Organic Syntheses, Vol. 77, 231
Submitted by Edward G. Corley, Andrew S. Thompson, and Martha Huntington
1.
Checked by Paul J. Hergenrother and Stephen F. Martin.
1. Procedure
Caution!
Butane gas is evolved during the course of the reaction. This preparation should be conducted in a
well-ventilated hood.
A
3-L, three-necked, round-bottomed flask is equipped with a
mechanical stirrer, a
1-L pressure-equalizing addition funnel, and a
reflux condenser that is topped with a
nitrogen inlet. The flask is charged with
102 g (1.0 mol) of 5-chloro-1-pentyne and
250 mL of cyclohexane (Note
1), and the mixture is cooled to 0°C. The cooled solution is reacted with
1.05 L of butyllithium (2.0 M in
cyclohexane, 2.1 mol, 2.1 equiv) (Note
2) that is added dropwise via the addition funnel over 1.5 hr maintaining the temperature < 20°C (Note
3). After the addition is complete, the mixture is heated to reflux (78°C) and maintained at reflux for 3 hr (Note
4), (Note
5). The reaction is cooled to 0° to −10°C and then quenched carefully by the
dropwise addition of aqueous saturated
ammonium chloride (750 mL) (
Caution: the quench is very exothermic; (Note
6).) After the quench is complete, the lower (aqueous) layer is separated and the organic layer is fractionally distilled through a
40-cm × 2.3-cm Hempel column containing Pro-Pak® Monel distillation packing, 0.24" × 0.24" (from Ace Glass). A total of 80-110 mL in the boiling range of
35-78°C is collected. This fraction typically contains
60-80 wt% of
cyclopropylacetylene with the remainder being
cyclohexane and
butane (Note
7), (Note
8). The fraction is then distilled a second time through a
30-cm × 2.3-cm packed column and
39-41 g of
cyclopropylacetylene, bp
52°-55°C, is collected (
58% yield, corrected for purity) (Note
9), (Note
10).
2. Notes
1.
5-Chloro-1-pentyne was purchased from Farchan Laboratories. It is also available from Aldrich Chemical Company, Inc. A freshly opened bottle of
cyclohexane contained 16 μg/mL of water (Karl Fisher). If needed, the
cyclohexane can be dried over 3Å or 4Å molecular sieves.
3. A thick precipitate was formed as the
butyllithium was added. Care should be taken to avoid excessive splashing of the solid onto the walls of the flask, which can result in decreased yield.
4. The reaction was kept under a slight positive pressure of
nitrogen that was vented through an oil bubbler. The
butane gas escapes through the bubbler during the reflux. An efficient condenser cooled with water from an
ice/water bath is necessary.
5. The reaction was monitored by GLC using an HP-5 column:
25-m × 0.32-mm × 0.52-mm fused silica capillary column with a flow rate of 0.5 mL/min of
helium.
6. The temperature of the reaction mixture in this highly exothermic manipulation should be kept below 20°C to avoid loss of the low-boiling product. An addition funnel can be used for the dropwise delivery of the aqueous saturated
ammonium chloride solution, while leaving the reflux condenser in place.
7. The receiving flask should be cooled in an
ice bath to minimize loss of product.
8. If the distillation was terminated sooner, e.g. at 60°C, a significant amount of
cyclopropylacetylene was left in the pot. The pot residue should be assayed to ensure that a significant amount of product was not left behind.
9. This fraction typically contains
5-7 mol% of cyclohexane as measured by NMR. Collection of a narrower boiling range can yield product with less
cyclohexane but at lower recovery.
10. The product showed the following NMR data:
1H (300 MHz, CDCl
3) δ: 0.65-0.78 (m, 4 H), 1.17-1.27 (m, 1 H), 1.73 (d, 1 H, J = 2.2). The sample also exhibited a singlet at δ 1.4 corresponding to
7.6 mol% of cyclohexane;
13C (75 MHz, CDCl
3) δ: −0.8, 8.1, 63.4, 87.6 and cyclohexane at 26.9.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Cyclopropylacetylene has been prepared in a two-step procedure by dichlorination of
cyclopropyl methyl ketone with
phosphorus pentachloride (PCl
5) followed by double dehydrohalogenation with strong base.
2,3,4,5,6,7 This sequence presented significant scale-up problems and the overall yields were low (
20-25%). Results in our hands have been unreliable, especially for the chlorination step that employs solid PCl
5 followed by quenching over ice. The reaction must be kept cold to prevent opening of the cyclopropyl ring by
hydrogen chloride (HCl) to give
2,5-dichloro-2-pentene, which was a major by-product and often the only product of the reaction. Hanack and Bässler
5 report quantitative cyclopropane ring opening unless highly purified PCl
5 was employed. Hanack
6 was able to improve the chlorination step by using
carbon tetrachloride (CCl
4) as the reaction solvent, but his overall yield to
cyclopropylacetylene was only
21%. Salaun
7 improved the elimination step by use of
potassium t-butoxide in
dimethyl sulfoxide (DMSO). In a similar manner
cyclopropylacetylene has been prepared by base-induced dehydrohalogenation of
bromovinylcyclopropane.
2 Cyclopropylacetylene has also been prepared from the 1-trimethylsilyl derivative of
cyclopropylacetylene, which was prepared by treatment of
5-chloro-1-trimethylsilyl-1-pentyne with
lithium diisopropylamide at −78°C followed by warming to room temperature, although no details for the desilylation reaction and product isolation are given.
8
The method presented here offers the advantage of being a one-pot procedure from a commercially available starting material. The initially formed acetylide anion of
5-chloro-1-pentyne undergoes a second deprotonation to the dianion that then cyclizes to cyclopropylacetylide anion.
Cyclopropylacetylene itself is a useful building block, but this method can be extended as an in situ source of cyclopropylacetylide anion that can be trapped with a variety of electrophiles to give other useful building blocks. For example, we have used this method to synthesize
trifluoromethyl cyclopropylethynyl ketone in 60% isolated yield by quenching the acetylide anion with
ethyl trifluoroacetate.
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved