The preparation of 2-isoxazolines from O-propargylic hydroxylamines via a tandem rearrangement-cyclisation reaction

Article abstract of DOI:10.1055/s-2006-926232

A method for the conversion of O-propargylic hydroxylamines into 2-isoxazolines in 60-84% yield is described. For 3-alkylpropargyl or 3-arylpropargyl hydroxylamines this was achieved by heating a methanolic solution of the hydrochloride salt in the presen

Full text of DOI:10.1055/s-2006-926232

LETTER
463
The Preparation of 2-Isoxazolines from O-Propargylic Hydroxylamines via a
Tandem Rearrangement–Cyclisation Reaction
Preparation of
2
e
-Isoxazolin
w
es from
O
-Proparg
i
ylic
H
s
ydroxylamines Pennicott, Stephen Lindell*
Bayer CropScience GmbH, Werk Höchst G836, 65926 Frankfurt am Main, Germany
Fax +49(69)30517768; E-mail: Stephen.lindell@bayercropscience.com
Received 11 November 2005
R2
ONH2·HCl
R1
R2
K2CO3
Abstract: A method for the conversion of O-propargylic hydroxyl-
amines into 2-isoxazolines in 60–84% yield is described. For 3-
R1
MeOH, ∆
N
O
alkylpropargyl or 3-arylpropargyl hydroxylamines this was
achieved by heating a methanolic solution of the hydrochloride salt
in the presence of K2CO3. In the case of the 3-unsubstituted com-
pounds, the hydrochloride salts were first converted to the free
bases, which rearranged upon heating in methanol. In one case, the
methodology was extended to enable the direct transformation of a
O-propargyl phthalimide into a 2-isoxazoline in 65% yield by treat-
ment with methyl hydrazine at room temperature over 19 hours.
1–10
11–20
Scheme 1
O-Propargylic hydroxylamine hydrochloride salts 1–10
were synthesised using a literature method9 for use in a
project connected with the preparation of insecticidal
muscarinic acetyl choline receptor agonists.10 While nor-
mally the salts 1–10 were found to be stable upon even
prolonged storage, during the course of our work we dis-
covered that they could be induced to undergo intramolec-
ular rearrangement to give the 2-isoxazolines 11–20 in
good yields. The best general conditions involved heating
a 0.3 M solution of the hydroxylamine hydrochloride and
K2CO3 (1 equiv) in dry methanol at reflux for 7.5 hours.
Under these conditions, 3-aryl substituted O-propargylic
hydroxylamines were converted cleanly to the corre-
sponding 2-isoxazolines, which were isolated in 71–84%
yield after chromatography (Table 1, compounds 11, 12,
13, 14, 17 and 18).11 3-Alkyl substituted hydroxylamines
were also smoothly converted but the yields were slightly
lower, 60–74% (Table 1, compounds 15 and 16). In con-
trast, 3-unsubstituted propargylic hydroxylamines gave
none of the expected isoxazoline using these standard
conditions. In the case of the n-pentyl substituted com-
pound 10, the b-hydroxynitrile 21 was isolated in 79%
from this reaction, presumably due to a base-catalysed
opening of the isoxazoline ring (Scheme 2). In order to try
and prevent this undesired side reaction the procedure was
repeated using the free hydroxylamine bases and without
addition of the K2CO3. Under these modified conditions
the desired isoxazolines 19 and 20 were isolated in 63%
and 61% yield, respectively (Table 1).11
Key words: isoxazoline synthesis, O-propargylic hydroxylamine,
sigmatropic rearrangement
The 2-isoxazoline ring is an important constituent of a
number of biologically active molecules including the
antitumour drug Acivicin1 and the antithrombotic agent
DMP 802.2 In addition, due to their ability to undergo fac-
ile reductive ring-opening reactions they are of interest as
synthetic intermediates.3 As a consequence, many syn-
thetic methods have been developed to produce 2-isox-
azolines of which the reaction of a,b-unsaturated ketones
with hydroxylamine and the cycloaddition of nitrile ox-
ides to alkenes are the most important.3,4 The 1,3-dipolar
cycloaddition route is especially versatile5 but has some
disadvantages due to the tendency of nitrile oxides to
dimerise to furoxans.4 To compensate for dimerisation
losses it is common to use an excess of the dipolarophile,6
or in some cases of nitrile oxide.7 However, this can com-
plicate the final purification and isolation of the product
and wastes potentially valuable intermediates. Conse-
quently, new synthetic methods are of interest and in this
communication we report a simple procedure for the syn-
thesis of 2-isoxazolines by intramolecular rearrangement
of O-propargylic hydroxylamines (Scheme 1). A search
of the literature has revealed a single prior example of this
rearrangement but the conditions were relatively severe
(18 equiv NaOH, MeOH, reflux, 3 h) and the scope of the
reaction was not explored.8 The conditions reported here-
in are considerably milder and the method has been gen-
eralised to yield a wide range of mono- and disubstituted
2-isoxazolines.
[B]–
K2CO3
H
MeOH
N
O
ONH2·HCl
H
OMe
10
NC
OH
21
SYNLETT 2006, No. 3, pp 0463–0465
Advanced online publication: 06.02.2006
1
5.
0
2.
2
0
0
6
Scheme 2
DOI: 10.1055/s-2006-926232; Art ID: G36405ST
© Georg Thieme Verlag Stuttgart · New York

464
L. Pennicott, S. Lindell
LETTER
precursors as described in the literature.9 The utility of the
current transformation would be greatly increased if these
precursors could be directly transformed into 2-isoxazo-
lines. Consequently, a 0.3 M solution of the phthalimide
25 and methyl hydrazine (1 equiv) in CH2Cl2 were stirred
together at room temperature for 19 hours. After workup
and chromatography, the 2-isoxazoline 13 was isolated in
65% yield (Scheme 4).11 Conducting the same experiment
under the literature conditions,9 whereby the reaction was
worked up after four hours, yielded the non-rearranged O-
propargyl hydroxylamine hydrochloride 3 in 80% yield.
Table 1 The Synthesis of 2-Isoxazolines from O-Propargylic
Hydroxylamine Hydrochloride Salts11
Hydroxyl-
amine hydro-
chloride
R1
R2
2-Isox-
azoline
Isolated
yield (%)
1
2
2-ClC6H4
H
11
12
13
14
15
16
17
18
19
74
78
71
83
60
74
84
84
63
61
3-MeOC6H4
H
3
4-ClC6H4
H
4
3,5-(CF3)2C6H3
H
5
n-Pr
H
O
6
Et2NCH2
H
O
N
MeNHNH2
CH2Cl2
Cl
Cl
O
7
Ph
Ph
H
Me
i-Pr
Ph
N
O
25
13
8
Scheme 4
9a
10a
In summary, O-propargyl hydroxylamine hydrochlorides
1–10 have been smoothly transformed into substituted 2-
isoxazolines 11–20 in isolated yields of 60–84%.11 In one
case, the methodology has been extended to enable the di-
rect transformation on an O-propargyl phthalimide into
the 2-isoxazoline 13 in 65% yield. Since the phthalimide
25 is readily synthesised from the corresponding propar-
gylic alcohol,9 the methodology formally represents a
two-step route for converting propargylic alcohols into 2-
isoxazolines.
H
n-Pentyl 20
a Rearrangement performed on the free hydroxylamine without
K2CO3.
The mechanism for the transformation of O-propargylic
hydroxylamines to 2-isoxazolines has not been in-
vestigated, however, one possibility involves an initial
2,3-sigmatropic rearrangement to give the N-allenic hy-
droxylamines 22 (Scheme 3). These could then rearrange
to give the a,b-unsaturated oximes 23 which could under-
go a 5-endo-trig cyclisation to give the 3-isoxazolines 24.
Finally, isomerisation of the enamine to the more stable
imine would give the observed 2-isoxazoline products
11–20. The previously reported rearrangement of N-ben-
zyl-O-allylic hydroxylamines to give N-allylic hydroxyl-
amines provides good precedent for the initial
rearrangement step to give allenes 22.12
Acknowledgment
We wish to thank Professor Philip Parsons of Sussex University for
helpful discussions during the course of this work.
References and Notes
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The propargylic hydroxylamines used in this work were
synthesised from the corresponding phthalimide protected
H
OMe
R2
H
OMe
R2
R1
R1
O
HN
22
NH2
OH
(b) Sutharchanadevi, M.; Muragan, R. Comprehensive
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R1
N
R2
MeO
H
HO
23
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R1
11–20
HN
R2
O
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G.; Mella, M.; Mortoni, A.; Paio, A.; Quadrelli, P.; Seneci,
P. Eur. J. Org. Chem. 2002, 1175. (b) Tsuji, M.; Inomata,
K. Chem. Lett. 2002, 1112. (c) Fader, L. D.; Carreira, E. M.
24
Scheme 3
Synlett 2006, No. 3, 463–465 © Thieme Stuttgart · New York

