Synthesis of dihydrobenzisoxazoles by the [3 + 2] cycloaddition of arynes and oxaziridines

Article abstract of DOI:10.1021/jo101656c

Dihydrobenzisoxazoles are readily prepared in good yields by the [3 + 2] cycloaddition of oxaziridines and arynes. The reaction involves an unusual cleavage of the C-O bond of the oxaziridine and tolerates a variety of substituents on the oxaziridine and the o-(trimethylsilyl)aryl triflate to form aryl-, heteroaryl-, alkyl-, and naphthyl-substituted dihydrobenzisoxazoles. The resulting halogen-substituted dihydrobenzisoxazoles are readily elaborated to more complex products using palladium-catalyzed crossing-coupling processes.

Full text of DOI:10.1021/jo101656c

pubs.acs.org/joc
Synthesis of Dihydrobenzisoxazoles by the [3 þ 2] Cycloaddition of
Arynes and Oxaziridines
Arif Kivrak†,‡ and Richard C. Larock*,†
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States, and ‡Department of
Chemistry, Middle East Technical University, Ankara 06531, Turkey
larock@iastate.edu
Received August 21, 2010
Dihydrobenzisoxazoles are readily prepared in good yields by the [3 þ 2] cycloaddition of
oxaziridines and arynes. The reaction involves an unusual cleavage of the C-O bond of the
oxaziridine and tolerates a variety of substituents on the oxaziridine and the o-(trimethylsilyl)aryl
triflate to form aryl-, heteroaryl-, alkyl-, and naphthyl-substituted dihydrobenzisoxazoles. The
resulting halogen-substituted dihydrobenzisoxazoles are readily elaborated to more complex pro-
ducts using palladium-catalyzed crossing-coupling processes.
Introduction
we hypothesized that arynes, which are readily prepared
in situ from o-(trimethylsilyl)aryl triflates,6 and oxaziridines
might provide a novel synthetic route to synthesize dihydro-
benzisoxazoles under mild reaction conditions.
Oxaziridines consisting of a nitrogen, oxygen, and carbon
in a three-membered ring exhibit unusually high reactivity
because of the inherently weak N-O bond.7 Oxaziridines
have been used as both oxygenating and aminating agents
for enolates,8 alkenes,9 nitrogen nucleophiles,10 and C-H
bonds.11 In addition, oxaziridines undergo some useful
rearrangements with low-valent metals12 and cycloaddition
reactions with a variety of heterocumulenes to form a
very diverse set of five-membered ring heterocycles.13 The
For decades, an intense research effort has been devoted to
the synthesis of biologically and pharmaceutically important
heterocyclic compounds. However, there are relatively few
methods to synthesize dihydrobenzisoxazoles, which appear
to have considerable pharmaceutical promise.1 Recently, the
reactions of oxaziridines2 bearing a three-membered strained
heterocyclic ring and alkynes3 or alkenes4 have been reported
to produce isoxazolines and isoxazolidines, respectively, by a
[3 þ 2] cycloaddition involving C-O bond cleavage. Since
arynes are generally more reactive than alkynes and alkenes,5
(1) (a) Barluenga, J.; Andina, F.; Aznar, F.; Valds, C. Org. Lett. 2007, 9,
4143. (b) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki, K. Angew.
Chem., Int. Ed. 2006, 45, 6842. (c) Barluenga, J.; Aznar, F.; Palomero, M. A.
Chem.;Eur. J. 2001, 7, 5318. (d) Hart, H.; Ok, D. J. Org. Chem. 1986, 51,
979. (e) Bigdeli, M. A.; Tipping, A. E. J. Fluorine Chem. 1992, 58, 101.
(f) Matsumoto, T.; Sohma, T.; Hatazaki, S.; Suzuki, K. Synlett 1993, 843.
(g) Kitamura, T.; Todaka, M.; Shin-machi, I.; Fujiwara, Y. Heterocycl.
Commun. 1998, 205.
(6) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
(7) Bjørgo, J.; Boyd, D. R. J. Chem. Soc., Perkin Trans. 2 1973, 1575.
(8) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc.
1985, 107, 4346.
