Catalyst-free arylation of sulfonamidesviavisible light-mediated deamination

Article abstract of DOI:10.1039/d1sc02266k

A novel arylation of sulfonamides with boronic acids to afford numerous diaryl sulfonesviaa visible light-mediated N-S bond cleavage other than the typical transition-metal-catalyzed C(O)-N bond activation is described. This methodology, which represents the first catalyst-free protocol for the sulfonylation of boronic acids, is characterized by its simple reaction conditions, good functional group tolerance and high efficiency. Several successful examples for the late-stage functionalization of diverse sulfonamides indicate the high potential utility of this method in pharmaceutical science and organic synthesis.

Full text of DOI:10.1039/d1sc02266k

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Catalyst-free arylation of sulfonamides via visible
light-mediated deamination†
Cite this: Chem. Sci., 2021, 12, 9556
a
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Yong Luo,
Hao Ding,b Jing-Song Zhen,a Xian Du,a Xiao-Hong Xu,a Han Yuan,a
Yi-Hui Li,a Wan-Ying Qi,a Bing-Zhe Liu,a Shi-Man Lu,a Can Xue
and Qiuping Ding
c
*
b
*
A novel arylation of sulfonamides with boronic acids to afford numerous diaryl sulfones via a visible light-
mediated N–S bond cleavage other than the typical transition-metal-catalyzed C(O)–N bond activation
is described. This methodology, which represents the first catalyst-free protocol for the sulfonylation of
boronic acids, is characterized by its simple reaction conditions, good functional group tolerance and
high efficiency. Several successful examples for the late-stage functionalization of diverse sulfonamides
indicate the high potential utility of this method in pharmaceutical science and organic synthesis.
Received 23rd April 2021
Accepted 4th June 2021
DOI: 10.1039/d1sc02266k
rsc.li/chemical-science
phosphine reagent (Scheme 1a). Further with the addition of
electrophiles, a variety of sulfones and modied sulfonamides
could be obtained. By utilizing Pyry-BF4, Cornella5 found that
primary sulfonamides could react with nucleophiles to generate
sulfonyl chlorides, uorides, and sulfonic acids. Despite these
signicant progresses, the functionalization of tertiary sulfon-
amides, which are usually considered as terminal functional
groups to synthesize sulfones and related compounds, has not
been achieved yet.
On the other hand, despite sulfonyl chlorides,6 sodium sul-
nates,7 and sulfur dioxide8 being widely used for sulfonylation
towards aryl sulfones in recent years, novel sulfonylation
reagents still need to be explored to extend the research in this
area. The stability and good tolerance for other functional
groups make tertiary sulfonamides to be good sulfonylation
reagents. Herein, we report that N-acylsulfonamides as novel
sulfonyl radical precursors react with aryl boronic acids to
generate various diaryl sulfones via visible-light-mediated N–S
Introduction
Sulfonamide drugs discovered in the 1930s rst systemically
used as antibacterials have continuously received renewed
interest for the treatment of numerous diseases.1 Since then,
a large number of synthetic routes towards diverse sulfon-
amides have been developed, which make the sulfonamide
moiety prevalent in bioactive molecules and commercial
chemicals.2 Therefore, the transformation of sulfonamide
skeleton to other groups, such as sulfones, is a convenient
method to construct a pharmacophore-containing molecule
library for drug discovery. Moreover, the activation of sulfon-
amides could be used for the deprotection of sulfonyl group-
protected amines,3 late-stage functionalization of sulfonamide
drugs,4 and sulfonylation with sulfonamides as stable and good
functional group-tolerant reagents. However, sulfonamides are
usually considered as the nal products of the construction of
N–S bonds rather than reactive substrates because efficient
strategies for the functionalization of N–S bonds are limited.
