Novel rearrangement of 4-aroyloxy-3-bromomethyl-2-isoxazolines to 3-aroyloxymethylisoxazoles and a mechanistic study

Article abstract of DOI:10.1016/S0040-4039(00)01538-0

Treatment of 4-aroyloxy-3-bromomethyl- and 4-aroyloxy-3-aroyloxymethyl-2-isoxazolines with NaHCO₃ in DMF at 120°C gave 3-aroyloxymethylisoxazoles in moderate to good yields. A concerted mechanism is proposed to explain the formation of the rearrangement products. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01538-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8499–8503
Novel rearrangement of
4-aroyloxy-3-bromomethyl-2-isoxazolines to
3-aroyloxymethylisoxazoles and a mechanistic study
Rae-Kyu Chang and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, South Korea
Received 19 July 2000; revised 4 September 2000; accepted 8 September 2000
Abstract
Treatment of 4-aroyloxy-3-bromomethyl- and 4-aroyloxy-3-aroyloxymethyl-2-isoxazolines with
NaHCO3 in DMF at 120°C gave 3-aroyloxymethylisoxazoles in moderate to good yields. A concerted
mechanism is proposed to explain the formation of the rearrangement products. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: isoxazolines; isoxazoles; deprotonation; labeling; rearrangements.
2-Isoxazolines are useful for the synthesis of various functionalized organic compounds. Their
synthetic methods including 1,3-dipolar cycloaddition involving nitrile oxides and alkenes have
been extensively studied.1 A survey of the recent literature shows some interesting methods for
the synthesis of 2-isoxazolines which include nitrosative cyclization of 3-chloro-1-nitropropane
using sodium nitrite and n-propyl nitrite in DMSO,2 the reactions of 3-isoxazolin-5-one with
olefins,3 photochemical reactions of 1,2-disubstituted cyclopropanes with NOBF4,4 deprotona-
tion of 2-isoxazolines by a strong base, followed by addition of alkyl iodides.5
More recently we reported synthesis of 3-substituted 4-aroyloxy-2-isoxazolines 2 by treatment
of allylic arenecarboxylates 1 with NOBF4 in CH3CN at −23°C6 (Scheme 1). Of them,
Scheme 1. a. Y=H; b. Y=CH2Br; c. Y=XC6H4C(ꢀO)OCH2
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01538-0

8500
compound 2b attracted our attention since it was expected that replacement of the bromine
atom with appropriate nucleophiles would give various 3-substituted 4-aroyloxy-2-isoxazolines.
In the course of our study on the nucleophilic displacement of the bromine atom of 2b, we
found that treatment of 2b (X=H) with NaHCO3 in DMF at 120°C afforded 3-benzoyl-
oxymethylisoxazole 3a (X=H) in 53% yield (Scheme 2). Similarly the reaction of compound 2c
(X=H) under the same conditions afforded 3a (48%). The results led us to investigate the
reactions with other 2-isoxazoline derivatives 2b and 2c.
Scheme 2. Reagents and conditions: (i) NaHCO3, DMF, 120°C
Typical procedure: to a solution of 2b in DMF (10 mL) was added NaHCO3 (5 equiv.). The
mixture was heated at 120°C for an appropriate time, followed by addition of water (30 mL),
which was extracted with CH2Cl2 (30 mL×2). The extracts were worked up as usual and the
residue was chromatographed on a silica gel (70ꢀ230 mesh, ASTM) column.
Elution with a mixture of n-hexane and EtOAc (5:1) gave 3. Reaction times, yields and mps
of 3-aroyloxymethylisoxazoles 3 are summarized in Table 1.
Table 1
Reaction times, yields, and mps of isoxazoles 3
Compd
X
Time (days)
Y=XC6H4CO2CH2 Y=CH2Br
Yielda (%)
Mp (°C)
Y=CH2Br
Y=XC6H4CO2CH2
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
1.5
1
1.5
2
2
1.5
1
1.5
2
2
0.5
1.5
1
53
72
65
43
56
48
65
54
42
52
53
Liquid
73–74b
Liquid
Liquid
Liquid
Liquid
4-MeO
4-Me
2-Br
4-Cl
2-Ph
4-O2N
1-Naphthyl
4-NC
1.5
2
70
3c
1
d
77
58
13
102–104b
Liquid
e
a Isolated yields.
b Recrystallized from n-hexane.
c Hours.
d 4-Nitrobenzoic acid was isolated in 85% yield.
e Compound 2b (X=4-CN) was not prepared. Compounds 3 were characterized satisfactorily by the spectroscopic
1
(IR, H and 13C NMR, MS) and analytical data.
For mechanistic information on the conversion of either compounds 2b or 2c into 3,
2-isoxazoline 4, which possessed two different aryloxy groups, was subjected to the same
reaction conditions. From the reaction only 3b (63%) was isolated. No 4-cyanobenzolyoxy
incorporated product was detected (Scheme 3).

