New Approach for the Synthesis of Isoxazoline-N-oxides

Article abstract of DOI:10.1021/ol0360602

(Equation Presented) A strategy for the synthesis of isoxazoline-N-oxides (cyclic five-membered nitronates) from primary nitro compounds and olefins is described. The key step of the process involves 1,3-dipolar cycloaddition of corresponding 1-bromosilyl

Full text of DOI:10.1021/ol0360602

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4907-4909
New Approach for the Synthesis of
Isoxazoline-N-oxides
Roman A. Kunetsky, Alexander D. Dilman,* Sema L. Ioffe,* Marina I. Struchkova,
Yury A. Strelenko, and Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry,
119991 Moscow, Leninsky prosp. 47, Russian Federation
dilman@ioc.ac.ru; iof@ioc.ac.ru
Received October 21, 2003
ABSTRACT
A strategy for the synthesis of isoxazoline-N-oxides (cyclic five-membered nitronates) from primary nitro compounds and olefins is described.
The key step of the process involves 1,3-dipolar cycloaddition of corresponding 1-bromosilyl nitronates with alkenes.
In recent years cyclic six-membered alkyl nitronates 1
(oxazine-N-oxides) have been extensively investigated.1 This
is primarily associated with their employment as intermedi-
ates in natural product synthesis.1a At the same time, five-
membered nitronates 2 (isoxazoline-N-oxides), though dis-
covered much earlier than six-membered analogues, are
seldom used.2 The conventional strategy for the preparation
of cyclic five- and six-membered nitronates implies intramo-
lecular O-alkylation of properly functionalized aliphatic nitro
compounds (Scheme 1, eq a).3 However, no general method
for the synthesis of such starting nitro compounds is
available, and each particular substrate requires special
approach.
A [4 + 2] cycloaddition between conjugate nitro alkenes
and olefins represents a more advanced and efficient way to
access oxazine-N-oxides 1 (Scheme 1, eq b).1
Scheme 1. Synthesis of Cyclic Nitronates
(1) (a) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137. (b)
Seebach, D.; Lyapkalo, I. M.; Dahinden, R. HelV. Chim. Acta 1999, 82,
1829.
(2) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001; pp 267-274.
(3) (a) Kohler, E. P.; Barrett, G. R. J. Am. Chem. Soc. 1924, 46, 2105.
(b) Tartakovsky, V. A.; Gribov, B. G.; Savostianova, I. A.; Novikov, S. S.
Bull. Acad. Sci. USSR, DiV. Chem. Sci. (Engl. Transl.) 1965, 14, 1602. (c)
Clagett, M.; Gooch, A.; Graham, P.; Holy, N.; Mains, B.; Strunk, J. J. Org.
Chem. 1976, 41, 4033. (d) Kaji, E.; Zen, S. Chem. Pharm. Bull. 1980, 28,
479. (e) Arai, N.; Narasaka, K. Bull. Chem. Soc. Jpn. 1997, 70, 2525. (f)
Scardovi, N.; Casalini, A.; Peri, F.; Righi, P. Org. Lett. 2002, 4, 965. (g)
Kanemasa, S.; Yoshimiya, T.; Wada, E. Tetrahedron Lett. 1998, 39, 8869.
(h) Rosini, G.; Marotta, E.; Righi, P.; Seerden, J.-P. J. Org. Chem. 1991,
56, 6258. (i) Marotta, E.; Baravelli, M.; Maini, L.; Righi, P.; Rosini, G. J.
Org. Chem. 1998, 63, 8235. (j) Rosini, G.; Galarini, R.; Marotta, E.; Righi,
P. J. Org. Chem. 1990, 55, 781. (k) Galli, C.; Marotta, E.; Righi, P.; Rosini,
G. J. Org. Chem. 1995, 60, 6624. (l) Gil, M. V.; Roman, E.; Serrano, J. A.
Tetrahedron Lett. 2000, 41, 3221.
Similarly, isoxazoline-N-oxides 2 could be retrosyntheti-
cally disconnected by means of 1,3-dipolar cycloaddition.
The forward reaction would require nitrocarbenes as 1,3-
dipoles (Scheme 1, eq c).
Along these lines, 40 years ago several isoxazoline-N-
oxides were obtained (Scheme 2).4 However, mechanistic
(4) Chlenov, I. E.; Kashutina, M. V.; Ioffe, S. L.; Novikov, S. S.;
Tartakovsky, V. A. Bull. Acad. Sci. USSR, DiV. Chem. Sci. (Engl. Transl.)
1969, 18, 1948.
10.1021/ol0360602 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2003

