Synthesis of 2-substituted bamipine derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00082-6

2-Substituted derivatives of bamipine and its 1-phenyl analogue have been prepared in several steps from dihydropyridine-2(1H)-thiones. The configurations and the conformations of the formed diastereoisomers have been investigated by NMR spectroscopy. The antimycobacterial activities of the title compounds have been examined.

Full text of DOI:10.1016/S0040-4020(03)00082-6

Tetrahedron 59 (2003) 1395–1402
Synthesis of 2-substituted bamipine derivatives
*
Robert Weis and Werner Seebacher
¨
Institute of Pharmaceutical Chemistry and Pharmaceutical Technology, University of Graz, Universitatsplatz 1, A-8010 Graz, Austria
Received 19 November 2002; revised 20 December 2002; accepted 10 January 2003
Abstract—2-Substituted derivatives of bamipine and its 1-phenyl analogue have been prepared in several steps from dihydropyridine-
2(1H)-thiones. The configurations and the conformations of the formed diastereoisomers have been investigated by NMR spectroscopy.
The antimycobacterial activities of the title compounds have been examined. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
from 1-substituted 4-piperidones 1. Those were treated with
anilines giving the corresponding Schiff’s bases which were
reduced to 4-anilinopiperidines 22,5,7,13 and finally alkylated
with benzylhalides2,7,12 or a heteroaryl analogue5 yielding
compounds 4. Besides the following methods have been
applied: alkylation of 2 with benzaldehyde by the Wallach
method,6 benzoylation of 2 to anilides 3 which are
converted to compounds 4 by reduction,1 copper catalyzed
coupling of 4-arylmethylaminopiperidines 5 with bromo-
benzene or 2-bromopyridine11,13 and aminolysis of 4-chloro-
piperidines 6 with aryl-8 or heteroaryl-methylanilines16
have been reported for the preparation of compounds 4
(Scheme 1).
4-Aminopiperidines are substances of sustaining interest,
because of their manifold pharmacological activities.1 The
4-benzylanilinopiperidine bamipine (R¼H) 4a is used as
antiallergic therapeutic agent. Besides it exhibits anti-
choline action2 and a remarkable specific activity against
mycobacteria.3 Substances with both antihistaminic and
antimycobacterial activity may be favorable for the therapy
of leprosy because the incidence of cutaneous inflamma-
tions necessitates sometimes the use of an antihistaminic
instead of the chemotherapeutic agent and thus the
interruption of the therapy.4
Many derivatives of bamipine with different substitution of
the aromatic rings1,2,5–8 or replacement of one aromatic by
a heteroaromatic ring1,5,9 – 13 have been synthesized.
Furthermore, the substitution of the piperidino nitrogen
atom has been varied.5,9 – 14 The derivatives possess
antihistaminic,9–14 antiserotonergic15 or antiinflammatory
properties.5 However, analogues with substituents at ring
positions 2 or 3 of the piperidine ring have not yet been
reported, with the exception of a 2,5-dimethyl derivative.6
The biologic activity of the latter substance has not been
investigated. This paper deals with the synthesis of
2-substituted derivatives of bamipine and its 1-phenyl
analogue which were prepared via new synthetic pathways.
The antimycobacterial activities of those compounds have
been examined.
2-Substituted derivatives of bamipine might be prepared
from 2-substituted 4-piperidones. Their synthesis has been
accomplished by various methods. They were prepared by
2. Results and discussion
Bamipine 4a and its analogues were usually synthesized
Keywords: anilinopiperidines; antibacterials; bamipine; hydrogenation;
piperidines; stereoisomerism.
*
Corresponding author. Tel.: þ43-316-380-5379; fax: þ43-316-380-9846;
e-mail: robert.weis@uni-graz.at
Scheme 1. 4a: R¼Me, Ar¼Ph; 1–6: Ar¼aryl, heteroaryl.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00082-6

1396
R. Weis, W. Seebacher / Tetrahedron 59 (2003) 1395–1402
Scheme 2. 7: R1¼H, alkyl; R2¼alkyl; 7a: R1¼H; R2¼iPr. Reagents and reaction conditions: (i) NaOH, 608C, 72 h; (ii) aniline, 1608C, 16 h; (iii) (1) CH3I,
CHCl3, room temperature, 6 h, (2) NaOH, room temperature, 30 min; (iv) (1) CH3I, CHCl3, room temperature, 16 h, (2) NaOH, room temperature, 1 h;
(v) (Ac)2O, pyridine, 1558C, 5 h; (vi) BzlBr, NaNH2, PhMe, 1208C, 16 h; (vii) N-benzylaniline, 1208C, 8 h; (viii) (1) CH3I, CHCl3, room temperature, 16 h, (2)
NaOH, room temperature, 1 h.
cyclization of a,b-unsaturated ketones in Mannich reac-
tions17–19 or by intermolecular double Michael reactions
of a,b-unsaturated g-ketosulfones with benzylamine.20–22
Besides, cyclizations of imino acetales23–25 and of pent-1,4-
diene-3-ones with amines26–29 have been reported. The
flash vacuum thermolysis of 4-oxa-5-azaspiro[2.4]heptanes
gave mixtures containing 1,2-disubstituted 4-piperidones.30–32
chromatographic separations only less than 40% of the
desired anilide 13 were afforded. The distinction of the
isomers was accomplished by NMR spectroscopy: we
observed a NOE from the aromatic ortho protons of 13 to
the acetyl protons as well as a long-range coupling from the
H at C-6 of 14 to the CO carbon. Attempts to protect the
anilino nitrogen of 11 by benzylation failed, since 16 was
obtained in unsatisfactory yields after troublesome workup
(Scheme 2).
Although there were plenty of methods for the preparation
of 4-piperidones we decided to synthesize the bamipine
derivatives via a new pathway using 6-alkyl-4-dialkyl-
amino-5,6-dihydropyridine-2(1H)-thiones 7 as synthons.