(9) Prieur, D.; El Kazzi, A.; Kato, T.; Gornitzka, H.; Baceiredo, A. Org.
Lett. 2008, 10, 2291.
(2) Emmons, W. D. J. Am. Chem. Soc. 1956, 78, 6208.
(10) White, J. D.; Hansen, J. D. J. Am. Chem. Soc. 2002, 124, 4950.
(11) Arnone, A.; Foletto, S.; Metrangolo, P.; Pregnolato, M.; Resnati, G.
Org. Lett. 1999, 1, 281.
(3) Fabio, M.; Ronzini, L.; Troisi, L. Tetrahedron 2008, 64, 4979.
(4) Fabio, M.; Ronzini, L.; Troisi, L. Tetrahedron 2007, 63, 12896.
(5) For reviews on the use of arynes in organic synthesis, see: (a) Kessar,
S. V. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 4, p 483. (b) Pellissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701. (c) Chen, Y.; Larock, R. C. Arylation Reactions
Involving the Formation of Arynes. In Modern Arylation Methods;
Ackermann, L., Ed.; Wiley-VCH: New York, 2009; Chapter 12, p 401.
€
ꢀ
(12) Usuki, Y.; Peng, X.; Gulgeze, B.; Manyem, S.; Aube, J. Arkivoc 2006,
189.
(13) (a) Kraiem, J.; Grosvalet, L.; Perrin, M.; Hassine, B. B. Tetrahedron
Lett. 2001, 42, 9131. (b) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45,
5703. (c) Komatsu, M.; Ohshiro, Y.; Hatta, H.; Sato, M.; Agawa, T. J. Org.
Chem. 1974, 39, 948.
DOI: 10.1021/jo101656c
r
Published on Web 10/11/2010
J. Org. Chem. 2010, 75, 7381–7387 7381
2010 American Chemical Society

Kivrak and Larock
JOCArticle
TABLE 1. Synthesis of Oxaziridines
aThe overall yield from the carbonyl starting material.
7382 J. Org. Chem. Vol. 75, No. 21, 2010

Kivrak and Larock
JOCArticle
mechanism of these reactions appears to involve nucleophilic
attack on the oxaziridine nitrogen with N-O or C-N bond
cleavage.
TABLE 2. Optimization of the Reaction of Oxaziridine 2a and Benzyne
Precursor 1a
Highly reactive arynes have been extensively used for the
preparation of a wide range of aromatic heterocycles.14-16
Many biologically important heterocycles have been ob-
tained from arynes by Pd-catalyzed annulation reactions,17
electrophilic and nucleophilic reactions,18 inter- or intramo-
lecular cycloaddition reactions,19 and insertion reactions.20
In our previous studies, we have reported the synthesis of
benzotriazoles,21 indazoles,22 and benzisoxazoles23 by the
[3 þ 2] cycloaddition reaction of azides, diazo compounds,
and nitrile oxides with arynes, respectively. We now wish to
report the synthesis of dihydrobenzisoxazoles by the [3 þ 2]
cycloaddition of arynes and oxaziridines.
entry CsF (equiv) base (equiv) solvent temp (°C) % 3aa % 2a
1
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
4.5
6
4.5
3
4.5
3
3
4.5
CH3CN
CH3CN
DME
rt
65
90
110
110
90
90
90
90
90
90
65
90
90
90
65
65
90
90
90
>98
66
tr
59
13
toluene
DMF
Na2CO3 (1.1) DME
Cs2CO3 (1.1) DME
NaHCO3 (1.1) DME
5
6a
77
36
42
45
55
66
15
64
46
29
12
5
7b
8
Results and Discussion
8
9b
K2CO3 (1.1)
Li2CO3 (1.1) DME
NaCl (1.1) DME
DME
7
25
First, a number of oxaziridines have been prepared from
the corresponding aldehydes and amines, followed by oxida-
tion. A simple method for the preparation of oxaziridines
involves the oxidation of imines by m-chloroperoxybenzoic
10b
11
12b
13c
14
15
16
17b
18d
19 e
20e
Na2CO3 (1.1) DME
DME
DME
Na2CO3 (1.1) DME
Na2CO3 (1.1) THF
THF
Na2CO3 (1.1) DME
Na2CO3 (1.1) DME
DME
85
88
5
63
(14) (a) Wittig, G.; Pohmer, L. Angew. Chem. 1955, 67, 348. (b) Wittig,
G.; Hoffmann, R. W. Chem. Ber. 1962, 95, 2718. (c) Kornfeld, E. C.; Barney,
P.; Blankley, J.; Faul, W. J. Med. Chem. 1965, 8, 342.
