Copper-catalyzed synthesis of sulfonamides from nitroarenes: Via the insertion of sulfur dioxide

Article abstract of DOI:10.1039/d0cc00721h

Nitroarenes are used as the coupling partners in the preparation of sulfonamides via the insertion of sulfur dioxide. A three-component reaction of arylboronic acids, nitroarenes, and potassium metabisulfite under copper catalysis proceeds smoothly, giving rise to a range of sulfonamides in good to excellent yields with broad substrate scope. Various functional groups including hydroxyl, cyano, amino, and carbonyl are all tolerated. A plausible mechanism is proposed, showing that arylsulfinate is the intermediate and the copper-assisted interaction of the nitroarene and arylsulfinate is the key step. This approach is also extended to the late-stage modification of a currently marketed drug (flutamide).

Full text of DOI:10.1039/d0cc00721h

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DOI: 10.1039/D0CC00721H
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Copper-catalyzed synthesis of sulfonamides from nitroarenes with
the insertion of sulfur dioxide
Xuefeng Wang,a Min Yang,b Yunyan Kuang,a Jin-Biao Liu,c Xiaona Fan,*b and Jie Wu*d
Received 00th January 20xx,
Accepted 00th January 20xx
Nitroarenes are used as the coupling partner in the preparation of sulfonamides via the insertion of sulfur dioxide. A three-
component reaction of arylboronic acids, nitroarenes, and potassium metabisulfite under copper catalysis proceeds
smoothly, giving rise to a range of sulfonamides in good to excellent yields with broad substrate scope. Various functional
groups including hydroxyl, cyano, amino, and carbonyl are all tolerated. A plausible mechanism is proposed, showing that
arylsulfinate is the intermediate and the copper-assisted interaction of nitroarene and arylsulfinate is the key step. This
approach is also extended to the late-stage modification of current marketed drug (Flutamide).
DOI: 10.1039/x0xx00000x
www.rsc.org/
It is known that nitroarenes are basic raw chemical materials, which In the past few years, incorporation of sulfonyl unit into small
are well applied in the fields of pharmaceuticals, pesticide, and dye molecules via the insertion of sulfur dioxide under metal catalysis or
industries. They can be easily accessed through the nitration of through radical process has developed.10,11 For example, we
arenes.1 So far, the applications of nitroarenes have been extensively disclosed a palladium-catalyzed three-component coupling of
explored in synthetic chemistry. For instance, the Sandmeyer-type arylboronic acids, sulfur dioxide and hydrazines,11a and subsequently
reactions of anilines originated from nitroarenes could afford many reported the first example by using potassium metabisulfite as the
functionalized haloarenes. Recently, using nitroarenes as the aryl source of sulfur dioxide.11b Sulfonamides could also be obtained via
sources in metal-catalyzed cross-coupling reactions were developed
a
one-pot process through
a
reaction of aryldiazonium
as well, although the inertness of C−N bond toward oxidative tetrafluoroborates, DABCO·(SO2)2 and amines in the presence of N-
addition hampered its further development.2 For example, synthesis hydroxybenzotrizole,11c
or
through
a
copper-catalyzed
of aromatic ethers through C−O coupling of electron-deficient aminosulfonylation
of
aryldiazonium
tetrafluoroborates,
nitroarenes and arylboronic acids by using rhodium or nano-sized DABCO·(SO2)2 and N-chloroamines.11d Willis and co-workers
copper catalyst was described.3 Nakao and co-workers reported the described
a copper-catalyzed three-component synthesis of
hydrodenitration, Suzuki coupling, and Buchwald−Hartwig amination sulfonamides from arylboronic acids at high temerpature.11e Jiang
of nitroarenes under palladium catalysis by using Buchwald biaryl and co-workers reported the construction of primary sulfonamides
monophosphines (BrettPhos) as the ligand.4 Chen and co-workers through a reaction of aryldiazonium tetrafluoroborates, sodium
disclosed the preparation of diarylamines and N-alkylanilines via a metabisulfite and sodium azide in the presence of large excess
palladium/NHC-catalyzed dinitrative C−N coupling of nitroarenes amount of triphenylphosphine.11f Synthesis of sulfonamides through
and amines.5
a
copper-catalyzed reaction of triarylbismuthines, sodium
metabisulfite, and nitro compounds was developed by using deep
eutectic solvent as a reaction medium, as reported by Guillena and J.
