A convenient synthesis of 3-benzoylisoxazoles by 1,3-dipolar cycloaddition

Article abstract of DOI:10.3987/COM-02-9618

A convenient, efficient method for the preparation of 3-benzoylisoxazoles is described. Nitrile oxides generated in situ from phenylglyoxylohydroxamyl chlorides and NaHCO₃ in isopropyl alcohol smoothly react with dipolarophiles at room temperat

Full text of DOI:10.3987/COM-02-9618

HETEROCYCLES, Vol. 57, No. 12, 2002, pp. 2299 - 2308, Received, 2nd September, 2002
A CONVENIENT SYNTHESIS OF 3-BENZOYLISOXAZOLES BY 1,3-
DIPOLAR CYCLOADDITION
Hiroyuki Kai,* Minoru Tomida, Toru Nakai, and Akira Takase
Discovery Research Laboratories, Shionogi & Co., Ltd., Koka-cho, Koka-gun, Shiga
520-3423, Japan E-mail: hiroyuki.kai@shionogi.co.jp
Abstract – A convenient, efficient method for the preparation of 3-benzoylisoxazoles
is described. Nitrile oxides generated in situ from phenylglyoxylohydroxamyl
chlorides and NaHCO3 in isopropyl alcohol smoothly react with dipolarophiles at
room temperature to provide the cycloadducts.
INTRODUCTION
Isoxazoles are well known to constitute structural parts of a number of natural products, pharmaceuticals,
agrochemicals, polymers and other useful compounds.1 During the course of our ongoing program on the
synthesis of drug candidates, 3-benzoylisoxazoles (1) have become interesting key building blocks. For
example, 3-[2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl]isoxazole (2) shows a potent fungicidal
activity against crop diseases2 while 2-(1H-1,2,4-triazol-1-yl)-1-(3-isoxazolyl)-1-phenylethanols (3) show
potent oral antifungal activities.3 Although a few synthetic methods for 4,5-unsubsituted 3-benzoylisoxazoles
by means of 1,3-dipolar cycloaddition were reported,4 those methods comprised rather complicated reaction
procedures and the over-all yields were unsatisfactory. Recently, we found a new and convenient method for
the construction of 3-benzoylisoxazoles (1) by means of 1,3-dipolar cycloaddition between benzoylnitrile
oxides (4) and dipolarophiles, which is the subject of this paper.
Me
Me
MeO
O
N
O
O
N
N
N
2
O
N
C N O
R1
R1
N
N
O
1
4
HO
R1
O
Scheme 1
3

RESULTS AND DISCUSSION
First, we attempted to develop a method for constructing 3-benzoylisoxazoles by means of 1,3-dipolar
cycloaddition between benzoylnitrile oxide and vinyl ether followed by aromatization. For this purpose, 2-
methylphenylglyoxylohydroxamyl chloride (5a) and butyl vinyl ether was chosen to optimize the reaction
conditions, and the results are shown in Table 1. Compound (5a) was prepared by chloro-oximation5 of 2’-
methylacetophenone and the product was used for the cycloaddition reaction without further purification. The
cycloaddition of 5a with butyl vinyl ether by the known method6 resulted in the formation of 5-alkoxy-3-
benzoyl-2-isoxazoline (6a) in a 64% yield (Entry 1). However, the addition of triethylamine as a base was so
exothermic that this reaction condition seemed unsuitable for large scale production. Thermal in situ
generation7 of benzoylnitrile oxide (4a) by refluxing a mixture of 5a with excess butyl vinyl ether, provided a
cycloaddition product in only 19% yield (Entry 2). Eventually, the cycloaddition reaction of the nitrile oxide,
which generated in situ through the reaction of 5a with NaHCO3 in isopropyl alcohol at room temperature,8
proceeded smoothly and non-exothermically to produce a cycloadduct as a single regioisomer in 79% yield
(Entry 3). The NaHCO3 in the reaction was presumed to effect dehydrochlorination for the
phenylglyoxylohydroxamyl chloride giving rise to nitrile oxide and NaCl, while preserving the neutral and
mild reaction conditions leading to an improved yield.
