Synthesis and stereochemistry of 3-hydroxy-1,2,3,6-tetrahydropyridines

Article abstract of DOI:10.1007/s11178-005-0156-4

A series of 1-benzyl-3-hydroxy-1,2,3,6-tetrahydropyridines, multipurpose synthons for fine organic synthesis and potential antiviral compounds, was prepared by the rearrangement of a number of 1-benzyl-3,4- epoxypiperidines under treatment with lithium am

Full text of DOI:10.1007/s11178-005-0156-4

Russian Journal of Organic Chemistry, Vol. 41, No. 2, 2005, pp. 272-278. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 2, 2005,
pp. 281-287.
Original Russian Text Copyright Ó 2005 by Grishina, Borisenko, Veselov, Petrenko.
Synthesis and Stereochemistry
of 3-Hydroxy-1,2,3,6-tetrahydropyridines
G.V. Grishina, A.A. Borisenko, I.S. Veselov, and A.M. Petrenko
Lomonosov Moscow State University, Moscow, 119992 Russia
e-mail: grishina@org.chem.msu.su
Received July 5, 2004
Abstract—A series of 1-benzyl-3-hydroxy-1,2,3,6-tetrahydropyridines, multipurpose synthons for fine organic
synthesis and potential antiviral compounds, was prepared by the rearrangement of a number of 1-benzyl-3,4-
epoxypiperidines under treatment with lithium amides. 3,4-Epoxypiperidines were obtained by oxidation of 1,2,5,6-
tetrahydropyridines trifluoroacetates with a trifluoroperacetic acid. Convenient synthetic routes were found and
developed. A conformation analysis of the series of stable 3,4-epoxypiperidines and 3-hydroxy-1,2,3,6-
tetrahydropyridines was carried out.
In the last decade an interest grew to polyhydroxylated
piperidine derivatives, synthetic substances related to
alkaloids from the series of castanospermin (I) [nojiro-
mycin (II), and fagomin (III)], which turned out to be
strong glucosidase inhibitors and also exhibited antiviral,
in particular, anti-HIV, activity [1].
The 3,4-epoxypiperidines with an N-amide group are
commonly prepared by oxidation with peracids of the
corresponding 1,2,5,6-tetrahydropyridines [4].At the same
time the data on the synthesis of N-alkyl-3,4-epoxy-
piperidines are scarce and ambiguous; the high lability of
N-alkylepoxypiperidines is often indicated that sig-
nificantly complicates their isolation and synthetic
application. Besides the preliminary formation of N-oxide
blocks the further oxidation of a double bond. Therefore
in the synthesis of N-alkyl-3,4-epoxypiperidines arises
a problem of nitrogen protection specific for each sub-
strate. In some cases the nitrogen was successfully
protected by a preliminary protonation [5–9] or by
complexing with a Lewis acid, e.g., with a trifluoroboron
etherate [10]. However this protection results in increased
negative induction effect of the nitrogen thus requiring
the use of more efficient oxidants (dimethyldioxirane,
trifluoro-methylmethyldioxirane [5]) or the prolongation
of the process.
2+
2+
2+
+2
2+ +2
2+
2+
2+
+
2
+
1
2+
1
+
1
+
,
,,
,,,
We recently found that racemic and chiral N- and
C-substituted trans-3,4-dihydroxypiperidines, substances
a lot simpler structurally and stereochemically than
castsnospermin alkaloids I–III, also exhibited to a dif-
ferent degree anti-HIV activity in vitro and were
characterized by a low toxicity. Thus the fragment of
The stability of N-alkyl-3,4-epoxypiperidines depends
to a large extent on the substrate structure. For instance,
we failed to isolate the target epoxide from the reaction
mixture obtained by treating 1-(1-phenyl-2-acetoxyethyl)-
“
trans-3,4-dihy-droxypiperidine” may be regarded as
anti-HIV pharmaco-phor [2, 3].
Looking for new hydroxylated piperidine derivatives
with a potential anti-HIV activity, including also chiral
nonracemic compounds, we used as synthons for further
functionalization 3-hydroxy-1,2,3,6-tetrahydropyridines
IVa–IVe that could be interesting on their own as potential
antiviral agents.
1,2,5,6-tetrahydropyridine with m-chloroperbenzoic acid.
However already the introduction of an ethyl group into
the position 3 of the piperidine ring favored the formation
of a more stable 3,4-epoxy-1-(1-phenyl-2-acetoxyethyl)-
3
-ethyl-1,2,5,6-tetrahydropyridine. GC-MS analysis
The most conveniently the synthesis of piperidine series
allyl alcohols IVa–IVe is performed using as precursors
N- and C-substituted 3,4-epoxypiperidines Va–Ve.
revealed in the epoxidation products of 1-(1-phenyl-2-
oxyethyl)-1,2,5,6-tetrahydropyridine a complex mixture
of compounds where we succeeded to identify a dimer
1070-4280/05/4102-0272Ó2005 Pleiades Publishing, Inc.

SYNTHESIS AND STEREOCHEMISTRY OF 3-HYDROXY-1,2,3,6-TETRAHYDROPYRIDINES
273
arising at the opening of the forming oxirane ring by the
N-(1-phenyl-2-oxyethyl) group of the second molecule
On completion of epoxidation the peracid excess was
deactivated with sodium sulfite saturated solution, and
the target epoxides were isolated as individual compounds
by means of column chromatography on silica gel.
[6].Although the GC-MS method detected the formation
of 1-(1-phenylethyl)-3,4-epoxypiperidine, the latter
compound was not sufficiently stable to be isolated by
chromatography, and only a mixture of isomer alcohols
was obtained [7].
Although an extreme instability of N-alkyl-3,4-epoxy-
piperidines was described in the literature epoxides Va–
Ve proved to be quite stable both during isolation and
purification, and were stored without changes for a year
at 5–10°C.
All the mentioned data indicate the necessity of
a cautious search for the synthesis conditions and for
an appropriate oxidant in order to successfully prepare
The structure of epoxides Va–Ve was confirmed by
1
-benzyl-3,4-epoxypiperidines.
elemental and GC-MS analysis data. The presence of
3
the epoxy ring is demonstrated by the signals of C and
By careful adjustment of the process conditions and
4
C atoms of the epoxy ring in the region 50–60 ppm in
detailed chromatographic monitoring of the oxidation
course we found that the optimum synthetic procedure
for the target series of 1-benzyl-3,4-epoxypiperidines Va–
Vd affording them in 60–72% yields was oxidation of
tetrahydropyridines trifluoroacetates VIa–VId [7] with
trifluoroperacetic acid at–5–0°C for 10–20 min. Even an
insignificantly longer reaction period results in a drastic
decrease in the yield of the target epoxides and leads not
only to the opening of the oxirane ring but also to the
other side products. GC-MS monitoring of the oxidation
process of 1-benzyl-3-methyl-1,2,5,6-tetrahydropyridine
1
3
the C NMR spectra and by characteristic multiplets of
the protons attached to these carbons at 3 ppm in the
1
H NMR spectra. The oxidation of 1-benzyl-6-methyl-
1,2,5,6-tetrahydropyridine (VId) gave rise to an insepar-
able mixture of epoxides Vd, Ve in 1:1 ratio and an overall
yield 65%, as was established from the integral intensity
values of resonances corresponding to protons attached
5
1
to C . In the H NMR spectrum of the isomer mixture of
epoxides Vd, Ve only the following proton signals were
5
assigned: from methylene protons attaced to C , from
6-methyl, and N-benzyl groups. Due to strong overlapping
(VIb) demonstarated that after 1.5 h the main reaction
the precise attribution of the other signals to cis- or trans-
isomer was too complicated. Inasmuch as the
chromatographic mobility of cis- and trans-epoxides Vd,
Ve proved to be identical we were obliged to use further
the isomer mixture.
products were 1-benzyl-3-methyl-3,4-dihydroxypiperidine
+
(58%, retention time 8.27 s, [M] 221) and its monotri-
+
fluoroacetate (35%, retention time 7.38 s, [M] 317). In
the overall yield of 7% were obtained the target epoxide
Vb (retention time 6.81 s) revealed in the mass spectrum
by the characteristic fragment ion m/z 186 (hydroxide
loss) and the tetrahydropyridine N-oxide (VIb) (retention
time 7.03 s) with a fragment ion characteristic of
N-oxides, m/z 187 (oxygen loss). The end of epoxidation
we fixed by disappearance in the H NMR spectrum of
the reaction mixture of the vinyl protons signals at
5
Target 1-benzyl-3-hydroxy-1,2,3,6-tetrahydropyridines
IVa–IVe were obtained by a rearrangement of Va-Ve
derivatives effected by lithium diisopropylamide (LDA)
(
sometimes lithium diethylamide was applied) in THF
under argon atmosphere within 2 h at room temperature
7, 8]. The column chromatography on silica gel permitted
1
[
isolation of the series of 1-benzyl-3-hydroxy-1,2,3,6-tetra-
hydropyridines IVa–IVe in a 61–80% yield. The
rearrangement of the isomer mixture of 6-methyl-3,4-
epoxypiperidines Vd, Ve gave rise to isomeric 1-benzyl-
–6 ppm corresponding to the initial 1,2,5,6-tetrahydro-
pyridines. Thus just the length of the epoxidation period
is crucial: The careful monitoring in the course if oxidation
provides a possibility to successfully obtain and isolate
individual 3,4-epoxypiperidines Va–Ve (Scheme 1).
3-hydroxy-6-methyl-1,2,3,6-tetrahydropyridines IVd, IVe
that were isolated by column chromatography as individual
substances in a 63% yield in a 1:1 weight ratio.According
to GC-MS data the chemical purity of the first isomer
IVd (retention time 14.28 s) attained 99%, the purity of
the second isomer IVe (retention time 14.62 s) was 98%.
The decomposition of both isomers IVd, IVe in the mass
spectrometer was of a similar character although the
Scheme 1.
2
2
+
5
5
5
1
1
1
%
Q
%Q
9D 9H
%Q
+
fragment ions [M – Me] formed in different amounts
9
,D 9,G
,9D ,9H
The relative intensities (I , %) of fragment ions in
rel
R = H (a), 3-Me (b), 4-Me (c), 6-Me (d, cis-), (e, trans-).
the mass spectra of isomers IVd, IVe are given below:
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005

274
GRISHINA et al.
,RQꢀ
,9Gꢀ
,9Hꢀ
ꢁꢀ
Scheme 2.
>
0@ ꢀ
ꢁꢀ
1
2(6<ꢀꢁ12(ꢀꢂꢃꢄꢅꢆ
>0ꢀ±ꢀ0H@ ꢀ
>0ꢀ±ꢀ& + 2@ ꢀ
>& + @ ꢀ
ꢀ
ꢁꢂꢀ
ꢄꢂꢀ
ꢃꢂꢀ
ꢅꢄꢀ
+
2
+
'062
0H
%
Q
ꢁꢂꢂꢀ
ꢁꢂꢂꢀ
0
H
1
+
2+
+
&'&O
+
1
+
%
Q
The presence of a hydroxyallyl system in compounds
+
+
+
IVa–IVe is confirmed by the presence in their IR spectra
of bands belonging to the stretching vibrations of the
double bond at 1660 and of hydroxy group at 3410 cm .
Further proof of the structure of compounds IVa–IVe
provides the presence in their 13C NMR spectra of
characteristic signals in the region 120–135 ppm
$
FLVꢀ$%
%
–
1
1
2(ꢀꢂꢃꢇꢅ
+
0
H
+
'062
&'&O
%Q
+
0H
1
+
4
5
corresponding to C and C atoms of the double bond
and of signal from the C atom linked to the hydroxy
+
1
+
2+
3
%Q
2+
+
+
group at 64–68 ppm. The vinyl proton signals in the
1
&
'
H NMR spectra of compounds IVa–IVe appear in the
WUDQVꢀ&'
region 5.4–5.9 ppm.
elucidation of the isomers structure required more
thorough investigation.
