A convenient preparation of 3-Acetyl-5-methylisoxazole

Article abstract of DOI:10.1002/jhet.5570400415

Starting from 2,5-hexanedione (4), a one-pot preparation of 3-acetyl-5-methylisoxazole (1) is described. 3-Acetyl-5-methylisoxazole (1) is a useful compound for the preparation of 3-oxobutyronitrile (10) and for 3-vinyl-(5-methyl isoxazolyl) ketone (2).

Full text of DOI:10.1002/jhet.5570400415

Jul-Aug 2003
A Convenient Preparation of 3-Acetyl-5-methylisoxazole
655
*
Ronald R. Sauers and Susan D. Van Arnum
Wright and Rieman Laboratories; Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08903
Email: sauers@rutchem.rutgers.edu
Received November 25, 2002
Starting from 2,5-hexanedione (4), a one-pot preparation of 3-acetyl-5-methylisoxazole (1) is described.
3-Acetyl-5-methylisoxazole (1) is a useful compound for the preparation of 3-oxobutyronitrile (10) and for
3-vinyl-(5-methyl isoxazolyl) ketone (2).
J. Heterocyclic Chem., 40, 655(2003).
During studies relating to the photochemistry of the nor-
bornenyl isoxazole ketone 3, a synthesis of 3-acetyl-5-
methylisoxazole (1) was required.[1]
tained reflux. This temperature was required in order to
ensure a complete consumption of starting material 4. For
use in the synthesis of ketone 3 and also, ultimately for the
Figure 1
A known preparation of 3-acetyl-5-methylisoxazole (1)
study of the photochemistry of isoxazole ketone 1, a safer
involves a nitric acid oxidation of an aqueous solution of
and more reliable procedure was required [1,3].
Figure 2
2,5-hexanedione (4).[2] In our laboratories, this procedure
yielded varying amounts of isoxazole ketone 1 and
5-methylisoxazolyl-3-carboxylic acid (5). Although these
compounds could be readily separated from one another,
this oxidation was extremely violent in that the heat of
reaction from the oxidation was able to maintain a sus-
Although the isoxazole ketone 1 could be prepared from
Z-3-azido-3-hexene-2,5-dione (6), a more direct approach
would use 2,5-hexanedione (4) as the starting material.[3]
We had also considered the addition of hydroxylamine
to diacetylacetylene (7) since this method was useful for
the preparation of hexane-2,3,5-trione-3-(O-methyoxime)
(9) [4]. This potential method was compromised by the
fact that diacetylacetylene (7) is not a shelf stable com-
pound and the preparation of gram quantities of this com-
pound is hindered by its instability. For our purposes, a
reliable multi-gram preparation was necessary.
In the method described by Cusmano, 2,5-hexanedione
(4) is initially nitrosated to yield in-situ hexane-2,3,5-tri-
one-3-oxime (8) [2]. Cyclization and dehydration of oxime
Figure 1
Figure 4

