A novel one-pot synthesis of 3-acetyl- and 3-benzoylisoxazole derivatives using ammonium cerium nitrate (CAN)

Article abstract of DOI:10.1016/S0040-4039(02)01612-X

The reaction of dipolarophiles (several alkenes and alkynes) with ammonium cerium(IV) nitrate ((NH₄)₂Ce(NO₃)₆, CAN(IV)) in acetone under reflux gave 3-acetylisoxazole derivatives. In the case of acetophenone, 3-benzoylisoxazole derivatives were obtained. Moreover, it was found that yields of isoxazole derivatives were improved using ammonium cerium(III) nitrate tetrahydrate ((NH₄)₂Ce(NO₃)₅·4H ₂O, CAN(III))-formic acid.

Full text of DOI:10.1016/S0040-4039(02)01612-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7035–7037
A novel one-pot synthesis of 3-acetyl- and 3-benzoylisoxazole
derivatives using ammonium cerium nitrate (CAN)
a
a
a
b
c
Ken-ichi Itoh, Shigeo Takahashi, Tetsuya Ueki, Takashi Sugiyama, T. Tomoyoshi Takahashi
a,
and C. Akira Horiuchi *
a
Department of Chemistry, Rikkyo (St. Paul’s) University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
b
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
c
Department of Chemistry, The Jikei University School of Medicine, Kokuryo-cho Chofu, Tokyo 182-8570, Japan
Received 1 July 2002; revised 22 July 2002; accepted 26 July 2002
Abstract—The reaction of dipolarophiles (several alkenes and alkynes) with ammonium cerium(IV) nitrate ((NH ) Ce(NO ) ,
4
2
3 6
CAN(IV)) in acetone under reflux gave 3-acetylisoxazole derivatives. In the case of acetophenone, 3-benzoylisoxazole derivatives
were obtained. Moreover, it was found that yields of isoxazole derivatives were improved using ammonium cerium(III) nitrate
tetrahydrate ((NH ) Ce(NO ) ·4H O, CAN(III))–formic acid. © 2002 Elsevier Science Ltd. All rights reserved.
4
2
3 5
2
Isoxazole derivatives have been reported to possess
interesting biological activities and pharmacological
properties such as analgesic, anti-inflammatory and
reported a novel synthesis of 4,5-dihydroisoxazoles
from alkenes using CAN(IV) or CAN(III)–formic
14
acid. However, the yields of products were unsatisfac-
tory because of the formation of nitroalkene and
nitroalcohol from alkene as by-products. So we tried a
novel one-pot synthesis of isoxazole derivatives using
CAN. In this paper, we report that the reaction of
dipolarophiles (alkenes 1–5 and alkynes 6–8) with CAN
in acetone or acetophenone yields the corresponding
isoxazole derivatives.
1
,2
hypoglycemic. In addition, 4,5-dihydroisoxazoles are
recognized as useful intermediates in organic synthesis.
For example, they can be converted into various impor-
3
tant synthetic units such as b-hydroxy ketones, g-
4
5
amino alcohols,
b,g-unsaturated ketones
and
6
b-hydroxy nitriles. Isoxazole derivatives are usually
prepared by one of the following methods: 1,3-dipolar
cycloaddition of dipolarophiles (several alkenes and
alkynes) with nitrile oxides from nitro compounds by
dehydration using aqueous sodium hypochlorite with
The reaction of several alkenes 1–5 with CAN(IV) in
acetone under reflux gave 3-acetyl-4,5-dihydro-
7
triethylamine in methylene chloride, or from oxime
16
isoxazoles (1a–5a). In the case of acetophenone at
compounds by dehydrogenation using sodium acetate
8
0°C, 3-benzoyl-4,5-dihydroisoxazoles (1b–5b) were
8
in acetic anhydride. In particular, the formation of
obtained (Scheme 1). Moreover, a similar reaction
nitrile oxide using hydroxylamine from b-keto esters or
using several alkynes 6–8 afforded the corresponding
a,b-unsaturated ketones is known as a one-pot synthe-
3
8
1
-acetylisoxazole (6a–8a) and 3-benzoylisoxazoles (6b–
b) (Scheme 2). These results are summarized in Table
. As can be seen from Table 1, it was found that this
9,10
sis of isoxazole derivatives.
CAN(IV) has been utilized extensively for a variety of
oxidative transformations. We have investigated the
development of some novel reaction systems using
CAN. In a previous paper we reported a novel a-iodi-
1
1
nation of ketones in acetic acid or alcohol, a new
alkoxyiodination and nitratoiodination of olefins and
12
a,b-unsaturated esters, and a new a,a%-diiodination of
1
3
ketones using iodine–CAN(IV). One of our group
*
Corresponding author. Tel.: +81 3 3985 2397; fax: +81 3 3985 2397;
e-mail: horiuchi@rikkyo.ac.jp
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01612-X

