Organic Syntheses, CV 9, 387
(1R,2R)-(+)- AND (1S,2S)-(−)- 1,2-DIPHENYL-1,2-ETHYLENEDIAMINE
[1,2-Ethanediamine, 1,2-diphenyl-, [R-(R,R)]- and [S-(R,R)]-]
Submitted by S. Pikul
1 and E. J. Corey
2.
Checked by Scott C. Jeffrey and James D. White.
1. Procedure
CAUTION! Parts A and B of this procedure should be carried out in an
efficient hood to avoid exposure to noxious vapors (
acetic acid,
ammonia).
A.
2,2-Spirocyclohexane-4,5-diphenyl-2H-imidazole (Note
1). A
2-L, three-necked, round-bottomed flask equipped with a
mechanical stirrer and a
reflux condenser is charged with
1.0 L of glacial acetic acid (Note
2),
158 g (0.75 mol) of benzil (Note
2),
400 g of ammonium acetate (Note
2) and
80 mL (0.77 mol) of cyclohexanone (Note
2). The mixture is stirred and heated at reflux temperature for 1.5 hr (Note
3) and then, while hot, poured into 3 L of vigorously stirred water. The mixture is left overnight to cool to ambient temperature, the crystals are collected by filtration, washed 4 times with 300 mL of water, crushed in a
mortar and dried under reduced pressure to give
205–210 g (
95–97%) of the
imidazole as yellowish-green crystals, mp
105–106°C, lit.
3 mp
107–108°C (Note
4).
B.
(±)-1,2-Diphenyl-1,2-ethylenediamine. A
2-L, four-necked, round-bottomed flask equipped with a mechanical stirrer,
thermometer and
dry ice condenser is charged with
72.0 g (0.250 mol) of 2,2-spirocyclohexane-4,5-diphenyl-2H-imidazole. The flask is flushed with
argon, and
400 mL of tetrahydrofuran (Note
5) is added. The mixture is stirred until all solids dissolve, cooled to −78°C (
dry ice/acetone bath) and treated with a stream of gaseous
ammonia (Note
6) until the volume of liquid increases by about 400 mL (Note
7). One of the side necks is then equipped with a solids addition funnel and
6.94 g (1.00 mol) of lithium (Note
8) is slowly introduced by cutting the wire with scissors in a gentle stream of
argon. The rate of
lithium addition is such that the temperature does not rise above −65°C. Following the addition of
lithium, the mixture is stirred for 30 min and
30 mL (1.0 mol) of ethanol (Note
9) is slowly added. The mixture is stirred for an additional 20 min and
70 g of ammonium chloride is added. The cooling bath is removed, the mixture is allowed to warm to 0°C, 400 mL of water is carefully introduced, and the phases are separated. The aqueous phase is washed 3 times with
300 mL of ether and the combined organic extracts are washed with
brine, dried over anhydrous
sodium sulfate, filtered and concentrated with a
rotary evaporator to about 200 mL. The solution is transferred to a
1-L, one-necked, round-bottomed flask equipped with a mechanical stirrer, cooled to 0°C and treated with
300 mL of 2 N aqueous hydrochloric acid. The biphasic mixture is vigorously stirred at ambient temperature for 1 hr, 500 mL of water is added and phases are separated. The organic phase is washed with 150 mL of water and the combined aqueous phases are extracted with
300 mL of dichloromethane. The aqueous solution is then carefully treated with
300 mL of 2 N aqueous sodium hydroxide and the mixture is extracted 4 times with
150 mL of methylene chloride. The combined organic extracts are washed with
brine, dried over anhydrous
sodium sulfate, and filtered. Removal of volatile material under reduced pressure (
water aspirator) gives
47–50 g (
89–94%) of racemic diamine as a pale yellow solid, mp
81–82°C, lit.
4 mp
82°C corr. (Note
10).
C.
