Checked by Wataru Nagata and Norbuhiro Haga.
1. Procedure
A.
2-Acetoxy-trans-1-phenylpropene. A dry,
500-ml., three-necked flask is fitted with a
mechanical stirrer, a
pressure-equalizing dropping funnel, and a
rubber septum, and the apparatus is arranged so that the flask may be cooled intermittently with an
ice bath. After the reaction vessel has been flushed with
nitrogen (admitted through a hypodermic needle in the rubber septum) a static
nitrogen atmosphere is maintained in the reaction vessel for the remainder of the reaction. The flask is charged with
35 g. of a 57% dispersion of sodium hydride (20 g., 0.83 mole) in mineral oil (Note
1). The mineral oil is washed from the
hydride with
200 ml. of anhydrous pentane. The supernatant
pentane layer is removed with a
stainless-steel cannula inserted through the rubber septum (Note
2). The residual
sodium hydride is mixed with
250 ml. of anhydrous 1,2-dimethoxyethane (Note
3) before
65 g. (0.48 mole) of phenylacetone (Note
4) is added dropwise and with stirring over 50–60 minutes. During this addition an open hypodermic needle should be inserted in the rubber septum to permit the escape of
hydrogen, and intermittent cooling with an ice bath may be necessary to keep the reaction solution from boiling. The resulting mixture is stirred for 3 hours while it is allowed to cool, then the mixture is allowed to stand for approximately 2 hours, permitting the excess
sodium hydride to settle. The supernatant liquid is transferred under positive
nitrogen pressure through a stainless-steel cannula (Note
2) into a
1-l., three-necked flask containing
108 g. (100 ml., 1.00 mole) of cold (0°), freshly distilled acetic anhydride (b.p.
140°) and fitted with a mechanical stirrer, a
thermometer, an ice bath, and a rubber septum into which are inserted a hypodermic needle to admit
nitrogen and a cannula to transfer the enolate solution.
The enolate solution is added slowly with cooling and vigorous stirring so that the temperature of the reaction mixture remains below 30°. After all the supernatant enolate solution has been transferred, the residual slurry of
sodium hydride is washed with an additional
50-ml. portion of anhydrous 1,2-dimethoxyethane (Note
3); these washings are also added to the
acetic anhydride solution. The resulting viscous mixture is stirred at room temperature for an additional 30 minutes and poured cautiously into a mixture of
500 ml. of pentane, 500 ml. of water, and
130 g. (1.54 moles) of sodium hydrogen carbonate. When hydrolysis of the excess
acetic anhydride and neutralization of the acetic acid are complete, the
pentane layer is separated, and the aqueous phase is extracted with
100 ml. of pentane. The combined
pentane solutions are dried over anhydrous
magnesium sulfate and concentrated with a
rotary evaporator. Distillation of the residual orange liquid through a
20–30-cm. Vigreux column (Note
5) provides
61.7–80.6 g. (
73–95%) of
2-acetoxy-trans-1-phenylpropene, b.p.
82–89° (1 mm.),
nD25 1.5320–1.5327 (Note
6).
B.
