Keywords sulfonamides - S−N bond formation - C−N cross-coupling - N−H functionalization - C−H
amination
Introduction
Sulfonamide is one of the most representative small-molecule drug modification groups.
In drug discovery, the sulfonamide group has significant electron-withdrawing properties,
hydrolysis stability, polarity, hydrogen bonding ability, and good resistance to reduction
and oxidation. It has the effects of increasing hydrophilicity and changing the site
of action in drug design. Many commercial therapeutic drugs contain a sulfonamide
group ([Fig. 1 ]).[1 ]
[2 ] At present, sulfonamides have been listed as one of the priority structural motifs
in the pharmaceutical industry. In 2019, sulfonamides accounted for 25% of all sulfur-containing
drugs approved by the Food and Drug Administration (FDA), and their application in
medicinal chemistry has been extended to antibiotics and treatable diseases such as
cancer, central nervous system diseases, diabetes, and dementia.[3 ]
Fig. 1 Representative sulfonamide drugs.
With good physical and chemical properties and metabolic stability, sulfonamide compounds
have been pushed to the forefront of modern bioactive molecular design. Their synthesis
and modification methods have attracted the interest of many researchers. The construction
method of sulfonamide structure has become one of the research hotspots in the field
of drug synthesis. In this review, we intend to analyze and evaluate the synthetic
methods for sulfonamides in recent years, as well as briefly introduce the latest
progress in their synthesis and modification from the perspective of green and practical
chemistry. According to the existing reports, the synthesis schemes for sulfonamides
can be easily divided into four categories through analysis of synthesis and modification
methods for sulfonamides: S−N bond construction, C−N bond cross-coupling, N−H bond
functionalization, and C−H bond amination ([Fig. 2 ]). This article will discuss the new technologies following the above construction
methods.
Fig. 2 Synthesis and derivatization of sulfonamides.
Construction of S−N Bond
In the chemical structure of sulfonamides, the S−N bond is the most easily formed
chemical structure. Usually, sulfonamides can be prepared in high yields by amidation
reaction with sulfonyl chloride or sulfonic acid. This method ranks among the most
classic sulfonamide synthesis processes. At present, most simple sulfonamide drug
intermediates are synthesized by this method.
Although the methods usually provide high yields and low prices, they still suffer
from many problems from an environmental protection perspective. The active groups
such as intermediate sulfonic acid and sulfonyl chloride need to be synthesized by
chlorosulfonic acid, concentrated sulfuric acid, and other chemicals. These reagents
are highly acidic and polluting, making them unsuitable for unstable intermediates.
The sulfonation reaction is a dangerous process, so this method is mainly used for
simple aryl sulfonamide drug intermediates.
In view of the above problems, recent studies have found a new strategy for the construction
of sulfonamides by catalytic oxidation, which usually occurs through a free radical
or ionic mechanism under the interaction of S reagent, N reagent, and oxidant. Sulfinic
acid and its salts, sulfur, and sulphonates are usually used as the S reagents. Aliphatic
amines and aromatic amines are usually used as the N reagents. In the oxidizing construction
of S−N bonds, the oxidants can facilitate the oxidation of S reagents, enabling the
resulting active species to react with N reagents and form S−N coupling products.
In the process, mild oxidants such as hypervalent iodine compounds and copper salts
are often selected, so that the starting compounds are not over-oxidized. As a simple,
effective, and environmentally friendly sulfonamide synthesis method, it is widely
used in organic chemistry and pharmaceutical chemistry. The most critical factor is
the choice of S reagent, N reagent, and oxidant.
S-reagents from Thiols or Disulfides for S−N Construction
The catalytic oxidative sulfonylation of thiols has attracted much attention due to
the availability of raw materials, low cost, and high efficiency. Zhu et al reported
a method for synthesizing sulfonamides via oxidative S−N coupling between aryl thiols
and amines under mild, metal-free conditions using an I2 O5 -mediated reaction ([Fig. 3 ]).[4 ] This method avoids the use of metals and peroxides and affords a variety of sulfonamides
in moderate to good yields.
Fig. 3 Construction of sulfonamides from thiols and amines.
In 2018, Tota's group reported the conversion of thiols to sulfonimidates and sulfonamides
in methanol. For thiols containing substituted alkoxy groups, conversion to sulfonamides
occurs in the presence of lower ammonia concentrations, but extended reaction times
are required ([Fig. 3 ]).[5 ] The product distribution in the reaction highly depends on the electronic structure
of the aryl group. This method applies to thiols containing polysubstituted aromatics,
electron-rich heterocycles, and alkyl groups, with good yields. A drawback of this
process is the poor tolerance of amines and thiols to strong oxidants.
Recently, Hayashi et al found that (β-MnO2 -HS) nanoparticles with high specific surface area can be used as an effective and
reusable bifunctional solid catalyst for the oxidative sulfonylation of thiols ([Fig. 3 ]).[6 ] By utilizing molecular oxygen and ammonia as oxygen and nitrogen sources, both aromatic
and heteroaromatic thiols can be oxidized in a single step to produce primary sulfonamide
compounds without additives. Recently, Kushwaha et al introduced an eco-friendly,
metal-free photoredox-catalyzed method for synthesizing sulfonamides using eosin Y
and thiols with phenylhydrazines in MeCN:H2 O ([Fig. 3 ]).[7 ] This approach offers a broad substrate scope, excellent functional group compatibility,
and efficient production of pharmaceutical analogues under mild conditions.
As a green and efficient synthesis method, electrochemistry can solve the problems
of transition metals, toxic solvents, excessive oxidants, and cumbersome purification
processes in the production of pharmaceutical products. Laudadio et al reported an
electrochemical method for the oxidative coupling of thiols and amines to obtain sulfonamides
([Fig. 4 ]),[8 ] enabling S−N bond formation and subsequent sulfur atom oxidation at room temperature,
thus avoiding transition metal catalysis and hazardous reagents. Due to the malodorous
properties of thiol compounds, Blum et al recently proposed the first method for electrochemical
synthesis of sulfonamides by dehydrogenation ([Fig. 4 ]),[9 ] when using the inherent reactivity of (heterocyclic) aromatic hydrocarbons, sulfonamides
can be selectively synthesized by polymerization of sulfamate intermediates with SO2 and amines in the presence of boron-doped diamond electrode and HFIP–MeCN mixed solvent.
Because this method avoids harsh conditions and can be scaled up for continuous systems,
it is more conductive to industrial adoption. In addition, Vicente et al realized
the electrochemical synthesis of sulfonamides from sodium arylsulfinates by using
graphite powder rough electrode and LiClO4 as an electrolyte in a cavity cell ([Fig. 4 ]).[10 ] This method is especially suitable for rapid and efficient synthesis of complex
sulfonamides.
Fig. 4 Electrochemical synthesis of sulfonamides.
Thiosulfonate is a stable and nontoxic metal sulfite substitute because of its easy
catalytic aerobic dimerization reaction and good reactivity with various amines. Shyam's
group reported a method for synthesizing sulfonamides via direct coupling of thiosulfonates
with amines in the presence of Cs2 CO3 and N -bromosuccinimide or under copper-catalyzed conditions ([Fig. 5 ]).[11 ]
[12 ] Among them, the thiosulfonate is cracked by the nucleophile to form a sulfite anion,
which then reacts with the amine group to obtain the required sulfonamide. Because
the reaction has characteristics such as simple reaction mode and high yields, it
can be used as an effective synthesis strategy.
Fig. 5 Synthesis of sulfonamides via thiosulfonates.
Sulfosalts as the Sulfur Source
Sulfur dioxide insertion is considered to be an effective strategy for the synthesis
of sulfonyl-containing compounds. For example, sulfur dioxide substitutes, such as
K2 S2 O5 and 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO) have been used as starting
materials to introduce sulfonyl groups into small molecules to obtain various functional
sulfonamides. Compared with traditional sulfide oxidation, this method is highly compatible
with different functional groups present in the compound molecules, providing an effective
way for the conversion of sulfonamide compounds.
Sulfur-Containing Organic Salts as the Sulfur Source
Sulfites have been widely used as an S reagent for oxidative S−N coupling due to their
easy oxidation to S-centered sulfonyl radicals. Compared with sulfonyl chloride, they
have characteristics such as moisture resistance and easy synthesis. Alvarez et al
have reported a method for obtaining aryl sulfonamides through C−H sulfonation of
thianthrenium salts ([Fig. 6 ]).[13 ] Utilizing inexpensive and readily available sodium hydroxymethylsulfinate (Rongalite)
as a coupling agent, aryl hydroxymethyl sulfones (intermediate A ) were generated under the catalysis of Pd(dppf)Cl2 , which then lost formaldehyde to form aryl sulfites in the presence of alkali. Finally,
sulfonamides B were obtained by oxidative amination with morpholine. To further prove the practicability
of this method, the authors have also realized the postfunctionalization of some complex
active drugs through experiments and found that when the solubility of raw materials
in the solvent isopropanol is low, the conversion rate decreases. However, the conversion
rate can be improved by using polar aprotic acetonitrile as a co-solvent.
Fig. 6 Thianthrenium salts for palladium-catalyzed coupling with rongalite toward synthesis
of sulfonamides.
Sodium arylsulfinate is an effective aryl reagent with advantages such as stability
and ease of operation. Eid et al first revealed a sustainable method for one-step
synthesis of sulfonamides using sodium arylsulfinate as a sulfur source ([Fig. 7 ]).[14 ] The key step of the reaction is the nucleophilic attack of the sulfur atom by the
nitro group of the substrate, forming the S−N bond before the N−O bond is reduced
by sodium bisulfite, leading to the formation of sulfate ions and sulfonamide groups.
As a result, electron-deficient nitroarenes are more reactive than their electron-rich
counterparts.
Fig. 7 Synthesis of n -arylsulfonamides from nitroarenes and sodium sulfinate.
Additionally, Li et al reported a method for synthesizing N -arylsulfonamides through the reaction of sodium arylsulfinate with nitroaromatics,
utilizing an iron-based metal-organic framework MIL-101 (Fe) as the catalyst and water
as a solvent, offering benefits such as recyclable catalytic system, high chemical
selectivity, and high yields ([Fig. 7 ]).[15 ]
Yang et al reported a one-step direct reduction coupling reaction of nitroarenes and
sodium arylsulfinates using an inexpensive Pd/C catalyst ([Fig. 7 ]).[16 ] In this process, sodium arylsulfinate acts as both a sulfur source and a reducing
agent. This method, without the need for additional reducing agents or ligands, features
low catalyst loading, good functional group tolerance, and high efficiency, providing
a straightforward synthesis strategy for producing N -arylsulfonamide. Gatarz et al have devised an innovative method for the synthesis
of (hetero)aryl sulfonamides via the reductive coupling of nitro-heteroarenes with
aryl sulfinates, utilizing sodium bisulfite, optionally in the presence of SnCl2 , in DMSO ([Fig. 7 ]).[17 ] Enhanced by ultrasound to optimize reaction homogeneity, this method presents a
valuable alternative to conventional sulfonamide synthesis, particularly advantageous
for the production of heteroaryl derivatives. The research further elucidates the
transformation mechanism by identifying nitrosoarene intermediates.
Similarly, Poeira's group[18 ] has developed a sulfonylation method using hypervalent iodine reagents, with sodium
arylsulfinate as a sulfur source ([Fig. 8 ]). This method employs the polarity reversal and atomic transfer properties of benzoimidazole
derivatives to combine sulfonyl groups with aliphatic or aromatic amines. As an environmentally
friendly approach, it provides sulfonamides with moderate to excellent yields on a
gram-scale. Lam et al have established an innovative copper-catalyzed S−N coupling
method for synthesizing sulfonamides from sodium arylsulfinates and aryl amines ([Fig. 8 ]).[19 ] This approach utilizes stable solid chemicals in sulfolane or environmentally friendly
solvents with acetic acid, effectively accommodating a range of functional groups
commonly found in pharmaceuticals. The reaction mechanism involves radical coupling
between sulfonyl and anilinium radicals facilitated by K2 S2 O8 and a copper catalyst. Recently, Dong's group has developed an innovative method
for the selective synthesis of sulfenamides using I2 as a catalyst ([Fig. 8 ]).[20 ] This approach offers mild reaction conditions, a wide substrate scope, and high
efficiency, making it highly suitable for drug discovery and scalable synthesis.
Fig. 8 Synthesis of sulfonamides from sodium sulfinates and amines.
Sulfur-Containing Inorganic Salts as the Sulfur Source
The insertion of sulfur dioxide by combining stable and safe sodium pyrosulfite or
potassium pyrosulfite with nitroaromatics offers a rapid method to obtain sulfonamides.
Jiang's group first introduced a metal-free, three-component reaction method for the
construction of primary sulfonamides using arenediazonium tetrafluoroborates, sodium
pyrosulfite (Na2 S2 O5 ), and sodium azide ([Fig. 9 ]).[21 ] This method was used to synthesize the nonsteroidal anti-inflammatory drug celecoxib
and the antipsychotic drug sulpiride, demonstrating the practicability of this three-component
coupling approach. However, further study is needed to avoid the use of hazardous
sodium azide.
Fig. 9 Construction of primary sulfonamides through arenediazonium, Na2 S2 O5 , and NaN3 .
Mechanistic studies revealed that an aryl radical intermediate is generated through
a single electron transfer between the arenediazonium salt and triphenylphosphine.
This intermediate reacts with Na2 S2 O5 to form a sulfonyl radical, releasing Na2 SO3 . The sulfonyl radical then couples with a conjugated phosphine imine radical intermediate,
followed by hydrolysis to yield the sulfonamide compound.
According to the report by Marset et al, Na2 S2 O5 , nitro compounds and nontoxic triaryl bismuth were used to obtain sulfonamide compounds
under copper-catalyzed reaction conditions, using a deep eutectic solvent (DES) as
a green reaction solvent ([Fig. 10 ]).[22 ] In this process, triaryl bismuth reacts with 3 equiv. of Na2 S2 O5 , demonstrating high atom economy. The bismuth salt produced by the reaction can be
easily removed by water precipitation, and the generation of toxic organic by-products
can be avoided. Therefore, it can be used as a green and effective method for the
synthesis of sulfonamides.
Fig. 10 Sequential C−S and S−N coupling approach to sulfonamides.
Recently, Wu's group reported a copper-catalyzed three-component reaction of arylboronic
acids, nitroarenes, and potassium pyrosulfite (K2 S2 O5 ), to obtain sulfonamides ([Fig. 10 ]).[23 ] Among them, the interaction between arylsulfinates, as intermediates, and nitroarenes,
is a key step in the reaction, which has good tolerance to functional groups such
as hydroxyl, cyano, amino, and carbonyl groups, and is extended to the synthesis of
currently marketed drugs (flutamide) in good yield. In the same year, Chen et al reported
a method for the synthesis of sulfonamides by continuous C−S and S−N coupling reactions
of nitroaromatics, (hetero)arylboronic acids, and K2 S2 O5 under metal-free catalytic conditions ([Fig. 10 ]).[24 ] The scheme is compatible with a range of electron-rich and electron-deficient boric
acids, though it is not suitable for nitroaromatics containing hydroxyl and formyl
groups. The expected sulfonamide compounds can be isolated in good yield by amplifying
more complex bioactive molecules into gram-scale preparation, validating the practicability
of this heavy metal-free synthesis method.
