Intramolecular 1,3-dipolar cycloaddition of nitrile N-oxide accompanied by dearomatization

Article abstract of DOI:10.1021/ol300125s

Intramolecular 1,3-dipolar cycloaddition of 2-phenoxybenzonitrile N-oxides to benzene rings, accompanied by dearomatization, formed the corresponding isoxazolines in high yields. The X-ray single-crystal structure analysis revealed that the reaction formed the cis-adduct as a single isomer. The substituents on the benzene rings markedly affected the reaction rate, yield, and structure of the final product.

Full text of DOI:10.1021/ol300125s

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1164–1167
Intramolecular 1,3-Dipolar Cycloaddition
of Nitrile N-Oxide Accompanied by
Dearomatization
Morio Yonekawa,† Yasuhito Koyama,*,† Shigeki Kuwata,‡ and Toshikazu Takata*,†
Department of Organic and Polymeric Materials, Department of Applied Chemistry,
Tokyo Institute of Technology 2-12-1 (H-126), Ookayama, Meguro-ku, Tokyo 152-
8552, Japan
ttakata@polymer.titech.ac.jp; ykoyama@polymer.titech.ac.jp
Received January 18, 2012
ABSTRACT
Intramolecular 1,3-dipolar cycloaddition of 2-phenoxybenzonitrile N-oxides to benzene rings, accompanied by dearomatization, formed the
corresponding isoxazolines in high yields. The X-ray single-crystal structure analysis revealed that the reaction formed the cis-adduct as a single
isomer. The substituents on the benzene rings markedly affected the reaction rate, yield, and structure of the final product.
Nitrile N-oxide is an important class of 1,3-dipoles,
which facilitates catalyst-free [2 þ 3] cycloaddition to
various unsaturated bonds, such as alkenes, alkynes, and
nitriles.1ꢀ3 In particular, the cycloaddition of nitrile N-
oxide is regarded as an effective tool for the synthesis of
pharmaceuticals, natural products, polymeric materials,
and supramolecules because it is accompanied by CꢀC
bond formation; in addition, the resulting heterocycles
serve as versatile scaffolds for a variety of reactive deriv-
atives, such as aldol, diketone, β-aminoalcohol, and
β-aminoenone.4,5 Typically, nitrile N-oxide is labile and
dimerizes easily to form furoxan; however, it can be made
sufficiently stable by the introduction of bulky substituents,
which are capable of preventing dimerization, and thus
can be isolated.6
Recently, we developed a kinetically stabilized homo-
ditopic nitrile N-oxide as a new chemical ligation tool
between unsaturated bond-containing compounds, mainly
directed toward both catalyst-free cross-linking reactions
of common polymers, such as fibers, rubbers, and resins,
and catalyst-free polycycloaddition of bisdipolarophiles.7
In the elaborate process of developing the homoditopic
nitrile N-oxide, we encountered a very interesting fact:
bisphenol A-skeleton-linked homoditopic nitrileN-oxide 1
exhibited low stability, which rapidly decomposed at room
temperature, whereas the tetramethylated analogue 2 ex-
hibited sufficient stability to be isolated without loss in
the reactivity of the 1,3-dipole (Figure 1). The structural
analysis of the resultant mixture from 1 revealed that
† Department of Organic and Polymeric Materials.
‡ Department of Applied Chemistry.
(1) Quilico, A.; Fusco, R. Gazz. Chim. Ital. 1937, 67, 589–603.
(2) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565–598.
(3) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339–
5342.
(4) For selected reviews on 1,3-dipolar cycloaddition of nitrile N-
oxides in targeted syntheses, see: (a) Kozikowski, A. P. Acc. Chem. Res.
1984, 17, 410–416. (b) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–
12275.
(6) For selected reports of stable nitrile N-oxides, see: (a) Beltrame,
P; Veglio, C.; Simonetta, M. J. Chem. Soc. (B) 1967, 867–873. (b)
Grundmann, C; Richter, R. J. Org. Chem. 1968, 33, 476–478.
(7) (a) Koyama, Y.; Yonekawa, M.; Takta, T. Chem. Lett. 2008, 37,
918–919. (b) Lee, Y. G.; Koyama, Y.; Yonekawa, M.; Takata, T.
Macromolecules 2009, 42, 7709–7717. (c) Lee, Y. G.; Koyama, Y.;
Yonekawa, M.; Takata, T. Macromolecules 2010, 43, 4070–4080. (d)
Lee, Y. G.; Yonekawa, M.; Koyama, Y.; Takata, T. Chem. Lett. 2010,
39, 420–421. (e) Matsumura, T.; Ishiwari, F.; Koyama, Y.; Takata, T.
Org. Lett. 2010, 12, 3828–3831. (f) Koyama, Y.; Takata, T. Kobunshi
Ronbunshu 2011, 68, 147–159. (g) Koyama, Y.; Seo, A.; Takata, T.
Nippon Gomu Kyokaishi 2011, 84, 111–116.
€
(5) (a) Caramella, F.; Grunanger, P. 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Intersciences: New York, NY, 1984; p
€
291. (b) Jager, V.; Colinas, P. A. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons: New Jersey, NJ, 2003;
p 361.
r
10.1021/ol300125s
Published on Web 02/09/2012
2012 American Chemical Society

intramolecular 1,3-dipolar cycloadditions of nitrile N-
oxides to the neighboring bis-A benzene rings proceeded
to afford the corresponding dihydrobenzoisoxazole 10 as a
diastereomixture via the dearomatization of benzene rings.
from 2-fluoro-6-methoxybenzaldehyde via the aromatic
nucleophilic substitution of p-cresol, oxime formation,
and oxidation.
Scheme 1. Intramolecular Cycloaddition of Nitrile N-Oxide 4a
Figure 1. Homoditopic nitrile N-oxides (1 and 2) and bisdihy-
drobenzoisoxazole 10.
According to Huisgen’s procedure,2 the treatment of 3a
with N-chlorosuccinimide (NCS) in the presence of Et3N
in CHCl3 (5 mM) at 0 °C immediately afforded the cor-
responding nitrile N-oxide 4a in 91% yield (NMR yield).
Although 4a was isolable, it gradually isomerized to iso-
xazoline 5a at rt. Therefore, after confirming the genera-
tion of 4a by TLC analysis, the reaction mixture of 3a was
refluxed for 3 h to afford 5a, without the isolation of 4a, in
71% yield as a single regioisomer.
The evidence for dearomatization was confirmed un-
ambiguously by 1H NMR spectroscopy (Figure 2). During
the reaction, the aromatic signals originating from the tolyl
group of 4a disappeared as the peaks at 5.76, 5.54, 5.37,
To the best of our knowledge, only Coustard et al.
reported a study on the direct addition of nitrile N-oxide
to a nonstrained, monocyclic phenyl ring.8ꢀ11 They
claimed that the treatment of 1-substituted-2-nitroethene
derivatives with an excess amount of trifluoromethanesul-
fonic acid (TfOH) generated the corresponding nitrile
N-oxides in situ, and successive intramolecular cycloaddi-
tions to the benzene rings afforded tricyclic isoxazolines in
41%ꢀ75% yields.
Herein, we report the intramolecular cycloaddition re-
actions of the nitrile N-oxide moiety to the neighboring
benzene ring using kinetically stabilized 2-phenoxybenzo-
nitrile N-oxide derivatives. The reaction was accompanied
by dearomatization, leading to the formation of dihydro-
benzoisoxazoles (isoxazolines) in excellent yield and high
regioselectivity. The X-ray crystal-structure analysis of the
product revealed the formation of the cis-adduct as a single
isomer. By investigating the scope of various substrates, we
observed that the substituents on the benzene ring mark-
edly affected the reaction rate, yield, and structure of the
final product.
and 4.31 ppm increased. The former two peaks (JHH
=
6.4 Hz) were assignedto the conjugated diene signals, while
the latter two (JHH = 15.6 Hz) were assigned to the
isoxazoline methine protons. Finally, the structure of 5a
was determined by X-ray crystallographic analysis.
First, we investigated the use of 6-methoxy-2-(p-tolyoxy)-
benzonitrile N-oxide (4a) (Scheme 1), which was prepared
(8) Soro, Y.; Bamba, F.; Siaka, S.; Coustard, J. M. Tetrahedron Lett.
2006, 47, 3315–3319.
(9) For selected reports of cycloaddition of nitrile N-oxides to poly-
cyclic aromatic hydrocarbons, see: (a) Corsaro, A.; Librando, V.;
ꢀ
Chiacchio, U.; Pistara, V. Tetrahedron 1996, 52, 13027–13034. (b)
Librando, V.; Chiacchio, U.; Corsaro, A.; Gunima, G. Polycyclic
Aromat. Compd. 1996, 11, 313–316. (c) Corsaro, A.; Librando, V.;
ꢀ
Chiacchio, U.; Fisichella, S.; Pistara, V. Heterocycles 1997, 45, 1567–
ꢀ
1572. (d) Corsaro, A.; Librando, V.; Chiacchio, U.; Pistara, V.; Rescifina,
ꢀ
A. Tetrahedron 1998, 54, 9187–9194. (e) Corsaro, A.; Pistara, V.;
Rescifina, A.; Piperno, A; Chiacchio, M. A.; Romeo, G. Tetrahedron
2004, 60, 6443–6451.
(10) For report of cycloaddition of nitrile N-oxides to benzocyclo-
propene, see: Nitta, M; Sogo, S; Nakayama, T. Chem. Lett. 1979, 12,
1431–1434.
(11) For selected reports of cycloaddition of nitrile N-oxides to
fullerenes, see: (a) Meier, M. S.; Poplawska, M. J. Org. Chem. 1993,
58, 4524–4525. (b) Meier, M. S.; Poplawska, M.; Compton, A. L.; Shaw,
J. P.; Selegue, J. P.; Guarr, T. F. J. Am. Chem. Soc. 1994, 116, 7044–7048.
(c) Irngartinger, H.; Weber, A. Tetrahedron Lett. 1996, 37, 4137–4140.
(d) Irngartinger, H.; Weber, H.; Escher, T.; Fettel, P. W.; Gassner, F.
Eur. J. Org. Chem. 1999, 9, 2087–2092.
Figure 2. 1H NMR spectra of nitrile N-oxide 4a and isoxazoline
5a (400 MHz, CDCl3, 298 K).
(12) Koyama, Y.; Yamaguchi, R.; Suzuki, K. Angew. Chem., Int. Ed.
2008, 47, 1084–1087.
Org. Lett., Vol. 14, No. 4, 2012
1165

yield (entry 2) in the same manner as entry 1, whereas the
expected product 5c was hardly observed, and the nitrile
N-oxide 4c was almost recovered (entry 3). It is suggested that
the introduction of substituents at the R1 positions would
effectively suppress the cycloaddition reaction to the benzene
ring, probably because the substituents would kinetically
prevent the approach of the benzene ring to the nitrile
N-oxide moiety. This is consistent with the successful synthe-
sis of the stable homoditopic nitrile N-oxide 2. Meanwhile,
it is very interesing that the methyl groups at the R2
positions negligibly affected the [2 þ 3] cycloaddition.
The electron demand of the benzene ring also influenced
the cycloaddition reaction. The reaction of 4d, which has
nosubstituentson the benzene ring, required aslightlylong
time, probably because of the electron density of the
benzene ring. The yield of 5d was lower than that of 5a
(entry 4), because an additional reaction occurred between
the other nitrile N-oxide and the disubstituted olefin of
cyclohexadiene. On the other hand, p-methoxy substituted
4e was sufficiently reactive to form the cycloadduct 5e in
high yield (93%, entry 5).
In the case of 4f, which has an electron-withdrawing
group, an unexpected result was obtained (entry 6, Scheme 2).
During the reflux of the 4f solution, we noticed that the
reaction was considerably slow, and a few spots appeared
on the TLC after several hours. After 3 days, the reaction
was quenched and purified by silica-gel column chromato-
graphy because the spots mainly converged at one spot. As
a result, the main product was not the expected isoxazoline
5f but iminophenol 6f (75% yield) via the intramolecular
redox reaction of isoxazoline12 and cyclohexadiene rings.
The structure of 6f was determined from the following
reasons: In the 1H NMR spectrum, two new singlet peaks
were observed in the downfield region (imine and phenol
protons); the integral ratios of the five peaks in the
aromatic region were equal, indicating disubstitution and
Figure 3. ORTEP structure of isoxazoline 5a. Thermal ellipsoids
are drawn at 50% probability.
Figure 3 shows an ORTEP drawing of 5a. It revealed
that the nitrile N-oxide moiety was added to the benzene
ring in a cis-manner. The four rings are not periplanar
because two carbons, C9 and C10, adopt sp3 hybrid
orbitals. Notably, the dihedral angle N1ꢀC8ꢀC9ꢀH7 is
117.15°, which can result in the decreased acidity of H7 by
the stereoelectronic effect, thereby efficiently preventing
the rearomatization of the cyclohexadiene ring via the
E1cB reaction of the O1 atom. The distortion of the
dihedral angle appears to be mainly attributed to the steric
repulsion between the methoxy group at the peri position
and the CdN bond of the isoxazoline moiety.
To clarify the effects of steric hindrance and electron
demand of the benzene ring on the reaction, the reactions
of 2-phenoxy-6-methoxybenzonitrile N-oxides with var-
ious substituents were examined, as shown in Table 1.
Initially, we investigated the effects of the substituted
position of the methyl group (entries 1ꢀ3). Interestingly,
4b resulted in the corresponding cycloadduct 5b in 81%
Table 1. Intramolecular Cycloaddition of 2-Phenoxynitrile N-Oxides 4aꢀe
entrya
3
R1
R2
R3
Me
4
yieldb/%
time/h
5
yieldc/%
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
H
4a
4b
4c
4d
4e
4f
91
3
5a
5b
5c
5d
5e
5f
71
H
Me
H
H
92
3
81
Me
H
H
quant
92
3
trace
52
H
H
4.5
3
H
H
OMe
CO2Et
91
93
d
H
H
94
3 d
ꢀ
a Reaction was carried out by using 3, NCS (1.5 equiv), and Et3N (1.5 equiv) in CHCl3. The mixture was stirred at 0 °C for 10 min and then refluxed
for 3ꢀ4.5 h. b NMR yield. c Isolated yield. d Not isolated.
1166
Org. Lett., Vol. 14, No. 4, 2012

desymmetrization of the p-ester benzene moiety; and the
signals from olefinic protons were not observed from 4.6 to
6.6 ppm. Moreover, 13C NMR, IR spectra, and elemental
analysis of 6f were consistent with the structure of 6f.13
As a plausible reaction mechanism, isoxazoline 5f would
probably be formed as an intermediate, following the
redox pathway (Scheme 2). Namely, the reaction of 4f
initiated the [2 þ 3] cycloaddition of nitrile N-oxide to the
benzene ring, as well as other examples, although the
reaction rate was very slow because of the electron defi-
ciency of the ester-substituted benzene ring. With the help
of the ester carbonyl group, the resulting cyclohexadiene
ring was aromatized to obtain 6f.
Scheme 3. Reaction of 3g and Plausible Reaction Pathway of 6g
In conclusion, we investigated the intramolecular 1,3-
dipolar cycloaddition of nitrile N-oxides to the neighbor-
ing benzene ring and clarified the scope and limitation of
the reaction. The reaction simply proceeded by refluxing
the solutions of isolatable nitrile N-oxide for several hours
toaffordthe corresponding isoxazolines inhighyields. The
X-ray single-crystal structure analysis of the resulting
isoxazoline not only revealed that the reaction formed
the cis-adduct as a single isomer but also indicated the
chemical stability of the dearomatized structure. The
present study features the development of not only the
strong acid-free cycloaddition reaction to the non-
strained, monocyclic phenyl ring but also the easy
synthetic method of partially dearomatized dihydro-
benzoisoxazole frameworks, which could provide a
promising synthetic method for benzopyrano-fused
natural products such as flavonoids.
Scheme 2. Reaction of 4f and Plausible Reaction Pathway to 6f
Finally, the reaction of 2-phenoxybenzonitrile N-oxide
4g, the most simplified substrate, was utilized to evaluate
the effect of the methoxy group at the C6 position on the
cycloaddition reaction (Scheme 3). The reaction of hydro-
xamoyl chloride 3g with Et3N in CHCl3 was carried out to
generate 2-phenoxybenzonitrile N-oxide 4g in situ, which
could not be isolated because of the lack of the substituent
at the C6 position. After refluxing for 1 h, xanthone oxime
6g was obtained in 76% yield.13,14
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from MEXT,
Japan (No. 22750101) and the Eno Foundation for the
Promotion of Science.
A plausible reason for the formation of a different
skeleton is the absence of steric repulsion from the peri
position of the isoxazoline moiety, providing relatively
small amount of torsion to enable the E1cB reaction of 5g.
Supporting Information Available. Detailed experi-
mental procedures and spectroscopic data for all new
compounds and X-ray crystal data of 5a. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(13) See Supporting Information.
(14) Campbell, N.; McCallum, S. R.; Mackenzie, D. J. J. Chem. Soc.
1957, 1922–1924.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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