Skupinska et al.
Resolu tion of 1f. Following the general procedure, 3,4-
dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (1f) (243 mg, 1.62
mmol), CALB (73 mg), and EtOAc (6.0 mL) were stirred for 2
Resolu tion of 1j. Following the general procedure, 6,7,8,9-
tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (1j) (195 mg,
1.20 mmol), CALB (59 mg), EtOAc (0.48 mL), and Pr2O (4.6
i
1
h. The conversion determined from H NMR by integration of
mL) were stirred for 24 h. The conversion determined from
1H NMR by integration of the peaks at 5.05 ppm (CHNHAc)
and 4.34 ppm (CHNH2) was 58%. Flash chromatography of
the material on silica gel using 1:10 MeOH-CH2Cl2 followed
by 1:1:4 NH4OH-MeOH-CH2Cl2 furnished the (R)-N-(6,7,8,9-
tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetamide ((R)-2j) (134
mg, 55%) in 45% ee (chiral GC method: 180 °C for 15 min,
ramp rate of 10 °C/min to 210 °C, hold 10 min, tR(S) ) 17.4
the peaks at 7.93 and 8.16 ppm was 50% (CHNH2 and
CHNHAc signals were not distinct). Flash chromatography of
the material on silica gel using 1:10 MeOH-CH2Cl2 followed
by 1:1:10 NH4OH-MeOH-CH2Cl2 furnished (R)-N-(3,4-dihy-
dro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide ((R)-2f) (145 mg,
47%) in 98% ee (chiral GC method: 140 °C for 16 min, ramp
rate 5 °C/min to 160 °C, hold at 160 °C for 50 min, tR(S) )
41.5 min, tR(R) ) 40.9 min); [R]D ) -69 (c 1.45, CHCl3); 1H
NMR δ 1.91-2.00 (m, 1H), 1.97 (s, 3H), 2.47-2.57 (m, 1H),
4.18-4.22 (m, 2H), 4.85-4.92 (m, 1H), 6.97 (m, 2H), 7.24 (br
s, 1H), 7.93-7.95 (dd, 1H, J ) 1.8, 3.9 Hz); 13C NMR δ 23.3,
28.9, 47.2, 64.4, 124.3, 124.7, 141.3, 141.7, 152.0, 170.9; MS
m/z 215 (M + Na+). The unreacted (S)-3,4-dihydro-2H-pyrano-
[3,2-b]pyridin-4-ylamine ((S)-1f) was isolated in 43% yield (104
1
min, tR(R) ) 17.1 min); [R]D ) -10 (c 1.34, CHCl3); H NMR
δ1.09-1.31 (m, 2H), 1.80-2.03 (m, 3H), 2.06 (s, 3H), 2.24 (d,
1H, J ) 13.5 Hz), 2.65-2.71 (m, 1H), 2.75-2.85 (m, 1H), 4.96-
5.01 (m, 1H), 7.06 (dd, 1H, J ) 7.0, 4.8 Hz), 7.38 (d, 1H, J )
7.0 Hz), 8.11 (br s, 1H), 8.28 (d, 1H, J ) 4.8 Hz); 13C NMR δ
24.0, 27.3, 30.1, 34.5, 34.8, 53.8, 122.8, 137.0, 137.5, 145.5,
159.2, 169.6; MS m/z 205 (M + H+). The unreacted (S)-6,7,8,9-
tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine ((S)-1j) was iso-
lated in 41% yield (81 mg) and 61% ee (chiral GC, tR(S) ) 5.81
min, tR(R) ) 6.00 min); [R]D ) +2 (c 1.13, CHCl3); and
displayed spectra identical to the starting material: 1H NMR
δ 1.20-1.35 (m, 1H), 1.36-1.53 (m, 1H), 1.75-2.01 (m, 4H),
2.15 (br s, 2H), 2.69-2.77 (m, 2H), 4.16 (d, 1H, J ) 8.7 Hz),
6.95-7.06 (m, 1H), 7.32 (d, 1H, J ) 6.0 Hz), 8.34 (br s, 1H).
mg) and 99% ee (tR(S) ) 14.7 min, tR(R) ) 15.6 min); [R]D
)
-13 (c 0.72, CHCl3) and displayed spectra identical with those
of the starting material.
