A novel route to substituted 4-methylene-4,5-dihydroisoxazoles mediated by hafnium(IV) chloride

Article abstract of DOI:10.1039/b105561p

Heating alkyl vinyl ketones and N-tert-butylarylmethylide-neamine N-oxides in the presence of HfCl₄ results in the formation of 4-methylene-4,5-dihydroisoxazoles in good yield.

Full text of DOI:10.1039/b105561p

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A novel route to substituted 4-methylene-4,5-dihydroisoxazoles
mediated by hafnium(IV) chloride
a
b
b
a
Peter J. Dunn, Alison B. Graham, Ronald Grigg,* Paul Higginson, Visuvanthar Sridharan and
Mark Thornton-Pettb
a
Pfizer Global Research & Development (UK), Sandwich, Kent, UK CT13 9NJ
b
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, The
University of Leeds, Leeds, UK LS2 9JT. E-mail: R.Grigg@chem.leeds.ac.uk
Received (in Cambridge, UK) 26th June 2001, Accepted 23rd August 2001
First published as an Advance Article on the web 19th September 2001
Heating alkyl vinyl ketones and N-tert-butylarylmethylide-
neamine N-oxides in the presence of HfCl results in the
formation of 4-methylene-4,5-dihydroisoxazoles in good
yield.
but, instead, furnished 4-methylene-4,5-dihydroisoxazole 8a
4
(80% conversion of nitrone, 51% yield). The structure of 8a was
determined by X-ray crystallography (Fig. 1).† Anhydrous
Sc(OTf)
3
3
also induced the formation of 8a (0.5 eq. Sc(OTf) ,
THF, reflux, 8 h) in slightly lower yield (80% nitrone
We recently reported that hafnium(IV) chloride is an excellent
catalyst for the tandem 1,3-azaprotio cyclotransfer–cycloaddi-
tion reaction between aldoximes and divinyl ketone, inducing
the formation of the exo-isomers of substituted 1-aza-8-oxa-
bicyclo[3.2.1]octan-4-ones 3 and reversing the natural re-
2
conversion, 48% yield) whereas the addition of ZnBr (0.5 eq.)
under otherwise identical reaction conditions did not induce the
1
formation of 8a ( H NMR indicated that the crude reaction
mixture was comprised of starting material and traces of the
products of a 1,3-dipolar cycloaddition).
1
gioselectivity of the thermally promoted cascade (Scheme 1).
We proposed that the dramatic effect on regioselectivity was
due to coordination of the Lewis acid to the carbonyl moiety of
the intermediate nitrone enhancing nucleophilicity at the b-
carbon and promoting the formation of 3.
Fig. 1 X-Ray crystal structure of 8a.†
Further development of this process identified conditions that
afford reproducible results (Scheme 3).2 The methodology
encompasses both electron-donating and electron-withdrawing
groups on the aromatic ring and variation of the ketone
component (6a–c) (Table 1). In addition to 8a–h, which were
obtained as single stereoisomers, traces (5%) of the correspond-
ing aromatic aldehydes (from degradation of 5a–f, vide infra)
Scheme 1
To study the effect of HfCl
4
on a similar intermolecular
1
,3-dipolar cycloaddition we reacted N-tert-benzylideneamine
N-oxide 5a with methyl vinyl ketone 6a. Under thermal
conditions (MeCN, reflux, 48 h) a 4+1 mixture of 5-substituted
isoxazolidines exo-7 and endo-7 was obtained in 34% com-
bined yield (Scheme 2). When the same substrates were
1
were visible in the H NMR spectra of crude products. The
stereochemistry of the double bond in compounds 8b–h was
assigned by correlation of the chemical shift and coupling
4
subjected to the HfCl catalysed conditions outlined in Scheme
1
constants of the CNCH and CH
with those obtained for 8a.
2
moieties in the H NMR spectra
1
only starting material was obtained after the usual reaction
time of 30 min. Increasing the reaction time to 8 h did not result
in the formation of the expected 4-substituted isoxazolidine 9
Scheme 2
Scheme 3
1968
Chem. Commun., 2001, 1968–1969
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105561p

