Organic Syntheses, CV 8, 371
Submitted by M. Olomucki and J. Y. Le Gall
1.
Checked by H. T. M. Le and M. F. Semmelhack.
1. Procedure
A
250-mL, round-bottomed flask is equipped with
stirring bar (Note
1),
thermometer, and
pressure-equalizing dropping funnel (dried in an
oven at 80°C, assembled while still hot), and the system is placed under
argon (Note
2). Via syringe,
7.45 g (7.16 mL, 0.1 mol) of propargyl chloride (Note
3) and
35 mL of anhydrous diethyl ether (Note
4) are added. The solution is stirred and cooled to −50 to −60°C (Note
5) with an
alcohol–dry ice bath (Note
6). Under gentle
argon pressure,
72.4 mL of a 1.41 M solution of methyllithium in
diethyl ether (Note
7) is added dropwise over ca. 20 min (Note
8). Stirring is continued for 15 min and
18.9 g (0.2 mol) (Note 9) of methyl chloroformate (Note
10) is added through the dropping funnel over ca. 10 min. The reaction mixture is allowed to warm slowly (3–4 hr) to 0 to −5°C, during which time a fine precipitate appears. Water (40 mL) is added dropwise with efficient stirring; the ether layer is separated and the aqueous layer is extracted 2 times with
ether. The combined
ether solutions are dried over anhydrous
magnesium sulfate, and the
ether is removed under reduced pressure with a
rotary evaporator. The residual liquid is distilled in a simple distillation assembly under reduced pressure, affording
10.7–11.1 g (
81–83%) of
methyl 4-chloro-2-butynoate as a colorless liquid, bp
41°C (0.25 mm),
n22D 1.4728 (Note
11).
2. Notes
1. The submitters specify a
mechanical stirrer; the checkers find magnetic stirring to be more convenient and equally effective.
2. The system was alternately evacuated with an oil pump and then filled with
argon 3 or more times, and a positive pressure was maintained throughout the reaction period. The submitters used
nitrogen in place of
argon.
3.
Propargyl chloride (98% purity), obtained from Fluka AG, was used without further purification.
5. Although cooling to −20 to −30°C is sufficient, the addition of
methyllithium is more convenient at lower temperatures.
6. The checkers used a constant temperature
refrigerated bath (Cryocool).
7.
Methyllithium in the form of solutions in diethyl ether is supplied by Aldrich Chemical Company, Inc. in
rubber septum stoppered bottles, which should be stored in a refrigerator.
8. The solution of
methyllithium was conveniently handled using techniques for the manipulation of air-sensitive reagents.
2
11. The product gives satisfactory elemental analysis and shows the following IR spectrum (film) cm
−1: 2267, 1725, 720.
3. Discussion
The present synthesis illustrates a convenient preparation of chlorotetrolic esters that can be performed in one step starting from commercially available and inexpensive products; it is faster and gives better yields as compared with the overall yields of the multistep preparations described earlier. Since
chlorotetrolic acid is not an intermediate in this synthesis, the necessity of distilling this explosive product is eliminated. In contrast to the acid, explosions were never observed during distillations of the lower-boiling chlorotetrolic esters.
Chlorotetrolic esters are small, highly functionalized, reactive molecules; of particular interest is the possibility of using them as reagents for chemical modification of biological macromolecules. Different protein nucleophiles react under mild conditions with
methyl 4-chloro-2-butynoate by addition across the triple bond and/or substitution of
chlorine7 while the triple bond and the ester group are involved in the reaction of chlorotetrolic esters with nucleic acid bases.
8
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