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5272 J . Org. Chem. 1998, 63, 5272-5274
Sch em e 1
Use of Diisocya n a tes for in Situ
P r ep a r a tion of Nitr ile Oxid es: P r ep a r a tion
of Isoxa zoles a n d Isoxa zolin es
Eric J . Kantorowski, Sean P. Brown, and
Mark J . Kurth*
Department of Chemistry, University of California, Davis,
Davis, California 95616
Received March 4, 1998
Isoxazole and isoxazoline heterocycles have been em-
ployed for a wide variety of uses in chemistry. Typically,
these ring systems are derived from the [3 + 2] cycload-
dition of a nitrile oxide to an alkyne or alkene, respec-
tively.1 The nitrile oxide 1,3-dipole is generated in situ
from the corresponding primary nitroalkane2 or hydroxi-
moyl chloride.3 Other methods have also been utilized.4
The primary nitroalkane f nitrile oxide reaction
requires the use of a dehydrating agent with phenyl
isocyanate (1a , X ) H) being the most popular. It is
necessary to use 2 equiv of 1a as the second equivalent
serves to trap aniline (2, X ) H) which is formed during
the course of the reaction. The resulting byproduct, 1,3-
diphenylurea (3, X ) H), exhibits only moderate solubility
in organic solvents and low solubility in water (acidic,
neutral, or basic). Consequently, product isolation and
purification is often complicated by contamination with
3 (X ) H).5
either reflux or ambient temperatures. The dimer of
CH3CtN+-O- was a minor side product (∼5%) in some
reactions even when excess dipolarophile was used (entry
4). Nitrile oxide dimers were not observed for the other
primary nitroalkanes employed. When diisocyanate 4
was employed, yields were lower and the polyurea was
partially soluble and thus not completely removed by
filtration.
We have recently demonstrated6 that polymer-bound
nitrile oxide cycloaddition reactions employing phenyl
isocyanate have the experimental advantage of removing
the urea byproduct by simply washing the resin with
solvent. This observation, coupled with our general
interest7 in the [3 + 2] cycloaddition reactions of 1,3-
dipoles, and an intriguing literature report8 prompted us
to explore the use of aryl diisocyanates for generating
nitrile oxides from primary nitroalkanes.
By employing 1,4-phenylene diisocyanate (1b) in place
of phenyl isocyanate, the aniline (2, X ) NCO) +
isocyanate reaction initially gives 3 (X ) NCO) and,
ultimately, a polyurea which may be removed from
product by simple filtration (Scheme 1). We found it
necessary to employ more than the theoretical amount
of diisocyanate 1b (i.e., 1 mol equiv, Table 1) which may
be attributed to reduced reactivity between 2 (X ) NCO)
and the growing polymer chain. The polyurea derived
from 3 (X ) NCO) was insoluble in the reaction solvent
(THF, CH2C12, or PhH), and the reaction worked well at
The utility of 1b (OCNC6H4NCO) is well-demonstrated
in 5 f 6 (Scheme 2). In the conventional reaction (5 +
THPOCH2CH2NO2 + C6H5NCO), the product (6) and 1,3-
diphenylurea (from C6H5NCO) have near-identical Rf
values.6 Multiple precipitations of diphenylurea were
attempted, but proved inefficient and time-consuming as
did chromatographic methods of separation. Alterna-
tively, when 1b was employed, purification was greatly
expedited. Filtration and a single chromatographic ap-
plication provided pure 6 in 74% yield (Table 1, entry
14). The yield was comparable to the solution-phase
results (Table 1, entry 13), but more importantly, isola-
tion of the product was simplified.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1,4-Phenylene diisocyanate was pur-
chased from Aldrich and used as received. Solvents were
purified as follows: tetrahydrofuran (THF) was distilled from
sodium/benzophenone ketyl; methylene chloride (CH2Cl2) was
distilled from CaH2; benzene was distilled from potassium. All
reactions, unless otherwise stated, were conducted under an
inert atmosphere of N2. 1H and 13C NMR spectra were measured
in CDCl3 at 300 and 75 MHz, respectively, and chemical shifts
are reported in ppm downfield from internal tetramethylsilane.
Thin-layer chromatography (TLC) was performed on silica gel
plates, and components were visualized by UV light or by iodine
or by heating the plates after treatment with a phosphomolybdic
acid reagent (1:1 in EtOH).
(1) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416. (b) For a
general discussion, see: 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1.
(2) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 82, 5339-
5342.
(3) Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345-3367.
(4) (a) Basel, Y.; Hassner, A. Synthesis 1997, 309-312. (b) Maugein,
N.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 1997, 38, 1547-1550.
(5) 1,3-Diphenylurea crystallizes from various solvents (EtOH, THF,
CH2Cl2); however, in practice, complete crystallization is never fully
realized.
(6) Kantorowski, E. J .; Kurth, M. J . J . Org. Chem. 1997, 62, 6797-
6803.
(7) Kurth, M. J .; Ahlberg Randall, L. A.; Takenouchi, K. J . Org.
Chem. 1996, 61, 8755-8761.
(8) Leslie-Smith, M. G.; Paton, R. M.; Webb, N. Tetrahedron Lett.
1994, 35, 9251-9254.
5-Hexyl-4,5-d ih yd r o-3-m eth ylisoxa zole. 1,4-Phenylene di-
isocyanate (1b) (0.992 g, 6.19 mmol), nitroethane (0.150 g, 2.00
mmol), and 1-octene (0.225 g, 2.00 mmol) were dissolved in
benzene (20 mL). Triethylamine (5-10 drops) was added, and
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