An improved synthesis of 1,2-benzisoxazoles: TBAF mediated 1,3-dipolar cycloaddition of nitrile oxides and benzyne

Article abstract of DOI:10.1039/b922489k

An efficient synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation of the reactive nitrile oxide and benzyne reaction partners medi

Full text of DOI:10.1039/b922489k

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An improved synthesis of 1,2-benzisoxazoles: TBAF mediated 1,3-dipolar
cycloaddition of nitrile oxides and benzynew
ab
Christian Spiteri,z Pallavi Sharma,ab Fengzhi Zhang,a Simon J. F. Macdonald,b
Steve Keelingb and John E. Moses*a
Received (in Cambridge, UK) 27th October 2009, Accepted 16th December 2009
First published as an Advance Article on the web 11th January 2010
DOI: 10.1039/b922489k
An efficient synthesis of a range of 1,2-benzisoxazoles using an
improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne
is described. Key to the procedure is the in situ generation of the
reactive nitrile oxide and benzyne reaction partners mediated by
TBAF. Reactions are complete within 30 s, giving the target
products in good to excellent yield.
Since the early pioneering work of Huisgen et al., 1,3-dipolar
cycloadditions have emerged as one of the most important
synthetic approaches to five-membered ring heterocycles.1 The
recent advancement of the copper catalysed azide–alkyne
cycloaddition, ‘click’ reaction (CuAAC),2 has somewhat
stimulated a demand for the discovery, or perhaps ‘re-investigation’
of reliable and efficient 1,3-dipolar cycloadditions. In this
Scheme 1 Synthetic approaches to 1,2-benzisoxazoles.
context, there have been a number of reports focussing upon
cycloadditions of 1,3-dipoles to arynes as a promising exten-
sion of ‘‘Huisgen regime’’, including azides,3 diazomethane
derivatives,4 diazo compounds, azamethine imides,5 azaallyl
examples of the synthesis of benzisoxazoles using the 1,3-dipolar
terms of convergence and step-economy, there are limited
cycloaddition strategy (iv, Scheme 1).12b,13 During the early
development of this chemistry, Minisci and Quilico, in 1964,
reported the synthesis of 3-phenyl-1,2-benzisoxazole (3) in
53% yield, by reacting benzyne (1) generated in situ from
anthranilic acid with preformed benzonitrile oxide.13a Despite
almost half a century, little advance has been made towards a
general and reliable method for benzisoxazole synthesis using
benzyne–nitrile oxide cycloaddition chemistry. This is no
doubt a consequence of the short life span of the benzyne
and nitrile oxide reaction partners, both of which are known
to undergo alternative side reaction pathways. Benzyne (1)
undergoes rapid dimerisation via a stepwise [2+2] cyclo-
addition to yield diphenylene.14 On the other hand, the half-
life of nitrile oxides varies from seconds to days,15 with a
tendency to undergo dimerisation to furoxans.16
lithium species, pyridazine N-oxides, 1,2,4-triazine 1-oxides6
and nitrones.7 Building upon our own work in aryne cyclo-
addition chemistry,3d we were compelled to investigate the
partnering of benzyne with alternative 1,3-dipoles, and were
drawn towards nitrile oxides as attractive candidates for the
synthesis of 1,2-benzisoxazoles. These pharmaceutically relevant
structures can be found embedded in a number of biologically
active compounds,8 and therefore have immediate application.
In general, four distinct synthetic approaches to 1,2-
benzisoxazoles have evolved (Scheme 1):9 (i) cyclisation of
o-hydroxy benzyloxime sulfonates and acetates to form the
1–2, O–N bond;10 (ii) formation of the 2–3 double bond by
intramolecular condensation with aminoxy functionality;11
(iii) formation of the 1–7a bond, represented by the cyclisation
of o-halo or o-nitrobenzyloximes;12 and (iv) the simultaneous
formation of the 1–7a and 3–3a bonds, by the 1,3-dipolar
cycloaddition reaction between benzyne (1) and a nitrile oxide
(e.g. 2) (Scheme 1).13 Each approach has limitations and
drawbacks. For example, strategies i–iii involve multiple-steps
and often require exposure to strong bases, sometimes leading
to undesirable side products.9 Although most attractive in
We reasoned that simultaneous in situ generation of both
the reactive benzyne and nitrile oxide intermediate would be
essential for reaction efficiency and practicality. Although the
annulation of arynes by 1,3-dipoles is not conceptually
new,3–8,13 efforts to modernise the reaction are certainly
necessary. Early examples utilising diazotised anthranilic acid
as the benzyne precursors suffer from potentially dangerous
reaction conditions,14,17 and more recent examples utilising
o-(trimethylsilyl)aryliodonium salts18 are limited due to the
availability and difficulties in the preparation of these reagents.3a
These days, arynes are commonly accessed in situ by fluoride-
promoted ortho-elimination of o-(trimethylsilyl)aryl triflates,3,19
which we considered a particularly attractive method for our
studies. Base induced dehydrohalogenation of hydroximoyl
a School of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: john.moses@nottingham.ac.uk;
Fax: +44 (0)115 951 3533; Tel: +44 (0)115 951 3533
b GlaxoSmithKline, Research Medicines Centre, Stevenage, UK
w Electronic supplementary information (ESI) available: Experimental
data and procedures for the synthesis of new compounds. See DOI:
10.1039/b922489k
z C. S. performed the vast majority of the experimental work.
