Metal-Free Iodine-Catalyzed Direct Arylthiation of Substituted Anilines with Thiols

Article abstract of DOI:10.1021/acs.joc.5b00540

Iodine-catalyzed direct arylthiation of substituted anilines for the synthesis of various diaryl sulfides has been developed under metal- and solvent-free conditions. The present method uses readily available thiols as the arylthiation reagents, and envir

Full text of DOI:10.1021/acs.joc.5b00540

Subscriber access provided by NEW YORK UNIV
Article
Metal-Free Iodine-Catalyzed Direct Arylthiolation
of Substituted Anilines with Thiols
Daoshan Yang, Kelu Yan, Wei Wei, Jing Zhao, Mengqi Zhang,
Xuguang Sheng, Guoqing Li, Shenglei Lu, and Hua Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00540 • Publication Date (Web): 01 Jun 2015
Downloaded from http://pubs.acs.org on June 7, 2015
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 36
The Journal of Organic Chemistry
1
2
3
4
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 36
1
2
3
4
5
6
7
Metal-Free Iodine-Catalyzed Direct Arylthiolation of
Substituted Anilines with Thiols
8
9
Daoshan Yang, Kelu Yan, Wei Wei, Jing Zhao, Mengqi Zhang, Xuguang Sheng,
Guoqing Li, Shenglei Lu, and Hua Wang*
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
The Key Laboratory of LifeꢀOrganic Analysis and Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical
Engineering, Qufu Normal University, Qufu 273165, Shandong P. R. China.
* Eꢀmail: huawang_qfnu@126.com
ABSTRACT: Iodineꢀcatalyzed direct arylthiation of substituted anilines for the
synthesis of various diaryl sulfides has been developed under metalꢀ and solventꢀfree
conditions. The present method uses readilyꢀavailable thiols as the arylthiation
reagents, environmentally friendly and inexpensive I2 as the catalyst. Importantly, no
base or ligand was necessary. Such a simple, efficient, and economical transformation
provides an attractive approach to various diaryl sulfides in good to excellent yield.
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
5
INTRODUCTION:
6
7
8
9
Diaryl sulfides are ubiquitous in natural products, pharmacologically active
compounds and organic materials.1 Therefore, the development of novel, practical,
and highly efficient methods for the construction of diaryl sulfide motifs continues to
stimulate a large number of research groups. The classical methods for the formation
of diaryl sulfides traditionally involve two approaches. One is the transition
metalꢀcatalyzed crossꢀcouplings of disulfides or thiols with aryl halides, pseudo
halides or arylboronic acids,2 where transition metal catalysts mainly focus on
palladium,3 copper,4 iron,5 nickel,6 cobalt,7 and rhodium8 (Scheme 1, a). Another
method typically relies on the coupling of sulfenyl chlorides with organozinc9 or
Grignard reagents10 (Scheme 1, b). In recent years, seeking mild, and selective
methods for the direct functionalization of inert CꢀH bonds has been received much
more attention in organic chemistry.11 Undoubtedly, direct arylthiolation of CꢀH bonds
is more economical and practical.12 However, research survey of this synthetic
strategy for the preparation of diaryl sulfides are rather limited,13 and in this respect,
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
several
examples
using
diaryl
disulfides
or
1ꢀ(substituted
phenylthio)pyrrolidineꢀ2,5ꢀdione as the arylthiation reagents under Pd,14 Cu,15 and
Fe16 catalytic conditions have been reported (Scheme 1, c). Very recently, Fu and
coꢀworkers demonstrated an elegant work for the synthesis of diaryl sulfides via iron
or boronꢀcatalyzed CꢀH arylthiation of phenols at room temperature.17 Despite some
great advantages, these reactions could encounter with certain limitations including
readily unavailable precursors, harsh reaction conditions, and toxic metal salt catalysts.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
5
6
7
As a consequence, it remains a challenging but very attractive task to develop more
efficient, economical, and practical synthesis methods for constructing the diaryl
8
9
sulfide derivatives.
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. Strategies for the synthesis of diaryl sulfides
Recently, there are increasing demand in metalꢀfree transformations owing to
traceꢀmetal impurities might be avoided in the target molecules.18 As a consequence,
the development of a metalꢀfree protocol for the CꢀS bond formation via direct aryl
CꢀH bond functionalization appears desirable and synthecially attractive. On the other
hand, molecular iodine as an inexpensive, green and efficient reagent has been
extensively used in organic transformations.19 In 2012, Bolm and coꢀworkers reported
a facile procedure for the synthesis of thioethers via transition metalꢀfree thiolation of
1,3,4ꢀoxadiazoles.20 In 2013, Deng and coꢀworkers described an iodineꢀpromoted
method for the synthesis of 2ꢀarylsulfanylphenols under metalꢀfree conditions.21 In
2014, Huang’ group reported the direct use of arylsulfonyl hydrazide as the
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
arylthiation reagents for iodineꢀmediated thiolation of substituted Naphthols and
Naphthylamines.22 Herein, we report a metalꢀfree molecular iodineꢀcatalyzed
approach to diaryl sulfides containing amino groups from readily available thiols and
substituted anilines under solvent freeꢀconditions (Scheme 1, d).
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
RESULTS AND DISCUSSION
First, 4ꢀmethoxybenzenethiol (1a) and aniline (2a) were selected as the model
substrates to optimize the reaction conditions including the catalysts, oxidants,
reaction temperatures and the amounts of oxidant under a nitrogen atmosphere. As
n
shown in Table 1, four catalysts such as I2, Bu4NI, KI and NIS were investigated at
o
90 C by using 5.0 equiv of DTBP (Diꢀtertꢀbutyl peroxide) as the oxidant, and I2
provided 4ꢀ(4ꢀmethoxyphenylthio)aniline (3a) in 51% yield with the corresponding
orthoꢀsubstituted product (3a’) appearing in 10% yield (entries 1ꢀ4). We have
compared different oxidants (compare entries 1, 5 and 6), and DTBP was superior to
the other oxidants (entry 1). In addition, Various temperatures were investigated
(entries 7ꢀ9), and 120 oC was discovered to be more suitable for this transformation
(entry 9). Elevated the reaction temperature did not enahance the yield (entry 12,
Table 1). Besides that, different amounts of DTBP were used in the reactions (entries
9ꢀ11), and the 5 equiv. of DTBP provided the highest yield (entry 9). Futhermore, 8
equiv of DTBP at 110 oC gave a 65% yield, indicating that the temperature is crucial
for this reaction (entry 12, Table 1). Notably, no conversion was observed in the
absence of iodine (entry 14). After the optimization process for catalysts, temperature
and oxidants, the various diaryl sulfide derivatives were synthesized under our
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
5
6
7
standard conditions: 15 mol % I2 as the catalyst, 5 equiv. of DTBP as the oxidant
under solventꢀfree conditions at 120 oC.