(15) For some examples of the synthesis of heterocycles from arynes, see:
(a) Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40, 3784. (b) Yoshida, H.;
Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002, 41, 3247.
(c) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198. (d) Beltran-Rodil, S.;
36
61
48
aMethod A: the reaction was carried out on 1a (0.3 mmol), 1.2 equiv
of 2a, 1.1 equiv of Na2CO3, and 3 equiv of CsF in DME (7 mL) at 90 °C
for 24 h. bYields were determined by proton NMR spectral analysis.
cMethod B: the reaction was carried out on 1a (0.3 mmol), 1.2 equiv of
2a, and 4.5 equiv of CsF in DME (7 mL) at 90 °C for 24 h. dThe yield was
calculated from the crude product and the reaction time was 12 h.
e1.5 equiv of o-(trimethylsilyl)phenyl triflate (1a) was used for these
cyclization reactions.
~
ꢀ
Pena, D.; Guitian, E. Synlett 2007, 1308. (e) Zhao, J.; Larock, R. C. Org.
Lett. 2005, 7, 4273. (f) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583. (g)
Rogness, D. C.; Larock, R. C. Tetrahedron Lett. 2009, 50, 4003. (h) Zhang,
X.; Larock, R. C. Org. Lett. 2005, 7, 3973.
(16) For recent reviews of arynes, see: (a) Wenk, H. H.; Winkler, M.;
Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (b) Pellissier, H.; Santelli,
M. Tetrahedron 2003, 59, 701.
(17) (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
15716. (b) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973. (c) Liu, Z.;
Larock, R. C. Org. Lett. 2004, 6, 3739. (d) Liu, Z.; Larock, R. C. Tetrahedron
2007, 63, 347. (e) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am.
Chem. Soc. 2006, 128, 7426. (f) Jayanth, T. T.; Cheng, C.-H. Chem. Commun.
acid (m-CPBA).2,24 Using this approach, a variety of aro-
matic, aliphatic, heterocyclic, and polycyclic oxaziridines
have been synthesized as mixtures of diastereoisomers
(Table 1).25 We have focused our efforts on the synthesis of
only more thermally stable oxaziridines. For instance, more
stable N-tert-butyl oxaziridines26 are readily prepared from
tert-butyl amine and aromatic aldehydes, followed by oxida-
tion.
Optimization of the Cycloaddition. The reaction of
o-(trimethylsilyl)phenyl triflate (1a) with 2-tert-butyl-3-
phenyl-1,2-oxaziridine (2a) and CsF was optimized (Table 2).
Benzyne precursor 1a was allowed to react with 2a and
3 equiv of CsF for 24 h at room temperature, but the starting
oxaziridine 2a was recovered (entry 1). A trace amount of the
desired product 3aa was formed when the temperature was
increased to 65 °C in acetonitrile (entry 2). Thus, elevated
temperatures were used for all subsequent cycloaddition reac-
tions of 1a and 2a. The desired product was obtained in 59%
yield by using dimethoxyethane (DME) as the solvent at 90 °C
(entry 3). Not only a much lower yield but also decomposition
of the starting compounds were observed when the reaction
was run in toluene or dimethylformamide (DMF) at 120 °C for
24 h (entries 4 and 5). A yield of 77% of 3aa was observed when
o-(trimethylsilyl)phenyl triflate (1a) was allowed to react with
~
2006, 894. (g) Pena, D.; Perez, D.; Guitian, E.; Castedo, L. Org. Lett. 1999, 1,
1555. (h) Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron
ꢀ
ꢀ
~
Lett. 1999, 40, 7533. (i) Pena, D.; Perez, D.; Guitian, E.; Castedo, L. J. Am.
Chem. Soc. 1999, 121, 5827.
ꢀ
ꢀ
(18) (a) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem.
Commun. 2001, 1880. (b) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama,
T. Angew. Chem., Int. Ed. 2002, 41, 3247. (c) Liu, Z.; Larock, R. C. Org. Lett.
2003, 5, 4673. (d) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99. (e)
Jeganmohan, M.; Cheng, C.-H. Synthesis 2005, 1693. (f) Bhuvaneswari, S.;
Jeganmohan, M.; Yang, M. C.; Cheng, C. H. Chem. Commun. 2008, 2158.
(19) (a) Raminelli, C.; Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 4689.
(b) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P.
Org. Lett. 2009, 11, 3430. (c) Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc.
2008, 130, 17270. (d) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am.
ꢀ
ꢀ
Chem. Soc. 2008, 130, 1558. (e) Perez, D.; Guitian, E.; Castedo, L. J. Org.
Chem. 1992, 57, 5911. (f) Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am.
Chem. Soc. 1992, 114, 3568. (g) Hosoya, T.; Takashiro, E.; Matsumoto, T.;
Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004. (h) Hussain, H.; Kianmehr, E.;
Durst, T. Tetrahedron Lett. 2001, 42, 2245. (I) Soorukram, D.; Qu, T.;
Barrett, A. G. M. Org. Lett. 2008, 10, 3833.
(20) (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112.
(b) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
(21) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2409.
(22) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C.
J. Org. Chem. 2008, 73, 219.
(23) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180.
(24) (a) Widmer, J.; Keller-Schierlein, W. Helv. Chim. Acta 1974, 57, 657.
(b) Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 36, 1570.
(25) (a) Troisi, L.; Lorenzis, S. D.; Fabio, M.; Rosato, F.; Granito, C.
Tetrahedron: Asymmetry 2008, 19, 2246. (b) Davis, F. A.; Chen, B. C. Chem.
Rev. 1992, 92, 919. (c) Armstrong, A.; Draffan, A. G. Tetrahedron Lett. 1999,
40, 4453. (c) Mohajer, D.; Iranpoor, N.; Rezaeifard, A. Tetrahedron Lett.
2004, 45, 631.
(26) (a) Emmons, W. D. J. Am. Chem. Soc. 1957, 79, 5739. (b) Pews, R. G.
J. Org. Chem. 1966, 32, 1628.
J. Org. Chem. Vol. 75, No. 21, 2010 7383

Kivrak and Larock
JOCArticle
TABLE 3. Synthesis of Substituted Dihydrobenzisoxazoles from Arynes and Oxaziridines
aThe yield was calculated from integration of the 1H NMR spectrum. b4,5-Dimethyl-2-(trimethylsilyl)phenyl triflate was used as the aryne
precursor. c4,5-Difluoro-2-(trimethylsilyl)phenyl triflate was used as the aryne precursor. d2-(Trimethylsilyl)naphthlen-1-yl triflate was used as the
aryne precursor.
7384 J. Org. Chem. Vol. 75, No. 21, 2010

Kivrak and Larock
JOCArticle
2a in the presence of Na2CO3 in DME at 90 °C for 24 h
(entry 6). When Cs2CO3, NaHCO3, K2CO3, or Li2CO3 was
used as the base, the yields ranged from 36% to 55% (entries
7-10). Surprisingly, the substitution of Na2CO3 by NaCl gave
a 66% yield (entry 11). When the reaction was carried out in
DME at 65 °C for 24 h, the conversion was only 15% (entry 12).
When the amount of CsF was increased with or without the
addition of a base in DME at 90 °C, only 29-64% yields of
the desired product were obtained (entries 13-15). When the
reactions were repeated in THF at 65 °C for 24 h, the yields
were only 5% and 12% (entries 16 and 17). When the reaction
was refluxed for 12 h, only a 36% yield of the desired product
was obtained (entry 18). If additional (1.5 equiv) 1a was used in
the reaction, the desired product was still formed in only 61%
and 48% yields (entries 19 and 20).
The cycloaddition of 1a and 2a was also examined using
2 equiv of tetrabutylammonium difluorotriphenylsilicate
(TBAT) as the source of fluoride in DME for 24 h. The
starting 2-tert-butyl-3-phenyl-1,2-oxaziridine was recovered
at room temperature, and none of the desired product was
formed at 90 °C. Thus, CsF has been found to be a better
source of fluoride for the formation of dihydrobenzisoxa-
zoles.
FIGURE 1. Aryne precursors.
nitro group was present on the aromatic ring (2g), the dihydro-
benzisoxazole product was not observed even after 24 h
(entry 8). While the highest yield (88%) was obtained from
the reaction of 1a and 2-tert-butyl-3-(fur-2-yl)-1,2-oxaziridine
(entry 9), the electron-poor 3-pyridyl heterocyclic substrate 2f
gave a very low yield of the desired product (entry 10). The
reaction of aliphatic-substituted oxaziridines, such as 2-tert-
butyl-3-isopropyl-1,2-oxaziridine (2i), with 1a was performed
to investigate the effect of aliphatic groups on the formation
of dihydrobenzisoxazoles. A very low yield was observed for
3ai (entry 11) under our optimized conditions. When 2-(1-
ethynylcyclohexyl)-3-phenyl-1,2-oxaziridine (2o) was used for
the synthesis of 3ao, only a 12% yield was obtained (entry 12).
Dihydrobenzisoxazoles 3an, 3aq, 3ar, 3as, and 3ax were
synthesized in 40-53% isolated yields from the corresponding
ortho-substituted aryl oxaziridines (entries 13-17). These rela-
tively low yields are apparently caused by steric effects arising
from the ortho positions of the aromatic rings. Analogous meta-
substituted aryl oxaziridines on the other hand afforded good
yields of the corresponding dihydrobenzisoxazoles 3ap and 3at
(entries 18 and 19). While benzyne precursor 1a appeared to
react with bicyclic oxaziridine 2l to afford the corresponding
polycyclic dihydrobenzisoxazole (entry 22), the desired poly-
cyclic product 3al could not be isolated cleanly from the
reaction.
Additional examples of the reaction of oxaziridines 2e and
2m with a variety of aryne precursors (Figure 1) were con-
ducted under our optimized conditions to obtain a variety
of substituted dihydrobenzisoxazoles in moderate yields
(entries 23-26). The electron-rich dimethyl-substituted ben-
zyne gave lower yields (21%, entry 23; 56%, entry 24) than
the analogous reactions of the parent benzyne. The electron-
poor difluoroaryne analogue reacted with 3-[4-(benzyloxy)-
phenyl]-2-tert-butyl-1,2-oxaziridine (2m) to form the corre-
sponding product in a good yield (64%, entry 25). In addi-
tion, the unsymmetrical naphthalyne precursor 1d reacted
with 2-tert-butyl-3-(4-methoxyphenyl)-1,2-oxaziridine (2e)
to produce 3de in a 32% isolated yield as the only regioi-
somer (entry 26). This regioselectivity presumably arises
from nucleophilic attack of the oxaziridine selectively at
the C-2 position of the naphthalyne intermediate due to
more favorable steric and electronic effects. In fact, similar
regioselectivity has been observed in our previous studies
with substituted arynes.23,27 Suzuki et al. have also pointed
out that the regiochemistry of [3 þ 2] dipolar cycloaddition
reactions depends on the C-3 substituent of the aryne.1f The
reaction between arynes and oxaziridines generally gives a
diastereomeric mixture of dihydrobenzisoxazoles as a result
of the diastereomeric starting compound. However, the
diastereomers have not been separated by column chroma-
tography. The stereogenic carbon atom present in the dia-
stereomers is evident as two peaks in the 13C NMR spectrum.
Two different “optimized” conditions, Method A [1a (0.3
mmol), 1.2 equiv of 2a, 3 equiv of CsF, and 1.1 equiv of
Na2CO3 at 90 °C for 24 h] and Method B [1a (0.3 mmol),
1.2 equiv of 2a, and 4.5 equiv of CsF at 90 °C for 24 h] were
chosen for the synthesis of additional dihydrobenzisoxazoles
by this [3 þ 2] cycloaddition process.
