5-Bromomethyl-4,5-dihydroisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2009.07.106

The preparation of substituted 4,5-dihydroisoxazoles can be accomplished via the treatment of β,γ-unsaturated oximes with liquid bromine. The reaction provides a convenient route to the highly functionalized title compounds.

Full text of DOI:10.1016/j.tetlet.2009.07.106

Tetrahedron Letters 50 (2009) 5647–5648
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Tetrahedron Letters
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5-Bromomethyl-4,5-dihydroisoxazoles
à
*
Michael D. Mosher , Amber L. Norman , Khriesto A. Shurrush
Department of Chemistry, University of Nebraska at Kearney, Kearney, NE 68849, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of substituted 4,5-dihydroisoxazoles can be accomplished via the treatment of
b, -unsaturated oximes with liquid bromine. The reaction provides a convenient route to the highly func-
tionalized title compounds.
Received 26 June 2009
Revised 16 July 2009
Accepted 17 July 2009
Available online 23 July 2009
c
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
4,5-Dihydroisoxazole
Cyclization
Bromination
4,5-Dihydroisoxazoles are often used as intermediates in the
preparation of or protecting groups for a wide variety of difunc-
tionalized compounds. For example, cleavage of the 4,5-dihydrois-
dihydroisoxazole.7 Such information implies that strong electro-
philes could be employed to affect the cyclization of the unsatu-
rated oxime directly.
Herein, we wish to report that the cyclization of a series of
b,c-unsaturated oximes in the presence of bromine in dichloro-
oxazole can give rise to b-hydroxyketones1,
a,b-unsaturated
ketones2, and
c
-aminoalcohols.3 The dihydroisoxazole moiety is
also found as the end product in many pharmaceutically active
compounds.
methane affords the expected 5-bromomethyl-3-substituted-4,5-
dihydroisoxazoles (Scheme 2). We have noted that the reaction is
relatively rapid at room temperature, and, due to the color of the
bromine reagent and the lack of color in the desired products,
the reaction can be titrated to completion. However, in practice,
we have noted that a 10% excess of bromine typically provides
the best yield of the desired product.8
The product of the reaction, a primary bromide, was easily iden-
tifiable by proton NMR.9 In fact, monitoring the reaction progress
by TLC was often misleading due the presumed reaction of the
This ring system is typically prepared via an intramolecular 1,3-
dipolar cycloaddition.4 This reaction often involves the preparation
of a substituted nitrile oxide in the presence of a dipolarophile,
whether it is an intermolecular or intramolecular process. The reg-
iochemical outcome of the reaction favors the formation of a 3,5-
disubstituted-4,5-dihydroisoxazole in the intermolecular case,
though in some cases 3,4-disubstituted products predominate.
Control of the substitution in the product is due primarily to the
electron density distribution of the dipolarophile.5
In our recent search for a regiochemically controlled route to
the 4,5-dihydroisoxazole ring system, we noted that the palla-
dium(II) catalyzed cyclization of a b,
to 3,5-disubstituted-4,5-dihydroisoxazoles in good yield.6 In that
study, we also noted that treatment of a b, -unsaturated ketone
c-unsaturated oxime gives rise
c
with hydroxylamine hydrochloride in excess aqueous base re-
sulted in the direct formation of the dihydroisoxazole (Scheme
1).7 Further study indicated that in the course of the reaction, the
alkene moiety underwent isomerization to the conjugated system
prior to internal addition of the oxygen nucleophile to form the
Scheme 1. Previous cyclizations of b,c-unsaturated carbonyls.
* Corresponding author. Tel.: +1 308 865 8385; fax: +1 308 865 8399.
E-mail address: mosherm@unk.edu (M.D. Mosher).
Present address: Department of Chemistry, University of Kansas, Lawrence, KS
66045, USA.
à
Present address: Department of Chemistry, Purdue University, West Lafayette, IN
47907, USA.
Scheme 2. Electrophilic bromination yields the title compounds.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.106

