Checked by Paul A. Johnson and Albert I. Meyers.
1. Procedure
Caution! All operations should be conducted in a
well-ventilated hood with breathing protection. The
chromium carbene complex generally is contaminated with the
very volatile and toxic chromium hexacarbonyl, which is also generated as a by-product of the reaction.
An
oven-dried, 2-L, three-necked, round-bottomed flask, equipped with a
nitrogen inlet,
magnetic stirring bar,
thermometer, and
reflux condenser, under an inert
nitrogen atmosphere (Note
1), is charged with
1.22 g (10 mmol) of 4-dimethylaminopyridine (Note
2),
500 mL of tetrahydrofuran (Note
3),
11.0 mL (95.7 mmol) of 1-hexyne (Note
4),
13.2 mL (140 mmol) of acetic anhydride (Note
5),
9.8 mL (70 mmol) of triethylamine (Note
2),
20.0 g (64.0 mmol) of pentacarbonyl[phenyl(methoxy)chromium]carbene (Note
1) and (Note
6), and a final
100-mL rinse of tetrahydrofuran. The solution is heated to reflux with an
oil bath and heating is maintained until TLC indicates that the chromium complex is totally consumed (about 45–60 min, (Note
7)). The solution is then cooled to ambient temperature,
30 g of silica gel is added (Note
8), and volatile organic material is removed under reduced pressure (
rotary evaporator). The green solids are transferred to a filter funnel and washed with
hexane until TLC indicates that all products have been removed (5 × 100 mL) (Note
9). The
hexane filtrate is then concentrated under reduced pressure to give crude product contaminated with
chromium hexacarbonyl. To the mixture is added
20 mL of isopropyl alcohol and the insoluble
chromium hexacarbonyl is removed by filtration (Note
9). The filtrate is concentrated under reduced pressure to give
14.0 g of crude product which is purified by silica gel chromatography (Note
10). Appropriate fractions are combined and the solvent is removed under reduced pressure to give
1-acetoxy-2-butyl-4-methoxynaphthalene (
11.8 g,
>95% pure based on HPLC,
68% yield based on the
carbene complex, (Note
6) and (Note
11)) as a light yellow oil which crystallizes on standing (Note
12). If desired, the product can be crystallized from
isopropyl alcohol (2.5 mL/g) to give white crystals, mp
49–50°C (>99% pure based on HPLC).
2. Notes
1. Although slowly decomposed by exposure to air (
oxygen), the
chromium carbene complex is sufficiently stable to handle using ordinary
nitrogen drybox techniques. The complex should be stored at refrigerator temperature. All solvents and liquid reagents were routinely deoxygenated prior to use with a slow stream of
nitrogen.
4.
1-Hexyne was obtained from Farchan Chemical Company or Aldrich Chemical Company, Inc., and used without further purification.
5.
Acetic anhydride was obtained from Mallinckrodt Inc. or Aldrich Chemical Company, Inc., and used without further purification.
6.
Pentacarbonyl[phenyl(methoxy)carbene]chromium was prepared by the checkers in
75% yield according to the literature: Hegedus, L. S.; McGuire, M. A.; Schultze, L. M.
Org. Synth., Coll. Vol. VIII 1993, 216. This material was stored under
nitrogen at −30°C and purified immediately prior to use by filtration through a plug of Celite (
hexane solvent). If the
chromium carbene is purchased from Aldrich Chemical Company, Inc., the submitters found it was only 65% pure based on capillary GLC analysis.
7. Analytical thin layer chromatography (TLC) was conducted on
10 × 2.5-cm precoated glass plates (silica gel GF, 0.25-mm thickness, Analtech), eluted with
10% ethyl acetate in hexane, and visualized with both UV (254 nm) and aqueous
50% sulfuric acid spray/heating. The carbene complex moves as an orange spot on TLC; the reaction is complete when this spot is no longer visible.
8. The chromium complex degrades into
chromium hexacarbonyl and an intractable green
chromium tar. The addition of silica gel prior to solvent removal adsorbs this material before it can form a tar.
9. The solid material containing
chromium waste was placed in a
container for heavy metal wastes and disposed of by a commercial service according to approved procedures
10.
Silica gel (obtained from E. Merck or Alfa Products, Morton/Thiokol Inc.) was used (420 g, 70–230 mesh) in a
5.5 × 60-cm column eluted with
10% ethyl acetate in hexane.
11. This reaction has been performed on a scale up to 20 times larger by the submitters (
400 g of chromium carbene complex) with identical results.
12. The NMR spectrum was as follows:
13C NMR (75 MHz, CDCl
3) δ: 17.3, 20.2, 23.1, 31.4, 67.4, 127.1, 127.2, 127.9, 128.2, 128.3, 128.6, 128.7, 130.1, 130.3, 141.2, 172.0, 216.1.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995. (See (Note
9)).
3. Discussion
The regioselective preparation of 2-substituted naphthalenediol derivatives having the diols differentially protected in a predictable and straightforward manner, previously not directly attainable, is readily accomplished using
chromium carbene complexes. First prepared by E. O. Fischer,
chromium carbene complexes react readily with alkynes (extensively investigated by K. H. Dötz, and others).
3 Steric effects dictate the substitution pattern observed
2,4 and the reaction mechanism has been widely studied.
2
The title compound (U-66,858) and analogues are of interest as lipoxygenase inhibitors with potential application to the treatment of asthma and related disorders.
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