Those are available in good yields from a,b-unsaturated
ketones and ammonium thiocyanates in a one-pot reac-
tion.33 Exchange of the amino function has been accom-
plished by hydrolysis of 7a yielding a mixture of the
tautomeric compounds 8 and 9. Those were treated with
aniline giving the 4-anilino derivative 10. Its methylthio
derivative 11 has been prepared by a known procedure.33,34
But further methylation of 11 afforded instead of the desired
1-methyl derivative the 4-(N-methylanilino)-dihydro-
pyridine 12, which was determined by NMR spectroscopy.
Upon irradiation of the methylamino protons, we observed
NOEs at the olefinic proton and at the aromatic ortho
protons. Consequently, we tried to protect the anilino
nitrogen by acetylation. However, both nitrogen atoms of
10 were readily acylated leading to a mixture containing
compounds 13 and 14, small quantities of the diacetyl
product 15 and some starting material. After repeated
However, good overall yields were obtained by the
following synthetic pathway: compounds 8, 9 were fused
with N-benzylaniline. The formed 4-(N-benzylanilino)
derivative 17 was alkylated to the 2,3-dihydro-6-
methylthiopyridine 16. Further methylation of 16 with
iodomethane yielded the dihydro-1-methylpyridinium salt
18 (Scheme 3). A possible alkylation of the anilino nitrogen
was ruled out by a HMBC NMR experiment which was
optimized for 5 Hz couplings. Long-range couplings from
the 1-methyl protons to the C-2 and the C-6 of the
dihydropyridine confirmed the formation of 18. Our
attempts to convert the latter selectively to the 2-isopropyl
derivatives 20a, b of bamipine were not successful. The use
of Raney nickel that was inactivated with acetic acid yielded
multicomponent mixtures containing 20a as a by-product.
Good yields of 19a and small amounts of 20a were obtained
by treatment of 18 with Raney nickel W-235 at atmospheric
pressure giving a mixture of both 4-aminopiperidines
accompanied by low quantities of side products.

R. Weis, W. Seebacher / Tetrahedron 59 (2003) 1395–1402
1397
Scheme 3. Reagents and reaction conditions: (i) CH3I, CHCl3, room temperature, 16 h; (ii) method A: Raney nickel W-2, ethanol, room temperature;
(iii) Raney nickel W-7, ethanol, 30 psi (H2), room temperature; (iv) DMF, 1608C, 16 h; (v) (1) CH3I, CHCl3, room temperature, 18 h, (2) Raney nickel W-2,
ethanol, 30 psi (H2), room temperature; (vi) BzlBr, NaNH2, PhMe, 1108C, 16 h.
Compounds 19a and 20a were separated by CC. The
formation of their isomers 19b and 20b was not observed in
the H NMR spectra of the collected fractions. To avoid
(H,H-COSY and ge-HMQC). In the 13C NMR spectra of
compounds 20, 27 and 28 we observed typical downfield
shifts of ca. 5 ppm for the C-4s and upfield shifts of ca.
3 ppm for the C-3s and C-5s in comparison to compounds
19, 25 and 26. The relative configurations at C-2 and C-4 of
compounds 20, 27 and 28 were identified from the 3J(2-H, 3-H)
and 3J(3-H, 4-H) coupling constants in their 1H NMR spectra.
1
chromatographic separations we tried to hydrogenize 18
selectively to 19a. Since the prolongation of the reaction
period or further addition of catalyst did not increase the
yield of 4-anilinopiperidine 19a we treated 18 with the more
active Raney nickel W-736 varying pressure and amount of
catalyst. Indeed, most of the obtained mixtures were free of
compound 20a but the afforded 19a was always
accompanied by N-benzylaniline and several other
products. The chromatographic separations gave pure 19a
but the yields were far worse than by the above-mentioned
method.
3
The J(3-Hax, 4-H) couplings were ca. 12 Hz for all com-
pounds indicating axial positions of the Hs at C-4.
3
Furthermore, 12 Hz J(2-H,3-Hax) couplings detected the
axial positions of their Hs at C-2 in 20a, 27a and 28a,
whereas the equatorial Hs at C-2 in 27b and 28b caused
3
typical 5 Hz J(2-H,3-Hax) couplings.
The average conformations of compounds 20, 27 and 28
were investigated by NOE and homodecoupling NMR
experiments. An NOE from the axial protons in ring
position 6 to the Hs at C-4 was observed for all prepared
compounds 20, 27 and 28. The NOEs from the axial protons
in ring position 3 to the axial Hs at C-5 were detectable with
the exception of 20a and 27b where they were hidden due to
the superposition of peaks. Upon irradiation of the axial Hs
at C-2 in compounds 20a, 27a and 28a we observed NOEs
at the axial Hs at C-4 and C-6. Besides, w-couplings40 were
removed by homodecoupling experiments and detected in
this way without measuring their exact values. We observed
w-couplings between the equatorial protons in positions 3
and 5 with the exception of 20a and 27a where they were
invisible due to the superposition of the signals of the
involved protons. Furthermore, the w-couplings between
the equatorial Hs at C-2 and C-6 of compounds 27b and 28b
were revealed (Fig. 1). All above-mentioned observations
indicate that the piperidine rings of compounds 20, 27 and
28 prefer chair conformations.
Alkylation of the 4-anilinopiperidine 19a with benzyl
bromide afforded 20a in good yields. For the present this
pathway seems to be limited to the preparation of 2-alkyl
derivatives of bamipine because 6-aryl-5,6-dihydro-
pyridine-2(1H)-thiones have so far been afforded in
unsatisfactory yields.37,38
However, we were able to prepare 2-alkyl and 2-aryl
derivatives of the corresponding 1-phenyl analogues of
bamipine. Those were synthesized from the corresponding
1-phenyl analogues of compounds 7. The 1-phenylpyridine-
2(1H)-thiones 23 and 24 are accessible by a Dimroth
rearrangement of the 6-phenylimino-2H-thiopyran-4-
amines 21 and 22.39 The hydrogenation of the methoiodides
of 23 and 24 gave the isomeric 4-anilino-1-phenylpiperi-
dines 25a,b and 26a,b which were separated by CC.39
Final alkylation with benzyl bromide afforded the 4-(N-
benzylanilino)piperidines 27a,b and 28a,b.
