ꢀ
Mangas-Sanchez et al.
JOCArticle
yield): Rf (CH2Cl2/MeOH/NH3 96/4/0.4) 0.17; 1H NMR
(MeOD, 300.13 MHz) δ 1.41 (d, 3H, 3JHH = 6.8 Hz, H1), 3.81
heated to 100 °C for 12 h. NaOH 3 N was added until basic pH
and the mixture extracted with CH2Cl2 (3 ꢀ 15 mL). The organic
layers were combined and dried under Na2SO4, and the solvent
was evaporated under reduced pressure. The reaction crude was
purified by flash chromatography on silica gel (CH2Cl2/MeOH/
NH3 96/4/0.4), affording (S)-8 as a yellow oil (59% isolated
yield): Rf (CH2Cl2/MeOH/NH3 96/4/0.4) 0.38; 1H NMR
(s, 3H, H9), 4.04 (q, 1H, 3JHH = 6.8 Hz, H2), 6.82 (ddd, 3JHH
=
8.3 Hz, 4JHH = 2.3 Hz, 4JHH = 1.0 Hz, H6), 6.94-6.97 (m, 2H,
H4þH8), 7.26 (t, 1H, 3JHH = 8.3 Hz, H7); 13C NMR (MeOD,
75.5 MHz) δ 25.6 (C1), 52.7 (C2), 56.1 (C9), 113.0 (C4), 113.9
(C6), 119.6 (C8), 131.1 (C7), 150.0 (C3), 161.8 (C5); [R]20
-13.6 (c = 0.74, MeOH) for >99% ee.
=
D
3
(CDCl3, 300.13 MHz) δ 1.38 (d, 3H, JHH = 6.6 Hz, H1), 2.22
Synthesis of N-[1-(3-Methoxyphenyl)ethyl]acetamide (6a). To
a solution of racemic amine 5 (37.2 mg, 0.25 mmol) in dry
CH2Cl2 (1.6 mL) was added pyridine (24.8 μL, 0.31 mmol)
under nitrogen atmosphere. The resulting solution was cooled
to 0 °C, and acetyl chloride (43.8 μL, 0.62 mmol) was carefully
added. The mixture was allowed to warm to room temperature
and stirred for an additional 14 h until no starting material was
detected by TLC analysis. The organic solvent was evaporated
under reduced pressure and the reaction crude purified by flash
chromatography on silica gel (80% EtOAc/hexane), isolating
the amide (()-6a as an orange oil (85% isolated yield): Rf (80%
EtOAc/hexane) 0.26; 1H NMR (MeOD, 300.13 MHz) δ 1.45 (d,
3JHH = 7.1 Hz, 3H, H1), 1.99 (s, 3H, H11), 3.82 (s, 3H, H9), 5.00
(s, 6H, H10), 3.24 (q, 1H, 3JHH = 6.6 Hz, H2), 3.80 (s, 3H, H9),
6.78 (ddd, 1H, 3JHH = 8.1 Hz, 3JHH = 2.4 Hz, 3JHH = 0.9 Hz,
3
H6), 6.89-6.87 (m, 2H, H4 þ H8), 7.22 (t, 1H, JHH = 8.1 Hz,
H7); 13C NMR (CDCl3, 75.5 MHz) δ 20.2 (C1), 43.1 (C10), 55.1
(C9), 66.1 (C2), 112.4 (C4), 112.9 (C6), 119.9 (C8), 129.1 (C7),
145.2 (C3), 159.5 (C5); [R]20 = -43.6 (c = 1, MeOH) for
>99% ee.
