Cycloaddition/ring opening sequence of α-hydroxy cyclic nitronates as a synthetic equivalent of functionalized aliphatic nitrile oxides

Article abstract of DOI:10.1246/cl.2008.144

α-Hydroxy cyclic nitronates act as synthetic equivalents of nitrile oxides. Cycloaddition of 3-substituted 4-hydroxy-2-isoxazoline N-oxides or 4-hydroxy-3-hydroxymethyl-2-isoxazoline N-oxides with electron-deficient alkenes produce bicyclic isoxazolidines

Full text of DOI:10.1246/cl.2008.144

1
44
Chemistry Letters Vol.37, No.2 (2008)
Cycloaddition/Ring Opening Sequence of ꢀ-Hydroxy Cyclic Nitronates
as a Synthetic Equivalent of Functionalized Aliphatic Nitrile Oxides
Ã
Masaki Nishiuchi, Hiroyasu Sato, and Hiroyuki Ohmura
Department of Life System, Institute of Technology and Science, The University of Tokushima,
Minamijosanjima, Tokushima 770-8506
(Received October 15, 2007; CL-071133; E-mail: nishiuch@chem.tokushima-u.ac.jp)
ꢀ
-Hydroxy cyclic nitronates act as synthetic equivalents of
R3
nitrile oxides. Cycloaddition of 3-substituted 4-hydroxy-2-iso-
xazoline N-oxides or 4-hydroxy-3-hydroxymethyl-2-isoxazoline
N-oxides with electron-deficient alkenes produce bicyclic isoxa-
zolidines, which undergo ring opening of one of the ring-fused
isoxazolidines on acid treatment to give 2-isoxazoline deriva-
tives by elimination of hydroxyacetaldehyde or carbon–carbon
bond cleavage.
HO
CHO
R1
O N O
R1
R2
O
N
O
R3
R2
N O
R3
R2
2
R1
HO
HO
4
1
3
a R1 = Me
3a,4a R1 = Me, R2 = H, R3 = CO Me
1
1
2
1
3b,4b R1 = Me, R2 = H, R3 = CN
b R = CO Et
2
1
1
= Me, R2 = Me, R = CO Me
d,4d R = CO Et, R = H, R3 = CO Me
3
3
3
c,4c
R
2
2
2
2
Cycloaddition reactions of nitrile oxides with alkenes
produce 2-isoxazolines as cycloadducts in which a variety of
synthetically important functionalities are masked such as ꢁ-
hydroxy ketones, 1,3-diols, ꢂ-amino alcohols, and others. Al-
though 2-isoxazolines have been often utilized in synthetic
works of complex molecules, synthesis of 3-substituted 2-isoxa-
zolines still remains difficult owing to the limited availability of
Scheme 1.
Table 1. Cycloadditions of hydroxy nitronate 1 and alkenea
b
d.s.c
Entry
1
2
Time/day
3
Yield /%
1
2
3
1a 2a
1a 2b
1a 2c
1b 2a
2
2
4
4
3a
3b
3c
3d
quant
quant
97
74:21:5
69:23:8
29:66:2:3
74:19:7
1
functionalized or aliphatic nitrile oxides as starting materials.
On the other hand, it is known that isoxazolidines derived
from nitronate 1,3-dipoles with one oxidation level lower than
nitrile oxides and alkenes can be effectively converted into
4
96
a
All reactions were run by using 10 equiv. of alkenes 2 with-
out solvent at room temperature. Isolated yields of products
2
b
2-isoxazolines through acid treatment. However, there are few
examples reported for the use of nitronates having two substitu-
c
purified by column chlomatography on silica gel. Based on
H NMR of the crude product.
1
2
ents at the nitronate sp -carbon atom as synthetic equivalents of
nitrile oxides.3
We have found that 3-substituted 4-hydroxyisoxazoline
N-oxides as cyclic nitronates, readily available from the nitro
bicyclic isoxazolidine 3b or 3c, respectively, in high yield
(Entries 2 and 3). Cyclic nitronate 1b having an electron-with-
drawing esteric substituent at 3-position also reacted with 2a
without solvent to give the bicyclic isoxazolidine 3d in a high
yield after 4 days at room temperature (Entry 4). Although much
less reactive, styrene (2d) could be used as dipolarophile to give
the corresponding cycloadduct in 22% yield together with the
recovered nitronate 1a in 78% yield.
Heating 3a under reflux in chloroform caused a slow ring
opening fragmentation reaction to give 2-isoxazoline 4a albeit
in the disappointingly low yield of 10% after two days: it
took a prolonged reaction time of fifteen days for the complete
transformation of this reaction. Since this fragmentation reaction
formally includes the elimination of hydroxyacetaldehyde from
3a, we have examined a variety of reaction conditions based on
the possible reaction mechanism shown in Scheme 2. It was our
delight to find that treatment of bicyclic isoxazolidine 3a with
silica gel was much more effective to give 4a in a quantitative
yield after two days at room temperature (Table 2). No fragmen-
tation reaction took place under the silica-gel-promoted reaction
conditions either when the 4-hydroxy moiety of 3a is protected
with an acetyl group or when 3a is treated with triethylamine as
base (five days at room temperature).
4
aldol reactions with chloroacetaldehyde, play as effective syn-
5
thetic equivalents of nitrile oxides. In this communication, we
will report the reactions of 3-substituted 4-hydroxy-2-isoxazo-
line N-oxides with a variety of electron-deficient alkenes; the
resulting perhydroisoxazolo[2,3-b]isoxazoles as cycloadducts
are then chemoselectively transformed under the acidic condi-
tions to give 2-isoxazolines through elimination of hydroxylace-
taldehyde.
Reaction of 4-hydroxy-3-methyl-2-isoxazoline N-oxide (1a)
with a large excess amount of methyl acrylate (2a), 10 equiv. to
1a, without solvent at room temperature gave a 74:21:5 diaster-
eomeric mixture of methyl 4-hydroxy-3a-methylperhydroisoxa-
zolo[2,3-b]isoxazole-2-carboxylate (3a) in a quantitative yield
(
Scheme 1 and Table 1, Entry 1). Two major diastereomers were
isolated in pure forms through silica gel column chromatogra-
phy. Cyclic nitronate 1a was readily synthesized by the reaction
of nitroethane with chloroacetaldehyde under the amine cataly-
4
sis according to the Rosini’s method. Under reflux in chloro-
form, the reaction was complete in one day to give 3a in 97%
yield.
A similar reaction of nitronate 1a with acrylonitrile (2b) or
methyl methacrylate (2c) as electron deficient alkene under the
reaction conditions without solvent produced the corresponding
These results show that the following factors are essential
for the effective fragmentation reaction of 3a-substituted 4-hy-
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.2 (2008)
145
H
BF3
O
7
N
O
O
O
N
1
O
N
6
O
N
O
N
O
O
a)
b)
a) or b)
4
OY
3a
3a
O Me
CO Me
Me
CO Me
CO Me
2
2
2
CO Me
2
XO
H
O
4
a
XO
OY
1
c,d
3e,f
O
H
a) CHCl , reflux, 15 days, quant.
Me
3
1
1
c, 3e; X = Ac, Y = H
O
b) silica gel, CHCl , rt, 2days, quant.
3
c)
d, 3f; X = TBS, Y = THP
Scheme 2.
Table 2. Conversions of 3 to 4
Entry Substrate Methoda Time/h Product Yield /%
OH
O
N
N
O
N
O
b
CO Me HO
CO Me
CO Me
2
2
2
OTBS
OAc
OTBS 4f
4g
4e
1
2
3
4
3a
3b
3c
3d
A
B
A
B
48
1
48
1
4a
4b
4c
4d
quant
88
quant
94
Scheme 3. a) 2a (5 equiv.), neat, rt, 3e (3 days, 80% yield), 3f
4 days, quant.); b) BF3/Et2O (0.1 equiv.), CH2Cl2, rt, 1 h, 81%;
c) silica gel, MeOH, rt, 15 days, 83% (4f:4g = 87:13).
(
aMethod A: 3 (100 mg) was treated with 1 g of silica gel in
chloroform at room temperature. Method B: 3 was treated
with 0.1 equiv. of boron trifluoride diethyl etherate in chloro-
form at room temperature. Isolated yields of products puri-
fied by column chlomatography on silica gel.
In summary, we have demonstrated a new synthetic method
of isoxazolines through a sequence of the following three-step
reaction. The first step is nitro aldol reaction with chloroacetal-
dehyde giving 3-substituted cyclic nitronates bearing a 4-hy-
droxy group. The second step is cycloadditions of those cyclic
nitronates with electron-withdrawing alkenes to give ring-fused
isoxazolidines. And the final step is fragmentation reactions of
the resulting ring-fused isoxazolidines through the oxygen–
nitrogen or carbon–carbon bond cleavage. Mode of ring opening
of the fused isoxazolidine rings can be selectively performed by
the proper choice of protecting groups on the hydroxy moieties.
b
droxyperhydroisoxazolo[2,3-b]isoxazoles: 1) The 4-hydroxy
group should be free, 2) the oxygen(6)–nitrogen(7) bond should
be activated by an acid catalyst, and totally 3) the acid activation
is more effective than ionization of the hydroxy group by base.
