Design and Applications of a SO2 Surrogate in Palladium-Catalyzed Direct Aminosulfonylation between Aryl Iodides and Amines

Article abstract of DOI:10.1002/anie.202014111

A new SO₂ surrogate is reported that is cheap, bench-stable, and can be accessed in just two steps from bulk chemicals. Essentially complete SO₂ release is achieved in 5 minutes. Eight established sulfonylation reactions proceeded smoothly by ex situ formation of SO₂ by utilizing a two-chamber system in combination with the SO₂ surrogate. Furthermore, we report the first direct aminosulfonylation between aryl iodides and amines. Broad functional group tolerance is demonstrated, and the method is applicable to pharmaceutically relevant substrates, including heterocyclic substrates.

Full text of DOI:10.1002/anie.202014111

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7353–7359
International Edition: doi.org/10.1002/anie.202014111
German Edition: doi.org/10.1002/ange.202014111
Sulfonylation Reactions
Hot Paper
Design and Applications of a SO2 Surrogate in Palladium-Catalyzed
Direct Aminosulfonylation between Aryl Iodides and Amines
Xiuwen Jia, Søren Kramer, Troels Skrydstrup, and Zhong Lian*
Abstract: A new SO2 surrogate is reported that is cheap, bench-
stable, and can be accessed in just two steps from bulk
chemicals. Essentially complete SO2 release is achieved in
5 minutes. Eight established sulfonylation reactions proceeded
smoothly by ex situ formation of SO2 by utilizing a two-
chamber system in combination with the SO2 surrogate.
Furthermore, we report the first direct aminosulfonylation
between aryl iodides and amines. Broad functional group
tolerance is demonstrated, and the method is applicable to
pharmaceutically relevant substrates, including heterocyclic
substrates.
synthesis of sulfonamides.[4] However, the existing methods
for transition-metal-catalyzed aminosulfonylation of aryl
halides are limited to the use of hydrazines as nucleophiles
(Figure 1c).[5] Simple amine coupling partners cannot be used
in the aminosulfonylation except for the only intramolecular
process reported by Manable in 2017.[6a] In 2018, Willis and
co-workers disclosed a copper-catalyzed three-component
oxidative cross-coupling reaction between aryl boronic acids,
amines, and DABSO (DABCO·SO2, a SO2 surrogate reagent)
for the synthesis of sulfonamides (Figure 1d).[6b] Nonetheless,
complementary cross-coupling reactions with aryl electro-
philes would represent a valuable alternative to the nucleo-
philic aryl boronic acids. In addition, the limited stability of
organoboron compounds could complicate their use in the
later stages of multistep syntheses of complex molecules.
Due to the toxic nature and difficulties with storage and
use of gaseous SO2 especially in academic laboratories, the
use of SO2 surrogates is generally preferred. The most
common surrogate reagents include Na2SO3,[5d] Na2S2O5 (or
K2S2O5),[7] HOCH2SO2Na·2H2O,[8] DABSO[9] and others.[10]
Na2S2O3 reacts with conc. H2SO4 to release gaseous SO2
instantaneously. However, this method of SO2 generation
occurs via an exothermic reaction, which in combination with
the use of conc. H2SO4 has limited the usage of this procedure.
The application of other inorganic sulfur dioxide surrogates
such as Na2S2O5 and K2S2O5 usually requires addition of
phase transfer catalysts to promote exchange between two
solvent phases. In addition, HOCH2SO2Na·2H2O suffers
from strong hygroscopicity, and it easily forms decomposition
products such as sodium sulfite, sodium thiosulfate, and
sodium sulfide. DABSO is a mild SO2 surrogate reagent and
was first employed in sulfonylation reactions by Willis.[5a]
DABSO is moderately sensitive to temperature and moisture,
and during SO2 release a basic byproduct (DABCO) is
generated directly in the reaction mixture. This can poten-
tially lead to incompatibility with highly electrophilic and/or
base-sensitive groups. Overall, there is a need for a general
method for controllable ex situ SO2 release (Figure 1e).
