Stereoselective transformation of 2H-1,4-oxazin-2-ones into 2,(2),5,5- tri- and tetrasubstituted analogues of cis-5-hydroxy-2-piperidinemethanol and cis-5-hydroxy-6-oxo-2-piperidinecarboxylic acid

Article abstract of DOI:10.1016/S0040-4020(00)00193-9

2,(2),5,5-Tri- and tetrasubstituted analogues of 5-hydroxy-2- piperidinemethanol and 5-hydroxy-6-oxo-2-piperidinecarboxylic acid have been prepared via Diels-Alder reaction of 3-substituted 2H-1,4-oxazin-2-ones with ethene followed by functional group transformation of the resulting imidoyl chloride and lactone groups. Some of the 2-piperidinemethanol products are convened further into potential substance P antagonists. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00193-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3043±3051
Stereoselective Transformation of 2H-1,4-Oxazin-2-ones
into 2,(2),5,5-Tri- and Tetrasubstituted Analogues
of cis-5-Hydroxy-2-piperidinemethanol and
cis-5-Hydroxy-6-oxo-2-piperidinecarboxylic Acid
Xiujuan Wu, Kristof Dubois, Joeri Rogiers, Suzanne Toppet, Frans Compernolle
*
and Georges J. Hoornaert
Laboratorium voor Organische Synthese, Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, 3001 Leuven (Heverlee), Belgium
Received 10 November 1999; revised 11 February 2000; accepted 2 March 2000
AbstractÐ2,(2),5,5-Tri- and tetrasubstituted analogues of 5-hydroxy-2-piperidinemethanol and 5-hydroxy-6-oxo-2-piperidinecarboxylic
acid have been prepared via Diels±Alder reaction of 3-substituted 2H-1,4-oxazin-2-ones with ethene followed by functional group trans-
formation of the resulting imidoyl chloride and lactone groups. Some of the 2-piperidinemethanol products are converted further into
potential substance P antagonists. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
considered as conformationally constrained cyclic analogues
of bioactive b-aminoalcohols showing various activity
pro®les.4 Recently, Merck researchers have claimed
substance P antagonist activity for the b-hydroxypiperidine
derivatives [IV]5 and [V].6 Substance P, a neurotrans-
mitter in the central nervous system, is postulated to
play an important role in a number of biological
processes including pain transmission, asthma and neuro-
genic in¯ammation.
Substituted piperidines exhibit an extensive range of bio-
logical activities and are of great interest in the pharmaceu-
tical industry. In particular the structural framework of
b-hydroxypiperidines is widely found in naturally occurring
piperidine alkaloids, such as (1)-pseudoconhydrine (I)
(Fig. 1),1 (2)hydroxysedamine (II)2 and (2)desoxoproso-
philline (III).3 These b-hydroxypiperidines can be
Figure 1.
Keywords: substituted piperidines; 3-piperidinols; substance P antagonists; Diels±Alder reaction.
* Corresponding author. Tel.: 132-16-32-7409; fax: 132-16-32-7990; e-mail: georges.hoornaert@chem.kuleuven.ac.be
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00193-9

3044
X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
Scheme 1.
Clearly, a short, versatile and stereocontrolled route for the
synthesis of substituted piperidines is highly important.
Such a route could proceed via Diels±Alder reaction of
cyclic 2-azadiene systems. Previously we reported a non-
stereoselective synthesis of 2,3,5-substituted piperidines:
this involved cycloaddition of 2H-1,4-oxazin-2-ones and
acetylenic compounds with concomitant elimination of
carbon dioxide, followed by catalytic hydrogenation.7 In
contrast to the cycloaddition±elimination reaction observed
for acetylenic dienophiles, cycloadducts of 2H-1,4-oxazin-
2-ones and ole®ns can be isolated and derivatised.8 In the
present study, we wish to report a short and stereoselective
approach to the title compounds, i.e. 2,(2),5,5-tri- and tetra-
substituted analogues of 5-hydroxy-6-oxo-2-piperidine-
carboxylic acid and 5-hydroxy-2-piperidinemethanol. Our
approach involves the cycloaddition of variously substituted
oxazinones with ethene, followed by functional group trans-
formation of the resulting lactone and imidoyl chloride
groups; some of the b-hydroxypiperidine products were
elaborated further into potential substance P antagonists
(SPA).
The starting 3,5-dichloro-oxazinones9 1a,b were prepared
from the corresponding a-hydroxynitriles, and subsequently
functionalised (Ph, Me) or dechlorinated at the 3 position
(Scheme 2). Due to the lactone function of 1a,b, nucleo-
philic attack at the reactive 3-position does not proceed
selectively when using organolithium or Grignard reagents.
However, a convenient alternative for regioselective intro-
duction of the desired C-substituents was provided by palla-
dium-catalysed coupling with organotin reagents. This mild
and selective coupling reaction serves to form a C±C bond
with vinylic and aromatic halides, with formation of tri-
organotin halide as a driving force. Thus a mixture of 1a
or 1b and the tetramethyl- or tetraphenyltin reagent was
heated with a catalytic amount of tetrakis(triphenylphos-
phine)palladium at re¯ux temperature in degassed toluene
under inert atmosphere to produce the 3-methyl and 3-phenyl
substituted oxazinones 2a±c as the sole products in high
yield. Similarly 2d was obtained by using tributyltin hydride
at room temperature. When, in the latter reaction, the
temperature was raised above 508C, the 3-butyl and 3-tri-
butylstannyl substituted oxazinones were formed as side
products. The 3-substituted oxazinones 2a±d then were
made to react with ethene in toluene at 1108C in a sealed
tube. Following cycloaddition and evaporation of the
solvent, the crude adducts 3a±d were used directly in the
next step without further puri®cation.
Results and Discussion
Our synthetic approach is summarised in Scheme 1.
Scheme 2.

X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
3045
Scheme 3.
To convert adducts 3 to compounds of type 4, both the
imidoyl chloride and lactone function must be reduced.
From examination of various reaction conditions including
the use of NaBH4, LiBH4, BH3´SMe2 and LiAlH4, we found
the best yields of the desired piperidinols 4 when using
LiAlH4 in THF. Thus a solution of the crude adducts
3a±d in freshly distilled THF was added carefully to an
ice-cooled suspension of LiAlH4 in THF under N2 atmos-
phere. Following reaction at room temperature for 4±12 h,
reduction of both the imidoyl chloride and lactone groups
was completed to afford products 4a±d in 56±78% yield
over two steps. Therefore our two-step sequence, consisting
of cycloaddition and reduction, allows for the stereo-
selective synthesis of 2,2,5,5-tetrasubstituted analogues of
cis-5-hydroxy-2-piperidinemethanol having variable R3 and
R6 substituents (Scheme 2). Other substituent combinations
than those described in the scheme can be accessible via the
corresponding oxazinones 1; however it should be
mentioned that compound 1 (R6ˆH) could only be obtained
in a low yield.9
and 8 uniformly assume the conformational structure indi-
cated in Fig. 2. This conformational preference seems to be
governed by the favourable equatorial disposition of the
5-phenyl or 5-methyl group and an equally favourable
axial orientation of the 5-hydroxyl group. The latter may
form an internal H-bridge with the piperidine-N-atom as
found in other 3-piperidinols4a,4e (see also below). In the
preferred conformational structure of compound 8, both
these stabilising factors co-operate to force the large
2-hydroxymethyl substituent in the axial position. In this
context it should be noticed that in model compound V,
the 2-phenyl and 2-benzyloxymethyl groups adopt an
axial and equatorial orientation, respectively. In the 1H
coupled 13C NMR spectra of 4a±c, the 2-methyl carbon or
the ipso carbon of the 2-phenyl group exhibited a large
3
coupling JC±H (6.0±7.0 Hz) with the axial proton in
3-position, while the coupling between the 5-methyl or
5-phenyl ipso carbon and the protons in 4- or 6-position
3
could not be resolved. These JC±H coupling values con-
clusively show the axial orientation for the 2-Ph-groups in
4a,b and the 2-Me in 4c. Similarly, in the 1H NMR spectrum
of 4d, a large coupling (Jˆ11.6 Hz) was observed between
H-2 (d 2.52) and the axial H-3 (d 1.55), indicating an axial
Reduction was also carried out on the adduct 7 formed via
cycloaddition of 3,5-dichloro-oxazinone 1b with ethene (the
angular Cl-substituent derives from the 3-Cl-atom in 1b).
