Synthesis of benzisoxazoles by the [3 + 2] cycloaddition of in situ generated nitrile oxides and arynes

Article abstract of DOI:10.1021/ol902921s

"Chemical Equation Presented" A variety of substituted benzisoxazoles has been prepared by the [3 + 2] cycloaddition of nitrile oxides and arynes. Both components, being highly reactive intermediates, have been generated in situ by fluoride anion from readily prepared aryne precursors and chlorooximes, The reaction scope is quite general, affording a novel, direct route to functionalized benzisoxazoles under mild reaction conditions

Full text of DOI:10.1021/ol902921s

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1180-1183
Synthesis of Benzisoxazoles by the
[3 + 2] Cycloaddition of in situ
Generated Nitrile Oxides and Arynes
Anton V. Dubrovskiy and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received December 18, 2009
ABSTRACT
A variety of substituted benzisoxazoles has been prepared by the [3 + 2] cycloaddition of nitrile oxides and arynes. Both components, being
highly reactive intermediates, have been generated in situ by fluoride anion from readily prepared aryne precursors and chlorooximes. The
reaction scope is quite general, affording a novel, direct route to functionalized benzisoxazoles under mild reaction conditions.
Benzisoxazoles are present in a large number of pharma-
ceutically important products with antipsychotic,1 antitumor,2
anticonvulsant,3 antimicrobial,4 antithrombotic,5 and cho-
linesterase-inhibiting (Alzheimer’s disease6) properties. The
traditional approach to the synthesis of benzisoxazoles is a
3-4 step synthesis, which in some cases involves the
strongly acidic conditions of a Friedel-Crafts reaction and
the use of one of the substrates as a solvent, while in other
cases requires the use of strongly basic organometallics.
Employing these methods, it is possible to synthesize
particular benzisoxazoles on a large scale, but it is not as
convenient to synthesize large numbers of diverse benzisox-
azoles readily for biological activity screening.
(1) (a) Davis, L.; Effland, R. C.; Klein, J. T.; Dunn, R. W.; Geyer, H. M.,
III.; Petko, W. M. Drug Design DiscoVery 1992, 8, 225. (b) Strupczewski,
J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Stache, U.; Glamkowski,
E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R. W. J. Med. Chem.
1985, 28, 761. (c) Janssen, P. A. J.; Niemegeers, C. J. E.; Awouters, F.;
Schellekens, K. H. L.; Megens, A. A. H. P.; Meert, T. F. J. Pharmacol.
Exp. Ther. 1988, 244, 685. (d) Strupczewski, J. T.; Bordeau, K. J.; Chiang,
Y.; Glamkowski, E. J.; Conway, P. G.; Corbett, R.; Hartman, H. B.;
Szewczak, M. R.; Wilmot, C. A.; Helsley, G. C. J. Med. Chem. 1995, 38,
1119.
The idea of forming two bonds at a time, by means of a
[3 + 2] cycloaddition reaction of a benzyne with a nitrile
oxide, has been reported previously,7 although the low yields
(10 and 53%), limited possibilities for diversification, and
the challenging experimental procedures employed were not
very encouraging for the widespread utility of this approach.
Our recent interest8 in the chemistry of arynes generated
from the corresponding o-(trimethylsilyl)aryl triflates under
mild fluoride ion treatment has encouraged us to reexamine
this approach to benzisoxazoles. Fluoride ion not only
induces the formation of benzyne due to initial nucleophilic
attack on the silicon of the trimethylsilyl group9 but, being
(2) (a) Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.; Johnson,
M.; Lee, F.; Nilakantan, R.; Petersen, R.; Svenson, K.; Chopra, R.; Tam,
M. S.; Wen, Y.; Ellingboe, J.; Arndt, K.; Boschelli, F. J. Med. Chem. 2008,
51, 373. (b) Jain, M.; Kwon, C.-H. J. Med. Chem. 2003, 46, 5428.
(3) (a) Stiff, D. D.; Zemaitis, M. A. Drug Metab. Dispos. 1990, 18,
888. (b) Uno, H.; Kurokawa, M.; Masuda, Y.; Nishimura, H. J. Med. Chem.
1979, 22, 180.
(4) Priya, B. S.; Basappa; Swamy, S. N.; Rangappa, K. S. Bioorg. Med.
Chem. 2005, 13, 2623.
(5) Nuhrich, A.; Varache-Lembege, M.; Renard, P.; Devaux, G. Eur.
J. Med. Chem. 1994, 29, 75.
(6) (a) Villalobos, A.; Blake, J. F.; Biggers, C. K.; Butler, T. W.; Chapin,
D. S.; Chen, Y. L.; Ives, J. L.; Jones, S. B.; Liston, D. R.; Nagel, A. A.;
Nason, D. M.; Nielsen, J. A.; Shalaby, I. A.; White, W. F. J. Med. Chem.
1994, 37, 2721. (b) Rangappa, K. S. Basappa J. Phys. Chem. 2005, 18,
773.
(7) (a) Minisci, F.; Quilico, A. Gazz. Chim. Ital. 1964, 46, 428. (b)
Sasaki, T.; Yoshioka, T. Bull. Chem. Soc. Jpn. 1969, 42, 826.
(8) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2409.
10.1021/ol902921s  2010 American Chemical Society
Published on Web 02/25/2010

