Cycloaddition of benzynes and nitrile oxides: synthesis of benzisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2010.02.103

A mild and efficient process has been developed for the synthesis of benzisoxazoles through the cycloaddition of benzynes and nitrile oxides. This method allows access to both (hetero)aromatic and alkenyl-substituted benzisoxazoles. Preliminary studies concerning regioselectivity are also reported.

Full text of DOI:10.1016/j.tetlet.2010.02.103

Tetrahedron Letters 51 (2010) 2271–2273
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Tetrahedron Letters
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Cycloaddition of benzynes and nitrile oxides: synthesis of benzisoxazoles
*
James A. Crossley, Duncan L. Browne
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient process has been developed for the synthesis of benzisoxazoles through the cycload-
dition of benzynes and nitrile oxides. This method allows access to both (hetero)aromatic and alkenyl-
substituted benzisoxazoles. Preliminary studies concerning regioselectivity are also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 January 2010
Revised 9 February 2010
Accepted 19 February 2010
Available online 1 March 2010
The development of new reactions featuring the employment of
benzynes has received increasing attention over recent years.
Although arynes have been known since the 1950s,1 a recent surge
in this research area can be partly attributed to the realisation of a
mild method for the generation of these reactive intermediates. A
plethora of recent literature employs the tactic developed by
Kobayashi and co-workers2 whereby, the treatment of easily pre-
pared or commercially available o-(trimethylsilyl)aryl triflates
with a mild fluoride source leads to the in situ release of arynes
through ortho-elimination. Such generated benzynes have been
successfully employed in, for example, inter-3 and intra-molecular
cycloaddition-,4 domino-,5 copper-mediated-,6 palladium-medi-
ated-7 and rearrangement-processes.8 Arynes derived in this man-
ner have also found utility in a number of recent elegant total
syntheses.9 Complementary but less mild methods for the genera-
tion and employment of benzynes have also been the subject of
widespread attention in the literature.10 Considering the popular-
ity of this chemistry we were rather surprised to find scant cover-
age of the reactivity of benzynes with nitrile oxides. We thought
that this could reflect the potential difficulties of bringing together
two highly reactive intermediates to participate in the desired
cycloaddition event (Fig. 1). Indeed, when we started this work
only two isolated reports existed, both of which offered one exam-
ple which proceeded in poor yield and started from anthranilic acid
(a potentially explosive benzyne precursor).11 However, during the
course of our studies, Moses and co-workers reported their preli-
minary work in this area,12 prompting us to detail our own efforts
towards this goal. Herein we describe our differing optimisation
process, the synthesis of heteroaromatic and alkenyl-substituted
benzisoxazoles as well as initial studies on the regioselectivity of
the cycloaddition.
homodimerisation process, to give furoxan products.13 For the pur-
poses of our studies we simplified our initial investigations by
employing mesityl N-oxide, which is known to participate reluc-
tantly in furoxan synthesis.14 Given the consistency of fluoride
source/solvent combination seen in the literature, our first condi-
tions featured CsF and MeCN. Pleasingly, on subjecting 2-(trimeth-
ylsilyl)phenyl trifluoromethanesulfonate (1) and mesityl N-oxide
(2) to CsF in MeCN the desired benzisoxazole product 3 could be
isolated in quantitative yield (Table 1, entry 1). However, the reac-
tion was extremely sluggish, requiring 3 days at room temperature
for complete conversion. Attempts to increase the rate of reaction
by increasing the temperature resulted in the observation of an
oxadiazole byproduct 4, derived from the cycloaddition of N-oxide
Nitrile oxides are reactive intermediates, commonly generated
in situ from the treatment of their chloro-oxime counterparts with
base. Such intermediates are known to undergo an irreversible
* Corresponding author. Tel.: +44 114 222 9457.
E-mail address: d.browne@sheffield.ac.uk (D.L. Browne).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.

2272
J. A. Crossley, D. L. Browne / Tetrahedron Letters 51 (2010) 2271–2273
Table 1
O
O
N
N
O
OTf
N
fluoride source
temp, solvent
Me
N
TMS
4
1
3
2
Entry
Solvent
Fluoride source
Time
72 h
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
1,4-Dioxane
DME
Acetone
DMF
THF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
TBAF
22
120
80
101
85
57
153
66
99
20 min
24 h
24 h
36 h
24 h
24 h
24 h
1 h
99 (1:1, 3:4)
99 (7:3, 3:4)
Complex mixture
Complex mixture
Complex mixture
Complex mixture
Trace
THF
22
99
2 with MeCN (Table 1, entries 2 and 3). We therefore tested a range
of alternative polar solvents (Table 1, entries 4–8). Disappointingly,
all of those assessed delivered complex mixtures.15 This was pre-
sumed to be due to the poor solubility of CsF in this selection of
solvents.16 Gratifyingly, treatment of benzyne precursor 1 and
nitrile oxide 2 with a solution of TBAF in THF furnished the desired
benzisoxazole within 1 h at room temperature (Table 1, entry 9).
From the outset we appreciated that a useful protocol would re-
quire both the in situ generation of the benzyne and nitrile oxide
species simultaneously. Moreover, this could be further compli-
cated if the rate of furoxan synthesis was competitive with the rate
of benzisoxazole formation. We hoped to harness the basic proper-
ties of TBAF to our advantage and see if this reagent could initiate
the unveiling of both reactive intermediates.17 Proof that TBAF
could function in this way was discovered upon the treatment of
chloro-oxime 5 and benzyne precursor 1 with TBAF in THF (using
the ratios employed for the mesityl N-oxide chemistry). However,
conducting the reaction under these conditions delivered poor
yields of the desired product. Carrying out the reaction with a
2:1 excess of aldoxime 5 to benzyne precursor 1 resulted in only
a trace amount of product (Table 2, entry 1). Reversal of this ratio
appeared to overcome this shortfall, furnishing the product 6 in
59% yield (Table 2, entry 2). Probing this a little further highlighted
that indeed an excess in the concentration of benzyne was required
for a successful cycloaddition. A ratio of 3:1 (1:5) appeared to suf-
fice, delivering benzisoxazole 6 in 95% yield (Table 2, entry 3).
We next turned our attention to the scope of the reaction with
respect to the nitrile oxide partner. As shown in Scheme 1, a selec-
tion of both substituted and unsubstituted benzaldehyde derived
chloro-oximes underwent smooth cycloaddition to afford the ben-
zisoxazole products in excellent yields. Furthermore, 5-methyl-2-
carboxythiophene and 2-carboxypyridyl-derived chloro-aldoximes
also gave rise to some interesting bis-heterocyclic scaffolds in good
effect (7 and 10). A preliminary effort with a primary substituted
alkyl chloro-oxime failed to provide any benzisoxazole product.
However, cinnamaldehyde-based chloro-oxime did undergo
smooth cycloaddition to afford the styrene-substituted benzisox-
azole 8.
O
N
OH
Cl
N
TBAF, THF
rt, 1 h
1
R
R
O
N
O
O
N
N
S
Cl
3, 99%
6, 95%
7, 71%
F
O
N
O
N
O
N
N
Ph
Cl
8, 73%
9, 99% (59%)
10, 87%
O
O
O
N
N
N
OMe
tBu
11, 84%
12, 86%
13, 97%
Scheme 1. Number in parentheses represents the yield when the reaction was
conducted under the molar ratios in Table 2, entry 2.
Previous studies on benzyne cycloadditions have offered mixed
outcomes with regard to regioselectivity.18 Prior work from Larock
and co-workers demonstrated that a 1,3-dipolar cycloaddition of
an azide with an ortho-MeO-substituted benzyne precursor could
give rise to a regioselective cycloaddition.3c We therefore next
endeavoured to see if simple ortho substituents could affect regio-
Table 2
OH
O
N
N
O
O
N
a
R
TBAF, THF
rt, 1 h
1
Cl
R = Me
3:2 16a:16b,
64% yield
R
Cl
OTf
Cl
TBAF, THF
5
6
2
N
rt, 4 h
TMS
R = OMe
8:2 17a:17b,
55% yield
Entry
Equiv 1
Equiv 5
Equiv TBAF
Yield (%)
R = Me = 14
R = OMe = 15
b
1
2
3
1
2
3
2
1
1
3
3
4
Trace
59
95
R
Scheme 2.

J. A. Crossley, D. L. Browne / Tetrahedron Letters 51 (2010) 2271–2273
2273
4. (a) Hayes, M. E.; Shinokubo, H.; Danheiser, R. L. Org. Lett. 2005, 7, 3917; (b)
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Biehl, E. Tetrahedron Lett. 2009, 50, 1809.
7. (a) Lynett, P. T.; Maly, K. E. Org. Lett. 2009, 11, 3726; (b) Worlikar, S. A.; Larock,
R. C. Org. Lett. 2009, 11, 2413; (c) Henderson, J. L.; Edwards, A. S.; Greaney, M. F.
Org. Lett. 2007, 9, 5589; (d) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 46,
2535.
8. Raminelli, C.; Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 4689.
9. (a) Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270; (b) Gilmore, C. D.;
Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558; (c) Dai, M.; Wang, Z.;
Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613.
10. Some examples include: (a) Soorukram, D.; Qu, T.; Barrett, A. G. M. Org. Lett.
2008, 10, 3833; (b) Vézouët, R.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M.
Tetrahedron 2006, 62, 12252; (c) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11, 1587.
11. (a) Sasaki, T.; Yoshioka, T. Bull. Chem. Soc. Jpn. 1969, 42, 826; (b) Yamamori, T.;
Hiramatsu, Y.; Adachi, I. J. Heterocycl. Chem. 1981, 18, 347.
control over this process. Treatment of 2-methyl-6-(trimethyl-
silyl)phenyl trifluoromethanesulfonate (14) with mesityl N-oxide
and TBAF provided some interesting findings (Scheme 2). Firstly,
the reaction was notably slower, with 4 h required for complete con-
sumption of the N-oxide starting material, resulting in the isolation
of an inferior yield (64%, combined yield). Secondly, the methyl sub-
stituent appeared to offer poor control over regioselectivity, deliver-
ing a 3:2 mixture in favour of the sterically less congested system
16a.19
Conversely, although the same reduced reactivity was observed
with the methoxy-substituted congener 15 an improvement in
selectivity was apparent, delivering the desired products 17a,b in
an 8:2 ratio These findings suggest that a moderate improvement
in regioselectivity can be imparted to this cycloaddition by the
presence of a
r-withdrawing group.
12. For a recent report, see: Spiteri, C.; Sharma, P.; Zhang, F.; Macdonald, S. J. F.;
Keeling, S.; Moses, J. E. Chem. Commun. 2010. doi:10.1039/b922489k.
13. Grundmann, C. Synthesis 1970, 344.
In conclusion we have designed and optimised a mild method
for the synthesis of benzisoxazoles.20 Aromatic, heteroaromatic
and alkenyl-substituted chloro-oximes are all competent 1,3-di-
pole precursors and provide the products in good to excellent
yields. We have also shown, and in line with previous findings
on dipolar cycloadditions of benzynes, that methoxy benzyne of-
fers improved regiocontrol over simple alkyl analogues.
14. Grundmann, C.; Frommeld, H.-D.; Flory, K.; Datta, S. K. J. Org. Chem. 1968, 33,
1464.
15. As determined by 1H NMR spectroscopy and TLC analysis of the crude reaction
mixture.
16. Notwithstanding the possibility of the solvent reacting with the benzyne
intermediate.
17. For the use of TBAF as a base, see: Li, H.-Y.. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; vol. 7, p 4728.
18. For some interesting work on this topic, see: Matsumoto, T.; Sohma, T.;
Hatazaki, S.; Suzuki, K. Synlett 1993, 843.
Acknowledgements
19. Regiochemical assignment of 16a and 16b was deduced by nOe analysis after
preparative TLC isolation of the individual isomers. The regiochemistry of
17a,b is made by inference.
We are grateful to Professor Joseph P. A. Harrity and Professor
Iain Coldham for support and useful discussions. The EPSRC and
the University of Sheffield are thanked for a Doctoral Prize Fellow-
ship (D.L.B.).
20. Representative experimental procedure as applied to the synthesis of benzisoxazole
7: To a stirring solution of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate
(1) (150 mg, 0.500 mmol) and 5-methylthiophene-2-hydroximoyl chloride (5)
(29 mg, 0.167 mmol) in THF (3 mL) was added TBAF (1 M solution in THF,
0.67 mL, 0.67 mmol). After 1 h the reaction mixture was evaporated to dryness
and purified by flash column chromatography (stepwise gradient: starting
with petroleum ether, finishing with 10% EtOAc in petroleum ether) to give the
product 7 as a colourless solid, 26 mg, 71% yield; mp 75–78 °C. 1H NMR
(250 MHz, CDCl3): d 2.60 (s, 3H), 6.88–6.92 (m, 1H), 7.35–7.44 (m, 1H), 7.55–
7.65 (m, 3H), 7.99 (d, J = 8.0 Hz, 1H). 13C NMR (62.9 MHz, CDCl3): d 15.4, 110.2,
120.1, 122.0, 123.9, 126.2, 127.6, 128.2, 129.9, 143.3, 152.3, 163.7 ppm. FT-IR
3104 (w), 1611 (m), 1558 (m), 1506 (m), 1463 (m), 1375 (m) cmÀ1. HRMS (EI+):
calcd for C12H10NOS [M+H]+ 216.0483, found: 216.0481.
References and notes
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