Advances in the Synthesis of Sulfur-Containing Cyclic Architectures via Insertion of SO₂

Abstract

Sulfur-containing heterocycles, where the S(R) moiety is located within the cyclic structure, have found tremendous applications in the fields of chemical, pharmaceutical, and materials sciences due to their unique chemical, biological and pharmaceutical activities. Recent years have witnessed increasing interest in sulfur-containing heterocycles, and new methods for their synthesis have been reported by adopting modern methodologies and technologies through insertion of sulfur dioxide. The main objective of this Account is to overview the latest major developments on the synthesis of sulfur-containing heterocyclic systems, mainly covering thermo-, photo- and electron-induced cyclization through the insertion of sulfur dioxide (SO₂). We aim to provide the readership with a comprehensive understanding of this topic and offer a positive outlook on the promising future of this field.

1 Introduction

2 Thermal-Induced Cyclization

3 Photoinduced Radical Cyclization

4 Electron-Induced Radical Cyclization

5 Conclusion

Introduction

Sulfur-containing heterocycles, where the S(R) moiety is within the cyclic structure, are not only frequently found in numerous natural products, biologically and pharmaceutically active molecules, and functional materials (Figure [1]),[1] but also serve as valuable heterocycle building blocks in the fields of industrial and medicinal chemistry. For example, benzosultams, the fused cyclic analogues of sulfonamides, are among an important subclass of sulfonamide drug scaffolds with potent biological activities,[1c] [2] whilst sultines (lactones of sulfinic acids) are well-known and important sulfur heterocycles that are present in various natural and synthetic products, and can be used as valuable intermediates in drug discovery.[3,4]

Accordingly, considerable attention has been focused on the development of efficient approaches to access these valuable scaffolds. However, the requirement for harsh/toxic conditions, moisture-sensitive and corrosive reagents, for example, sulfonyl halides, low atom-economy, elaborate starting materials, and limited functional group tolerance are disadvantages of many of the developed methods, which has severely limited the potential applications of sulfur-containing heterocycles. To this end, the development of new methods for the efficient and selective construction of sulfur-containing heterocycles is highly desirable, especially those with different ring sizes and substitution patterns. Indeed, significant progress related to new strategies has recently been reported towards the synthesis of sulfur-containing heterocycles.

Direct incorporation of sulfur dioxide into organic molecules offers an alternative synthetic strategy, with step- and redox-economical features, towards the assembly of SO₂-containing compounds.[5] [6] Since the development of easily handled DABSO (1,4-diazabicyclo[2.2.2]octane–bis(sulfur dioxide) adduct) and the inorganic sulfites M₂S₂O₅ (M = Na, K) as a replacement for toxic gaseous sulfur dioxide in organic transformations, rapid progress has been made on the generation of S-containing compounds via the insertion of sulfur dioxide. Indeed, the construction of sulfur-containing cyclic scaffolds using easy-to-handle SO₂ surrogates, through the direct insertion of SO₂, has recently received considerable attention through thermal catalysis (transition-metal catalysis), visible-light catalysis and electron catalysis. However, to date, a comprehensive summary of these advances is yet to be compiled. Thus, in this Account, we summarize the latest advances and provide a more comprehensive understanding of this topic with emphasis on the product diversity, selectivity, and applicability, with the mechanistic rationale being presented where possible. In order to highlight representative methods for the construction of sulfur-containing heterocycles via the insertion of SO₂ published in last 10 years, this Account is divided into three parts: thermal-induced cyclization, photoinduced cyclization and electron-induced cyclization.