also a base, potentially10 induces formation of the nitrile
oxide from the corresponding chlorooximes. Such an ap-
proach would eliminate potential problems arising from
interaction of the reagents needed for generating the two
highly reactive intermediates, as well as the requirement that
the two species be generated separately from each other.
Indeed, our initial attempt to react o-(trimethylsilyl)-phenyl
triflate (1a) with N-hydroxybenzimidoyl chloride (2a) in the
presence of 3 equiv of CsF in acetonitrile led to formation
of the desired 3-phenylbenzisoxazole (3a) in a 46% yield
(Table 1, entry 1). High resolution GC-MS of the crude
decrease the rate of benzyne formation, which resulted in a
lower (23%) yield of benzisoxazole (entry 6). Since the rate
of nitrile oxide dimerization seemed to be greater than the
rate of [3 + 2] cycloaddition, we examined the use of an
excess of the benzyne precursor (entries 7 and 8). Indeed,
the use of 2 equiv of the benzyne precursor was found to
increase the yield to 61%. To further increase the local
concentration of benzyne relative to the nitrile oxide, we
examined slow addition of the chloroxime to the reaction
mixture via syringe pump (entries 9-11). The optimal time
of addition, which best aligned the rates of formation of the
benzyne and the nitrile oxide, was found to be 2.5 h, which
allowed the benzisoxazole (3a) to be isolated in a 90% yield
(entry 10).
Table 1. Optimization Studies of the Reaction of
o-(Trimethyl-silyl)phenyl Triflate (1a) and
N-Hydroxybenzimidoyl Chloride (2a)
Employing the optimal conditions shown in Table 1, entry
10, we examined the scope of this reaction using various
aryne precursors (Table 2, entries 1-3). Both electron-rich
and electron-poor aryne precursors successfully participated
in the [3 + 2] cycloaddition reaction, providing the desired
benzisoxazoles. Symmetrical 3,4-dimethoxybenzyne pro-
vided the corresponding benzisoxazole 3b in a 65% yield
(entry 1). The lowest yield (36%) was observed in the
reaction of the highly reactive 3,4-difluorobenzyne (entry 2).
Unsymmetrical 3-methoxybenzyne provided a mixture of
regioisomers in a ∼1.8:1 ratio (entry 3).12 Interestingly,
electronic factors dominate over steric factors with isomer
3d being the major product in the mixture (Scheme 1).
1a
fluoride
temp add. time
%
entry equiv source (equiv) solvent (°C) of 2a (h) yieldb
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
2.0
3.0
2.0
2.0
2.0
CsF (3)
TBAT (3)
CsF (3)
CsF (3)
CsF (3)
CsF (2.5)
CsF (6)
CsF (6)
CsF (6)
CsF (6)
CsF (6)
CH3CN Rt
CH3CN Rt
-
-
-
-
-
-
-
-
46
<5c
<5c
<5c
9
23
61
58
70
90
73
THF
THF
Rt
65
CH3CN 65
CH3CN Rt
CH3CN Rt
CH3CN Rt
CH3CN Rt
CH3CN Rt
CH3CN Rt
Scheme 1. Electronic and Steric Factors in the Reaction of
3-Methoxybenzyne and Phenyl Nitrile Oxide
9
10
11
5.0
2.5
1.0
a All reactions were carried out on a 0.25 mmol scale. b Isolated yields,
c
unless stated otherwise. 1H NMR spectroscopic yields.
mixture revealed the expected dimerization products11 of
phenyl nitrile oxide as the major byproduct of the reaction.
Our optimization studies of this process are summarized
in Table 1. The use of tetrabutylammonium triphenyldifluo-
rosilicate (TBAT), an alternative anhydrous fluoride source,
failed to provide the desired product under analogous
conditions (entry 2). The use of THF, a less polar solvent,
did not lead to formation of the desired benzisoxazole either
(entries 3 and 4). An attempt to run the reaction at an elevated
temperature to increase the rate of [3 + 2] cycloaddition at
the expense of nitrile oxide dimerization did not work well
(entry 5). To decrease the rate of formation of the nitrile
oxide, thus decreasing self-dimerization products, we at-
tempted to use less of the base CsF and at the same time
Various chlorooximes were prepared from the correspond-
ing readily available aldehydes in 53-99% overall yield as
follows. Reaction of the aldehyde with hydroxylamine
hydrochloride in the presence of Na2CO3 afforded the
corresponding oximes, which without isolation were chlo-
rinated using NCS and catalytic amounts of Py at room
temperature in chloroform (Scheme 2).13 An alternative
protocol,14 which employs chlorination by oxone and HCl,
failed to provide chlorooximes bearing alkyl moieties.
We next investigated the scope of the reaction between
o-(trimethylsilyl)phenyl triflate (1a) and various chlorooximes
(Table 2, entries 4-11). Aromatic chlorooximes provided the
corresponding benzisoxazoles in good to excellent yields. Lower
yields were observed when electron-withdrawing substituents
(9) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
(10) In the literature, Na2CO3 or aliphatic amines are most commonly
used, see: Lam, P. Y. S.; Adams, J. J.; Clark, C. G.; Calhoun, W. J.;
Luettgen, J. M.; Knabb, R. M.; Wexler, R. R. Bioorg. Med. Chem. Lett.
2003, 13, 1795.
1
(12) The ratios were determined by H NMR spectroscopy.
(11) Kelly, D. R.; Baker, S. C.; King, D. S.; de Silva, D. S.; Lord, G.;
Taylor, J. P. Org. Biomol. Chem. 2008, 6, 787.
(13) Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984, 40, 2985.
(14) Vela, M. A.; Kohn, H. J. Org. Chem. 1992, 57, 6650.
Org. Lett., Vol. 12, No. 6, 2010
1181

