S(vi) in three-component sulfonamide synthesis: Use of sulfuric chloride as a linchpin in palladium-catalyzed Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/d1sc01351c

Sulfuric chloride is used as the source of the -SO2- group in a palladium-catalyzed three-component synthesis of sulfonamides. Suzuki-Miyaura coupling between the in situ generated sulfamoyl chlorides and boronic acids gives rise to diverse sulfonamides in moderate to high yields with excellent reaction selectivity. Although this transformation is not workable for primary amines or anilines, the results show high functional group tolerance. With the solving of the desulfonylation problem and utilization of cheap and easily accessible sulfuric chloride as the source of sulfur dioxide, redox-neutral three-component synthesis of sulfonamides is first achieved. This journal is

Full text of DOI:10.1039/d1sc01351c

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S(VI) in three-component sulfonamide synthesis:
use of sulfuric chloride as a linchpin in palladium-
catalyzed Suzuki–Miyaura coupling†
Cite this: Chem. Sci., 2021, 12, 6437
All publication charges for this article
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of Chemistry
c
ade
Xuefeng Wang,ab Min Yang,
Shengqing Ye,a Yunyan Kuangb and Jie Wu
*
Sulfuric chloride is used as the source of the –SO2– group in a palladium-catalyzed three-component
synthesis of sulfonamides. Suzuki–Miyaura coupling between the in situ generated sulfamoyl chlorides
and boronic acids gives rise to diverse sulfonamides in moderate to high yields with excellent reaction
selectivity. Although this transformation is not workable for primary amines or anilines, the results show
high functional group tolerance. With the solving of the desulfonylation problem and utilization of cheap
and easily accessible sulfuric chloride as the source of sulfur dioxide, redox-neutral three-component
synthesis of sulfonamides is first achieved.
Received 8th March 2021
Accepted 5th April 2021
DOI: 10.1039/d1sc01351c
rsc.li/chemical-science
Since its development in the 1970s,1 Suzuki–Miyaura coupling of the –SO2– group. Willis and co-workers rst reported the use
has become a widely used synthetic step in diverse areas. With of DABCO$(SO2)2, a bench-stable solid adduct of DABCO and
two of the most widely sourced materials, organoborons and gaseous SO2 discovered by Santos and Mello,9a as the source of
alkyl/aryl halides, a number of C–C coupling reactions are sulfur dioxide in the synthesis of sulfonylhydrazines.9b Soon
established and the Suzuki–Miyaura reaction has successfully aer, alkali metal metabisultes were found to provide sulfur
acted as the key step in the synthesis of medicines and dioxide for the formation of sulfonyl compounds.10 In the recent
agrochemicals.2
developments in this eld, DABCO$(SO2)2 and metabisultes
In addition to the well-known aryl halides and esters, various have become the most popular SO2 surrogates for the insertion
other substrates such as acid chlorides,3 anhydrides,4 diazo- of sulfur dioxide.8 However, the practical applications of sulfur
nium salts5 and sulfonyl chlorides6 were also reported for the dioxide insertion reactions are limited by atom-efficiency
coupling in the past decades. As far as acid chlorides are con- problems and the unique properties of reactants. For
cerned, carbamoyl chlorides were successfully transformed to instance, the three-component synthesis of aryl sulfonylhy-
the corresponding benzamides in the early years of the 21st drazines using aryl halides, SO2 surrogates and hydrazines by
century.7 However, the use of sulfamoyl chlorides as coupling a SO2-doped Buchward–Hartwig reaction was realized in the
partners is challenging due to the strong electron-withdrawing earliest developments in this eld.10 However, similar trans-
properties of the sulfonyl group, which cause the tendency of formations from aryl halides and amines to the corresponding
desulfonylation to form tertiary amines.
sulfonamides still remain unresolved (Scheme 1a).11,12
Synthesis of sulfonyl-containing compounds, especially
In order to provide a simple and efficient method for the
sulfones and sulfonamides, via the insertion of sulfur dioxide three-component synthesis of aryl sulfonamides without the
has been extensively studied during the last decade.8 A series of pre-synthesis of sulfonyl chlorides, many scientists have made
sulfur-containing surrogates have been developed as the source various attempts. Interestingly, the use of arylboronic acids
instead of aryl halides provided an alternative route. An oxida-
tive reaction between boronic acids, DABCO$(SO2)2 and amines
for the preparation of aryl sulfonamides at high temperature
was realized,12 while reductive couplings of boronic acids, SO2
aSchool of Pharmaceutical and Materials Engineering, Institute for Advanced Studies,
Taizhou University, 1139 Shifu Avenue, Taizhou 318000, China. E-mail: jie_wu@
fudan.edu.cn
surrogates and nitroarenes were also reported (Scheme 1b).13
However, due to the reversed electronic properties of boronic
acids from halides, additional additives and restrictions had to
be considered. Extra oxidants and harsh conditions were
usually used, and some of the transformations required
“oxidative” substrates, such as nitroarenes and chloroamines.14
Early in 2020, a reductive hydrosulfonamination of alkenes
by sulfamoyl chlorides was reported,15 which gave us the
bDepartment of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438,
China
cDepartment of Forensic Science, Gannan Medical University, 1 Yixueyuan Road,
Ganzhou 341000, China
dState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
eSchool of Chemistry and Chemical Engineering, Henan Normal University, 46 East
Jianshe Road, Xinxiang 453007, China
† Electronic supplementary information (ESI) available: Experimental details,
spectral data, and 1H and 13C NMR spectra. See DOI: 10.1039/d1sc01351c
© 2021 The Author(s). Published by the Royal Society of Chemistry
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a base would be essential to remove the acid generated in situ
during the reaction process. Additionally, we expected that the
addition of a ligand would improve the oxidative addition of
Pd(0) to sulfamoyl chloride, thus leading to the desired
sulfonamide product.
