Efficient Routes to Chiral 2-Substituted and 2,6-Disubstituted Piperidines

Article abstract of DOI:10.1021/jo980719d

The syntheses of chiral 2-substituted and 2,6-disubstituted piperidines, and piperidin-2-ylphosphonates, via benzotriazole methodology are described.

Full text of DOI:10.1021/jo980719d

J . Org. Chem. 1998, 63, 6699-6703
6699
Efficien t Rou tes to Ch ir a l 2-Su bstitu ted a n d 2,6-Disu bstitu ted
P ip er id in es
Alan R. Katritzky,*,§ Guofang Qiu,§ Baozhen Yang,§ and Peter J . Steel‡
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, and Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
Received April 20, 1998
The syntheses of chiral 2-substituted and 2,6-disubstituted piperidines, and piperidin-2-ylphos-
phonates, via benzotriazole methodology are described.
The piperidine ring system is present in many natu-
rally occurring and biologically important compounds1-3
such as (+)-pinidione (1), (+)-monomorine (2), (+)-sole-
nopsin (3), (-)-lasubinel (4), and (+)-myrtine (5), etc.
Meyers et al. have continued studies on chiral bicyclic
lactams 6, which were prepared by condensation of an
optically pure amino alcohol with dicarbonyl compounds,
and their application to the synthesis of natural and
unnatural products, including 2-substituted and 2,6-
disubstituted piperidines.4-6 Recently, Amart and co-
workers reported using this type of lactam 6 to prepare
enantiopure 3-alkylpiperidines.7 Husson et al. have
elegantly demonstrated the advantages of 3(S)-5-cyano-
3-phenylperhydropyrido[2,1-b][1,3]oxazole (7) as a chiral
1,4-dihydropyridine equivalent for the preparation of
chiral 2-substituted8 and 2,6-disubstituted piperidines,8-10
and chiral aminophosphonates.11 However, this meth-
odology requires the use of KCN as starting material,
and AgBF4 for removal of the cyano group. Lhommet et
al. reported recently the preparation of (+)- and (-)-
trans-2,6-dimethylpiperidines starting from Meyers’s lac-
tam 6 and Husson’s synthon 7.12 Chackalamannil and
Wang synthesized (S)-2-methyl-2,3,4,5-tetrahydropyri-
dine N-oxide, as a key intermediate for the enantiose-
lective construction of trans-2,6-disubstituted piperidine,
from N-Cbz-L-alanine methyl ester in six steps.13 Kiba-
yashi et al.14 found that 2-substituted piperidines were
enantioselectively prepared by Et2AlCl-mediated nucleo-
philic alkylation with Grignard reagents on chiral per-
hydropyrido[2,1-b]pyrrolo[1,2-d][1,3,4]oxadiazine. Comins
and co-workers reported the synthesis of chiral 2-substi-
tuted and trans-2,6-disubstituted piperidines from pyri-
dine derivatives.15-17
F igu r e 1.
Recently, benzotriazole was used as an auxiliary18 for
the synthesis of drug candidates and natural products.
Bishop and McNutt reported an efficient route to the
highly selective, nonpeptidal, δ opioid agonist (+)-4-[(RR)-
R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy-
benzyl]-N,N-diethylbenzamide [(+)BW373U86],19 and
Shankar et al. described a new method for the synthesis
of polyhydroxylated piperidines as potential glycosidase
inhibitors.20 We have reported the preparation of chiral
2,5-disubstituted pyrrolidines from the reaction of (4S,5R)-
5-(benzotriazol-1-yl)-4-phenyl[1,2-a]oxazolopyrrolidine and
Grignard reagents.21
§ University of Florida.
‡ University of Canterbury.
(1) Hamana, M. Total Synthesis of Heterocyclic Natural Products.
Heterocycles 1997, 45, 1861.
(2) Toyooka, N.; Tanaka, K.; Momose, T. Tetrahedron 1997, 53, 9553.
(3) Bailey, P. D. J . Chem. Soc., Chem. Commun. 1998, 633.
(4) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503.
(5) Munchhof, M. J .; Meyers, A. I. J . Am. Chem. Soc. 1995, 117,
5399.
(6) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7086.
