2-Substituted 4-anilinopiperidines from 2H-thiopyran-2-thiones

Article abstract of DOI:10.1016/S0040-4020(01)00830-4

4-Dimethylamino-5,6-dihydro-2H-thiopyran-2-thiones were converted to 4-anilinodihydropyridine-2(1H)-thiones in several steps. The latter were alkylated giving a mixture of isomeric methylthioderivatives which were hydrogenated with Raney nickel yielding 2-alkyl- and 2-aryl-substituted 4-anilinopiperidines. The configurations as well as the conformations of the formed diastereoisomers are investigated by means of NMR.

Full text of DOI:10.1016/S0040-4020(01)00830-4

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 8305±8311
2-Substituted 4-anilinopiperidines from 2H-thiopyran-2-thiones
Robert Weis,p Klaus Schweiger and Werner Seebacher
È
Institute of Pharmaceutical Chemistry, University of Graz, Universitatsplatz 1, 8010 Graz, Austria
Received 8 May 2001; revised 17 July 2001; accepted 10 August 2001
AbstractÐ4-Dimethylamino-5,6-dihydro-2H-thiopyran-2-thiones were converted to 4-anilinodihydropyridine-2)1H)-thiones in several
steps. The latter were alkylated giving a mixture of isomeric methylthioderivatives which were hydrogenated with Raney nickel yielding
2-alkyl- and 2-aryl-substituted 4-anilinopiperidines. The con®gurations as well as the conformations of the formed diastereoisomers are
investigated by means of NMR. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
1-Substituted 4-anilinopiperidines 4 are used as precursors
for the synthesis of narcotic analgesics and antihistamines
which are used in medical therapy.1±3 A number of ana-
logues has already been prepared,4±18 some of them showing
Our method is based on the conversion of 6-iminodihydro-
2H-thiopyrans to dihydropyridine-2-thiones by a Dimroth-
type33 rearrangement. The 6-phenylimino-3,6-dihydro-2H-
thiopyran-4-anilines 13 were synthesized from 5,6-dihydro-
2H-thiopyran-2-thiones 8, which are available from a,b-
unsaturated methylketones 6 and dimethylammonium
enhanced activity. Furthermore the 4-anilinopiperidine unit
19
was inserted as linker groupin antibacterial
and anti-
arrhythmic agents,20 in adrenoceptor21 and platelet-acti-
vating factor antagonists22 and in orally active, nonpeptide
oxytocin23,24 and vasopressin antagonists.25 Quite recently,
1-substituted 4-anilinopiperidines had been reported as
serotonin antagonists26, neurokinin receptor antagonists27
and N-type calcium channel blockers.28±30
Usually they are prepared by the reaction of aniline with
1-substituted 4-piperidones 1 and the subsequent reduction
of the resulting Schiff bases 2.5±14,20±30 Moreover they were
synthesized by the reaction of the corresponding 4-chloro-
piperidines 3 with aniline derivatives1 or by the nucleophilic
aromatic substitution of electron-de®cient halobenzenes
with 1-substituted 4-aminopiperidines.19 Another conveni-
ent method is the hydrogenation of the respective 4-anilino-
pyridines 5.15 )Scheme 1).
4-Anilino-1-arylpiperidines 4 with no further substitution
of the piperidine ring have already been prepared from
4-bromo-1-arylpiperidines 3,31,32 but ring-substituted
4-anilino-1-phenylpiperidines have not yet been reported.
This paper deals with the synthesis of 2-alkyl- and 2-aryl-
substituted 4-anilino-1-phenylpiperidines by an alternative
pathway.
Keywords: piperidines; rearrangement; hydrogenation; stereoisomerism.
Corresponding author. Tel.: 143-316-380-5379; fax: 143-316-380-
9846; e-mail: robert.weis@uni-graz.at
Scheme 1. R1: alkyl; R2: H, acyl, alkyl, aryl; R3: H, acyl, alkyl; Ar: aryl; X:
halogen.
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00830-4

8306
R. Weis et al. / Tetrahedron 57 )2001) 8305±8311
Table 1. Ratio of isomeric methoiodides determined by 1H NMR inte-
gration
from the NHs to C-3 and C-5 of the thiopyran ring establish-
ing the 4-amino compounds 13 against the 4-imino
tautomers 14 as main components. Compounds 13 were
converted to 1-phenyl-5,6-dihydropyridine-2)1H)-thiones
16 by a Dimroth rearrangement, which was obvious from
the signal of the thioxo carbon at 192 ppm in their 13C NMR
spectra. The transposition starts with the removal of a proton
in position 3 of the thiopyran ring, whereupon ring cleavage
between S-1 and C-2 occurs. The formed a,b,g,d-unsatu-
rated anions 15 undergo protonation and ring closure to the
dihydropyridinethiones 16 )Scheme 2).
Isomer
11a, 12a
11b, 12b
17a, 18a
17b, 18b
syn-Isomer
anti-Isomer
73
27
60
40
86
14
67
33
N,N-dimethyldithiocarbamate 7 in a one-pot reaction.34 The
4-dimethylamino groupof the latter was removed by
alkaline hydrolysis yielding the 4-hydroxy derivatives 9,
which gave upon treatment with aniline the 4-phenyl-
amino-2H-thiopyran-2-thiones 10. The thiones 10 were
quantitatively alkylated to a mixture of the isomeric
methylthioderivatives 11, 12 with the syn-isomers 11a, b
as main components )Table 1). The relative con®gurations
Their methoiodides 17 and 18 were a mixture of syn- and
anti-isomers. In 1H NMR spectra the syn-isomers 17a,
b were revealed as main components by characteristic
up®eld shifts of the signals for the protons in syn position
to the 4-anilino ring )Table 1).