Herein, we report the development of a SO2 surrogate
(tetrabromothiophene S,S-dioxide, SOgen), which can release
SO2 in a highly controlled and predictable fashion. SOgen is
a cheap, solid, and bench-stable reagent, easily accessible in
two steps from bulk chemicals. SOgen is used in combination
with the two-chamber system developed by Skrydstrup.[11]
Using this technique, we demonstrate the compatibility with
previously reported sulfonylation reactions, which normally
use in situ SO2 generation. Furthermore, we report the first
direct aminosulfonylation reaction between aryl halides and
amines (Figure 1 f). The method displays broad functional
Introduction
The sulfonamide moiety is found in a wide range of
pharmaceutical compounds (Figure 1a).[1] Accordingly, the
development of convenient and efficient methods for instal-
ling this functional group has been a long-term interest of
chemists. The classical method for sulfonamide synthesis is
the condensation between sulfonyl chlorides and amines.[2]
Due to their limited commercial availability and sensitivity
toward moisture and basic conditions, the need for sulfonyl
chlorides restricts the applications of this classical method. In
the past decade, strategies for transition-metal-catalyzed
synthesis of sulfonamides have been developed.[3] In the
presence of a palladium or copper catalyst, aryl halides or
pseudohalides can react with SO2 to generate aryl sulfinates,
which subsequently can be oxidized by NaOCl, forming aryl
sulfonyl chlorides. Finally, these aryl sulfonyl chlorides can
À
react with amines, forming S N bond (Figure 1b). The
complexity and handling of this multistep process have
limited its practical applications. Recently, sulfonylative
cross-coupling reactions have received increasing attention
due to diversity and availability of starting materials, straight-
forward reaction procedures, and potential applications in the
[*] X. Jia, Prof. Dr. Z. Lian
Department of Dermatology, State Key Laboratory of Biotherapy and
Cancer Center, West China Hospital, Sichuan University
Chengdu 610041 (China)
E-mail: lianzhong@scu.edu.cn
Prof. Dr. S. Kramer
Department of Chemistry, Technical University of Denmark
2800 Kgs. Lyngby (Denmark)
Prof. Dr. T. Skrydstrup
Carbon Dioxide Activation Center, Interdisciplinary Nanoscience
Center (iNANO) and Department of Chemistry, Aarhus University
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202014111.
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Figure 1. Outline of the importance of sulfonamides for pharmaceuticals and different strategies for their synthesis.
group tolerance including heterocycles, and it can be applied
to pharmaceutically relevant molecules.
Results and Discussion
Inspired by a literature method,[12] we set out to explore
the potential of SO2 release by a Diels–Alder/retro-cyclo-
addition strategy (Scheme 1a). The study was initiated by the
synthesis of SOgen (1), derived from the bromination of
commercially available thiophene (0.02$gÀ1) followed by
oxidation by mCPBA.[13] Using SOgen (1) as an electron-
deficient diene, we screened various dienophiles, such as
dibenzo-fused cyclooctyne (2a), phenylacetylenes (2b–d),
and styrenes (2e,f). Tetradecane was used as the solvent
because of SO2ꢀs poor solubility. The results are summarized
in Scheme 1b. In terms of rapid SO2 release, it quickly
becomes apparent that 4- methyl styrene (2 f) is the best
choice as dienophile reacting with SOgen (1) at 808C and
providing complete SO2 release in just 30 minutes.
To explore the temperature-dependence on SO2 release,
we monitored the yield of byproduct 3 f after 10 minutes at
temperatures between 60 and 1008C in 58C increments
(Scheme 2). A clear correlation is observed, and, at 1008C,
the yield reached 97%. Subsequently, we monitored the yield
Scheme 1. Design of tetrabromothiophene S,S-dioxide (1) as a new
SOgen. [a] The majority of the corresponding dienophile was recov-
ered.
at 1008C from 1 to 10 min. Encouragingly, the yield of 3 f
reached 90% within just 4 minutes and nearly 100% in
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also be applied to aminosulfonylation reactions by
coupling aryldiazonium or anilines with hydrazines
under metal-free conditions. The corresponding
products 5 and 6 were obtained in excellent yields
(Scheme 3-2 and -3).[9k,15] The radical reaction
between naphthols and aryldiazonium tetrafluor-
oborates catalyzed by FeCl3 was also compatible
with gaseous SO2 leading to the sulfonated naph-
thol 7 in 93% yield (Scheme 3-4).[16] Our SO2
precursor could furthermore successfully be uti-
lized in the four-component reaction between
aryldiazonium tetrafluoroborates, sulfur dioxide,
hydroxylamines, and alkenes, generating the de-
sired compound 8 in 80% yield (Scheme 3-5).[17] In
addition, ex-situ-generated gaseous SO2 could be
applied as the source of the sulfonyl group in the
synthesis of (E)-alkenyl sulfone 9 starting from
aryldiazonium tetrafluoroborates and alkenes cat-
alyzed by CuBr2 (Scheme 3-6).[18] Lastly, the two-
chamber method with our new SOgen proved
compatible with small heterocyclic molecules such
as indole and 8-aminoquinoline for producing the
Scheme 2. A) Yields of 3 f in 10 minutes at different temperatures. B) Yields of 3 f in
1 to 10 minutes at 1008C. Reactions in this Scheme were performed under an air
atmosphere at 0.1 mmol scale. Yields were determined by GC using dodecane as an
internal standard.
