Solid-phase synthesis of isoxazoles using vinyl ethers as chameleon catches

Article abstract of DOI:10.1021/ol016479x

(figure presented) Regioselective 1,3-dipolar cycloadditions of supported vinyl ethers R¹C(=CH₂)O-CH₂-polymer, prepared by the Tebbe olefination of R¹CO₂-CH₂-polymer with ethyl cyanoformate

Full text of DOI:10.1021/ol016479x

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3165-3168
Solid-Phase Synthesis of Isoxazoles
Using Vinyl Ethers as Chameleon
Catches
Anthony G. M. Barrett,* Panayiotis A. Procopiou, and Ulrike Voigtmann
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London SW7 2AY, and GlaxoSmithKline Research and DeVelopment Ltd. Medicine
Research Centre, Gunnels Wood Road, SteVenage, Hertfordshire SG1 2NY, U.K.
agmb@ic.ac.uk
Received July 23, 2001
ABSTRACT
1
1
Regioselective 1,3-dipolar cycloadditions of supported vinyl ethers R C(dCH )O-CH -polymer, prepared by the Tebbe olefination of R CO -
2
2
2
CH -polymer, with ethyl cyanoformate N-oxide gave supported isoxazoline derivatives. Release from the support under mild acidic conditions
2
1
1
gave the isoxazoles ethyl 5-R -isoxazole-3-carboxylates. Alternatively, further on-resin functionalization of the R substituent using Suzuki
coupling reactions and release from the support under acidic conditions gave more structurally diverse isoxazoles.
The application of solid-phase organic synthesis (SPOS) in
the preparation of small compound libraries is of considerable
significance in the discovery and development of new drug
compounds.1 An important aspect of any solid-phase meth-
odology is the choice of the linker, which is crucial for the
attachment and detachment of the requisite substrates to and
from the resin.2 Many solid-phase syntheses rely on the
release of carboxylic acids, esters, or amides from an ester-
or amide-bound substrate.2b Alternative methods that allow
the cleavage of resin-bound carboxylate derivatives, yet with
access to more variable functionalities, are extremely desir-
able. Previous work in the group3 has shown that carboxylic
esters 1 supported on Wang or Merrifield resin underwent
smooth methylenation using the Tebbe reagent to produce
supported vinyl ethers 2 (Scheme 1). These vinyl ethers are
convenient substrates for further on-resin functionalization
or cleavage with additional chemical change. They could be
released from the resin under mildly acidic conditions to
produce methyl ketones 3 or be subjected to further on-resin
transformations followed by release as amines, thiazoles, or
cyclohexanone derivatives. As such the vinyl ethers 2
represent examples of Chameleon Catches for combinatorial
chemistry.4
Isoxazole moieties represent a class of unique pharma-
cophores that are constituent units of diverse therapeutic
agents.5 Therefore, they are interesting targets in the devel-
Scheme 1a
(1) Haap, W. J.; Kaiser, D.; Walk, T. B.; Jung, G. Tetrahedron 1998,
54, 3705 and references therein.
(2) (a) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV 2000, 100, 2091-
2157. (b) Comely, A. C.; Gibson, S. E. Angew. Chem., Int. Ed. 2000, 40,
1021-1032.
(3) Ball, C. P.; Barrett, A. G. M.; Commercon, A.; Compere, D.; Kuhn,
C.; Roberts, R. S.; Smith, M. L.; Venier, O. Chem. Commun. 1998, 2019-
2020.
a Reagents and conditions: (a) Tebbe reagent (Aldrich), THF,
25 °C, 16 h; (b) 3% TFA, CH2Cl2, 25 °C, 30 min.
10.1021/ol016479x CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

opment of new drug leads in solid-phase combinatorial
chemistry. Several authors have studied the synthesis of
isoxazoles using solid-phase chemistry.6 These include the
condensation of 1,3-dicarbonyl compounds with hydroxyl-
amine,7 the addition of nitrile oxides to supported alkynes,8
or the anchoring of a nitrile oxide precursor onto the solid
phase.9 However, all methods suffer from a lack of regiose-
lectivity, and the linker remains unchanged in the released
product. Herein we report a regioselective 1,3-dipolar cy-
cloaddition reaction of nitrile oxides to vinyl ethers for the
synthesis of supported isoxazolines and their subsequent
transformation to isoxazoles by elimination and release from
the support. This strategy, in combination with Suzuki
couplings to enhance diversity, allows a rapid synthesis of a
wide range of isoxazoles. Effectively, the linker remains
traceless in the product of cleavage. In addition, [3 + 2]
cycloadditions of nitrile oxides in solution are known to
suffer from many side reactions including dimerization as a
result of their high reactivity.10 Therefore it is synthetically
interesting to carry out these reactions on the solid phase,
which makes isolation of the product easier.
Methylenation of the resin bound esters 1 with the
commercially available Tebbe reagent (Aldrich) in THF at
room temperature gave the corresponding vinyl ethers 2
(Scheme 1). The reaction mixtures were quenched with 10%
aqueous sodium hydroxide, and the resin was washed
consecutively with THF, H2O, EtOAc, and MeOH followed
by removal of the solvent in vacuo. The transformation could
easily be monitored by using single bead microscope IR
spectroscopy for the disappearance of the carbonyl stretch
(νmax, 1720-1740 cm-1). Acid-catalyzed cleavage of ethers
2 with trifluoroacetic acid in dichloromethane brought about
cleavage from the resin and gave the corresponding ketones
3 in good yields (51-77%) and excellent purities (>95%,
1H NMR).
Scheme 2a
a Reagents and conditions: (a) 3 equiv of ethyl chlorooximi-
doacetate 4, Et3N, THF, 1 h, four times; (b) 5% TFA, CH2Cl2,
25 °C, 30 min.
supported isoxazolines was again easily monitored by IR
spectroscopy for the appearance of a new carbonyl stretch
(νmax, 1724 cm-1). The products were cleaved from the resin
by treatment with 5% trifluoroacetic acid in dichloromethane.
As a result of the rapid dimerization of the nitrile oxide,
incomplete cycloaddition was observed, resulting in a mixture
of the desired heterocycle 6 and the ketone 3 after the acidic
cleavage. This could be optimized by repeating the [3 + 2]
cycloaddition step four times prior to cleavage. Remaining
traces of ketone were removed by using a polystyrene-
supported phenyl sulfonylhydrazine as scavenger. Isoxazoles
6 a-h (Figure 1) were obtained as single regioisomers in
Nitrile oxides can be generated in situ by dehydration of
primary nitroalkanes using a base and phenyl isocyanate11
following the Mukaiyama method or by base-induced
elimination of HCl from hydroximinoyl chlorides.9,12 Pre-
liminary model studies in solution showed that heating in
the presence of a base, which is usually required in the
Mukaiyama method, would lead to premature cleavage of
the supported isoxazoline 5. Thus, the more convenient
procedure for the synthesis of reactive nitrile oxides was
dehalogenation of hydroximinoyl chlorides, which can be
purchased or be obtained by chlorination of the correspond-
ing aldoximes with N-chlorosuccinimide. We concentrated
our work on the application of commercially available ethyl
chlorooximidoacetate to obtain supported ethyl isoxazoline-
3-carboxylates 5 and ethyl isoxazole-3-carboxylates 6,
respectively (Scheme 2).
Figure 1. Synthesis of isoxazoles 6 via [3 + 2] cycloaddition of
nitrile oxide 4 onto vinyl ether 2.
Vinyl ethers 2 were allowed to react with ethyl chloroox-
imidoacetate 4 (3 equiv) and triethylamine (10 equiv) in THF.
The addition of the reagent was carried out incrementally
over 1 h, and then the resin was consecutively washed with
THF, H2O, EtOAc, and MeOH. The formation of the
good purity (>93% by HPLC) and with 36-83% yield based
on the loading of the Wang resin (1.2 mmol g-1) to which
the acids had been attached.
Because the Tebbe reagent is not compatible with a range
of functional groups, Suzuki coupling reactions13 after the
formation of 2 were examined in order to increase the
diversity of the isoxazoles formed (Scheme 3).
(4) Other Chameleon Catches in SPOS: Gowravram, M. R.; Gallop, M.
A. Tetrahedron Lett. 1997, 38, 6973-6976.
3166
Org. Lett., Vol. 3, No. 20, 2001

Alternatively, the solid-supported vinyl ether intermediates
7 were further treated with ethyl chlorooximidoacetate 4 as
described for 6 to produce isoxazoles 10 (Scheme 4). Thus,
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) 3 equiv of ethyl chlorooximi-
doacetate 4, Et3N, THF, 1 h, four times; (b) 5% TFA, CH2Cl2,
25 °C, 30 min.
a Reagents and conditions: (a) 10 mol % Pd(OAc)2, 20 mol %
dppf, 10 equiv of K2CO3, DMF, 90 °C, 16 h; (b) 3% TFA, CH2Cl2,
25 °C, 30 min.
several ethyl 5-biphenyl-3-yl-isoxazole-3-carboxylates 10
a-g could be synthesized in good purities (∼90%) and
reasonable yields (38-80%, Figure 3). 1,3-Dipolar cycload-
ditions as well as the Suzuki coupling reactions were carried
Best results for the Suzuki coupling on solid support were
achieved using Pd(OAc)2 (10 mol %), dppf (20 mol %), and
K2CO3 (10 equiv) at 90 °C in degassed DMF. Subsequent
washing of the resin with DMF, THF, H2O, EtOAc, and
MeOH and treatment of the supported biaryl vinyl ether 7
with 3% trifluoroacetic acid in dichloromethane gave the
corresponding ketones 8 (Figure 2) in good yields (60-79%)
Figure 2. Synthesis of biarylic ketones 8 via Suzuki couplings
onto vinyl ether 2.
and excellent purities (>95% by NMR). Traces of phenyl
methyl ketone as a result of hydrolysis of an aryl-palladium-
halide species were observed after cleavage but could easily
be evaporated under vacuo. Palladium-containing side prod-
ucts, which were soluble under the cleavage conditions, were
removed by filtration of the crude products in dichlo-
romethane or acetone through silica gel.
Figure 3. Synthesis of isoxazoles 10 via Suzuki coupling and
[3 + 2] cycloaddition of nitrile oxides onto vinyl ether 2.
Org. Lett., Vol. 3, No. 20, 2001
3167

out using the Quest Synthesizer from Argonaut Technologies
Inc.
Acknowledgment. We thank GlaxoSmithKline for their
endowment (to A.G.M.B.), the EPSRC, and the German
Academic Exchange Service for a postdoctoral fellowship
(to U.V.).
In conclusion, Tebbe olefination of supported esters gave
the corresponding vinyl ethers, which are convenient sub-
strates for further on-resin functionalization or cleavage with
additional chemical change. 1,3-Dipolar cycloaddition of
nitrile oxide onto these vinyl ethers results in the formation
of supported isoxazolines, which were released under acidic
conditions to produce isoxazoles. Suzuki coupling reactions
were applied to introduce further functionalities and enhanced
diversity. So, starting with easily accessible solid-supported
carboxylic esters, a small library of diverse isoxazoles could
be synthesized. Further reactions of the supported enol ethers
will be reported in due course.
Supporting Information Available: Detailed experi-
mental data and proton and carbon NMR spectra for
compounds 6a-h, 8a-f, and 10a-g. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL016479X
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