Synthesis of 4-sulfenyl isoxazoles through AlCl3-mediated electrophilic cyclization and sulfenylation of 2-alkyn-1-one O-methyloximes

Article abstract of DOI:10.1021/acs.joc.9b00256

An efficient method for the synthesis of 4-sulfenyl isoxazoles has been developed via AlCl₃-mediated electrophilic cyclization/sulfenylation of 2-alkyn-1-one O-methyloximes. Remarkably, N-arylsulfanylsuccinimides are employed as electrophiles for the construction of 4-arylsulfanyl isoxazoles, and 4-alkylsulfanyl isoxazoles are accessed with dialkyl disulfides as electrophiles.

Full text of DOI:10.1021/acs.joc.9b00256

Subscriber access provided by UNIV OF TEXAS DALLAS
Article
Synthesis of 4-Sulfenyl Isoxazoles through AlCl3-Mediated Electrophilic
Cyclization and Sulfenylation of 2-Alkyn-1-one O-Methyloximes
Wen-Chao Gao, Yu-Fei Cheng, Hong-Hong Chang, Xing Li, Wen-Long Wei, and Peng Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00256 • Publication Date (Web): 13 Mar 2019
Downloaded from http://pubs.acs.org on March 13, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of 4-Sulfenyl Isoxazoles through AlCl3-Mediated Electrophilic
Cyclization and Sulfenylation of 2-Alkyn-1-one O-Methyloximes
Wen-Chao Gao,a* Yu-Fei Cheng,a Hong-Hong Chang,a Xing Li,a Wen-Long Weia and Peng Yangb*
a College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, P. R. China
b College of Chemistry, Chemical Engineering and Material Science, Shandong Normal University, Jinan
250014, P. R. China
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*E-mail: gaowenchao@tyut.edu.cn; yangpeng@sdnu.edu.cn
Abstract: An efficient method for the synthesis of 4-sulfenyl isoxazoles has been
developed via AlCl3-mediated electrophilic cyclization/sulfenylation of 2-alkyn-1-one
O-methyloximes. Remarkably, N-arylsulfanylsuccinimides are employed as electrophiles
for the construction of 4-arylsulfanyl isoxazoles, and 4-alkylsulfanyl isoxazoles are
accessed with dialkyl disulfides as electrophiles.
O
O
N
OMe
SR'
N
N
R
AlCl3 (1.0 eq)
+
O
SR'
or
MeNO2 or Neat
R
SR'
SR'
Electrophilic cyclization/sulfenylation
21 examples of 4-sulfenylated isoxazoles
up to 91% yield



Introduction
Isoxazole skeleton is an important framework and a critical pharmacophore with a variety
of biological activities (Figure 1),1 and it ranked 33rd in frequency among the 351 ring
systems found in marketed drugs according to a recent survey.2 Sulfur is also a ubiquitous
element in biologically active natural products and medicinal molecules,3 and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 24
1
2
3
4
5
6
7
8
9
replacement of heterocycle rings with sulfenylated ones provides a useful way to
modulate substituent trajectories for optimizing complementarity and fitting within a
ligand binding pocket in drug design.4 Although many synthetic methods have been
developed to construct functionalized isoxazole derivatives,5 the synthetic route to access
4-sulfenyl isoxazoles has been less studied. A representative and conventional synthetic
route for 4-sulfenyl isoxazoles was the reaction of thiosulfonates or disulfides with
4-isoxazolyl anion species, which was generated at low temperature under strong basic
conditions (Scheme 1, eq 1).6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Examples Containing Isoxazole Skeleton
SO2NHR
OCH3
Ph
S
N
tBu
SO2NH
O
CH3
Valdecoxib
CHO
N
O
R = H,
R = COEt,
anti-inflammatory
Parecoxib
Endothelin antagonist
O
SO2CH3
HO
NH2
N
O
N
O
CF3
Muscinol
psychoactive compounds
Isoxaflutole
(herbicide)
Since the pioneer work for the synthesis of 4-iodo isoxazoles via electrophilic
cyclization of 2-alkyn-1-one O-methyloximes was developed by Larock,7 electrophilic
cyclization of oximes employing different electrophiles has become a powerful protocol
to building 4-functionalized isoxazoles,8 due to its easy availability of starting materials,
high efficiency and excellent regioselectivity. A series of isoxazole derivatives such as
4-fluoro, selenyl, and boryl isoxazoles have been successfully accessed using this
ACS Paragon Plus Environment

Page 3 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
protocol (Scheme 1, eq 2).8c-e However, the electrophilic sulfenylation of 2-alkyn-1-one
O-methyloximes, which can enable the construction of 4-sulfenyl isoxazoles, seems
feasible but never been established. Principally this is attributed to the
sulfenylation/halogenation of alkynyl derivatives with traditional S-electrophile (e.g.
sulfenyl choloride), which is competitive to electrophilic cyclization and cannot be
avoided properly.9 As our continuous work in the preparation of sulfur-containing
compounds,10 herein we would like to report the electrophilic sulfenylation of
2-alkyn-1-one O-methyloximes using N-sulfanylsuccinimides or disulfides as
electrophiles, which could access the synthesis of 4-sulfenyl isoxazoles under mild
reaction conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Different Methods for the Synthesis of 4-Functionalized Isoxazoles
Previous work
O
R2
O
R
R2
O
R2
R'
Thiosulfonate
or disulfide
N
N
N
M
(1)
(2)
SR3
R1
R1
R
[M]
X
M = MgBr or Li
O
OMe
N
N
Cyclization
Base
X
"X+"
R
X = F, Cl, Br, I, B, SeR
This work
O
N
OMe
N
R
(3)
Cyclization
SR'
"S+"
R
R = (hetero)aryl, Me, Et
Results and Discussion
We commenced our study with the reaction of 2-alkyn-1-one O-methyloxime 1a and
N-tolylsulfanylsuccinimde 2a using ClCH2CH2Cl (DCE) as solvent. In the absence of any
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 24
1
2
3
4
5
6
7
8
9
additives, neither of starting materials were consumed (entry 1). The desired
4-tolylsulfanyl isoxazole 3a was produced in 67% yield (entry 2) when 1.0 equiv of AlCl3
was employed. Further investigation on the reaction solvents showed that CH3NO2 was
the optimal solvent for this transformation (entries 3-7), and 3a could be isolated in 86%
yield (entry 7). Lowering the amount of AlCl3 would resulted in the decrease of yield of
3a (entry 8). Other kinds of additives such as ZnCl2, BF3•Et2O, FeCl3, trifluoroacetic acid
(TFA), and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were all tried for this reaction,
while none of them gave a better result than AlCl3 (entries 9-13). Attempts to increase or
lower the reaction temperature lead to the decrease of reaction efficiency (entries 14 and
15). We also attempted this cyclization using the known S-electrophiles 4 and 5,
however, the formation of disulfides or chlorothiolation of C-C triple bond was detected
as major process (entries 16 and 17). In addition, the disulfide 6 was also tested for this
cyclization, and the desired product 3a was only afford in 32% yield (entry 18).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of Reaction Conditionsa
Me
OMe
O
O
Ph
Additive
Solvent
N
N
+
Ph
S
N
60 oC
3-6 h
Ph
S
Me
Ph
O
1a
3a
2a
Entry
Additive (eq)
--
Solvent
DCE
Yieldb(%)
1
0
2
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
DCE
67
32
86
3c
4
CH2Cl2
CHCl3
ACS Paragon Plus Environment

Page 5 of 24
The Journal of Organic Chemistry
1
2
3
4
5
AlCl3 (1.0)
MeCN
46
5
6
7
8
6
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (0.75)
ZnCl2 (1.0)
BF3•Et2O (1.0)
FeCl3 (1.0)
TFA (1.0)
Toluene
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
12
7
91 (86d)
9
8
78
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
10
11
12
13
14e
15f
16g
17h
18i
3
6
0
DBU (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
0
67
74
16
10
32
Me
Me
O
Me
Cl
S
S
S
N
S
Me
O
6
5
4
a Reaction conditions: 1a (0.15 mmol), 2a (0.225 mmol), and additive (0.15 mmol) in solvent (1.5 mL)
at 60 oC for 3-6 h. b Yield determined by GC analysis using n-dodecane as the internal standard. c The
reaction was run at reflux. d Isolated yield. e Reaction temperature: 45 oC. f Reaction temperature: 90
oC. g 2a was replaced by 4. h 2a was replaced by 5. i 2a was replaced by 6.
With the optimal conditions in hand (Table 1, entry 7), we explored the substrate
scope of this cyclization reaction. As is shown in Table 2, a series of
N-arylsulfanylsuccinimides, regardless of electron-donating or -withdrawing group on the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 24
1
2
3
4
5
6
7
8
9
phenyl ring, could efficiently induce the cyclization to produce the desired 4-isoxazolyl
sulfides in good to excellent yields (3a-f). Notably, the present transformation could be
effectively scaled up to gram scale despite slight decrease in reaction efficiency (73%
yield of 3a). Next, the influence of electronic effects on the aromatic rings directly linked
to the triple bond of the alkynone O-methyloximes was examined. The results
demonstrated that substrates bearing electron-donating groups (Me and MeO) could give
better yields than the ones with electron-withdrawing groups (3g, h vs 3i, j), and the
thienyl group could also be tolerated in this transformation (3k). The structure of 3i was
further confirmed by X-ray crystallographic analysis. When the aromatic ring tethered to
the triple bond was replaced by alkyl or silyl group, the reaction could still work well,
despite a little decrease in reaction efficiency (3l-o). Additionally, the variation on the
O-methyloxime moiety were also tried, and products containing either the bulkyl
tert-butyl group or substituted phenyl ring attached to the O-methyloxime moiety were
afforded in moderate yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Synthesis of 4-Arylsulfanyl Isoxazolesa
ACS Paragon Plus Environment

Page 7 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
OMe
R2
O
N
O
N
AlCl3 (1 eq)
3
+
R1
N
S
2
N
R
MeNO2
R1
R
3
60 oC, 3-7 h
S
R2
3
O
1
N O
N O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S
S
S
Cl
Me
3b
, 85%
3c
, 90%
N O
b
3a
, 91% (0.9 g, 73% )
N O
N O
Ph
Ph
Ph
Ph
S
S
S
Br
OMe
NO2
3e
, 76%
3f
, 84%
O
3d
, 87%
O
N
N
R
Ph
Ph
R
3g
= Me, , 90%
= OMe, , 91%
3i
= Cl, , 72%
= CO2Me, , 66%
S
S
S
R
R
R
3h
3j
Me
Me
3k
, 63%
N O
N O
Ph
R
R
R
R
R
3l
= Me, , 60%
= n-Bu,
= t-Bu, , 79%
3o
= TMS, , 60%
R
Ph
3m
3n
, 46%
S
S
Me
R
R
3p
= t-Bu, , 63%
3q
= 4-MeC6H4, , 67%
Me
a Reaction conditions: 1 (0.15 mmol), 2 (0.225 mmol), AlCl3 (0.15 mmol), MeNO2 (1.5 mL), at 60 oC
for 3-7 h. Isolated yields are shown. b The reaction was run on a 3.6 mmol scale.
Notably, methyl sulfides are valuable units in modern pharmaceutical science (e.g.,
Thioridazine and Simetryn), and many synthetic methods have been developed to
introduce the “MeS” group to organic molecules.11 In our initial attempt to the synthesis
of 4-sulfenyl isoxazoles, when N-methylthiosuccinimide was subjected to the cyclization
process, no desired 4-methylthio isoxazoles were detected under the optimized conditions.
Fortunately, inspired by Zeni’s work,12 it was found that in the presence of AlCl3, the
dimethyl disulfide could induce the cyclization to access 4-methylthio isoxazoles under
neat conditions (For details, see SI). The generality of this cyclization/methylthiolation
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 24
1
2
3
4
5
6
7
8
9
was also tested (Table 3), and all the 4-isoxazolyl methyl sulfides could be produced in
moderate yields (3r-v). Furthermore, the diethyl disulfide could also be served as an
electrophile to induce the cyclization of 2-alkyn-1-one oxime 1a to afford 3w in 48%
yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Synthesis of 4-Alkylsulfanyl Isoxazolesa
OMe
R2
O
N
N
AlCl3 (1.0 eq)
3
3
S
S
R
R1
+
neat, rt
6-12 h
R
R1
R
3
R2
S
3
1
7
O
N
O
N
O
N
Ph
Ph
Ph
Ph
OMe
Ph
Cl
SMe
3r, 63%
SMe
3t, 53%
SMe
3s, 46%
O
N
O
O
N
N
Ph
Ph
Ph
SMe
SMe
SEt
3u, 52%
3v, 55%
3w, 48%b
a Reaction conditions: 1 (0.15 mmol), 7 (0.225 mmol), AlCl3 (0.15 mmol), stirred at room temperature
for 6-12 h. Isolated yields are shown. b The reaction was run in DCE (1.5 mL) at 60 oC.
To give a clear understanding of the mechanism, several control experiments were
consequently carried out. When the oxime 1a was submitted to AlCl3-mediated reaction
in the absence of N-arylsulfanylsuccinimides (2a) (Scheme 2, eq 1), or likewise when the
same substrate reacted with 2a in the absence of AlCl3 (Table 1, entry 1), no cyclized
product was detected in both reactions. Furthermore, the reaction of 4-unsubstituted
isoxazoles 8 with 2a could not give any product under standard conditions (Scheme 2, eq
2). These results indicated that the sulfenylation and cyclization process probably
underwent simultaneously. In addition, the reaction mixture was also detected using MS
ACS Paragon Plus Environment

