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B.-Y. Hao et al.
PAPER
placed in an ice-H2O bath. A soln of 15 (3.5 g, 8.96 mmol) in THF
(4 mL) was added and the mixture stirred for 30 min. The reaction
progress was monitored by TLC, and following completion was
quenched with sat. NaHCO3 soln (20 mL). After stirring for an ad-
ditional 30 min the mixture was extracted with EtOAc (3 × 50 mL),
the combined organic phase dried over Na2SO4 and evaporated to
afford alcohol 16.
HRMS: m/z [M + Na]+ calcd for C20H32N2O2Na: 355.2352; found:
355.2361.
cis-(3R,4R)-N-(tert-Butoxycarbonyl)-4-methyl-3-(methylami-
no)piperidine (19)
Compound 18 (0.2 g, 0.60 mmol) in MeOH (5 mL) was treated with
5% Pd/C (0.05 g) and HCOONH4 (0.2 g, 3.17 mmol). The resulting
mixture was heated at reflux temperature for 5 h. The progress of
the reaction was monitored by TLC, and following completion the
catalyst was removed by filtration and the filtrate evaporated to af-
ford the target product 19.
Light-yellow oil; yield: 2.89 g (93%); [a]D25 –2.5 (c 0.55, MeOH).
1H NMR (400 MHz, CDCl3): d = 7.30–7.15 (m, 5 H), 4.04 (d, J =
7.3 Hz, 2 H), 3.78–3.49 (m, 2 H), 3.43 (dt, J = 12.8, 4.6 Hz, 1 H),
3.29 (dd, J = 13.3, 8.7 Hz, 1 H), 3.50 (s, 1 H), 2.83 (dt, J = 8.5, 4.2
Hz, 1 H), 2.31–2.19 (m, 1 H), 2.14 (s, 3 H), 1.67–1.49 (m, 2 H), 1.36
(t, J = 6.1 Hz, 13 H).
13C NMR (100 MHz, CDCl3): d = 153.5, 140.1, 127.5, 127.3, 127.0,
126.7, 126.3, 124.5, 78.8, 63.0, 58.1, 42.1, 40.8, 39.5, 32.5, 29.3,
27.4, 25.5, 12.5.
Light-yellow oil; yield: 0.14 g (100%); [a]D25 –0.9 (c 0.65, MeOH).
1H NMR (400 MHz, CDCl3): d = 3.93–3.82 (m, 1 H), 3.68–3.57 (m,
1 H), 3.41–3.39 (m, 1 H), 3.22 (s, 1 H), 3.07 (s, 1 H), 2.68 (s, 3 H),
2.18–2.14 (m, 1 H), 1.68–1.57 (m, 2 H), 1.46 (s, 9 H), 1.14 (d,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.8, 80.5, 57.8, 53.5, 41.9, 33.2,
31.2, 28.9, 28.3, 23.1.
ESI-MS: m/z = 348.8 [M + 1]+.
(3R,4R)-4-(Acetylthiomethyl)-1-(tert-butoxycarbonyl)-3-{meth-
yl[(1R)-1-phenylethyl]amino}piperidine (17)
ESI-MS: m/z = 229.2 [M + 1]+.
HRMS: m/z [M + Na]+ calcd for C12H24N2O2Na: 251.1731; found:
PPh3 (0.6 g, 2.28 mmol) was dissolved in anhyd THF (8 mL), the
atm was exchanged three times with N2 and the reaction vessel was
placed in an ice-H2O bath. Diisopropylazodicarboxylate (DIAD)
(0.6 mL, 2.42 mmol) was added and the mixture stirred for 30 min.
Next, a soln of 16 (0.58 g, 1.66 mmol) in anhyd THF (5 mL) was
added and stirred for 30 min. Then, thioacetic acid (0.2 mL, 2.81
mmol) was added and stirred for 30 min at r.t., then the resulting
mixture was heated at reflux temperature overnight. The reaction
progress was monitored by TLC, and following completion the
mixture was concd under reduced pressure. The residue was puri-
fied on a silica gel column (EtOAc–PE, 30:1 to 2:1) to yield com-
pound 17.
251.1735.
Supporting Information for this article is available online at
Acknowledgment
We are grateful for generous support from the National Natural Sci-
ence Foundation of China (21076183) and the Natural Science
Foundation of the Zhejiang Province (Y4090045).
Light-yellow oil; yield: 0.6 g (88%); [a]D25 –8.8 (c 1.34, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.39–7.18 (m, 5 H), 4.16–3.99 (m,
1 H), 3.53 (s, 1 H), 3.28 (dd, J = 13.7, 4.6 Hz, 1 H), 3.04 (dd, J =
13.7, 10.2 Hz, 1 H), 2.77–2.67 (m, 1 H), 2.35 (s, 3 H), 2.09 (s, 2 H),
1.73 (dd, J = 7.8, 4.0 Hz, 1 H), 1.67 (s, 1 H), 1.59 (s, 1 H), 1.43 (s,
9 H), 1.38 (d, J = 6.8 Hz, 3 H), 1.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 195.2, 142.3, 128.0, 127.2, 127.0,
126.7, 125.6, 78.6, 56.9, 42.4, 41.0, 38.9, 36.0, 29.6, 27.4, 26.0,
21.7.
References
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ESI-MS: m/z = 406.9 [M + 1]+.
HRMS: m/z [M + Na]+ calcd for C22H34N2O3NaS: 429.2180; found:
429.2188.
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(3R,4R)-1-(tert-Butoxycarbonyl)-4-methyl-3-{methyl[(1R)-1-
phenylethyl]amino}piperidine (18)
Substituted piperidine 17 (0.4 g, 0.98 mmol) in EtOH (4 mL) was
treated with Raney-Ni (catalytic amount). The atm was exchanged
three times with N2 and the mixture stirred for 4 h at r.t. The reaction
progress was monitored by TLC, and following completion the
Raney-Ni was removed by filtration and the filtrate evaporated un-
der reduced pressure to afford product 18.
Light-yellow oil; yield: 0.32 g (98%); [a]D25 14.5 (c 0.88, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.35–7.20 (m, 5 H), 4.27–3.97 (m,
2 H), 3.78 (s, 1 H), 2.94 (t, J = 12.8 Hz, 1 H), 2.48 (dt, J = 10.7, 4.2
Hz, 1 H), 2.28 (s, 1 H), 2.01 (s, 3 H), 1.73 (d, J = 11.1 Hz, 1 H), 1.66
(d, J = 12.6 Hz, 1 H), 1.55–1.52 (m, 1 H), 1.44 (s, 9 H), 1.36 (d, J =
6.8 Hz, 3 H), 1.03 (d, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 155.0, 143.4, 127.9, 126.4, 79.4,
59.3, 56.0, 41.5, 32.7, 29.7, 29.4, 28.4.
(c) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem. Int.
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Beijing, 2005.
ESI-MS: m/z = 332.8 [M + 1]+.
Synthesis 2011, No. 8, 1208–1212 © Thieme Stuttgart · New York