ꢀc
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Table 1 Screening for optimal conditions
Table 2 Synthesis of 1,2-benzisoxazoles
Entrya
Product
Yieldb/%
99
Entrya Fꢁ source
Equiv.
Solvent T/1C Time
Yieldb/(%)
1
2
3
4
CsF
CsF
CsF
KF
2.4
2.4
2.4
2.4
DCM
THF
MeCN rt
MeCN rt
rt
rt
48 h
48 h
48 h
48 h
24 h
trace
trace
21
trace
44
1
93
92
75
99
5
CsF/18-C-6 2.4 : 2.4 MeCN rt
6
7
8
9
10
11
12
13
14
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
2.4
2.4
1
2
3
2.4
2.4
2.4
2.4
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
1 min trace
2
3
4
30 s
30 s
30 s
30 s
30 s
1 h
75
0
53
75
75
32
MeCN rt
DCM
Et2O
THF
rt
rt
0
10 min 36
2 min 48
a
b
Reactions were performed on 0.32 mmol scale over 24 h. Isolated
yields.
chlorides to nitrile oxides appeared straight forward and
practical.20 Given that fluoride is a nucleophilic base (H–F bond
5
6
strength B569 kJ molꢁ1
; ;
cf. H–Cl, B432 kJ molꢁ1
H–O, B428 kJ molꢁ1; H–N, B314 kJ molꢁ1),21 we considered
exploiting this dual nature22 for both benzyne and nitrile oxide
generation.23 Table 1 illustrates our findings using a range of
inorganic and organic fluoride sources in a variety of solvents,
with phenyl hydroximoyl chloride 5. Using CsF, 4 and 5
reacted to furnish the corresponding 1,2-benzisoxazole 3,
albeit in low yield (entries 1, 2 and 3, Table 1). Changing the
fluoride source from CsF to KF led to a decrease in yield
(entry 4, Table 1) which could be attributed to its stronger
ion pair. Furthermore, increasing the solubility and nucleo-
philicity of the fluoride ion by using a 1 : 1 mixture of
CsF to 18-crown-6 gave 3 with an improved yield of 44%
(entry 5, Table 1).3c
85
87
7
8
95
TBAF, known to form a weak ion pair even in organic solvents,
was next chosen as a suitable nucleophilic source of fluoride.24
Accordingly, 5 and TBAF were dissolved in THF at room
temperature followed by the addition of 4 (1 : 2.4 : 1.5 equiv.)
(entry 6, Table 1). The reaction was notably exothermic and
resulted in full consumption of 5 (TLC), whereas 4 was faintly
visible on TLC. Unfortunately, the formation of 3 could only
be detected by HRMS (ESIw) of the crude reaction mixture,
with furoxan dimer 6 as the only isolated product. Changing
the order of reagent addition had a profound effect. Thus,
when 4 and 5 were premixed in THF for 5 minutes, followed
by TBAF addition, the reaction was complete within 30 s
(TLC) and 1,2-benzisoxazole 3 was obtained in 75% isolated
yield (entry 7, Table 1). Interestingly, when only 1.0 equiv. of
TBAF was used, (entry 8, Table 1), only dimer 6 was isolated,
with full recovery of 5. This suggested that TBAF was
exclusively inducing dehydrohalogenation, calling for higher
quantities of fluoride. In fact a mole ratio of 1 : 2 of 5 and
TBAF gave 3 in 53% (entry 9, Table 1). Increasing to 3 equiv.
78
50
9
10
92
11
a
0.32 mmol of hydroximoyl chloride, 4 (1.5 equiv.), THF, TBAF
b
(2.4 equiv.), rt, 30 s. Isolated yields.
ꢀc
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did not have any beneficiary effect on the yield of 3 (entry 10,
Table 1). Thus, room temperature addition of 2.4 equiv. of
TBAF to a premixed solution of starting materials in THF was
found to be optimal.
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49, 6613.
To test the scope of this protocol several substrates were
examined. The reaction was found to be tolerant of a variety
of substituents on the aromatic ring of hydroximoyl chlorides,
including alkyl (entries 1, 2 and 7, Table 2), electron-
withdrawing (entries 4 and 9, Table 2) and electron-donating
groups (entries 3, 5, 6, 8 and 11, Table 2). Excellent yields were
observed for most substrates, especially those having their
fulmido group sterically congested by the presence of one or
two ortho-substituents (entries 1–5, Table 2). Even when less
sterically hindered benzonitrile oxides were used, yields were
high (entries 6–11, Table 2). Slightly lower yields were
observed with electron deficient nitrile oxides (entries 4 and 9,
Table 2). Furthermore, this improved methodology could be
extended to the challenging and less stable aliphatic nitrile
oxides, as exemplified by the formation of 16 in moderate yield
(50%) (entry 10, Table 2). The lower yield could be attributed
to self-decomposition of the unstable aliphatic hydroximoyl
chloride.25
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9 For examples see: F. Gualtieri and M. Giannella, The Chemistry of
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In summary, the present protocol describes an expedient
one-pot access to 1,2-benzisoxazoles in good to excellent
yields, from readily accessible starting materials. Furoxans
were the only observed by-products and were easily removed
by simple chromatographic techniques. The reaction demonstrates
the feasibility of TBAF as an efficient reagent for nitrile oxide
generation and ring annulations. The methodology surpasses
those already described for its simplicity, mild reaction
conditions and ease of product purification.
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We thank The EPSRC, GlaxoSmithKline, Association for
International Cancer Research (AICR) and The University of
Nottingham for financial support.
Notes and references
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ꢀc
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1274 | Chem. Commun., 2010, 46, 1272–1274