Page 9 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
analysis, and the signal of a sulfenium cation intermediate [358.13]+ was obviously
captured (for details, see SI), which further confirmed that the cyclization was induced by
S-electrophiles.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Control Experiments
OMe
N
AlCl3 (1.0 eq)
CH3NO2, 60 oC
No Reaction
No Reaction
(1)
(2)
Ph
Ph
Ph
1a
2a
(1.0 eq)
N O
AlCl3 (1.5 eq)
CH3NO2, 60 oC
Ph
H
8
Based on these experimental results, a possible reaction mechanism was proposed in
Scheme 3. The activation of N-arylsulfanylsuccinimides or dimethyl disulfide with AlCl3
would give sulfenium cation A, which could react with C-C triple bond to form
intermediate B. Subsequently, intramolecular cyclization via nucleophilic attack of
oxygen to the activated Csp resulted in the formation of intermediate D, which underwent
demethylation to afford the desired 4-isoxazolyl sulfides 3.
Scheme 3. Proposed Reaction Mechanism
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 24
1
2
3
4
O
MeS
Ph
N
5
6
7
8
OMe
N
or
OMe
N
O
O
N
O
AlCl3
S
Ar
Ph
S
R
A
or
Ph
9
S
Ph
S
S
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
B
Me
Cl-
Ph
Me
O
N
Me
O
O
Ph
N
Ph
N
Ph
-MeCl
S
S
R
Ph
S
Ph
R
R
3
C
D
Diversified derivation is further demonstrated using the obtained 4-sulfenyl isoxazoles.
For example, desilylation of 3o proceeded smoothly to access the 3-unsubsituted
4-sulfenyl isoxazoles 9 (Scheme 4, eq 1). Furthermore, using different oxidative
conditions, the 4-sulfenyl isoxazoles products could be successfully transformed to either
N-tosyl sulfilimine 10 or 4-sulfinyl isoxazole 11.
Scheme 4. Derivation of 4-sulfenyl isoxazoles
Ph
Ph
N
O
N
O
TBAF (2 eq)
S
S
(1)
H
TMS
CH3OH, rt
61%
3o
Me
Ph
9
Me
Ph
N
O
N
O
HOAc (20 mol%)
Chloramine-T (2.1 eq)
TsN
S
S
Ph
Ph
CH3CN, reflux
61%
(2)
10
3a
Me
Ph
Me
Ph
N
O
N
O
H2O2 (4 eq)
O
(3)
S
S
CHCl3/HOAc, r.t.
Me
Me
Ph
3r
Ph
11
80%
Conclusions
ACS Paragon Plus Environment

Page 11 of 24
The Journal of Organic Chemistry
1
2
3
4
5
In summary, this work provides a simple and practical protocol to 4-sulfenylated
6
7
isoxazoles,
which
were
formed
through
AlCl3-mediated
electrophilic
8
9
cyclization/sulfenylation of 2-alkyn-1-one O-methyloximes. N-Arylsulfanylsuccinimides
were used as electrophiles for 4-arylsulfanyl isoxazoles whereas the 4-alkylsulfanyl ones
were accessed by employing dialkyl disulfides as electrophiles instead. For the
mechanism studies, the key sulfenium cation was obviously detected by MS analysis. The
diversified derivation of desired products expressed the synthetic potential for
4-sulfur-containing isoxazoles construction. Further study on the application of this
methodology and biological activities of these isoxazolyl sulfides is underway.
Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
General. H NMR (400 MHz) and 13C NMR (100 MHz), were recorded using NMR
spectrometers with CDCl3 as the solvent. Chemical shifts (δ) were measured in ppm and
referenced to the deuterated chloroform (1H: δ = 7.26 ppm, 13C: δ = 77.00 ppm).
High-resolution mass spectrometry (HRMS) was performed on a Q-TOF spectrometer
instrument with an ESI source. Melting points were measured with a RD-II type melting
point apparatus (uncorrected). X-ray structural analysis was obtained with an X-ray
single-crystal diffractometer. Commercially available reagents were used without further
purification. 2-Alkyn-1-one O-methyloximes8 and N-Sulfanylsuccinimides10 are prepared
following previous reports. Petroleum ether (PE), where used, has the boiling point range
of 60−90 °C. For column chromatography, silica gel (200−300 mesh) was used with
EtOAc and PE as eluent.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 24
1
2
3
4
5
General Procedure for the Synthesis of 3a-q.
6
7
8
9
In a 10 mL flask, under ambient atmosphere, the solution of 3-diphenylprop-2-yn-1-one
O-methyl oxime (1a, 0.15 mmol), N-tolylthiosuccinimides (2a, 0.225 mmol, 1.5 equiv)
and AlCl3 (0.15 mmol, 1.0 equiv) in CH3NO2 (1.5 mL) was stirred at 60 °C using oil bath
for 6 h. After that time, the residue was purified by chromatography column on silica gel
or preparative TLC to afford the desired product 3a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Gram scale synthesis of 3a. In a 25 mL flask, under ambient atmosphere, the solution of
3-diphenylprop-2-yn-1-one
O-methyl
oxime
(1a,
3.6
mmol,
0.85
g),
N-tolylthiosuccinimides (2a, 5.4 mmol, 1.2 g) and AlCl3 (3.6 mmol, 0.48 g) in CH3NO2
(6 mL) was stirred at 60 °C using oil bath for 12 h. The resulted reaction mixture was
diluted with CH2Cl2 (30 mL), and washed with H2O (10 mL×3). The organic phase was
dried with anhydrous Na2SO4, concentrated under vacuum and purified by
chromatography column to afford 3a (0.90 g, 73% yield).
3,5-Diphenyl-4-(p-tolylthio)isoxazole (3a)
Yield: 46.8 mg (91%); time: 3 h; yellow solid; m.p. 82-84 oC; TLC, Rf = 0.37 (PE:EtOAc
= 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.16-8.13 (m, 2H), 7.81 (dd, 2H, J = 7.6 Hz, J =
1.2 Hz), 7.50-7.39 (m, 6H), 7.05-6.98 (m, 4H), 2.26 (s, 3H); 13C{1H} NMR (CDCl3, 100
MHz): δ 172.2, 165.1, 135.8, 132.5, 130.9, 130.1, 130.0, 128.8, 128.53, 128.47, 128.2,
127.4, 127.0, 126.2, 102.3, 20.9; HRMS (ESI) m/z calcd for C22H18NOS [M + H]+:
344.1104, found: 344.1102.
3,5-Diphenyl-4-(phenylthio)isoxazole (3b)
ACS Paragon Plus Environment

Page 13 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Yield: 41.9 mg (85%); time: 3 h; yellow solid; m.p. 88-90 oC; TLC, Rf = 0.35 (PE:EtOAc
= 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.15-8.11 (m, 2H), 7.80 (dd, 2H, J = 7.6 Hz, J =
1.2 Hz), 7.49-7.47 (m, 3H), 7.42-7.39 (m, 3H), 7.22 (t, 2H, J = 7.6 Hz), 7.12 (t, 3H, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
8.4 Hz); C{1H} NMR (CDCl3, 100 MHz): δ 172.4, 165.1, 136.1, 131.0, 130.0, 129.3,
128.8, 128.5, 128.1, 127.4, 127.0, 126.0, 125.9, 101.8; HRMS (ESI) m/z calcd for
C21H16NOS [M + H]+: 330.0947, found: 330.0941.
4-((4-Chlorophenyl)thio)-3,5-diphenylisoxazole (3c)
o
Yield: 49.0 mg (90%); time: 3.5 h; white solid; m.p. 124-126 C; TLC, Rf = 0.40
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.13-8.09 (m, 2H), 7.78 (dd, 2H, J =
7.6 Hz, J = 1.2 Hz), 7.50-7.41 (m, 6H), 7.19 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz);
13C{1H} NMR (CDCl3, 100 MHz): δ 172.5, 164.9, 134.6, 131.9, 131.1, 130.1, 129.4,
128.9, 128.6, 128.4, 127.9, 127.4, 127.2, 126.8, 101.4; HRMS (ESI) m/z calcd for
C21H15ClNOS [M + H]+: 364.0557, found: 364.0558.
4-((4-Nitrophenyl)thio)-3,5-diphenylisoxazole (3d)
o
Yield: 48.8 mg (87%); time: 3.5 h; yellow solid; m.p. 128-130 C; TLC, Rf = 0.33
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.06 (t, 4H, J = 8.8 Hz), 7.76 (dd, 2H,
J = 7.6 Hz, J = 1.2 Hz), 7.52-7.38 (m, 6H), 7.21 (d, 2H, J = 8.8 Hz); 13C{1H} NMR
(CDCl3, 100 MHz): δ 173.1, 164.8, 145.8, 145.6, 131.5, 130.4, 129.0, 128.7, 128.2, 127.6,
127.3, 126.4, 126.3, 125.4, 124.5, 124.4, 99.4; HRMS (ESI) m/z calcd for C21H15N2O3S
[M + H]+: 375.0798, found: 375.0788.
4-((2-Bromophenyl)thio)-3,5-diphenylisoxazole (3e)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 24
1
2
3
4
o
Yield: 46.4 mg (76%); time: 7 h; yellow solid; m.p. 149-151 C; TLC, Rf = 0.35
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.10-8.06 (m, 2H), 7.79 (dd, 2H, J =
7.6 Hz, J = 2.0 Hz), 7.53 (dd, 1H, J = 7.6 Hz, J = 1.2 Hz), 7.50-7.46 (m, 3H), 7.43-7.40
(m, 3H), 7.11 (t, 1H, J = 8.8 Hz), 6.98 (t, 1H, J = 9.2 Hz), 6.84 (d, 1H, J = 8.0 Hz);
13C{1H} NMR (CDCl3, 100 MHz): δ 172.8, 164.9, 137.3, 133.1, 131.2, 130.1, 128.9,
128.6, 128.1, 127.9, 127.4, 126.8, 126.7, 126.2, 120.5, 101.3; HRMS (ESI) m/z calcd for
C21H15BrNOS [M + H]+: 408.0052, found: 408.0063.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-((4-Methoxyphenyl)thio)-3,5-diphenylisoxazole (3f)
Yield: 45.2 mg (84%); time: 4 h; yellow solid; m.p. 76-78 oC; TLC, Rf = 0.32 (PE:EtOAc
= 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.20-8.16 (m, 2H), 7.83 (d, 1H, J = 1.6 Hz), 7.81
(d, 1H, J = 2.0 Hz), 7.50-7.48 (m, 3H), 7.44-7.41 (m, 3H), 7.03 (d, 2H, J = 8.8 Hz), 6.74
(d, 2H, J = 8.8 Hz), 3.73 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 171.8, 165.0,
158.3, 130.9, 129.9, 128.8, 128.62, 128.59, 128.5, 128.3, 127.5, 127.1, 126.5, 115.0,
103.5, 55.3; HRMS (ESI) m/z calcd for C22H18NO2S [M + H]+: 360.1053, found:
360.1060.
3-Phenyl-5-(p-tolyl)-4-(p-tolylthio)isoxazole (3g)
o
Yield: 48.2 mg (90%); time: 3 h; yellow solid; m.p. 106-108 C; TLC, Rf = 0.35
1
(PE:EtOAc = 19:1); H NMR (CDCl3, 400 MHz): δ 7.96 (d, 2H, J = 8.4 Hz), 7.72 (dd,
2H, J = 7.6 Hz, J = 1.6 Hz), 7.34-7.31 (m, 3H), 7.18 (d, 2H, J = 8.4 Hz), 6.96-6.90 (m,
4H), 2.31 (s, 3H), 2.18 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 172.4, 165.1, 141.4,
135.7, 132.7, 130.1, 129.9, 129.5, 128.5, 128.4, 127.3, 126.1, 124.3, 115.3, 101.5, 21.5,
ACS Paragon Plus Environment

