Org. Synth. 1986, 64, 138
DOI: 10.15227/orgsyn.064.0138
α-HYDROXYLATION OF A KETONE USING o-IODOSYLBENZOIC ACID: α-HYDROXYACETOPHENONE VIA THE α-HYDROXY DIMETHYLACETAL
[Ethanone, 2-hydroxy-1-phenyl-]
Submitted by Robert M. Moriarty, Kwang-Chung Hou, Indra Prakash, and S. K. Arora
1.
Checked by Janice Klunder and K. Barry Sharpless.
1. Procedure
A 250-mL, two-necked, round-bottomed flask is equipped with a magnetic stirring bar, 100-mL pressure-equalized addition funnel to which is attached a drying tube, and a stopper. Anhydrous methanol (80 mL) (Note 1) is added to the flask, which is cooled to 5–10°C. Stirring is begun and 8.4 g (0.15 mol) of powdered potassium hydroxide is added. Acetophenone (6.0 g; 0.05 mol) (Note 2) dissolved in 20 mL of methanol is added dropwise over a period of 10 min. After the solution is stirred for 15 min, 14.52 g (0.055 mol) of o-iodosylbenzoic acid (Note 3) is added during 30 min. The ice bath is removed and the resultant yellow-colored slurry is stirred overnight at room temperature to give a clear red solution (Note 4). The mixture is concentrated under reduced pressure in a rotary evaporator until one-half of the methanol is removed, and then 30 mL of water is added followed by extraction with four 50-mL portions of dichloromethane. The combined dichloromethane extracts are washed with two 10-mL portions of water, and the combined organic extracts are dried over anhydrous magnesium sulfate for 1 hr. After filtration, the methylene chloride is removed under reduced pressure in a rotary evaporator, and the crude acetal is distilled to give a fraction at 73–76°C (0.4 mm) weighing 6.0 g (65%) (Note 5). The acetal is of high purity, as shown by spectral analysis (Note 6).
α-Hydroxyacetophenone. In a
500-mL, round-bottomed flask equipped with a magnetic stirrer are placed
6.0 g (0.33 mol) of α-hydroxy dimethylacetal and
100 mL of dichloromethane. Stirring is begun and the flask is cooled to about 10°C with ice water. Aqueous
5% sulfuric acid (100 mL) is added dropwise from a
pressure-equalized addition funnel and the mixture is stirred for another 30 min. The
dichloromethane layer is separated and the aqueous layer is extracted twice with
25-mL portions of dichloromethane. The combined extracts are washed with two 10-mL portions of water and dried over anhydrous
magnesium sulfate, and the solvent is removed under reduced pressure using a rotary evaporator. The resulting yellow crystalline solid is recrystallized from
carbon tetrachloride to give a white crystalline material, mp
86–87.5°C (lit.
2 mp
86–87°C), yield
3.7 g (
83%)
(Note 7).
2. Notes
1.
Anhydrous
methanol is obtained by treatment with
magnesium methoxide, obtained by refluxing
50 mL of methanol,
5 g of magnesium turnings, and
0.5 g of sublimed iodine together until the
iodine color disappears. The
1 L of methanol is added and the system is kept at reflux for 1 hr and distilled to yield purified
methanol (bp
64.5°C).
2.
Acetophenone was used as purchased from Fisher Scientific Company.
3.
o-Iodosylbenzoic acid was used as purchased from Sigma Chemical Company.
4.
TLC (
ethyl acetate:
hexane) shows residual starting material.
5.
The
α-hydroxy dimethylacetal obtained must be used immediately in the next step because at room temperature it undergoes a dimerization reaction by loss of two molecules of
methanol.
6.
The spectral properties of the product are as follows: IR (neat) cm
−1: 3470 (-OH):
1H NMR (CDCl
3) δ: 1.83 (s, 1 H, OH), 3.23 (s, 6 H, (OCH
3)
2), 3.73 (s, 2 H, CH
2), 7.27–7.67 (m, 5 H, Ar H);
13C NMR (CDCl
3) δ: 139.3 (s), 128.4 (d), 127.4, (d) 102.4 (s), 65.3 (t) 49.1 (q); mass spectrum:
m/e 151 (M
+-OCH
3 100%), 105 (29.7%), 91 (31.7%), 77 (7.0%).
7.
The product has the following spectral properties:
1H NMR (CDCl
3) δ: 3.63 (s, 1 H, OH), 4.86 (s, 2 H, CH
2), 7.25–7.90 (m, 5 H, Ar H);
13C NMR (CDCl
3) δ: 198.6 (s), 134.4 (s), 129.1 (d), 127.8 (d), 65.6 (t).
3. Discussion
The procedure reported here provides a convenient method for the α-hydroxylation of ketones that form enolates under the reaction conditions. The reaction has been applied successfully to a series of para-substituted acetophenones,
1-phenyl-1-propanone,
3-pentanone,
cyclopentanone,
cyclohexanone,
cycloheptanone,
cyclododecanone,
2-methylcyclohexanone,
2-norbornanone, and
benzalacetone.
3 In the case of a steroidal example it was shown that a carbon–carbon double bond and a secondary hydroxyl group are not oxidized.
4 A primary amino function, as in the case of
p-aminoacetophenone, is not affected.
5 Similarly, a tertiary amino ketone such as
tropinone undergoes the α-hydroxylation reaction.
5The present procedure using
o-iodosylbenzoic acid is an improvement over our original method, which uses either
iodosylbenzene or
diacetoxyphenyliodine(III).
6,7,8 The advantage of the present method is the solubility of the product
iodobenzoic acid under the basic reaction conditions. Thus the
α-hydroxy dimethylacetal may be isolated by direct extraction. Using the original procedure, both carboxylic acids and esters underwent high yield α-hydroxylation.
8The pathway by which the reactions are considered to occur involves attack of the enolate anion at the I=O bond of o-iodosylbenzoic acid followed by reductive elimination of o-iodobenzoic acid upon addition of methoxide to the carbonyl group. Ring opening of the epoxide thus formed yields the hydroxy dimethylacetal:
Other methods for α-hydroxy ketone synthesis are as follows: addition of
3O
2 to an enolate followed by reduction of the α-hydroperoxy ketone using
triethyl phosphite;
9 the
molybdenum peroxide–
pyridine/
HMPA oxidation of enolates;
10 photooxygenation of enol ethers followed by
triphenylphosphine reduction;
11 the epoxidation of trimethylsilyl enol ethers by peracid;
12 the oxidation of trimethylsilyl enol ethers by
osmium tetroxide in
N-methylmorpholine N-oxide;
13 and, finally, the classical method of hydrolysis of an α-bromo ketone.
14This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
α-HYDROXY DIMETHYLACETAL
hydroxy dimethylacetal
HMPA
sulfuric acid (7664-93-9)
ethyl acetate (141-78-6)
methanol (67-56-1)
magnesium turnings (7439-95-4)
Cyclohexanone (108-94-1)
carbon tetrachloride (56-23-5)
iodine (7553-56-2)
Benzalacetone (122-57-6)
Acetophenone (98-86-2)
pyridine (110-86-1)
potassium hydroxide (1310-58-3)
Cyclopentanone (120-92-3)
magnesium methoxide
iodobenzoic acid,
o-iodobenzoic acid (88-67-5)
methylene chloride,
dichloromethane (75-09-2)
1-phenyl-1-propanone (93-55-0)
magnesium sulfate (7487-88-9)
α-Hydroxyacetophenone,
Ethanone, 2-hydroxy-1-phenyl- (582-24-1)
3-pentanone (96-22-0)
osmium tetroxide (20816-12-0)
iodosylbenzene (536-80-1)
hexane (110-54-3)
2-methylcyclohexanone (583-60-8)
Cycloheptanone (502-42-1)
tropinone (532-24-1)
Triethyl phosphite (122-52-1)
triphenylphosphine (603-35-0)
cyclododecanone (830-13-7)
2-Norbornanone (497-38-1)
diacetoxyphenyliodine(III)
molybdenum peroxide
N-methylmorpholine N-oxide (80913-66-2)
p-aminoacetophenone (99-92-3)
o-IODOSYLBENZOIC ACID (304-91-6)
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