Iron-catalyzed N -arylsulfonamide formation through directly using nitroarenes as nitrogen sources

Article abstract of DOI:10.1021/acs.joc.5b00130

One-step, catalytic synthesis of N-arylsulfonamides via the construction of N-S bonds from the direct coupling of sodium arylsulfinates with nitroarenes was realized in the presence of FeCl₂ and NaHSO₃ under mild conditions. In this process, stable and readily available nitroarenes were used as nitrogen sources, and NaHSO₃ acted as a reductant to provide N-arylsulfonamides in good to excellent yields. A broad range of functional groups were very well-tolerated in this reaction system. In addition, mechanistic studies indicated that the N-S bond might be generated through direct coupling of nitroarene with sodium arylsulfinate prior to the reduction of nitroarenes by NaHSO₃. Accordingly, a reaction mechanism involving N-aryl-N-arenesulfonylhydroxylamine as an intermediate was proposed.

Full text of DOI:10.1021/acs.joc.5b00130

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Article
Iron-Catalyzed N-Arylsulfonamides Formation through
Directly Using Nitroarenes as Nitrogen Sources
Weixi Zhang, Junyao Xie, Bin Rao, and Meiming Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00130 • Publication Date (Web): 05 Mar 2015
Downloaded from http://pubs.acs.org on March 14, 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 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Iron-Catalyzed N-Arylsulfonamides Formation
through Directly Using Nitroarenes as Nitrogen
Sources
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
Weixi Zhang, Junyao Xie, Bin Rao, and Meiming Luo*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China.
Fax: (+86)ꢀ28ꢀ85462021; Tel: (+86)ꢀ28ꢀ85462021; eꢀmail: luomm@scu.edu.cn
TOC Graphic
Abstract
A oneꢀstep, catalytic synthesis of Nꢀarylsulfonamides via construction of N–S bonds
from the direct coupling of sodium arylsulfinates with nitroarenes was realized in the
presence of FeCl2 and NaHSO3 under mild conditions. In this process, stable and
readily available nitroarenes were used as nitrogen sources and NaHSO3 acted as a
reductant to provide Nꢀarylsulfonamides in good to excellent yields. A broad range of
functional groups were very wellꢀtolerated in this reaction system. In addition,
mechanistic studies indicated that N–S bond might be generated through direct
coupling of nitroarene with sodium arylsulfinate prior to the reduction of nitroarenes
by
NaHSO3.
Accordingly,
a
reaction
mechanism
involving
NꢀarylꢀNꢀarenesulfonylhydroxylamine as an intermediate was proposed.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
Introduction
5
6
7
8
NꢀArylsulfonamides are ubiquitous functional scaffolds among medicinally
interesting molecules.1 Over 30 drugs containing this moiety are widely used in
clinical therapy.2 As such, significant efforts have been made towards the
development of efficient methods for their preparation.
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
To date, one of the most conventional routes to Nꢀarylsulfonamides involve the direct
N–S bond formation (Scheme 1, path a).3,4 While generally effective, this approach
often suffers from the use of aromatic amines as nitrogen sources, which are
genotoxic and are undesired potential impurities in the synthesis of active
pharamaceutial ingredients.5 To obviate this drawback, the construction of
Nꢀarylsulfonamides via metalꢀcatalyzed C–N bond formation has been extensively
studied in the past few years (Scheme 1, path b). Such an approach includes the
reactions of sulfonamides as nitrogenꢀbased nucleophiles with aryl halides,6 alcohols,7
activated esters8 or arylboronic acids,9 and the aminosulfonation of hydrocarbons.10
This alternative route offers a straightforward strategy for the preparation of
Nꢀarylsulfonamides without the use of anilines, however, it is limited by the harsh
conditions, requirement of additional bases and/or ligands, and comparatively
complicated starting materials which must be firstly synthesized. It is highly desirable
in this area to develop shortcut approaches to Nꢀarylsulfonamides from simple,
inexpensive, and stable nitrogen sources. In this regard, readily available nitroarenes
are a potential target for reactivity investigation. As abundant nitrogen sources,
nitroarenes have been directly converted to a wide range of useful nitrogenꢀcontaining
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
compounds, such as Nꢀalkylated amines,11 imines,12 amides,13 and aza heterocycles14
without prior reduction into anilines as in most traditional approaches.15 Hence, the
facile assembly of Nꢀarylsulfonamides directly from nitroarenes would be highly
attractive.
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. Methods for the Synthesis of Sulfonamides.
Results and Discussion
When conducting the catalytic homocoupling of sodium arylsulfinates containing
nitro group,16 we accidentally noticed the formation of trace amount of sulfonamide.
Further exploration revealed that 91% yield of sulfonamide could be obtained under
the optimized conditions (see ESI, Table S1). To our disappointment, harsh conditions
(e.g., above 100 °C and 6 equiv. of sodium arylsulfinates) were indispensable to this
reaction, which limited its practical application. During our investigation on this
reaction, similar situation was reported in a patent by others.17 Moreover, how this
unexpected reaction occurred is not clear yet.
Being curious about the mechanism of this reaction, we then performed controlled
reactions between nitrobenzene and sodium pꢀacetaminobenzenesulfinate hoping to
obtain some insights into its mechanism (Scheme 2). Surprisingly, in addition to the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
7
8
9
expected sulfonamide product, acetanilide and NaHSO4 were obtained as well
(Scheme 2, eq.1). After 12 h at 60 °C, only a small amount of products were
generated (Scheme 2, eq.2), and no reaction took place in the absence of CuCl even at
100 °C after 12 h (Scheme 2, eq.3). These results indicated that the desulfitative
reaction of sodium arylsulfinates occurred in the presence of CuCl at elevated
temperature, which is consistent with the reported observation,18 and the released
sulfur dioxide was oxidized to NaHSO4 even under argon atmosphere. The generation
of NaHSO4 suggested that NaHSO3 which could be in situ generated from the
desulfitative reaction of large excess amount of sodium arylsulfinates and water in
solvents might function as a reductant in the sulfonamide formation process.19 It was
then reasonable to envision that if NaHSO3 was added to replace the in situ generated
NaHSO3, this unexpected direct sulfonylation of nitroarenes with sodium
arylsulfinates might proceed at much lower temperature and without the need of large
excess amount of sodium arylsulfinates.
