Efficient Synthesis of Piperidine Derivatives
J . Org. Chem., Vol. 66, No. 3, 2001 821
was purified by silica gel chromatography to afford 33 in 44%
yield as a syrup, and the starting material (32-m a jor ) was
recovered (50%, 88% conversion). X-ray quality single crystals
were obtained by crystallization from ether/n-hexane in 86%
yield as colorless plates. The configuration was determined as
trans by X-ray crystallography. Mp 88-89 °C; IR (KBr) 1708,
46.9, 51.3, 66.2, 70.5, 77.4, 127.4, 128.0, 128.4, 138.1, 177.7;
HRMS (ESI) calcd for C17H26NO3 292.1912, found (M + H)+
292.1913.
tr a n s-Meth yl 1-(N-Ben zyloxyca r bon yl-3-h yd r oxyp ip -
er id in -2-yl)-1-m eth ylp r op ion a te (35). A solution of 13b
(0.130 mmol) and NaOMe (0.259 mmol) in MeOH (1.5 mL) was
stirred for 10 h at room temperature. The reaction was
quenched with an aqueous 1 N HCl solution (0.27 mL) and
the solvent was evaporated in vacuo. The residue was purified
by silica gel chromatography to afford 35 in 97% yield as a
pale yellow oil (a single diastereomer). IR (neat) 1726, 1676
cm-1; 1H NMR (CDCl3), rotamers, δ 1.14-1.60 (m, 7H), 1.63-
1.86 (m, 3H), 2.43 (br, 1H), 2.84 (t, 0.5H, J ) 12.3 Hz), 2.92 (t,
0.5H, J ) 13.1 Hz), 3.58 (s, 3H), 3.95-4.04 (m, 1.5 H), 4.16 (d,
0.5 H, J ) 12.3 Hz), 4.31 (d, 1 H, J ) 14.3 Hz), 4.99-5.14 (m,
2H), 7.20-7.28 (m, 5H); 1H NMR (DMSO-d6), rotamers, δ
1.14-1.30 (m, 7H), 1.53-1.70 (m, 3H), 2.81 (t, 0.5 H, J ) 12.8
Hz), 2.90 (t, 0.5 H, J ) 13.4 Hz), 3.56 (s, 3H), 3.84 (d, 1H, J )
9.4 Hz), 4.00 (t, 1H, J ) 16.3 Hz), 4.19 (d, 1H, J ) 10.8 Hz),
4.81 (d, 1H, J ) 11.9 Hz), 5.07-5.13 (m, 2H), 7.34 (m, 5H); 1H
NMR (DMSO-d6, 90 °C) δ 1.17 (s, 3H), 1.21 (s, 3H), 1.26-1.42
(m, 1H), 1.55-1.81 (m, 3H), 2.88 (t, 1H, J ) 11.3 Hz), 3.58 (s,
3H), 3.87 (s, 1H), 4.01 (d, 1H, J ) 13.6 Hz), 4.24 (s, 1H), 4.51
(s, 1H), 5.09 (s, 2H), 7.28-7.61 (m, 5H); 13C NMR (CDCl3),
rotamers, δ 18.6, 19.0, 22.9, 25.5, 25.7, 27.3, 27.6, 40.3, 40.6,
45.8, 52.0, 64.2, 64.4, 64.6, 64.9, 67.3, 127.6, 127.7, 127.8, 128.4,
136.7, 156.9, 157.2, 177.2; 13C NMR (DMSO-d6), rotamers, δ
18.4, 18.8, 22.8, 23.1, 25.1, 25.3, 27.45, 27.54, 45.26, 45.35, 51.8,
62.7, 62.8, 64.0, 66.2, 66.4, 127.3, 127.4, 127.7, 128.3, 128.4,
136.9, 137.2, 156.1, 156.3, 176.5; 13C NMR (DMSO-d6, 90 °C)
δ 18.2, 22.6, 24.6, 27.3, 45.2, 51.1, 62.8, 63.9, 65.9, 126.9, 127.2,
127.8, 136.7, 155.9, 175.9; HRMS (ESI) calcd for C18H26NO5
336.1811, found (M + H)+ 336.1811.
