Cascade formation of isoxazoles: Facile base-mediated rearrangement of substituted oxetanes

Article abstract of DOI:10.1002/anie.201100260

Give me five! Nitro compounds and oxetan-3-one react through an intriguing cascade sequence to give isoxazole-4-carbaldehydes using inexpensive reagents in a one-pot procedure (see scheme; Ms=methanesulfonyl). A variety of 3-substituted isoxazole-4-carbaldehydes were obtained in high overall yields.

Full text of DOI:10.1002/anie.201100260

DOI: 10.1002/anie.201100260
Synthetic Methods
Cascade Formation of Isoxazoles: Facile Base-Mediated
Rearrangement of Substituted Oxetanes**
Johannes A. Burkhard, Boris H. Tchitchanov, and Erick M. Carreira*
Heterocycles play an important role in pharmaceutical
sciences and many other areas of organic chemistry. Among
the most widely employed nitrogen-containing five-mem-
bered rings are the isoxazoles. Their preparation has been
extensively discussed in the literature and typical access
routes involve condensations with hydroxylamine, cycliza-
tions of ketoxime dianions, and propargylic oximes, and in
particular 1,3-dipolar cycloaddition reactions.[1–3] Surprisingly,
only few of the reported methods are general and versatile, as
many suffer from low functional group tolerance, and modest
regioselectivities and yields. Herein, we report a novel
approach to 3-substituted isoxazoles-4-carbaldehydes 3 from
the condensation reaction of nitroalkanes 1 with 3-oxetanone
(2) [Eq. (1)].[4] The process represents not only a mechanis-
tically intriguing cascade transformation but also provides
preparative access to 3,4-disubstituted isoxazoles, which are
otherwise underrepresented structures as building blocks in
the drug discovery process. Given the fact that oxetanone has
become commercially available[5,6] and that 3,4-disubstituted
isoxazoles are underrepresented in the literature, we have
examined the scope of this intriguing process.
room temperature. Oxetane building blocks have only
recently become widely available and in turn have generated
considerable interest in the pharmaceutical sector (for
example, Abbott, AstraZeneca, Genentech, Merck, Novartis,
Roche, Sanofi Aventis, Takeda).[8,9] Consequently, it is
important to define their reactivity landscape. In examining
further their chemistry and reactivity profile, we have
observed that treatment of 4 with dibenzylamine led to an
unexpected rearrangement, producing isoxazole-4-carbalde-
hyde 3a (Scheme 1). We speculate that the key difference
Scheme 1. Differential reactivity of nitromethyleneoxetanes reacting
We have been engaged in a program aimed at the
development and study of substituted oxetanes and azetidines
as small molecule modulators of key biophysical and chemical
properties of pharmaceutically relevant compound scaf-
folds.[7] In this context we have reported that 3-(nitromethy-
lene)oxetane is in general a good acceptor, a property that can
be employed in the preparation of compounds bearing the
oxetane moiety.[7a,8] Thus, treatment of 4 with benzylamine
affords the conjugate addition product 5 within 30 minutes at
with either benzyl- or dibenzylamine.
between these two reaction processes stems from steric
demands inherent to dibenzylamine that lead to significant
attenuation in the rate of conjugate addition to nitromethy-
leneoxetane 4 versus Bn2NH and instead favors a cascade
process initiated by deprotonation.
A survey of a collection of bases and solvents revealed
that in general tertiary amines (in particular iPr2NEt) were
superior to other bases (e.g., Cs2CO3, LiHMDS, NaOMe, or
pyridine) in favoring the formation of isoxazoles. When the
reaction was conducted in THF clean product formation was
observed; in contrast, in CH3CN, pyridine, or MeOH
significant amounts of oligomeric side products were noted.
The synthesis of the nitroalkene acceptor is effected by
condensation of oxetan-3-one with nitroalkanes. Our initial
findings suggested that a one-pot operation as shown in
Scheme 2 would be feasible, since amine bases can be
employed for all steps: the Henry addition (step A), the
elimination/condensation (step B), and, as highlighted above,
the rearrangement to isoxazole (step C).
[*] J. A. Burkhard, B. H. Tchitchanov, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich, HCI H335
8093 Zꢀrich (Switzerland)
Fax: (+41)44-632-1328
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] We thank Fabienne Felder for the preparation of some starting
materials. Pablo Rivera Fuentes is acknowledged for performing
calculations. J.A.B. is grateful to Novartis and Roche Research
Foundation for graduate fellowship support. This research has been
supported by a grant from ETH-Z (0-20449-07).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100260.
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Communications
Table 1: Scope of the one-pot synthesis of isoxazoles.[a,b]
Entry Substrate 1, R
Product
Yield [%][b]
82
1
2
3
4
5
6
1a, Bn
3a
3b
3c
3d
3e
3 f
Scheme 2. Pathway toward isoxazole-4-carbaldehydes through a
cascade reaction.
1b, piperonyl
75
74
86
71
60
The Henry addition proved to be most effective when run
neat or at high concentrations in CH2Cl2 using catalytic
amounts of Et3N (typically ca. 0.2 equiv), and the subsequent
elimination step to the corresponding nitroalkene was best
carried out at a 0.1m concentration using MsCl and Et3N at
low temperature. Optimal results were observed when run-
ning the Henry addition neat, then diluting the oxetanyl
alcohol in THF with subsequent cooling to À788C, addition of
Et3N and MsCl, and then slow warming to room temperature.
Subsequent addition of iPr2NEt and stirring the mixture at
room temeprature for 12 hours led to isolation of the
isoxazole 3a, as a test substrate, in an overall yield of 70%.
Careful optimization of the individual reagent amounts
allowed isolation of the targeted isoxazole 3a in 82% yield
over the three steps (Table 1, entry 1).
With the optimized reaction conditions in hand, we were
keen to define the scope of the one-pot rearrangement
sequence. To our delight, replacement of the phenyl group
with electron-rich and electron-deficient aromatic and
heteroaromatic entities afforded the products in similarly
high overall yields (Table 1, entries 2–7). In addition to
aliphatic groups (entry 8), a variety of functional groups
such as remotely positioned ester groups, terminal alkenes, as
well as protected amines and alcohols were tolerated
(entries 9–14). Furthermore, aryl nitromethanes were suc-
cessfully converted into the corresponding 3-aryl isoxazole-4-
carbaldehydes (entries 15 and 16). By using this procedure,
3,4-disubstituted isoxazoles, which are otherwise rather
difficult to make selectively,[10] are readily available from
commercially available or easily prepared nitroalkanes. The
unveiled aldehyde serves as a convenient handle for further
functionalization.[11]
1c, CH2C6F5
1d, CH2(3-pyridyl)
1e, CH2(p-CF3C6H4)
1 f, CH2(p-NO2C6H4)
7
1g, CH2(3-indolyl)
3g
60
8
9
1h, CH2Cy
3h
3i
86
91
1i, CH2CH2CO2Me
10
11
12
13
14
1j, CH2CO2Et
3j
3k
3l
73
65
1k, (CH2)3OAc
1l, CH2CH2CHCH2
1m, CH2CH2NHBoc
1n, CH2OTBS
85[c]
65
3m
3n
60
15
16
1o, Ph
3o
3p
62[c]
Mechanistic studies were carried out to shed light on the
final step of the cascade. The sequence originates from the
nitroalkene intermediate, which can be observed when
1p, p-tBuC6H4
58[c,d]
1
aliquots of the reaction mixture are analyzed by H NMR
[a] General procedure: nitro compound (0.75 mmol, 1.0 equiv), oxetan-
3-one (0.98 mmol, 1.3 equiv), THF (0.1m). [b] Yields of isolated products
are given. [c] Rearrangement required 48 h. [d] 0.65 mmol of substrate
was used. Boc=tert-butoxycarbonyl, Cy=c-C6H11, TBS=tert-butyldime-
thylsilyl.
spectroscopy at various times. Subjecting isolated nitroalkene
4 to iPr2NEt in [D8]THF at room temperature leads smoothly
to the isoxazole-4-carbaldehyde 3a within 24 hours. Other
than starting material and product, no intermediates were
1
observed when monitored by H NMR spectroscopy. Inter-
estingly, in two separate experiments when the reaction was
conducted in [D4]CH3OH/[D8]THF (1:1) and iPr2NEt or in
THF and a mixture of iPr2NEt and iPr2NEt·DCl (1:1) no
deuterium incorporation was observed in the product. There-
fore, we suggest that the first step of the sequence is rate
limiting and involves deprotonation of oxetane A to give a
strained oxetene intermediate B (Scheme 3). Subsequently,
the nitronate anion may undergo in ring opening to form C/C’.
Dehydration of this putative intermediate then furnishes D.
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Angew. Chem. Int. Ed. 2011, 50, 5379 –5382