7
036
K. Itoh et al. / Tetrahedron Letters 43 (2002) 7035–7037
Table 2. Reaction of dipolarophiles (alkenes 1–5 and alky-
nes 6–8) with CAN(III)–formic acid in acetone or aceto-
phenone
Entrya Substrate Solvent
Time (h)
Product (%)b
1
2
3
4
5
6
7
8
9
1
1
1
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
10
10
10
10
8
10
8
8
15
10
12
12
5
1a (84)
2a (73)
3a (74)
4a (81)
5a (72)
6a (85)
7a (87)
8a (83)
1b (84)
2b (80)
3b (70)
4b (66)
5b (64)
6b (85)
7b (76)
8b (57)
Scheme 2.
method is a novel one-pot synthesis of 3-acetyl- and
3
-benzoylisoxazole derivatives from dipolarophiles
(
alkenes or alkynes) and acetone or acetophenone using
0
1
2
CAN(IV).
We further attempted to elaborate the reaction condi-
tions to improve the yields of the isoxazole derivatives.
In the case of CAN(III)–formic acid, 3-acetyl- and
13
14
1
1
8
5
8
5
6
3-benzoylisoxazole derivatives were obtained in good
yields. These results are summarized in Table 2. From
these results, it is apparent that this reaction is general
for the synthesis of 3-acetylisoxazole derivatives and
a
Substrate (0.5 mmol), CAN(III) (0.5 mol), formic acid (10.0 mol)
and solvent (3.0 ml) were employed under reflux.
b
Determined by GLC analysis using n-dodecane as an internal
hydrocarbon standard. All products were identified by satisfactory
3-benzoylisoxazole derivatives in good yields.
1
13
spectral data (IR, H, C NMR and MS).
CAN has the ability of nitration for alkenes and aro-
15
matic compounds. Wade and co-workers reported
that a-nitroketones were converted to nitrile oxide by
1
6
acid-catalyst. It is known that nitrile oxides dimerize
to furoxans. If a furoxan is confirmed in this reaction,
it is possible to prove the existence of nitrile oxide as an
intermediate. The formation of the dimer (3,4-diacetyl-
cloaddition with the alkenes or alkynes. From these
viewpoints and results, we suggest the reaction mecha-
nism in Scheme 4.
1
,2,5-oxadiazole 2-oxide (furoxan) (9)) of nitrile oxide
In conclusion, this method is simple and convenient to
obtain 3-acetyl- and 3-benzoylisoxazole derivatives. It is
particularly noteworthy that this reaction affords a new
synthetic method for isoxazole and dihydroisoxazole
derivatives that is more convenient than the methods
used heretofore.
generated from acetone was confirmed (Scheme 3). This
result suggests that acetone is converted into the corre-
sponding nitrile oxide via a process involving a nitra-
tion of acetone by cerium(IV) or cerium(III), and then
undergoes competitive dimerization and 1,3-dipolarcy-
Table 1. Reaction of dipolarophiles (alkenes 1–5 and alkynes 6–8) with CAN(IV) in acetone or acetophenone
Entrya
Substrate
Solvent
Time (h)
Product (%)b
1
2
3
4
5
6
7
8
9
1-Octene (1)
Cyclooctene (2)
Allylcyclohexane (3)
Allylbenzene (4)
Allylcyanide (5)
1-Octyne (6)
Ethyl acetylenecarboxylate (7)
1-Ethynyl-1-cyclohexanol (8)
1
2
3
4
5
6
7
8
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
14
12
10
5
1a (72)
2a (59)
3a (69)
4a (72)
5a (55)
6a (59)
7a (49)
8a (68)
1b (77)
2b (71)
3b (67)
4b (54)
5b (60)
6b (80)
7b (71)
8b (49)
12
10
10
14
16
10
16
16
10
12
8
10
11
12
13
14
15
16
10
a
Substrate (0.5 mmol), CAN(IV) (0.5 mmol) and solvent (3.0 ml) were employed.
b
Determined by GLC analysis using n-dodecane as an internal hydrocarbon standard. All products were identified by satisfactory spectral data
13
(
IR, 1H, C NMR and MS).

K. Itoh et al. / Tetrahedron Letters 43 (2002) 7035–7037
7037
Scheme 3. Reaction conditions: acetone (0.5 mmol), CAN(IV) (1.0 mmol) and acetonitrile (3.0 ml) were employed under reflux for
0 h.
1
O
Ce(IV) or Ce(III)
NO3-
H+
H+
O
O
OH
OH
NO2
N+
N O
N O
R
R
R
H+
-H2O
O
H
N
O
+OH
O
O
O
R
C N O
+
C N
O
-
H O
2
O
O
O
Dimerization
N
N
O
O
Scheme 4. Reaction mechanism.
Typical procedures: Reaction of 1-octyne with CAN(IV)
in acetone. A mixture of 1-octyne (6) (0.0551 g, 0.5
mmol) and ammonium cerium(IV) nitrate (0.2791 g, 0.5
mmol) in acetone (3.0 ml) was stirred under reflux for
T.; You, Z.; Lee, H. J. Med. Chem. Res. 1998, 8, 313.
3. Kim, B. H.; Chung, Y. J.; Ryu, E. J. Tetrahedron Lett.
1993, 34, 8465.
4. Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826.
5. Curran, D. P.; Kim, B. H. Synthesis 1986, 312.
6. Kozikowski, A. P.; Stein, P. D. J. Am. Chem. Soc. 1982,
104, 4023.
14 h. The mixture was extracted with diethyl ether (30
ml) and washed with aq. sodium hydrogencarbonate
solution (2×2.0 ml), saturated aq. NaCl (2×2.0 ml) and
water (2×2.0 ml). The ethereal solution was dried over
Na SO and concentrated in a vacuum. The resulting
7. Maugein, N.; Wagner, A.; Mioskowski, C. Tetrahedron
Lett. 1997, 38, 1547.
2
4
oil was chromatographed on silica gel. Elution with
hexane–ether (3:1) gave 3-acetyl-5-hexylisoxazole (6a)
as a pale-yellow oil (0.060 g, 62%). 3-Acetyl-5-
hexylisoxazole (6a): Pale-yellow oil; IR (NaCl) 1707
8. Lee, G. A. Synth. Commun. 1982, 12, 508.
9. Sørensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org.
Chem. 2000, 65, 1003.
10. Martin, M. A. P.; Flores, A. F. C.; Bastos, G. P.;
Sinhorin, A.; Bonacorso, H. G.; Zanatta, N. Tetrahedron
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11. Horiuchi, C. A.; Kiji, S. Bull. Chem. Soc. Jpn. 1997, 70,
421.
12. Horiuchi, C. A.; Ochiai, K.; Fukunishi, H. Chem. Lett.
−
1
1
and 1593 cm ; H NMR (CDCl ) l=6.36 (s, 1H),
3
2
0
9
1
1
.77–2.81 (s, 1H), 2.63 (s, 3H), 1.29–1.75 (m, 4H) and
1
3
.89 (t, 3H); C NMR (CDCl ) l=192.5, 175.7, 162.1,
3
9.2, 31.4, 28.7, 27.4, 26.8, 22.5 and 14.0; MS (EI) m/z
+
95 (M ), 152, 134, 111, 83, 68, 55 and 43; MS (CI) m/z
+
96 ([M+1] ).
1994, 185.
1
3. Horiuchi, C. A.; Takahashi, E. Bull. Chem. Soc. Jpn.
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14. Sugiyama, T. Appl. Organomet. Chem. 1995, 9, 399.
1
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