We planned to determine the spatial structure of
isomers IVd, IVe from the coupling constants values of
the protons attached to pairs of atoms C ,C and C ,C
of the 1,2,3,6-tetrahydropyridine ring applying the double
resonance technique. However the measured coupling
constants given below proved to be very close, apparently
due to a fast conformational equilibrium. Therefore we
considered these coupling constants values as unsuitable
for the exact assignment of reciprocal orientation of the
methyl and the hydroxy groups in the isomers.
Presumably the conformational equilibrium for cis- and
trans-isomers IVd, IVe may be represented as conformer
pairs cis-AB and trans-CD (Scheme 2).
2
3
3
4
In the spectrum of the first isomer IVd registered in
the NOESY mode in DMSO-d appeared a cross-peak
6
for 6-Me and H2a signals that should be expected for
cis-isomer IVd in B conformation with a pseudoaxial
orientation of the 6-Me group. Consequently, conformer
B is predominant in DMSO. Similar results for isomer
IVd were obtained in the NOE experiment carried out
&
-
RXSOLQJꢀFRQVWDQWꢆꢀ+]ꢀ
ꢀꢇ+ + ꢈ ꢀ
,9Gꢀ
ꢃꢉꢊꢀ
ꢋꢉꢂꢀ
ꢄꢉꢂꢀ
,9Hꢀ
ꢄꢉꢁꢀ
ꢅꢉꢂꢀ
ꢋꢉꢄꢀ
in DMSO-d : a considerable (1.2%) response of the
6
2
proton at C (2.48 ppm) was observed at irradiation of
-
ꢀꢇ+ + ꢈꢀ
the 6-Me group evidencing the prevalence of con-
former B.
-
ꢀꢇ+ + ꢈ ꢀ
-
ꢀꢇ+ + ꢈꢀ
ꢃꢉꢂꢀ
ꢋꢉꢅꢀ
In the nonpolar CDCl in the NOE experiment with
ꢀ
3
1
3
the first, presumably cis-isomer IVd, the irradiation of
The comparative data on the changes in the C NMR
spectra taken in CDCl and DMSO-d were far more
the 6-Me group caused but insignificant intensity increase
3
6
2
interesting and informative. Depending on the polarity of
solvent the position of the signal from the methyl group
attached to position 6 (d, ppm) suffered significant
changes occurring in the opposite direction for different
isomers:
(0.2%) in the peak of the proton at C suggesting the
prevailing presence of conformer A.
In the spectrum registered in the NOESY mode for
the second isomer IVe in DMSO-d no cross-peak
6
between the 6-Me group and the axial proton at C2 was
observed suggesting that the 6-Me and 3-hydroxy groups
were present in the diequatorial orientation, and thus
conformer D of the trans-isomer IVe prevailed. The
NOE experiment for trans-isomer IVe in DMSO-d6
completely confirmed the results obtained by the NOESY
6
ROYHQWꢀ
,9Gꢀ
ꢁꢌꢉꢃꢀ
ꢁꢄꢉꢅꢀ
,9Hꢀ
ꢁꢅꢉꢄꢀ
ꢁꢌꢉꢂꢀ
&
'
ꢀ
'&O ꢀ
062ꢍG ꢀ
Inasmuch as no studies on conformational analysis of
such compounds were found in the literature the
method: In DMSO-d the irradiation of the methyl did
6
2
not cause a response of the protons at C demonstrating
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005

SYNTHESIS AND STEREOCHEMISTRY OF 3-HYDROXY-1,2,3,6-TETRAHYDROPYRIDINES
275
that in the equilibrium (C D D) of trans-isomer IVe
conformer D was the dominant.
In CDCl NOE experiment for trans-isomer IVe
3
revealed a considerable (1.3%) increase in the integral
2
intensity of the signal of proton linked to C (2.35 ppm)
at irradiation of the 6-Me group thus indicationg the
prevalence of conformer C. According to the above data
isomers IVd, IVe posess really cis- and trans-structure
respectively.
The effects observed evidence the strong influence
of the solvent polarity on the conformational equilibrium
of cis- and trans-isomers IVd, IVe that exist in a
semichair conformation.
À (Å = –12.17 kcal/mol)
B (Å = –10.05 kcal/mol)
The conclusion on the cis- and trans-structure of
isomers IVd, IVe was confirmed by semiempirical
calculations using PM3 procedure for conformational
simulation involving geometry and energy optimization of
the preferential conformers of isomers IVd, IVe
According to the results obtained the isomers cis- IVd
and trans- IVe are involved into a fast, practically
degenerate conformational equilibrium where the
conformations A and C with a pseudoaxial orientation
of the hydroxy group are preferable. The slightly greater
stability of conformations A and C may be due to the
possibility to form an intramolecular hydrogen bond
between the hydroxy group and the lone electron pair of
the nitrogen.
C (Å = –12.25 kcal/mol)
D (Å = –10.16 kcal/mol)
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
UR-20. NMR spectra were registered on spectrometers
Varian VXR-400 and Brucker DRX-500 at operating
frequencies 400 and 500 MHz respectively from solutions
in CDCl and DMSO-d with TMS as internal reserence
The results of the molecular simulation are well
consistent with the experimental findings showing that in
3
6
the nonpolar CDCl the conformational equilibrium of cis-
3
GC-MS analyses were performed on spectrometers
HP5989x-G and Finnigan SSQ7000, ionizing electrons
energy 70 eV, column DB5 30 m.
and trans-isomers IVd and IVe is displaced to conformers
A and C respectively with a pseudoaxial orientation of
the hydroxy group. The prevalence of conformers A and
C in the nonpolar environment might actually originate
from the stabilization provided by an intramolecular
hydrogen bond between the hydroxy group and the lone
electron pair of the nitrogen from the piperidine ring.
The thin-layer chromatography was carried out on
plates Silufol (Kavalier, Czechia) and Kodak (BRD). For
column chromatography was used a column charged by
wet procedure with silica gel of the grade Silica gel 60-
4
0 (Merck, BRD).
Consequently, according to the molecular simulation
and conformational analysis isomers IVd, IVe are really
cis- and trans-isomers, and the shift in their fast
conformational equilibrium essentially depends on the
solvent polarity.
1
-Benzyl-3,4-epoxypiperidine (Va). To a mixture
of 0.390 g (5.4 mmol) of 46.7% water solution of hydrogen
peroxide and 15 ml of anhydrous methylene chloride
was added at 0°C and vigorous stirring a solution of
2
.52 g (12.0 mmol) of trifluoroacetic anhydride in 6 ml of
In this way we found and refined convenient synthetic
procedures and carried out a conformational analysis for
a series of stable 3,4-epoxypiperidines and 3-hydroxy-
anhydrous methylene chloride. The stirring at the same
temperature was continued for 1.5 h. To thus obtained
solution of trifluoroperacetic acid was added 1-benzyl-
1,2,5,6-tetrahydropyridinium trifluoroacetate prepared
from 0.390 g (2.3 mmol) of 1-benzyl-1,2,5,6-
tetrahydropyridine (VIa) and 0.640 g (5.6 mmol) of
1,2,3,6-tetrahydropyridines, multipurpose synthons for the
fine organic synthesis and for preparation of new
biologically active substances.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005

276
GRISHINA et al.
trifluoroacetic acid in 7 ml of anhydrous methylene chloride
at 0°C. The epoxidation was monitored by TLC till
complete consumption of the initial tetrahydropyridine.
In 20 min the excess oxidant was decomposed by addition
of 20 ml of aqueous sodium sulfite while vigorous stirring
at 0–5°C. The organic layer was separated, washed with
7.30 m (5H, ArH). 13C NMR spectrum (100 MHz,
5
CDCl ), d, ppm: 22.09 (3-CH ), 25.52 (C ), 45.61, 56.56,
3
3
2
4
6
3
57.65, 62.04 (C , C , C , PhCH ), 56.71 (C ), 126.88,
2
128.04 (2C), 128.85 (2C), 137.78 (ArC). Picrate, mp 168–
169°C (EtOH). Mass spectrum, m/z (I , %): 203 (6)
rel
+
[M] , 202 (7), 188 (3), 186 (11) 174 (2), 146 (5), 133 (7),
2
0 ml of saturated water solution of sodium hydrogen
132 (10), 126 (2), 120 (3), 118 (4), 112 (16), 104 (3), 98
(2), 92 (9), 91 (100). Found, %: C 53.18; H 4.68; N 12.34.
C H N O . Calculated, %: C 52.78; H 4.66; N 12.96.
carbonate, with water (3´10 ml), and dried on sodium
sulfate. The solvent was removed on a rotary evaporator,
1
8
18
4
8
0
.4 g of the crude product was applied to a column packed
1
-Benzyl-3,4-epoxy-4-methylpiperidine (Vc) was
prepared similarly to compound Va from 0.410 g
2.2 mmol) of 1-benzyl-4-methyl-1,2,5,6-tetrahydro-
with silica gel (6 g) with hexane. Elution was performed
with a mixture hexane–ethyl acetate, 3:1. Chromato-
graphically uniform fractions were combined, the solvent
was removed in a vacuum. We obtained 0.310 g (72%)
of 1-benzyl-3,4-epoxypiperidine (Va). Colorless oily sub-
(
pyridine (VIc). Yield of epoxide Vc 0.230 g (60%).
Colorless oily substance, R 0.59 (Silufol, hexane–acetone,
:1). IR spectrum (thin film), n, cm : 865 (epoxide).
H NMR spectrum (400 MHz, CDCl ), d, ppm: 1.34 s
f
–1
2
stance, R 0.7 (Silufol, hexane–acetone, 5:1). IR spectrum
1
f
3
–
1
1
(
thin film), n, cm : 905, 3010 (epoxide). H NMR
3
6a
3
(
CH ), 1.90 m [2H, 5-CH , J(5-CH H ) 7.2, J(5-
3 2 2
5
a
spectrum (400 MHz, CDCl ), d, ppm: 1.99 m [1H, H ,
6e
6a 2
6a 6e
3
3
CH H ) 4.6 Hz], 2.14 d.t [1H, H , J(H H ) 11.4, J(5-
2
2
3
3
5a 5e
3
5a 6a
3
5a 6e
J(H H ) 14.6, J(H H ) 9.4, J(H H ) 5.5,
J(H H ) 2.6 Hz], 2.03 d.d.t [1H, H , J(H H ) 14.6,
J(H H ) 4.4, J(H H ) 4.4, J(H H ) 1.5 Hz],
6a
6e
2
6e 6a
CH H ) 7.2 Hz], 2.38 d.d.t [1H, H , J(H H ) 11.4,
2
5a
4
5e
2
5e 5a
3
6e
5
5e 2e
2a
J(5-CH H ) 4.6, J(H H ) 1.3 Hz], 2.57 d [1H, H ,
J(H H ) 13.2 Hz], 3.02 d [1H, H , J(H H ) 4.7 Hz],
.08 d.d.d [1H, H , J(H H ) 13.2, J(H H ) 4.7,
J(H H ) 1.4 Hz], 3.43 d (1H, PhCH N, J 12.9 Hz),
.46 d (1H, PhCH N, J 13.2 Hz), 7.21–7.32 m (5H,
ArH). C NMR spectrum (100 MHz, CDCl ), d, ppm:
2.08 (3-CH ), 30.65 (C ), 46.25, 52.48, 58.32, 62.12 (C ,
C , C , PhCH ), 56.35 (C ), 126.96, 128.12 (2C), 128.92
2C), 137.93 (ArC). Picrate, mp 150–151°C (EtOH).
Mass spectrum, m/z (I , %): 203 (3) [M] , 188 (3), 186
16) 160 (2), 144 (5), 133 (4), 132 (7), 120 (5), 112 (9), 98
3), 92 (10), 91 (100). Found, %: C 53.08; H 4.62;
N 12.91. C H N O . Calculated, %: C 52.78; H 4.66;
2
5e 6a
3
5e 6e
3
5e
4
2
2a 2e
3 3
3
2e
6
a
2
6a 6e
3
6a 5a
2
.19 d.d.d [1H, H , J(H H ) 11.8, J(H H ) 9.2,
2e
2
2e 2a
3
2e
3
3
3
6a 5e
6e
2
6e 6a
J(H H ) 4.4 Hz], 2.32 m [1H, H , J(H ,H ) 11.8,
J(H H ) 5.8, J(H H ) 4.2, J(H H ) 1.2 Hz],
4
2e 6e
2
2
3
6e 5a
3
6e 5e
4
6e 2e
2
3
2
2
a
2
2a 2e
2
.67 d [1H, H ), J(H H ) 13.5 Hz], 3.01 d.d.d [1H,
13
3
2
e 2
2e 2a
3
2e
3
4
2e 6e
H , J(H H ) 13.5, J(H H ) 4.1, J(H H ) 1.5 Hz],
3
7
5
2
2
3
3
4
.18–3.23 m (2H, H , H ), 3.44 s (2H, PhCH ), 7.21–
.32 m (5H, ArH).
3
6
4
2
2
1
3
C NMR spectrum (100 MHz,
5
(
CDCl ), d, ppm: 25.51 (C ), 45.71, 50.54, 51.19, 52.25,
3
+
rel
2
3
4
6
62.24 (C , C , C , C , PhCH ), 127.00, 128.14 (2C), 128.92
2
(
(
(
2C), 137.88 (ArC). Picrate, mp 155–157°C (EtOH).
+
Mass spectrum, m/z (I , %): 189 (17) [M] , 188 (5),
rel
1
8
18
4
8
1
1
72 (4), 160 (2), 146 (2), 133 (19), 132 (10), 118 (3),
12 (4), 104 (3), 98 (15), 92 (13), 91 (100). Found, %:
N 12.96.
Diastereomers of 1-benzyl-3,4-epoxy-6-methyl-
piperidine (Vd, e) were prepared similarly to compound
Va from a mixture of products obtained by reduction of
-benzyl-2-methylpyridinium bromide with sodium
borohydride that contained according to H NMR
spectrum 16% of 1-benzyl-2-methylpiperidine, 6% of
C 52.04; H 4.26; N 13.52. C H N O . Calculated, %:
1
8
18
4
8
C 51.68; H 4.34; N 13.39.
-Benzyl-3,4-epoxy-3-methylpiperidine (Vb) was
prepared similarly to compound Va from 0.410 g
2.2 mmol) of 1-benzyl-3-methyl-1,2,5,6-tetrahydro-
1
1
1
(
pyridine (VIb). Yield 0.250 g (61%). Light-yellow oily
substance, R 0.8 (Silufol, hexane–acetone, 4:1). IR
1
-benzyl-2-methyl-1,2,5,6-tetrahydropyridine, and 78%
f
–
1
1
(0.320 g, 1.7 mmol) of 1-benzyl-6-methyl-1,2,5,6-tetra-
hydropyridine (VId). Yield 0.230 g (67%) of a mixture
of cis- and trans-1-benzyl-3,4-epoxy-6-methylpiperidines
(Vd, Ve) in the ratio 1:1 according to H NMR spectrum.
Colorless oily substance, R 0.72 (Silufol, hexane–acetone,
4:1). IR spectrum (thin film), n, cm : 830, 1265 (epoxide).
H NMR spectrum (400 MHz, CDCl , for isomers
mixture), d, ppm: 1.08 d [3H, CH , J(CH H ) 6.4 Hz],
1.10 d [3H, CH , J(CH H ) 6.5 Hz], 1.71 d.d.d [1H,
3 3
spectrum (thin film), n, cm : 905, 1240 (epoxide). H
NMR spectrum (400 MHz, CDCl ), d, ppm: 1.30 s (3H,
3
5
a 2
5a 5e
3
5a 6a
CH ), 1.93 m [1H, H , J(H H ) 14.7, J(H H ) 7.8,
3
1
3
2
3
5a 6e
3
5a
4
5e
J(H H ) 6.3, J(H H ) 2.9 Hz], 2.00 m [1H, H ,
J(H H ) 14.7, J(H H ) 5.0, J(H H ) 5.0,
J(H H ) 1.7 Hz], 2.22–2.26 m (2H, 6-CH ), 2.66 d [1H,
5e 5a
3
5e 6a
3
5e 6e
f
5e
4
–1
2
2
2
2
2
2
2
2
2
1
H , J(H H ) 12.9 Hz], 2.74 d [1H, H , J(H H )
3
4
3
6
1
2.9 Hz], 3.04 m (1H, H ), 3.44 d (1H, PhCH N,
2
3 3
2
2
3
6
J 12.9 Hz), 3.46 d (1H, PhCH N, J 13.2 Hz), 7.20–
2
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005

SYNTHESIS AND STEREOCHEMISTRY OF 3-HYDROXY-1,2,3,6-TETRAHYDROPYRIDINES
277
5
a
2
5a 5e
3
3
2
6
H , J(H H ) 14.8, J 8.2, J 3.1 Hz], 1.85 d.d [1H,
CDCl ), d, ppm: 52.43, 57.49, 62.31 (C , C , PhCH ),
3 2
5
a
2
5a 5e
3
5e
3
4
5
H , J(H H ) 15.2, J 7.6 Hz], 2.00 d.d.d [1H, H ,
64.37 (C ), 127.93, 128.25 (C , C ), 127.11, 128.16 (2C),
128.99 (2C), 137.47 (ArC). Picrate, mp 152–153°C
(EtOH). Found, %: C 51.80; H 4.37; N 13.28.