1
The resonances in H and 13C NMR spectra of all new
compounds were assigned with the aid of 2D NMR spectra
The antimycobacterial activities of compounds 20, 27 and

1398
R. Weis, W. Seebacher / Tetrahedron 59 (2003) 1395–1402
K-2400 RI detector (Knauer); thin-layer chromatography
(TLC): TLC plates (Merck) silica gel 60 F254
.
3.2. (RS)-(6)-4-Anilino-5,6-dihydro-6-isopropyl-
pyridine-2(1H)-thione (10)
Compounds 8, 943 (0.05 mol) were dissolved in aniline
(1 mol). A stream of argon was passed through the reaction
mixture for 15 min and the reflux condenser was sealed with
a balloon. The solution was heated on an oil-bath at 1608C
for 16 h. Then the mixture was cooled and the solvent
removed in vacuo. The residue was triturated with ethanol,
filtered with suction and recrystallized. Yield: 8.70 g
(70.6%); mp 1698C (ethanol); Rf¼0.29 (toluene–
methanol¼4:1); IR (KBr): n¼3171 (m), 3002 (m), 1582
˜
(s), 1543 (s), 1513 (s), 1494 (s), 1445 (s), 1121 (s), 1055 (m),
1
690 (m) cm21; H NMR (CDCl3, d, 400 MHz): 0.97, 0.99
Figure 1. NOEs (arrows) and w-couplings (bold) in 1H NMR spectra of
compounds 20, 27, 28.
(2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.85 (dsept, J¼6.6, 6.6 Hz,
1H, CH(CH3)2), 2.36 (dd, J¼15.9, 5.1 Hz, 1H, 5-H), 2.48
(dd, J¼15.9, 12.7 Hz, 1H, 5-H), 3.35–3.41 (m, 1H, 6-H),
5.97 (s, 1H, 3-H), 6.60 (s, 1H, NHPh), 6.87 (s, 1H, NHCS),
7.14–7.35 (m, 5H, aromatic H) ppm. 13C NMR (CDCl3, d,
100 MHz): 18.14, 18.42 (CH(CH3)2), 30.38 (C-5), 31.04
(CH(CH3)2), 57.83 (C-6), 99.07 (C-3), 123.47, 125.60,
129.42, 137.83 (aromatic C), 149.93 (C-4), 192.87 (C-
2) ppm. Anal. calcd for C14H18N2S (246.37): C, 68.25; H,
7.36; N, 11.37; S, 13.01%. Found: C, 67.85; H, 7.41; N,
11.50; S, 12.76%.
28 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 inhibi-
tory activity was determined from the absorption of the
compound-containing media at 600 nm using bamipine 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 & Coordinating
Facility (TAACF, Southern Research Institute, America).
3.3. 2,3-Dihydro-6-methylthiopyridines (11, 16)
Isomeric 2-substituted 4-(N-benzylanilino)piperidines
have been prepared via different pathways. Their configu-
rations and their preferred conformations have been
investigated by NMR spectroscopy. The title compounds
have antimycobacterial activity.
General procedure. To an ice-cooled solution of the
dihydropyridine-2-thiones 10, 17 (0.03 mol) in 80 ml of
chloroform, iodomethane (0.036 mol) was added through a
dropping funnel within 1 h. The reaction mixture was stirred
for 6 h at room temperature and the solvent was removed
in vacuo. The residue was triturated with ethyl acetate,
filtered with suction and dried. The crude yellow iminium
salts were stirred in a 1 M solution of caustic soda (0.09 mol)
in water for 30 min. The suspension was extracted with
ether repeatedly. The combined organic layers were washed
three times with water and dried with sodium sulphate. The
solvent was removed and the residue recrystallized.
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 (298 K) 5 mm
3.3.1. (RS)-(6)-4-Anilino-2,3-dihydro-2-isopropyl-6-
methylthiopyridine (11). Yield: 7.57 g (96.9%); mp 978C
1
tubes, TMS as internal standard. H- and 13C-resonances
(ethanol–water); IR (KBr): n¼3382 (m), 2951 (m), 2871
˜
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; quite normally some of
the crystals of the dihydrochlorides of 19, 20, 27 and 28
contained some C2H5OH and H2O as has already been
reported for the dihydrochloride of bamipine.41,42 Hydro-
genations were performed in a Parr hydrogenation apparatus
shaker type 3911 at 30 psi or in an Erlenmeyer flask at
atmospheric pressure. Chromatography: column chroma-
tography (CC): LC: silica gel 60 (Merck), 0.063–0.200 mm,
(m), 1629 (s), 1562 (s), 1517 (s), 1497 (m), 1443 (s), 1105
(m), 932 (m), 758 (m), 694 (m) cm21; 1H NMR (CDCl3, d,
400 MHz): 0.97, 1.01 (2d, J¼6.6 Hz, 6H, CH(CH3)2),
1.77–1.88 (m, 1H, CH(CH3)2), 2.09–2.30 (m, 2H, 3-H),
2.25 (s, 3H, SCH3), 3.01–3.09 (m, 1H, 2-H), 5.27 (s, 1H,
5-H), 7.00–7.35 (m, 5H, aromatic H), 8.40 (s, 1H,
NH) ppm. 13C NMR (CDCl3, d, 100 MHz): 11.20 (SCH3),
19.24, 19.45 (CH(CH3)2), 30.08 (C-3), 33.13 (CH(CH3)2),
62.67 (C-2), 89.43 (C-5), 121.08, 122.89, 129.30, 140.53
(aromatic C), 149.52 (C-4), 161.93 (C-6) ppm. Anal. calcd
for C15H20N2S (260.40): C, 69.19; H, 7.74; N, 10.76; S,
12.31%. Found: C, 68.80; H, 7.83; N, 11.09; S, 12.01%.
