Organic Syntheses, Vol. 75, 37
Checked by Barry C. Peterson and William R. Roush.
1. Procedure
(S)-(−)-2-Bromo-3-hydroxypropanoic acid.
L-Serine (Note 1) (52.5 g, 0.5 mol) and
potassium bromide, KBr, (200 g, 1.7 mol) (Note
2) are dissolved in water (400 mL).
Hydrobromic acid (48%,123 mL, 1.09 mol) is added at room temperature and the mixture is cooled to −13°C with stirring (Note
3).
Nitrogen, N
2, is bubbled through the solution and
sodium nitrite (42.8 g, 0.62 mol) is slowly added in small portions (ca. 5 g every 15 min) (Note
4). After each addition, the reaction mixture turns brown and then the color slowly fades, but the solution does not decolorize entirely. The total time required for addition of all the
sodium nitrite is approximately 2.5 hr. The solution is then allowed to warm to 0°C, the N
2 purge is stopped, and the mixture is stirred for 6 hr. Excess
nitrogen oxides are removed by bubbling N
2 through the solution for 1 hr. The pale green solution is then extracted with
ether (6 × 300 mL). The combined organic extracts are concentrated to 0.5 L by rotary evaporation and dried over anhydrous
magnesium sulfate. After filtration, the
ether is evaporated and the residual solvent is removed under reduced pressure (0.1 mm). The pale yellow or green oil (
74-75 g,
87-89%) is used immediately in the next reaction without purification (Note
5), (Note
6), (Note
7).
Potassium (R)-(+)-2,3-epoxypropanoate (Potassium glycidate). The crude acid from the preceding step (74.5 g, 0.44 mol) is dissolved in
absolute ethanol (300 mL) and cooled to −20°C. Under N
2, a filtered solution of
potassium hydroxide (86%, 55.5 g, 0.85 mol) in absolute ethanol (300 mL) is slowly added. After 2 hr, the mixture is allowed to warm to 0°C and stirred at this temperature for 14 hr. The solution is filtered to remove precipitated salts. Half of the solvent is removed by rotary evaporation without warming and an additional crop of salt (2-4 g) is isolated by filtration. The combined salts are dried under vacuum to give 105 g of a 1 : 1 mixture of
KBr and
potassium glycidate.
One third of this mixture (35 g) is extracted by refluxing in a mixture of
585 mL of absolute ethanol and 15 mL of water in a
1-L flask with good stirring for 45 min (Note
8). After filtration of the hot suspension, the glycidate crystallizes from the filtered solution to give
12-13 g of product. Another third of the 1 : 1
KBr-potassium glycidate mixture is heated at reflux with stirring in the mother liquors for 45 min. After the second batch of crystalline
potassium glycidate is isolated by filtration, the procedure is repeated with the last portion of the
KBr-glycidate mixture. The solids collected from the three hot filtrations are combined and extracted a fourth time with the same solution, then crystallized to give additional product. After drying, the total weight of recrystallized
potassium glycidate is
47-50 g. This salt contains
9.5-13% of KBr, and the yield is thus
74-80% (corrected for KBr content) (Note
9), (Note
10).
Ethyl (R)-(+)-2,3-epoxypropanoate (Ethyl glycidate). A suspension of dry
potassium glycidate (26 g of an 90.5:9.5 potassium glycidate:KBr mixture, 0.186 mol),
benzyltriethylammonium chloride (42.4 g, 0.186 mol), and
ethyl bromide (76 g, 0.7 mol) in methylene chloride, CH2Cl2, (300 mL) is heated at reflux for 16 hr with good stirring (Note
11). The solvent and excess
ethyl bromide are then slowly removed by rotary evaporation without warming, and the resulting viscous solid is triturated with anhydrous
diethyl ether (3 × 100 mL) to extract the
ethyl glycidate. The combined ethereal extracts are filtered and dried over anhydrous
magnesium sulfate. The solvent is slowly removed by rotary evaporation (without warming) and the residue is distilled at
40°C (2.4 mm) with 0°C water circulated through the condenser to afford
17.6 g of
ethyl glycidate (
81%) (Note
12), (Note
13).
2. Notes
1.
L- or D-Serine are available from chemical suppliers such as Aldrich Chemical Company, Inc., Fisher Scientific Company, Fluka Chemical Corp., Acros Organics. In Europe, they may be obtained in bulk quantities from Degussa (Germany) and Rexim (France).
2. The excess of
potassium bromide allows the required reaction temperature to be achieved; moreover, a high concentration of bromide ion suppresses the formation of the corresponding α-hydroxy acid.
3. An
ice-sodium chloride mixture is used.
4. The exhaust gas is very acidic (pH ≤ 1 using wet pH paper), and therefore should be scrubbed by bubbling through a solution of
potassium hydroxide.
5. The checkers obtained
74.5-78 g (
88-92% yield) of product with
[α]D20 −10.2° (
MeOH,
c 5.1).
6.
