2145360,
1972; Chem. Abstr. 1972, 77, 88333j.
18. Schuler, W. A. (Chem. Fabr. Promonta GmbH). DE 934890,
1955; Chem. Abstr. 1958, 52, 20065i.
19. Levy, J. (Nopco Chem. Co.). US 2751388, 1956; Chem. Abstr.
1957, 51, 2866h.
3.8.6. (2RS,4RS)-(6)-4-Benzhydryloxy-1,2-diphenyl-
piperidine (22b). Yield (A): 0.81 g (29.6%), (D): 0.76 g
(83.3%); mp (HCl): 1918C (ethanol/ethyl acetate); Rf
20. Papa, D.; Coan, S. B. (Schering Corp.). US 2745837, 1956;
Chem. Abstr. 1957, 51, 1297f.
(base)¼0.46 (toluene); IR (KBr): n¼3056 (m), 2364 (s),
21. Levy, J.; Chodroff, S.; Kapp, R. (Nopco Chem. Co.). US
2716122, 1955; Chem. Abstr. 1956, 50, 7149d.
22. Abou-Gharbia, M.; Moyer, J. A.; Nielsen, S. T.; Webb, M.;
Patel, U. J. Med. Chem. 1995, 38, 4026–4032.
23. Iwasaki, N.; Sakaguchi, J.; Ohashi, T.; Takahara, E.; Ogawa,
N.; Yasuda, S.; Koshinaka, E.; Kato, H.; Ito, Y.; Sawanishi, H.
Chem. Pharm. Bull. 1994, 42, 2276–2284.
˜
2338 (s), 1598 (m), 1489 (s), 1061 (s), 757 (s), 706 (s) cm21
;
1
NMR (base): H NMR (CDCl3, d, 400 MHz): 1.84–2.01
(m, 2H, 5-H), 2.06 (ddd, J¼13.2, 8.2, 5.1 Hz, 1H, 3-H),
2.23–2.30 (m, 1H, 3-H), 3.16 (ddd, J¼12.8, 8.6, 4.0 Hz, 1H,
6-H), 3.60 (ddd, J¼12.8, 7.0, 4.0 Hz, 1H, 6-H), 3.68–3.74
(m, 1H, 4-H), 4.88 (dd, J¼5.1, 5.1 Hz, 1H, 2-H), 5.52 (s, 1H,
OCH), 6.75–7.39 (m, 20H, aromatic H) ppm. 13C NMR
(CDCl3, d, 100 MHz): 31.04 (C-5), 37.02 (C-3), 45.75
(C-6), 57.96 (C-2), 70.37 (C-4), 80.64 (OCH), 117.95,
119.36, 126.33, 126.89, 127.05, 127.14, 127.32, 127.38,
128.29, 128.32, 128.33, 128.91, 142.46, 142.79, 151.16
(aromatic C) ppm. Anal. calcd for C30H30ClNO (456.03): C,
79.01; H, 6.63; Cl, 7.77; N, 3.07%. Found: C, 78.80; H,
6.72; Cl, 7.68; N, 3.03%.
24. Yakuo, I.; Yabuuchi, M.; Ito, T. Pharmacol. Toxicol. 2001, 89,
171–176.
25. Hurst, M.; Spencer, C. M. Drugs 2000, 59, 981–1006.
26. Shizawa, T.; Inaba, K.; Yoshida, F.; Iizuka, T.; Hijikuro, K.;
Yanoshita, R.; Kamitani, T. Arzneim.-Forsch./Drug Res. 1998,
48(II), 979–984.
27. Upton, C.; Jaffar, M. Pharm. Sci. 1996, 2, 411–414.
28. Zigeuner, G.; Schweiger, K. Monatsh. Chem. 1976, 107,
1361–1367.
29. Zigeuner, G.; Schweiger, K.; Fuchsgruber, A. Monatsh. Chem.
1981, 112, 187–197.
30. Adkins, H.; Billica, H. R. J. Am. Chem. Soc. 1948, 70,
695–698.
References
31. Weis, R.; di Vora, U.; Seebacher, W.; Schweiger, K. Monatsh.
Chem. 1995, 126, 1367–1374.
1. Knox, L. H.; Kapp, R. (NOPCO Chemical Co.). US 2479843,
1949; Chem. Abstr. 1950, 44, 1144a.
32. Mozingo, R. Organic Syntheses; Horning, E. C., Ed.; Wiley:
New York, 1955; Collect. Vol. 3, pp 181–183.