Table 1 Examination of 1,3-dipolar cycloaddition
Me
O
Me
O
Me
O
BuOCH=CH2
(3 eq.)
Cl
C N O
OBu
N
N
OH
O
5a
4a
6a
Entry
Base (2 eq.)
Et3N
Solvent
Ether
Conditions
rt 15 h
reflux 4 h
rt 15 h
6a (%)a
64
1
2
3
b
–
–
19
79
NaHCO3
i-PrOH
a
b
Isolated yields. BuOCH=CH2 (10 eq.)
Next, we examined the aromatization reaction (elimination of alcohol)9 of 6a under either basic or acidic
conditions (Table 2). Treatment of 6a with MeONa (0.1 eq.) in methanol at room temperature for 23 h
provided a benzoylisoxazole (1a) in 48% yield (Entry 1). The desired elimination reaction was completed
under refluxing conditions to give 1a in 87% yield (Entry 2). On the other hand, when 6a was treated with p-
TsOH (0.1 eq.) in toluene, elimination reaction did not proceed at room temperature even after 19 h (Entry 3),
but the desired product was obtained in high yield after heating (Entries 4 and 5). Among the applied catalysts,
H2SO4 gave the best result, and the reaction was completed in a shorter time (Entry 6).

Table 2 Examination of aromatization (elimination of alcohol)
Me
O
Me
O
– BuOH
OBu
N
N
O
O
6a
1a
Entry
1
2
3
4
5
6
Catalyst (0.1 eq.)
MeONa
Solvent
MeOH
MeOH
Toluene
Toluene
Toluene
Toluene
Conditions
1a (%)a
48
6a (%)b
rt 23 h
reflux 7 h
rt 19 h
60°C 19 h
reflux 12 h
reflux 3 h
38
–
100
62
–
MeONa
p-TsOH
p-TsOH
p-TsOH
87
0
31
93
H2SO4
Recovery.
94
–
a
b
Isolated yields.
Finally, we applied the optimized reaction conditions (Entry 3 of Table 1 and Entry 6 of Table 2) to the
synthesis of various benzoylisoxazoles (1) starting from suitable acetophenones (7) (Table 3). The 1,3-dipolar
cycloaddition was not influenced by either electronic or steric effects of the substituent (R1), providing
isoxazolines (6a–f) in good yields (Entries 1–8). It is worth to mention that the reaction with ethyl 1-propenyl
ether as a dipolarophile proceeded regioselectively to provide 4-methylisoxazolines (6g–h) (Entries 7 and 8).
These results also suggested that an electron-donating group attached to one side of the double bond in
dipolarophile controlled the regioselectivity in the reaction.1, 10 Treatment of 6 with sulfuric acid in toluene
under reflux provided benzoylisoxazoles (1) in excellent yields.
Table 3 Preparation of 3-benzoylisoxazoles (1) from acetophenones (7) through cycloaddition followed by
aromatization
1) BuONO (3 eq.)
R2
R2
H2SO4
(0.1 eq.)
O
O
O
HCl (4 eq.)
Et2O, rt, 5-18 h
Me
R1
OR3
R1
R1
2) R3OCH=CHR2 (3 eq.)
NaHCO3 (2 eq.)
PhMe
reflux 3 h
N
N
O
O
7
6
1
i-PrOH, rt, overnight
Entry
R1
R2
H
H
H
H
H
H
Me
Me
R3
Isoxazoline Yield (%)a
Isoxazole Yield (%)a
1
2b
3
4
5
6
7
8
2-Me
H
4-F
2-Cl
4-Cl
Bu
Bu
Bu
Bu
Bu
Et
6a
6b
6c
6d
6e
6f
79
91
73
83
82
80
60
50
1a
1b
1c
1d
1e
1f
94
93
87
91
99
91
92
94
2-(2,5-Me2-C6H3)OCH2
4-Cl
Et
Et
6g
6h
1g
1h
3,4-Cl2
a
b
Isolated yields.
