readily available cyclic diketones and activated oximes to
afford isoxazoles. Utilizing hydroximinoyl chloride 1, derived
from commercially available salicylaldoxime,5 we undertook
an investigation on the reaction protocol (Table 1). Critical
Alternatively, utilization of isolated 2d as a suspension in
toluene slightly improved the yield (entry 9).8 Reducing the
amount of 2d employed diminished the rate of the reaction
but not the chemical yield (entry 10).
The reaction conditions, thus identified, were amenable
to the synthesis of a wide variety of functionalized isoxazoles
(Table 2). Yields, reaction protocol, and conversion times
were largely unaffected by variation of the reaction partners.
Notably, no apparent complications were experienced with
substrates containing sensitive functional groups. Thus, aryl
bromides (entry 3), phenols (entries 1, 5, and 6), and ester
groups (entries 5 and 6) were readily tolerated.
Table 1. Optimization of Isoxazole Formation from Phenolic
Hydroximinoyl Chloride 1
Scheme 2 highlights the salient features of this methodol-
ogy in the regioselective formation of 11 from highly
entry
X
solvent equiv 2 time (h) yield (%)
1
2
3
4
5
6
7
8
9
OH (2a )
OEt (2b)
CHCl3
CHCl3
2.0
18
18
1
2
0.5
-
<10
60
63
77
34
35
52
83
1.0a
1.2b
2.0b
2.0b
2.0b
2.0c
2.0
Scheme 2
O-N+HEt3 (2c) EtOH
O-Na+ (2d )
O-Na+ (2d )
O-K+ (2e)
O-Cs+ (2f)
O-Li+ (2g)
O-Na+ (2d )
O-Na+ (2d )
EtOH
iPrOH
toluene
EtOH
2
4.5
5.5
0.25
3.5
EtOH
toluene
toluene
2.0d
1.2d
10
82
a 5 equiv of 1 and 5 equiv of NEt3 were used; reaction temperature was
60 °C. b Salt of 2 generated in situ from 2a (X ) OH). c Cs2CO3 (2 equiv)
was used as base. d Preformed, isolated 2d (X ) O-Na+) was used.
to the successful development of this methodology was the
discovery that use of a slight excess of the 1,3-diketone salts,
relative to the nitrile oxide precursor 1, resulted in the rapid
and high-yielding formation of the desired product 3 (entry
3).6 In contrast, typical reaction protocols for thermal
cycloadditions with 2a or 2b were unsuccessful, even when
high temperatures or slow addition techniques were em-
ployed.7
Further studies identified the use of readily prepared
sodium salt 2d as advantageous (entries 4 and 5). From these
studies, two useful reaction protocols emerged. In the first,
addition of the free diketone 2a to a solution of NaOiPr in
iPrOH followed by addition of the hydroximinoyl chloride
1 afforded the desired isoxazole 3 in 77% yield (entry 5).
functionalized diketone salt 7. Although several possible
reaction products were possible, the optimized conditions
afforded predominantly 11. Simple precipitation of the
product from Et2O provided isoxazole 11 as a single
diastereomer in good yield, and the structure was confirmed
by X-ray crystallographic analysis. While the diketone
corresponding to 7 is commercially available, it was more
convenient to directly prepare the sodium salt via the single-
Scheme 3
(5) (a) Thomsen, I.; Torssell, K. B. G. Acta Chem. Scand. 1988, B42,
303-308. (b) This compound was obtained as an analytically pure solid
by oxime chlorination with 1.1 equiv of NCS in the presence of 10 mol %
pyridine as a catalyst and used without further purification. It could be stored
for several weeks without decomposition. See Supporting Information for
an experimental procedure.
(6) (a) A few examples of base-promoted isoxazole formations have
appeared. To the best of our knowledge, no comprehensive study of the
isoxazole formation from diketone enolates has been undertaken. For a
related reaction with R-nitroketones, see: Dal Piaz, V.; Pinzauti, S.;
Lacrimini, P. Synthesis 1975, 664-665. (b) For an isolated example
employing a cyclic diketone and trifluoroacetonitrile oxide in modest yield,
see: Tanaka, K.; Kishida, M.; Maeno, S.; Mitsuhashi, K. Bull. Chem. Soc.
Jpn. 1986, 59, 2631-2632.
(7) We have identified nitrile oxides as the key reactive intermediates
in the isoxazole-forming reaction. The role of the base, however, is not
solely to effect elimination of chloride from the hydroximinoyl chloride.
The reaction of isolated nitrile oxides and diketones in the absence of base
does not proceed on a useful time scale. Bode, J. W.; Hachisu, Y.; Matsuura,
T.; Suzuki, K. Unpublished results.
392
Org. Lett., Vol. 5, No. 4, 2003