Straightforward Sulfonamidation via Metabisulfite-Mediated Cross Coupling of Nitroarenes and Boronic Acids under Transition-Metal-Free Conditions?

Article abstract of DOI:10.1002/cjoc.202000198

A straightforward multicomponent sulfonamidation of nitroarenes, sodium metabisulfite and boronic acids was established under transition-metal-free conditions to access diverse sulfonamides from readily available and low-cost materials modularly. Inorganic salt sodium metabisulfite not only served as a sulfur dioxide source, but also played a key role for both activator and reductant during sulfonamidation. Notably, naturally occurring biomolecules and pharmaceuticals with multiple heteroatoms and sensitive functional groups were intensively investigated in this transformtion providing versatile sulfonamides collectively. Further mechanistic studies demonstrated that nitrosoarene is the key intermediate, and the activation of boronic acid is the rate-determining step in the transformation.

Full text of DOI:10.1002/cjoc.202000198

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Straightforward Sulfonamidation via Metabisulfite-Mediated Cross Coupling
of Nitroarenes and Boronic Acids under Transition-Metal-Free Conditions
Authors: Yaping Li, Ming Wang,* and Xuefeng Jiang*
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This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000198.
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Chin. J. Chem.
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DOI: 10.1002/cjoc.201800XXX
Straightforward Sulfonamidation via Metabisulfite-Mediated Cross
Coupling of Nitroarenes and Boronic Acids under Transition-Metal-Free
Conditions†
Yaping Li,a Ming Wang,*,a and Xuefeng Jiang*,a,b
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
ABSTRACT A s tra ightforwa rd multicomponent sulfonamidation of nitroarenes, sodium metabisulfite and boronic acids was established under
transition-metal-free conditions to access diverse sulfona mides from rea dily available and low-cost materials modula rly. Inorganic salt sodium
metabisulfite not only served as a sulfur dioxide source, but also played the key role for both activa tor and reductant during sulfonamidation. Notably,
naturally occurring biomolecules and pha rma ceutica ls with multiple heteroatoms and sensitive functional groups were intensively investigated in this
tra ns formtion providing versatile sulfonamides collectively. Further mecha nistic studies demonstrated that nitros oarene is the key intermediates, a nd the
activation of boronicacid is the rate-determining step in the transformation.
KEYWORDS sulfonamide, s odium metabisulfite, sulfur dioxide,nitroarene, transition-metal-free
transition metal vi a 1,5-mi grati on to affo rd S O2-con juga te (Figu re
1B ). He rei n , we disclose a modular sulfonamidation coupling of
nitroarenes, sodium metabisulfite and bo roni c acids to afford
Introduction
Sulfonamide, as a significant motif of widely prescribed
pharmaceuticals,[1] has been demonstrated to exhibit high-level
untra mmeled-va ryi ng
sulfonamides
under
expedite
bioactivity for multifarious aspects, especiallysupporting the basis
of antibacterial drugs.[2] Besides, sulfonamide, on account of
excellent water solubility and molecule stability for drug discovery,
is co nsidered as a preeminent carboxylic acid isostere. Several
representitive secondary sulfonamides a re shown in Figu re 1A as
well -known pharmaceuticals and agrochemicals.[3] Conventionally,
access to sulfonamides involves amine nucleophiles in
combination with sulfonyl halides,[4] or undergoes C-N bond
coupling between aryl halides and primary sulfonamides under
transition-metal-free conditions (Figure 1C). [13]
transition-me tal-catalyzed
conditions.[5]
Re cen tl y,
multicomponent cross-coupling strategies for direct insertion of
SO2 into two coupling partners have been intensivelys tu died, due
to the ready variation between dual modules for versatile
SO2-containing molecular synthesis.[6] The Willis’ group developed
a pioneering cop pe r-catalyzed sulfonamide synthesis by using
DABSO [DABCO·(SO2)2] as a sulfur dioxide surrogate, in whi ch
amines underwent oxidative couplings with DABSO and bo roni c
a cids .[7] Re cen tl y, Ramón e t al also e xpl o red a copper-catalyzed
synthesis of sulfonamides from triarylbismuthines, nitro
compounds and sodium metabisulfite, and metabisulfite was used
as the reductant for arylnitro molecules.[8] On the other hand,
ni troa renes as an amino source have emerged as an appealing
research area due to its high accessibility, stability and low cost.[9]
However, the acti va tio n of nitroarene without transition-metal
catalysis is an enormous challenge, owing to the high potential
energy of nitrogen radical generation fro m nitroarenes (62.01
kcal/mol).[10] According to our mask co n cep t of sulfur salts,[11] we
envision tha t sodium metabisulfite not only serves as a sul fu r
dioxide source,[12] but also ena cts to a cti vate ni troa rene to
ni trosoa rene accompanied with the transformation from S(IV) to
S(VI ), which will be followed by the radical addition with sulfinate
radical and the second oxygen a to m redu ctio n . Simultaneously,
the mask fro m sodium metabisulfite as an anion counterpart
a cti vate C-B bond from bo roni c a cids wi th ou t the assistance of
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Chin. J. Chem.
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and
A. Pharmaceuticals
agrochemicals
6
7
8
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
nBu4NPF6
nBu4NPF6
nBu4NPF6
TBAB
K3PO4
KOH
44
41
51
43
70
66
28
80
73
F
tBu
HN
O
O
N
N
N
N
S
N
H2N
S
N
nPr
N
N
H
O
S
O
O
F
N
LiOH
LiOH
LiOH
LiOTf
LiBF4
Li3PO4
LiCl
F
O
OH
F
N
O
O
S
H
O
tBu
9
N
H
Cl
F
MeO
Bosentan
10
11
12
13
14
Chcl
Vemurafenib
Dabrafenib
BRAF inhibitor
Roche
anti-neoplastic drug
Actelion
anti-pulmonary hypertension
GSK
cancer
drug
drug
Chcl
O2N
O
S
O
O2N
Cl
O
O
O
S
O
Chcl
N
S
CF3
Cl
N
Me
H
N
H
H
HN
HOOC
O
O
Chcl
N
O
H
O
tBu
Chcl
sulfanitran
Sivelestat
lung drug
Flusul famide
insecticide
anti-coccidial drug
injury
a Reaction conditions: 1 a Reaction conditions: 1a (0.2 mmol), Na2S2O5 (0.6 mmol),
boronic acid 2 (0.3 mmol), P TA (0.2 mmol) , additive (0.4 mmol), DMF (2 mL), 130 °C,
N2, 10 h. b Isolated yields. PTA = phase transfer agent.
B. Our design
♦
activation of
R-B(OH)2
O
O
S
Na
O
S
NaO
ion-coordination
activation
O
S
ONa
+
O
B
OH
OH
S
NaO
O
B(OH)2
O
R
R
B(OH)2
Na2S2O5
R
We co mme n ced multicomponent sulfonamidation wi th p-me th yl
nitrobenzene 1a, sulfur dioxide surrogates and bo roni c a cids (2a)
only in the existen ce of phase transfer agent. However, no
product was detected when thiourea dioxide or sodium dithionite
served as SO2 sou rces (Table 1, entries 1-2). To our delight,
desired sulfonamidation product 3 was afforded in 28% yield
when sodium metabisulfite was used as inorganic sulfur dioxide
surrogate (Table 1, entry 3). This resul t demonstrates tha t the
mask group in sodium metabisulfite possesses a unique role fo r
the current transformation. Further improvement was achieved
via the addition of base, in which lithium hydroxide promoted the
yield to 51% (Table 1, entries 4-8). Considering the solubility of
ionic salt components, various phase transfer agents we re
+
1,5-migration
O
O
O
O
S
Ar
S
Ar
N
R
N
R
H
♦
O
activation of R-NO2
redutive radical
O
62.01
kcal/mol)
Ar NO2
(unit:
Ar NO
Ar NH
ONa
activation
O
O S
O
N
Ar
N
O
Ar
N
Na2S2O5
O
SO3Na
Ar
23.22
38.79
work
C. This
O
O
transition-metal-free
O
S
O
+
+
Ar
B(OH)2
S
NO2
Ar
R1
N
R1
one-step
H
sp2
p
d
:
versatile
The
Na2S2O5
O
S
O
S
activate
activate "N"
radical
-B(OH)2
acid
active state
NaO
ONa
activation of boronic
①
①
O
activation of nitroarenes
source
Mask
ionicity
Na2S2O5
s ys tema ti call y
((2-hydroxyethyl)trimethyl-ammoniuchloride),
tes ted ,
and
choline
which
chloride
was
"SO "
①
inorganic
①
2
①
&
①
Figure
1
The applications and construction of functional
explored by Ra món e t al in the inorganic sulfur dioxide surrogate
s ys te m ,[8] was found to provide 70% yield (Table 1, entries 9-10).
