Synthetic Route to Dihydropipercide and Pipercide
J . Org. Chem., Vol. 63, No. 19, 1998 6671
with water and brine and dried (MgSO4). Removal of solvent
gave 42 g of amber oil that was purified by flash column
chromatography on silica gel using ether as eluent and
afforded 37.02 g of 6 (80.5% yield) as a light amber oil; TLC
(SS-3) Rf ) 0.55; GLC: tR 6.07 and 6.49 min, ratio ca. 3:7. A
portion distilled through a short path still had bp 169 °C/0.04
mm; IR (NaCl, 10% in CH2Cl2) 1735 (vs), 1600 (m); NMR (60
MHz, CDCl3) δ 1.55 (m, 4H), 2.25 (m, 4H), 3.63 (s, 3H), 5.87
(s, 2H), 5.5-7.3 (m, 5H); MS m/e 262 (M+). Anal. Calcd for
6.65 (s, 1H), 6.70 (dd, 1H, J ) 7.8, 1.5 Hz), 7.24 (dd, 1H, J )
15.5, 9.5 Hz); MS 330 m/e (M+). Anal. Calcd for C20H26O4:
C, 72.70; H, 7.93. Found: C, 72.95; H, 8.13.
11-(3,4-Meth ylen ed ioxyp h en yl)-(2E,4E)-u n d eca d ien o-
ic Acid 11. To a magnetically stirred solution of 10 (3.30 g,
0.010 mol) in 100 mL of ethanol was added a solution of KOH
(2.24 g, 0.04 mol) in 100 mL of ethanol/water 3:1. The reaction
was stirred overnight at ambient temperature, diluted with
ethanol, and evaporated to dryness in vacuo. The residue was
dissolved in water, extracted with ether, acidified to pH 2 with
concentrated HCl, and re-extracted with ether. The combined
extracts were washed with water and brine, dried (MgSO4),
and evaporated in vacuo to afford 5.90 g of crude product as a
colorless solid. This material was recrystallized from Et2O/
hexane to provide 2.96 g (98% yield) of 11 as a colorless solid,
mp 94.5-96.0 °C (lit.5 mp 103-104 °C): IR (NaCl, 2% KBr)
3200-2800 (m, br), 1684 (vs), 1630 (s), 1613 (s); NMR (60 MHz,
CDCl3) δ 1.4 (m, 8H), 2.15 (m, 2H), 2.50 (m, 2H), 5.73 (d, 1H,
J ) 15 Hz), 5.87 (s, 2H), 6.13 (m, 2H), 6.63 (m, 3H), 6.9-8.0
(m, 2H); MS 302 m/e (M+) Anal. Calcd for C18H22O4: C, 71.50;
H, 7.33. Found: C, 71.60; H, 7.25.
C
15H18O4: C, 68.69; H, 6.92. Found: C, 68.62; H, 7.20.
Meth yl 7-(3,4-Meth ylen ed ioxyp h en yl)h ep ta n oa te 7. A
mixture of 6 (6.55 g, 0.025 mol) and palladium on charcoal
(0.5 g, 10%) in 75 mL of methanol was hydrogenated on a Parr
Shaker for 3 h at 37 psi. After suction filtration through
Celite, the filtrate was concentrated in vacuo to give 6.36 g
(96% yield) of 7 as a light amber oil; GLC tR 6.32 min; IR (NaCl,
10% CH2Cl2) 1720 (vs); NMR (60 MHz, CDCl3) δ 1.47 (m, 8H),
2.40 (m, 4H), 3.62 (s, 3H), 5.85 (s, 2H), 6.63 (m, 3H); MS 264
m/e (M+). Anal. Calcd for C15H20O4: C, 68.16; H, 7.63.
Found: C, 68.43; H, 7.83.
7-(3,4-Meth ylen ed ioxyp h en yl)h ep ta n ol 8. To a mag-
netically stirred solution of 7 (5.72 g, 0.022 mol) in 100 mL of
anhydrous THF was added portionwise at 21 °C lithium
aluminum hydride (0.84 g, 0.022 mol), raising the temperature
to 29 °C and providing vigorous gas evolution. After stirring
1 h and diluting with 300 mL of ether, about 5 mL of water
was added dropwise until no further reaction was apparent.