Resolu tion of 1g. Following the general procedure, 2-meth-
yl-5,6,7,8-tetrahydroquinolin-8-ylamine (1g) (412.7 mg, 2.78
i
mmol), CALB (128 mg), EtOAc (0.63 mL), and Pr2O (7 mL)
1
were stirred for 9 h. The conversion determined from H NMR
Resolu tion of 1k . Following the general procedure, 4,5,6,7-
tetrahydrobenzofuran-7-ylamine (1k ) (150 mg, 1.09 mmol),
CALB (45 mg), EtOAc (0.43 mL), and Pr2O (4.0 mL) were
by integration of the peaks at 4.73 ppm (CHNHAc) and 4.00
ppm (CHNH2) was 51%. Flash chromatography of the material
on silica gel using 1:10 MeOH-CH2Cl2 then 10:1:1 CH2Cl2-
MeOH-NH4OH furnished (R)-N-(2-methyl-5,6,7,8-tetrahyd-
roquinolin-8-yl)acetamide2 ((R)-2g) (167 mg, 47%) in 88% ee
(chiral GC method: initial temperature 140 °C, initial time
22 min, ramp rate 1 °C/min, final temperature 150 °C, final
time 70 min, tR(S) ) 89.4 min, tR(R) ) 91.6 min); [R]D ) -102
(c 1.67, CHCl3). The unreacted (S)-2-methyl-5,6,7,8-tetrahy-
droquinolin-8-ylamine ((S)-1g) was isolated in 38% yield (107
mg) and 91% ee (chiral GC: tR(S) ) 19.9 min, tR(R) ) 20.6
min); [R]D ) +65 (c 1.07, CHCl3);1H NMR δ 1.62-1.82 (m, 2H),
1.84-2.00 (m, 3H), 2.11-2.20 (m, 1H), 2.49 (s, 3H), 2.61-2.82
(m, 2H), 3.93-4.00 (m, 1H), 6.91 (d, 1H, J ) 7.8 Hz), 7.25 (d,
1H, J ) 7.8 Hz); 13C NMR δ 20.4, 24.6, 29.1, 32.6, 51.8, 121.7,
128.6, 137.6, 155.9, 159.0; MS m/z 163 (M + H+), 146 (M -
NH2).
i
stirred for 17 h. The conversion determined from 1H NMR by
integration of the peaks at 5.09 ppm (CHNHAc) and 3.95 ppm
(CHNH2) was 55%. Flash chromatography of the material on
silica gel using 1:20 MeOH-CH2Cl2 followed by 1:1:4 NH4OH-
MeOH-CH2Cl2 furnished (R)-N-(4,5,6,7-tetrahydrobenzofu-
ran-7-yl)acetamide ((R)-2k ) (104 mg, 53%) in 79% ee (chiral
GC method: 120 °C for 15 min, ramp rate of 2 °C/min to 160
°C, hold 20 min at 160 °C, tR(S) ) 43.6 min, tR(R) ) 45.8 min);
[R]D ) +58 (c 1.04, CHCl3); 1H NMR δ 1.65-1.86 (m, 3H),
1.90-1.2.04 (m, 1H), 1.94 (s, 3H), 2.30-2.50 (m, 2H), 5.01-
5.05 (m, 1H), 6.07 (br s, 1H), 6.16 (s, 1H), 7.24 (s, 1H); 13C
NMR δ 20.6, 22.4, 23.6, 31.0, 43.6, 110.7, 120.9, 142.2, 148.8,
170.1; MS m/z 180 (M + H+). The unreacted (S)-4,5,6,7-
tetrahydrobenzofuran-7-ylamine ((S)-1k ) was isolated in 39%
yield (59 mg) and 94% ee (chiral GC, tR(S) ) 12.6 min, tR(R) )
13.5 min); [R]D ) -18 (c 0.59, CHCl3).
Resolu tion of 1i. Following the general procedure, 6,7-
dihydro-5H-[1]pyrindin-7-ylamine (1i) (271 mg, 2.02 mmol),
CALB (81 mg), and EtOAc (6.5 mL) were stirred for 7 h. The
conversion determined from 1H NMR by integration of the
peaks at 5.17 ppm (CHNHAc) and 4.21 ppm (CHNH2) was
55%. Flash chromatography of the material on silica gel using
1:10 MeOH-CH2Cl2 followed by 1:1:4 NH4OH-MeOH-CH2-
Cl2 furnished (R)-N-(6,7-dihydro-5H-[1]pyrindin-7-yl)aceta-
mide ((R)-2i) (194 mg, 41%). The two enantiomers of the
acetamide could not be resolved by GC nor HPLC, and hence
the % ee had to be determined indirectly. A small sample of
the acetamide was treated with 1N HCl to convert it to the
amine, and the resulting amine was resolved by chiral GC
(chiral GC method: 85 °C for 120 min, ramp rate 5 °C/min to
210 °C, final time 5 min; tR(S) ) 124.3 min, tR(R) ) 126.1 min)
Resolu tion of 1l. Following the general procedure, 1-quin-
olin-4-ylethylamine (1l) (279 mg, 1.62 mmol), CALB (84 mg),
i
EtOAc (0.63 mL), and Pr2O (6.0 mL) were stirred for 24 h.