(1S,2S)-(−)- and (1R,2R)-(+)-1,2-Diphenyl-1,2-ethylenediamine (Note
11). A
1-L, round-bottomed flask equipped with a mechanical stirrer is charged with
42.5 g (0.200 mol) of the racemic diamine and
230 mL of ethanol (Note
9). The solids are dissolved by heating the mixture to 70°C whereupon a hot (70°C), homogeneous solution, of
30.0 g (0.200 mol) of L-(+)-tartaric acid (Note
12) in
230 mL of ethanol is added (Note
13). The tartrate salts precipitate immediately, and after the mixture is cooled to ambient temperature, the crystals are collected by filtration, washed twice with
60 mL of ethanol, and dried under reduced pressure. The solids are dissolved in 230 mL of boiling water,
230 mL of ethanol is added and the homogeneous solution is allowed to cool slowly to room temperature. The crystals are collected by filtration, washed with
40 mL of ethanol and dried under reduced pressure. The recrystallization procedure is then repeated twice using the same volumes of solvents (230 mL of water and
230 mL of ethanol) to give
23–25 g (
63–69%) of the tartrate salt as colorless crystals,
[α]23D −10.8 ± 0.2° (H
2O,
c 1.3), lit.
5 [α]23D −11° (H
2O).
The salt is transferred to a
1-L, one-necked, round-bottomed flask equipped with a
magnetic stirring bar and suspended in 300 mL of water. After the mixture is vigorously stirred and then cooled to 0–5°C,
23 mL of 50% aqueous sodium hydroxide is added dropwise followed by
150 mL of dichloromethane, and stirring is continued for 30 min. The phases are separated, the aqueous phase is washed twice with
50 mL of dichloromethane and the combined organic extracts are washed with
brine, dried over anhydrous
sodium sulfate and filtered. Removal of the volatile material under reduced pressure gives a colorless solid that is recrystallized from
hexane to yield
12–14 g (
57–66%) of
(S,S)-(−)-diamine as colorless crystals,
[α]23D −106 ± 1° (MeOH,
c 1.1) lit.
6 [α]23D −106.5° (MeOH,
c 1.09) (Note
14).
The filtrates from all crystallizations are combined and the solvent is evaporated on a rotary evaporator under vacuum (
water aspirator). The residual solid is transferred to a 1-L, one-necked, round-bottomed flask equipped with a
magnetic stirring bar, and suspended in 250 mL of water. To this vigorously stirred mixture is slowly added
25 mL of aqueous 50% sodium hydroxide followed by
200 mL of dichloromethane and the stirring is continued for 30 min. The phases are separated, the aqueous phase is washed twice with
50 mL of dichloromethane and the combined organic extracts are washed with
brine, dried over anhydrous
sodium sulfate and filtered. Removal of volatile material under reduced pressure gives
24–27 g of the enriched
(R,R)-diamine as pale yellow crystals. This material is treated with
D-(−)-tartaric acid (Note
12) and the resulting salt is recrystallized in exactly the same manner as described for the other enantiomer to give
29–31 g (
80–85%) of colorless crystals,
[α]23D +4 ± 0.5 ° (H
2O,
c 1.3). (The checkers found that the salt from
(−)-tartaric acid was optically impure even after five recrystallizations. However, this did not affect the optical purity of the
(R,R)-(+)-diamine.) Treatment with
sodium hydroxide, as described above, followed by crystallization from
hexane gives
11.5–13 g (
54–61%) of
(R,R)-(+)-diamine as colorless crystals,
[α]23D +106 ± 1° (MeOH,
c 1.1) (Note
14).
