Organic Syntheses, Coll. Vol. 3, p.281 (1955); Vol. 21, p.22 (1941).
(I). In a 5-l. three-necked round-bottomed flask
, fitted with a mechanical stirrer
, a thermometer
reaching to the bottom, and a dropping funnel
, is placed 2 l. of concentrated sulfuric acid
(sp. gr. 1.84). The flask is surrounded by an ice bath
, and when the temperature falls below 10° a solution of 220 g. (2 moles) of resorcinol
in 260 g. (2 moles) of freshly distilled ethyl acetoacetate
is added dropwise. The mixture is stirred, and the temperature is kept below 10° by means of ice and salt. After all the solution has been added (about 2 hours) the reaction mixture is set aside for 12–24 hours without further cooling. The reaction mixture is now poured with vigorous stirring into a mixture of 4 kg. of ice and 6 l. of water. The precipitate is collected on a filter and washed with three 50-ml. portions of cold water. The crude product is then dissolved in 3 l. of 5% aqueous sodium hydroxide
solution, the solution is filtered, and the substituted coumarin
is reprecipitated from the filtrate by the slow addition of dilute (1:10) sulfuric acid
until the solution is acid to litmus. About 1.1 l. of dilute sulfuric acid
is required. During the neutralization, the reaction mixture must be well stirred. The product is collected on a Büchner funnel
, washed with four 50-ml. portions of cold water, and dried. The yield of 4-methyl-7-hydroxycoumarin
is 290–320 g.
). It is sufficiently pure for use in the next step but may be purified by recrystallization from 95% ethanol
using about 15 ml. of ethanol
for 5 g. of product. The recrystallized material forms stout almost colorless needles melting at 185°
(II). A mixture of 286 g. (1.6 moles) of crude, dry 4-methyl-7-hydroxycoumarin
and 572 g. (5.6 moles) of acetic anhydride
is placed in a 2-l. round-bottomed flask
fitted to a reflux condenser
by a ground-glass joint. The mixture is refluxed for 1.5 hours, cooled to about 50°, and poured with vigorous stirring into a mixture of 4 kg. of cracked ice and 4 l. of water. The precipitate is collected on a Büchner funnel, washed with five 50-ml. portions of cold water, and spread on absorbent paper to dry. The drying is completed by placing the product in a steam oven
for 10 hours. The yield of crude 4-methyl-7-acetoxycoumarin
is 320–340 g.
). It may be purified by recrystallization from 95% ethanol
(5 g. of compound to 20 ml. of solvent) and forms fibrous needles melting at 150–151°
. The crude oven-dried product is finely powdered and used in the next step.
(III). In a clean, dry, 5-l. round-bottomed flask
are placed 200 g. (0.92 mole) of dry, powdered 4-methyl-7-acetoxycoumarin
and 453 g. (3.4 moles) of technical anhydrous aluminum chloride
. The flask is stoppered and shaken vigorously for 3–5 minutes in order to mix the ingredients thoroughly. The stopper is removed and the flask attached to a reflux condenser fitted with a gas-absorption tube. The flask is placed in an oil bath
the temperature of which is raised quickly to 125° and then slowly over a period of 2 hours to 170°. At the end of this time the flask is removed from the oil bath, allowed to cool, and immersed in an ice bath. About 1 kg. of cracked ice is added, and then 2.4 l. of dilute (1:7) hydrochloric acid
is added over a period of about 2 hours. The mixture is then heated on a steam bath
for 30 minutes with vigorous stirring in order to effect complete decomposition. The mixture is filtered and the precipitate washed with four 50-ml. portions of cold water and sucked dry. This crude product is recrystallized by dissolving it in 4 l. of hot 95% ethanol
, filtering the hot solution through a warm funnel, and chilling the filtrate. The crystals are collected on a funnel and air-dried. The product melts at 162–163°
, and the yield is 145–155 g.
) (Note 1)
(IV). A 5-l. three-necked round-bottomed flask is fitted with a reflux condenser, a dropping funnel, and a glass tube, extending to the bottom of the flask, connected to a cylinder of nitrogen (Note 2)
. In the flask are placed 148 g. (0.68 mole) of 4-methyl-7-hydroxy-8-acetylcoumarin
and 500 ml. of distilled water. A rapid stream of nitrogen
is bubbled through the water suspension until all the air in the apparatus is displaced, and then a slow stream of the gas is kept passing through the solution (Note 3)
. A solution of 129 g. (3.23 moles) of sodium hydroxide
in 580 ml. of water is added through the dropping funnel, and the mixture is heated on a steam bath for 5 hours. The solution is then cooled and acidified by the addition of about 1 l. of dilute (1:3) hydrochloric acid
. The stream of nitrogen
gas is continued throughout the period of heating and while the solution is cooling. It may be stopped after the solution is acid. The crude 2,6-dihydroxyacetophenone
which separates on acidification is collected on a filter, washed three times with 50-ml. portions of cold water, and air-dried. A yield of 90–95 g.
based on the 4-methyl-7-hydroxy-8-acetylcoumarin
) of light-yellow solid is obtained.
The purification is accomplished by dissolving the crude product in 1 l. of 95% ethanol
, adding 20 g. of Norit
, and heating the mixture on a steam cone for 15 minutes with occasional shaking. After this time, 800 ml. of warm water is added, and the solution is heated 5 more minutes and filtered through a hot funnel. The greenish filtrate is chilled in an ice-salt bath
, and the first crop (about 65 g.
) of lemon-yellow needles of 2,6-dihydroxyacetophenone
is removed by filtration. The filtrate is then concentrated under reduced pressure to a volume of 800 ml., again chilled, and the second crop of product (about 15 g.
) collected on a filter. The total yield of purified 2,6-dihydroxyacetophenone
, melting at 154–155°
, is 75–85 g.
(a recovery of 83–89%
) (Note 4)
or illuminating gas may be used in place of nitrogen
, provided that proper precautions are taken to conduct the gas from the condenser to a flue.
It is important to prevent oxygen
from coming in contact with the alkaline solution of the 2,6-dihydroxyacetophenone
since it causes the formation of oxidation products which materially lower the yield and cause difficulty in purification. The inert atmosphere must be maintained until after the mixture is acidified.
The first two steps in this preparation have been carried out using four times the quantities stated with no reduction in the yields. The third step, involving the Fries rearrangement, usually gives lower yields when larger amounts are used. The amounts of materials in the fourth step may be doubled.
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