Anhydrous MgSO4 (15 g) was added, the mixture was stirred
for 3 h and filtered, and the filtrate was concentrated in vacuo
to give 5.65 g of crude product. Recrystallization from ether/
hexane afforded 5.19 g (96% yield) of 8 as a colorless solid,
mp 20.0-22.0 °C: TLC (SS-2) Rf ) 0.13; IR (KBr) 3300 (s,
br); NMR (60 MHz, CDCl3) δ 1.35 (m, 10H), 1.97 (s, 1H), 2.47
(m, 2H), 3.53 (m, 2H), 5.78 (s, 2H), 6.53 (m, 3H); MS 236 m/e
(M+). Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found:
C, 71.51; H, 8.80.
7-(3,4-Meth ylen ed ioxyp h en yl)h ep ta n a l 9. To a mag-
netically stirred solution of oxalyl chloride (2.79 g, 0.022 mol)
in 80 mL of dry CH2Cl2 at -65 °C under nitrogen was added
dropwise anhydrous DMSO (3.78 g, 0.048 mol). After stirring
at this temperature for 30 min, a solution of 8 (4.76 g, 0.020
mol) in 20 mL of anhydrous CH2Cl2 was added dropwise. Four
hours later, the reaction was quenched with Et3N (10.3 g, 0.10
mol) and warmed to -10 °C overnight. The mixture was
stirred for 2 h at room temperature, diluted with CH2Cl2, and
extracted with water. The organic phase was washed with
brine, dried (MgSO4), and concentrated in vacuo to afford 5.17
g of yellow oil. Flash chromatography on silica using a
gradient of SS-1 to SS-2 afforded 4.46 g (95% yield) of 9 as a
light amber oil: TLC (SS-2) Rf ) 0.39; GLC tR 5.82 min; IR
(NaCl, 10% CH2Cl2) 1723 (vs); NMR (60 MHz, CDCl3) δ 1.37
(m, 8H), 2.41 (m, 4H), 5.80 (s, 2H), 6.57 (m, 3H), 9.73 (t, 1H,
J ) 1.5 Hz); MS 234 m/e (M+). Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 71.57; H, 7.65.
Eth yl 11-(3,4-Meth ylen ed ioxyp h en yl)-(2E,4E)-u n d eca -
d ien oa te 10. To a magnetically stirred solution of anhydrous
diisopropylamine (7.86 g, 0.078 mol, distilled from CaH2) in
10 mL of anhydrous THF was added dropwise under N2 at
-74 °C n-butyllithium (5.0 g, 0.078 mol, 52.0 mL of 1.5 M in
hexane). After stirring 30 min, triethyl-4-phosphonocrotonate
(18.5 g, 0.074 mol) in 20 mL of anhydrous THF was added
dropwise at -23 °C over 45 min. After 5 min, aldehyde 9 (8.64
g, 0.037 mol) in 10 mL of anhydrous THF was added dropwise
at -23 °C. After stirring for 2 h, the mixture was warmed to
ambient temperature, poured into 300 mL of a saturated
aqueous NaHCO3 solution, and extracted with ether (4×). The
combined extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo to provide 23.42 g of dark amber oil.
Flash chromatography with 5% Et2O/hexane afforded 10.15 g
(83% yield) of 10 as an amber oil: TLC (SS-2) Rf ) 0.42; IR
(NaCl, 10% in CH2Cl2) 1695 (vs), 1625 (s), 1600 (m); NMR (360
MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.1 Hz), 1.29 (m, 4H), 1.43 (m,
2H), 1.57 (m, 2H), 2.15 (dt or q, 2H, J ) 6.5 Hz), 2.51 (t, 2H,
J ) 7.6 Hz), 4.19 (q, 2H, J ) 7.1 Hz), 5.77 (d, 1H, J ) 15.3
Hz), 5.90 (s, 2H), 6.05-6.19 (m, 2H), 6.60 (d, 1H, J ) 7.9 Hz),
(2E,4E)-N-Isobu tyl-11-(3,4-m eth ylen ed ioxyp h en yl)-2,4-
u n d eca d ien a m id e, Dih yd r op ip er cid e 1. To a magnetically
stirred solution of 11 (3.62 g, 0.012 mol) in 100 mL of benzene
at ambient temperature was added dropwise oxalyl chloride
(3.81 g, 0.030 mol) with moisture exclusion (CaCl2 drying tube).
