Synthesis of (-)-(2R,5S)-1-Allyl-2,5-dimethylpiperazine
distillation of this base and its enantiomers (see below) is
complicated by considerable foaming under the conditions
described below.
The procedure described above on a 2 mol scale has been
repeated numerous times and also using as much as 4 mol of
trans-2,5-dimethylpiperazine, with similar success.
aspirator vacuum (bp 85-90 °C/12-14 Torr) provided 76 g
(96%) of pure (-)-3 from the tartrate salt (41.8% from (()-3):
[R]D -57.1 (c 4.02, EtOH) (lit.7 [R]D -52.3 (c 2.5, EtOH)).
Optical purity was found to be >99% by HPLC of the urea
formed with 1-naphthyl isocyanate, as noted:7 1H NMR δ 5.84-
5.93 (m, 1H), 5.14-5.20 (m, 2H) 5.15 (s, 1H), 3.47 (ddd, 1H, J
) 3.3, 5.4, 13.8 Hz) 2.80-2.91 (m, 4H), 2.58 (dd, 1H, J ) 10.2,
12.3), 2.16-2.19 (m, 1H), 1.77 (dd, 1H, J ) 10.2, 12.3 Hz), 1.4
(br s, 1H), 1.05 (d, 3H, J ) 6.0 Hz), 1.02 (d, 3H, J ) 6.09 Hz);
MS (CI) m/z 155 (M + 1).
(2S,5R)-1-Allyl-4-benzyloxycarbonyl-2,5-dimethylpip-
erazine (8). A biphasic mixture of (+)-3 (32.7 g, 0.212 mol) in
CHCl3 (400 mL) and saturated NaHCO3 (400 mL) was cooled
to 0 °C, and benzyl chloroformate (33.3 mL, 0.233 mol) was
added slowly over a period of 5-10 min with vigorous stirring.
Stirring was continued for 4 h at rt. The layers were separated,
and the aqueous layer was extracted with CHCl3. The com-
bined organic extracts were dried over Na2SO4 and concen-
trated. Distillation (bp 167 °C/0.7 Torr) provided pure 8 (60.2
g, 98%) as a colorless viscous oil: 1H NMR δ 7.35 (s, 5H) 5.72-
5.88 (m, 1H) 5.08-5.24 (m, 4H) 4.22-4.36 (m, 1H) 3.75 (d,
1H, J ) 12.6 Hz) 3.35 (dd, 1H, J ) 3.9, 13.8 Hz) 3.07 (dd, 1H,
J ) 5.7, 13.8 Hz) 2.92-3.01 (m, 1H) 2.94 (dd, 1H J ) 6.9, 13.8
Hz) 2.64 (dd, 1H, J ) 3.9, 11.7 Hz) 2.31 (dd, 1H, J ) 1.8, 11.7
Hz) 1.26 (d, 3H, J ) 6.9 Hz) 0.92 (d, 3H, J ) 6.0 Hz); MS m/z
(CI) 289 (M + 1); [R]D -46.3 (c 2.9, EtOH). Anal. Calcd for
C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.71; H,
8.31; N, 9.47.
(2S,5R)-1-Methoxycarbonyl-4-benzyloxycarbonyl-2,5-
dimethylpiperazine (9). To a stirred solution of 8 (35.3 g,
0.122 mol) in 1,2-dichloroethane (350 mL) were added K2CO3
(17.0 g, 0.122 mol) and methyl chloroformate (20.0 mL, 0.26
mol). After the mixture had been refluxed for 15 h, additional
methyl chloroformate (20 mL, 0.26 mol) was added and
refluxing was continued for an additional 10 h. Upon cooling,
the mixture was filtered and concentrated. The residue was
dissolved in EtOAc, and the solution was washed with
saturated NaHCO3, 10% KHSO4, and brine and dried over Na2-
SO4. Removal of the solvent gave 9 (37.4 g, 100%) as a clear
light yellow oil. An analytical sample was prepared by passage
through a short column of silica gel (acetone/hexane, 1:1): 1H
NMR δ 7.32-7.42 (m, 5H) 5.08-5.22 (m, 2H) 4.18-4.52 (m,
2H) 3.60-3.85 (m, 5H) 3.18-3.34 (m, 2H) 1.10-1.22 (m, 6H);
MS m/z (CI) 307 (M + 1); [R]D +1.53 (c 5.4, EtOH). Anal. Calcd
for C16H22N2O4: C, 62.72; H, 7.24; N, 9.14. Found: C, 62.86;
H, 7.21; N, 9.02.
(2S,5R)-1-Methoxycarbonyl-2,5-dimethylpiperazine (10).
A solution of 9 (37.1 g, 0.121 mol) in absolute EtOH (150 mL)
was hydrogenated over 10% Pd/C (3.2 g) at 40 lb/in.2 for 14 h.
The catalyst was removed by filtration through Celite, and the
solvent was evaporated to give 10 as a clear and colorless oil
(20.3 g, 98%). An analytical sample was prepared by distilla-
tion (66-68 °C/0.5 Torr): 1H NMR δ 9.92 (br s, 1H) 4.52-
4.64 (m, 1H) 3.86 (d, 1H, J ) 14.6 Hz) 3.70-3.80 (m, 4H) 3.60
(dd, 1H, J ) 2.9, 14.6 Hz) 3.30 (dd, 1H, J ) 4.9, 12.7 Hz) 3.00
(d, 1H, J ) 14.6 Hz) 1.48 (t, 6H, J ) 6.8 Hz); [R]D +90.6 (c 7.7,
EtOH); HRMS (FAB) calcd for (M + H+) C8H16N2O2 173.1296,
found 173.1290.
trans-1,4-Diallyl-2,5-dimethylpiperazine‚2HBr (5‚2HBr).
The filtrate and washing from the preparation of the disucci-
nate salt of (()-3 were evaporated to a syrup and partitioned
between a mixture of NH4OH (180 mL), H2O (50 mL), and
CHCl3 (150 mL). The aqueous phase was extracted further
with CHCl3 (3×). The combined organic extracts were evapo-
rated to give the crude free base, which was dissolved in warm
acetone (600 mL). Upon addition of HBr (48%, 100 mL), the
dihydrobromide salt of 5 crystallized almost immediately. After
the mixture was cooled to rt and filtered, the crystalline
material was washed with acetone and dried to afford 135.0 g
(19%) of 5‚2HBr: mp 264-265 °C dec. Anal. Calcd for
C12H24N2Br2: C, 40.47; H, 6.79; N, 7.87. Found: C, 40.56; H,
6.73; N, 7.80.
(+)-(2S,5R)-1-Allyl-2,5-dimethylpiperazine [(+)-3]. Iso-
lation of (+)-3 through resolution with (+)-camphoric acid was
carried out in a manner similar to that outlined previously.7
(+)-Camphoric acid (118.0 g, 0.59 mol) was dissolved in hot
acetone (1 L), and (()-3 (181.7 g, 1.18 mol) in acetone (88 mL)
was added. The camphorate salt began crystallization from
the warm solution within 15 min. After being cooled to rt, the
mixture was filtered and the salt washed with acetone (5×).
This salt was recrystallized by dissolving it in hot MeOH (650
mL), adding acetone (1.3 L), and cooling to 15 °C. After being
washed with acetone (3×), the salt was recrystallized once
more from MeOH and acetone to yield 138.0 g (33% of the
theoretically possible 50%) of the (+)-3‚(+)-camphoric acid:
[R]D +47.7 (c 1.08, MeOH) (lit.7 [R]D +46.8 (c 1.0, MeOH)).