1
of compounds 11 and 12 were deduced from their H- and
13C NMR spectra: the shielding of the 4-anilino ring causes
up®eld shifts of the signals for neighbouring protons and
carbons in syn position. Furthermore, NOE measurements
proved the 3-Hs in 11a, b and the 5-Hs in 12a, b to be cis
relative to the corresponding NHs. The reactions of 11 and
12 with aniline gave their 6-phenyliminoderivatives 13. In
1H NMR spectra we observed signals for ca. 16% of a
second isomeric form, however we did not investigate
if there is an equilibrium with tautomer 14 or if it is a
rotational isomer of 13. In ge-HMQC spectra which were
optimized for 10 Hz we observed long-range couplings
These results were con®rmed by NOE measurements. Upon
irradiation of the NHs we observed NOEs at the 3-Hs in 17a,
b and at the 5-Hs in 18a, b. The hydrogenation of the
dihydropyridine-2)1H)-thiones 16 to 4-anilinopiperidines
19 and 20 with Raney nickel failed under mild reaction
conditions, whereas an increase of the pressure, the
temperature or the activity of the catalyst always caused
the cleavage of the heterocyclic ring. The hydrogenations
of the methoiodides 17 and 18 with Raney nickel W-735
gave even at ambient temperature and atmospheric pressure
Scheme 2.

R. Weis et al. / Tetrahedron 57 )2001) 8305±8311
8307
with the aid of 2D NMR spectra )H,H-COSY and ge-
HMQC). The relative con®gurations at C-2 and C-4 of
3
compounds 19 and 20 were deduced from the J)2-H,
3-H)
3
1
and J)3-H, 4-H) coupling constants in H NMR spectra. The
3J)3-H,
couplings were ca. 11 Hz for all compounds
4-H)
indicating axial positions of 3-Hs and 4-Hs. Furthermore,
11 Hz 3J)2-H, 3-H) couplings revealed the axial positions of the
2-Hs in 19a, b, whereas the equatorial 2-Hs in 20a, b caused
3
typical 5 Hz J)2-H, 3-H) couplings.
The conformations of compounds 19 and 20 were investi-
gated by NOE and homodecoupling NMR experiments.
NOEs from the axial protons in ring position 3 to the
axial 5-Hs as well as from the axial protons in ring position
6 to the 4-Hs were detected. Upon irradiation of the axial
2-Hs in compounds 19 we observed NOEs at the axial 6-Hs
and 4-Hs. Besides, w-couplings37 between the equatorial
protons in positions 3 and 5 of 19 and 20 were detected
by homodecoupling experiments. Additional w-couplings
were established between the equatorial 2-Hs and 6-Hs
of compounds 20 )Fig. 1). Their values were estimated
from the reduction of the signal half-width during homo-
decoupling.
All above-mentioned observations indicate that the piperi-
dine rings of compounds 19 and 20 prefer chair confor-
mations.
The present method provides an access to 2-alkyl and 2-aryl
substituted 4-anilino-1-arylpiperidines from easily available
a,b-unsaturated methylketones.
3. Experimental
3.1. General
Scheme 3.
mixtures of 4-anilinopiperidines with large amounts of non-
cyclized compounds. Therefore 17 and 18 were treated with
Raney nickel W-236 at room temperature affording mixtures
of 19 and 20 in good yields. The isomers were separated by
LC yielding larger amounts of compounds 19, which are
energetically favoured due to the equatorial substituent in
ring position 2 )Scheme 3).
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 )298 K) 5 mm
1
tubes, TMS as internal standard. H- and 13C-resonances
1
1
were assigned using H,1H- and H,13C-correlation spectra.
Assignments marked with an asterisk are interchangeable
between syn- and anti-isomers. Isomeric ratios were deter-
mined by 1H NMR integration. Microanalyses: Micro-
analytical 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±
The resonances in 1H- and 13C NMR spectra were assigned
Ê
0.025 mm, pore-diameter 60 A; column diameter 40 mm,
,
layer thickness 410 mm, rate of ¯ow: 15 ml min21
detection: Wellchrom K-2400 RI detector )Knauer), thin-
layer chromatography )TLC): TLC plates )Merck) silica
gel 60 F254
.
3.1.1. 'RS)-'^)-4-Dimethylamino-6-'1-methylethyl)-5,6-
dihydro-2H-thiopyran-2-thione '8a). 5-Methylhex-3-en-
2-one 6a )1.0 mol) and dimethylammonium N,N-dimethyl-
dithiocarbamate 7 )0.5 mol) were suspended in 350 ml of
bromobenzene. The mixture was re¯uxed at a water sepa-
rator for 6 h and the solvent removed in vacuo. The residue
Figure 1. NOEs )arrows) and w-couplings )bold) in 1H NMR spectra of 19
and 20.

8308
R. Weis et al. / Tetrahedron 57 )2001) 8305±8311
was triturated with ethanol, ®ltered and recrystallized.
Yield: 62.5 g )58.0%); mp161 8C )ethanol); IR )KBr):
)2-propanol); IR )KBr): nˆ3005 )w), 1519 )s), 1507 )s),
Ä
1
1448 )m), 1391 )m), 1237 )m), 966 )m) cm21; H NMR
nˆ2962 )m), 2865 )w), 1548 )s), 1486 )s), 1262 )s), 989
)DMSO-d6, d, 400 MHz): 3.02 )dd, Jˆ16.6, 3.1 Hz, 1H,
5-H), 3.39 )dd, Jˆ16.6, 12.4 Hz, 1H, 5-H), 4.84 )dd, Jˆ
12.4, 3.1 Hz, 1H, 6-H), 6.50 )s, 1H, 3-H), 7.28±7.51 )m,
10H, aromatic H), 9.98 )br, s, 1H, NH) ppm. 13C NMR
)DMSO-d6, d, 100 MHz): 34.92 )C-5), 46.57 )C-6),
111.01 )C-3), 124.70, 126.55, 127.69, 128.10, 128.87,
129.60, 137.33, 138.54 )aromatic C), 156.80 )C-4), 208.28
)C-2); Anal. Calcd for C17H15NS2 )297.44): C, 68.65; H,
5.08; N, 4.71; S, 21.56%. Found: C, 68.53; H, 5.16; N,
4.69; S, 21.63%.
