Ring Functionalized trans-2,6-Disubstituted Piperidines
(2S,6R)-(+)-Benzyl 2-methyl-6-phenyl-5,6-dihydropyridine-
stirred for 2 h. At this time the reaction was quenched by addition
of saturated NH4Cl (30 mL), warmed to room temperature, and
diluted with H2O (10 mL). The solution was extracted with Et2O
(50 mL) and EtOAc (2 × 50 mL), and the combined organic phases
were washed with brine (20 mL), dried (MgSO4), and concentrated.
Flash chromatography (EtOAc) gave a colorless oil, which was
subjected to Kugelrohr vacuum distillation (60 °C under 2.5 mmHg)
to remove the diethyl methylphosphonate, affording 3.15 g (85%)
1-carboxylate (10a). Yield 69%; colorless oil; [R]20 +184.7 (c
D
0.55, CHCl3); IR (neat) 3312, 2987, 1699 cm-1; 1H NMR (CDCl3)
δ 7.23-7.06 (m, 8 H), 7.02 (m, 2 H), 5.90 (m, 1 H), 5.56 (m, 1
H), 5.25 (m, 1 H), 4.95 (m, 2 H), 4.52 (m, 1 H), 2.72 (m, 1 H),
2.28 (m, 1 H), 1.34 (d, J ) 6.4 Hz, 3 H); 13C NMR (CDCl3) δ
156.0, 145.1, 136.9, 132.0, 128.4, 128.2, 127.7, 126.6, 126.1, 122.0,
67.0, 55.2, 49.4, 30.6, 21.4; HRMS calcd for C20H21NO2Na (M +
Na) 330.1470, found 330.1477.
of a colorless oil; [R]20 +26.9 (c 3.3, CHCl3); IR (neat) 3420,
D
3180, 1721, 1226 cm-1; 1H NMR (CDCl3) δ 7.48 (m, 2 H), 7.31-
7.13 (m, 7 H), 4.51 (d, J ) 9.2 Hz, 1 H), 4.43 (s, 2 H), 4.05 (m,
4 H), 3.61 (m, 1 H), 3.42 (t, J ) 6.4 Hz, 2 H), 2.98 (d, J ) 22.8
Hz, 2 H), 2.88 (q, J ) 5.2, 3.2 Hz, 2 H), 2.33 (s, 3 H), 1.66-1.34
(m, 6 H), 1.25 (m, 6 H); 13C NMR (CDCl3) δ 201.1 (J ) 6.1 Hz),
142.8, 141.5, 139.0, 129.8, 128.6, 127.9, 127.8, 125.8, 73.2, 70.4,
62.9 (J ) 6.3 Hz), 52.7, 50.0, 43.4 (J ) 125.2 Hz), 35.8, 29.6,
23.1, 21.6, 16.6 (J ) 6.0 Hz); 31P NMR (CDCl3) δ 19.53; HRMS
calcd for C26H39NO6PS (M + H) 524.2236, found 524.2239.
(S)-(+)-tert-Butyl 2-(4-(Benzyloxy)butyl)-5-(diethoxyphospho-
ryl)-4-oxo-3,4- dihydropyridine-1-carboxylate (21). In a 100-mL,
oven-dried, single-necked round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon inlet was placed
(+)-20 (1.92 g, 3.66 mmol) in toluene (30 mL). To the solution
was added DMF dimethyl acetal (5.2 mL, 36.6 mmol), and the
reaction mixture was stirred for 12 h and concentrated to give a
yellow solid. To the solid was added 4 N HCl (20 mL), the solution
was stirred for 1 h, 6 N NaOH (12 mL) was added, and the solution
was neutralized to pH >10 with saturated NaHCO3 solution. The
aqueous solution was extracted with EtOAc (3 × 50 mL), and the
combined organic phases were washed with brine (20 mL), dried
(Na2SO4), and concentrated. The residue was dissolved in THF (20
mL), and TEA (1.53 mL, 11.0 mmol), DMAP (0.20 g), and benzyl
chloroformate (1.03 mL, 7.3 mmol) were added. After 3 h of
stirring, saturated NH4Cl (10 mL) was added. The solution was
extracted with EtOAc (3 × 40 mL), and the combined organic
phases were washed with brine (20 mL), dried (Na2SO4), and
concentrated. Flash chromatography (EtOAc) afforded 1.63 g (90%)
(2S,6R)-(+)-Benzyl 2-Propyl-6-phenylpiperidine-1-carboxy-
late (13). Typical Hydrogenation Procedure. In a 25-mL, single-
necked round-bottom flask equipped with a magnetic stirring bar
and rubber septum was placed (+)-10b (0.034 g, 0.1 mmol) and
5% Pt/C (0.015 g) in MeOH (10 mL). The solution was stirred
under 1 atm of H2 (balloon) for 0. 5 h, filtered, and concentrated.