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 on the Reaction of Sodium
p-Acetaminobenzenesulfinate with Nitrobenzene
Then the coupling of sodium pꢀtoluenesulfinate (1a) and nitrobenzene (2a) at 60 °C
was selected as a platform to evaluate the proposed chemistry (Table 1). As we
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
anticipated, the desired product could be formed in 43% yield in DMSO (Table 1,
entries 1 and 2) while NaHSO3 was used as a reductant. As the amount of NaHSO3
increased, the yield decreased possibly due to the side reaction between nitrobenzene
and NaHSO3 which is known as Piria reaction (Table 1, entry 3).20 We next explored
the reaction in other solvents (Table 1, entries 4ꢀ7), and DMSO was found to be the
best of choice (Table 1, entry 1).
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 the Reaction Conditionsa
Entry Catalyst (mol%) Solvent
Additive
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
Yieldb (%)
43
36
35
1
ꢀꢀꢀꢀꢀ
DMSO
DMSO
DMSO
DMF
2c
3d
4
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
12
5
ꢀꢀꢀꢀꢀ
NMP
ꢀꢀꢀꢀꢀ
7
6
7
8
9
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ZnCl2 (10)
CuCl (10)
THF
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
n.r.
n.r.
44
Dioxane
DMSO
DMSO
38
10
11
12
13
14
15
16e
17f
18
19
20
21
22
23
Cu(OAc)2 (10) DMSO
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
DMEDA
TMEDA
DACH
DMDACH
DMDACH
DMDACH
75
40
79
81
76
80
71
80
84
71
85
90
86
83
FeS (10)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
FeCl3 (10)
FeCl2 (10)
FeCl2 (5)
FeCl2 (20)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl3 (10)
Cu(OAc)2 (10) DMSO
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
9
a Reaction conditions (unless otherwise stated): nitrobezene (0.5 mmol),
sodium pꢀtoluenesulfinate (0.75 mmol), NaHSO3 (1.5 mmol), catalyst
(0.05 mmol), additive (0.1 mmol), solvent (2.0 mL), 60 °C, 12 h, under
b
c
d
e
argon. Yield based on 2a. NaHSO3 (1.0 mmol). NaHSO3 (2.0 mmol).
f
Reaction temperature: 50 °C. Reaction temperature: 70 °C. n.r. = no
reaction.
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
DMEDA = N,N’ꢀdimethylethaneꢀ1,2ꢀdiamine.
TMEDA = tetramethylethylenediamine.
DACH = cyclohexaneꢀ1,2ꢀdiamine.
DMDACH = transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane.
Remarkably, during the study of catalysts (Table 1, entries 8ꢀ13), we noticed that
the addition of FeCl2 to the reaction system led to significant increase in yields of the
isolated product (Table 1, entry 13). Cu(OAc)2 and FeCl3 also promoted the reaction
with slightly lower efficiency (Table 1, entries 10 and 12). With Cu(OAc)2 as the
catalyst, biaryl side product generated from the desulfitative homocoupling of sodium
arylsulfinates was also detected (Table 1, entry 10). Other metal salts were not active
and gave poor yields. The influence of the amount of FeCl2 on the reactions was
investigated (Table 1, entries 14 and 15), and the results showed that a FeCl2 loading
of 10 mol% gave the best product yield. The reaction temperature was also screened
(Table 1, entries 16 and 17), and 60 °C was found to be an appropriate choice. We
observed
that
the
combination
of
FeCl2
and
transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane (DMDACH) showed the best
efficiency (Table 1, entry 21), while FeCl2 plus N,N’ꢀdimethylethaneꢀ1,2ꢀdiamine
(DMEDA) or cyclohexaneꢀ1,2ꢀdiamine (DACH) gave a lower reaction yield (Table 1,
entries 18 and 20). Meanwhile, the addition of tetramethylethylenediamine (TMEDA)
just led to a decrease in yield (Table 1, entry 19).
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
With the optimized reaction conditions in hand, we then evaluated the scope of the
reactions of pꢀtoluenesulfinate (1a) with various nitroarenes. As shown in Table 2,
most of the substrates with a variety of substituents afforded the products in good to
excellent yields under the optimum reaction conditions. Nitroarenes both bearing
electronꢀdonating methyl, methoxy, amido, and electronꢀwithdrawing chloro, cyano,
trifluoromethyl, carbonyl, ester and carboxylic acid groups generated the desired
products in good to excellent yields. Due to the steric hindrance, orthoꢀnitrotoluene
2d gave a slightly lower reaction yield (Table 2, entry 4) compared to its para and
meta isomers (Table 2, entries 2 and 3). Similar trend was also observed in the
reactions of 1a with methyl nitrobenzoates 2e−2g (Table 2, entries 5ꢀ7). A further
increase in the steric bulk on the nitroarene 2h was accompanied by a reduction in the
product yield (Table 2, entry 8). It has been reported that aryl sulfones could be
formed through SNArꢀbased reaction of sodium arylsulfinates with arylchloride in
some reaction systems.21 With the present protocol, it is noteworthy that when
pꢀnitrochlorobenzene (2i) and mꢀnitrochlorobenzene (2j) were employed as substrates,
1a reacted exclusively with the nitro group to give the products 3ai and 3aj in 93%
and 96% yield, respectively (Table 2, entries 9 and 10), demonstrating good
selectivity. Ketone and aldehyde were also well tolerated to afford the corresponding
products 3ap and 3aq in good yields (Table 2, entries 16 and 17). Possibly due to
steric hindrance and side reaction of 1ꢀnitronaphthalene (2r) with NaHSO3,22 reaction
of 1a with 2r afforded corresponding 3ar in a moderate yield of 51% (Table 2, entry
18). Finally, the reaction of 3ꢀnitropyridine (2s) also proceeded smoothly to give
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 33
1
2
3
4
sulfonamide 3as in 93% yield (Table 2, entry 19). When nitromethane (2t) was
5
6
7
conducted under standard conditions, no desired product was detected.
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
Table 2. Reaction of 1a with Various Nitroarenesa
Entry
1
Nitroarene
Product
Yield (%)b
90
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
H
N
Ts
Ts
2
3
88
85
H
N
4
82
5c
6c
7c
8d
9
86
95
80
2g
2h
2i
57
93(85)e
96
10
2j
3aj
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
11
12
90
85
98
97
78
84
2k
2l
3ak
3al
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
13d
14d
15d
16c
2m
2n
2o
2p
3am
3an
3ao
3ap
17d
18
75
51
2q
2r
3aq
3ar
3as
19d
20
93
2s
2t
n.r.
a Reaction conditions: 1a (0.75 mmol), 2 (0.5 mmol), NaHSO3 (1.5 mmol), FeCl2
b
(10 mol%), DMDACH (20 mol%), DMSO (2 mL), 12 h, Ar. Yield based on
nitroarene. Reaction time: 16 h. d Reaction time: 20 h. 20 mmol of 2i was
c
e
added, reaction time was 20 h. n.r. = no reaction.