656
R. R. Sauers and S. D. Van Arnum
Vol. 40
8 affords the isoxazole ketone 1. Due to the harsh reaction
conditions, this isoxazole ketone 1 is subsequently
nitrosated and undergoes an abnormal Beckman
rearrangement to ultimately yield the carboxylic acid 5
[5]. If milder conditions could be developed for the initial
nitrosation, then the subsequent nitrosation could be sup-
pressed.
Figure 6
Attempts to use nitrous acid as a reagent were unsucc-
essful due to the fact that ketone 4 was unreactive under
conditions by which this reagent was stable. The use of
commercially available isoamyl nitrite was fruitful in con-
verting the ketone to the isoxazole; however the separation
of the by-product, isoamyl alcohol, from the ketone by dis-
tillation was difficult. For this reason, we investigated the
use of ethyl nitrite as a nitrosating agent.
reaction as well as for the preparation of 3-oxobutyroni-
trile (10) are also disclosed. The preparation of cyanoace-
tone (10) and related compounds from the isoxazole
ketone 1 and its derivatives may also have potential utility
in combinatorial synthesis due to the fact that the isoxazole
ketone 1 is a latent protecting group for cyanoacetone (10)
[8]. Tethering of the acyl group to a polymer chain by
polymerization of ketone 2, followed by base-catalyzed
cleavage would allow for release of the cyanoacetone frag-
ment from the polymer [9].
Further, addition of an O-resin-bound hydroxylamine
reagent to diacetylacetylene (7) and related compounds,
followed by deprotection, would also allow for a combina-
torial synthesis of isoxazoles [10,11]. Although diacetyl-
acetylene (7) is not a stable compound, when neat, its good
reactivity in the conjugate addition reaction with
methoxyamine may be useful in solid state synthesis
wherein the reactivity of the polymer-bound nucleophile is
reduced [12]. In addition, the likely acidity of carbon 4 in
polymer-bound derivatives of oxime 9 may allow for the
introduction of additional functionality at the 4 position of
3-acyl substituted isoxazole ketones.
Concentrated hydrochloric acid was added to a neat
40 °C solution of 2,5-hexanedione (4). A gaseous stream
of ethyl nitrite was slowly added to the solution and the
reaction temperature was maintained below 50 °C. The
1
course of the reaction was monitored by H nmr. The reac-
tion was selective and there was no evidence for nitrosa-
tion at the methyl group of either the starting material 4 or
the product 1. After an extractive workup, the product was
distilled to afford a 67% yield of the 3-acetyl-5-
methylisoxazole (1). The spectral properties of the ketone
1 were in agreement with the product obtained by the
nitric acid oxidation of 2,5-hexanedione (4).
Acknowledgement.
We are grateful to the Garden State Fellowship
Commission and the J. L. R. Morgan Fellowship Fund for
financial support.
Figure 5
In addition to its use as a substrate for the preparation of
the vinyl isoxazole ketone 2, this isoxazole ketone 1
proved to be useful for the synthesis of 3-oxobutyronitrile
(10). In the course of the study on the photochemistry of
isoxazole ketone 1, a product that was observed was
cyanoacetone (10) [6]. A known method to prepare cyano-
acetone (10) is by the base-catalyzed cleavage of
5-methylisoxazole in which the driving force in this
cleavage reaction is the formation of the carbanion of
cyanoacetone [7]. Alternatively, this same anion can be
generated by the base-catalyzed cleavage of isoxazole
ketone 1. As expected, treatment of isoxazole ketone 1
with sodium methoxide in methanol afforded cyano-
acetone (10) in a 75% yield. The spectral properties of this
compound were in agreement with the assigned structure.
In summary, a convenient one-pot procedure for the
preparation of isoxazole ketone 1 is described. In addition,
uses for this ketone 1 such as a substrate in the Mannich
EXPERIMENTAL
3-Acetyl-5-methylisoxazole (1).
2,5-Hexanedione (4) (42.8 g, 0.375 mole) was heated to 40 °C
at which point, 4.5 mL (0.055 mole) of concentrated hydrochlo-
ric acid was added. Ethyl nitrite was generated by the addition of
a solution of 54.36 g (0.79 mole) of sodium nitrite in a mixture of
24 mL of 95% ethanol and 215 mL of water to a solution of 22
mL of sulfuric acid in a mixture of 24 mL of 95% ethanol and
215 mL of water [13,14]. Ethyl nitrite was bubbled into the reac-
tion mixture over a 6.5 hour period while maintaining the tem-
perature below 50 °C. Upon completion of the reaction as evident
by 1H nmr, the batch was cooled and ether was added. The
organic layer was washed with saturated sodium bicarbonate
solution and saturated sodium chloride solution. The organic
layer was dried over magnesium sulfate and the solvent was
evaporated. The product was distilled at 73-77 °C at 13 mm (lit
76-77 °C at 19 mm)[15] to afford 31.30 g (67%) of 3-acetyl-5-
methylisoxazole (1); ir (film): 1701 (C=O), 1600 (C=N), 1460,

