Formation of isoxazole derivatives via nitrile oxide using ammonium cerium nitrate (CAN): A novel one-pot synthesis of 3-acetyl- and 3-benzoylisoxazole derivatives

Article abstract of DOI:10.1016/j.tet.2003.11.088

The reactions of alkenes and alkynes with ammonium cerium(IV) nitrate ((NH₄)₂Ce(NO₃)₆, CAN(IV)) in acetone under reflux gave the corresponding 3-acetyl-4,5-dihydroisoxazole and 3-acetylisoxazole derivatives. In the case of acetophenone, 3-benzoyl-4,5- dihydroisoxazole and 3-benzoylisoxazole derivatives were obtained. Reaction of acetone with CAN(IV) afforded the corresponding furoxan (3,4-diacetyl-1,2,5- oxadiazole 2-oxide) as the dimer of nitrile oxide. Moreover, it was found that yields of isoxazole derivatives were improved using ammonium cerium(III) nitrate tetrahydrate ((NH₄)₂Ce(NO₃) ₅·4H₂O, CAN(III))-formic acid. The reaction mechanisms based on nitration and formation of nitrile oxide mediated by CAN(IV) or CAN(III) from acetone or acetophenone are also proposed.

Full text of DOI:10.1016/j.tet.2003.11.088

Tetrahedron 60 (2004) 1671–1681
Formation of isoxazole derivatives via nitrile oxide using
ammonium cerium nitrate (CAN): a novel one-pot synthesis of
3-acetyl- and 3-benzoylisoxazole derivatives
†
*
Ken-ichi Itoh and C. Akira Horiuchi
Department of Chemistry, Rikkyo (St Paul’s) University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, 171-8501 Tokyo, Japan
Received 10 September 2003; accepted 21 November 2003
Abstract—The reactions of alkenes and alkynes with ammonium cerium(IV) nitrate ((NH4)2Ce(NO3)6, CAN(IV)) in acetone under reflux
gave the corresponding 3-acetyl-4,5-dihydroisoxazole and 3-acetylisoxazole derivatives. In the case of acetophenone, 3-benzoyl-4,5-
dihydroisoxazole and 3-benzoylisoxazole derivatives were obtained. Reaction of acetone with CAN(IV) afforded the corresponding furoxan
(3,4-diacetyl-1,2,5-oxadiazole 2-oxide) as the dimer of nitrile oxide. Moreover, it was found that yields of isoxazole derivatives were
improved using ammonium cerium(III) nitrate tetrahydrate ((NH4)2Ce(NO3)5·4H2O, CAN(III))-formic acid. The reaction mechanisms based
on nitration and formation of nitrile oxide mediated by CAN(IV) or CAN(III) from acetone or acetophenone are also proposed.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In particular, it is known that the reaction of b-keto esters or
a,b-unsaturated ketones with hydroxylamine yields the
isoxazole derivatives via intramolcular nitrile oxide
cycloaddition (INOC) by a one-pot method.16,17
Isoxazole derivatives are an important class of heterocyclic
compounds and their chemical properties have been studied
over the years. Isoxazole derivatives have served as a
versatile building block in organic synthesis. They can be
converted into several important synthetic units such as
b-hydroxy ketones,1–5 g-amino alcohols,6 a,b-unsaturated
oxime,7 and b-hydroxy nitriles.8 For example, the trans-
formation of b-hydroxy ketones is commonly accomplished
by reduction of 4,5-dihydroisoxazoles with H2-Raney Ni,1
TiCl3,2 Mo(CO)6,3 and SmI2,4 and oxidation with ozone.5 In
addition, isoxazole derivatives have long been targeted in
synthetic investigation for their known biological activities
and pharmacological properties such as hypoglycemic,9
analgesic,10 anti-inflammatory,11 and anti-bacterial
activity.12 Recently, Srivastava et al.13 reported that on
evaluation of HIV-inhibitory activity of 5-(2,2-dibromo-
acetyl)-3-phenylisoxazole, reduction of infected cells was
indicated. Two methods have been employed generally to
prepare isoxazole derivatives: 1,3-dipolar cycloaddition of
alkenes or alkynes with nitrile oxides from the dehydro-
halogenation of hydroximoyl chlorides in the presence of
triethylamine,14 and the dehydration of primary nitroalkanes
with ethyl chloroformate in the presence of triethylamine.15
CAN(IV) has been utilized extensively for a variety of
oxidative transformations. In addition, it is known that CAN
transform several alkenes and aromatic compounds into
nitro compounds.18,19 We have investigated the develop-
ment of some novel reaction systems using CAN. During
the course of our studies, we reported a novel a-iodination
of ketones in acetic acid or alcohols,20 a new alkoxyiodina-
tion and nitratoiodination of olefins and a,b-unsaturated
esters,21 and a new a,a0-diiodination of ketones using
iodine-CAN(IV).22 One of our group reported a one-pot
synthesis of 4,5-dihydroisoxazole derivatives from alkenes
by the use of CAN(IV) or CAN(III) in acetonitrile-formic
acid at 57 8C for 48 h.23 However, the yields of products
were unsatisfactory because of the formation of nitroalkene
and nitro alcohol from alkene as by-products. Still earlier,
we described a novel one-pot synthesis of 3-acetyl- and
3-benzoylisoxazole derivatives using ammonium cerium
nitrate (CAN).24 Now, in this paper we report details
concerning a new and improved synthesis of 3-acetyl- and
3-benzoylisoxazole derivatives(1a–19a, 1b–19b) using
CAN.
Keywords: Ammonium cerium(IV) nitrate; Ammonium cerium(III) nitrate;
Formic acid; Isoxazole derivatives; Nitrile oxide.
*
Corresponding author. Tel.: þ81-3-3985-2397; fax: þ81-3-3985-2397;
2. Results and discussion
e-mail address: horiuchi@rikkyo.ac.jp
Present address: College of Science and Technology, Nihon University,
7-24-1 Funabashi-si, Chiba 274-8501, Japan.
†
The reaction of alkenes 1–13 with CAN(IV) in acetone
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.088

1672
K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
under reflux gave 3-acetyl-4,5-dihydroisoxazole derivatives
(1a–13a). In the case of acetophenone at 80 8C, 3-benzoyl-
4,5-dihydroisoxazole derivatives (1b–13b) were obtained
(Schemes 1 and 2). These results are summarized in Tables 1
and 2. Compound 1a showed absorption at 1688 (CvO) and
1577 cm21 (CvN) in its IR spectrum. The CI-MS spectrum
1
of 1a showed an [MþH]þ peak at m/z 170. The H NMR
spectrum showed a singlet at d 2.49 (3H, COCH3), and two
double doublets at d 2.76 (1H, J¼8.4, 17.6 Hz, CH2) and
3.16 (1H, J¼11.0, 17.6 Hz, CH2). The 13C NMR spectra
exhibited signals at 193.4, 158.3 and 84.9 ppm, which were
assigned as commonly known carbonyl carbon and carbons
of the 4,5-dihydroisoxazole ring, respectively. Therefore,
compound 1a was identified to be 3-acetyl-5-butyl-4,5-
dihydroisoxazole. Moreover, a similar reaction using
alkynes 14–19 afforded the corresponding 3-acetyl- and
3-benzoylisoxazole derivatives (14a–19a, 14b–19b)
(Scheme 3). The IR spectrum of 14a showed absorption at
1705 (CvO) and 1593 cm21 (CvN). The CI-MS spectrum
Scheme 1.
1
of 14a showed an [MþH]þ peak at m/z 154. The H NMR
spectra exhibited a singlet at d 6.37 (1H). The 13C NMR
spectra exhibited signals at 192.5, 175.5, 162.1 and
99.2 ppm, which were assigned as commonly known
carbonyl carbon and carbons of the isoxazole ring,
respectively. Therefore, compound 14a was identified to
be 3-acetyl-5-propylisoxazole. On the basis of these results,
Scheme 2.
Table 1. Reaction of alkenes 1–13 with CAN(IV) in acetone or acetophenone
Entrya
Substrate
CAN(IV) (mol equiv.)
Solvent
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Time (h)
Product (%)b
1
2
3
4
5
6
7
8
1-Hexene (1)
1-Heptene (2)
1-Octene (3)
1-Octene (3)
1-Octene (3)
1-Octene (3)
1-Octene (3)
1-Octene (3)
Allylcyclohexane (4)
Allylbenzene (5)
Allylmethylsulfide (6)
Allylcyanide (7)
Allylphenylether (8)
Allylacetate (9)
Cyclopentene (10)
Cyclohexene (11)
1.0
1.0
0.5
1.0
1.25
1.5
2.0
4.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
1.25
1.5
2.0
4.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
15
14
30
14
8
8
5
5
10
10
5
15
10
8
20
30
12
12
18
16
30
16
10
8
1a (67)
2a (72)
3a (47)
3a (72)
3a (68)
3a (62)
3a (54)
3a (35)
4a (69)
5a (72)
6a (33)
7a (55)
8a (29)
9a (44)
10a (47)
11a (22)
12a (56)
13a (59)
1b (68)
2b (78)
3b (50)
3b (77)
3b (73)
3b (68)
3b (62)
3b (27)
4b (67)
5b (54)
6b (18)
7b (60)
8b (39)
9b (66)
10b (73)
11b (49)
12b (57)
13b (71)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Cycloheptene (12)
Cyclooctene (13)
Acetone
Acetone
1
2
3
3
3
3
3
3
4
5
6
7
8
9
10
11
12
13
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
5
5
16
16
5
10
12
10
10
20
10
10
a
Substrate (0.5 mmol), CAN(IV) (0.5–1.0 mmol), and solvent (3.0 ml) were employed under reflux.
