Checked by R. Andersen and G. Büchi.
1. Procedure
Caution!
Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving
benzene should be carried out in a
well-ventilated hood, and glove protection is required.
After 20 hours at reflux, the mixture is cooled to room temperature with a
water bath and poured with vigorous stirring into
500 ml. of 10% aqueous potassium carbonate contained in a
1-l. separatory funnel. The
benzene layer is washed successively with two
250-ml. portions of 10% aqueous potassium carbonate and
250 ml. of brine containing potassium carbonate (Note
3), dried over
sodium sulfate for 10 minutes, and filtered. Removal of the solvent on a
rotary evaporator with a 25–35° water bath provides a solid yellow residue, which is dried under vacuum.
To obtain a crystalline product, a solution of the residue in
30 ml. of benzene containing a few drops of
triethylamine (Note
4) is placed in a
250-ml. Erlenmeyer flask, heated gently on a
steam bath, and diluted with
150 ml. of hexane. Heating is continued for about 5 minutes (Note
5), after which the solution is allowed to cool to room temperature, seeded, and put in a freezer at −15° for at least 5 hours. The resulting solid is collected by suction filtration, washed with cold
hexane, and vacuum dried, giving
5.8 g. (
94%) of light cream-colored crystals, m.p.
75–77°.
B.
4-Ethoxy-3-hydroxybenzaldehyde. A
100-ml., three-necked flask containing a magnetic stirring bar and fitted with an argon inlet, a
rubber septum, and a
ground-glass stopper in the center neck is evacuated, flame-dried, and allowed to cool under a positive pressure of
argon, which is maintained throughout the following sequence. Using a syringe,
30 ml. of dry tetrahydrofuran (Note
6) and
5.0 ml. (0.029 mole) of diphenylphosphine (Note
7) are added through the septum. The resulting solution is stirred and cooled with an
ice bath, and
15 ml. (0.032 mole) of cold 2.1 M n-butyllithium–hexane solution (Note
8) is added by syringe over
ca. 3 minutes. Stirring is continued as the red solution is allowed to warm to room temperature over about 30 minutes before
5.0 g. (0.022 mole) of 4-ethoxy-3-methoxybenzaldehyde ethylene acetal is added through the center neck. The flask is stoppered, and the mixture is stirred at room temperature for 2 hours.
The reaction mixture is then poured into a
500-ml. Erlenmeyer flask containing 200 ml. of vigorously stirred water,
10 ml. of 10% aqueous sodium hydroxide is added, and the mixture is transferred to a
500-ml. separatory funnel. The reaction vessel and Erlenmeyer flask are rinsed with water, and the rinsings are also poured into the funnel. Alkali-insoluble impurities are removed by washing the basic aqueous phase with four
100-ml. portions of diethyl ether, which are combined and backextracted with two
50-ml. portions of 10% aqueous sodium hydroxide. The combined aqueous layers are then put into a
1-l. Erlenmeyer flask, cooled in an ice bath, and acidified with concentrated
hydrochloric acid to a Congo red end point. During acidification the clear yellow basic solution becomes cloudy white. This milky suspension is stirred without cooling for 3 minutes then extracted with
200 ml. of ether and two
100-ml. portions of ether. The combined
ether layers are washed successively with 100 ml. of water and
100 ml. of saturated aqueous sodium chloride, dried over
magnesium sulfate, and filtered. Removal of solvent with a rotary evaporator provides a residue that is vacuum dried, yielding
3.58–3.60 g. (
97–98%) of a slightly yellow solid, m.p.
121.5–126°. One recrystallization from
20 ml. of benzene gives almost white crystals which are vacuum dried, affording
3.21–3.29 g. (
87–88%) of
4-hydroxy-3-ethoxybenzaldehyde, m.p.
125.5–127° (Note
9) and (Note
10).
2. Notes
1.
Reagent grade benzene was used without further purification.
2.