Ä
1
)s) cm21; H NMR )CDCl3, d, 400 MHz): 1.05, 1.06 )2d,
Jˆ6.8 Hz, 6H, CH)CH3)2), 1.91±2.02 )m, 1H, CH)CH3)2),
2.53 )dd, Jˆ16.4, 12.2 Hz, 1H, 5-H), 2.86 )dd, Jˆ16.4,
3.5 Hz, 1H, 5-H), 3.14 )s, 6H, N)CH3)2), 3.26 )ddd, Jˆ
12.2, 6.2, 3.5 Hz, 1H, 6-H), 6.52 )s, 1H, 3-H) ppm. 13C
NMR )CDCl3, d, 100 MHz): 19.44, 19.99 )CH)CH3)2),
30.43 )C-5), 31.24 )CH)CH3)2), 40.72 )N)CH3)2), 50.08
)C-6), 112.74 )C-3), 159.15 )C-4), 208.05 )C-2); Anal.
Calcd for C10H17NS2 )215.38): C, 55.77; H, 7.96; N, 6.50;
S, 29.77%. Found: C, 55.77; H, 8.04; N, 6.53; S, 29.52%.
3.3. 6-Methylthio-N-phenyl-2H-thiopyran-4'3H)-
iminiumiodides '11, 12)
3.1.2. 'RS)-'^)-4-Dimethylamino-6-phenyl-5,6-dihydro-
2H-thiopyran-2-thione '8b). 8b was obtained from
methylstyrylketone 6b and dimethylammonium-N,N-
dimethyldithiocarbamate 7 according to a reported pro-
General procedure. A solution of iodomethane )0.12 mol)
in 50 ml of CHCl3 was added through a dropping funnel to a
suspension of 10 )0.1 mol) in CHCl3 )200 ml) within 1 h.
The reaction mixture was stirred for 16 h at room tempera-
ture. The solvent was removed in vacuo. The residue
was triturated with ethyl acetate, ®ltered with suction and
recrystallized.
cedure.34 Mp192 8C )mp34 1948C); IR )KBr): nˆ2870
Ä
)w), 1536 )s), 1469 )s), 1432 )s), 1411 )s), 1250 )s), 979
)s) cm21; 1H NMR )CDCl3, d, 400 MHz): 2.94 )dd, Jˆ17.1,
13.0 Hz, 1H, 5-H), 3.08 )dd, Jˆ17.1, 3.4 Hz, 1H, 5-H), 3.12
)s, 6H, N)CH3)2), 4.57 )dd, Jˆ13.0, 3.4 Hz, 1H, 6-H), 6.61
)s, 1H, 3-H), 7.31±7.39 )m, 5H, aromatic H) ppm. 13C NMR
)CDCl3, d, 100 MHz): 34.00 )C-5), 40.88 )N)CH3)2), 47.70
)C-6), 112.65 )C-3), 127.60, 128.34, 128.97, 137.86
)aromatic C), 158.69 )C-4), 207.67 )C-2) ppm.
3.3.1. 'RS)-'^)-2-'1-Methylethyl)-6-methylthio-N-phenyl-
2H-thiopyran-4'3H)-iminiumiodide '11a, 12a). Yield:
38.4 g )94.7%); mp145 8C )chloroform/ethyl acetate); IR
)KBr): nˆ2769 )m), 1601 )m), 1570 )m), 1514 )s), 1491
Ä
)m), 1452 )m), 1282 )m), 1269 )m) cm21; 11a )main com-
ponent): 1H NMR )CDCl3, d, 400 MHz): 1.15, 1.18 )2d, Jˆ
6.9 Hz, 6H, CH)CH3)2), 2.09±2.23 )m, 1H, CH)CH3)2), 2.59
)s, 3H, SCH3), 3.19 )dd, Jˆ17.2, 13.3 Hz, 1H, 3-H), 3.55
)ddd, Jˆ13.3, 6.1, 3.0 Hz, 1H, 2-H), 4.36 )dd, Jˆ17.2,
3.0 Hz, 1H, 3-H), 6.53 )s, 1H, 5-H), 7.41±7.51 )m, 5H,
aromatic H), 12.95 )br, 1H, NH) ppm. 13C NMR )CDCl3,
d, 100 MHz): 16.18 )SCH3), 19.59, 20.01 )CH)CH3)2),
31.37 )CH)CH3)2), 32.76 )C-3), 50.41 )C-2), 105.49 )C-5),
125.07, 129.35, 129.86, 134.37 )aromatic C), 167.14 )C-4),
183.71 )C-6) ppm. 12a )minor constituent): 1H NMR
)CDCl3, d, 400 MHz): 0.97, 1.04 )2d, Jˆ6.9 Hz, 6H,
CH)CH3)2), 1.96±2.10 )m, 1H, CH)CH3)2), 2.79 )s, 3H,
SCH3), 2.92 )dd, Jˆ17.3, 12.2 Hz, 1H, 3-H), 3.11 )dd, Jˆ
17.3, 3.2 Hz, 1H, 3-H), 3.36 )ddd, Jˆ12.2, 6.1, 3.1 Hz, 1H,
2-H), 7.41±7.51 )m, 5H, aromatic H), 8.11 )s, 1H, 5-H),
12.95 )br, 1H, NH) ppm. 13C NMR )CDCl3, d, 100 MHz):
17.83 )SCH3), 19.45, 19.87 CH)CH3)2, 30.73 )C-3), 31.07
)CH)CH3)2), 49.88 )C-2), 109.33 )C-5), 125.04, 129.40,
129.78, 133.95 )aromatic C), 168.32 )C-4), 179.53 )C-6);
Anal. Calcd for C15H20INS2 )405.36): C, 44.45; H, 4.97; I,
31.31; N, 3.46; S, 15.82%. Found: C, 44.53; H, 4.92; I,
31.29; N, 3.44; S, 15.77%.