The starting material was consumed after reaction at 08C for
1 h. Following workup and chromatographic separation,
two isomeric products were isolated that showed the same
molecular ion as that observed in the mass spectrum of
compound 4d described above. The isomers were charac-
terised further as the cis and trans compounds 4d and 8
(Scheme 3). Presumably, reduction of the lactone and
imidoyl chloride proceeds as described for the conversion
3a±d!4a±d (see Scheme 2). However, in this case a
2-chloropiperidine is formed as an intermediate whichÐ
probably following loss of HCl and generation of an
imineÐis reduced in a non-stereoselective way.
1
orientation of H-2. In the H NMR spectrum of 8, proton
H-2 displayed a down®eld (d 3.00) double quartet signal
(Jˆ10.0 and 4.5 Hz). By selective decoupling it was shown
that the larger coupling value (Jˆ10.0 Hz) corresponds to
an anti-oriented proton in the hydroxymethyl side chain,
whereas the other vicinal protons displayed an equal value
of 4.5 Hz for the coupling constant with H-2. On the other
hand, no coupling could be observed between the 5-phenyl
ipso carbon and protons H-4 and H-6. On the basis of these
observations, the trans-5-hydroxy-2-piperidinemethanol
con®guration was assigned to 8, with H-2 equatorially
oriented.
Besides the direct conversion of adducts 3 to the 5-hydroxy-
2-piperidinemethanol products 4, we also investigated step-
wise approaches proceeding via intermediates 5 or 6. Partial
From a conformational study using NMR spectroscopy, it
appears that the 5-hydroxy-2-piperidinemethanol products 4
Figure 2.

3046
X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
Scheme 4. The yields for 5 and 6 refer to the isolated pure products formed over two steps from 2; the yields of 4 refer to reduction of 5 and 6 respectively.
reduction of 3 to form the bridged lactone compounds 5 was
accomplished using sodium cyanoborohydride (NaBH3CN)
in a 4:1 mixture of THF and an aqueous buffer system (1 M
NaOAc/HOAc, pH 5.0). It has been reported10 that
NaBH3CN reduces the imine function with remarkable
selectivity in slightly acidic medium. Generally the reduc-
tion is performed in a protic solvent, e.g. methanol.
However, the HCl produced under these conditions resulted
in the autocatalytic solvolysis of the imidoyl chloride while
the lactam product was found to be stable to the reducing
agent. Hence, the slightly acidic buffer system used may act
both as a proton source required for generation and reduc-
tion of the intermediate iminium ions, and as a proton accep-
tor which counteracts hydrolysis by avoiding a severe
change in pH of the system. Complete and selective reduc-
tion of the imidoyl chloride was effected by heating 3 in the
buffered reducing medium, affording the bicyclic amino-
lactones 5 in moderate to good yields. The relatively low
yield of 5d possibly was due to facilitated hydrolysis of 3d.
The structures of these novel compounds were assigned on
the basis of spectral data. The 1H NMR spectra displayed an
AB system for the two H-6 protons, while the pseudoaxial
proton H-6ax showed an additional long-range coupling with
the exo proton H-7 (4Jˆ2.9 Hz for 5a) (Scheme 4). In the IR
spectra, a strong absorption at 1733 cm21 revealed the
presence of the lactone group. Reductive cleavage of the
lactone group of compounds 5 was effected by treatment
with LiAlH4, offering an alternative route to the 2-piper-
idinemethanol products 4.
Solvolysis of the ethene adducts 3 was carried out with
methanol in chloroform. This resulted ®rst in hydrolysis
of the imidoyl chloride to form the bridged lactam inter-
mediate 9, and then opening of the lactone group catalysed
by the HCl released. This observation is similar to that
reported for the ethene adducts of 3,5-dichloro-oxazinone.11
The yield of the monocyclic ester compounds 6 was found
to be dependent on the nature of the substituents R6 and R3,
being highest (85%) for 6d and lowest (48%) for 6c.
Presumably, the solvolysis reaction of the imidoyl chloride
and especially that of the lactone are slowed down by the
steric congestion imposed by the substituents R3 and R6,
respectively, during conversion of the planar imidoyl and
lactone groups into tetrahedral intermediates. Consequently,
6d was the only product isolated upon treatment of 3d with
acidic methanol, whereas bicyclic lactone 9c was detected
as a major side product. Upon treatment of lactam esters 6
with LiAlH4, complete reduction of both the amide and ester
function was achieved, providing a third way for accessing
compounds 4. Apparently the stepwise approaches proceeding
Scheme 5. (i) MeI (1.2 equiv.), K2CO3, acetone, re¯ux, 4 h. (ii) PhCH2Br (1.2 equiv.), K2CO3, acetone, re¯ux, 3 h. (iii) (1) NaH (2 equiv.), DMF; (2) 3,5
bis(tri¯uromethyl)benzylbromide (1.1 equiv.), THF, rt, 1 d.

X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
3047
via 5 or 6 are less ef®cient than the one-step reduction
described above. However, compounds 5 and 6 display a
stereospeci®c arrangement of multiple functionalities that
may prove useful in further transformations.
spectrometer. For the determination of OH stretching
frequencies corresponding to OH´´´N intermolecular
H-bridge formation, compounds 10a±d were dissolved in
CCl4, using a quartz cell of 0.5 cm optical length, at concen-
trations of 0.01 M or lower to suppress intermolecular
1
In view of the SP potency displayed by compounds IV and
V, we transformed the 2-piperidinemethanol compounds
4a,b into potential SP antagonists 10a±d mimicking the
model compounds IV and V; this involved chemo- and
regioselective derivatisation of the amine and/or alcohol
functions (Scheme 5). Compounds 10a,b were prepared
by selective O-benzylation of the primary alcohol group
of the 2-phenyl substituted compounds 4a,b following
deprotonation with NaH in DMF. The corresponding
N-substituted derivatives 10c,d were prepared via initial
N-methylation or N-benzylation (MeI or BnBr with
K2CO3 in acetone/DMF) to form 4e,f, followed by O-benzyl-
ation of the primary alcohol function.
association. H NMR and 13C NMR spectra were recorded
on a Bruker WM 250 or on a Bruker AMX 400 instrument.
