Organic Syntheses, Vol. 75, 45
Checked by Brian Brown and Louis S. Hegedus.
1. Procedure
A. (4R,5S)-4,5-Diphenyl-2-oxazolidinone. A
1-L, three-necked, round-bottomed flask equipped with a
magnetic stirrer,
thermometer,
reflux condenser, and a
dropping funnel is charged with
(1S,2R)-(+)-2-amino-1,2-diphenylethanol (20.0 g, 94 mmol) (Note
1) and
dichloromethane, CH2Cl2, (140 mL), and cooled in an
ice-water bath. After addition of
triethylamine (28.4 mL, 204 mmol), a solution of
triphosgene [bis (trichloromethyl) carbonate] (9.8 g, 33 mmol) (Note 2) in dichloromethane (20 mL) is added dropwise with a dropping funnel over 1 hr, keeping the temperature below 10°C (Note
3). After the addition is over, the mixture is stirred for 2 hr at the same temperature (Note
4). Water (40 mL) and
methanol (20 mL) are added to the resulting suspension, and the mixture is stirred for 30 min. The mixture is concentrated under reduced pressure on a
rotary evaporator. Water (100 mL) is poured onto the residue and the suspension is stirred vigorously for several minutes. The resulting precipitate is collected by filtration, and washed with
1 M hydrochloric acid (10 mL) and water (50 mL) to give
(4R,5S)-4,5-diphenyl-2-oxazolidinone as colorless crystals (Note
5). The combined organic extracts are washed with
brine, then evaporated under reduced pressure. A small amount of water is added to the residue, and the precipitate is collected by filtration and washed with a small amount of water to obtain additional
(4R,5S)-4,5-diphenyl-2-oxazolidinone as colorless crystals. The two lots of crystals are air-dried, then completely dried in a desiccator over
phosphorus pentoxide (P2O5) under reduced pressure for 24 hr. The (4R,5S)-4,5-diphenyl-2-oxazolidinone (
22.3 g,
99.2%) (Note
6) obtained is used for the next step without further purification.
B. (4R,5S)-3-(1-Methoxyethyl)-4,5-diphenyl-2-oxazolidinone. A
2-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, thermometer, and a reflux condenser is charged with
(4R,5S)-4,5-diphenyl-2-oxazolidinone (20.0 g, 84 mmol),
(±)-10-camphorsulfonic acid (9.7 g, 42 mmol) (Note
7), and
acetaldehyde dimethyl acetal (700 mL) (Note
8). The mixture is heated at gentle reflux in an
oil bath (bath temperature 80°C) for 5 hr (Note
9). The mixture is allowed to cool to ambient temperature, then concentrated under reduced pressure on a rotary evaporator (Note
10).
Ethyl acetate (100 mL) is added to the residue, and the
ethyl acetate solution is transferred to a
beaker. The solution is neutralized with saturated
sodium bicarbonate solution (100 mL) (Note
11), and transferred into a
separatory funnel. The two layers are separated, and the lower aqueous layer is extracted with
ethyl acetate (100 mL). The organic layers are combined, washed with
brine, dried over anhydrous
sodium sulfate, filtered, then concentrated under reduced pressure on a rotary evaporator. The residue is stirred with
2-propanol-hexane (1 : 1, 60 mL) for several minutes. The solid product is collected by filtration. The filtrate is concentrated on a rotary evaporator, and the residue is again stirred with
2-propanol-hexane (1 : 1, 5 mL). The precipitate is collected by filtration. The two lots of the products are dried in a
desiccator over
phosphorus pentoxide (P
2O
5) under reduced pressure for 12 hr.
(4R,5S)-3-(Methoxyethyl)-4,5-diphenyl-2-oxazolidinone (
22.2 g,
89.3%) (Note
12) is obtained as a diastereomeric mixture. In some runs, small amounts of impurities remained after trituration. These impurities can be carried through the next step without a problem although final yields will be reduced.
2. Notes
2.
Triphosgene4 was purchased from Tokyo Kasei Kogyo Co., Ltd. This is also available from Aldrich Chemical Company, Inc. The submitters recommend the use of
triphosgene which is more convenient to handle than
diphosgene (trichloromethyl chloroformate).
3. This is an extremely exothermic reaction.
5. The submitters extracted the combined filtrates with
CH2Cl2; the checkers omitted this operation after finding it made less than 1% difference in the yield of final product.
6. A pure sample can be obtained by recrystallization (
toluene). The spectral and physical properties are as follows: mp
232.5-233.5°C;
[α]D20 +60.6° (MeOH,
c 0.86); IR (CHCl
3) cm
−1: 3580, 1765, 1540;
1H NMR (CDCl
3): 5.20 (d, 1 H, J = 8.0), 5.85 (br, 1 H), 5.96 (d, 1 H, J = 8.0), 6.8-7.6 (m, 10 H); MS (m/z): 239 (M
+), 108, 107. Anal. Calcd for C
15H
13NO
2: C, 75.30; H, 5.48; N, 5.86. Found: C, 75.09; H, 5.38; N, 5.86.
9. TLC analysis on Merck silica gel 60 F254 plates (
hexane :
ethyl acetate 1 : 1) showed clean formation of the diastereomeric products, Rf 0.69, and Rf 0.61 (cf. the starting material, Rf 0.45, visualized with
phosphomolybdic acid in
ethanol). The checkers found Rf 0.32 for the oxazolidinone starting material and Rf 0.50 and 0.61 for the diastereomeric products in 1:1
ethyl acetate:
hexane.
11. The pH of the aqueous layer was 7-8. Care should be taken because of foaming on neutralization.
12. The spectral properties of the diastereomeric mixture are as follows: IR (CHCl
3) cm
−1: 3000, 1750, 1410, 1100, 1055;
1H NMR (CDCl
3) δ: 0.96 (d, 3 H × 2/3, J = 6.2), 1.46 (d, 3 H × 1/3, J = 6.2), 3.25 (s, 3 H × 1/3), 3.46 (s, 3 H × 2/3), 5.0-6.1 (m, 3 H), 6.6-7.5 (m, 10 H); MS (m/z): 297 (M
+), 238, 222, 165, 59.
13. A pure sample can be obtained by vacuum distillation or recrystallization (
hexane-
ethyl acetate), but some decomposition occurs under drastic conditions. The spectral and physical properties are as follows: mp
170-171°C;
[α]D20 +21.7° (
CHCl3,
c 0.78); IR (CHCl
3) cm
−1: 1760, 1640, 1540, 1382, 1364;
1H NMR (C
6D
6): 3.88 (dd, 1 H, J = 1.0 and 16.0), 4.10 (dd, 1 H, J = 1.0 and 9.2), 4.42 (d, 1 H, J = 8.1), 5.08 (d, 1 H, J = 8.1), 6.5-6.9 (m, 10 H), 7.13 (dd, 1 H, J = 9.2 and 16.0); MS (m/z): 265 (M
+), 180, 132, 131, 104. Anal. Calcd for C
17H
15NO
2: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.80; H, 5.65; N, 5.25.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Optically active 2-oxazolidinones and 2-thiazolidinones are versatile compounds as chiral auxiliaries.
5 6 (4R,5S)-4,5-Diphenyl-2-oxazolidinone has been used for the synthesis of optically active amines
7 because of its high stereoselectivity and easy deprotection by hydrogenolysis after the reaction. Compared with several preparations
8 9 10 of
(4R,5S)-4,5-diphenyl-2-oxazolidinone reported so far, this method, which makes use of
triphosgene, seems to have the following advantages: simple and easy procedure, mild reaction conditions, and quantitative chemical yield. This procedure can also be used for preparing 2-oxazolidinones from various 2-aminoethanol derivatives.
Hegedus and co-workers
11 reported the synthesis of
(4S,5R)-4,5-diphenyl-3-vinyl-2-oxazolidinone (the enantiomer of the compound prepared here) via the chromium carbene complex in a fair yield. This is an interesting method, but the procedure is complicated (e.g., low temperature,
argon atomsphere) and the chromium waste must be disposed of in an appropriate way. On the other hand, this procedure, consisting of transacetalization
12 and pyrolysis,
13 is simple and safe. Optically active
3-vinyl-2-oxazolidinone is also used for the synthesis of
(1R,2S)-2-fluorocyclopropylamine14 15 that is the key intermediate for novel antibacterial quinolonecarboxylic acids.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(4R,5S)-4,5-Diphenyl-3-vinyl-2-oxazolidinone: 2-Oxazolidinone, 3-ethenyl-4,5-diphenyl-, (4R-cis)- (13); (143059-81-8)
(4R,5S)-4,5-Diphenyl-2-oxazolidinone: 2-Oxazolidinone, 4,5-diphenyl-, (4R-cis)- (11); (86286-50-2)
(1S,2R)-(+)-2-Amino-1,2-diphenylethanol: Ethanol, 2-amino-1,2-diphenyl-, L-erythro-(+)- (8); Benzeneethanol, β-amino-α-phenyl-, [S-(R*,S*)]- (9); (23364-44-5)
Triethylamine (8); Ethanamine, N,N-diethyl- (9); (121-44-8)
Triphosgene: Carbonic acid, bis(trichloromethyl) ester (8,9); (32315-10-9)
(4R,5S)-3-(1-Methoxyethyl)-4,5-diphenyl-2-oxazolidinone: 2-Oxazolidinone, 3-(1-methoxyethyl)-4,5-diphenyl-, [4R-[3(R*),4a,5a]]- (13); 142977-52-4)
Camphorsulfonic acid monohydrate: Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (±)- (9); (5872-08-2)
Acetaldehyde dimethyl acetal (8); Ethane, 1,1-dimethoxy- (9); (534-15-6)
Ammonium chloride (8,9); (12125-02-9)
(4S,5R)-4,5-Diphenyl-3-vinyl-2-oxazolidinone: 2-Oxazolidinone, 3-ethenyl-4,5-diphenyl-, (4S-cis)- (12); (128947-27-3)
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