Checked by Marc J. McKennon and Albert I. Meyers.
1. Procedure
B.
2,3-O-Isopropylidene-D-glyceraldehyde. A
large, magnetic stir bar is added to the flask that contains the crude solid diacetonide from procedure A above and
700–800 mL of dichloromethane (10 mL/g of diacetonide) is added. The flask is equipped with a condenser and heating mantle, and the slurry is stirred vigorously and heated to reflux until the solids are digested to an even consistency. The mantle is removed, the slurry is allowed to cool below reflux, and Celite (10 g) is added with stirring. The contents are further cooled to room temperature and vacuum-filtered through a pad of Celite on a
glass frit filter into a
three-necked, 2-L vessel. The flask is rinsed with
50 mL of dichloromethane and the rinse is filtered through the funnel. The 2-L vessel is then equipped with an overhead stirrer,
thermometer, and
water bath, and stirring is begun at 300–350 rpm. A solution of
30–40 mL of saturated aqueous sodium bicarbonate (0.4 mL/g of diacetonide) is added with stirring, followed by
130–140 g of sodium metaperiodate (2.0 mol equiv), added portionwise over 2–3 min. The resulting mixture is stirred while the internal temperature is maintained below 35°C with water bath cooling. After the solution is stirred for 2 hr,
35–50 g of magnesium sulfate (0.5 g/g of diacetonide) is added and stirring is continued for 20 min. The slurry is vacuum-filtered through a glass frit filter into a
2-L, one-necked, round-bottomed flask. The filter cake is removed, transferred back into the three-necked vessel,
200 mL of dichloromethane is added, and the resulting slurry is stirred for 10 min. The slurry is vacuum-filtered (Note
3) and the filtrate is added to the one-necked flask (Note
4).
The filtrate-containing flask is equipped with a
12"-Vigreux column,
distillation head,
receiver, and heating mantle, and
dichloromethane is removed by distillation (head temperature to 40°C) (Note
5). The residual oil is cooled and transferred to a
250-mL, round-bottomed flask and the flask is equipped with a simple distillation head, cow receiver, and heating mantle. After a brief forerun (
2–3 g), product is collected by distillation at
30 mm (65–120°C) into a chilled receiver (5°C) to afford
54–68 g (
75–85%) of crude
2,3-O-isopropylidene-D-glyceraldehyde (Note
6). The crude product is transferred to a
100-mL, round-bottomed flask equipped with a
6"-Vigreux column, cow receiver, and heating mantle, and redistilled (Note
7) at 30 mm, collecting the fraction distilling at
67–73°C into a chilled receiver to afford
50–64 g of product (
70–80%,
34–45% overall, (Note
8)).
2. Notes
2. Samples of about 50 mg are weighed and dissolved in
0.5 mL of (methyl sulfoxide)-d6(DMSO-d6) and
10 μL of dichloromethane is added. A small portion of this solution is then withdrawn and diluted in an NMR tube with
DMSO-d6.
1H NMR integration parameters are as follows: 32K data points, recycle delay of 5 s, 30° pulse angle. Measurement is against the hydroxyl proton doublet (2 H) at δ 4.63. If the hydroxyl doublet is not satisfactorily resolved, additional dilution is performed.
Physical data for material purified by slurry in
dichloromethane followed by recrystallization from
butyl ether is as follows: mp
121.8–123.4°C (lit.
3 mp
118–120°C);
[α]D23 +1.9° (CH
3OH,
c 1.74), lit.
4 [α]D20 +1.9° (CH
3OH,
c 2);
1H NMR (CDCl
3) δ: 1.36 (s, 6 H), 1.42 (s, 6 H), 2.70 (d, 2 H, J = 6.7), 3.75 (approx. t, 2 H, J = 6.2), 3.98 (dd, 2 H, J = 8.4, 5.4), 4.10–4.22 (m, 4 H);
13C NMR (CDCl
3) δ: 25.19, 26.72, 66.74, 71.16, 76.22, 109.39; IR (KBr) cm
−1: 3400, 3292, 2980, 2933, 2895, 1386, 1372, 1265, 1212, 1070, 859. Anal. Calcd. for C
12H
22O
6: C, 54.95; H, 8.45. Found: C, 54.80; H, 8.50.
3. In the presence of water,
2,3-O-isopropylidene-D-glyceraldehyde forms the highly water soluble hydrate
1. Failure to dry the reaction and reslurry the filter cake results in loss of about 10% yield.
4. On standing, the filtered solids take on a color characteristic of
iodine; the solids can be decomposed by treatment in water with
sodium thiosulfate or bisulfite to a negative starch-iodide endpoint.
5. Removal of
dichloromethane (CH
2Cl
2) in the final step was performed by the checkers using a rotary evaporator. The pressure was monitored during evaporation and was not allowed to drop below 100 mm. In this fashion the same yield of material was obtained as reported.
6. On standing, both the initially distilled and redistilled material may deposit a small amount of flocculent solid or gel characteristic of polymerized material, which results in some thickening of the product oil.
7. The checkers found that a single distillation of the final product was sufficient to obtain pure material.
8. The physical characteristics are as follows:
[α]D23 +70–80° (
c 1.0–1.5,
benzene, taken immediately upon completion of distillation);
1H NMR (CDCl
3) δ: 1.40 (s, 3 H), 1.47 (s, 3 H), 4.12 (m, 2 H), 4.36 (m, 1 H), 9.70 (d, 1 H, J = 1.9);
13C NMR (CDCl
3) δ: 24.73, 25.84, 65.11, 79.49, 110.79, 201.38; IR (neat) cm
−1: 2990, 2940, 2890, 2820, 1730, 1375, 1250, 1215, 1150, 1070, 840. Material obtained from this scale procedure is approximately 90% monomeric; the presence of polymeric material is shown in the
1H NMR by broad signals at δ 4.7, 3.9 and 1.23.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
A review article reports information regarding the preparation, handling, and storage of this important 3-carbon chiral source.
23 Our experience with the compound demonstrates that it tends to polymerize and readily adds water to form hydrate
1 in aqueous solution, from which it is extracted only with difficultly. Both hydrated and polymerized aldehyde can contaminate samples and result in lowered optical rotation values, even though no racemization has occurred. The present procedure provides anhydrous aldehyde, that polymerizes on standing. Polymerized material can be cracked by redistillation (threshold temperature ca. 90°C) at reduced pressure to provide monomer without compromise of enantiomeric integrity; monomeric aldehyde has been obtained routinely in our labs by distillation from still pots that contain substantially polymerized material. Although polymeric material can be stored for months at room temperature in sealed containers and recracked to provide monomer with good recovery, refrigerated storage retards polymerization rates and probably extends the useful lifetime of the compound, as polymerized material failed in some instances to recrack to monomer. Other workers have recommended storage in a frozen
benzene matrix,
24 and a report on successful recracking of refrigerated polymerized material has appeared.
25 We recommend the use of freshly-distilled material in synthetic applications.
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