The salt (138.0 g, 0.39 mol) was partitioned between 15%
NaOH (300 mL) and CHCl3 (250 mL). The aqueous layer was
extracted with CHCl3 (4×), and the combined extracts were
evaporated. Purification by distillation at aspirator vacuum
(bp 85-95 °C/12-14 Torr) afforded 60 g (100%) of (+)-3 from
the camphorate salt (33% of the theoretically possible 50%
from (()-3): [R]D +58.2 (c 3.18, EtOH) (lit.7 [R]D +55.5 (c 1.4,
EtOH)).
(-)-(2R,5S)-1-Allyl-2,5-dimethylpiperazine [(-)-3]. All
of the filtrates and washings from the initial crystallization
and recrystallizations of (+)-3‚(+)-camphoric acid were com-
bined and evaporated. To remove residual acetone, toluene
(200 mL) was added and removed under reduced pressure. A
solution of NaOH (26.0 g) in H2O (140 mL) was added, and
the solution (pH g13) was extracted with CHCl3. After
separation of the phases, the aqueous layer was further
extracted with CHCl3 (3×). The combined organic extracts
were evaporated to give 113.0 g (0.733 mol) of mixed bases
enriched in (-)-3. These mixed bases were dissolved together
with (+)-tartaric acid (220.5 g, 1.47 mol) in hot MeOH (670
mL). The tartrate salt crystallized rapidly in 10-15 min from
the hot solution. After being cooled to rt, the solids were
filtered and washed with MeOH (3×), MeOH/acetone (1:1, 2×),
and petroleum ether (2×). After the solids were dried in vacuo,
270.0 g of the tartrate salt of (-)-3 was obtained. This salt
was dissolved by portionwise addition to warm DMF (up to
100 °C, 200 mL) and then diluted with MeOH (800 mL),
whereupon crystallization occurred. After being cooled to rt,
the crystalline material was collected by filtration and washed
with MeOH (3×), MeOH/acetone (1:1, 3×), and petroleum
ether (2×). After the material was dried in vacuo, 250.0 g (87%)
of (-)-3‚2(+)-tartaric acid salt containing 1 mol of MeOH was
obtained: mp 119-121 °C (softens), 148-150 °C dec. Anal.
Calcd for C17H30N2O12‚CH3OH: C, 44.44; H, 7.05; N, 5.76.
Found: C, 44.11; H, 6.96; N, 5.83. The salt was partitioned
between 15% NaOH (600 mL) and CHCl3 (300 mL). The
aqueous portion was extracted with CHCl3 (4×), and the
combined organic extracts were evaporated. Distillation at
(2S,5R)-1-Methoxycarbonyl-4-allyl-2,5-dimethylpiper-
azine (11). To a mixture of 10 (20.3 g, 0.118 mol) and Na2-
CO3 (12.7 g, 0.120 mol) in THF (250 mL) was added freshly
distilled allyl bromide (10.4 mL, 0.120 mol) dropwise at 0 °C
over a period of 5-10 min. Stirring was continued for 8-10 h
at rt. After the mixture was filtered, the solvent was removed
in vacuo and the residue was dissolved in CHCl3. The CHCl3
solution was washed with saturated NaHCO3 and brine, dried
over Na2SO4, and concentrated to give 11 (23.8 g, 95%) as a
yellow oil. An analytical sample was prepared by distillation
(69-70 °C/0.44 Torr): 1H NMR δ 5.74-5.89 (m, 1H) 5.20 (dd,
1H, J ) 2.0, 17.6 Hz) 5.12 (d, 1H, J ) 9.8 Hz) 4.18-4.30 (m,
1H) 3.65-3.72 (m, 4H) 3.34 (dd, 1H, J ) 3.9, 12.7 Hz) 3.08
(dd, 1H, J ) 5.8 Hz, 13.6 Hz) 2.95 (dd, 2H, J ) 6.8, 13.6 Hz)
J. Org. Chem, Vol. 68, No. 10, 2003 3979