Organic Syntheses, Vol. 79, p. 130
Checked by Christopher E. Neipp and Stephen F. Martin.
1. Procedure
C. N-Methyl-(1R,2S,6R,7S)-1,10,10-trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane,
4. All glassware for this step
must be oven-dried. A
500-mL, three-necked, round-bottomed flask
equipped with a
magnetic stirring bar, an
argon
inlet, a
125-mL pressure-equalizing addition funnel,
and a
rubber septum is flushed with
argon
and charged with 9.47 g (0.083 mol) of a
35%
dispersion of potassium hydride (KH) in mineral oil
(Note
12). The mineral oil is removed by introducing
85 mL of hexane with
a syringe, gently stirring the mixture, allowing the
potassium
hydride to settle, and then withdrawing the liquid by syringe.
The KH is washed twice using this procedure. The flask is further charged with
300 mL of dry tetrahydrofuran
(THF), Note
13), and the dropping
funnel is charged by syringe with a solution of
8.06
g (0.041 mol) of crude (1R,2S,3R,4S)-3-exo-amino-2-exo-hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptane
(
3) in
90 mL of dry THF.
The magnetically stirred suspension of
potassium
hydride is cooled to 0°C, and the solution of
3 is
added dropwise over a 10-min period. After the addition is complete, the mixture is
stirred at 0°C for 20 min, and
13 mL
(0.21 mol) of methyl iodide (Note
14) is introduced dropwise via syringe. The cooling bath is removed,
and the reaction mixture is stirred at room temperature for 10 hr. The reaction is
quenched by cautious addition of 15 mL of water, and the resulting mixture is transferred
to a
1-L separatory funnel containing 125 mL of water. The
layers are separated, and the aqueous layer is extracted three times with
100 mL of ethyl acetate.
The combined organic extracts are washed with
300
mL of saturated sodium chloride solution,
dried over
magnesium sulfate,
and concentrated by rotary evaporation to give crude
4. Recrystallization of
this material from
15 mL of cyclohexane
provides brown crystals, which are dissolved in
15
mL ethyl acetate and decolorized with Norit
SA3 (100 mesh)
activated carbonat reflux. This
solution is cooled to room temperature, and the Norit is removed by vacuum filtration
through Celite. The filtrate is concentrated by rotary evaporation, and the resulting
pale yellow crystals are recrystallized twice from
5
mL of cyclohexane to provide
2.77 g (
32%)
of
N-methyl-(1R,2S,6R,7S)-1,10,10-trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane
(
4) as colorless crystals,
mp 124-125°C,
[α]D22 −39.6°
(CH2Cl2, c 0.62) (Note
15).
2. Notes
1.
Anhydrous, analytical reagent
grade diethyl ether was purchased from Mallinckrodt
Inc. and was used without additional drying.
4.
Caution! A large volume of gas is produced.
5. This is an exothermic reaction and a large volume of gas is produced.
Great care must be exercised at this stage to avoid adding the
saturated
aqueous sodium sulfate solution too rapidly.
6. In order to achieve efficient product recovery, it is important
to add only sufficient
saturated aqueous sodium
sulfate solution to change the appearance of the reaction mixture
from a gray slurry to a white slurry. At this point the white precipitate settles
rapidly when stirring is stopped.
7. The spectral properties of
(2S)-(−)-3-exo-aminoisoborneol
(
2) are as follows:
1H
NMR (300 MHz, CDCl
3) δ: 0.76 (s, 3 H), 0.79-1.03
(comp, 8 H), 1.35-1.42 (m, 1 H), 1.52 (d, 1 H, J = 4.6),
1.60-1.72 (m, 1 H), 2.4 (br s, 3 H), 3.02 (d, 1 H,
J = 7.4), 3.34 (d, 1 H, J = 7.4 );
13C (125 MHz, CDCl
3) δ:
11.4, 21.2, 21.9, 26.9, 33.1,
46.6, 48.7, 53.4, 57.3, 79.0
; IR (CHCl
3) cm
−1:
3279, 3019, 2957, 2884, 1478;
mass spectrum (CI) m/z 170.1540
[C
10H
19NO (M+1) requires 170.1545], 170 (base),
166, 152.
8.
Triphosgene (98%)
was purchased from Aldrich Chemical Company, Inc.
9. Washing the organic layer with
saturated
sodium bicarbonate is accompanied by the vigorous
evolution of large quantities of gas, so great care must be taken in this step to
avoid loss of material.
10. This crude
3 can be purified by crystallization from a
mixture of
hexane and
ethyl
acetate to afford pure
3 as colorless crystals,
mp 154-155°C (lit
2.
mp 156-158°C),
[α]D22 −48°
(CH2Cl2, c 0.63).