DMDACH = transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane.
Subsequently, a range of sodium sulfinates were reacted with nitrobenzene and the
results are listed in Table 3. The reaction of sodium bezenesulfinate (1b) with
nitrobenzene, pꢀnitrotoluene and pꢀchloronitrobenzene gave the desired products 3ba,
3bb and 3bi in excellent yields (Table 3, entries 1ꢀ3). The reaction of sodium
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
8
9
4ꢀmethoxybenzenesulfinate (1c) with nitrobenzene furnished 3ca in 92% yield (Table
3, entry 4). When the 2,4,6 positions of sodium benzenesulfinate were substituted
with methyl groups (1d), the yield was reduced dramatically to 31%, probably due to
the steric hindrance (Table 3, entry 5). Meanwhile, this reaction is also tolerant with
bromo, chloro and fluoro substituents on the aromatic rings of sodium arylsulfinates
and the corresponding target products 3ea−3ga were obtained in excellent yields
(85ꢀ91%; Table 3, entries 6ꢀ8). When sodium sulfinate with amino group (1h) was
subjected to this transformation, the desired product 3ha could be obtained directly in
84% yield with the amino group unaffected (Table 3, entry 9). It is noteworthy that
this kind of structural moiety in which the amino group is at the para position of
arylsulfonamides is decisive for the antibacterial action23 and can only be prepared
through multistep synthetic processes by the traditional methods.24 The protocol was
also applied to the synthesis of thiophene sulfonamide, giving the desired product 3ia
and 3is in 94% and 81% yield, respectively (Table 3, entries 10 and 11). However,
sodium alkylsulfinate (1j) was not a suitable substrate for this transformation (Table 3,
entry 12).
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. Reaction of Nitroarenes with Various Sodium Sulfinatesa
Entry
1
Sodium sulfinate
Product
Yieldb (%)
93
1b
3ba
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
86
91
92
31
85
89
91
84
94
1b
1b
1c
1d
1e
1f
3bb
3bi
3ca
3da
3ea
3fa
3ga
3ha
3ia
3
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
5c
6c
7c
8c
9d
10c
1g
1h
1i
11
12
81
1i
1j
3is
n.r.
a Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), NaHSO3 (1.5 mmol), FeCl2
b
(10 mol%), DMDACH (20 mol%), DMSO (2 mL), 12 h, Ar. Yield based on
nitroarene. c Reaction time: 20 h. d Na2CO3 (0.75 mmol) was added.
n.r. = no reaction. DMDACH = transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane.
To gain some understanding of the mechanism for this reaction, some control
experiments were tentatively examined (for details see ESI). Release of NaHSO4 was
firstly detected under standard conditions (for details see ESI). Subsequently, 1a and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
7
8
9
2a were subjected to the conditions in the presence of 1.1 equivalent amount of FeCl2,
however, no reaction was detected in the absence of NaHSO3 (Scheme 3, eq.1). This
evidence indicated that FeCl2 or sodium sulfinate could not act as the reductant and
replace the role of NaHSO3 in this transformation. Nitrosobenzene (4) and
Nꢀphenylhydroxylamine (5) which are thought to be the intermediates in the reduction
of nitroarenes by NaHSO3 in Piria reaction,20,22,25 were then tested under the standard
conditions (Scheme 3, eq. 2 and 3). The yields of sulfonamide 3aa were very low.
The reaction between sodium pꢀtoluenesulfinate (1a) and aniline (6) did not occur at
all (Scheme 3, eq. 4). These results suggested that the NꢀS bond of the sulfonamide
might not be formed through the reaction of 1a with nitrosobenzene (4),
Nꢀphenylhydroxylamine (5) or aniline (6). That was, in this reaction nitroarenes might
not be reduced to nitrosobenzene, Nꢀphenylhydroxylamine or aniline as in the Piria
reaction. It was more reasonable to assume that the NꢀS bond was generated through
direct coupling of nitroarene with sodium sulfinate prior to the Piria reaction. The
direct coupling of nitroarene with sodium sulfinate implied that
NꢀphenylꢀNꢀtosylhydroxylamine (7) might be involved as an intermediate in the
reaction. Consequently, NꢀphenylꢀNꢀtosylhydroxylamine (7) was prepared following
literature procedure26 and treated with NaHSO3 to furnish the sulfonamide 3aa in 86%
yield (Scheme 3, eq. 5).
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

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
Scheme 3. Control Experiments
5
6
7
8
FeCl2 (1.1 eq.)
additive
DMSO, 60 oC, 12 h
NO2
SO2Na
SO2Na
+
no reaction occured
(1)
(2)
9
1a
2a
4
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
NaHSO3, FeCl2
DMDACH
DMSO, 60 oC, 12 h
H
N Ts
NO
+
3aa
1-9%
1a
NaHSO3, FeCl2
DMDACH
DMSO, 60 oC, 12 h
H
SO Na
NHOH
N Ts
(3)
+
2
3aa 6-12%
1a
1a
5
FeCl2, DMDACH
NH2
OH
SO2Na
+
no reaction occured
(4)
(5)
DMSO, 60 oC, 12 h
6
7
standard conditions
or NaHSO3 (1.1 eq.)
DMSO, 60 oC, 1 h
H
N
N Ts
Ts
3aa
82-86%
Based on the above observations, a plausible mechanism for this reaction is
proposed in Scheme 4. The reaction starts from the coordination between sodium
arylsulfinate and Fe2+ to form the arylsulfinic acid salt A. Subsequently, complexation
and nucleophilic addition of A to nitro group of nitroarene lead to the cyclic
fiveꢀmembered intermediate B which is then attacked by bisulfite to afford
2ꢀ
intermediate C. Release of Fe2+ and SO4 from intermediate C produces
NꢀarylꢀNꢀarenesulfonylhydroxylamine D. Addition of D to bisulfite gives intermediate
E. Finally, intermediate E decomposes to the corresponding Nꢀarylsulfonamide and
bisulfate which accounts for the acidity of the reaction mixture (for details see ESI).
The reductions of intermediate B by bisulfite to NꢀarylꢀNꢀarenesulfonylhydroxylꢀ
amine D, and D to the final product Nꢀarylsulfonamide are mechanistically similar to
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
the reductions occurred in the Piria reaction.20b
5
6
7
8
9
Scheme 4. Proposed Mechanism
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
Fe
H
O
O
Fe
Fe+
O
O
S
O
O
N
O
O N
O
S O
O
N
O
S O
Fe2+
O
Ar2
O
HSO3
S
O
S O
Ar1
Ar2 Ar1
Ar2 Ar1
Ar1
A
C
2-
B
Fe2+, SO4
O
O
O
O
S
H
N
O
S O
HSO3
Ar2
S Ar1
O
N
S O
HO
+ HSO4
HO
N
O
H
Ar2 Ar1
Ar2 Ar1
E
D
Conclusion
In summary, an efficient and convenient FeCl2–catalyzed system for the construction
of sulfonamide directly from nitroarenes and sodium arylsulfinates under mild
conditions has been developed. The important feature of this method is using stable
and readily available nitroarenes as nitrogen source and inexpensive sodium bisulfite
as reductant, which makes it efficient and practical. The process also exhibits
significant functional group tolerance and allows for the preparation of a number of
Nꢀarylsulfonamides in good to excellent yields. The importance of the sulfonamide
scaffold would render this protocol attractive for both synthetic and medicinal
chemistry. Meanwhile, based on the experimental observations, a novel and
interesting mechanism for this reaction is proposed.
Experimental Section
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General. All commercially reagents were used without further purification. Sodium
arylsulfinate27 and NꢀphenylꢀNꢀtosylhydroxylamine (6)26 were prepared according to
previous literatures. Melting points were determined on a melting point apparatus and
were uncorrected. Column chromatography was performed with silica gel. Thin layer
chromatography was carried out using silica gel plates. Highꢀresolution mass spectra
(HRMS) were obtained with a QꢀTOFꢀPremier (ESI). 1H NMR and 13C NMR spectra
were recorded on 400 MHz instrument. Spectra were reported relative to Me4Si (δ 0.0
ppm), CDCl3 (δ 7.26 ppm) and DMSOꢀd6 (δ 2.50 ppm). 13C NMR were reported
relative to CDCl3 (δ 77.0 ppm) and DMSOꢀd6 (δ 39.5 ppm). Splitting patterns are
designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, etc.
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
Products were characterized by comparison of H and 13C NMR spectroscopic data
with those available in the literature. pH was recorded on a pH meter.
Control Experiments on the Reaction of Sodium p-Acetaminobenzenesulfinate
with Nitrobenzene. Sodium 4ꢀacetamidobenzenesulfinate (663 mg, 3 mmol),
nitrobenzene (0.051 mL, 0.5 mmol) and CuCl (7.42 mg, 0.075 mmol) were added in
DMSO (2 mL). The pH of the mixture was about 8.3 by pH meter. The mixture was
allowed to react in a sealed tube at 100 °C under argon for 12 h. After cooling to room
temperature, the pH of the resulting mixture was reduced to 3.4, indicating production
of H+. The mixture was then extracted with dichloromethane (3 × 10 mL). Saturated
aqueous BaCl2 was added to the aqueous solution (0.5 mL), and there formed white
precipitates which were not dissolved in aqueous HCl (1 M), indicating formation of
BaSO4.28 The combined organic layer was dried with anhydrous Na2SO4. The solvent
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
5
6
was removed. Product and acetanilide were separated by a short flash chromatography
on a silica gel column. Isolated yield was based on nitrobenzene.
7
8
9
Determination of NaHSO4 Released from Standard Reaction Conditions.
pꢀToluenesulfinate (133.5 mg, 0.75 mmol), nitrobenzene (0.051 mL, 0.5 mmol),
NaHSO3 (156 mg, 1.5 mmol), FeCl2 (6.3 mg, 10 mol%) and
transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane (14.2 mg, 20 mol%) were dissolved in
DMSO (2 mL). The pH of the mixture was about 9.6 by a pH meter. Then the mixture
was stirred at 60 °C for 12 h in a sealed tube under argon atmosphere. After cooling to
room temperature, the pH of the resulting mixture was reduced to 3.0. The mixture
was then extracted with dichloromethane (3 × 10 mL). Saturated aqueous BaCl2 was
added to the aqueous solution (0.5 mL), and there formed white precipitates which
were not dissolved in aqueous HCl (1 M), indicating formation of BaSO4.19
General Procedure for the Synthesis of Sulfonamides. A mixture of sodium
arylsulfinates (0.75 mmol), nitroarenes (0.051 mL, 0.5 mmol), NaHSO3 (156 mg, 1.5
mmol), FeCl2 (6.3 mg, 10 mol%) and transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane
(14.2 mg, 20 mol%) in DMSO (2 mL) were stirred at 60 °C for 12 h in a sealed tube
under argon atmosphere. After cooling to room temperature, water (8 mL) was added,
the aqueous solution was extracted with dichloromethane (3 × 10 mL), and the
combined extract was dried with anhydrous Na2SO4. The solvent was removed and
the crude product was separated by a short flash chromatography on a silica gel
column to afford the pure product.
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

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4-Methyl-N-phenyl-benzenesulfonamide (3aa).28 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3aa
as white solid in 90% yield (111 mg); m.p.: 104−105 °C (lit.: 104−105 °C); 1H NMR
(400 MHz, CDCl3): δ = 7.70−7.68 (m, 2H), 7.40−7.20 (m, 4H), 7.10−7.07 (m, 4H),
2.36 (s, 3H); 13C {1H}NMR (100 MHz, CDCl3): δ = 143.9, 136.6, 136.0, 129.7, 129.3,
127.3, 125.3, 121.5, 21.6 ppm; HRMS (ESI): m/z calcd for C13H14NO2S [M+H]+:
248.0745, found: 248.0741.
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-N-(p-tolyl)benzenesulfonamide (3ab).8b Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3ab
as white solid in 88% yield (115 mg); m.p.: 116−117 °C (lit.: 118−118.7 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 10.04 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz,
2H), 7.02−6.96 (m, 4H), 2.32 (s, 3H), 2.17 (s, 3H); 13C {1H}NMR (100 MHz,
DMSOꢀd6): δ = 143.0, 136.7, 135.1, 133.2, 129.6, 129.5, 126.7, 120.4, 20.9, 20.2 ppm;
HRMS (ESI): m/z calcd for C14H16NO2S [M+H]+: 262.0902, found: 262.0901.
