Switch in regioselectivity of epoxide ring-opening by changing the organometallic reagent

Article abstract of DOI:10.1039/c1ob06216f

The regio- and stereoselective ring-opening of a 2-(2′-oxiranyl)-1,2, 3,6-tetrahydropyridine using organometallic reagents is reported. The choice of the organometallic reagent determines the formation of either 2-[(R)-1-hydroxyalkyl]- or 2-[(S)-2-hydroxy

Full text of DOI:10.1039/c1ob06216f

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PAPER
Switch in regioselectivity of epoxide ring-opening by changing the
organometallic reagent†
Jose´ A. Ga´lvez,* Mar´ıa D. D´ıaz de Villegas,* Ramo´n Badorrey and Pilar Lo´pez-Ram-de-V´ıu
Received 20th July 2011, Accepted 2nd September 2011
DOI: 10.1039/c1ob06216f
The regio- and stereoselective ring-opening of a 2-(2¢-oxiranyl)-1,2,3,6-tetrahydropyridine using
organometallic reagents is reported. The choice of the organometallic reagent determines the formation
of either 2-[(R)-1-hydroxyalkyl]- or 2-[(S)-2-hydroxy-1-alkyl]-1,2,3,6-tetrahydropyridines. The
formation of 2-[(S)-2-hydroxy-1-alkyl]-1,2,3,6-tetrahydropyridines is a rare example of epoxide
ring-opening with retention of configuration. The process has been applied to the asymmetric synthesis
of b-(+)-conhydrine and to the formal synthesis of (2S,2¢R)-erythro-methylphenidate from a common
precursor. Extension of the structural diversity of the process has allowed the synthesis of several
b-(+)-conhydrine analogs.
Epoxide ring-opening using carbon nucleophiles is
a
common synthetic methodology for the preparation of
hydroxyalkyl-substituted compounds.4 In this context, (2S,2¢S)-
Introduction
Many structurally diverse alkaloids and compounds with thera-
peutically interesting biological activities possess a piperidine ring
in their structures.1 Among them, piperidines with a hydroxyalkyl
substituent at C2 are abundant in nature and are of special interest
due to their potent antiviral, antitumor and anti-HIV activities.2
In particular, 2-(1-hydroxyethyl)piperidines, conhydrines (Fig.
1), which are isolated from the seeds and leaves Conium mac-
ulatum L. (a poisonous plant, the extracts of which have been
used throughout history to murder individuals), have attracted
considerable interest from a synthetic point of view.3
1-benzyloxycarbonyl-2-(2¢-oxiranyl)piperidine
has
proven
to be useful intermediate in the asymmetric synthesis
a
of (+)-a-conhydrine,5 and (2R,4R,2S¢)-4-acetamido-1-tert-
butoxycarbonyl-2-(2¢-oxiranyl)piperidine has proven to be a
useful intermediate in the asymmetric synthesis of orthogonally
protected 2-substituted 4-aminopiperidines.6
In the course of our research into the development of new stere-
ocontrolled and versatile approaches to the synthesis of bioactive
molecules from the chiral pool, we showed that easily accessi-
ble N-benzylimines derived from D-glyceraldehyde are excellent
synthetic precursors to obtain compounds with very different
structures.6,7 We wish to discuss here the stereoselective synthesis
of 2-(2¢-oxiranyl)-1,2,3,6-tetrahydropiperidine derivatives from
N-benzyl imines derived from D-glyceraldehyde acetonide. We
also investigated the nucleophilic ring-opening of the epoxide
with C-nucleophiles under different reaction conditions in an
effort to achieve the asymmetric synthesis of piperidines with a
hydroxyalkyl substituent at C2.
Results and discussion
Based on our previous results on the diastereoselective addition of
allylmagnesium bromide to N-benzylimines derived from (R)-2,3-
di-O-benzylglyceraldehyde8 and the potential of the 2,2-dimethyl-
1,3-dioxolan-4-yl moiety in the installation of different functional
groups,6 the proposed synthesis of the 2-(2¢-oxiranyl)-1,2,3,6-
tetrahydropyridine derivative A with a well defined stereochem-
istry relies on the following key steps: (a) diastereoselective
addition of allylmagnesium bromide to N-benzylimines derived
from D-glyceraldehyde acetonide D, (b) ring-closing metathesis to
construct the piperidine ring and (c) appropriate stereoselective
Fig. 1 Structures of the four conhydrine stereoisomers.
Instituto de S´ıntesis Qu´ımica y Cata´lisis Homoge´nea (ISQCH), CSIC - Uni-
versidad de Zaragoza, Departamento de Qu´ımica Orga´nica, Pedro Cerbuna
12, E-50009 Zaragoza, Spain. E-mail: loladiaz@unizar.es,jagl@unizar.es;
Fax: +34976761202; Tel: +34976762274
† Electronic supplementary information (ESI) available: Characterisation
spectra for compounds 2–10 and crystal structure data for compound 9e.
CCDC reference number 837207. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob06216f
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The use of imines 1b and 1c derived from chiral (S)-
phenylethylamine and (R)-phenylethylamine, respectively, gave
excellent (matched pair) to good (mismatched pair) diastereose-
lectivities. The use of imine 1b as substrate gave diastereomerically
pure syn-2b on addition of allylmagnesium bromide in diethyl
ether at -20 ◦C. On the other hand, the addition of allylmag-
nesium bromide to the BF3·OEt2 pre-complexed imine led to
homoallylamine anti-2b with total diastereoselectivity. At this
point compound syn-2b (isolated in 80% yield) was selected to
proceed with the proposed synthetic route.
Ring-closing metathesis is nowadays a well-established synthetic
strategy for the construction of nitrogen heterocyles11 and it
has already been applied to the formation of the piperidine
ring in several previously described syntheses of conhydrines.3,12
The required dialkene 3 was cleanly obtained in 87% yield by
reaction of syn-2b with allyl bromide in acetonitrile using sodium
hydrogen carbonate as base in the presence of lithium iodide.
RCM performed on 3 using Grubbs’ first generation catalyst led
to tetrahydropyridine 4 in 87% yield. From this compound 2-(2¢-
oxiranyl)-1,2,3,6-tetrahydropyridine 6 was obtained in ca. 51%
yield by deprotection of the diol moiety with HCl in THF–water
followed by formation of the epoxide ring (Scheme 2).
Scheme
1
Retrosynthesis approach to 2-(2¢-oxiranyl)-1,2,3,6-
tetrahydropyridine derivatives.
manipulation of the substituent at C2 in B (Scheme 1). Starting
N-benzylimines can be obtained from D-glyceraldehyde acetonide,
which is readily available on a gram scale from the inexpen-
sive precursor D-mannitol,9 according to previously described
procedures.10
The first step of the proposed synthetic route involved a study
of the nucleophilic addition of allylmagnesium bromide to imine
1a under different reaction conditions (Table 1). This reaction
allowed the creation of the stereogenic center at C2 in the target
molecule.
