Synthesis of Isoxazolines and Isoxazoles via Metal-Free Desulfitative Cyclization

Article abstract of DOI:10.1055/s-0037-1609480

A novel, one-pot reaction for the synthesis of isoxazolines and isoxazoles is developed via a cascade process under metal-free conditions. The approach involves the formation of intramolecular C-N and C-O bonds and intermolecular C-C bonds from aromatic alkenes or alkynes and N -hydroxysulfonamides using hypervalent iodine(VII) and iodine as the oxidant. Activation of C-H and C-C bonds/construction of C-O bonds/elimination of SO ₂ /C-N bond formation is achieved in sequence in the reaction system.

Full text of DOI:10.1055/s-0037-1609480

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
J. Cheng et al.
Paper
Synthesis
Synthesis of Isoxazolines and Isoxazoles via Metal-Free Desulfitative
Cyclization
Jiaxin Chenga
Ze Yanga
Yuansheng Lia
Yulan Xia
Ar
O
H
N
R'
O
N
N
n-Bu4NIO4, I2
n-Bu4NIO4, I2
S
OH
Ar
R'
R
O
O
R
AIBN, CH2Cl2
AIBN, CH2Cl2
Qiu Sun*b
Ling He*a
hn
hn
R = H, p-Br
up to 73% yield
up to 82% yield
21 examples
a Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu, Sichuan, 610041,
P. R. of China
lhe2001@sina.com
b West China Medical Center of Sichuan University, Chengdu,
Sichuan, 610041, P. R. of China
sunqiu@scu.edu.cn
Received: 03.02.2018
Accepted after revision: 09.03.2018
Published online: 14.05.2018
oximes or nitro compounds.5–8 These synthetic methods are
shown in Figure 1. Among these methods, the [3+2] dipolar
cycloaddition of olefins and nitrile oxides has historically
been recognized as the most common approach.9 In addi-
tion, both the reaction of α,β-unsaturated ketones with hy-
droxylamine10 and the reaction of alkenes with ketones11,12
resulted in the formation of isoxazolines. Isoxazolines have
also been synthesized via the intramolecular cyclization of
oximes13 and hydroxylamines.14 Alkynyl oxime ethers un-
derwent a reaction sequence involving cyclization and sub-
sequent Claisen-type rearrangement to afford trisubstitut-
ed isoxazoles.15
DOI: 10.1055/s-0037-1609480; Art ID: ss-2018-f0062-op
Abstract A novel, one-pot reaction for the synthesis of isoxazolines
and isoxazoles is developed via a cascade process under metal-free con-
ditions. The approach involves the formation of intramolecular C–N and
C–O bonds and intermolecular C–C bonds from aromatic alkenes or
alkynes and N-hydroxysulfonamides using hypervalent iodine(VII) and
iodine as the oxidant. Activation of C–H and C–C bonds/construction of
C–O bonds/elimination of SO2/C–N bond formation is achieved in
sequence in the reaction system.
Key words isoxazolines, isoxazoles, desulfurization, radical cyclization,
tandem reaction
However, there is still a great need for new synthetic
methods, particularly a simplified method with fewer reac-
tion steps and a more easily available source for the starting
material. The direct insertion of nitrogen groups into hy-
drocarbons, without relying on the prefunctionalization of
simple compounds to the corresponding organic halides,
has become an attractive synthetic strategy as an atom-
economic and environmentally benign method for C–N
bond formation. Although an approach based on nitrenoid
transfer to C–H bonds by using Rh, Ru or Pd catalysts16 has
been investigated extensively, the oxidative amination of
alkenes or (hetero)arenes has been explored only recent-
ly.17,18 As part of our efforts to investigate the formation of
Compounds containing the isoxazoline and isoxazole
moiety demonstrate a wide variety of biological activities
and have been developed as human leukocyte elastase
inhibitors,1 herbicides,2 and insecticides.3 These com-
pounds are also important synthetic intermediates for a va-
riety of biological compounds4 and serve as the building
blocks or key structural units for the construction of asym-
metric ligands in organic synthesis. Therefore, many meth-
ods for the synthesis of the isoxazoline and isoxazole skele-
ton have been developed. A broad literature survey revealed
that isoxazolines and isoxazoles are usually prepared from
H
O–
O
OTBDPS
NH
N+
R3
R1
O
R1
O–
R1
R2CH=CHR3
or
N+
O–
R1
N
O
R1
R2
N
Cl
OSiMe3
OH
N
O
Cl
R1
R2
R3
N
R1
Figure 1 Synthesis of isoxazolines
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Paper
Synthesis
Previous work
HO
N
O
O
O
O
n-Bu4NIO4
S
OH
S
N
+
H
CH2Cl2
Cl
Cl
2a
1b
4s
81%
HO
N
O
O
O
O
S
OH
n-Bu4NIO4
S
+
N
H
CH2Cl2
Cl
2b
1b
4r
Cl
56%
This work
O
N
O
N
1
Ar
n-Bu4NIO4, I2
3
R'
H
Ar
R'
N
n-Bu4NIO4, I2
S
OH
R
R
O
O
AIBN, CH2Cl2
visible light
AIBN, CH2Cl2
visible light
4
5
R = H, 2c
R = p-Br, 2d
33–82%
44–73%
Scheme 1 Effect of the structure of the N-hydroxysulfonamide on the outcome of the reaction. Reaction conditions: 1b (0.1 mmol), 2c (0.1 mmol), n-
Bu4NIO4 (0.1 mmol), CH2Cl2, 15 h, reflux.