The conversion determined from 1H NMR by integration of
the peaks at 5.77 ppm (CHNHAc) and 4.90 ppm (CHNH2) was
51%. Flash chromatography of the material on silica gel using
1:4 MeOH-CH2Cl2 followed by 1:1:4 NH4OH-MeOH-CH2-
Cl2 furnished (R)-N-(1-quinolin-4-ylethyl)acetamide ((R)-2l)
(177 mg, 51%) in 94% ee (determined by chiral HPLC,
Chiralcel OD column, solvent A (90%) hexanes-reagent
alcohol + 0.1% DEA, solvent B (10%) hexanes, column tem-
perature 10 °C: tR(S) ) 7.8 min, tR(R) ) 22.0 min); [R]D ) +70
1
(c 1.58, CHCl3); H NMR δ 1.60 (d, 3H, J ) 6.9 Hz), 2.01 (s,
1
3H), 5.81-5.90 (m, 1H), 6.13 (br s, 1H), 7.33 (d, 1H, J ) 4.5
Hz), 7.58 (ddd, 1H, J ) 8.1, 6.9, 1.2 Hz), 7.72 (ddd, 1H, J )
7.5, 6.9, 0.9 Hz), 8.07 (d, 1H, J ) 8.1 Hz), 8.10 (d, 1H, J ) 7.5
Hz), 8.82 (d, 1H, J ) 4.5 Hz); 13C NMR δ 21.2, 23.6, 44.7, 117.3,
123.6, 126.5, 127.4, 129.8, 130.5, 148.7, 149.0, 150.4, 169.7;
MS m/z 237 (M + Na+). The unreacted (S)-1-amino-1-(4-
quinolyl)ethane ((S)-1l) was isolated in 48% yield (134 mg) and
97% ee (chiral GC method: isothermal at 180 °C for 20 min:
tR(S) ) 12.6 min, tR(R) ) 13.2 min); [R]D ) -53 (c 1.33, CHCl3).
1H NMR δ 1.53 (d, 3H, J ) 6.6 Hz), 1.88 (s, 3H), 4.95 (q, 1H,
J ) 6.6 Hz), 7.52-7.60 (m, 2H), 7.70 (ddd, 1H, J ) 8.4, 6.9,
1.5 Hz), 8.07 (d, 1H, J ) 8.4 Hz), 8.13 (dd, 1H, J ) 8.4, 0.9
Hz), 8.89 (d, 1H, J ) 4.5 Hz).
to give % ee of 79%; [R]D ) -41 (c 1.49, CHCl3); H NMR δ
1.75-1.89 (m, 1H), 2.07 (s, 3H), 2.80-2.98 (m, 3H), 5.19-5.27
(m, 1H), 6.32 (br s, 1H), 7.14 (dd, 1H, J ) 7.5, 5.0 Hz), 7.55 (d,
1H, J ) 7.5 Hz), 8.39 (d, 1H, J ) 4.5 Hz); 13C NMR δ 23.6,
28.3, 33.9, 55.7, 123.0, 133.3, 137.2, 148.2, 148.4, 162.7, 171.0.
The unreacted (S)-6,7-dihydro-5H-[1]pyrindin-7-ylamine ((S)-
1i) was isolated in 42% yield (113 mg) and 99% ee (chiral GC,
tR(S) ) 124.3 min, tR(R) ) 126.1 min) and displayed spectra
identical to the starting material: 1H NMR (CDCl3, 300 MHz)
δ 1.68-1.88 (m, 1H), 2.50-2.61 (m, 3H), 2.75-2.86 (m, 1H),
2.92 (ddd, 1H, J ) 13.2, 9.0, 3.0 Hz), 4.32 (dd, 1H, J ) 7.8, 7.8
Hz), 7.08 (dd, 1H, J ) 7.8, 4.8 Hz), 7.51 (d, 1H, J ) 7.8 Hz),
8.40 (d, 1H, J ) 4.8 Hz). The dark color of the amine after
purification by column chromatography prevented determi-
nation of its optical rotation.
P r oced u r e for Aceta m id e Hyd r olysis. A stirred solution
of (R)-(-)-N-(5,6,7,8-tetrahydroquinolin-8-yl)acetamide (230
3550 J . Org. Chem., Vol. 68, No. 9, 2003