After stirring for 1 h at ambient temperature and 2 h at reflux,
the solution was cooled. Excess oxalyl chloride and benzene
were removed in vacuo and the crude acid chloride 12 was
redissolved twice in fresh portions of benzene and reevapo-
rated. The resultant material was held under high vacuum
until a constant theoretical yield of 3.85 g of product 12 was
obtained. The residue was dissolved in 25 mL of anhydrous
diethyl ether and added dropwise to a solution of isobutyl-
amine (1.32 g; 0.018 mol) and triethylamine (2.43 g; 0.024 mol)
in 50 mL of ether at 0 °C. After warming to room temperature
overnight, the reaction was diluted with ether and washed
with portions of water, 3 N HCl, a saturated NaHCO3 solution,
water, and brine. The organic phase was dried (MgSO4) and
evaporated in vacuo to afford 4.9 g of colorless solid. Recrys-
tallization from ether/ethyl acetate/hexane 4/1/5 provided 3.86
g (90% yield) of Dihydropipercide 1 as colorless needles, mp
89.5-91.5 °C (lit.7d mp 94-95 °C): TLC (SS-3) Rf ) 0.25; IR
(NaCl, 10% CH2Cl2) 3400 (m), 3270 (m), 1650 (s), 1615 (s), 1600
(s); NMR (300 MHz, CDCl3) δ 0.92 (d, 6H, J ) 6.7 Hz), 1.32
(m, 4H), 1.41 (m, 2H), 1.56 (m, 2H), 1.80 (septet, 1H, J ) 6.7
Hz), 2.13 (dt or q, 2H, J ) 6.6 Hz), 2.51 (t, 2H, J ) 7.6 Hz),
3.16 (t, 2H, J ) 6.7 Hz), 5.52 (brs, 1H), 5.75 (d, 1H, J ) 15.1
Hz), 5.90 (s, 2H), 6.04-6.11 (m, 2H), 6.67 (m, 3H), 7.18 (dd,
1H, J ) 15.1, 9.8 Hz); MS 357 m/e (M+). Anal. Calcd for
C
22H31NO3: C, 73.92; H, 8.74; N, 3.92. Found: C, 74.20; H,
8.84; N, 3.83.
Meth yl 7-(3,4-Meth ylen edioxyph en yl)-6-(E)-h epten oate
13. To a magnetically stirred solution of 6 (44.59 g, 0.17 mol)
and thiophenol (4.46 g, 10 wt %) under N2 at 95-100 °C was
injected a 10 mL aliquot of air by syringe. Heating was
continued for 20 min, during which time an additional 10 mL
aliquot of air was injected by syringe. Flash silica gel
chromatography of the reaction mixture with 1% THF in
hexane as eluent afforded 42.36 g (95.0% yield) of 13 as a
colorless liquid: TLC (hexane/ether 9/1) Rf ) 0.18; GLC tR 6.50
min; IR (NaCl, 10% in CH2Cl2) 1735 (vs); NMR (360 MHz,
CDCl3) δ 1.49 (m, 2H), 1.66 (m, 2H), 2.19 (m, 2H), 2.33 (t, 2H,
J ) 7.5 Hz), 3.67 (s, 3H), 5.92 (s, 2H), 6.02 (dt, 1H, J ) 15.7,
7.0 Hz), 6.29 (d, 1H, J ) 15.7 Hz), 6.73 (m, 2H), 6.88 (s, 1H);
MS 262 m/e (M+). Anal. Calcd for C15H18O4: C, 68.69; H, 6.92.
Found: C, 68.86; H, 7.10.
7-(3,4-Meth ylen ed ioxyp h en yl)-6-(E)-h ep ten ol 14. To a
magnetically stirred solution of 13 (5.79 g, 0.022 mol) in 100
mL of anhydrous THF under N2 at room temperature was
added portionwise lithium aluminum hydride (0.84 g, 0.022
mol). After 3 h, 4 mL of water was added dropwise followed
by anhydrous MgSO4 (20 g). After stirring for 3 h, the solids
were removed by suction filtration. The filtrate was evapo-
rated in vacuo to afford 5.87 g of crude alcohol product as an