In addition, using K2 S2 O5 as a substitute for SO2 , Manabe's group first reported a method for selective synthesis of cyclosulfonamides
and sulfinamides with amino-containing halogenated aromatic hydrocarbons under palladium
catalysis ([Fig. 11 ]).[25 ] The alkali concentration is crucial for the selective synthesis. Through mechanism
research, amino-containing halogenated aromatic hydrocarbons are first inserted into
sulfur monoxide to form sulfinamides, and then oxidized to sulfonamides under the
action of iodine ions and dimethyl sulfoxide. Among them, iodide as an oxidant and
dimethyl sulfoxide as an oxygen source play important roles in the formation of sulfonamides.
However, the reaction mechanism of sulfonamide formation needs to be further explored.
Fig. 11 Pd-Catalyzed selective synthesis of cyclic sulfonamides using K2 S2 O5 .
Recently, Mkrtchyan and Iaroshenko achieved a three-component coupling reaction of
K2 S2 O5 , primary or secondary amines with aryl bromides or aromatic carboxylic acids via
a mechanochemical method under palladium-catalyzed conditions ([Fig. 12 ]).[26 ] This novel green synthesis strategy enables the production of sulfonamides with
diverse structures and broad functional group tolerance. It is worth mentioning that
this method can be prepared on a gram scale with a yield of 69 to 80%.
Fig. 12 Mechanochemical synthesis of aromatic sulfonamides.
DABSO as Sulfur Source
DABSO is a stable, air-resistant reagent that safely facilitates the introduction
of sulfonyl groups into molecules, making it an ideal sulfur source for the construction
of sulfonamides.
Du et al reported a highly selective oxidative coupling reaction of DABSO with hydrazine
and amines under copper-catalyzed conditions, achieving sulfonamide compounds in good
yields ([Fig. 13 ]).[27 ] The reaction can be carried out under mild reaction conditions without other additives.
However, there is a need to use excessive amines and hydrazine nucleophiles. Chen
et al developed a Cu(II)-catalyzed one-step synthesis of sulfonamides by replacing
hydrazine with boric acid, utilizing (hetero)arylboronic acids, amines, and DABSO
([Fig. 13 ]).[28 ] This reaction is compatible with aryl, heteroaryl, and alkenylboronic acids, as
well as cyclic and acyclic secondary amines and primary amines, and has a wide range
of functional group tolerance. The author verified the good reactivity of the method
through a variety of complex drugs and active drug molecules. Notably, these complex
drug molecules yield the expected sulfonamide compounds under standard reaction conditions,
though the related reaction mechanism remains under investigation. In previous studies,
electron-deficient amines exhibited poor reactivity. Recently, Zhang et al developed
a method leveraging synergetic photoredox and copper catalysis for the synthesis of
sulfonamides from various aryl radical precursors, amines, and a sulfur dioxide source
under ambient conditions ([Fig. 13 ]).[29 ] This one-step process effectively accommodates both electron-rich and electron-deficient
amines. Oxygen in the air plays a critical role, facilitating the catalytic cycles.
The method shows excellent functional group compatibility and broad substrate applicability,
successfully enabling the synthesis of sulfanitran and an N -aryl sulpiride derivative.
Fig. 13 Copper-catalyzed three-component synthesis of sulfonamides.
Additionally, Willis' group pioneered a nickel (II)-catalyzed (hetero)arylboronic
acid sulfonation reaction under neutral redox conditions ([Fig. 14 ]).[30 ] By using commercially available and air-stable phenanthroline ligands NiBr2 •(Glyme) and DABSO, boric acid can be effectively converted into corresponding sulfinates,
which can be further converted into active pharmaceutical molecules containing sulfonyl
groups such as sulfonamides. Notably, the reaction achieves good yields of sulfonamides
from both electron-rich and electron-deficient aryl and heteroarylboronic acids and
can be scaled up to a gram-scale with just 2.5 mol% catalyst dosage.
Fig. 14 Nickel-catalyzed preparation of sulfonamides from aryl and heteroaryl boronic acids.
Similarly, sulfite served as a key intermediate in the transformation process. Tu's
group developed a bimetallic-catalyzed sulfonamide reaction of DABSO with O -benzoylhydroxylamine without ligand participation. In this method, aryl iodides or
arylboronic acids were used as aryl sources, and low-loading Pd(OAc)2 and CuBr2 were used as catalysts. Under mild reaction conditions, sulfonamide compounds were
obtained in good yield by one-pot reaction ([Fig. 15 ]).[31 ]
[32 ] The reaction performs better with substrates having electron-donating groups but
shows reduced efficacy with sterically hindered substrates.
Fig. 15 Aminosulfonylation of DABSO with O -benzoyl hydroxylamines. DABSO, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide).
In the absence of a catalyst, Wu's group reported an effective way to prepare sulfonamides
by a one-pot two-step continuous reaction with DABSO as a sulfur source ([Fig. 16 ]).[33 ] The three-component reaction of aryldiazotetrafluoroborate, DABSO, and an amine
in the presence of N -hydroxybenzotriazole yields sulfonamide compounds in good amounts. Among them, the
tertiary amine radical cation produced by the reaction of aryldiazotetrafluoroborate
with DABSO extracts the H atom from the nucleophilic substrate to produce a free-radical
intermediate, which is then captured by the sulfonyl group, to form a sulfonated product.
In addition, the research group reported the aminosulfonylation of aryldiazotetrafluoroborate
and DABSO, with chloramine as an electrophilic amine source under copper-catalyzed
conditions ([Fig. 16 ]).[34 ] As a simple and effective method, the coupling reaction shows a wide range of substrates.
In addition, the author also described the mechanism that may involve free-radical
processes and transition metal catalysis.
Fig. 16 Aminosulfonylation of aryldiazonium tetrafluoroborates with DABSO. DABSO, 1,4-diazabicyclo
[2.2.2] octane bis (sulfur dioxide).
Sulfonyl Fluorides
Nowadays, green chemistry encourages the design of process routes that can reduce
or eliminate the use and production of harmful substances. Sulfonyl fluorides are
considered an attractive alternative to sulfonyl chlorides due to their excellent
stability and adjustable reactivity. Sharpless coined the term “sulfur (VI) fluoride
exchange (SuFEx) chemistry” to emphasize the unique reactivity associated with the
S (VI)−F bond, and the corresponding sulfonyl fluorides have received increasing attention
in drug discovery and other aspects.[35 ] For example, Willis' group reported a method for preparing sulfonamides from alkenyl
sulfonyl fluorides.[36 ]
Ball's group utilized calcium trifluoride [Ca(NTf2 )2 ] as Lewis acid to activate less active sulfonyl fluoride in tert -amyl alcohol, followed by nucleophilic addition with amines to produce various aryl,
alkyl, and heteroaryl sulfonamides ([Fig. 17 ]).[37 ] This may be transformed by the interaction between divalent cations and triflimide
anion. Moreover, they also reported a method for efficiently obtaining sulfonamides
by activating sulfonyl fluorides at room temperature with calcium triflimide and DABCO.[38 ] Compared with previous work, this method can obtain comparable or improved yields
at lower reaction temperatures while significantly increasing the reaction rate.
Fig. 17 Amidation of sulfonyl fluorides with amine.