Previous exploration on the N–S bond cleavage of sulfon-
amides mainly focused on desulfonylation to generate corre-
sponding amines.3 The functionalization of the sulfonyl group
resulted from the deamination of sulfonamides still meets great
challenges. Recently, Fier and Maloney4 reported an efficient
pathway to convert primary and secondary sulfonamides to
sulnate anions in the presence of an NHC catalyst or
aSchool of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou,
510275, China. E-mail: luoyong5@mail.sysu.edu.cn
bKey Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi
Normal University, Nanchang, 330022, China. E-mail: dingqiuping@jxnu.edu.cn
cSchool of Chemical Engineering and Technology, Sun Yat-sen University, Zhuhai,
519082, China. E-mail: xuecan@mail.sysu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc02266k
Scheme 1 Strategies for the functionalization of sulfonamides and the
synthesis of sulfones.
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bond activation without any catalyst (Scheme 1b), while these
The scope of boronic acids was then explored (Table 2).
substrates typically proceed a C(O)–N bond cleavage in the Substituents with a large p system showed high efficiency. For
presence of transition metals.9 The mechanism investigation example, 2- or 1-naphthylboronic acid provided 97% and 87%
showed that a radical cross-coupling is probably involved in our yields of the desired product, respectively (3b and 3c). Methyl
protocol, which provides an alternative strategy for the late- group substitution had nearly no affect on this reaction (3e).
stage functionalization of sulfonamides. Moreover, N-acylsul- Methoxy and phenyl group-attached substrates gave lower
fonamides synthesized from sulfonyl chlorides and amides yields probably owing to the instability of these sulfonamides
could act as the surrogates of the sulfonyl chlorides under under blue LED irradiation (3d and 3f). It should be noted that
incompatible reaction conditions to proceed with late-stage in some cases, product 3 was inseparable from the generated
sulfonylation.
amide 4. Therefore, 1b, which showed no obvious reactivity
difference compared with 1a, was employed for the convenience
of the isolation of product 3 (3b, 3c, 3e and 3f). Heterocycles,
such as quinoline and benzofuran, are compatible in this
system (3g–3k). Aldehyde, ketone, and amide group-attached
aryl boronic acids also could afford moderate yields of the
desired products (3l–3o), although an elevated concentration by
the addition of only 1 mL solvent was necessary in several
examples. Diverse electron-withdrawing (phenyl, cyano, and
silane) and electron-donating group (methoxy, methyl, and
Results and discussion
In our investigation, sulfonamide 1a went through arylation
with boronic acid 2a in the presence of K3PO4 and CH3CN under
blue LED irradiation, providing diaryl sulfone 3a with 57% yield
(Table 1, entry 1). No ketone product was observed. Further
screening showed that DMF, PhCF3, or DCE was inefficient
(entries 2–4). However, ether solvents exhibited superiority in
this reaction (entries 5–7), and 70% yield was obtained with 1,4-
dioxane. A lower yield was detected when Cs2CO3 or K2CO3 was
employed (entries 8 and 9). CsF (99.99% metal basis) gave the
best result in the screening of the bases, affording the desired
product 3a in 75% yield (entry 10). The decomposition of
sulfonamide 1a was observed in these reactions and hampered
the elevation of the product yield. Therefore, the ratio of 1a and
2a was changed to 2 to 1, resulting in a signicant increase of
the yield of 3a (95%, entry 11). The corresponding amide 4 was
also collected and identied with a yield of 114% based on 2a
owing to the visible light-mediated desulfonylation of the
starting material 1a. Visible light and base were proved to be
necessary since no product was detected when this reaction was
performed in dark or without base (entries 12 and 13).
Table 2 Scope of boronic acidsa
Table 1 Optimization of the reaction conditionsa
Entry
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
CH3CN
DMF
PhCF3
DCE
THF
DME
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
CsF
57
Trace
n.r.
n.r.
66
61
70
53
57
75
9
10
11b
12b,d
13b
CsF
CsF
—
95 (114c)
n.r.
n.r.