When the reaction was performed in diethyl ether at -20 ◦C,
homoallylamine syn-2a was obtained preferentially (syn/anti =
80/20). The presence of Lewis acids had a noticeable influence on
the stereochemical course of the reaction. The presence of ZnI2
in the reaction medium was detrimental in terms of diastereos-
electivity (syn/anti = 68/32). When imine 1a was pre-complexed
with BF3·OEt2 before the addition of the organometallic reagent,
the opposite stereochemical course was observed and anti-2a
was the major product (syn/anti = 13/87). This observation is
consistent with previous results for BF3·OEt2 precomplexation of
the imine.7e,10
Table 1 Addition of allylmagnesium bromide to imine 1
Scheme 2 Synthesis of 2-(2¢-oxiranyl)-1,2,3,6-tetrahydropyridine 6.
Deprotection smoothly led to diol 5 in nearly quantitative yield,
but epoxide ring formation proved problematic. All attempts to
perform the cyclization of tosylate or mesylate intermediates were
unsuccessful and under Mitsunobu conditions;13 the use of chloro-
form as solvent proved necessary to obtain epoxide 6. When THF
or toluene were used as reaction medium, the cyclization did not
occur and the use of methylene chloride as solvent preferentially
gave 2-(1,2-dichloroethyl)-1,2,3,6-tetrahydropyridine.
With diastereomerically pure 6 in hand we focused our attention
on its use as a synthetic intermediate to obtain a range of
stereochemically well defined 2-(1-hydroxalkyl)piperidines from
a common precursor. To this end, regioselective cleavage of the
epoxide ring with methyl organometallic reagents was first tested.
Imine
Lewis Acid
Product
Yielda (%)
syn/antib
1a
1a
1a
1b
1b
1c
1c
none
ZnI2
2a
2a
2a
2b
2b
2c
2c
70
60
72
80
55
70
53
80/20
68/32
13/87
>98/2
<2/98
80/20
9/91
BF3·OEt2
none
BF3·OEt2
none
BF3·OEt2
a Isolated yield. b Determined by 1H NMR spectroscopy.
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Table 2 Regioselective epoxide ring-opening
Fig. 2 Proposed model for epoxide ring-opening by organomagnesium
reagents.
of compounds 7a–c with neat retention of configuration (Fig. 2).
This proposal is in accordance with that of Saigo et al.16 for the
reaction of 2,3-epoxyamines with organoaluminium reagents.
Exposure of compound 8a to molecular hydrogen in the
presence of catalytic Pd(OH)2/C led to enantiomerically pure b-
(+)-conhydrine 9a in 82% yield by hydrogenation of the unsatu-
rated moiety with concomitant N-deprotection (Scheme 3). This
methodology was extended to the synthesis of (+)-b-conhydrine
analogs 9b (81%), 9d (80%) and 9e (82%), which incorporate the
2-(1-hydroxyalkyl)piperidine pattern. The stereochemistry of the
products was confirmed by physical and spectroscopic data for
compound 9a and also by single-crystal X-ray diffraction analysis
of compound 9e.
Entry
Nucleophilic system
Product
7/8a
Yieldb (%)
1
2
3
4
5
6
7
8
MeMgBr
MeMgBr/CuBr(cat)
Me2CuLi
PhMgBr
PhMgBr/CuBr(cat)
VinylMgBr
7a
8a
8a
7b
8b
7c
8d
8e
>98/2
<2/98
<2/98
>98/2
<2/98
>98/2
<2/98
<2/98
73
82
61
77
97
87
86
78
i-PrMgBr/CuBr(cat)
BnMgBr/CuBr(cat)
a Determined by 1H NMR spectroscopy. b Isolated yield.
To our surprise, the reaction of epoxide 6 with methylmagne-
sium bromide—a strong nucleophile—yielded regioselectively 2-
(2-hydroxyethyl)-1,2,3,6-tetrahydropyridine derivative 7a, which
resulted from the nucleophile attacking the more substituted end
of the epoxide with retention of configuration (entry 1, Table 2).
In combination with a catalytic amount of cuprous bromide the
attack of methylmagnesium bromide occurred as expected on the
less substituted end of the epoxide (entry 2, Table 2) and the same
behavior was observed when lithium dimethyl cuprate was used
as the nucleophilic system (entry 3, Table 2). This was a general
trend when organomagnesium reagents were used in combination
with or in the absence of catalytic cuprous bromide (entries 4 and
6 vs. 5, 7 and 8, Table 2).
Examples of epoxide ring-opening with a strong nucleophile
proceeding at the more substituted end of the epoxide are rare and
retention of configuration in the attack is very unusual. A similar
behavior has been observed in the reaction of epoxy sulfides,14
epoxy selenides15 and epoxy amines16 with organoaluminium
reagents or epoxy sulfides with phenylboronic acid,17 but as
far as we know, retention of configuration in the attack of
organomagnesium reagents has not been described previously.
It has been previously reported18 that under Lewis acidic
conditions 2,3-epoxyamines can generate reactive aziridinium
ions. To explain the formation of compounds 7a–c we propose the
formation of an intermediate aziridinium ion—by coordination of
the organomagnesium reagent to the epoxide oxygen and attack of
the nitrogen on the C2 of the epoxide from the back side—followed
by the intramolecular attack of the nucleophile on the C2 of the
aziridinium ion from the coordinated magnesium reagent from
the back side. This mechanism would account for the formation
Scheme 3 Synthesis of b-(+)-conhydrine and its analogs.
Some approaches to the synthesis of the psychostimulant
drug for the treatment of attention-deficit hyperactivity disorder,
R
(2R,2¢R)-(+)-threo-methylphenidate (Ritalinꢀ), are based on the
enantioselective synthesis of (2S,2¢R)-methylphenidate followed
by epimerization.19 Compound 7b was transformed into com-
pound 10—a formal precursor of (2S,2¢R)-methylphenidate20—
by exposure to molecular hydrogen in the presence of catalytic
Pd(OH)2/C followed by tert-butoxycarbonylation of the piperi-
dine nitrogen by treatment with di-tert-butyl dicarbonate in the
presence of a catalytic amount of triethylamine (Scheme 4). The
physical and spectroscopic data for compound 10 are consistent
with those previously described for the (2S,2¢R)-diastereoisomer20
and proved that epoxide ring-opening had occurred with retention
of configuration.
Summary
In summary, we have developed a stereoselective and flexi-
ble methodology for the synthesis of structurally diverse 2-
(1-hydroxyalkyl)- and 2-(2-hydroxyalkyl)piperidines with a well
defined stereochemistry from a common precursor, epoxide 6.
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X-Ray diffraction
The X-ray diffraction data were collected at room tempera-
ture on an Oxford XCalibur diffractometer, using graphite-
˚
monochromated Mo-Ka radiation (l = 0.71073 A). Reflections
were measured in the q/2q-scan mode in the q range 2.85 to 29.02◦.
The structure was solved by direct methods using SHELXS 97 and
refinement was performed using SHELXL 97 by the full-matrix
least-squares technique with anisotropic thermal factors for heavy
atoms. The hydrogen atom bonded to nitrogen was located on
the difference Fourier map and refined with an isotropic thermal
factor, all other hydrogen atoms were calculated at idealized
positions, and during refinement they were allowed to ride on
their carrying atom with an isotropic thermal factor fixed to 1.2
times the Ueq value of the carrier atom.
Scheme 4 Formal synthesis of (2S,2¢R)-methylphenidate.
Colourless single crystals of 9e were obtained by slow evapora-
tion from an ethanol solution. Crystallographic data: crystal size
0.35 ¥ 0.15 ¥ 0.14 mm3. M = 219.32, crystal system orthorhombic,
Epoxide ring-opening using Grignard-derived organocuprates ex-
clusively occurred at the less substituted carbon of the epoxide ring
whereas attack of Grignard reagents on the epoxide ring only took
place at the more hindered carbon and with complete retention
of configuration. Moreover, a wide variety of compounds can be
easily obtained from epoxide 6 by changing the hydrocarbon chain
of the organometallic reagent.
˚
˚
unit cell dimensions a = 6.3355(6) A, b = 7.4390(8) A, c = 26.291(2)
3
˚
˚
A, V = 1239.1(2) A , T = 293(2) K, space group P212121, Z = 4,
absorption coefficient m(Mo-Ka) = 0.073 mm-1, 21730 reflections
measured, 2988 independent reflections (Rint = 0.1681) which were
used in all calculations. Final R indices [I > 2s(I)] R1 = 0.0520,
wR(F2) = 0.0762, R indices (all data) R1 = 0.0944, wR(F2) = 0.0836.
General procedure for the addition of allylmagnesium bromide to
chiral imines
Experimental section
All reagents for reactions were of analytical grade and were used
as obtained from commercial sources. Reactions were carried
out using anhydrous solvents. Whenever possible the reactions
were monitored by TLC. TLC was performed on precoated silica
gel polyester plates and products were visualized using UV light
(254 nm), ninhydrin and ethanolic phosphomolybdic acid solution
followed by heating. Column chromatography was performed
using silica gel (Kiesegel 60, 230–400 Mesh). N-Benzylimines 1a–c
were prepared according to previously described procedures.10
Melting points were determined in open capillaries using
a Gallenkamp capillary melting point apparatus and are not
corrected. FTIR spectra of oils were recorded as thin films on
NaCl plates and FTIR spectra of solids were recorded as nujol
dispersions on NaCl plates using a Thermo Nicolet Avatar 360
FT-IR spectrometer, nmax values expressed in cm-1 are given for
the main absorption bands. Optical rotations were measured on
a Jasco 1020 polarimeter at l 589 nm and 25 ◦C in a cell with
10 cm path length, [a]D values are given in 10-1 deg cm g-1 and
Method A. A solution of the starting chiral imine 1a–c
(1.0 mmol) in dry Et2O (1 mL) was slowly added to a stirred 1.0
M solution of allylmagnesium bromide in Et2O (2 mL, 2.0 mmol)
diluted with dry Et2O (5 mL) under argon at -20 ◦C, and stirring
was continued for 12 h at the same temperature. The reaction
mixture was then quenched with water (5 mL), the organic phase
separated and the aqueous layer extracted with Et2O (2 ¥ 5 mL).
The combined organic extracts were dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was purified
by silica gel column chromatography to give the corresponding
allylamine 2a–c.
Method B. A solution of the starting chiral imine 1a–c
(1.0 mmol) in dry Et2O (1 mL) was slowly added to a stirred
solution of the corresponding Lewis acid (1.0 mmol) in dry Et2O
(5 ml) under argon at -20 ◦C. After stirring for 5 min at -20 ◦C a 1.0
M solution of allylmagnesium bromide in Et2O (2 mL, 2.0 mmol)
was slowly added under argon at -20 ◦C and stirring was continued
for 12 h at the same temperature. The reaction mixture was then
quenched with water (5 mL), the organic phase separated and
the aqueous layer extracted with Et2O (2 ¥ 5 mL). The combined
organic extracts were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Purification of the residue by silica gel
column chromatography yielded the corresponding allylamine
2a–c.
1
concentrations are given in g/100 mL. H NMR and 13C NMR
spectra were acquired on a Bruker AV-400 spectrometer or a
Bruker AV-300 spectrometer operating at 400 or 300 MHz for
1H NMR and 100 or 75 MHz for 13C NMR at room temperature
unless otherwise stated using a 5 mm probe. The chemical shifts
(d) are reported in parts per million from tetramethylsilane
with the solvent resonance as the internal standard. Coupling
constants (J) are quoted in hertz. The following abbreviations are
used: s, singlet; d, doublet; q, quartet; dd, doublet of doublets;
m, multiplet; bs, broad singlet; ddd, doublet of doublets of
doublets; dddd, doublet of doublet of doublets of doublets. High
resolution mass spectra were recorded using a Bruker Daltonics
MicroToF-Q instrument from methanolic solutions using the
positive electrospray ionization mode (ESI+).
(R)-N-[(S)-1-Phenylethyl]-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-3-buten-1-amine (syn-2b). Following procedure A, treatment
of imine 1b (5.13 g, 22.0 mmol) with a 1.0 M solution of
allylmagnesium bromide in Et2O (44 mL, 4.0 mmol) yielded
compound syn-2b as a single diastereoisomer. Purification of
the crude product by silica gel column chromatography (eluent:
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Et2O/hexanes, 1 : 2) yielded compound syn-2b (4.85 g, 80%) as
126.6 (CH), 127.6 (CH), 128.0(CH), 136.7 (CH), 139.2 (CH), 144.6
(C); HRMS (FAB+) calcd for C20H30NO2 (MH+) 316.2271; found
316.2259.
an oil. [a]D = -10.5 (c 1.00, CHCl3); IR absorptions (pure) nmax
25
3340, 1639, 1602; 1H NMR (400 MHz, CDCl3) d 1.24 (s, 3H), 1.26
(d, J = 6.6, 3H), 1.27 (s, 3H), 1.71 (bs, 1H), 2.03–2.12 (m, 1H),
2.16–2.24 (m, 1H), 2.36 (ddd, J = 6.2, J = 6.2, J = 4.9, 1H), 3.60
(dd, J = 7.9, J = 7.3, 1H), 3.78 (dd, J = 7.9, J = 6.5, 1H), 3.85 (q,
J = 6.6, 1H), 3.89–3.94 (m, 1H), 4.95–4.98 (m, 1H), 4.98–5.30 (m,
1H), 5.72 (dddd, J = 17.5, J = 10.3, J = 7.2, J = 7.2, 1H), 7.11–
7.28 (m, 5H); 13C NMR (100 MHz, CDCl3) d 25.2 (CH3), 25.3
(CH3), 26.4 (CH3), 34.9 (CH2), 54.8 (CH), 55.8 (CH), 66.4 (CH2),
77.6 (CH), 108.7 (C), 117.2 (CH2), 126.6 (CH), 126.7 (CH), 128.3
(CH), 135.1 (CH), 145.6 (C); HRMS (FAB+) calcd for C17H26NO2
(MH+) 276.1958; found 276.1963.
(R)-N-[(S)-1-Phenylethyl]-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
1,2,3,6-tetrahydropyridine (4)
A solution of 3 (1.0 mmol) in CH2Cl2 (50 mL) was slowly
added to a solution of Grubbs’ first generation catalyst (823
mg, 1.0 mmol) in CH2Cl2 (200 mL) at room temperature. The
resulting solution was stirred for 12 h at the same temperature
and then evaporated in vacuo. Purification of the residue by silica
gel column chromatography (eluent: Et2O/hexanes, 1 : 4) yielded
compound 4 (2.67 g, 87%) as an oil. [a]D25 = -17.2 (c 1.00, CHCl3);
1
(S)-N-[(S)-1-Phenylethyl]-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-3-buten-1-amine (anti-2b). Following procedure B, treatment
of imine 1b (233 mg, 1.0 mmol) precomplexed with BF3·OEt2
(127 mL, 1.0 mmol) with a 1.0 M solution of allylmagnesium
bromide in Et2O (2 mL, 2.0 mmol) yielded compound anti-2b as a
single diastereoisomer. Purification of the crude product by silica
gel column chromatography (eluent: Et2O/hexanes, 1 : 2) yielded
IR absorptions (pure) nmax 1659; H NMR (400 MHz, CDCl3) d
1.39 (s, 3H), 1.42 (d, J = 6.5, 3H), 1.44 (s, 3H), 1.64–1.73 (m, 1H),
2.43–2.51 (m, 1H), 3.00–3.13 (m, 2H), 3.35–3.41 (m, 1H), 3.59 (dd,
J = 8.0, J = 8.0, 1H), 3.98 (dd, J = 8.0, J = 6.2, 1H), 4.02 (q, J =
6.5, 1H), 4.48 (ddd, J = 8.1, J = 8.0, J = 6.2, 1H), 5.56–5.62 (m,
1H), 5.64–5.71 (m, 1H), 7.18–7.25 (m, 1H), 7.26–7.34 (m, 2H),
7.35–7.44 (m, 2H)); 13C NMR (100 MHz, CDCl3) d 21.3 (CH3),
25.6 (CH3), 26.6 (CH3), 27.0 (CH2), 45.4 (CH2), 53.7 (CH), 61.0
(CH), 67.9 (CH2), 74.5 (CH), 108.7 (C), 123.1 (CH), 126.1 (CH),
126.5 (CH), 127.2 (CH), 128.2 (CH), 146.8 (C); HRMS (FAB+)
calcd for C18H26NO2 (MH+) 288.1958; found 288.1962.
compound anti-2b (151 mg, 55%) as an oil. [a]D = +3.3 (c 0.50,
25
1
CHCl3); IR absorptions (pure) nmax 3332, 1639, 1602; H NMR
(400 MHz, CDCl3) d 1.24 (d, J = 6.6, 3H), 1.27 (s, 3H), 1.36 (s, 3H),
2.00–2.14 (m, 2H), 2.57–2.62 (m, 1H), 3.74–3.81 (m, 1H), 3.82 (q,
J = 6.6, 1H), 3.90–3.98 (m, 2H), 4.92–5.00 (m, 2H), 5.58 (dddd,
J = 16.7, J = 10.5, J = 7.3, J = 7.3, 1H), 7.11–7.26 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 24.2 (CH3), 25.2 (CH3), 26.6 (CH3),
35.4 (CH2), 55.7 (CH), 55.9 (CH), 66.8 (CH2), 77.5 (CH), 108.7
(C), 117.8 (CH2), 126.6 (CH), 126.8 (CH), 128.3 (CH), 135.1 (CH),
146.1 (C); HRMS (FAB+) calcd for C17H26NO2 (MH+) 276.1958;
found 276.1958.
(R)-N-[(S)-1-Phenylethyl]-2-[(S)-1,2-dihydroxyethyl]-1,2,3,6-
tetrahydropyridine (5)
A solution of 4 (2.58 g, 9.0 mmol) in THF (15 mL) was treated with
a 2 N aqueous solution of HCl (15 mL) and stirred for 2 h at 50 ◦C.
The reaction mixture was then evaporated in vacuo and the residue
dissolved in Et2O (50 mL). The organic solution was washed with
2 N aqueous solution of NaOH (20 mL) and the aqueous layer was
extracted with Et2O (2 ¥ 20 mL). The combined organic extracts
were dried over anhydrous MgSO4, filtered and concentrated in
vacuo. Purification of the crude product by silica gel column
chromatography (1st eluent: Et2O, 2nd eluent Et2O/EtOH, 4 : 1)
yielded compound 5 (2.20 g, 99%) as an oil. [a]D25 = -21.9 (c 1.00,
(R)-N-Allyl-N-[(S)-1-phenylethyl]-1-[(S)-2,2-dimethyl-1,3-
dioxolan-4-yl]-3-buten-1-amine (3)
A mixture of syn-2b (3.30 g, 12.0 mmol), allyl bromide (2.18
g, 18.0 mmol), NaHCO3 (2.52 g, 30.0 mmol) and LiI (160 mg,
1.2 mmol) in CH3CN (30 mL) was heated under reflux for 36
h. Then the resulting reaction mixture was evaporated in vacuo
and the residue partitioned between Et2O (50 mL) and water (30
mL). The organic phase was separated and the aqueous layer was
extracted with Et2O (2 ¥ 20 mL). The combined organic extracts
were dried over anhydrous MgSO4, filtered and concentrated in
vacuo. Purification of the crude product by silica gel column
chromatography (eluent: Et2O/hexanes, 1 : 4) yielded compound 3
(3.53 g, 87%) as an oil. [a]D25 = -6.2 (c 1.00, CHCl3); IR absorptions
(pure) nmax 1639; 1H NMR (400 MHz, CDCl3) d 1.26 (s, 3H), 1.31
(d, J = 6.9, 3H), 1.33 (s, 3H), 1.74–1.82 (m, 1H), 1.89–1.97 m, 1H),
2.85 (ddd, J = 8.4, J = 6.6, J = 6.5, 1H), 3.11 (dddd, J = 15.1, J =
6.8, J = 1.2, J = 1.2, 1H), 3.50 (dddd, J = 15.1, J = 5.6, J = 1.7,
J = 1.7, 1H), 3.72 (dd, J = 7.5, J = 5.9, 1H), 3.82 (dd, J = 7.5,
J = 6.1, 1H), 4.01 (q, J = 6.9, 1H), 4.10 (ddd, J = 8.4, J = 6.1,
J = 5.9, 1H), 4.79–4.86 (m, 1H), 4.83–4.89 (m, 1H), 4.98 (dddd,
J = 10.2, J = 1.6, J = 1.6, J = 1.6, 1H), 5.08 (dddd, J = 17.1, J =
1.7, J = 1.7, J = 1.7, 1H), 5.61 (dddd, J = 17.0, J = 10.3, J = 7.1,
J = 7.1, 1H), 5.82 (dddd, J = 17.1, J = 10.2, J = 6.8, J = 5.6, 1H),
7.11–7.29 (m, 5H); 13C NMR (100 MHz, CDCl3) d 19.9 (CH3),
25.4 (CH3), 26.6 (CH3), 33.2 (CH2), 50.6 (CH2), 57.2 (CH), 57.3
(CH), 67.1 (CH2), 77.5 (CH), 108.3 (C), 115.4 (CH2), 116.0 (CH2),
1
CHCl3); IR absorptions (pure) nmax 3373, 1645; H NMR (400
MHz, CDCl3) d 1.42 (d, J = 6.6, 3H), 1.61–1.69 (m, 1H), 2.25–
2.32 (m, 1H), 2.86 (dd, J = 10.2, J = 7.0, 1H), 3.33 (dd, J = 11.7,
J = 3.9, 1H), 3.33–3.47 (m, 2H), 3.61 (ddd, J = 10.2, J = 3.9, J =
2.9, 1H), 3.70 (dd, J = 11.7, J = 2.8, 1H), 3.95 (q, J = 6.6, 1H),
5.67–5.75 (m, 1H), 5.73–5.80 (m, 1H), 7.21–7.29 (m, 1H), 7.27–
7.36 (m, 4H); 13C NMR (100 MHz, CDCl3) d 20.6 (CH2), 21.6
(CH3), 40.3 (CH2), 52.9 (CH), 59.9 (CH), 63.2 (CH2), 69.4 (CH),
124.1 (CH), 124.9 (CH), 127.1 (CH), 127.2 (CH), 128.5 (CH),
144.5 (C); HRMS (FAB+) calcd for C15H22NO2 (MH+) 248.1645;
found 248.1635.