The 1H and 13C chemical shifts are reported in ppm relative
to tetramethylsilane or the deuterated solvent as an internal
reference. Mass spectra were run using a Hewlett Packard
MS-Engine 5989A apparatus for EI and CI spectra, and a
Kratos MS50TC instrument for exact mass measurements
performed in the EI mode at a resolution of 10,000. For the
chromatography, analytical TLC plates (Alugram Sil G/
UV254) and 70±230 mesh silica gel 60 (E.M. Merck) were
used. Microanalyses were performed by Janssen Pharma-
ceutica. The spectroscopic data of 2H-1,4-oxazin-2-one
2a,b12 and the preparation of adducts 3a and 78 have been
described in previous papers.
From the 1H and 13C NMR spectra, compounds 10a±d were
shown to adopt the `2-Ph axial' conformational structure, in
accordance with that reported for the bioactive model V.
Apparently, as argued above for the alcohol analogues
4a±d and 8, this conformer is further stabilised by the
favourable disposition of the equatorial 5-Me or 5-Ph and
axial 5-OH substituents. For compounds 10a±c, the occur-
rence of intramolecular H-bonding (as discussed above) was
demonstrated by the characteristic IR absorption at about
3505 cm21 in dilute solutions of carbon tetrachloride.
However, this intramolecular OH´´´N interaction was
largely suppressed for the N-benzyl compound 10d, prob-
ably due to distortion of the regular chair conformation.
Accordingly, the long range coupling between H-4eq and
H-6eq (4Jˆ1.1±3.0 Hz), which uniformly characterises the
chair forms of 10a±c and 4a±e, was no longer observed in
5-Chloro-3,6-dimethyl-2H-1,4-oxazin-2-one (2c). A mix-
ture of 540 mg (3 mmol) 3,5-dichloro-6-methyl-2H-1,4-
oxazin-2-one, 644 mg (3.6 mmol) tetramethyl tin, and
34 mg (0.03 mmol) Pd[PPh3]4 in 6 ml dry toluene was
heated at 1108C under N2 atmosphere until completion of
the reaction (two days). The mixture was stirred with 2.0 g
KF at room temperature for 2 h, then it was ®ltered and the
solids washed with dry toluene. The ®ltrate was evaporated,
the residue dissolved in CH3CN (50 ml) and washed with
pentane (2£30 ml). After evaporation the residue was puri-
®ed by Kugelrohr distillation or ¯ash chromatography.
Yield: 429 mg, 90%; white crystals; mp: 908C (CH2Cl2/
1
n-C6H14); IR (KBr) cm21: 1746 (CO), 1619 (CvN); H
NMR (CDCl3): 2.35 (s, 3H, CH3), 2.45 (s, 3H, CH3); 13C
NMR(CDCl3): 16.8, 20.2 (2£CH3), 124.7 (C-5), 147.4
(C-6), 152.1 p(C-3), 154.0 (C-2); m/z (%): 159 (7, M1),
131 (12, M1 2CO), 43 (100, CH3CO1); exact mass for
C6H6ClNO2: 159.0087; found:159.0081.
1
the H NMR spectrum of 10d.
Conclusion
5-Chloro-6-phenyl-2H-1,4-oxazin-2-one (2d). To a solu-
tion of 1.210 g (5 mmol) 3,5-dichloro-6-phenyl-2H-1,4-
oxazin-2-one and 0.05 g tetrakis (Pd[PPh3]4) (0.05 mmol)
in 50 ml dry toluene, 1.60 g n-Bu3SnH (5.5 mmol) was
added via a syringe under argon atmosphere. The reaction
mixture was stirred at room temperature for one day and
then KF (3.0 g) was added. After being stirred for 2 h, the
mixture was ®ltered and the solids washed with dry toluene.
The ®ltrate was concentrated in vacuo, the residue was taken
up in 50 ml dry MeCN and the solution washed with two
30 ml portions of pentane. The MeCN layer was evaporated
and the residue was puri®ed by Kugelrohr distillation or
¯ash chromatography. Yield: 890 mg, 86%; yellow crystals;
mp: 888C (CH2Cl2/n-C6H14); IR (KBr) cm21: 1738 (CO),
1585 (CvN); 1H NMR (CDCl3): 7.48±7.53 (m, 3H,
Ph-H), 7.85 (s, 1H, H-3), 7.90±7.93 (m, 2H, Ph-H); 13C
NMR: 125.2 (C-5), 128.6, 128.7, 128.8, 131.6 (C-Ph),
142.2 (C-3), 148.7 (C-6), 152.5 (C-2); m/z (%): 207 (25,
M1.), 179 (47, M1.2CO), 105 (85, PhCO1), 77 (100,
Ph1); exact mass for C10H6ClNO2: 207.0087; found:
207.0089.
Cycloaddition of 3-substituted 5-chloro-2H-1,4-oxazinones
with ethene followed by transformation of the resultant
imidoyl chloride and lactone functions was shown to be a
highly ef®cient route for the synthesis of 2,(2),5,5-tri- and
tetrasubstituted analogues of cis-5-hydroxy-2-piperidine-
methanol and cis-5-hydroxy-6-oxo-2-piperidinecarboxylic
acid. This approach allows for the stereoselective intro-
duction of variable substituents on the piperidine ring and
further elaboration of the 2-piperidinemethanol inter-
mediates into potential substance P antagonists. Extension
of this approach including reactions with other ole®ns is in
progress.
Experimental
General methods
Melting points were taken using a Reichert±Jung Thermo-
var apparatus and an Electrothermal IA 9000 digital melting
point apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin±Elmer 297 grating IR spectro-
photometer and a Perkin±Elmer 1720 Fourier transform
Generation of adducts 3 and their reduction to piper-
idinols (4). A solution of 2H-1,4-oxazin-2-one 2 (5 mmol)

3048
X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
in 10 ml dry toluene was heated at 1108C for 4 h under
ethene pressure (20 atm.) in a stainless steel tube. The
progress of the cycloaddition was controlled by TLC,
which showed the disappearance of the starting oxazinone
detected as a typical dark spot under UV light of 366 nm.
After evaporation of the solvent, the crude products 3 (e.g.
3b) were used directly in the next step.
Jˆ7.4 Hz, H-meta), 7.60 (d, 2H, Jˆ7.5 Hz, H-ortho); 13C
NMR (DMSO-d6): 24.2 (C-3), 32.8 (C-4), 52.7 (C-6), 59.2
(C-2), 69.1 (C-5), 71.4 (CH2OH), 124.6, 126.0, 126.2, 127.2,
127.7, 128.1 (C-Ph), 142.3(C-ipsoat C-2), 148.5(C-ipsoat C-5);
m/z (%): 284 (0.4, MH1), 252 (100, M12CH2OH), 234 (44,
M12CH2OH±H2O); exact mass for C17H18NO1 (M1±
CH2OH): 252.1388; found: 252.1391; anal. calcd for
C18H21NO2: C 76.30, H 7.47, N 4.94; found: C 75.98, H
7.53, N 4.76.
6-Chloro-1,4-diphenyl-2-oxa-5-azabicyclo[2.2.2]oct-5-en-
1
3-one (3b). IR (KBr) cm21: 1758 (CO), 1678 (CvN); H
NMR (CDCl3): 2.10 (m, 1H, ±CH2CH2±), 2.53±2.64 (m,
3H, ±CH2CH2±), 7.40±7.75 (m, 10H, Ph-H); 13C NMR
(CDCl3): 29.5 and 30.4 (C-7 and C-8), 70.8 (C-4), 85.6
(C-1), 126.6, 127.4, 128.3, 128.4, 128.6, 129.5 (C-Ph),
134.5, 136.4 (C-ipso), 164.6 (C-6), 169.5 (C-3); m/z (%)
(CI): 312 (1, MH1), 267 (33, M1.2CO2), 232 (12,
M1.2CO22Cl), 103 (100, C6H5C2H12 ).
