PAPER
A Two-Step Synthesis of 3,4-Disubstituted Piperidines
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2.86 (dd, J = 13.7, 2.0 Hz, 1 H), 3.30 and 3.50 (AB q, J = 13.1 Hz,
2 H), 3.84 (s, 6 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.62–6.66 (m, 2 H),
6.74 (d, J = 8.7 Hz, 1 H), 7.19–7.25 (m, 5 H).
13C NMR: d = 14.2, 31.3, 37.5, 37.6, 38.7, 42.0, 52.5, 55.7, 55.8,
58.5, 60.2, 63.2, 111.0, 112.0, 120.9, 126.8, 128.0, 129.0, 132.7,
138.1, 147.1, 148.6, 173.0.
13C NMR: d = 10.5 (trans), 11.5 (cis), 13.8, 20.0 (br, cis), 23.2,
28.2, 31.3, 32.8, 32.9, 34.0 (br, cis), 34.6 (br, cis), 36.7 (trans), 38.0,
39.4 (cis), 41.4 (trans), 51.5 (br, cis), 53.0, 54.7, 55.1, 55.2, 58.0,
59.6, 60.5, 60.6, 110.6 (cis), 110.6 (trans), 111.4, 119.9, 132.6
(trans), 132.7 (cis), 146.6 (cis), 146.7 (trans), 148.2 (cis), 148.2
(trans), 172.5 (trans), 172.6 (cis).
HRMS: m/z [M]+ calcd for C21H33NO4: 363.2410; found: 363.2408.
Anal. Calcd for C25H33NO4: C, 72.95; H, 8.09; N, 3.41. Found: C,
73.07; H, 8.17; N, 3.30.
Ethyl {3-Benzyl-1-[2-(3,4-dimethoxyphenyl)ethyl]piperidin-4-
yl}acetate (10j)
Chromatography: hexanes–EtOAc–Et3N, 78:20:2; colorless oil;
ratio cis/trans 22:78.
cis-Isomer
IR (neat): 1740 cm–1 (C=O).
1H NMR: d = 1.26 (t, J = 7.1 Hz, 3 H), 1.52–1.68 (m, 2 H), 1.87–
1.93 (m, 1 H), 2.02–2.22 (m, 3 H), 2.30–2.48 (m, 2 H), 2.53 (dd,
J = 13.0, 3.9 Hz, 2 H), 2.74–2.84 (m, 2 H), 3.40 (s, 2 H), 3.77 (s, 3
H), 3.82 (s, 3 H), 4.15 (q, J = 7.1 Hz, 2 H), 6.58 (dd, J = 8.1, 1.9 Hz,
1 H), 6.66 (d, J = 1.9 Hz, 1 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.19–7.34
(m, 5 H).
IR (neat): 1730 cm–1 (C=O).
1H NMR: d = 1.26 (t, J = 7.1 Hz, 3 H), 1.41–1.51 (m, 1 H), 1.63–
1.72 (m, 3 H), 1.81–1.87 (m, 1 H), 1.95–2.04 (m, 1 H), 2.15–2.31
(m, 2 H), 2.37–2.78 (m, 6 H), 2.92–2.99 (m, 2 H), 3.81–3.85 (m, 6
H), 4.10–4.19 (m, 2 H), 6.63–6.79 (m, 3 H), 7.07–7.28 (m, 5 H).
13C NMR: d = 14.2, 28.1, 32.1 (br), 35.6 (br), 37.2 (br), 40.3, 52.8
(br), 55.6, 55.6, 55.7, 60.1, 63.0, 110.9, 112.2, 121.0, 126.7, 128.0,
128.9, 133.8, 138.8, 146.8, 148.5, 172.8.
13C NMR: d = 14.1, 28.2 (cis), 31.5, 33.1, 35.5 (cis), 36.7 (trans),
37.7 (trans), 37.8, 38.6, 40.1 (cis), 42.0 (trans), 53.0, 55.1 (cis),
55.5, 55.7, 55.7 (cis), 58.5, 60.2, 60.7, 110.9, 111.6 (trans), 111.8
(cis), 120.2 (trans), 120.4 (cis), 125.6 (cis), 125.8 (trans), 128.0
(cis), 128.1 (trans), 128.8 (trans), 129.0 (cis), 132.8 (trans), 133.2
(cis), 139.9 (trans), 141.1 (cis), 147.0, 148.5, 172.8 (cis), 172.8
(trans).
HRMS: m/z [M]+ calcd for C25H33NO4: 411.2410; found: 411.2409.
Ethyl {1-Benzyl-3-[3-(ethoxycarbonyl)but-3-enyl]piperidin-4-
yl}acetate (10g)
Chromatography: hexanes–EtOAc–Et3N, 96:2:2; pale yellow oils.
HRMS: m/z [M]+ calcd for C26H35NO4: 425.2566; found: 425.2572.
trans-Isomer
Debenzylated Piperidines 11; General Procedure
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
A deoxygenated mixture of 9 (1.5 mmol), 10% Pd/C (22 mg), and
EtOH (7 mL) was treated with H2 (3.45 bar) at r.t. for 48 h. The mix-
ture was filtered through Celite, which was washed with CH2Cl2
(100 mL). The combined filtrate and washings were evaporated un-
der reduced pressure and the residue was purified by flash chroma-
tography (silica gel saturated with Et2NH). Purification details and
characterization data are provided below for the individual cases.
