Asymmetric Synthesis
FULL PAPER
trated in vacuo yielding a clear, colorless oil (2.77 g, 52%). The spectral
data were consistent with those reported in the literature.[21]
(R)-2-Isopropylamino-4-methoxy-1-methylpentane (2): Same procedure
as for the preparation of (S)-1-isopropylamino-3-methoxy-1-phenylpro-
pane, but with (R)-3-isopropylamino-4-methylpentanol. Yield 40% as a
clear colorless oil. B.p. 358C, 0.02 mbar; [a]2D0 =+14.08 (c=1.03 in di-
chloromethane); IR (thin film): n˜ =3340, 2959, 2931, 2872, 1465, 1380,
(R)-3-Amino-4-methylpentanol: The same procedure as for the prepara-
tion of (S)-3-amino-3-phenylpropanol was used, but with (R)-3-(N-tert-
butoxycarbonylamino)-4-methylpentanenitrile. Yield 64% as
a pale
1
1171, 1119 cmÀ1; H NMR (400 MHz, CDCl3): d=0.86 (d, J=6.6 Hz, 3H;
yellow oil. Spectral data were consistent with those reported in the litera-
ture.[22]
(CH3)2CH), 0.88 (d, J=6.6 Hz, 3H; (CH3)2CH), 1.01 (d, J=6.1 Hz, 3H;
(CH3)2CHN), 1.03 (d, J=6.1 Hz, 3H; (CH3)2CHN), 1.42 (m, 1H;
(CH3)2CH), 1.67 (m, 1H; CH2CH2O), 1.77 (m, 1H; CH2CH2O), 2.47 (m,
1H; CHCH2CH2O), 2.82 (septet, J=6.1 Hz, 1H; (CH3)2CHN), 3.33 (s,
3H; CH3O), 3.47 ppm (m, 2H; CH2O); 13C NMR (100 MHz, CDCl3): d=
17.8 ((CH3)2CH), 19.0 ((CH3)2CH), 23.5 ((CH3)2CHN), 24.1
((CH3)2CHN), 30.9 ((CH3)2CH), 31.7 (CH2CH2O), 46.7 ((CH3)2CHN),
57.5 (CHCH2CH2O), 58.8 (CH3O), 71.2 ppm (CH2O); HRMS (ESI+):
m/z calcd for C10H24NO: 174.1858; found: 174.1850.
(S)-3-Isopropylamino-3-phenylpropanol: The amino alcohol (S)-3-amino-
3-phenylpropanol (2.77 g, 18.3 mmol, 1.0 equiv) and acetone (10.63 g,
13.44 mL, 183 mmol, 10 equiv) were dissolved in benzene (125 mL) and
refluxed for six hours. The solution was allowed to cool to room tempera-
ture and concentrated in vacuo. The residue was dissolved in dry ethanol
(125 mL) and NaBH4 (1.38 g, 36.6 mmol, 2.0 equiv) was added. The mix-
ture was stirred overnight at room temperature. Water (50 mL) was
added and the ethanol removed under reduced pressure. The remaining
aqueous phase was extracted with dichloromethane (350 mL). The
combined organic extract was washed with brine (50 mL), dried over
Na2SO4, and concentrated in vacuo resulting in a white solid (3.48 g,
98%). M.p. 858C; [a]2D0 =À77.38 (c=0.99 in dichloromethane); IR (KBr):
n˜ =3262, 3196, 2971, 2926, 2864, 1490, 1452, 1384, 1178, 1055, 1035, 892,
Kinetics: Reaction vessels and syringes were thoroughly oven-dried
before use. THF, Et2O, hexane, and toluene were distilled from sodium
benzophenone and kept inside a glovebox. n-Decane, 1-hexanol and cy-
clohexene oxide were distilled from calcium hydride and kept inside a
glovebox. Stock solutions of cyclohexene oxide in n-decane (2.00m) and
1-hexanol in toluene (3.53 mm) were prepared inside the glovebox and
used in the experiments. The concentrations of the nBuLi (2.45m in
hexane) and the nBuNa suspension (0.53m in hexane) were determined
by employing double Gilman titrations.[23] GC analyses were carried out
by using a Varian Star 3400CXgas chromatograph equipped with a
chiral stationary-phase column (CP-Chirasil-DEXCB, 25 m, 0.32 mm)
from Chrompack. Analyses were performed using He (1.5 mLminÀ1) as
carrier gas (injector 2258C, detector 2508C).
761, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.00 (d, J=6.3 Hz, 3H;
;
(CH3)2CH), 1.09 (d, J=6.3 Hz, 3H; (CH3)2CH), 1.76 (m, 1H;
CH2CH2OH), 1.94 (m, 1H; CH2CH2OH), 2.63 (septet, J=6.3 Hz, 1H;
(CH3)2CH), 3.81 (m, 1H; PhCH), 3.91 (m, 2H; CH2OH), 7.23–7.38 ppm
(m, 5H; Ar); 13C NMR (100 MHz, CDCl3): d=21.7 ((CH3)2CH), 24.4
((CH3)2CH), 39.1 (CH2CH2OH), 45.5 ((CH3)2CH), 61.6 (PhCH), 63.5
(CH2OH), 126.4 (o-Ar), 127.5 (p-Ar), 128.9 (m-Ar), 143.5 ppm (i-Ar);
HRMS (ESI+): m/z calcd for C12H20NO: 194.1545; found: 194.1544.
Synthesis of n-butylsodium: Inside the glovebox sodium tert-butoxide
(1.5 g, 15.6 mmol, 1.0 equiv) was added to the reaction vessel equipped
with a magnetic stirring bar. Dry hexane (10 mL) was added and the
vessel sealed and taken out of the glovebox and cooled to 08C in an ice
bath. n-Butyllithium (2.45m in hexane, 12.49 mL, 31.2 mmol, 2.0 equiv)
was added dropwise through a septum, and the suspension was stirred for
one hour at 08C before being allowed to warm up to room temperature
and was then stirred for an additional 6 h. The resulting suspension was
centrifuged and the precipitate was washed with dry hexane (510 mL).
The precipitate was then suspended in hexane (10 mL) and transferred to
another airtight vessel and stored at À208C. The concentration of the
nNaBu suspension was determined to be 0.53m as evidenced from a
double Gilman titration.
(R)-3-Isopropylamino-4-methylpentanol: The same procedure as for the
preparation of (S)-3-isopropylamino-3-phenylpropanol was used, but
with (S)-3-amino-4-methylpentanol. Yield 86% as a clear colorless oil.
B.p. 60 8C, 0.05 mbar; [a]2D0 =+60.58 (c=1.01 in dichloromethane); IR
(thin film): n˜ =3274, 2961, 2870, 1466, 1382, 1370, 1171, 1076, 855,
678 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=0.84 (d, J=6.9 Hz, 3H;
(CH3)2CH), 0.93 (d, J=6.9 Hz, 3H; (CH3)2CH), 1.07 (d, J=6.1 Hz, 6H;
(CH3)CHN), 1.42 (m, 1H; CH2CH2OH), 1.52 (m, 1H; CH2CH2OH), 1.95
(m, J=4.2, 6.9 Hz, 1H; (CH3)2CH), 2.70 (m, 1H; CHCH2CH2OH), 2.96
(septet, J=6.1 Hz, 1H; (CH3)CHN), 3.79 (m, 1H; CH2OH), 3.86 ppm
(m, 1H; CH2OH); 13C NMR (100 MHz, CDCl3): d=16.3 ((CH3)2CH),
20.4 ((CH3)2CH), 22.4 ((CH3)2CHN), 22.5 ((CH3)2CHN), 28.9
((CH3)2CH),
29.7
(CH2CH2OH),
45.2
((CH3)2CHN),
61.8
Typical kinetic procedure: The chiral amine (0.20 mmol) was dissolved in
dry solvent (THF or Et2O), in amounts making the total volume of the
reaction 1 mL, in an airtight reaction vessel inside the glovebox. The re-
action vessel was sealed and taken out of the glovebox, placed under a
nitrogen atmosphere and the solution cooled to À788C in a dry ice/ace-
tone cooling bath. The nBuNa suspension was sonicated briefly in order
to make it homogenous and a portion (0.53m, 0.10 mmol) was withdrawn
by syringe. This homogenous suspension was then added dropwise to the
reaction vessel. The mixture was allowed to react for 5 min before nBuLi
(2.45m, 0.10 mmol) was added dropwise using a syringe. The mixture was
allowed to react for a further 5 min and then allowed to reach room tem-
perature, and was placed in a thermostat bath and equilibrated to 20.08C
for 5 min. The reaction was started by addition of a solution of cyclohex-
ene oxide (2.0m, 0.10 mmol) in n-decane (0.050 mL) with a syringe. Sam-
ples of the reaction mixture were quenched in hydrochloric acid (0.64m,
100 ml) at even intervals with a syringe and extracted with toluene
(500 ml) containing an internal standard of 1-hexanol (3.53 mm). The or-
ganic phases were transferred to vials and analysed by capillary gas chro-
matography.