Page 15 of 24
The Journal of Organic Chemistry
1
2
3
4
5
20.9; HRMS (ESI) m/z calcd for C23H20NOS [M + H]+: 358.1260, found: 358.1254.
6
7
5-(4-Methoxyphenyl)-3-phenyl-4-(p-tolylthio)isoxazole (3h)
8
9
o
Yield: 50.3 mg (90%); time: 3 h; white solid; m.p. 107-109 C; TLC, Rf = 0.41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(PE:EtOAc = 19:1); H NMR (CDCl3, 400 MHz): δ 8.12 (d, 2H, J = 9.2 Hz), 7.79 (dd,
2H, J = 8.0 Hz, J = 1.6 Hz), 7.44-7.37 (m, 3H), 7.05-6.95 (m, 6H), 3.85 (s, 3H), 2.27 (s,
3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 172.2, 165.1, 161.6, 135.6, 132.8, 130.1, 129.9,
129.1, 128.5, 128.4, 125.9, 119.7, 114.2, 100.4, 55.3, 20.9; HRMS (ESI) m/z calcd for
C23H20NO2S [M + H]+: 374,1209, found: 374.1217.
5-(4-Chlorophenyl)-3-phenyl-4-(p-tolylthio)isoxazole (3i)
o
Yield: 40.7 mg (72%); time: 7.5 h; yellow solid; m.p. 112-114 C; TLC, Rf = 0.42
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, 2H, J = 8.8 Hz), 7.72 (d, 2H,
J = 8.0 Hz), 7.34 (t, 5H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.90 (d, 2H, J = 8.4 Hz),
2.18 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 171.0, 165.2, 137.1, 136.0, 132.1,
130.2, 130.0, 129.1, 128.6, 128.5, 128.0, 126.2, 125.4, 102.8, 20.9; HRMS (ESI) m/z
calcd for C22H17ClNOS [M + H]+: 378.0714, found: 378.0719.
Methyl 4-(3-phenyl-4-(p-tolylthio)isoxazol-5-yl)benzoate (3j)
1
Yield: 39.7 mg (66%); time: 4 h; yellow liquid; TLC, Rf = 0.32 (PE:EtOAc = 19:1); H
NMR (CDCl3, 400 MHz): δ 8.24 (d, 2H, J = 8.0 Hz), 8.13 (d, 2H, J = 8.0 Hz), 7.81 (d,
2H, J = 7.2 Hz), 7.48-7.39 (m, 3H), 7.04-6.96 (m, 4H), 3.94 (s, 3H), 2.26 (s, 3H); 13C{1H}
NMR (CDCl3, 100 MHz): δ 170.8, 166.3, 165.3, 140.0, 136.1, 131.95, 131.90, 130.9,
130.2, 130.1, 129.9, 128.6, 128.5, 128.0, 127.6, 127.3, 126.5, 52.4, 20.9; HRMS (ESI)
m/z calcd for C24H20NO3S [M + H]+: 402.1158, found: 402.1152.
3-Phenyl-5-(thiophen-3-yl)-4-(p-tolylthio)isoxazole (3k)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
1
2
3
4
5
o
Yield: 33.0 mg (63%); time: 3.5 h; yellow solid; m.p. 76-78 C; TLC, Rf = 0.36
6
7
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.26 (dd, 1H, J = 2.8 Hz, J = 1.2 Hz),
8
9
13
7.85-7.81 (m, 3H), 7.45-7.39 (m, 4H), 7.06-6.99 (m, 4H), 2.27 (s, 3H); C{1H} NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(CDCl3, 100 MHz): δ 169.2, 164.8, 135.9, 132.2, 130.1, 130.0, 128.50, 128.48, 128.1,
127.9, 127.3, 126.4, 126.1, 126.0, 125.2, 101.0, 33.7, 28.6, 20.8; HRMS (ESI) m/z calcd
for C20H16NOS2 [M + H]+: 350.0668, found: 350.0667.
5-Methyl-3-phenyl-4-(p-tolylthio)isoxazole (3l)
Yield: 25.3 mg (60%); time: 6 h; yellow oil liquid; TLC, Rf = 0.37 (PE:EtOAc = 19:1);
1H NMR (CDCl3, 400 MHz): δ 7.87-7.84 (m, 2H), 7.43-7.37 (m, 3H), 7.04 (d, 2H, J = 8.0
13
Hz), 6.95 (d, 2H, J = 8.4 Hz), 2.52 (s, 3H), 2.27 (s, 3H); C{1H} NMR (CDCl3, 100
MHz): δ 175.3, 165.1, 135.7, 132.7, 129.94, 129.90, 128.5, 128.4, 128.1, 126.3, 103.5,
20.8, 11.7; HRMS (ESI) m/z calcd for C17H16NOS [M + H]+: 282.0947, found: 282.0948.
5-Butyl-3-phenyl-4-(p-tolylthio)isoxazole (3m)
1
Yield: 22.3 mg (46%); time: 7 h; yellow liquid; TLC, Rf = 0.38 (PE:EtOAc = 19:1); H
NMR (CDCl3, 400 MHz): δ 7.85 (dd, 2H, J = 7.6 Hz, J = 2.0 Hz), 7.41-7.37 (m, 3H),
7.03 (d, 2H, J = 8.0 Hz), 6.94 (d, 2H, J = 8.4 Hz), 2.89 (t, 2H, J = 9.6 Hz) , 2.27 (s, 3H),
13
1.75-1.66 (m, 2H), 1.41-1.34 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz); C{1H} NMR (CDCl3,
100 MHz): δ 178.9, 163.2, 135.6, 133.0, 129.9, 129.8, 128.5, 128.1, 126.2, 102.8, 29.3,
25.7, 22.3, 20.8, 13.6; HRMS (ESI) m/z calcd for C20H22NOS [M + H]+: 324.1417, found:
324.1415.
5-(tert-Butyl)-3-phenyl-4-(p-tolylthio)isoxazole (3n)
ACS Paragon Plus Environment