Although the above scheme is also effective for the activation of less active sulfonyl
fluoride, completion of the reaction requires the participation of stoichiometric
calcium activators. Li's group developed a broad-spectrum synthesis method for the
synthesis of sulfonamides from sulfonyl fluorides ([Fig. 17 ]).[39 ] High yields of sulfonamide compounds are achieved under the combined catalysis of
1-hydroxybenzotriazole (HOBt) and silicon additives, making this protocol particularly
effective for substrates with large steric hindrance. It has been successfully applied
in the synthesis of the orphan drug fedratinib for the treatment of bone marrow fibrosis
in gram-scale preparation, which was approved by the U.S. FDA recently.[40 ] The original synthesis route for fedratinib involved early-stage amidation of sulfonyl
chloride with tert -butylamine, followed by two nucleophilic aromatic substitutions. In contrast, Li's
group utilized readily available 3-nitrobenzenesulfonyl fluoride as the starting material.
Through a sequence of reduction and nucleophilic aromatic substitutions, they generated
a key intermediate, sulfonyl fluoride. This intermediate was then amidated to produce
the desired product, fedratinib, achieving a yield of 93% and a final product weight
of 1.22 g ([Fig. 17 ]). The use of sulfonyl fluoride enables late-stage functionalization and diversification
at the sulfonamide terminal, facilitating the development of fedratinib analogues
for further biological screening.
Recently, Lin et al have developed an organocatalytic SuFEx reaction employing N -heterocyclic carbene (NHC) to effectively mediate the transformation of sulfonyl
fluorides with amines ([Fig. 17 ]).[41 ] NHCs function as carbon-centered Brønsted bases, facilitating substrate activation
through hydrogen bonding. This approach provides mild reaction conditions, broad substrate
compatibility, high yields, and scalability, establishing a robust platform for synthesizing
a diverse array of valuable sulfonamide compounds.
C−N Cross-Coupling
The synthesis of sulfonamides through C−N bond formation is a widely used transformation
method in pharmaceutical chemical synthesis. The critical structural motif in these
important compounds is N -(hetero)aryl sulfonamides. Although the technique of direct cross-coupling of amines
with aryl halides has advanced rapidly, the reduced nucleophilicity of sulfonamides
compared to alkylamines remains a significant challenge.
Due to the lower nucleophilicity of sulfonamides relative to nucleophilic substrates
like alkylamines, achieving metal-catalyzed C−N cross-coupling reactions with sulfonamide
is challenging, particularly with (hetero)aryl chlorides or phenol derivatives. Zu
et al reported a copper-catalyzed chemoselective Chan–Evans–Lam cross-coupling reaction
between unprotected aminobenzenesulfonamides and arylboronic acids to synthesize N -arylsulfonamides ([Fig. 18 ]).[42 ] Notably, the N -arylation of aminobenzene sulfonamide on either the amino or sulfonamide nitrogen
atoms can be tuned by varying the reaction conditions, such as the copper catalyst,
solvent, and base source, at room temperature and in the presence of air. However,
the rate of this reaction is somewhat low and thus needs to be improved.
Fig. 18 Chemoselective N -arylation of aminobenzene sulfonamides.
Palladium-catalyzed C−X (X=C, N, O, S) coupling reactions are classic methods for
forming carbon–nitrogen bonds, with the effectiveness hinging on suitable biarylphosphine
ligands. Shashank' group developed a library of biarylphosphines, which have been
applied as ligands in palladium-catalyzed cross-coupling reactions, such as those
involving aryl sulfonamides ([Fig. 19 ]).[43 ] Their various ligand combinations enhance the reductive elimination steps in the
palladium-catalyzed formation of aryl sulfonamides, effectively catalyzing reactions
of aryl bromides, aryl chlorides, and aryl trifluorides with (alkyl) aryl sulfonamides.
Fig. 19
N -Arylation of primary sulfonamides and secondary sulfonamides.
Among tertiary sulfonamides, N ,N -diaryl sulfonamides are challenging to obtain via arylation due to the low nucleophilicity
of secondary sulfonamides.[44 ] Dobereiner's group introduced a simple and efficient Pd/AdBippyPhos catalyst system
to achieve N -arylation of secondary sulfonamides ([Fig. 19 ]).[45 ] This method demonstrated the catalyst's adaptability to various heterocyclic electrophiles
and sulfonamide structures, consistently yielding a range of N ,N -diaryl sulfonamide compounds with pharmaceutical relevance. Compatible heterocycles
include substituted pyridines, pyrazines, thiazoles, thiophenes, furans, benzothiazoles,
and azaindoles. However, five-membered N-containing heterocycles like pyrroles and
pyrazoles remain challenging. Notably, several tertiary sulfonamide products have
been successfully isolated on a 0.2–2 mmol scale with yields ranging from good to
excellent. Additionally, the above N -arylation reactions of primary and secondary sulfonamides have been validated through
targeted high-throughput experiments to confirm their practicability and effectiveness.
In metal-catalyzed C−N cross-coupling reactions, nickel is an effective substitute
for copper or palladium due to its low price and tendency to participate in oxidative
addition. However, the reductive elimination of Ni(II)C−NR2 as a high-barrier step limits its wide application. MacMillan's laboratory utilized
the excited state of a nickel photocatalyst to facilitate the challenging C−N bond
reductive elimination step, developing an efficient nickel-catalyzed method for the
formation of C−N bonds between primary sulfonamides and aryl electrophiles ([Fig. 20 ]).[46 ] Although this technology provides a broad pathway for the N -(hetero)aryl sulfonamide motif, it has poor catalytic performance for (hetero)aryl
chlorides and phenol derivatives.
Fig. 20 Synthesis of sulfonamides by nickel-catalyzed cross-coupling of C−N.
Thus, Mcguire et al reported a nickel-catalyzed C−N cross-coupling reaction of primary
(secondary) sulfonamides with (hetero)aryl chlorides ([Fig. 20 ]).[47 ] The reaction employs a “photoless redox” method complementary to the work of MacMillan's
group. The design of (L)NiCl (o -tol) precatalysts (L=PhPAd-DalPhos and PAd2 -DalPhos) featuring diphosphine auxiliary ligands is noteworthy for enabling nickel-catalyzed
C−N cross-coupling. The sulfonamide N -arylation reaction is effective for (hetero)aryl chlorides and phenol derivatives
and adapts to many (hetero) aryl electrophiles (X=Cl, Br, I, Ots, and OC(O)NEt2 ).
You and Li have introduced a novel C−N cross-coupling reaction utilizing Ni(cod)(DQ)
as a single-component catalyst ([Fig. 20 ]).[48 ] This advancement enables the synthesis of N ,N -diarylsulfonamides from N -arylsulfonamides and aryl bromides without the need for additional ligands. The method
demonstrates broad compatibility with both electron-deficient and electron-rich aryl/heteroaryl
bromides. Notably, this approach is distinguished by its simplicity, air stability,
rapid reaction times, and suitability for gram-scale synthesis. This study represents
the first application of Ni(cod)(DQ) for C−N cross-coupling under these specific conditions.
Recently, Song et al presented a Ni-catalyzed photochemical C−N coupling of (hetero)aryl
chlorides with sulfonamides ([Fig. 20 ]),[49 ] employing mild organic amines as the base and removing the need for an external
photocatalyst. This method is distinguished by its broad substrate scope and excellent
functional group tolerance, enabling selective coupling even in the presence of multiple
NH2 groups. The utility of this protocol is demonstrated through the synthesis and late-stage
modification of pharmaceutical compounds, providing a cost-effective and practical
solution for electron-rich (hetero)aryl chlorides.
N−H Functionalization
Pre-synthesis of sulfonamide groups through early C−N bond formation reactions may
limit the type of functional groups on the sulfonamide substituents, resulting in
incompatibility of downstream chemical functional groups. Post-functionalization of
sulfonamide compounds offers an effective solution to this limitation. The functionalization
of sulfonamides can be achieved by using different reactants, such as sodium arylsulfinate,
ketones, alcohols, olefins, aldehydes, boric acid, etc.