3.2. 4-Anilino-5,6-dihydro-2H-thiopyran-2-thiones '10)
General procedure. The 4-dimethylamino-2H-thiopyran-2-
thiones )0.2 mol) were suspended in a 2 M solution of
sodium hydroxide )0.5 mol) and stirred at 608C for 24 h.
The mixture was cooled and ®ltered. The ice-cooled
solution was acidi®ed with HClconc and repeatedly extracted
with toluene )300 ml). The organic layers were carefully
washed with H2O and brine. After drying over Na2SO4,
ca. 50 ml of the solvent were removed in vacuo. Without
further puri®cation of the formed 4-hydroxy compounds 9,
aniline )0.2 mol) and acetic acid )0.12 mol) were added to
the solution and the mixture was heated at a water separator
for 8 h. The mixture was cooled and the solvents removed in
vacuo. The residue was triturated with 2-propanol, ®ltered
with suction and recrystallized.
3.2.1. 'RS)-'^)-4-Anilino-6-'1-methylethyl)-5,6-dihydro-
2H-thiopyran-2-thione '10a). Yield: 37.2 g )70.6%); mp
2058C )2-propanol); IR )KBr): nˆ2958 )w), 1518 )s),
Ä
1494 )m), 1449 )m), 1395 )m), 1236 )m), 980 )m) cm21
;
1H NMR )CDCl3, d, 400 MHz): 1.02, 1.03 )2d, Jˆ6.8 Hz,
6H, CH)CH3)2), 1.88±1.97 )m, 1H, CH)CH3)2), 2.73 )dd,
Jˆ16.2, 11.9 Hz, 1H, 5-H), 2.82 )dd, Jˆ16.2, 3.7 Hz, 1H,
5-H), 3.28 )ddd, Jˆ11.9, 6.4, 3.7 Hz, 1H, 6-H), 6.66 )s, 1H,
3-H), 7.17±7.37 )m, 5H, aromatic H), 7.49 )br, s, 1H,
NH) ppm. 13C NMR )CDCl3, d, 100 MHz): 19.66, 19.86
)CH)CH3)2), 31.22 )CH)CH3)2), 33.63 )C-5), 50.48 )C-6),
112.23 )C-3), 124.73, 127.00, 129.59, 136.61 )aromatic C),
155.91 )C-4), 212.22 )C-2); Anal. Calcd for C14H17NS2
)263.42): C, 63.83; H, 6.50; N, 5.32; S, 24.34%. Found:
C, 63.64; H, 6.71; N, 5.30; S, 24.21%.
3.3.2.
'RS)-'^)-6-Methylthio-N,2-diphenyl-2H-thio-
pyran-4'3H)-iminiumiodide '11b, 12b). Yield: 42.7 g
)97.2%); mp168 8C )chloroform/ethyl acetate); IR )KBr):
nˆ2812 )m), 1601 )m), 1569 )m), 1508 )s), 1490 )s),
Ä
1454 )s), 1281 )m), 1265 )m) cm21; 11b )main component):
1H NMR )CDCl3, d, 400 MHz): 2.56 )s, 3H, SCH3), 3.73
)dd, Jˆ17.4, 13.7 Hz, 1H, 3-H), 4.40 )dd, Jˆ17.4, 3.1 Hz,
1H, 3-H), 5.01 )dd, Jˆ13.7, 3.1 Hz, 1H, 2-H), 6.55 )s, 1H,
5-H), 7.29±7.56 )m, 10H, aromatic H), 12.90 )br, 1H,
NH) ppm. 13C NMR )CDCl3, d, 100 MHz): 16.15 )SCH3),
35.28 )C-3), 46.60 )C-2), 105.90 )C-5), 125.30, 127.65,
3.2.2. 'RS)-'^)-4-Anilino-6-phenyl-5,6-dihydro-2H-thio-
pyran-2-thione '10b). Yield: 40.3 g )67.7%); mp234 8C

R. Weis et al. / Tetrahedron 57 )2001) 8305±8311
8309
129.28, 129.30, 129.35, 129.74, 134.25, 134.47 )aromatic
C), 166.61 )C-4), 183.32 )C-6) ppm. 12b )minor con-
stituent): 1H NMR )CDCl3, d, 400 MHz): 2.72 )s, 3H,
SCH3), 3.30 )dd, Jˆ17.6, 2.9 Hz, 1H, 3-H), 3.53 )dd, Jˆ
17.6, 13.9 Hz, 1H, 3-H), 4.77 )dd, Jˆ13.9, 2.9 Hz, 1H, 2-H),
7.29±7.56 )m, 10H, aromatic H), 8.14 )s, 1H, 5-H), 12.90
)br, 1H, NH) ppm. 13C NMR )CDCl3, d, 100 MHz): 17.58
)SCH3), 33.73 )C-3), 46.56 )C-2), 109.39 )C-5), 125.14,
127.66, 129.26, 129.30, 129.42, 129.62, 133.83, 135.05
)aromatic C), 168.25 )C-4), 179.10 )C-6); Anal. Calcd for
C18H18INS2 )439.38): C, 49.21; H, 4.13; I, 28.88; N, 3.19; S,
14.60%. Found: C, 49.03; H, 4.15; I, 28.68; N, 3.16; S,
14.53%.
76.72; H, 5.71; N, 7.78; S, 8.90%. Found: C, 76.82; H,
5.74; N, 7.89; S, 8.73%.
3.5. 4-Anilino-1-phenyl-5,6-dihydropyridine-2'1H)-
thiones '16)
General procedure. Compounds 13 )0.05 mol) were added
to 200 ml of freshly distilled DMF. A stream of argon was
passed through the suspension for 5 min. The re¯ux con-
denser was closed with a balloon and the reaction mixture
was re¯uxed for 16 h. The solvent was removed in vacuo.
The residue was triturated with ethanol/ethyl acetate,
®ltered with suction and recrystallized.
3.5.1. 'RS)-'^)-4-Anilino-6-'1-methylethyl)-1-phenyl-5,6-
dihydropyridine-2'1H)-thione '16a). Yield: 11.5 g
3.4. N-Phenyl-6-phenylimino-3,6-dihydro-2H-thiopyran-
4-amines '13)
)71.3%); mp199 8C )ethanol); IR )KBr): nˆ3174 )w),
Ä
3029 )w), 2960 )w), 1611 )m), 1583 )s), 1534 )m), 1492
)m), 1444 )m), 1427 )m), 1276 )m), 1163 )m), 699
General procedure. The respective N-phenyl-6-methylthio-
2H-thiopyran-4)3H)-iminiumiodides 11 and 12 )0.09 mol)
were dissolved in aniline )2 moles). The mixture was stirred
at 608C for 18 h, while a stream of nitrogen was passed
through. The formed mercaptan was captured in a gas-
washing bottle with dilute caustic soda. The excess of
aniline was removed in vacuo. The residue was triturated
with ethyl acetate, ®ltered with suction, dried and subse-
quently stirred in a 2 M solution of sodium hydroxide
)0.8 mol) in water for 1 h. The resulting suspension was
extracted with ether or toluene repeatedly. The combined
extracts were washed three times with water and dried over
Na2SO4. The solvent was evaporated. The residue was tri-
turated with ethanol/water, ®ltered with suction, dried and
recrystallized.
1
)m) cm21; H NMR )CDCl3, d, 400 MHz): 0.89, 1.01 )2d,
Jˆ6.8 Hz, 6H, CH)CH3)2), 2.19±2.28 )m, 1H, CH)CH3)2),
2.49 )dd, Jˆ16.4, 3.1 Hz, 1H, 5-H), 3.01 )dd, Jˆ16.4,
7.8 Hz, 1H, 5-H), 3.83±3.88 )m, 1H, 6-H), 5.98 )s, 1H,
NH), 6.28 )s, 1H, 3-H), 7.13±7.44 )m, 10H, aromatic
H) ppm. 13C NMR )CDCl3, d, 100 MHz): 17.49, 19.75
)CH)CH3)2), 28.11 )C-5), 30.27 )CH)CH3)2), 65.15 )C-6),
101.83 )C-3), 123.03, 125.05, 127.29, 128.66, 128.84,
129.32, 138.36 )aromatic C), 145.70 )C-4), 191.99 )C-2);
Anal. Calcd for C20H22N2S )322.47): C, 74.49; H, 6.88; N,
8.69; S, 9.94%. Found: C, 74.27; H, 7.05; N, 8.74; S, 9.77%.
3.5.2. 'RS)-'^)-4-Anilino-1,6-diphenyl-5,6-dihydropyri-
dine-2'1H)-thione '16b). Yield: 14.4 g )80.8%); mp
2168C )ethanol); IR )KBr): nˆ3260 )m), 3190 )w), 3120
)m), 1240 )m), 1160 )s), 755 )s), 695 )s) cm21; H NMR
Ä
)w), 3050 )w), 1580 )s), 1530 )s), 1490 )s), 1425 )s), 1370
3.4.1. 'RS)-'^)-2-'1-Methylethyl)-N-phenyl-6-phenyl-
imino-3,6-dihydro-2H-thiopyran-4-amine '13a). Yield:
1
24.4 g )84.1%); mp143 8C )ethanol/water); IR )KBr): nˆ
Ä
2958 )w), 1585 )m), 1531 )s), 1494 )m), 1229 )m), 695
)CDCl3, d, 400 MHz): 2.59 )dd, Jˆ16.1, 2.5 Hz, 1H, 5-H),
3.48 )dd, Jˆ16.1, 6.2 Hz, 1H, 5-H), 5.07 )dd, Jˆ6.2, 2.5 Hz,
1H, 6-H), 5.94 )s, 1H, NH), 6.42 )s, 1H, 3-H), 7.07±7.35 )m,
15H, aromatic H) ppm. 13C NMR )CDCl3, d, 100 MHz):
36.63 )C-5), 63.99 )C-6), 103.48 )C-3), 123.18, 125.27,
126.91, 127.30, 127.51, 128.01, 128.71, 128.95, 129.40,
138.09, 139.36 )aromatic C), 143.77 )C-4), 146.11
)aromatic C), 192.76 )C-2); Anal. Calcd for C23H20N2S
)356.49): C, 77.49; H, 5.65; N, 7.86; S, 9.00%. Found: C,
77.08; H, 5.78; N, 7.70; S, 8.92%.