Page 17 of 24
The Journal of Organic Chemistry
1
2
3
4
5
o
Yield: 38.3 mg (79%); time: 4.5 h; yellow solid; m.p. 75-77 C; TLC, Rf = 0.37
6
7
1
(PE:EtOAc = 19:1); H NMR (CDCl3, 400 MHz): δ 7.73 (d, 2H, J = 7.2 Hz), 7.39-7.34
8
9
(m, 3H), 7.01 (d, 2H, J = 8.0 Hz), 6.89 (d, 2H, J = 8.4 Hz), 2.26 (s, 3H), 1.49 (s, 9H);
13C{1H} NMR (CDCl3, 100 MHz): δ 183.6, 165.1, 135.1, 133.9, 129.8, 129.7, 128.4,
128.3, 125.5, 100.7, 34.9, 28.5, 20.8; HRMS (ESI) m/z calcd for C20H22NOS [M + H]+:
324.1417, found: 324.1415.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Phenyl-4-(p-tolylthio)-5-(trimethylsilyl)isoxazole (3o)
Yield: 30.5 mg (60%); time: 3 h; yellow solid; m.p. 68-70 oC; TLC, Rf = 0.45 (PE:EtOAc
= 19:1); 1H NMR (CDCl3, 400 MHz): δ 7.79 (d, 2H, J = 8.4 Hz), 7.36 (t, 3H, J = 7.6 Hz),
13
7.01 (d, 2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.0 Hz), 2.26 (s, 3H), 0.39 (s, 9H); C{1H}
NMR (CDCl3, 100 MHz): δ 184.0, 162.5, 135.3, 133.7, 129.8, 129.7, 128.42, 128.38,
128.1, 125.9, 114.7, 20.8, 1.9; HRMS (ESI) m/z calcd for C19H22NOSSi [M + H]+:
340.1186, found: 340.1189.
3-(tert-Butyl)-5-phenyl-4-(p-tolylthio)isoxazole (3p)
o
Yield: 30.5 mg (63%); time: 3.5 h; yellow solid; m.p. 72-74 C; TLC, Rf = 0.40
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.01 (dd, 2H, J = 7.6 Hz, J = 1.6 Hz),
7.42-7.39 (m, 3H), 7.04 (d, 2H, J = 8.0 Hz), 6.94 (d, 2H, J = 8.4 Hz), 2.27 (s, 3H), 1.43 (s,
9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 172.6, 135.2, 133.3, 130.6, 129.9, 128.6, 127.3,
127.2, 125.2, 101.0, 33.7, 28.6, 20.8; HRMS (ESI) m/z calcd for C20H22NOS [M + H]+:
324.1417, found: 324.1418.
5-Phenyl-3-(p-tolyl)-4-(p-tolylthio)isoxazole (3q)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 24
1
2
3
4
5
6
7
8
9
Yield: 36 mg (67%); time: 5.5 h; yellow solid; m.p. 99-101 oC; TLC, Rf = 0.38
(PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.15-8.12 (m, 2H), 7.72 (d, 2H, J =
7.6 Hz), 7.48-7.45 (m, 3H), 7.21 (d, 2H, J = 7.6 Hz), 7.05-6.99 (m, 4H), 2.37 (s, 3H), 2.27
(s, 3H); 13C NMR (CDCl3, 100 MHz): δ 172.2, 165.1, 140.0, 135.7, 132.7, 130.8, 130.1,
129.2, 128.8, 128.4, 127.4, 127.1, 126.1, 125.3, 102.2, 21.4, 20.9; HRMS (ESI) m/z calcd
for C23H20NOS [M + H]+: 358.1260, found: 358.1251.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Synthesis of 3r-w.
In a 10 mL flask, under ambient atmosphere, the solution of 3-diphenylprop-2-yn-1-one
O-methyl oxime (1a, 0.15mmol), dimethyl disulfide (2a, 0.3 mmol, 2.0 equiv) and AlCl3
(0.15 mmol, 1.0 equiv) was stirred at room temperature for 6 h. After that time, the
residue was purified by chromatography column on silica gel or preparative TLC to
afford the desired product 3r. For the synthesis of 3w, the reaction mixture was dissolved
in 1,2-dichloroethane (1.5 mL) and stirred at 60 oC for 12 h.
4-(Methylthio)-3,5-diphenylisoxazole (3r)
Yield: 24.8 mg (62%); time: 6 h; yellow solid; m.p. 66-68 oC; TLC, Rf = 0.36 (PE:EtOAc
= 19:1); 1H NMR (CDCl3, 400 MHz): δ 8.21 (dd, 2H, J = 8.4 Hz, J = 2.0 Hz), 8.02-7.99
13
(m, 2H), 7.54-7.50 (m, 6H), 2.11 (s, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 169.7,
164.1, 130.5, 129.9, 128.7, 128.6, 128.4, 127.5, 127.4, 106.7, 19.0; HRMS (ESI) m/z
calcd for C16H13NOSNa [M + Na]+: 290.0610, found: 290.0609.
5-(4-Methoxyphenyl)-4-(methylthio)-3-phenylisoxazole (3s)
Yield: 20.5 mg (46%); time: 7 h; white solid; m.p. 92-94 oC; TLC, Rf = 0.38 (PE:EtOAc
ACS Paragon Plus Environment

Page 19 of 24
The Journal of Organic Chemistry
1
2
3
4
5
1
= 19:1); H NMR (CDCl3, 400 MHz): δ 8.19 (d, 2H, J = 9.2 Hz), 8.00-7.97 (m, 2H),
6
7
13
7.52-7.50 (m, 3H), 7.04 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H), 2.11 (s, 3H); C{1H} NMR
8
9
(CDCl3, 100 MHz): δ 169.7, 164.1, 161.2, 129.8, 128.9, 128.6, 128.4, 120.2, 114.1, 105.0,
55.4, 19.0; HRMS (ESI) m/z calcd for C17H16NO2S [M + H]+: 298.0896, found:
298.0882.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(4-Chlorophenyl)-4-(methylthio)-3-phenylisoxazole (3t)
1
Yield: 23.9 mg (53%); time: 24 h; yellow solid; TLC, Rf = 0.36 (PE:EtOAc = 19:1); H
NMR (CDCl3, 400 MHz): δ 8.18 (d, 2H, J = 8.8 Hz), 8.00-7.97 (m, 2H), 7.53-7.49 (m,
5H), 2.10 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 168.6, 164.2, 136.6, 130.0, 129.1,
128.7, 128.6, 128.5, 128.3, 125.9, 107.0, 18.9; HRMS (ESI) m/z calcd for
C16H12ClNOSNa [M + H]+: 302.0401, found: 302.0423.
5-Butyl-4-(methylthio)-3-phenylisoxazole (3u)
1
Yield: 19.3 mg (52%); time: 7 h; yellow liquid; TLC, Rf = 0.37 (PE:EtOAc = 19:1); H
NMR (CDCl3, 400 MHz): δ 8.03 (dd, 2H, J = 8.0 Hz, J = 4.0 Hz), 7.48 (t, 3H, J = 4.0 Hz),
2.92 (t, 2H, J = 8.0 Hz), 2.09 (s, 3H), 1.80-1.70 (m, 2H), 1.50-1.40 (m, 2H), 0.97 (t, 3H, J
= 8.0 Hz); 13C{1H} NMR (CDCl3, 100 MHz): δ 176.6, 162.3, 129.8, 129.0, 128.6, 127.9,
126.4, 106.6, 29.7, 25.6, 22.3, 19.5, 13.7; HRMS (ESI) m/z calcd for C14H18NOS [M +
H]+: 248.1104, found: 248.1105.
3-(tert-Butyl)-4-(methylthio)-5-phenylisoxazole (3v)
1
Yield: 20.3 mg (55%); time: 9 h; yellow liquid; TLC, Rf = 0.35 (PE:EtOAc = 19:1); H
NMR (CDCl3, 400 MHz): δ 8.21 (d, 2H, J = 7.6 Hz), 7.50-7.46 (m, 3H), 2.19 (s, 3H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 24
1
2
3
4
5
6
7
8
9
1.53 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 172.2, 170.0, 130.3, 128.7, 127.8,
126.9, 106.2, 33.6, 28.5, 19.8; HRMS (ESI) m/z calcd for C14H18NOS [M + H]+:
248.1104, found: 248.1100.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(Ethylthio)-3,5-diphenylisoxazole (3w)
Yield: 23.9 mg (51%); time: 9.5 h; yellow liquid; TLC, Rf = 0.31 (PE:EtOAc = 19:1); 1H
NMR (CDCl3, 400 MHz): δ 8.25 (d, 2H, J = 6.4 Hz), 8.00 (d, 2H, J = 6.4 Hz), 7.52-7.50
(m, 6H), 2.51-2.48 (m, 2H), 1.01 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (CDCl3, 100 MHz):
δ 170.3, 164.5, 130.5, 129.8, 128.7, 128.54, 128.48, 127.6, 127.4, 104.8, 29.8, 14.3;
HRMS (ESI) m/z calcd for C17H16NOS [M + H]+: 282.0947, found: 282.0952.
Synthesis of 9. To TBAF (0.2 mmol, 2 equiv) in THF solution (1M) was added 0.1 mmol
of 3o in 1 mL of CH3OH at room temperature. The reaction was allowed to stir at room
temperature for 2 hours until the starting material was consumed. After the reaction, the
resulting mixture was diluted with EtOAc (30 mL), washed with H2O (10 mL × 3), dried
with Na2SO4, and concentrated under vacuum. The residue was purified by column
chromatography (eluent: PE/EtOAc = 19:1) to give the desired 9. Yield: 24.4 mg (61%);
time: 2 h; yellow liquid; TLC, Rf = 0.39 (PE:EtOAc = 19:1); 1H NMR (CDCl3, 400 MHz):
δ 8.49 (s, 1H), 7.80-7.77 (m, 2H), 7.37-7.32 (m, 3H), 7.01-6.96 (m, 4H), 2.21 (s, 3H);
13C{1H} NMR (CDCl3, 100 MHz): δ 163.1, 162.0, 136.7, 131.8, 130.05, 130.03, 129.6,
128.6, 128.2, 128.0, 127.7, 109.1, 20.9; HRMS (ESI) m/z calcd for C16H14NOS [M + H]+:
268.0791, found: 268.0797.
Synthesis of N-tosyl sulfilimine 10. To a mixture of 3a (0.1 mmol) and Chloramine-T
ACS Paragon Plus Environment

Page 21 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(0.21 mmol, 2.1 eq) in CH3CN (1 mL) was added AcOH (20 mol%) slowly and the
mixture was stirred at reflux for 18 hours. After that time, the resulting mixture was
diluted with EtOAc (30 mL), washed with H2O (10 mL × 3), dried with Na2SO4, and
concentrated under vacuum. The residue was purified by column chromatography (eluent:
PE/EtOAc = 7:3) to give the desired 10. Yield:31.2 mg (61%); time: 18 h; white solid;
m.p. 114-116 oC; TLC, Rf = 0.28 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.95
(d, 2H, J = 7.6 Hz), 7.71 (d, 2H, J = 7.6 Hz), 7.58 (t, 3H, J = 7.6 Hz), 7.52 (t, 2H, J = 7.2
Hz), 7.36 (t, 1H, J = 7.6 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.19 (s, 2H), 7.10 (d, 2H, J = 7.6
Hz), 6.95 (d, 2H, J = 7.6 Hz), 2.34 (s, 3H), 2.22 (s, 3H); 13C{1H} NMR (CDCl3, 100
MHz): δ 174.3, 163.2, 141.9, 141.8, 141.1, 132.4, 130.4, 129.70, 129.68, 129.2, 129.1,
129.0, 128.2, 126.5, 126.3, 126.0, 125.7, 124.7, 109.7, 21.4, 21.1. HRMS (ESI) m/z calcd
for C29H24N2O3S2 [M+H]+: 513.1301, found: 513.1304.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 4-sulfinyl isoxazole 11. To H2O2 (0.17 mL, 0.4 mmol, 4 equiv) contained in
a 10 mL round-bottomed flask was slowly added 0.1 mmol of 3r in 2 mL of
HOAc/CHCl3 (1:1) at room temperature. The reaction vessel was allowed to stir at room
temperature about 15 hours until the starting material was consumed. After that, the
resulting mixture was diluted with EtOAc (30 mL), washed with H2O (10 mL × 3), dried
with Na2SO4, and concentrated under vacuum. The residue was purified by column
chromatography (eluent: PE/EtOAc = 7:3) to give the desired 11. Yield:34.0 mg (80%);
o
1
time: 15 h; yellow solid; m.p. 152-154 C; TLC, Rf = 0.22 (PE:EtOAc = 7:3); H NMR
(CDCl3, 400 MHz): δ 8.06-8.03 (m, 2H), 7.97 (dd, 2H, J = 7.6 Hz, J = 1.6 Hz), 7.60-7.54
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
1
2
3
4
5
6
7
8
9
13
(m, 6H), 2.72 (s, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 172.6, 162.8, 131.9, 130.8,
129.9, 129.1, 129.0, 127.7, 125.9, 116.7, 37.8. HRMS (ESI) m/z calcd for C6H14NO2S
[M+H]+: 284.0340, found :284.0336.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgments
We acknowledge the financial support from the Key Research and Development Program
of Shanxi Province (international cooperation) (No. 201803D421093) and the National
Natural Science Foundation of China (No. 21602126).
Supporting Information
Condition optimization for the synthesis of 3r, MS study for the synthesis of 3a, crystal
1
13
structure of 3i and the corresponding data, copies of H and C NMR spectra, found in
the SI.
References
(1) Zhu, J.; Mo, J.; Lin, H.; Chen, Y.; Sun, H. The Recent Progress of Isoxazole in
Medicinal Chemistry. Bioorg. Med. Chem. 2018, 26, 3065-3075.
(2) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014,
57, 5845-5859.
(3) (a) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-Mining for Sulfur and Fluorine: An
Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery.
J. Med. Chem. 2014, 57, 2832-2842. (b) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X.
Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry.
Curr. Top. Med. Chem. 2016, 16, 1200-1216.
(4) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A
Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. J. Med. Chem.
ACS Paragon Plus Environment