As designed based on our assumption, we used a commer-
cialized sulfamoyl chloride intermediate A, which would be
generated from morpholine 1a and SO2Cl2, to start our early
investigations. The results showed that the direct Suzuki–
Miyaura coupling of sulfamoyl chloride intermediate A and 2-
naphthaleneboronic acid 2a mostly led to the generation of
byproduct 3a0 with traditional phosphine ligands added to the
reaction, and the desired product 3a was obtained in poor yields
(Table 1, entries 1 and 2). It is known that an electron-rich ligand
would enhance the oxidative addition of Pd(0) to the electrophile,
and the bulky factor would facilitate the reductive elimination
process. As expected, the yield of product 3a was increased
signicantly when electron-rich and bulky tris-(2,6-dimethox-
yphenyl)phosphine was used as the ligand (Table 1, entry 3).
Moreover, the reaction could proceed more efficiently by using
a mixture of THF and MeCN as the co-solvent (Table 1, entry 4).
With that brief conclusion in hand, we then shied our focus
to the in situ generation of sulfamoyl chloride intermediate A in
the reaction process, and a number of attempts were made with
morpholine 1a and SO2Cl2 (for details, see the ESI†). Aer
careful measurement of product 3a and desulfonylated
byproduct 3a0 generated during the transformation, the selec-
tive formation of compound 3a was realized and “standard
conditions” were identied. By using PdCl2(PhCN)2 as the
catalyst and Na2HPO4 as the base, the desired product 3a was
isolated in 71% yield, giving the least amount of desulfonylated
product 3a0 (Table 2, entry 1). The control experiment showed
that 3a or 3a0 was not detected in the absence of the palladium
catalyst (Table 2, entry 2). It was also observed that compound
3a0 could not be generated when SO2Cl2 was omitted (Table 2,
entry 3), indicating that the byproduct wasn't produced by the
direct coupling of boronic acid and amine. Other changes to the
catalyst, ligand, base or solvent all resulted in lower yields of
compound 3a or higher yields of desulfonylated product 3a0
(Table 2, entries 4–7).
Scheme 1 Synthetic approaches to sulfonamides.
inspiration to use in situ generated sulfamoyl chlorides as the
electrophile for the synthesis of aryl sulfonamides by Suzuki–
Miyaura coupling. In this way, sulfamoyl chlorides could be
formed by nucleophilic substitution of an amine to sulfuric
chloride, and the S(VI) central atom introduced into the reaction
could reverse the electronic properties of the amine, which
would eliminate the addition of oxidants (Scheme 1c). With the
utilization of boronic acids as the coupling partner, a palla-
dium-catalyzed Suzuki–Miyaura coupling could provide the
sulfonamide products. Compared with traditional attempts,
reversing the electronic properties of an amine from nucleo-
philic to electrophilic could reverse the whole reaction process,
and two-step synthesis starting from the amine side could
bypass the existing difficulty of S–N bond forming reductive
elimination.12 Instead, a C–S bond formation could be the key
for success (Scheme 2). In this proposed route, the presence of
Table 1 Early investigations using morpholine-4-sulfonyl chloride A
as the starting material
Entry
Solvent
Ligand
Yielda (%)
1
2
3
4
1,4-Dioxane
THF
THF
PtBu3$HBF4
14
23
57
72
PtBu3$HBF4
PAr3$Ar ¼ 2,6-di-OMe–C6H3
THF/MeCN
PAr3$Ar ¼ 2,6-di-OMe–C6H3
a 1H NMR yield obtained using 1,3,5-trimethoxybenzene as the internal
standard.
Scheme 2 Comparison between the traditional route and designed
work.
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Table 2 Effects of variation of reaction parametersa
Entry
Variation from “standard conditions”
Yield of 3a0b (%)
Yield of 3ab (%)
1
2
3
4
5
6
7
None
No PdCl2(PhCN)2
No SO2Cl2
Pd(OAc)2 instead of PdCl2(PhCN)2
PPh3 instead of PAr3
K2CO3 instead of Na2HPO4
MeCN instead of THF/MeCN
5
80 (69)
n.d.
n.d.
80
68
23
n.d.
n.d.