D
Route B. To a solution of (S)-5 (95.3 mg, 0.63 mmol) in
CH2Cl2 (7.9 mL) were successively added a 37% aqueous
solution of formaldehyde in water (142 μL, 1.89 mmol), Na2SO4
(30 mg), and sodium triacetoxyborohydride (802 mg,
3.78 mmol). The mixture was stirred during 17 h at room
temperature until no starting material was detected by TLC
analysis (CH2Cl2/MeOH/NH3 96/4/0.4), a saturated aqueous
solution of sodium bicarbonate was added until pH 8-9, and
the mixture was extracted with CH2Cl2 (5 ꢀ 10 mL). The organic
phases were combined and dried over Na2SO4, the desiccant
agent was filtered off, and the solvent was evaporated under
reduced pressure, obtaining a crude that was purified by flash
chromatography on silica gel (CH2Cl2/MeOH/NH3 96/4/0.4),
affording (S)-7 as a yellow oil (67% isolated yield).
Synthesis of (S)-3-[1-(Dimethylamino)ethyl]phenol (8). A 48%
solution of HBr in water was added over (S)-7 (135 mg, 0.75
mmol)ina sealed tube. The reactionwasheatedat 100°C for 10h.
After this time, HBr was evaporated, and an aqueous K2CO3
saturated solution was added until basic pH. The resulting
mixture was extracted with EtOAc (3 ꢀ 15 mL), the organic
layers were combined, filtered, and dried over Na2SO4, and the
solvent was evaporated under reduced pressure. The crude was
finally purified by flash chromatography on silica gel (CH2Cl2/
MeOH/NH3 96/4/0.4), affording (S)-8 (69% isolated yield): Rf
(q, 3JHH = 7.1 Hz, 1H, H2), 6.82 (ddd, 3JHH = 8.2 Hz, 4JHH
=
2.6 Hz, 4JHH = 1.0 Hz, 1H, H6), 6.93-6.91 (m, 2H, H4 þ H8),
7.26 (t, 3JHH = 8.2 Hz, 1H, H7); 13C NMR (MeOD, 75.5 MHz)
δ 22.9 (C1), 23.1 (C11), 50.6 (C2), 56.1 (C9), 113.5 (C4), 113.8 (C6),
119.8 (C8), 131.0 (C7), 147.3 (C3), 161.8 (C5), 172.0 (C10).
Synthesis of 2-Methoxy-N-[1-(3-methoxyphenyl)ethyl]acet-
amide (6b). To a solution of racemic amine 5 (37.2 mg, 0.25
mmol) in dry CH2Cl2 (1.6 mL) was added pyridine (24.8 μL, 0.31
mmol) under nitrogen atmosphere. The resulting solution was
cooled to 0 °C, and methoxyacetyl chloride (56.3 μL, 0.62 mmol)
was carefully added. The mixture was allowed to warm to room
temperature and stirred for an additional 4 h until no starting
material was detected by TLC analysis. The organic solvent was
evaporated under reduced pressure and the reaction crude
purified by flash chromatography (80% EtOAc/hexane), isolat-
ing the corresponding amide (()-6b as a pale yellow solid (62%
isolated yield): Rf (80% EtOAc/hexane) 0.29; 1H NMR (MeOD,
3
300.13 MHz) δ 1.51 (d, JHH = 7.1 Hz, 3H, H1), 3.44 (s, 3H,
H12), 3.82 (s, 3H, H9), 3.93 (d, 2JHH = 2.0 Hz, 2H, H11), 5.09 (q,
3JHH = 7.1 Hz, 1H, H2), 6.83 (ddd, 3JHH = 8.1 Hz, 4JHH = 2.5
Hz, 4JHH = 0.8 Hz, 1H, H6), 6.96-6.93 (m, 2H, H4þH8), 7.26 (t,
3JHH = 8.1 Hz, 1H, H7); 13C NMR (MeOD, 75.5 MHz) δ 22.6
(C1), 50.2 (C2), 56.1 (C9), 60.0 (C12), 73.2 (C11), 113.5 (C4), 114.0
(C6), 119.9 (C8), 131.1 (C7), 147.0 (C3), 161.9 (C5), 172.0 (C10).