33. Pavlic, A. A.; Adkins, H. J. Am. Chem. Soc. 1946, 68, 1471.
34. Stern, P.; Trska, P.; Ferles, M. Collect. Czech. Chem.
Commun. 1974, 39, 2267–2275.
2. Zechel, H.-J.; Brock, N.; Lenke, D.; Achterrath-Tuckermann,
U. Arzneim.-Forsch./Drug Res. 1981, 31(II), 1184–1193.
3. Meindl, W. Arch. Pharm. 1989, 322, 493–497.
4. Ohno, T.; Kobayashi, S.; Hayashi, M.; Sakurai, M.;
Kanazawa, I. J. Neuro. Sci. 2001, 182, 95–97.
ˆ
35. Haddad, M.; Larchefeque, M. Tetrahedron: Asymmetry 1999,
5. Ramappa, P. G.; Somasekharappa, K. G. Syn. React. Inorg.
Met. 1998, 28, 263–274.
10, 4231–4237.
36. Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000,
14, 2106–2112.
6. Ramappa, P. G.; Somasekharappa, K. G. Indian J. Chem. Sect.
A 1994, 33A, 66–68.
´
37. Bosch, J.; Rubiralta, M.; Domingo, A.; Sistare, J.
J. Heterocycl. Chem. 1981, 18, 47–54.
7. Kikuchi, Y.; Mori, K.; Morino, Y.; Fukui, A. (Central Glass
Co.). JP 2001261678, 2001; Chem. Abstr. 2001, 135, 272881d.
8. D’Ambra, T. E. (Albany Molecular Research Inc.). WO
9709983, 1997; Chem. Abstr. 1997, 126, 293268p.
9. Shizawa, T.; Ohmori, S.; Maeda, K.; Sakata, K.; Ishii, T.;
Kamitani, T. Arzneim.-Forsch./Drug Res. 1996, 46(II),
1072–1076.
38. Bosch, J.; Rubiralta, M. An. Quim., Ser. C 1983, 79, 27–32.
39. Hohenlohe-Oehringen, K. Monatsh. Chem. 1963, 94,
1222–1224.
40. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron Lett. 1998, 39, 1973–1976.
41. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron Lett. 1998, 39, 7591–7594.
10. Zhang, M.-Q.; Wada, Y.; Sato, F.; Timmerman, H. J. Med.
Chem. 1995, 38, 2472–2477.

R. Weis et al. / Tetrahedron 59 (2003) 1403–1411
1411
42. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Eur. J. Org. Chem. 2001, 975–986.
43. Bosch, J.; Rubiralta, M.; Moral, M. Heterocycles 1982, 19,
473–476.
49. Vartanyan, R. S.; Martirosyan, V. H.; Vartanyan, S. A. Arm.
Khim. Zh. 1984, 37, 724–725.
50. Cordero, F. M.; Goti, A.; De Sarlo, F.; Gurana, A.; Brandi, A.
Tetrahedron 1989, 45, 5917–5924.
44. Bosch, J.; Rubiralta, M.; Moral, M.; Valls, M. J. Heterocycl.
Chem. 1983, 20, 595–605.
51. Brandi, A.; Garro, S.; Gurana, A.; Goti, A.; Cordero, F. M.;
De Sarlo, F. J. Org. Chem. 1988, 53, 2430–2434.
52. Brandi, A.; Gurana, A.; Goti, A.; De Sarlo, F. Tetrahedron
Lett. 1986, 27, 1727–1730.
45. Giralt, E.; Feliz, M.; Rubiralta, M.; Bosch, J. J. Heterocycl.
Chem. 1984, 21, 715–720.
46. D’yakov, M. Y.; Peretokin, A. V.; Sokolova, T. D.;
Moskovkin, A. S.; Unkovskii, B. V. SU 1490116, 1989;
Chem. Abstr. 1989, 111, 214397.
53. Phillips, R. F. (Merck and Co., Inc.). US 2595405, 1952;
Chem. Abstr. 1953, 47, 2218h.
54. Jackman, L. M.; Sternhell, S. Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry;
2nd ed., Pergamon: Oxford, 1969; pp 334–341.
47. Markaryan, R. E.; Airapetyan, G. K.; Noravyan, A. S. Arm.
Khim. Zh. 1988, 41, 311–313.
48. Vartanyan, R. S.; Martirosyan, V. H.; Kolozyan, K. R. Arm.
Khim. Zh. 1987, 40, 391–392.