Jul-Aug 2003
A Convenient Preparation of 3-Acetyl-5-methylisoxazole
657
1361 (C-O), 1271, 1181, 1149 cm-1; 1H nmr (deuteriochloro-
form): d 2.50 (s, 3H, CH3), 2.60 (s, 3H, CH3), 6.30 (s, 1H, CH);
uv (acetonitrile): l = 306 (e = 77.5), l = 245 (e = 1950).
inorganic salts were filtered and the cake was washed with 100
mL of ether. The layers were separated and the aqueous layer was
extracted with an additional 50 mL of ether. The combined
organic layers were washed with saturated sodium bicarbonate
solution (50 mL), saturated sodium chloride solution (50 mL) and
dried over magnesium sulfate. The solvent was evaporated at
room temperature at reduced pressure. The product was distilled
at 20-25 °C and 0.2 mm. (lit bp 26-38 °C at 0.1 mm) [17b] and
condensed in a Dry Ice-acetone bath to yield 2.21 g (40% yield)
of hex-3-yne-2,5-dione (7) as a yellow oil [18]; ir (film): 1715
(C=O), 1361, 1220 cm-1; 1H nmr (deuteriochloroform): d 2.36 (s,
6H, CH3).
3-Oxobutyronitrile (10).
Under a nitrogen atmosphere, 0.30 g (0.013 mole) of sodium
was added to 25 mL of methanol. After the reaction had subsided,
1.25 g (0.01 mole) of 3-acetyl-5-methylisoxazole (1) was added.
The solution was heated to reflux for 5 hours. The solvent was
removed under vacuum and ether and water were added. The lay-
ers were separated and the aqueous layer was washed with addi-
tional ether. The aqueous layer was acidified with concentrated
hydrochloric acid and saturated with solid sodium chloride.
Drying over magnesium sulfate was followed by evaporation of
the solvent. There was obtained 0.62 g (75%) of impure 3-oxobu-
tyrontrile (10). A molecular distillation at 50 °C and 0.6 mm (lit
bp 92-94 °C at 10 mm)[16] purified the product; ir (methylene
REFERENCES AND NOTES
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1
chloride): 3497-3401, 2252 (Cº N), 1730 (C=O), 1600 cm-1; H
nmr (deuteriochloroform): d 2.37 (s, 3H, CH3), 3.46 (s, 2H,
CH2).
Hexane-2,3,5-Trione-3-(O-methyloxime) (9).
To a magnetically stirred solution of 0.33 g (5.00 mmole) of
potassium hydroxide in 2 mL of water, 10 mL of chloroform was
added. Methoxyamine hydrochloride (0.42 g, 5 mmole) was added
and the mixture was held for 5 minutes. Hex-3-yne-2,5-dione (7)
(0.55 g, 5 mmole) was added. After the addition, the reaction was
complete as shown by 1H nmr. Drying of the chloroform layer over
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methyloxime) (9). An analytical sample was prepared by flash
chromatography using a mixture of 65% hexane and 35% ethyl
acetate as the eluent; ir (film): 1721 (C=O), 1689 (C=O), 1600
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1
(C=N), 1361 cm-1. H nmr (deuteriochloroform): d 2.17 (s, 3H,
CH3), 2.40 (s,3H, CH3), 3.62 (s, 2H, CH2), 4.05 (s, 3H, OCH3).
Anal. Calcd. For C7H11NO3: C, 53.49; H, 7.05; N, 8.91.
Found: C, 53.30; H, 7.44; N, 8.89.
Hex-3-yne-2,5-dione (7).
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(0.3 mole) of hex-3-yne-2,5-diol in 300 mL of spectrograde
acetone, a solution of 3.2 M CrO3 in 4 M aqueous H2SO4
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supernatant was decanted. The reduced salts were washed with
600 mL of ether. The organic layer was separated and the aque-
ous layer was extracted with an additional 300 mL of ether. The
organic extracts were combined and washed with aqueous
sodium bicarbonate solution (250 mL) and saturated sodium
chloride solution (100 mL). The organic layer was dried over
magnesium sulfate and the dessicant was removed by filtration.
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distilled at 58-60 °C and 0.25 mm (lit bp 57-63 °C at 0.10 mm)
[17b] to afford 18.53 g (55% yield) of 5-hydroxy-hex-3-yne-2-
th
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1
one (11) [17,18]; H nmr (deuteriochloroform): d 1.56 (d, 3H,
CH3), 2.36 (s, 3H, CH3), 4.40 (b, 1H, OH), 4.66 (q, 1H, CH).
To a –10 °C solution of 5.6 g (0.05 mole) of 5-hydroxy-hex-3-
yne-2-one (11) in 50 mL of spectrograde acetone, a 3.2 M CrO3
solution in 4 M sulfuric acid (11 mL, 3.3 mmole) was added over
a 0.5 hour period. The suspension was stirred for an additional
0.5 h. Saturated sodium chloride solution (50 mL) was added; the

658
R. R. Sauers and S. D. Van Arnum
Vol. 40
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