(S)-(−)-2-Bromo-3-hydroxypropanoic acid was characterized as follows:
[α]D20 −12.8° (MeOH,
c 5.6);
1H NMR (400 MHz, D
2O) δ: 3.76 (d, 2 H, J = 6.0), 4.29 (t, 1 H, J = 6.0);
13C NMR (100 MHz, d
6-acetone) δ: 46.1, 64.2, 170.1; IR (neat) cm
−1: 3400-3000, 2960, 2660, 1735, 1465, 1410, 1260, 1200, 1170, 1080, 1040, 945, 850; MS m/z 169 (M+H); HRMS (CI, CH
4) for C
3H
6BrO
3 [M+H] calcd 168.9500, found 168.9499; Anal. Calcd for C
3H
5BrO
3: C, 21.33; H, 2.98. Found: C, 21.66; H, 2.92.
7. The checkers found that the product partially decomposed when stored for a day at ambient temperature. Therefore it is recommended that the bromo acid be used immediately in the next step.
8. The success of this extraction is highly dependent on the efficiency of the stirring; best results are obtained with a good
magnetic stirrer at 1200 rpm using an
egg-shaped magnetic stir bar (40 × 13 mm).
10. An analytical sample was generated by an additional recrystallization from
EtOH: mp
180°C (dec);
[α]D20 +32.1° (H
2O,
c 20);
1H NMR (400 MHz, D
2O) δ: 2.64-2.66 (m, 1 H), 2.79-2.82 (m, 1 H), 3.22-3.24 (m, 1 H);
13C NMR (100 MHz, d
6-DMSO/D
2O) δ: 46.0, 50.3, 174.7; IR (KBr) cm
−1: 1620 (br), 1440, 1240, 915, 860, 820, 770, 680.
11. A 50°C
oil bath was used to maintain gentle reflux.
12. The purity of the
ethyl glycidate prepared according to this procedure was ≥97% as measured by gas chromatography (BP5 capillary column from SGE). The enantiomeric purity was greater than 99% ee as determined by chiral gas chromatography on a
50-m CYDEX-B capillary column (β-cyclodextrin stationary phase) from SGE: bp
68-69°C (15 mm); bp
40°C (2.4 mm);
[α]D20 +15.8° (neat);
[α]D20 +12.3° (MeOH,
c 5.0);
1H NMR (400 MHz, CDCl
3) δ: 1.24 (t, 3 H, J = 7.2), 2.87 (A of ABX, 1 H, J
AB = 6.6, J
A,X = 4.2), 2.89 (B of ABX, 1 H, J
AB = 6.6, J
BX = 2.4), 3.36 (X of ABX, 1 H, J
AX = 4.2, J
BX = 2.4), 4.16 (B of AB as q, 1 H, J
BA = 10.8, J
B,Me = 7.2), 4.19 (A of AB as q, 1 H, J
AB = 10.8, J
A,Me = 7.2);
13C NMR (100 MHz, CDCl
3) δ: 13.9, 46.1, 47.2, 61.5, 169.1; IR (neat) cm
−1: 2995, 1752, 1417, 1392, 1298, 1260, 1211, 1040, 922, 866, 760; MS m/z 117 (M+H); HRMS (CI, CH
4) for C
5H
9O
3 [M+H] calcd 117.0552, found 117.0551. Anal. Calcd for C
5H
8O
3: C, 51.72; H, 6.94. Found: C, 51.59; H, 6.90.
13.
Ethyl glycidate is a rather sensitive compound (it cannot be chromatographed on silica gel) and distillation at low temperature under high vacuum (0.1-2 mm) avoids the formation of undistillable residues resulting from polymerization. The product should be stored at 5°C (or lower) and is perfectly stable at this temperature.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Ethyl 2,3-epoxypropanoate is a very interesting chiron. It may be opened by various organometallic compounds such as dialkyl, diaryl, and divinyl lithium cuprates, dialkylmagnesium cuprates, trialkylalanes and aluminum acetylides.
5,6 The epoxide ring is attacked regiospecifically at the β-position and produces α-hydroxy esters exclusively without racemization. The same result is observed with heteronucleophiles such as azide anion. However, thiolates afford a mixture of α and β opening.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Ethyl glycidate: Oxiranecarboxylic acid, ethyl ester, (R)- (12); (111058-33-4)
(S)-Serine: L-Serine (8,9); (56-45-1)
(S)-(−)-2-Bromo-3-hydroxypropanoic acid: Propanoic acid, 2-bromo-3-hydroxy-, (S)- (10); (70671-46-4)
Potassium bromide (8,9); (7758-02-3)
Hydrobromic acid (8,9); (10035-10-6)
Sodium nitrite: Nitrous acid, sodium salt (8,9); (7632-00-0)
Potassium (R)-(+)-2.3-epoxypropanoate: Oxiranecarboxylic acid, potassium salt, (R)-(11); (82044-23-3)
Benzyltriethylammonium chloride: Ammonium, benzyltriethyl-, chloride (8);
Benzenemethanaminium, N,N,N-triethyl-, chloride (9); (56-37-1)
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