8501
Scheme 3.
The reaction of 2b (X=H) in the presence of p-anisic acid (2 equiv.) under the same
conditions afforded only 3a (44%). Similarly only 3b (62%) was obtained from the reaction of
2b (X=4-MeO) in the presence of benzoic acid under the same conditions. No 4-anisic acid and
benzoic acid derived products were detected from the former and the latter reactions, respec-
tively. The results suggest that the aroyloxy group at C-4 of 2-isoxazolines migrates to the
methylene carbon atom at C-3, presumably by a concerted mechanism.
The reaction of 2b did not proceed in the absence of NaHCO3, whereas substitution of
NaHCO3 for organic bases such as pyridine and N,N-dimethylaniline under the same conditions
led to decreased yields of 3b in 27 and 28%, respectively, indicating the efficiency of NaHCO3
compared with the organic bases for the formation of 3. Unexpectedly treatment of 2b (X=H,
4-MeO) with AgNO3 in DMF at rt afforded formates 5a and 5b in 29 and 83% yields,
respectively (Scheme 4). Since DMF was envisaged to be involved as a source of formyl group,
DMF was substituted for EtOH as a solvent.
Scheme 4. Reagents and conditions: (i) AgNO3, DMF, rt, 12 h. (ii) AgNO3, EtOH, rt, 12 h
The bromine atom of 2b (X=4-MeO) was then replaced by an ethoxy group, leading to
compound 6 in 55% yield. No rearranged product such as 3b was detected. The results suggest
that generation of an electron deficient center at the migration terminus by the interaction of the
bromine atom of 2b with Ag+ ion does not act as a driving force for the migration of the aryloxy
group at C-4 in the molecules. In order to confirm the migrating oxygen atom, the 18O-enriched
compound 2b* prepared (Scheme 5) was subjected to the same conditions mentioned foregoing
to trace where the 18O is.
The enrichment of 18O in the labeling compounds compared with the normal (unlabeling)
compounds was compared by mass spectroscopy. By introducing % (M++2) obtained from the
abundances of M+ and M++2 ions into the following equation,7 one can calculate h values that
represent the contribution of % 18O in % (M++2) in 18O-enriched molecular ion and its
fragmented ions.

8502
Scheme 5. Reagents and conditions: (i) SOCl2, reflux, 4 h. (ii) H2O18 (10 mol%). (iii) Crotyl alcohol, 5 h. (iv) NBS,
CCl4, reflux, 12 h. (v) NOBF4, CH3CN, −23°C. (vi) NaHCO3, DMF, 120°C
% (M++2)=[(1.1×a)2+(0.016×b)2]/200+0.2×c+h
a: number of C atoms in the molecule; b: number of H atoms in the molecule
c: number of O atoms in the molecule; h: contribution of 18O to % (M++2)
× in the molecule
% (M++2) and h values calculated based on the abundances of M+, M++2 ions of labeled and
normal compounds 7, a fragment (MeOC6H4C(ꢀO)OCH2CHꢀCHCH2)+ from the molecule 8, a
fragment (MeOC6H4C(ꢀO)OH)+ from the molecule 2b* and a fragment (MeOC6H4C(ꢁO+))
’
from the molecule 3b* are summarized in Table 2.
Table 2
Percent (M++2) and h-values
7+
(8-Br)+
(MeOC6H4C(ꢀO)O18H)+ a MeOC6H4C(ꢁO18+ b
)
’
’
’
Ions
Labeled
% (M++2) 3.69
Normal
Labeled
Normal
Labeled
Normal
Labeled
Normal
1.33
1.44
6.65
2.33
1.60
1.47
3.58
2.78
1.05
0.99
2.21
1.62
0.76
0.79
h
2.42
a A fragment ion from 2b*.
b A fragment ion from 3b*.
In order to avoid the interference of 91Br in the calculations of % (M++2) of compounds 8 and
values ions were calculated based on the abundances of fragments
2b*, the
h
(MeOC6H4C(ꢀO)OCH2CHꢀCHCH2)+ and (MeOC6H4C(ꢀO)OH)+ derived from the molecular
ions of 8 and 2b*, respectively. The data clearly show that fragments from labeled compound
possess a higher 18O than the corresponding fragments from normal molecule. Indeed, the h
value (1.62) obtained from labeled p-methoxybenzoyl cation generated from 3b* is higher than
that (0.79) obtained from the corresponding unlabeled ion. This result clearly indicates that the
18O atom in the molecule 2b* becomes the carbonyl oxygen of 3b*.
’
Based on the data in hand, the rearrangement can be explained by deprotonation from C-5
of 2-isoxazolines, concomitant with migration of electrons to form a CꢀC double bond, followed
by an intramolecular nucleophilic attack of the carbonyl oxygen to the carbon atom bearing a
leaving group (Z=Br, ArC(ꢀO)O) to give 3 (Scheme 6).

8503
Scheme 6.
Acknowledgements
The authors are grateful to the S.N.U., Daewoo Research Fund for financial support.
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