1
)m) cm21; H NMR )DMSO-d6, d, 400 MHz): 0.93, 0.94
)2d, Jˆ6.8 Hz, 6H, CH)CH3)2), 1.80±1.87 )m, 1H,
CH)CH3)2), 2.66 )dd, Jˆ16.2, 11.2 Hz, 1H, 3-H), 2.76
)dd, Jˆ16.2, 2.5 Hz, 1H, 3-H), 3.18±3.26 )m, 1H, 2-H),
5.84 )s, 1H, 5-H), 6.72±7.42 )m, 10H, aromatic H), 8.42
)s, 1H, NH) ppm. 13C NMR )DMSO-d6, d, 100 MHz):
19.88 )CH)CH3)2), 31.63 )CH)CH3)2), 33.28 )C-3), 46.80
)C-2), 96.87 )C-5), 120.84, 122.56, 123.67, 128.79,
129.36, 140.14, 151.45 )aromatic C), 152.40 )C-4), 159.44
)C-6); Anal. Calcd for C20H22N2S )322.47): C, 74.49; H,
6.88; N, 8.69; S, 9.94%. Found: C, 74.30; H, 7.02; N,
8.68; S, 9.82%.
3.6. 6-Methylthio-N,1-diphenyl-2,3-dihydropyridine-
4'1H)-iminiumiodides '17, 18)
3.4.2. 'RS)-'^)-N,2-Diphenyl-6-phenylimino-3,6-dihydro-
2H-thiopyran-4-amine '13b). Yield: 25.0 g )77.1%); mp
General method. A solution of iodomethane )0.036 mol) in
20 ml of chloroform was added through a dropping funnel to
a suspension of 16 )0.03 mol) in 80 ml of chloroform within
1 h. The solution was stirred for 18 h at room temperature.
The solvent was removed in vacuo. The residue was tri-
turated with ethanol/ethyl acetate, ®ltered with suction and
recrystallized.
1658C )ethanol); IR )KBr): nˆ3200 )w), 3040 )m), 1620
Ä
)m), 1590 )s), 1530 )s), 1490 )s), 1445 )s), 1290 )m), 1230
)s), 1170 )s), 695 )s) cm21 1H NMR )DMSO-d6, d,
;
400 MHz): 2.89 )dd, Jˆ16.3, 2.9 Hz, 1H, 3-H), 3.23 )dd,
Jˆ16.3, 12.1 Hz, 1H, 3-H), 4.62 )dd, Jˆ12.1, 2.9 Hz, 1H,
2-H), 5.92 )s, 1H, 5-H), 6.74±7.52 )m, 15H, aromatic H),
8.39 )s, 1H, NH) ppm. 13C NMR )DMSO-d6, d, 100 MHz):
36.42 )C-3), 43.72 )C-2), 96.55 )C-5), 120.80, 122.80,
122.99, 123.89, 127.90, 128.12, 128.75, 128.85, 129.44,
139.84, 139.91, 151.27 )aromatic C), 152.40 )C-4), 159.56
)C-6); Anal. Calcd for C23H20N2S10.2 H2O )360.09): C,
3.6.1. 'RS)-'^)-2-'1-Methylethyl)-6-methylthio-N,1-di-
phenyl-2,3-dihydropyridine-4'1H)-iminiumiodide '17a,
18a). Yield: 12.4 g )87.1%); mp215 8C )chloroform/ethyl
acetate); IR )KBr): nˆ3036 )m), 2960 )m), 1602 )m),
Ä
1579 )s), 1560 )s), 1479 )s), 1408 )m), 1281 )s), 764 )m),

8310
R. Weis et al. / Tetrahedron 57 )2001) 8305±8311
697 )m) cm21; 17a )main component): 1H NMR )DMSO-d6,
d, 400 MHz): 0.90, 0.97 )2d, Jˆ6.8 Hz, 6H, CH)CH3)2),
2.04±2.14 )m, 1H, CH)CH3)2), 2.39 )s, 1H, SCH3), 3.01±
3.09 )m, 1H, 3-H), 3.49±3.59 )m, 1H, 3-H), 4.12±4.17 )m,
1H, 2-H), 5.65 )s, 1H, 5-H), 7.33±7.62 )m, 10H, aromatic
H), 11.07 )br, 1H, NH) ppm. 13C NMR )DMSO-d6, d,
100 MHz): 15.56 )SCH3), 17.32, 19.03 )CH)CH3)2), 27.53
)C-3), 29.53 )CH)CH3)2), 65.52 )C-2), 86.19 )C-5), 123.89,
127.56, 128.37, 130.01, 130.14, 136.69, 140.75 )aromatic
C), 159.34 )C-4), 175.83 )C-6) ppm. 18a )minor con-
piperidine '19a). Yield: 1.16 g )56.1%); mp)diHCl): 196 8C
)ethanol/ethyl acetate); Rf )base)ˆ0.39 )cyclohexane:ethyl
acetateˆ4:1); IR )KBr): nˆ3386 )s), 2969 )s), 2637 )s),
Ä
2488 )s), 1599 )m), 1495 )s), 1452 )m), 1409 )m), 1031
)m), 757 )s), 697 )s) cm21; NMR )base): 1H NMR
)CDCl3, d, 400 MHz): 0.78, 0.82 )2d, Jˆ6.8 Hz, 6H,
CH)CH3)2), 1.30 )ddd, Jˆ11.6, 11.6, 11.0 Hz, 1H, 3-Hax),
1.49 )dddd, Jˆ11.4, 11.4, 10.8, 4.1 Hz, 1H, 5-Hax), 1.76±
1.86 )m, 1H, CH)CH3)2), 2.05±2.18 )m, 2H, 3-Heq, 5-Heq),
2.88±2.99 )m, 2H, 6-Hax, 2-Hax), 3.19 )ddd, Jˆ12.5, 4.4,
4.4 Hz, 1H, 6-Heq), 3.37±3.45 )m, 1H, 4-Hax), 3.56 )br, s,
1H, NH), 6.60±7.32 )m, 10H, aromatic H) ppm. 13C NMR
)CDCl3, d, 100 MHz): 15.62, 19.73 )CH)CH3)2), 28.48
)CH)CH3)2), 31.30 )C-3), 33.05 )C-5), 50.26 )C-4), 54.06
)C-6), 63.20 )C-2), 113.20, 117.21, 123.37, 123.69, 129.03,
129.36, 147.13, 152.25 )aromatic C); Anal. Calcd for
C20H28Cl2N21C2H5OH )413.43): C, 63.91; H, 8.29; Cl,
17.15; N, 6.78%. Found: C, 63.57; H, 8.10; Cl, 17.12; N,
6.83%.