11. The spectral properties of
3 are as follows:
1H NMR (300 MHz, CDCl
3)
δ: 0.88 (s, 3 H), 1.01 (s, 3 H), 1.08 (s, 3
H), 1.45-1.74 (comp, 4 H), 1.84 (d, 1 H, J = 4.6),
3.75 (d, 1 H, J = 8.0), 4.37 (d, 1 H, J = 8.0 Hz), 5.83
(br s, 1 H);
13C
(75 MHz, CDCl
3) δ: 10.7, 19.3, 23.2,
24.7, 31.6, 46.3, 48.1, 48.6,
60.5, 88.3, 160.4; IR (CHCl3) cm
−1: 3470, 3268,
3019, 2962, 1746; mass spectrum (CI) m/z 196.1342 [C
11H
17NO
2
(M+1) requires 196.1338], 196 (base), 166,
89.
12.
Potassium hydride
(35 wt. % dispersion in mineral oil) was purchased from Aldrich Chemical
Company, Inc.
14.
Methyl iodide
was purchased from Aldrich Chemical Company, Inc.
15. The spectral properties of
4 are as follows:
1H NMR (300 MHz, CDCl
3)
δ: 0.87 (s, 3 H), 0.90-1.06 (comp, 8 H), 1.49-1.57
(m, 1 H), 1.70-1.79 (m, 1 H), 1.96 (d, 1 H, J = 4.6),
2.82 (s, 3 H), 3.55 (d, 1 H, J = 8.1), 4.22 (d, 1
H, J = 8.1);
13C
(75 MHz, CDCl
3) δ: 10.5, 18.8, 23.1,
24.6, 29.2, 31.7, 45.3, 46.1 48.2,
65.9, 84.6, 158.3; IR (CHCl
3) cm
−1: 3009, 2960,
1741, 1482, 1435, 1407;
mass spectrum (CI) m/z 210.1491
[C
12H
19NO
2 (M+1) requires 210.1494],
210 (base).
16. The spectral properties of
(2S)-(−)-exo-(dimethylamino)isoborneol,
[(2S)-(−)-DAIB (
5) are as follows:
1H NMR (300 MHz, CDCl
3) δ: 0.74
(s, 3 H), 0.90-0.98 (m, 5 H), 1.02 (s, 3 H), 1.32-1.43
(m, 1 H), 1.62-1.71 (m, 1 H), 1.92 (d, 1 H, J = 4.6) 2.21
(d, 1 H, J = 7.0), 2.26 (br s, 6 H), 3.41 (d, 1 H, J = 7.0);
13C (75 MHz, CDCl
3)
δ: 11.5, 20.7, 22.0, 27.8,
32.2, 46.3, 47.0, 49.0, 74.1,
78.7 (only ten carbon signals are observed at 25°C due
to line broadening of one of the N-methyl signals); IR
(CHCl
3) cm
−1: 3310, 2991, 2956,
2875, 2830, 2784, 1469;
mass spectrum (CI) m/z 198.1860
[C
12H
23NO (M+1) requires 198.1858], 198 (base).
17. This material is enantiomerically pure, as confirmed by HPLC
analysis of the
3,5-dinitrophenyl carbamate
using a chiral stationary phase. The carbamate derivative of DAIB is prepared in the
following manner:
3,5-Dinitrophenyl isocyanate
(Sumika Chemical Analysis Service) and
5 mL
of pyridine are added to a vigorously stirred solution
of
10 mg (0.051 mmol) of DAIB
(
5) in
2 mL of toluene.
After stirring for 30 min at 20°C, the reaction mixture is passed through 0.5
g of
Merck 9385 silica gel,
eluting with
diethyl ether.
The eluent is concentrated by rotary evaporation to give the crude
N-3,5-dinitrophenyl
carbamate. This material is analyzed by HPLC (
Shimadzu
LC-6A chromatograph equipped with a
Rheodyne 7125 injector
and a
Shimadzu SPD-6A UV detector. A Sumitomo Chemical Co.
Sumipax OA-4000 column is employed and the carbonate is eluted
with a 99.5:0.5 mixture of
hexane and
isopropyl alcohol
(flow rate, 1.0 mL/min; detection, 254 nm; tR, 23.7 min).The signal due to the minor
R isomer could not be detected under the analysis conditions, and the ee of the sample
is estimated to be at least 99.9%. (We are indebted to Professor Ryoji Noyori for
this analysis.)
18. Toward the end of the distillation, a small amount of colored
material begins to distill over, so the distillation must be stopped at this point.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
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