Org. Synth. 2002, 79, 130
DOI: 10.15227/orgsyn.079.0130
(2S)-(−)-3-exo-(DIMETHYLAMINO)ISOBORNEOL [(2S)-(−)-DAIB]
[
Bicyclo[2.2.1]heptan-2-ol, 3-(dimethylamino)-1,7,7-trimethyl-,
[1R-(exo,exo)]-
]
Submitted by James D. White, Duncan J. Wardrop, and Kurt F. Sundermann
1
.
Checked by Christopher E. Neipp and Stephen F. Martin.
1. Procedure
A.
(2S)-(−)-3-exo-Aminoisoborneol
,
2. All glassware for this step must be oven-dried prior to use. A 2-L,
three-necked, round-bottomed flaskequipped with an efficient mechanical
stirrer attached to a Teflon stirring blade, a
thermometer, and a 1-L pressure-equalizing addition
funnel connected to an argon inlet is flushed with
argon and charged with
475 mL
of dry diethyl ether
(Note 1)
and
5.12 g (0.14 mol) of lithium
aluminum hydride
Note 2.
The addition funnel is charged with a solution of
8.46
g (0.047 mol) of (1R,4S)-(−)-camphorquinone
monoxime
(1) (Note 3) in
350 mL of dry ether. The reaction mixture
is cooled to 0°C in an ice-water bath with stirring, and
the solution of 1 is added slowly to the reaction mixture over 30 min (Note 4). After the addition is complete, the addition funnel is replaced
with a reflux condenser connected to the argon inlet,
and the reaction flask is removed from the cooling bath. The reaction mixture is stirred
and heated at reflux for 1.5 hr and then cooled to 0°C in an ice-water
bath. The reaction is quenched very carefully by dropwise addition of
75 mL of saturated aqueous sodium
sulfate solution (Notes 5
and 6). The resulting white granular precipitate
or slurry is removed by vacuum filtration through Celite, and the filter cake is washed
with three portions of
75 mL of chloroform
.
The combined filtrate and washings are dried over
sodium
sulfate
, filtered, and concentrated by rotary evaporation at
40°C to give 8.07 g of crude
(2S)-(−)-3-exo-aminoisoborneol
(2) as an off-white solid (Note 7). This material is suitable
for the next reaction without purification.
B.
(1R,2S,6R,7S)-1,10,10-Trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane
,
3. A 500-mL, single-necked, round-bottomed flask equipped
with a 250-mL pressure-equalizing dropping funnel and a magnetic
stirring bar is charged with
8.06 g
(0.048 mmol) of crude (2S)-(−)-3-exo-aminoisoborneol
(2),
70 mL of toluene
,
and
55 mL (0.12 mol) of 12.5%
aqueous potassium hydroxide
solution. The reaction
flask is cooled to 0°C in an ice-water bath, the dropping
funnel is charged with a solution of
50 mL
(0.095 mol) of triphosgene
(1.9 M in toluene
) (Note 8),
and the
triphosgene
solution
is slowly added over 40 min with vigorous stirring to the two-phase reaction mixture.
After the reaction is complete, the reaction mixture is stirred at 0°C for 1 hr
and diluted with
130 mL of ethyl
acetate
. The mixture is transferred to a 1-L separatory
funnel, and the layers are separated. The organic layer is washed successively
with
150 mL of saturated aqueous sodium
bicarbonate
solution (Note 9) and
150 mL of saturated sodium chloride
solution. The organic layer is dried over
magnesium
sulfate
, filtered, and concentrated by rotary evaporation to
give 8.07 g of crude
(1R,2S,6R,7S)-1,10,10-trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane
(3) as a waxy pale yellow solid that is suitable for further reaction without
purification (Notes 10 and 11).
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]D
22 −39.6°
(CH2Cl2, c 0.62)
(Note 15).
D.
(2S)-(−)-3-(−)-exo-(Dimethylamino)isoborneol,
[(−)-DAIB]
,
5.
Caution! Since DAIB slowly decomposes in air
, samples of DAIB should be stored under
nitrogen or argon
. All glassware for this step must be oven-dried. A
250-mL, three-necked, round-bottomed flask equipped with a
reflux condenser connected to an argon inlet,
a magnetic stirring bar, a rubber septum,
and a Teflon stopper, is flushed with argon
and charged with
55 mL of dry THF
and
5.20 g (0.075 mol) of lithium
aluminum hydride
(Note 4). The solution
is cooled to 0°C in an ice-water bath, and a solution of
2.77 g (0.013 mol) of N-methyl-(1R,2S,6R,7S)-1,10,10-trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane
(4) in
35 mL of dry THF
is introduced slowly with a cannula. After addition is complete, the flask is removed
from the cooling bath, and the reaction mixture is heated at reflux for 18 hr. The
reaction flask is cooled to 0°C in an ice-water bath, and
the mixture is quenched by successive addition of
20
mL of ethyl acetate
and
17
mL of saturated aqueous sodium sulfate
solution
(Notes 5 and 6).
