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C.-C. Tseng et al.
Paper
Synthesis
13C NMR (100.6 MHz, CDCl3): δ = 160.6, 158.8, 156.0, 155.6, 155.5,
149.5, 137.82, 137.77, 135.8, 130.8, 122.0, 119.8, 117.8, 111.6, 111.0,
62.9, 58.8, 58.7, 40.9, 40.3, 40.1, 36.5, 35.12, 35.09, 31.93, 31.87, 31.8,
30.22, 30.19, 28.6, 28.1, 27.67, 27.65, 27.1, 27.0, 26.74, 26.72, 26.67,
26.23, 26.21, 26.15, 26.0, 17.9, 17.8, 14.5, 14.4.
MS (ESI): m/z = 397 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C25H37N2O2+: 397.2850; found:
397.2843 (Δ –1.6 ppm).
Table 1, Entry 4
(R)-2 (85 mg, 0.214 mmol) and wet 20% Pd(OH)2/active charcoal (18
mg) were employed, following the procedure of entry 1, modified as
follows. The suspended solution was stirred at 23 °C for 24 h under an
atmosphere of H2 before it was heated to 65 °C for 24 h. Purification
by flash column chromatography [silica gel, MeOH–CH2Cl2 (0:100 to
10:90)] gave (S)-1; yield: 52.3 mg (88%, 92% ee).
Table 1, Entry 5
(R)-2 (60 mg, 0.151 mmol) and 5% Rh/Al2O3 (24 mg) were employed,
following the procedure of entry 1, modified as follows. The suspen-
sion was stirred at 23 °C for 24 h under an atmosphere of H2 then
heated to 80 °C (ESI-MS monitoring). The majority of products were
found to be partially hydrogenated, and no further progress was
made after stirring at 80 °C for over 144 h.
(S)-3-[6-(2,2-Dicyclohexylvinyl)pyridin-2-yl]-4-isopropyl-1,3-ox-
azolidin-2-one and (S)-3-[6-(2-Cyclohexyl-2-cyclohexylideneeth-
yl)pyridin-2-yl]-4-isopropyl-1,3-oxazolidin-2-one [(S)-2]
Prepared by the same procedure as above by using 2-pyridines 3 (110
mg, 0.362 mmol), (S)-(–)-4-isopropyl-2-oxazolidinone (56.1 mg,
0.434 mmol, 98% ee), CuI (20 mg, 0.105 mmol), N,N′-dimethylethane-
1,2-diamine (14 mg, 0.16 mmol, 17 μL), and K2CO3 (100 mg, 0.725
mmol) to give regioisomeric adducts (S)-2 as a white amorphous sol-
id; yield: 129 mg (90%, ~2:1 mixture of regioisomers by 1H NMR). The
analytical and spectroscopic data were identical to those of (R)-2.
(R)-(+)-Perhexiline [(R)-1]
This was prepared by the same method as described above for pre-
paring (S)-1, but using (S)-2 (55 mg, 0.139 mmol) and wet 20%
Pd(OH)2 on active charcoal (11 mg). Purification by flash column
chromatography [silica gel, MeOH–CH2Cl2 (0:100 to 10:90)] gave a
(2S)-(–)-2-(2,2-Dicyclohexylethyl)piperidine [(S)-(–)-Perhexiline]
[(S)-1]; Hydrogenation Procedure (Table 1, Entry 1)
20
pale-yellow oil; yield: 34.6 mg (90%, 88% ee); [α]D +5.3 (c 3.4,
CH2Cl2). The analytical and spectroscopic data were identical to those
This procedure is a modified version of the method reported by Glori-
us.10 To a stirred solution of the pyridine–oxazolidinone adducts (R)-2
(72 mg, 0.182 mmol) in AcOH (10 mL) was added 20% Pd(OH)2/active
charcoal (15 mg, ~50% H2O; 2% catalyst-to-substrate by weight). The
reaction vessel was charged with H2 (1 atm), evacuated, and back-
filled with H2, and the mixture was stirred at 23 °C under an atmo-
sphere of H2. When the hydrogenation was complete (ESI-MS analy-
sis), the mixture was filtered through a plug of Celite and flushed
with MeOH (5 mL) and EtOAc (10 mL). The combined filtrates were
neutralized with sat. aq NaHCO3 until effervescence ceased. The lay-
ers were separated and the organic layer was washed with brine (20
mL), dried (Na2SO4), and concentrated in vacuo. Flash column chro-
matography [silica gel, MeOH–CH2Cl2 (0:100 to 10:90)] gave a pale-
yellow oil; yield: 46.4 mg (92%, 93% ee); [α]D20 –6.1 (c 3.3, CH2Cl2). The
ee value was determined by HPLC analysis of the corresponding ben-
zamide derivative 7 (see below).
for (S)-1.