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), CsF (0.5 mmol), 1,4-
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (0.5 mmol), dioxane (2 mL), 50 W blue LED, 12 h, 40 ꢀC. b 1b was used instead of 1a.
a
b
c
d
solvent (2 mL), 50 W blue LED, 12 h, 40 ꢀC, isolated yield. 1a (0.4
Only 1 mL of 1,4-dioxane was added. K3PO4 (0.5 mmol) was used
instead of CsF.
mmol), 2a (0.2 mmol). c Yield of 4 in the parenthesis. d In dark.
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Table 4 Scope of amidesa
amine) substituted diaryl sulfones could be synthesized using
corresponding boronic acids (3p–3v). The substrate bearing an
ortho methyl group could afford 3x in 68% yield. However,
aliphatic boronic acids, aryl triuoroborates, or aryl boronic
acid pinacol esters could not result in any product under these
reaction conditions or with a photocatalyst.
Aer that, the scope of sulfonyl groups was investigated
(Table 3). With an electron-donating group on either para- or
meta-position, sulfonamide 1 could react smoothly with boronic
acid 2a to generate the desired product in good yield (3y–3aa).
The arylation of naphthyl and phenyl sulfonamides also pro-
ceeded efficiently to afford sulfones 3ab and 3ac. Electron-
withdrawing groups, such as uorine, ester, cyano, and
sulfone, could all be tolerated in this system very well (3ad–3ag).
However, the alkyl sulfonyl group-embedded sulfonamide
showed no reactivity.
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), CsF (0.5 mmol), 1,4-
dioxane (2 mL), 50 W blue LED, 12 h, 40 ꢀC. n.d. ¼ not detected.
The protecting groups on the nitrogen atom were also
examined (Table 4). Alkyl group-attached sulfonamides 1b and
1c exhibited an inferior efficiency than 1a, leading to 76% and
60% yields of 3a, respectively. Aliphatic acyl group-protected
sulfonamides 1d and 1e could provide the desired product 3a
with moderate yields. Sulfonamide 1f bearing acetyl and benzyl
units, which were usually used as the protecting groups of
nitrogen atom, could also result in 3a with 53% yield, which
largely expands the practical utilization of our protocol in
organic synthesis. However, secondary sulfonamides 1g and 1h
only afforded trace amounts of 3a. Moreover, the acyl group in 1
was proved to be necessary since the two aryl group-attached
substrate 1i gave no desired product under the standard
conditions.
To examine our strategy in the late-stage functionalization of
sulfonamides, several commercial drugs were used to proceed
acylation and methylation to provide the starting material 1.
Aer that, diverse aryl groups and heterocycles could be
introduced under the standard arylation reaction conditions
(Table 5). The 6-quinoline group could be installed into the
drugs derived from Celecoxib and Valdecoxib with 67% and
61% yields, respectively (3ah and 3ai). 4-Methox-
ycarbonylphenylboronic acid could give 91% yield of the
desired product (3aj). The amide group remained intact in this
procedure, affording corresponding products 3ak and 3al
stemmed from glibenclamide precursor in 90% and 65% yields,
respectively. Free alkyl and aryl amine groups were protected by
acylation under the prefunctionalization conditions, affording
the products 3am and 3an in moderate yields.
Besides the arylation of the sulfonyl group in sulfonamides,
alkylation could also be achieved by altering the reaction
conditions. The N–S bond of sulfonamides was cleaved by
photocatalysis to deliver the sulfonyl radical. Then, the in situ
methylation of the sulnate resulted from the reduction of the
sulfonyl radical proceeded to afford methyl sulfones (Table 6).
Table 5 Late-stage arylation of drugsa
Table 3 Scope of sulfonyl groupsa
a
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), CsF (0.5 mmol), 1,4-
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), CsF (0.5 mmol), 1,4- dioxane (2 mL), 50 W blue LED, 12 h, 40 ꢀC. Isolated yields of the
dioxane (2 mL), 50 W blue LED, 12 h, 40 ꢀC.
arylation step. b 1 (0.2 mmol), 2 (0.4 mmol).