Practical grade 4-ethoxy-3-methoxybenzaldehyde was obtained by the submitters from MC and B Manufacturing Chemists and by the checkers from Aldrich Chemical Company, Inc. This material was purified by distillation (b. p.
125–135°/0.1 mm.), followed by one recrystallization from
cyclohexane (100 ml./10 g. crude solid). Colorless crystals, m.p.
60–62°, were obtained after filtration and vacuum drying. Purification of
20 g. of the commercial material gave about
15 g. of recrystallized product.
5. It is not necessary to boil the solution. This heating merely prevents crystals from coming out of solution too fast on addition of the
hexane.
7. Commercial
diphenylphosphine obtained from Orgmet, Inc., may be used without further purification. Alternatively, the material may be prepared from
triphenylphosphine as follows. A
2-l., three-necked flask containing a magnetic stirring bar and fitted with an argon inlet is charged with
120 g. (0.458 mole) of triphenylphosphine and
1 l. of dry tetrahydrofuran ((Note
6)). To the stirred solution is added
18.42 g. (2.670 g.-atoms, 542 cm. of 0.32 cm.-diameter wire) of lithium wire, which has been washed with
hexane and dried carefully with a paper towel.
(Caution! If the towel is rubbed against the lithium too fast, a fire will result.) Lithium is added by cutting 3–5-mm. segments directly into the center neck of the flask with scissors. A slow
argon flow is maintained throughout the addition, which requires about 20 minutes. The flask is stoppered, and the red solution is stirred for 2.5 hours under
argon.
The solution is then filtered through a piece of glass wool (fitted loosely in a funnel) into a
2-l. beaker containing 600 g. of crushed ice. A
glass rod is used to stir the mixture, and the reaction vessel and filter are rinsed with
ether. The resulting two clear phases are transferred to a
2-l. separatory funnel and extracted with four
200-ml. portions of ether. The combined
ether layers are washed with
250 ml. of 5% hydrochloric acid, 250 ml. of water, and two
250-ml. portions of saturated aqueous sodium chloride, then dried over
magnesium sulfate for

hour. Since
diphenylphosphine is susceptible to air oxidation, especially in dilute
ether solution, the extractions should be carried out as quickly as possible. After gravity filtration, the
ether solution is concentrated on a rotary evaporator, and the residue is vacuum dried, yielding
83.7 g. (
99%) of crude product. Pure material is then obtained by distillation. The submitters used a
small (14/20 joints, 15 cm. long) Vigreux column and observed b.p.
90–103° (0.06 mm.). Using a
20-cm. Vigreux column, the checkers observed b.p.
95–115° (0.06 mm.). In either case, the yield of clear liquid was
62 g. (
74%). If the product is stored under
argon in a bottle sealed with a rubber serum cap, it is stable for months at room temperature.
Caution! Care should be taken not to get any diphenylphosphine on a paper towel, as it may ignite spontaneously.
9. The literature m.p. for the colorless crystals is
127–128°.
3
10. IR (CHCl
3) cm.
−1: 3550 (OH), 1680 (C=O), 1610, 1580, 1510, 1470;
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons): 1.47 (t,
J = 7,
3. Discussion
The present procedure illustrates the facile demethylation of methyl aryl ethers with
lithium diphenylphosphide.
4 This reaction is specific for methyl ethers and may be carried out in the presence of ethyl ethers in high yield.
5 Use of excess reagent allows cleavage in the presence of enolizable ketones.
6 In the present case, the cleavage may be performed without protection of the aldehyde, but two equivalents of reagent are required, and the yield is reduced to
ca. 60%.
The exact time and temperature required for complete reaction must be determined for each individual compound. It has been observed that nucleophilic demethylation of methyl
o-alkoxyaryl ethers is accelerated relative to
anisole,
7 and this reaction is no exception.
Lithium diphenylphosphide cleavage of
anisole is complete in about 4 hours in refluxing
tetrahydrofuran, whereas the present reaction is complete within 2 hours at 25°.
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