(R)-N-[(S)-1-Phenylethyl]-2-[(S)-oxiran-2-yl]-1,2,3,6-
tetrahydropyridine (6)
A solution of compound 5 (741 mg, 3.0 mmol), PPh3 (943 mg,
3.6 mmol) and 40% solution in toluene of diethyl azodicarboxylate
(1.57 g, 3.6 mmol) in dry CHCl3 (60 mL) was stirred under argon
at 60 ◦C until complete disappearance of 5 (monitored by TLC). In
the event that some of starting material remained unaltered after
2 days a solution of PPh3 (471 mg, 1.8 mmol) and 40% solution
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in toluene of diethyl azodicarboxylate (785 mg, 1.8 mmol) in dry
CHCl3 (5 mL) was added at room temperature and the resulting
reaction mixture stirred under argon at 60 ◦C for an additional 12h.
Upon completion solvent was evaporated in vacuo. Purification of
the crude product by silica gel column chromatography (eluent:
Et2O/hexanes) yielded compound 6 (350 mg, 51%) as an oil.
NMR (100 MHz, CDCl3) d 19.1 (CH3), 23.3 (CH2), 41.9 (CH2),
48.3 (CH), 55.2 (CH), 59.0 (CH), 65.0 (CH2), 124.1 (CH), 126.1
(CH), 126.5 (CH), 126.7 (CH), 127.6 (CH), 128.0 (CH), 128.1
(CH), 128.8 (CH), 141.5 (C), 145.2 (C); HRMS (FAB+) calcd for
C21H26NO (MH+) 308.2009; found 308.2020.
(R)-N-[(S)-1-Phenylethyl]-2-[(S)-1-hydroxy-3-buten-2-yl]-1,2,
3,6-tetrahydropyridine (7c). Following the general procedure
described above 7c (112 mg, 87%) was obtained by treatment of
6 (115 mg, 0.5 mmol) with a 1 M solution of vinylmagnesium
[a]D = -18.9 (c 1.00, CHCl3); IR absorptions (pure) nmax 1666;
25
1H NMR (400 MHz, CDCl3) d 1.32 (d, J = 6.5, 3H), 1.95–2.02
(m, 1H), 2.28–2.35 (m, 1H), 2.44 (dd, J = 5.0, J = 2.7, 1H), 2.70
(dd, J = 5.0, J = 4.4, 1H), 2.78–2.85 (m, 1H), 2.87–3.02 (m, 2H),
3.14 (ddd, J = 7.2, J = 4.1, J = 2.8, 1H), 4.10 (q, J = 6.5, 1H),
5.48–5.55 (m, 1H), 5.58–5.66 (m, 1H), 7.11–7.20 (m, 1H), 7.18–
7.28 (m, 2H), 7.29–7.37 (m, 2H); 13C NMR (100 MHz, CDCl3) d
17.8 (CH3), 28.5 (CH2), 44.0 (CH2), 45.6 (CH2), 51.7 (CH), 55.0
(CH), 60.5 (CH), 123.0 (CH), 125.6 (CH), 126.6 (CH), 127.4 (CH),
128.2 (CH), 145.5 (C); HRMS (FAB+) calcd for C15H20NO (MH+)
230.1539; found 230.1539.
bromide in dry THF (1.00 mL, 1.0 mmol). Oil, [a]D = +4.9 (c
25
1
1.00, CHCl3); IR absorptions (pure) nmax 3405, 1852; H NMR
(400 MHz, CDCl3) d 1.22 (d, J = 6.6, 3H), 1.67–1.77 (m, 1H),
2.14–2.25 (m, 1H), 2.36–2.47 (m, 1H), 2.78 (ddd, J = 7.0, J = 7.0,
J = 2.8, 1H), 3.02–3.19 (m, 2H), 3.25 (bs, 1H), 3.31 (dd, J = 10.8,
J = 6.9, 1H), 3.59 (dd, J = 10.8, J = 4.8, 1H), 3.94 (q, J = 6.6, 1H),
5.02–5.07 (m, 1H), 5.06–5.11 (m, 1H), 5.48–5.56 (m, 1H), 5.60–
5.69 (m, 1H), 5.72–5.83 (m, 1H), 7.08–7.16 (m, 1H), 7.15–7.24
(m, 2H), 7.22–7.29 (m, 2H); 13C NMR (100 MHz, CDCl3) d 19.5
(CH3), 23.3 (CH2), 42.2 (CH2), 47.8 (CH), 54.4 (CH), 59.0 (CH),
64.0 (CH2), 116.7 (CH2), 124.3 (CH), 125.3 (CH), 126.8 (CH),
127.4 (CH), 128.3 (CH), 138.6 (CH), 145.3 (C); HRMS (FAB+)
calcd for C17H24NO (MH+) 258.1852; found 258.1838.
General procedure for the addition of Grignard reagents to
epoxide 6
A solution of the corresponding Grignard reagent (1.0 mmol) was
slowly added to a solution of compound 6 (115 mg, 0.5 mmol)
in dry THF (10 mL) under argon at room temperature and the
mixture was stirred for 20 h. The reaction mixture was then
quenched with water (10 mL) and extracted with diethyl ether
Et2O (2 ¥ 5 mL). The combined organic extracts were dried over
anhydrous MgSO4, filtered and concentrated in vacuo. Purification
of the crude products by silica gel column chromatography (eluent:
Et2O/hexanes, 1 : 1) yielded the corresponding tetrahydropyridine
7.
General procedure for the addition of Grignard-derived
organocuprate reagents to epoxide 6
A solution of the corresponding Grignard reagent (1.0 mmol) was
added to a suspension of CuBr (14 mg, 0.1 mmol) in dry THF (4
mL) under argon at 0 ◦C and the mixture was stirred for 10 min at
the same temperature. Then a solution of compound 6 (115 mg,
0.5 mmol) in dry THF (10 mL) was slowly added under argon at
◦
0 C and the mixture was stirred for 14 h at room temperature.
(R)-N-[(S)-1-Phenylethyl]-2-[(S)-1-hydroxypropen-2-yl]-1,2,3,
6-tetrahydropyridine (7a). Following the general procedure de-
scribed above, 7a (90 mg, 73%) was obtained by treatment of 6
(115 mg, 0.5 mmol) with a 3 M solution of methylmagnesium
The reaction mixture was quenched with water (10 mL) and
extracted with diethyl ether Et2O (2 ¥ 5 mL). The combined
organic extracts were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Purification of the crude products by silica
gel column chromatography (eluent: Et2O/hexanes, 1 : 1) yielded
the corresponding tetrahydropyridine 8.
bromide in dry THF (0.34 mL, 1.0 mmol). Oil, [a]D = -10.2
25
1
(c 0.78, CHCl3); IR absorptions (pure) nmax 3363; H NMR (400
MHz, CDCl3) d 0.94 (d, J = 7.0, 3H), 1.26 (d, J = 6.7, 3H), 1.86–
1.96 (m, 1H), 2.02–2.12 (m, 1H), 2.12–2.22 (m, 1H), 2.72 (ddd, J =
5.5, J = 5.5, J = 5.5, 1H), 2.94–3.11 (m, 2H), 3.49 (dd, J = 10.9,
J = 5.4, 1H), 3.60 (dd, J = 10.9, J = 6.3, 1H), 4.20 (q, J = 6.7,
(R)-N-[(S)-1-Phenylethyl]-2-[(R)-1-hydroxypropyl]-1,2,3,6-tet-
rahydropyridine (8a). Following the general procedure described
above, 8a (101 mg, 82%) was obtained by treatment of 6 (115 mg,
0.5 mmol) with the organocuprate reagent obtained from catalytic
CuBr and a 3 M solution of methylmagnesium bromide in dry
THF (0.34 mL, 1.0 mmol). Oil, [a]D25 = -10.4 (c 1.00, CHCl3); IR
absorptions (pure) nmax 3399, 1602; 1H NMR (400 MHz, CDCl3)
d 0.83 (t, J = 7.3, 3H), 0.93–1.07 (m, 1H), 1.32 (d, J = 6.5, 3H),
1.35–1.49 (m, 1H), 1.52–1.64 (m, 1H), 2.06–2.18 (m, 1H), 2.44 (dd,
J = 9.9, J = 7.1, 1H), 3.22–3.38 (m, 2H), 3.34–3.42 (m, 1H), 3.84
(q, J = 6.5, 1H), 4.01 (bs, 1H), 5.57–5.65 (m, 1H), 5.63–5.71 (m,
1H), 7.11-7.20 (m, 1H), 7.18-7.31 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 10.0 (CH3), 20.4 (CH2), 21.9 (CH3), 26.8 (CH2), 40.2
(CH2), 57.1 (CH), 59.7 (CH), 69.7 (CH), 124.3 (CH), 124.8 (CH),
127.0 (CH), 127.2 (CH), 128.5 (CH), 144.8 (C); HRMS (FAB+)
calcd for C16H24NO (MH+) 246.1852; found 246.1841.
1H), 5.50–5.57 (m, 1H), 5.67–5.74 (m, 1H), 7.11–7.33 (m, 5H); 13
C
NMR (100 MHz, CDCl3) d 14.5 (CH3), 16.1 (CH3), 23.2 (CH2),
35.5 (CH), 42.6 (CH2), 56.7 (CH), 57.9 (CH), 66.7 (CH2), 124.6
(CH), 125.2 (CH), 126.8 (CH), 127.6 (CH), 128.2 (CH), 144.6
(C); HRMS (FAB+) calcd for C16H24NO (MH+) 246.1852; found
246.1852.
(R)-N-[(S)-1-Phenylethyl]-2-[(S)-2-hydroxy-1-phenylethyl]-1,2,
3,6-tetrahydropyridine (7b). Following the general procedure
described above, 7b (354 mg, 77%) was obtained by treatment
of 6 (345 mg, 1.5 mmol) with a 3 M solution of phenylmagnesium
bromide in dry Et2O (1.00 mL, 3.0 mmol). Oil, [a]D = +49.8 (c
25
1
0.88, CHCl3); IR absorptions (pure) nmax 3398, 1652; H NMR
(400 MHz, CDCl3) d 1.14 (d, J = 6.6, 3H), 1.90–1.99 (m, 1H), 2.00
(bs, 1H), 2.21–2.32 (m, 1H), 2.90–2.98 (m, 1H) 2.98–3.09 (m, 2H),
3.15 (ddd, J = 8.1, J = 8.0, J = 5.3, 1H), 3.62 (dd, J = 10.9, J =
7.8, 1H), 3.82 (dd, J = 10.9, J = 5.3, 1H), 3.87 (q, J = 6.6, 1H),
5.55–5.62 (m, 1H), 5.66–5.74 (m, 1H), 7.03–7.27 (m, 10H); 13C
(R)-N-[(S)-1-Phenylethyl]-2-[(R)-2-phenyl-1-hydroxyethyl]-1,2,
3,6-tetrahydropyridine (8b). Following the general procedure
described above, 8b (149 mg, 97%) was obtained by treatment
of 6 (115 mg, 0.5 mmol) with the organocuprate reagent obtained
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from catalytic CuBr and a 3 M solution of phenylmagnesium
(R)-2-[(R)-1-Hydroxypropyl]piperidine (9a). Following the
general procedure described above, 9a (41 mg, 82%) was obtained
bromide in dry Et2O (0.34 mL, 1.0 mmol). Oil, [a]D = +30.7 (c
25
1.00, CHCl3); IR absorptions (pure) nmax 3344, 1604;1H NMR (400
MHz, CDCl3) d 1.35 (d, J = 6.5, 3H), 1.69–1.79 (m, 1H), 2.17–2.29
(m, 1H), 2.38 (dd, J = 14.1, J = 8.1, 1H), 2.56 (dd, J = 9.6, J = 7.3,
1H), 2.75 (dd, J = 14.1, J = 2.7, 1H), 3.24–3.41 (m, 2H), 3.76 (ddd,
J = 9.6, J = 8.1, J = 2.7, 1H), 3.87 (q, J = 6.5, 1H), 4.01 (bs, 1H),
5.62–5.69 (m, 1H), 5.70–5.78 (m, 1H), 7.09–7.28 (m, 10H); 13C
NMR (100 MHz, CDCl3) d 20.7 (CH2), 21.7 (CH3), 40.4 (CH2),
40.5 (CH2), 57.1 (CH), 59.8 (CH), 69.7 (CH), 124.1 (CH), 125.0
(CH), 125.9 (CH), 127.0 (CH), 127.1 (CH), 128.1 (CH), 128.5
(CH), 129.2 (CH), 139.1 (C), 144.6 (C); HRMS (FAB+) calcd for
C21H26NO (MH+) 308.2009: found 308.2012.
by hydrogenation of 8a (86 mg, 0.35 mmol). Oil, [a]D = +8.1 (c
25
1.00, EtOH) {lit12e [a]D25 = +7.9 (c 0.6, EtOH), [a]D25 = +8.3 (c 0.9,
1
EtOH)}; IR absorptions (pure) nmax 3316; H NMR (400 MHz,
CDCl3) d 0.96 (t, J = 7.4, 3H), 1.10–1.50 (m, 4H), 1.50–1.70 (m,
3H), 1.75–1.84 (m, 1H), 2.41 (ddd, J = 10.7, J = 7.9, J = 2.7, 1H),
2.59 (ddd, J = 12.1, J = 12.0, J = 2.8, 1H), 3.09–3.17 (m, 1H), 3.27
(ddd, J = 8.4, J = 8.4, J = 3.2, 1H), 3.99 (bs, 2H); 13C NMR (100
MHz, CDCl3) d 9.9 (CH3), 23.9 (CH2), 25.5 (CH2), 26.3 (CH2),
28.4 (CH2), 46.0 (CH2), 60.9 (CH), 74.8 (CH); HRMS (FAB+)
calcd for C8H18NO (MH+) 144.1383; found 144.1389.
(R)-2-[(R)-1-Hydroxy-2-phenylethyl]piperidine (9b). Follow-
ing the general procedure described above, 9b (58 mg, 81%) was
obtained by hydrogenation of 8b (107 mg, 0.35 mmol). M.p.
