S. Arrasate et al. / Tetrahedron: Asymmetry 12 (2001) 2077–2082
2081
dried over Na SO . Evaporation of the solvent followed
NH), 3.45–3.53 (m, 1H, CH
6
CH NH), 3.83 (s, 3H,
2
4
3
by purification by column chromatography (silica gel,
0% hexane/AcOEt) gave (S)-N-(1-butylbenzyl)-N-(4-
OCH ), 6.61 (d, J=9.1 Hz, 2H, Harom), 6.87 (d,
3
3
J=9.1 Hz, 2H, Harom), 7.27–7.38 (m, 5H, Harom);
3
a
13
methoxyphenyl)amine (3b), as an oil (61 mg, 95%):
C NMR (CDCl ) 20.7, 32.4, 38.7, 48.7, 55.6, 114.6,
3
2
D 2 2 3
0
1
[
1
h] =−1.9 (c=1.2, CH Cl ); H NMR (CDCl ) 1.05–
114.8, 125.7, 128.2, 128.3, 141.6, 141.9, 151.7; MS(EI)
m/z (rel. intens.): 257 (5), 256 (33), 255 (M , 76), 240
(11), 150 (100), 134 (5), 122 (6), 108 (7), 104 (28), 91
(25), 89 (8), 73 (59), 65 (5), 59 (48). The enantiomeric
excess was determined by CSP HPLC to be 23% (Chi-
+
.11 (m, 3H, CH ), 1.43–1.53 (m, 4H, CH -CH
6
-CH2
6 -
3
2
2
CH ), 1.93–1.96 (m, 2H, CH6 -CH -CH -CH ), 3.81 (s,
3
2 2 2 3
3H, OCH ), 4.08 (s, 1H, NH), 4.42 (t, J=6.7 Hz, 1H,
3
CHN), 6.67 (d, J=8.9 Hz, 2H, Harom), 6.87 (d, J=8.9
13
Hz, 2H, Harom), 7.3–7.5 (m, 5H, Harom) C NMR
CDCl ) 13.8, 22.4, 28.3, 38.4, 55.4, 58.9, 114.4, 114.6,
ralcel OD, 2% hexane/2-propanol, 0.5 mL/min) t (R)=
r
(
3
2
3.6 (61.5%) min; t (S)= 26.6 min (38.5%).
r
1
26.3, 126.6, 128.3, 141.6, 144.4, 151.7; MS(EI) m/z
+
(
1
rel. intens.): 269 (M , 19), 213 (16), 212 (100), 134 (6),
23 (7), 108 (8), 91 (23). The e.e. was determined by
4
1
.5. (−)-Sparteine mediated addition of RLi to imine
0. Synthesis of phenethylamines 11
CSP HPLC to be 14% (Chiralcel OD, 3% hexane/2-
propanol, 0.6 mL/min) t (R)=11.0 min (57%); t (S)=
r
r
A solution of RLi (3.5 mmol) was added to a cold
solution of (−)-sparteine (0.94 mL, 4.1 mmol) in Et O
12.0 min (43%).
2
(
16 mL), and the mixture was stirred at −78°C for 30
4
.3. Synthesis of (−)-(1R,2S)-N,O-dimethylephedrine 7
min. A solution of imine 8, immediately prepared from
homoveratraldehyde (285 mg, 1.6 mmol) and p-ani-
sidine (195 mg, 1.6 mmol) in the presence of Na SO , in
(
−)-(1R,2S)-Methylephedrine (841 mg, 4.7 mmol) was
2
4
added to a suspension of NaH (468 mg, 18.7 mmol) in
THF (60 mL) and the mixture was stirred at rt for 2 h.
MeI (0.3 mL, 5.2 mmol) was added and the resulting
mixture was stirred for 4 days. Water was added and
Et O (16 mL) was transferred via cannula, and the
2
resulting solution was stirred at this temperature for 2
h. The reaction was quenched by addition of water, and
allowed to warm to rt. The mixture was separated,
extracted with Et O (3×10 mL) and the combined
organic layers were washed with brine and dried over
the mixture was separated, extracted with Et O (3×20
mL) and the combined organic layers were washed with
brine and dried over Na SO . Evaporation of the sol-
vent followed by purification by column chromatogra-
phy (silica gel, AcOEt) gave aminoether 7, as a yellow
oil (844 mg, 93%): [h] =−60.0 (c=7.7, CH Cl ); H
NMR (CDCl ) 0.94 (d, J=6.7 Hz, 3H, CHCH
2
2
2
4
Na SO . Evaporation of the solvent followed by purifi-
2
4
cation by column chromatography (silica gel, 60% hex-
ane/AcOEt) gave amines 11a and 11b. (−)-(R)-N-[2-
(3,4-Dimethoxyphenyl)-1-butylethyl]-N-(4-methoxy-
phenyl)amine 11a (65 mg, 12%): [h] =−23.2 (c=0.3,
CHCl ); H NMR (CDCl ) 0.88 (t, J=6.9 Hz, 3H,
2
0
1
D
2
2
6
3), 2.29
CH ), 3.17 (s,
3
2
0
(
s, 6H, N(CH
6
) ), 2.55–2.65 (m, 1H, CH
6
3
2
3
D
1
3
7
5
H, OCH ), 4.33 (d, J=3.2 Hz, 1H, CHOCH ), 7.13–
3
3
3
3
1
3
.29 (m, 5H, Harom); C NMR (CDCl ) 7.5, 41.4,
CH CH CH CH
6
), 1.26–1.54 (m, 6H, CH2
6
CH CH
6
6
2-
CH ), 2.75–2.78 (m, 2H, CH6 CHN), 3.21 (broad s, 1H,
3 2
3
2
2
2
3
2
6.3, 64.8, 83.9, 126.3, 126.7, 127.8, 140.7; MS(EI) m/z
(
8
5
rel. intens.): 149 (13), 97 (6), 91 (12), 87 (11), 85 (63),
3 (100), 72 (47), 71 (12), 69 (12), 58 (9), 57 (9), 56 (9),
5 (17).