Synthesis of Dihydrobenzisoxazoles. Five different oxazir-
idines were allowed to react with o-(trimethylsilyl)phenyl
triflate (1a) using our two optimized conditions, Methods A
or B, to compare the yields of the desired products. Using
Method A, a 77% yield of 3aa was achieved, while only a
64% yield of 3aa was obtained using Method B (Table 3,
entry 1). Higher yields were also observed using Method A
when oxaziridines 2b or 2c were allowed to react with the
benzyne precursor 1a (entries 2 and 3). However, 3aj and
3ak, containing cyclohexyl and isopropyl groups on the
nitrogen of the oxaziridine, respectively, produced less than
5% yields of the desired products using these methods
(entries 4 and 5). These results may be related to the
instability of the oxaziridines or the corresponding dihydro-
benzisoxazoles at these reaction temperatures. Dihydroben-
zisoxazoles have relatively weak N-O bonds, which may
result in decomposition of the product at higher tempera-
tures. In the light of these results, Method A would appear to
be a better procedure for the synthesis of dihydrobenzisox-
azoles. It appears that the thermal stability of the oxaziridine
significantly affects the [3 þ 2] cycloaddition reaction with
arynes. As noted above, the more stable oxaziridines give the
higher yields of the desired products.
The scope and limitations of this methodology for the
formation of dihydrobenzisoxazoles using a wide range of
oxaziridines, including aromatic, polycyclic, heterocyclic,
and aliphatic oxaziridines, were examined (Table 3). The
reaction of oxaziridines bearing substituted aromatic rings
usually afforded the corresponding products in moderately
good yields (entries 2, 3, 6-8, 13-21, and 23-26). The
para-substituted benzyloxy- and methoxy-aryl oxaziridines
gave higher yields of cycloadduct than our model system
(entries 6 and 7). However, when a strong electron-withdrawing
(27) Troisi et al. have observed how steric interactions affect the regios-
electivity of the cycloaddition reaction of alkynes and oxaziridines; see ref 3.
J. Org. Chem. Vol. 75, No. 21, 2010 7385

Kivrak and Larock
JOCArticle
SCHEME 1. Possible Mechanisms for Formation of the Dihydrobenzisoxazoles
SCHEME 2. Suzuki-Miyaura Coupling of Dihydrobenzisoxazoles with Boronic Acids
SCHEME 3. Sonogashira Coupling of a Dihydrobenzisoxazole and a Terminal Alkyne
Mechanism for Formation of the Dihydrobenzisoxazoles.
Two reaction mechanisms are possible for the cycloaddition
of oxaziridines and arynes (Scheme 1). In the first possible
mechanism (Path A), insertion of the aryne into the C-O
bond of the oxaziridine ring occurs by a concerted mecha-
nism. Agawa28 and Troisi4 have suggested a similar cycload-
dition mechanism for the formation of diarylisoxazolidine
derivatives from oxaziridines. Another possible mechanism
involves initial formation of a nitrone at the higher tempera-
tures employed. We have recently observed that nitrones
react readily with arynes to give dihydrobenzisoxazoles.29
Troisi et al. have also compared the one-step mechanism to
the nitrone mechanism in similar cyclization reactions.3,4
They suggest that Path A is more probable than the nitrone
mechanism. It is important to note that this is one of only a
few known reactions of oxaziridines in which insertion
occurs between the carbon and oxygen of the oxaziridine,
rather than the oxygen and nitrogen.30
Recently, the synthesis of a wide variety of polysubstituted
heterocyclics and polycyclics has been reported using various
palladium-catalyzed cross-couplings, such as Sonogashira,31
Suzuki-Miyaura,32 and Heck33 cross-couplings. We believe
that our approach to halogen-substituted dihydrobenzisox-
azoles could be very useful for the synthesis of additional,
more highly substituted dihydrobenzisoxazoles. Thus, we
(30) For other examples of C-O insertion, see: (a) Padwa, A.; Koehler,
K. F. Heterocycles 1986, 24, 611. (b) Abou-Gharbia, M. A.; Joullie, M. M.
Synth. Commun. 1979, 9, 871.
(31) Sonogashira, K.; Tohda, H.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(32) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147.