1H NMR: d = 1.24 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H),
1.32–1.45 (m, 3 H), 1.46–1.77 (m, 4 H), 1.98–2.25 (m, 4 H), 2.52
(dd, J = 15.0, 4.3 Hz, 1 H), 2.76–2.81 (m, 1 H), 2.83–2.88 (m, 1 H),
3.45 and 3.51 (AB q, J = 13.2 Hz, 2 H), 4.07–4.21 (m, 4 H), 5.75
(dt, J = 15.6, 1.4 Hz, 1 H), 6.89 (dt, J = 15.6, 6.9 Hz, 1 H), 7.20–
7.37 (m, 5 H).
13C NMR: d = 14.2, 29.2, 29.5, 31.3, 37.1, 38.4, 39.8, 53.1, 58.0,
60.1, 60.3, 63.2, 121.4, 126.9, 128.1, 129.0, 138.2, 148.7, 166.5,
173.0.
Ethyl (3-Isopropylpiperidin-4-yl)acetate (11c)
Chromatography: EtOAc–Et2NH, 98:2; colorless oil; ratio cis/trans
26:74.
IR (neat): 3300 (N–H), 1735 cm–1 (C=O).
HRMS: m/z [M]+ calcd for C23H33NO4: 387.2410; found: 387.2406.
1H NMR: d = 0.78 (d, J = 7.1 Hz, 3 H, trans), 0.88 (d, J = 6.0 Hz, 6
H, cis), 0.92 (d, J = 7.0 Hz, 3 H, trans), 1.09–1.30 (m, 5 H), 1.23 (t,
J = 7.1 Hz, included in m at d = 1.09–1.30), 1.57–2.05 (m, 4 H),
2.21–3.02 (m, 6 H), 4.10 (q, J = 7.1 Hz, 2 H).
13C NMR: d = 14.1, 15.9, 20.0, 21.0, 21.1, 26.1, 27.3, 30.7, 32.9,
35.4, 38.5, 40.7, 45.2, 45.5, 46.5, 47.0, 47.2, 60.0, 60.1, 173.1,
173.5.
cis-Isomer
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 1.22 (t, J = 7.1 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H),
1.19–1.36 (m, 1 H), 1.51–1.62 (m, 4 H), 1.85–2.27 (m, 5 H), 2.22
(d, J = 7.6 Hz, 2 H), 2.46 (br, 1 H), 2.64 (br, 1 H), 3.30 and 3.51 (AB
q, J = 13.1 Hz, 2 H), 4.05–4.19 (m, 4 H), 5.72 (d, J = 15.6 Hz, 1 H),
6.89 (dt, J = 15.4, 7.0 Hz, 1 H), 7.17–7.32 (m, 5 H).
13C NMR: d = 14.1, 24.8 (br), 28.2, 29.7, 35.2 (br), 36.3 (br), 37.1,
52.9 (br), 55.1, 60.0, 60.1, 63.0, 121.2, 126.8, 128.0, 128.7, 138.8,
149.0, 166.5, 172.8.
HRMS: m/z [M]+ calcd for C12H23NO2: 213.1729; found: 213.1723.
Ethyl {3-[3-(Ethoxycarbonyl)propyl]piperidin-4-yl}acetate
(11f)
Chromatography: EtOAc–Et2NH, 98:2 EtOAc–Et2NH; pale yellow
oil; ratio cis/trans 30:70.
Anal. Calcd for C23H33NO4: C, 71.27; H, 8.59; N, 3.62. Found: C,
71.43; H, 8.61; N, 3.31.
IR (neat): 3340 (N–H), 1740 cm–1 (C=O).
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-3-ethylpiperidin-4-
yl}acetate (10h)
Chromatography: hexanes–EtOAc–Et3N, 84:14:2; pale yellow oil;
1H NMR: d = 1.07–1.25 (m, 2 H), 1.22 (t, J = 7.1 Hz, 6 H), 1.27–
1.76 (m, 7 H), 2.02 (dd, J = 14.8, 8.9 Hz, 1 H, trans), 2.14–2.31 (m,
3 H), 2.49–3.12 (m, 4 H), 4.09 (q, J = 7.1 Hz, 4 H).
ratio cis/trans 37:63.
IR (neat): 1730 cm–1 (C=O).
13C NMR: d = 14.1, 21.9, 22.7, 26.1, 29.0, 30.4, 32.6, 34.3, 34.4,
35.2, 35.9, 37.8, 38.1, 38.8, 41.3, 44.7, 46.3, 48.4, 51.3, 60.1, 173.0,
173.4, 173.4.
1H NMR: d = 0.86–0.94 (m, 3 H), 1.05–1.46 (m, 6 H), 1.26 (t,
J = 7.1 Hz, included in m at d = 1.05–1.46), 1.51–1.81 (m, 3 H),
1.93–2.08 (m, 1 H), 2.17–2.64 (m, 6 H), 2.67–2.79 (m, 2 H), 2.95–
3.04 (m, 1 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.13 (q, J = 7.1 Hz, 2 H),
6.72–6.81 (m, 3 H).
HRMS: m/z [M]+ calcd for C15H27NO4: 285.1940; found: 285.1938.
Synthesis 2010, No. 4, 605–612 © Thieme Stuttgart · New York