C18H18N4O8. Calculated, %: C 51.68; H 4.34; N 13.39.
2
5e 5a
3
3
5e
J(H H ) 15.2, J 5.3, J 4.4 Hz], 2.09 d.d [1H, H ,
J(H H ) 14.7 Hz], 2.56–2.66 m (4H), 2.97–3.12 m
4H), 3.20–3.26 m (3H), 3.40 d (1H, PhCH2,
J 13.2 Hz), 3.78–3.84 m (2H, PhCH ), 7.20–7.33 m
10H, ArH). C NMR spectrum (100 MHz, CDCl ), d,
ppm: 17.02, 17.86 (6-CH ), 31.42, 32.45 (C ), 48.58 (2C),
2
5a 5e
(
2
2
1-Benzyl-3-methyl-1,2,3,6-tetrahydropyridin-3-ol
(IVb) was prepared in the same way as compound IVa
from 0.140 g (0.69 mmol) of 1-benzyl-3-methyl-3,4-
epoxypiperidine (Vb). Yield of compound IVb 0.112 g
(80%). Light-yellow oily substance, R 0.82 (Silufol,
hexane–acetone, 4:1). IR spectrum (thin film), n, cm :
1660 (C=C), 3435 (bound OH). H NMR spectrum
1
3
(
3
5
3
2
3
4
4
9.48 (2C), 50.63, 50.92, 50.95, 56.55, 56.81 (C , C , C ,
6
C , PhCH ), 126.73, 126.76, 128.13 (4C), 128.69 (2C),
2
f
–
1
1
1
[
28.77 (2C), 138.98, 139.19 (ArC). Picrate, mp 164–
65°C (EtOH). Mass spectrum, m/z (I , %): 203 (5)
M] , 187 (13), 188 (84), 146 (3), 92 (8), 91 (100). Found,
1
rel
+
(400 MHz, CDCl ), d, ppm: 1.20 C (3H, CH ), 2.24 d
[1H, H , J(H H ) 11.2 Hz], 2.67 m [1H, H , J(H H )
3
3
2
2
2
2
2
6
6
6
%
%
: C 52.86; H 4.68; N 12.84. C H N O . Calculated,
: C 52.78; H 4.66; N 12.96.
1
8
18
4
8
2
2
2
2
17.3 Hz], 2.73 d [2H, H J(H H ) 11.1 Hz and OH],
6
2
6
6
3
6
5
3
.15 d.d [1H, H , J(H H ) 16.4, J(H H ) 3.8 Hz],
1
-Benzyl-1,2,3,6-tetrahydropyridin-3-ol (IVa).
5
3
5
4
3
.62 s (2H, PhCH ), 5.67 m [1H, H , J(H H ) 10.0,
Into a round-bottom flask of 25 ml capacity equipped
with a magnetic stirrer and a septum was introduced with
a syringe under argon atmosphere 0.18 g (2.5 mmol) of
diisopropylamine in 5 ml of anhydrous tetrahydrofuran.
The mixture was cooled to –15°C, and 1.57 ml (2.5 mmol)
of 1.6 M butyllithium solution in hexane was added. The
temperature was gradually raised to –5°C, the solution
was stirred for 20 min, and then into the reaction mixture
was slowly added a solution of 0.195 g (1.0 mmol) of
2
3
5
6
4
3
4
5
J(H H ) 4.0 Hz], 5.72 m [1H, H , J(H H ) 10.0 Hz],
1
3
7
.23–7.36 m (5H, ArH). C NMR spectrum (100 MHz,
CDCl ), d, ppm: 24.67 (3-CH ), 52.63, 62.28, 63.09 (C ,
C , PhCH ), 67.37 (C ), 126.42, 127.19, 128.28 (2C),
28.92 (2C), 132.73, 137.84 (C , C , ArC). Picrate, mp
60–161°C (EtOH). Mass spectrum, m/z (I , %): 203
1) [M] , 121 (5), 120 (62), 94 (1), 92 (8), 91 (100). Found,
2
3
3
6
3
2
4
5
1
1
(
rel
+
%
%
: C 52.74; H 4.67; N 12.84. C H N O . Calculated,
18 18 4 8
: C 52.78; H 4.66; N 12.96.
1-Benzyl-4-methyl-1,2,3,6-tetrahydropyridin-3-ol
(IVc). was prepared in the same way as compound IVa
from 0.190 g (0.94 mmol) of 1-benzyl-4-methyl-3,4-
epoxypiperidine (Vc). Yield of compound IVc 0.116 g
(61%). Light-yellow oily substance, Rf 0.51 (Silufol,
hexane–acetone, 2:1). IR spectrum (thin film), n, cm :
1655 (C=C), 3410 (bound OH). H NMR spectrum (400
MHz, CDCl3), d, ppm: 1.78 m (3H, CH3), 2.43 d.d.d [1H,
H , J(H H ) 11.5, J(H H ) 3.0, J 0.9 Hz], 2.66 m [2H,
H , J(H H ) 16.4 Hz and 3-OH], 2.83 d.d.d [1H, H ,
J(H H ) 11.7, J(H H ) 3.0, J 0.9 Hz], 3.08 m [1H, H ,
J(H H ) 16.4 Hz], 3.57 s (2H, PhCH ), 3.78 m (1H,
H ), 5.44 m (1H, H ), 7.22–7.32 m (5H, ArH). C NMR
spectrum (100 MHz, CDCl ), d, ppm: 20.21 (4-CH ),
52.74, 57.81, 62.30 (C , C , PhCH ), 68.15 (C ), 122.50
2
(C ), 134.97 (C ), 127.11, 128.21 (2C), 129.00 (2C),
137.79 (ArC). Picrate, mp 155–157°C (EtOH). Found,
1
-benzyl-3,4-epoxypiperidine in 3 ml of anhydrous
tetrahydrofuran, the cooling was removed, and the
reaction mixture was stirred for 2 h at room temperature.