The white mixture is stirred at room temperature for 2 hr, and the resulting white
granular precipitate or slurry is removed by vacuum filtration through Celite. The
filter cake is washed with three
100-mL
portions of ethyl acetate
, and the combined filtrates
are thoroughly dried over
sodium sulfate
,
filtered, and concentrated by rotary evaporation to furnish crude 5 as an oil.
Crude 5 is purified by bulb-to-bulb distillation to give 2.19 g (84%)
of
(2S)-(−)-3-exo-(dimethylamino)isoborneol,
[(2S)-(−)-DAIB] (5) as a nearly colorless oil, bp 150°C (25 mm), [α]D
22
36° (ethanol, c 4.65) (Notes 16,
17, and 18).
2. Notes
1.
Anhydrous, analytical reagent
grade
diethyl ether was purchased from Mallinckrodt
Inc.
and was used without additional drying.
2.
Lithium aluminum hydride
was purchased from Aldrich Chemical Company, Inc.
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]D
22 −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.
13.
Tetrahydrofuran
(THF) was distilled from sodium-benzophenone ketyl under an atmosphere
of argon
immediately prior to use.
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.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
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3. Discussion
The chiral β-dialkylamino alcohol
DAIB
serves as an efficient asymmetric catalyst for the addition of organozinc reagents
to aldehydes.
3
The reaction of
diethylzinc
with
benzaldehyde
in the
presence of
2 mol % of (2S)-(−)-DAIB to
give
(S)-1-phenyl-1-propanol
in
89% ee is described in the procedure
which follows.
4
DAIB exhibits the property of "chiral amplification," enabling
the preparation of alcohols of high enantiomeric purity to be effected with catalyst
of much lower enantiomeric purity.
Conversion of the keto ketoxime
1 to the exo-exo-amino alcohol
2
has been accomplished by hydrogenation over Adams' catalyst
5
and by reduction with
lithium aluminum hydride.
6
Amino alcohol
2 has also been prepared from
1 by a two-stage process
in which selective reduction of the ketone is carried out with
sodium borohydride,
and the resultant hydroxy oxime is reduced with
lithium aluminum hydride
6 or by hydrogenation over Adams catalyst.
7
Conversion of
2 to the highly crystalline
oxazolidinone
3 with
phosgene has been described by
Thornton
7 who has employed this substance as a chiral
auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also
used an oxazoline derived from
3 as a chiral auxiliary in asymmetric alkylation
of a glycolate enolate.
8
Oxazolidinone
3 has also been
prepared from
2 with
diethyl carbonate
in the presence of
potassium carbonate
.
2 The conversion of
2 to the
oxazolidinone
3 is accomplished using
triphosgene in this procedure
because of the high toxicity of
phosgene.
N-Methylation of
3 and reduction of the crystalline
oxazolidinone
4
with
lithium aluminum hydride was found to give a superior yield
of DAIB (
5) and a more easily purified product than exhaustive methylation
of
2 with
methyl iodide and reduction of the quaternary
methiodide with Super-Hydride.
9 Recently, a modified version of
DAIB,
3-exo-morpholinoisoborneol (MIB), was prepared by Nugent
that is crystalline and that is reported to give alcohols in high enantiomeric excess
from the reaction of
diethylzinc with aldehydes.
10
This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(2S)-(−)-3-exo-(Dimethylamino)isoborneol: (2S)-(−)-DAIB:
Bicyclo[2.2.1]heptan-2-ol, 3-(dimethylamino)-1,7,7-trimethyl-, [1R-(exo,exo)]-
(11); (103729-96-0)
(2S)-(−)-3-exo-Aminoisoborneol:
Bicyclo[2.2.1]heptan-2-ol,
3-amino-1,7,7-trimethyl-, (1R,2S,3R,4S)- (9); (41719-73-7)
Lithium aluminum hydride:
Aluminate (1−),
tetrahydro-, lithium (8);
Aluminate (1−), tetrahydro-,
lithium, (T-4)- (9); (16853-85-3)
(1R,4S0-(−)-Camphorquinone monoxime:
2,3-Bornanedione,
3-oxime (9);
Bicyclo[2.2.1]heptane-2,3-dione, 1,7,7-trimethyl-,
3-oxime (12); (663-17-2)
(1R,2S,6R,7S)-1,10,10-Trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane:
4,7-Methanobenzoxazol-2(3H)-one, hexahydro-7,8,8-trimethyl-, [3aR-(3aα,
4β, 7β, 7aα)]- (12); (131897-87-5)
Triphosgene:
Carbonic acid, bis(trichloromethyl)
ester (8,9); (32315-10-9)
Potassium hydride (8,9); (7693-26-7)
Methyl iodide:
Methane, iodo-
(8,9); (74-88-4)
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