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Table 1 Hafnium(iv) chloride mediated synthesis of 4-methylene-4,5-di-
In summary, we report a novel route to 4-methylene-
hydroisoxazoles
4
,5-dihydroisoxazoles from readily available starting materi-
7
als. The synthetic value of these systems, and conventional
methods to generate them are the subject of a recent review by
b
Nitrone
Vinyl ketone
Producta
Yield (%)
8
Zecchi et al. Further studies of the mechanism and scope of the
5
5
5
5
5
5
5
5
a
a
b
c
d
e
f
6a
6a
6a
6a
6a
6a
6b
6c
8a
8b
8c
8d
8e
8f
75
76
68
54
64
70
64
31
reaction are in progress.
We thank Pfizer Global Research & Development (UK),
Leeds University and the EPSRC for support.
Notes and references
a
a
8g
8h
† Crystal data. C11
12.3331(2), b = 7.3853(2), c = 20.0230(9) Å, U = 1823.77(10) Å , Z =
8, Mo-Ka radiation, l = 0.71073 Å, m = 0.081 mm , T = 150(2) K, R
0.0449 for 1319 reflections with I > 2s(I), wR = 0.1063 for all 1787
H11NO, M = 173.21, orthorhombic, Pcba, a =
3
In all cases apart from 5a + 6a, small amounts (5–10%) of the
2
1
1
b
1
corresponding aldehydes were detected by H NMR. Yield isolated by
flash chromatography.
=
2
independent data. CCDC 168614. See http://www.rsc.org/suppdata/cc/b1/
b105561p/ for crystallographic data in .cif or other format. Methods and
programmes were standard from the SHELX suite.9
The mechanism of the reaction is a matter of conjecture at
present. HfCl
4
catalysed degradation of nitrone 5a may generate
1 P. J. Dunn, A. B. Graham, R. Grigg and P. Higginson, Chem. Commun.,
benzaldehyde and a hafnium complexed hydroxylamine if
traces of water are present in the system. Indeed small amounts
2000, 2035.
2
Typical experimental procedure: methyl vinyl ketone 6a (0.75 mmol)
1
was added to a solution of nitrone 5a (0.5 mmol) and HfCl (0.75 mmol)
4
of the corresponding aromatic aldehydes are visible in the H
in dry THF (20 mL) under a nitrogen atmosphere and the resulting
homogeneous solution stirred at reflux for 24 h. The reaction mixture was
quenched by the addition of saturated NaHCO solution and extracted
3
NMR spectra of the crude products and the amount of these was
found to be proportional to the quantity of catalyst and reaction
time. The hydroxylamine may react with 6a to generate nitrone
with dichloromethane. The combined organic extracts were washed with
3
1
0 followed by a 6p-electrocyclisation–aldol condensation–
water, dried (MgSO ), filtered and the filtrate concentrated in vacuo. The
4
dehydration sequence to generate 8a (Scheme 4). Analogous
residue was purified by flash chromatography, eluting with 1+1 v/v
4–6
6
p-electrocyclisation reactions are well known.
diethyl ether–pentane to afford the product 8a as a colourless crystalline
solid (0.065 g, 75%). Recrystallisation from dichloromethane–pentane
afforded the product as colourless needles, mp 107.5–109 °C.
3
When the corresponding oxime of 6a and benzaldehyde were heated
under the reaction conditions (HfCl (0.5 eq.), THF, reflux, 8 h) no traces
4
of 8a were detected and only unreacted material was recovered.
4
5
6
7
R. Grigg, P. Myers, A. Somasunderam and V. Sridharan, Tetrahedron,
1
992, 48, 9735.
R. Grigg, P. Kennewell, V. Savic and V. Sridharan, Tetrahedron, 1992,
8, 10 423.
4
E. C. Taylor and I. J. Turchi, Chem. Rev., 1979, 79, 181; R. Huisgen,
Angew. Chem., Int. Ed. Engl., 1980, 19, 947.
N-tert-Butylarylmethylideneanine N-oxides are readily prepared in high
yields by treatment of the corresponding aldehyde with commercially
available N-tert-butylhydroxylamine hydrochloride (1.5 eq.) and
Na
days.
2
CO
3
(0.75 eq.) in 1+1 THF–H
2
O solution and heating at 60 °C for 2
8
9
G. Broggini, C. La Rosa and G. Zecchi, Synlett, 1995, 12, 1208.
G. M. Sheldrick, SHELX97, University of Göttingen, Germany, 1997;
G. M. Sheldrick, SHELXTL Manual, Bruker AXS Inc., Madison, WI,
USA, 1994 and 1998.
Scheme 4
Chem. Commun., 2001, 1968–1969
1969