8
9
Table 1. I2-catalyzed coupling reaction of 4-methoxybenzenethiol (1a) with
aniline (2a) leading to 4-(4-methoxyphenylthio)aniline (3a): optimization of
conditions.a
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
entry catalyst
oxidant
DTBP
DTBP
DTBP
DTBP
H2O2
temp. [oC] yield (3a) [%]b yield (3a’) [%]b
1
2
I2
nBu4NI
KI
NIS
I2
90
90
90
51
Trace
Trace
42
10
Trace
Trace
7
3
4
90
5
90
47
9
6
7
8
9
10
11
12
13
14
I2
I2
I2
I2
I2
I2
I2
I2
TBHP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
90
16
59
66
75
Trace
12
14
11
14
15
10
11
0
100
110
120
120
120
130
110
120
68 c
56d
75
65e
0
none
a
Reaction conditions: 4ꢀmethoxybenzenethiol (1a) (0.5 mmol), aniline (2a) (1.0 mmol), catalyst
(0.075 mmol), oxidant (2.5 mmol), reaction time (24 h) under nitrogen atmosphere. b Isolated yield.
d
e
c In the presence of DTBP (3 equiv). In the presence of DTBP (2 equiv), In the presence of
DTBP (8 equiv).
With the optimized conditions in hand, a variety of substituted thiols were
employed for coupling with aniline derivatives (Table 2ꢀTable 4). It was found that
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the moderate to excellent yields were obtained under the standard conditions. It
should be pointed out that the reaction sites for the arylthiolation of aniline derivatives
could depend on the position of the substituents of anilines. As shown in Table 2, the
arylthiolation mainly occurred at paraꢀsite of amino group in anilines, due to the
ortho steric hindrance effects (Table 2, 3a-3d’). When amino group was substituted by
other groups, such as methyl and amino, the arylthiation only took place only at
paraꢀsite of substituted amino groups in anilines (Table 2, 3e-3p). Heteroaromatic
thiol (i.e., thiopheneꢀ2ꢀthiol) could be tolerated in this transformation, affording the
desired products in 76% yield (Table 2, 3p). Although aromatic thiols exhibited high
reactivity, unfortunately, aliphatic ones were poor substrates (Table 2, 3n and 3o).
Importantly, phenylhydrazine was a excellent substrate in the transformation, and
afforded the only paraꢀsubstituted products (Table 2, 3k-3m). Besides, the reaction
could be performed only at paraꢀsite of amino when the amino orthoꢀsite was
occupied by a substituent, as shown in Table 3. On the other hand, the reaction could
occur at the amino orthoꢀsite when the amino paraꢀsite was occupied (Table 4). For
substituted thiols the substrates containing electronꢀdonating functional groups
showed higher reactivity than the others (Table 2, 3a, 3b, 3k and 3m; Table 3, 5a, 5b,
5f and 5g; Table 4, 7c, 7d, 7e and 7f). The catalytic efficiency was not affected by
steric hindrance in thiols (Table 2, 3j and 3l; Table 3, 5d; Table 4, 7b, 7h and 7k).
Further, for substituted anilines, the substrates containing electronꢀdonating groups
showed higher reactivity than those with electronꢀwithdrawing groups (Table 3, 5a, 5e,
5c, and 5h; Table 4, 7a, 7g, 7e, and 7m). Notablely, when naphthalenꢀ2ꢀamine was
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 36
1
2
3
4
5
6
7
8
9
used as the substrate, the arylthiation reaction occurred on the ortho αꢀcarbon of NH2
due to the highest electron density of αꢀcarbon (Table 4, 7oꢀ7r). In addition, the
I2ꢀcatalyzed reactions could tolerate some functional groups such as amino groups
(Table 2ꢀTable 4), hydrazine (products 3k-3m), methyl ether (products 3m, 5f, and
7k), CꢀCl bond (products 3g, 5g, and 7g), and CꢀBr bond (products 3h, 5h, and 7f).
Table 2. I2-catalyzed Synthesis of diaryl sulfides from phenthiols (1) with anilines
(2) a, b, c
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
NH2
Cl
NH2
Cl
NH2
OCH3
H3CO
NH2
S
S
S
S
3b' (9%)
3b (65%)
3a (75%)
3a' (11%)
OCH3
NH2
NH2
NH2
NH2
S
OCH3
S
S
S
3d (68%)
3d' (6%)
3c (71%)
3c' (7%)
H
H
H
Cl
N
H3C
N
H3CO
N
CH3
CH3
CH3
S
S
S
3g (61%)
3f (69%)
3e (73%)
CH3
H
N
H
CH3
N
Br
N
CH3
CH3
CH3
S
S
S
3j (47%)
3h (64%)
3i (78%)
H3CO
NHNH2
Cl
NHNH2
CH3
NHNH2
S
S
S
3m (62%)
3l (47%)
3k (52%)
H
N
NH2
NH2
CH3
S
S
S
S
3n (13%)
3o (22%)
3p (76%)
a Reaction conditions: substituted thiols (0.5 mmol), anilines (1.0 mmol), I2 (0.075 mmol), DTBP
(2.5 mmol). b Isolated yield. c Reaction time (24 h).
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Table 3. I2-catalyzed Synthesis of diaryl sulfides from coupling phenthiols (1)
8
9
with ortho-substituted anilines (4) a,b, c
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
Cl
NH2
CH3
H3C
NH2
CH3
Br
NH2
CH3
S
S
S
5b (88%)
5c (91%)
5a (99%)
H3C
NH2
Cl
CH3
H3CO
NH2
Cl
NH2
CH3
S
S
S
5f (86%)
5d (86%)
5e (95%)
CH3
Br
NH2
Cl
NH2
NH2
Cl
S
Cl
S
Cl
S
5g (75%)
5h (78%)
5i (79%)
Cl
NH2
CH3
H3C
NH2
H3CO
NH2
CH3
CH3
S
S
S
5l(97%)
5j (99%)
5k (99%)
CH3
CH3
H3C
NH2
CH3
Br
NH2
CH3
Cl
NH2
CH3
S
S
S
5m (97%)
5o (99%)
5n (99%)
a
Reaction conditions: substituted thiols (0.5 mmol), orthoꢀsubstituted anilines (1.0 mmol), I2
(0.075 mmol), DTBP (2.5 mmol). b Isolated yield. c Reaction time (24 h).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
Table 4. I2-catalyzed Synthesis of diaryl sulfides from coupling phenthiols (1)
6
7
8
with para-substituted anilines (6) a,b, c
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
NH2
NH2
NH2
CH3
H3C
S
H3C
S
CH3
Cl
S
CH3
Cl
7a (84%)
7c (86%)
7b (81%)
NH2
S
NH2
Br
NH2
OCH3
Cl
Cl
S
Cl
Cl
S
7f (84%)
7e (88%)
7d (72%)
NH2
NH2
CH3
NH2
H3CO
S
Cl
S
S
CH3
CH3
7h (62%)
7g (69%)
7i (64%)
NH2
NH2
OCH3
NH2
S
H3CO
S
H3CO
S
H3CO
H3CO
CH3
Cl
CH3
7l (57%)
7j (64%)
7k (61%)
NH2
NH2
Br
Cl
S
H3CO
S
NH2
S
7m (87%)
7n (85%)
7o (97%)
Br
S
CH3
S
OCH3
S
NH2
NH2
NH2
7p (94%)
7q (90%)
7r (89%)
a
Reaction conditions: substituted thiols (0.5 mmol), paraꢀsubstituted anilines (1.0 mmol), I2
(0.075 mmol), DTBP (2.5 mmol). b Isolated yield. c Reaction time (24 h).