Ramón.11g This is a breakthrough for the transformation of
nitroarenes, which combine with sulfur dioxide under copper
catalysis. Encouraged by these results and prompted by the recent
progress for the metal-catalyzed cross-coupling reactions of
nitroarenes, we envisioned that nitroarenes might be used as the
coupling partner with arylboronic acids in the preparation of
sulfonamides via the insertion of sulfur dioxide. Herein, we report a
three-component reaction of arylboronic acids, nitroarenes, and
potassium metabisulfite under copper catalysis, giving rise to a range
of sulfonamides in good to excellent yields with broad substrate
scope. Various functional groups including hydroxyl, cyano, amino,
and carbonyl are all tolerated. A plausible mechanism is proposed,
showing arylsulfinate is the intermediate and the copper-assisted
interaction of nitroarene and arylsulfinate is the key step.
A recent focus of our laboratory has been centred on the synthesis
of sulfonyl-containing compounds through the insertion of sulfur
6
dioxide by using DABCO·(SO2)2
or potassium/sodium
metabisulfite.7,8 Since sulfonamides are broadly found in
pharmaceuticals and agrochemicals,9 we conceived that the
insertion of sulfur dioxide and the application of nitroarenes could
be combined, which would provide a rapid access to sulfonamides.
a. Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai
200438, China.
b. School of Pharmacy, Gannan Medical University, 1 Yixueyuan Road, Ganzhou
341000, China. Email: fxn918@126.com
c. School of Metallurgical and Chemical Engineering, Jiangxi University of Science
and Technology, Ganzhou 341000, China.
d. School of Pharmaceutical and Materials Engineering & Institute for Advanced Studies,
Taizhou University, 1139 Shifu Avenue, Taizhou 318000, China. Email:
jie_wu@fudan.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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At the outset, nitrobenzene 1a and 4-fluorobenzeneboronic
ChemComm
Under the optimized conditions as above,Vieaw ArraticnlegOenlionef
DOI: 10.1039/D0CC00721H
acid 2a were selected as model substrates for reaction nitroarenes 1 and arylboronic acids 2 were employed in the
development. After careful optimization of the reaction copper-catalyzed sulfur dioxide insertion reaction. The results
conditions (see SI for details), a “standard condition” was are showed in Table 2. It was found that the corresponding
established (Table 1). The corresponding product of 4-fluoro-N- sulfonamides were afforded in good to excellent yields with
phenylbenzenesulfonamide 3aa was obtained and isolated in broad substrate scope. Various functional groups including
77% yield with Cu(MeCN)4PF6 as catalyst and 1,10- hydroxyl, cyano, amino, and carbonyl were all tolerated under
phenanthroline as ligand (Table 1, entry 1). The reaction could the conditions. For example, product 3ai was afforded in 77%
not proceed without the addition of copper catalyst (Table 1, yield when 4-acetylphenylboronic acid was employed. 4-
entry 2). It should be noted that the loading amount of the Hydroxyphenylboronic acid reacted with nitrobenzene and
ligand was the half of copper catalyst, since either increasing potassium metabisulfite gave rise to the desired product 3c in
and decreasing the ligand dosage would make the reaction less 61% yield. Boc-protected amino group and nitro-containing
effective (Table 1, entries 3 and 4). Reducing the catalyst loading heterocycles were also compatible under the copper-catalyzed
also led to inferior results (Table 1, entry 5). During the conditions. With regards to nitroarenes, iodo, boronic ester,
investigation of the impact of different copper catalysts, the aldehyde and pyrrolyl-substitutions were all susceptible during
addition of Cu(MeCN)4PF6 gave the best result while reactions the transformation. Additionally, during our attempts to lower
with other copper catalysts showed lower yields (Table 1, the catalyst loading in gram-scale synthesis, product 3i was
entries 6 and 7). Moreover, isopropanol was employed as the obtained in 73% yield with 2 mol % of Cu(MeCN)4PF6 and 1 mol %
reductant in the coupling reaction because of its low cost and of ligand on 3.0 mmol scale (see ESI for details). However, the
ease of separation. The reaction performed less efficiently reaction time was prolonged to 96 h.
when isopropanol was omitted, indicating the indispensable
role of the reductant in the reaction (Table 1, entry 8). Only a Table 2. Copper-catalyzed three-component reaction of arylboronic
trace amount of product was observed when DABCO·(SO2)2 was acids, nitroarenes, and potassium metabisulfite.a
applied as the sulfur dioxide surrogate (Table 1, entry 9).
Reducing the amount of boronic acid to 2.0 equiv resulted in a
slightly lower yield (Table 1, entry 10). Additionally, both the
reaction solvent and temperature were critical for the success
of this transformation (Table 1, entries 11 and 12).
"standard conditions"
Cu(MeCN)4PF6 (20 mol %)
1,10-phenanthroline (10 mol %)
iPrOH (2.0 equiv), NMP
70 C, 48 h
K2S2O5
O
O
Ar NO2
1
2
Ar
S
N
+
(Het)Ar
H
(Het)Ar B(OH)2
3
3aa
3ab
3ac
3ad
3ae
: R = 4-F, 77%
: R = H, 72%
: R = 4-Me, 63%
: R = 3-Me, 56%
: R = 4-Cl, 82%
: R = 2-Me, 80%
3ah
: R = 3-Cl, 83%
O
O
Ph
S
3ai
3aj
: R = 4-COMe, 77%
: R = 4-CN, 75%
a
N
Table 1. Effects of variation of reaction parameters.
H
R
3ak
: R = 4-OMe, 71%
"standard conditions"
3al
: R = 4-Ph, 68%
3af
3ag
Cu(MeCN)4PF6 (20 mol %)
1,10-phenanthroline (10 mol %)
O
O
3am: R = 4-CO2Me, 75%
K2S2O5
Ph NO2 1a
: R = 4-Br, 80%
Ph
S
N
+
iPrOH (2.0 equiv), NMP
70 C, 48 h
Cl
H
Cl
p-FC6H4 B(OH)2 2a
O
O
F
3aa
O
O
O
O
S
S
S
N
N
N
H
H
H
Entry
1
Variation from “standard conditions”
none
Yield (%)b
87 (77)
trace
46
N
R
3b
3c
, R = NHBoc, 61%
, R = OH, 61%
3an
, 68%
3d
, 44%
Cl
2
No Cu(MeCN)4PF6
3f
: Ar = p-MeC6H4, 80%
O
O
O
O
3g
3h
3i
3j
: Ar = m-MeC6H4, 66%
: Ar = o-MeC6H4, 56%
: Ar = p-ClC6H4, 92%
: Ar = m-ClC6H4, 89%
S
Ar
S
N
3
No 1,10-phenanthroline
N
H
H
4
20% of 1,10-phenanthroline instead of 10%
10% Cu(MeCN)4PF6 and 5% ligand
CuCl instead of Cu(MeCN)4PF6
Cu(OTf)2 instead of Cu(MeCN)4PF6
No iPrOH
33
N
H
Cl
5
64
3e
3k
: Ar = p-FC6H4, 87%
, 90%
O
6
41
O
O
O
3l
: Ar = p-CHOC6H4, 76%
7
63
S
S
Ar
N
N
3m
3n
: Ar = p-BrC6H4, 87%
: Ar = p-IC6H4, 86%
H
H
8
42
N
Cl
Cl
9
DABCO·(SO2)2 instead of K2S2O5
2.0 equiv ArB(OH)2 instead of 3.0 equiv
DMAc instead of NMP
trace
71
3o
, 61%
BPin
N
10
11
12
O
O
O
O
S
S
73
N
N
H
H
60 oC instead of 70 oC
49
Cl
Cl
3q
, 45%
3p
, 71%
a
Standard conditions: nitrobenzene 1a (0.2 mmol, 1.0 equiv), 4-
fluorobenzeneboronic acid 2a (0.6 mmol, 3.0 equiv), K2S2O5 (0.6 mmol,
a Isolated yield based on nitroarene 1.
3.0 equiv), isopropanol (0.4 mmol, 2.0 equiv), Cu(MeCN)4PF6 (20 mol %),
o
1,10-phenanthroline (10 mol %), NMP (2.0 mL), 70 C, 48 h. b 19F NMR
This approach was further extended to the late-stage
modification of current marketed pharmaceuticals. For
instance, Flutamide (an anti-prostatic cancer drug) reacted with
4-chlorophenylboronic acid and potassium metabisulfite under
yield using 4-fluoroanisole as internal standard. Isolated yield of entry 1
is shown in parentheses.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx

Page 3 of 5
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Communication
the standard conditions leading to the corresponding product assistance of transition metal,12 a plausible mecVihewanAritsicmle Ownlianes
DOI: 10.1039/D0CC00721H
4a in 75% yield (Scheme 1).
proposed in Scheme 3. At the beginning, arylboronic acid 2
would be converted into the arylsulfinate intermediate D by the
developed copper-phenanthroline catalytic system in the
presence of the sulfur dioxide surrogate (A-B-C-D).11e,13 The
successive trapping of the generated arylsulfinate D by free
Cu(I) species and nitroarene would construct the S-N bond
giving rise to the key intermediate F, which would be
protonated to afford intermediate G. Subsequently, reduction
H
H
N
CF3
N
CF3
K2S2O5
standard conditions
O
+
NH
S
O
NO2 p-ClC6H4 B(OH)2
O
Flutamide
an anti-prostatic cancer drug
O
4a,
75%
Cl
Scheme 1. Late-stage modification of Flutamide
of intermediate
G
by isopropanol would produce
sulfonylhydroxylamine H, and the final product 3 would be
provided by further reduction. It was found that S(VI) sulfuric
species could be detected in the reaction mixture, indicating
that some S(IV) species might serve as the reductant in the
To gain more insight into the mechanism of this reaction,
several control experiments were performed as shown in
Scheme 2. Only a trace amount of product 3aa was detected
when nitrosobenzene 5 was employed as a replacement of
nitrobenzene 1a in the reaction of 4-fluorobenzeneboronic acid
2a with potassium metabisulfite under the standard conditions
(Scheme 2, eq a). No reaction occurred when aniline 6 was used
instead (Scheme 2, eq b). Interestingly, the reaction proceeded
smoothly to afford the desired product 3aa when 4-
fluorophenylsulfinate was utilized as the substrate in the
copper-catalyzed reaction with or without the addition of 1,10-
phenanthroline (Scheme 2, eq c and d), indicating the
unnecessity of phenanthroline ligand in the process of S-N bond
construction. The reaction of nitrobenzene 1a, 4-
fluorobenzeneboronic acid 2a and potassium metabisulfite in
HFIP worked efficiently as well, giving rise to product 3aa in 61%
yield with the release of hexafluoropropan-2-one (Scheme 2, eq
e). From these results, it seemed that the reaction pathway
didn’t include the reduction of nitrobenzene to nitrosobenzene
5 or aniline 6.
i
whole process.11g,12 However, PrOH was a better reductant
than the S(IV) species themselves in the reaction, giving rise to
a higher yield.