(33) Heck, R. F. Org. React. 1982, 27, 345.
(28) Komatsu, M.; Ohshiro, Y.; Hatta, H.; Sato, M.; Agawa, T. J. Org.
Chem. 1974, 39, 948.
(29) (a) Lu, C.; Larock, R. C. work in progress. (b) Dai, M.; Wang, Z.;
Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613.
7386 J. Org. Chem. Vol. 75, No. 21, 2010

Kivrak and Larock
JOCArticle
have been able to convert 3at and 3av to the corresponding
methoxypyridyl-substituted dihydrobenzisoxazoles using a
modified Suzuki-Miyaura literature procedure (Scheme
2).34 The halogen-substituted dihydrobenzisoxazoles 3at
and 3av were allowed to react with the indicated boronic
acids to form 4at and 4av in the presence of Cs2CO3 and
10 mol % of Pd(PPh3)4 under microwave irradiation for
20 min. Dihydrobenzisoxazoles 4at and 4av were obtained in
58% and 72% yields, respectively. By allowing compound
3av to react with a terminal alkyne in the presence of 2 mol %
of PdCl2(PPh3)2 and 1 mol % CuI under microwave condi-
tions for 20 min at 65 °C, the elaborated product 5av was
isolated in a 76% yield by Sonogashira coupling (Scheme 3).
Thus, halogen-substituted dihydrobenzisoxazoles produced
by the cycloaddition of oxaziridines and arynes can be easily
elaborated to more highly substituted derivatives to afford
potentially biologically active derivatives.
General Procedure for the Suzuki-Miyaura Coupling with
Boronic Acids. To a solution of the dihydrobenzisoxazole (0.15
mmol) and boronic acid (0.18 mmol) in a microwave vial in 1:1
DMF/EtOH (2 mL) were added Pd(PPh3)4 (0.015 mmol) and
Cs2CO3 (0.20 mmol). The resulting vial was sealed and stirred
under microwave irradiation at the appropriate temperature for
20 min. The resulting solution was diluted with satd aq NH4Cl
(15 mL) and extracted with dichloromethane (20 mL). The
combined organic layers were dried over anhydrous MgSO4
and concentrated under reduced pressure to yield the crude
product, which was purified by flash chromatography on silica
gel using ethyl acetate/hexane as the eluent.
2-tert-Butyl-3-[3-(5-methoxypyridin-2-yl)phenyl]-2,3-dihydro-
benz[d]isoxazole (4at). The reaction was carried out at 120 °C.
Purification by flash chromatography (1:20 ethyl acetate/
1
hexane) afforded the product as an oil: H NMR (400 MHz,
CDCl3) δ 8.37 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.42
(m, 3H), 7.17 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.82
(m, 3H), 5.67 (s, 1H), 3.98 (s, 3H), 1.21 (s, 9H); 13C NMR (400
MHz, CDCl3) δ 163.8, 156.4, 145.3, 144.9, 138.4, 137.7, 132.2,
130.1, 129.7, 129.4, 128.9, 126.5, 125.9, 123.8, 120.9, 110.9,
107.0, 67.0, 61.3, 53.8, 25.7. HRMS (EI) calcd for C23H24-
N2O2: 360.1838, found 360.1848.
General Procedure for Sonogashira Coupling with a Terminal
Alkyne. To a solution of the dihydrobenzisoxazole (0.15 mmol)
and terminal alkyne (0.18 mmol) in a microwave vial in 1:1
DMF/Et3N (2 mL) were added PdCl2(PPh3)2 (0.003 mmol) and
CuI (0.0015 mmol). The resulting vial was sealed and stirred
under microwave irradiation at 65 °C for 20 min. The resulting
solution was diluted with satd aq NH4Cl (15 mL) and extracted
with dichloromethane (20 mL). The combined organic layers
were dried over anhydrous MgSO4 and concentrated under
reduced pressure to afford the crude product, which was purified
by flash chromatography on silica gel using ethyl acetate/hexane
as the eluent.