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The arylthiolation reactions were investigated using different amounts of anilines. The
results are shown in Scheme 2. Under the standard conditions, the control experiments
with 4ꢀchloroaniline 6b alone, gave out the messy yields detected by TLC, indicating
that 4ꢀchloroaniline 6b could be oxidized into other substances in this transformation
[Eq. (1)]. Furthermore, different amounts of 6b ranging from 0.5 mmol to 3.0 mmol
were applied in the reactions. The obtained yields increased as the 6b amounts
increased up to 1.5 mmol to reach the maximum [Eq. (2)]. 1.0 mmol of 6b gave a
slightly lower yield than 1.5 mmol of 6b; however, it is economical and of practical
application in the arylthiolation. Notably, the yields could decrease dramatically when
the amount of 6b was changed from 1.0 mmol to 0.5 mmol. It is thereby thought that
the aniline could be oxidized before it could react with the thiols under the given
conditions, As a result, 2 equiv of aniline should be sufficient for this reaction,
whereas the excess of the aniline might make up for the loss.
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. Investigation of the amount of anilines in the present method
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
4
5
6
7
8
9
Further, we explored the synthetic applicability of the present method. The
gramꢀscale reaction was performed between 1f and 6b, and the reaction afforded 7c in
89% yield (Scheme 3). Therefore, this simple protocol could be served as an efficient
and practical method for the synthesis of various diaryl sulfide derivatives containing
amino groups.
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 3. Synthesis of 7c on gram scale
further
modification
NH2
NH2
S
SH
I2 (15%)
DTBP
+
H3C
H3C
5 mmol,
1f
6b
Cl
7c
Cl
10 mmol, 1.90g
0.62g
1.11g, 89% isolated yield
Inspired by these excellent results above, we applied this I2ꢀcatalyzed method to
construct some potential medicinal agents. As shown in Scheme 4, coupling of
2,4ꢀdichlorobenzenethiol (1r) with 3ꢀchloroaniline (8b) provided 9a in 92% yield
under the standard conditions which was used as inhibitors of LFAꢀ1/CAMꢀ123,
suggesting the developed method would be applied in medical industry.
Scheme 4. Synthesis of 3-chloro-4-(2,4-dichlorophenylthio)aniline (9a) under the
standard conditions.
In order to explore the possible mechanism of I2ꢀcatalyzed direct CꢀH
arylthiation of substituted anilines, several control experiments were performed as
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
shown in Scheme 5. When 4ꢀmethylbenzenethiol (1f) was added independently under
the standard conditions, 1,2ꢀdipꢀtolyldisulfane (10) was obtained in 97% yield.
Furthermore, treatment of 1,2ꢀdipꢀtolyldisulfane (10) with 4ꢀchloroaniline (6b) under
the standard conditions led to 7c in 90% yield, indicating that 1,2ꢀdiphenyldisulfane
might be intermediates for this transformation. Additionally, the reaction of
1,2ꢀdipꢀtolyldisulfane (10) with 4ꢀchloroaniline (6b) was tested without iodine. As
expected, no conversion was observed. To investigate the mechanism further, the
reaction of 1,2ꢀdipꢀtolyldisulfane (10) with 4ꢀchloroaniline (6b) was tested in the
presence of one equivalent of 2,2,6,6ꢀtetramethylpiperidinylꢀ1ꢀoxy (TEMPO), a
classical radical inhibitor, the CꢀH arylthiation reaction was completely suppressed,
indicating that the present reaction might involve a radical process.
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 5. Control experiments
CH3
SH
S
I2, DTBP
H3C
S
(1)
H3C
1f
10
0.243 mmol, 97%
0.5 mmol
CH3
NH2
I2, DTBP
S
7c (2)
S
+
90%
6b
Cl
1.0 mmol
H3C
10
0.25 mmol
CH3
NH2
DTBP
S
S
(3)
(4)
7c
+
10
trace
H3C
6b
Cl
CH3
+
NH2
TEMPO
I2, DTBP
S
S
7c
trace
10
H3C
6b
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
5
6
7
8
9
On the basis of these preliminary results above and together with previous
reports in the literature24, a possible mechanism for I2ꢀcatalyzed synthesis of diaryl
sulfide derivatives was proposed in Scheme 6. Initially, 4ꢀmethylbenzenethiol (1f)
was oxidized to 1,2ꢀdipꢀtolyldisulfane (10) under the standard conditions. The
reaction of 10 with I2 formed 2 equiv of an electrophilic species pꢀMePhSI (I),21
which attacked of 4ꢀchloroaniline (6b) to yield II. Then, followed by the loss of HI
resulted in the desirable product (7c). Finally, treatment of tꢀBuOꢁ radical with HI led
to the catalyst I2. Further investigations on the more detailed mechanism are ongoing
in our laboratory.
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 6. A proposed mechanism for the direct transformation.
CH3
S
SH
S
I2, DTBP
oxidant
10
H3C
I2
H3C
1f
SI
t-BuO.
DTBP
2
H3C
I
HI
NH2
Cl
NH2
S
Cl
NH2
Cl
6b
S
CH3
I-
7c
CH3
II
In conclution, a novel and efficient method has been developed for the synthesis
of diaryl sulfide derivatives containing amino groups via the I2ꢀcatalyzed direct
arylthiation of substituted anilines under solventꢀfree condtions. A series of diaryl
sulfide derivatives could be efficiently obtained in moderate to excellet yields. This
method can enjoy the following advantages: (a) commercial available and nonꢀtoxic
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
molecular iodine as the catalyst; (b) solventꢀfree conditions; (c) no addition of any
ligand, base or additive; (d) easy workup procedure. The developed synthesis
approach would extend the scope of synthetic methods for diverse diaryl sulfides in
the academic and industrial fields. Further investigation on the practical application of
this method is in progress.
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
EXPERIMENTAL SECTION
General.
All commercially available reagent grade chemicals were purchased from chemical
1
13
suppliers and used as received without further purification. H NMR and C NMR
spectra were recorded in CDCl3 on a 400 MHz spectrometer with TMS as internal
1
standard (400 MHz H, 100 MHz 13C) at room temperature, the chemical shifts (δ)
were expressed in ppm and J values were given in Hz. The following abbreviations
are used to indicate the multiplicity: singlet (s), doublet (d), triplet (t), quartet (q) and
multiplet (m). Column chromatography was performed on silica gel (200ꢀ300 mesh).
Mass analyses and HRMS were obtained by ESI on a TOF mass analyzer.
General experimental procedures.
A 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with I2 (19
mg, 0.075 mmol), substituted various thiols (1) (0.5 mmol) and anilines or
phenylhydrazine (1.0 mmol). The tube was evacuated twice and backfilled with
nitrogen, and DTBP (2.5 mmol) was added into the tube. The tube was sealed and
o
then the mixture was allowed to stir under nitrogen atmosphere at 120 C for 24 h.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 36
1
2
3
4
5
6
7
8
9
After completion of the reaction, the resulting solution was cooled down to room
temperature, and the solvent was removed with the aid of a rotary evaporator. The
desired product was obtained by column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent.
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-methoxyphenylthio)aniline (3a):25 Compound 3a was obtained in 75% yield
(87 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(50:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.25 (d, 2H, J = 2.4 Hz), 7.23 (d, 2H, J =
2.4 Hz), 6.83 (d, 2H, J = 8.0 Hz), 6.65 (d, 2H, J = 8.0 Hz), 3.80 (s, 3H), 3.75 (s, br,
13
2H). C NMR (CDCl3, 100 MHz, ppm) δ 158.5, 146.2, 133.9, 131.5, 128.9, 123.6,
115.8, 114.7, 55.4; HRMS m/z calcd. for C13H13NOS [M+H]+: 232.0796, found:
232.0785.
2-(4-methoxyphenylthio)aniline (3a’):26 Compound 3a’ was obtained in 11% yield
(13 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(50:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.44 (d, 1H, J = 8.0 Hz), 7.21 (t, 1H, J =
8.0 Hz), 7.16 (d, 2H, J = 8.0 Hz), 6.83 (d, 2H, J = 8.0 Hz), 6.79ꢀ6.74 (m, 2H), 4.29 (s,
br, 2H), 3.79 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 158.4, 148.1, 136.3, 130.4,
129.7, 126.9, 118.7, 116.8, 115.4, 114.8, 55.4; HRMS m/z calcd. for C13H13NOS
[M+H]+: 232.0796, found: 232.0785.
4-(4-chlorophenylthio)aniline (3b):27 Compound 3b was obtained in 65% yield (77
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (50:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.32 (d, 2H, J = 8.0 Hz), 7.20 (d, 2H, J = 8.0 Hz),
7.06 (d, 2H, J = 8.0 Hz), 6.70 (d, 2H, J = 8.0 Hz), 3.87 (s, br, 2H). 13C NMR (CDCl3,
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
100 MHz, ppm) δ 158.5, 146.2, 133.9, 131.5, 128.9, 123.6, 115.8, 114.7; HRMS m/z
5
6
calcd. for C12H10ClNS [M+H]+: 236.0301, found: 236.0312.
7
8
9
2-(4-chlorophenylthio)aniline (3b’):26 Compound 3b’ was obtained in 9% yield
(11 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(50:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.47 (d, 2H, J = 8.0 Hz), 7.28 (t, 1H, J =
8.0 Hz), 7.21 (d, 2H, J = 8.0 Hz), 7.02 (d, 2H, J = 8.0 Hz), 6.83ꢀ6.77 (m, 2H), 4.32 (s,
br, 2H). 13C NMR (CDCl3, 100 MHz, ppm) δ 148.8, 137.5, 135.5, 131.5, 131.3, 129.1,
127.7, 118.9, 115.5, 113.8; HRMS m/z calcd. for C12H10ClNS [M+H]+: 236.0301,
found: 236.0312.
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-(3-methoxyphenylthio)aniline (3c):28 Compound 3c was obtained in 71% yield
(82 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(50:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.35 (d, 2H, J = 8.0 Hz), 7.15 (t, 1H, J =
8.0 Hz), 6.74ꢀ6.66 (m, 5H), 3.88 (s, br, 2H), 3.75 (s, 3H). 13C NMR (CDCl3, 100 MHz,
ppm) δ 159.9, 147.2, 141.3, 136.4, 129.6, 119.9, 119.4, 115.9, 112.5, 110.8, 55.2;
HRMS m/z calcd. for C13H13NOS [M+H]+: 232.0796, found: 232.0790.
2-(3-methoxyphenylthio)aniline (3c’):29 Compound 3c’ was obtained in 7% yield (8
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (50:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.43 (d, 1H, J = 8.0 Hz), 7.21 (t, 1H, J = 8.0 Hz),
7.16 (d, 2H, J = 8.0 Hz), 6.83 (d, 2H, J = 8.0 Hz), 6.79ꢀ6.74 (m, 2H), 4.29 (s, br, 2H),
13
3.79 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 158.4, 148.1, 136.3, 130.4, 129.7,
126.9, 118.7, 116.8, 115.4, 114.8, 55.4; HRMS m/z calcd. for C13H13NOS [M+H]+:
232.0796, found: 232.0790.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
4-(naphthalen-2-ylthio)aniline (3d):30 Compound 3d was obtained in 68% yield (86
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (50:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 8.45 (d, 1H, J = 8.0 Hz), 7.90 (d, 1H, J = 8.0 Hz),
7.43 (d, 1H, J = 8.0 Hz), 7.62ꢀ7.54 (m, 2H), 7.39ꢀ7.34 (m, 3H), 7.27 (d, 1H, J = 8.0
Hz), 6.69 (d, 2H, J = 8.0 Hz), 3.76 (s, br, 2H). 13C NMR (CDCl3, 100 MHz, ppm) δ
146.8, 136.3, 135.3, 133.9, 131.7, 128.5, 126.7, 126.6, 126.4, 126.3, 125.8, 124.7,
120.8, 116.1; HRMS m/z calcd. for C16H13NS [M+H]+: 252.0847, found: 252.0846.
3
4
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
2-(naphthalen-2-ylthio)aniline (3d’):26 Compound 3d’ was obtained in 6% yield (7
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (50:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 8.38 (d, 1H, J = 8.0 Hz), 7.89 (d, 1H, J = 8.0 Hz),
7.68 (d, 1H, J = 8.0 Hz), 7.63ꢀ7.49 (m, 2H), 7.50 (d, 1H, J = 8.0 Hz), 7.33ꢀ7.28 (m,
2H), 6.99 (d, 2H, J = 8.0 Hz), 6.86ꢀ6.80 (m, 2H), 4.30 (s, br, 2H). 13C NMR (CDCl3,
100 MHz, ppm) δ 148.7, 137.3, 133.9, 133.6, 131.1, 131.0, 128.6, 126.3, 126.2, 126.1,
125.9, 124.0, 123.7, 119.0, 115.5, 114.1; HRMS m/z calcd. for C16H13NS [M+H]+:
252.0847, found: 252.0846.
4-(4-methoxyphenylthio)-N-methylaniline (3e): Compound 3e was obtained in 73%
yield (90 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.32 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J =
8.0 Hz), 6.84 (d, 2H, J = 8.0 Hz), 6.59 (d, 2H, J = 8.0 Hz), 3.87 (s, br, 1H), 3.80 (s,
13
3H), 2.85 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 148.7, 137.3, 133.9, 133.6,
131.1, 131.0, 128.6, 126.3, 126.2, 126.0, 125.9, 124.0, 123.7, 119.0, 115.5, 114.1;
HRMS m/z calcd. for C14H15NOS [M+H]+: 246.0953, found: 246.0961.
N-methyl-4-(p-tolylthio)aniline (3f): Compound 3f was obtained in 69% yield (79
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
1H NMR (CDCl3, 400 MHz, ppm) δ 7.36 (d, 2H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.0 Hz),
7.06 (d, 2H, J = 8.0 Hz), 6.60 (d, 2H, J = 8.0 Hz), 3.91 (s, br, 1H), 2.88 (s, 3H), 2.31
(s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 149.5, 136.2, 135.7, 135.1, 129.6, 127.8,
119.5, 113.1, 30.6, 20.9; HRMS m/z calcd. for C14H15NS [M+H]+: 230.1003, found:
230.1011.
3
4
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-chlorophenylthio)-N-methylaniline (3g): Compound 3g was obtained in 61%
yield (76 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.37 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J =
8.0 Hz), 7.05 (d, 2H, J = 8.0 Hz), 6.63 (d, 2H, J = 8.0 Hz), 3.96 (s, br, 1H), 2.89 (s,
13
3H). C NMR (CDCl3, 100 MHz, ppm) δ 150.0, 139.1, 136.5, 130.8, 128.8, 128.0,
117.3, 113.2, 30.5; HRMS m/z calcd. for C13H12ClNS [M+H]+: 250.0457, found:
250.0449.
4-(4-bromophenylthio)-N-methylaniline (3h): Compound 3h was obtained in 64%
yield (94 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.37 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J =
8.0 Hz), 6.99 (d, 2H, J = 8.0 Hz), 6.63 (d, 2H, J = 8.0 Hz), 3.98 (s, br, 1H), 2.88 (s,
13
3H). C NMR (CDCl3, 100 MHz, ppm) δ 150.0, 139.9, 136.6, 131.7, 128.2, 118.5,
117.4, 113.2, 30.5; HRMS m/z calcd. for C13H12BrNS [M+H]+: 293.9952, 295.9932,
found: 293.9943, 295.9921.
N-methyl-4-(naphthalen-1-ylthio)aniline (3i): Compound 3i was obtained in 78%
yield (104 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.43 (d, 1H, J = 8.0 Hz), 7.88 (d,
1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.61ꢀ7.55 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J
= 8.0 Hz), 7.34 (t, 1H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 8.0 Hz),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3.90 (s, br, 1H), 2.87 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 149.6, 137.0,
135.8, 133.8, 131.4, 128.5, 126.3, 126.2, 126.1, 125.8, 125.7, 124.5, 118.5, 113.3,
30.6; HRMS m/z calcd. for C17H15NS [M+H]+: 266.1003, found: 266.1012.
3
4
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
N,N-dimethyl-4-(o-tolylthio)aniline (3j): Compound 3j was obtained in 47% yield
(57 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.38 (d, 2H, J = 8.0 Hz), 7.17 (d, 1H, J =
8.0 Hz), 7.06ꢀ7.04 (m, 2H), 6.88ꢀ6.85 (m, 1H), 6.75 (d, 2H, J = 8.0 Hz), 3.08 (s, 6H),
13
2.42 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 150.5, 139.2, 136.0, 135.4, 129.9,
126.9, 126.3, 125.0, 117.4, 113.1, 40.4, 20.1; HRMS m/z calcd. for C15H17NS [M+H]+:
244.1160, found: 244.1151.
(4-(4-chlorophenylthio)phenyl)hydrazine (3k): Compound 3k was obtained in 52%
yield (65 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.32 (d, 2H, J = 8.0 Hz), 7.20 (d, 2H, J =
8.0 Hz), 7.06 (d, 2H, J = 8.0 Hz), 6.70 (d, 2H, J = 8.0 Hz), 3.08 (s, br, 2H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 147.4, 138.5, 136.3, 131.0, 128.9, 128.4, 119.8, 115.9.
HRMS m/z calcd. for C12H11ClN2S [M+H]+: 251.0410, found: 251.0411.
(4-(m-tolylthio)phenyl)hydrazine (3l): Compound 3l was obtained in 47% yield (54
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.36 (d, 2H, J = 8.0 Hz), 7.18 (t, 1H, J = 8.0 Hz),
7.02 (s, 1H), 6.97 (d, 2H, J = 8.0 Hz), 6.70 (d, 2H, J = 8.0 Hz), 3.85 (s, br, 2H), 2.31
(s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 147.0, 139.4, 138.7, 136.1, 128.8, 128.0,
126.3, 124.5, 120.6, 115.9; HRMS m/z calcd. for C13H14N2S [M+H]+: 231.0956,
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
5
found: 231.0967.
6
7
8
9
(4-(4-methoxyphenylthio)phenyl)hydrazine (3m): Compound 3m was obtained in
62% yield (77 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.25ꢀ7.23 (m, 4H), 6.84 (d, 2H, J
= 8.0 Hz), 6.65 (d, 2H, J = 8.0 Hz), 3.80 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ
158.5, 146.2, 134.0, 131.5, 128.8, 123.5, 115.8, 114.6, 55.4; HRMS m/z calcd. for
C13H14N2OS [M+H]+: 247.0905, found: 247.0911.
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-(butylthio)aniline (3n):25 Compound 3n was obtained in 13% yield (12 mg)
1
according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1). H
NMR (CDCl3, 400 MHz, ppm) δ 7.26 (d, 2H, J = 8.0 Hz), 6.64 (d, 2H, J = 8.0 Hz),
3.74 (s, br, 2H), 2.79 (t, 2H, J = 8.0 Hz), 1.57 (dt, 2H, J = 8.0 Hz), 1.42 (dt, 2H, J =
13
8.0 Hz), 0.91 (t, 3H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ 145.7, 133.7,
123.9, 115.6, 36.1, 31.5, 21.8, 13.7; HRMS m/z calcd. for C10H15NS [M+H]+:
182.1003, found: 182.1012.
4-(butylthio)-N-methylaniline (3o): Compound 3o was obtained in 22% yield (22
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.30 (d, 2H, J = 8.0 Hz), 6.58 (d, 2H, J = 8.0 Hz),
3.78 (s, br, 1H), 2.85(s, 3H), 2.79 (t, 2H, J = 8.0 Hz), 1.57 (dt, 2H, J = 8.0 Hz), 1.42
13
(dt, 2H, J = 8.0 Hz), 0.93 (t, 3H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ
148.7, 134.1, 122.0, 112.4, 36.5, 31.6, 30.7, 21.9, 13.7; HRMS m/z calcd. for
C11H17NS [M+H]+: 196.1160, found: 196.1147.
4-(thiophen-2-ylthio)aniline (3p): Compound 3p was obtained in 79% yield (13 mg)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
9
1
according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1). H
NMR (CDCl3, 400 MHz, ppm) δ 7.34 (d, 2H, J = 4.0 Hz), 7.24 (d, 2H, J = 8.0 Hz),
7.19 (d, 1H, J = 4.0 Hz), 7.00 (dd, 1H, J = 4.0 Hz), 6.63 (d, 2H, J = 8.0 Hz), 3.74 (s,
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
br, 2H). C NMR (CDCl3, 100 MHz, ppm) δ 148.7, 134.1, 122.0, 112.4, 36.5, 31.6,
30.7, 21.9, 13.7; HRMS m/z calcd. for C10H9NS2 [M+H]+: 208.0255, found:
208.0261.
2-methyl-4-(p-tolylthio)aniline (5a): Compound 5a was obtained in 99% yield (114
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.25 (s, 1H), 7.22 (d, 1H, J = 8.0 Hz), 7.12 (d,
2H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.0 Hz), 6.68 (d, 1H, J = 8.0 Hz), 3.75 (s, br, 2H),
13
2.35 (s, 3H), 2.17 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 145.1, 136.4, 135.9,
135.3, 133.2, 129.7, 128.1, 123.3, 121.2, 115.6, 21.0, 17.3; HRMS m/z calcd. for
C14H15NS [M+H]+: 230.1003, found: 230.1017.
4-(4-chlorophenylthio)-2-methylaniline (5b): Compound 5b was obtained in 88%
yield (110 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.25ꢀ7.19 (s, 1H), 7.07 (d, 2H, J =
8.0 Hz), 6.69 (d, 1H, J = 8.0 Hz), 3.80 (s, br, 2H), 2.18 (s, 3H). 13C NMR (CDCl3, 100
MHz, ppm) δ 145.7, 138.8, 137.1, 134.0, 130.9, 128.9, 128.3, 123.4, 119.4, 115.7,
17.3. HRMS m/z calcd. for C13H12ClNS [M+H]+: 250.0457, found: 250.0462.
4-(4-bromophenylthio)-2-methylaniline (5c): Compound 5c was obtained in 91%
yield (134 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.34 (d, 2H, J = 8.0 Hz), 7.25 (s,
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
5
1H), 7.23 (d, 1H, J = 8.0 Hz), 7.00 (d, 2H, J = 8.0 Hz), 6.69 (d, 2H, J = 8.0 Hz), 3.81
6
7
13
(s, br, 2H), 2.18 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 145.8, 139.6, 137.2,
8
9
134.1, 131.8, 128.5, 123.5, 119.2, 118.7, 115.7, 17.3; HRMS m/z calcd. for
C13H12BrNS [M+H]+: 293.9952, 295.9932, found: 293.9941, 295.9926.
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
2-methyl-4-(o-tolylthio)aniline (5d): Compound 5d was obtained in 86% yield (99
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.26 (s, 1H), 7.24ꢀ7.20 (m, 2H), 7.12ꢀ7.09 (m,
13
2H), 6.72 (d, 1H, J = 8.0 Hz), 3.76 (s, br, 2H), 2.47 (s, 3H), 2.20 (s, 3H). C NMR
(CDCl3, 100 MHz, ppm) δ 145.3, 138.8, 136.8, 135.7, 133.7, 130.1, 127.3, 126.4,
125.3, 123.5, 119.8, 115.8, 20.3, 17.4. HRMS m/z calcd. for C14H15NS [M+H]+:
230.1003, found: 230.1015.
2-chloro-4-(p-tolylthio)aniline (5e): Compound 5e was obtained in 95% yield (119
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.42 (d, 1H, J = 4.0 Hz), 7.21 (dd, 1H, J = 8.0
Hz), 7.17 (d, 2H, J = 8.0 Hz), 7.11 (d, 2H, J = 8.0 Hz), 6.74 (d, 1H, J = 8.0 Hz), 4.16
13
(s, br, 2H), 2.35 (s, 3H), 2.20 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 143.0,
136.2, 134.4, 134.3, 133.2, 129.9, 129.1, 123.0, 119.5, 116.3, 21.1; HRMS m/z calcd.
for C13H12ClNS [M+H]+: 250.0457, found: 250.0462.
2-chloro-4-(4-methoxyphenylthio)aniline (5f): Compound 5f was obtained in 86%
yield (114 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.33 (s, 1H), 7.32 (d, 2H, J = 8.0
Hz), 7.13 (d, 1H, J = 8.0 Hz), 6.86 (d, 2H, J = 8.0 Hz), 6.70 (d, 1H, J = 8.0 Hz), 4.13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
5
13
(s, br, 2H), 3.81 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 158.9, 142.5, 132.8,
6
7
8
9
132.4, 131.7, 127.6, 124.9, 119.5, 116.3, 114.8, 55.4; HRMS m/z calcd. for
C13H12ClNOS [M+H]+: 266.0406, found: 266.0411.
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
2-chloro-4-(4-chlorophenylthio)aniline (5g): Compound 5g was obtained in 75%
yield (101 mg) according to the general procedure. Eluent petroleum ether/ethyl
1
acetate (20:1). H NMR (CDCl3, 400 MHz, ppm) δ 7.44 (s, 1H), 7.23ꢀ7.20 (m, 3H),
7.10 (d, 2H, J = 8.0 Hz), 6.76 (d, 1H, J = 8.0 Hz), 4.26 (s, br, 2H). 13C NMR (CDCl3,
100 MHz, ppm) δ 143.7, 137.4, 135.2, 134.1, 131.6, 129.1, 129.0, 121.0, 119.5, 116.4;
HRMS m/z calcd. for C12H9Cl2NS [M+H]+: 269.9911, found: 269.9923.
4-(4-bromophenylthio)-2-chloroaniline (5h): Compound 5h was obtained in 78%
yield (122 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.44 (s, 1H), 7.36 (d, 2H, J = 8.0
Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.02 (d, 2H, J = 8.0 Hz), 6.77 (d, 2H, J = 8.0 Hz), 4.26
13
(s, br, 2H). C NMR (CDCl3, 100 MHz, ppm) δ 143.8, 138.2, 135.4, 134.3, 132.0,
129.2, 120.7, 119.5, 119.4, 116.4; HRMS m/z calcd. for C12H9BrClNS [M+H]+:
313.9406, 315.9385, found: 313.9417, 315.9392.
2-chloro-4-(o-tolylthio)aniline (5i): Compound 5i was obtained in 79% yield (99
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.43 (s, 1H), 7.25ꢀ4.13 (m, 4H), 7.05 (d, 2H, J =
8.0 Hz), 6.76 (d, 2H, J = 8.0 Hz), 4.22 (s, br, 2H), 2.48 (s, br, 3H). 13C NMR (CDCl3,
100 MHz, ppm) δ 143.2, 137.3, 136.7, 134.6, 133.5, 130.4, 128.6, 126.7, 126.2, 121.7,
119.7, 116.5, 20.4; HRMS m/z calcd. for C13H12ClNS [M+H]+: 250.0457, found:
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
5
250.0462.
6
7
8
9
2-ethyl-4-(p-tolylthio)aniline (5j): Compound 5j was obtained in 99% yield (121
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.31 (s, 1H), 7.24 (d, 1H, J = 8.0 Hz), 7.15 (d,
2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.0 Hz), 6.70 (d, 1H, J = 8.0 Hz), 3.76 (s, br, 2H),
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
2.52 (dd, 2H, J = 8.0 Hz), 2.35 (s, 3H), 1.30 (t, 3H, J = 8.0 Hz). C NMR (CDCl3,
100 MHz, ppm) δ 144.6, 136.8, 136.1, 135.3, 134.4, 133.1, 129.7, 129.0, 128.0, 116.1,
23.9, 21.0, 12.9; HRMS m/z calcd. for C15H17NS [M+H]+: 244.1160, found:
244.1154.
2-ethyl-4-(4-methoxyphenylthio)aniline (5k): Compound 5k was obtained in 99%
yield (128 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.26 (d, 2H, J = 8.0 Hz), 7.22 (s,
1H), 7.15 (d, 2H, J = 8.0 Hz), 6.85 (d, 2H, J = 8.0 Hz), 6.65 (d, 1H, J = 8.0 Hz), 3.81
(s, 3H), 3.74 (s, br, 2H), 2.50 (dd, 2H, J = 8.0 Hz), 1.26 (t, 3H, J = 8.0 Hz). 13C NMR
(CDCl3, 100 MHz, ppm) δ 158.4, 144.1, 133.1, 131.7, 131.1, 129.2, 128.9, 123.1,
116.1, 114.7, 55.4, 23.9, 12.9; HRMS m/z calcd. for C15H17NOS [M+H]+: 259.1031,
found: 259.1022.
4-(4-chlorophenylthio)-2-ethylaniline (5l): Compound 5l was obtained in 97% yield
(128 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
1
(20:1). H NMR (CDCl3, 400 MHz, ppm) δ 7.30 (s, 1H), 7.26ꢀ7.21 (m, 3H), 7.09 (d,
2H, J = 8.0 Hz), 6.71 (d, 2H, J = 8.0 Hz), 3.84 (s, br, 2H), 2.53 (dd, 2H, J = 8.0 Hz),
13
1.29 (t, 3H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ 145.2, 138.9, 136.8,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
5
6
7
135.5, 135.2 133.9, 128.9, 128.2, 117.4, 116.2, 23.9, 12.8; HRMS m/z calcd. for
C14H14ClNS [M+H]+: 264.0614, found: 264.0603.
8
9
4-(4-bromophenylthio)-2-ethylaniline (5m): Compound 5m was obtained in 97%
yield (150 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.35 (d, 2H, J = 8.0 Hz), 7.29 (s,
1H), 7.24 (d, 1H, J = 8.0 Hz), 7.02 (d, 2H, J = 8.0 Hz), 6.71 (d, 1H, J = 8.0 Hz), 3.85
(s, br, 2H), 2.53 (dd, 2H, J = 8.0 Hz), 1.29 (t, 3H, J = 8.0 Hz). 13C NMR (CDCl3, 100
MHz, ppm) δ 145.3, 139.7, 136.8, 135.2, 134.0, 131.8, 129.1, 128.4, 23.8, 12.8;
HRMS m/z calcd. for C14H14BrNS [M+H]+: 308.0109, 310.0088, found: 309.0121,
310.0095.
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-chlorophenylthio)-2,6-dimethylaniline (5n): Compound 5n was obtained in
99% yield (130 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.22ꢀ7.19 (m, 4H), 7.09 (d, 2H, J
= 8.0 Hz), 3.72 (s, br, 2H), 2.21 (s, 6H). 13C NMR (CDCl3, 100 MHz, ppm) δ 144.0,
139.1, 136.5, 135.1, 128.9, 128.2, 122.8, 118.5, 17.6; HRMS m/z calcd. for
C14H14ClNS [M+H]+: 263.0535, found: 263.0528.
2,6-dimethyl-4-(p-tolylthio)aniline (5o): Compound 5o was obtained in 99% yield
(121 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
1
(20:1). H NMR (CDCl3, 400 MHz, ppm) δ 7.19 (s, 2H), 7.16ꢀ7.09 (m, 4H), 3.76 (s,
br, 2H), 2.36 (s, 3H), 2.22 (s, 6H). 13C NMR (CDCl3, 100 MHz, ppm) δ 143.4, 136.2,
135.2, 134.4, 129.7, 127.9, 122.6, 120.2, 21.0, 17.6. HRMS m/z calcd. for C15H17NS
[M+H]+: 244.1160, found: 244.1154.
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4-methyl-2-(m-tolylthio)aniline (7a): Compound 7a was obtained in 84% yield (97
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.35 (s, 1H), 7.16 (t, 1H, J = 8.0 Hz), 7.10 (d, 1H,
J = 8.0 Hz), 7.01ꢀ6.79 (m, 2H), 6.93 (d, 1H, J = 8.0 Hz), 6.76 (d, 1H, J = 8.0 Hz),
4.17 (s, br, 2H), 2.33 (s, 3H), 2.31 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 146.5,
138.9, 137.5, 136.8, 131.9, 128.9, 128.1, 127.1, 126.4, 123.6, 115.5, 114.5, 21.5, 20.3;
HRMS m/z calcd. for C14H15NS [M+H]+: 230.1003, found: 230.1017.