The reaction mixture was treated with 10 ml of saturated
water solution of ammonium chloride and extracted with
methylene chloride (10´10 ml). The combined organic
extracts were dried over sodium sulfate. The solvent was
removed in a vacuum. The crude reaction product was
applied to a column packed with silica gel in hexane. The
elution was performed with a system hexane–ethyl
acetate with ethyl acetate gradient from 0 to 40%.
Chromatographically uniform fractions were combined.
We obtained 0.155 g (79%) of 1-benzyl-3-hydroxy-
,2,3,6-tetrahydropyridine (IVa) as a colorless viscous oily
substance, R 0.53 (Silufol, hexane–acetone, 5:1). IR
spectrum (thin film), n, cm : 1660 (C=C), 3410 (bound
OH). H NMR spectrum (400 MHz, CDCl ), d, ppm:
.53 d.d.d [1H, H , J(H H ) 11.4, J(H H ) 3.6,
J 0.6 Hz], 2.71 d.d [1H, H , J(H H ) 11.4, J(H H )
.8 Hz], 2.76 m [1H, H , J(H H ) 16.7 Hz], 2.93 br.s
1H, OH), 3.05 m [1H, H , J(H H ) 16.7 Hz], 3.59 d
–
1
1
2
2
2
2
3
2
3
6
2
6
6
2
2
2
2
3
2
3
6
2
6
6
2
3
5
13
1
3
3
f
2
6
3
–
1
5
4
1
3
2
2
2
2
3
2
3
2
2
2
2
2
3
2
3
%: C 52.72; H 4.77; N 12.66. C H N O . Calculated,
18 18 4 8
6
2
6
6
%: C 52.78; H 4.66; N 12.96.
3
(
(
2
6
2
6
6
cis- and trans-Isomers of 1-benzyl-6-methyl-
1,2,3,6-tetrahydropyridin-3-ol (IVd, IVe) were
obtained from 0.200 g (0.99 mmol) of the equimolar
mixture of cis- and trans-isomers of 1-benzyl-6-methyl-
3,4-epoxypiperidine (Vd, Ve).
2
1H, PhCH , J 13.2 Hz), 3.57 d (1H, PhCH ,
J 13.2 Hz), 4.05 m (1H, H ), 5.76 m [1H, H , J(H H )
0.0 Hz], 5.85 m [1H, H , J(H H ) 10.0 Hz], 7.21–
.33 m (5H, ArH). 13C NMR spectrum (100 MHz,
2
2
4
3
5 3
5
4
3
4
5
1
7
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005

278
GRISHINA et al.
6
2
cis-1-Benzyl-6-methyl-1,2,3,6-tetrahydropyridin-
-ol (IVd) was isolated as a light-yellow oily substance,
R 0.6 (Silufol, hexane–acetone, 4:1), yield 30%. IR
2.92 br.s (1H, H ), 3.26 d (1H, PhCH , J 13.8 Hz), 3.97–
2
3
3
4.00 m (2H, PhCH , H ), 4.67 br.s (1H, 3OH), 5.52 d
[1H, H , J(H H ) 9.9 Hz], 5.61 d [1H, H , J(H H )
10.3 Hz], 7.24–7.26 m (1H, H ), 7.32 m (4H, H , H ,
H , H ). C NMR spectrum (100 MHz, CDCl ), d,
ppm: 14.46 (6-CH ), 53.03, 53.07, 57.79 (C , C , PhCH ),
3 2
64.84 (C ), 127.11, 127.40, 128.28 (2C), 128.89 (2C),
134.44, 138.48 (C , C , ArC). C NMR spectrum
2
5
3
5
4
4
3
4
5
f
–
1
4'
2'
3'
spectrum (thin film), n, cm :1665 (C=C), 3410 (bound
1
5'
6'
13
OH). H (400 MHz, CDCl ), d, ppm: 1.28 d [3H, CH ,
3
3
2
3
6
2
6
J(CH H ) 6.4 Hz], 2.38 br.s (1H, OH) 2.40 d.d [1H, H ,
J(H H ) 11.7, J (H H ) 2.6 Hz], 2.85 d.d.d [1H, H ,
3
2
2
2
3
2
3
2
3
2
2
2
3
2
3
4
2
4
4
5
13
J(H H ) 11.8, J (H H ) 3.0, J(H H ) 0.9 Hz), 3.01 m
6
2
(
1H, H ), 3.33 d (1H, PhCH , J 13.5 Hz), 3.91 m (1H,
(125 MHz, DMSO-d ), d, ppm: 18.95 (6-CH ), 54.50
2
6
3
3
2
5
6
2
3
H ), 4.08 d (1H, PhCH , J 13.5 Hz), 5.65 d.d [1H, H ,
J(H H ) 10.0, J(H H ) 2.0 Hz], 5.78 m [1H, H
J(H H ) 9.6, J(H H ) 5.0, J(H H ) 2.2, J(H H )
.0 Hz], 7.22–7.32 m (5H, ArH). H NMR spectrum
(C ), 55.66 (C ), 57.11 (PhCH ), 64.14 (C ), 126.67
2
2
3
5
4
3
5
6
4
4'
3'
5'
2'
6'
4
(C ), 128.03 (C , C ), 128.58 (C , C ), 129.84 (C ),
131.92 (C ), 139.00 (C ). Mass spectrum, m/z (I , %):
203 (1) [M] , 189 (3), 188 (20), 170 (1), 121 (4), 120
3
4
5
3
4
3
4
4
6
4
4
2
5
1'
rel
1
+
1
(
500 MHz, DMSO-d ), d, ppm: 1.09 d [3H, CH ,
(45), 96 (1), 92 (8), 91 (100).
