Badioli et al.
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of
Mor p h olin e Am id es. Syn th esis of (9Z,12Z)-1-Mor p h olin -
4-ylocta d eca -9,12-d ien -1-on e (17a ). To a mixture containing
5.0 mmol of linoleic acid and 25 mL of dry benzene was added
thionyl chloride (30 mL), and the mixture was stirred for 24 h
at 50 °C. The solvent and excess of thionyl chloride were
evaporated off under reduced pressure, and the residual acid
chloride was used in the next stage of preparation without
purification.
To a stirred solution of the acid chloride in 60 mL of EtOH-
free CHCl3 was added dry morpholine (0.48 g, 5.5 mmol) in
EtOH-free CHCl3 (1 mL). The mixture was cooled at 0 °C, and
pyridine (0.43 g, 5.5 mmol) was added dropwise via syringe.
Stirring was continued for 20 h at room temperature, and then
the mixture was evaporated under reduced pressure. The
residue was diluted with a 1:1 mixture of Et2O and CH2Cl2,
washed with brine containing sufficient 2 N HCl to remove
the amines, washed with saturated aqueous NaHCO3, and
dried over Na2SO4. After evaporation of solvent the crude
product was purified by flash chromatography (30% EtOAc/
hexane), affording 17a (88% yield) as a pale yellow oil: IR
(neat, cm-1) 3025, 1670, 1575; 1H NMR δ 0.92 (t, 3H, J ) 6.97
Hz), 1.15-1.37 (m, 14H), 1.58-1.70 (m, 2H), 1.96-2.10 (m,
4H), 2.31 (t, 2H, J ) 6.54 Hz), 2.75-2.85 (m, 2H), 3.40-3.51
(m, 2H), 3.53-3.67 (m, 6H), 5.25-5.40 (m, 4H); 13C NMR δ
18.95, 20.67, 24.65, 25.01, 25.96, 26.01, 26.76, 27.05, 27.80,
29.77, 30.05, 34.00, 42.60, 44.76, 46.92, 66.96, 127.04, 128.54,
131.26, 133.05, 170.96. Anal. Calcd for C22H39NO2: C, 75,59;
H, 11,25; N, 4,01. Found: C, 75,19; H, 11,35; N, 4,02.
R ea ct ion b et w een Mor p h olin e a n d Or ga n ocer iu m
Rea gen ts. A 250 mL three-neck flask fitted with septum and
gas inlet was charged with CeCl3‚7H2O (4.46 g, 12 mmol),
which was dried by heating to 140 °C at 0.2 Torr for 2 h.34
The flask was allowed to cool at room temperature and vented
to dry nitrogen, and THF (40 mL) was added from a syringe.
This slurry was stirred overnight at room temperature and
cooled to -78 °C. To this white suspension was added slowly
organomagnesium or organolithium compound (12 mmol) from
a syringe, and the reaction mixture was stirred for 2 h at -78
°C. A solution of morpholine amides (4 mmol) in THF (25 mL)
was added dropwise, and the reaction mixture was stirred for
1.5 h at -78 °C. Then, it was quenched by addition of 10%
aqueous acetic acid (90 mL) and extracted with Et2O (5 × 75
mL). The combined organic layers were washed with saturated
NaHCO3 and brine, dried over anhydrous Na2SO4, and con-
centrated to afford an oil. Purification by flash chromatography
on a silica gel column by a mixture of hexane/ethyl acetate
(8:2) as eluent afforded ketone in good yield.
EtOH (18 mL) was added to a solution of ketones 5a -c (2.25
mmol), and the mixture was stirred for 24 h until the formation
of tosylhydrazone was completed. Then, the reaction mixture
was evaporated to dryness under reduced pressure and washed
with pentane to give a crystalline product, which was used in
the next stage without purification. To tosylhydrazone in 4.5
mL of dry CH2Cl2 was added at 0 °C under N2 5.2 mL of 1 M
diisobutylaluminum hydride (DIBAL-H) in hexane. All the
tosylhydrazone was dissolved during DIBAL-H addition. Stir-
ring was continued for 30 min, and the solution was carefully
decomposed with 2.5 mL of 3 N aqueous NaOH and extracted
with pentane (4 × 40 mL). The organic layer was dried
(MgSO4), the solvent was removed by distillation, and the
crude product was purified by column chromatography (1%
ethyl acetate in petroleum ether) to give pure C-21 hydrocar-
bons 4a -c.
(6Z,9Z)-Hen icosa -6,9-d ien e (4a ): pale yellow oil (80%); IR
1
(neat, cm-1) 3009,1475; H NMR δ 0.90 (t, 6H, J ) 6.85 Hz),
1.24-1.40 (m, 24H), 2.03-2.09 (m, 4H), 2.92 (t, 2H, J ) 6.05),
5.29-5.36 (m, 4H); 13C NMR δ 14.60, 14.74, 21.04, 21.46, 23.22,
26.04, 26.10, 27.89, 29.72, 30.01, 30.15, 30.24, 32.51, 128.15,
128.84, 128.99, 132.68; EI-MS m/z 292 [M+], 99, 96, 81, 67
(100), 55, 43, 41. Anal. Calcd for C21H40: C, 86.21; H, 13.78.
Found: C, 86.19; H, 13.82.
(3Z,6Z,9Z)-Hen icosa -3,6,9-tr ien e (4b): pale yellow oil
(82%); IR (neat, cm-1) 3015, 1494; 1H NMR δ 0.88 (t, 3H, J )
6.63 Hz), 0.92 (t, 3H, J ) 6.19 Hz),1.25-1.42 (m, 18H), 2.01-
2.13 (m, 4H), 2.82 (t, 4H, J ) 6.05 Hz), 5.31-5.42 (m, 6H); 13
C
NMR δ 14.48, 14.75, 21.04, 21.37, 23.18, 26.01, 26.10, 27.74,
29.71, 29.84, 30.05, 30.14, 32.41, 36.06, 127.61, 128.10, 128.72,
128.77, 130.89, 132.42; EI-MS m/z 290 [M+], 99, 96, 85, 81, 67
(100), 55, 43, 41. Anal. Calcd for C21H38: C, 86.81; H, 13.18.
Found: C, 86.79; H, 13.15.
Hen icosa n e (4c): colorless oil (87%); 1H NMR δ 0.88 (t, 6H,
J ) 7.03 Hz), 1.25-1.39 (m, 38H); 13C NMR δ 14.10, 21.64,
23.76, 29.07, 29.25, 29.46, 29.79, 30.04, 32.02; EI-MS m/z 296
[M+], 267, 113, 99, 85, 71, 57 (100), 43, 41. Anal. Calcd for
C
21H44: C, 85,05; H, 14,95. Found: C, 85.08; H, 14.96.
Ack n ow led gm en t. Financial support from Fondazi-
one Cassa di Risparmio della Provincia di Macerata
(Italy) is gratefully acknowledged. The authors warmly
also thank University of Camerino and MIUR (Research
National Project “Stereoselection in Organic Synthesis.
Methodologies and Applications”) for the continued
financial support of their programs.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and spectral and analytical data of amides
12 and 17 and ketones 15. This material is available free of
Syn th esis of P h er om on es 4a -c. Typ ica l P r oced u r e. A
solution of (p-tolylsulfonyl)hydrazine (0.47 g, 2.5 mmol) in
(34) Imamoto, T.; Takeda, N. Org. Synth. 1998, 76, 228.
J O0263061
8942 J . Org. Chem., Vol. 67, No. 25, 2002