Page 23 of 24
The Journal of Organic Chemistry
1
2
3
4
2015, 58, 4383-4438.
5
6
7
8
(5) (a) Morita, T.; Yugandar, S.; Fuse, S.; Nakamura, H. Recent Progresses in the
Synthesis of Functionalized Isoxazoles. Tetrahedron Lett. 2018, 59, 1159-1171. (b) Hu,
F.; Szostaka, M. Recent Developments in the Synthesis and Reactivity of Isoxazoles:
Metal Catalysis and Beyond. Adv. Synth. Catal. 2015, 357, 2583-2614.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Morita, T.; Fuse, S.; Nakamura, H. Generation of an 4-Isoxazolyl Anion Species:
Facile Access to Multifunctionalized Isoxazoles. Angew. Chem. Int. Ed. 2016, 55,
13580-13584. (b) Kanda, Y.; Takahashi, T.; Araki, Y.; Konoike, T.; Mihara, S.; Fujimoto,
M. Discovery and Synthesis of a Potent Sulfonamide ETB Selective Antagonist. Bioorg.
Med. Chem. Lett. 2000, 10, 1875-1878.
(7) Waldo, J. P.; Larock, R. C. Synthesis of Isoxazoles via Electrophilic Cyclization. Org.
Lettt. 2005, 7, 5203-5205.
(8) (a) Waldo, J. P.; Larock, R. C. The Synthesis of Highly Substituted Isoxazoles by
Electrophilic Cyclization: An Efficient Synthesis of Valdecoxib. J. Org. Chem. 2007, 72,
9643-9647. (b) Kaewsri, W.; Thongsornkleeb, C.; Tummatorn, J. ;Ruchirawat, S.
Isomerizable (E/Z)-alkynyl-O-methyl oximes employing TMSCl-NCS in chlorinative
cyclization for the direct synthesis of 4-chloroisoxazoles. RSC Adv. 2016, 6, 48666-48675.
(c) Jeong, Y.; Kim, B.-I; Lee, J. K.; Ryu, J.-S. Direct Synthesis of 4-Fluoroisoxazoles
through Gold-Catalyzed Cascade Cyclization-Fluorination of 2-Alkynone O-Methyl
Oximes, J. Org. Chem. 2014, 79, 6444-6455. (d) Sperança, A.; Godoi, B.; Zeni, G.
Iron(III) Chloride/Diorganyl Diselenides: A Tool for Intramolecular Cyclization of
Alkynone O-Methyloximes. J. Org. Chem. 2013, 78, 1630-1637. (e) Tu, K. N.; Hirner, J.
J.; Blum, S. A. Oxyboration with and without a Catalyst: Borylated Isoxazoles via B-O
σ-Bond Addition. Org. Lett. 2016, 18, 480-483.
(9) (a) Iwasaki, M.; Fujii, T.; Nakajima, K.; Nishihara, Y. Iron-Induced Regio- and
Stereoselective Addition of Sulfenyl Chlorides to Alkynes by a Radical Pathway, Angew.
Chem. Int. Ed. 2014, 53, 13880-13884. (b) Huang, H.; Fan, J.; He, G.; Yang, Z.; Jin, X.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
1
2
3
4
5
6
7
8
Liu, Q.; Zhu, H. Generation of Oxazolidine-2,4-diones Bearing Sulfur-Substituted
Quaternary Carbon Atoms by Oxothiolation/Cyclization of Ynamides, Chem. Eur. J.
2016, 22, 2532-2538.
9
(10) (a) Gao, W.-C.; Cheng, Y.-F.; Shang, Y.-Z.; Chang, H.-H.; Li, X.; Zhou, R.; Qiao,
Y.; Wei, W.-L. Copper(II)-Catalyzed Four-Component Oxysulfonylation/Diazenylation:
Synthesis of α-Arylhydrazo-β-keto Sulfones, J. Org. Chem. 2018, 83, 11956-11962. (b)
Gao, W.-C.; Liu, T.; Cheng, Y.-F.; Chang, H.-H.; Li, X.; Zhou, R.; Wei, W.-L.; Qiao, Y.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AlCl3-Catalyzed
Intramolecular
Cyclization
of
N-Arylpropynamides
with
N-Sulfanylsuccinimides: Divergent Synthesis of 3-Sulfenyl Quinolin-2-ones and
Azaspiro[4,5]trienones, J. Org. Chem. 2017, 82, 13459-13467. (c) Liu, T.; Tian, J.; Gao,
W.-C.; Chang, H.-H.; Liu, Q.; Li, X.; Wei, W.-L. Intermolecular Sulfenoamination of
Alkenes with Sulfonamides and N-Sulfanylsuccinimides to Access β-Sulfonylamino
Sulfides and Dihydrobenzothiazines, Org. Biomol. Chem. 2017, 15, 5983-5992. (d) Gao,
W.-C.; Liu, T.; Zhang, B.; Li, X.; Wei, W.-L.; Liu, Q.; Tian, J.; Chang, H.-H. Synthesis
of 3‑Sulfenylated Coumarins: BF3·Et2O‑Mediated Electrophilic Cyclization of Aryl
Alkynoates Using N-Sulfanylsuccinimides, J. Org. Chem. 2016, 81, 11297-11304.
(11) Wang, M.; Qiao, Z.; Zhao, J.; Jiang, X. Palladium-Catalyzed Thiomethylation via a
Three-Component Cross-Coupling Strategy, Org. Lett. 2018, 20, 6193–6197, and
references therein.
(12) Bilheri, F. N.; Stein, A. L.; Zeni, G. Synthesis of Chalcogenophenes via Cyclization
of 1,3-Diynes Promoted by Iron(III) Chloride and Dialkyl Dichalcogenides, Adv. Synth.
Catal. 2015, 357, 1221-1228.
ACS Paragon Plus Environment