˚
pore-diameter 60 A, column diameter 40 mm, layer thick-
ness 400 mm, rate of flow: 2 ml/min; MPLC: pump:
Labomatic MD-80, silica gel 60 (Merck), 0.005–0.02 mm,
3.3.2. (RS)-(6)-4-(N-Benzylanilino)-2,3-dihydro-2-iso-
propyl-6-methylthiopyridine (16). Yield: 9.53 g (90.6%);
˚
pore-diameter 60 A; column diameter 30 mm, layer thick-
ness 340 mm, rate of flow: 9 ml/min, detection: Wellchrom
mp 1188C (ethanol–water); IR (KBr): n¼2962 (w), 2930
˜

R. Weis, W. Seebacher / Tetrahedron 59 (2003) 1395–1402
1399
(w), 1619 (s), 1522 (s), 1396 (m), 1369 (m), 1329 (m), 1108
(s) cm21; 1H NMR (DMSO-d6, d, 400 MHz): 0.84, 0.89 (2d,
J¼6.6 Hz, 6H, CH(CH3)2), 1.71 (dsept, J¼6.6, 6.6 Hz, 1H,
CH(CH3)2), 1.96–2.09 (m, 2H, 3-H), 2.22 (s, 3H, SCH3),
2.99 (ddd, J¼13.2, 6.6, 6.6 Hz, 1H, 2-H), 4.83, 4.88 (2d,
J¼17.7 Hz, 2H, NCH2), 4.89 (s, 1H, 5-H), 7.19–7.39 (m,
10H, aromatic H) ppm; 13C NMR (DMSO-d6, d, 100 MHz):
11.01 (SCH3), 18.76, 19.43 (CH(CH3)2), 28.71 (C-3), 32.63
(CH(CH3)2), 55.38 (NCH2), 62.91 (C-2), 92.66 (C-5),
126.14, 126.70, 126.92, 128.47, 129.30, 137.56, 144.35
(aromatic C), 153.07 (C-4), 161.86 (C-6) ppm. Anal. calcd
for C22H26N2S (350.53): C, 75.38; H, 7.48; N, 7.99; S,
9.15%. Found: C, 75.10; H, 7.80; N, 8.20; S, 8.89%.
contained small amounts of the diacetylated compound 15
(Rf¼0.55, toluene–methanol¼4:1). Attempts to purify this
product have failed so far due to its decomposability.
Besides 0.37 g (0.0015 mol) of unchanged 10 (Rf¼0.29,
toluene–methanol¼4:1) were recovered. The fractions
containing mixtures of compounds 13 and 14 were collected
and the isomers were separated by MPLC eluting with
toluene–methanol (79:1). The solvent was evaporated and
the residues recrystallized.
3.5.1. (RS)-(6)-N-(1,2,3,6-Tetrahydro-2-isopropyl-6-
thioxo-4-pyridyl)acetanilide (13). Yield: 1.14 g (39.5%);
mp 1248C (heptane); Rf¼0.42 (toluene–methanol¼4:1); IR
(KBr): n¼3194 (m), 2970 (m), 1698 (s), 1601 (s), 1581 (s),
˜
3.4. (RS)-(6)-2,3-Dihydro-2-isopropyl-4-(N-methyl-
anilino)-6-methylthiopyridine (12)
1365 (s), 1236 (s), 1114 (s), 704 (m) cm21
;
1H NMR
(CDCl3, d, 400 MHz): 1.02, 1.03 (2d, J¼6.6 Hz, 6H,
CH(CH3)2), 1.88–1.97 (m, 1H, CH(CH3)2), 1.93 (s, 3H,
CH3CO), 2.80–2.93 (m, 2H, 3-H), 3.36–3.43 (m, 1H, 2-H),
5.63 (s, 1H, 5-H), 7.18–7.51 (m, 6H, NH, aromatic H) ppm.
13C NMR (CDCl3, d, 100 MHz): 18.34, 18.50 (CH(CH3)2),
25.22 (CH3CO), 29.47 (C-3), 31.08 (CH(CH3)2), 58.80
(C-2), 118.28 (C-5), 128.51, 129.14, 130.36, 140.50
(aromatic C), 149.19 (C-4), 170.89 (CH3CO), 192.78
(C-6) ppm. Anal. calcd for C16H20N2OS (288.41): C,
66.63; H, 6.99; N, 9.71; S, 11.12%. Found: C, 66.44; H,
7.33; N, 9.85; S, 10.64%.
A stream of argon was passed through an ice-cooled
solution of 11 (0.005 mol) in 30 ml of chloroform. The
reflux condenser was sealed with a balloon and iodomethane
(0.015 mol) was added through a dropping funnel within
1 h. The reaction mixture was stirred for 16 h at room
temperature and the solvent was removed in vacuo. The oily
residue was treated with a 1 M solution of caustic soda
(0.025 mol) in water for 1 h. The suspension was extracted
with ether repeatedly. The combined organic layers were
washed three times with water and dried with sodium
sulphate. The solvent was removed. The residue was
purified by MPLC eluting with toluene–methanol (4:1).