Further evaluation of lithium salt additives revealed that lithium
phosphate furnished a better yield (80% yield) (Table 1, entries
11-14).
sulfonamide.
Results and Discussion
With optimized conditions in hand, versatile functionalized
sulfonamides were comprehensively afforded in Scheme 1. A
diverse set of para- and ortho-s ubs ti tu ted a ryl boronic acids
bearing electron-donating and electron-withdrawing groups we re
coupled wi th sodium metabisulfite and p-methyl nitrobenzene to
furnish the desired sulfonamides in good to excellent yields (3-9).
Aryl boronic a cids wi th fused ring systems were converted to the
desired sulfones in excellent yields (10-13), and the structure of
12 was fu rthe r confirmed via X-ray diffraction analysis.[14] This
sulfonamidation was quite efficient for heteroarylboronic aci ds,
such as piperonly, benzothiazolyl, furyl , thi en yl and
dibenzo[b,d]furyl-derived substrates (14-18), whi ch p resages the
utility of the protocol for rapid access to library of drug-like
molecules. Furthermore, a varietyof nitroarenes, including
Table 1 Condition Optimizationa
PTC
equiv)
Me
Choline chloride
(Chcl):
(1.5
Additive
Me
O
O
B(OH)2
equiv)
(1.0
"
"SO2
S
N
DMF, 130 °C
OH
Cl
NO2
H
N
1a
2a
3
entry
“SO2” surrogate
thiourea dioxide
Na2S2O4
PTA
additiv e
yield (%)b
1
2
3
4
5
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
-
NP
NP
28
-
Na2S2O5
-
Na2S2O5
DABCO
DIPEA
42
Na2S2O5
15
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Scheme 1 Collective sulfonamides construction.a
ChCl
Li3PO
1
equiv)
(
O
O
equiv)
4 (2
Na2S2O5
S
Ar
Ar-NO2
R-B(OH)2
N
R
DMF, 130 °C, N2
H
variation of boric acids
=
=
=
=
=
=
=
3
,
4
,
5
,
6
,
7
,
8
,
9
,
R
R
R
R
R
R
R
4-H,
80%
Me
Me
Me
O
O
Me
4-Cl, 66%
O
O
O
O
O
O
S
4-OMe, 88%
S
S
N
S
N
N
H
N
4-SMe,
83%
R
H
H
H
N
4-COOEt, 45%
t
4- Bu,
2-Me,
82%
76%
12
,
85%
Me
10
,
11
90%
,
86%
Me
x-ray
12
(
)
Me
Me
Me
Me
O
O
O
O
O O
O
O
O
O
O
O
O
S
S
S
S
O
O
S
S
N
S
N
N
N
N
N
H
H
H
H
H
H
O
S
13
,
83%
14 77%
,
15
,
16
,
17
,
18
75%
,
50%
41%
80%
variation of nitrobenzenes
Me
Me
O
Cl
Cl
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
F
N
S
N
N
N
N
N
H
H
H
H
O
H
H
Me
22
N
Me
19
20
21
54%
,
23 71%
24
, 83%
88%
83%
,
,
,
52%
N
,
OCH3
O
S
O
O
Me
O
O
O
O
S
N
nBu
O
O
O
nBu
O
O
O
S
O
O
O
S
S
N
H
N
S
S
Me
N
O
O
N
N
N
H
S
N
H
H
H
H
OMe
S
28
,
29
85%
,
61%
26
,
30
,
54%
25
,
78%
O
27
,
72%
80%
N
Me
Me
O
O
Me
O
O
O O
O
O
S
Ph
O
O O
N
H
Cl
S
S
Me
S
S
N
N
N
N
H
H
H
H
31 72%
,
32
,
33
,
34
,
35
60%
,
60%
58%
63%
a Reaction conditions: nitroarenes 1 (0.2 mmol), Na2S2O5 (0.6 mmol), boronic acids 2 (0.3 mmol), ChCl (0.2 mmol), Li3PO4 (0.4 mmol), DMF (2 mL), 130 oC, 10 h, isolated yields.