For the later functionalization of sulfonamides, Fier's and Cornella's groups reported
a general method for converting complex primary sulfonamides into various common functional
groups by in situ formation of sulfinates under mild reaction conditions ([Fig. 21 ]).[50 ]
[51 ] Based on the fact that sulfites are easily converted to other functional groups
by electrophilic capture or loss of sulfur dioxide,[52 ] primary sulfonamides can be condensed with aldehydes to form sulfonylimide intermediates
under mild conditions, and then release nitrile by-products, which are finally converted
into sulfites. Notably, this late-stage functionalization method exhibits excellent
selectivity, even in the presence of other amino groups in primary sulfonamides. This
approach has been validated with several complex primary sulfonamide drugs. Additionally,
it is suitable for the gram-scale preparation of new sulfonamide derivatives, illustrating
the value of this predictable and high-yield post-functionalization technique. The
method's utility is further highlighted by its ability to enable rapid access to 15 N-labeled sulfonamide drugs directly from their 14 N parent molecules, without requiring multistep syntheses. This capability is particularly
valuable for supporting pharmacological studies in drug discovery.
Fig. 21 Late-stage functionalization of primary sulfonamides.
In addition to the simple C−N bonding reaction, the secondary sulfonamide has been
regarded as the terminal functional group because there is no other method to modify
it later. In the same year, Fier's group developed a general method for the late functionalization
of secondary sulfonamides ([Fig. 22 ]),[53 ] and demonstrated the practicability of this method in drug discovery by applying
it in the synthesis of metabolites and labeled compounds. The reaction initially produces
an active phosphine intermediate from ethyl benzoylformate and tris(dimethylamino)phosphine,
subsequently forming an N -sulfonylphenylglycine ester intermediate that features an acidic C−H bond adjacent
to the nitrogen when combined with a secondary sulfonamide. The intermediate releases
sulfinate anions under alkaline conditions and generates imines at the same time,
thereby achieving subsequent functionalization of sulfites or amines after imine cleavage.
Fig. 22 Late-stage functionalization of secondary sulfonamides.
N -(Aryl)alkyl Sulfonamides
At present, N -alkyl sulfonamides can be synthesized by substituting alcohols with nitrogen nucleophiles
under the catalysis of transition metals[54 ] and Lewis acids[55 ] or Brønsted acids,[56 ] producing water as the sole by-product. Verdelet et al developed a catalytic method
for the direct conversion of primary and secondary benzyl alcohol into various sulfonamide
compounds under mild conditions using 2,3,4,5-tetrafluorophenylboronic acid and oxalic
acid dihydrate as co-catalyst systems ([Fig. 23 ]).[57 ] In gram-scale preparations, this reaction is characterized by high yields and the
excess sulfonamides can be recycled.
Fig. 23 Direct sulfonamidation of primary and secondary benzylic alcohols catalyzed by a
boronic acid/oxalic acid system.
Subsequently, Morrill's group described the N -alkylation of sulfonamides by benzyl alcohol under FeCl2 -catalyzed conditions.[58 ] Given that the aforementioned methods predominantly utilize benzyl alcohol and require
excess alkylating agents, Morrill's group developed a manganese-based PNP [MnH(PNPNH −i Pr)(CO)2 ] pincer complex to catalyze the N -alkylation of primary sulfonamides using either benzyl alcohol or primary fatty alcohol,
resulting in a series of aryl and alkyl sulfonamides with excellent separation yields
([Fig. 24 ]).[59 ] A limitation on the substrate scope is that the N -alkylation of secondary sulfonamides has not been achieved. The author has explored
its mechanism. First, the active manganese complex was formed in the dehydrogenation
bromination reaction, which then reacted with alcohol to obtain an alkoxy complex.
Subsequently, the aldehyde and manganese hydride complex formed by dehydrogenation
condensed with p -toluenesulfonamide to form N -sulfonylimide. Finally, N -sulfonylimide was reduced by manganese hydride to provide N -alkylated products.
Fig. 24 Manganese-catalyzed N -alkylation of sulfonamides with alcohols.
Although the above method exhibits good atom economy, it may involve toxic precious
metals, high reaction temperature, and the use of excess amines or alcohols. To address
these issues, Guru et al introduced a metal-free, green, and sustainable boron-catalyzed
method for selective N -alkylation of sulfonamides with benzyl alcohols ([Fig. 25 ]).[60 ] This method operates with a catalyst loading of 1 to 2 mol% and is compatible with
functional groups such as carbonyl, cyano, carboxylic acid, halogen, and nitro. Recently,
Ban et al have developed an improved protocol utilizing In(OTf)3 as a Lewis acid catalyst for the direct sulfonamidation of unactivated alkyl alcohols,
eliminating the need for preactivation ([Fig. 25 ]).[61 ] This method efficiently transforms unactivated aliphatic alcohols into sulfonamides
with good to excellent yields and is compatible with a diverse range of substrates,
including allylic and benzylic alcohols. The procedure involves E1 elimination of
alcohols to form alkenes, followed by hydroamination, demonstrating both scalability
and practicality.
Fig. 25
N -Alkylation of sulfonamides with alcohols.
Jiang et al demonstrated a scheme for direct N -arylation of sulfonamides to N -arylsulfonamides by desulfitative protocols using sodium arylsulfinate as an effective
aryl reagent ([Fig. 26 ]).[62 ] This approach uses CuCl2 as a catalyst and demonstrates good functional group tolerance without the need for
ligand participation, offering a novel and practical method for the synthesis of sulfonamides.
Fig. 26
N -Arylation of sulfonamides with sodium arylsulfinates.
Song et al reported a palladium-catalyzed asymmetric reductive amination of ketones
with weakly nucleophilic sulfonamides in the presence of a Brønsted acid ([Fig. 27 ]).[63 ] This strategy employs N -tert -butyl-protected ketosulfonamide as the starting material, which avoids the need for
removing protective groups and simplifies the separation of N -sulfonylimide intermediates by enabling a tandem reaction of amine deprotection and
followed by asymmetric reduction amination. Finally, a large number of chiral γ-,
ε-, and δ-sulfonamide compounds with high enantioselectivity (up to 99 %) can be obtained.
Recently, Olu-Igbiloba et al presented a cobalt-catalyzed three-component synthesis
of α-substituted N -sulfonyl amines, utilizing aryl aldehydes, primary sulfonamides, and (hetero)arenes
([Fig. 27 ]).[64 ] This method enables the efficient construction of highly substituted sulfonamide
frameworks via direct C(sp2 )−H activation, providing a more atom-economical alternative to traditional approaches
such as the Petasis- or Mannich-type reactions.
Fig. 27 Amination of ketones and aromatic aldehydes.
Sulfonyl Amino Ketone Derivatives
Compared to aminoketones, the synthesis of N -sulfonylaminoketones is rarely reported due to the challenges in preparation and
the use of hazardous chemicals. Mahato et al reported a highly selective method for
the synthesis of α-sulfonamide derivatives by a coupling reaction of terminal alkynes
with sulfonamides using diacetoxy iodobenzene (PIDA) as a catalyst ([Fig. 28 ]).[65 ] This method showed good applicability in the gram-scale preparation. The mechanism
study showed that alkynes reacted with PhI(OAc)2 to form ethyl phenylethynyl iodate intermediate A , which was subjected to Michael's addition with AcOH to form intermediate B . After removing acetate ions, the intermediate carbene C was generated and was then reacted with acetyloxynucleophiles or acid. The diacetoxy
olefin intermediate D was generated, and the final product was obtained by the reaction between α-acetoxy
ketone and sulfonamide.