The solvents were removed in vacuo. 0.39 g (0.0016 mol) of
unchanged 11 were recovered. The fractions containing 12
were evaporated and the residue was triturated with heptane
overnight. The mixture was sucked off giving 12 as an
amorphous solid. Yield: 0.77 g (56.1%); Rf¼0.12 (toluene–
3.5.2. (RS)-(6)-1-Acetyl-4-anilino-5,6-dihydro-6-isopro-
pylpyridine-2(1H)-thione (14). Yield: 0.92 g (31.9%); mp
938C (heptane); Rf¼0.33 (toluene–methanol¼4:1); IR
(KBr): n¼3231 (w), 2961 (m), 2927 (m), 1672 (m), 1569
˜
(s), 1536 (s), 1222 (s), 1163 (m), 1028 (m), 693 (w) cm21
;
1H NMR (CDCl3, d, 400 MHz): 0.95, 0.97 (2d, J¼6.8 Hz,
6H, CH(CH3)2), 2.03–2.15 (m, 1H, CH(CH3)2), 2.45 (br, d,
J¼17.4 Hz, 1H, 5-H), 2.64 (s, 3H, CH3CO), 2.88 (ddd,
J¼17.4, 5.6, 1.5 Hz, 1H, 5-H), 4.80 (ddd, J¼10.2, 5.6,
1.3 Hz, 1H, 6-H), 6.31 (s, 1H, NH), 6.40 (br, s, 1H, 3-H),
7.17–7.41 (m, 5H, aromatic H) ppm. 13C NMR (CDCl3, d,
100 MHz): 19.78, 20.21 (CH(CH3)2), 26.98 (CH3CO),
28.59 (CH(CH3)2), 31.61 (C-5), 58.14 (C-6), 108.04 (C-3),
123.79, 126.39, 129.66, 137.26 (aromatic C), 150.13 (C-4),
173.83 (CH3CO), 196.42 (C-2) ppm. Anal. calcd for
C16H20N2OS (288.41): C, 66.63; H, 6.99; N, 9.71; S,
11.12%. Found: C, 66.45; H, 7.35; N, 9.87; S, 10.66%.
methanol¼2:1); IR (KBr): n¼2956 (m), 2923 (m), 2871
˜
(m), 1609 (s), 1549 (s), 1495 (s), 1385 (s), 1108 (s), 924 (m),
1
767 (m), 701 (m) cm21; H NMR (CDCl3, d, 400 MHz):
0.87, 0.95 (2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.73–1.85 (m,
1H, CH(CH3)2), 1.91–2.01 (m, 2H, 3-H), 2.39 (s, 3H,
SCH3), 3.05 (ddd, J¼11.2, 8.3, 6.1 Hz, 1H, 2-H), 3.17 (s,
3H, NCH3), 4.99 (s, 1H, 5-H), 7.04–7.37 (m, 5H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 11.74 (SCH3),
19.07, 19.42 (CH(CH3)2), 28.75 (C-3), 32.93 (CH(CH3)2),
40.24 (NCH3), 63.46 (C-2), 92.33 (C-5), 126.10, 126.62,
129.20, 145.56 (aromatic C), 153.36 (C-4), 162.87
(C-6) ppm. Anal. calcd for C16H22N2S (274.43): C, 70.03;
H, 8.08; N, 10.21; S, 11.68%. Found: C, 69.86; H, 8.24; N,
10.23; S, 11.53%.
3.6. (RS)-(6)-4-(N-Benzylanilino)-6-isopropyl-5,6-
dihydropyridine-2(1H)-thione (17)
Compounds 8, 943 (0.04 mol) were added to melted N-
benzylaniline (0.05 mol) at 608C on an oil-bath. Then a
stream of argon was passed through the stirred reaction
mixture for 5 min and the reflux condenser was sealed with
a balloon. The temperature was increased to 1208C and
heating was continued for 8 h. The mixture was cooled and
the residue was triturated with ethanol and filtered with
suction. The yellow precipitate was suspended in boiling
chloroform, cooled and filtered. The filtrate was concen-
trated and the residue recrystallized. Yield: 9.16 g (68.1%);
3.5. Acetylation of compound 10
The dihydropyridine-2(1H)-thione 10 (0.01 mol) was dis-
solved in 40 ml of dry pyridine. A stream of argon was
passed through the solution and the reflux condenser was
sealed with a balloon. After the mixture was heated on an
oil-bath to 1558C acetic anhydride (0.01 mol) was added
slowly through a dropping funnel and the mixture was
heated for 5 h. The solution was cooled and the solvent was
removed in vacuo. The residue was dissolved in dichloro-
methane and the solution was extracted three times with
water. The organic layer was dried and the solvent
evaporated. The residue was preliminary purified by LC
eluting with toluene–methanol (19:1). The first fractions
mp 1548C (ethanol); IR (KBr): n¼3179 (m), 2966 (m), 1564
˜
(s), 1501 (s), 1455 (m), 1394 (m), 1359 (m), 1116 (s) cm21
;
1H NMR (DMSO-d6, d, 400 MHz): 0.77, 0.79 (2d,
J¼6.8 Hz, 6H, CH(CH3)2), 1.83–1.96 (m, 1H,
CH(CH3)2), 2.25 (dd, J¼ 16.4, 8.9 Hz, 1H, 5-H), 2.31 (dd,

1400
R. Weis, W. Seebacher / Tetrahedron 59 (2003) 1395–1402
J¼16.4, 6.3 Hz, 1H, 5-H), 3.17–3.25 (m, 1H, 6-H), 4.90,
4.95 (2d, J¼17.8 Hz, 2H, NCH2), 5.33 (s, 1H, 3-H), 7.23–
7.44 (m, 10H, aromatic H), 8.62 (s, 1H, NH) ppm; 1H NMR
(100 MHz, d, DMSO-d6): 18.00, 18.78 (CH(CH3)2), 27.27
(C-5), 29.86 (CH(CH3)2), 55.81 (NCH2), 57.04 (C-6),
101.13 (C-3), 126.78, 127.16, 127.26, 127.58, 128.74,
129.70, 137.14, 143.86 (aromatic C), 152.01 (C-4), 190.44
(C-2) ppm. Anal. calcd for C21H24N2S (336.50): C, 74.96;
H, 7.19; N, 8.32; S, 9.53%. Found: C, 74.66; H, 7.44; N,
8.61; S, 9.32%.
and the residue dissolved in dichloromethane and H2O. The
layers were separated and the aqueous phase was extracted
once with dichloromethane. The combined organic layers
were dried over sodium sulphate. The solvent was
evaporated and the residue was purified by LC eluting
with toluene–ethyl acetate–methanol (1:1:1). The fractions
containing 19a were collected and the solvents were
removed in vacuo. The oily residue was treated with
hydrogen chloride as mentioned under method A. Thus
0.23 g (35.0%) of the dihydrochloride of 19a were yielded.
3.7. (RS)-(6)-4-(N-Benzylanilino)-2-isopropyl-1-methyl-
6-methylthio-2,3-dihydropyridiniumiodide (18)
Mp (diHCl): 2248C (ethanol–ethyl acetate); Rf (base)¼0.26
(toluene–ethyl acetate–methanol¼1:1:1); IR (diHCl, KBr):
n¼3426 (m), 2967 (s), 2649 (s), 2479 (s), 1583 (m), 1460
˜
A stream of argon was passed through a solution of the
dihydropyridine 16 (0.02 mol) in 40 ml of chloroform for
2 min. Then iodomethane (0.1 mol) diluted with 10 ml of
chloroform was added and the apparatus sealed with a
balloon. The reaction mixture was stirred for 16 h at room
temperature, and the solvent was removed in vacuo. The
oily residue was used for the synthesis of the 4-
aminopiperidines 19a and 20a without further purification.
(s), 1393 (m), 1042 (m), 756 (s), 696 (s) cm21; NMR (base):
1H NMR (CDCl3, d, 400 MHz): 0.86, 0.89 (2d, J¼6.6 Hz,
6H, CH(CH3)2), 1.09 (ddd, J¼11.8, 11.8, 11.8 Hz, 1H,
3-Hax), 1.45 (dddd, J¼12.7, 12.7, 12.2, 4.0 Hz, 1H, 5-Hax),
1.87–1.92 (m, 1H, 3-Heq), 1.95–2.13 (m, 3H, CH(CH3)2,
2-Hax, 5-Heq), 2.26 (ddd, J¼12.2, 12.2, 2.4 Hz, 1H, 6-Hax),
2.27 (s, 1H, NCH3), 2.99 (ddd, J¼12.2, 4.0, 2.9 Hz, 1H,
6-Heq), 3.22–3.30 (m, 1H, 4-Hax), 3.53 (br, s, 1H, NH),
6.53–7.17 (m, 5H, aromatic H) ppm. 13C NMR (CDCl3, d,
100 MHz): 14.74, 19.81 (CH(CH3)2), 27.46 (CH(CH3)2),
30.65 (C-3), 32.54 (C-5), 41.66 (NCH3), 50.64 (C-4),
56.50 (C-6), 67.88 (C-2), 113.01, 117.01, 129.16, 146.90 (aro-
matic C) ppm. Anal. calcd for C15H26Cl2N2þ0.3C2H5OHþ
0.5H2O (328.12): C, 57.10; H, 8.85; Cl, 21.61; N, 8.54%.
Found: C, 57.13; H, 8.83; Cl, 21.62; N, 8.53%.
Yield: 8.22 g (83.5%); yellow oil; IR (KBr): n¼2963 (m),
˜
2922 (m), 1644 (m), 1570 (s), 1513 (s), 1464 (s), 1418 (s),
1358 (m), 1327 (m), 1292 (m), 1242 (m), 1096 (m), 751 (s),
1
702 (m) cm21; H NMR (DMSO-d6, d, 400 MHz): 0.70,
0.83 (2d, J¼6.4 Hz, 6H, CH (CH3)2), 2.04–2.20 (m, 2H,
CH(CH3)2, 3-H), 2.53 (s, 3H, SCH3), 3.14 (dd, J¼17.6,
6.4 Hz, 1H, 3-H), 3.36 (s, 3H, NCH3), 3.59–3.67 (m, 1H, 2-
H), 5.09, 5.33 (2d, J¼16.1 Hz, 2H, NCH2), 5.64 (s, 1H, 5-
H), 7.28–7.56 (m, 10H, aromatic H) ppm; 13C NMR
(DMSO-d6, d, 100 MHz): 15.09 (SCH3), 18.90, 19.54
CH(CH3)2, 27.99 (C-3, CH(CH3)2), 41.82 (NCH3), 57.28
(NCH2), 65.94 (C-2), 87.97 (C-5), 127.75, 127.98, 128.85,
129.07, 130.02, 135.09, 141.79 (aromatic C), 159.48 (C-4),
173.34 (C-6) ppm.
3.9. 4-(N-Benzylanilino)-1-methylpiperidines 20, 27 and
28
General procedure. A solution of the 4-anilinopiperidines
19, 25 or 26 (0.0005 mol) in 30 ml of dry toluene was kept
in an inert-gas atmosphere. Sodium amide (0.003 mol) was
added and the mixture was heated to 1108C on an oil-bath.
When the evolution of ammonia ceased, benzyl bromide
was added through a dropping funnel. After 16 h the mixture
was cooled and poured into a separatory funnel where it was
shaken twice with water. The organic layer was dried over
potassium carbonate and the solvent removed in vacuo.
The residue was purified by CC. The fractions containing
compounds 19, 25 or 26 were collected and concentrated.
The oily residues were weighed out and treated with the
double-molar amount of a 1 M solution of hydrogen
chloride in diethylether. The solvent was evaporated and
the residue recrystallized.
3.8. (2RS, 4SR)-(6)-4-Anilino-2-isopropyl-1-methyl-
piperidine (19a)
Method A. Raney nickel W-235 was added in portions to a
solution of 18 (0.002 mol) in 50 ml of ethanol which was
stirred in an Erlenmeyer flask at room temperature under a
nitrogen atmosphere. The progress of reaction was
monitored by TLC. The addition of the catalyst was stopped
when compound 18 was no more detectable. The mixture
was filtered, the solvent was removed in vacuo and the
residue was purified by LC eluting with toluene–ethyl
acetate–methanol (1:1:1). The fractions containing 19a
resp. 20a were collected and the solvents were removed in
vacuo. The oily residues were weighed out and treated with
the double-molar amount of a 1 M solution of hydrogen
chloride in diethylether. The solvents were evaporated and
the residues recrystallized giving 0.56 g (85.3%) of 19a and
0.036 g (4.4%) of 20a.