1,2,3,4,5,6-Hexahydro-5a-hydroxy-2b,5b-dimethyl-2a-
pyridinemethanol (4c). Yield: 445 mg; colourless oil; IR
1
(NaCl, ®lm) cm21: 3324 (OH, NH); H NMR (DMSO-d6):
0.87 (s, 3H, CH3
C-2), 0.99 (dt, 1H, 2Jˆ14.0 Hz,
at
3Jˆ4.0 Hz, H-3eq), 1.02 (s, 3H, CH3 at C-5), 1.47 (m, 2H,
2
3
3
H-4), 1.72 (ddd, 1H, Jˆ14.0 Hz, Jˆ9.5 Hz, Jˆ6.0 Hz,
2
4
H-3ax), 2.37 (dd, 1H, Jˆ13.2 Hz, Jeeˆ1.4 Hz, H-6eq),
2
2.52 (d, 1H, Jˆ13.2 Hz, H-6ax), 3.10 (br.s, 1H, OH, or
2
To a stirred solution of 570 mg LiAlH4 (15 mmol) in 60 ml
dry THF at 08C under nitrogen atmosphere, a solution of
5 mmol crude adduct 3 in 50 ml dry THF was added
dropwise. When the addition was ®nished, the ice bath
was removed and the reaction mixture was stirred for
4±12 h at room temperature. The excess of hydride was
decomposed by careful addition of a saturated NH4Cl solu-
tion to form a white granular precipitate. The organic layer
was decanted and the precipitate washed three times with
diethyl ether. The combined organic layers were dried over
MgSO4, ®ltered, and concentrated to afford crude
compounds 4, which could be puri®ed by crystallisation
from dichloromethane and n-hexane. The yields (%) are
given in Scheme 2.
NH), 3.12, 3.16 (2£d, 2H, Jˆ9.9 Hz, CH2OH), 4.10 (br.s,
2H, NH, or OH); 13C NMR (DMSO-d6): 19.6 (CH3 at C-2),
27.5 (CH3 at C-5), 28.0 (C-3), 33.3 (C-4), 51.7 (C-2), 51.9
(C-6), 65.3 (C-5), 69.2 (CH2OH); m/z (%): 160 (8, MH1),
128 (100, M1.2CH2OH), 110 (64, M1.2CH2OH±H2O);
exact mass for C8H18NO2 (MH): 160.1338, found:
160.1338.
1,2,3,4,5,6-Hexahydro-5a-hydroxy-5b-phenyl-2a-pyridine-
methanol (4d). Yield: 621 mg; white crystals; mp: 142.58C
1
(MeOH/Et2O); IR (KBr) cm21: 3392, 3058 (OH, NH); H
NMR (DMSO-d6): 1.45(m, 1H, H-3eq), 1.55 (qd, 1H,
3
3
2Jˆ3Jaaˆ13.0 Hz, Jaaˆ11.6 Hz, Jaeˆ4.0 Hz, H-3ax), 1.69
(m, 1H, H-4eq), 1.91 (td, 1H, Jˆ3Jaaˆ 13.0 Hz, Jaeˆ
2
3
3
4.6 Hz, H-4ax), 2.10 (br., 1H, NH), 2.52 (m, 1H, Jaaˆ
3
2
1,2,3,4,5,6-Hexahydro-5a-hydroxy-5b-methyl-2b-phenyl-
2a-pyridinemethanol (4a). Yield: 796 mg; white crystals;
mp: 1428C (CH2Cl2/n-C6H14); IR (KBr) cm21: 3334, 3279
(OH, NH); 1H NMR (CD3OD): 0.95 (s, 3H, CH3), 1.39 (td,
11.6 Hz, Jaeˆ3.0 Hz, H-2ax), 2.65 (dd, 1H, Jˆ12.8 Hz,
4Jeeˆ2.6 Hz, H-6eq), 2.77 (d, 1H, 2Jˆ12.8 Hz, H-6ax),
3
3.35 (d, 2H, Jˆ5.0 Hz, CH2OH), 4.50 (br.s, 1H, CH2OH),
4.71 (s, 1H, OH), 7.20 (t, 1H, H-para), 7.30 (t, 2H, H-meta),
7.50 (d, 2H, H-ortho); 13C NMR (DMSO): 24.5, 36.1 (C-3,
C-4), 56.9 (C-2), 57.2 (C-6), 65.3 (CH2OH), 69.7 (C-5),
124.8, 126.1, 127.7 (C-Ph), 148.1 (C-ipso); m/z (%): 208
(1, MH1), 190 (1, M1.2H2O), 176 (100, M1.2OCH3),
158 (28, M1.2OCH3±H2O); exact mass for C12H17NO2:
207.1259, found: 207.1251; anal. calcd for C12H17NO2: C
69.54, H 8.27, N 6.76; found: C 69.56, H 8.50, N 6.87.
2
3
1H, Jˆ3Jaaˆ14.0 Hz, Jaeˆ4.0 Hz, H-4ax), 1.62 (dq, 1H,
2Jˆ14.0 Hz, Jeaˆ3Jeeˆ4.0 Hz, Jeeˆ2.7 Hz, H-4eq), 2.08
3
4
(dt, 1H, Jˆ14.0 Hz, Jeaˆ3Jeeˆ4.0 Hz, H-3eq), 2.32 (td,
2
3
2
3
1H, Jˆ3Jaaˆ14.0 Hz, Jaeˆ4.0 Hz, H-3ax), 2.50 (d, 1H,
2Jˆ13.7 Hz, H-6ax), 2.58 (dd, 1H, 2Jˆ13.7 Hz,
4Jeeˆ2.7 Hz, H-6eq), 3.34, 3.38 (2£d, 2H, 2Jˆ11.0 Hz,
CH2OH), 7.25 (tt, 1H, 3Jˆ7.0 Hz, 4Jˆ1.2 Hz, H-para),
7.35 (t, 2H, H-meta), 7.50 (d, 2H, H-ortho); 13C NMR
(CD3OD): 26.0 (C-3), 28.1 (CH3), 34.3 (C-4), 53.1 (C-6),
61.5 (C-2), 67.3 (C-5), 72.6 (CH2OH), 127.8 (C-para),
128.3 (C-ortho), 129.5 (C-meta), 141.9 (C-ipso); m/z (%):
190 (100, M12CH2OH), 172 (28, M12CH2OH±H2O);
exact mass for C12H16O1N1 (M12CH2OH): 190.1232;
found: 190.1235; anal. calcd for C13H19O2N1: C 70.56, H
8.65, N 6.33; found: C 70.29, H 8.88, N 6.21.
Preparation of N-alkyl piperidinols (4e,f). To a solution
of 663 mg 4a (3 mmol) in 30 ml acetone was added 829 mg
(6 mmol) potassium carbonate and then dropwise 3.3 mmol
MeI (for 4e) or PhCH2Br (for 4f) at room temperature. The
reaction mixture was heated at re¯ux temperature for one
day; after removal of the solvent in vacuo the residue was
treated with 30 ml of water. The aqueous suspension was
extracted three times with 30-ml of dichloromethane. The
combined extracts were dried (MgSO4) and evaporated to
give crude products, which were puri®ed by recrystallisa-
tion (dichloromethane/n-hexane). The yields (%) are given
in Scheme 5.
1,2,3,4,5,6-Hexahydro-5a-hydroxy-2b,5b-diphenyl-2a-
pyridinemethanol (4b). Yield: 1.10 g; white crystals; mp:
179.2±180.58C (CH2Cl2/n-C6H14); IR (KBr) cm21: 3316,
3199 (OH, NH); 1H NMR (DMSO-d6): 1.68 (m, 1H,
3
H-4eq), 1.75 (td, 1H, 2Jˆ3Jaaˆ13.5 Hz, Jaeˆ3.5 Hz,
2
H-4ax), 2.04 (m, 1H, H-3eq), 2.43 (td, Jˆ3Jaaˆ13.5 Hz,
N-Methyl-1,2,3,4,5,6-hexahydro-5a-hydroxy-5b-methyl-
2b-phenyl-2a-pyridinemethanol (4e). Yield: 564 mg;
white crystals; mp: 109.68C (MeOH/Et2O); IR (KBr)
2
3Jaeˆ4.0 Hz, H-3ax), 2.57 (d, 1H, Jˆ14.0 Hz, H-6), 2.59
(d, 1H, 2Jˆ14.0 Hz, H-6), 2.68 (br.s, 1H, NH), 3.17 (d, 2H,
3Jˆ5.5 Hz, CH2OH), 4.98 (s, 1H, OH), 5.02 (t, 1H,
3Jˆ5.5 Hz, CH2OH), 7.1±7.3 (m, 6H, Ph-H), 7.36 (t, 2H,
1
cm21: 3747, 3371 (OH); H NMR (CDCl3): 1.15 (s, 3H,
2
3
CH3), 1.51 (td, 1H, Jˆ3Jaaˆ13.3 Hz, Jaeˆ4.2 Hz, H-4ax),

X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
3049
2
3
4
1.60 (dtd, 1H, Jˆ13.3 Hz, Jaeˆ3Jeeˆ4.2 Hz, Jeeˆ2.3 Hz,
(C-ipso), 173.8 (CO); m/z (%): 218 (17, MH1), 188 (31,
M1.2CH2vNH), 173 (100, M1.2CO2); exact mass for
C13H15NO2: 217.1103, found: 217.1104.
H-4eq), 1.86 (dt, 1H, 2Jˆ14.3 Hz, Jaeˆ3Jeeˆ4.2 Hz,
3
2
H-3eq), 2.30 (br., 1H, OH), 2.34 (ddd, 1H, Jˆ14.3 Hz,
3
3Jaaˆ13.3 Hz, Jaeˆ4.2 Hz, H-3ax), 2.56 (dd, 1H, 2Jˆ
4
12.3 Hz, Jeeˆ2.3 Hz, H-6eq), 2.60 (s, 3H, N-CH3), 2.70
1,4-Diphenyl-2-oxa-5-azabicyclo [2.2.2]octan-3-one (5b).
Yield: 716 mg; white crystals; mp: 1578C (CH2Cl2/Et2O);
IR (KBr) cm21: 3294 (NH), 1741 (CO); 1H NMR (CDCl3):
2.22 (m, 1H, H-7exo), 2.15 (br. s, 1H, NH), 2.30±2.42 (m,
3H, H-8, and H-7endo), 3.35 (dd, 1H, 2Jˆ11.6 Hz,
4Jˆ3.2 Hz, H-6ax), 3.75 (d, 1H, 2Jˆ11.6 Hz, H-6eq),
7.30±7.60 (m, 10H, Ph-H); 13C NMR (CDCl3): 31.9, 33.2
(C-7 and C-8), 52.5 (C-6), 58.0 (C-4), 82.1 (C-1), 124.6,
126.6, 127.8, 128.1, 128.2, 128.6 (C-Ph), 138.4 and 139.6
(C-ipso), 173.4 (C-3); m/z (%): 235 (100, M1.2CO2); exact
mass for C18H18NO2 (MH1): 280.1338, found: 280.1333;
anal. calcd for C18H17O2N1: C 77.40, H 6.13, N 5.01;
found: C 77.19, H 6.12, N 4.97.
2
(br., 1H, OH), 2.91 (d, 1H, Jˆ12.3 Hz, H-6ax), 3.67 (d,
1H, 2Jˆ11.2 Hz, CH2OH), 3.88 (d, 1H, 2Jˆ11.2 Hz,
CH2OH), 7.26 (tt, 1H, 3Jˆ7.2 Hz, 4Jˆ1.5 Hz, H-para),
7.33±7.40 (m, 4H, H-meta and H-ortho); 13C NMR
(CDCl3): 26.8 (CH3), 28.8, 34.0 (C-3, C-4), 39.3 (N-CH3),
61.9 (C-6), 62.7 (C-2), 66.8 (CH2OH), 67.9 (C-5), 124.9,
127.6, 128.3 (C-Ph), 141.1 (C-ipso); m/z (%) (CI): 236 (100,
MH1), 218 (54, M1H2H2O), 204 (26, MH12CH3OH);
exact mass for C14H22NO2 (MH1): 236.1251, found:
236.1646; anal. calcd for C14H21NO2: C 71.46, H 8.99, N
5.95; found: C 71.60, H 9.11, N 5.83.
N-Benzyl-1,2,3,4,5,6-hexahydro-5a-hydroxy-5b-methyl-
2b-phenyl-2a-pyridinemethanol (4f). Yield: 765 mg;
white crystals; mp: 125.48C (MeOH/Et2O); IR (KBr)
1-Phenyl-2-oxa-5-azabicyclo [2.2.2]octan-3-one (5d). Yield:
308 mg; colourless oil; IR (NaCl, ®lm) cm21: 3327 (NH),
1755 (CO); H NMR (CDCl3): 2.02±2.05 (m, 2H, H-7),
1
1
cm21: 3419 (OH); H NMR (CDCl3): 1.13 (s, 3H, CH3),
1.51 (m, 1H, H-4ax), 1.62 (m, 1H, H-4eq), 1.91 (br., 1H,
CH2OH), 1.94 (m, 1H, H-3eq), 2.30 (m, 1H, H-3ax), 2.40
2.25±2.29 (m, 2H, H-8), 2.30 (s, 1H, NH), 3.16 (dd, 1H,
2Jˆ11.6 Hz, Jˆ2.6 Hz, H-6ax), 3.38 (d, 1H, Jˆ11.6 Hz,
H-6eq), 3.57 (m, 1H, H-4), 7.31±7.44 (m, 5H, Ph-H); 13C
NMR (CDCl3): 24.4, 30.7 (C-7, C-8), 50.2 (C-4), 51.9 (C-6),
82.7 (C-1), 124.5, 127.9, 128.6 (C-Ph), 139.5 (C-ipso),
173.8 (C-3); m/z (%), 204 (4, MH1), 176 (10, MH12CO),
159 (100, M1.2CO2); exact mass for C12H13NO2, 203.0946,
found: 203.0948.