Scheme 2. Functional molecules cross-linked with sulf onamide.a
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O
O
O2N
Functional
B(OH)
+
S
group
standard conditions
N
Functional
Functional
group
group
+
Functional
H
Na2S2O5
group
acid
NH
-Amino
acid
SO
Saccharide-
NH
-Amino
SO
O
Steroid-
2
2
COOMe
NHBoc
Me
O
S
O
H
CO2Me
NHBoc
N
MeOOC
NHBoc
O
Me
Me
N
Me
Me
O
S
H
O
Me
N
O
O
O
O
H
H
O
O
O
O
S
O
N
H
O
H
O
O
Me
Me
O
38 57%
O
,
Me Me
37
63%
,
36
,
73%
NH
Pharmaceutical-SO2 -Pharmaceutical
H
Cl
N
Me
Me
O
S
Cl
O O
O
O
O
O
Me
S
O
O
O O
N
Me
O
O
O
S
H
Me Me
N
Cl
S
MeOOC
Cl
H
N
Me Me
EtO2C
H
N
Ph
O
O
Me
39 72%
,
41
50%
,
40
,
46%
Me
NH
SO2 -containing drug
NH
Amino acid-SO2 -Steroid
NH
SO
-Pharmaceutical
Me
Me
Saccharide-
Me
2
H
NO2
H
Me
O
O
O
N
H
H
S
O
O
O
N
Me
O
O
O
O
O
H
S
O
O
N
S
O
N
H
BocHN
MeOOC
N
O
H
CF3
Me
Me
H
O
sulfanitran, 44 50%
42 77%
,
,
43
,
60%
a Reaction conditions: nitroarenes 1 (0.2 mmol), Na2S2O5 (0.6 mmol), boronic acids 2 (0.3 mmol), ChCl (0.2 mmol), Li3PO4 (0.4 mmol), DMF (2 mL), 130 oC, 10 h, isolated yields.
(39-41). Ami ne fragment from drug flutamide allowed the
diversely subs ti tu ted a ryl s and fused aromatic rings (19-23) a re
well compatible for the transformation. (42). Cholesterol-derivatived sulfonamidation product was
Benzophenone-containing nitroarene fu rnished the
e ffi cientl y obtained via the cross-linkage wi th L-phenylalanine
incorporation of fructose derivative wi th sulfonamide as a linker
corresponding sulfonamide product (24) in 83% yield. fragment (43). The representitive sulfonamide drug sulfanitran
Hetero-ni troa renes, such as nitrobenzodioxole, nitrobenzofuran , (44), which is a kind of sulfonamide anti-infective drug, was
nitrobenzothiazole, nitroquinoline and nitropyridine derivatives, achieved through the developed transformation.
we re all successfully tolerant providing the corresponding
sulfonamides in excellent yields (25-31). It should be noted that
the transformation is not limited to arylboronic a cids , alkenyl
bo roni c acids were accommodated for the corresponding
sulfonamidation products as well (32). Notably, this
straightforward coupling can be applicable to alkylboronic aci ds,
delivering a broad range of sp3-sulfonamides (33-35).
Since the current mul ti component cross-coupling possesses the
advantage of untrammeled combination of bilateral partners, we
sought to tes t its cross linka ge with naturally occurring
Control experiments were conducted in order to fi gure out the
mechanism of the multicomponent sulfonamidation reaction.
