Organic Syntheses, Coll. Vol. 9, p.1 (1998); Vol. 71, p.72 (1993).
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
, 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
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).
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
1-Hexyne was obtained from Farchan Chemical Company or Aldrich Chemical Company, Inc.
, and used without further purification.
Acetic anhydride was obtained from Mallinckrodt Inc. or Aldrich Chemical Company, Inc.
, and used without further purification.
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.
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.
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.
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
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
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.
The NMR spectrum was as follows: 13
C NMR (75 MHz, CDCl3
) 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.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995. (See (Note 9)
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 observed2,4
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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