(7) Amat, M.; Llor, N.; Hidalgo, J .; Bosch, J . Tetrahedron: Asymmetry
1997, 8, 2237.
(15) Comins, D. L.; Hong, H.; Salvador, J . M. J . Org. Chem. 1991,
(8) Guerrier, L.; Royer, J .; Grierson, D. S.; Husson, H.-P. J . Am.
Chem. Soc. 1983, 105, 7754.
(9) Grierson, D. S.; Royer, J .; Guerrier, L.; Husson, H.-P. J . Org.
Chem. 1986, 51, 4475.
(10) Royer, J .; Husson, H.-P. J . Org. Chem. 1985, 50, 670.
(11) Maury, C.; Wang, Q.; Gharbaoui, T.; Chiadmi, M.; Tomas, A.;
Royer, J .; Husson, H.-P. Tetrahedron 1997, 53, 3627.
(12) Freville, S.; Bonin, M.; Celerier, J .-P.; Husson, H.-P.; Lhommet,
G.; Quirion, J .-C.; Thuy, V. M. Tetrahedron 1997, 53, 8447.
(13) Chackalamannil, S.; Wang, Y. Tetrahedron 1997, 53, 11203.
(14) Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1997, 38, 4623.
56, 7197.
(16) Al-awar, R. S.; J oseph, S. P.; Comins, D. L. J . Org. Chem. 1993,
58, 7732.
(17) Comins, D. L.; Benjelloun, N. R. Tetrahedron Lett. 1994, 35,
829.
(18) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
(19) Bishop, M. J .; McNutt, R. W. Bioorg. Med. Chem. Lett. 1995,
5, 1311.
(20) Shankar, B. B.; Kirkup, M. P.; McCombie, S. W.; Ganguly, A.
K. Tetrahedron Lett. 1993, 34, 7171.
S0022-3263(98)00719-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/02/1998

6700 J . Org. Chem., Vol. 63, No. 19, 1998
Katritzky et al.
Sch em e 1
Sch em e 2
F igu r e 2. The X-ray structure of 9a .
that product 8 is obtained as a diastereoisomeric mixture
of Bt1 and Bt2 derivatives. Our previous work has
demonstrated that22,23 (i) Bt1 and Bt2 groups are both
good leaving groups, and can be replaced by a nucleo-
phile; (ii) the mechanism of substitution of the Bt group
from adduct type A involves a planar iminium salt B as
intermediate (Scheme 1). Therefore, the position at
which the substituent is attached to the benzotriazole
ring is not important. Thus, we used the intermediate
8 directly as a diastereomeric mixture of Bt1 and Bt2
isomers in subsequent reactions.
Su bstitu tion of th e Ben zotr ia zolyl Gr ou p fr om 8
Usin g Gr ign a r d Rea gen ts. P r ep a r a tion of 2-Su b-
stitu ted P ip er id in es, a n d (+)- a n d (-)-Con iin e.
Treatment of intermediate 8 with 1 equiv of arylmagne-
sium bromide at -78 °C gave crystalline (3S,5R)-5-aryl-
3-phenylperhydropyrido[2,1-b][1,3]oxazole (9a and 9b) as
a single diastereoisomer in yields of 85% and 82%,
respectively (Scheme 2). The configuration of 9a was
demonstrated to be that shown in Figure 2 by X-ray
crystallography. The two phenyl groups in 9a are trans,
while the two substituents on the piperidine ring are cis.
Hydrogenation of 9a ,b gave 12a ,b in good yields.
By contrast and for reasons which are not understood,
the reactions of 8 with five alkylmagnesium bromides
(RMgBr, R ) n-Pr, n-Bu, PhCH2CH2, allyl, and C3H5O2-
CH2CH2) at -95 °C gave in each case a mixture of two
(3S ,5S )-5-a lkyl-3-ph en ylper h ydr opyr ido[2,1-b][1,3]-
oxazoles 9c-g (diastereoisomers at C-8a) and two (3S,5R)-
5-alkyl-3-phenylperhydropyrido[2,1-b][1,3]oxazoles 10c-g
(also diastereoisomers at C-8a). The position of asym-
metry in the diastereomeric pairs is demonstrated to be
C-8a by the following experiments. Reduction of the 9c
diastereomeric mixture with NaBH4 gave (2S)-2-[(2S)-
2-propylhexahydro-1-pyridinyl]-2-phenylethan-1-ol (11)
in 73% yield as a single diastereoisomer as determined
We now show that (3S)-5-benzotriazolyl-3-phenylper-
hydropyrido[2,1-b][1,3]oxazole (8) is a convenient chiral
1,4-dihydropyridine equivalent for the synthesis of chiral
2-substituted and cis-2,6-disubstituted piperidines, and
piperidin-2-ylphosphonates.
Intermediate 8 was prepared in 95% yield from (S)-2-
phenylglycinol, glutaraldehyde (aqueous solution) and
benzotriazole in methylene chloride at room temperature
1
for 12 h (Scheme 1). The H and 13C NMR spectra show
(22) Katritzky, A. R.; Fan, W.-Q. J . Org. Chem. 1990, 55, 3205.
(23) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J . Tetrahedron
1991, 47, 2683.
(21) Katritzky, A. R.; Cui, X.-L.; Yang, B. Tetrahedron Lett. 1998,
39, 1697.

Chiral 2-Substituted and 2,6-Disubstituted Piperidines
J . Org. Chem., Vol. 63, No. 19, 1998 6701
Sch em e 3
Sch em e 4
F igu r e 3. The X-ray structure of 16a .
isomer in 92% yield {[R]20 ) +202.5° (c 1.0, CH2Cl2)}.
D
The structure of 16a was confirmed by X-ray analysis
(see Figure 3): the methyl and phenyl substituents on
the piperidine ring are cis. Hydrogenation of 16a gave
compound 17a in 95% yield.
The mixture of oxazolidines 9c (with R configuration
at position 5 in ratio 9:4) reacted with MeMgBr to give
(2S)-2-[(2R,6S)-2-methyl-6-propylhexahydro-1-pyridinyl]-
2-phenylethan-1-ol (16d ) in 98% yield as a single stere-
oisomer, as demonstrated by the 1H and 13C NMR
1
by H and 13C NMR spectroscopy. Hydrogenation of the
9c mixture gave (S)-(+)-propylpiperidine 12c ((S)-(+)-
coniine) in 83% yield, isolated as the hydrochloride salt.
Similarly, hydrogenation of 10c generated (R)-(-)-pro-
pylpiperidine 13c ((R)-(-)-coniine) in 85% yield, also
isolated as the hydrochloride salt. Hydrogenation of
9d ,e,g and 10d ,e gave 12d ,e,g and 13d ,e, respectively.
In the hydrogenation of 9f, the allyl group was reduced
to a propyl group to give 12c (Scheme 2).
P r ep a r a tion of P ip er id in -2-ylp h osp h on a te. In-
termediate 8 reacted with lithium diethyl phosphite to
form diethyl [(3S)-3-phenylhexahydrooxazolo[3,2-a]pyri-
din-5-yl]phosphonate (14). Compound 14 is a 93:7 mix-
ture of two diastereoisomers, and the NMR spectra (1H
and 13C) of 14 are consistent with the literature11 except
for the ratio. In their analogous work, Husson and co-
workers reported10 a diastereomeric ratio of 33:67. Hy-
drogenation of 14 gave diethyl (hexahydro-2-pyridinyl)-
phosphonate (15) as a colorless oil in 68% yield and 86%
ee.
analysis, oil, [R]20 ) +18.3° (c 1.16, EtOH). Hydrogena-
D
tion of 16d in turn formed chiral (2R,6S)-2-methyl-6-
propylpiperidine (17d ) in 85% yield, isolated as the
hydrochloride salt, mp 190-194 °C, [R]20 ) +11.9° (c
D
0.69, EtOH) {lit.8 [R]20 ) +12.5° (c 1.0, EtOH)}.
D
Procedures similar to those used for 9d afforded 16e,f.
Hydrogenation of 16e gave 17e. This provides a novel
and general method to chiral cis-2,6-disubstituted pip-
eridines.