Flash chromatography (EtOAc/hexane, 10:90) afforded 0.031 g
(92%) of a colorless oil; [R]20 +61.1 (c 0.36, CHCl3); IR (neat)
D
3269, 1743 cm-1; 1H NMR (CDCl3) δ 7.26-7.00 (m, 10 H), 5.07-
4.95 (m, 3 H), 3.92 (m, 1 H), 2.06 (m, 2 H), 1.81-1.20 (m, 8 H),
0.84 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3) δ 156.5, 143.3, 137.0,
128.4, 128.3, 127.9, 127.8, 126.3, 125.9, 66.9, 55.1, 52.7, 36.9,
27.4, 23.7, 20.4, 14.6, 14.2; HRMS calcd for C22H27NO2Na (M +
Na) 360.1940, found 360.1947.
(2S,6R)-(+)-Benzyl 2-Methyl-6-phenylpiperidine-1-carboxy-
late (14). Yield 91%; colorless oil; [R]20D +66.0 (c 0.22, CHCl3);
IR (neat) 3287, 1741 cm-1; 1H NMR (CDCl3) δ 7.25-7.06 (m, 10
H), 5.04 (m, 2 H), 5.01 (m, 1 H), 4.17 (m, 1 H), 2.09 (m, 2 H),
1.73 (m, 1 H), 1.57 (m, 1 H), 1.40 (m, 2 H), 1.28 (d, J ) 6.8 Hz,
3 H); 13C NMR (CDCl3) δ 156.5, 143.6, 137.1, 128.4, 127.8, 126.3,
125.8, 66.9, 54.9, 48.1, 27.4, 26.7, 21.0, 14.1; HRMS calcd for
C15H19NO2Na (M + Na) 332.1626, found 332.1633.
(2S,6R)-(+)-2-Propyl-6-phenylpiperidine (11). In a 25-mL,
single-necked round-bottom flask equipped with a magnetic stirring
bar and rubber septum was placed (+)-13 (0.034 g, 0.1 mmol) in
MeCN (10 mL). To the solution was added TMS-I (57.0 mL, 0.4
mmol), and the reaction mixture was stirred for 15 min, concen-
trated, and quenched with 1 N HCl (10 mL). The solution was
extracted with ether (2 × 5 mL), and the aqueous phase was
neutralized 3 N NaOH until a white precipitate was formed. At
this time the solution was extracted with DCM (3 × 10 mL), and
the combined DCM extracts were washed with brine (5 mL), dried
(Na2SO4), and concentrated. Flash chromatography (EtOAc) af-
forded 0.2 g (96%) of a colorless oil; [R]20D +28.1 (c 0.2, acetone);
IR (neat) 3280, 3060, 1231, 1033 cm-1; 1H NMR (CDCl3) δ 7.38
(m, 2 H), 7.32 (m, 2 H), 7.24 (m, 1 H), 3.96 (m, 1 H), 3.05 (m, 1
H), 2.01-1.21 (m, 11 H), 0.94 (d, J ) 6.8 Hz, 3 H); 13C NMR
(CDCl3) δ 145.3, 128.5, 126.9, 54.4, 52.1, 34.8, 33.6, 29.8, 20.4,
19.9, 14.3; HRMS calcd for C14H22N (M + H) 204.1752, found
204.1753.
of a colorless oil; [R]20 +31.2 (c 1.0, CHCl3); IR (neat) 3211,
D
1
1731, 1654, 1256 cm-1; H NMR (CDCl3) δ 8.49 (dd, J ) 14.8,
1.2 Hz, 1 H), 7.36-7.24 (m, 5 H), 4.56 (m, 1 H), 4.47 (s, 2 H),
4.13 (m, 4 H), 3.42 (m, 2 H), 2.77 (m, 1 H), 2.48 (m, 1 H), 1.65-
1.35 (m, 6 H), 1.53 (s, 9 H), 1.31 (q, J ) 7.2 Hz, 6 H); 13C NMR
(CDCl3) δ 190.5, 151.9 (J ) 18.5 Hz), 150.7, 138.8, 126.7, 127.9,
127.8, 104.9 (J ) 195.2 Hz), 85.3, 73.3, 70.2, 62.6, 40.2 (J ) 8.9
Hz), 31.0, 29.7, 28.2, 22.8, 16.7; 31P NMR (CDCl3) δ 15.27; HRMS
calcd for C25H39NO7P (M + H) 496.2464, found 496.2461.