threo-4-Hydroxy-3-phenyl-2-heptanone. A dry, 500-ml., three-necked flask is fitted with a Teflon®-coated
magnetic stirring bar, a gas-inlet tube equipped with a stopcock, a low-temperature thermometer, and a rubber septum and mounted to permit the use of an external cooling bath. The apparatus is flushed with
nitrogen, and a static
nitrogen atmosphere is maintained in the reaction vessel throughout the reaction. After
10–20 mg. of 2,2'-bipyridyl has been added to the reaction flask as an indicator, an ethereal solution containing
0.412 mole of halide-free methyllithium (Note
7) is added to the reaction flask with a hypodermic syringe or stainless-steel cannula inserted through the rubber septum. The
diethyl ether is removed under reduced pressure (Note
8) while the flask is warmed to 40° with a
water bath, the reaction vessel is refilled with
nitrogen, and
120 ml. of anhydrous 1,2-dimethoxyethane is added (Note
3). The resulting purple solution is cooled to −10 to −20° with a
2-propanol–dry ice bath before
35.2 g. (0.200 mole) (Note 9) of 2-acetoxy-trans-1-phenylpropene is added from a hypodermic syringe dropwise and with stirring over 15 minutes while the temperature of the reaction mixture is kept in the range −20 to +10°. The resulting red-brown solution is stirred for an additional 10 minutes at −10 to 0° before 285 ml. of an ethereal solution containing
0.202 mole of anhydrous zinc chloride (Note
10) is added to the cold (−10 to +10°) reaction mixture from a hypodermic syringe dropwise and with stirring over 10 minutes. The reddish-yellow cloudy reaction mixture (Note
11) is stirred at 0° for 10 minutes before
14.50 g. (0.2014 mole) of freshly distilled butyraldehyde (Note
12) is added rapidly (30 seconds) and with stirring to the cold (−5 to +10°) reaction mixture. After the mixture has been stirred at 0–5° for 4 minutes, it is poured with vigorous stirring into a cold (0–5°) mixture of
500 ml. of 4 M ammonium chloride and
200 ml. of ether. The
ether layer is separated, and the aqueous phase is extracted with two
200-ml. portions of ether. The combined organic solutions are washed successively with two
100-ml. portions of 1 M ammonium chloride and with two
50-ml. portions of saturated aqueous sodium chloride, and the combined aqueous washings are extracted with an additional
100-ml. portion of ether. The combined
ether solutions are dried over anhydrous
magnesium sulfate and concentrated under reduced pressure (
water aspirator) with a rotary evaporator, removing the solvents and residual
1,2-dimethoxyethane. The residual liquid, which may crystallize on standing (Note
13), is triturated with
50 ml. of pentane, and the crystalline solid that separates is collected on a filter. The filtrate is concentrated under reduced pressure and again triturated with
pentane, yielding an additional crop of the crude product. The combined crops of the crude
threo-aldol product total
26.2–28.4 g. (
64–69%), m.p.
57–62°. The crude product is recrystallized from
125–150 ml. of hexane. After the solution has been cooled to 0°,
21.3–24.1 g. of the
threo-aldol product is collected as white needles, m.p.
71.5–72.5° (Note
14). The mother liquors are concentrated and cooled, separating additional fractions of the product (
0.5–0.8 g.), m.p.
71–72°. The total yield of the
threo-aldol product is
22.1–24.6 g. (
53–60%).
2. Notes
1. The submitters used a
57% dispersion of sodium hydride in mineral oil obtained from Alfa Inorganics, Inc., and the checkers used a
50% dispersion of sodium hydride in mineral oil obtained from Metal Hydrides, Inc.
2. As a stainless-steel cannula was not available, the checkers made a minor modification in the operation without any trouble. They transferred the supernatant
pentane and the solution of the sodium enolate using a Luer-lock hypodermic syringe with a stainless-steel needle preflushed with
nitrogen, sweeping the apparatus with
nitrogen during this operation.
4. The submitters used a commercial sample of
phenylacetone obtained from Aldrich Chemical Company, Inc.; the checkers used material of the same grade obtained from Maruwaka Chemical Industries Ltd. (Japan) without further purification.
5. The checkers used a
15 × 1 cm., unpacked, vacuum-jacketed column instead of
Vigreux column for the distillation.
6. The results of GC analysis of the products made by the submitters are as follows: On a
3-m. GC column, packed with silicone fluid QF1 supported on Chromosorb P, and heated to 190°, the product exhibits peaks at 5.8 minutes corresponding to
2–3% phenylacetone, at 7.5 minutes corresponding to 97–98% of the enol acetate (
cis and
trans isomers not resolved), and at 8.0 minutes corresponding to a trace (<1%) of
3-phenyl-2,4-pentanedione. On a second,
7-m. GC column, packed with silicone fluid DC-710 on Chromosorb P and heated to 190°, the product exhibits peaks at 21.0 minutes corresponding to
phenylacetone, at 39.0 minutes corresponding to the
trans-enol acetate (97–98% of the product), and at 42.2 minutes corresponding to the
cis-enol acetate (2–3% of the product). The checkers used a
45 m. × 0.25 mm. stainless-steel column (Golay type) coated with Apiezon L, heated to 150° and swept with
helium at 1.5 kg./cm.