was warmed to RTand stirred for 90 min. In most cases formation of a
solid was observed. The reaction mixture was diluted with THF
(7.5 mL). Et3N (1.5 mmol, 2.0 equiv) was added and the solution was
cooled to À788C. MsCl (0.83 mmol, 1.1 equiv) was then added
dropwise and the mixture was stirred at À788C for 30 min, after which
time it was allowed to slowly warm to RT over a 60 min period.
iPr2NEt (0.75 mmol, 1.0 equiv) was added and the mixture was stirred
at RT for 12 h. The mixture was then diluted with CH2Cl2 (15 mL),
quenched with H2O (5 mL), and the aqueous phase was extracted
with CH2Cl2 (3 ꢀ 5 mL). The combined organic phases were washed
with brine (10 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. The product was obtained after purification by flash column
chromatography on silica gel.
Received: January 12, 2011
Published online: April 28, 2011
Scheme 3. Proposed reaction mechanism.
Keywords: aldehydes · heterocycles · nitro compounds ·
.
oxetanes · rearrangements
An alternative mechanistic pathway is possible in which
electrocyclic ring opening of the oxetene in B is followed by
conjugate addition through a 5-exo-trig cyclization[12] that
leads to the product isoxazoles. However, the fact that 2-
unsubstituted oxetes at room temperature have half-lives of
several hours in solution[13] would argue against the second
alternative, because we did not observe the accumulation of
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toward isoxazoles from nitroalkanes and oxetan-3-one. The
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products in high overall yields. Moreover, the aldehyde
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General procedure for the one-pot reaction sequence: The nitro
compound (0.75 mmol, 1.0 equiv) and oxetan-3-one (0.98 mmol,
1.3 equiv) were combined in a 10 mL flask under Ar, and the mixture
was cooled to 08C. Et3N (0.15 mmol, 0.2 equiv) was then added, and
the reaction mixture was stirred at 08C for 10 min, after which time it
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