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-methyl-2-(o-tolylthio)aniline (7b): Compound 7b was obtained in 81% yield (93
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.34 (s, 1H), 7.25 (d, 1H, J = 8.0 Hz), 7.16ꢀ7.12
13
(m, 3H), 6.81 (t, 2H, J = 8.0 Hz), 4.18 (s, br, 2H), 2.53 (s, br, 3H), 2.34 (s, 3H). C
NMR (CDCl3, 100 MHz, ppm) δ 146.6, 137.5, 136.0, 135.2, 131.9, 130.3, 128.3,
126.7, 125.5, 125.2, 115.6, 114.0, 20.4, 20.2; HRMS m/z calcd. for C14H15NS [M+H]+:
230.1003, found: 230.1017.
4-chloro-2-(p-tolylthio)aniline (7c): Compound 7c was obtained in 86% yield (108
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.42 (d, 1H, J = 4.0 Hz), 7.17(d, 1H, J = 8.0 Hz),
7.11ꢀ7.06 (m, 4H), 6.72 (d, 1H, J = 8.0 Hz), 4.28 (s, br, 2H), 2.32 (s, 3H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 146.9, 136.2, 135.6, 131.8, 130.5, 130.0, 127.7, 122.5,
117.2, 116.3, 21.0; HRMS m/z calcd. for C13H12ClNS [M+H]+: 250.0457, found:
250.0462.
4-chloro-2-(4-methoxyphenylthio)aniline (7d): Compound 7d was obtained in 72%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
5
6
7
8
9
yield (96 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.38 (d, 1H, J = 4.0 Hz), 7.21(d, 2H, J =
8.0 Hz), 7.14 (d, 1H, J = 8.0 Hz), 6.86 (d, 2H, J = 8.0 Hz), 6.68 (d, 1H, J = 8.0 Hz),
4.29 (s, br, 2H), 3.80 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 155.8, 146.3,
134.6, 130.7, 130.0, 125.5, 122.6, 118.9, 116.3, 115.0, 55.4; HRMS m/z calcd. for
C13H12ClNOS [M+H]+: 266.0406, found: 266.0411.
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-chloro-2-(4-chlorophenylthio)aniline (7e):23 Compound 7e was obtained in 88%
yield (118 mg) according to the general procedure. Eluent petroleum ether/ethyl
1
acetate (20:1). H NMR (CDCl3, 400 MHz, ppm) δ 7.45 (s, 1H), 7.24ꢀ7.20 (m, 3H),
7.05 (d, 2H, J = 8.0 Hz), 6.74 (d, 1H, J = 8.0 Hz), 4.31 (s, br, 2H). 13C NMR (CDCl3,
100 MHz, ppm) δ 147.3, 136.2, 134.4, 131.8, 131.3, 129.3, 128.2, 122.6, 116.4, 115.5;
HRMS m/z calcd. for C12H9Cl2NS [M+H]+: 269.9911, found: 269.9923.
2-(4-bromophenylthio)-4-chloroaniline (7f): Compound 7f was obtained in 84%
yield (132 mg) according to the general procedure. Eluent petroleum ether/ethyl
acetate (20:1).1H NMR (CDCl3, 400 MHz, ppm) δ 7.46 (s, 1H), 7.37 (d, 2H, J = 8.0
Hz), 7.22 (d, 1H, J = 8.0 Hz), 6.98 (d, 2H, J = 8.0 Hz), 6.73 (d, 1H, J = 8.0 Hz), 4.31
13
(s, br, 2H). C NMR (CDCl3, 100 MHz, ppm) δ 147.3, 136.2, 135.1, 132.2, 131.3,
129.3, 128.4, 122.6, 119.7, 116.5. HRMS m/z calcd. for C12H9BrClNS [M+H]+:
313.9406, 315.9385, found: 313.9417, 315.9392.
4-chloro-2-(m-tolylthio)aniline (7g): Compound 7g was obtained in 69% yield (86
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.48 (s, 1H), 7.22ꢀ7.16 (m, 2H), 7.01 (d, 2H, J =
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
5
8.0 Hz), 6.94 (d, 1H, J = 8.0 Hz), 6.74 (d, 1H, J = 8.0 Hz), 4.31 (s, br, 2H), 2.33 (s,
6
7
13
3H). C NMR (CDCl3, 100 MHz, ppm) δ 147.3, 139.1, 136.1, 135.4, 130.8, 129.1,
8
9
127.7, 127.0, 124.2, 122.5, 116.4, 116.3, 21.5; HRMS m/z calcd. for C13H12ClNS
[M+H]+: 250.0457, found: 250.0462.
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-chloro-2-(o-tolylthio)aniline (7h): Compound 7h was obtained in 62% yield (78
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.39 (s, 1H), 7.21 (d, 2H, J = 8.0 Hz), 7.14ꢀ7.07
(m, 2H), 6.82 (d, 1H, J = 8.0 Hz), 6.75 (d, 1H, J = 8.0 Hz), 4.27 (s, br, 2H), 2.45 (s,
13
3H). C NMR (CDCl3, 100 MHz, ppm) δ 147.1, 135.9, 135.7, 134.5, 130.6, 130.4,
126.7, 126.3, 125.9, 122.7, 116.3, 116.0, 20.1; HRMS m/z calcd. for C13H12ClNS
[M+H]+: 250.0457, found: 250.0462.
4-methoxy-2-(p-tolylthio)aniline (7i): Compound 7i was obtained in 64% yield (79
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.10ꢀ7.04 (m, 4H), 7.04 (s, 1H), 6.88 (d, 1H, J =
8.0 Hz), 6.77 (d, 1H, J = 8.0 Hz), 4.01 (s, br, 2H), 3.77 (s, 3H), 2.32 (s, 3H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 152.4, 142.4, 135.7, 132.7, 129.9, 127.4, 120.6, 117.7,
116.7, 116.4, 55.9, 21.0; HRMS m/z calcd. for C14H15NOS [M+H]+: 246.0953, found:
246.0961.
4-methoxy-2-(m-tolylthio)aniline (7j): Compound 7j was obtained in 64% yield (79
mg) according to the general procedure. Eluent petroleum ether/ethyl acetate (20:1).
1H NMR (CDCl3, 400 MHz, ppm) δ 7.16 (t, 1H, J = 8.0 Hz), 7.06 (s, 1H), 6.98 (d, 2H,
J = 8.0 Hz), 6.94ꢀ6.88 (m, 2H), 6.79 (d, 1H, J = 8.0 Hz), 3.99 (s, br, 2H), 3.78 (s, 3H),
ACS Paragon Plus Environment