2 The product exhibits peaks at 5.5 minutes corresponding to
phenylacetone (2–3% of product), at 14.2 minutes corresponding to the
trans-enol acetate (91–92% of the product), and at 15.8 minutes corresponding to the
cis-enol acetate (5–6% of the product). The product has IR absorption (CCl
4) at 1765 (enol ester C=O) and 1685 cm
−1 (enol ester C=C) with UV maxima (95% C
2H
5OH) at 248.5 nm (ε 18,000) and 325 nm (ε 415) and
1H NMR peaks (CCl
4) at δ 2.01 (partially resolved m, 6H, C
H3CO and vinyl C
H3), 5.82 (partially resolved m, 1H, vinyl C
H), and 7.0–7.4 (m, 5H, C
6H5). The mass spectrum of the product has a parent ion at
m/e 176 with abundant fragment peaks at
m/e 134, 91, 45, 43, and 39.
7. The submitters used an
ether solution of
halide-free methyllithium, purchased from Foote Mineral Company, while the checkers prepared the compound from
methyl chloride and
lithium metal in
ether according to the literature.
2 The solution was standardized before use by the titration procedure described in
Org. Synth., Coll. Vol. 6, 121 (1988). The checkers observed that use of a halide-containing
ether solution of
methyllithium resulted in a considerable decrease in yield of the product, principally due to difficulty in following the subsequent procedure described in the text.
9. If the violet color of the reaction solution is completely discharged, indicating that all the
methyllithium has been consumed, addition of the enol acetate should be stopped at that point. The actual concentration of enolate anion in the solution can be calculated from the amount of enol acetate added.
10. To prepare an ethereal solution of anhydrous
zinc chloride (m.p.
283°), the submitters placed
50.0 g. (0.369 mole) of pulverized zinc chloride, obtained from either Mallinckrodt Chemical Works or Fisher Scientific Company, in a
1-l., round-bottomed flask, and the vessel was evacuated to about 1 mm. pressure. The flask was heated strongly with a burner with swirling until as much of the solid as practical had been melted. The evacuated flask was cooled and shaken
(Caution! Perform this operation behind a safety shield in a hood and with heavy gloves to protect the operator's hands in case the flask should implode) to break up the large lumps of
zinc chloride. This fusion under reduced pressure should be repeated three times. To the resulting anhydrous
zinc chloride was added
500 ml. of anhydrous diethyl ether, freshly distilled from
lithium aluminum hydride. The mixture was refluxed for 3 hours under a static
nitrogen atmosphere and allowed to stand until the undissolved solid had settled. The resulting supernatant solution was transferred with a stainless-steel cannula under positive
nitrogen pressure (Note
2) into a second dry flask or
Schlenk tube capped with a rubber septum. Aliquots of this solution, diluted with aqueous
ammonia, can be titrated with standard
EDTA solution to a Erichrome Black T endpoint to determine the
zinc content.
3 Alternatively, the chloride ion concentration of aliquots can be determined by a Volhard titration. Typical values found for these ether solutions are 0.73
M in zinc ion and 1.38
M in chloride ion, or 0.69–0.73
M in
zinc chloride. If the final solution is significantly less concentrated than 0.7
M in
zinc chloride, it is probable that the dehydration of the solid
zinc chloride was not complete. In this event, the submitters recommend that a fresh solution of
zinc chloride be prepared with more attention to the initial dehydration of the solid
zinc chloride. The checkers used pulverized
zinc chloride, obtained from Wako Pure Chemical Industries Ltd. (Japan).
11. The white precipitate that separates is a part of the
lithium chloride formed in the reaction mixture. Separation of the material is not necessary.
12. The submitters used a
commercial grade of butyraldehyde from Eastman Organic Chemicals; the checkers used
butyraldehyde of the same grade from Wako Pure Chemical Industries Ltd. (Japan) and distilled it before use, b.p.