Typical Procedure for the Enzymatic Kinetic Resolution of
1-(3-Methoxyphenyl)Ethanamine (()-5. To a suspension of race-
mic amine 6 (50 mg, 0.33 mmol) and CAL-B (100 mg) in dry
TBME (3.3 mL) was added ethyl acetate (97 μL, 0.99 mmol)
under nitrogen atmosphere. The reaction was shaken at 30 or
45 °C and 250 rpm, taking regularly aliquots that were analyzed
by HPLC until around 50% conversion was reached (19 h for
45 °C or 27 h for 30 °C). Then the reaction was stopped and
the enzyme filtered with CH2Cl2 (5 ꢀ 1 mL). The solvent was
evaporated and the crude of the reaction purified by flash
chromatography (CH2Cl2/MeOH/NH3 96/4/0.4) affording
(CH2Cl2/MeOH/NH3 96/4/0.4) 0.15; H NMR (CDCl3, 300.13
1
MHz) δ 1.40 (d, 3H, 3JHH = 6.8 Hz, H1), 2.23 (s, 6H, H10), 3.34
(c, 1H, 3JHH = 6.8, H2), 6.74 (m, 3H, H4 þ H6 þ H8), 7.12 (t, 1H,
3JHH = 7.9, H7), 8.47 (s, 1H, H9); 13C NMR (CDCl3, 75.5 MHz)
δ 21.5 (C1), 45.0 (C10), 68.1 (C2), 117.6 (C4), 117.8 (C6), 121.8
(C8), 131.8 (C7), 145.4 (C3), 159.6 (C5); [R]20D = -36.1 (c = 1,
EtOH) for >99% ee.
Synthesis of (S)-3-[1-(Dimethylamino)ethyl]phenyl Ethyl-
(methyl)carbamate (Rivastigmine, 1a). To a suspension of Na-
HCO3 (1.31 g, 13.5 mmol) in dry CH2Cl2 (6 mL) under N2
atmosphere was added triphosgene (1.33 g, 4.50 mmol), and the
mixture was cooled to 10 °C under stirring. Then N-ethylmethy-
lamine (580 μL, 6.80 mmol) was added at 10 °C over 2 h. The
reaction was allowed to reach room temperature and was
stirred for an additional 3 h. After this time, the reaction mixture
was filtered to remove NaCl and the solvent of the reaction
filtrate removed by distillation at reduced pressure to give
800 mg of N-ethyl-N-methylcarbamoyl chloride as a crude that
was employed for the next step without further purification.
Over a solution of (S)-(-)-3-[1-(dimethylamino)ethyl]phenol
(33 mg, 0.20 mmol) in dry CH2Cl2 under N2 atmosphere and
at 0 °C were added sodium hydride (20 mg, 0.40 mmol)
and N-ethyl-N-methylcarbamoyl chloride (49 mg, 0.40 mmol).
The suspension was allowed to reach room temperature and was
stirred for 4 h. After this time, the reaction was carefully stopped
with H2O (1 mL) and extracted with CH2Cl2 (3 ꢀ 5 mL),
the organic phases were combined and dried over Na2SO4,
and the solvent was removed under reduced pressure to
afford a crude that was purified by flash chromatography
(S)-(-)-5 [34% isolated yield and 97.5% ee, [R]20 = -13.6
D
(c = 0.74, MeOH)]18 and (R)-(þ)-6a [43% isolated yield and
>99% ee, [R]20D = þ166.13 (c = 1, CHCl3)]. See Table 3.
Synthesis of (S)-1-(3-Methoxyphenyl)-N,N-dimethylethan-
amine (7). Route A. To a solution of (S)-5 (240 mg, 1.58 mmol)
in formic acid (2.4 mL) was added a 37% solution of formaldehyde
in water (1.84 mL, 22.22 mmol), and then the mixture was
(18) (a) Mereyala, H. B.; Koduru, S. R.; Cheemalapati, V. N. Tetrahe-
dron: Asymmetry 2006, 17, 259–267: [R]20D = -18.1 (c = 2, MeOH) . (b) Hu,
M.; Zhang, F.-L.; Xie, M.-H. Lett. Org. Chem. 2007, 4, 126–128:
[R]20D = -18.8 (c = 1, EtOH) .
J. Org. Chem. Vol. 74, No. 15, 2009 5309