Synthesis of isoxazolidines using polymer supported perruthenate (PSP)

Article abstract of DOI:10.1039/a707340b

Polymer supported perruthenate (PSP) has been used in mild and selective oxidations of secondary hydroxylamines to give nitrones; in the presence of dipolarophiles isoxazolidines are obtained in one-pot processes in good yields.

Full text of DOI:10.1039/a707340b

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Synthesis of isoxazolidines using polymer supported perruthenate
(PSP)
Berthold Hinzen and Steven V. Ley
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
Polymer supported perruthenate (PSP) has been used in
mild and selective oxidations of secondary hydroxylamines
to give nitrones; in the presence of dipolarophiles isoxazol-
idines are obtained in one-pot processes in good yields.
room temperature. Upon consumption of the starting material
as indicated by thin layer chromatography the yield of the corre-
1
sponding nitrone was estimated to be 94% by H NMR spec-
troscopy. When this oxidation was performed in the presence of
electron-poor dipolarophiles e.g. methyl acrylate, acrylonitrile
or methyl vinyl ketone the corresponding isoxazolidines were
obtained in good yields. Similarly, hydroxypyrrolidine has been
oxidised to the corresponding 1,3-dipole and reacted in situ
with diethyl fumarate to give an isoxazolidine in good yield
(Table 1, entry 3). Owing to the high chemoselectivity of the
perruthenate oxidant these transformations are possible in the
presence of other functional groups. For example the tertiary
amine functionality in a piperazine derivative (Table 1, entry
2a,b) was inert under the reaction conditions and the cycloaddi-
tion products from the reaction with methyl acrylate and
diethyl fumarate were obtained in good yields. In summary, this
process allows the preparation of isoxazolidines from sym-
metrical secondary hydroxylamines.
The synthesis of chemical libraries is of great importance in the
pharmaceutical and agrochemical industries. These libraries of
small molecules are normally prepared either in solution or on
a solid support. The greater flexibility of the solution-chemistry
approach is outweighed by the need for purification of the
library.1 As a consequence solid supported reagents2 have been
developed which allow the synthesis of chemical libraries in
solution using an excess of reagent which can finally be
removed by simple filtration without the need for a chromato-
graphic work-up. We have recently reported the use of polymer
supported perruthenate (PSP) as a mild oxidant for the clean
conversion of primary and secondary alcohols to carbonyl
compounds.3 Here we report the use of PSP for the in situ prep-
aration of nitrones to give isoxazolidines in one-pot processes.
Nitrones are synthetically useful intermediates since they
provide, via [2 ϩ 3]cycloadditions, an excellent route to isox-
azolidines which are not only interesting targets in themselves,
but are also precursors for highly functionalised open chain
derivatives.4 These 1,3-dipoles are commonly prepared either
from secondary hydroxylamines by oxidation with HgO,5
A second route towards isoxazolidines starts from an alcohol
(Scheme 2). After oxidation with PSP the resulting carbonyl
+
–
NMe3
RuO4
O
+
AcO–
NMe3
O–
+
Ph
N
7
TPAP6 or PdCl2 or from condensation of aldehydes and
Ph
CH3
monosubstituted hydroxylamines.8
H
Hydroxylamines can be prepared either sequentially or in
situ from the corresponding amines using dimethyldioxirane
(DMDO).9 PSP can oxidise these substrates to the corres-
ponding nitrones (Scheme 1). Owing to their limited stability it
OH
+
COOCH3
H3C
N
RT, 12 h
81%
HCl
OH
Ph
H3C
N
Ph
+
–
NMe3
RuO4
R1
+
O
R2
R2
R1
N
CHCl3
– H2O
CHCl3, 60 ˚C
N
O–
CH3
O
O
O
R3
Scheme 2
R4
R3
R1
R2
compound can be condensed with a primary hydroxylamine to
afford the corresponding nitrone which can then be used in a
cycloaddition to afford isoxazolidines. This process is illus-
trated in the synthesis of N-methyl-5-methoxycarbonyl-3-
phenylisoxazolidine from benzyl alcohol, hydroxymethylamine
and methyl acrylate (Scheme 2). After PSP-oxidation of benzyl
alcohol† (0.5 mmol) the solution of crude benzaldehyde in
dichloromethane (1 cm3) was added to a mixture of solid
supported acetate,‡ hydroxymethylamine hydrochloride salt
(1.1 equiv.) and methanol (3 cm3) and stirred at room temper-
N
+
R4
OH
Scheme 1
is advantageous to perform this oxidation in the presence of an
electron-poor dipolarophile. The oxidation and the cycloaddi-
tion reaction can be performed as a one-pot process affording
isoxazolidines in good yields after removal of the solid sup-
ported reagent by filtration (Table 1). The immobilised oxidant
can be regenerated by stirring it over a solution of N-methyl-
morpholine N-oxide (NMO).
† This is a quantitative reaction, as reported earlier (ref. 3).
In initial experiments, diethylhydroxylamine (0.5 mmol) was
added to a mixture of dichloromethane or deuteriochloroform
‡ This reagent is used to buffer the reaction mixture and was prepared
from an ion exchange resin (IR 27, OHϪ-form) by washing the resin
thoroughly with glacial acetic acid and drying in vacuo for several days.
(3 cm3) and PSP (500 mg, 1.0 mmol RuO4 per gram resin) at
Ϫ
J. Chem. Soc., Perkin Trans. 1, 1998
1

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Table 1 Oxidations of secondary hydroxylamines in the presence of dipolarophiles to yield isoxazolidines
Entry
1a
Hydroxylamine
Nitrone
Dipolarophile
methyl acrylate
Isoxazolidinea
Reaction time/h
Yield/%
91b
+
N
Et
N
N
R = COOCH3
16
13
17
O–
"
OH
O
1b
1c
acrylonitrile
89b
81b
"
"
R = CN
R
methyl vinyl ketone
R = COCH3
"
"
Et
N
13
16
72c
89c
O
1d
diethyl fumarate
R = COOEt
"
R
R
ArN
2ad
2bd
methyl acrylate
diethyl fumarate
COOCH3
F3C
Cl
N
O
ArN
N
+
COOEt
COOEt
O–
N
N
NOH
ArN
N
19
14
55b
84c
O
3
diethyl fumarate
N
N
+
COOEt
N
OH
O–
O
COOEt
a The products indicated correspond to the major diastereoisomer. The assignment of regio- and stereo-chemistry is based on literature precedence
(ref. 11). b Yield determined by 1H NMR spectroscopy. c Isolated yield. d Ar = 2-(3-Chloro-5-trifluoropyridyl).
ature for 12 h.10 The solution of the crude nitrone was then
J. Chem. Soc., Chem. Commun., 1986, 1287; S. Cicchi, I. Hoeld and
A. Bondi, J. Org. Chem., 1993, 58, 5274.
transferred to a mixture of methyl acrylate (1.5 equiv.) and
6 A. Goti, F. De Carlo and M. Romani, Tetrahedron Lett., 1994, 35,
toluene (3 cm3) and stirred overnight. The cycloaddition prod-
6571; S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden,
uct was isolated in 81%.
Synthesis, 1994, 639.
In conclusion we have shown the use of Polymer Supported
Perruthenate (PSP) in the preparation of nitrones for the syn-
thesis of isoxazolidines. We believe the processes described are
suitable for automated synthesis and thus offer interesting
opportunities for the synthesis of chemical libraries.
We gratefully acknowledge financial support from the Swiss
National Science Foundation (Fellowship to B. H.), the BP
endowment and the Novartis Research Fellowship (to S. V. L.).
7 S. Murahashi, H. Mitsui, T. Watanabe and S. Zenki, Tetrahedron
Lett., 1983, 24, 1049.
8 A. Freer, K. Overton and R. Tomanek, Tetrahedron Lett., 1990,
31, 1471; P. R. West and G. C. Davis, J. Org. Chem., 1989, 54, 5176;
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Paper 7/07340B
Received 10th October 1997
Accepted 4th November 1997
2
J. Chem. Soc., Perkin Trans. 1, 1998