6 minutes. Overall, these results indicate that complete SO2
release can be achieved rapidly by the Diels–Alder/retro-
cycloaddition strategy.
corresponding 2-sulfonated indole 10[19] and 5-sulfonyl-8-
aminoquinoline amide (11),[20] respectively, through metal-
À
catalyzed direct C H functionalization (Scheme 3-7 and -8).
With the optimal conditions for SO2 release in hand, we
turned to investigating the compatibility of our new SOgen
with previously reported sulfonylation reactions. Ex situ SO2
release was achieved by employing a two-chamber system:
SO2 was generated in Chamber A and consumed in the
sulfonylation reaction in Chamber B. Eight different sulfony-
lation reactions were performed (Scheme 3). In the first
example, 4-bromoaniline reacted smoothly furnishing the
desired homo-coupling product, diarylsulfamide 4, in 90%
yield using 5.5 equiv SO2 (Scheme 3-1).[14] Gaseous SO2 could
After having demonstrated the compatibility of the new
SOgen with various sulfonylation reactions in the two-
chamber system, we set out to investigate the potential of
this method to address a yet unsolved challenge in sulfony-
lation chemistry. Specifically, we were interested in transition-
metal-catalyzed aminosulfonylation between aryl halides and
amines. Although hydrazines have been utilized for amino-
sulfonylation, the use of amines would constitute an impor-
tant advancement providing directly arylsulfonamides, which
are ubiquitous in medicinal chemistry. To initiate the inves-
Scheme 3. Compatibility of ex situ SO2 generation (two-chamber method) from our new SOgen with previously reported sulfonylation reactions.
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Scheme 4. Scope of the palladium-catalyzed aminosulfonylation reactions. Reaction conditions: aryl iodides (0.2 mmol), amine (2.6 equiv), SO2
(6.0 equiv), Pd(acac)2 (12.5 mol%), nBuPAd2 (20.0 mol%), DMAP (2.5 equiv), DMSO, 958C, 24 h. Isolated yields. [a] Using aryl bromide instead
of iodide failed to give the corresponding product.
tigation, we chose to study the cross-coupling of 4-iodo-1,2-
dimethoxybenzene (12a), N-methylphenethylamine (13a),
and sulfur dioxide as a model reaction (Scheme 4). It was
found when employing Pd(acac)2 (12.5 mol%) and nBuPAd2
(20 mol%) as the catalyst system, DMAP (2.5 equiv) as base,
and DMSO as the solvent, the desired sulfonamide 14a could
be formed in a satisfying 74% yield.[21] Specific deviations
from the optimized conditions and the corresponding effect
on reaction efficiency are also shown in Table 1. Solvent
effects were very pronounced for this reaction as DMSO
proved to be the only solvent compatible for this trans-
formation (Entry 1). Both nitrogen and phosphine ligands
could be utilized for the aminosulfonylation, however,
nBuPAd2 (L7) turned out to be the most effective ligand
(Entry 2). Other bases than DMAP were tested for the
aminosulfonylation. In general, they decreased the product
yield compared to DMAP, while switching to NaOtBu
completely inhibited the reaction (Entries 3–7). Lastly, the
amount of sulfur dioxide had an impact on the reaction
outcome. An increase in yield was observed with up to
6.0 equiv SO2. The addition of more than 6.0 equiv SO2 led to
reduced yields probably due to poisoning of the palladium
[10b]
catalyst by excess SO2 (Entry 8). Using DMAP·SO2
and
DABSO as SO2 surrogate both had a negative influence on
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Table 1: The optimization of palladium-catalyzed aminosulfonylation
reactions.
sulfonamides in 56–80% yields (14h–l). Electron-neutral aryl
iodides underwent the aminosulfonylation affording arylsul-
fonamides (14m–o). The high reactivity of the aryl iodides
allowed for the synthesis of sulfonamides bearing fluoro,
chloro, and bromo substituents (14p–r). A strong electron-
withdrawing group represented by a carboxylate ester was
tolerated, but the product 14s was isolated in a moderate
yield. Aryl iodides in more complex structures reacted well
under optimal reaction conditions, and the corresponding
products were obtained in moderate to good yields (14t–v).
Next, various amine fragments were evaluated in combi-
nation with different aryl iodide coupling partners. A series of
N-methyl phenylmethanamines performed well, providing
the corresponding sulfonamides (14w–aa) in 62–71% yields.
Notably, electronic properties of the substituents on the
N-methyl phenylmethanamines had little influence on the
catalytic efficiency. Acyclic aliphatic amines were compatible
with the protocol leading to 66–72% yields of the desired
products (14ab,ac). Octahydro-isoindole could couple with
different aryl iodides producing sulfonamides in an efficient
manner (14ad,ae). Furthermore, the aminosulfonylation
protocol worked well for other cyclic amines, such as indoline,
piperidine, and piperazine derivatives as well as an aliphatic
amine containing a silyl ether, thus allowing the synthesis of
14af–aj in 47–70% yields. Morpholine proved to be a suitable
amine substrate for this coupling reaction, affording the
desired products in 60% yield (14ak). Unfortunately, more
steric secondary amines (14al–ao) and primary amine (14ap)
failed to proceed this aminosulfonylation.