1
stituent): H NMR )DMSO-d6, d, 400 MHz): 0.70, 0.80
)2d, Jˆ6.2 Hz, 6H, CH)CH3)2), 1.96±2.06 )m, 1H,
CH)CH3)2), 2.53 )s, 1H, SCH3), 2.73±2.81 )m, 1H, 3-H),
3.41-3.51 )m, 1H, 3-H), 4.01±4.08 )m, 1H, 2-H), 5.86 )s,
1H, 5-H), 7.33±7.62 )m, 10H, aromatic H), 11.07 )br, 1H,
NH) ppm. 13C NMR )DMSO-d6, d, 100 MHz): 15.86
)SCH3), 17.79, 18.95 )CH)CH3)2), 23.12 )C-3), 29.45
)CH)CH3)2), 66.10 )C-2), 90.14 )C-5), 162.67 )C-4),
173.66 )C-6), residual 13C resonances were not detected;
Anal. Calcd for C21H25IN2S10.5 H2O )474.43): C, 53.17;
H, 5.74; I, 26.75; N, 5.90; S, 6.76%. Found: C, 53.15; H,
5.59; I, 26.78; N, 5.85; S, 6.42%.
3.7.2.
'2RS,4RS)-'^)-4-Anilino-2-'1-methylethyl)-1-
phenylpiperidine '20a). Yield: 0.43 g )23.4%); mp
)diHCl): 2078C )ethanol/ethyl acetate); Rf )base)ˆ0.48
3.6.2. 'RS)-'^)-6-Methylthio-N,1,2-triphenyl-2,3-dihydro-
pyridine-4'1H)-iminiumiodide '17b, 18b). Yield: 14.7 g
)98.3%); mp223 8C )chloroform/ethyl acetate); IR )KBr):
)cyclohexane:ethyl acetateˆ4:1); IR )KBr): nˆ3417 )m),
Ä
3044 )m), 2970 )m), 2510 )s), 1597 )m), 1492 )s), 1445
)s), 1405 )m), 750 )s), 698 )s) cm21; NMR )base): 1H
NMR )CDCl3, d, 400 MHz): 0.92, 1.04 )2d, Jˆ6.5 Hz,
6H, CH)CH3)2), 1.37 )ddd, Jˆ12.5, 12.5, 4.9 Hz, 1H,
3-Hax), 1.36±1.44 )m, 1H, 5-Hax), 2.01±2.05 )m, 1H,
5-Heq), 2.17±2.22 )m, 1H, 3-Heq), 2.23±2.30 )m, 1H,
CH)CH3)2), 3.19 )ddd, Jˆ13.6, 13.6, 2.4 Hz, 1H, 6-Hax),
3.32 )br, s, 1H, NH), 3.55 )dddd, Jˆ9.7, 4.9, 2.0, 1.5 Hz,
1H, 2-Heq), 3.66±3.74 )m, 2H, 4-Hax, 6-Heq), 6.58±7.22 )m,
10H, aromatic H) ppm. 13C NMR )CDCl3, d, 100 MHz):
20.55, 20.57 )CH)CH3)2), 27.81 )CH)CH3)2), 31.40 )C-5),
32.36 )C-3), 41.08 )C-6), 46.56 )C-4), 62.40 )C-2), 113.24,
114.69, 116.97, 117.35, 129.21, 129.33, 146.91, 150.71
)aromatic C); Anal. Calcd for C20H28Cl2N2 )367.36): C,
65.39; H, 7.68; Cl, 19.30; N, 7.63%. Found: C, 65.38; H,
7.68; Cl, 18.96; N, 7.47%.
nˆ3170 )w), 3130 )w), 2980 )m), 2930 )m), 1610 )m),
Ä
1570 )s), 1470 )s), 1340 )s), 1230 )m), 1170 )m), 770 )s),
1
700 )s) cm21; 17b )main component): H NMR )CDCl3, d,
400 MHz): 2.34 )s, 3H, SCH3), 4.01 )d, Jˆ6.3 Hz, 2H, 3-H),
5.16 )t, Jˆ6.3 Hz, 1H, 2-H), 5.72 )s, 1H, 5-H), 7.20±7.53
)m, 15H, aromatic H), 11.10 )br, 1H, NH) ppm. 13C NMR
)CDCl3, d, 100 MHz): 16.05 )SCH3), 35.15 )C-3), 64.91
)C-2), 87.18 )C-5), 124.65, 127.14, 127.69, 127.83p,
128.96p, 129.09, 129.44p, 129.58, 129.78p, 135.55, 135.90,
140.46 )aromatic C), 159.58 )C-4), 175.54 )C-6) ppm. 18b
)minor constituent): 1H NMR )CDCl3, d, 400 MHz): 2.61 )s,
3H, SCH3), 3.24 )dd, Jˆ17.2, 6.1 Hz, 1H, 3-H), 3.68 )dd,
Jˆ17.2, 7.0 Hz, 1H, 3-H), 5.09 )dd, Jˆ7.0, 6.1 Hz, 1H,
2-H), 7.23 )s, 1H, 5-H), 7.20±7.53 )m, 15H, aromatic H),
11.10 )br, 1H, NH) ppm. 13C NMR )CDCl3, d, 100 MHz):
16.96 )SCH3), 31.18 )C-3), 64.74 )C-2), 92.01 )C-5),
124.88, 127.16, 127.53p, 127.88p, 129.05p, 129.15p,
135.32, 136.26, 140.51 )aromatic C), 160.35 )C-4), 174.99
)C-6); Anal. Calcd for C24H23IN2S )498.43): C, 57.85; H,
4.65; I, 25.46; N, 5.62; S, 6.43%. Found: C, 57.98; H, 4.66;
I, 25.39; N, 5.49; S, 6.50%.