C–N bonds,19 we found that N-hydroxysulfonamides were
useful reagents for the preparation of sulfonylethanone
oximes from aromatic alkenes using n-Bu4NIO4 as the oxi-
dant (Scheme 1).20 In continuation of our exploration of N-
hydroxysulfonamides as a nitrogen source, we obtained an
isoxazoline as an unexpected product from N-hydroxy-1-
phenylmethanesulfonamide (2c) (Scheme 1). The differ-
ence in the reaction of N-hydroxy-1-phenylmethanesulfon-
amide (2c) relies on the activity of the allyl group and the
stability of the allyl free radical. Herein, we report our pre-
liminary results on this subject. The reaction of N-hydroxy-
2-phenylethanesulfonamide (2b) with 1-chloro-4-vinyl-
benzene (1b) using n-Bu4NIO4 as the oxidant gave the α-
sulfonylethanone oxime product 4r in 56% yield. We also
found that the reaction of N-hydroxy-4-methylbenzenesul-
fonamide (2a) with 1-chloro-4-vinylbenzene (1b) gave 1-p-
chlorophenyl-2-tosylethanone oxime (4s) in a yield of 81%.
However, only the reaction of N-hydroxy-1-phenylmeth-
anesulfonamide (2c) with arylalkenes 3 under identical
conditions led to the formation of isoxazolines 4. Addition-
ally, isoxazole derivatives were obtained under the same
conditions when using alkynes 1 as the substrates.
neither metal salts nor additives had an effect on the reac-
tion. Solvent effects on the reaction were also investigated
and indicated that dichloromethane was the most effective
for the reaction; however, the reaction barely proceeded in
THF, toluene, acetone, DME, 1,4-dioxane and cyclohexane.
Reactions performed in CHCl3, CCl4 and MeCN resulted in
the formation of trace amounts of products at approximate-
ly 40 °C. The temperature also affected the reaction and did
not yield the corresponding products at lower tempera-
tures, even after reaction times of more than 30 hours. In-
creasing the temperature (83 °C in 1,2-dichloroethane) de-
creased the reaction time from 18 hours to 3 hours with a
similar yield (Table 1, entry 3). Next, we used oxidants oth-
er than n-Bu4NIO4 (Table 1, entries 4–7) and found that
none of these were successful in the reaction. It is known
that 2,2′-azobis(isobutyronitrile) (AIBN) is widely used in
atom transfer radical polymerization reactions as an azo
free-radical initiator.21 In order to realize control of the rad-
ical polymerization reaction, AIBN was used as a free-radi-
cal initiator to improve the reaction yield under visible-
light irradiation in this work (Table 1, entries 8,10–12). At
the same time, we found that iodine was beneficial in pro-
moting the reaction. Perhaps the color of iodine makes the
reaction mixture absorb visible light more easily. Next, n-
Bu4NIO4 and iodine were simultaneously used as oxidants
in order to increase the oxidizing ability, and it was found
that the reaction time was shortened and that the yield was
increased (Table 1, entry 9–11).
The reaction of N-hydroxy-1-phenylmethanesulfon-
amide (2c) with 1-chloro-4-vinylbenzene (1b) was used to
optimize the reaction conditions. First, we tested a variety
of metal salts in the reaction, including Ru(TTP)CO, copper
salts, iron salts, palladium salts, ZnCl2 and Rh2(OAc)4, in ad-
dition to additives such as AcOH, Et3N, pyridine, molecular
sieves and activated carbon. The results showed that
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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Synthesis
Table 1 Optimization of the Reaction Conditionsa
O
N
NHOH
oxidant
CH2Cl2
S
Cl
O2
Cl
1b
2c
4b
Entry
Oxidant
Temp
Time
Yield
1
2
n-Bu4NIO4
40 °C
r.t.
15 h
15 h
3 h
22%
trace
18%
0
n-Bu4NIO4
3b
4
n-Bu4NIO4
83 °C
40 °C
40 °C
40 °C
40 °C
40 °C
25 °C
25 °C
25 °C
25 °C
n-Bu4NClO4
PhI(OAc)2
18 h
18 h
18 h
18 h
15 h
10 h
10 h
10 h
10 h
5
0
6
PhI(OH)OTs
PhI=O
0
7
0
8
n-Bu4NIO4/AIBN
n-Bu4NIO4/I2
n-Bu4NIO4/I2/AIBN
I2/AIBN
24%
34%
51%
45%
25%
9c
10d
11e
12f
n-Bu4NIO4/AIBN
a Reaction conditions: 1b (0.1 mmol), 2c (0.1 mmol), oxidant (0.1 mmol), CH2Cl2.
b Reaction in 1,2-dichloroethane.
c Reaction conditions: 1b (excess), 2c (0.1 mmol), n-Bu4NIO4 (0.05 mmol), I2 (0.05 mmol), CH2Cl2, 10 h, visible-light irradiation.
d Reaction conditions: 1b (excess), 2c (0.1 mmol), n-Bu4NIO4 (0.1 mmol), I2 (0.05 mmol), AIBN (0.01 mmol), CH2Cl2, 10 h, visible-light irradiation.
e Reaction conditions: 1b (excess), 2c (0.1 mmol), I2 (0.1 mmol), AIBN (0.01 mmol), CH2Cl2, 10 h, visible-light irradiation.
f Reaction conditions: 1b (excess), 2c (0.1 mmol), n-Bu4NIO4 (0.1 mmol), AIBN (0.01 mmol), CH2Cl2, 10 h, visible-light irradiation.
