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 (
78–92%) (Note
15);
n22D 1.4559 (Note
16);
1H NMR (90 MHz, neat) δ: 1.18–1.93 (br m, 6, H
2',2'', H
3',3'', H
4',4''); 2.47 (t, 1,
J = 2, C

C-
H), 3.17–3.84 (m, 2, H
5',5''), 4.03 (d, 2,
J = 2, C

C-
CH2O), 4.63 (s, 1, H
1); IR (neat) cm
−1: 3300 (C

C-
H), 2117 (C

C stretch).
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 in
tetrahydrofuran 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 (H
+ 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 (
60–65%), by
66–69°C/0.2 mm,
n22D 1.4684 (Note
17);
1H NMR [(CD
3)
2SO] δ: 3.79 (s, 3, OCH
3), 4.31 (d, 2, CH
2,
J = 6), 5.57 (t, 1, OH); IR (neat) cm
−1: 3410 (OH), 2240 (-C

C-), 1715 (ester).