Actually, boron trifluoride etherate as a stronge Lewis acid
worked much more effectively to accelerate the fragmentation
reaction of 3a. This is a striking contrast to the base-catalyzed
transformation of 3-hydroxy-3a-nitroperhydroisoxazolo[2,3-b]-
isoxazole to the corresponding 2-isoxazolines, reported by
References and Notes
1
2
S. Kanemasa, O. Tuge, Heterocycles 1990, 30, 719.
a) J. J. Tufariello, in 1,3-Dipolar Cycloaddition Chemistry,
ed. by A. Padwa, Wiley-Interscience, New York, 1984,
Vol. 2, Chap. 9, pp. 83–168. b) S. Kanemasa, S. Kaga, E.
Wada, Tetrahedron Lett. 1998, 39, 8865. c) S. Kanemasa,
T. Yoshimiya, E. Wada, Tetrahedron Lett. 1998, 39, 8869.
d) S. E. Denmark, A. Thorarensen, Chem. Rev. 1996, 96, 137.
a) O. A. Ivanova, E. B. Averina, Y. K. Grishin, T. S.
Kuznetsova, A. A. Korlyukov, M. Y. Antipin, N. S. Zefirov,
Dokl. Chem. 2002, 382, 21. b) V. F. Rudchenko, V. G.
Shtamburg, A. P. Pleshkova, R. G. Kostyanovskii, Izv. Akad.
Nauk SSSR Ser. Khim. 1981, 2549. c) O. A. Ivanova, E. M.
Budynina, E. B. Averina, T. S. Kuznetsova, N. S. Zefirov,
Synthesis 2006, 706. d) V. F. Rudchenko, S. M. Ignatov,
V. S. Nosova, I. I. Chervin, R. G. Kostyanovskii, Izv. Akad.
Nauk SSSR Ser. Khim. 1986, 2272.
3
a
Ivanova and co-workers.
Although the silica-gel-mediated fragmentation method was
also successfully applied to the transformation of 3c leading to
4c (Table 2, Entry 3), the reaction of 3b and 3d was unfortunate-
6
ly slow under the comparable reaction conditions. Use of a
catalytic amount of boron trifluoride etherate in the reactions
of 3b and 3d in chloroform produced 4b and 4d in excellent
yields in 1 h at room temperature (Entries 2 and 4). However,
p-toluenesulfonic acid was a less effective acid catalyst in the
reaction of 3b, leading to the formation of complex mixture of
side products.7
3
When cycloadduct 3e, obtained in the reaction of 4-acetoxy-
-hydroxymethyl-2-isoxazoline N-oxide (1c) with methyl acry-
late, was treated with a catalytic amount (10 mol %) of boron tri-
fluoride etherate at room temperature for 1 h, methyl 3-acetoxy-
methyl-2-isoxazoline-5-carboxylate (4e) was given in 81% yield
3
4
a) G. Rosini, R. Marotta, P. Righi, J. Org. Chem. 1990,
55, 781. b) G. Rosini, E. Marotta, P. Righi, J. P. Seerden,
J. Org. Chem. 1991, 56, 6258. c) P. Righi, E. Marotta, A.
Landuzzi, G. Rosini, J. Am. Chem. Soc. 1996, 118, 9446.
Presented at the 82nd Annual Meeting of the Chemical
Society of Japan, Toyonaka, September 25–28, 2002, Abstr.,
No. 3PA-086.
Treatment of 3b with silica gel: rt, 48 h to give 4b in 4% yield
with the recovery of 96% of 3b; under reflux, 48 h to give 4d
in 38% yield with the recovery of 62% of 4d.
Treatment of 3b with a catalytic amount (0.1 equiv.) of
p-toluenesulfonic acid in chloroform at room temperature
for 1 h provided 36% yield of 4d.
Acetylation of 4f and 4g mixture gave 49:51 and 47:53
diastereomeric mixture respectively in 90% yield.
(
Scheme 3). Production of 4e can be rationalized through acetyl
group migration after ring opening fragmentation of 3e. On the
other hand, methyl perhydroisoxazolo[2,3-b]isoxazole-2-car-
boxylate (3f) having two hydroxy groups protected differently
with t-butyldimethylsilyl (at 4-OH) and tetrahydropranyl groups
5
6
7
8
(
at 3a-CH2OH) was treated with silica gel at room temperature
8
to give a 87:13 mixture of 2-isoxazolines 4f and 4g in 83%
yield, depending upon the relative reactivity of each isoxazoli-
dine rings of 3f. Thus, the carbon–carbon bond cleavage of the
protected hydroxymethyl group at 3a-position of 3f induced
the ring opening of ring-fused isoxazolidine rings at both sides.
The isoxazolidine ring substituted by an electron-withdrawing
ester group was more reactive for the oxygen(1)–nitrogen(7)
bond-cleavage reaction.
Published on the web (Advance View) December 29, 2007; doi:10.1246/cl.2008.144