One-pot synthesis of isoxazolines from aldehydes catalyzed by iodobenzene

Article abstract of DOI:10.1055/s-0033-1340464

A convenient one-pot, three-step procedure for the synthesis of isoxazolines starting from aldehydes has been developed involving catalytic cycloaddition between nitrile oxides and alkenes, in which iodobenzene is used as the catalyst for the in situ generation of a hypervalent iodine intermediate. In this approach, the aldehydes are first transformed with hydroxylamine sulfate into aldoximes, which are then oxidized to nitrile oxides by the in situ generated hypervalent iodine intermediate; finally, a 1,3-dipolar cycloaddition between the nitrile oxides and alkenes occurs to provide the isoxazolines in moderate to good yields.

Full text of DOI:10.1055/s-0033-1340464

PAPER
▌503
pOapnere-Pot Synthesis of Isoxazolines from Aldehydes Catalyzed by Iodobenzene
One-Pot Synthesis of Isoxazolines from Aldehydes
Liuquan Han, Bijun Zhang, Changbin Xiang, Jie Yan*
College of Chemical Engineering and Materials Sciences, Zhejiang University of Technology, Hangzhou 310032, P. R. of China
Fax +86(571)88320238; E-mail: jieyan87@zjut.edu.cn
Received: 24.10.2013; Accepted after revision: 25.11.2013
valent iodine intermediates. At the same time, we have
Abstract: A convenient one-pot, three-step procedure for the syn-
also developed a similar catalytic cycloaddition between
thesis of isoxazolines starting from aldehydes has been developed
nitrile oxides derived from aldoximes and alkenes using
iodobenzene (PhI) as the catalyst and m-chloroperoxy-
involving catalytic cycloaddition between nitrile oxides and al-
kenes, in which iodobenzene is used as the catalyst for the in situ
generation of a hypervalent iodine intermediate. In this approach, benzoic acid (m-CPBA) as the terminal oxidant. Based on
the aldehydes are first transformed with hydroxylamine sulfate into
aldoximes, which are then oxidized to nitrile oxides by the in situ
generated hypervalent iodine intermediate; finally, a 1,3-dipolar cy-
obtain and mostly commercially available aldehydes is
cloaddition between the nitrile oxides and alkenes occurs to provide
the isoxazolines in moderate to good yields.
this, a convenient one-pot, three-step procedure for the
synthesis of isoxazolines starting from the easier-to-
now reported. To our knowledge, such a one-pot synthesis
of isoxazolines starting from aldehydes using PhI as the
Key words: one-pot synthesis, isoxazolines, iodobenzene, hyper-
catalyst and m-CPBA as the terminal oxidant has not been
valent iodine intermediate, catalytic cycloaddition
reported previously.
Initially, benzaldehyde was chosen as the representative
aldehyde for reaction with hydroxylamine hydrochloride
to form the corresponding aldoxime; however, it was
erocycles, which are found in a large number of natural
Isoxazolines are very important nitrogen-containing het-
products and biologically active compounds.1 A variety of
synthetic methods have been developed for the prepara-
tion of isoxazolines, of which the most convenient and at-
tractive route is probably the 1,3-dipolar cycloaddition of
nitrile oxides to alkenes.2 Nitrile oxides are commonly
generated from aldoximes via oxidation using various ox-
idants, including NBS, NCS, NaOCl, t-BuOCl and t-
BuOI.3 All of these methods involve two steps and give
highly variable yields. With low toxicity, ready availabil-
ity, easy handling and reactivity similar to that of heavy
metal reagents, hypervalent iodine reagents have been
used to induce the 1,3-dipolar cycloaddition of nitrile ox-
ides derived from aldoximes to alkenes in a new improve-
ment of the process.4 However, a stoichiometric amount
of the hypervalent iodine reagent is usually needed in this
process, a situation which is not perfect from both envi-
ronmental and economic viewpoints.
found that the byproduct NaCl can be oxidized by m-
CPBA into Cl2, which disturbed the catalytic cycloaddi-
tion. To avoid formation of Cl2, hydroxylamine sulfate
was selected for use in the reaction. Then, the one-pot re-
action of benzaldehyde (1a) with hydroxylamine sulfate
(0.6 equiv), styrene (2a, 2.0 equiv) and m-CPBA (1.4
equiv) in the presence of a catalytic amount of PhI (0.2
equiv) in different solvents was investigated (Table 1). As
hydroxylamine sulfate is an ionic compound with poor
solubility in organic solvents, we first examined three
kinds of high polarity organic solvents, namely methyl al-
cohol, glycol and 2,2,2-trifluoroethanol (TFE); however,
although the reaction in TFE provided a 47% yield of
isoxazoline 3a, the other solvents usually led to rather
poor yields (Table 1, entries 1–3). The same experiment
was conducted in water, but none of the desired product
was found as the oxidant m-CPBA is nearly water insolu-
ble (Table 1, entry 4). In order to improve the reaction, a
mixed solvent was used to ensure that both organic com-
pounds and ionic salts have good solubility. TFE and wa-
ter were mixed as the mixed solvent; when the one-pot
reaction was carried out in TFE–H2O (3:1, v/v), a surpris-
ing improvement to 70% isolated yield was obtained (Ta-
ble 1, entry 5). Encouraged by this result, we undertook a
series of experiments with different solvent volume ratios;
TFE–H2O (2.6:1, v/v) was found to be the most effective
for the one-pot reaction (Table 1, entries 6–12). Other
organic–water mixed solvents were also tested, but none
of the yields exceeded 36% (Table 1, entries 13–18).
In recent years, the catalytic utilization of hypervalent io-
dine reagents has been increasing in importance, with a
growing interest in the development of environmentally
benign synthetic transformations.5 In these catalytic reac-
tions, a catalytic amount of an iodine-containing com-
pound together with a stoichiometric oxidant is used.
Very recently, Zhdankin and co-workers have published
two papers on the organocatalytic cycloaddition of nitrile
oxides to alkenes.6 Using Oxone® (2KHSO5–KHSO4–
K2SO4) as the terminal oxidant, they found that the inor-
ganic salt potassium iodide and aryl iodides can improve
the cycloaddition when used in various methods as cata-
lysts via the in situ generated hypoiodous acid and hyper-
SYNTHESIS 2014, 46, 0503–0509
Advanced online publication: 12.12.2013
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DOI: 10.1055/s-0033-1340464; Art ID: SS-2013-F0700-OP
© Georg Thieme Verlag Stuttgart · New York

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3,5-diphenyl-4,5-dihydroisoxazole (3a), was observed
(Table 2, entry 1). When catalytic amounts of PhI were
added under the same reaction conditions, the reaction
was improved and the product 3a was provided in moder-
ate to good yields; use of 0.2 equivalents of PhI to mediate
the reaction resulted in the best yield of 82% (Table 2, en-
tries 2–4), which is higher than that obtained by Zhdankin
and co-workers.6b
Table 1 Synthesis of Isoxazoline 3a in Different Solvents
OH
N
O
(H2NOH)2·H2SO4
r.t., 25 min
Ph
1a
Ph
m-CPBA, PhI
r.t., 25 min
O–
N+
Ph
O
The optimal amounts of hydroxylamine sulfate, m-CPBA
and styrene (2a) were also investigated and finally deter-
mined: 0.6 equivalents of hydroxylamine sulfate for step
one (Table 2; entries 3, 5 and 6), 1.4 equivalents of m-
CPBA for step two (entries 3, 7 and 8) and 2.0 equivalents
of 2a for the last step (entries 3, 9 and 10) were selected.
The suitable reaction times for the three steps are 60 min-
utes (Table 2; entries 3, 11 and 12), 30 minutes (entries 3,
13 and 14) and 5 hours (entries 3, 15 and 16), respectively.
PhCH=CH2 2a
N
r.t., 20 h
Ph
Ph
3a
Entry
Solvent
Yielda (%)
1
2
MeOH
glycol
TFE
22
13
47
–
With the optimal reaction conditions in hand, the one-pot,
three-step procedure starting from aldehydes was investi-
gated, and a series of isoxazolines was obtained; the re-
sults are summarized in Table 3. When benzaldehyde (1a)
was used as starting material, the reaction was compatible
with the studied alkenes and provided the corresponding
isoxazolines in moderate to good yields, except for the re-
action with indene (2f) (Table 3, entries 1–8). Other aro-
matic aldehydes, such as 2-naphthaldehyde (1b) and
substituted benzaldehydes which bear an electron-donat-
ing group (1c, 1d) or electron-withdrawing group(s) on
the benzene ring (1e–h), all reacted easily with styrene
(2a) and afforded the isoxazolines in good to excellent
yields (Table 3, entries 9–15). When aliphatic rather than
aromatic aldehyde was used, the results were quite differ-
ent: use of phenylacetaldehyde (1i) led to a rather low
yield of 36%, while no product was observed with
propanal (1j) (Table 3, entries 16 and 17). In the same
manner, phenylacetylene (2i) was used, taking the place
of alkene, to explore the possibility of the synthesis of
isoxazoles. The yield of the desired isoxazole 3q, howev-
er, was poor (Table 3, entry 18), indicating that this one-
pot, three-step procedure is more suitable for the synthesis
of isoxazolines.
3
4
H2O
5
TFE–H2O (3:1)
70
21
64
68
75
72
71
68
36
16
3
6
TFE–H2O (6:1)
7
TFE–H2O (5:1)
8
TFE–H2O (4:1)
9
TFE–H2O (2.6:1)
TFE–H2O (2:1)
10
11
12
13
14
15
16
17
18
TFE–H2O (1.5:1)
TFE–H2O (1:1)
MeOH–H2O (2.6:1)
EtOH–H2O (2.6:1)
MeCN–H2O (2.6:1)
THF–H2O (2.6:1)
DMF–H2O (2.6:1)
glycol–H2O (2.6:1)
9
9
32
a Isolated yields.
Based on the remarkable catalytic effect of iodobenzene
for the oxidation of aldoxime, a plausible catalytic mech-
anism is proposed (Scheme 1). Thus, iodobenzene is first
oxidized by m-CPBA to the hypervalent iodine intermedi-
ate, which then transforms the aldoxime, derived from the
aldehyde, into the nitrile oxide. Finally, a 1,3-dipolar cy-
cloaddition of the nitrile oxide to the alkene occurs to pro-
vide the corresponding isoxazoline. The reduced
byproduct, PhI, is reoxidized to the hypervalent iodine re-
agent by m-CPBA in the recycling reaction.
Using the mixture of TFE–H2O (2.6:1, v/v) as solvent,
other reaction conditions were optimized. As shown in
Table 2, when 1.0 equivalent of benzaldehyde (1a) was
treated consecutively with 0.6 equivalents of hydroxyl-
amine sulfate, 1.4 equivalents of m-CPBA and 2.0 equiv-
alents of styrene (2a) in the absence of PhI at room
temperature for several hours, none of the desired product,
Synthesis 2014, 46, 503–509
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One-Pot Synthesis of Isoxazolines from Aldehydes
505
Table 2 Optimization of the Catalytic Cycloaddition for the Synthesis of Isoxazoline 3a in TFE–H2O (2.6:1)
O–
Ph
OH
N
O
O
(H2NOH)2·H2SO4
r.t., 25 min
m-CPBA, PhI
N+
Ph
PhCH=CH2 2a
N
r.t., 20 h
r.t., 25 min
Ph
1a
Ph
Ph
3a
Entry
(H2NOH)2·H2SO4
(equiv)
Time 1
(min)
m-CPBA
(equiv)
PhI
(equiv)
Time 2
(min)
2a
(equiv)
Time 3
(h)
Yielda
(%) of 3a
1
0.6
0.6
0.6
0.6
0.5
0.7
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
60
60
60
60
60
60
60
60
60
60
40
80
60
60
60
60
1.4
1.4
1.4
1.4
1.4
1.4
1.2
1.6
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0
30
30
30
30
30
30
30
30
30
30
30
30
20
40
30
30
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
2.5
2.0
2.0
2.0
2.0
2.0
2.0
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
7
0
51
82
62
71
70
54
67
80
83
77
78
81
70
75
80
2
0.1
0.2
0.3
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a Isolated yields.
Table 3 One-Pot Synthesis of Isoxazolines from Aldehydes Catalyzed by Iodobenzene
R3
(H2NOH)2·H2SO4
(0.6 equiv)
m-CPBA (1.4 equiv)
alkene 2
R2
R4
O–
N+
O
HO
N
PhI (0.2 equiv)
(2.0 equiv)
R1
R1
1
R1
r.t., 5 h
O
r.t., 30 min
TFE–H2O (2.6:1)
r.t., 1 h
R1
N
3
Entry
1
Aldehyde
Alkene
Product
Yielda (%)
82
O
O
N
N
O
1a
2a
3a
2
3
1a
1a
2b
2c
3b
3c
62
73
N
O
O
N
4
1a
2d
3d
80
© Georg Thieme Verlag Stuttgart · New York
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L. Han et al.
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Table 3 One-Pot Synthesis of Isoxazolines from Aldehydes Catalyzed by Iodobenzene (continued)
R3
(H2NOH)2·H2SO4
(0.6 equiv)
m-CPBA (1.4 equiv)
alkene 2
R2
R4
O–
N+
O
HO
N
PhI (0.2 equiv)
(2.0 equiv)
R1
R1
1
R1
r.t., 5 h
O
r.t., 30 min
TFE–H2O (2.6:1)
r.t., 1 h
R1
N
3
Entry
5
Aldehyde
Alkene
Product
Yielda (%)
63
N
O
1a
1a
2e
2f
3e
3f
O
N
6
49
N
O
Br
Br
7
8
1a
1a
2g
2h
3g
3h
82
67
N
O
HO
OH
O
O
O
N
O
9b
1b
1c
1d
1e
2a
3i
82
84
78
90
N
N
O
10
2a
3j
3k
3l
O
11c
12d
2a
Cl
Br
Cl
Br
O
N
O
2a
2a
O
N
N
N
O
13d
14d
15d
1f
1g
1h
3m
3n
3o
94
71
O
O
O
2a
2a
F
F
Br
Br
O
82
36
Cl
Cl
O
N
16
17
1i
1j
2a
2a
3p
O
O
e
–
–
–
O
N
18
1a
2i
3q
29
a Isolated yields.
b The time for the oxidation of aldoxime was 50 min.
c The time for the oxidation of aldoxime was 45 min.
d The time for the oxidation of aldoxime was 1 h.
e Not detected.
Synthesis 2014, 46, 503–509
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One-Pot Synthesis of Isoxazolines from Aldehydes
507
1H NMR (500 MHz, CDCl3): δ = 7.74–7.70 (m, 2 H), 7.45–7.39 (m,
7 H), 7.38–7.33 (m, 1 H), 5.77 (dd, J = 10.0, 5.0 Hz, 1 H), 3.81 (dd,
J = 15.0, 10.0 Hz, 1 H), 3.37 (dd, J = 15.0, 10.0 Hz, 1 H).
R3
N
R1
R2
O
13C NMR (125 MHz, CDCl3): δ = 156.09, 140.93, 130.12, 129.47,
128.75, 128.73, 128.21, 126.73, 125.86, 82.56, 43.15.
R3
R2
MS (ESI): m/z (%) = 224 (100) [M+ + 1].
PhI
–
O
5-Methyl-3,5-diphenyl-4,5-dihydroisoxazole (3b)
+
Yield: 73 mg (62%); white solid; mp 75–76 °C (Lit.7 72–76 °C).
N
m-CPBA
IR (neat): 1445, 1360, 902, 749, 700, 537 cm–1.
R1
1H NMR (500 MHz, CDCl3): δ = 7.72–7.68 (m, 2 H), 7.56–7.53 (m,
2 H), 7.42–7.38 (m, 5 H), 7.33–7.30 (m, 1 H), 3.53 (q, J = 15.0 Hz,
2 H), 1.85 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.07, 145.41, 129.86, 129.79,
128.57, 128.41, 127.27, 126.45, 124.59, 87.98, 48.58, 28.12.
OH
N
m-CBA
PhI(III)
R1
H
MS (ESI): m/z (%) = 238 (100) [M+ + 1].
5-Benzyl-3-phenyl-4,5-dihydroisoxazole (3c)
Yield: 87 mg (73%); white solid; mp 67–69 °C (Lit.1h 67.5–
68.2 °C).
IR (neat): 1446, 1360, 917, 755, 700, 511 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.69–7.65 (m, 2 H), 7.43–7.39 (m,
3 H), 7.38–7.33 (m, 2 H), 7.31–7.26 (m, 3 H), 5.05–4.99 (m, 1 H),
3.34 (dd, J = 15.0, 10.0 Hz, 1 H), 3.20 (dd, J = 15.0, 5.0 Hz, 1 H),
3.08 (dd, J = 15.0, 5.0 Hz, 1 H), 2.92 (dd, J = 15.0, 10.0 Hz, 1 H).
(H2NOH)2H2SO4
R1CHO
Scheme 1 Proposed reaction mechanism for the one-pot synthesis of
isoxazolines
13C NMR (125 MHz, CDCl3): δ = 156.40, 136.90, 129.95, 129.68,
129.35, 128.90–128.60 (m), 127.07, 126.65 (d, J = 16.3 Hz), 81.83,
41.01, 39.35.
In conclusion, we have developed a convenient one-pot,
three-step procedure for the synthesis of isoxazolines
starting from aldehydes. This approach, which was im-
proved by the addition of a catalytic amount of iodoben-
zene for the in situ generation of a hypervalent iodine
intermediate, has advantages such as the use of easily
available aldehydes, mild reaction conditions and a simple
procedure, and provided a series of isoxazolines in mod-
erate to good yields. Furthermore, the scope of hyperva-
lent iodine reagents in organic synthesis was extended.
MS (ESI): m/z (%) = 238 (100) [M+ + 1].
3-Phenyl-3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxa-
zole (3d)
Yield: 85 mg (80%); white solid; mp 97–98 °C (Lit.8 97–100 °C).
IR (neat): 2969, 1448, 1357, 913, 774, 695 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.74–7.70 (m, 2 H), 7.43–7.38 (m,
3 H), 4.64 (d, J = 10.0 Hz, 1 H), 3.50 (d, J = 10.0 Hz, 1 H), 2.63 (d,
J = 5.0 Hz, 1 H), 2.53 (s, 1 H), 1.62–1.51 (m, 3 H), 1.38–1.32 (m, 1
H), 1.23–1.15 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 156.83, 129.63, 129.36, 128.63,
126.78, 87.82, 57.00, 42.95, 39.22, 32.27, 27.37, 22.67.
Melting points were measured with an XT-4 melting point appara-
tus and are uncorrected. IR spectra were recorded on a Thermo
Nicolet 6700 instrument, 1H and 13C NMR spectra were measured
on a Bruker AVANCE III (500 MHz) spectrometer, and mass spec-
tra were determined on a Thermo ITQ 1100 mass spectrometer. Al-
dehydes, alkenes, hydroxylamine sulfate, m-CPBA, PhI and
phenylacetylene were commercially available.
MS (ESI): m/z (%) = 214 (100) [M+ + 1].
5-Butyl-3-phenyl-4,5-dihydroisoxazole (3e)
Yield: 64 mg (63%); white solid; mp 39–41 °C (Lit.9 40–42 °C).
IR (neat): 2955, 2929, 2858, 1360, 918, 903, 756, 691, 549 cm–1.
One-Pot Synthesis of Isoxazolines 3; General Procedure
To a mixture of TFE (2.2 mL) and H2O (0.8 mL), an aldehyde 1 (0.5
mmol) and hydroxylamine sulfate (0.3 mmol) were first added, and
the mixture was stirred at r.t. for 1 h. Then, m-CPBA (0.7 mmol) and
PhI (0.1 mmol) were added and stirring was continued. After 30
min, an alkene 2 (1 mmol) was added to the mixture which was
stirred for another 5 h, until the reaction was completed. Then, H2O
(10 mL), sat. aq Na2S2O3 (2 mL) and sat. aq Na2CO3 (2 mL) were
added, and the mixture was stirred for 10 min. The mixture was ex-
tracted with CH2Cl2 (3 × 4 mL) and the combined organic phase
was dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by TLC on a silica gel
plate (petroleum ether–EtOAc, 3:1) to provide the corresponding
pure isoxazoline 3.
1H NMR (500 MHz, CDCl3): δ = 7.72–7.64 (m, 2 H), 7.44–7.37 (m,
3 H), 4.78–4.71 (m, 1 H), 3.40 (dd, J = 15.0, 10.0 Hz, 1 H), 2.98 (dd,
J = 15.0, 10.0 Hz, 1 H), 1.84–1.77 (m, 1 H), 1.69–1.62 (m, 1 H),
1.54–1.45 (m, 1 H), 1.43–1.36 (m, 3 H), 0.94 (t, J = 10.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.32, 129.89, 129.79, 128.58,
126.51, 81.43, 39.87, 34.96, 27.59, 22.49, 13.93.
MS (ESI): m/z (%) = 204 (65) [M+ + 1], 181 (100).
3-Phenyl-3a,8b-dihydro-4H-indeno[2,1-d]isoxazole (3f)
Yield: 58 mg (49%); pale yellow solid; mp 125–127 °C (Lit.10 134–
135 °C).
IR (neat): 1443, 1349, 913, 891, 758, 744, 692 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.77–7.70 (m, 2 H), 7.62–7.58 (m,
1 H), 7.47–7.40 (m, 3 H), 7.36–7.31 (m, 2 H), 7.24–7.20 (m, 1 H),
6.24 (d, J = 10.0 Hz, 1 H), 4.56 (td, J = 10.0, 5.0 Hz, 1 H), 3.51 (dd,
J = 15.0, 10.0 Hz, 1 H), 3.26 (dd, J = 15.0, 5.0 Hz, 1 H).
3,5-Diphenyl-4,5-dihydroisoxazole (3a)
Yield: 91 mg (82%); white solid; mp 72–73 °C (Lit.7 74–75 °C).
IR (neat): 1448, 1365, 896, 752, 696, 545 cm–1.
© Georg Thieme Verlag Stuttgart · New York
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L. Han et al.
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13C NMR (125 MHz, CDCl3): δ = 158.50, 140.60 (d, J = 12.5 Hz),
129.74, 129.42, 128.69, 127.48, 127.01, 125.70, 124.69, 89.41,
50.25, 36.41.
MS (ESI): m/z (%) = 266 (75) [M+ + 1], 167 (100).
HRMS: m/z [M+] calcd for C18H19NO: 265.1467; found: 265.1468.
3-(2-Chlorophenyl)-5-phenyl-4,5-dihydroisoxazole (3l)12
Yield: 116 mg (90%); yellow oil.
MS (ESI): m/z (%) = 236 (100) [M+ + 1].
IR (neat): 3064, 3032, 1434, 1078, 1038, 900, 756, 699 cm–1.
5-(4-Bromophenyl)-3-phenyl-4,5-dihydroisoxazole (3g)
Yield: 124 mg (82%); white solid; mp 128–129 °C (Lit.6a 129.8–
130.3 °C).
IR (neat): 2872, 1487, 1447, 1356, 883, 804, 761, 690 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.79–7.62 (m, 2 H), 7.60–7.50 (m,
2 H), 7.47–7.38 (m, 3 H), 7.29 (dd, J = 8.8, 2.0 Hz, 2 H), 5.72 (dd,
J = 11.0, 8.0 Hz, 1 H), 3.81 (dd, J = 16.6, 11.0 Hz, 1 H), 3.31 (dd,
J = 16.6, 8.0 Hz, 1 H).
1H NMR (500 MHz, CDCl3): δ = 7.76–7.67 (m, 1 H), 7.49–7.29 (m,
8 H), 5.78 (dd, J = 10.8, 8.5 Hz, 1 H), 3.94 (dd, J = 17.1, 10.8 Hz, 1
H), 3.54 (dd, J = 17.1, 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.15, 140.55, 132.87, 130.90,
130.61 (d, J = 5.6 Hz), 129.03, 128.78, 128.31, 127.03, 125.97,
83.29, 45.45.
MS (ESI): m/z (%) = 258 (100) [M+ + 1].
13C NMR (125 MHz, CDCl3): δ = 156.06, 140.04, 131.90, 130.30,
129.24, 128.80, 127.57, 126.77, 122.15, 81.81, 43.20.
MS (ESI): m/z (%) = 302 (52) [M+ + 1], 383 (100).
3-(2-Bromophenyl)-5-phenyl-4,5-dihydroisoxazole (3m)
Yield: 142 mg (94%); yellow oil.
IR (neat): 3063, 3032, 1431, 1341, 1028, 894, 755, 699 cm–1.
5-(Hydroxymethyl)-3-phenyl-4,5-dihydroisoxazole (3h)
1H NMR (500 MHz, CDCl3): δ = 7.68–7.62 (m, 1 H), 7.62–7.55 (m,
1 H), 7.50–7.33 (m, 6 H), 7.29 (dt, J = 7.6, 1.6 Hz, 1 H), 5.79 (dd,
J = 10.8, 8.5 Hz, 1 H), 3.94 (dd, J = 17.1, 10.9 Hz, 1 H), 3.59–3.48
(m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 157.08, 140.46, 133.69, 131.09,
130.95, 130.87, 128.71, 128.24, 127.49, 125.93, 121.83, 83.18,
45.49.
Yield: 59 mg (67%); white solid; mp 78–79 °C (Lit.1i 83–84 °C).
IR (neat): 3393, 1361, 1052, 895, 755, 691 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.70–7.65 (m, 2 H), 7.45–7.39 (m,
3 H), 4.91–4.86 (m, 1 H), 3.90–3.86 (m, 1 H), 3.72–3.68 (m, 1 H),
3.40 (dd, J = 20.0, 10.0 Hz, 1 H), 3.30 (dd, J = 15.0, 5.0 Hz, 1 H),
2.24 (dd, J = 5.0, 5.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 157.07, 130.16, 129.30, 128.69,
126.69, 81.26, 63.62, 36.31.
MS (ESI): m/z (%) = 302 (19) [M+ + 1], 167 (100).
HRMS: m/z [M+] calcd for C15H12BrNO: 301.0093; found:
MS (ESI): m/z (%) = 178 (8) [M+ + 1], 195 (100).
301.0102.
3-(Naphthalen-2-yl)-5-phenyl-4,5-dihydroisoxazole (3i)11
3-(4-Fluorophenyl)-5-phenyl-4,5-dihydroisoxazole (3n)13
Yield: 112 mg (82%); orange-red solid; mp 125–127 °C.
Yield: 86 mg (71%); white solid; mp 91–92 °C.
IR (neat): 3056, 2920, 909, 863, 822, 767, 703, 478 cm–1.
IR (neat): 3068, 2885, 1349, 1230, 902, 844, 758, 699, 596, 541
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.76–7.65 (m, 2 H), 7.46–7.31 (m,
5 H), 7.17–7.05 (m, 2 H), 5.76 (dd, J = 11.0, 8.3 Hz, 1 H), 3.84–3.70
(m, 1 H), 3.39–3.28 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 164.79, 162.80, 155.15, 140.80,
128.88–128.54 (m), 128.30, 125.94–125.65 (m), 115.98, 115.81,
82.69, 43.22.
1H NMR (500 MHz, CDCl3): δ = 8.05 (dd, J = 8.6, 1.7 Hz, 1 H),
7.92 (d, J = 0.5 Hz, 1 H), 7.86 (ddd, J = 12.7, 7.7, 5.2 Hz, 3 H), 7.58–
7.51 (m, 2 H), 7.48–7.38 (m, 4 H), 7.35 (ddt, J = 5.9, 4.5, 2.3 Hz, 1
H), 5.82 (dd, J = 11.0, 8.3 Hz, 1 H), 3.92 (dd, J = 16.5, 11.0 Hz, 1
H), 3.56–3.45 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.30, 140.97, 134.07, 133.02,
128.82, 128.60, 128.34 (d, J = 13.6 Hz), 127.88, 127.28–126.92
(m), 126.73, 125.95, 123.64, 82.79, 43.11.
MS (ESI): m/z (%) = 242 (100) [M+ + 1].
MS (ESI): m/z (%) = 274 (100) [M+ + 1].
3-(2-Bromo-4-chlorophenyl)-5-phenyl-4,5-dihydroisoxazole
3-(4-Methylphenyl)-5-phenyl-4,5-dihydroisoxazole (3j)
(3o)
Yield: 100 mg (84%); white solid; mp 96–97 °C (Lit.3i 97 °C).
Yield: 137 mg (82%); yellow oil.
IR (neat): 1350, 901, 824, 758, 698, 532 cm–1.
IR (neat): 3065, 3032, 1474, 1336, 1103, 901, 861, 822, 757, 699
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 2.1 Hz, 1 H), 7.55 (d,
J = 8.4 Hz, 1 H), 7.46–7.39 (m, 4 H), 7.38–7.33 (m, 2 H), 5.79 (dd,
J = 10.8, 8.6 Hz, 1 H), 3.96–3.87 (m, 1 H), 3.51 (dd, J = 17.1, 8.5
Hz, 1 H).
1H NMR (500 MHz, CDCl3): δ = 7.61 (d, J = 5.0 Hz, 2 H), 7.44–
7.37 (m, 4 H), 7.36–7.32 (m, 1 H), 7.24 (d, J = 5.0 Hz, 2 H), 5.74
(dd, J = 10.0, 10.0 Hz, 1 H), 3.79 (dd, J = 15.0, 10.0 Hz, 1 H), 3.35
(dd, J = 15.0, 5.0 Hz, 1 H), 2.40 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.03, 141.03, 140.34, 129.41,
13C NMR (125 MHz, CDCl3): δ = 156.28, 140.29, 136.34, 133.50,
131.67, 129.70, 128.81, 128.39, 127.92, 125.94, 122.21, 83.46,
45.31.
MS (ESI): m/z (%) = 336 (23) [M+ + 1], 181 (100).
HRMS: m/z [M+] calcd for C15H11BrClNO: 334.9713; found:
128.70, 128.14, 126.67, 125.86, 82.38, 43.26, 21.41.
MS (ESI): m/z (%) = 238 (100) [M+ + 1].
3-(4-Isopropylphenyl)-5-phenyl-4,5-dihydroisoxazole (3k)
Yield: 103 mg (78%); yellow solid; mp 57–59 °C.
IR (neat): 2957, 1457, 1433, 898, 839, 761, 701, 559 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.67–7.62 (m, 2 H), 7.43–7.36 (m,
4 H), 7.36–7.26 (m, 3 H), 5.74 (dd, J = 10.9, 8.1 Hz, 1 H), 3.83–3.75
(m, 1 H), 3.35 (dd, J = 16.6, 8.1 Hz, 1 H), 2.96 (heptet, J = 6.9 Hz,
1 H), 1.28 (d, J = 6.9 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 155.99, 151.25, 141.06, 128.69,
128.13, 127.00, 126.80, 125.84, 82.36, 43.28, 34.04, 23.75.
334.9729.
3-Benzyl-5-phenyl-4,5-dihydroisoxazole (3p)1h
Yield: 43 mg (36%); pale yellow oil.
IR (neat): 3062, 3029, 2916, 1494, 1454, 758, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.41–7.21 (m, 10 H), 5.55 (dd, J =
10.8, 8.4 Hz, 1 H), 3.75 (q, J = 14.9 Hz, 2 H), 3.26 (dd, J = 17.1,
10.9 Hz, 1 H), 2.82 (dd, J = 17.1, 8.4 Hz, 1 H).
Synthesis 2014, 46, 503–509
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Isoxazolines from Aldehydes
509
13C NMR (125 MHz, CDCl3): δ = 157.43, 141.02, 135.66, 128.94–
128.58 (m), 128.05, 127.15, 125.76, 81.86, 44.50, 34.16.
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MS (ESI): m/z (%) = 238 (100) [M+ + 1].
3,5-Diphenylisoxazole (3q)
Yield: 32 mg (29%); pale yellow solid; mp 130–132 °C (Lit.4b 138–
140 °C).
IR (neat): 3114, 3048, 2199, 1451, 1402, 950, 917, 821, 764, 693
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.93–7.84 (m, 4 H), 7.53–7.44 (m,
6 H), 6.85 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 170.41, 162.98, 130.21, 130.00,
129.15, 129.00, 128.92, 127.47, 126.81, 125.83, 97.47.
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Acknowledgment
Financial support from the Natural Science Foundation of China
(Project 21072176) is greatly appreciated.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 503–509