Furthermore, we examined the influence of the sub-
strate and its substituent (Scheme 2). The reactions of ole-
fins with electron-withdrawing substituents resulted in
moderate yields; however, styrenes with electron-donating
groups gave only trace amounts of the corresponding isox-
azoline products. The negative result with cyclopentene
implies that it is important for the reaction that the double
bond conjugates directly with the aromatic ring. Mean-
while, the reaction was also applied to 1-vinylnaphthalene
and phenylacetylene derivatives (Scheme 2). Under the op-
timized conditions, the reaction was extended to a variety
of acetylenes to give the corresponding isoxazoles in 44–
73% yield. We speculate that only moderate yields are ob-
tained because of the possibility that the reactions undergo
multiple reaction pathways, and also due to the oxidizing
defects and deficiencies of the oxidants used.20
To gain further insight into the reaction mechanism,
several mechanistic experiments were performed (Scheme
3). Initially, the possibility of benzaldehyde oxime as an in-
termediate could be ruled out, because benzaldehyde
oxime reacted directly with phenylacetylene to form 3,5-di-
phenylisoxazole and 3,4-diphenylisoxazole in a molar ratio
of about 6.5:1, while only 3,5-diphenylisoxazole was de-
tected in the reaction of N-hydroxy-1-phenylmethanesul-
fonamide with phenylacetylene when using n-Bu4NIO4 and
iodine as the oxidant and CH2Cl2 as the solvent (Scheme 3,
b). Secondly, formation of 3-(4-chlorophenyl)-5-phenyl-
4,5-dihydroisoxazole via benzyl radical addition to the
alkene and subsequently with a NO free radical was not ob-
served, which implies that the main reaction pathway was
not that shown: homolysis of the presumed N-sulfonylni-
troso intermediate and loss of SO2 leads to a benzylic radi-
cal, which recombines with a NO free radical, ultimately
yielding an oxime. The latter is then oxidized to a nitrile ox-
ide by n-Bu4NIO4, and the nitrile oxide combines with 4-
chlorostyrene to afford the product (Scheme 3, a). Further-
more, the reaction of p-methoxybenzeneacetylene with N-
hydroxy-1-phenylmethanesulfonamide under identical
conditions yielded p-methoxy-α-iodoacetophenone, but
only trace amounts of the isoxazole. This result indicates
that the main reaction pathway was also not the α-iodoace-
tophenone pathway (Scheme 3, c).
The suggested mechanism for the reaction based on the
trapping of the intermediates and related literature re-
ports13,21,22 is depicted in Scheme 4. Initially, the N-hydrox-
ysulfonamide is oxidized by n-Bu4NIO4 to give an N-sulfo-
nylnitroso radical intermediate. Addition of the N-sulfonyl-
nitroso radical intermediate to either 4-chlorostyrene or 4-
chlorophenylacetylene yields the corresponding radical in-
termediate, which is further attacked by its own nitroso
group. Finally, the loss of SO2 ultimately leads to the forma-
tion of the isoxazolines and isoxazoles. Two effective radical
scavengers, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)
and 2,6-di-tert-butyl-4-methylphenol (BHT) both halted
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
J. Cheng et al.
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Synthesis
O
N
O
N
H
R'
n-Bu4NIO4, I2
N
Ar
S
OH
or
R
R
AIBN, CH2Cl2
visible light
R
+
O
O
Ar
or
R'
3a–i
1a–j
2c R = H
4a–l
5a–i
2d R = p-Br
O
O
O
N
O
O
N
N
N
N
Cl
CF3
Cl
Cl
4a 53%
4b 51%
4c 49%
4d 51%
4e 33%
O
N
O
O
N
O
N
O
N
N
Br
Br
Br
Br
4i 70%
4j 56%
4f 49%
4g 53%
4h 82%
O
N
O
O
N
O
N
O
N
N
Cl
Cl
Br
Br
Br
5a 63%
5b 59%
5c 44%
4k 50%
4l 47%
O
N
O
O
O
O
O
N
N
N
N
Br
F
OEt
5d 50%
5e 48%
5f 73%
5g 58%
5h 58%
O
N
S
5i 56%
4b
Scheme 2 Formation of isoxazolines 4 and isoxazoles 5. N-hydroxy-1-phenylmethanesulfonamide 2, n-Bu4NIO4, I2, AIBN and CH2Cl2 were added to a
flask and the resulting mixture was stirred under visible-light irradiation for about 10 h at r.t. Excess alkene (at least 3 equiv) was used. Molar ratio of
alkyne/N-hydroxysulfonamide/n-Bu4NIO4/I2/AIBN = 1.0:1.0:1.0:0.50:1.
the reactions, and no product was formed. Meanwhile, the
radical-trapping products, 2,2,6,6-tetramethyl-1-[(nitroso-
sulfonyl)(phenyl)methoxy]piperidine and 3,5-diphenyl-2-
[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]isoxazolidine were
detected in the reaction by LCMS. Based on these results,
we speculate that the reaction may involve a radical reac-
tion process.