LETTER
Preparation of 2-Isoxazolines from O-Propargylic Hydroxylamines
465
Org. Lett. 2004, 6, 2485. (d) Xu, W.-M.; Wang, Y.-G.;
mmol, 74%). IR: nmax = 3066 (w), 2954 (m), 2887 (m), 1584
(m), 1476 (m), 1434 (s), 1342 (s), 1037 (m), 934 (m), 880 (s),
643 (m) cm–1. 1H NMR (300 MHz, CDCl3): d = 3.48 (2 H, t,
J = 8.7 Hz, C4-H2), 4.51 (2 H, t, J = 8.7 Hz, C5-H2), 7.26–
7.38 (2 H, m, Ph), 7.43 (1 H, dd, J = 0.7, 6.3 Hz, Ph), 7.64 (1
H, dd, J = 0.8, 7.9 Hz, Ph). MS (EI): m/z (%) 183 (33) [M+],
181 (100) [M+], 155 (20), 153 (79), 151 (87), 137 (65), 113
(20), 111 (53), 75 (74). Anal. Calcd for C9H8ClNO: C, 59.52;
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Preparation of 5-Phenyl-2-isoxazoline (19).
The O-propargylic hydroxylamine hydrochloride salt 9
(1.84 g, 10.0 mmol) was dissolved in CH2Cl2 (20 mL) and
washed with sat. NaHCO3 solution (20 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL) and the
combined extracts were dried over MgSO4 and concentrated
in vacuo at 40 °C to give the free hydroxylamine (1.44 g, 9.8
mmol). A portion of this material (300 mg, 2.04 mmol) was
dissolved in dry MeOH (5 mL) and heated at reflux under a
nitrogen atmosphere for 8 h. The solution was then
concentrated in vacuo at 40 °C and the crude product
purified by flash chromatography (gradient elution; EtOAc–
heptane) to give the isoxazoline 19 as an oil (188 mg, 1.28
mmol, 63%). IR and 1H NMR spectra as previously
reported.16 Compound 20 was prepared using an analogous
procedure.
Preparation of 3-(4-Chlorophenyl)-2-isoxazoline (13).
Methyl hydrazine (0.15 g, 3.3 mmol) was instilled into a
cooled solution (0 °C) of the phthalimide (25) (1.00 g, 3.2
mmol) in CH2Cl2 (10 mL) under a nitrogen atmosphere. The
mixture was stirred at r.t. for 19 h, after which time the
precipitated 2-methyl-2,3-dihydrophthalazine-1,4-dione
was removed by filtration and discarded. The filtrate was
diluted with Et2O (50 mL), cooled to 0 °C and anhyd HCl(g)
was bubbled through for approximately 5 min to give a small
amount of brown precipitate which was filtered off and
discarded. The filtrate was then concentrated in vacuo at
40 °C and the crude product purified by flash
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A mixture of the O-propargylic hydroxylamine
chromatography (gradient elution; EtOAc–heptane) to give
the isoxazole 13 as a crystalline solid (380 mg, 2.1 mmol,
65%); mp 114–116 °C (lit.13 116–117 °C). IR and 1H NMR
spectra as previously reported.13
hydrochloride salt 1 (275 mg, 1.26 mmol), K2CO3 (175 mg,
1.27 mmol) and dry MeOH (5 mL) was heated at reflux
under a nitrogen atmosphere for 7.5 h. The solution was then
concentrated in vacuo at 40 °C, H2O (5 mL) was added and
the mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were dried with MgSO4 and
concentrated in vacuo at 40 °C. The crude product was
purified by flash chromatography (gradient elution; EtOAc–
heptane) to give the isoxazoline 11 as an oil (169 mg, 0.93
Compounds 17–20 were isolated as racemic mixtures.
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Synlett 2006, No. 3, 463–465 © Thieme Stuttgart · New York