4-Methyl-N-(m-tolyl)benzenesulfonamide (3ac).28 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3ac
1
as white solid in 85% yield (111 mg); m.p.: 114−115 °C (lit.: 115 °C); H NMR (400
MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 7.6
Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), (6.67 (s, 1H), 2.38 (s, 3H),
2.27 (s, 3H); 13C {1H}NMR (100 MHz, CDCl3): δ = 143.8, 139.4, 136.4, 136.2, 129.6,
129.1, 127.3, 126.1, 122.2, 118.4, 21.5, 21.3 ppm; HRMS (ESI): m/z calcd for
C14H16NO2S [M+H]+: 262.0902, found: 262.0904.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
6
7
8
9
4-Methyl-N-(o-tolyl)benzenesulfonamide (3ad).8b Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3ad
as white solid in 82% yield (107 mg); m.p.: 105−107 °C (lit.: 108−109 °C); 1H NMR
(400 MHz, CDCl3): δ = 7.63 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.22 (d, J =
8.0 Hz, 2H), 7.13−7.06 (m, 3H), 6.61 (s, 1H), 2.38 (s, 3H), 2.01 (s, 3H); 13C
{1H}NMR (100 MHz, CDCl3): δ = 143.8, 136.7, 134.5, 131.4, 130.8, 129.6, 127.2,
126.9, 126.2, 124.3, 21.6, 17.6 ppm; HRMS (ESI): m/z calcd for C14H16NO2S
[M+H]+: 262.0902, found: 262.0905.
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
Methyl-4-(4-methylphenylsulfonamido)benzoate (3ae).9c Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 3/2, v/v) afforded 3ae
1
as white solid in 86% yield (131 mg); m.p.: 166−168 °C; H NMR (400 MHz,
DMSOꢀd6): δ = 10.80 (s, 1H), 7.83 (d, J = 8.8 Hz 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.37
(d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 2.33 (s, 3H); 13C {1H}NMR
(100 MHz, DMSOꢀd6): δ = 165.6, 143.7, 142.4, 136.3, 130.6, 129.8, 126.7, 124.3,
118.1, 51.9, 20.9 ppm; HRMS (ESI): m/z calcd for C15H16NO4S [M+H]+: 306.0800,
found: 306.0803.
Methyl-3-(4-methylphenylsulfonamido)benzoate (3af).29 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 3/2, v/v) afforded 3af as
1
white solid in 95% yield (145 mg); m.p.: 152−154 °C (lit.: 152−154 °C); H NMR
(400 MHz, DMSOꢀd6): δ = 10.50 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H),
7.62−7.60 (m, 1H), 7.41ꢀ7.34 (m, 4H), 3.82 (s, 3H), 2.32 (s, 3H); 13C {1H}NMR (100
MHz, DMSOꢀd6): δ = 165.6, 143.5, 138.3, 136.3, 130.5, 129.8, 129.7, 126.6, 124.5,
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
124.2, 120.0, 52.2, 20.9 ppm; HRMS (ESI): m/z calcd for C15H16NO4S [M+H]+:
306.0800, found: 306.0805.
7
8
9
Methyl-2-(4-methylphenylsulfonamido)benzoate (3ag).30 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 1/1, v/v) afforded 3ag
as white solid in 80% yield (122 mg); m.p.: 110−112 °C (lit.: 115−116 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 10.43 (s, 1H), 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.70 (d, J =
8.4 Hz, 2H), 7.57 (td, J = 7.8, 1.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0
Hz, 2H), 7.16 (td, J = 7.6, 0.8 Hz, 1H), 3.83 (s, 3H), 2.33 (s, 3H); 13C {1H}NMR
(100MHz, DMSOꢀd6): δ = 167.6, 144.0, 138.8, 135.7, 134.4, 131.0, 129.8, 126.9,
123.8, 119.7, 117.6, 52.6, 20.9 ppm; HRMS (ESI): m/z calcd for C15H16NO4S [M+H]+:
306.0800, found: 306.0801.
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-Mesityl-4-methylbenzenesulfonamide (3ah).31 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10/1, v/v) afforded 3ah
as white solid in 57% yield (82 mg); m.p. = 136−138 °C; 1H NMR (400 MHz, CDCl3):
δ = 7.64 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 6.85 (s, 2H), 5.93 (s, 1H), 2.45
(s, 3H), 2.27 (s, 3H), 2.02 (s, 6H); 13C {1H}NMR (100 MHz, CDCl3): δ = 143.5,
137.9, 137.6, 137.5, 130.0, 129.6, 129.5, 127.2, 21.6, 20.9, 18.6 ppm; HRMS (ESI):
m/z calcd for C16H20NO2S [M+H]+: 290.1215, found: 290.1213.
N-(4-Chlorophenyl)-4-methylbenzenesulfonamide (3ai).32 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3ai as
1
white solid in 93% yield (131 mg); m.p.: 118−119 °C (lit.: 118−119 °C); H NMR
(400 MHz, DMSOꢀd6): δ = 10.40 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
9
2H), 7.31 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 2.33 (s, 3H); 13C {1H}NMR
(100MHz, DMSOꢀd6): δ = 143.4, 136.8, 136.2, 129.7, 129.1, 128.0, 126.7, 121.4, 20.9
ppm; HRMS (ESI): m/z calcd for C13H13ClNO2S [M+H]+: 282.0356, found:
282.0355.
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 reaction was also carried out on a larger scale following the general procedure.
A mixture of sodium pꢀtoluenesulfinate (1a) (5.34 g, 0.03 mol), pꢀnitrochlorobenzene
(2i) (3.151 g, 0.02 mol), NaHSO3 (6.24 g, 0.06 mol), FeCl2 (0.253g, 10 mol%) and
transꢀN,N’ꢀdimethylꢀ1,2ꢀdiaminocyclohexane (0.568 g, 20 mol%) in DMSO (50 mL)
were stirred at 60 °C for 20 h in a sealed tube under argon atmosphere, purification by
the general procedure , the product was obtained in 85% yield (4.789 g).
N-(3-Chlorophenyl)-4-methylbenzenesulfonamide (3aj).28 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3aj as
1
white solid in 96% yield (135 mg); m.p.: 135−137 °C (lit.: 135−137 °C); H NMR
(400 MHz, CDCl3): δ = 7.70 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.17−6.89
(m, 5H), 2.39 (s, 3H); 13C {1H}NMR (100 MHz, CDCl3): δ = 144.3, 137.8, 135.8,
134.9, 130.3, 129.8, 127.3, 125.3, 121.0, 119.0, 21.6 ppm; HRMS (ESI): m/z calcd for
C13H13ClNO2S [M+H]+: 282.0356, found: 282.0356.
N-(4-(4-Methylphenylsulfonamido)phenyl)acetamide (3ak).33 Purification by
column chromatography on silica gel (petroleum ether/ethyl acetate = 3/1, v/v)
afforded 3ak as white solid in 90% yield (137 mg); m.p.: 184−185 °C (lit.: 184 °C);
1H NMR (400 MHz, DMSOꢀd6): δ = 9.98 (s, 1H), 9.83 (s, 1H), 7.60 (d, J = 8.4 Hz,
2H), 7.41 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 2.32
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(s, 3H), 1.98 (s, 3H); 13C {1H}NMR (100 MHz, DMSOꢀd6): δ = 168.0, 143.0, 136.6,
135.9, 132.5, 129.5, 126.7, 121.4, 119.7, 23.8, 20.9 ppm; HRMS (ESI): m/z calcd for
C15H17N2O3S [M+H]+: 305.0960, found: 305.0959.
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-(4-Methoxyphenyl)-4-methylbenzenesulfonamide (3al).28 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3al as
1
white solid in 85% yield (118 mg); m.p.: 114−116 °C (lit.: 114.5−115 °C); H NMR
(400 MHz, CDCl3): δ = 7.59 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.97 (dd, J
= 6.8, 2.0 Hz, 2H), 6.77 (dd, J = 6.8, 2.4 Hz, 2H), 6.33 (s, 1H), 3.76 (s, 3H), 2.39 (s,
3H); 13C {1H}NMR (100 MHz, CDCl3): δ = 157.9, 143.7, 136.0, 129.6, 129.0, 127.3,
125.4, 114.4, 55.4, 21.5 ppm; HRMS (ESI): m/z calcd for C14H16NO3S [M+H]+:
278.0851, found: 278.0854.
4-Methyl-N-(3-(trifluoromethyl)phenyl)benzenesulfonamide (3am).28 Purification
by column chromatography on silica gel (petroleum ether/ethyl acetate = 3/1, v/v)
afforded 3am as white solid in 98% yield (154 mg); m.p.: 94−95 °C (lit.:
1
94.5−96.5 °C); H NMR (400 MHz, DMSOꢀd6): δ = 7.71 (d, J = 8.0 Hz, 2H),
13
7.36−7.24 (m, 6H), 7.15 (s, 1H), 2.39 (s, 3H); C {1H}NMR (100 MHz, DMSOꢀd6):
δ = 144.5, 137.3, 135.6, 131.8 (q, JCꢀF = 32.5 Hz), 130.0, 129.9, 127.3, 124.9, 123.5 (q,
JCꢀF = 271 Hz), 121.7 (q. JCꢀF = 3.8 Hz), 117.6 (q, JCꢀF = 3.8 Hz), 21.5 ppm; HRMS
(ESI): m/z calcd for C14H13F3NO2S [M+H]+: 316.0619, found: 316.0617.
N-(4-Cyanophenyl)-4-methylbenzenesulfonamide (3an).8b Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 2/1, v/v) afforded 3an
1
as white solid in 97% yield (132 mg); m.p.: 183−184 °C (lit.: 180 °C); H NMR (400
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
MHz, CDCl3): δ = 7.77 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H),
7.29 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 2.40 (s, 3H); 13C {1H}NMR (100
MHz, CDCl3): δ = 144.9, 141.0, 135.5, 133.6, 130.1, 127.3, 119.3, 118.5, 107.7, 21.6
ppm; HRMS (ESI): m/z calcd for C14H13N2O2S [M+H]+: 273.0698, found: 273.0699.
4-(4-Methylphenylsulfonamido)benzoic acid (3ao).34 Purification by column
chromatography on silica gel (dichloromethane/methanol = 5/1, v/v) afforded 3ao as
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
white solid in 78% yield (113 mg); m.p.: 230−232 °C (lit.: 230−232 °C); H NMR
(400 MHz, DMSOꢀd6): δ = 12.74 (s, 1H), 10.74 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.72
(d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 2.33 (s, 3H);
13C {1H}NMR (100 MHz, DMSOꢀd6): δ = 166.7, 143.6, 142.0, 136.4, 130.7, 129.8,
126.7, 125.5, 118.0, 20.9 ppm; HRMS (ESI): m/z calcd for C14H14NO4S [M+H]+:
292.0644, found: 292.0641.
N-(3-Acetylphenyl)-4-methylbenzenesulfonamide (3ap).35 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 2/1, v/v) afforded 3ap
1
as white solid in 84% yield (121 mg); m.p.:129−131 °C (lit.: 129 °C); H NMR (400
MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 3H), 7.62 (s, 1H), 7.40−7.33 (m, 2H), 7.24 (d,
J = 8.0 Hz, 2H), 7.10 (s, 1H), 2.55 (s, 3H), 2.37 (s, 3H); 13C {1H}NMR (100 MHz,
CDCl3): δ = 197.4, 144.2, 138.1, 137.3, 135.9, 129.8, 129.7, 127.3, 125.6, 125.1,
120.7, 26.7, 21.5 ppm; HRMS (ESI): m/z calcd for C15H16NO3S [M+H]+: 290.0851,
found: 290.0853.
N-(4-Formylphenyl)-4-methylbenzenesulfonamide (3aq).8b Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 2/1, v/v) afforded 3aq
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
as white solid in 75% yield (103 mg); m.p.: 186−188 °C (lit.: 190.8−191.5 °C); H
NMR (400 MHz, DMSOꢀd6): δ = 10.95 (s, 1H), 9.81 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H),
7.76 (d, J= 8.4 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 2.33 (s,
3H); 13C {1H}NMR (100 MHz, DMSOꢀd6): δ = 191.5, 143.8, 143.5, 136.3, 131.3,
131.1, 129.9, 126.7, 118.0, 20.93 ppm; HRMS (ESI): m/z calcd for C14H14NO3S
[M+H]+: 276.0694, found: 276.0690.
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-N-(naphthalen-1-yl)benzenesulfonamide (3ar).36 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3ar
1
as white solid in 51% yield (76 mg); m.p.: 143−145 °C (lit.: 143−145 °C); H NMR
(400 MHz, CDCl3): δ = 7.86ꢀ7.79 (m, 2H), 7.71 (d, J = 6.4 Hz, 1H), 7.65 (d, J = 8.0
13
Hz, 2H), 7.46−7.33 (m, 4H), 7.16 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 2.33 (s, 3H); C
{1H}NMR (100 MHz, CDCl3): δ = 143.8, 136.4, 134.2, 131.5, 129.6, 128.9, 128.4,
127.4, 127.2, 126.6, 126.3, 125.4, 122.7, 121.5, 21.5 ppm; HRMS (ESI): m/z calcd
for C17H16NO2S [M+H]+: 298.0902, found: 298.0903.