In summary, we have developed a new, one-pot proce-
dure for the formation of isoxazolines and isoxazoles by a
cascade of intermolecular C–C and intramolecular C–N and
C–O bond-forming reactions under mild conditions. A vari-
ety of isoxazolines and isoxazoles have been prepared in
yields of 33–82% and 44–73%, respectively. The reaction re-
quires n-Bu4NIO4 and I2 as the oxidant, AIBN as a free-radi-
cal initiator, but no metal salt catalysts or other additives.
Further efforts are now underway to expand the scope of
the substrates.
All reactions were performed under a N2 atmosphere. Anhydrous sol-
vents were purified according to standard procedures. Silica gel F254
plates were used for thin-layer chromatography (TLC) in which the
spots were examined under UV light at 254 nm and then developed
using iodine vapor. Flash chromatography was performed on silica gel
H (300~400 mesh). Melting points were obtained using a YRT-3 melt-
ing Point instrument (Tianjin Tianda Fat Co., Ltd.) temperature uncor-
rected. IR spectra were recorded using a VECTOR 22 infrared spec-
trometer. NMR spectra were recorded on Varian Mercury spectrome-
ters (400 MHz and 600 MHz), using CDCl3 or DMSO-d6 as the solvent.
LRMS/HRMS were recorded on a Bruker Daltonics Data Analysis 3.4
mass spectrometer. High-performance liquid chromatography (HPLC)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
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Paper
Synthesis
was performed with a YoungLin instrument SP930D, equipped with
Dikma C18 columns and using methanol as the eluent. X-ray data
were collected on a Bruker APEX-II instrument, equipped with a CCD
area detector, using Mo/Kα radiation. The structures were solved by
direct methods using SHELXL-97.
(a)
O
N
NO
Cl
Cl
Cl
O
SO2
S
O
H
N
N
O
S
S
OH
n-Bu4NIO4
O
O
O
O
O
N
NO
tautomerization
[O]
OH
O
O
N
N
N
Cl
Cl
O
N
(b)
O
N
O
30% yield
0
N
OH
n-BuNIO4, I2
N
O
N
AIBN, CH2Cl2
O
N
6.5
39% yield
:
1
6% yield
H
N
O
N
O
N
S
OH
n-BuNIO4, I2
O
O
AIBN, CH2Cl2
63% yield
OMe
0
H
N
S
OH
(c)
O2
n-Bu4NIO4
OMe
I
O
OMe
OMe
OMe
H2O
SO2
O
N
OH
OH
NH
O
N
S
S
O
O
O
O
Scheme 3 Mechanistic studies
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
J. Cheng et al.
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Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 156.7, 140.2, 132.8, 130.4, 129.3,
129.0, 128.8, 128.3, 127.0, 126.9, 81.4, 42.3.
HRMS (ESI): m/z [M + Na]+ calcd for C15H12NOClNa: 280.0500; found:
n-Bu4NIO4
I2
H
N
O
N
S
S
OH
O
O
O
O
Cl
280.0492.
Cl
or
5-(3-Chlorophenyl)-3-phenyl-4,5-dihydroisoxazole (4c)
Yield: 25 mg (49%); white solid; mp 82–85 °C.
Cl
Cl
Cl
1H NMR (400 MHz, CDCl3): δ = 7.69–7.67 (m, 2 H, Ph-H), 7.42–7.39
(m, 4 H, Ph-H), 7.31–7.28 (m, 3 H, Ph-H), 5.74–5.69 (m, 1 H, 5-H),
3.84–3.77 (m, 1 H, 4-H), 3.35–3.29 (m, 1 H, 4-H).
13C NMR (100 MHz, CDCl3): δ = 151.1, 138.2, 129.8, 125.4, 125.2,
124.2, 123.9, 123.4, 121.9, 121.1, 119.0, 76.7, 38.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H13NOCl: 258.0679; found:
258.0680.
O
O
N
O
N
N
S
S
S
O
O
O
O
O
O
SO2
5-(2-Chlorophenyl)-3-phenyl-4,5-dihydroisoxazole (4d)
Cl
Yield: 26 mg (51%); white solid; mp 76–78 °C.
Cl
1H NMR (400 MHz, CDCl3): δ = 7.70–7.67 (m, 2 H, Ph-H), 7.43–7.39
(m, 4 H, Ph-H), 7.31–7.28 (m, 3 H, Ph-H), 5.74–5.69 (m, 1 H, 5-H),
3.84–3.77 (m, 1 H, 4-H), 3.35–3.29 (m, 1 H, 4-H).
H
13C NMR (100 MHz, CDCl3): δ = 151.1, 138.2, 129.8, 125.4, 125.2,
O
O
N
124.2, 123.9, 123.4, 121.9, 121.1, 119.0, 76.7, 38.4.
LRMS (ESI): m/z = 258 [M + H]+.
N
3-Phenyl-5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole
(4e)
Scheme 4 Proposed mechanism for the formation of isoxazolines and
isoxazoles
Yield: 19 mg (33%); white solid; mp 142–143 °C.