In conclusion, the chemistry described above provides
a convenient and efficient method to prepare chiral
2-substituted piperidines, chiral cis-2,6-disubstituted pi-
peridines, and chiral piperidin-2-ylphosphonates, which
are biologically active compounds of importance for the
synthesis of natural products. For comparison, we note
that Moody et al.24 reported the synthesis of (R)-(-)-
coniine from chiral 1-phenylbutanol in six steps in an
overall yield of 23%. Kibayashi’s method14 provided (S)-
(+)-coniine in 20% yield, while Husson’s method gave (S)-
(+)-coniine in 39% yield and Comins’ method offered (R)-
(-)-coniine in five steps with total yield 54%.16 Our
method gave (S)-(+)-coniine in three steps in an overall
Syn th esis of 2,6-Disu bstitu ted P ip er id in es. In-
termediates 9a -d can further react with another Grig-
nard reagent to give compounds 16a -f, which after
hydrogenation afford 2,6-disubstituted piperidines 17a -
e. For example, compound 9a reacted with 1 equiv of
MeMgBr to give (2S)-2-[(2R,6R)-2-methyl-6-phenylhexahy-
dro-1-pyridinyl]-2-phenylethan-1-ol (16a ) as a single
(24) Moody, C. J .; Lightfoot, A. P.; Gallagher, P. T. J . Org. Chem.
1997, 62, 746.

6702 J . Org. Chem., Vol. 63, No. 19, 1998
Katritzky et al.
aqueous NaOH solution (2 N, 2 × 10 mL) and water (2 × 10
mL) and extracted with diethyl ether (2 × 20 mL). The
combined organic layers were dried over anhyd Na2SO4. After
the removal of solvent, the residue was purified by column
chromatography (silica gel) to give product 16.
yield of 45% from glutaraldehyde. Advantages of 8 in
comparison to (3S)-5-cyano-3-phenylperhydropyrido[2,1-
b][1,3]oxazole include avoiding the use of KCN as starting
material, and of AgBF4 for removal of the cyano group,8
as well as higher yields and stereoselectivity.
(2S)-2-[(2R,6R)-2-Meth yl-6-p h en ylp ip er id in yl]-2-p h en -
yl-1-eth a n ol (16a ): 0.81 g, 92% yield, mp 76-78 °C; [R]20
)
D
+202.5° (c 1.0, CH2Cl2); 1H NMR δ 7.42-7.75 (m, 10H), 4.19-
4.31 (m, 2H), 4.13 (t, 1H, J ) 7.2 Hz), 3.75-3.84 (m, 1H), 3.70
(s, 1H), 3.06-3.16 (m, 1H), 1.84-2.05 (m, 3H), 1.70-1.58 (m,
3H), 1.54 (d, 3H, J ) 6.4 Hz); 13C NMR δ 145.2, 137.1, 128.8,
128.7, 128.2, 127.8, 127.4, 127.2, 64.8, 62.2, 61.8, 50.5, 35.2,
32.4, 23.9, 21.2. Anal. Calcd for C20H25NO: C, 81.30; H, 8.54;
N, 4.74. Found: C, 81.22; H, 8.77; N, 4.38.
Exp er im en ta l Section
(3S)-5-Ben zotr ia zolyl-3-p h en ylp er h yd r op yr id o[2,1-b]-
[1,3]oxa zole (8). A mixture of (S)-2-phenylglycinol (7.9 g, 50
mmol), glutaraldehyde (aqueous solution) (50 mmol), and
benzotriazole (6.0 g, 50 mmol) in methylene chloride was
stirred at room temperature for 12 h. The reaction mixture
was washed with aqueous sodium hydroxide (2 N) to remove
excess benzotriazole. The organic layer was dried over anhyd
Na2SO4. After the removal of the solvent, a yellowish oil was
obtained (15.2 g, 95%). 1H NMR δ 7.80-8.10 (m, 1.5H), 6.80-
7.50 (m, 7.5H), 5.70-5.90 (m, 1H), 5.00-5.10 (m, 0.5H), 4.75-
4.80 (m, 0.5H), 3.40-4.60 (m, 3H), 1.70-2.55 (m, 6H). From
NMR, this is a mixture of several compounds, comprising Bt1
or Bt2 isomers and diastereomers.
Gen er a l P r oced u r e for th e Syn th esis of Ch ir a l 5-Su b-
stitu ted -3-p h en ylp er h yd r op yr id o[2,1-b][1,3]oxa zole (9).
To a solution of (3S)-5-benzotriazolyl-3-phenylperhydropyrido-
[2,1-b][1,3]oxazole (8) (0.96 g, 3 mmol) in dry THF (20 mL)
was added Grignard reagent (3 mmol) at low temperature (for
aryl Grignard reagents, -78 °C; for alkyl Grignard reagents,
-95 °C) under nitrogen. The mixture was kept at this
temperature for 12 h and then quenched by adding water. The
mixture was washed with aqueous NaOH solution (2 N, 2 ×
10 mL) and water (2 × 10 mL) and extracted with ethyl acetate
(2 × 20 mL). The combined organic layers were dried over
anhyd Na2SO4. After removal of solvent, the residue was
applied to a column of silica gel to give products 9 and 10.
(3S,5R,8a R)-3,5-Dip h en ylp er h yd r op yr id o[2,1-b][1,3]-
oxa zole (9a ): 0.71 g, 85% yield, mp 88-90 °C; [R]20D ) +183.8°
(c 0.89, EtOH); 1H NMR δ 7.16-7.38 (m, 8H), 6.79 (d, 2H, J )
6.6 Hz), 4.28-4.38 (m, 3H), 4.06-4.14 (m, 1H), 2.98-3.05 (m,
1H), 2.08-2.17 (m, 1H), 1.76-1.86 (m, 1H), 1.60-1.68 (m, 1H),
1.24-1.60 (m, 3H); 13C NMR δ 143.2, 138.2, 129.3, 128.2, 127.6,
127.5, 127.2, 127.0, 89.7, 71.5, 61.1, 61.0, 36.5, 30.8, 22.3.
Syn th esis of Dieth yl [(3S)-3-P h en ylh exa h yd r ooxa zolo-
[3,2-a ]p yr id in -5-yl]p h osp h on a te (14). To a solution of
diethyl phosphite (0.41 g, 3 mmol) in dry THF (20 mL) was
added a solution of n-butyllithium in hexane (1.9 mL, 3 mmol)
at -78 °C. The mixture was stirred 15 min before the addition
of a solution of 2-benzotriazolyl-9-phenyloxazolopiperidine
(0.96 g, 3 mmol) in dry THF (10 mL) at the same temperature.
The mixture was kept at this temperature for 2 h and then
allowed to warm to room temperature and stirred for 20 h.
The reaction mixture was quenched with water, and washed
with aqueous NaOH solution (2 N, 2 × 15 mL) and water (2 ×
20 mL). The mixture was extracted with ethyl acetate (3 ×
30 mL), and the combined organic layers were dried over
anhyd Na2SO4. After removal of solvent, the residue was
applied to a column (silica gel) to give product as a colorless
oil11 14 (a mixture of diastereomers, ratio is 93:7), 0.75 g, 81%
yield; 1H NMR δ 7.20-7.46 (m, 5H), 4.75 (dt, 1H, J ) 3.3, 9.5
Hz), 4.52 (q, 1H, J ) 7.4 Hz), 4.16 (t, 1H, J ) 7.8 Hz), 3.94-
4.12 (m, 4H), 3.59 (t, 1H, J ) 7.2 Hz), 3.29 (t, 1H, J ) 6.1 Hz),
1.20-2.20 (m, 12H); 13C NMR δ 139.6, 128.5, 128.3, 127.7,
127.2, 87.7, 73.4, 62.0, 61.5 (d, J ) 7.1 Hz), 60.9 (d, J ) 7.7
Hz), 50.8 (d, J ) 125.5 Hz), 31.3, 25.6 (d, J ) 3.8 Hz), 19.7,
16.5 (d, J ) 5.7 Hz).