Conclusions
In the present study, a novel synthetic route to a variety of
dihydrobenzisoxazoles by the [3 þ 2] cycloaddition reaction
of arynes and oxaziridines has been developed. The reaction
tolerates a variety of oxaziridines and silylaryl triflates
and affords the corresponding cycloadducts in moderate to
good yields. This process is one of the few such reactions of
oxaziridines, which observed to proceed by carbon-oxygen
bond cleavage of the oxaziridine. The resulting halogen-
substituted dihydrobenzisoxazoles are readily elaborated to
more complex products using known organopalladium
chemistry. This methodology provides a useful new route
for the synthesis of substituted dihydrobenzisoxazoles,
which should find application in the construction of mole-
cules with interesting biological properties and pharmaceu-
tical potential.
2-tert-Butyl-3-[3,4-dimethoxy-5-(2-(3,5-dimethoxyphenyl)-
ethynyl)phenyl]-2,3-dihydrobenz[d]isoxazole (5av). Purification
by flash chromatography (1:20 ethyl acetate/hexane) afforded
1
the product as an oil: H NMR (400 MHz, CDCl3) δ 7.16 (m,
Experimental Section
2H), 6.94 (d, J = 7.6 Hz, 1H), 6.82 (m, 2H), 6.71 (s, 2H), 6.47 (s,
1H), 5.55 (s, 1H), 3.98 (s, 3H), 3.84 (s, 3H), 3.81 (s, 6H), 1.20 (s,
9H); 13C NMR (400 MHz, CDCl3) δ 160.7, 156.1, 153.1, 149.8,
139.9, 129.5, 128.9, 124.8, 123.8, 123.4, 120.9, 117.5, 112.2,
109.5, 107.0, 102.0, 93.6, 85.4, 66.8, 61.2, 56.3, 55.6, 25.7. HRMS
(EI) calcd for C29H31NO5: 473.2202, found 473.2215.
General Procedure for the Synthesis of Dihydrobenzisoxazoles.
To a mixture of CsF (0.90 mmol, 3 equiv) and Na2CO3 (0.33
mmol, 1.1 equiv) in a 4-dram vial was added a solution of the
o-(trimethylsilyl)aryl triflate (0.30 mmol) and oxaziridine (0.36
mmol, 1.2 equiv) in 5 mL of DME. The resulting mixture was
flushed with Ar and stirred at 90 °C for 24 h. After the reaction
was over, the DME was removed under reduced pressure. The
residue was purified by flash column chromatography on silica
gel using ethyl acetate/hexane as the eluent to afford the desired
product.
Acknowledgment. We thank the National Institute of
General Medical Sciences (GM070620 and GM079593)
and the National Institutes of Health Kansas University
Center of Excellence in Chemical Methodologies and Library
Development (P50 GM069663) for their generous financial
support. We also thank the Scientific and Technological
Research Council of Turkey (TUBITAK) and the Faculty
Development Program (OYP-Yuzuncu Yil University) for a
scholarship to A.K.
2-tert-Butyl-3-phenyl-2,3-dihydrobenz[d]isoxazole (3aa). Puri-
fication by flash chromatography (1:20 ethyl acetate/hexane)
1
afforded the product as a white solid: mp 93.3-95.2 °C; H
NMR (300 MHz, CDCl3) δ 7.39 (m, 2H), 7.33 (t, J = 7.5 Hz,
2H), 7.25 (m, 1H), 7.15 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 7.5 Hz,
1H), 6.80 (m, 2H), 5.60 (s, 1H), 1.19 (s, 9H); 13C NMR (400
MHz, CDCl3) δ 156.3, 144.1, 130.0, 128.8, 127.6, 127.5, 123.8,
120.9, 106.9, 67.2, 61.3, 25.7. HRMS (EI) calcd for C17H19NO:
253.1467, found 253.1471.
Supporting Information Available: Characterization of
the new oxaziridines and dihydrobenzisoxazole final pro-
ducts, including full 1H and 13C NMR spectra. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
(34) (a) Chen, Y.; Markina, N. A.; Larock, R. C. Tetrahedron 2009, 65,
8908. (b) Nilsson, P.; Olofsson, K.; Larbed, M. Microwaves in Organic
Synthesis: Springer: Heidelberg, 2006; p 103.
J. Org. Chem. Vol. 75, No. 21, 2010 7387