Organic Syntheses, Coll. Vol. 7, p.334 (1990); Vol. 60, p.81 (1981).
A. Tetrahydropyranyl derivative of propargyl alcohol [tetrahydro-2-(2-propynyloxy)-2H-pyran]
. Two crystals (ca. 10 mg) of p-toluenesulfonic acid monohydrate
are added to 268 g (291.3 mL, 3.2 mol) of warm (60°C) dihydropyran (Note 2)
in a 1-L, three-necked, round-bottomed flask
equipped with a magnetic stirring bar
, a thermometer
, a dropping funnel
containing 168 g (174.5 mL, 3.0 mol) of propargyl alcohol (Note 2)
and a reflux condenser fitted with a drying tube
. Stirring is started, and the propargyl alcohol
is added (Note 3)
as a thin stream during a period of ca. 30 min. The reaction is mildly exothermic, and the temperature is maintained at 60–65°C by controlling the rate of addition of the propargyl alcohol
and by occasional external cooling with an ice bath. After the addition is completed, the temperature is monitored for another 30 min; slight cooling is sometimes necessary to keep the temperature in the range of 60–65°C. The reaction mixture is stirred for a total of 1.5 hr after the addition is completed, and then 0.5 g of powdered sodium bicarbonate
is added and the mixture stirred for another hour. The mixture is then gravity-filtered into a 1-L, round-bottomed flask
. The reaction mixture is distilled through a 45-cm Vigreux column
under reduced pressure (Note 15)
. A small forerun (ca. 40 mL) with a bp of 45°C (15–20 mm) is followed by the product, bp 47–50°C (3.5–5 mm)
, 330–355 g
) (Note 15)
1.4559 (Note 16)
H NMR (90 MHz, neat) δ: 1.18–1.93 (br m, 6, H2',2''
); 2.47 (t, 1, J
= 2, C
), 3.17–3.84 (m, 2, H5',5''
), 4.03 (d, 2, J
= 2, C
O), 4.63 (s, 1, H1
); IR (neat) cm−1
: 3300 (C
), 2117 (C
B. Methyl 4-hydroxy-2-butynoate
. One mole of ethylmagnesium bromide (Note 4)
in diethyl ether
is poured into a dry (Note 5) 2-L, three-necked, round-bottomed flask
fitted with a mechanical stirrer
and a glass stirrer
bearing (Note 6)
, a dropping funnel fitted with a nitrogen-inlet tube
, and an efficient condenser fitted with a drying tube. Stirring is started, and a solution of 140 g (1.0 mol, 141 mL) of the tetrahydropyranyl derivative of propargyl alcohol
in 1-L of dry (Note 7) tetrahydrofuran
is added during ca. 30 min (Note 8)
. Stirring is continued for an additional 1.5 hr, during which time a dry 3-L, three-necked flask
is fitted with a mechanical stirrer, immersion thermometer
, and dropping funnel. The 3-L flask is charged with a solution of 104 g (1.10 mol, 85.4 mL) of methyl chloroformate (Note 2)
in 250 mL of tetrahydrofuran
and the contents stirred and cooled to −20°C with a dry ice-acetone bath
. Under gentle nitrogen
pressure the acetylenic Grignard reagent is transferred portionwise through a -in. polypropylene tube
to the dropping funnel attached to the 3-L, three-necked flask (Note 9)
. The acetylenic Grignard reagent is then added dropwise during 1.5 hr to the well-stirred solution of methyl chloroformate
while the temperature is maintained at −15 to −20°C by external cooling. After the addition is completed, the light-brown reaction mixture is stirred another 30 min at −15°C, followed by another 1.5 hr at ice temperature. The reaction mixture is then stored without stirring for 12 hr at +3°C, during which time the remaining magnesium salts separate from solution. The salts are removed by filtration (Note 10)
and washed with three 150-mL portions of cold (0°C), dry toluene
. The supernatant and washings are combined and concentrated (Note 11)
to ca. 500-mL volume. The dark-brown solution is then washed five times with 100-mL portions of saturated brine
followed by drying over anhydrous sodium sulfate
. The solution is concentrated to remove the toluene
and then dissolved (Note 12)
in 1 L of anhydrous methanol
; 25 mL of Dowex 50-X4 cation resin
form, prewashed with anhydrous methanol
) is then added and the mixture stirred for 1.5 hr at 25°C. The ion-exchange resin is removed by filtration through a sintered-glass filter
and is then washed with two 50-mL portions of anhydrous methanol
. Solvent and 2-methoxytetrahydropyran
are removed by concentration using a water aspirator
and then an oil pump
at 0.5-mm pressure. The residue from the concentration is then treated a second time (Note 13)
with 1 L of anhydrous methanol
and 25 mL of Dowex 50
, followed by concentration as before. The residue is then distilled through a Claisen head
to give methyl 4-hydroxy-2-butynoate (Note 14)
, 69–74 g
), by 66–69°C/0.2 mm
1.4684 (Note 17)
H NMR [(CD3
SO] δ: 3.79 (s, 3, OCH3
), 4.31 (d, 2, CH2
= 6), 5.57 (t, 1, OH); IR (neat) cm−1
: 3410 (OH), 2240 (-C
C-), 1715 (ester).
