A convenient and efficient one-pot synthesis of 3-acylisoxazoles using iron(III) salts

Article abstract of DOI:10.1055/s-2005-916041

3-Acylisoxazoles were synthesized by the reaction of alkenes or alkynes with ketones (acetone or acetophenone), as both a reagent and the solvent, by three methods: iron(III) nitrate under reflux, iron(III) salt-nitrogen dioxide (NO2) at room temperature,

Full text of DOI:10.1055/s-2005-916041

PAPER
3541
A Convenient and Efficient One-Pot Synthesis of 3-Acylisoxazoles Using
Iron(III) Salts
O
ne-Pot Synthesis
e
of 3-Acylis
n
oxazole
s
U
s
-
ing Iron(
i
III) Sa
c
lts hi Itoh,a Hiroshi Sakamaki,a Noriko Nakazato,b Atsuo Horiuchi,b Ernst Horn,b C. Akira Horiuchi*b
a
College of Science and Technology, Nihon University, 7-24-1 Narashinodai Funabashi-shi, Chiba 274-8501, Japan
Department of Chemistry, Rikkyo (St. Paul’s) University, 3-34-1 Nishi-Ikebukuro, Toshima-ku Tokyo 171-8501, Japan
Fax +81(3)39852397; E-mail: horiuchi@rikkyo.ac.jp
b
Received 12 May 2005; revised 29 June 2005
CAN(IV)
or
CAN(III)–HCOOH
Abstract: 3-Acylisoxazoles were synthesized by the reaction of
alkenes or alkynes with ketones (acetone or acetophenone), as both
a reagent and the solvent, by three methods: iron(III) nitrate under
reflux, iron(III) salt–nitrogen dioxide (NO2) at room temperature,
and iron(III) nitrate under microwave irradiation (MW).
O
N
R2
R1
R1
acetone (R2 = Me)
or
acetophenone (R2 = Ph)
O
CAN(IV): (NH4)2Ce(NO3)6
CAN(III): (NH4)2Ce(NO3)5
Key words: alkenes, alkynes, ketones, iron(III) nitrate, 3-acylisox-
azoles
CAN(IV)
or
O
N
CAN(III)–HCOOH
R2
R3
R3
Isoxazoles play an important role in biochemistry, organic
chemistry, and bioorganic chemistry. The isoxazole ring
is a mimic of both carboxylic acid and amide functions,
isoxazoles are frequently used in agrochemicals and med-
icines.1–3 In synthetic organic chemistry, 4,5-dihydroisox-
azoles are versatile synthetic intermediates in the
preparation of a variety of compounds with 1,3-difunc-
tional groups such as b-hydroxy ketones,4 g-amino alco-
hols,5 a,b-unsaturated oximes,6 and b-hydroxy nitriles.7
We have recently reported the novel one-pot synthesis of
3-acylisoxazoles using CAN.8 The reaction of alkenes or
alkynes with CAN(IV) [(NH4)2Ce(NO3)6] or CAN(III)
[(NH4)2Ce(NO3)5·4H2O] and formic acid in acetone under
reflux gave the 3-acetylisoxazole derivatives. In the case
of acetophenone, 3-benzoylisoxazole derivatives were
obtained (Scheme 1).9 In the literature, 3-acetylisoxazole
derivatives were transformed into N-{4-[4-isoxazolyl]-2-
thiazolyl} oxamic acid derivatives, potent orally active
antianaphylactic agents.10 The 3-benzoylisoxazole deriva-
tives have also become interesting key building blocks for
drug candidates such as 3-[2-(2,5-dimethylphenoxymeth-
yl)-a-methoxyiminobenzyl]isoxazole which possess po-
tent fungicidal activity against crop diseases11 and 3-(1-
hydroxybenzyl)-5-dimethylaminomethylisoxazole me-
thiodide, an antimuscarinic agents.12
acetone (R2 = Me)
or
acetophenone (R2 = Ph)
O
Scheme 1 One-pot synthesis of 3-acylisoxazoles using CAN8,9
It is known that iron(III) nitrate converts aromatic com-
pounds into nitro compounds,14 while clayfen [iron(III)
nitrate impregnated on K-10 bentonite clay] was em-
ployed for the oxidation of alcohols,15 the nitration of al-
kenes,16 the cleavage of thioacetals to aldehydes or
ketones,17 and the conversion of hydrazines to azides.18 In
this paper, we would like to propose a convenient and ef-
ficient one-pot synthesis of 3-acylisoxazoles using
iron(III) salts: iron(III) nitrate under reflux and iron(III)
chloride–nitrogen dioxide (NO2) at room temperature. In
addition, to increase the reactivity and to shorten the reac-
tion time, a microwave-assisted reaction was developed.
Synthesis of 3-Acylisoxazoles by Iron(III) Nitrate
In order to develop a new one-pot synthesis of 3-acylisox-
azoles using inexpensive and non-toxic metal nitrate, the
reactions of 1-octene (1) with several metal nitrates in ac-
etone were carried out (Scheme 2 and Table 1). Although
nitrates such as ammonium, magnesium(II), and alumi-
num(III) gave undesired results (Table 1, entries 1–3), the
use of iron(III) or copper(II) nitrate afforded 3-acetyl-5-
hexyl-4,5-dihydroisoxazole (2)9 in 85% and 22% yields,
respectively (Table 1, entries 4 and 5). In particular, the
reaction using iron(III) nitrate gave the best yield of 2.
We have investigated many novel reaction systems using
cerium salts13 for selective oxidations. Although reactions
with cerium salts proceeded smoothly, a reaction using
non-toxic and inexpensive metal salts is required from an
economic, practical, and environmental point of view.
Along this line, we selected iron(III) nitrate as a mild and
safe oxidizing reagent for isoxazole formation. Iron(III)
nitrate is an abundant, cheap, and non-toxic metal nitrate.
Initially the effect of the amount of iron(III) nitrate was
examined (Table 2, entries 1–5). The corresponding isox-
azole derivative 2 was obtained in 85% yield when
equimolar amounts of iron(III) nitrate and olefin were
used (Table 2, entry 2). Increasing or decreasing the
amount of iron(III) nitrate decreased the yield. It seems
SYNTHESIS 2005, No. 20, pp 3541–3548
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-916041; Art ID: F08505SS
© Georg Thieme Verlag Stuttgart · New York

3542
K.-i. Itoh et al.
PAPER
O
N
O N
Fe(NO3)3
metal nitrate
R2
R2
R1
R1
R1
R1
acetone (R2 = Me)
or
acetophenone (R2 = Ph)
acetone
O
O
1
1
: R1 = n-C H
2
6
13
1, 3–11
2, 16–24
29–38
2 : R1 = n-C6H13, R2 = Me
Scheme 2
2: R1 = n-C6H13, R2 = Me
16: R1 = n-C5H11, R2 = Me
17: R1 = n-Bu, R2 = Me
29: R1 = n-C6H13, R2 = Ph
30: R1 = n-C5H11, R2 = Ph
31: R1 = n-Bu, R2 = Ph
18: R1 = n-Pr, R2 = Me
32: R1 = n-Pr, R2 = Ph
Table 1 Reaction of 1-Octene (1) with Metal Nitrate in Acetone
19: R1 = CH2C6H11, R2 = Me
20: R1 = CH2Ph, R2 = Me
21: R1 = CH2SMe, R2 = Me
22: R1 = CH2CN, R2 = Me
23: R1 = CH2OPh, R2 = Me
24: R1 = CH2CO2Me, R2 = Me
33: R1 = CH2C6H11, R2 = Ph
34: R1 = CH2Ph, R2 = Ph
35: R1 = CH2SMe, R2 = Ph
36: R1 = CH2CN, R2 = Ph
37: R1 = CH2OPh, R2 = Ph
Entrya
Metal nitrate
NH4NO3
Time (h)
Product (%)b
No reaction
No reaction
No reaction
2 (85)
1
2
3
4
5
30
25
25
10
20
38: R1 = CH2CO2Me, R2 = Ph
Mg(NO3)2
Al(NO3)3
Fe(NO3)3
Cu(NO3)2
Scheme 3
N
O
Fe(NO3)3
R2
2 (22)
acetone (R2 = Me)
n
O
a 1-Octene (1; 0.5 mmol), metal nitrate (0.5 mmol), and acetone (3.0
mL) were reacted under reflux.
or
n
acetophenone (R2 = Ph)
b Determined by GLC analysis using n-dodecane as internal hydrocar-
bon standard.
12–15
25–28
39–42
25: n = 0, R2 = Me
26: n = 1, R2 = Me
27: n = 2, R2 = Me
28: n = 3, R2 = Me
39: n = 0, R2 = Ph
40: n = 1, R2 = Ph
41: n = 2, R2 = Ph
42: n = 3. R2 = Ph
that the product or intermediate was oxidized by an excess
of iron(III) nitrate. On the basis of these results, we further
examined the reaction of alkenes 3–15 and alkynes 43–48
using iron(III) nitrate (0.5 mmol, 1.0 equiv) in acetone or
acetophenone (Schemes 3– 5). These results are shown in
Tables 2 and 3. The reaction of 1-alkenes 3–5, allyl com-
pounds 6–11, and cycloalkenes 12–15 using iron(III) ni-
trate in acetone under reflux gave the corresponding 3-
acetyl-4,5-dihydroisoxazoles 16–28 in about 39–80%
yields (Table 2, entries 6–18). In the case of acetophe-
none, the corresponding 3-benzoyl-4,5-dihydroisoxazoles
29–42 were obtained in 39–88% yields (Table 2, entries
19–32). Also, the reaction of several alkynes 43–48 using
iron(III) nitrate in acetone or acetophenone afforded the
corresponding isoxazole derivatives 49–54 and 55–60 in
high yields of 65–87% (Table 3). This reaction by the ap-
plication of iron(III) nitrate gave the corresponding isox-
azole derivatives in similar high yields, compared with the
reaction using CAN(III)–formic acid.8,9 It seems that this
reaction mediated by Fe3+ accelerates the formation of
isoxazole derivatives, while not promoting side-reactions
including the nitration of alkenes. The iron salt was re-
moved by filtration using hyflo super-cel® as a filter aid
after the reaction, thus, the isoxazole derivatives were
simply isolated by silica gel column chromatography,
compared with the more complicated techniques required
for the reaction using CAN. This reaction uses inexpen-
sive and non-toxic iron(III) nitrate, providing a conve-
nient and useful one-pot synthesis of the 3-acetyl- and 3-
benzoylisoxazole derivatives.
Scheme 4
O
N
Fe(NO3)3
R2
R3
R3
acetone (R2 = Me)
or
acetophenone (R2 = Ph)
O
43–48
49–54
55–60
49: R3 = n-C6H13, R2 = Me
50: R3 = n-C5H11, R2 = Me
51: R3 = n-Bu, R2 = Me
52: R3 = n-Pr, R2 = Me
53: R3 = CO2Et, R2 = Me
54: R3 = c-C6H10OH, R2=Me
55: R3 = n-C6H13, R2 = Ph
56: R3 = n-C5H11, R2 = Ph
57: R3 = n-Bu, R2 = Ph
58: R3 = n-Pr, R2 = Ph
59: R3 = CO2Et, R2 = Ph
60: R3 = c-C6H10OH, R2 = Ph
Scheme 5
Structural Analysis (X-ray Analysis)
We previously reported the structures of 2, 16–42, and
49–60 determined by spectral methods such as 1H NMR,
13C NMR, IR spectroscopy, EIMS, and HRMS.9 In this
paper, the structure of ethyl 3-benzoylisoxazolecarboxy-
late (59) was confirmed by X-ray analysis and the ORTEP
drawing is shown in Figure 1.