3.9.1. (2RS,4SR)-(6)-4-(N-Benzylanilino)-2-isopropyl-1-
methylpiperidine (20a). Purification was accomplished by
LC eluting with toluene–ethyl acetate–methanol (1:1:1).
Yield: 0.176 g (85.5%); mp (diHCl): 1958C (ethanol–ethyl
acetate); Rf (base)¼0.39 (toluene–ethyl acetate–methanol¼
1:1:1); IR (diHCl, KBr): n¼3456 (s), 2965 (m), 2933 (m),
˜
2526 (s), 1599 (w), 1495 (m), 1461 (m), 1417 (m), 1053 (m),
Method B. 10 g of freshly prepared Raney nickel W-736
were added to a solution of compound 18 (0.002 mol) in
50 ml of ethanol. The mixture was shaken in a shaker
apparatus at room temperature at 30 psi. The reaction was
stopped when compound 20a was no more detectable on
TLC. The mixture was sucked off and the residue rewashed
with 100 ml of ethanol. The solvent was removed in vacuo
750 (m), 698 (s) cm21; NMR (base): H NMR (CDCl3, d,
1
400 MHz): 0.81, 0.85 (2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.35
(ddd, J¼11.9, 11.9, 11.9 Hz, 1H, 3-Hax), 1.69–1.81 (m, 3H,
3-Heq, 5-H), 1.82–1.88 (m, 1H, 2-Hax), 2.03–2.12 (m, 1H,
CH(CH3)2), 2.22 (s, 1H, NCH3), 2.23 (ddd, J¼11.6, 11.6,
3.9 Hz, 1H, 6-Hax), 2.95 (ddd, J¼11.6, 3.3, 3.3 Hz, 1H,
6-Heq), 3.77–3.86 (m, 1H, 4-Hax), 4.44, 4.52 (2d,

R. Weis, W. Seebacher / Tetrahedron 59 (2003) 1395–1402
1401
J¼17.8 Hz, 2H, NCH2), 6.65–7.31 (m, 10H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 14.90, 19.98
(CH(CH3)2), 27.04 (C-3), 27.86 (CH(CH3)2), 29.84 (C-5),
41.95 (NCH3), 49.39 (NCH2), 56.00 (C-4), 57.16 (C-6),
68.38 (C-2), 112.95, 116.49, 126.21, 126.40, 128.35,
129.20, 140.76, 149.16 (aromatic C) ppm. Anal. calcd for
C22H32Cl2N2þ0.2C2H5OHþ0.4H2O (411.84): C, 65.33; H,
8.32; Cl, 17.22; N, 6.80%. Found: C, 65.36; H, 8.31; Cl,
17.11; N, 6.77%.
IR (diHCl, KBr): n¼3425 (w), 3043 (w), 2412 (m), 2364
˜
(m), 1599 (m), 1494 (s), 753 (m), 696 (s) cm21; NMR
(base): 1H NMR (CDCl3, d, 400 MHz): 1.86 (ddd, J¼11.8,
11.8, 11.8 Hz, 1H, 3-Hax), 1.98–2.08 (m, 2H, 5-H), 2.16–
2.23 (m, 1H, 3-Hequ), 2.95–3.02 (m, 1H, 6-Hax), 3.57 (ddd,
J¼12.3, 3.6, 3.6 Hz, 1H, 6-Hequ), 4.04–4.14 (m, 1H, 4-Hax),
4.17 (dd, J¼11.8, 2.9 Hz, 1H, 2-Hax), 4.44, 4.52 (2d, J¼
17.7 Hz, 2H, NCH2), 6.66–7.27 (m, 20H, aromatic H) ppm.
13C NMR (CDCl3, d, 100 MHz): 30.76 (C-5), 39.82 (C-3),
49.37 (NCH2), 55.80 (C-4), 56.78 (C-6), 63.99 (C-2),
113.48, 116.95, 122.67, 123.65, 126.16, 126.45, 126.48,
127.06, 128.19, 128.39, 128.42, 129.15, 140.34, 143.80,
148.90, 152.00 (aromatic C) ppm. Anal. calcd for
C30H32Cl2N2þ0.6 C2H5OH (519.15): C, 72.18; H, 6.91;
Cl, 13.66; N, 5.40%. Found: C, 72.16; H, 6.72; Cl, 13.27; N,
5.45%.
3.9.2. (2RS,4SR)-(6)-4-(N-Benzylanilino)-2-isopropyl-1-
phenylpiperidine (27a). Purification was accomplished by
MPLC eluting with cyclohexane–ethyl acetate (39:1).
Yield: 0.18 g (74.2%); mp (diHCl): 2068C (ethanol–ethyl
acetate); Rf (base)¼0.17 (cyclohexane–toluene¼1:2); IR
(diHCl, KBr): n¼3397 (m), 2968 (m), 2919 (m), 2591 (m),
˜
2551 (m), 1597 (m), 1490 (s), 1030 (m), 769 (m), 699
1
(s) cm21; NMR (base): H NMR (CDCl3, d, 400 MHz):
3.9.5. (2RS,4RS)-(6)-4-(N-Benzylanilino)-1,2-diphenyl-
piperidine (28b). Purification was accomplished by
MPLC eluting with cyclohexane–ethyl acetate (59:1).