NH
6 ), 3.51–3.57 (m, 1H, CH CH6 N), 3.75 (s, 3H,
2
OCH ), 3.82 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 6.54–
3
3
3
6
6
2
1
.59 (m, 2H, Harom), 6.64–6.67 (m, 2H, Harom), 6.71–
13
.80 (m, 3H, Harom); C NMR (CDCl 14.1, 22.7,
3
4
.4. Addition of MeLi to imine 8 mediated by 7.
8.3, 33.8, 39.3, 54.4, 55.8, 55.8, 111.0, 112.9, 114.6,
Synthesis of (R)-9
15.0, 121.5, 131.1, 141.9, 147.4, 148.6, 151.7; MS(EI)
+
m/z (rel. intens.): 343 (M ), 193 (13), 192 (100), 149 (8),
A solution of MeLi (1.6 mL of a 1.4 M solution in
Et O, 2.2 mmol) was added to a cold solution of (−)-7
1
6
36 (11). The e.e. was determined by CSP HPLC to be
7% (Chiralcel OD, 5% hexane/2-propanol, 0.7 mL/
2
(
194 mg, 1 mmol) in Et O (11 mL), and the mixture
2
min) t (R)=16.6 (83.3%) min; t (S)=18.4 min (16.7%).
r
r
was stirred at −90°C for 30 min. A solution of imine 8,
freshly prepared from 3-phenylpropionaldehyde (0.15
mL, 1.1 mmol) and p-anisidine (137 mg, 1.1 mmol) in
(
(
−)-(R)-N-[2-(3,4-Dimethoxyphenyl)-1-methylethyl]-N-
4-methoxyphenyl)amine 11b (12 mg, 8%, 34% conver-
Et O (11 mL) was added and the resulting solution was
2
20
D
1
sion):%): [h] =−3.5 (c=0.3, CHCl3);
H NMR
stirred at this temperature for 1 h. The reaction was
quenched by addition of MeOH (10 mL), and allowed
to warm to rt. The mixture was separated, extracted
with Et O (3×10 mL) and the combined organic layers
were washed with brine and dried over Na SO . Evapo-
ration of the solvent followed by purification by
column chromatography (silica gel, 20% hexane/
AcOEt) gave (R)-N-(4-methoxyphenyl)-N-(1-methyl-3-
(CDCl ) 1.18 (d, J=6.3 Hz, 3H, CH ), 2.71 (dd, J=9.2,
3
3
1
CH
3
6
4
1
3 Hz, 1H, CH H
6
bCHN), 3.14 (dd, J=6.6, 13 Hz, 1H,
a
6
H CHN), 3.61–3.68 (m, 1H, CH CH
6
N), 3.76 (s,
a
b
2
2
H, OCH ), 3.83 (s, 3H, OCH ), 3.85 (s, 3H, OCH ),
3
3
3
2
4
13
.65–6.84 (m, 7H, Harom); C NMR (CDCl ): 20.3,
3
1.7, 50.4, 55.8, 55.9, 111.1, 112.8, 114.9, 115.2, 121.5,
31.0, 141.3, 147.5, 148.7, 152.1; MS(EI) m/z (rel.
+
6
intens.): 301 (M , 2), 151 (14), 150 (100), 135 (5), 119
(3), 108 (4), 77 (4). The enantiomeric excess was deter-
mined by CSP HPLC to be 66% (Chiralcel OD, 4%
hexane/2-propanol, 1 mL/min) t (R)=24.8 (83%) min;
tr(S)=26.7 min (17%).
phenylpropyl)amine 9 as a yellow oil (148 mg, 52%):
2
D 2 2 3
0
1
[
(
h] =−9.1 (c=1.2, CH Cl ); H NMR (CDCl ) 1.28
d, J=6.3 Hz, 3H, CH3), 1.75–1.89 (m, 1H,
H CHNH), 1.92–2.03 (m, 1H, CH HbCHNH),
CH
6
6
a
b
a
r
2.82 (t, J=7.7 Hz, 2H, CH
6
CH CHNH), 3.18 (s, 1H,
2
2