Catalytic asymmetric syntheses of isoxazoline-N-oxides under phase-transfer conditions

Article abstract of DOI:10.1039/c0cc05786j

Catalytic asymmetric syntheses of various isoxazoline-N-oxides have been accomplished by asymmetric phase-transfer conjugate addition of bromomalonate to nitroolefins and subsequent ring-closing O-alkylation.

Full text of DOI:10.1039/c0cc05786j

Chemical Communications
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Volume 47 | Number 15 | 21 April 2011 | Pages 4305–4556
ISSN 1359-7345
COMMUNICATION
Keiji Maruoka et al.
Catalytic asymmetric syntheses
of isoxazoline-N-oxides under
phase-transfer conditions
1359-7345(2011)47:15;1-G

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Cite this: Chem. Commun., 2011, 47, 4358–4360
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COMMUNICATION
Catalytic asymmetric syntheses of isoxazoline-N-oxides under
phase-transfer conditionsw
Taichi Kano, Akihiro Yamamoto, Sunhwa Song and Keiji Maruoka*
Received 25th December 2010, Accepted 13th January 2011
DOI: 10.1039/c0cc05786j
Catalytic asymmetric syntheses of various isoxazoline-N-oxides
have been accomplished by asymmetric phase-transfer conjugate
addition of bromomalonate to nitroolefins and subsequent ring-
closing O-alkylation.
Table 1 Asymmetric synthesis of cyclic nitronate with 2a and diethyl
a
bromomalonate catalyzed by chiral PTC 1
Isoxazoline-N-oxides serve as versatile building blocks for
1
the preparation of complex molecules, biologically active
2
compounds and natural products. While a number of synthetic
b
Yield (%)
c
ee (%)
3
methods have been developed to date, there is still a need
Entry
PTC
Config.
d
1
to expand synthetic approaches for their preparation. Chiral
(R,R)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1d
95
87
92
73
58
46
56
30
S
2
3
4
R
R
R
isoxazoline-N-oxides are known to be synthesized by using
4
optically pure starting material or stoichiometric amounts of
5
a chiral reagent; however, general methods for their prepara-
a
The reaction of 2a (1 equiv.) with diethyl bromomalonate (1 equiv.)
was carried out in THF in the presence of chiral PTC 1 (0.01 equiv.)
6
tion based on the catalytic asymmetric reaction are quite rare.
In this context, we have been interested in the development of
catalytic asymmetric syntheses of chiral isoxazoline-N-oxides
through asymmetric phase-transfer conjugate addition and
b
c
2 3
and K CO (2 equiv.) at 0 1C for 24 h. Isolated yield. Determined
by HPLC analysis using chiral column (Chiralpak AD-H, Daicel
d
Chemical Industries, Ltd.). The reaction was performed for 7.5 h.
7
ring-closing O-alkylation. Here we wish to report efficient
asymmetric syntheses of isoxazoline-N-oxides based on the
asymmetric conjugate addition under phase-transfer conditions.
the desired isoxazoline-N-oxide 3a was obtained in excellent
yield with moderate enantioselectivity (entry 1).
Having identified a suitable catalyst, the reaction conditions
were then optimized, and the selected results are summarized in
Table 2. When reactions were conducted in various solvents,
mesitylene gave the highest enantioselectivity (entry 4). In
an attempt to further improve enantioselectivity, lowering
temperature was effective, although a longer reaction time was
2 3
required (entry 5). The use of 70% aqueous Cs CO as a
stronger base successfully increased the reaction rate without
loss of enantioselectivity (entry 6). When the reaction was
performed at À35 1C for 12 h, the desired product was obtained
in excellent yield with good enantioselectivity (entry 8).
With the optimal reaction conditions, catalytic asymmetric
syntheses of isoxazoline-N-oxides with several other nitro-
olefins 2 were examined (Table 3). The reaction of nitroolefins 2
We first examined the synthesis of isoxazoline-N-oxide 3a
by the reaction between diethyl bromomalonate and nitroole-
8
fin 2a using 1 mol% of chiral PTC 1 as catalyst and K
2
2
CO
3
in
having a primary alkyl group (R = Et or Bu) at the
THF (Table 1). Among the catalysts used, (R,R)-1a was found
a-position gave the corresponding isoxazoline-N-oxides with
good enantioselectivity (entries 2 and 3). On the other hand,
2
the reaction of sterically demanding nitroolefins 2 (R = i-Pr)
to be the most efficient catalyst for the present reaction, and
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81 75-753-4041;
Tel: +81 75-753-4041
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc05786j
proceeded slowly to give the product in lower yield and
enantioselectivity (entry 4). We then investigated the effects
of the b-substituent on nitroolefins 2. The reaction of 2 having
either electron-deficient or electron-rich phenyl group gave the
corresponding isoxazolines in good yield and enantioselectivity
4
358 Chem. Commun., 2011, 47, 4358–4360
This journal is c The Royal Society of Chemistry 2011

Table 2 Asymmetric synthesis of cyclic nitronate with 2a and diethyl
bromomalonate catalyzed by (R,R)-1a
a
Fig. 1 Plausible transition state model.
Conditions
(1C, h)
b
Yield (%) ee (%)
c
Entry Base
Solvent
THF
1
2
3
4
5
6
7
8
9
K
2
CO
3
0, 7.5
0, 8.5
0, 7.5
95
84
94
83
80
70
97
95
29
58
63
64
70
77
79
81
83
77
50% K
50% K
50% K
50% K
70% Cs
70% Cs
70% Cs
70% Cs
2
2
2
2
CO
CO
CO
CO
3
3
3
3
2
aq. Et O
aq. Toluene
aq. Mesitylene 0, 7.5
aq. Mesitylene À20, 24
aq. Mesitylene À20, 2
aq. Mesitylene À30, 8
aq. Mesitylene À35, 12
aq. Mesitylene À40, 12
2
2
2
2
CO
CO
CO
CO
3
3
3
3
a
The reaction of 2a (1 equiv.) with diethyl bromomalonate (1 equiv.)
was carried out in a solvent in the presence of (R,R)-1a (0.01 equiv.)
b
c
and a base. Isolated yield. Determined by HPLC analysis using
chiral column (Chiralpak AD-H, Daicel Chemical Industries, Ltd.).
Scheme 1 Transformation of isoxazoline-N-oxide 3b.
2
3b was treated with Pd/C in MeOH under a H atmosphere,
oxime 4 was obtained in good yield with complete retention of
stereochemistry. Treatment of 4 with methanesulfonyl chloride
and triethylamine in dichloromethane gave isoxazoline 5 in
(
entries 6–8). The use of 2 with an alkyl substituent resulted in
decreased enantioselectivity (entry 9).
The absolute stereochemistry of the obtained isoxazoline-
N-oxide (Table 3, entry 6) was confirmed to be S by X-ray
9
crystallographic analysis. Based on the observed stereochem-
10
excellent yield without loss of optical purity. Selective reduction
of one ester group in 5 with lithium tri(tert-butoxy)aluminium
1
hydride gave mono-alcohol 6 exclusively.
1
istry, a plausible transition state model can be proposed as
shown in Fig. 1. The chiral ammonium enolate, which is
generated from diethyl bromomalonate and chiral phase-transfer
catalyst (R,R)-1a under basic conditions, approaches the Si face
of nitroolefins.
In summary, we have developed efficient asymmetric syn-
theses of isoxazolidine-N-oxides by the asymmetric phase-transfer
conjugate addition and the subsequent ring-closing O-alkylation.
Further investigations to expand the substrate scope of this
reaction are currently underway.
The obtained isoxazoline-N-oxide was a useful intermediate
in organic synthesis and readily converted to the corresponding
oxime and isoxazoline (Scheme 1). When isoxazoline-N-oxide
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. We thank Mr Masahiko Bando
for X-ray crystallographic expertise, and Dr Masakazu
Nagasawa and Ms Kayoko Yamamoto for mass-spectrometric
analysis.
Table 3 Asymmetric synthesis of cyclic nitronate with 2 with diethyl
bromomalonate catalyzed by (R,R)-1a
a
Notes and references
1
(a) P. Righi, E. Marotta, A. Landuzzi and G. Rosini, J. Am. Chem.
Soc., 1996, 118, 9446; (b) P. Righi, E. Marotta and G. Rosini,
Chem.–Eur. J., 1998, 4, 2501; (c) K. Harada, K. Sasaki,
K. Kumazawa, S. Hirotani and E. Kaji, Heterocycles, 2001, 54,
1
R
2
R
b
Yield (%)
c,d
ee (%)
Entry
1
033; (d) T. Sommermann, B. G. Kim, E.-M. Peters and T. Linker,
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
4-Br-C
4-NO -C
2
Me
Et
Bu
i-Pr
Ph
Et
Et
Et
Et
95
92
56
63
97
84
90
84
63
83 (99)
86
86
Chem. Commun., 2004, 2624; (e) M. Nishiuchi, H. Sato,
N. Umemoto and S. Murakami, Chem. Lett., 2008, 37, 146;
(f) V. O. Smirnov, A. S. Sidorenkov, Y. A. Khomutova,
S. L. Ioffe and V. A. Tartakovsky, Eur. J. Org. Chem., 2009, 3066.
e
77
81 (99)
85 (97)
87
87
77
2 (a) B. M. Trost, L. Li and S. D. Guile, J. Am. Chem. Soc., 1992,
114, 8745; (b) B. M. Trost, L. S. Chupak and T. Lubbers, J. Am.
Chem. Soc., 1998, 120, 1732; see also ref. 5b.
e
6
H
4
¨
6
H
H
4
f
4-MeO-C
Bu
6
4
3 For selected example, see: (a) M. Clagett, A. Gooch, P. Graham,
N. Holy, B. Mains and J. Strunk, J. Org. Chem., 1976, 41, 4033;
(
1
1
b) T. Sakakibara and R. Sudoh, J. Chem. Soc., Chem. Commun.,
977, 7; (c) T. Shimizu, Y. Hayashi and K. Teramura, J. Org. Chem.,
983, 48, 3053; (d) G. Kumaran and G. H. KulKarni, Synthesis,
a
The reaction of 2 (1 equiv.) with diethyl bromomalonate (1 equiv.)
was carried out in mesitylene in the presence of (R,R)-1a (0.01 equiv.)
b
c
and 70% Cs
mined by HPLC analysis using chiral column (Chiralpak AD-H or
d
Chiralcel OD-H, Daicel Chemical Industries, Ltd.). Enantiomeric
2
CO
3
aq. at À35 1C for 12 h. Isolated yield. Deter-
1995, 1545; (e) C. Galli, E. Marotta, P. Righi and G. Rosini, J. Org.
Chem., 1995, 60, 6624; (f) S. Kanemasa, T. Yoshimiya and E. Wada,
Tetrahedron Lett., 1998, 39, 8869; (g) G. J. T. Kuster, R. H.
J. Steeghs and H. W. Scheeren, Eur. J. Org. Chem., 2001, 553;
(h) A. Chatterjee, S. C. Jha and N. N. Joshi, Tetrahedron Lett., 2002,
excesses in parentheses were obtained after a single recrystallization
e
from cold ethanol. The reaction was performed for 24 h. The
reaction was performed for 36 h.
f
43, 5287; (i) R. A. Kunetsky, A. D. Dilman, S. L. Loffe,
M. I. Struchkova, Y. A. Strelenko and V. A. Tartakovsky,
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4358–4360 4359