Starting material; PhCOCH2Cl, BuONO (1.5 eq.), HCl (2 eq.).

Although the 1,3-dipolar cycloaddition of nitrile oxides with alkynes is well documented as a useful method
especially for preparation of isoxazole derivatives, only a few cycloaddition reactions between nitrile oxides
and simple acetylene or 3,3,3-trifluoropropyne were reported.11 We next attempted to extend this method to
1,3-dipolar cycloaddition with acetylene or trifluoropropyne, and the results are shown in Table 4. The
cycloaddition with acetylene produced the corresponding benzoylisoxazoles in good yields (Entries 1 and 2).
On the other hand, the reactions with trifluoropropyne gave 5-trifluoromethyl-3-benzoylisoxazoles as a single
regioisomer in moderate yields (Entries 3 and 4).
Table 4 Preparation of 3-benzoylisoxazoles (1) from acetophenones (7) through cycloaddition of alkynes.
O
O
1) BuONO, HCl
Et2O, rt, 18 h
Me
R4
R1
R1
R4 C CH
2)
N
O
NaHCO3
i-PrOH, rt, overnight
7
1
Entry
R1
R4
H
H
CF3
CF3
Isoxazole
Yield (%)a
1
2
3
4
2-Me
1a
1f
1i
76
84
53
53
2-(2,5-Me2-C6H3)OCH2
2-Me
4-Cl
1j
a
Isolated yields.
In conclusion, a convenient method for in situ generation of nitrile oxides from chloro-oxime derivatives was
developed using NaHCO3 as the base in isopropyl alcohol. By use of this method, a series of
3-benzoylisoxazoles (1) were efficiently synthesized in high yield and with high regioselectivity.
EXPERIMENTAL
1H NMR spectra were recorded on a JEOL JNM-GSX 270 spectrometer at 270 MHz using tetramethylsilane
(TMS) as an internal standard. The melting points were measured using a Büchi 535 melting point apparatus,
and the values are given uncorrected. IR spectra were recorded on a JASCO FT/IR-300E spectrophotometer
using a potassium bromide disk. Column chromatography (CC) was carried out on Merck silica gel 60 (0.063–
0.200 mm).
The general procedure for the synthesis of 5-alkoxy-3-benzoyl-2-isoxazolines (6a–h).
Butyl nitrite (30.94 g, 0.3 mol) was added dropwise below 10°C over 20 min to a mixture of acetophenones 7
(0.1 mol), 5N hydrogen chloride in dioxane (80 mL, 0.4 mol), and Et2O (300 mL), then the mixture was stirred

at rt for 5–18 h. The reaction mixture was poured into Et2O (100 mL) and washed with brine (400 mL × 2).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to
give crude phenylglyoxylohydroxamyl chlorides (5), which was subjected to cycloaddition reaction without
further purification.
NaHCO3 (16.80 g, 0.2 mol) was added to a mixture of crude 5, butyl vinyl ether (30.05 g, 0.3 mol) and
isopropyl alcohol (200 mL) in an ice bath, and the mixture was stirred at rt for 15–24 h. The reaction mixture
was concentrated under reduced pressure, poured into ice-cold water (400 mL) and extracted with Et2O (400
mL). The organic layer was washed with brine (400 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by CC to give the isoxazolines (6).
5-Butoxy-3-(2-methylbenzoyl)-2-isoxazoline (6a). From 2’-methylacetophenone (7a). CC (AcOEt/
hexane: 1/9 v/v) gave 6a (79%) as a slightly brownish oil. 1H NMR (CDCl3) δ 0.93 (t, J=7.3 Hz, 3H), 1.36 (m,
2H), 1.56 (m, 2H), 2.44 (s, 3H), 3.22 (dd, J=18.5, 2.3 Hz, 1H), 3.36 (dd, J=18.5, 6.6 Hz, 1H), 3.58 (td, J=9.3,
6.6 Hz, 1H), 3.88 (td, J=9.3, 6.6 Hz, 1H), 5.73 (dd, J=6.6, 2.3 Hz, 1H), 7.22–7.36 (m, 2H), 7.74 (m, 1H), 7.74
(dd, J=7.9, 1.3 Hz, 1H). IR (KBr): 2959, 2872, 1660, 1573, 1258, 1188, 1095, 902 cm–1. Anal. Calcd for
C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.70; H, 7.33; N, 5.33.
3-Benzoyl-5-butoxy-2-isoxazoline (6b).12 From 2-chloroacetophenone (7b). CC (AcOEt/hexane:1/9 v/v)
gave 6b (90%) as a colorless oil. 1H NMR (CDCl3) δ 0.93 (t, J=7.3 Hz, 3H), 1.36 (m, 2H), 1.58 (m, 2H), 3.24
(dd, J=18.5, 2.3 Hz, 1H), 3.39 (dd, J=18.5, 6.6 Hz, 1H), 3.58 (td, J=9.3, 6.6 Hz, 1H), 3.89 (td, J=9.3, 6.6 Hz,
1H), 5.71 (dd, J=6.6, 2.3 Hz, 1H), 7.45–7.51 (m, 2H), 7.61 (m, 1H), 8.20–8.24 (m, 2H). IR (KBr): 2959, 2873,
1655, 1265, 1190, 1097 cm–1. Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.74; H,
6.82; N, 5.47.
5-Butoxy-3-(4-fluorobenzoyl)-2-isoxazoline (6c). From 4’-fluoroacetophenone (7c). CC (AcOEt/hexane:
2/8 v/v) gave 6c (73%) as a colorless oil. 1H NMR (CDCl3) δ 0.93 (t, J=7.3 Hz, 3H), 1.39 (m, 2H), 1.56 (m,
2H), 3.23 (dd, J=18.5, 2.3 Hz, 1H), 3.38 (dd, J=18.5, 6.6 Hz, 1H), 3.59 (td, J=9.5, 6.6 Hz, 1H), 3.89 (td, J=9.5,
6.6 Hz, 1H), 5.72 (dd, J=6.6, 2.3 Hz, 1H), 7.15 (m, 2H), 8.30 (m, 2H). IR (KBr): 2960, 2873, 1655, 1599, 1266,
1157, 1098, 902, 849 cm–1. Anal. Calcd for C14H16NO3F: C, 63.39; H, 6.08; N, 5.28; F, 7.16. Found: C,
63.35; H, 6.05; N, 5.19; F, 7.02.
5-Butoxy-3-(2-chlorobenzoyl)-2-isoxazoline (6d). From 2’-chloroacetophenone (7d). CC (AcOEt/hexane:
15/85 v/v) gave 6d (83%) as a colorless oil. 1H NMR (CDCl3) δ 0.92 (t, J=7.3 Hz, 3H), 1.38 (m, 2H), 1.56 (m,
2H), 3.22 (dd, J=18.5, 2.3 Hz, 1H), 3.34 (dd, J=18.5, 6.6 Hz, 1H), 3.57 (td, J=9.2, 6.3 Hz, 1H), 3.86 (td, J=9.2,
6.3 Hz, 1H), 5.77 (dd, J=6.6, 2.3 Hz, 1H), 7.36 (m, 1H), 7.43–7.48 (m, 2H), 7.55 (m, 1H). IR (KBr): 2959,
2873, 1674, 1573, 1254, 1192, 1099, 917, 833 cm–1. Anal. Calcd for C14H16NO3Cl: C, 59.68; H, 5.72; N,

4.97; Cl, 12.58. Found: C, 59.44; H, 5.58; N, 5.02; Cl, 12.33.
5-Butoxy-3-(4-chlorobenzoyl)-2-isoxazoline (6e). From 4’-chloroacetophenone (7e). CC (AcOEt/hexane:
15/85 v/v) gave 6e (82%) as a colorless oil. 1H NMR (CDCl3) δ 0.93 (t, J=7.3 Hz, 3H), 1.39 (m, 2H), 1.59 (m,
2H), 3.23 (dd, J=18.5, 2.3 Hz, 1H), 3.38 (dd, J=18.5, 6.6 Hz, 1H), 3.59 (td, J=9.5, 6.6 Hz, 1H), 3.89 (td, J=9.5,
6.6 Hz, 1H), 5.71 (dd, J=6.6, 2.3 Hz, 1H), 7.46 (m, 2H), 8.20 (m, 2H). IR (KBr): 2959, 2872, 1654, 1587,
1264, 1190, 1093, 913, 840 cm–1. Anal. Calcd for C14H16NO3Cl: C, 59.68; H, 5.72; N, 4.97; Cl, 12.58.
Found: C, 60.05; H, 5.84; N, 4.63; Cl, 12.31.
3-[2-(2,5-Dimethylphenoxymethyl)benzoyl]-5-ethoxy-2-isoxazoline (6f). From 2’-(2,5-dimethylphenoxy-
methyl)acetophenone (7f). CC (AcOEt/hexane: 1/9 v/v) gave 6f (80%) as a pale yellow solid.
Recrystallization (AcOEt/hexane) afforded pale yellow crystals, mp 87–88°C. 1H NMR (CDCl3) δ 1.21 (t,
J=7.3 Hz, 3H), 2.18 (s, 3H), 2.30 (s, 3H), 3.17 (dd, J=18.1, 3.0 Hz, 1H), 3.26 (dd, J=18.1, 6.3 Hz, 1H), 3.60 (m,
1H), 3.90 (m, 1H), 5.20 (d, J=13.2 Hz, 1H), 5.29 (d, J=13.2 Hz, 1H), 5.67 (dd, J=6.3, 3.0 Hz, 1H), 6.67 (s, 1H),
6.68 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 7.43 (td, J=7.6, 1.3 Hz, 1H), 7.57 (td, J=7.6, 1.3 Hz, 1H), 7.70
(d, J=7.6 Hz, 1H), 7.91 (dd, J=7.6, 1.3 Hz, 1H). IR (KBr): 2978, 2925, 1664, 1577, 1509, 1261, 1129, 897
cm–1. Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.19; H, 6.18; N, 3.97.
3-(4-Chlorobenzoyl)-5-ethoxy-4-methyl-2-isoxazoline (6g). From 4’-chloroacetophenone (7e). CC
(AcOEt/hexane: 1/9 v/v) gave 6g (60%, a diastereomeric mixture) as a colorless oil. 1H NMR (CDCl3) δ
1.22–1.34 (m, 6H), 3.48-3.72 (m, 2H), 3.87–4.04 (m, 1H), 5.28 (d, J=1.3 Hz, 0.5H), 5.60 (d, J=7.3 Hz, 0.5H),
7.42–7.50 (m, 2H), 8.10–8.21 (m, 2H). IR (KBr): 2979, 2936, 1654, 1587, 1255, 1092, 851 cm–1. Anal.
Calcd for C13H14NO3Cl: C, 58.32; H, 5.27; N, 5.23; Cl, 13.24. Found: C, 58.25; H, 5.29; N, 5.04; Cl, 13.36.
3-(3,4-Dichlorobenzoyl)-5-ethoxy-4-methyl-2-isoxazoline (6h). From 3’,4’-dichloroacetophenone (7g).
CC (AcOEt/hexane: 1/9 v/v) gave 6h (50%, a diastereomeric mixture) as a colorless oil. 1H NMR (CDCl3) δ
1.22–1.34 (m, 6H), 3.46–3.72 (m, 2H), 3.87–4.04 (m, 1H), 5.29 (d, J=1.7 Hz, 0.5H), 5.62 (d, J=7.3 Hz, 0.5H),
7.54–7.58 (m, 1H), 8.01–8.11 (m, 1H), 8.28 (d, J=2.0 Hz, 0.5H), 8.34 (d, J=2.0, 0.5H). IR (KBr): 3096, 2979,
2936, 1656, 1572, 1390, 1108, 858 cm–1. Anal. Calcd for C13H13NO3Cl2: C, 51.68; H, 4.34; N, 4.64; Cl, 23.47.
Found: C, 51.65; H, 4.30; N, 4.43; Cl, 23.41.
The general procedure for the synthesis of 3-benzolylisoxazoles (1a–h) from 5-alkoxy-3-benzoyl-2-isoxazolines (6a–h).
A mixture of 6 (0.1 mol) and sulfuric acid (0.98 g, 0.01 mol) in toluene (200 mL) was heated under reflux with
stirring for 3 h. The mixture was poured into ice-cold water (400 mL) and extracted with toluene (200 mL).
The organic layer was washed with brine (400 mL), dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by CC to give 3-benzoylisoxazoles (1).

3-(2-Methylbenzoyl)isoxazole (1a). From 6a. CC (AcOEt/hexane: 1/9 v/v) gave 1a (94%) as a pale yellow
solid, mp 35–37°C. 1H NMR (CDCl3) δ 2.51 (s, 3H), 6.91 (d, J=1.7 Hz, 1H), 7.29–7.34 (m, 2H), 7.46 (td,
J=7.6, 1.7 Hz, 1H), 7.82 (dd, J=7.6, 1.7 Hz, 1H), 8.55 (d, J=1.7 Hz, 1H). IR (KBr): 3129, 3071, 2969, 1672,
1419, 1302, 1193, 885 cm–1. Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.40; H,
4.60; N, 7.45.
3-Benzoylisoxazole (1b).4 From 6b. CC (AcOEt/hexane: 1/9 v/v) gave 1b (93%) as a colorless oil. 1H
NMR (CDCl3) δ 6.93 (d, J=1.7 Hz, 1H), 7.51–7.57 (m, 2H), 7.67 (m, 1H), 8.30–8.34 (m, 2H), 8.56 (d, J=1.7
Hz, 1H). IR (KBr): 3160, 3131, 3073, 1662, 1451, 1294, 1199, 1179, 881 cm–1. Anal. Calcd for C10H7NO2:
C, 69.36; H, 4.07; N, 8.09. Found: C, 69.23; H, 4.09; N, 8.05.
3-(4-Fluorobenzoyl)isoxazole (1c). From 6c. Recrystallization (AcOEt/hexane) gave 1c (87%) as slightly
brownish prisms, mp 78–79°C. 1H NMR (CDCl3) δ 6.93 (d, J=1.7 Hz, 1H), 7.21 (m, 2H), 8.41 (m, 2H), 8.56
(d, J=1.7 Hz, 1H). IR (KBr): 3163, 3139, 3062, 1658, 1601, 1421, 1302, 1239, 1166, 893, 858 cm–1. Anal.
Calcd for C10H6NO2F: C, 62.83; H, 3.16; N, 7.33; F, 9.94. Found: C, 62.98; H, 3.05; N, 7.39; F, 9.70.
3-(2-Chlorobenzoyl)isoxazole (1d). From 6d. CC (AcOEt/hexane: 2/8 v/v) gave 1d (91%) as a white solid.
Recrystallization (AcOEt/hexane) afforded colorless prisms, mp 63.5–64.5°C. 1H NMR (CDCl3) δ 6.94 (d,
J=1.7 Hz, 1H), 7.37–7.50 (m, 3H), 7.66 (m, 1H), 8.56 (d, J=1.7 Hz, 1H). IR (KBr): 3132, 1686, 1591, 1421,
1300, 1199, 1038, 889 cm–1. Anal. Calcd for C10H6NO2Cl: C, 57.85; H, 2.91; N, 6.75; Cl, 17.08. Found: C,
58.05; H, 2.79; N, 6.79; Cl, 16.76.
3-(4-Chlorobenzoyl)isoxazole (1e). From 6e. CC (AcOEt/hexane: 2/8 v/v) gave 1e (99%) as a white solid.
Recrystallization (AcOEt/hexane) afforded colorless needles, mp 57–58.5°C. 1H NMR (CDCl3) δ 6.93 (d,
J=1.7 Hz, 1H), 7.51 (m, 2H), 8.31 (m, 2H), 8.56 (d, J=1.7 Hz, 1H). IR (KBr): 3153, 3114, 1670, 1587, 1297,
1199, 1093, 883 cm–1. Anal. Calcd for C10H6NO2Cl: C, 57.85; H, 2.91; N, 6.75; Cl, 17.08. Found: C, 58.04;
H, 2.83; N, 6.76; Cl, 16.76.
3-[2-(2,5-Dimethylphenoxymethyl)benzoyl]isoxazole (1f). From 6f. CC (AcOEt/hexane: 2/8 v/v) gave 1f
(91%) as a white solid. Recrystallization (AcOEt/hexane) afforded colorless needles, mp 90.5–92°C. 1H
NMR (CDCl3) δ 2.16 (s, 3H), 2.29 (s, 3H), 5.32 (2, s), 6.66 (s, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.86 (d, J=1.6 Hz,
1H), 7.00 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.64 (td, J=7.6, 1.3 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 8.02
(dd, J=7.6, 1.3 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H). IR (KBr): 2923, 1664, 1509, 1415, 1300, 1263, 1130, 1037,
887 cm–1. Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 74.19; H, 5.28; N, 4.56.
3-(4-Chlorobenzoyl)-4-methylisoxazole (1g). From 6g. CC (toluene/hexane: 5/95 v/v) gave 1g (92%) as a
white solid. Recrystallization (AcOEt/hexane) afforded colorless needles, mp 93.5–94.5°C. 1H NMR
(CDCl3) δ 2.27 (d, J=1.0 Hz, 3H), 7.49 (m, 2H), 8.19 (m, 2H), 8.34 (q, J=1.0 Hz, 1H). IR (KBr): 3114, 3088,

1664, 1587, 1444, 1282, 1095, 884 cm–1. Anal. Calcd for C11H8NO2Cl: C, 59.61; H, 3.64; N, 6.32; Cl, 16.00.
Found: C, 59.69; H, 3.50; N, 6.37; Cl, 15.65.
3-(3,4-Dichlorobenzoyl)-4-methylisoxazole (1h). From 6h. CC (AcOEt/hexane: 2/8 v/v) gave 1h (94%)
as a white solid. Recrystallization (AcOEt/hexane) afforded colorless crystals, mp 75–76°C. 1H NMR
(CDCl3) δ 2.28 (d, J=1.0 Hz, 3H), 7.60 (d, J=8.6 Hz, 1H), 8.11 (dd, J=8.6, 2.0 Hz, 1H), 8.35–8.36 (m, 2H).
IR (KBr): 3123, 3092, 1669, 1440, 1282, 1233, 964, 911 cm–1. Anal. Calcd for C11H7NO2Cl2: C, 51.59; H,
2.76; N, 5.47; Cl, 27.69. Found: C, 51.55; H, 2.61; N, 5.62; Cl, 27.52.
The general procedure for the synthesis of 3-benzoylisoxazoles (1a) and (1f) from alkyne.
Acetylene gas (excess) was passed through a solution of crude 5 (0.02 mol) in isopropyl alcohol (60 mL) at rt
over 30 min, and NaHCO3 (3.36 g, 0.04 mol) was added to the mixture. Acetylene gas (excess) was passed
through the above mixture at rt over 8 h, and the mixture was stirred at rt for 18 h. The reaction mixture was
poured into Et2O (200 mL) and washed with water (200 mL). The organic layer was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure, and the residue was purified by CC to give the
isoxazoles.
3-(2-Methylbenzoyl)isoxazole (1a). From 2’-methylacetophenone (7a). CC (AcOEt/hexane: 1/9 v/v) gave
1a (76%) as a pale yellow solid.
3-[2-(2,5-Dimethylphenoxymethyl)benzoyl]isoxazole (1f). From 2’-(2,5-dimethylphenoxymethyl)aceto-
phenone (7f). CC (AcOEt/hexane: 2/8 v/v) gave 1f (84%) as a white solid.
The general procedure for the synthesis of 3-benzoyl-5-trifluoromethylisoxazoles (1i–j).
3,3,3-Trifluoropropyne gas (0.02 mmol) was passed through a solution of crude 5 (0.01 mmol) in isopropyl
alcohol (30 mL) below –50°C over 30 min, and NaHCO3 (1.68 g, 0.02 mol) was added to the mixture, and the
mixture was stirred at rt for 20 h. The reaction mixture was poured into Et2O (150 mL) and washed with
water (100 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure, and the residue was purified by CC to give 3-benzoyl-5-trifluoromethylisoxazoles.
3-(2-Methylbenzoyl)-5-trifluoromethylisoxazole (1i). From 2’-methylacetophenone (7a). CC (AcOEt/
hexane: 1/9 v/v) gave 1i (53%) as a pale yellow oil. 1H NMR (CDCl3) δ 2.54 (s, 3H), 7.23 (d, J=1.0 Hz, 1H),
7.31-7.37 (m, 2H), 7.51 (td, J=7.6, 1.3 Hz, 1H), 7.87 (dd, J=7.6, 1.3 Hz 1H). IR (KBr): 3141, 2970, 2932,
1682, 1316, 1243, 1167, 966, 895 cm–1. Anal. Calcd for C12H8NO2F3: C, 56.47; H, 3.16; N, 5.49; F, 22.34.
Found: C, 56.56; H, 3.33; N, 5.58; F, 22.63.
3-(4-Chlorobenzoyl)-5-trifluoromethylisoxazole (1j). From 4’-chloroacetophenone (7e). CC (AcOEt/

hexane: 1/9 v/v) gave 1j (53%) as a white solid. Recrystallization (AcOEt/hexane) afforded colorless prisms,
mp 46–47°C. 1H NMR (CDCl3) δ 7.25 (d, J=1.0 Hz, 1H), 7.54 (m, 2H), 8.31 (m, 2H). IR (KBr): 3144,
1663, 1587, 1255, 1202, 1149, 898 cm–1. Anal. Calcd for C11H5NO2ClF3: C, 47.94; H, 1.83; N, 5.08; Cl,
12.86; F, 20.68. Found: C, 47.77; H, 1.88; N, 5.57; Cl, 12.51; F, 20.18.
Preparation of 2’-(2,5-dimethylphenoxymethyl)acetophenone (7f).
A solution of methylmagnesium bromide in THF (0.92 M, 16.3 mL, 15 mmol) was added dropwise to a
solution of N-methoxy-N-methyl-2-(2,5-dimethylphenoxymethyl)benzamide13 (2.99 g, 10 mmol) in THF (20
mL) below –45°C over 5 min and the mixture was stirred at –45 to 20°C for 2 h. After completion of the
reaction, saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) were added, and the
mixture was extracted with Et2O (100 mL). The organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure, and the residue was purified by CC (AcOEt/hexane: 2/8 v/v) to give
1.69 g (66 %) of 7f as a white solid. Recrystallization (AcOEt/hexane) afforded colorless plates, mp 86–87°C.
1H NMR (CDCl3) δ 2.30 (s, 3H), 2.31 (s, 3H), 2.66 (s, 3H), 5.40 (s, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.76 (s, 1H),
7.05 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.3 Hz, 1H), 7.59 (td, J=7.6, 1.3 Hz, 1H), 7.88 (dd, J=7.6, 1.3 Hz, 1H), 7.92
(d, J=7.6 Hz, 1H).
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