13
15
43
16
63
a
Standard conditions: morpholine 1a (0.2 mmol, 1.0 equiv.), SO2Cl2 (0.5 mmol, 2.5 equiv.), Et3N (0.53 mmol, 2.65 equiv.), 2-naphthaleneboronic
acid 2a (0.4 mmol, 2.0 equiv.), Na2HPO4 (0.6 mmol, 3.0 equiv.), PdCl2(PhCN)2 (10 mol%), tris-(2,6-dimethoxyphenyl)phosphine (20 mol%), THF (1.0
mL)/MeCN (1.5 mL), 70 ꢀC, 16 h. See the ESI for the detailed procedure. b 1H NMR yield obtained using 1,3,5-trimethoxybenzene as the internal
standard. The isolated yield of entry 1 is shown in parentheses.
With the “standard conditions” in hand, various secondary process for the oxidative addition of the sulfamoyl chloride
amines 1 and arylboronic acids 2 were subjected to the reaction intermediate to the palladium catalyst, Pd–SO2–NHR would be
for the exploration of substrate adaptability (Scheme 3). To our formed when a primary amine was used. Thus, b-hydride
delight, most of the reactions proceeded smoothly, giving rise to elimination would occur instead of the desired process.
the desired product 3 in moderate to high yields. Considering
Furthermore, the practicality of this method was also veried
the scope of boronic acids, a number of para-, meta- and ortho- by gram-scale synthesis and late-stage functionalization
(3t) substituted boronic acids showed good reactivities. (Scheme 4). The reaction worked smoothly on the 4.0 mmol
However, lower yields were observed for some substrates with scale, and reducing the loading amount of the palladium cata-
electron-withdrawing substituents, providing more desulfony- lyst to 1 mol% showed no obvious impact on the trans-
lated byproducts due to the electron-deciency of the palladium formation. With a boronic acid synthesized from estrone and
intermediate. Aryl boronic acids with acid-sensitive Boc- desloratadine, an antihistamine drug used as the substrate, the
substituted amine, oxidation-sensitive phenol, sulde and target products 4a and 4b were achieved in moderate to good
vinyl substitution were all tolerated. It is noteworthy that yields, showing potential possibilities for synthetic
bromo- and acetoxy-substrates could also be efficiently con- applications.
verted to the corresponding products 3f and 3r, showing quite
In conclusion, a redox-neutral three-component synthesis of
high selectivity during the reaction process. A series of hetero- sulfonamides is established through a palladium-catalyzed
aromatic products were afforded successfully as well, and Suzuki–Miyaura coupling of sulfuric chloride, secondary
compounds with indole, indazole, dibenzothiophene and pyri- amines and arylboronic acids. Sulfuric chloride is used as the
dine were all compatible (3aa–3af).
source of sulfur dioxide, and the S(VI) linchpin makes the
Subsequently, with respect to amines, 4-phenylboronic acid transformation possible without the assistance of oxidants.
and 4-(methylthio)phenylboronic acid were selected as coupling Although this transformation is not workable for primary
partners based on their electronic properties and cost. Satu- amines or anilines, the results show high functional group
rated cyclic products 3ah–3an were obtained in moderate yields, tolerance and good selectivity. A clear reaction process is
among which an a-amino acid derivative showed high reac- described, in which the in situ generated sulfamoyl chloride
tivity, giving rise to product 3aj in 71% yield. Methylallylamine undergoes a palladium-catalyzed Suzuki–Miyaura reaction with
was transformed to the corresponding product 3ao smoothly, boronic acids, giving rise to the corresponding sulfonamide
and thiomorpholine 1,1-dioxide was also tolerated under the products. Additionally, the desulfonylation problem is sur-
conditions (3ap). Various sensitive groups including acetyl, Boc, mounted during the reaction process. With a boronic acid
Cbz and cyclopropylcarbonyl (3aq–3at) on amines remained synthesized from estrone and an antihistamine drug, deslor-
intact during the transformation. However, the amine scope atadine, used as the substrate, the target products are achieved
was limited, since the transformation failed to provide the in moderate to good yields, showing potential possibilities for
corresponding products when primary amines or anilines were synthetic applications in organic chemistry and medicinal
used as the substrates. We assumed that during the reaction chemistry.
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Scheme 3 Synthesis of sulfonamides via a palladium-catalyzed Suzuki–Miyaura coupling. Isolated yields.
all authors. All authors discussed the results and commented
on the manuscript.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (No. 21871053), the Leading Innovative and
Entrepreneur Team Introduction Program of Zhejiang (No.
2019R01005) and the Open Research Fund of School of Chem-
istry and Chemical Engineering, Henan Normal University
(2020ZD04), is gratefully acknowledged.
Scheme 4 Gram-scale synthesis and late-stage functionalization.
Author contributions
X. Wang and J. Wu conceived the study. X. Wang, M. Yang and
S. Ye conducted the experiments and analyzed the data. J. Wu
and Y. Kuang directed the project. X. Wang and J. Wu prepared
the manuscript and supplemental information with input from
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