Application of silica gel-supported polyphosphoric acid (PPA/SiO 2) as a reusable solid acid catalyst to the synthesis of 3-benzoylisoxazoles and isoxazolines

Article abstract of DOI:10.1016/j.tetlet.2011.10.038

3-Benzoylisoxazoles were synthesized by the reaction of alkynes and benzoylnitromethane using silica gel-supported polyphosphoric acid (PPA/SiO ₂). This reaction provides a convenient, efficient, and reusable synthetic method of isoxazole deriv

Full text of DOI:10.1016/j.tetlet.2011.10.038

Tetrahedron Letters 52 (2011) 6892–6895
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Application of silica gel-supported polyphosphoric acid (PPA/SiO2) as a
reusable solid acid catalyst to the synthesis of 3-benzoylisoxazoles and
isoxazolines
Ken-ichi Itoh a, , Tadashi Aoyama b, Hiroaki Satoh b, Yuki Fujii b, Hiroshi Sakamaki a, Toshio Takido b,
⇑
Mitsuo Kodomari c
a Department of Liberal Arts and Science, College of Science and Technology, Nihon University, 7-24-1, Narashinodai, Funabashi-shi, Chiba 274-8501, Japan
b Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai, Chiyoda-ku, Tokyo 101-8303, Japan
c Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Fukasaku, Minuma-ku, Saitama 337-8570, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Benzoylisoxazoles were synthesized by the reaction of alkynes and benzoylnitromethane using silica
gel-supported polyphosphoric acid (PPA/SiO2). This reaction provides a convenient, efficient, and reus-
able synthetic method of isoxazole derivatives.
Received 5 September 2011
Revised 4 October 2011
Accepted 7 October 2011
Available online 14 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazoles
Alkynes
Alkenes
Ketones
Supported reagents
Isoxazoles have played an important role in organic and medic-
inal chemistry. In synthetic chemistry, isoxazoles have served as a
versatile building block, and they can be converted into many
useful synthetic intermediates such as 1,3-diketones,1 b-hydroxy
intramolecular and intermolecular acylations, heterocyclic synthe-
sis, and acid-catalyzed reactions. For instance, in the recent reports,
the cyclization reaction of N,N0-bis(oxotrifluoroalkenyl)-1,3-
phenylenediamines in PPA medium gave the bis-trifluoromethy-
lated 1,7-phenanthrolines and 7-aminoquinolines,13 the acylation
of benzene and its derivatives with 2-, 3-, 4-aminobenzoic and 4-
aminophenylacetic acid in PPA afforded the aminobenzophenon-
es,14 and the reaction of tryptamine with carboxylic acid in PPA
was obtained by the 1-substitued 3,4-dihydro-9H-b-carboline
derivatives.15 However, the use of PPA has several drawbacks:
since 10- to 50-fold excess is generally employed, it is difficult to
pour and stir at room temperature, and necessary to carefully alka-
lize before the extraction.
Recently, PPA/SiO2 has been used as an efficient heterogeneous
catalyst for many organic transformations. PPA/SiO2 has some
advantages including its low cost, ease of preparation, and ease
of handling. In addition, the catalyst can be easily separated from
the reaction mixture by simple filtration and is reusable. Previ-
ously, we have reported the conversion of carbonyl compounds
into oxathioacetals or dithioacetals using PPA/SiO2.16 Here, we
wish to report a novel and convenient method for the synthesis
of isoxazole derivatives using PPA/SiO2 as a reusable catalyst. The
reaction of benzoylnitromethane and alkynes in the presence of
PPA/SiO2 yielded the corresponding 3-benzoylisoxazoles
(Scheme 1).
ketones,2 and
ring is
c
-amino alcohols.3 In addition, since the isoxazole
c-amino alcohol analogue, compounds having isoxazole ring
are frequently used in agrochemicals and medicines. For example,
hymexazol (3-hydroxy-5-methylisoxazole) is widely used as
fungicides and plant growth regulators,4 and sulfamethoxazole
(4-amino-N-(5-methyl-3-isoxazolyl)-benzenesulfonamide) which
belongs to a family of the sulfonamides are well known as
anti-infective agents.5 Isoxazoles are usually prepared by following
methods: 1,3-dipolar cycloaddition of dipolarophiles6 (alkynes,
alkenes and so on) with nitrile oxides from aldoximes7 or
nitroketones. Among them, in the case of
a
-
a
-nitroketones, nitrile
oxides are synthesized by dehydration using acid (sulfuric acid8
or p-toluenesulfonic acid9) or base (N-methylimidazole,10 1,4-
diazabicyclo[2.2.2]octane (DABCO)11 and copper(II) acetate/N-
methylpiperidine (NMP)12). However, reagents used there are
expensive, toxic, and dangerous.
Polyphosphoric acid (PPA) is a strong mineral acid which has
powerful dehydrating properties and widely used for
⇑
Corresponding author. Tel./fax: +81 80 47 467 5307.
E-mail address: k-itoh@chem.ge.cst.nihon-u.ac.jp (K.-i. Itoh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.038

K.-i. Itoh et al. / Tetrahedron Letters 52 (2011) 6892–6895
6893
52% yield (Table 1, entries 5 and 6), whereas the yield of 3a was im-
proved up to 70% when a mixture of PPA (0.07 g) and silica gel
(0.5 g) was used as a catalyst (Table 1, entry 7). The yield obtained
by using TsOH was nearly equal to that obtained by PPA/SiO2
(Table 1, entry 4). Moreover, the reaction using PPA/SiO2 gave 3a
in highest yield when compared with acidic supported reagent
and solid acid (Table 1, entries 8–11).
Effects of the loading ratio (wt. %) of PPA/SiO2, reaction time,
and solvent (such as PPA was not eluted from supported reagent)
on the reaction of 1 with 2a in the presence of PPA/SiO2 were
Ph
PPA/SiO2
-H2O
Ph
O
NO2
C
N
O
O
N
O
R
Ph
O
R
Scheme 1. The transformation of benzoylnitromethane to nitrile oxides via the
dehydration.
investigated (Table 2). Among various wt. % PPA/SiO2 tested,
17
20 wt. % PPA/SiO2
was the most effective and 3a was obtained
in 96% yield (Table 2, entry 4).18 The optimum reaction time was
4 h and the most suitable solvent for the reaction was toluene
(Table 2, entry 3). In case of the solvents such as benzene, n-
hexane, dichloromethane, and 1,2-dichloroethane, the yield of 3a
was decreased (Table 2, entries 6, 7, 9 and 10). Cyclohexane was
also a good solvent for the reaction. However, the yield of 3a was
slightly lower than that of toluene (Table 2, entry 8).
At first, reaction of benzoylnitromethane 1 with 1-octyne 2a in
the presence of various acid catalysts was performed in toluene
under reflux. The results were summarized in Table 1. PPA/SiO2
was the most effective among other acids tested except TsOH
and gave 3-benzoyl-5-hexylisoxazole 3a in high yield (Table 1, en-
tries 1–4 and 8). SiO2 gave trace amounts of 3a and PPA gave 3a in
Table 1
Generally, PPA is used large excess and is thrown away as a
waste after the reaction. In contrast, PPA/SiO2 has two merits:
PPA is required only as a catalytic amount and the catalyst can
be reused. PPA/SiO2 is easily recovered from the reaction mixture
by filtration. The recovered PPA/SiO2 is regenerated by washing
and drying, and can be used for a subsequent reaction. The results
of recycling were summarized in Table 3. As can be seen from
Table 3, PPA/SiO2 was able to recycle five times and 3a was
obtained in satisfactory yield (Table 3, entry 5).
Reaction of benzoylnitromethane 1 with 2a in the presence of various catalysts in
toluene
N
O
Catalyst
Toluene
Ph
NO2
Ph
+
C6H13
2a
C6H13
O
O
1
3a
The reaction of 1 with alkynes 2b–2h in the presence of PPA/
SiO2 was carried out in toluene under reflux for 4 h. These results
were summarized in Table 4. In the case of terminal alkynes, the
corresponding 3-benzoylisoxaozles 3b–3g were obtained in good
Entrya
Catalyst
Amount (g) of catalyst
Yield (%) of 3ab
1
2
3
4
5
Concd. HCl (37%)
Concd. HNO3 (70%)
Concd. H2SO4 (96%)
TsOH
PPA
SiO2
0.1
0.1
0.1
0.1
0.1
1.0
NDc
6
43
90
52
6
Table 3
Reusability of recovered catalyst on the reaction 1 with 2a
Entrya
Run
Yield of 3a (%)b
6
7
8
9
10
11
PPA, SiO2
PPA/SiO2
HClO4/SiO2
ZnCl2/SiO2
0.07, 0.5
0.5
0.25
0.5
70
90
87
58
75
1
2
3
4
5
1
2
3
4
5
96
94
92
85
82
d
e
f
Amberlyst 15
0.1
a
1 (0.5 mmol), 2a (0.5 mmol), catalyst and toluene (5.0 mL) were employed
a
1 (0.5 mmol), 2a (0.5 mmol), PPA/SiO2 (20 wt. %: 0.25 g) and toluene (5.0 mL)
were employed under reflux for 4 h.
under reflux for 5 h.
b
Isolated yields.
Not detected.
% By weight: 10.
0.5 mmol/g.
b
Isolated yields.
c
d
e
Table 4
f
Reaction of 1 with alkynes 2b–2h in the presence of PPA/SiO2 in toluene
1.5 mmol/g.
N
O
PPA/SiO2
Toluene
Ph
Ph
Table 2
NO2
+
R2
R1
R2
Effects of the loading ratio (wt. %) of PPA/SiO2, reaction time and solvent on the
O
O
R1
3b-3h
reaction of 1 with 2a in the presence of PPA/SiO2
1
2b-2h
Entrya
% By
weight
Weight/g
Solvent
Time/h
Yield
(%) of 3ab
1
2
3
4
5
6
7
8
9
10
20
20
20
30
20
20
20
20
20
0.5
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
n-Hexane
Cyclohexane
Dichloromethane
1,2-Dichloroethane
5
3
4
5
3
5
5
5
5
5
90
90
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
Entrya
Alkyne
R1
R2
Product
Yield (%)b
96
96
90
51
25
89
N.D.c
24
1
2
3
4
5
6
7
2b
2c
2d
2e
2f
H
H
H
H
H
H
n-C4H9
CH(CH3)2
C(CH3)3
CH2Cl
Si(CH3)3
Ph
3b
3c
3d
3e
3f
85
70
66
83
97
6
2g
2h
3g
3h
10
COOCH3
COOCH3
65
a
1 (0.5 mmol), 2a (0.5 mmol), PPA/SiO2 and solvent (5.0 mL) were employed
under reflux.
a
1 (0.5 mmol), alkynes 2b–2h (0.5 mmol), PPA/SiO2 (20 wt. %: 0.25 g) and tolu-
ene (5.0 mL) were employed under reflux for 4 h.
b
Isolated yields.
Not detected.
b
Isolated yields.
c

6894
K.-i. Itoh et al. / Tetrahedron Letters 52 (2011) 6892–6895
to excellent yields except 3g (Table 4, entries 1–6). It seems that
the yield of 3g was very low because 2g is sluggish toward the
cycloaddition with nitrile oxide from 1. From the disubstituted al-
kyne 2h, isoxazole derivative 3h was obtained in 65% yield (Table 4,
entry 7).
N O
PPA/SiO2
Toluene
Ph
Ph
NO2
+
O
O
1
5l
6l (20%)
The reaction with alkynes 2i–2j gave the corresponding 3-ben-
zoylisoxazoles in excellent yields, which were a mixture of 5-
substituted (3i and 3j) and 4-substituted-3-benzoylisoxazoles (4i
and 4j) (Table 5). Wade and co-workers also have reported that
the reaction of nitronic ester and 2i in the presence of TsOH affor-
ded a mixture of 3i and 4i in 74 and 7 yields, respectively (ratio 3i/
4i = 100/10).8 The ratio of 3i and 4i was determined by 1H NMR
compared with the area ratio between 4-position of 3i and 5-pos-
sition of 4i. Compared with the previous work, in the present
Scheme 2. Reaction of 1 with cyclohexene 5l in the presence of PPA/SiO2 in toluene.
Table 7
Reaction of 7 with 2a in the presence of PPA/SiO2 in solvent
N
O
PPA/SiO2
Toluene
H3CO
H3CO
NO2 +
C6H13
2a
C6H13
O
O
7
8a
Table 5
Reaction of 1 with alkynes 2i–2j in the presence of PPA/SiO2 in toluene
Entrya
Solvent
Time/h
Yield (%) of 8ab
1
2
3
4
5
Toluene
Toluene
o-Dichlorobenzene
o-Dichlorobenzene
o-Dichlorobenzene
4
24
1
2
4
15
7
33
50
43
Ph
NO2
+
R3
O
1
2i, 2j
a
7 (0.5 mmol), 2a (0.5 mmol), PPA/SiO2 (20 wt. %: 0.25 g), and solvent (5.0 mL)
N
O
N
O
were employed under reflux.
PPA/SiO2
Toluene
Ph
b
Ph
+
Isolated yields.
R3
O
O
R3
investigation the yield (total yield: 97%) and selectivity of the prod-
uct (ratio 3i/4i = 100/7) was higher (Table 5, entry 1).
3i, 3j
4i, 4j
In addition, reaction of 1 with alkenes 5a–5k in the presence of
PPA/SiO2 was carried out in toluene under reflux for 4 h. The re-
sults were summarized in Table 6. The corresponding 3-benzoylis-
oxazolines 6a–6k were obtained in good to excellent yields except
6k. In the case of cyclohexene 5l, the corresponding isoxazoline 6l
was obtained in 20% yield (Scheme 2). From the results, it seems
that 5k and 5l are sluggish in the cycloaddition similar to 2g.
Finally, reaction of methyl nitroacetate 7 or 1-nitropropane with
2a in the presence of PPA/SiO2 was carried out in toluene under re-
flux. Methyl 5-hexyl-3-isoxazolecarboxylate 8a was obtained from
the reaction using 7 in low yield, however, the reaction using 1-
nitropropane did not give the corresponding isoxazoles. In the reac-
tion using 7 (Table 7), when o-dichlorobenzene was used instead of
toluene as the solvent, the yield of 8a was increased up to 50% yield
(Table 7, entry 4.). As can be seen from Table 7, it seems that the
dehydration of 7 required high temperature compared with 1.
In conclusion, we developed a convenient and reusable synthe-
sis of 3-benzoylisoxazoles from benzoylnitromethane and alkynes
using PPA/SiO2. It is particularly noteworthy that this reaction af-
fords an efficient synthetic method for isoxazoles, therefore, we
Entrya Alkyne R3
Product Yield of 3 and 4 (%)b Ratio (3/4)c
1
2
2i
2j
COOCH3
COOC2H5 3j, 4j
3i, 4i
97
96
100/7
100/5
a
1 (0.5 mmol), alkynes 2i–2j (0.5 mmol), PPA/SiO2 (20 wt. %: 0.25 g) and toluene
(5.0 mL) were employed under reflux for 4 h.
b
Isolated yields.
Ratio was determined by 1H NMR compared with area ratio between 4-position
c
proton of 3 and 5-position proton of 4.
Table 6
Reaction of 1 with alkenes 5a–5k in the presence of PPA/SiO2 in toluene
N
O
PPA/SiO2
Toluene
Ph
NO2
Ph
+
R4
5a-5k
R4
O
O
1
6a-6k
continuously tried to investigate the reaction with several
nitroketones, alkynes and alkenes.
a-
References and notes
Entrya
Alkene
R4
Product
Yield (%)b
1. Kozikowski, A. P.; Li, C.-S. J. Org. Chem. 1985, 50, 778–785.
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
n-C4H9
n-C6H13
n-C8H17
n-C10H21
CH2Cl
6a
6b
6c
6d
6e
6f
6g
6h
6i
86
93
99
99
93
75
87
99
99
64
25
2. (a) Kozikowski, A. P.; Adamczyk, M. Tetrahedron Lett. 1982, 23, 3123–3126; (b)
Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833.
}
3. Muller, I.; Jäger, V. Tetrahedron Lett. 1982, 46, 4777–4780.
4. (a) Takahi, Y.; Nakanishi, T.; Tomita, K.; Kamimura, S. Ann. Phytopath. Soc. Jpn.
1974, 40, 354–361; (b) Sørensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org.
Chem. 2000, 65, 1003–1007.
5. (a) Naisbitt, D. J.; O’Neill, P. M.; Pirmohamed, M.; Park, B. K. Bioorg. Med. Chem.
Lett. 1996, 6, 1511–1516; (b) Garcia-Echeverria, C. Tetrahedron Lett. 1997, 38,
8933–8934.
6. (a) Padwa, A.; Pearson, W. H. Synthetic Application of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Wiley: New Jersey, 2003;
(b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–909.
7. (a) Collington, E. W.; Knight, J. G.; Wallis, C. J.; Warren, S. Tetrahedron Lett. 1989,
30, 877–880; (b) Bhosale, S.; Kurhade, S.; Prasad, U. V.; Palle, V. P.; Bhuniya, D.
Tetrahedron Lett. 2009, 50, 3948–3951.
CH2Br
CH2OCOCH3
CH2OPh
CH2CN
CH2Ph
10
11
5j
5k
6j
6k
Ph
a
1 (0.5 mmol), alkenes 5a–5k (0.5 mmol), PPA/SiO2 (20 wt. %: 0.25 g) and tolu-
ene (5.0 mL) were employed under reflux for 4 h.
b
Isolated yields.

K.-i. Itoh et al. / Tetrahedron Letters 52 (2011) 6892–6895
6895
8. Nazarenko, K. G.; Shvidenko, K. V.; Pinchuk, A. M.; Tolmachev, A. A. Synth.
Commun. 2003, 33, 4241–4252.
9. (a) Shimizu, T.; Hayashi, Y.; Teramura, K. Bull. Chem. Soc. Jpn. 1984, 57, 2531–
2534; (b) Wade, P. A.; Amin, N. V.; Yen, H.-K.; Price, D. T.; Huhn, G. F. J. Org.
Chem. 1984, 49, 4595–4601.
10. Yavari, I.; Piltan, M.; Moradi, L. Tetrahedron 2009, 65, 2067–2071.
11. Machetti, F.; Cecchi, L.; Trogu, E.; Sarlo, F. D. Eur. J. Org. Chem. 2007, 4352–4359.
12. Cecchi, L.; Sarlo, F. D.; Machetti, F. Chem. Eur. J. 2008, 14, 7903–7912.
13. Bonacorso, H. G.; Andrighetto, R.; Zanatta, N.; Martins, M. A. P. Tetraheron Lett.
2010, 51, 3752–3755.
17. Preparation of PPA/SiO2: PPA was purchased from Aldrich. PPA (4.0 g) was
charged in the round-bottom flask, and CHCl3 (100 mL) was added. After the
mixture was stirred at 50 °C for 1 h, followed by SiO2 (16.0 g, Wakogel C-200;
Wako Pure Chemical Ind., Ltd.) was added to the solution, and the mixture was
stirred for another 1 h. CHCl3 was removed by evaporation, and the resulting
solid was dried in vacuo (10 mmHg) at room temperature for 3 h.
18. (a) Typical procedure:
A mixture of a-nitroketones (0.5 mmol), alkynes
(0.5 mmol) and PPA/SiO2 (20 wt. %, 0.25 g) was stirred in toluene (5.0 mL)
under reflux for 4 h. After the reaction, the used supported reagents were
removed by filtration. The filtrate was evaporated to leave crude product,
which was purified by column (ethyl acetate/n-Hexane = 1:5). (b) Gram-scale
reaction: The reaction of 1 (6.0 mmol), 2a (6.0 mol) and PPA/SiO2 (20 wt. %,
3.0 g) in toluene (60 mL) under reflux for 4 h gave 3a in 84% yield.
14. Ivanov, I.; Nikolova, S.; Statkova-Abeghe, S. Synth. Commun. 2006, 36, 1405–
1411.
15. Ivanov, I.; Nikolova, S.; Statkova-Abeghe, S. Heterocycles 2005, 65, 2483–2492.
16. Aoyama, T.; Takido, T.; Kodomari, M. Synlett 2004, 2307–2310.