Aniline co uld not furnish the desired product 20, indicating that
free amino group was not involved in the current transformation
(Scheme 3a-1). Under the standard conditions, the reaction of
nitrosobenzene (1b-II) and sodium p-tolylsulfinate didn’t delivere
sulfonamide product 20 (Sche me 3a-2). The coupling of sodium
p-tolylsulfinate and nitrosobenzene (1b-II) was also unable to
access desired product 20 regardless of sodium metabisulfite was
present or not (Scheme 3a-3). These results indicated that sodium
p-tolylsulfinate was not the actual in te rmedia te . The current
biomolecules and pharmaceuticals
containing multiple
heteroatoms and sensitive functional groups to afford
sulfonamide-linked hybrid molecules (Sche me 2). The linkage of
gl u cose and fructose derivatives wi th L-phenylalanine and
reaction
was
suppressed
when
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was added under
oligopeptide derivatives can be successfully a chie ved to deliver the standard conditions, which indicated that a radical pathwayis
sulfonamidation products in good efficiency, respectively (36-37).
The connection of estrone derivative and L-phenylalanine was
readily realized to afford the corresponding functionalized
sulfonamide product (38). The cross-linkage of di ve rs e drugs, such
as nitrofen, clofibrate, carprofen, nimesulide and fenofibrate, was
accomplished successfully via the cu rren t s tra te gy, whi ch
possible in the transformation (Scheme 3b ). Kinetic studies
fu rthe r elucidated the insight of this transformation in Scheme 3c.
The concentration of boronic a cid had a significant effect on the
ra te of product formation (Sche me 3c, II), precisely speaking, the
rea ction ra te shows 1.00th-order dependence on boronic acids
and ze ro o rde r fo r ni troa re ne (Sche me 3c, I). These results
illustrate the great potential with respect to drug discovery demonstrated that the a cti va tion of bo roni c a cid is the
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ra te -determining step, and the re du ctio n o f ni troa rene is rapid.
The order with respect to sodium metabisulfite is unable to be
Scheme 3 Mechanisticstudy
Control
(a)
experiment:
detected, since of its i n co mple te solubility in
a higher
O
O
NH2
B(OH)
2
standard conditions
standard conditions
standard conditions
S
Na2S2O5
(1)
(2)
(3)
concentration. Thus, the postulated reaction pathway is depicted
in Sche me 3d. Sodium metabisulfite as an anion counterpart
simultaneously activated C-B bond of boronic a cids to a ffo rd
SO2-conjugate in te rmedia te A, leading to the generation of radical
in te rmedia tes B wi th the releasing of C through a 1,5-migration
and a SET process. The reduction of nitroarenes was achieved via
the nucleophilic substitution of the mask group in sodium
metabisulfite fro m nitro group (D) gene ra ting nitrosobenzene
N
H
Me
Me
Me
1b-I
No
product
O
S
O
O
NO2
S
ONa
N
H
Me
No
product
O
O
O
1b-II. The radical addition from in te rmedia tes
B
to
NO
S
S
ONa
N
nitrosobenzene 1b-II provides the hydroxylamine radical E. The
coupling of radical intermediates C and E delivered in te rmedia te F,
followed by the se con d-reduction via hydrolysis to afford desired
sulfonamide product 3.
H
Me
Me
20
:
with Na S O
5
1b-II
trace
1)
2)
2
2
:
without Na S O trace
2
2
5
Radical-trapping
(b)
experiment:
Me
Me
O
O
B(OH)2 standard conditions
TEMPO
Na2S2O5
S
N
equiv)
(3
NO2
H
1a
2a
trace
3,
Kinetic study
(c)
Me
Me
O
O
B(OH)2
Chcl, Li3PO4
DMF, 130 °C
Na2S2O5
S
N
NO2
H
1a
2a
3
Ln[rate]
Ln[rate]
-2.5
0.0196th-order of ArNO2
y = 0.0196x - 3.7908
0.9336th-order of
PhB(OH)2
(I)
(II)
-2.5
-3.5
-4.5
-5.5
y = 0.9336x - 1.6939
R² = 0.9961
-3
-3.5
-4
Ln[ArNO2]
-1.4
Ln[PhB(OH)2]
-1.4
-2.4
-1.9
-2.4
-1.9
mechanism:
(d) Proposed
Na2S2O5
O
N
O
Ar
1
O
O
N
S
R
+
B(OH)2
O
ONa
SO3Na
Ar
2
A
O
S
O
O
O
S
O
O
B
S
Na2SO3
NaO
S
ONa
NaO
Na
+
O
OH
OH
SO3
R
1,5-migration
B
&
O
SET
N
H
Ar
O
N
R
S
S
Ar
1b-II
O
O
ONa
R
O
NaO
C
3
S
O
HO
B
NaHSO4
OH
D
O
S
O
H2O
N
R
O
ONa
R
S
base
Ar
N
O
O
S
Ar
E
O
O
F
NaOB(OR')2
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δ 7.80 – 7.77 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 – 7.39 (m, 2H),
7.11 (s, 1H), 7.05 – 6.96 (m, 4H), 2.26 (s, 3H); 13C NMR(100 MHz,
CDCl 3) δ 138.9, 135.4, 133.6, 132.9, 129.8, 128.9, 127.2, 122.3,
20.8; HRMS (EI ) for C13H13NO2S Calculated: 247.0667, found:
247.0664.
Conclusions
In
summa ry,
a
straightforward
multi comp onen t
sulfonamidation of ni troa renes , sodium metabisulfite and bo roni c
acids was developed under transition-me tal-free conditions fo r
modular sulfonamide constructi on fro m readil y available and
low-cost materials. The inorganic salt sodium metabisulfite no t
only served as the sulfur dioxide source, but also acted as an
efficient reductant and activator for this sulfonamidation. Notabl y,
naturally occurring biomolecules and pharmaceutical systems
with multiple heteroatoms and sensitive functional groups we re
sucessfully in ves tiga ted in this transformtion to provide diverse
sulfonamide-containing cross-linkages. Mechanistic studies
demonstrated that ni trosoa rene c is the intermediate and the
activation of boronic a cid is the rate -de te rminin g step i n the
current protocol. The convenient and practical s trate gy fo r the
synthesis of multifunctional sulfonamides from readily available
sta rtin g materials p ro vi des a grea t po te n tial for drug discovery.
Fu rthe r drug discovery studies with this cross-linking protocol a re
in progressin our laboratory.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
The authors are grateful for the financial support provided by
The National Key Research and Development Program of China
(2017YFD0200500), NSFC (21971065, 21722202, 21672069 and
21871089 for M.W.), S&TCSM of Shanghai (Grant 18JC1415600),
Professor of Special Appointment (Eastern Scholar) at Shanghai
Institutions of Higher Learning, the National Program for Support
o f Top -notch Young Professionals, and Innovative Research Team
of High-Level Local Universities in Shanghai.
References
Experimental
General information
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Under a N2 atmosphere, ni troa renes (0.2 mmol , 1.0 equiv),
Na2S2O5 (0.6 mmol , 3.0 equiv), boronic acid (0.3 mmol, 1.5 equiv),
Li3PO4 (0.4 mmol , 2.0 equiv), choline chloride (0.2 mmol, 1.0 equiv)
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Revised ma nuscript received: XXXX, 2017
Accepted manuscript online: XXXX,2017
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Entry for the Table of Contents
Page No.
Straightforward Sulfonamidation via
Metabisulfite-Mediated Cross Coupling of
Nitroarenes and Boronic Acids under
Transition-Metal-Free Conditions
O
O
transition-metal-free
O
O
+
+
Ar
B(OH)2
S
NO2
Ar
R1
S
N
R1
one-step
H
sp2
p
d
:
versatile
The
Na
2S2O5
activate
activate "N"
radical
-B(OH)2
active state
activation
of
boroniacid
①
①
activation of nitroarenes
source
ionicity
Na2S2O5
"
"SO
inorganic
①
2
A s traightforward sulfonamidation of nitroarenes, sodium metabisulfite a nd boronic acids was
developedunder transition-metal-free conditions for modular sulfonamide construction.
YapingLi, Ming Wang*, Xuefeng Jiang*
www.cjc.wiley-vch.de
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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