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A. L. Norman et al. / Tetrahedron Letters 48 (2007) 6849–6851
NH2OH·HCl
OH
O
NOH
NH2OH
R
R
1
N
O
NHOH
NOH
NOH
intramolecular
intermolecular
R
R
R
3
4
5
Scheme 2. Proposed steps in the title reaction.
Table 1. Hydroxide-mediated Tandem oximation/cyclization reaction
In summary, treatment of substituted 3-buten-1-ones
with hydroxylamine hydrochloride and sodium hydrox-
ide gives 3,5-disubstituted D2-isoxazolines (3) as the
major product of the reaction. The reaction is applicable
to the preparation of compounds with both aliphatic
and aryl substituents at C-3 of the isoxazoline ring.
The variable yields appear to be indicative of both the
disfavored 5-endo-trig ring closure and the fact that
the overall reaction involves three separate mechanistic
steps: oximation, rearrangement to the conjugated
alkene, and ring closure via Michael addition. Current
efforts to explore this tandem reaction are being concen-
trated on the capture of the anion generated by Michael
addition and elucidation of the effect of steric bulk in the
cyclization event.
O
N O
NH2OH·HCl
R
R
NaOH
CH3CH2OH / H2O
R = aryl, alkyl
Compound
3;
30-63%
R
Yield (%)
3a
3b
3c
3d
3e
3f
Ph
p-MePh
62
54
39
30
63
37
51
p-MeOPh
1-Naphthyl
2-Naphthyl
2-Phenylethyl
n-Pentyl
3g
mechanism of this unexpected ring forming reaction.
With reasonable mass balance (>95%), only the follow-
ing compounds were isolated in yields that varied based
on specific reaction conditions: the expected b,c-unsatu-
rated oxime (1), the rearranged a,b-unsaturated oxime
(4), the product D2-isoxazoline (3), and an interesting
b-hydroxylamino oxime (5). The existence of the a,b-
unsaturated oxime (4) and the b-hydroxylamino oxime
(5) in the reaction mixture indicates that the mechanism
of the reaction proceeds via oximation (ketone ! 1),
rearrangement of the alkene into conjugation (1 ! 4),
and Michael addition9 (4 ! 3) to form the desired isox-
azoline (3).
Acknowledgments
The donors of the American Chemical Society Petro-
leum Research Fund (ACS PRF#40443-B1) are
acknowledged for partial support of this research.
Supplementary data
Supplementary data associated with this article can
Additional evidence of this mechanism was obtained by
subjecting 1 (R = Ph) to the conditions of the reaction.7
The product isoxazoline, 3a (R = Ph), and the byprod-
ucts 4 (R = Ph) and 5 (R = Ph), were identified in pro-
portions similar to those of the reaction of the
corresponding ketone with hydroxylamine and sodium
hydroxide. In a similar fashion, the isolated a,b-unsatu-
rated oxime, 4 (R = Ph), was also submitted to the
reaction conditions7 to yield the desired product D2-
isoxazoline (3a) in 62% yield.
References and notes
1. (a) Al-Abed, Y.; Dabideen, D.; Aljabari, B.; Valster, A.;
Messmer, D.; Ochani, M.; Tanovic, M.; Ochani, K.;
Bacher, M.; Nicoletti, F.; Metz, C.; Pavlov, V. A.; Miller,
E. J.; Tracey, K. J. J. Biol. Chem. 2005, 280, 36541–36544;
(b) Al-Abed, Y.; Cvetkovic, I.; Miljkovic, D.; Metz, C.;
Nicoletti, F.; Stosic-Grujicic, S. Abstracts of Papers, 229th
ACS National Meeting, San Diego, CA, United States,
March 13–17, 2005; (c) Lubetsky, J. B.; Dios, A.; Han, J.;
Aljabari, B.; Ruzsicska, B.; Mitchell, R.; Lolis, E.; Al-
Abed, Y. J. Biol. Chem. 2002, 277, 24976–24982.
2. For examples, see: (a) Coutouli-Argyropoulou, E.; Lianis,
P.; Mitakou, M.; Giannoulis, A.; Nowak, J. Tetrahedron
2006, 62, 1494–1501; (b) Mosher, M. D.; Natale, N. R. J.
Heterocycl. Chem. 1995, 32, 779–781.
3. Mosher, M. D.; Emmerich, L. G.; Frost, K. S.; Anderson,
B. J. Heterocycl. Chem. 2006, 43, 535–539.
To explore the scope of this reaction, a series of 1-alkyl
and 1-aryl substituted 3-buten-1-ones was prepared
from commercially available materials by the method
described previously.3 The ketones were then subjected
to the hydroxide-driven oximation reaction (Table 1).
In each case, the D2-isoxazolines (3) were obtained as
the major product of the reaction mixture, with a contri-
bution of each of the byproducts (1, 4, and 5) mentioned
earlier.
4. Coates, R. M.; Senter, P. D.; Baker, W. R. J. Org. Chem.
1982, 47, 3597–3607.