72–74°.
13. The
1H NMR spectrum (C
6D
6) of the crude product exhibits benzylic CH doublets at δ 3.42 (
J = 5.3 Hz., attributable to 4–10% of the
erythro aldol isomer) and 3.58 (
J = 9.4 Hz., attributable to 90–96% of the
threo-aldol isomer). This mixture may be separated by chromatography on acid-washed
silicic acid, permitting the isolation of both the
threo and the
erythro diastereoisomers.
4
14. The
threo-hydroxy ketone exhibits IR absorption (CCl
4) at 3540 (associated OH) and 1705 cm.
−1 (C=O) with a series of weak (ε 300 or less) UV maxima (95% C
2H
5OH) in the region 240–270 nm as well as a maximum at 286 nm (ε 345). The
1H NMR spectrum (CCl
4) of the product shows resonance at δ 0.6–1.9 [m, 7H, (C
H2)
2C
H3], 2.03 (s, 3H, C
H3CO), 3.35 (s, 1H, O
H), 3.65 (d,
J = 9.5 Hz., 1H, benzylic C
H), 4.0–4.4 (m, 1H, C
HO), and 7.1–7.5 (m, 5H, C
6H5). The mass spectrum of the product exhibits the following relatively abundant peaks:
m/e (relative intensity), 206 (M
+, 0.1), 188 (8), 146 (20), 135 (26), 134 (100), 117 (52), 92 (48), 91 (76), 65 (31), 44 (36), and 43 (60).
3. Discussion
The methods previously used to obtain single aldol products (or their dehydrated derivatives) from reactants where several aldol products are possible
7 include the reaction of bromozinc enolates, from α-bromoketones, with aldehydes;
8 the reaction of bromomagnesium enolates, from either α-bromoketones, ketones and bromomagnesium amides or sterically hindered Grignard reagents, with aldehydes;
9,10 and the reaction of α-lithio derivatives of imines with aldehydes or ketones.
11 Like the present procedure, each of these methods relies upon trapping the intermediate β-keto alkoxide derivative as a metal chelate in an aprotic reaction solvent. The present procedure increases the versatility of the aldol condensation by utilizing the variety of specific lithium enolates that can be generated from unsymmetrical ketones.
5 In this procedure the lithium enolate is treated successively with anhydrous
zinc chloride and an aldehyde, forming the zinc(II) chelate of a β-keto alkoxide. The optimum quantity of
zinc chloride is that amount required to form zinc(II) salts of all strong bases in the reaction mixture. Thus,
1 mole of zinc chloride should be added for each mole of lithium enolate (and accompanying
lithium tert-butoxide) formed from an enol acetate as in the present example. If the lithium enolate is formed from the ketone and
lithium diisopropylamide or from a trimethylsilyl enol ether and
methyllithium, then
0.5 mole of zinc chloride should be used for each mole of lithium enolate. The optimum reaction solvent is either
ether or
ether–
1,2-dimethoxyethane mixtures, with a reaction temperature of −10 to +10° and a reaction time of 2–5 minutes. Longer reaction times and higher reaction temperatures may lead to a variety of by-products resulting from polycondensation and dehydration. The aldol products are efficiently isolated by
adding the reaction mixtures to a cold (0–5°), aqueous solution of
ammonium chloride followed by rapid separation of the aldol products. Since many of the aldol products are especially prone to epimerization, dehydration, or reversal of the aldol condensation, they should not be exposed to strong acids or strong bases. Mixtures of stereoisomeric aldol products with similar physical properties can usually be separated by chromatography on acid-washed
silicic acid.
4,12
In several cases (including the present example) where diastereoisomeric aldol products are possible, there is a preference for the formation of the threo-diastereoisomer. This stereochemical preference presumably arises because the six-membered cyclic zinc chelate of the threo-isomer can exist in a chair conformation with both substituents in equatorial positions. Table I summarizes the results obtained from several aldol condensations performed by the present procedure.
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved