The Journal of Organic Chemistry
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(0.200 g, 1.46 mmol), triethylamine (0.24 mL, 1.75 mmol),
chloroacetyl chloride (0.14 mL, 1.75 mmol), and CH2Cl2
(6.49 mL). Step 2: sodium hydride (60% in mineral oil, 0.062
g, 2.60 mmol) and THF (6.10 mL). Step 3: LiAlH4 (0.149 g,
3.93 mmol) and THF (8.10 mL). The title compound was
isolated as a white solid: 23.2 mg, 14.2% yield over three steps.
1H NMR (400 MHz, CDCl3) δ 7.41−7.32 (m, 5H), 4.15 (dd,
J = 8.1, 6.5 Hz, 1H), 3.98−3.95 (m, 2H), 3.90−3.85 (m, 2H),
3.03 (ddd, J = 12.9, 10.4, 5.4 Hz, 1H), 2.76 (dt, J = 13.0, 1.9
Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 132.4, 130.0,
129.4, 128.1, 68.8, 63.4, 59.1, 43.5; HRMS (ESI-TOF) m / z
calcd for C10H13NOH (M + H)+: 164.1070, found 164.1064;
anhydrous sodium sulfate and concentrated in vacuo. Products
were purified by flash chromatography on silica gel (0−10%
MeOH in CH2Cl2).
(R)-2-(2,4-Dimethylphenyl)Piperidine (51). Following
General Procedure 2, benzylated piperidine (58.7 mg, 0.210
mmol) and 10% Pd/C (111.8 mg, 0.105 mmol) were
suspended in ethyl acetate (2.10 mL), and 2 M HCl (0.15
mL) was added. Subsequently, the mixture was sparged with
hydrogen for 10 min and was allowed to stir under a hydrogen
atmosphere for 36 h. Upon completion of the reaction as
monitored by ESI-MS, the mixture was filtered through a pad
of Celite. Subsequently, 1 M NaOH (3 mL) was added, and
the mixture was stirred for 20 min. The organic layer was
separated, and the aqueous phase was extracted with ethyl
acetate (3 x 5 mL). The product was isolated as stated to afford
[α]22 = −0.7 (c 3.26, MeOH).
D
(R)-3-Benzylmorpholine (26). (R)-3-benzylmorpholine
was prepared according to General Procedure 1 using the
following amounts of reagents. Step 1: D-phenylalaninol
(0.200 g, 1.32 mmol), triethylamine (0.22 mL, 1.56 mmol),
chloroacetyl chloride (0.13 mL, 1.56 mmol), and CH2Cl2
(6.49 mL). Step 2: sodium hydride (60% in mineral oil, 0.053
g, 0.002 mmol) and THF (6.10 mL). Step 3: LiAlH4 (0.127 g,
3.35 mmol) and THF (6.10 mL). The title compound was
isolated as a white solid: 17 mg, 7.4% yield over three steps. 1H
NMR (400 MHz, CDCl3) δ 9.93 (m, 1H), 7.35−7.27 (m, 3H),
7.19−7.15 (m, 2H), 3.98 (ddd, J = 12.7, 3.9, 2.1 Hz, 1H), 3.87
(ddt, J = 12.8, 7.0, 3.0 Hz, 2H), 3.66 (dd, J = 12.7, 9.9 Hz,
1H), 3.47 (dt, J = 11.9, 6.3 Hz, 1H), 3.26 (dt, J = 13.0, 2.5 Hz,
1H), 3.22−3.14 (m, 1H), 3.10 (dd, J = 13.7, 5.2 Hz, 1H), 2.83
(dd, J = 13.6, 9.8 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3)
δ 134.3, 129.2, 129.2, 127.8, 68.0, 63.7, 55.8, 43.4, 35.6;
HRMS (ESI-TOF) m / z calcd for C11H15NOH (M + H)+:
178.1227, found 178.1219; [α]22 = +31.2 (c 3.55, MeOH).
(R)-3-IsopropylmorpholineD(27). (R)-3-isopropylmor-
pholine was prepared according to General Procedure 3
using the following amounts of reagents. Step 1: D-valinol
(0.200 g, 1.94 mmol), triethylamine (0.33 mL, 2.33 mmol),
chloroacetyl chloride (0.19 mL, 2.328 mmol), and CH2Cl2
(6.49 mL). Step 2: sodium hydride (60% in mineral oil, 0.069
g, 2.859 mmol) and THF (6.10 mL). Step 3: LiAlH4 (0.136 g,
3.595 mmol) and THF (8.10 mL). The title compound was
isolated as a white solid: 3.1 mg, 1.2% yield over three steps.
1H NMR (400 MHz, CDCl3) δ 4.04 (dd, J = 12.6, 3.5 Hz,
1H), 3.98−3.92 (m, 1H), 3.82 (ddd, J = 12.8, 11.8, 2.6 Hz,
1H), 3.63 (dd, J = 12.7, 10.8 Hz, 1H), 3.24 (dt, J = 13.0, 2.2
Hz, 1H), 3.13 (ddd, J = 12.9, 11.8, 3.9 Hz, 1H), 2.95 (ddd, J =
10.8, 7.5, 3.5 Hz, 1H), 1.92 (m (8), J = 6.9 Hz, 1H), 1.06 (d, J
= 6.9 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 67.2, 63.7, 60.5, 44.0, 28.6, 18.8, 18.4; HRMS
(ESI-TOF) m / z calcd for C7H15NOH (M + H)+: 130.1227,
1
51 as a yellow oil (21.3 mg, 54% yield). H NMR (500 MHz,
CDCl3) δ 7.41 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H),
6.95 (s, 1H), 3.76 (d, J = 10.5 Hz, 1H), 3.21 (d, J = 11.6 Hz,
1H), 2.81 (dt, J = 11.7, 2.6 Hz, 1H), 2.29 (s, 3H), 1.89 (d, J =
11.9 Hz, 1H), 1.78−1.64 (m, 3H), 1.62−1.41 (m, 3H).;
13C{1H} NMR (126 MHz, CDCl3) δ 140.7, 136.1, 134.7,
131.1, 127.0, 125.9, 58.1, 48.3, 34.0, 26.2, 25.8, 21.0, 19.2;
HRMS (ESI-TOF) m / z calcd for C13H19NH (M + H)+:
190.1591, found 190.1591; [α]22 = +68.9 (c 2.13, CDCl3).
(R)-2-(3,5-di-tert-Butyl-2-MDethoxyphenyl)Piperidine
(52). Following General Procedure 2, benzylated piperidine
(41.5 mg, 0.105 mmol) and 10% Pd/C (56.1 mg, 0.053 mmol)
were suspended in ethanol (0.8 mL) and ethyl acetate (0.26
mL), and 2 M HCl (0.08 mL) was added. The product was
isolated as stated to afford 52 as a white sticky solid (17.9 mg,
1
56%). H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 2.5 Hz,
1H), 7.24 (d, J = 2.6 Hz, 1H), 3.95 (dd, J = 10.6, 2.3 Hz, 1H),
3.22−3.16 (m, 1H), 2.83 (td, J = 11.6, 2.9 Hz, 1H), 1.95−1.88
(m, 1H), 1.80−1.71 (m, 2H), 1.69−1.64 (m, 1H), 1.63−1.52
(m, 2H), 1.40 (s, 9H), 1.31 (s, 9H); 13C{1H} NMR (126
MHz, CDCl3) δ 154.8, 146.0, 141.5, 137.9, 123.1, 63.0, 56.0,
48.5, 35.5, 34.8, 34.5, 31.7, 31.4, 26.3, 26.0; HRMS (ESI-
TOF) m / z calcd for C20H33NOH (M + H)+: 304.2635, found
304.2628; [α]22 = +34.8 (c 1.79, CDCl3).
D
(R)-2-(2-Trifluoromethylphenyl)Piperidine (53). Fol-
lowing General Procedure 2, benzylated piperidine (67.2 mg,
0.210 mmol) and 10% Pd/C (112 mg, 0.105 mmol) were
suspended in ethanol (1.6 mL) and ethyl acetate (0.53 mL),
and 2 M HCl (0.15 mL) was added. The product was isolated
as stated to afford 53 as a yellow oil (34.7 mg, 72%). 1H NMR
1H NMR (600 MHz, Chloroform-d) δ 7.85 (d, J = 7.9 Hz,
1H), 7.60 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.32 (t,
J = 7.6 Hz, 1H), 3.98 (app. d, J = 9.3 Hz, 1H), 3.18 (app. d, J =
11.4 Hz, 1H), 2.83 (td, J = 11.7, 2.6 Hz, 1H), 2.01 (s, 1H),
1.92−1.83 (m, 1H), 1.81−1.74 (m, 1H), 1.71−1.65 (m, 1H),
1.59 (qt, J = 12.3, 4.0 Hz, 1H), 1.54−1.45 (m, 2H); 13C{1H}
NMR (151 MHz, CDCl3) δ 144.4, 132.2, 128.9, 127.6 (q, J =
29.5 Hz), 127.0, 125.5 (q, J = 5.9 Hz), 124.7 (q, J = 273.7 Hz),
77.2, 57.8, 48.0, 34.9, 25.8, 25.5; HRMS (ESI-TOF) m / z
calcd for C12H14F3NH (M + H)+: 230.1152, found 230.1149;
found 130.1221; [α]21 = +16.0 (c 2.58, MeOH).
D
GENERAL PROCEDURE 2
■
Debenzylation of Piperidines. Benzylated piperidine and
Pd/C (5 or 10 wt %, 0.5 equiv) were suspended in either ethyl
acetate, absolute ethanol, or a mixture of the two. Aqueous
HCl (1 or 2 M, 1.2−1.5 equiv) was added, and the mixture was
sparged with hydrogen for 10 min. The mixture was then
allowed to stir under an atmosphere of hydrogen until the
reaction was complete as monitored by ESI-MS. Upon
completion, the reaction mixture was filtered through a pad
of Celite, and aqueous NaOH was added. The organic phase
was separated, and the aqueous phase was extracted with ethyl
acetate. The combined organic layers were dried over
[α]22 = +50.9 (c 3.47, CDCl3).
D
Methyl (R)-2,3,4,9-Tetrahydro-1H-Pyrido[3,4-b]-
Indole-3-Carboxylate (23). (R)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-3-carboxylic acid (30 mg, 0.14 mmol)
was dissolved in methanol (1.4 mL), and thionyl chloride (15
μL, 0.21 mmol) was added. The mixture was heated to 80 °C
for 2 h and was then evaporated in vacuo. The amine salt was
suspended between a mixture of CH2Cl2 (1 mL) and saturated
G
J. Org. Chem. XXXX, XXX, XXX−XXX