Organic Syntheses, CV 9, 640
Submitted by Ruen Chu Sun
1, Masami Okabe
1, David L. Coffen
1, and Jeffrey Schwartz
2.
Checked by Daniel J. Keavy and Robert K. Boeckman, Jr..
1. Procedure
3-(1-Octen-1-yl)cyclopentanone.
3 A
38.7-g quantity (0.150 mol) of chlorobis(η5-cyclopentadienyl)hydridozirconium, Schwartz's reagent, (Note
1) is weighed into an oven-dried,
250-mL, three-necked flask. The flask, equipped with
argon inlet and exit tubes, a
thermometer and
magnetic stirrer, is placed in an
ice/water cooling bath. Under an atmosphere of
argon,
50 mL of dry tetrahydrofuran (Note
2) and
23.6 mL (0.16 mol) of freshly distilled 1-octyne (Note
3) are added. The ice/water cooling bath is used to keep the temperature between 15°C and 25°C during the addition. Stirring is continued in the ice bath for 2 hr to control a mildly exothermic reaction; then the flask is wrapped in
aluminum foil and stirred overnight at room temperature (elapsed time is 18 hr). At this point,
10.9 mL (0.130 mol) of freshly distilled 2-cyclopentenone (Note
3) is added and the reaction mixture is chilled in an ice bath for 10 min. To the cooled reaction mixture a total of
3.34 g (0.0130 mol) of vacuum-sublimed (at 180°C), powdered, solid nickel acetylacetonate (Note
3),(Note
4) is added in three portions at 10-min intervals, keeping the temperature of the reaction mixture below 50°C (Note
5),(Note
6).
The mixture is stirred for 2 hr in the ice bath and for 2 hr at room temperature, then poured into a
large Erlenmeyer flask containing
150 mL of 1 N hydrochloric acid and 200 mL of ice/water mixture.
Hexane (400 mL) is added and the quenched reaction mixture is stirred for 30 min. Solid material is removed by vacuum filtration (Note
7) and the solids are washed with
hexane (3 × 70 mL). The combined filtrates are transferred to a separatory funnel and the organic layer is removed. The aqueous layer (Note
7) is extracted with
300 mL of hexane and the extract is combined with the original organic layer. After the organic layer is washed successively with
300-mL portions of saturated sodium bicarbonate solution and
brine, it is dried over
sodium sulfate and concentrated under reduced pressure to give
24.8 g of crude product. The crude product is placed on a chromatography column prepared from
550 g of silica gel and
hexane. The column is eluted with
2% ethyl acetate in hexane until 3.5 L of eluant has been collected. Then
4% ethyl acetate in hexane is used. The fractions containing the product (TLC) are combined and evaporated, finally under high vacuum, to afford
15.4 g (
61%) of a very pale yellow liquid (Note
8). GC analysis of this product on an OV17 50-m capillary column (100°C to 200°C at 5°C/min) shows it to be 98.2% pure.
The material is distilled in a Kugelrohr apparatus at 0.15 mm and an oven temperature of 95–105°C to give
15.0 g (
59% overall yield) of material with GC purity of 98.3% (Note
9).
2. Notes
1.
Chlorobis(η5-cyclopentadienyl)hydridozirconium was prepared by
lithium aluminum hydride reduction of the dichloro compound using the procedure of Buchwald and co-workers.
4 When carried out using
chlorobis(η5-cyclopentadienyl)-hydridozirconium obtained from a commercial source, the procedure afforded only a
28% yield of final product.
4. For some applications of this chemistry, it may be preferable first to reduce the
nickel catalyst with DIBAL.
3
5. The checkers observed a significant induction period prior to onset of the exothermic reaction. Care must be taken to avoid addition of the
nickel acetylacetonate too rapidly initially or temperature control becomes difficult.
7. Disposal of waste materials containing nickel salts should be carried out in an environmentally acceptable manner.
8. The checkers employed a flash chromatography technique, and
4% ethyl acetate/hexanes as the TLC solvent system to monitor the chromatographic separation.
9. The NMR spectrum of the product [
1H NMR (CDCl
3) δ] showed a characteristic set of multiplets from 0.8 to 2.9 ppm and olefinic protons at 5.43 (dd, 1 H, J = 15.4 and 6.4) and 5.49 ppm (dt, 1 H, J = 15.4 and 5.8);
13C NMR (75 MHz, CDCl
3) δ: 14.0, 22.6, 28.7, 29.3, 29.9, 31.6, 32.4, 38.1, 39.7, 44.9, 130.6, 131.9, 219.0; IR (neat) cm
−1: 1743; MS m/e 194 (M
+). Anal. Calcd for C
13H
22O: C, 80.35; H, 11.41. Found: C, 80.40; H, 11.35. The checkers employed a
30-m Durawax DX3 column for the GC analysis and found a purity of 97%.
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
This example does not illustrate the highest yield application of this chemistry. Coupling of
1-octyne and
cyclopentenone was selected because these materials are commercially available and because this coupling exemplifies, in a prototypical fashion, the application of this powerful chemistry to prostaglandin synthesis. Several additional examples are presented in the original publication.
3
A closely related coupling reaction is a key step in a synthesis of the anti-ulcer prostaglandin
1, a synthesis that was developed for large scale preparation of this compound.
5
The simplicity of operation and flawless rendering of (E)-geometry make this an attractive alternative to vinylcuprate additions.
This preparation is referenced from:
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved