Org. Synth. 2002, 79, 251
DOI: 10.15227/orgsyn.079.0251
[4+3] CYCLOADDITION IN WATER. SYNTHESIS OF 2,4-endo,endo-DIMETHYL-8-OXABICYCLO[3.2.1]OCT-6-EN-3-ONE
[
8-Oxabicyclo[3.2.1]oct-6-en-3-one, 2,4-dimethyl-, (endo,endo)-
]
Submitted by Mark Lautens and Giliane Bouchain
1
.
Checked by Patrick Foyle and Steven Wolff.
1. Procedure
A.
2-Chloropentan-3-one
,
2
. A 500-mL, two-necked, round-bottomed flask,
containing a magnetic stirring bar, is equipped with a 100-mL
pressure-equalizing addition funnel and a reflux condenser
fitted with a calcium chloride trap. The flask is charged with
85 mL (69.40 g, 0.80
mol) of pentan-3-one
1
(Note 1) and
200 mL
of carbon tetrachloride
and the mixture is heated to 45°C
in an oil bath. The addition funnel is charged with
71 mL (0.88 mol, 1.1 mol equiv) of
sulfuryl chloride
that is added dropwise over a period
of 2 hr. The resulting mixture is stirred for 3 hr at 45°C,
carbon
tetrachloride
is removed by distillation under atmospheric pressure
at 85°C (Note 2) and the residue is purified by distillation
under reduced pressure (Note 3). After a forerun at 65-80°C
(62 mm) containing mainly
3-pentanone
,
2-chloropentan-3-one
2
is collected (bp 80-102°C, 62 mm)
as a pale yellow liquid (77.0 g,
80%) (Notes 4, 5).
B.
2,4-endo,endo-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one
,
3
. A 500-mL round-bottomed flask is equipped
with a magnetic stirring bar and a 50-mL pressure-equalizing
addition funnel. The flask is charged with
15.0
g (0.12 mol) of 2
(Note 6),
36.1 mL (0.50 mol, 4 mol
equiv) of furan
and 125 mL of distilled water. The mixture is stirred vigorously at room temperature
and
triethylamine
(18.05 mL, 0.13 mol, 1.05 mol equiv) is
placed in the addition funnel and added dropwise to the reaction over a period of
30 min (Note 7). The reaction mixture is stirred for 12 hr and
quenched by adding a saturated solution of
ammonium
chloride (50 mL). The mixture is poured into
a 500-mL separatory funnel. The layers are separated and the
aqueous layer is extracted with
dichloromethane
(3 × 50 mL). The combined organic layers are washed
with brine, dried over anhydrous magnesium sulfate
,
and the organic layer is filtered and concentrated under reduced pressure. The crude
reaction mixture is resubjected to the reaction conditions by adding additional
furan
and
triethylamine
(1.05 mol equiv based on the amount of unreacted starting material as determined by
1H NMR), (Notes 8, 9). After 5 hr of vigorous stirring at room temperature, the reaction
is quenched by adding a saturated solution of
ammonium
chloride (50 mL). The layers are separated,
the aqueous layer is extracted with
dichloromethane
(3 × 25 mL) and the combined organic layers are
washed with brine and dried over anhydrous magnesium
sulfate
. After filtration, the solvent is removed with a rotatory
evaporator and the crude reaction mixture is dried for 2 hr on a high
vacuum pump. The oil is cooled to −20°C in the freezer overnight
and pale yellow crystals are filtered on a Buchner funnel and
washed with cold
pentane
.
The mother liquors are concentrated, placed on a high vacuum pump
for 5 hr, and cooled in the freezer. The procedure is repeated once more so that a
total of 6.10 g (33%) of pure 3
(Note 10) is
obtained.
The filtrate is concentrated under reduced pressure and the residue is purified
by flash column chromatography on silica gel [500
mL, 230-400 mesh, eluted sequentially with hexane/ethyl
acetate (90% to 70%)]
to afford the cycloadduct 3 as a white powder (2.25 g, 12%);
total 8.35 g (45%) (Note 11).
2. Notes
1.
Pentan-3-one, furan
and sulfuryl chloride were purchased from Aldrich Chemical
Company, Inc.
, and used without further purification.
2.
The condenser and the addition funnel are removed and replaced
by a simple distillation head and a condenser.
3.
The residue is cooled to room temperature and transferred into
a
200-mL round-bottomed flask equipped with a 6"-Vigreux column,
distillation head, condenser and a cow receiver to be purified by distillation
under reduced pressure.
4.
A small quantity of
2,4-dichloropentan-3-one
(5%) is obtained with the
α-monochloropentanone
2
during the distillation. The NMR analysis for
2-chloropentan-3-one
2
is described by Wyman and Kaufman
2.
5.
The monochloroketone must be stored in a refrigerator.
6.
Trace amounts of dichloroketone do not interfere with the [4+3]
cycloaddition.
7.
The mixture becomes a pale orange, biphasic solution. This mixture
becomes red if the addition of
triethylamine
is too fast.
8.
The reaction cannot be monitored by TLC because the monochloro
ketone cannot be visualized.
9.
The starting material remaining is usually about 40% of the crude
weight.
10.
Spectral data for the α,α-cycloadduct
3 are
identical to that reported by Hoffmann and coworkers
3.
11.
The submitters report the isolation of 0.75 g (4%) of the corresponding
exo-exo isomer; the checkers could not isolate this material in pure form.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Seven membered ring heterocycles are valuable synthetic intermediates for various
natural products. The uses and synthesis of [4+3] cycloadducts have been the subject
of extensive reviews.
4
The usual method to prepare these compounds is the [4+3] cycloaddition between an
oxyallylic cation and various dienes. The procedure described here provides a simple
and efficient method for the construction of
8-oxabicyclo[3.2.1]oct-6-ene
on a large scale in water using common reagents and mild conditions. To date, the
two main routes reported in the literature involve the generation of oxyallylic cations
starting from α,α'-dihalo ketones
5
or α-monohalo ketones.
6
All these reactions were carried out using sophisticated promotors [Zn-B(OEt)
3,
7 CeCl
3-SnCl
2,
8 etc.] or an expensive and highly toxic
reductive agent [Fe
2(CO)
9],
9 under nitrogen in anhydrous solvents. Lubineau
and Bouchain
10
reported the [4+3] cycloaddition in water using α,α'-dibromo ketones
or α-monochloro ketones to provide [3.2.1]oxabicyclic compounds in good yields.
Moreover, these conditions afford a good to excellent stereoselectivity in favor of
the α,α-cis isomers. By using the monochloro ketone in excess (2 equiv),
the yield of the [4+3] cycloadduct is 88% based on
furan
,
but this procedure, which uses
furan
in excess, is less cost effective. In order to optimize the yield, after a cycloaddition
reaction, the crude mixture containing some starting
monochloropentan-3-one
was worked-up and resubjected to the same conditions without any intermediate purification.
Moreover the pure α,α-cycloadduct is easily obtained by crystallization.
In conclusion, this is the most practical and least expensive method available
for the synthesis of [3.2.1]oxabicyclic compounds.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2,4-endo,endo-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one:
8-Oxabicyclo[3.2.1]oct-6-en-3-one, 2,4-dimethyl-, (endo,endo)-
(9); (37081-58-6)
2-Chloropentan-3-one:
3-Pentanone, 2-chloro-
(8,9); (17042-21-6)
Carbon tetrachloride: CANCER SUSPECT AGENT (8);
Methane,
tetrachloro- (9); (56-23-5)
Sulfuryl chloride (8,9); (7791-25-5)
Furan (8,9); (110-00-9)
Triethylamine (8);
Ethanamine, N,N-diethyl-
(9); (121-44-8)
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