(2S)-2-[(2S)-2-P r op ylh exa h yd r o-1-p yr id in yl]-2-p h en yl-
1-eth a n ol (11). A mixture of 9c (0.26 g, 1 mmol) and NaBH4
(0.27 g, 0.75 mmol) in ethanol (20 mL) was stirred at room
temperature for 20 h. Then water was added to quench the
reaction. After removal of ethanol, the mixture was extracted
with CHCl3 (2 × 20 mL), and the organic layer was dried over
anhyd Na2SO4. The solvent was removed, and crude product
was applied to a column (silica gel) to give pure product 11 as
colorless oil,8 0.18 g, 73%; 1H NMR δ 7.17-7.39 (m, 5H), 4.31
(dd, 1H, J ) 5.2, 10.2 Hz), 3.97 (t, 1H, J ) 10.4 Hz), 5.58 (dd,
1H, J ) 5.2, 10.2 Hz), 2.83-2.92 (m, 1H), 2.14-2.43 (m, 1H),
1.21-1.75 (m, 10H), 1.02-1.20 (m, 1H), 0.95 (t, 3H, J ) 7.4
Hz); 13C NMR δ 136.2, 128.8, 128.0, 127.5, 60.4, 59.5, 57.2,
45.5, 34.8, 31.5, 26.3, 24.1, 17.8, 14.7.
Anal. Calcd for
C19H21NO: C, 81.67; H, 7.58; N, 5.02.
Found: C, 81.64; H, 7.54; N, 4.94.
(3S,5S)-5-P r op yl-3-p h en ylp er h yd r op yr id o[2,1-b][1,3]-
oxa zole (9c): 0.42 g, 57% yield, oil; as a mixture of two
diastereoisomers in ratio of 9:4, the data for the minor isomer
is given in brackets. 1H NMR δ 7.22-7.42 (m, 5H), 4.23 (dd,
1H, J ) 9.3, 3.0 Hz) [4.55 (dd, 1H, J ) 6.6, 1.9 Hz)], 4.10 (t,
1H, J ) 7.2 Hz) [4.38 (t, 1H, J ) 8.2 Hz)], 4.02 (t, 1H, J ) 7.8
Hz) [4.34 (dd, 1H, J ) 2.7, 9.0 Hz)], 3.57 (t, 1H, J ) 7.2 Hz)
[3.97-4.02 (m, 1H, overlapped)], 2.83-2.92 (m, 1H) [2.14-2.23
(m, 1H)], 1.97-2.06 (m, 1H), 1.14-1.82 (m, 9H), 0.92-1.06 (m,
1H), 0.74-0.85 (m, 3H); 13C NMR δ 139.5, 128.4 [128.8], 127.8
[128.1], 127.5 [127.2], 87.6 [90.4], 73.3 [72.5], 61.2 [61.0], 52.2
[54.8], 31.6 [36.0], 27.4 [30.7], 24.7 [30.3], 20.5 [21.6], 17.9
[18.5], 14.2 [14.1].
(3S,5R)-5-P r op yl-3-p h en ylp er h yd r op yr id o[2,1-b][1,3]-
oxa zole (10c):8 0.06 g, 8% yield, oil; as a mixture of two
diastereoisomers in ratio of 14:9, the data for the minor isomer
is given in brackets. 1H NMR δ 7.22-7.42 (m, 5H), 4.34 (t,
1H, J ) 7.7 Hz) [4.49 (t, 1H, J ) 3.0 Hz)], 4.15 (t, 1H, J ) 7.5
Hz) [4.35-4.42 (m, 1H)], 3.60-3.78 (m, 2H), 2.26-2.38 (m, 1H)
[2.45-2.55 (m, 1H)], 1.95-2.08 (m, 1H), 1.70-1.91 (m, 1H),
1.50-1.70 (m, 3H), 0.98-1.49 (m, 5H), 0.51 (t, 3H, J ) 6.9
Hz) [0.86 (t, 3H, J ) 6.9 Hz)]; 13C NMR δ 144.8 [143.1], 128.2
[128.4], 127.2 [126.9], 126.8 [126.7], 96.2 [89.3], 74.7 [69.6],
65.6 [65.8], 62.2 [57.3], 36.9 [38.3], 30.3 [31.0], 27.1 [29.7], 22.5
[18.8], 18.6 [18.2], [14.4] 13.9.
Hyd r ogen a tion for P r ep a r a tion of Com p ou n d s 12, 13,
15, 17. Typ ica l P r oced u r e. A solution of 9a (1 mmol) in
methanol (50 mL) with Pd/C catalyst (10%, 60 mg) was
hydrogenated at room temperature under 20 psi of hydrogen
for 24 h. The catalyst was filtered off, and hydrochloric acid
(12 N, 1 mL) was added into the filtrate. The pure hydrochlo-
ride salt precipitated to give product 12a as a white solid, 0.18
g, 92% yield.