Acetylenic compounds are potentially explosive, and all concentrations and distillations should be carried out behind a safety shield. Methyl 4-hydroxy-2-butynoate
is a potent vesicant that causes painful burns on contact with skin. All operations should be carried out in an efficient fume hood
and gloves should be worn at all times.
As supplied by Aldrich Chemical Company, Inc. (97% purity).
The general method of Robertson,3
whereby toluenesulfonic acid monohydrate
is added to a mixture of an alcohol and dihydropyran
, is not recommended for this preparation since the reaction is rather exothermic. Reaction temperatures below 60°C are to be avoided for the same reason since unreacted reagents accumulate and the reaction may suddenly get out of hand with resulting boiling and colorization of the reaction mixture.
Glassware was dried in an oven
at 110°C, assembled while still hot, and flushed with dry nitrogen
as the assembly cooled to room temperature. All reactions involving the Grignard reagents were carried out under an atmosphere of dry nitrogen
and in a fume hood.
The bearing was lubricated with mineral oil.
Anhydrous tetrahydrofuran from MCB, Inc.
was used for the reactions. Freshly opened bottles gave no effervescence when mixed with powdered calcium hydride
. If smaller amounts of tetrahydrofuran
are used, the acetylenic Grignard reagent often crystallizes out of the reaction mixture.
Vigorous gas evolution (highly flammable ethane
gas) and boiling take place during the addition.
This type of transfer technique5
is preferred to open-air transfer to minimize losses due to hydrolysis by atmospheric moisture.
Filtration and subsequent washing of the hygroscopic salts are best carried out by replacing the dropping funnel in the reaction vessel with a sintered-glass filter stick. The reaction mixture is kept under a slightly positive nitrogen
pressure while the supernatant is led from the filter stick through a polypropylene tube to a suction flask that is kept under a slightly negative pressure with the help of an aspirator.
Concentrations were carried out using a rotary evaporator
and at a pressure of 12–15 mm and a temperature not exceeding 35°C unless otherwise noted.
The crude product at this stage shows the following 1
H NMR (CDCl3
) δ: 1.22–1.97 (m, 6 H, H2',2''
), 3.26–4.08 (m, 2, H5',5''
), 3.76 (s, 3, OCH3
), 4.36 (s, 2, C
), 4.81 (bs, 1, H1
Distillation of the residue after the first treatment with Dowex 50 and methanol
gives a product containing 7–10% of the tetrahydropyranyl derivative of methyl 4-hydroxy-2-butynoate
. Removal of the by-product 2-methoxytetrahydropyran
and retreatment with Dowex 50 and methanol
gives a product containing only 0.5–1.5% of the undeblocked alcohol.
The distillate often turns a light pink or yellow color in the receiver flask.
The checkers found that distillation at a pressure of 15–20 mm (submitters) gave a somewhat lower yield (78–84%
). A slight yield improvement (78–94%
) was obtained by the checkers by using lower pressure in the distillation.
The submitters reported n22D
The submitters reported n22D
The preparation of the tetrahydropyranyl derivative of propargyl alcohol
is a modification of a published3
general procedure that is simple and useful for large-scale preparations.
The first part of the procedure illustrates a method for the preparation of the tetrahydropyranyl derivative of an alcohol which requires no extraction or wash procedures during the workup of the product.
The second part of the preparation illustrates a very efficient, mild method for the preparation of a highly reactive α,β-acetylenic ester via the carbomethoxylation of the Grignard reagent of a terminal acetylenic compound with methyl chloroformate
. This preparation of methyl 4-hydroxy-2-butynoate
obviates the necessity6
of carrying out the carboxylation of an acetylenic Grignard reagent in an autoclave. This procedure also eliminates the necessity6
of carrying out the continuous ether
extraction of 4-hydroxy-2-butynoic acid
from an aqueous phase.
The use of a mixture of a strongly acidic cation-exchange resin and methanol
to remove a tetrahydropyranyl protecting group offers a very mild method of deblocking that does not require the use of a base during the workup.
has been used6
as a starting material for the preparation of a δ-hydroxy-α,β-acetylenic ester. It has also been employed8
as a dipolarophile in a 1,3-dipolar cycloaddition reaction that resulted in the first synthesis of 8-aza-3-deazaguanosine.
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