4
2
2
4
(br. s, 1H, OH), 2.61 (dd, 1H, Jˆ12.0 Hz, Jeeˆ1.7 Hz,
2
H-6eq), 2.83 (d, 1H, Jˆ12.0 Hz, H-6ax), 3.77 (d, 1H,
2
2Jˆ14.0 Hz, CH2Ph), 4.20 (d, 1H, Jˆ14.0 Hz, CH2Ph),
3.89 (d, 1H, 2Jˆ11.0 Hz, CH2OH), 4.01 (d, 1H, 2Jˆ
11.0 Hz, CH2OH), 7.22±7.50 (m, 10H, Ph-H); 13C
NMR(CDCl3): 26.4 (CH3), 30.6 (C-3), 34.2 (C-4), 54.9
(PhCH2N), 58.5 (C-6), 64.2 (C-2), 66.3 (CH2OH), 68.1
(C-5), 126.9, 127.0, 127.6, 127.9, 128.6, 128.7 (C-Ph),
140.6, 142.4 (C-ipso); m/z (%): 312 (1, MH1), 280 (100,
M12CH2OH), 91 (88, Bn1); exact mass for C19H22NO1
(M12CH2OH): 280.1701, found, 280.1701; anal. calcd
for C20H25NO2: C 77.14, H 8.09, N 4.50; found: C 77.04,
H 8.21, N 4.53.
General procedure for the generation of methyl 6-oxo-
5a-hydroxy-2a-piperidinecarboxylates (6). Methanol
(5 ml) was added to the crude cycloadduct 3 (5 mmol)
dissolved in CHCl3 (10 ml). The mixture was stirred at
room temperature for one day. After evaporation of the
solvent, puri®cation was done by chromatography (silica
gel, eluent: MeOH/CH2Cl2). The conversion of 6 to 4 was
carried out with LiALH4 in THF at re¯ux for 8±14 h. The
yields are given in Scheme 5. The yield of 6c was rather low
and 9c was isolated as major side product.
General procedure for NaCNBH3 reduction of adducts 3
to yield lactones (5). To a clear solution of 502 mg
NaCNBH3 (8 mmol) in a mixture of 16 ml of THF and
4 ml buffered solution (1 M NaOAc/HOAc, pHˆ5.0) was
added 4 mmol crude adduct 3. The reaction mixture was
heated at 758C for one day; after removal of solvent in
vacuo the residue was treated with 10 ml saturated
NaHCO3 solution. The aqueous suspension was extracted
with three 20-ml portions of dichloromethane. The
combined extracts were dried (MgSO4) and evaporated to
give the crude product 5. Further puri®cation was carried
out by chromatography and crystallisation. The conversion
of 5 to 4 was carried out by treatment with LiAlH4 in THF at
room temperature for 3±8 h. The yields (%) are given in
Scheme 5.
Methyl 5a-hydroxy-5b-methyl-6-oxo-2b-phenyl-2a-piperi-
dinecarboxylate (6a). Yield: 855 mg; white crystals; mp:
1508C (CH2Cl2/n-C6H14); IR (KBr) cm21: 3351, 3210 (OH,
NHCO), 1740 (COOMe), 1663 (CONH); 1H NMR (CDCl3):
2
3
1.50 (s, 3H, CH3), 1.74 (ddd, 1H, Jˆ14.0 Hz, Jˆ8.0 Hz,
3Jˆ3.0 Hz, H-4eq), 1.95 (ddd, 1H, 2Jˆ14.0 Hz, 3Jˆ
3
2
10.0 Hz, Jˆ3.0 Hz, H-3ax), 2.17 (ddd, 1H, Jˆ14.0 Hz,
3Jˆ10.0 Hz, 3Jˆ3.0 Hz, H-4ax), 2.76 (dddd, 1H, 2Jˆ
3
3
4
14.0 Hz, Jˆ8.0 Hz, Jˆ3.0 Hz, Jeeˆ1 Hz, H-3eq), 3.45
(s, 1H, OH), 3.77 (s, 3H, COOMe), 6.69 (br., 1H, HNCO),
7.32±7.42 (m, 5H, Ph-H); 13C NMR (CDCl3): 27.3 (CH3),
31.0 (C-3), 32.0 (C-4), 53.2 (OMe), 66.3 (C-2), 69.6 (C-5),
124.6 (C-meta), 128.4 (C-para), 129.0 (C-ortho), 140.2
(C-ipso), 171.5 (C-6), 176.2 (COOMe); m/z (%): 204
(100, M1.2COOCH3), 186 (44, M1.2COOCH3-H2O),
176 (54, M1.2COOMe±CO); exact mass for C12H14NO2
(M1.2COOCH3): 204.1025; found: 204.1032.
1-Methyl-4-phenyl-2-oxa-5-azabicyclo [2.2.2]octan-3-one
(5a). Yield: 608 mg; white crystals; mp: 113.5±115.28C
(CH2Cl2/n-C6H14); IR (KBr) cm21: 3290 (NH), 1733
1
(CO); H NMR(CDCl3): 1.45 (s, 3H, CH3), 1.92 (m, 1H,
H-7endo), 1.97 (m, 1H, H-7exo), 2.10 (br. s, 1H, NH),
2
4
2.21 (m, 2H, H-8), 3.16 (dd, 1H, Jˆ11.3 Hz, Jˆ2.9 Hz,
2
H-6ax), 3.20 (d, 1H, Jˆ11.3 Hz, H-6eq), 7.30±7.39 (m,
Methyl 5a-hydroxy-5b-methyl-2b-methyl-6-oxo-2a-piperi-
dinecarboxylate (6c). Yield: 482 mg; white crystals; mp:
146±1488C (MeOH/Et2O); IR (KBr) cm21: 3344, 3211
3H, Ph-H), 7.51±7.54 (m, 2H, Ph-H); 13C NMR (CDCl3):
23.0 (CH3), 31.5 and 33.0 (C-7 and C-8), 51.7 (C-6), 57.4
(C-4), 79.8 (C-1), 126.6, 127.7, 128.0 (C-Ph), 138.5
1
(OH, NHCO), 1739 (COOMe), 1659 (CONH); H NMR

3050
X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
(CDCl3): 1.44 (s, 3H, CH3), 1.47 (s, 3H, CH3), 1.81±1.90
(m, 3H), 2.45 (m, 1H) (CH2CH2), 3.60 (s, 1H, OH), 3.76 (s,
3H, COOMe), 6.33 (br.s, 1H, HNCO); 13C NMR (CDCl3):
27.2 (CH3), 27.6 (CH3), 30.5, 32.3 (C-3, C-4), 52.9 (OMe),
60.5 (C-2), 69.6 (C-5), 174.0 (C-6), 176.6 (COOMe); m/z
(%): 202 (6, MH1), 142 (100, M12COOMe), 124 (39,
M12COOMe±H2O), 114 (93, M12COOMe±CO); exact
mass for C9H16NO4 (MH1): 202.1079, found: 202.1084;
anal. calcd for C9H15O4N1: C 53.72, H 7.51, N 6.96;
found: C 53.87, H 7.56, N 6.88.
bromide in 5 ml dry THF over a 15 min period. The result-
ing mixture was stirred for one day followed by careful
addition of a saturated ammonium chloride solution to pH
8.5±9.0, and 20 ml of water. The aqueous layer was
extracted with three 20 ml portions of dichloromethane,
and the combined organic layers were dried (MgSO4), and
concentrated in vacuo. The residual yellow oil was chroma-
tographed over silica gel (dichloromethane±ethyl acetate,
4:1) to give 3,5 bis(tri¯uromethyl)benzyl ether 10. The
yields (%) are given in Scheme 5.