Table 2. Synthesis of 3-Substituted Benzisoxazoles by the Reaction of Chlorooximes and Aryne Precursors in the Presence of CsFa
a Reaction conditions: a solution of the appropriate chlorooxime (0.25 mmol) in 3 mL of acetonitrile was added via syringe pump to a stirring mixture
b
1
of silylaryl triflate (0.50 mmol) and CsF (1.50 mmol) in 3 mL of acetonitrile over the course of 2.5 h. Ratio was determined by H NMR spectroscopy.
reside on the benzene ring. For example, 3-(2-nitrophenyl)ben-
zisoxazole (3f) was isolated in a 57% yield (entry 4).15 Excellent
yields were observed using chlorooximes bearing electron-
donating (through resonance) substituents (entries 5-7), and
even chlorooxime 2e bearing a bulky o-bromo substituent
afforded benzisoxazole 3i in a 93% isolated yield.
1182
Org. Lett., Vol. 12, No. 6, 2010

ably due to Diels-Alder reactions9 of the furan ring with
the benzyne. On the other hand, the 3-thiophenyl chlo-
rooxime 2i successfully provided the desired benzisoxazole
3n in a 54% yield (entry 11).
Scheme 2. Preparation of the Chlorooximes
In summary, a simple, convenient and efficient protocol
has been developed for the synthesis of benzisoxazoles. The
reaction tolerates a variety of functional groups and provides
an alternative route to potentially important benzisoxazoles
bearing aryl, alkyl, alkenyl and heterocyclic substituents at
the 3 position of the benzisoxazole moiety. Further applica-
tions of this process and the synthesis of biologically active
products are currently underway.
Despite the reported instability of chlorooximes bearing
alkyl moieties,16 3-isopropylbenzisoxazole was isolated in
an 83% yield. Surprisingly, an alkene was also readily
tolerated in the reaction. Thus, (E)-3-styrylbenzisoxazole (3k)
was isolated in a 70% yield (entry 9).
Next, we studied the cycloaddition reaction of benzyne
with chlorooximes derived from heterocyclic aldehydes.
3-(N-Methylindolyl)chlorooxime (2h) furnished the desired
product 3l in a 61% yield (entry 10). Unfortunately, we could
not obtain the desired product from the 2-furyl chlorooxime.
The reaction produced many inseparable products, presum-
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM079593 and GM070620) and the Kansas
University NIH Center of Excellence in Chemical Methodo-
logy and Library Development (P50 GM069663) for their
generous financial support. We also thank Dr. Feng Shi at
Iowa State University for the preparation of noncommercially
available benzyne precursors.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Electron-withdrawing groups are known to stabilize nitrile oxides
thus making them more reluctant to cyclize, see: Wakefield, B. J.; Wright,
D. J. J. Chem. Soc. C 1970, 1165.
(16) Kumar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 1457.
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