nitrocarbenes.8 Under the reaction conditions the silyl
nitronates 6 are initially produced and undergo 1,3-dipolar
cycloaddition with the alkene to form N-silyloxyisoxazo-
lidines 7.9,10 Rapid elimination of tert-butyldimethylbromosi-
lane from 7 finally affords nitronates 2.
Scheme 2. Formation of 3-Nitroisoxazoline-N-oxides
The cycloaddition of silyl nitronates 6 to alkenes is the
rate-determining step of the process. Thus, monitoring the
reaction between 1-bromonitroethane and methyl acrylate,
the intermediate isoxasolidine 7 (R1 ) Me, R2 ) CO2Me,
R3 ) H) was not detected at any time.
The main results of the synthesis of isoxazoline-N-oxides
are collected in Table 1.
studies demonstrated that reaction proceeded not via dini-
trocarbene but through the intermediacy of silyl nitronate
and isoxazolidines 3, which underwent elimination of silyl
nitrite.5
Table 1. Synthesis of Isoxazoline-N-oxidesa
entry
4
R1
5
R2
R3
2
time, days yieldb 2, %
Because of the low yields of the products, the approach
shown in Scheme 2 does not have preparative value, and no
other reports on construction of isoxazoline-N-oxides by
means of nitrocarbenes (or their equivalents) have been
published.6
Herein we present a new convenient method for the
synthesis of nitronates 2 from primary aliphatic nitro
compounds (Scheme 3). The starting nitro compounds are
1c
2
4a Me 5a COOMe
4a Me 5b COOMe
4a Me 5c COMe
4a Me 5d Ph
4a Me 5e 2-Py
4a Me 5f OEt
H
2a
4
8
4
7
3
14
8
7
3
31
8
67
78
77d
73
91
78
77
67
81
57
62
79
40
56
17
Me 2b
3c
H
H
H
H
2c
2d
2e
2f
4
5
6
7
8
9
10
11
12
13
14
4b Et 5b COOMe
4b Et 5d Ph
Me 2g
H
H
H
2h
2i
2j
4b Et 5e 2-Py
4c Ph 5a COOMe
4d Bn 5b COOMe
4d Bn 5e 2-Py
4d Bn 5g Me(CH2)4
4d Bn 5h SiEt3
Me 2k
Scheme 3. Synthesis of Isoxazoline-N-oxides
H
H
H
H
2l
3
2m
2n
2o
30
14
3
15c 4e
H
5d Ph
a All reactions were carried out in CH2Cl2 with reagent ratio 4:TBSCl:
NEt3 ) 1:1.1:1.1. The ratio 4:5 ) 1:5 unless mentioned otherwise. b Isolated
yield unless mentioned otherwise. c The ratio 4:5 ) 1:1.05. d The yield was
determined by 1H NMR spectrum with internal standard (trans-stilbene)
because 2c partially decomposes upon isolation.
A wide variety of 3,5-substituted cyclic nitronates 2 can
be readily obtained. Starting bromonitro compounds 4 may
contain alkyl, benzyl, or phenyl groups. Terminal alkenes
with either donor or acceptor substituents, as well as with
alkyl and phenyl groups, are suitable substrates for the
reaction. The successful utilization of ethyl vinyl ether is of
special interest, because the cycloaddition of electron-rich
olefins is not typical for silyl nitronates.11 Even an example
first brominated according to literature procedures.7 Treat-
ment of 1-bromonitroalkanes 4 in dichloromethane with tert-
butyldimethylchlorosilane and triethylamine followed by
addition of alkene 5 gives rise to the desired products 2.
Apparently, the formation of nitronates 2 from 4 occurs
through silyl nitronates 6 rather than through corresponding
(8) Attempts to generate and trap nitrocarbene from 4a by deprotonation
and bromide abstraction with silver salts failed.
(9) Silyl nitronates 6 can be isolated and characterized as air-sensitive
species (see Supporting Information for details). Probably because of the
hydrolytic sensitivity of 6 it is better to use tert-butyldimethylsilyl rather
than trimethylsilyl derivatives. In contrast to other types of silyl nitronates,
1-bromosilyl nitronates have not been studied. Only silylation of bromoni-
tromethane was briefly mentioned; see: Kashutina, M. V. Ph.D. Dissertation,
Zelinsky Institute of organic chemistry, Moscow, 1974.
(10) 1,3-Dipolar cycloaddition with alkenes is the most typical reaction
of silylnitronates. See: (a) Ioffe, S. L.; Kashutina, M. V.; Shitkin, V. M.;
Jankelevich, A. Z.; Levin, A. A.; Tartakovsky, V. A. Bull. Acad. Sci. USSR,
DiV. Chem. Sci. (Engl. Transl.) 1972, 21, 1292. (b) Torssell, K. B. G. Nitrile
Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH: Weinheim,
1988.
(5) Ioffe, S. L.; Makarenkova, L. M.; Kashutina, M. V.; Tartakovsky,
V. A.; Rozhdestvenskaya, N. N.; Kovalenko, L. I.; Isagulianz, G. V. J.
Org. Chem. USSR (Engl. Transl.) 1973, 9, 931.
(6) Recently Charette demonstrated that some equivalents of nitrocarbenes
react with alkenes upon catalysis by transition metals, affording not
isoxazoline-N-oxides but nitrocylopropanes. The rearrangement of nitro-
cylopropanes into isoxazoline-N-oxides promoted by Lewis acids was
occasionaly observed. See: (a) Charette, A. B.; Wurz, R. P.; Ollevier, T.
HelV. Chim. Acta 2002, 85, 4468. (b) Wurz, R. P.; Charette, A. B. Org.
Lett. 2003, 5, 2327.
(7) (a) Erickson, A. S.; Kornblum, N. J. Org. Chem. 1977, 42, 3764. (b)
Fishwick, B. R.; Rowles, D. K.; Stirling, C. J. M. J. Chem. Soc., Perkin
Trans. 1 1986, 1171.
(11) Only intramolecular cycloaddition of silyl nitronate with a vinyl
ether fragment was reported. See: Hassner, A.; Friedman, O.; Dehaen, W.
Liebigs Ann./Recueil 1997, 587.
4908
Org. Lett., Vol. 5, No. 25, 2003

of selective trapping of another intermediate on ethyl vinyl
ether in the presence of silyl nitronate was described.12
Surprisingly, internal alkenes such as dimethyl maleate,
trans-stilbene, indene, and norbornene do not react with silyl
nitronates 6, presumably owing to steric reasons.
Scheme 4. Double Cycloaddition Process
For complete conversion of silyl nitronates 6 to the
products reaction time from several days to 1 month at room
temperature is required. At elevated temperature the yield
of isoxazoline-N-oxides decreases, which can be associated
with their thermal instability.
1,3-Dipoles isoxazoline-N-oxides could also cycloadd to
the alkenes. However, the diminished reactivity of five-
membered nitronates in 1,3-dipolar cycloaddition was noted
in earlier reports.13 As a result, even when active dipolaro-
philes are employed, the contribution of double addition does
not exceed 10%. Nevertheless, using 50 equiv of methyl
acrylate in reaction with 4a during 5 days allows isolation
of bicyclic adduct 8a (Scheme 4).
In summary, we developed a convenient method for the
construction of 3,5-substituted isoxazoline-N-oxides 2 from
simple precursors, primary nitro compounds and terminal
alkenes. We believe that 1,3-cycloaddition strategy will
broaden the scope of available nitronates. Our further efforts
will involve elaboration of this new methodology, as well
as investigation of transformations of obtained isoxazoline-
N-oxides.
Acknowledgment. This work was performed at the
Scientific Educational Center for young chemists and sup-
ported by the Russian Foundation for Basic Research (grants
03-03-33350, 03-03-04001), Federal Target Program Integra-
tion (project B-0062), and Scientific School (1442.2003.3).
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(12) Ioffe, S. L.; Lyapkalo, I. M.; Tishkov, A. A.; Strelenko, Yu. A.;
Tartakovsky, V. A. Tetrahedron 1997, 53, 13085.
(13) Chlenov, I. E.; Khudak, V. I.; Tartakovsky, V. A.; Novikov, S. S.
Bull. Acad. Sci. USSR, DiV. Chem. Sci. (Engl. Transl.) 1969, 18, 2113.
OL0360602
Org. Lett., Vol. 5, No. 25, 2003
4909