Fig. 28 Metal-free amidation reactions of terminal alkynes with benzenesulfonamide.
Hong's group introduced a new gold-catalyzed method for synthesizing N -sulfonyl amino ketones ([Fig. 29 ]),[66 ] utilizing sulfonamides and alkynes as starting materials to achieve two different
N -sulfonyl enaminone isomers through chemically controlled and stereoselective synthesis.
As the first example of transition metal-catalyzed synthesis of enamines from sulfonamides
and alkynes, it showed moderate to excellent yield and selectivity.
Fig. 29 Gold-catalyzed selective synthesis of N -sulfonyl enaminone isomers.
In addition, Liang et al reported a method for the synthesis of N -sulfonyl enaminones in high yields by copper-catalyzed N−H olefination of sulfonamides
using saturated ketones as olefin sources and TEMPO derivatives and O2 as oxidants ([Fig. 30 ]).[67 ] This method introduces an unsaturated structure by modifying β-carbon, offering
a novel approach to the functionalization of ketones.
Fig. 30 Copper-catalyzed N−H olefination of sulfonamides.
Axially Chiral Sulfonamide Compounds
Non-biaryl C−N axially chiral compounds often exist in drugs and bioactive natural
products, which can be used as chiral organic catalysts or ligands ([Fig. 31 ]). The direct functionalization of benzenesulfonamides is usually used as the most
direct strategy for obtaining axially chiral sulfonamides. Due to their significant
application potential in the pharmaceutical industry, these chiral sulfonamides have
been extensively studied.
Fig. 31 Asymmetric synthesis of axially chiral benzenesulfonamide.
Kikuchi's group first synthesized optically active N -allyl sulfonamide derivatives with the N−C axial chiral structure in the presence
of (S ,S )-trost ligand and (allyl−Pd−Cl)2 catalyst ([Fig. 31 ]).[68 ] The reaction of allyl acetate with various N -(2-tert -butylphenyl) sulfonamides shows high yield and enantioselectivity (95% ee), and it
has been found that the spatial properties of the substrate can significantly affect
the enantioselectivity. In addition, the absolute configuration of the main enantiomers
was determined by single-crystal X-ray structure analysis, and the reason for enantioselectivity
was explained.
In addition, Zhao's group proposed a commercial chiral amine catalyst for the N -alkylation of sulfonamides ([Fig. 31 ]).[69 ] This method has advantages such as simple operation and direct recovery of the chiral
catalyst used. This method efficiently converts benzenesulfonamides into axially chiral
N -arylsulfonamides with excellent yield and enantioselectivity and can be easily amplified.
It was found that the presence of halogen substituents on the benzene ring was the
key to this catalytic system, and the practicability of the catalytic system was further
proved by the derivatization reaction.
Then, the group turned to the asymmetric acylation of axially chiral sulfonamides,
and reported a commercial isothiourea catalyst (S )-HBTM for the selective N -acetylation of sulfonamides ([Fig. 31 ]),[70 ] and obtained N -arylbenzenesulfonamides with high enantiomeric purity. The product was successfully
used as a chiral iodine catalyst for asymmetric α-hydroxybenzenesulfonylation of phenylpropanone.
Notably, an ortho -methyl substituent on the aryl group is essential for the reaction, as its absence
reduces the enantioselectivity.
In the same year, Dong's group also developed a new method for the synthesis of axially
chiral benzene sulfonamides by isothiourea-catalyzed N -acetylation of sulfonamides with α,β-unsaturated carbonic anhydride ([Fig. 31 ]).[71 ] This method achieves high yields and enantioselectivity for axially chiral sulfonamide
compounds, irrespective of the substituent configuration and electronic properties
of the aryl group, and allows for gram-scale production. Until recently, methods for
synthesizing axially chiral benzene sulfonamides have been rather limited in obtaining
highly enantioselective products with various ortho -substitutions, such as tert- butyl, iodine, and bromine, on the benzene ring. Recently, Gao et al reported a palladium-catalyzed
enantioselective hydroamination of olefins ([Fig. 31 ]),[72 ] achieving effective conversion with various ortho - groups, including ester, ketone, nitro, chlorine, fluorine, methoxy, and tert -butyl, iodine, and bromine. This method provides an efficient synthetic route for
axially chiral unnatural amino acids and eight-membered ring sulfonamides.
C−H Amination
Sulfonamidation of C−H bonds offers high atomic economy, directly functionalizing
C−H substrates without pre-synthesis of sulfonamide groups, thereby improving overall
conversion efficiency. Recently, the direct sulfonamide reaction of (hetero)aromatic
C−H bonds with sulfonyl azides become an effective method for synthesizing N -(heteroaryl)aryl sulfonamides, with nitrogen as the only by-product.[73 ] Given that the C−H amination strategy typically selectively targets the desired
C−H bond under an efficient catalyst system, this section will discuss three aspects:
metal catalysis, enzyme catalysis, and metal-free catalysis.
Metal-Catalyzed C−H Sulfonamidation
Metal-catalyzed direct C−H sulfonylation allows for the introduction of sulfonamides
at the ideal position on the substrate. Late transition metal catalysts, in particular,
exhibit high reactivity and excellent selectivity in amination reactions.
Iridium-Catalyzed C−H Sulfonamidation
In metal catalysis applications, iridium is widely used for synthesizing sulfonamides
through C−H sulfonamide and sulfonyl azide denitrogenation coupling. Kim et al utilized
a catalytic system with an IrCp*(OAc)2 catalyst combined with AgNTf2 to selectively amidate N-protected indole derivatives with various sulfonyl azides,
yielding the expected sulfonyl amidation products in moderate to good yields ([Fig. 32 ]).[74 ] Electron-donating groups on the indole ring were found to enhance the efficiency
of the C−N bond formation reaction. Inspired by this work, Chen et al[75 ] demonstrated that sulfonyl azides selectively amidate indoles with carbonyl directing
groups (such as aldehydes, ketones, esters, and amides) at the C3 position in DCE
([Fig. 32 ]). Notably, indoles with or without N protection exhibit good functional group tolerance
and can be easily scaled up. Additionally, Lanke and Prabhu[76 ] described the synthesis of C4-sulfonamidoindoles from corresponding indole-3-carbaldehydes
and sulfonyl azides.
Fig. 32 Iridium-catalyzed C−H amidation of indoles with organic azides.
In this context, several research teams have developed ortho -C−H sulfamidation reactions for aromatic hydrocarbons with various directing groups
(such as amide,[77 ] sulfonamide,[78 ] sulfonylimide,[79 ] 1,2-diaminobenzenes,[80 ] triazole N -oxide,[81 ]
N -sulfonyl ketimines,[82 ] quinazolinone,[83 ] and tetrazine[84 ]) using the standard [IrCp*Cl2 ]2 as a catalyst ([Fig. 33 ]).
Fig. 33 Iridium-catalyzed selective C−H amidation.
Xu et al demonstrated that 1-(sulfonyl)-2-aryl-1H -benzimidazoles could be synthesized through C−H activation, sulfonyl amidation, and
cyclization of phenylbenzylimidazole derivatives with sulfonyl azides in the presence
of [IrCp*Cl2 ]2 /AgNTF2 /phenylacetic acid ([Fig. 34 ]).[85 ] Additionally, Das and Samanta recently achieved a regioselective synthesis of C3
sulfonamide isoquinolones from 2-pyridyl-protected isoquinolones and sulfonyl azides
in moderate to excellent yields using catalytic amounts of [IrCp*Cl2 ]2 and AgSbF4 , with NaOAc as an additive ([Fig. 34 ]).[86 ]
Fig. 34 Iridium-catalyzed selective C−H amidation of imidamides and isoquinolones.