(2R)-(+)-2-(2,2-Dicyclohexylethyl)piperidine hydrochloride
[(R)-(+)-Perhexiline Hydrochloride] (6)8
This was prepared by the same method as that described previously
for preparing (S)-1, using (S)-2 (857 mg, 2.16 mmol) and wet 20%
Pd(OH)2 on active charcoal (172 mg) in AcOH (25 mL). The reaction
was monitored by ESI-MS analysis until hydrogenation was complete.
The mixture was filtered through a plug of Celite and flushed with
MeOH (3 × 10 mL). The collected filtrates were combined, mixed with
12 N aq HCl (0.36 mL), and concentrated in vacuo until no AcOH re-
mained. Flash column chromatography [silica gel, hexanes–
EtOAc (50:50 to 0:100)] gave (S)-(–)-4-isopropyl-2-oxazolidinone
(237 mg, 85%) as
a white solid. Further elution with EtOH–
CH2Cl2 (10:90 to 20:80) gave 6 as a pale-yellow solid; yield: 617 mg
(91%, 88% ee). This was crystallized from 1:1 CH2Cl2–EtOAc to give
white needle crystals; yield: 420 mg (68%, 98% ee); mp 233–235 °C;
[α]20D +17.6 (c 2.4, EtOH) {Lit.8 [α]D24 +18.2 (c 2.78, EtOH)}.
IR (film): 3391 (br), 2922, 2850, 2709, 2499, 1447, 1268, 732, 700 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.57 (br s, 1 H, NH), 9.13 (br s, 1 H, NH),
IR (film): 3258 (br), 2922, 2851, 1447, 1403, 1260, 1014, 894, 734,
704 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.00 (d, J = 10.9 Hz, 1 H), 2.54 (td,
J = 11.7, 2.2 Hz, 1 H), 2.33 (dt, J = 10.3, 6.7 Hz, 1 H), 1.82–0.74 (m, 32
H).
.
3.76–3.06 (m, 1 H), 3.04–2.55 (m, 2 H), 2.17–0.77 (m, 31 H).
13C NMR (100.6 MHz, CDCl3): δ = 56.9, 47.4, 45.4, 40.0, 39.9, 36.6,
33.3, 31.8, 31.8, 29.9, 29.8, 27.03, 26.98, 26.8 (2 C), 26.70, 26.6, 26.6,
25.0.
13C NMR (100.6 MHz, CDCl3): δ = 57.4, 44.9, 44.8, 40.0, 39.1, 32.3,
31.9, 31.4, 30.0, 29.5, 28.4, 27.0, 26.9, 26.7, 26.7, 26.49, 26.47, 22.5,
22.3.
MS (ESI): m/z = 278 [M + H]+.
Crystal structure:17 C19H36ClN, Mr = 313.94, orthorhombic, space
group P212121 (No. 19), a = 6.19730(10) Å, b = 10.8191(2) Å,
c = 27.3890(6) Å, V = 1836.41(6) Å3, Z = 4, T = 100 K; absolute struc-
ture parameter = 0.13(8); 3411 reflections, 216 parameters,
R(F) = 0.048, wR(F2) = 0.127.
HRMS (ESI): m/z [M + H]+ calcd for C19H36N+: 278.2842; found:
278.2838 (Δ –1.4 ppm).
Table 1, Entry 2
(R)-2 (60 mg, 0.151 mmol) and PtO2 (1.2 mg, 2% w/w) were employed,
following the procedure of entry 1 above, to give (S)-1; yield: 35.6 mg
(85%, 87% ee).
(±)-1-Benzoyl-2-(2,2-dicyclohexylethyl)piperidine (rac-7)
BzCl (23 mg, 0.164 mmol, 19 μL), DMAP (1 mg, 0.01 mmol), and Et3N
(36 mg, 0.359 mmol, 50 μL) were added to a stirred solution of rac-
perhexiline (30 mg, 0.108 mmol) in CH2Cl2 (2 mL) at 0 °C, and the
mixture was stirred at 0 °C for 16 h. The reaction was then quenched
with sat. aq NH4Cl (5 mL), and the mixture was diluted with EtOAc
(10 mL). The layers were separated and the organic layer was washed
Table 1, Entry 3
(R)-2 (62 mg, 0.156 mmol) and dry 10% Pd/active charcoal (12 mg)
were employed, following the procedure of entry 1 above, to give (S)-
1; yield: 26.8 mg (62%, 90% ee).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 73–78