1,4-Dimethyl-2-oxa-5-azabicyclo[2.2.2]octane-3,6-dione
(9c). Yield: 45%, 380 mg; white powder; mp: 96±978C
(MeOH/Et2O); IR (KBr) cm21: 3212 (NHCO), 1769
O-[3,5-Bis(tri¯uoromethyl)benzyl]-1,2,3,4,5,6-hexahydro-
5a-hydroxy-5b-methyl-2b-phenyl-2a-pyridinemethanol
(10a). Yield: 250 mg; colourless oil; IR (NaCl, ®lm) cm21
:
1
(COO), 1715, 1672 (CONH); H NMR (CDCl3): 1.54 (s,
3383 (OH, NH); 1H NMR (CDCl3): 1.03 (s, 3H, CH3), 1.37
3H, CH3), 1.58 (s, 3H, CH3), 1.93±2.02 (m, 3H, CH2CH2),
2.18 (m, 1H, CH2CH2), 7.84 (s, 1H, NHCO); 13C NMR
(DMSO): 17.8 (CH3), 18.4 (CH3), 29.5, 30.8 (C-7 and
C-8), 55.3 (C-4), 82.1 (C-1), 170.0, 171.9 (C-3 and C-6);
m/z (%): 170 (1, MH1), 125 (60, M1.2CO2), 97 (100,
M1.2CO2±CO), exact mass for C8H11NO3: 169.0739,
found: 169.0742.
(td, 1H, 2Jˆ3Jaaˆ13.6 Hz, 3Jaeˆ4.0 Hz, H-4ax), 1.59 (dddd,
1H, 2Jˆ13.6 Hz, Jeaˆ4.0, Jeeˆ3.5 Hz, Jeeˆ2.2 Hz,
3
3
4
H-4eq), 2.08 (td, 1H, 2Jˆ3Jaaˆ13.6 Hz, Jeaˆ4.0 Hz,
3
2
3
3
H-3ax), 2.17 (ddd, 1H, Jˆ13.6 Hz, Jaeˆ4.0 Hz, J
ˆ
ee
3.5 Hz, H-3eq), 2.54 (d, 1H, 2Jˆ12.5 Hz, H-6ax), 2.59
2
4
(dd, 1H, Jˆ12.5 Hz, Jeeˆ2.2 Hz, H-6eq), 2.80 (br., s, 2H,
OH and NH), 3.39 (d, 1H, 2Jˆ8.7 Hz, CH2OCH2C6H3(CF3)2),
2
3.47 (d, 1H, Jˆ8.7 Hz, CH2O CH2C6H3(CF3)2), 4.43 (d,
Methyl 5a-hydroxy-6-oxo-5b-phenyl-2a-piperidinecar-
boxylate (6d). Yield: 1058 mg; white crystals; mp: 158±
1618C (MeOH/Et2O); IR (KBr) cm21: 3274 (OH, NHCO),
1760 (COOMe), 1660 (CONH); 1H NMR (DMSO-d6):
1.81±1.95 (m, 4H, CH2CH2), 3.70 (s, 3H, COOMe), 4.19
(m, 1H, H-2), 7.25±7.38 (m, 5H, Ph-H), 7.94 (br. s, 1H,
NHCO); 13C NMR (DMSO): 21.9, 34.7 (C-3, C-4), 52.1
(OMe), 54.0 (C-2), 74.1 (C-5), 125.8, 126.9, 127.6 (C-Ph),
145.3 (C-ipso), 172.4, 172.6 (C-6, COOMe); m/z (%): 250
(3, MH1), 249 (3, M1), 232 (7, MH12H2O), 221 (18,
M12CO), 204 (40, MH12H2O±CO), 162 (100,
M1.2CO±COOMe); exact mass for C13H15NO4:
249.1001, found: 249.1004; anal. calcd for C13H15O4N1: C
62.64, H 6.07, N 5.62; found: C 62.46, H 6.08, N 5.54.
1H, 2Jˆ13.0 Hz, OCH2C6H3(CF3)2), 4.50 (d, 1H, 2Jˆ
13.0 Hz, OCH2C6H3(CF3)2), 7.29±7.50 (m, 5H, H-Ph),
7.57 (s, 2H), 7.74 (s, 1H); 13C NMR (CDCl3): 26.6 (C-3),
26.7 (CH3), 33.4 (C-4), 52.6 (C-6), 58.9 (C-2), 66.8 (C-5),
71.7 (CH2OCH2C6H3(CF3)2), 81.8 (CH2OCH2C6H3(CF3)2),
121.2±128.4 (C-Ar), 131.5 (CF3), 140.3 (C-ipso), 141.0
(C-ipso); m/z (%) (CI): 448 (30, MH1), 428 (20,
MH12HF), 190 (25, MH12CH2OCH2C6H3(CF3)2); exact
mass for C22H23O2N1F5 (MH12HF): 428.1649; found:
428.1640; anal. calcd for C22H23O2N1F6: C 59.04, H 5.18,
N 3.13; found: C 58.96, H 5.16, N 3.10.
O-[3,5-Bis(tri¯uoromethyl)benzyl]-1,2,3,4,5,6-hexahydro-
5a-hydroxy-2b,5b-diphenyl-2a-pyridinemethanol (10b).
Yield: 331 mg; colourless oil; IR (NaCl, ®lm) cm21: 3377
(OH, NH); 1H NMR (CDCl3): 1.78 (m, 1H, H-4eq), 1.93 (m,
1,2,3,4,5,6-Hexahydro-5a-hydroxy-5b-phenyl-2b-pyridine-
methanol (8). Preparation of compound 8 from 7 (5 mmol)
was carried out using the same procedure as for compounds
4a±d, except that the reaction time was 1 h (Scheme 3).
Yield: 288 mg; white crystals; mp: 988C (MeOH/Et2O);
2
1H, H-4ax), 2.31 (m, 2H, H-3), 2.75 (dd, 1H, Jˆ12.8 Hz,
4Jeeˆ2.6 Hz, H-6eq), 2.90 (d, 1H, 2Jˆ12.8 Hz, H-6ax), 3.43
(d, 1H, 2Jˆ8.7 Hz, CH2OCH2C6H3(CF3)2), 3.52 (d, 1H,
2Jˆ8.7 Hz, CH2OCH2C6H3(CF3)2), 4.47 (d, 1H, 2Jˆ
13.0 Hz, OCH2C6H3(CF3)2), 4.53 (d, 1H, 2Jˆ13.0 Hz,
OCH2C6H3(CF3)2), 7.18±7.54(m, 10H, 2£Ph), 7.60 (s,
2H), 7.75 (s, 1H); 13C NMR (CDCl3): 26.5 (C-3), 33.0
(C-4), 52.8 (C-6), 58.9 (C-2), 70.5 (C-5), 71.7
(CH2OCH2C6H3(CF3)2), 81.1 (CH2OCH2C6H3(CF3)2),
125.0 (CF3), 124.6, 126.0, 126.9, 127.0, 127.2, 128.1,
128.5 (C-Ph), 131.4, 131.7 (C-CF3), 140.0 (C-ipsoax),
140.9(C-ipsoAr), 145.8 (C-ipsoeq); m/z (%) (CI): 510 (100,
MH1), 490 (49, MH12HF), 252 (56, MH12CH2OCH2Ar);
exact mass for C27H25O2N1F6: 509.1789; found: 509.1790;
anal. calcd for C27H25O2N1F6: C 63.65, H 4.95, N 2.75,
found: C 63.40, H 5.14, N 2.50.