Recent studies have shown that this catalytic strategy enables the efficient synthesis
of fluorescent sulfonamide compounds, which hold significant promise as optical imaging
agents. For instance, Choi and colleagues reported the direct C−H amidation polymerization
of disulfonyl azides and dibenzamides ([Fig. 35 ], top).[87 ] This results in a fluorescent polysulfonamide compound due to the formation of a
unique intramolecular hydrogen bond between the protons on the sulfonamide group and
the adjacent carbonyl group along the polymer backbone. Moreover, Hwang and Choi also
introduced a robust method for synthesizing various fluorescent sulfonamides via iridium-catalyzed
direct C−H amidation of p -toluenesulfonyl azides under uniform conditions ([Fig. 35 ], bottom).[88 ] This method achieves excellent luminescence efficiency across the visible spectrum
with yields up to 99%. Additionally, the synthesis of multicolor fluorescent sulfonamides
can be fine-tuned by modifying the electronic properties of the substituents.
Fig. 35 Iridium-catalyzed C−H amidation for synthesizing fluorescent sulfonamides.
Although sulfonyl azides are highly reactive, their postprocessing and storage are
cumbersome and unfavorable. In contrast, sulfonamides are more stable. The hydroamination
of olefins can yield anti-Markovnikov addition products.[89 ] Based on the proton-coupled electron transfer (PCET) of the N−H bond of sulfonamides,
Knowles and colleagues reported a method for the co-catalyzed intermolecular anti-Markovnikov
hydroamination of unactivated olefins using primary and secondary sulfonamides, facilitated
by an iridium(II) photocatalyst, dialkyl phosphate, and thiol hydrogen atom donors
under room temperature illumination ([Fig. 36 ]).[90 ] Building on these results, the research group also achieved enantioselective hydroamination
of various substituted olefins with complex sulfonamide substrates, producing pyrrolidine
products with high enantioselectivity ([Fig. 36 ]).[91 ] Recently, Knowles and colleagues have developed an innovative light-driven method
for anti-Markovnikov hydroamination of alkenes using primary sulfonamides. This method
employs a ternary catalytic system consisting of an iridium(III) chromophore, a fluorinated
alkoxide base, and a thiol hydrogen atom donor ([Fig. 36 ]).[92 ] The reaction operates via a PCET mechanism, where the alkoxide base aids in activating
strong N−H bonds to generate N-centered radicals. These radicals facilitate C−N bond
formation with various alkenes. This protocol demonstrates a broad substrate scope
and functional group tolerance, underscoring excited-state PCET as a versatile platform
for catalytic radical generation. In addition, Sihag and Jeganmohan proposed a possible
reaction mechanism involving π-allyl intermediates and thus achieved Ir(III)-catalyzed
direct allyl C−H amidation of unactivated substituted ene with substituted sulfonamides
([Fig. 36 ]).[93 ]
Fig. 36 Iridium-catalyzed C−H amidation of alkenes with sulfonamides.
Other Mental-Catalyzed C−H Sulfonamidation
Other late-transition metals have also made great progress in the study of C−H amidation
reactions. Recently, Shi's team discovered that nitrazine [Ar(R)C=N−N=C(R)Ar] can
serve as an ideal directing group for C−H amidation via C−H activation, leading to
the first development of a mild and efficient rhodium(III)-catalyzed ortho -amidation of sulfonamides with nitrazines ([Fig. 37 ]).[94 ] Azine can be obtained from the corresponding acetophenone and hydrazine in the laboratory,
and it is easy to remove from the reaction. The method is highly regioselective, and
has a broad substrate range and good functional group tolerance, providing a simple
method for the synthesis of sulfonamide derivatives.
Fig. 37 Rhodium-catalyzed C−H amidation of azine with sulfonamides.
Moreover, Kumar et al reported a simple and effective copper-mediated cross-dehydrogenative
coupling reaction of indoles with sulfonamides ([Fig. 38 ]).[95 ] The reaction demonstrated good functional group tolerance, accommodating a range
of substitutions on the sulfonamide scaffold. Both electron-donating and electron-withdrawing
substituents were compatible, resulting in the desired benzenesulfonamide products
in moderate to good yields. Notably, the substitution pattern (ortho- , meta- , and para- ) had minimal effect on the yield, consistently producing similar results. Additionally,
halogenated sulfonamides were also successfully incorporated. This methodology was
effectively utilized for the synthesis of the sulfonamide derivative antiproliferative
agent, ER-67836. Recently, Hajra et al introduced a novel protocol for copper(II)-mediated,
picolinamido-directed C8−H sulfonamidation of 1-naphthylamine derivatives ([Fig. 38 ]),[96 ] celebrated for its simplicity, broad substrate range, and excellent yields with
precise site selectivity. Mechanistic studies highlight the role of organometallic
chelation. These advancements pave the way for efficient synthesis of N -arylated and alkylated sulfonamide derivatives.
Fig. 38 Cu(II)-mediated and iron-catalyzed C−H amination.
Cyclosulfonamide compounds are often introduced into target molecules as stable lactam
compounds in medicinal chemistry. For example, Zhong et al reported a method for direct
synthesis of cyclosulfonamides by intramolecular C(sp3 )−H amidation reaction using iron complexes formed by easily available Fe(ClO4 )2 and aminopyridine ligands as raw materials ([Fig. 38 ]).[97 ] This method can achieve gram-scale preparation and product derivatization reaction,
so it has good practicability. Recently, Song et al have developed an iron-catalyzed
α-amination of ketones using sulfonamides through an oxidative coupling process, effectively
eliminating the necessity for pre-functionalization ([Fig. 38 ]).[98 ] The method successfully employs both primary and secondary sulfonamides as efficient
partners. This innovative approach enables the direct amination of benzyl ketones
with a variety of sulfonamide substituents under oxidative conditions. Current studies
are focused on elucidating the underlying reaction mechanism.
Qian et al provided a method for the direct synthesis of bicyclic sulfonamide compounds
by ruthenium-catalyzed intermolecular coupling reaction of alkynes with alkenyl sulfonamides
([Fig. 39 ]).[99 ] In this scheme, a ruthenium(II)-catalyzed tandem reaction involving cyclization
and amination enables the synthesis of [3.3.0] and [4.3.0] bicyclic sulfonamides with
high enantioselectivity.
Fig. 39 Ruthenium(II)-catalyzed C−H amidation of alkenyl sulfonamides with alkynes.
In addition, Zhang's group developed a Co(II)-based metal system as an effective catalyst
for the enantioselective 1,5-C−H amination of sulfonyl azides to synthesize chiral
five-membered cyclic sulfonamides ([Fig. 40 ]).[100 ] The catalytic system achieves asymmetric C−H amination through free-radical reactions
under neutral and nonoxidative conditions. It is effective not only for arylsulfonyl
azides but also for the more challenging alkylsulfonyl azides, yielding chiral five-membered
ring sulfonamide compounds with high yields and excellent enantioselectivity.
Fig. 40 Co(II)-catalyzed C−H amination.
Enzyme-Catalyzed C−H Sulfonamidation
While developing catalytic C−H amination reactions, progress has also been made in
enzyme-catalyzed C−H amination. An enzymatic strategy enables intermolecular benzyl
C−H amination with p -toluenesulfonyl azides.[101 ] Additionally, genetically engineered iron-containing enzymes have shown good catalytic
effects in the C−H sulfonamide reaction of azides.[102 ] Hartwig's team developed an asymmetric intramolecular C−H amination reaction of
sulfonyl azides, using a CYP119 variant with an iridium engineering P450 enzyme, achieving
chiral benzene sulfonamides with good chemical selectivity ([Fig. 41 ]).[103 ]
Fig. 41 Ir(Me)-PIX-CYP119-catalyzed intramolecular C−H amination.