1
1688 cm-1; H NMR (CDCl3), rotamers, δ 1.26-1.12 (m, 4H),
3.10 (t, 1H, J ) 11.0 Hz), 3.26-3.38 (m, 2H), 4.29 (s, 1H), 4.87-
5.25 (m, 4H), 7.00-7.97 (m, 16H), 8.50 (s, 1H); 13C NMR
(CDCl3), rotamers, δ 19.8, 23.8, 38.4, 51.9, 67.1, 69.9, 125.1,
126.5, 127.4, 127.7, 128.1, 128.2, 128.7, 129.4, 131.1, 132.3,
133.3, 135.5, 136.2, 155.7, 165.6, 196.5; HRMS (ESI) calcd for
C32H30NO5 508.2124, found (M + H)+ 508.2111. Anal. Calcd
for C32H29NO5: C, 75.72; H, 5.76; N, 2.76. Found: C, 75.45;
H, 5.92; N, 2.78.
tr a n s-2-(3-Ben zyloxy-N-ben zyloxyca r bon ylp ip er id in -
2-yl)a cetop h en on e (tr a n s-11a ). To a solution of 32-m a jor
(0.250 mmol) and benzyl trichloroacetoimidate (1.00 mmol) in
ether (2 mL) was added a solution of trifluoromethanesulfonic
acid in ether (0.17 M, 0.1 mL) at room temperature. After the
reaction mixture was stirred for 20 h at the same temperature,
the reaction was quenched with a saturated aqueous NaHCO3
solution. The mixture was extracted with ethyl acetate (twice).
The combined organic layers were washed with water and
brine, dried over Na2SO4, filtered, and evaporated in vacuo.
After silica gel chromatography of the residue, tr a n s-11a was
obtained in 38% yield as a colorless oil (2% of epimerization
was observed by HPLC analysis. However, cis-11a was not
observed by 1H NMR analysis). The starting material (32-
m a jor ) was recovered without epimerization (58%, 90%
conversion). tr a n s-11a : IR (neat) 1690 cm-1; 1H NMR (CDCl3),
rotamers, δ 1.48-2.05 (m, 4H), 2.95-3.38 (m, 3H), 3.54 (s, 1H),
4.24 (br, 1H), 4.45-5.19 (m, 5H), 7.01-7.59 (m, 13H), 7.80-
7.96 (m, 2H); 13C NMR (CDCl3), rotamers, δ 19.5, 19.8, 23.8,
24.4, 38.4, 38.9, 39.1, 39.7, 50.2, 51.9, 67.1, 67.5, 69.7, 70.2,
73.0, 76.6, 127.3, 127.5, 127.7, 127.8, 128.1, 128.2, 128.3, 128.4,
128.7, 129.6, 130.1, 133.0, 133.4, 136.3, 136.4, 136.7, 138.6,
Similarly, 13d (0.319 mmol) was treated with NaOMe (0.555
mmol) in THF-MeOH (2/1, 15 mL) for 6 h under reflux. After
the usual workup and purification by silica gel chromatogra-
phy, 35 and 36 were obtained in 59% and 21% yields,
respectively.
141.1, 155.7, 155.9, 196.6, 197.5; HRMS (ESI) calcd for C28H30
-
La cton e 36. To a suspension of NaH (60% dispersion in
mineral oil, 0.51 mmol) in dry THF (2 mL) was added a
solution of 18-crown-6 (0.04 mmol) and 35 (0.43 mmol) in dry
THF (5 mL) at 0 °C. The mixture was warmed to room
temperature and stirred for 24 h at the same temperature.
The reaction was quenched with a saturated aqueous NH4Cl
solution. The mixture was extracted with ethyl acetate (twice).
The combined organic layers were washed with water and
brine, dried over Na2SO4, filtered, and evaporated in vacuo.
The crude product was purified by silica gel chromatography
to afford 36 in 77% yield as a single diastereomer. Colorless
NO4 444.2175, found (M + H)+ 444.2207
tr a n s-2-(3-Acet oxy-N-b en zyloxyca r b on ylp ip er id in -2-
yl)a cetop h en on e (tr a n s-11b). A solution of 32-m a jor (0.203
mmol), triethylamine (0.494 mmol), 4-N,N-(dimethylamino)-
pyridine (0.0221 mmol) and acetic anhydride (0.353 mmol) in
CH2Cl2 (5 mL) was stirred for 4 h at room temperature. The
resulting mixture was concentrated under reduced pressure.
The residue was purified by silica gel chromatography to afford
tr a n s-11b in 89% yield as a colorless oil. IR (neat) 1734, 1695
1
cm-1; H NMR (CDCl3), rotamers, δ 1.45 (m, 1H), 1.73-1.99
(m, 6H), 2.92 (s, 1H), 3.12-3.20 (m, 2H), 4.11 (s, 1H), 4.83-
5.03 (m, 4H), 7.12-7.49 (m, 8H), 7.84 (m, 2H); 13C NMR
(CDCl3), rotamers, δ 19.5, 21.0, 13.6, 38.4, 39.0, 51.7, 67.0, 69.1,
127.6, 127.8, 128.2, 128.4, 128.6, 133.3, 136.2, 155.6, 170.2,
196.6; HRMS (ESI) calcd for C23H26NO5 396.1810, found (M
+ H)+ 396.1835.