2. Notes
1. Step A is a modified literature procedure.
3
3. As the reaction progresses there is a change of color from light yellow to dark green.
4. This material is pure enough for use in the next step. If necessary, it can be recrystallized from
hexane or
methanol-water. The properties of
2,2-spirocyclohexane-4,5-diphenyl-2H-imidazole are as follows: R
f = 0.48 (hexane-ether 1:1, v/v;
1H NMR (CDCl
3) δ: 1.65–1.92 (m, 6 H), 1.95–2.00 (m, 4 H), 7.33–7.53 (m, 10 H);
13C NMR (CDCl
3) δ: 24.1, 25.7, 34.7, 104.1, 128.3, 128.9, 129.9, 133.1, 164.0.
6.
Anhydrous ammonia (99.98%) was obtained from Matheson Gas Products, Inc., and used as received.
7. The mixture stays homogeneous when cooled to −78°C.
8.
Lithium wire (99% with 1% of sodium) was purchased from the Aldrich Chemical Company, Inc. The mineral oil is wiped off with a paper towel before use.
9.
Absolute ethanol (200 proof) was obtained from Aaper Alcohol and Chemical Co. and used as received.
10. The racemic diamine contains 5–10% of an impurity (by
13C NMR analysis) that does not interfere with the subsequent resolution. The product has the following spectral properties:
1H NMR (400 MHz, CDCl
3) δ: 1.59 (bs, 4 H), 4.10 (s, 2 H), 7.2–7.3 (m, 10 H);
13C NMR (100 MHz, CDCl
3) δ: 61.9, 126.8, 126.9, 128.2, 143.4.
11. This resolution procedure is essentially the same as described in the literature.
5
12.
L-(+)- and D-(−)-Tartaric acids (99+ and 99%, respectively) were obtained from the Aldrich Chemical Company, Inc., and used as received.
14. The spectral properties of this product are the same as that of the racemate (see (Note
10)). The optical purity is higher than 98% as confirmed by
1H NMR of its salt with
L-mandelic acid.
7
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Enantiomerically pure
(+)- and (−)-diphenylethylenediamines have recently been used for highly stereoselective Diels-Alder,
8 aldol,
8 allylation,
9 osmylation,
10 and epoxidation
11 reactions. Other synthetic applications involve enantioselective Michael addition
12 and asymmetric hydrogenation.
13
The present two-step procedure for preparation of the racemic
diphenylethylenediamine is significantly shorter and more suitable for scale-up than that described in the literature.
4 The resolution of the racemate has also been reported using the commercially available enantiomers of
mandelic acid.
6
This preparation is referenced from:
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
brine
2,2-Spirocyclohexane-4,5-diphenyl-2H-imidazole
(1R,2R)-(+)- AND (1S,2S)-(−)- 1,2-DIPHENYL-1,2-ETHYLENEDIAMINE
1,2-Ethanediamine, 1,2-diphenyl-, [R-(R,R)]- and [S-(R,R)]-
(1S,2S)-(−)- and (1R,2R)-(+)-1,2-Diphenyl-1,2-ethylenediamine
(S,S)-(−)-diamine
(R,R)-diamine
D-(−)-tartaric acid
(−)-tartaric acid
(R,R)-(+)-diamine
L-(+)- and D-(−)-Tartaric acids
(+)- and (−)-diphenylethylenediamines
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ammonia (7664-41-7)
methanol (67-56-1)
ether (60-29-7)
ammonium acetate (631-61-8)
ammonium chloride (12125-02-9)
sodium hydroxide (1310-73-2)
Mandelic acid,
L-mandelic acid (90-64-2)
Cyclohexanone (108-94-1)
sodium sulfate (7757-82-6)
Benzil (134-81-6)
Benzophenone (119-61-9)
sodium (13966-32-0)
tartaric acid,
L-(+)-tartaric acid (87-69-4)
methylene chloride,
dichloromethane (75-09-2)
lithium (7439-93-2)
Tetrahydrofuran (109-99-9)
Imidazole (288-32-4)
hexane (110-54-3)
argon (7440-37-1)
(±)-1,2-Diphenyl-1,2-ethylenediamine
diphenylethylenediamine
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