Metal-Free C−H Sulfonamidation
For metal-free C−H amination of sulfonamides, Michael's group reported a widely used
selenium-catalyzed allyl C−H amination reaction ([Fig. 42 ]).[104 ] This method offers unique regioselectivity, introduction of new C−N bonds at the
allyl position of olefins, from monosubstituted to tetrasubstituted, with sulfonamides,
successfully applied to synthesize terpenoids with high yields and regioselectivity.
Fig. 42 Se-catalyzed allylic C−H amination of terpenoids.
The excited 1,5-hydrogen atom transfer (HAT) process based on acyl radicals can selectively
replace C(sp3 )−H with C(sp3 )−N bonds in medicinal chemistry. Muñiz's group developed a nonpolluting iodine redox
catalysis combined with light for intramolecular radical C−H amination reaction ([Fig. 43 ]),[105 ]
[106 ]
[107 ] achieving highly regioselective amination between sulfonamides and aliphatic molecules.
Fig. 43 Iodine-catalyzed C−H amination.
Additionally, Wu et al used photochemical methods to induce sulfonamides to form nitrogen
radicals via halogen-bonded charge-transfer complexes, thereby stimulating the HAT
process for regioselective C−H amination of alkanes ([Fig. 44 ]).[108 ] This approach enabled the synthesis of pyrrolidine compounds through two consecutive
C(sp3 )−H amination steps, offering a novel way for halogen-enhanced charge transfer complexes
to participate in chemical reactions. Yu et al introduced an effective metal-free
method for synthesizing N -(2-quinolinyl) sulfonamides ([Fig. 45 ]).[109 ] The intermolecular amidation of quinoline N -oxides with sulfonamides was accomplished via a 1,3-dipolar [3 + 3]-cycloaddition
reaction in the presence of PhI(OAc)2 and PPh3 , yielding the desired N -(2-quinolinyl) sulfonamides in high yields. This method also addresses the challenge
of poor reactivity of sulfonamide compounds as nucleophiles.
Fig. 44 Halogen-bond-induced consecutive C(sp3 )−H aminations.
Fig. 45 Amidation of quinoline N-oxide with benzenesulfonamide derivatives under metal-free
conditions.
Other Methods
Luo et al reported a novel and practical method for the synthesis of sulfonamides
from sulfamoyl chloride ([Fig. 46 ]).[110 ] First, the N,N -disubstituted sulfamoyl chlorides were catalyzed by photoredox to generate sulfonyl
radicals, which then were attacked by 1-phenyl-1-trimethylsiloxane to generate enol
silyl ether radical intermediates. Finally, β-ketosulfonamides were obtained by oxidation
and deprotonation. This method can be conducted under mild and economical conditions,
featuring a broad substrate range and good functional group compatibility. At the
same time, this method has been successfully applied in the synthesis of antiepileptic
drug zonisamide. At present, its detailed mechanism is being further studied. Recently,
Sookezian and Molander presented a groundbreaking multicomponent reaction for the
1,2-difunctionalization of olefins, incorporating both a sulfonamide moiety and an
additional functional group. By utilizing radical/polar crossover, the method leverages
commercially available sulfamoyl chlorides and organotrifluoroborates as coupling
partners ([Fig. 46 ]).[111 ] The process initiates with the generation of sulfur-centered radicals, which react
with alkenes to produce sulfamoylated intermediates. These intermediates undergo oxidation
to form benzylic carbocations that are then trapped by various nucleophiles, including
organotrifluoroborates and heterocycles. This versatile approach effectively accommodates
a wide range of functional groups and represents the first direct use of chlorosulfonamide
species in a three-component reaction.
Fig. 46 Sulfonamidation of enol silyl ether with chlorosulfonamide.
Nguyen and Retailleau described a catalyst-free method for the synthesis of sulfonamides
from 2-nitrochalcone and elemental sulfur in the presence of 3-methylpyridine or N -methylmorpholine ([Fig. 47 ]).[112 ] Under heating conditions, two oxygen atoms from the 2-nitro group migrate to the
sulfur atom, facilitating the formation of S−N, C−S, and S−O bonds between the nitrogen
atom, α-carbon of chalcone, and elemental sulfur. Since the structure of nitrochalcone
is easy to construct and the reaction is easy to operate, and sulfur as a sulfur source
shows a strong atomic economy, it provides a more effective synthesis method for sulfonamide
compounds.
Fig. 47 Synthesis of sulfonamides from 2-nitrochalcones with sulfur.
Willis' group reported a method for direct synthesis of primary sulfonamides from
organometallic reagents and a new sulfonamide reagent t -BuONSO ([Fig. 48 ], top).[113 ] It is worth noting that t -BuONSO can be prepared on a 10-gram scale using commercially available O -tert -butylhydroxylamine hydrochloride, thionyl chloride, and triethylamine. Reactions
with various (hetero)aryl or alkyl organometallic nucleophiles (such as Grignard reagents
or organic lithium reagents) can obtain primary sulfonamide compounds in good to excellent
yields and are well applied to the synthesis of the drug celecoxib. The authors explain
that initially, the Grignard reagent reacts with t -BuONSO to form sulfinamide intermediate I , which is then converted into sulfinimide ester anion II through a sulfinyl nitro intermediate or N→S o -migration, accompanied by intramolecular proton transfer to the nitrogen atom. After
the elimination of isobutene, the sulfonamide anion III was obtained, and the final sulfonamide product was obtained by the quenching process.
Recently, Willis' group has developed a scalable and versatile methodology for synthesizing
sulfonamides from a wide array of alkyl carboxylic acids ([Fig. 48 ], bottom).[114 ] By employing acridine photocatalysts in conjunction with 400 nm light, the process
efficiently generates alkyl radicals. These radicals subsequently react with the sulfinylamine
reagent t -BuONSO to form N -alkoxy sulfinamide intermediates. Through treatment with sodium hydroxide, these
intermediates can be selectively transformed into sulfonamides. This method is robust,
accommodating a diverse range of functional groups, and applies to complex biologically
active compounds.
Fig. 48 Primary sulfonamide synthesis using the sulfinylamine reagent t -BuONSO.
Summary
Sulfonamide drugs are popular in the field of drug research and development. Despite
significant progress, urgent issues remain in meeting sustainable development goals
in chemical production: (1) reducing the reaction times, lowering the reaction temperatures,
avoiding the use of toxic solvents, and minimizing the catalyst loading. These methods
offer significant potential for further improvement, such as the use of green, recyclable
solvents and catalysts. (2) Improving the reaction safety and chemical selectivity
and reducing waste generation by improving the reaction catalytic system is also one
of the important development directions in the future, such as the use of green synthesis
technologies like enzyme catalysis, photocatalysis, and electrocatalysis. (3) Exploring
green production processes remains an important challenge, such as designing process
routes that reduce or eliminate the use and production of hazardous substances. This
article systematically reviews the ideas and methods for synthesis and structural
modification of sulfonamide structural drugs and drug intermediates in the past 5
years. Four strategies for the synthesis of sulfonamide structural compounds are presented:
S−N construction, C−N cross-coupling, N−H functionalization, and C−H sulfonamidation.
In particular, efficient, practical, and green new synthetic schemes are summarized,
and the related reaction conditions, mechanisms, and applications are discussed. Herein,
we hope that this review can provide new ideas and reference value for green and efficient
preparation technology of sulfonamides and their intermediates.