4-Methyl-N-(pyridin-3-yl)benzenesulfonamide (3as).8b Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 1/1, v/v) afforded 3as
as white solid in 93% yield (115 mg); m.p.: 191−192 °C (lit.: 192−194 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 10.49 (s, 1H), 8.28−8.24 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H),
7.51 (dt, J = 8.4, 2.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.4, 4.4 Hz, 1H),
2.34 (s, 3H); 13C {1H}NMR (100 MHz, DMSOꢀd6): δ = 145.2, 143.6, 141.6, 136.2,
134.4, 129.8, 127.2, 126.7, 123.9, 20.9 ppm; HRMS (ESI): m/z calcd for
C12H13N2O2S [M+H]+: 249.0698, found: 249.0696.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
N-Phenylbenzenesulfonamide (3ba).28 Purification by column chromatography on
silica gel (petroleum ether/ethyl acetate = 6/1, v/v) afforded 3ba as white solid in 93%
7
8
9
1
yield (108 mg); m.p.: 105−106 °C (lit.: 110−111 °C); H NMR (400 MHz, CDCl3): δ
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
= 7.79 (d, J = 8.0 Hz, 2H), 7.55−7.51 (m, 1H), 7.43 (td, J = 6.8, 1.6 Hz, 2H), 7.24 (td,
J = 6.8, 1.6 Hz, 2H), 7.13−7.06 (m, 3H), 6.85 (s, 1H); 13C {1H}NMR (100 MHz,
CDCl3): δ = 139.0, 136.3, 133.0, 129.4, 129.0, 127.2, 125.5, 121.8 ppm; HRMS (ESI):
m/z calcd for C12H12NO2S [M+H]+: 234.0589, found: 234.0591.
N-(p-Tolyl)benzenesulfonamide (3bb).37 Purification by column chromatography
on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3bb as white solid in
1
86% yield (106 mg); m.p.: 116−118 °C (lit.: 118−120 °C); H NMR (400 MHz,
DMSOꢀd6): δ = 10.12 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.62−7.52 (m, 3H), 7.03−6.95
(m, 4H), 2.18 (s, 3H); 13C {1H}NMR (100 MHz, DMSOꢀd6): δ = 140.0, 135.4, 133.9,
133.2, 130.0, 129.6, 127.1, 121.1 ppm; HRMS (ESI): m/z calcd for C13H14NO2S
[M+H]+: 248.0745, found: 248.0746.
N-(4-Chlorophenyl)benzenesulfonamide
(3bi).9b
Purification
by
column
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3bi as
white solid in 91% yield (121 mg); m.p.: 120−121 °C (lit.: 122−123 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 10.46 (s, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.64−7.55 (m, 3H),
7.32 (d, J = 8.4 Hz, 2H), 7.12−7.10 (d, J = 8.8 Hz, 2H); 13C {1H}NMR (100 MHz,
DMSOꢀd6): δ = 144.4, 141.9, 138.3, 134.6, 134.4, 133.4, 131.8, 126.8 ppm; HRMS
(ESI): m/z calcd for C12H11ClNO2S [M+H]+: 268.0199, found: 268.0195.
4-Methoxy-N-phenylbenzenesulfonamide (3ca).38 Purification by column
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3ca
as white solid in 92% yield (121 mg); m.p.: 107−108 °C (lit.: 109−110 °C); 1H NMR
(400 MHz, CDCl3): δ = 7.72 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 8.0 Hz, 2H), 7.12 (d, J =
7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 3.82 (s,
3H); 13C {1H}NMR (100 MHz, CDCl3): δ = 163.1, 136.6, 130.6, 129.4, 129.3, 125.4,
121.7, 114.2, 55.6 ppm; HRMS (ESI): m/z calcd for C13H14NO3S [M+H]+: 264.0694,
found: 264.0694.
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
2,4,6-Trimethyl-N-phenylbenzenesulfonamide (3da).9c Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/v) afforded 3da
as white solid in 31% yield (43 mg); m.p.: 97−99 °C; 1H NMR (400 MHz, CDCl3): δ
= 7.21 (t, J = 8.0 Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 2H), 6.91 (s,
13
2H), 6.76 (s, 1H), 2.60 (s, 6H), 2. 27 (s, 3H); C {1H}NMR (100 MHz, CDCl3): δ =
142.6, 139.3, 136.5, 133.4, 132.1, 129.3, 125.2, 121.4, 23.0, 21.0 ppm; HRMS (ESI):
m/z calcd for C15H18NO2S [M+H]+: 276.1058, found: 276.1060.
4-Fluoro-N-phenylbenzenesulfonamide (3ea).39 Purification
by
column
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3ea
as white solid in 85% yield (107 mg); m.p.: 109−111 °C (lit.: 109−111 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 10. 30 (s, 1H), 7.83−7.79 (m, 2H), 7.41−7.37 (m, 2H),
7.26−7.22 (m, 2H), 7.10ꢀ7.02(m, 3H); 13C {1H}NMR (100 MHz, DMSOꢀd6): δ =
165.5 (d, JCꢀF = 250 Hz), 137.4, 135.8 (d, JCꢀF = 3 Hz), 129.7 (d, JCꢀF = 9.6 Hz), 129.2,
124.3, 120.3, 116.5 (d, JCꢀF = 22.6 Hz) ppm; HRMS (ESI): m/z calcd for
C12H11FNO2S [M+H]+: 252.0495, found: 252.0496.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
4-Chloro-N-phenylbenzenesulfonamide (3fa).39
Purification
by
column
5
6
7
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3fa as
8
9
1
white solid in 89% yield (119 mg); m.p.: 104−105 °C (lit.: 104−105 °C); H 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
(400 MHz, DMSOꢀd6): δ = 10.36 (s, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz,
2H), 7.25 (t, J = 8.0 Hz, 2H), 7.10−7.03 (m, 3H); 13C {1H}NMR (100 MHz,
DMSOꢀd6): δ = 138.3, 137.7, 137.3, 129.4, 129.2, 128.6, 124.4, 120.4 ppm; HRMS
(ESI): m/z calcd for C12H11ClNO2S [M+H]+: 268.0199, found: 268.0194.
4-Bromo-N-phenylbenzenesulfonamide (3ga).39
Purification
by
column
chromatography on silica gel (petroleum ether/ethyl acetate = 4/1, v/v) afforded 3ga
as white solid in 91% yield (142 mg); m.p.: 116−117 °C (lit.: 116−117 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 10.36 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz,
2H), 7.24 (t, J = 7.6 Hz, 2H), 7.10−7.03 (m, 3H); 13C {1H}NMR (100 MHz,
DMSOꢀd6): δ = 138.7, 137.3, 132.3, 129.2, 128.6, 126.7, 124.4, 120.3 ppm; HRMS
(ESI): m/z calcd for C12H11BrNO2S [M+H]+: 311.9694, found: 311.9690.