(CHCH2CH2OH), 63.8 ppm (CH2OH); HRMS (ESI+): m/z calcd for
C9H22NO: 160.1701; found: 160.1703.
(S)-1-Isopropylamino-3-methoxy-1-phenylpropane (1): The amino alco-
hol (S)-3-isopropylamino-3-phenylpropanol (3.48 g, 18.0 mmol, 1.0 equiv)
dissolved in dry THF (50 mL) was added dropwise to a suspension of
NaH (60% in mineral oil, 0.94 g, 23.4 mmol, 1.3 equiv) in dry THF
(50 mL). The mixture was warmed at 508C for 1 h before being cooled to
room temperature. Methyl iodide (3.32 g, 1.46 mL, 23.4 mmol, 1.3 equiv)
dissolved in dry THF (10 mL) was added dropwise and the mixture al-
lowed to react overnight at room temperature. Water (50 mL) was added
and the mixture concentrated in vacuo. The remaining aqueous phase
was extracted with dichloromethane (350 mL) and the combined organ-
ic extract was washed with brine (50 mL), dried over Na2SO4, and con-
centrated in vacuo yielding a clear yellow oil. The product was purified
using flash chromatography on Al2O3 with ethyl acetate/hexane 1:4 as
eluent, followed by short-path distillation, yielding a clear colorless oil
(1.28 g, 34%). B.p. 758C, 0.07 mbar; [a]2D0 =À33.48 (c=1.00 in dichloro-
methane); IR (thin film): n˜ =3337, 2964, 2927, 2869, 1453, 1380, 1174,
1119, 702 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.97 (d, J=6.3 Hz, 3H;
;
NMR sample preparation: The solution studies of the lithium amides and
the mixed sodium/lithium amides were performed in deuterated Et2O
and THF solvents using 6Li-labeled nBuLi. The nBuNa suspension in
hexane (0.53m) was transferred to an NMR tube under N2 atmosphere.
The hexane was removed under reduced pressure and deuterated solvent
was added followed by rapid cooling of the sample at À788C.
(CH3)2CH), 1.02 (d, J=6.3 Hz, 3H; (CH3)2CH), 1.79 (m, 1H;
CH2CH2O), 2.00 (m, 1H; CH2CH2O), 2.59 (septet, J=6.3 Hz, 1H;
(CH3)2CH), 3.23 (m, 1H; CH2O), 3.29 (s, 3H; CH3O), 3.34 (m, 1H;
CH2O), 3.87 (t, J=7.0 Hz, 1H; PhCH), 7.23–7.35 ppm (m, 5H; Ar);
13C NMR (100 MHz, CDCl3): d=22.3 ((CH3)2CH), 24.5 ((CH3)2CH), 38.6
(CH2CH2O), 45.8 (CH3)2CH), 57.8 (PhCH), 58.8 (CH3O), 70.4 (CH2O),
127.1 (p-Ar), 127.3 (Ar), 128.6 (Ar), 144.5 ppm (i-Ar); HRMS (ESI+):
m/z calcd for C13H22NO: 208.1701; found: 208.1699.
NMR studies: All NMR spectra were recorded using a Varian Unity500
spectrometer equipped with three channels using 5 mm 13C, 6Li, or 1H
Chem. Eur. J. 2005, 11, 4785 – 4792
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4791