(2R)-2-P h en ylp ip er id in e Hyd r och lor id e Sa lt (12a ): mp
196-198 °C; [R]20 ) -3.1° (c 1.0, MeOH); 1H NMR δ 9.55 (br
D
s, 2H), 7.55-7.65 (m, 2H), 7.20-7.40 (m, 3H), 3.80-3.94 (m,
1H), 2.92-3.06 (m, 1H), 2.62-2.79 (m, 1H), 1.84-2.22 (m, 4H),
1.45-1.75 (m, 2H); 13C NMR δ 136.4, 129.0, 128.9, 127.9, 61.2,
45.5, 30.2, 23.1, 21.6. HRMS Calcd for C11H16NCl: 161.1204
(M+ - HCl). Found 161.1202.
(2R)-2-P r op ylp ip er id in e Hyd r och lor id e Sa lt (13c): mp
218-221 °C; [R]20 ) -7.3° (c 1.0, EtOH) [lit.8 mp 217-218
D
°C, [R]20D ) -5.8° (c 1.0, EtOH)]; 0.14 g, 83% yield; 1H NMR δ
9.53 (br s, 1H), 9.23 (br s, 1H), 3.40-3.52 (m, 1H), 2.70-3.02
(m, 2H), 1.60-2.10 (m, 7H), 1.35-1.58 (m, 3H), 0.95 (t, 3H, J
) 6.9 Hz); 13C NMR δ 57.2, 44.8, 35.4, 28.2, 22.5, 22.3, 18.6,
13.7.
Gen er a l P r oced u r e for Syn th esis of 2-(2,6-Disu bsti-
tu ted p ip er id in yl)-(2S)-P h en yleth a n ol (16): To a solution
of compound 9 (3 mmol) in dry THF (20 mL) was added
Grignard reagent (9 mmol) at -20 °C under nitrogen. The
mixture was kept at this temperature for 20 h and then
quenched by adding water. The mixture was washed with
Dieth yl (2R)-(P ip er id in -2-yl)p h osp h on a te (15): colorless
1
oil;11 0.30 g, 68% yield; H NMR δ 4.16 (qd, 4H, J ) 7.4 Hz),

Chiral 2-Substituted and 2,6-Disubstituted Piperidines
J . Org. Chem., Vol. 63, No. 19, 1998 6703
3.07-3.16 (m, 1H), 2.94 (td, 1H, J ) 11.8, 1.9 Hz), 2.59 (td,
1H, J ) 11.5, 2.1 Hz), 1.82-2.02 (m, 4H), 1.25-1.65 (m, 3H),
1.34 (t, 6H, J ) 6.9 Hz); 13C NMR δ 62.1 (d, J ) 6.7 Hz), 54.2
(d, J ) 159.1 Hz), 47.3 (d, J ) 16.4 Hz), 26.2 (d, J ) 3.8 Hz),
25.9, 24.5 (d, J ) 15.4 Hz), 16.4.
Calcd for C12H17N: C, 82.22; H, 9.78; N, 8.00. Found: C, 81.86;
H, 10.07; N, 7.80.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra, and CHN analyses or HRMS (if new compounds), for
compounds 9b,d -g, 10d -g, 12b-e,g, 13d ,e, 16b-f, 17b-e
(10 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
(2R,6R)-2-Meth yl-6-p h en ylp ip er id in e (17a ): oil; [R]20
)
D
1
+22.17° (c 0.69, EtOH); 0.17 g, 95% yield; H NMR δ 7.20-
7.42 (m, 5H), 3.68 (dd, 1H, J ) 2.4, 10.5 Hz), 2.77-2.89 (m,
1H), 1.87-1.96 (m, 1H), 1.72-1.82 (m, 1H), 1.44-1.72 (m, 4H),
1.15-1.22 (m, 1H), 1.14 (d, 3H, J ) 6.2 Hz); 13C NMR δ 145.5,
128.2, 126.9, 126.6, 62.4, 53.1, 34.2, 33.8, 25.3, 23.0. Anal.
J O980719D