5648
M. D. Mosher et al. / Tetrahedron Letters 50 (2009) 5647–5648
Table 1
a
3-substituted-4-bromo-5-methyl-4,5-dihydroisoxazole—is not
Yield of title reaction outlined in Scheme 2
observed in the reaction mixture. We postulate, however, that a
tri-substituted 4,5-dihydroisoxazole could be produced if the start-
ing oxime was conjugated. Efforts are currently underway to ex-
plore such a possibility.
Entry
Compound (R=)
Spectroscopic yielda (%)
Isolated yieldb (%)
1
2
3
4
5
p-CH3O–Ph–
p-CH3–Ph–
20-naphthyl
Ph–CH2–CH2–
CH3(CH2)4CH2–
>98%
>97
95
>90
>90
79
65
84
In summary, treatment of substituted b,c-unsaturated oximes
35c
40c
with bromine provides the expected 3-substituted-5-bromo-
methyl-4,5-dihydroisoxazoles. Isolated yields were consistently
better for the aryl substituted dihydroisoxazoles, but even the alkyl
substituted oximes provided the desired products in acceptable
yield. The products, primary bromides, provide a functional group
handle that should be able to be further modified by nucleophilic
substitution.
a
Spectroscopic yields were determined by H NMR of an aliquot of the crude
reaction mixture.
b
Isolated yields express the yield of the product after workup and chromato-
graphic separation.
c
Isolated products spectroscopically agreed with the literature values. See Ref. 13.
primary bromide with the TLC stationary phase. Instead, reaction
progress was monitored by withdrawing aliquots from the reaction
mixture and obtaining proton NMR data on the crude reaction mix-
ture. In all cases examined, the reaction appeared to be complete
(the presence of the starting material was not detected) after
30 min stirring at room temperature. Isolation of the desired prod-
ucts was, in some cases, significantly lower than the NMR yield.
Again, this was mostly likely due to the ease of reaction of the pri-
mary bromide with the chromatographic stationary phase.
Based on the data given in Table 1, the reaction appears to be
compatible with both aryl and alkyl substitutions. While the iso-
lated yield of the 4,5-dihydroisoxazole does appear to reflect the
geometry of the starting oxime (syn or anti) mixture as determined
by proton NMR, that geometry was judged to not play a role in the
reaction due to the spectroscopically determined yield prior to iso-
Acknowledgment
Acknowledgment is made to the Department of Chemistry at
the University of Nebraska at Kearney for partial financial support
of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.106.
References and notes
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4. (a) Moriya, O.; Nakamura, H.; Kageyama, T.; Urata, Y. Tetrahedron Lett. 1989, 30,
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Xuebao 2005, 63, 567. Chem. Abs. 143:439724; (d) Houk, K. N.; Chang, Y.-M.;
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lation. In fact, the aryl substituted b,c-unsaturated oximes were
very well behaved in the reaction, and the isolation of the aryl-
dihydroisoxazoles from the reaction mixture was relatively easy.
The alkyl substituted compounds were less well behaved and dif-
ficult to isolate—as evidenced by extensive streaking on TLC plates.
We postulate that the mechanism of this reaction (Scheme 3)
involves the initial addition of bromine to the alkene to form the
well-defined cyclic bromonium ion.10 Formation of this intermedi-
ate activates the molecule for attack by the internal hydroxyl
nucleophile. Subsequent ring opening gives the expected 4,5-
dihydroisoxazole with a C5-bromomethyl group. The 4,5-dihyd-
roisoxazole formed in this regiochemically controlled fashion is
racemic at C5. This mechanism stands in contrast to the isomeriza-
tion observed in the base-catalyzed cyclization of b,
c
-unsaturated
oximes7—where the thermodynamically more stable
a
,b-unsatu-
6. Norman, A. L.; Mosher, M. D. Tetrahedron Lett. 2008, 49, 4153.
7. Norman, A. L.; Shurrush, K. A.; Calleroz, A. T.; Mosher, M. D. Tetrahedron Lett.
2007, 48, 6849.
rated oxime forms rapidly under the reaction conditions.
Evidence that the alkene moiety does not migrate into conjuga-
tion is illustrated by the fact that the product of such a migration—
8. General procedure for the preparation of the title compounds: to a 250 mL round-
bottomed flask containing a stir bar and wrapped in aluminum foil were added
80 mL anhydrous CH2Cl2 (freshly distilled from calcium hydride) and the
respective oxime (6.0 mmol).11 The solution was vigorously stirred at room
temperature while a CH2Cl2 solution of Br2 (approximately 0.10 M, 6.6 mmol)
was added dropwise by glass syringe. The red solution was stirred for 30 min in
the dark. Then 25 mL distilled water was added and stirring was continued for
an additional 5 min. The contents of the reaction vessel were then transferred
to
a separatory funnel and the organic phase was washed with water
(80 mL ꢀ 1), sodium bisulfite solution (80 mL ꢀ 1), water (80 mL ꢀ 1), sodium
bicarbonate solution (5%, 80 mL ꢀ 1), and brine (80 mL). The yellow organic
phase was then dried over sodium sulfate, filtered, and evaporated to dryness
on the rotary evaporator to give
a crude yellow–red mixture. Flash
chromatography12 of the crude product on silica gel (8:2 hexane/ethyl
acetate) gave the desired product as an off-white solid.
9. (a) Nagarajan, A.; Pillay, M. K. J. Ind. Chem. Soc. 1993, 70, 174; (b) Dondoni, A.;
Taddei, F. Boll. Sci. Fac. Chim. Ind. Bologna. 1967, 25, 145.
10. Modro, A.; Schmid, G. H.; Yates, K. J. Org. Chem. 1977, 42, 3673.
11. Mosher, M. D.; Emmerich, L. G.; Frost, K. S.; Anderson, B. J. Heterocycl. Chem.
2006, 43, 535.
12. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
13. Ha, S. J.; Lee, G. H.; Yoon, I. K.; Pak, C. S. Synth. Commun. 1999, 29, 3165.
Scheme 3. Proposed mechanism of electrophilic bromination.