4-Amino-N-phenylbenzenesulfonamide (3ha).40 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 1/1, v/v) afforded 3ha
as white solid in 84% yield (104 mg); m.p.: 180−182 °C (lit.: 180−181 °C); 1H NMR
(400 MHz, DMSOꢀd6): δ = 9.84 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.6 Hz,
2H), 7.07 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 2H), 5.95
(s, 2H); 13C {1H}NMR (100 MHz, DMSOꢀd6): δ = 152.8, 138.5, 128.9, 128.7, 124.4,
123.2, 119.4, 112.5 ppm; HRMS (ESI): m/z calcd for C12H13N2O2S [M+H]+:
249.0698, found: 249.0701.
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
N-Phenylthiophene-2-sulfonamide (3ia).41 Purification by column chromatography
on silica gel (petroleum ether/ethyl acetate = 6/1, v/v) afforded 3ia as white solid in
7
8
9
1
94% yield (112 mg); m.p.: 80−82 °C; H NMR (400 MHz, CDCl3): δ = 7.54 (dd, 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
4.8, 1.2 Hz, 1H), 7.50 (dd, J = 3.6, 1.2 Hz, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.18−7.13 (m,
3H), 7.00 (dd, J = 5.2, 4.0 Hz, 1H), 6.90 (s, 1H); 13C {1H}NMR (100 MHz, CDCl3): δ
= 139.4, 136.1, 132.9, 132.5, 129.4, 127.3, 125.9, 121.9 ppm; HRMS (ESI): m/z calcd
for C10H10NO2S2 [M+H]+: 240.0153, found: 240.0150.
N-(Pyridin-3-yl)thiophene-2-sulfonamide (3is).42 Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate = 2/1, v/v) afforded 3is as
white solid in 81% yield (97 mg); m.p.: 182−184 °C; 1H NMR (400 MHz, DMSOꢀd6):
δ = 10.71 (s, 1H), 8.32 (d, J = 4.8 Hz, 2H), 7.94 ((d, J = 4.8 Hz, 2H), 7.59−7.55 (m,
2H), 7.36 (dd, J = 8.0, 4.4 Hz, 1H), 7.14 (t, J = 4.4 Hz, 1H); 13C {1H}NMR (100 MHz,
DMSOꢀd6): δ = 146.1, 142.5, 139.8, 134.6, 134.3, 133.3, 128.3, 124.5 ppm; HRMS
(ESI): m/z calcd for C9H9N2O2S2 [M+H]+: 241.0105, found: 241.0101.
N-Phenyl-N-tosylhydroxylamine (7).26 m.p.:138−140 °C (lit.: 142−143 °C); 1H NMR
(400 MHz, CDCl3): δ = 7.45 (t, J = 8.4 Hz, 2H), 7.31−7.22 (m, 5H), 7.29−7.18 (m,
13
2H); C {1H}NMR (100MHz, CDCl3): δ = 145.0, 141.6, 129.9, 129.0, 128.9, 128.2,
127.4, 123.0, 21.7 ppm; HRMS (ESI): m/z calcd for C13H14NO3S [M+H]+: 264.0694,
found: 264.0690.
Author Information
Corresponding Authors
*Eꢀmail: luomm@scu.edu.cn
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
Acknowledgements
5
6
7
8
We gratefully acknowledge the National Natural Science Foundation of China
(21321061, 21072134 and J1103315/J0104) for financial support, and the
Comprehensive Training Platform of Specialized Laboratory, College of Chemistry,
Sichuan University for NMR and MS measurements.
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
Supporting Information. The details of controlling experiments for the mechanistic
1
13
investigation. Copies of H NMR and C NMR spectra of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
(1) Smith, D. A.; Jones, R. M. Curr. Opin. Drug Discovery Dev. 2008, 11, 72–79.
(2) (a) Hansch, C.; Sammes, P. G.; Taylor, J. B. Comprehensive Medicinal
Chemistry; Pergamon Press: Oxford, 1990; Vol. 2, Chapter 7, pp 255. (b) Drew, J.
Science 2000, 287, 1960–1964.
(3) For selected examples, see: (a) Caddick, S. J.; Wilden, D.; Judd, D. B. J. Am.
Chem. Soc. 2004, 126, 1024–1025. (b) DeBergh, J. R.; Niljianskul, N.; Buchwald,
S. L. J. Am. Chem. Soc. 2013, 135, 10638–10641.
(4) For selected examples, see: (a) Nishikawa, M.; Inaba, Y.; Furukawa, M. Chem.
Pharm. Bull. 1983, 31, 1374–1377. (b) Tang, X. D.; Huang, L. B.; Qi, C. R.; Wu,
X.; Wu, W. Q.; Jiang, H. F. Chem. Commun. 2013, 49, 6102–6104.
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
(5) Skipper, P. L.; Kim, M. Y.; Sun, H. L.; Wogan, N.; Tannenbaum, S. R.
5
6
7
Carcinogenesis 2010, 31, 50–58.
8
9
(6) For selected examples, see: (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043–6048. (b) Baffoe, J.; Hoe, M. Y.; Toure, B. B. Org. Lett. 2010, 12,
1532–1535. (c) Rosen, B. R.; Ruble, J. C.; Beauchamp, T. J.; Navarro, A. Org.
Lett. 2011, 13, 2564–2567. (d) Tan, B. Y.ꢀH.; Teo, Y.ꢀC.; Seow, A.ꢀH. Eur. J.
Org. Chem. 2014, 1541–1546.
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
(7) For selected examples, see: (a) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki,
M. Angew. Chem. Int. Ed. 2007, 46, 409–413. (b) Shi, F.; Tse, M. K.; Zhou, S.;
Pohl, M.ꢀM.; Radnik, J.; Hübner, S.; Jähnisch, K.; Brückner, A.; Beller, M. J. Am.
Chem. Soc. 2009, 131, 1775–1779. (c) Shi, F.; Tse, M. K.; Cui, X.; Gӧrdes, D.;
Michalik, D.; Thurow, K.; Deng, Y.; Beller, M. Angew. Chem. Int. Ed. 2009, 48,
5912–5915. (d) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. J. Org.
Chem. 2011, 76, 2328–2331. (e) Yu, X. C.; Liu, C. Z.; Jiang, L.; Xu, Q. Org. Lett.
2011, 13, 6184–6187. (f) Qu, P.; Sun, C.; Ma, J.; Li, F. Adv. Synth. Catal. 2014,
356, 447–459.
(8) For selected examples, see: (a) Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 16720–16734. (b) Shekhar, S.;
Dunn, T. B.; Kotecki, B. J.; Montavon, D. K.; Cullen, S. C. J. Org. Chem. 2011,
76, 4552–4563.
(9) For selected examples, see: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon,
S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (b) Pan, C.; Cheng, J.;
ACS Paragon Plus Environment