Determined by GLC analysis using n-dodecane as an internal hydrocarbon standard. All products were identified by satisfactory spectral data (IR, 1H NMR,
13C NMR and MS).
b

K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
Table 2. Reaction of alkynes 14–19 with CAN(IV) in acetone or acetophenone
1673
Entrya
Substrate
Solvent
Time
(h)
Product
(%)b
1
2
3
4
5
6
7
8
1-Pentyne (14)
1-Hexyne (15)
1-Heptyne (16)
1-Octyne (17)
Ethyl acetylenecarboxylate (18)
1-Ethynyl-1-cyclohexanol (19)
14
15
16
17
18
19
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
10
10
10
14
12
12
12
12
12
12
8
14a (31)
15a (45)
16a (45)
17a (59)
18a (49)
19a (68)
14b (64)
15b (66)
16b (71)
17b (80)
18b (71)
19b (49)
9
10
11
12
10
a
Substrate (0.5 mmol), CAN(IV) (0.5 mmol), and solvent (3.0 ml) were employed under reflux.
Determined by GLC analysis using n-dodecane as an internal hydrocarbon standard. All products were identified by satisfactory spectral data (IR, 1H NMR,
13C NMR and MS).
b
the existence of nitrile oxide as an intermediate. The
formation of the dimer (3,4-diacetyl-1,2,5-oxadiazole
2-oxide (furoxan) (20)) of nitrile oxide generated from
acetone was confirmed. As shown in Scheme 4, the reaction
of acetone with CAN(IV) gave compound 20. Its IR
spectrum showed absorption at 1718 (CvO) and
1605 cm21 (CvN–O). The CI-MS spectrum of 20 showed
an [MþH]þ peak at m/z 172. The 1H NMR spectrum
showed two singlets at d 2.74 (3H, COCH3) and 2.63 (3H,
COCH3). The 13C NMR spectra exhibited signals at 188.9,
185.5, 153.4 and 111.5 ppm, which were assigned to 1,2,5-
oxadiazole 2-oxide, respectively. Therefore, compound 20
Scheme 3.
was identified to be 3,4-diacetyl-1,2,5-oxadiazole 2-oxide
(furoxan). In addition, the formation of nitrile oxide from
acetophenone was confirmed in the GC-MS spectra. This
result suggests that acetone is converted into the corre-
sponding nitrile oxide via a process, which involves
nitration of acetone by cerium(IV) or cerium(III), and then
undergoes competitive dimerization, and 1,3-dipolarcyclo-
addition with the alkenes or alkynes.
it was found that this reaction gives a novel one-pot
synthesis of 3-acetyl- and 3-benzoylisoxazole derivatives
(1a–19a, 1b–19b) from dipolarophiles (alkenes 1–13 or
alkynes 14–19) and acetone or acetophenone using
CAN(IV). When substrate (0.5 mmol), CAN(IV)
(0.5 mmol: 1.0 mol equiv.), and ketone (3.0 ml) were
employed (Table 1, run 4 and 21), 3-acetyl- and 3-benzoyl-
isoxazole derivatives were obtained in good yields of 72 and
77%, respectively. But the yields of isoxazole derivatives
were lowered under reaction conditions using excess
CAN(IV) (Table 1, run 5–8 and 23–26). It seems that the
reaction products or intermediates were further oxidized due
to the oxidative power of excess CAN(IV).
In order to investigate the relationship between yields of
isoxazole derivatives and ketone as a precursor of nitrile
oxide in the presence of CAN(IV), the reaction of 1-octene
(3) and acetophenone with CAN(IV) in acetonitrile as
solvent was carried out (Scheme 5). These results are
summarized in Figure 1. From these results, it was found
that the yields of isoxazole derivatives depended on the
quantity of acetophenone. The reaction of 3 (0.5 mmol) and
It is known that nitrile oxides dimerize to furoxans. If a
furoxan is confirmed in this reaction, it is possible to prove
Scheme 4. Reaction conditions: acetone (3.0 ml) and CAN(IV) (1.0 mmol) were employed under reflux for 10 h.
Scheme 5.

1674
K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
Figure 1. The relationship between acetophenone and products using CAN(IV) Reaction conditions: 1-octene (0.5 mmol), CAN(IV) (0.5 mmol),
acetophenone (0–20 mol equiv.), and acetonitrile (3.0 ml) were employed for 20 h under reflux.
acetophenone (2.5 mmol, 5.0 mol equiv.) for 28 h with
CAN(IV) in acetonitrile gave 3b, 1-nitro-1-octene (3c),25
and 1-nitro-2-octanol (3d)25 in 33, 31 and 14% yields,
respectively. In the reaction of 3 (0.5 mmol) and aceto-
phenone (10.0 mmol, 20.0 mol equiv.) for 10 h, 3c (12%),
3d (9%) and 3b (77%) as major products were obtained.
(Scheme 6). Therefore, it seems that the reaction of Path
A and B competitively proceeded, and the yields of
isoxazole derivatives depended on the quantity of ketone.
We further examined the reaction conditions, to improve the
yields of the isoxazole derivatives. Recently, Sugiyama
Previously, Sugiyama reported that the reaction of several
alkenes and a small amount of additive such as cyclo-
hexanone with CAN(IV) in acetonitrile-formic acid gave
the corresponding 1-nitroalkenes and 1-nitro alcohols.25 In
this reaction mechanism, Ce4þ was at first converted into
Ce3þ by ketones, and then the nitration of alkenes occurs by
Ce3þ, proton, and nitrate ion. In the present reaction, it
seems that the nitration by CAN(IV) proceeded by a similar
reaction mechanism. Ce4þ was at first converted into Ce3þ
by acetone or acetophenone, and the nitration of alkenes or
ketones occurs by Ce3þ, proton and nitrate ion. From
Figure 1, it is seen the nitration of acetone or acetophenone
preferentially occurs to the nitration of alkenes under these
reaction conditions using excess ketones. Therefore, the
formation of nitrile oxide from acetone or acetophenone
proceeds, and dipolarophiles (alkenes or alkynes) were
consumed in 1,3-dipolar cycloaddition to nitrile oxide. A
few by-products such as 1-nitroalkenes and 1-nitro alcohols
were obtained. From these results mentioned above, it
seems that this reaction proceeds via two reaction pathways:
the formation of isoxazole derivatives by 1,3-dipolar
cycloaddition of alkenes with nitrile oxide from acetone
or acetophenone (Path A), and the formation of 1-nitro-
alkenes and 1-nitro alcohols from alkenes (Path B)
Table 3. Reaction of alkenes 1–13 with CAN(III)-formic acid in acetone or
acetophenone
Entrya Substrate
CAN(III)
(mol equiv.)
Solvent
Time
(h)
Product
(%)b
1
2
3
4
5
6
7
8
1
2
3
3
3
3
3
4
5
6
7
8
1.0
1.0
0.5
1.0
1.25
1.5
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
5
5
30
10
8
5
5
10
10
5
1a (74)
2a (75)
3a (47)
3a (84)
3a (83)
3a (84)
3a (83)
4a (74)
5a (81)
6a (50)
7a (72)
8a (36)
9a (46)
10a (60)
11a (36)
12a (68)
13a (73)
1b (72)
2b (84)
3b (84)
4b (70)
5b (66)
6b (35)
7b (64)
8b (42)
9b (85)
10b (82)
11b (67)
12b (76)
13b (80)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
8
8
8
5
9
10
11
12
13
1
2
3
4
5
6
7
8
9
10
11
12
13
8
10
10
12
15
15
15
16
5
10
12
10
10
20
10
10
a
Substrate (0.5 mmol), CAN(III) (0.5 mol), formic acid (10.0 mol) and
solvent (3.0 ml) were employed under reflux.
Determined by GLC analysis using n-dodecane as internal hydrocarbon
standard. All products were identified by satisfactory spectral data (IR, 1H
NMR, 13C NMR and MS).
b
Scheme 6.

K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
1675
Table 4. Reaction of alkynes 14–19 with CAN(III)-formic acid in acetone
or acetophenone
acid in acetone under reflux for 10 h afforded 3-hexyl-5-
acetyl-4,5-dihydroisoxazole (3a) in 84% yield (Table 3, run
3). Furthermore, in the case of several alkynes, similarly the
yields of 3-acetyl- and 3-benzoylisoxaole derivatives were
improved. These results are summarized in Table 4. From
these results, it is apparent that these reactions using
CAN(III)-formic acid efficiently afford the corresponding
3-acetyl- and 3-benzoylisoxazole derivatives in preferable
yields. Also, the yields of products were not lowered under
the reaction conditions using excess CAN(III) (Table 3, run
4–7). It seems that CAN(III) did not further oxidize the
products.
Entrya
Substrate
Solvent
Acetone
Acetone
Time (h)
Product (%)b
1
2
14
15
16
17
18
19
14
15
16
17
18
19
8
8
14a (65)
15a (70)
16a (73)
17a (85)
18a (87)
19a (85)
14b (76)
15b (77)
16b (80)
17b (85)
18b (76)
19b (57)
3
4
5
6
Acetone
Acetone
Acetone
Acetone
8
10
8
8
7
8
9
10
11
12
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
8
8
8
8
5
8
The reaction of 1-octene (3) and acetophenone with
CAN(III)-formic acid in acetonitrile was carried out, and
the relationship between yields of products and ketone in the
presence of CAN(III) is shown in Figure 2. The reaction of 3
(0.5 mmol) and acetophenone (2.5 mmol, 5.0 mol equiv.)
for 28 h with CAN(III)-formic acid in acetonitrile gave 3b,
1-nitro-1-octene (3c), and 1-nitro-2-octanol (3d) in 32, 24
and 13% yields, respectively. In the reaction of 3
(0.5 mmol) and acetophenone (10.0 mmol, 20.0 mol equiv.)
for 10 h, 3b, 3c and 3d were given in 82, 10 and 4% yield,
respectively. As compared with the results using CAN(IV),
the formation of 1-nitrooctene (3c) and 1-nitro-2-octanol
(3d) was inhibited between 5 and 10%. Furthermore, the
yields of product were increased by over 5%. From these
results, the nitration of ketones or alkenes by Ce3þ, proton
and nitrate ion was confirmed. Also, it seems that the
nitration of ketones (Path A) efficiently proceeds under
reaction conditions using CAN(III) without reduction of
Ce4þ into Ce3þ. Since the formation of 1-nitroalkenes and
1-nitro alcohols was inhibited under reaction conditions
using CAN(III)-formic acid, the formation of nitrile
oxides from acetone or acetophenone smoothly proceeds.
Therefore, the yields of isoxazole derivatives were
increased.
a
Substrate (0.5 mmol), CAN(III) (0.5 mol), formic acid (10.0 mol) and
solvent (3.0 ml) were employed under reflux.
Determined by GLC analysis using n-dodecane as internal hydrocarbon
standard. All products were identified by satisfactory spectral data (IR, 1H
NMR, 13C NMR and MS).
b
reported that the reaction of 1-alkenes (1.5 ml) with
CAN(IV) (0.6 mmol) and cyclohexanone (0.5 mmol) as
additive in acetonitrile–formic acid (1.0 ml/0.5 ml) at 57 8C
for 48 h gave the corresponding 4,5-dihydroisoxazole
derivatives.23 Moreover, this reaction smoothly proceeded
by the use of CAN(III) instead of CAN(IV). From Figure 1
and Scheme 6, it was found that the nitration of ketones
proceeds by Ce3þ, proton and nitrate ion. In the present
reaction, we attempted to synthesize the isoxazole deriva-
tives from alkenes with CAN(III)-formic acid instead of
CAN(IV) in acetone or acetophenone. The reaction of
several alkenes with CAN(III)-formic acid in acetone or
acetophenone gave the corresponding 3-acetyl- and
3-benzoyl-4,5-dihydroisoxaole derivatives in preferable
yields. These results are summarized in Table 3. The yields
of isoxazole derivatives were increased by over 5–20%. For
example, the reaction of 1-octene (3) with CAN(III)-formic
Figure 2. The relationship between acetophenone and products using CAN(III)-formic acid Reaction conditons: 1-octene (0.5 mmol), CAN(III) (0.5 mmol),
formic acid (10.0 mol), acetophenone (0–20 mol equiv.), and acetonitrile (3.0 ml) were employed for 20 h under reflux.

1676
K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
Table 6. The effect of acid in the formation of isoxazole derivatives
Run
Substrate
Acid
Time (h)
Product (%)a
1b
2c
3c
4c
5c
6c
7c
8d
3
3
3
3
3
3
3
3
—
70
25
25
25
15
20
15
15
No reaction
No reaction
No reaction
No reaction
3a (82)
3a (81)
3a (82)
3a (84)
CH3COOH
CH3CH2COOH
C6H5COOH
HNO3
ClCH2COOH
(COOH)2
H2SO4
Scheme 7.
In order to investigate the reaction mechanism detailed in
the formation of isoxazole derivatives, the reactions of
1-octene (3) with several cerium salts–formic acid in
acetophenone were carried out (Scheme 7). These results
are summarized in Table 5. In this reaction, isoxazole
derivatives were not obtained in the absence of cerium salts
and formic acid (Table 5, run 1 and 2). Also, the reaction
using Ce(OH)4, Ce(NH4)4(SO4)2, CeCl3, and Ce(CH3-
COO)3 containing nitric acid gave isoxazole derivatives in
69, 74, 81 and 83% yields, respectively. Also, in the case of
using Ce3þ salts, the yields of isoxazole derivatives were
increased (Table 5, run 2–5). These results show this
reaction in the formation of isoxazole derivatives requires
Ce3þ, nitrate ion, and formic acid. Moreover, in order to
clarify the relationship between formation of isoxazole
derivatives and formic acid in this reaction mechanism, the
reactions of 1-octene (3) with CAN(III)-several acids in
acetone were carried (Scheme 8). These results are
summarized in Table 6. The reaction using acetic acid,
propionic acid, and benzoic acid did not proceed. However,
the reaction using nitric acid, monochloroacetic acid, oxalic
acid, and sulfuric acid gave isoxazole derivatives in 82, 81,
82 and 84% yield, respectively. When CAN(IV) was
dissolved in acetone or acetophenone, its solution revealed
high acidity. However, the solution dissolving CAN(III) did
not reveal the high acidity. Furthermore, this reaction
proceeds under reaction conditions using an acid containing
the acidity of formic acid or above. From these results, it
seems that the proton accomplishes a more essential role for
this reaction mechanism than nitration of acetone and
acetophenone.
a
Determined by GLC analysis using n-dodecane as internal hydrocarbon
standard. All products were identified by satisfactory spectral data (IR, 1H
NMR, 13C NMR and MS).
b
c
d
Substrate (0.5 mmol), CAN(III) (0.5 mmol), and acetone (3.0 ml) were
employed under reflux.
Substrate (0.5 mmol), CAN(III) (0.5 mmol), acid (5.0 mmol) were
employed under reflux.
Substrate (0.5 mmol), CAN(III) (0.5 mmol), acid (0.5 mmol) were
employed under reflux.
Wade and co-workers26 reported that acid-catalyzed
nitronate cycloaddition reactions gave 4,5-dihydroisoxazole
and isoxazole derivatives from nitro compounds and
dipolarophiles. In this reaction, nitronic esters were
transformed from primary nitro ketones in the presence of
nonaqueous protonic and Lewis acids or a strong acid. The
protonation of nitronic esters by Lewis acids or a strong acid
produced the nitroso cation with dehydration, followed by
the formation of nitrile oxide from the nitroso cation. The
reaction of nitrile oxide and dipolarphiles afforded the
corresponding isoxazole derivatives. On the basis of this
reaction mechanism, we proposed the present reaction
mechanism in Scheme 9. At first, the nitration of acetone or
acetophenone by Ce3þ, proton and nitrate ion gave the
corresponding nitroketones. In the presence of proton,
nitroketones were transformed into nitroso cations, followed
by the formation of nitrile oxides from the nitroso cations.
Finally, 3-acetyl- and 3-benzoylisoxazole derivatives were
obtained by 1,3-dipolar cycloaddition of dipolarophiles
(alkenes or alkynes) and nitrile oxide. In the absence of
dipolarophiles, nitrile oxide dimerized into furoxan. It is
known that nitrile oxides containing an acyl group were
obtained from primary nitro compounds27 and a-hydroxy-
imino carboxylic acids;28 however, in this reaction nitrile
oxide containing an acyl group was obtained in one-step.
Table 5. Reaction of 1-octene with Ce(IV) and Ce(III) salts in
acetophenone
Runa
Substrate
Ce salts
Time (h)
Product (%)b
1
3
3
3
3
3
3
—
Ce(OH)4
Ce(OH)4
Ce(NH4)4(SO4)2
CeCl3
Ce(CH3COO)3
25
25
12
12
8
No reaction
No reaction
3b (69)
3b (74)
3b (81)
3b (83)
2c
3
In conclusion, this method is simple and efficient to
obtain 3-acetyl- and 3-benzoylisoxazole derivatives. It is
particularly noteworthy that this reaction affords a new
synthetic method for isoxazole and 4,5-dihydroisoxazole
derivatives that is more convenient than the methods used
heretofore.
4
5
6
8
a
Substrate (0.5 mmol), Ce salts (0.5 mol), formic acid (5.0 mmol), nitric
acid (5.0 mmol), and acetophenone (3.0 ml) were employed under reflux.
Determined by GLC analysis using n-dodecane as internal hydrocarbon
standard.
Substrate (0.5 mmol), Ce salts (0.5 mol), nitric acid (5.0 mmol), and
acetophenone (3.0 ml) were employed under reflux. All products were
identified by satisfactory spectral data (IR, 1H NMR, 13C NMR and MS).
b
c
3. Experimental
3.1. General procedure
IR spectra were recorded on a Jasco FT-IR 230 spec-
1
trometer. H and 13C NMR spectra were measured using a
JEOL GSX 400 Model spectrometer in deuteriochloroform
solutions with tetramethylsilane used as an internal
standard.
Scheme 8.

K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
1677
Scheme 9. Reaction mechanism.
GC-MS (EI) analyses were performed on a Shimazu
GCMS-QP5050 with an ionizing energy of 70 eV. CIMS
(i-butane reagent gas) were recorded on a Shimazu GCMS-
QP5050 with an ionizing energy of 300 eV.
(CDCl3) d¼4.74–4.82 (m, 1H), 3.16 (dd, J¼10.8, 17.4 Hz,
1H), 2.75 (dd, J¼8.4, 17.4 Hz, 1H), 2.49 (s, 3H), 1.70–1.75
(m, 1H), 1.54–1.60 (m, 1H), 1.31–1.43 (m, 6H), and 0.90
(t, J¼7.1 Hz, 3H); 13C NMR (CDCl3) d¼193.4, 158.3, 84.9,
36.7, 35.1, 31.5, 26.6, 24.9, 22.5, and 14.0; CIMS m/z 184
[MþH]þ; EIMS m/z 140 [M2CH3CO]þ (1), 112
[M2C7H14NO]þ (3), 43 [M2C8H14NO]þ (100); HRMS
Found: m/z 183.1261 [M]þ. Calcd for C10H17NO2: M,
183.1259.
3.2. Synthesis of isoxazole derivatives using CAN(IV)
[M2C5H11]þ
(2),
99
[M2C6H12]þ
(2),
55
3.2.1. Typical procedures: reaction of 1-octene (3) with
CAN(IV) in acetone. A mixture of 1-octene (3) (0.0561 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
14 h. The reaction 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
Na2SO4 and concentrated in a vacuum. The resulting oil was
chromatographed on silica gel. Elution with hexane–diethyl
ether (5:1) gave 3-acetyl-5-hexyl-4,5-dihydroisoxazole (3a)
as a pale-yellow oil (0.0581 g, 59%).
3.2.1.3. 3-Acetyl-5-hexyl-4,5-dihydroisoxazole (3a).
1
Pale-yellow oil; IR (NaCl) 1686 and 1578 cm21; H NMR
(CDCl3) d¼4.74–4.82 (m, 1H), 3.16 (dd, J¼11.0, 17.6 Hz,
1H), 2.75 (dd, J¼8.6, 17.6 Hz, 1H), 2.49 (s, 3H), 1.60–1.74
(m, 4H), 1.34–1.44 (m, 6H), and 0.89 (t, J¼6.8 Hz, 3H);
13C NMR (CDCl3) d¼193.4, 158.3, 84.9, 36.7, 35.2, 31.7,
29.0, 26.6, 25.1, 22.5, and 14.0; CIMS m/z 198 [MþH]þ;
EIMS m/z 154 [M2CH3CO]þ (1), 136 [M2CH3CO–
CH3]þ (1), 112 [M2C6H13]þ (2), 95 [M2C6H14O]þ (2), 69
[M2C8H16O]þ (2), 55 [M2C8H16NO]þ (3), 43
[M2C9H16NO]þ (100); HRMS Found: m/z 197.1428
[M]þ. Calcd for C11H19NO2: M, 197.1416.
3.2.1.1. 3-Acetyl-5-butyl-4,5-dihydroisoxazole (1a).
1
Pale-yellow oil; IR (NaCl) 1688 and 1577 cm21; H NMR
(CDCl3) d¼4.74–4.83 (m, 1H), 3.16 (dd, J¼11.0, 17.6 Hz,
1H), 2.76 (dd, J¼8.4, 17.6 Hz, 1H), 2.49 (s, 3H), 1.60–1.74
(m, 2H), 1.34–1.43 (m, 4H), and 0.92 (t, J¼7.1 Hz, 3H);
13C NMR (CDCl3) d¼193.4, 158.3, 84.9, 36.7, 34.9, 27.3,
26.6, 22.4, and 13.9; CIMS m/z 170 [MþH]þ; EIMS m/z
126 [M2CH3CO]þ (1), 112 [M2C4H9]þ (2), 99
[M2C5H10]þ (2), 85 [M2C6H12]þ (4), 55 [M2C6H12NO]þ
(3), 43 [M2C7H12NO]þ (100); HRMS Found: m/z 169.1103
[M]þ. Calcd for C9H15NO2: M, 169.1103.
3.2.1.4. 3-Acetyl-5-cyclohexylmethyl-4,5-dihydro-
isoxazole (4a). Pale-yellow oil; IR (NaCl) 1686 and
1576 cm21
;
1H NMR (CDCl3) d¼4.83–4.91 (m, 1H),
3.18 (dd, J¼10.8, 17.4 Hz, 1H), 2.72 (dd, J¼8.6, 17.4 Hz,
1H), 2.49 (s, 3H), 1.68–1.77 (m, 6H), 1.38–1.45 (m, 2H),
1.21–1.27 (m, 3H), and 0.94–1.17 (m, 2H); 13C NMR
(CDCl3) d¼193.4, 158.3, 83.1, 43.1, 37.8, 34.6, 33.5, 33.0,
26.6, 26.4, 26.2, and 26.1; CIMS m/z 210 [MþH]þ; EIMS
m/z 166 [M2CH3CO]þ (1), 126 [M2C6H11]þ (1), 112
[M2C7H13]þ (1), 55 [M2C9H16NO]þ (3), 43
3.2.1.2. 3-Acetyl-5-pentyl-4,5-dihydroisoxazole (2a).
1
Pale-yellow oil; IR (NaCl) 1688 and 1577 cm21; H NMR

1678
K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
[M2C10H16NO]þ (100); HRMS Found: m/z 209.1407
[M]þ. Calcd for C12H19NO2: M, 209, 1416.
3.2.1.5. 3-Acetyl-5-benzyl-4,5-dihydroisoxazole (5a).
CIMS m/z 154 [MþH]þ; EIMS m/z 153 [M]þ (1), 110
[M2CH3CO]þ (4), 43 [M2C6H8NO]þ (100); HRMS
Found: m/z 153.0791 [M]þ. Calcd for C8H11NO2: M,
153.0790.
1
Pale-yellow oil; IR (NaCl) 1686 and 1577 cm21; H NMR
(CDCl3) d¼7.21–7.33 (m, 5H), 5.01–5.06 (m, 1H), 3.05–
3.13 (m, 2H), 2.83–2.91 (m, 2H), and 2.46 (s, 3H); 13C
NMR (CDCl3) d¼193.2, 158.2, 136.6, 129.4, 128.7, 127.0,
84.9, 40.9, 36.3, and 26.6; CIMS m/z 204 [MþH]þ; EIMS
m/z 203 [M]þ (1), 126 [M2C6H5]þ (1), 112 [M2C7H7]þ
(2), 43 [M2C10H10NO]þ (100); HRMS Found: m/z
203.0951 [M]þ. Calcd for C12H13NO2: M, 203.0946.
3.2.1.6. 3-Acetyl-5-methylthiamethyl-4,5-dihydro-
isoxazole (6a). Pale-yellow oil; IR (NaCl) 1687 and
3.2.1.11. 3-Acetyl-4,5-cyclohexa-4,5-dihydroisoxazole
(11a). Pale-yellow oil; IR (NaCl) 1686 and 1559 cm21
;
1H NMR (CDCl3) d¼4.52–4.56 (m, 1H), 3.15–3.21 (m,
1H), 2.49 (s, 3H), and 1.14–2.24 (m, 8H); 13C NMR
(CDCl3) d¼193.6, 164.3, 83.3, 42.1, 26.8, 25.4, 24.7, 21.4,
and 19.7; CIMS m/z 168 [MþH]þ; EIMS m/z 167 [M]þ (1),
150 [M2OH]þ (1), 124 [M2CH3CO]þ (4), 96
[M2CH3CO–C2H4]þ (3), 55 [M2CH3CO–C4H8]þ (3),
43 [M2C7H10NO]þ (100); HRMS Found: m/z 167.0940
[M]þ. Calcd for C9H13NO2: M, 167.0946.
1578 cm21
;
1H NMR (CDCl3) d¼4.97–5.04 (m, 1H),
3.24 (dd, J¼10.8, 17.7 Hz, 1H), 3.06 (dd, J¼7.7, 17.7 Hz,
1H), 2.81 (dd, J¼5.0, 14.1 Hz, 1H), 2.71 (dd, J¼6.8,
14.1 Hz, 1H), 2.50 (s, 3H), and 2.20 (s, 3H); 13C NMR
(CDCl3) d¼193.0, 158.2, 83.6, 38.0, 36.6, 26.7, and 16.4;
CIMS m/z 174 [MþH]þ; EIMS m/z 173 [M]þ (1), 130
[M2CH3CO]þ (1), 112 [M2C2H5S]þ (12), 61
[M2C5H6NO2]þ (23), 43 [M2C5H8NOS]þ (100); HRMS
Found: m/z 173.0513 [M]þ. Calcd for C7H11NO2S: M,
173.0510.
3.2.1.12. 3-Acetyl-4,5-cyclohepta-4,5-dihydroisoxazole
(12a). Pale-yellow oil; IR (NaCl) 1686 and 1560 cm21; 1H
NMR (CDCl3) d¼4.87–4.93 (m, 1H), 3.52–3.58 (m, 1H),
2.47 (s, 3H), and 1.39–2.01 (m, 10H); 13C NMR (CDCl3)
d¼193.5, 160.4, 88.2, 48.9, 31.0, 30.3, 28.2, 27.1, 26.7, and
23.8; CIMS m/z 182 [MþH]þ; EIMS m/z 181 [M]þ (1), 138
[M2CH3CO]þ (3), 43 [M2C8H12NO]þ (100); HRMS
Found: m/z 181.1101 [M]þ. Calcd for C10H15NO2: M,
181.1103.
3.2.1.7. 3-Acetyl-5-cyanomethyl-4,5-dihydroisoxazole
(7a). Yellow oil; IR (NaCl) 1687 and 1583 cm21
3.2.1.13. 3-Acetyl-4,5-cycloocta-4,5-dihydroisoxazole
;
1H
(13a). Pale-yellow oil; IR (NaCl) 1686 and 1570 cm21
;
NMR (CDCl3) d¼4.99–5.06 (m, 1H), 3.22 (dd, J¼11.5,
17.8 Hz, 1H), 2.97 (dd, J¼7.9, 17.8 Hz, 1H), 2.74–2.85 (m,
2H), and 2.51 (s, 3H); 13C NMR (CDCl3) d¼192.8, 158.0,
115.2, 77.0, 39.4, 26.7, and 23.7; CIMS m/z 153 [MþH]þ;
EIMS m/z 152 [M]þ (2), 138 [M2CH3]þ (2), 112
[M2CH2CN]þ (1), 109 [M2CH3CO]þ (1), 43
[M2C5H5N2O]þ (100); HRMS Found: m/z 152.0591
[M]þ. Calcd for C7H8N2O2: M, 152.0586.
1H NMR (CDCl3) d¼4.50–4.56 (m, 1H), 3.26–3.31 (m,
1H), 2.47 (s, 3H), 196–2.10 (m, 2H), 1.44–1.75 (m, 7H),
and 1.22–1.38 (m, 3H); 13C NMR (CDCl3) d¼193.4, 162.7,
88.7, 47.5, 29.8, 27.1, 27.0, 25.6, 25.5, 25.1, and 24.5; CIMS
m/z 196 [MþH]þ; EIMS m/z 152 [M2CH3CO]þ (3), 138
[M2CH3CO–CH2]þ (1), 124 [M2CH3CO–C2H4]þ (1),
110 [M2CH3CO–C3H6]þ (1), 96 [M2CH3CO–C4H8]þ
(1) 82 [M2CH3CO–C5H10]þ (3), 43 [M2C9H14NO]þ
(100); HRMS Found: m/z 195.1243 [M]þ. Calcd for
C11H17NO2: M, 195.1259.
3.2.1.8. 3-Acetyl-5-phenoxymethyl-4,5-dihydro-
isoxazole (8a). Pale-yellow oil; IR (NaCl) 1686 and
1581 cm21
;
1H NMR (CDCl3) d¼7.26–7.30 (m, 2H),
3.2.1.14. 3-Acetyl-5-propylisoxazole (14a). Pale-yellow
1
6.96–7.00 (m, 1H), 6.88–6.90 (m, 2H), 5.10–5.17 (m,
1H), 4.10 (q, J¼4.8 Hz, 2H), 3.50 (dd, J¼11.0, 17.6 Hz,
1H), 3.40 (dd, J¼7.7, 17.6 Hz, 1H), and 2.52 (s, 3H); 13C
NMR (CDCl3) d¼193.0, 158.2, 158.1, 129.6, 121.5, 114.7,
81.9, 68.3, 34.2, and 26.8; CIMS m/z 220 [MþH]þ; EIMS
m/z 176 [M2CH3CO]þ (1), 142 [M2C6H5]þ (1), 126
[M2OC6H5]þ (3), 112 [M2CH2OC6H5]þ (4), 43
[M2C10H10NO2]þ (100); HRMS Found: m/z 219.0904
[M]þ. Calcd for C12H13NO3: M, 219.0895.
oil; IR (NaCl) 1705 and 1593 cm21; H NMR (CDCl3)
d¼6.37 (s, 1H), 2.78 (t, J¼7.6 Hz, 2H), 2.64 (s, 3H), 1.71–
1.80 (m, 2H) and 1.00 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3)
d¼192.5, 175.5, 162.1, 99.2, 28.6, 27.3, 20.9 and 13.6;
CIMS m/z 154 [MþH]þ; EIMS m/z 153 [M]þ (2), 138
[M2CH3]þ (1), 110 [M2CH3CO]þ (1), 43 [M2C6H8NO]þ
(100); HRMS Found: m/z 153.0788 [M]þ. Calcd for
C8H11NO2: M, 153.0790.
3.2.1.15. 3-Acetyl-5-butylisoxazole (15a). Pale-yellow
1
3.2.1.9. 3-Acetyl-5-acetoxymethyl-4,5-dihydro-
isoxazole (9a). Pale-yellow oil; IR (NaCl) 1691 and
oil; IR (NaCl) 1707 and 1593 cm21; H NMR (CDCl3)
d¼6.36 (s, 1H), 2.76 (t, J¼7.7 Hz, 2H), 2.63 (s, 3H), 1.67–
1.74 (m, 2H), 1.34–1.45 (m, 2H), and 0.95 (t, J¼7.3 Hz,
3H); 13C NMR (CDCl3) d¼192.5, 175.6, 162.1, 99.2, 29.5,
27.2, 26.4, 22.1, and 13.6; CIMS m/z 168 [MþH]þ; EIMS
m/z 167 [M]þ (1), 152 [M2CH3]þ (1), 124 [M2CH3CO]þ
(2), 43 [M2C7H10NO]þ (100); HRMS Found: m/z
167.0929 [M]þ. Calcd for C9H13NO2: M, 167.0946.
1581 cm21
;
1H NMR (CDCl3) d¼4.99–5.06 (m, 1H),
4.26 (dd, J¼3.9, 12.3 Hz, 1H), 4.16 (dd, J¼5.5, 12.3 Hz,
1H), 3.22 (dd, J¼11.5, 17.8 Hz, 1H), 2.97 (dd, J¼7.9,
17.8 Hz, 1H), 2.51 (s, 3H), and 2.09 (s, 3H); 13C NMR
(CDCl3) d¼192.8, 170.6, 158.0, 81.2, 64.4, 34.1, 26.7, and
20.7; CIMS m/z 186 [MþH]þ; EIMS m/z 142
[M2CH3CO]þ (1), 126 [M2C2H3O2]þ (5), 112
[M2C3H5O2]þ (5), 43 [M2C6H8NO3]þ (100); HRMS
Found: m/z 185.0694 [M]þ. Calcd for C8H11NO4: M,
185.0688.
3.2.1.16. 3-Acetyl-5-pentylisoxazole (16a). Pale-yellow
1
oil; IR (NaCl) 1707 and 1593 cm21; H NMR (CDCl3)
d¼6.36 (s, 1H), 2.79 (t, J¼7.3 Hz, 2H), 2.63 (s, 3H), 1.69–
1.76 (m, 2H), 1.33–1.38 (m, 4H), and 0.91 (t, J¼7.0 Hz,
3H); 13C NMR (CDCl3) d¼192.5, 175.7, 162.2, 99.2, 31.2,
27.2, 27.0, 26.7, 22.3, and 13.9; CIMS m/z 182 [MþH]þ;
EIMS m/z 181 [M]þ (1), 166 [M2CH3]þ (1), 138
[M2CH3CO]þ (1), 55 [M2C7H12NO]þ (1), 43
[M2C8H12NO]þ (100); HRMS Found: m/z 181.1097
[M]þ. Calcd for C10H15NO2: M, 181.1103.
3.2.1.10. 3-Acetyl-4,5-cyclopenta-4,5-dihydroisoxazole
(10a). Pale-yellow oil; IR (NaCl) 1688 and 1571 cm21; 1H
NMR (CDCl3) d¼5.05–5.27 (m, 1H), 3.80–3.85 (m, 1H),
2.46 (s, 3H), 2.14–2.19 (m, 1H), 1.90–1.96 (m, 1H), 1.68–
1.83 (m, 3H), and 1.28–1.50 (m, 1H); 13C NMR (CDCl3)
d¼193.3, 160.0, 90.8, 49.4, 35.6, 31.4, 27.0, and 23.2;

K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
1679
3.2.1.17. 3-Acetyl-5-hexylisoxazole (17a). Pale-yellow
1
1H), 1.26–1.47 (m, 6H), and 0.90 (t, J¼7.0 Hz, 3H); 13C
NMR (CDCl3) d¼186.5, 157.8, 135.9, 133.4, 130.3, 128.3,
83.5, 38.8, 35.1, 31.5, 24.9, 22.5, and 14.0; CIMS m/z 246
[MþH]þ; EIMS m/z 174 [M2C5H11]þ (2), 140
[M2C6H5CO]þ (2), 105 [M2C8H14NO]þ (100), 77
[M2C8H14NO–CO]þ (38); HRMS Found: m/z 245.1399
[M]þ. Calcd for C15H19NO2: M, 245.1416.
oil; IR (NaCl) 1707 and 1593 cm21; H NMR (CDCl3)
d¼6.36 (s, 1H), 2.79 (t, J¼7.3 Hz, 2H), 2.63 (s, 3H), 1.67–
1.75 (m, 2H), 1.29–1.38 (m, 6H), and 0.89 (t, J¼7.0 Hz,
3H); 13C NMR (CDCl3) d¼192.5, 175.7, 162.1, 99.1, 31.3,
28.7, 27.3, 27.0, 26.7, 22.4, and 14.0; CIMS m/z 196
[MþH]þ; EIMS m/z 195 [M]þ (1), 180 [M2CH3]þ (1), 153
[M2CH3CO]þ (2), 55 [M2C8H14NO]þ (1), 43
[M2C9H14NO]þ (100); HRMS Found: m/z 195.1262
[M]þ. Calcd for C11H17NO2: M, 195.1259.
3.2.2.3. 3-Benzoyl-5-hexyl-4,5-dihydroisoxazole (3b).
1
Pale-yellow oil; IR (NaCl) 1652 and 1570 cm21; H NMR
(CDCl3) d¼8.17–8.19 (m, 2H), 7.37–7.55 (m, 3H), 4.64–
4.72 (m, 1H), 3.31 (dd, J¼10.8, 17.4 Hz, 1H), 2.92 (dd,
J¼8.6, 17.4 Hz, 1H), 1.66–1.71 (m, 1H), 1.50–1.56 (m,
1H), 1.26–1.41 (m, 8H), and 0.87 (t, J¼6.6 Hz, 3H); 13C
NMR (CDCl3) d¼186.1, 157.9, 136.0, 133.5, 130.3, 128.3,
83.4, 38.8, 35.2, 31.8, 29.1, 25.3, 22.6, and 14.1; CIMS m/z
260 [MþH]þ; EIMS m/z 174 [M2C6H13]þ (2), 154
[M2C6H5CO]þ (2), 105 [M2C9H16NO]þ (100), 77
[M2C9H16NO–CO]þ (32); HRMS Found: m/z 259.1587
[M]þ. Calcd for C16H21NO2: M, 259.1572.
3.2.1.18. Ethyl 3-acetylisoxazolecarboxylate (18a).
Colorless needless from EtOH; mp 42.3–435 8C; IR
1
(NaCl) 1710 and 1579 cm21; H NMR (CDCl3) d¼7.25
(s, 1H), 4.48 (q, J¼7.1 Hz, 2H), 2.71 (s, 3H), and 1.47 (t,
J¼7.1 Hz, 3H); 13C NMR (CDCl3) d¼190.3, 161.8, 161.4,
155.6, 106.9, 62.2, 26.7, and 13.6; CIMS m/z 184 [MþH]þ;
EIMS m/z 168 [M2CH3]þ (1), 140 [M2CH3CO]þ (1), 138
[M2C2H5O]þ (2), 43 [M2C6H6NO3]þ (100); HRMS
Found: m/z 183.0530 [M]þ. Calcd for C8H9NO4: M,
183.0532.
3.2.2.4. 3-Benzoyl-5-cyclohexylmethyl-4,5-dihydro-
isoxazole (4b). Pale-yellow oil; IR (NaCl) 1653 and
3.2.1.19. 3-Acetyl-6-hydroxy-5-cyclohexylisoxazole
(19a). Pale-yellow oil; IR (NaCl) 3400, 1706 and
1570 cm21
;
1H NMR (CDCl3) d¼8.18–8.20 (m, 2H),
1
1558 cm21; H NMR (CDCl3) d¼6.53 (s, 1H), 3.49 (brs,
7.43–7.62 (m, 3H), 4.83–4.91 (m, 1H), 3.40 (dd, J¼10.8,
17.4 Hz, 1H), 2.96 (dd, J¼8.8, 17.4 Hz, 1H), 1.70–1.83 (m,
6H), 1.44–1.54 (m, 2H), 1.11–1.28 (m, 3H), and 0.95–0.99
(m, 2H); 13C NMR (CDCl3) d¼186.6, 157.9, 135.9, 133.5,
130.3, 128.3, 81.7, 43.0, 39.5, 34.7, 33.5, 33.0, 26.4, 26.2,
and 26.1; CIMS m/z 272 [MþH]þ; EIMS m/z 271 [M]þ (2),
254 [M2OH]þ (1), 228 [M2C3H7]þ (1), 174 [M2C7H13]þ
(1), 166 [M2C6H5CO]þ (1), 105 [M2C10H16NO]þ (100),
77 [M2C10H16NO–CO]þ (32); HRMS Found: m/z
271.1558 [M]þ. Calcd for C17H21NO2: M, 271.1572.
3.2.2.5. 3-Benzoyl-5-benzyl-4,5-dihydroisoxazole (5b).
1H), 2.62 (s, 3H), and 1.17–2.00 (m, 10H); 13C NMR
(CDCl3) d¼192.3, 180.0, 161.5, 98.1, 36.1, 27.0, 24.8, 21.3,
and 20.4; CIMS m/z 210 [MþH]þ; EIMS m/z 194
[M2CH3]þ (1), 166 [M2CH3CO]þ (2), 139 [M2C5H10]þ
(1), 110 [M2C6H11O]þ (2), 98 [M2C7H11O]þ (2), 55
[M2C8H12NO2]þ (100), 43 [M2C9H12NO2]þ (100);
HRMS Found: m/z 209.1027 [M]þ. Calcd for C11H15NO3:
M, 209.1052.
3.2.2. Typical procedures: reaction of 1-octene (3) with
CAN(IV) in acetophenone. A mixture of 1-octene (3)
(0.0561 g, 0.5 mmol) and ammonium cerium(IV) nitrate
(0.2791 g, 0.5 mmol) in acetophenone (3.0 ml) was stirred
at 80 8C for 16 h. The reaction mixture was extracted with
diethyl ether (30 ml) and washed with aq. sodium hydro-
gencarbonate solution (2£2.0 ml), saturated aq. NaCl
(2£2.0 ml), and water (2£2.0 ml). The ethereal solution
was dried over Na2SO4 and concentrated in a vacuum,
followed by acetophenone removal by reduced pressure
distillation. The resulting oil was chromatographed on
silica gel. Elution with hexane–diethyl ether (5:1) gave
3-benzoyl-5-hexyl-4,5-dihydroisoxazole (3b) as a pale-
yellow oil (0.0829 g, 64%).
Pale-yellow oil; IR (NaCl) 1652 and 1572 cm21; H NMR
1
(CDCl3) d¼8.07–8.11 (m, 2H), 7.38–7.54 (m, 3H), 7.17–
7.30 (m, 5H), 4.96–5.03 (m, 1H), 3.29 (dd, J¼11.0,
17.6 Hz, 2H), 3.01–3.09 (m, 2H), and 2.90 (dd, J¼6.2,
17.6 Hz, 2H); 13C NMR (CDCl3) d¼186.3, 157.7, 136.1,
135.7, 133.5, 130.2, 129.4, 128.6, 128.3, 126.9, 83.5, 40.8,
and 38.2; CIMS m/z 266 [MþH]þ; EIMS m/z 265 [M]þ (1),
174 [M2C7H7]þ (2), 160 [M2C6H5CO]þ (1), 105
[M2C10H10NO]þ (100), 77 [M2C10H10NOCO]þ (49);
HRMS Found: m/z 265.1101 [M]þ. Calcd for C17H15NO2:
M, 265.1103.
3.2.2.6. 3-Benzoyl-5-methylthiamethyl-4,5-dihydro-
isoxazole (6b). Pale-yellow oil; IR (NaCl) 1654 and
3.2.2.1. 3-Benzoyl-5-butyl-4,5-dihydroisoxazole (1b).
1
1579 cm21
;
1H NMR (CDCl3) d¼8.17–8.20 (m, 2H),
Pale-yellow oil; IR (NaCl) 1652 and 1570 cm21; H NMR
7.42–7.67 (m, 3H), 4.97–5.05 (m, 1H), 3.47 (dd, J¼10.8,
17.6 Hz, 1H), 3.28 (dd, J¼7.7, 17.6 Hz, 1H), 2.85
(dd, J¼5.1, 14.0 Hz, 1H), 2.76 (dd, J¼6.8, 14.0 Hz,
1H), and 2.21 (s, 3H); 13C NMR (CDCl3) d¼186.2, 157.7,
135.7, 133.6, 130.2, 128.3, 82.3, 38.6, 38.0, and 16.4; CIMS
m/z 236 [MþH]þ; EIMS m/z 235 [M]þ (1), 174
[M2C2H5S]þ (11), 130 [M2C6H5CO]þ (1), 105
[M2C5H8NOS]þ (100), 77 [M2C5H5NOS–CO]þ (77);
HRMS Found: m/z 235.0662 [M]þ. Calcd for C12H13NO2S:
M, 235.0667.
(CDCl3) d¼8.17–8.19 (m, 2H), 7.38–7.53 (m, 3H), 4.65–
4.74 (m, 1H), 3.32 (dd, J¼10.8, 17.4 Hz, 1H), 2.93 (dd,
J¼8.4, 17.4 Hz, 1H), 1.67–1.75 (m, 2H), 1.28–1.43 (m, 4H),
and 0.88 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3) d¼186.2,
157.8, 136.0, 133.4, 130.3, 128.3, 83.4, 38.8, 35.1, 31.6, 22.6,
and 14.0; CIMS m/z 232 [MþH]þ; EIMS m/z 231 [M]þ (1),
214 [M2OH]þ (1), 202 [M2C2H5]þ (1), 185 [M2OH–
C2H5]þ (1),174[M2C4H9]þ (6),105[M2C7H12NO]þ (100),
77 [M2C7H12NO–CO]þ (45); HRMS Found: m/z 231.1269
[M]þ. Calcd for C14H17NO2: M, 231.1259.
3.2.2.7. 3-Benzoyl-5-cyanomethyl-4,5-dihydroisoxa-
1
3.2.2.2. 3-Benzoyl-5-pentyl-4,5-dihydroisoxazole (2b).
1
zole (7b). Yellow oil; IR (NaCl) 1654 and 1578 cm21; H
Pale-yellow oil; IR (NaCl) 1652 and 1571 cm21; H NMR
NMR (CDCl3) d¼8.17–8.20 (m, 2H), 7.46–7.64 (m, 3H),
5.01–5.09 (m, 1H), 3.63 (dd, J¼11.0, 18.0 Hz, 1H), 3.29
(dd, J¼7.0, 18.0 Hz, 1H), and 2.74–2.85 (m, 2H); 13C NMR
(CDCl3) d¼185.5, 158.0, 135.3, 133.9, 130.3, 128.5, 115.5,
(CDCl3) d¼8.17–8.20 (m, 2H), 7.42–7.59 (m, 3H), 4.73–
4.81 (m, 1H), 3.38 (dd, J¼10.8, 17.4 Hz, 1H), 2.98 (dd,
J¼8.6, 17.4 Hz, 1H), 1.73–1.81 (m, 1H), 1.57–1.66 (m,

1680
K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
76.8, 39.1, and 23.7; CIMS m/z 215 [MþH]þ; EIMS m/z
214 [M]þ (4), 174 [M2C2H2N]þ (2), 147 [M2C4H5N]þ
(6), 105 [M2C5H5N2O]þ (100), 77 [M2C5H5N2O–CO]þ
(80); HRMS Found: m/z 214.0749 [M]þ. Calcd for
C12H10N2O2: M, 214.0742.
160.0, 136.4, 133.4, 130.3, 128.3, 86.7, 50.3, 31.0, 30.5,
28.1, 23.9, and 22.3; CIMS m/z 244 [MþH]þ; EIMS m/z
243 [M]þ (5), 158 [M2C5H9O]þ (4), 138 [M2C6H5O]þ
(4), 105 [M2C8H12NO]þ (100), 77 [M2C8H12NO–CO]þ
(79); HRMS Found: m/z 243.1251 [M]þ. Calcd for
C15H17NO2: M, 243.1259.
3.2.2.13. 3-Benzoyl-4,5-cycloocta-4,5-dihydroisoxazole
(13b). Pale-yellow oil; IR (NaCl) 1652 and 1579 cm21; 1H
NMR (CDCl3) d¼8.14–8.18 (m, 2H), 7.43–7.63 (m, 3H),
4.54–4.60 (m, 1H), 3.54–3.59 (m, 1H), 2.02–2.13 (m, 2H),
and 1.27–1.79 (m, 10H); 13C NMR (CDCl3) d¼186.8,
162.3, 136.5, 133.4, 130.3, 128.3, 87.5, 49.1, 29.8, 25.7,
25.5, 25.3, 25.1, and 24.6; CIMS m/z 258 [MþH]þ; EIMS
m/z 257 [M]þ (5), 228 [M2CHO]þ (1), 186 [M2C4H7O]þ
(1), 172 [M2C5H9O]þ (2), 152 [M2C6H5CO]þ (7), 105
[M2C9H14NO]þ (100), 77 [M2C9H14NO–CO]þ (62);
HRMS Found: m/z 257.1423 [M]þ. Calcd for C16H19NO2:
M, 257.1416.
3.2.2.8. 3-Benzoyl-5-phenoxymethyl-4,5-dihydroisoxa-
zole (8b). Pale-yellow oil; IR (NaCl) 1653 and 1583 cm21
;
1H NMR (CDCl3) d¼8.19–8.21 (m, 2H), 7.44–7.61 (m,
3H), 7.23–7.30 (m, 2H), 6.86–6.99 (m, 3H), 5.09–5.16 (m,
1H), 4.12 (q, J¼4.6 Hz, 2H), 3.50 (dd, J¼11.0, 17.6 Hz,
1H), and 3.40 (dd, J¼7.7, 17.6 Hz, 1H); 13C NMR (CDCl3)
d¼186.2, 158.2, 157.6, 135.7, 133.6, 130.3, 129.5, 128.4,
121.4, 114.6, 80.5, 68.4, and 36.3; CIMS m/z 282 [MþH]þ;
EIMS m/z 281 [M]þ (3), 188 [M2C6H5O]þ (3), 174
[M2C7H7O]þ (4), 105 [M2C10H10NO2]þ (100), 77
[M2C10H10NO2–CO]þ (74); HRMS Found: m/z
281.1050 [M]þ. Calcd for C17H15NO3: M, 281.1052.
3.2.2.9. 3-Benzoyl-5-acetoxymethyl-4,5-dihydroisoxa-
zole (9b). Pale-yellow oil; IR (NaCl) 1654 and 1578 cm21
;
3.2.2.14. 3-Benzoyl-5-propylisoxazole (14b). Pale-
yellow oil; IR (NaCl) 1663 and 1597 cm21 1H NMR
;
1H NMR (CDCl3) d¼8.05–8.16 (m, 2H), 7.35–7.58 (m,
3H), 4.94–5.01 (m, 1H), 4.25 (dd, J¼3.7, 12.1 Hz, 1H),
4.16 (dd, J¼5.5, 12.1 Hz, 1H), 3.41 (dd, J¼11.4, 17.6 Hz,
1H), 3.16 (dd, J¼7.5, 17.6 Hz, 1H), and 2.04 (s, 3H); 13C
NMR (CDCl3) d¼185.5, 170.1, 157.2, 135.2, 133.3, 129.9,
128.0, 79.5, 64.2, 35.7, and 20.2; CIMS m/z 248 [MþH]þ;
EIMS m/z 188 [M2C2H3O2]þ (7), 174 [M2C3H5O2]þ (8),
105 [M2C6H8NO3]þ (86), 77 [M2C6H8NO3–CO]þ (51),
43 [M2C11H10NO3]þ (100); HRMS Found: m/z 247.0859
[M]þ. Calcd for C13H13NO4: M, 247.0845.
(CDCl3) d¼8.28–8.31 (m, 2H), 7.48–7.64 (m, 3H), 6.52 (s,
1H), 2.80 (t, J¼7.5 Hz, 2H), 1.73–1.84 (m, 2H) and 1.01 (t,
J¼7.3 Hz, 3H); 13C NMR (CDCl3) d¼185.9, 174.4, 161.7,
135.7, 133.7, 130.5, 128.4, 101.6, 28.4, 20.7, and 13.5;
CIMS m/z 216 [MþH]þ; EIMS m/z 215 [M]þ (1), 105
[M2C6H8NO]þ (100), 77 [M2C6H8NO–CO]þ (65);
HRMS Found: m/z 215.0924 [M]þ. Calcd for C13H13NO2:
M, 215.0946.
3.2.2.15. 3-Benzoyl-5-butylisoxazole (15b). Pale-yellow
1
3.2.2.10. 3-Benzoyl-4,5-cyclopenta-4,5-dihydroisoxa-
zole (10b). Pale-yellow oil; IR (NaCl) 1651 and
oil; IR (NaCl) 1663 and 1597 cm21; H NMR (CDCl3)
d¼8.28–8.31 (m, 2H), 7.47–7.63 (m, 3H), 6.51 (s, 1H),
2.82 (t, J¼7.7 Hz, 2H), 1.69–1.76 (m, 2H), 1.37–1.46 (m,
2H), and 0.95 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3)
d¼185.9, 174.6, 161.7, 135.7, 133.7, 130.5, 128.4, 101.5,
29.3, 26.1, 22.0 and 13.5; CIMS m/z 230 [MþH]þ; EIMS
m/z 229 [M]þ (1), 105 [M2C7H10NO]þ (100), 77
[M2C7H10NO–CO]þ (55); HRMS Found: m/z 229.1083
[M]þ. Calcd for C14H15NO2: M, 229.1062.
1566 cm21
;
1H NMR (CDCl3) d¼8.14–8.16 (m, 2H),
7.43–7.60 (m, 3H), 5.23–5.26 (m, 1H), 4.07–4.12 (m,
1H), 2.19–2.24 (m, 1H), 2.01–2.05 (m, 1H), 1.69–1.91 (m,
3H), and 1.39–1.50 (m, 1H); 13C NMR (CDCl3) d¼186.7,
159.6, 136.5, 133.4, 130.3, 128.3, 89.6, 51.5, 35.7, 31.7, and
23.3; CIMS m/z 216 [MþH]þ; EIMS m/z 215 [M]þ (4), 198
[M2OH]þ (1), 186 [M2CHO]þ (2), 172 [M2C2H3O]þ
(3), 158 [M2C3H5O]þ (3), 144 [M2C4H7O]þ (2), 131
[M2C5H8O]þ (2), 110 [M2C6H5CO]þ (4), 105
[M2C6H8NO]þ (100), 77 [M2C6H8NO–CO]þ (69);
HRMS Found: m/z 215.0929 [M]þ. Calcd for C13H13NO2:
M, 215.0946.