Yield: 0.23 g (90.2%); mp (diHCl): 1798C (ethanol–ethyl
acetate); Rf (base)¼0.22 (cyclohexane–toluene¼1:1); IR
0.73, 0.78 (2d, J¼6.8 Hz, 6H, CH(CH3)2), 1.55 (ddd, J¼
11.8, 11.8, 10.9 Hz, 1H, 3-Hax), 1.72–1.79 (m, 1H,
CH(CH3)2), 1.81 (dddd, J¼11.6, 11.6, 10.7, 4.0 Hz, 1H,
5-Hax), 1.88–1.96 (m, 2H, 3-Heq, 5-Heq), 2.91 (ddd, J¼12.1,
10.7, 3.2 Hz, 1H, 6-Hax), 2.99 (ddd, J¼10.9, 3.2, 3.2 Hz,
1H, 2-Hax), 3.17 (ddd, J¼12.1, 4.0, 4.0 Hz, 1H, 6-Heq), 3.96
(dddd, J¼11.7, 11.7, 4.0, 4.0 Hz, 1H, 4-Hax), 4.50, 4.60 (2d,
J¼17.8 Hz, 2H, NCH2), 6.69–7.33 (m, 15H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 15.35, 19.62
(CH(CH3)2), 27.62 (C-3), 28.52 (CH(CH3)2), 30.27 (C-5),
49.49 (NCH2), 55.41 (C-4), 55.60 (C-6), 63.84 (C-2),
113.02, 116.58, 123.81, 124.21, 126.20, 126.45, 128.39,
129.02, 129.22, 140.70, 149.14, 152.26 (aromatic C) ppm.
Anal. calcd for C27H34Cl2N2þ0.7C2H5OH (485.13): C,
69.65; H, 7.86; Cl, 14.48; N, 5.72%. Found: C, 69.77; H,
7.90; Cl, 14.13; N, 5.62%.
(diHCl, KBr): n¼3432 (w), 3043 (w), 2419 (s), 1597 (m),
˜
1493 (s), 1420 (m), 754 (m), 697 (s) cm21; NMR (base): 1H
NMR (CDCl3, d, 400 MHz): 1.84 (dddd, J¼11.6, 11.6, 11.6,
4.3 Hz, 1H, 5-Hax), 1.85–1.94 (m, 1H, 5-Heq), 2.13 (ddd,
J¼12.7, 12.7, 5.3 Hz, 1H, 3-Hax), 2.45–2.53 (m, 1H,
3-Hequ), 3.41 (ddd, J¼13.4, 11.4, 3.7 Hz, 1H, 6-Hax), 3.90
(ddd, J¼13.4, 3.2, 3.2 Hz, 1H, 6-Hequ), 3.96–4.06 (m, 1H,
4-Hax), 4.44, 4.50 (2d, J¼18.0 Hz, 2H, NCH2), 5.26–5.28
(m, 1H, 2-Heq), 6.54–7.38 (m, 20H, aromatic H) ppm. 13C
NMR (CDCl3, d, 100 MHz): 29.19 (C-5), 32.71 (C-3), 42.73
(C-6), 49.23 (NCH2), 50.80 (C-4), 57.36 (C-2), 112.96,
113.72, 116.77, 117.37, 126.15, 126.54, 126.69, 127.02,
128.45, 128.71, 129.14, 129.37, 140.43, 140.55, 148.83,
149.85 (aromatic C) ppm. Anal. calcd for C30H32Cl2N2þ0.4
C2H5OH (509.93): C, 72.55; H, 6.80; Cl, 13.90; N, 5.49%.
Found: C, 72.59; H, 6.79; Cl, 13.52; N, 5.28%.
3.9.3. (2RS,4RS)-(6)-4-(N-Benzylanilino)-2-isopropyl-1-
phenylpiperidine (27b). Purification was accomplished by
MPLC eluting with cyclohexane–ethyl acetate (59:1).
Yield: 0.184 g (80.4%); mp (diHCl): 1858C (ethanol–
acetone); Rf (base)¼0.50 (cyclohexane–toluene¼1:2); IR
(diHCl, KBr): n¼3426 (w), 3043 (m), 2964 (m), 2427 (s),
˜
1597 (w), 1494 (s), 758 (m), 697 (s) cm21; NMR (base): 1H
NMR (CDCl3, d, 400 MHz): 0.93, 1.06 (2d, J¼6.7 Hz, 6H,
CH(CH3)2), 1.67 (ddd, J¼12.8, 12.8, 5.1 Hz, 1H, 3-Hax),
1.71 (dddd, J¼12.1, 12.1, 12.1, 3.7 Hz, 1H, 5-Hax), 1.77–
1.84 (m, 1H, 5-Heq), 1.97–2.03 (m, 1H, 3-Heq), 2.33–2.45
(m, 1H, CH(CH3)2), 3.23 (ddd, J¼14.6, 12.1, 2.8 Hz, 1H,
6-Hax), 3.59 (ddd, J¼10.5, 5.1, 1.7 Hz, 1H, 2-Heq), 3.71–
3.78 (m, 1H, 6-Heq), 4.27–4.35 (m, 1H, 4-Hax), 4.36, 4.41
(2d, J¼17.9 Hz, 2H, NCH2), 6.64–7.30 (m, 15H, aromatic
H) ppm. 13C NMR (CDCl3, d, 100 MHz): 20.52, 20.85
(CH(CH3)2), 27.54 (CH(CH3)2), 28.12 (C-5), 28.86 (C-3),
41.21 (C-6), 49.04 (NCH2), 51.23 (C-4), 62.59 (C-2),
112.86, 114.32, 116.69, 126.12, 126.45, 128.38, 129.25,
140.41, 149.00, 150.55 (aromatic C) ppm. Anal. calcd for
C27H34Cl2N2 (457.49): C, 70.89; H, 7.49; Cl, 15.50; N,
6.12%. Found: C, 70.60; H, 7.56; Cl, 15.35; N, 5.91%.
Acknowledgements
Thanks go to Kemetmu¨ller H. for the examination of the
antimycobacterial activities.
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