Checked by Michael D. Gaul and Robert K. Boeckman, Jr..
1. Procedure
A.
Ethyl 3-hydroxy-4-pentenoate A dry,
2-L, two-necked, round-bottomed flask, capped with septa and equipped with a
thermometer (Note
1),
magnetic stirring bar, and an
argon inlet is flushed with
argon and charged with dry
tetrahydrofuran (400 mL, (Note 2)) and
diisopropylamine (30.8 mL, 220 mmol, (Note 3)). The solution is cooled to −30°C and
butyllithium (BuLi) (93.2 mL, 220 mmol, 2.36 M solution in hexanes, (Note 4)) is added. The reaction is stirred for 15 min and cooled to −76° to −78°C. Dry
ethyl acetate (19.5 mL, 200 mmol, (Note 5)) is added dropwise so that the internal reaction temperature remains below −66°C (addition time 10–15 min). When addition of the
ethyl acetate is complete, the reaction is stirred for 50 min at −70° to −78°C. A solution of freshly distilled
acrolein (13.4 mL, 200 mmol, (Note 6)) and
100 mL of dry tetrahydrofuran is then added rapidly via a cannula. The reaction is stirred for 5 min and quenched by the rapid addition of saturated aqueous
ammonium chloride (NH4Cl), (100 mL). The reaction mixture is poured immediately into a
2-L separatory funnel containing
500 mL of diethyl ether. The reaction flask is rinsed with 100 mL of distilled water and
100 mL of diethyl ether. After thorough mixing, the layers are separated and the aqueous layer is extracted with
diethyl ether (three, 100-mL portions). The combined organic layers are washed with
brine (200 mL), dried over
magnesium sulfate (MgSO4), filtered, and evaporated under reduced pressure (Note
7). Crude
ethyl 3-hydroxy-4-pentenoate is used in the next step (Note
8).
B.
Ethyl 3-oxo-4-pentenoate. A
1-L, round-bottomed flask equipped with a magnetic stirring bar and
pressure-equalizing dropping funnel is charged with
ethyl 3-hydroxy-4-pentenoate (Part A) and
400 mL of acetone. The mixture is cooled in an ice bath and
Jones reagent (175 mL, (Note 9)) is added dropwise via the dropping funnel (addition time is approximately 30–40 min). When addition of the Jones reagent is complete, the reaction mixture is allowed to warm slowly to room temperature and is stirred overnight (10–20 hr).
Methanol (20 mL) is added to quench excess Jones reagent and the reaction mixture is poured into a 2-L separatory funnel containing
diethyl ether (800 mL). After thorough mixing, the layers are separated and the aqueous layer is extracted with
diethyl ether (three 200-mL portions) (Note
10). The combined organic layers are washed with
brine (two 200-mL portions), dried over
MgSO4, filtered, and the solvent is removed by simple distillation (Note
11). Final purification is accomplished by Kugelrohr distillation (Note
12) at 0.60 mm (oven temp 45°C) with a 250-mL receiving bulb cooled to −78°C using a
dry ice/isopropyl alcohol cold bath. The purified product (
14.9 g,
52%) (Note
13) can be stored at −20°C for several months without decomposition.
2. Notes
1. A
Fluke 51 K/J digital thermometer with temperature probe is used to monitor internal reaction temperature.
2.
Tetrahydrofuran is distilled from
sodium-benzophenone ketyl under
argon. The reaction may be carried out using a freshly opened can of anhydrous
diethyl ether from Fisher Scientific or Mallinckrodt without further purification.
6.
Acrolein is purchased from Aldrich Chemical Company, Inc. It is freshly distilled under reduced pressure (

20 mm) employing a
dry ice/isopropyl alcohol cooled-receiver.
7. The rotary evaporator bath temperature should not exceed 40°C.
8. If desired,
ethyl 3-hydroxy-4-pentenoate can be purified by Kugelrohr distillation at 0.60 mm (oven temperature 57°C) using a dry ice/isopropyl alcohol cold bath to cool the receiver (
79% yield). Spectral properties are as follows: IR (film) cm
−1: 3437, 2984, 2938, 1732, 1373, 1275, 1030;
1H NMR (300 MHz CDCl
3) δ 1.22 (t, 3 H, J = 6.7, OCH
2CH
3), 2.4–2.6 (m, 2 H, C(OH)CH
2C(O)), 3.15–3.25 (br m, 1 H, OH), 4.10 (q, 2 H, J = 6.7, OCH
2CH
3), 4.44–4.57 (m, 1 H, HC(OH)), 5.05–5.35 (m, 2H), 5.78–5.90 (m, 1H); MS, m/z 145 (MH
+).
9. Jones reagent is prepared by dissolving
chromium oxide (CrO3) (23.5 g) in concd
sulfuric acid (21 mL) with cooling and then diluting with distilled water to give a total volume of 175 mL.
4
10. Aqueous
chromium waste must be bottled, labeled, and given to the waste management technical personnel.
11. The simple distillation is accomplished by using a rotary evaporator at atmospheric pressure and bath temperature ≤50°C. The last traces of solvent are removed under reduced pressure with an ambient temperature bath.
CAUTION: the product is volatile and will be lost by evaporation if care is not taken. If water should be present, the compound can be dissolved in
diethyl ether, dried again over
MgSO4, filtered and distilled.
12. During the Kugelrohr distillation a forerun of 3–4 mL is collected and discarded.
13. The spectral properties of
ethyl 3-oxo-4-pentenoate, which exists as a mixture of keto and enol forms, are: IR (film) cm
−1: 2984, 1741, 1659, 1588, 1423, 1242, 1150, 1038, 812;
1H NMR (CDCl
3) δ 1.2–1.3 (overlapping t, 3 H), 3.6 (s, ketonic H at C(2)), 4.1–4.3 (m, 2 H), 5.05 (s, enolic H at C(2)), 5.50 (app t, 1 H), 5.91–6.43 (m, 2 H), 11.8 (s, enol OH);
13C NMR δ 14.02, 14.19, 46.43, 60.23, 61.43, 91.84, 122.53, 130.16, 131.20; 135.74, 167.14, 168.61, 172.70, 192.62. Minor peaks are observed which may be the E enol form. The mass spectrum shows m/z 143 (MH
+).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Other preparations of Nazarov's reagent and its analogs have been reported,
7 but many of the procedures are labor-intensive and/or require special apparatus. The reported preparation of
ethyl 3-oxo-4-pentenoate is facile (2 steps) and efficient (
52% overall yield). All starting materials are commercially available, relatively inexpensive, and easily purified. The synthesis is also amenable to scale up and has been carried out successfully on a 1-mol scale. Other esters have also been synthesized by this method with overall yields ranging from 45–58% (see Scheme 1).
8 Finally,
methacrolein and
crotonaldehyde are also suitable reactants (see Scheme 1).
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved