Synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes

Article abstract of DOI:10.1039/c0cc04646a

Treatment of oximes with hypervalent iodine leads to substituted isoxazoles via rapid formation of nitrile oxides. Reaction with terminal alkynes led to a series of 3,5-disubstituted isoxazoles with complete regioselectivity and high yield, in a procedure

Full text of DOI:10.1039/c0cc04646a

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Synthesis of isoxazoles by hypervalent iodine-induced cycloaddition
of nitrile oxides to alkynesw
Anup M. Jawalekar, Erik Reubsaet, Floris P. J. T. Rutjes and Floris L. van Delft*
Received 27th October 2010, Accepted 6th January 2011
DOI: 10.1039/c0cc04646a
Treatment of oximes with hypervalent iodine leads to substituted
isoxazoles via rapid formation of nitrile oxides. Reaction with
terminal alkynes led to a series of 3,5-disubstituted isoxazoles
with complete regioselectivity and high yield, in a procedure mild
enough to prepare a range of nucleoside and peptide conjugates.
Exceptionally high reaction rates were found for the formation
of 3,4,5-trisubstituted isoxazoles from a cyclic alkyne.
the low yield (50%) of the reaction. Herein, we report a
methodology for a completely regioselective and high yielding
procedure for the preparation of 3,5-disubstituted and
3,4,5-trisubstituted isoxazoles from terminal or cyclic alkynes,
respectively. Key to the strategy is near instantaneous
generation of nitrile oxides from oximes by use of phenyl-
iodine bis(trifluoroacetate) as an oxidising agent. The versatility
of the procedure and applicability as a novel tool for
bioconjugation is demonstrated by preparation of a range of
nucleoside and peptide-containing isoxazoles.7
Isoxazoles form a major class of nitrogen heterocycles that are
molecular components in a variety of natural products (e.g.
ibotenic acid, muscimol, isoxazole-4-carboxylic acid) and drugs
(e.g. valdecoxib, leflunomide, cloxacillin).1 A variety of synthetic
methods has been developed for the preparation of isoxazoles,2 of
which the cycloaddition of nitrile oxides and alkynes is probably
the most direct.3 However, thermal nitrile oxide–alkyne cyclo-
additions typically give low yields, side-reactions and poor regio-
selectivity.4 Copper(I) and ruthenium(II)-induced preparation of
3,5- or 3,4-disubstituted isoxazoles has been reported,5 but
for many applications the use of (toxic) transition metals is
undesirable if not prohibited. Therefore, there exists a clear need
for metal-free, regioselective synthesis of isoxazoles.
Due to its low toxicity, ready availability and easy handling,
phenyliodine bis(trifluoroacetate) (PIFA) is a useful reagent
for oxidative dearomatisation, dehydrodimerisation and
selective cyanation.8 To date, however, PIFA has not been
applied for the generation of nitrile oxide from oximes. We
therefore investigated the reaction of phenylacetylene and
benzaldoxime under the action of PIFA (ESIw and Table 1).
A slow conversion was observed in MeCN, i-PrOH or in 1,4-
dioxane/H2O (5 : 1) mixtures but in MeOH/H2O (5 : 1), a
highly efficient reaction took place.9 A small excess (1.5 equiv.)
of oxime is required for the reaction as a result of the fact that
the in situ formed nitrile oxide slowly homodimerizes to
furoxan or 1,4-dioxo-2,5-diazine.4,10 Therefore, the effect of
portion-wise addition of PIFA and reaction concentration was
investigated (Table 1). When benzaldoxime (1.5 equiv.) and
PIFA (1.5 equiv.) were combined with phenylacetylene
(0.01 M), the expected 3,5-disubstituted isoxazole was
obtained in 65% yield. Addition of PIFA in two portions
(total 1.5 equiv.) improved the yield to 70%. Further increasing
the reaction concentration (with respect to alkyne) to 0.1 M
and addition of PIFA in three portions over 2 h intervals
Recently, it was reported that 3,5-disubstituted isoxazolines
can be prepared by cycloaddition to olefins and nitrile oxides,
generated in situ from oximes with (diacetoxyiodo)benzene
(DIB) with catalytic TFA (Scheme 1, top).6 A single example
of isoxazole preparation was also given, but the methodology
was not further elaborated, presumably as a consequence of
Table 1 Cycloaddition of phenylacetylene and benzonitrile-N-oxide
Scheme 1 Cycloaddition of nitrile oxides to alkenes or acetylenes via
hypervalent iodine-induced generation of nitrile oxide from oxime.
Institute for Molecules and Materials, Radboud University Nijmegen,
Heijendaalseweg 135, NL-6525 AJ, Nijmegen, the Netherlands.
E-mail: F.vanDelft@science.ru.nl; Fax: +31 24 3653393;
Tel: +31 24 3652373
w Electronic supplementary information (ESI) available: Solvent
screening, general synthetic procedures, structural characterisation
of oximes and isoxazoles, reaction analysis by NMR and HPLC. See
DOI: 10.1039/c0cc04646a
Oxime
PIFA addition
Entry Conc.a/M (equiv.) (1.5 equiv.)
Time/h Yield (%)
1
2
3
0.01
0.01
0.1
1.5
1.5
1.5
1 portion
2 portions/4 h 24
3 portions/2 h
24
65
70
90
7
a
Concentration of phenylacetylene.
c
3198 Chem. Commun., 2011, 47, 3198–3200
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(1.5 equiv. in total), gave the desired isoxazole in 90% yield