Entry
Variation from standard conditions
Yield [%][b]
1[c]
2[d]
3
other solvents instead of DMSO
Ligand 1–6 instead of Ligand 7
NaOtBu instead of DMAP
0
33–63
0
4
KF instead of DMAP
19
5
K3PO4 instead of DMAP
29
6
Cs2CO3 instead of DMAP
19
7
DABCO instead of DMAP
38
8
3.0, 4.0, 5.0,7.0 equiv SO2 in place of 6.0
DMAP·SO2 as SO2 surrogate
DABSO as SO2 surrogate
44–61
46
35
9[e]
10[e]
11[f]
Na2SO3 and conc. H2SO4 as SO2 surrogate
29
[a] Isolated yield. [b] Yields were determined by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as the internal standard. [c] Other
solvents include nbutyl ether, DMF, NMP, xylenes, and anisole.
[d] Ligands 1–3 and 6 (10.0 mol%); ligands 4 and 5 (20.0 mol%).
[e] SOgen (2.5 equiv) and reactions were carried out in a 4.0 mL vial.
[f] Chamber A: Na2SO3 (1.2 mmol, 152 mg) was dissolved in water
(1.0 mL), and conc. H2SO4 (1.5 mmol, 80 mL) was added dropwise in two
minutes at room temperature.
To highlight the compatibility of the aminosulfonylation
with pharmaceutically relevant molecules, we explored four
different amines that are either active pharmaceutical ingre-
dients (APIs) or closely related derivatives. Direct amino-
sulfonylation with these substrates that bear different nitro-
gen-containing heterocyclic motifs and functional groups,
proceeded well, allowing the incorporation of amine frag-
ments from enoxacin, amoxapine, desloratadine, and fenodo-
pam in moderate to good yields (14aq–at).
the yield of product (Entries 9 and 10). Ex-situ-formed SO2
[5d]
using Na2SO3 and conc. H2SO4
only gave the desired Conclusion
product in 29% yield, since the mositure in the reaction
system probably disturbed the transformation (Entry 11).
Having established the feasibility of palladium-catalyzed
sulfonamide synthesis in a two-chamber system, we next
investigated the scope of this transformation with respect to
both aryl iodides and amines. First, a variety of aryl iodides
were examined employing N-methyl-2-phenylethan-1-amine
(13a) as the amine coupling partner. In general, the amino-
sulfonylation tolerated various substituted aryl iodides pro-
viding the desired products in moderate to good yields
(14a–v). More specifically, electron-donating substituents
(e.g., 4-ethoxy, 4-phenoxy, 2- and 3-methoxyl, and 3,4-ethyl-
enedioxy) on the phenyl ring were compatible with the
transformation (14b–f). Notably, a potentially catalyst-poi-
soning thioether was compatible with the transformation,
producing the corresponding product 14g in a good 66%
yield. A series of alkyl-substituted (Me, Et, tBu) and cyclic
alkyl-substituted iodobenzenes afforded the corresponding
In summary, we have designed SOgen, which is cheap,
easily accessible, and bench-stable. This gas surrogate releases
SO2 in just a few minutes when heated in the presence of
a styrene. Subsequently, the compatibility of this gas-releasing
protocol with eight previously reported sulfonylation reac-
tions was demonstrated in a two-chamber system. Finally, we
developed the first method that allows use of amines in
aminosulfonylation reactions with aryl halides and SO2.
Broad functional group tolerance was demonstrated, and
the method can be applied to the preparation of pharmaceuti-
cally relevant substrates bearing a sulfonamide, including
heterocycle-containing substrates. SOgen has the limitation of
generating 6.0 equiv of an organic by-product when used in
the aminosulfonylation reactions, and efforts are underway to
reduce the amount of SOgen used. Overall, SOgen is
complementary to the existing SO2 surrogates.
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Acknowledgements
This work is supported by the National Natural Science
Foundation of China (21901168), “1000-Youth Talents Plan”,
and Sichuan University (Z.L.). S.K. thanks the Lundbeck
Foundation (R250-2017-1292) and the Technical University of
Denmark for generous financial support. T.S. is highly
appreciative of funding from the Danish National Research
Foundation (DNRF118), NordForsk (85378), and Aarhus
University.
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Conflict of interest
T.S. is co-owner of SyTracks A/S, which commercializes
COware (the two-chamber technology).
Keywords: aminosulfonylation ·aryl halides ·cross-couplings ·
SO2 surrogates ·sulfonamides
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