3.2.2.16. 3-Benzoyl-5-pentylisoxazole (16b). Pale-
yellow oil; IR (NaCl) 1663 and 1598 cm21 1H NMR
;
(CDCl3) d¼8.28–8.31 (m, 2H), 7.46–7.62 (m, 3H), 6.51 (s,
1H), 2.80 (t, J¼7.5 Hz, 2H), 1.69–1.76 (m, 2H), 1.33–1.40
(m, 4H), and 0.89 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3)
d¼185.7, 174.5, 161.6, 135.7, 133.6, 130.4, 128.2, 101.4,
30.9, 26.9, 26.4, 22.0, and 13.7; CIMS m/z 244 [MþH]þ;
EIMS m/z 243 [M]þ (1), 105 [M2C8H12NO]þ (100), 77
[M2C8H12NO–CO]þ (49); HRMS Found: m/z 243.1246
[M]þ. Calcd for C15H17NO2: M, 243.1259.
3.2.2.11. 3-Benzoyl-4,5-cyclohexa-4,5-dihydroisoxa-
zole (11b). Pale-yellow oil; IR (NaCl) 1651 and
1579 cm21
;
1H NMR (CDCl3) d¼8.14–8.19 (m, 2H),
7.45–7.64 (m, 3H), 4.57–4.61 (m, 1H), 3.39–3.49 (m,
1H), 2.17–2.23 (m, 1H), 2.04–2.08 (m, 1H), 1.77–1.86 (m,
1H), 1.51–1.64 (m, 3H), and 1.25–2.36 (m, 2H); 13C NMR
(CDCl3) d¼186.9, 163.7, 136.2, 133.5, 130.6, 128.4, 82.1,
44.1, 25.5, 24.9, 21.6, and 19.8; CIMS m/z 230 [MþH]þ;
EIMS m/z 229 [M]þ (4), 212 [M2OH]þ (1), 200 [M2CHO]þ
(1), 186 [M2C2H3O]þ (2), 172 [M2C3H5O]þ (2), 158
[M2C4H7O]þ (4), 124 [M2C6H5CO]þ (5), 105
[M2C7H10NO]þ (100), 77 [M2C7H10NO–CO]þ (71);
HRMS Found: m/z 229.1100 [M]þ. Calcd for C14H15NO2:
M, 229.1103.
3.2.2.17. 3-Benzoyl-5-hexylisoxazole (17b). Pale-yellow
1
oil; IR (NaCl) 1663 and 1597 cm21; H NMR (CDCl3)
d¼8.28–8.30 (m, 2H), 7.49–7.65 (m, 3H), 6.52 (s, 1H),
2.84 (t, J¼7.7 Hz, 2H), 1.65–1.79 (m, 2H), 1.19–1.44 (m,
6H), and 0.90 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d¼186.1, 174.7, 161.8, 135.8, 133.9, 130.6, 128.5, 101.6,
31.3, 28.7, 27.4, 26.6, 22.4, and 14.0; CIMS m/z 258
[MþH]þ; EIMS m/z 257 [M]þ (1), 105 [M2C9H14NO]þ
(100), 77 [M2C9H14NO–CO]þ (43); HRMS Found: m/z
257.1406 [M]þ. Calcd for C16H19NO2: M, 257.1416.
3.2.2.18. Ethyl 3-benzoylisoxazolecarboxylate (18b).
Colorless needles from EtOH; mp 51.8–53.5 8C; IR (NaCl)
3.2.2.12. 3-Benzoyl-4,5-cyclohepta-4,5-dihydroisoxa-
zole (12b). Pale-yellow oil; IR (NaCl) 1653 and
1579 cm21
;
1H NMR (CDCl3) d¼8.13–8.15 (m, 2H),
1
7.43–7.62 (m, 3H), 4.90–4.95 (m, 1H), 3.81–3.90 (m,
1H), 1.98–2.02 (m, 2H), 1.83–1.85 (m, 2H), 1.71–1.75 (m,
2H), and 1.45–1.55 (m, 4H); 13C NMR (CDCl3) d¼186.9,
1665 and 1598 cm21; H NMR (CDCl3) d¼8.26–8.29 (m,
2H), 7.48–7.68 (m, 3H), 7.40 (s, 1H), 4.45 (q, J¼7.1 Hz,
2H), and 1.42 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3)

K. Itoh, C. A. Horiuchi / Tetrahedron 60 (2004) 1671–1681
1681
105, 5826–5833. (c) Kim, B. H.; Chung, Y. J.; Ryu, E. J.
Tetrahedron Lett. 1993, 34, 8465–8472.
d¼184.1, 161.9, 160.9, 156.0, 135.2, 134.2, 130.4, 128.5,
109.8, 62.4, and 13.8; CIMS m/z 246 [MþH]þ; EIMS m/z
246 [M]þ (3), 105 [M2C6H6NO3]þ (100), 77
[M2C6H6NO3–CO]þ (69); HRMS Found: m/z 245.0687
[M]þ. Calcd for C13H11NO4: M, 245.0688.
2. Andersen, S. H.; Sharma, K. K.; Torsell, K. B. G. Tetrahedron
1983, 39, 2241–2245.
3. Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni,
D. Synthesis 1987, 276–278.
3.2.2.19. 3-Benzoyl-6-hydroxy-5-cyclohexylisoxazole
(19b). Pale-yellow oil; IR (NaCl) 3437, 1662, and
4. Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587–1590.
5. Kozikowski, A. P.; Adamczyk, M. Tetrahedron Lett. 1982, 23,
3123–3126.
1599 cm21
;
1H NMR (CDCl3) d¼8.27–8.29 (m, 2H),
7.49–7.66 (m, 3H), 6.70 (s, 1H), 3.50 (brs, 1H), and
1.19–2.02 (m, 10H); 13C NMR (CDCl3) d¼185.9, 178.8,
161.6, 135.6, 134.0, 130.6, 128.5, 100.7, 65.8, 36.5, 30.9,
25.0, 21.5, and 15.2; CIMS m/z 272 [MþH]þ; EIMS m/z
203 [M268]þ (1), 105 [M2C9H12NO2]þ (100), 77
[M2C9H12NO2–CO]þ (38); HRMS Found: m/z 271.1220
[M]þ. Calcd for C16H17NO3: M, 271.1208.
6. (a) Kozikowski, A. P.; Chen, Y. Y. J. Org. Chem. 1981, 46,
˝
¨
5248–5255. (b) Muller, I.; Jager, V. Tetrahedron Lett. 1982,
23, 4777–4780.
7. (a) Jager, V.; Grund, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
50–58. (b) Lee, S. Y.; Lee, B. S.; Lee, C.-W.; Oh, D. Y. J. Org.
Chem. 2000, 65, 256–257.
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3.2.3. Reaction of acetone with CAN(IV). A reaction
mixture of acetone (3.0 ml) and CAN(IV) (0.2971 g,
0.5 mmol) was stirred under reflux for 10 h. The mixture
was extracted with diethyl ether (30 ml) and washed with
aq. sodium hydrogencarbonate solution (2£2.0 ml), satu-
rated aq. NaCl (2£2.0 ml) and water (2£2.0 ml). The
ethereal solution was dried over Na2SO4, and concentrated
in a vacuum. The resulting oil was 3,4-diacetyl-1,2,5-
oxadiazole 2-oxide (20).
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1
(NaCl) 1718 and 1605 cm21; H NMR (CDCl3) d¼2.74
(s, 3H) and 2.63 (s, 3H); 13C NMR (CDCl3) d¼188.9, 185.5,
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153.4, 111.5, 29.2, 28.2; CIMS m/z 172 [MþH]þ.
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3.2.4. Reaction of 1-octene (3) with CAN(III)-formic acid
in acetone. A mixture of 1-octyne (3) (0.0561 g, 0.5 mmol),
ammonium cerium (III) nitrate (0.2741 g, 0.5 mmol), and
formic acid (0.2302 g, 5.0 mmol) in acetone (3.0 ml) was
stirred under reflux for 10 h. After the usual work up, the
resulting oil was chromatographed on silica gel. Elution
with hexane–diethyl ether (5:1) gave 3-acetyl-5-hexyl-
isoxazole (3a) (0.0670 g, 68%).
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3.2.5. Reaction of 1-octene (3) with CAN(III)-formic acid
in acetophenone. A mixture of 1-octyne (3) (0.0561 g,
0.5 mmol), ammonium cerium(III) nitrate (0.2741 g,
0.5 mmol), and formic acid (0.2302 g, 5.0 mmol) in
acetophenone (3.0 ml) was stirred under reflux for 15 h.
After the usual work up, the resulting oil was chromato-
graphed on silica gel. Elution with hexane–diethyl ether
(5:1) gave 3-benzoyl-5-hexylisoxazole (3b) (0.0920 g,
71%).
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421–426.
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Acknowledgement
This work was financially supported by Frontier Project
‘Environmental Changes and Lifes Adaptation Strategies’.
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References and notes
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