after 7 h. The beneficial role of PIFA is explained by the near
instantaneous formation (1 min) of nitrile oxide from
p-methylbenzaldoxime (Fig. S1, ESIw), while oxidation with
DIB is sluggish and incomplete after 60 min (Fig. S2, ESIw).
Having established optimal conditions for in situ generation
of nitrile oxide, and cycloaddition to acetylene, the scope of
isoxazole formation was evaluated for a range of substrates
(Table 2). A variety of aromatic or aliphatic oximes or
alkynes, with electron-deficient or electron-rich groups, was
converted to 3,5-disubstituted isoxazoles in good to excellent
yields. Aliphatic alkynes were less reactive than aromatic
alkynes giving 55–66% product based on the oxime used.
However, use of four-fold excess of oxime raised the yield to
94% (entry 16). No competitive cycloaddition of nitrile oxides
to olefins was observed in case of trans-cinnamaldoxime
(entries 9–12). It must be noted that the yields obtained in
our procedure compare favorably to the copper-catalysed
synthesis of isoxazoles, especially in case of benzaldoxime
(entry 1) and 4-nitrobenzaldoxime (entry 17).5a,b
Table 2 Isoxazoles from terminal alkynes and nitrile oxides
Yield
(%) Entry Product
Yield
(%)
Entry Product
1
90
80
81
11
12
13
65
2
61a
3
4
5
71
67a
72
The scope of nitrile oxide–alkyne cycloaddition for bio-
conjugation was explored by application to a range of
nucleosides and a model peptide (Fig. 1). To our delight,
PIFA-induced (3 + 2) cycloaddition works well with unpro-
tected nucleosides and a 20-alkyl adenosine-derived11 oxime,
leading to adducts 21–24, thereby tolerating various functional
groups (ESIw, Fig. S3). Finally, we successfully prepared an
isoxazole from a peptide with an N-terminal acetylene. To this
end, freshly generated nitrile oxide from benzaloxime
(3 equiv.) in MeOH (210 mL) was added to the peptide
(100 mM in H2O), which was repeated six times over 12 h,
leading to clean formation of isoxazole (495% conversion),
as confirmed by HPLC and HRMS (Fig. S4, ESIw).
49a 14
76
15
66a
94c
6
7
90
60
16
17
Having demonstrated the viability of PIFA-induced cyclo-
addition of nitrile oxides and terminal alkynes, we next investi-
gated strain-promoted reactions with cyclic alkynes, known to
undergo rapid cycloadditions with azides12,13 and nitrones.14
We recently developed a straightforward route to a novel
cyclooctyne analogue, namely bicyclo[6.1.0]nonyne (BCN),
for metal-free cycloaddition reactions.15 In this context, the
cycloaddition of BCN with nitrile oxide could constitute
another versatile metal-free ligation strategy.16 Thus, a series
of aromatic, aliphatic and unsaturated oximes was combined
with BCN (Scheme 2) in 1 : 1 mixture of MeOH/H2O (0.1 M),
before oxime and PIFA (each 1.2 equiv.) were added. As
expected, the reaction was extremely fast and efficient giving
3,4,5-trisubstituted isoxazoles (compounds 26–34, Scheme 2) in
excellent yields within 2–5 min in all cases. Based on NMR
experiments (ESIw), a reaction rate constant of 1.8 Mꢀ1 sꢀ1 was
determined for benzonitrile-N-oxide, a value that compares
highly favourably with that of benzyl azide cycloaddition to
73
59a
87
8
9
10b 18
82
72
19
20
10
80
BCN under identical conditions (0.18 Mꢀ1 ꢀ1).
s
In conclusion, we have demonstrated the use of
PhI(OCOCF3)2 for the rapid in situ conversion of aldoximes
into nitrile oxide and cycloaddition with alkynes. The procedure
is experimentally convenient, avoiding the isolation and handling
of potentially harmful and unstable hydroximoyl chlorides.
The resulting nitrile oxide traps terminal and cyclic alkynes
efficiently, in particular in the case of cyclic alkynes,17 to give
a
b
Based on oxime. Volatile. 4 equiv. oxime used.
c
3,5-disubstituted and 3,4,5-trisubstituted isoxazoles in high yield.
Because no transition metal catalyst is needed and a wide variety
of functional groups are tolerated, we foresee high usefulness of
c
This journal is The Royal Society of Chemistry 2011
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Fig. 1 Nucleoside and peptide-isoxazole conjugates.
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Scheme 2 Nitrile oxide cycloaddition to ring-strained BCN.
our PIFA-mediated synthesis of isoxazoles.18 Currently, we are
making progress on the application of our approach for labeling
of oligonucleotides7b–d and for nitrile oxide–acetylene cyclo-
addition to proteins, which may unveil unprecedented ways for
metal-free conjugation of proteins containing acetylenes.19
We gratefully acknowledge the Netherlands Organisation
for Scientific Research (NWO) for financial support (ECHO
07.BM3.038). We thank MSc Morten B. Hansen for his help
on the peptide synthesizer and Jan Dommerholt for determi-
nation of reaction rate constants.
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17 Reaction of benzonitrile-N-oxide (4 equiv.) with acyclic alkynes
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18 Other applications include reaction with alkynyliodide, see:
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c
3200 Chem. Commun., 2011, 47, 3198–3200
This journal is The Royal Society of Chemistry 2011