1H NMR (400 MHz, CDCl3): δ = 7.70–7.68 (m, 2 H, Ph-H), 7.64 (d, J =
8.0 Hz, 2 H, Ph-H), 7.52 (d, J = 8.0 Hz, 2 H, Ph-H), 7.43–7.42 (m, 3 H,
Ph-H), 5.83–5.78 (m, 1 H, 5-H), 3.89–3.82 (m, 1 H, 4-H), 3.35–3.29 (m,
1 H, 4-H).
13C NMR (100 MHz, CDCl3): δ = 156.0, 145.0, 130.4, 129.0, 128.8,
126.8, 126.0, 125.8, 81.6, 43.3.
Isoxazolines and Isoxazoles; General Procedure
N-Hydroxy-1-phenylmethanesulfonamide (0.2 mmol), n-Bu4NIO4 (0.2
mmol), I2 (0.1 mmol) and AIBN (10%) were added to a 25 mL round-
bottom flask. A solution of the alkene (excess) or alkyne (0.2 mmol) in
anhydrous CH2Cl2 (2 mL) was injected via a syringe and the mixture
was stirred under visible-light irradiation for 10 h at r.t. The mixture
was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous
NaCl (2 × 10 mL), dried over Na2SO4 and concentrated under reduced
pressure. Purification was accomplished by column chromatography
on silica gel H with petroleum ether/ethyl acetate (20:1) as the eluent
to give the pure product.
HRMS (ESI): m/z [M + Na]+ calcd for C16H12F3NNaO: 314.0763; found:
314.0753.
5-(4-Bromophenyl)-3-phenyl-4,5-dihydroisoxazole (4f)
Yield: 29 mg (49%); white solid; mp 130–131 °C (Lit.25 130.5–
131.5 °C).
1H NMR (600 MHz, CDCl3): δ = 7.70–7.68 (m, 2 H, Ph-H), 7.51 (d, J =
8.4 Hz, 2 H, Ph-H), 7.43–7.42 (m, 3 H, Ph-H), 7.28 (d, J = 8.4 Hz, 2 H,
Ph-H), 5.73–5.70 (m, 1 H, 5-H), 3.82–3.78 (m, 1 H, 4-H), 3.32–3.28 (m,
1 H, 4-H).
3,5-Diphenyl-4,5-dihydroisoxazole (4a)
Yield: 24 mg (53%); white solid; mp 75–76 °C (Lit.23 73–74 °C).
1H NMR (400 MHz, CDCl3): δ = 7.71–7.42 (m, 10 H, Ph-H), 5.77–5.73
(m, 1 H, 5-H), 3.83–3.76 (m, 1 H, 4-H), 3.39–3.32 (m, 1 H, 4-H).
13C NMR (150 MHz, CDCl3): δ = 156.0, 140.0, 131.9, 130.3, 129.2,
13C NMR (100 MHz, CDCl3): δ = 156.1, 140.9, 130.1, 129.4, 128.7,
128.2, 126.7, 125.9, 82.5, 43.2.
128.8, 127.6, 126.7, 122.1, 81.8, 43.2.
LRMS (ESI): m/z = 302 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H14NO: 224.1070; found:
224.1068.
5-(3-Bromophenyl)-3-phenyl-4,5-dihydroisoxazole (4g)
Yield: 32 mg (53%); white solid; mp 97–98 °C (Lit.26 97.5–98.5 °C).
5-(4-Chlorophenyl)-3-phenyl-4,5-dihydroisoxazole (4b)
Yield: 26 mg (51%); pale yellow solid; mp 111–112 °C (Lit.24 111–
112 °C).
1H NMR (400 MHz, DMSO-d6): δ = 7.73–7.70 (m, 2 H, Ph-H), 7.48–
7.42 (m, 7 H, Ph-H), 5.78–5.74 (m, 1 H, 5-H), 3.93–3.86 (m, 1 H, 4-H),
3.43–3.37 (m, 1 H, 4-H).
1H NMR (400 MHz, CDCl3): δ = 7.70–7.68 (m, 2 H, Ph-H), 7.55 (s, 1 H,
Ph-H), 7.46–7.40 (m, 4 H, Ph-H), 7.33 (d, J = 7.6 Hz, 1 H, Ph-H), 7.25–
7.23 (m, 1 H, Ph-H), 5.74–5.69 (m, 1 H, 5-H), 3.84–3.77 (m, 1 H, 4-H),
3.35–3.29 (m, 1 H, 4-H).
13C NMR (100 MHz, CDCl3): δ = 156.0, 143.3, 131.2, 130.3, 130.3,
129.1, 128.8, 126.7, 124.4, 122.8, 81.5, 43.2.
LRMS (ESI): m/z = 302 [M + H]+.
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5-(2-Bromophenyl)-3-phenyl-4,5-dihydroisoxazole (4h)
1H NMR (400 MHz, CDCl3): δ = 7.89–7.85 (m, 4 H, Ph-H), 7.51–7.46
(m, 6 H, Ph-H), 6.84 (s, 1 H, 4-H).
Yield: 49 mg (82%); white solid; mp 66–67 °C.
13C NMR (150 MHz, CDCl3): δ = 170.4, 163.0, 130.2, 130.0, 129.2,
128.9, 127.5, 126.9, 125.8, 97.6.
LRMS (ESI): m/z = 222.2 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.70–7.67 (m, 2 H, Ph-H), 7.59–7.55
(m, 2 H, Ph-H), 7.41–7.35 (m, 5 H, Ph-H), 6.02–5.98 (m, 1 H, 5-H),
4.01–3.94 (m, 1 H, 4-H), 3.24–3.18 (m, 1 H, 4-H).
13C NMR (100 MHz, CDCl3): δ = 156.0, 140.6, 132.7, 130.2, 129.3,
129.1, 128.7, 127.8, 126.8, 126.7, 120.8, 81.4, 42.9.
5-(4-Chlorophenyl)-3-phenylisoxazole (5b)
Yield: 30 mg (59%); pale yellow solid; mp 178–179 °C (Lit.29 178–
LRMS (ESI): m/z = 302 [M + H]+.
179 °C).
5-(Naphthalen-1-yl)-3-phenyl-4,5-dihydroisoxazole (4i)
1H NMR (400 MHz, CDCl3): δ = 7.87–7.86 (m, 2 H, Ph-H), 7.80–7.77
Yield: 38 mg (70%); white solid; mp 62–63 °C(Lit.27 62.5–63.5 °C).
(m, 2 H, Ph-H), 7.55–7.49 (m, 5 H, Ph-H), 6.83 (s, 1 H, 4-H).
13C NMR (150 MHz, CDCl3): δ = 170.4, 162.9, 130.2, 130.0, 129.1,
129.0, 128.9, 127.4, 126.8, 125.8.
LRMS (ESI): m/z = 255.9 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.93–7.90 (m, 2 H, Ph-H), 7.82 (d, J =
4.0 Hz, 1 H, Ph-H), 7.71–7.68 (m, 3 H, Ph-H), 7.58–7.46 (m, 3 H, Ph-H),
7.40–7.39 (m, 3 H, Ph-H), 6.45–6.40 (m, 1 H, 5-H), 4.03–3.96 (m, 1 H,
4-H), 3.43–3.37 (m, 1 H, 4-H).
13C NMR (100 MHz, CDCl3): δ = 156.4, 136.1, 133.9, 130.1, 129.6,
129.4, 129.1, 128.7, 128.5, 126.7, 126.3, 125.7, 125.5, 122.9, 122.9,
80.2, 42.9.
HRMS (ESI): m/z [M + Na]+ calcd for C19H15NNaO: 296.1046; found:
296.1040.
5-(Bromomethyl)-3-phenylisoxazole (5c)
Yield: 20 mg (44%); white solid; mp 85–86 °C (Lit.30 85–86 °C).
1H NMR (400 MHz, CDCl3): δ = 7.81–7.78 (m, 2 H, Ph-H), 7.47–7.45
(m, 3 H, Ph-H), 6.64 (s, 1 H, 4-H), 4.52 (s, 2 H, CH2).
13C NMR (150 MHz, CDCl3): δ = 146.3, 136.0, 129.0, 128.7, 128.5,
128.1, 103.1, 20.9.
LRMS (ESI): m/z = 237.8 [M + H]+.
3-(4-Bromophenyl)-5-phenyl-4,5-dihydroisoxazole (4j)
Yield: 33 mg (56%); pale yellow solid; mp 140–141 °C.
1H NMR (400 MHz, CDCl3): δ = 7.55 (s, 4 H, Ph-H), 7.39–7.32 (m, 5 H,
Ph-H), 5.78–5.73 (m, 1 H, 5-H), 3.79–3.72 (m, 1 H, 4-H), 3.35–3.28 (m,
1 H, 4-H).
13C NMR (150 MHz, CDCl3): δ = 155.2, 140.6, 131.9, 128.8, 128.35,
128.29, 128.1, 125.8, 124.4, 82.8, 42.8.
Ethyl 3-Phenylisoxazole-5-carboxylate (5d)
Yield: 21 mg (50%); white solid; mp 47 °C (Lit.31 45–46 °C).
1H NMR (400 MHz, CDCl3): δ = 7.843–7.839 (m, 2 H, Ph-H), 7.60–7.62
(s, 1 H, 4-H), 7.52–7.48 (m, 3 H, Ph-H), 4.47 (q, J = 7.2 Hz, 2 H,
CH2OCO) 1.38 (t, J = 7.2 Hz, 3 H, CH3CH2).
13C NMR (150 MHz, CDCl3): δ = 164.1, 162.8, 156.7, 130.4, 129.3,
128.9, 126.7, 107.2, 62.2, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H13BrNO: 302.0175; found:
302.0181.
LRMS (ESI): m/z = 217.9 [M + H]+.
3-(4-Bromophenyl)-5-(4-chlorophenyl)-4,5-dihydroisoxazole (4k)
Yield: 33 mg (50%); white solid; mp 119–120 °C.
3-Phenyl-5-(p-tolyl)isoxazole (5e)
Yield: 22 mg (48%); white solid; mp 138–138.5 °C (Lit.32 137 °C).
1H NMR (400 MHz, CDCl3): δ = 7.94–7.92 (m, 4 H, Ph-H), 7.31–7.27
(m, 5 H, Ph-H), 6.51 (s, 1 H, 3-H), 2.44 (s, 3 H, CH3).
13C NMR (150 MHz, CDCl3): δ = 187.9, 145.4, 129.6, 129.6, 128.5,
128.5, 128.3, 128.1, 127.6, 126.8, 125.9, 125.8, 125.7, 96.8, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H14NO: 236.1070; found:
236.1070.
1H NMR (400 MHz, CDCl3): δ = 7.55 (s, 4 H, Ph-H), 7.34 (q, J = 15.8 Hz,
4 H, Ph-H), 5.75–5.71 (m, 1 H, 5-H), 3.80–3.73 (m, 1 H, 4-H), 3.30–
3.24 (m, 1 H, 4-H).
13C NMR (150 MHz, CDCl3): δ = 155.2, 139.1, 134.1, 132.0, 129.0,
128.1, 127.2, 124.5, 82.0, 42.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H12BrClNO: 335.9785; found:
335.9792.
3-(4-Bromophenyl)-3a,8b-dihydro-4H-indeno[2,1-d]isoxazole (4l)
5-(4-Ethylphenyl)-3-phenylisoxazole (5f)
Yield: 29 mg (47%); pale yellow solid; mp 152–155 °C.
Yield: 36 mg (73%); colorless liquid.
IR (KBr): 2955 (w), 2921(s), 2851 (w), 1244 (w), 1586 (w, C=N) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.02–7.86 (m, 4 H, Ph-H), 7.36–7.28
(m, 5 H, Ph-H), 6.50 (s, 1 H, 3-H), 2.73 (q, J = 7.6 Hz, 2 H, CH2CH3), 1.26
(t, J = 7.6 Hz, 3 H, CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 188.0, 175.1, 151.5, 129.7, 128.9,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 126.8, 126.0, 96.9, 29.0, 15.0.
1H NMR (600 MHz, CDCl3): δ = 7.56 (s, 5 H, Ph-H), 7.33–7.31 (m, 2 H,
Ph-H), 7.22–7.20 (m, 1 H, Ph-H), 6.24 (d, J = 9.6 Hz, 1 H, 5-H), 4.52–
4.49 (m, 1 H, 4-H), 3.50–3.46 (m, 1 H, CH2CH-4), 3.21–3.18 (m, 1 H,
CH2CH-4).
13C NMR (150 MHz, CDCl3): δ = 157.8, 140.5, 140.4, 132.0, 129.7,
128.5, 127.7, 125.8, 124.8, 124.1, 89.8, 31.9, 29.4.
HRMS (ESI): m/z [M + H]+ calcd for C17H16NO: 250.1226; found:
250.1226.
HRMS (ESI): m/z [M + H]+ calcd for C16H13BrNO: 314.0175; found:
314.0185.
5-(4-Bromophenyl)-3-phenylisoxazole (5g)
Yield: 34 mg (58%); white solid; mp 178–179 °C (Lit.33 180.5 °C).
3,5-Diphenylisoxazole (5a)
Yield: 27 mg (63%); white solid; mp 140 °C (Lit.28 141–142 °C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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1H NMR (400 MHz, CDCl3): δ = 7.92 (d, 2 H, J = 8.4, Ph-H), 7.90–7.87
(m, 2 H,Ph-H), 7.85–7.64 (m, 2 H, Ph-H), 7.62 (d, J = 8.4, 2 H, Ph-H),
7.48–7.48 (m, 1 H, Ph-H), 6.42 (s, 1 H, 3-H).
13C NMR (150 MHz, CDCl3): δ = 169.2, 163.0, 132.3, 130.9, 130.1,
129.4, 128.9, 127.2, 126.7, 97.8.
Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Koski, S. R.;
Maskaev, A. V.; Zhdankin, V. V. Org. Lett. 2013, 15, 4010.
(d) Minakata S., Okumura S., Nagamachi, T.; Takeda, Y. Org. Lett.,
2011, 13, 2966; (e) Jia, Q-f.; Benjamin, P. M. S.; Huang, J.; Du, Z.;
Zheng, X.; Zhang, K.; Conney, A. H.; Wang, J. Synlett 2013, 24, 79.
(f) Grecian, S.; Fokin, V. V. Angew. Chem. Int. Ed. 2008, 47, 8285.
(g) Nishiwaki N., Kobiro K., Kiyoto, H.; Hirao, S.; Sawayama, J.;
Saigo, K.; Okajima, Y.; Uehara, T.; Maki, A.; Ariga, M. Org.
Biomol. Chem., 2011, 9, 2832 (h) Trogu, E.; Vinattieri, C.; De
Sarlo, F.; Machetti, F. Chem. Eur. J. 2012, 18, 2081. (i) Svejstrup, T.
D.; Zawodny, W.; Douglas, J. J.; Bidgeli, D.; Sheikh, N. S.; Leonori,
D. Chem. Commun. 2016, 52, 12302. (j) Zhang W., Su, Y.; Wang,
K.-H.; Wu, L.; Chang, B.; Shi, Y.; Huang, D.; Hu, Y. Org. Lett.,
2017, 19, 376. (k) Triandafillidi, I.; Kokotos, C. G. Org. Lett. 2017,
19, 106. (l) Maestri G., Cañeque, T.; Della Ca’, N.; Derat, E.; Catel-
lani, M.; Chiusoli, G. P.; Malacria, M. Org. Lett., 2016, 18, 6108.
(m) Chandrasekhar, B.; Ahn, S.; Ryu, J-S. J. Org. Chem. 2016, 81,
6740. (n) Rouf, A.; Şahin, E.; Tanyeli, C. Tetrahedron 2017, 73,
331. (o) Bhosale S., Kurhade, S.; Prasad, U. V.; Palle, V. P.; Bhu-
niya, D. Tetrahedron, 2009, 50, 3948. (p) Wang, L-J.; Chen, M.; Qi,
L.; Xu, Z.; Li, W. Chem. Commun. 2017, 53, 2056. (q) Han, B.;
Yang, X. L.; Fang, R.; Yu, W.; Wang, C.; Duan, X. Y.; Liu, S. Angew.
Chem. Int. Ed. 2012, 51, 8816.
HRMS (ESI): m/z [M + H]+ calcd for C15H11ONBr: 300.0019; found:
300.0019.
5-(4-Fluorophenyl)-3-phenylisoxazole (5h)
Yield: 27 mg (58%); white solid; mp 130–132 °C (Lit.34 131 °C).
1H NMR (400 MHz, CDCl3): δ = 8.10–8.07 (m, 2 H, Ph-H), 7.88–7.83
(m, 2 H, Ph-H), 7.49–748 (m, 2 H, Ph-H), 7.18–7.14 (m, 3 H, Ph-H),
6.45 (s, 1 H, 3-H).
13C NMR (150 MHz, CDCl3): δ = 186.8, 166.9, 165.2, 132.4, 132.3,
130.1, 128.9, 126.8, 116.3, 116.2, 116.1, 97.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H11ONF: 240.0819; found:
240.0819.
3-Phenyl-5-(thiophen-2-yl)isoxazole (5i)
Yield: 25 mg (56%); white solid; mp 96–97 °C (Lit.35 95.5 °C).
13C NMR (150 MHz, CDCl3): δ = 165.3, 162.9, 133.9, 130.1, 128.9,
127.0, 126.8, 124.4, 123.9, 97.2.
(8) Ibrar, A.; Khan, I.; Abbas, N.; Farooq, U.; Khan, A. RSC Adv. 2016,
6, 93016.
HRMS (ESI): m/z [M + H]+ calcd for C13H10ONS: 228.0478; found:
(9) (a) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539. (b) CecchI, L.; De Sarlo,
F.; Machetti, F. Chem. Eur. J. 2008, 14, 7903. (c) Yoshimura, A.;
Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Koski, S. R.;
Maskaev, A. V.; Zhdankin, V. V. Org. Lett. 2013, 15, 4010.
(d) Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y. Org.
Lett. 2011, 13, 2966. (e) Jia, Q. F.; Benjamin, P. M. S.; Huang, J.
Synlett 2013, 24, 79. (f) Grecian, S.; Fokin, V. V. Angew. Chem. Int.
Ed. 2008, 47, 8285. (g) Nishiwaki, N.; Kobiro, K.; Kiyoto, H.;
Hirao, S.; Sawayama, J.; Saigo, K.; Okajima, Y.; Uehara, T.; Maki,
A.; Ariga, M. Org. Biomol. Chem. 2011, 9, 2832. (h) Trogu, E.;
Vinattieri, C.; De Sarlo, F.; Machetti, F. Chem. Eur. J. 2012, 18,
2081. (i) Svejstrup, T. D.; Zawodny, W.; Douglas, J. J.; Bidgeli, D.;
Sheikh, N. S.; Leonori, D. Chem. Commun. 2016, 52, 12302.
(j) Zhang, W.; Su, Y.; Wang, K. H.; Wu, L.; Chang, B.; Shi, Y.;
Huang, D. F.; Hu, Y. L. Org. Lett. 2017, 19, 376. (k) Triandafillidi,
I.; Kokotos, C. Org. Lett. 2017, 19, 106. (l) Maestri, G.; Cañeque,
T.; DellaCa’, N.; Derat, E.; Catellani, M.; Chiusoli, G. P.; Malacria,
M. Org. Lett. 2016, 18, 6108. (m) Chandrasekhar, B.; Ahn, S.; Ryu,
J. J. Org. Chem. 2016, 81, 6740. (n) Rouf, A.; Sahin, E.; Tanyeli, C.
Tetrahedron 2017, 73, 331. (o) Bhosale, S.; Kurhade, S.; Prasad,
U. V.; Palle, V. P.; Bhuniya, D. Tetrahedron 2009, 50, 3948.
(p) Wang, L. J.; Chen, M.; Qi, L.; Xu, Z.; Li, W. Chem. Commun.
2017, 53, 2056. (q) Han, B.; Yang, X. L.; Fang, R.; Yu, W.; Wang,
C.; Duan, X. Y.; Liu, S. Angew. Chem. Int. Ed. 2012, 51, 8816.
(10) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. J. Org. Chem. 2010, 75,
1961.
228.0478.
Funding Information
We gratefully acknowledge the financial support from the National
Science Foundation of China (No. 21072131) and Sichuan University–
Lu Zhou Strategic Cooperation Projects (No. 2013 CDLZ-S18).
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Acknowledgment
We sincerely thank Prof. Dr. Burkhard Koenig (Institut für Organische
Chemie, Universität Regensburg, Germany) for his revisions and sug-
gestions on the work reported in this paper.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I