2-
F
G
OH
N
Cu
SO2SO3
Ar1
O
S
O
S
H+
-Cu+
O
S
O
N
O
O
LnCu
O
O
O
Ar2
O
S
Ar1
Ar2
O
Ar1
B
2-
SO3
O
LnCu Ar1
LnCu SO2Ar1
-H2O
-Me2CO
iPrOH
Ar2
A
O
C
N
O
1
O
Ar1
O
LnCu+
S
S
Ar2
N
Ar1 B(OH)2
Ar1
O
Cu+
Ar1
O
H
S
Cu
OH
S
2
O
O
-H2O
-Me2CO
iPrOH
D
E
O
Ar1
O
Ar2
N
3
H
Scheme 3. Plausible mechanism
Cu(MeCN)4PF6 (20 mol %)
5
B(OH)2
Ph NO
K2S2O5
1,10-phenanthroline (10 mol %)
+
3aa,
3aa,
trace (a)
In conclusion, we have discovered that nitroarenes can be
used as the coupling partner in the preparation of sulfonamides
via the insertion of sulfur dioxide. This three-component
reaction of arylboronic acids, nitroarenes, and potassium
metabisulfite under copper catalysis proceeds smoothly, giving
rise to a range of sulfonamides in good to excellent yields with
broad substrate scope. Various functional groups including
hydroxyl, cyano, amino, and carbonyl are all tolerated. A
plausible mechanism is proposed, showing arylsulfinate is the
intermediate and the copper-assisted interaction of nitroarene
and arylsulfinate is the key step. This approach is also extended
to the late-stage modification of current marketed drug
(Flutamide).
iPrOH (2.0 equiv), NMP
70 C, 48 h
2a
F
F
Cu(MeCN)4PF6 (20 mol %)
1,10-phenanthroline (10 mol %)
6
B(OH)2
Ph NH2
K2S2O5
+
n.d.
(b)
iPrOH (2.0 equiv), NMP
70 C, 48 h
2a
Cu(MeCN)4PF6 (20 mol %)
1,10-phenanthroline (10 mol %)
1a
SO2Na
Ph NO2
K2S2O5
+
(c)
(d)
3aa,
3aa,
59%
iPrOH (2.0 equiv), NMP
70 C, 48 h
7
F
Cu(MeCN)4PF6 (20 mol %)
no 1,10-phenanthroline
1a
SO2Na
Ph NO2
K2S2O5
+
63%
61%
iPrOH (2.0 equiv), NMP
70 C, 48 h
7
F
Financial support from National Natural Science Foundation
of China (Nos. 21871053 and 21532001) is gratefully
acknowledged.
Cu(MeCN)4PF6 (20 mol %)
1,10-phenanthroline (10 mol %)
3aa,
+
1a
B(OH)2
Ph NO2
K2S2O5
(e)
+
O
HFIP (2.0 equiv), NMP
70 C, 48 h
2a
F
39%
Conflicts of interest
There are no conflicts to declare.
F3C
CF3
Scheme 2. Investigation of the mechanism
Notes and references
On the basis of the above results and inspired by the
previous reports that the S-N bond could be formed by the
interaction of sulfinate species with nitro group with the
1
(a) N. Ono, The Nitro Group in Organic Synthesis, 1st Edition;
Wiley−VCH: New York, 2001. (b) C. Ma, F. Jiang, F.-T. Sheng, Y. Jiao,
G.-J. Mei and F. Shi, Angew. Chem. Int. Ed. 2019, 58, 3014; (c) D. Ren,
This journal is © The Royal Society of Chemistry 20xx
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ChemComm
View Article Online
DOI: 10.1039/D0CC00721H
Copper-catalyzed synthesis of sulfonamides from nitroarenes
with the insertion of sulfur dioxide
Xuefeng Wang, Min Yang, Yunyan Kuang, Jin-Biao Liu, Xiaona Fan,* and Jie Wu*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
Graphical Abstract
O
O
Ar
S
Cu
(Het)Ar B(OH)2
Ar NO2
+
K2S2O5
+
N
(Het)Ar
H
up to 97% yield
synthesis of sulfonamides from nitroarenes
copper-catalyzed three-cmponent reaction
insertion of sulfur dioxide
A three-component reaction of arylboronic acids, nitroarenes, and potassium metabisulfite under copper catalysis proceeds
smoothly, giving rise to a range of sulfonamides in good to excellent yields with broad substrate scope. This approach is also
extended to the late-stage modification of current marketed drug (Flutamide).