Synthesis of 3-Acylisoxazoles by Iron(III) Salts–NO2
System
It is known that iron(III) nitrate decomposes at high tem-
peratures, and nitrogen oxides (NOx) including nitrogen
Synthesis 2005, No. 20, 3541–3548 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Acylisoxazoles Using Iron(III) Salts
3543
Table 2 Reaction of Alkenes 1, 3–15 with Iron(III) Nitrate in Acetone or Acetophenone
Entrya
1
Substrate
Fe(NO3)3 (equiv)
Solvent
Time (h)
55
10
10
10
10
8
Product (%)b
2 (44)
1 (R1 = n-C6H13)
0.5
1.0
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
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
2
1
Acetone
2 (85)
3
1
Acetone
2 (80)
4
1
Acetone
2 (75)
5
1
Acetone
2 (68)
6
3 (R1 = n-C5H11)
Acetone
16 (77)
17 (77)
18 (75)
19 (79)
20 (80)
21 (49)
22 (68)
23 (70)
24 (58)
25 (57)
26 (39)
27 (65)
28 (83)
29 (88)
30 (86)
31 (85)
32 (82)
33 (87)
34 (88)
35 (56)
36 (79)
37 (84)
38 (88)
39 (68)
40 (69)
41 (72)
42 (82)
7
4 (R1 = n-Bu)
Acetone
8
8
5 (R1 = n-Pr)
Acetone
8
9
6 (R1 = CH2C6H11)
Acetone
10
10
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
7 (R1 = CH2Ph)
Acetone
8 (R1 = CH2SMe)
Acetone
9 (R1 = CH2CN)
Acetone
8
10 (R1 = CH2OPh)
Acetone
8
11 (R1 = CH2CO2Me)
Acetone
8
12 (n = 0)
Acetone
8
13 (n = 1)
Acetone
8
14 (n = 2)
Acetone
12
12
15
12
12
10
14
14
12
12
12
12
12
12
15
15
15 (n = 3)
Acetone
1
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
3
4
5
6
7
8
9
10
11
12
13
14
15
a Substrate 1, 3–15 (0.5 mmol), iron(III) nitrate (0.25–2.0 mmol), and acetone (3.0 mL) were reacted under reflux. Substrate 1, 3–15 (0.5 mmol),
iron(III) nitrate (0.5 mmol), and acetophenone (3.0 mL) were reacted at 80 °C.
b Determined by GLC analysis using n-dodecane as the internal hydrocarbon standard.
Synthesis 2005, No. 20, 3541–3548 © Thieme Stuttgart · New York

3544
K.-i. Itoh et al.
PAPER
Table 3 Reaction of Alkynes 43–48 with Iron(III) Nitrate in Ace-
tone or Acetophenone
monoxide (NO) and nitrogen dioxide (NO2) are generated
from iron(III) nitrate. Also, we previously proposed a 1,3-
dipolar cycloaddition mechanism for the reaction of dipo-
larophiles and nitrile oxides via the acid-catalyzed dehy-
dration of a-nitroketones from the nitration of acetone or
acetophenone (Scheme 6).9 In the present reaction, it
seems that nitrogen oxides play an important role in the
nitration of ketones. In order to investigate this reaction
mechanism, the reaction of 1-octene (1) using iron salts
and nitrogen dioxide gas in acetone was carried out
(Scheme 7, Table 4). Nitrogen dioxide is an inorganic
compound, but it may be regarded as the nitro group itself
from the standpoint of organic chemistry. Hence, nitrogen
dioxide was employed as the nitrating agent for several
organic compounds.19–23 The reaction using nitrogen di-
oxide in the absence of iron salts did not give the corre-
sponding isoxazole derivative, but gave 1-nitro-1-octene
(61) and 1-nitro-2-octanol (62) in 23% and 22% yields, re-
spectively (Table 4, entry 1). When nitrogen dioxide was
bubbled through (ca. 45 mL/min) 1-octene (1; 0.5 mmol),
iron(III) chloride (0.5 mmol, 1.0 equiv), and acetone (3.0
mL) at room temperature, the corresponding isoxazole de-
rivative 2 was obtained in a moderate yield of 68%
(Table 4, entry 8). The yields of the isoxazole derivative
decreased as the temperature or the amount of iron(III)
chloride increased (Table 4, entries 9–12). In addition, the
reaction using ammonium iron(III) sulfate gave the corre-
sponding isoxazole derivative 2 in 51% yield, however, in
the case of FeO(OH) as the oxidant, only trace amounts of
the isoxazole derivatives were obtained (Table 4, entries
13 and 14). On the other hand, the use of iron(II) chloride
gave the isoxazole derivative 2 in low yields of 10–19%
(Table 4, entries 15–20). Increasing of the amount of
iron(II) chloride did not accelerate the formation of isox-
azole derivative, but escalated the side reactions to nitro-
olefin and nitro-alcohol. Also, the reaction using iron(II)
acetate and iron(II) sulfate furnished very little of the cor-
responding isoxazole derivative (Table 4, entries 21 and
22). From the results, it is shown that the presence of Fe3+
is required for the formation of isoxazole derivatives, and
the application of Fe3+ efficiently produced the isoxazole
derivatives, compared with the application of Fe2+. We
propose the reaction pathway shown in Scheme 8. It
Entrya Substrate
Solvent
Time Product
(h)
12
12
10
10
15
15
(%)b
1
2
43 (R3 = n-C6H13)
Acetone
Acetone
Acetone
Acetone
Acetone
49 (79)
50 (78)
51 (71)
52 (65)
53 (86)
54 (87)
55 (85)
56 (82)
57 (74)
58 (74)
59 (79)
60 (79)
44 (R3 = n-C5H11)
45 (R3 = n-Bu)
46 (R3 = n-Pr)
3
4
5
47 (R3 = CO2Et)
6
48 (R3 = c-C6H10OH) Acetone
7
43
44
45
46
47
48
Acetophenone 14
Acetophenone 14
Acetophenone 12
Acetophenone 12
Acetophenone 18
Acetophenone 18
8
9
10
11
12
a Substrate 43–48 (0.5 mmol), iron(III) nitrate (0.5 mmol), and ace-
tone (3.0 mL) were reacted under reflux. Substrate 43–48 (0.5 mmol),
iron(III) nitrate (0.5 mmol), and acetophenone (3.0 mL) were reacted
at 80 °C.
b Determined by GLC analysis using n-dodecane as the internal hy-
drocarbon standard.
Figure 1 ORTEP drawing of ethyl 3-benzoylisoxazolecarboxylate
H+
O
O
O
OH
NO2H
N+
NO2
R2
R2
OH
R2
H+
– H2O
H
+
OH
O
O
O
C
N
O
C
N
O
N
R2
R2
+
R2
– H2O
O
Scheme 6 Formation of nitrile oxides from ketones9
Synthesis 2005, No. 20, 3541–3548 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Acylisoxazoles Using Iron(III) Salts
3545
Table 4 Reaction of 1-Octene (1) with Fe Salts–NO2 in Acetone
Entrya
1
Iron salts
–
Equivalents
–
Temperature(°C)Time (h)
2 (%)b
–
61 (%)b
23
8
62 (%)b
22
11
12
8
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
reflux
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
12
12
12
1
2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeNH4(SO4)2
FeO(OH)
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
0.1
trace
12
3
0.5
14
12
13
13
15
15
14
15
19
21
25
28
19
20
25
26
31
36
19
26
4
1.0
20
5
1.0
3
25
9
6
1.0
6
40
9
7
1.0
9
61
11
11
10
14
14
18
21
27
17
17
17
17
15
14
21
22
8
1.0
12
12
12
12
12
12
20
12
12
12
12
12
12
14
14
68
9
1.0
29
10
11
12
13
14
15
16
17
18
19
20
21
22
1.5
54
2.0
44
4.0
29
1.0
51
1.0
trace
trace
10
0.1
0.5
1.0
19
1.5
16
2.0
15
4.0
12
Fe(CH3COO)2 1.0
FeSO4 1.0
trace
4
a NO2 was bubbled (ca. 45 mL/min, 20 s) through 1-octene (1; 0.5 mmol), iron(III) salt (0–2.0 mmol), and acetone (3.0 mL).
b Determined by GLC analysis using n-dodecane as the internal hydrocarbon standard.
O
N
seems that this reaction can proceed by two reaction path-
ways: the nitration of alkenes by nitrogen dioxide (Path
A), and the 1,3-dipolar cycloaddition of dipolarophiles
and nitrile oxides in ketones (Path B). It seems that the
role of Fe3+ is to promote the nitration of ketones by nitro-
gen dioxide. Therefore a-nitroketones are transformed
into nitrile oxides through protonation and dehydration,
which is generated from the oxidation and nitration of ke-
tones by Fe3+ or nitrogen dioxide, followed by the forma-
tion of isoxazole derivatives (Path B). However, partial
direct nitration of alkenes by nitrogen dioxide occurs
(Path A), the isoxazole derivatives are obtained in only
moderate yield (68%).
OH
FeCl3/NO2
acetone
R2
NO2
R1
R1
R1
+
+
ON2
R1
O
1
2
61
62
2: R1 = n-C6H13, R2 = Me
61, 62: R1 = n-C6H13
Scheme 7
In the present method, the corresponding isoxazole deriv-
atives were obtained at room temperature using nitrogen
dioxide; therefore, we applied this method to highly reac-
tive acetylenic compounds. Although the reaction of ethy-
nylbenzene (63) using iron(III) nitrate under reflux
conditions gave a poor yield (15%), the corresponding
isoxazole derivative 64 was obtained in 51% yield when
iron(III) chloride and nitrogen dioxide were employed at
room temperature (Scheme 9). Consequently, the newly
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3546
K.-i. Itoh et al.
PAPER
OH
NO2
NO2
R1
+
NO2
R1
Path A
R1
O
N
R1
Path B
O
O
O
H+
Fe3+ / NO2
O
O
O
C
N
O
NO2
N
N
O
– H2O
O
Scheme 8 Reaction pathway using FeCl3–NO2 in acetone
proposed method provides an efficient one-pot synthesis Table 5 Application of Microwave Irradiation
of 3-acetylisoxazole derivatives from active alkynes and
shows a novel and efficient utilization of nitrogen dioxide.
Entry
Watts
80
Time (s)
20
Product 2 (%)b
1
2
19
44
45
56
76
53
34
79
75
72
O
N
FeCl3/NO2
acetone
R2
90
20
O
3
100
110
120
130
120
120
120
120
20
63
64: R2 = Me Yield: 51%
4
20
Scheme 9 NO2 was bubbled (ca. 45 mL/min, 20 s) through substrate
63 (0.5 mmol), iron(III) chloride (0.5 mmol), and acetone (4.0 mL)
were reacted at room temperature.
5
20
6
20
7
10
Effect of Microwave Irradiation on the Synthesis of
3-Acylisoxazoles by Iron(III) Nitrate
8
30
9
40
Microwave irradiation has been used to accelerate a vari-
ety of organic reactions.24 Varma and co-workers reported
that styrene derivatives were nitrated by the application of
iron(III) nitrate and microwave irradiation.16 Therefore,
we attempted to apply microwave irradiation to the reac-
tion using iron(III) nitrate (Scheme 10 and Table 5). When
1-octene (1; 0.5 mmol), iron(III) nitrate (0.5 mol), and ac-
etone (3.0 mL) were reacted under microwave irradiation
(120 W) for 30 minutes at 60 °C, the corresponding isox-
azole derivative 2 was obtained in 79% yield (Table 5, en-
try 8). We also found that irradiation time influenced the
yields of isoxazole derivatives (Table 5, entries 7–10).
The optimum irradiation time was 30 seconds, it appears
that longer irradiation times accelerated the nitration of
acetone. Based on these results, this method is shown to
be a new microwave-assisted one-pot synthesis of 3-
acetylisoxazole derivatives, which requires a short reac-
tion time.
10
50
a 1-Octene (1; 0.5 mmol), Fe(NO3)3 (0.5 mmol), and acetone (3.0 mL)
were employed. Microwave setting: power, 80–130 W; pressure, 15
bar; 60 °C.
b Determined by GLC analysis using n-dodecane as the internal hy-
drocarbon standard.
tion time, this reaction using microwave irradiation is a
novel and efficient method for synthesizing isoxazole de-
rivatives.
O
N
Fe(NO3)3/MW
R2
R1
R1
acetone (R2 = Me)
O
1 : R1 = n-C6H13
2 : R1 = n-C6H13, R2 = Me
1
2
In conclusion, the reaction using non-toxic and inexpen-
sive iron(III) nitrate provides a simple, convenient and ef-
ficient one-pot synthesis of 3-acetyl- and 3-
benzoylisoxazole derivatives. In addition, the method us-
ing iron(III) salts and nitrogen dioxide (NO2) gave new
isoxazole derivatives under mild conditions and repre-
sents a new and effective utilization of nitrogen dioxide.
Also, because the microwave-assisted synthesis of the 3-
acetylisoxazole derivatives appreciably reduces the reac-
Scheme 10
Melting points were determined on a Yanaco micro melting point
apparatus. The IR spectra were recorded using a Jasco FT-IR 230
spectrometer. The 1H and 13C NMR spectra were measured using a
JEOL GSX 400 Model spectrometer in CDCl3 with TMS as the in-
ternal standard. GLC analyses were performed using a GLC-col-
umn (DB-1, 25 m) equipped with a Shimazu GLC-17A. HRMS (EI)
Synthesis 2005, No. 20, 3541–3548 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Acylisoxazoles Using Iron(III) Salts
3547
analyses were performed on a JMS-GLC mate II/HP-6890 with an
ionizing energy of 70 eV. All chemicals were purchased from Kanto
Kagaku, Tokyo Kasei Kogyo Corporation and Wako Pure Chemical
Industries, Ltd. (silica gel 60: 0.063–0.200 nm). The yields of the
products were determined by GLC analysis using n-dodecane as the
internal hydrocarbon standard. The reaction conditions are shown in
Tables 1– 5. The spectral data (IR, 1H NMR, 13C NMR, EIMS, CI-
MS, and HRMS) of 3-acetylisoxazoles 2, 16–28, and 49–54 and 3-
benzoylisoxazoles 29–42, 55–60 were reported in our previous pa-
per.9
3-Acetyl-5-phenylisoxazole (64)
Colorless needles (hexane); mp 99.8–100.6 °C.
IR (KBr): 1707, 1559 cm–1.
1H NMR (CDCl3): d = 7.79–7.83 (m, 2 H), 7.47–7.54 (m, 3 H), 6.89
(s, 1 H), 2.70 (s, 3 H).
13C NMR (CDCl3): d = 192.2, 171.7, 162.7, 130.8, 129.1, 126.0,
97.7, 27.3.
HRMS: m/z calcd for C11H9NO2: 187.0633; found: 187.0634.
Microwave-Irradiated Reaction; Typical Procedure
Reaction of 1-Octene (1) with Iron(III) Nitrate in Acetone;
Typical Procedure
A mixture of 1-octene (1; 0.0561 g, 0.5 mmol), iron(III) nitrate no-
nahydrate (0.2020 g, 0.5 mmol) and acetone (3.0 mL) were irradiat-
ed (120 W) at 60 °C for 30 min in a self-tuning single-mode CEM
DiscoverTM Focused Synthesizer. The reaction mixture was filtered
through hyflo super-cel® and the residue on the funnel was washed
with acetone (2 × 3 mL). After the filtrate was concentrated in vac-
uo, the residue was dissolved in EtOAc (10 mL), washed with aq
NaHCO3 (2 × 2 mL), sat. aq NaCl (2 × 2 mL), and H2O (2 × 2 mL).
The combined organic phases were dried over Na2SO4 and concen-
trated in vacuo. The residue was chromatographed (hexane–EtOAc,
4:1) to give 29 as a pale yellow oil (0.0507 g, 51%).
A mixture of 1-octene (1; 1.122 g, 10.0 mmol) and iron(III) nitrate
nonahydrate (4.040 g, 10.0 mmol) in acetone (40 mL) was stirred
under reflux for 10 h. The reaction mixture was filtered through hy-
flo super-cel® and the residue on the funnel was washed with ace-
tone (2 × 10 mL). The filtrate was concentrated in vacuo, the residue
was dissolved in EtOAc (100 mL) and washed with aq NaHCO3
(2 × 5 mL), sat. aq NaCl (2 × 5 mL), and H2O (2 × 5 mL). The com-
bined organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was chromatographed (hexane–EtOAc, 4: 1) to
give 29 as a pale yellow oil (1.349 g, 68%).
Reaction of 1-Octene (1) with Iron(III) Nitrate in Acetophe-
none; Typical Procedure
Acknowledgment
A mixture of 1-octene (1; 1.122 g, 10.0 mmol) and iron(III) nitrate
nonahydrate (4.040 g, 10.0 mmol) in acetophenone (40 mL) was
stirred at 80 °C for 15 h. The reaction mixture was filtered through
hyflo super-cel® and the residue on the funnel was washed with ac-
etone (2 × 10 mL). The filtrate was concentrated in vacuo, the resi-
due was dissolved in EtOAc (100 mL), washed with aq NaHCO3
(2 × 5 mL), sat. aq NaCl (2 × 5 mL), and H2O (2 × 5 mL). The com-
bined organic phases were dried over Na2SO4, concentrated in vac-
uo, and acetophenone was removed by reduced pressure distillation.
The residue was chromatographed (hexane–EtOAc, 4:1) to give 299
as a pale yellow oil (1.843 g, 71%).
This work was partially supported by the Frontier Project ‘Environ-
mental Changes and Life Adaptation Strategies’ and a Grant-in-Aid
for Scientific Research (No. 15550140). The authors are indebted to
Mr Youhei Shimizu for his collaboration in the experimental work
using microwaves.
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Molecular formula: C13H11NO4, Fw: 245.23, clear plate-like, size:
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Synthesis 2005, No. 20, 3541–3548 © Thieme Stuttgart · New York