1
IR (KBr) cm21: 3294 (OH, NH); H NMR (CDCl3): 1.36
(m, 1H, H-3eq), 1.75 (m, 1H, H-4eq), 1.98 (m, 1H, H-3ax),
2.15 (m, 1H, H-4ax), 2.62 (br., 3H, NH, OH), 2.72 (dd, 1H,
4
3
2Jˆ13.0 Hz, Jeeˆ1.8 Hz, H-6eq), 2.99 (dq, 1H, Janti
ˆ
10.0 Hz, Jsynˆ3Jeeˆ3Jeaˆ4.5 Hz, H-2eq), 3.22 (d, 1H,
2Jˆ13.0 Hz, H-6ax), 3.46 (dd, 1H, 2Jˆ10.6 Hz, 3Jˆ
3
2
3
4.5 Hz, CH2OH), 3.70 (dd, 1H, Jˆ10.6 Hz, Jˆ10.0 Hz,
CH2OH), 7.26 (t, 1H, H-para), 7.34 (t, 2H, H-meta), 7.55
(d, 2H, H-ortho); 13C NMR (CDCl3): 23.4, 34.0 (C-3, C-4),
52.2 (C-6), 53.2 (C-2), 61.4 (CH2OH), 70.6 (C-5), 125.2,
127.1, 128.2 (C-Ph), 145.7 (C-ipso); m/z (%) (CI): 208 (100,
MH1), 190 (42, MH1±H2O), 176 (6, M1±CH3OH); exact
mass for C12H17NO2: 207.1259; found: 207.1251.
N-Methyl-O-[3,5-bis(tri¯uoromethyl)benzyl]-1,2,3,4,5,6-
hexahydro-5a-hydroxy-5b-methyl-2b-phenyl-2a-pyri-
dinemethanol (10c). Yield: 323 mg; colourless oil; IR
General procedure for the preparation of 3,5-bis(tri¯uro-
methyl)benzyl ethers (10). To a solution of 1 mmol of
piperidinol 4 in 10 ml DMF was added 50.4 mg (2.1
mmol) sodium hydride in a single portion at room tempera-
ture. The mixture was stirred for 30 min. followed by the
addition of 338 mg (1.1 mmol) 3,5-bis(tri¯uromethyl)benzyl
1
(NaCl, ®lm) cm21: 3413 (OH); H NMR (CDCl3): 1.23 (s,
3H, CH3), 1.56 (m, 2H, CH2), 1.90 (m, 1H, CH2), 2.14 (m,
2
1H, CH2), 2.53 (s, 3H, N-CH3), 2.56 (d, 1H, Jˆ12.0 Hz,
H-6ax), 2.76 (d, 1H, 2Jˆ12.0 Hz, 4Jeeˆ1.2 Hz, H-6eq), 3.82

X. Wu et al. / Tetrahedron 56 (2000) 3043±3051
3051
(s, 2H, CH2OCH2C6H3(CF3)2), 4.59 (d, 1H, 2Jˆ13.0 Hz,
OCH2C6H3(CF3)2), 4.61 (d, 1H, 2Jˆ13.0 Hz, OCH2C6H3
(CF3)2), 7.24±7.49 (m, 5H, Ph), 7.69 (s, 2H), 7.77 (s, 1H);
13C NMR (CDCl3): 26.3 (CH3), 30.6 (C-3), 34.8 (C-4), 40.1
(CH3), 61.9 (C-6), 62.3 (C-2), 68.4 (C-5), 71.9, 73.8
(CH2OCH2C6H3(CF3)2), 124.6 (CF3), 121.4, 126.7, 127.1,
127.5, 128.1, 131.5, 131.8, 140.1, 143.1 (C-Ph, Ar); m/z
(%) (CI): 462 (100, MH1), 444 (55, M1H2H2O), 442
(82, MH12HF); exact mass for C23H25N1O2F6: 461.1789,
found: 461.1786; anal. calcd for C23H25N1O2F6: C 59.87, H
5.46, N 3.04; found: C 59.82, H 5.52, N 3.05.
company for ®nancial support to the lab. They are also
grateful to R. De Boer for mass spectral analysis. X. Wu
wishes to thank the K.U. Leuven for the fellowships
received.
References
1. Hill, R. K. J. Am. Chem. Soc. 1958, 80, 1611±1613 and refer-
ences therein.
2. Ibekeke-Bomangwa, W.; Hootele, C. Tetrahedron 1987, 43,
935±945.
N-Benzyl-O-[3,5-bis(tri¯uoromethyl)benzyl]-1,2,3,4,5,6-
hexahydro-5a-hydroxy-5b-methyl-2b-phenyl-2a-pyri-
dinemethanol (10d). Yield: 468 mg; colourless oil; IR
3. Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull.
Soc. Chim. Belg. 1974, 81, 425±430.
1
(NaCl, ®lm) cm21: 3413 (OH); H NMR (CDCl3): 1.22 (s,
4. (a) Hirose, R.; Hamamichi, N.; Kitao, Y.; Matsuzaki, T.; Chiba,
K.; Fujita, T. Bioorg. Med. Chem. Lett. 1996, 6, 2647±2650. (b)
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3H, CH3), 1.60 (m, 2H, CH2CH2), 1.98 (m, 1H, CH2CH2),
2.22 (m, 1H, CH2CH2), 2.10 (br., 1H, OH), 2.49 (d, 1H,
2
2Jˆ12.0 Hz, H-6), 2.67 (d, 1H, Jˆ12.0 Hz, H-6), 3.80 (d,
1H, 2Jˆ14.0 Hz, PhCH2N), 3.84 (d, 1H, 2Jˆ14.0 Hz,
PhCH2N), 3.98 (d, 1H, 2Jˆ10.0 Hz, CH2OCH2C6H3(CF3)2),
2
4.01 (d, 1H, Jˆ10.0 Hz, CH2OCH2C6H3(CF3)2), 4.62 (d,
1H, 2Jˆ13.0 Hz, OCH2C6H3(CF3)2), 4.64 (d, 1H,
2Jˆ13.0 Hz, OCH2C6H3(CF3)2), 7.19±7.36 (m, 8H, Ph),
7.60±7.62 (m, 2H, Ph), 7.74 (s, 2H), 7.79 (s, 1H); 13C
NMR (CDCl3): 25.9 (CH3), 32.4 (C-3), 35.0 (C-4), 55.2
(C-6), 57.6 (PhCH2N), 63.4 (C-2), 68.4 (C-5), 71.9, 72.3
(CH2OCH2C6H3(CF3)2), 124.6 (CF3), 121.5, 126.8, 127.1,
131.5, 140.7, 140.9, 144.1 (C-Ph, Ar); m/z (%): 538 (100,
MH1), 520 (31, M1H2H2O), 518 (41, MH12HF); exact
mass for C29H29N1O2F6: 537.2102, found: 537.2091; anal.
calcd for C29H29N1O2F6: C 64.80, H 5.44, N 2.61; found: C
64.70, H 5.41, N 2.56.
5. Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg.
Med. Chem. Lett. 1994, 4, 2545±2550.
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Hoornaert, G. Tetrahedron 1997, 53, 12699±12715.
8. Fannes, C.; Meerpoel, L.; Toppet, S.; Hoornaert, G. Synthesis
1992, 705±709.
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3183±3186. (b) Meerpoel, L.; Hoornaert, G. Synthesis 1990,
905±908
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Acknowledgements
11. Dubois, K. J.; Fannes, C. C.; Compernolle, F.; Hoornaert, G.
Tetrahedron 1996, 52, 2591±2602.
The authors wish to thank the F.W.O. (Fund for Scienti®c
ResearchÐFlanders (Belgium)) and the `Ministerie voor
Wetenschapsbeleid', I.U.A.P. and the Janssen Pharmaceutica
12. Van Aken, K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel, L.;
Hoornaert, G. Tetrahedron 1994, 50, 5211±5224.