needles; mp 115 °C; IR (KBr) 1777, 1717 cm-1 1H NMR
;
(CDCl3) δ 1.29 (s, 3H), 1.57 (s, 3H), 1.59-1.92 (m, 2H), 2.29-
2.36 (m, 1H), 3.09 (d, 1H, J ) 10.4 Hz), 3.16 (ddd, 1H, J )
13.5, 9.8, 3.7 Hz), 3.98 (dt, 1H, J ) 13.5, 4.9 Hz), 4.09 (ddd,
1H, J ) 11.0, 10.4, 4.8 Hz), 5.12 (s, 2H), 7.32-7.39 (m, 5H);
13C NMR (CDCl3) δ 17.3, 22.0, 25.1, 26.9, 45.5, 45.8, 67.5, 69.1,
75.7, 128.26, 128.32, 128.6, 136.0, 155.5, 180.2; MS (EI) m/z
303. Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.34; H, 7.16; N, 4.57.
cis-2-(3-Acetoxy-N-ben zyloxyca r bon ylp ip er id in -2-yl)-
a cetop h en on e (cis-11b). Similarly, cis-11b was obtained
from 32-m in or in 54% yield as colorless oil. IR (neat) 1739,
1
1697 cm-1; H NMR (CDCl3), rotamers, δ 1.58-2.01 (m, 7H),
tr a n s-Meth yl 1-(3-Ben zyloxyp ip er id in -2-yl)-1-m eth yl-
p r op ion a te (34d ). Compound 13d (0.328 mmol) was dissolved
in MeOH (3 mL) and hydrogenated (10% Pd-C, 1atm) for 5
days at room temperature. After purification by silica gel
chromatography, 34d was obtained in 88% yield as a pale
2.97 (m, 2H), 3.48 (dd, 1H, J ) 15.2, 6.6 Hz), 4.07 (s, 1H), 4.92-
5.09 (m, 3H), 5.24 (q, 1H, J ) 6.3 Hz), 7.26-7.58 (m, 8H), 7.91
(m, 2H); 13C NMR (CDCl3), rotamers, δ 21.0, 23.6, 24.8, 35.4,
38.8, 50.3, 67.3, 70.1, 127.8, 127.9, 128.1, 128.4, 128.6, 133.1,
yellow oil (a single diastereomer). IR (neat) 1726, 1649 cm-1
;
136.4, 136.7, 155.1, 169.6, 197.2; HRMS (ESI) calcd for C23H26
-
NO5 396.1811, found (M + H)+ 396.1790.
1H NMR (CDCl3) δ 1.09 (s, 3H), 1.13 (s, 3H), 1.41-1.51 (m,
3H), 1.66-1.69 (m, 1H), 2.08-2.11 (m, 1H), 2.54 (td, 1H, J )
12.2, 2.9 Hz), 3.03 (dt, 1H, J ) 12.7, 2.0 Hz), 3.15 (d, 2H, J )
10.0 Hz), 3.34 (s, 3H), 3.78 (s, 3H), 4.83 (dt, 1H, J ) 10.0, 4.8
Hz), 6.82-6.86 (m, 2H), 7.85-7.89 (m, 2H); 13C NMR (CDCl3)
δ 19.6, 23.9, 26.4, 31.4, 44.7, 46.6, 51.8, 55.4, 64.7, 72.0, 113.5,
tr a n s-Meth yl 1-(3-Ben zyloxyp ip er id in -2-yl)-1-m eth yl-
p r op ion a te (34a ). Compound 13a (0.428 mmol) was dissolved
in MeOH (5 mL) and hydrogenated (10% Pd-C, 1atm) for 2.5
days at room temperature. After purification by silica gel
chromatography, 34a was obtained in 85% yield as a colorless
1
oil. IR (neat) 3363, 1731 cm-1; H NMR (CDCl3) δ 1.16-1.41
122.6, 131.7, 163.4, 165.1, 177.6; HRMS (ESI) calcd for C18H26-
(m, 9H), 1.72-1.76 (m, 1H), 2.28 (m, 1H), 2.95 (d, 1H, J ) 9.6
Hz), 3.05 (m, 1H), 3.16 (dt, 1H, J ) 9.6, 4.0 Hz), 3.31 (s, 3H),
4.30 (d, 1H, J ) 10.8 Hz), 4.50 (d, 1H, J ) 10.8 Hz), 7.24-
7.32 (m, 5H); 13C NMR (CDCl3) δ 18.2, 24.6, 26.2, 30.2, 43.6,
NO5 336.1811, found (M + H)+ 336.1839.
tr a n s-Dim eth yl 2-(3-Ben zyloxypiper idin -2-yl)m alon ate
(37). Compound 15b (0.196 mmol) was dissolved in 25% HBr/
AcOH (3 mL) at 0 °C, and the reaction mixture was stirred