3.7.3. '2RS,4SR)-'^)-4-Anilino-1,2-diphenylpiperidine
'19b). Yield: 1.59 g )71.1%); mp)diHCl): 195 8C )ethanol/
ethyl acetate); Rf )base)ˆ0.36 )cyclohexane:ethyl acetateˆ
4:1); IR )KBr): nˆ3386 )m), 2968 )w), 2612 )s), 2490 )s),
Ä
1598 )m), 1562 )m), 1496 )s), 1451 )m), 1414 )m), 1044
1
)m), 756 )s), 695 )s) cm21; NMR )base): H NMR )CDCl3,
d, 400 MHz): 1.63 )ddd, Jˆ11.7, 11.7, 10.3 Hz, 1H, 3-Hax),
1.74 )dddd, Jˆ12.0, 12.0, 11.5, 4.1 Hz, 1H, 5-Hax), 2.21±
2.28 )m, 1H, 5-Heq), 2.33±2.39 )m, 1H, 3-Heq), 3.04 )ddd,
Jˆ12.0, 12.0, 2.6 Hz, 1H, 6-Hax), 3.44 )br, s, 1H, NH),
3.54±3.61 )m, 1H, 4-Hax), 3.60 )ddd, Jˆ12.0, 4.1, 4.1 Hz,
1H, 6-Heq), 4.20 )dd, Jˆ10.3, 3.2 Hz, 1H, 2-Hax), 6.57±7.25
)m, 15H, aromatic H) ppm. 13C NMR )CDCl3, d, 100 MHz):
33.12 )C-5), 42.73 )C-3), 50.11 )C-4), 54.60 )C-6), 62.62
)C-2), 113.31, 117.30, 122.05, 122.65, 126.42, 126.93,
128.16, 128.41, 129.21, 143.69, 146.81, 151.78 )aromatic
C); Anal. Calcd for C23H26Cl2N21C2H5OH )447.45): C,
67.11; H, 7.21; Cl, 15.85; N, 6.26%. Found: C, 67.15; H,
7.22; Cl, 15.90; N, 6.55%.
3.7. 4-Anilino-1-phenylpiperidines '19, 20)
General method. 25 g of freshly prepared Raney nickel
W-236 were added to a solution of compounds 17 and 18
)0.005 mol) in 50 ml of ethanol. The mixture was shaken at
room temperature at 30 psi for 8 h. The reaction mixture
was sucked off. The residue was washed with ethanol.
The ®ltrate was concentrated in vacuo. The isomers were
separated by CC over silica gel eluting with cyclohexane/
ethyl acetate )19:1). The dihydrochlorides of 19 and 20 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)-'^)-4-Anilino-1,2-diphenylpiperidine
'20b). Yield: 0.35 g )17.0%); mp)diHCl): 220 8C )ethanol/
3.7.1. '2RS,4SR)-'^)-4-Anilino-2-'1-methylethyl)-1-phenyl-

R. Weis et al. / Tetrahedron 57 )2001) 8305±8311
8311
18. Essawi, M. Y. H. Pharmazie 1999, 54, 307±308.
ethyl acetate); Rf )base)ˆ0.45 )cyclohexane:ethyl acetateˆ
19. Kung, P.-P.; Casper, M. D.; Cook, K. L.; Wilson-Lingardo, L.;
Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt,
J. R.; Cook, P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705±
4713.
4:1); IR )KBr): nˆ3424 )w), 3030 )m), 2994 )m), 2640 )s),
Ä
2601 )s), 2566 )s), 2469 )s), 1598 )m), 1569 )m), 1492 )s),
1442 )m), 758 )s), 694 )s) cm21 1H NMR )CDCl3, d,
;
400 MHz): 1.60 )dddd, Jˆ13.3, 10.9, 8.8, 4.3 Hz, 1H,
5-Hax), 1.86 )ddd, Jˆ13.3, 10.5, 5.0 Hz, 1H, 3-Hax), 2.08±
2.16 )m, 1H, 5-Heq), 2.59±2.65 )m, 1H, 3-Heq), 3.37 )ddd,
Jˆ13.7, 10.9, 3.3 Hz, 1H, 6-Hax), 3.48±3.56 )m, 1H, 4-Hax),
3.79 )dddd, Jˆ13.7, 4.3, 4.3, 1.0 Hz, 1H, 6-Heq), 5.13 )ddd,
Jˆ5.0, 3.3, 1.0 Hz, 1H, 2-Heq), 6.52±7.33 )m, 15H, aro-
matic H) ppm. 13C NMR )CDCl3, d, 100 MHz): 31.77
)C-5), 36.46 )C-3), 43.17 )C-6), 45.95 )C-4), 57.29 )C-2),
113.20, 114.88, 117.36, 117.94, 126.54, 126.85, 128.59,
129.22, 129.27, 141.15, 146.71, 150.15 )aromatic C);
Anal. Calcd for C23H26Cl2N210.2 C2H5OH )410.59): C,
68.45; H, 6.68; Cl, 17.27; N, 6.82%. Found: C, 68.32; H,
6.59; Cl, 17.40; N, 6.81%.
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