119 ◦C, [a]D25 = +35.2 (c 1.20, CHCl3); IR absorptions (pure) nmax
3320; 1H NMR (400 MHz, CDCl3) d 1.25–1.48 (m, 3H), 1.44–1.56
(m, 1H), 1.67–1.84 (m, 2H), 2.43–2.56 (m, 2H), 2.58 (dd, J = 13.8,
J = 8.9, 1H), 2.87 (dd, J = 13.8, J = 3.4, 1H), 2.99–3.07 (m, 1H),
3.61 (ddd, J = 8.9, J = 8.8, J = 3.4, 1H), 4.37 (bs, 2H), 7.16–7.32
(m, 5H); 13C NMR (100 MHz, CDCl3) d 23.6 (CH2), 24.8 (CH2),
28.0 (CH2), 39.9 (CH2), 45.7 (CH2), 60.6 (CH), 74.2 (CH), 126.2
(CH), 128.3 (CH), 129.5 (CH), 138.6 (C); HRMS (FAB+) calcd
for C13H20NO (MH+) 206.1539; found 206.1547.
(R)-N-[(S)-1-1-Phenylethyl]-2-[(R)-1-hydroxy-3-methylbutyl]-
1,2,3,6-tetrahydropyridine (8d). According to the general proce-
dure described above 8d (117 mg, 86%) was obtained by treatment
of 6 (115 mg, 0.5 mmol) with the organocuprate reagent obtained
from catalytic CuBr and a 2 M solution of isopropylmagnesium
bromide in dry Et2O (0.50 mL, 1.0 mmol). Oil, [a]D = -8.6 (c
25
0.50, CHCl3); IR absorptions (pure) nmax 3400, 1653;1H NMR
(400 MHz, CDCl3) d 0.80 (d, J = 6.7, 3H), 0.81 (d, J = 6.7,
3H), 0.95–1.05 (m, 2H), 1.32 (d, J = 6.5, 3H), 1.53–1.63 (m, 1H),
1.73–1.85 (m, 1H), 2.10–2.21 (m, 1H), 2.38 (dd, J = 9.8, J = 7.1,
1H), 3.22–3.38 (m, 2H), 3.44–3.51 (m, 1H), 3.84 (q, J = 6.5, 1H),
5.59–5.64 (m, 1H), 5.65–5.71 (m, 1H), 7.12–7.26 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 20.4 (CH2), 21.6 (CH3), 21.8 (CH3),
24.1 (CH3), 25.0 (CH), 40.2 (CH2), 44.0 (CH2), 58.2 (CH), 59.7
(CH), 66.7 (CH), 124.3 (CH), 124.9 (CH), 127.0 (CH), 127.2 (CH),
128.5 (CH), 144.8 (C); HRMS (FAB+) calcd for C18H27NO (MH+)
274.2165; found 274.2153.
(R)-2-[(R)-1-Hydroxy-3-methylbutyl]piperidine (9d). Follow-
ing the general procedure described above, 9d (48 mg, 80%) was
obtained by hydrogenation of 8d (96 mg, 0.35 mmol). Oil, [a]D
=
25
+34.4 (c 1.70, CHCl3); IR absorptions (pure) nmax 3314; 1H NMR
(400 MHz, CDCl3) d 0.84 (d, J = 6.6, 3H), 0.87 (d, J = 6.7, 3H),
0.97–1.40 (m, 5H), 1.48–1.55 (m, 1H), 1.55–1.63 (m, 1H), 1.68–
1.76 (m, 1H), 1.76–1.87 (m, 1H), 2.21 (ddd, J = 10.3, J = 7.6, J =
2.4, 1H), 2.50 (ddd, J = 11.8, J = 11.7, J = 2.5, 1H), 2.98–3.05
(m, 1H), 3.29 (ddd, J = 10.0, J = 7.6, J = 2.5, 1H); 13C NMR (100
MHz, CDCl3) d 21.6 (CH3), 24.0 (CH3), 24.3 (CH2), 24.5 (CH),
26.1 (CH2), 29.1 (CH2), 43.0 (CH2), 46.4 (CH2), 61.8 (CH), 71.9
(CH); HRMS (FAB+) calcd for C10H22NO (MH+) 144.1383; found
144.1389.
(R)-N-[(S)-1-1-Phenylethyl]-2-[(R)-1-hydroxy-3-methylbutyl]-
1,2,3,6-tetrahydropyridine (8e). According to the general proce-
dure described above 8e (125 mg, 78%) was obtained by treatment
of 6 (115 mg, 0.5 mmol) with the organocuprate reagent obtained
from catalytic CuBr and a 1 M solution of benzylmagnesium
bromide in dry Et2O (1.00 mL, 1.0 mmol). Oil, [a]D = -6.1 (c
25
0.70, CHCl3); IR absorptions (pure) nmax 3392, 1602;1H NMR
(400 MHz, CDCl3) d 1.23–1.36 (m, 1H), 1.31 (d, J = 6.5, 3H),
1.50–1.59 (m, 1H), 1.59–1.69 (m, 1H), 2.06–2.17 (m, 1H), 2.45
(dd, J = 9.9, J = 7.0, 1H), 2.52 (ddd, J = 13.7, J = 11.0, J = 5.7,
1H), 2.75 (ddd, J = 13.7, J = 11.3, J = 5.0, 1H), 3.21–3.37 (m, 2H),
3.45–3.52 (m, 1H), 3.82 (q, J = 6.5, 1H), 4.04 (bs, 1H), 5.56–5.62
(m, 1H), 5.61–5.68 (m, 1H), 7.01–7.08 (m, 3H), 7.10–7.18 (m, 3H),
7.20–7.26 (m, 4H); 13C NMR (100 MHz, CDCl3) d 20.3 (CH2),
21.8 (CH3), 32.2 (CH2), 36.4 (CH2), 40.1 (CH2), 57.4 (CH), 59.6
(CH), 68.3 (CH), 124.2 (CH), 124.8 (CH), 125.5 (CH), 127.1 (CH),
127.2 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 142.6 (C), 144.7
(C); HRMS (FAB+) calcd for C22H28NO (MH+) 322.2165; found
322.2153.
(R)-2-[(R)-1-Hydroxy-3-phenylpropyl]piperidine (9e). Follow-
ing the general procedure described above, 9e (63 mg, 82%) was
obta◦ined by hydrogenation of 8e (112 mg, 0.35 mmol). M.p.
117 C, [a]D = +24.6 (c 0.95, CHCl3); IR absorptions (pure)
25
1
nmax 3312, 3171; H NMR (400 MHz, CDCl3) d 1.16–1.37 (m,
3H), 1.45–1.64 (m, 3H), 1.67–1.82 (m, 2H), 2.28 (ddd, J = 10.3,
J = 8.0, J = 2.3, 1H), 2.50 (ddd, J = 11.8, J = 11.7, J = 2.3, 1H),
2.59 (ddd, J = 13.8, J = 9.9, J = 6.7, 1H), 2.83 (ddd, J = 14.6, J =
10.1, J = 4.8, 1H), 2.98–3.06 (m, 1H), 3.22 (ddd, J = 9.9, J = 7.7,
J = 2.5, 1H), 7.07–7.24 (m, 5H); 13C NMR (100 MHz, CDCl3) d
24.3 (CH2), 26.3 (CH2), 29.0 (CH2), 32.1 (CH2), 35.4 (CH2), 46.4
(CH2), 61.3 (CH), 73.3 (CH), 125.7 (CH), 128.3 (CH), 128.4 (CH),
142.3 (C); HRMS (FAB+) calcd for C14H22NO (MH+) 220.1696;
found 220.2691.
General procedure for the hydrogenation of tetrahydropyridines 8
A solution of the corresponding tetrahydropyridines 8 (0.35 mmol)
in EtOH (5 mL) was hydrogenated with molecular hydrogen for 14
h at atmospheric pressure and room temperature in the presence of
20% Pd(OH)2/C (20 mg) as a catalyst. The catalyst was removed
(R)-N-[tert-Butoxycarbonyl]-2-[(S)-2-hydroxy-1-
phenylethyl]piperidine (10)
A solution of compound 8b (307 mg, 1.0 mmol) in EtOH (15
mL) was hydrogenated with molecular hydrogen for 14 h at
atmospheric pressure and room temperature in the presence of
R
by filtration through a Celiteꢀ pad and the solvent evaporated in
vacuo to afford the corresponding piperidine 9.
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20% Pd(OH)2/C (60 mg) as a catalyst. The catalyst was removed
4 See for example: (a) I. M. Pastro and M. Yus, Curr. Org. Synth., 2005,
9, 1; (b) L. P. C. Nielsen and E. N. Jacobsen, in Aziridines and Epoxides
in Organic Synthesis, ed. A. K. Yudin, Wiley-VCH, Weinheim, 2006;
(c) M. Pineschi, Eur. J. Org. Chem., 2006, 4979.
5 D. Rodr´ıguez, A. Pico´ and A. Moyano, Tetrahedron Lett., 2008, 49,
6866.
R
by filtration through a Celiteꢀ pad, washed with ethanol (2 ¥
10 mL) and the solvent was evaporated in vacuo. The resulting
compound, triethylamine (121 mg, 1.2 mmol) and di-tert-butyl
dicarbonate (436 mg, 2.0 mmol) were dissolved in THF (10 mL)
and the mixture was stirred for 16 h at room temperature. The
reaction mixture was evaporated in vacuo and the crude product
was purified by column chromatography (eluent: Et2O/hexanes,
6 R. Badorrey, E. Portan˜a, J. A. Ga´lvez and M. D. D´ıaz-de-Villegas, Org.
Biomol. Chem., 2009, 7, 2912.
7 See for example: (a) R. Badorrey, C. Cativiela, M. D. D´ıaz-de-Villegas,
R. D´ıez and J. A. Ga´lvez, Synlett, 2005, 1734; (b) P. Etayo, R. Badorrey,
M. D. D´ıaz-de-Villegas and J. A. Ga´lvez, Synlett, 2006, 2799; (c) P.
Etayo, R. Badorrey, M. D. D´ıaz-de-Villegas and J. A. Ga´lvez, J. Org.
Chem., 2008, 73, 8594; (d) P. Etayo, R. Badorrey, M. D. D´ıaz-de-Villegas
and J. A. Ga´lvez, Eur. J. Org. Chem., 2008, 3474; (e) A. C. Allepuz, R.
Badorrey, M. D. D´ıaz-de-Villegas and J. A. Ga´lvez, Eur. J. Org. Chem.,
6172; (f) P. Etayo, R. Badorrey, M. D. D´ıaz-de-Villegas and J. A. Ga´lvez,
Synlett, 2010, 1775.
8 R. Badorrey, C. Cativiela, M. D. D´ıaz-de-Villegas, R. D´ıez and J. A.
Ga´lvez, Eur. J. Org. Chem., 2002, 3763.
9 C. R. Schmid and J. D. Bryant, Org. Synth., 1998, Coll. Vol. 9, 450; C.
R. Schmid and J. D. Bryant, Org. Synth., 1995, 72, 6.
3 : 2) to yield compound 10 (259 mg, 85%) as an oil. [a]D
=
25
+52.7 (c 1.06, CH2Cl2) {lit20 [a]D = +52.3 (c 1.06, CH2Cl2)}; IR
25
absorptions (pure) nmax 3340, 1685, 1664; 1H NMR (300 MHz, 333
K, CDCl3) d 1.32 (s, 9H), 1.20–1.98 (m, 6H), 2.61 (ddd, J = 13.7, J =
12.8, J = 3.7, 1H), 3.24 (ddd, J = 9.8, J = 7.4, J = 5.6, 1H), 3.72–
3.92 (m, 3H), 4.52–4.61 (m, 1H), 7.17–7.32 (m, 5H); 13C NMR
(100 MHz, 333 K, CDCl3) d 19.2 (CH2), 25.1 (CH2), 26.9 (CH2),
28.3 (3 ¥ CH3), 39.4 (CH2), 48.5 (CH), 51.6 (CH), 65.0 (CH2),
79.1 (C), 126.9 (CH), 128.3 (CH), 129.0 (CH), 139.7 (C), 154.9
(C); HRMS (FAB+) calcd for C18H28NO3 (MH+) 328.1883; found
328.1883.
10 R. D´ıez, R. Badorrey, M. D. D´ıaz-de-Villegas and J. A. Ga´lvez, Eur. J.
Org. Chem., 2007, 2114.
11 For reviews on the synthesis of heterocycles using RCM see: (a) F. X.
Felpin and J. Lebreton, Eur. J. Org. Chem., 2003, 3693; (b) P. Compain,
Adv. Synth. Catal., 2007, 349, 1829; (c) H. Villar, M. Frings and C.
Bolm, Chem. Soc. Rev., 2007, 36, 55; (d) K. C. Majumdar, S. Muhuri,
R. U. Islam and B. Chattopadhyay, Heterocycles, 2009, 78, 1109.
12 See for example: (a) C. Agami, F. Couty and N. Rabasso, Tetrahedron
Lett., 2000, 41, 411; (b) C. Agami, F. Couty and N. Rabasso,
Tetrahedron, 2001, 57, 539; (c) M. Y. Chang, Y. H. Kung and S. T.
Chen, Tetrahedron, 2006, 62, 10843; (d) P. P. Saikia, G. Baishya, A.
Goswami and N. C. Barua, Tetrahedron Lett., 2008, 49, 6508; (e) S.
Lebrun, A. Couture, E. Deniau and P. Grandclauson, Tetrahedron:
Asymmetry, 2008, 19, 1245; (f) M. Venkataiah and N. W. Fadnavis,
Tetrahedron, 2009, 65, 6950; (g) A. Kamal, S. R. Vangala, N. V. Reddy
and V. S. Reddy, Tetrahedron: Asymmetry, 2009, 20, 2589.
13 O. Mitsunobu, Synthesis, 1981, 1.
Acknowledgements
Financial support from the Spanish Ministry of Science and In-
novation and European Regional Development Fund (CTQ2008-
00187/BQU) and the Government of Arago´n (GA E-71) is
acknowledged
Notes and references
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3 For conhydrines syntheses see: (a) E. Reyes, N. Ruiz, J. L. Vicario, D.
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16 C. Liu, Y. Hashimoto and K. Saigo, Tetrahedron Lett., 1996, 34, 6177.
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8162 | Org. Biomol. Chem., 2011, 9, 8155–8162
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