Org. Lett., 2003, 5, 4907; (j) M. A. Marsini, Y. Huang, R. W. Van De
Water and T. R. R. Pettus, Org. Lett., 2007, 9, 3229; (k) D. Duan,
X. Sun, W. Liao, J. L. Petersen and X. Shi, Org. Lett., 2008, 10, 4113;
Y. Tang, Tetrahedron, 2008, 64, 5583; (d) C. Zhong, L. N. S.
Gautam, J. L. Petersen, N. G. Akhmedov and X. Shi, Chem.–Eur.
J., 2010, 16, 8605.
(l) A. V. Chemagin, N. V. Yashin, Y. K. Grishin, T. S. Kuznetsova
and N. S. Zefirov, Synthesis, 2010, 259.
6 H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V. Marcos and
K. A. Jorgensen, Angew. Chem., Int. Ed., 2009, 48, 6844; see also
ref. 2a.
7 J. C. Le Menn, J. Sarrazin and A. Tallec, Bull. Soc. Chim. Fr.,
1991, 128, 562.
8 (a) T. Ooi, M. Takeuchi, M. Kameda and K. Maruoka, J. Am.
Chem. Soc., 2000, 122, 5228; (b) T. Ooi, Y. Uematsu and
K. Maruoka, J. Org. Chem., 2003, 68, 4576.
4
5
(a) E. Marotta, M. Baravelli, L. Maini, P. Righi and G. Rosini,
J. Org. Chem., 1998, 63, 8235; (b) E. Marotta, L. A. Micheloni,
N. Scardovi and P. Righi, Org. Lett., 2001, 3, 727; (c) P. Righi,
N. Scardovi, E. Marotta, P. ten Holte and B. Zwanenburg, Org.
Lett., 2002, 4, 497; (d) N. Scardovi, A. Casalini, F. Peri and
P. Righi, Org. Lett., 2002, 4, 965; (e) P. M. Khan, R. Wu and
K. S. Bisht, Tetrahedron, 2007, 63, 1116.
9 See ESIw for details.
(a) M. C. Maestro, M. C. Barquilla and M. R. Martı
´
n,
10 R. J. Cvetovich, J. Y. L. Chung, M. H. Kress, J. S. Amato,
L. Matty, M. D. Weingarten, F. Tsay, Z. Li and G. Zhou,
J. Org. Chem., 2005, 70, 8560.
Tetrahedron: Asymmetry, 1999, 10, 3593; (b) C.-Y. Zhu,
X.-M. Deng, X.-L. Sun, J.-C. Zheng and Y. Tang, Chem. Commun.,
2008, 738; (c) C.-Y. Zhu, X.-M. Sun, X.-M. Deng, J.-C. Zheng and
11 T. A. Ayers, Tetrahedron Lett., 1999, 40, 5467.
4
360 Chem. Commun., 2011, 47, 4358–4360
This journal is c The Royal Society of Chemistry 2011