6
3
6
J(CH H ) 6.6 Hz], 2.50–2.51 m (2H, 2-CH ), 3.08–
3
(
(
3
2
Picrate of the isomer mixture IVd, IVe, mp 145–
146°C (EtOH). Found, %: C 53.01; H 4.67; N 12.98.
C H N O . Calculated, %: C 52.78; H 4.66; N 12.96.
6
2
.10 m (1H, H ), 3.54 d (1H, PhCH , J 13.8 Hz), 3.74 d
2
1H, PhCH , J 13.8 Hz), 3.99 br.s (1H, H ), 4.56 br.s
1H, OH), 5.63–5.66 m (2H, H , H ), 7.23–7.25 m (1H,
2
3
2
1
8
18
4
8
4
5
4
'
2'
3'
5'
6'
13
H ), 7.31–7.36 m (4H, H , H , H , H ). C NMR
REFERENCES
spectrum (100 MHz, CDCl ), d, ppm: 19.19 (6-CH ),
3
3
1
. Huryn, S.K. and Okabe, M., Chem. Rev., 1992, vol. 92,
p. 1745; Bernotas, R.C. and Ganem, B., Tetrahedron Lett.,
2
6
3
5
5.24, 55.50, 57.94 (C , C , PhCH ), 63.80 (C ), 126.98
2
4
5
(
2C), 128.21 (2C), 128.84 (2C), 135.14, 138.36 (C , C ,
1984, vol. 25, p. 165.
1
3
ArC). C NMR spectrum (125 MHz, DMSO-d ), d,
ppm: 15.43 (6-CH ), 51.93 (C ), 53.01(C ), 57.36
6
2
. Grishina, G.V., Borisenko,A.A., Nosan’, Z.G., Ashkenad-
ze, L.D., Veselov, I.S., Zefirov, N.S., Karamov, E.V., and
Kornilaeva, G.V., Dokl. Akad. Nauk, 2003, vol. 391 (4),
p. 487.
2
6
3
3
4'
3'
5'
(
PhCH ), 62.86 (C ), 126.62 (C ), 128.01 (C , C ),
2
2
'
6'
4
5
1'
1
28.35 (C , C ), 128.89 (C ), 132.60 (C ), 139.19 (C ).
+
Mass spectrum, m/z (I , %): 203 (1) [M] , 188 (10),
3. Grishina, G.V., Karamov, E.V., Kornilaeva, G.V., Chuma-
kov, T.I., and Zefirov, N.S., RF Patent 2198658, 2003; Byull.
Izobr., 2003, no. 5.
rel
1
70 (1), 121 (5), 120 (50), 92 (8), 91 (100).
trans-1-Benzyl-6-methyl-1,2,3,6-tetrahydro-
4
. Kratzel, M. and Hiessbock, R., Heterocycles, 1995, vol. 41,
p. 897; D’Andrea, S.V., Michalson, E.T., Freeman, J.P.,
Chidester, C.G., and Szmuszkovicz, J., J. Org. Chem., 1991,
vol. 56, p. 3133.
pyridin-3-ol (IVe) was isolated as a light-yellow oily
substance, R 0.5 (Silufol, hexane–acetone, 4:1), yield
f
–
1
3
3
3%. IR spectrum (thin film), n, cm :1660 (C=C), 3380,
1
440 (OH). H NMR spectrum (400 MHz, CDCl ), d,
5. Asensio, G., Mello, R., Boix-Bernardini, C., Gonzalez-Nunez,
M.E., and Castellano, G., J. Org. Chem., 1995, vol. 60, p.
3692.
6. Diez, A., Vilaseca, L., Lopez, I., and Rubiralta, M.,
Heterocycles, 1991, vol. 37, p. 2139.
3
3
6
ppm: 1.12 d [3H, CH J(CH H ) 6.7 Hz], 2.25 br.s (1H,
OH) 2.36 d.d [1H, H , J(H H ) 11.6, J(H H ) 5.1 Hz],
.94 d.d [1H, H , J(H H ) 11.6, J(H H ) 4.0 Hz],
.22 m (1H, H ), 3.56 d (1H, PhCH , J 13.4 Hz), 4.07 d
1H, PhCH , J 13.5 Hz), 4.05 m (1H, H ), 5.67 d.d.d
1H, H , J(H H ) 10.0, J(H H ) 3.4, J(H H ) 0.8 Hz],
.78 d.d.d [1H, H , J(H H ) 10.0, J(H H ) 3.5,
J(H H ) 2.1 Hz], 7.22–7.36 m (5H,ArH). H (500 MHz,
3
2
3
2
2
2
3
2
3
2
2
2
2
3
2
3
2
3
(
[
6
2
2
7
. Gil, L., Compere, D., Gueloteau-Bertin, B., Chiaroni,A., and
Marazano, C., Synthesis, 2000, vol. 14, p. 2117.
. Fleishhacker, W., Haslinger, E., and Mueler-Uri, C., Monatsh.
Chem., 1986, vol. 117, p. 859.
2
3
2
5
3
5
4
3
5
6
4
5
3
8
4
3
4
5
3
4
3
5
4
4
6
1
9. Quick, J., Khandelwal, Y., Meltzer, P.C., and Weinberg, J.S.,
J. Org. Chem., 1983, vol. 48, p. 5199.
10. Ferrer, M., Sanchez-Baeza, F., Messenguer,A., and Rubiral-
6
DMSO-d ), d, ppm: 1.15 d [3H, CH , J(CH H ) 6.5 Hz],
.95 t [1H, H , J(H H ) 10.0, J(H H ) 8.9 Hz],
.83 d.d [1H, H , J(H H ) 10.6, J(H H ) 5.1 Hz],
6
3
3
2
a
2
2a 2e
3
2a
3
1
2
2
e
2
2e 2a
3
2e
3
ta, M., J. Chem. Soc., Chem. Commun., 1995, vol. 3, p. 293.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005