(2S,6S)-(-)-tert-Butyl 6-(4-(Benzyloxy)butyl)-3-(diethoxyphos-
phoryl)-4-hydroxy-2-methyl-5,6-dihydropyridine-1-carboxy-
late (22). In a 100-mL, oven-dried, single-necked round-bottom
flask equipped with a magnetic stirring bar, rubber septum, and
argon inlet was placed (+)-21 (0.496 g, 1.08 mmol) in THF (20
mL), and the solution was cooled to -78 °C. In a second 50-mL,
single-necked round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet was placed CuI (0.83 g, 4.32
mmol) in THF (20 mL). The reaction mixture was cooled to
-78 °C, and MeMgCl (1.4 mL, 3.0 M in THF, Aldrich) was added.
The reaction mixture was stirred for 45 min and cannulated to the
solution of (+)-21, and after 0.5 h saturated NH4Cl (10 mL) was
added. The solution was extracted with EtOAc (3 × 40 mL), and
the combined organic phases were washed with brine (10 mL), dried
(Na2SO4), and concentrated. Flash chromatography (EtOAc/hexane/
acetic acid, 30:70:4) afforded 0.357 g (70%) of a light yellow oil;
[R]20D -7.5 (c 0.8, CHCl3); IR (neat) 3450, 1737, 1697, 1256, 1109
(2S,6R)-(+)-2-Methyl-6-phenylpiperidine (15). Yield 95%;
colorless oil; [R]20 +34.2 (c 0.3, CHCl3) [lit.25 +33.4 (c 1.25,
D
CHCl3)]; IR (neat) 3287, 3050, 1233, 1042 cm-1; 1H NMR (CDCl3)
δ 7.38 (m, 2 H), 7.32 (m, 2 H), 7.23 (m, 1 H), 4.05 (m, 1 H), 3.30
(m, 1 H), 1.72 (m, 6 H), 1.42 (m, 1 H), 1.22 (d, J ) 6.8 Hz, 3 H);
13C NMR (CDCl3) δ 145.3, 128.5, 126.9, 54.3, 47.5, 33.5, 31.5,
20.1, 20.0; HRMS calcd for C12H17N (M) 175.1361, found
175.1358.
(SS,S)-(+)-Diethyl 8-(Benzyloxy)-4-(4-methylphenylsulfina-
mido)-2-oxooctylphosphonate (20). In a 250-mL, oven-dried,
single-necked round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon balloon was placed diethyl methyl
phosphonate (5.12 mL, 35.4 mmol) in THF (100 mL). The solution
was cooled to -78 °C, and n-BuLi (2.5 M in hexane, 14.2 mL,
35.4 mmol) was slowly added via syringe. In a second 500-mL
oven-dried, single-necked round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was placed
(+)-19 (2.85 g, 7.07 mmol) in THF (120 mL) at -78 °C. The
diethyl methyl phosphonate solution was transferred after 45 min
to the -78 °C solution of (+)-19, and the reaction mixture was
1
cm-1; H NMR (CDCl3) δ 10.90 (s, 1 H), 7.31-7.18 (m, 5 H),
4.42 (s, 2 H), 4.41 (m, 1 H), 4.04 (m, 4 H), 3.90 (m, 1 H), 3.39 (m,
2 H), 2.60 (m, 1 H), 2.24 (m, 1 H), 1.55 (m, 3 H), 1.40 (s, 9 H),
1.30-1.17 (m, 12 H); 13C NMR (CDCl3) δ 202.7 (J ) 6.4 Hz),
170.3, 154.6, 139.1, 128.7, 127.9, 127.8, 127.7, 92.9 (J ) 187.0
Hz), 80.0, 73.3, 70.7, 62.4, 52.5, 47.5 (J ) 14.2 Hz), 34.8, 32.3 (J
J. Org. Chem, Vol. 72, No. 6, 2007 2051