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Table 6 Late-stage methylation of drugsa
Substrates 1j and 1k synthesized from primary sulfonamides
furnished the methylated products with 93% and 90% yields,
respectively. Secondary sulfonamide-based substrates 1l and
1m could also be prefunctionalized and methylated with this
method. These successful transformations implied the poten-
tial for the rapid construction of a molecule library from not
only tertiary but also primary and secondary sulfonamides for
the screening of new lead compounds.
The mechanism of this reaction was investigated by
measuring the UV-Vis absorption spectra of substrates and
reaction solutions (Scheme 2). Individual solutions of sulfon-
amide 1a and boronic acid 2a in 1,4-dioxide showed
a maximum absorption at approx. 250 nm, and a very low
absorption at 460 nm (blue LED). A mixture of 1a and 2a dis-
played a slight red-shi of the absorption peak. When CsF was
added, a further red-shi and higher absorption under a blue
LED were observed. These details suggested that complex A,
which was formed with 1a, 2a, and base could be directly
photoexcited by blue LED without the presence of a photo-
catalyst (Scheme 2b). The Cs+-coordinated six-membered ring in
complex A might also explain the indispensability of the acyl
group (Table 4) in the substrate. This phenomenon of the
combination of a substrate and a reagent affording a photo-
excitable complex in situ has been reported in several
a
Reaction conditions: 1 (0.2 mmol), Hantzsch ester (0.4 mmol),
[Ir(ppy)2 (dtbbpy)]PF6 (5 mol%), K2CO3 (1.0 mmol), MeI (1.0 mmol),
DMF (2 mL), 50 W blue LED, 15 h, 40 ꢀC.
studies.10 With blue LED irradiation, complex A gave a rise to
the amide radical B and the sulfonyl radical C.3 Aer that, the
attack of a nitrogen radical to the boron complex D resulted in
an aryl radical E (ref. 11) with the concomitant generation of
amide 4. The capture of the sulfonyl radical by E provided the
product sulfone 3. This reaction was inhibited by the addition
of the radical scavenger TEMPO (Scheme 2b), also indicating
the involvement of a radical process.
Conclusions
In summary, we have developed an efficient and practical strategy
for the late-stage arylation of sulfonamides via a visible light-
mediated N–S bond cleavage other than typical transition-
metal-catalyzed C(O)–N bond activation. It also represented the
rst catalyst-free sulfonylation of boronic acids to synthesize aryl
sulfones. The employment of diverse boronic acids and sulfon-
amides exhibited good functional group tolerance and high
efficiency. The mechanism investigation revealed that the photo-
excitable complex formed from sulfonamide, boronic acid, and
base was crucial to afford sulfonyl radicals and furnish the
desired products. This achievement inspired us to explore other
strategies for the late-stage functionalization of sulfonamides.
Data availability
The electronic supplementary information include experi-
mental detail, NMR data and HRMS data.
Author contributions
Y. Luo conceived and designed the experiments. H. Ding con-
ducted most of the experiments. J.-S. Zhen and X. Du performed
Scheme 2 Mechanism investigation. (a) UV-Vis absorption spectra. (b)
Proposed mechanism.
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the arylation of sulfonamide drugs. X.-H. Xu, H. Yuan, Y.-H. Li,
W.-Y. Qi, B.-Z. Liu and S.-M. Lu synthesized the starting mate-
rials. C. Xue contributed to the mechanism research. Q. Ding
analylzed the data and prepared the manuscript.
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Conflicts of interest
There are no conicts to declare.
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We are grateful for nancial support from the National Natural
Science Foundation of China (21901260, 21908256, 21662017).
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9560 | Chem. Sci., 2021, 12, 9556–9560
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