Thermal-Induced Cyclization

In 2015, Wu’s group reported a copper(I)-catalyzed reaction of 2-alkynylaryldiazonium tetrafluoroborates 1 with morpholin-4-amine and DABSO, enabling the efficient synthesis of benzo[b]thiophene 1,1-dioxides 2 in moderate to good yields (Scheme [1]).[7] The fact that the reaction did not take place in the absence of morpholin-4-amine indicates that the transformation proceeded through the N-morpholino-2-(phenylethynyl)benzenesulfonamide intermediate A. Substrates with aromatic rings substituted with various functional groups (such as fluoro, chloro, methyl, and ester) were found to be applicable, as demonstrated by the production of the desired products in significant yields. Different substituents (R²) at the alkyne terminus, mainly aromatic groups, were also compatible. During the reaction process, the target product 2 was obtained through insertion of sulfur dioxide followed by an intramolecular 5-endo cyclization. As proposed in the mechanism, 2-alkynylphenyldiazonium tetrafluoroborate 1 reacts with DABSO and morpholin-4-amine to give N-morpholino-2-(phenylethynyl)benzenesulfonamide intermediate A. Next, sodium sulfinate B is formed in the presence of a base via cleavage of the S–N bond of the N-aminosulfonamide. Finally, a metal-catalyzed intramolecular 5-endo cyclization followed by protonation yields the desired benzosulfone 2.

Subsequently, the same group disclosed a copper(I)-catalyzed pathway for converting (2-alkynylaryl)boronic acids 3 into benzo[b]thiophene 1,1-dioxides 4 via the insertion of SO₂ (Scheme [2]).[8] A range of target products was achieved in good to excellent yields in the presence of 10 mol% of copper(I) acetate in DMF at 100 °C. (2-Alkynylaryl)boronic acids bearing groups with different electronic properties on the aromatic ring readily underwent the expected reaction to afford the corresponding products under the standard conditions. Substrates with different substituents (R²) attached to the triple bond, including aryl, alkyl, and heterocyclic groups, successfully underwent the transformation to give the expected products in good yields. The reaction proceeded through a similar pathway to that described above, where sulfur dioxide is firstly embedded into the intermediate A, itself formed through transmetalation of boronic acid 3 with the copper catalyst, to give intermediate B. Next, the copper catalyst activates the triple bond of intermediate B, which then undergoes intramolecular 5-endo cyclization to generate the desired benzo[b]thiophene 1,1-dioxides 4.

In 2017, Manabe and co-workers reported the Pd-catalyzed selective synthesis of cyclic sulfonamides 6 and sulfinamides 7 by utilizing haloarenes 5, bearing amino groups, and K₂S₂O₅ as a sulfur dioxide surrogate (Scheme [3]).[9] The authors demonstrated that this reaction could be conducted safely on a practical basis without the use of SO₂ gas or sulfonyl chlorides. Research has shown that the amount of base (Bu₃N) used in this transformation was crucial in determining the selectivity, and revealed the optimum amount for the synthesis of sulfonamides and sulfinamides, respectively. Various substrates were applied to test the selective synthesis of sulfonamides 6 or sulfinamides 7, with both types of product being obtained in moderate to good yields and with almost complete selectivity. A range of substituents on the aromatic ring were evaluated and the expected products were obtained in typically medium to good yields. This strategy enabled the selective synthesis of the desired products based on the corresponding reaction conditions, except for a substrate in which the benzene ring was substituted with a nitro group.

As for mechanism, Manabe’s team[9] carried out a series of experiments demonstrating that sulfonamides would be generated from sulfinamides when 1.0 equivalent or less of the base was used. Meanwhile, an iodide source and DMSO as an oxygen source proved to be a must to accomplish this conversion. However, whether sulfinamide 7 was formed first and whether the generation of unstable SO occurred still need further exploration. This synthetic method has provided a new approach to the direct introduction of sulfinyl groups onto haloarenes by using an inorganic sulfinate as a SO₂ surrogate, and turns out to be a useful tool for synthesizing cyclic sulfonamides and sulfinamides.

An efficient synthetic strategy to access diaryl-annulated sulfone molecules via SO₂/I exchange of cyclic diaryliodonium salts 8 using readily available inorganic Na₂S₂O₅ as a convenient SO₂ surrogate was reported by Jiang and colleagues in 2017 (Scheme [4]).[10] Initially, they explored the effects of different substituents on the reaction and disclosed results that divergent functionalized cyclic conjugated diaryl-annulated sulfones with different electronic properties were successfully produced in good to excellent yields, regardless of whether the substituents were electron-withdrawing or electron-donating groups. Additionally, conjugated phenyl groups and fused multi-rings proved to be completely compatible, being advantageous on account of their favorable structures for carrier mobility in semiconductor materials. Likewise, the synthesis of a series of six-membered diaryl-annulated sulfones was also proof of the excellent functional group compatibility of the protocol. Notably, product 9f, which possesses two readily modifiable bromides for constructing organic electroluminescent material molecules, was successfully achieved on gram scale by utilizing the developed reaction conditions. Jiang’s team has also constructed structurally novel π-conjugated molecules bearing unsymmetrical functional groups, which are useful for the preparation of OLED materials molecules.

A plausible radical pathway for this copper-catalyzed SO₂/I exchange process was proposed for this cyclization reaction.[10] Aromatic radical intermediate B was formed by oxidation of the Cu(I) species, followed by the capture of Na₂S₂O₅ for the formation of syntonic SO₂ radical anion intermediate C, which was oxidized to intermediate D by Cu(II), itself being converted into Cu(I). Subsequent oxidative addition of intermediate D with Cu(I) led to Cu(III) aryl species E, which was transformed into intermediate F through an intramolecular ligand exchange. Reductive elimination of F proceeded successfully to afford the desired product G and regenerate the Cu(I) catalyst. Interestingly, copper catalysts were of great significance in this conversion process. The method outlined in this particular study is expected to inspire new ideas for the development of organic materials science.

In 2020, Jiang and co-workers disclosed a multicomponent reductive cross-coupling in the presence of sodium metabisulfite to straightforwardly construct diverse sulfones 13 through a simple combination of aryl halides 11 and alkyl halides 12 (Scheme [5]).[11] This strategy was applied to modularly and systematically deliver a series of S-containing benzo-fused sulfones, containing five- to twelve-membered rings, in moderate to excellent yields, with some examples bearing heteroatoms on the ring. The proposed mechanism shows that a single-electron transfer process between alkyl halide B and tin resulted in the generation of alkyl radical intermediate C, which then reacted with sodium metabisulfite to give sulfonyl radical D. This could be reduced by tin to afford sulfonyl anion E, followed by oxidative addition of the aryl halide to Pd⁰ to afford intermediate F. Intermediate E reacted with F, resulting in the precipitation of intermediate G. The desired product H was obtained after reductive elimination from G. Moreover, this protocol has displayed great utility in the synthesis of drug-like sulfone molecules due to the high compatibility of several naturally occurring aliphatic systems with the SO₂-insertion–reductive cross-coupling, featuring good step economy, a high tolerance for a wide range of functionalities and no need for the participation of pre-prepared organometallic species.

Afterwards, the same group developed a transition-metal-free reductive cross-coupling of alkyl tosylates 14, unactivated alkyl halides 15, and sodium metabisulfite for the modular construction of alkyl-alkyl sulfones 16. In this reaction, inorganic sodium metabisulfite salt serves as the SO₂ source and as a robust connector (Scheme [6]).[12] Cyclic sulfones 16a and 16b were efficiently obtained under the current protocol in yields of 63% and 51%, respectively, which shows that this protocol was also feasible for the synthesis of cyclic sulfones. A plausible pathway for the reductive cross-coupling is proposed in Scheme [6]. This multicomponent reaction started with homolysis of the alkyl halide to afford alkyl radical C, followed by a SOMO interaction with sodium metabisulfite to generate sulfonyl radical D, which subsequently underwent reduction by utilizing a safe formate source as a highly efficient single-electron reductant to give intermediate E or E′. Finally, an intermolecular nucleophilic substitution with the alkyl tosylate provided the desired product F. The absence of a transition metal makes this protocol more environmentally friendly.

In 2020, Wu and co-workers developed a novel sulfur dioxide anion incorporation cascade for the preparation of 1-thiaflavanone sulfone derivatives 18 under copper-catalyzed conditions.[13] They employed 2′-iodochalcone derivatives 17 along with cheap and readily available rongalite (HOCH₂SO₂Na·2H₂O) as a sulfur dioxide anion equivalent (Scheme [7]).

The transformation was economical and environmentally friendly as toxic SO₂ gas and expensive SO₂ surrogates were avoided. The protocol encompassed a broad substrate scope. 2′-Iodochalcones bearing both electron-donating and electron-withdrawing groups were well tolerated, giving the target products in good to excellent yields. Strongly electron-withdrawing groups such as nitro and trifluoromethyl gave moderate to good yields. Meanwhile, 2′-iodochalcone starting materials bearing fluoro, chloro, bromo, phenyl, and alkynyl substituents (R¹) were successfully transformed into the corresponding products in excellent yields. A plausible mechanism is shown in Scheme [7] [13] in which the 2′-iodochalcone derivative A initially interacts with the copper catalyst to produce intermediate B. This intermediate then undergoes a reversible thia-Michael addition to afford intermediate C, followed by C–S bond formation to give the target product via intermediate D.

Subsequently, Wu’s group reported an interesting [1+1+1+1+1+1] annulation process for the assembly of tetrahydro-2H-thiopyran 1,1-dioxides 20 by utilizing rongalite. This reaction featured good functional group compatibility and employed a wide substrate scope (Scheme [8]).[14] Tetrahydro-2H-thiopyran 1,1-dioxides substituted with different functional groups were produced in moderate to good yields from the corresponding initial sulfoxonium ylides 19. The electronic effects of diverse substituents were investigated. It was discovered that substrates with electron-donating groups were amenable to this reaction, and that substrates bearing strongly electron-withdrawing groups (F, Cl, CF₃, OCF₃, and SCF₃) also furnished the desired products in reasonable yields. Moreover, steric effects had little influence on the transformation, with the reactions of para-, meta- and ortho-substituted sulfoxonium ylides all proceeding smoothly, generating the expected products with good yields.

The proposed mechanism shows that rongalite can be utilized as triple C1 units and as a source of sulfone. A nucleophilic substitution reaction between sulfoxonium ylide 19 and rongalite gave intermediate species A, which was transformed into intermediate C after dehydration and reduction via intermediate B with the assistance of NaOAc. Subsequently, linear intermediate D was formed through two consecutive thia-Michael additions initiated by rongalite or SO₂ ^2–, followed by tautomerization to yield species E. Next, species E participated in a nucleophilic attack on formaldehyde (decomposition from rongalite), resulting in the formation of hydroxymethylated intermediate F, which underwent an ensuing dehydration to give unsaturated ketone G. The target product 20 was obtained after an intramolecular Michael addition in the presence of a base. This whole process involved two different modes of carbon incorporation.

In 2022, Liao and co-workers disclosed a straightforward three-component coupling for the preparation of functionalized benzosultams 23 under transition-metal-free and mild reaction conditions. Their method employed readily available and environmentally friendly Na₂S₂O₅, readily obtainable bromodifluoroalkyl reagents 22, and N-(2-haloaryl)cyanamides 21 (Scheme [9]).[15] Diverse five-membered- and six-membered-embedded (A ring) difluorinated benzosultams 23 could be efficiently synthesized in good to excellent yields by utilizing this protocol. The reactivity of cyanamides 21 substituted with different halogen atoms was investigated under the standard conditions, and the results suggested that 2-bromo- and 2-chloro-substituted analogues gave the desired products in diminished yields compared with their N-(2-iodoaryl)cyanamide counterparts. Functional groups with different electronic properties at different positions of the aromatic ring system had a subtle effect on the reactivity, with the exception of ortho substitution of the aromatic ring system of the cyanamide. Different substituents (R²) in the linkage between N and the alkenyl moieties demonstrated good compatibility with this protocol. Diverse cyanamides with various gem-disubstituted linkers such as alkyl, aryl, heteroaryl, and cyclic substituents were employed, leading to the corresponding difluorinated benzosultams in reasonable yields. Cyanamides bearing multisubstituted alkene moieties (R¹) were also amenable in this reaction, providing the expected products in good yields. Regrettably, the attempted preparation of a difluorinated benzosultam embedded with a seven-membered ring (A ring, n = 2) failed.

The mechanism indicated that Na₂S₂O₅ first generated a SO₂ radical anion which reduced 22 via an SET process to produce a difluoroalkyl radical (^•R_f) and released SO₂.[15] The difluoroalkyl radical then added to the carbon–carbon double bond of substrate A resulting in formation of the radical intermediate B (n = 1), which cyclized via intramolecular addition of the C-radical to the cyano group to give iminyl radical intermediate C. The desired product F would be formed through a series of transformations after capture of SO₂ by the iminyl species C.

It was reported in 2023 by Jiang and co-workers that a metal-free radical multicomponent bicyclization of heteroatom-linked 1,7-diynes 24 or 25 with aryldiazonium tetrafluoroborates 26 and DABSO enabled annulative SO₂ insertion to access efficiently two skeletally diverse tricyclic sulfones, namely, thieno[3,4-c]quinoline 2,2-dioxides 27 and thieno[3,4-c]chromene 2,2-dioxides 28, by simply tuning the linkers of the 1,7-diynes (Scheme [10]).[16] These transformations proceeded smoothly under mild conditions, leading to a range of tricyclic sulfones in moderate to good yields. The reactivity of various arylamine-tethered 1,7-diynes bearing different substituents (R¹ to R⁴) was investigated. A broad scope of functional groups located at different positions on the arylamine-tethered 1,7-diynes was tolerated. In addition, a methyl group (R³) on the propargyl unit of substrate 24 was also amenable to this process, affording product 27c in 79% yield. Subsequently, reactions of aryldiazonium tetrafluoroborates containing different functional groups on the arene ring (Ar) were carried out, which confirmed the good functional group compatibility of the aryldiazonium tetrafluoroborates, irrespective of the position and electronic nature of the substituent(s) on the aryl ring.

The authors proposed a possible reaction mechanism (Scheme [10]).[16] The aryldiazonium cation and DABSO reacted via a SET process to yield an aryl radical and SO₂, together with radical cation intermediate H. The capture of SO₂ by the aryl radical led to the formation of arylsulfonyl radical intermediate I, which added regioselectively into the terminal alkyne of 1,7-diyne A to generate alkenyl radical B. This was followed by 6-exo-dig cyclization, interception of sulfur dioxide, 5-endo-trig cyclization, single-electron transfer, and deprotonation to access the desired tricyclic sulfone G. This transformation demonstrates significant compatibility regarding N- and O-linked 1,7-diynes with different substitution modes and aryldiazonium tetrafluoroborates. Moreover, the synthetic applicability of the protocol has also been experimentally confirmed.

In 2024, Huang and co-workers developed a three-component reaction where the difunctionalization of alkenes 29 with two different alkyl halides occurred by employing Na₂S₂O₄ as both a reductant and sulfone source (Scheme [11]),[17] enabling the generation of diverse dialkyl sulfones 32, including valuable cyclic sulfones, via a radical-anion relay process starting from easy-to-obtain alkenes and alkyl halides. The scope of the olefins and two types of alkyl halide were evaluated, respectively, with the results highlighting the excellent functional group compatibility of the protocol. By replacing the standard olefins with alkene-tethered alkyl bromides, a series of cyclic sulfones embedded with four- to eight-membered rings could be prepared in moderate to excellent yields (selected examples 32a–h, 60–92%). The addition of Na₂S₂O₄ shifted the reaction mechanism towards the generation of an alkyl sulfone anion intermediate, rather than the previously reported alkylmetal intermediate. Mechanistic studies revealed a pathway that included a carbon-centered alkyl radical and a sulfur-centered sulfone radical, which could be converted into an alkyl sulfone anion accelerated by iron electron-shuttle catalysis, leading to an efficient fluoroalkylative alkylsulfonylation reaction with high chemo- and regioselectivity. It is noteworthy that the conversion of carbon radical B into sulfone radical C was reversible via capture or extrusion of SO₂ released from Na₂S₂O₄ during the process.

Photoinduced Radical Cyclization

In 2017, Wu and co-workers delivered an innovative N-radical-initiated aminosulfonylation of unactivated C(sp³)–H bonds through insertion of sulfur dioxide under visible-light conditions. O-Aryl oximes 33 and DABCO·(SO₂)₂ reacted smoothly at room temperature under photoinduced catalyst-free conditions, affording diverse 5,6-dihydro-4H-1,2-thiazine 1,1-dioxides 34 in generally good yields (Scheme [12]).[18] Substrates bearing various substituents such as methyl, methoxy, fluoro, and chloro were compatible with this protocol. Of note, a thiophenyl-substituted substrate engaged in the reaction giving the desired product in a reasonable yield. The reaction also proceeded efficiently when a six- or five-membered carbocycle was present at the sp³ carbon of the substrate. The method could also be extended to the synthesis of 1H-benzo[d][1,2]thiazine 2,2-dioxides through a 1,5-HAT strategy using substrates containing a benzyl carbon.

The proposed mechanism indicated that the reaction proceeded via a radical process in the presence of visible light, where O-aryl oxime 33 and DABCO·(SO₂)₂ react to form a photosensitive complex A, which then generates an iminyl radical C through single-electron transfer induced by visible light, accompanied by the release of cation radical D.[18] Subsequently, the iminyl radical C undergoes 1,5-H atom abstraction and the insertion of sulfur dioxide to afford intermediate F. The synthesis of the target 5,6-dihydro-4H-1,2-thiazine 1,1-dioxide 34 is accomplished after reaction of intermediate F with cation radical D. This visible-light-promoted procedure opens up a unique pathway for the aminosulfonylation of ubiquitous aliphatic C–H bonds, with no requirement for metal catalysis and a simple and clean reaction system as advantages.

In 2023, Shu and co-workers disclosed a metal-free photoredox-catalyzed radical-polar crossover cyclization (RPCC) to access multifluoromethylated γ-sultines 37 by employing easily oxidizable multifluoroalkanesulfinates 36 as bifunctional reagents and cost-effective 4CzIPN as an organic photocatalyst (Scheme [13]).[19] A series of multifluoromethylated γ-sultines was delivered in moderate to excellent yields from a broad range of readily available substituted alkenes, in which the trans isomers were the major products. The protocol demonstrated good functional group compatibility and a broad substrate scope. Substrates 35 bearing either electron-donating (methyl, methoxy) or electron-withdrawing groups (carbonyl, phenyl, ester, halide, nitro, nitrile, aldehyde) on the aryl ring were well tolerated, efficiently yielding the corresponding sultines with good trans/cis ratios. Notably, an unactivated alkene was found to have good reactivity and gave the product 37j in moderate yield. Derivatives of the analgesic drugs ibuprofen, fenbufen, and ioxoprofen underwent this reaction smoothly, leading to the desired products in moderate to good yields, as examples for further applications in drug discovery. In addition, different sodium multifluoroalkanesulfinates (R_fSO₂Na), which contained long-chain multifluoroalkyl groups with stronger electronegativity, such as C₄F₉SO₂Na, C₆F₁₃SO₂Na, and C₈F₁₇SO₂Na, were investigated, and the results showed that multifluoromethylated γ-sultines could be obtained in considerable yields.

As for the proposed mechanism of this RPCC reaction, multifluoroalkanesulfinates produced the multifluoroalkyl radicals B and released SO₂ through a single-electron transfer (SET) process in the presence of the photocatalyst 4CzIPN when excited by light.[19] The addition of fluoromethyl radical B to the olefin gave the corresponding carbon radical intermediate C, which was followed by the insertion of SO₂ to produce the sulfonyl radical D. Subsequent single-electron reduction and polar 5-exo-tet cyclization occurred to generate the final product G. As an alternative pathway, intermediate I could be formed by the reduction of intermediate C via SET, then product G would be produced through SO₂ insertion and intramolecular nucleophilic substitution.

Very recently, Shu’s group adopted a similar strategy to realize the synthesis of fluoromethylated polycyclic γ-sultines 40, containing two adjacent tetrasubstituted carbon stereocenters, from benzo-fused homoallylic tosylates 38 and sodium fluoromethanesulfinates 39 through a visible-light-mediated RPCC reaction (Scheme [14]).[20] The protocol allowed substrates with different functional groups on the aromatic ring or at the R¹ position to be converted into corresponding polycyclic γ-sultines in moderate to excellent yields. Additionally, the synthesis of difluoroalkylated polycyclic sultines in high yields could be achieved through this strategy by using CHF₂SO₂Na, which may have potential applications in pharmaceuticals and agrochemicals. The protocol also facilitated the reaction between benzo-fused homoallylic tosylates 38 and sodium perfluoroalkanesulfinates for the synthesis of perfluoroalkylated tricyclic sultines in satisfactory yields. The proposed mechanism is similar to that of Shu’s previous work on the RPCC process.[19]

An unprecedented multicomponent fragment coupling of alkenes 41, sulfinates 42 and DABSO to achieve alkene 1,2-sulfonylsulfination by using an inexpensive 100–1000 ppm organic photocatalyst under mild and simple-to-operate conditions was disclosed by Shu and co-workers in 2024.[21] Of note, this is the first time that an S(IV)-sulfinate ester and an S(VI)-sulfone have been introduced simultaneously when compared with alternative alkene disulfidation methods. The scope of the alkenes and sulfinate salts was investigated and the protocol was found to exhibit remarkable compatibility regarding the two components bearing different substituents groups. As shown in Scheme [15], this transformation proceeded efficiently at room temperature under optimized conditions, leading to a range of disulfurized compounds in moderate to excellent yields and good to excellent diastereoselectivities. Several challenging sulfones containing polycyclic skeletons were successfully obtained with comparable yields. The scheme was also workable for reactions involving complex natural molecules or drug derivatives as components, furnishing the expected disulfide products with good to excellent yields, which further expanded the applicability of the strategy.

The transformation proceeded through a radical-polar crossover cyclization pathway, as demonstrated by the corresponding experimental and theoretical mechanistic investigations (Scheme [15]).[21] First, the photoredox catalytic cycle was achieved with the participation of the photocatalyst 4CzIPN. Single-electron transfer between the photoexcited state of 4CzIPN and sulfinate A led to the generation of an oxygen-centered radical B, accompanied by the formation of the resonance sulfonyl radical B′. Next, the addition of B′ to the double bond of the alkene gave the alkyl carbon-centered radical D. This radical then underwent a second single-electron transfer with 4CzIPN^•–, triggering reductive termination to give the carbanion intermediate E. After insertion of sulfur dioxide from the DABSO source, subsequent 5-exo-tet cyclization delivered the desired product G.

Electron-Induced Radical Cyclization

In 2020, Liao and co-workers reported an electrochemical cyclization reaction for converting N-cyanamide alkenes 44 into trifluoromethylated cyclic N-sulfonylimines 46 by utilizing the Langlois reagent (CF₃SO₂Na) (45) as CF₃ and SO₂ sources in a single operation and an atom-economic manner (Scheme [16]).[22] The substituents on the aromatic ring system of the cyanamides were investigated, with electron-rich N-arylcyanamides being converted into the corresponding products in moderate yields. However, the presence of electron-withdrawing substituents such as CF₃ and CO₂Et resulted in none of the desired products. Cyanamides with ortho or meta substituents on the aromatic ring system were feasible substrates, which were accompanied by the production of possible regioisomers. An N-phenylcyanamide with a methyl substituent connected to the terminal alkene gave the target product 46f in a decreased 33% yield, while phenyl-substituted analogues did not react with CF₃SO₂Na. N-Arylcyanamides containing cyclopentene and cyclohexene moieties gave trifluoromethylated N-sulfonylimines (such as 46h) incorporating spirocyclic moieties as the sole diastereoisomers under the reported conditions. It is worth noting that the cyanamide moiety was found to be critical to this electrolytic sequence.

The proposed mechanism for this electrochemical transformation indicated that the trifluoromethanesulfinate anion was first transformed into the corresponding radical through anodic oxidation, and then decomposed to a CF₃ radical and SO₂.[22] The CF₃ radical attacked the alkene moiety of cyanamide A resulting in carbon-centered radical intermediate B, which could subsequently deliver iminyl radical intermediate C via intramolecular cyclization. Next, iminyl radical intermediate C was captured by SO₂ leading to sulfonyl radical D, which underwent cyclization to produce intermediate E. Finally, a second anodic oxidation and aromatization resulted in the corresponding N-sulfonylimine 46a.

In 2023, the same group discovered a novel electrochemical three-component coupling of Na₂S₂O₅, N-cyanamide alkenes 47 and readily available sulfonyl hydrazides 48 for the assembly of various sulfonylated fused sultams 49 in a sustainable and modular fashion (Scheme [17]).[23a] The N–S and S–C bonds for the construction of fused sultams were established by applying cost-effective and easy-to-handle sodium metabisulfite as an SO₂ surrogate for the transformation in an undivided electrolysis cell without a supporting electrolyte. The protocol embraced a broad substrate scope, among which N-aryl cyanamide alkenes 47 with either electron-donating or electron-withdrawing groups at the para position of the benzene ring of the cyanamides were amenable to this reaction. Substituents at ortho or meta positions of the benzene ring were also tolerated. Variation of the R¹ and R² substituents further proved the compatibility of the protocol and expanded the chemical space of the products. Subsequently, sulfonyl hydrazides bearing substituents with different electronic properties were shown to exhibit good performance in this electrochemical SO₂-insertion transformation, affording the corresponding arylsulfonylated benzosultams in generally good yields.

The proposed mechanism[23b] indicated that the anodic oxidation of A led to the generation of a Ts radical. Subsequent addition of this Ts radical to the terminal alkyne of B gave intermediate C, which underwent intramolecular cyclization to afford iminyl radical D. The capture of SO₂ released from the inorganic sulfite by iminyl radical D delivers intermediate E, followed by a second intramolecular cyclization and oxidation to yield the expected product. Overall, this process represents a sustainable and environmentally friendly approach to assemble sulfonylated fused sultams.

Conclusion

Advances in the synthesis of S-containing cyclic architectures through the insertion of SO₂ that have been achieved in the last 10 years have been summarized herein. Various catalytic systems, involving thermal-induced cyclization, photoinduced cyclization and electron-induced cyclization, have been discovered and a wide range of value-added S-heterocycles have been prepared, such as sulfones, benzosulfones, sultines, benzosultines, sultams and benzosultams, from readily available starting materials with different SO₂ surrogates under mild conditions. So far, the full potential for synthesizing S-containing cyclic compounds through the insertion of SO₂ has not been fully realized, as there are relatively few publications on this topic compared to research on acyclic compounds. Hence, there is still a wide scope for further exploration in this intriguing field.

For example, the recent huge achievements in the field of photoredox catalysis have led to significant advances towards the visible-light mediated fixation of SO₂ over the last few years. New methods involving the construction of S-heterocycles via insertion of SO₂ are expected to grow in number in the near future.

DABSO, Na₂S₂O₅, and K₂S₂O₅ are the most notable sulfur dioxide surrogates that are typically employed in the insertion reactions of sulfur dioxide. However, reactions using inorganic sulfinites have been studied to a much lesser extent than those using relatively low-atom economic DABSO. Therefore, it is highly desirable to develop and utilize new sulfur dioxide surrogates to unlock the synthetic possibilities of S-heterocycles.

Furthermore, there is a need for continued advancement of the utilization of readily available building blocks, especially those derived from renewable and easily accessible sources. Of particular concern is the absence of efficient methods for the synthesis of highly functionalized S-heterocycles, which requires attention. Therefore, the further exploration and development of practical strategies for the synthesis of S-containing heterocycle skeletons using sulfur dioxide surrogates that are green, efficient, and atom-economical, with the potential for drug discovery in medical chemistry, still hold significant research significance. We anticipate that this work will garner more interest, leading to increased attention and significant development in this field in the near future.

Conflict of Interest

The authors declare no conflict of interest.

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For selected reviews, see:
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For selected reviews, see:
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For selected recent examples, see:
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• 13 Chen X, Tang B, He C, Ma J, Zhuang S, Wu Y, Wu A. Chem. Commun. 2020; 56: 13653
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• 14 Chen X, Wang H, He C, Wu C, Tang B, Hu Y, He C, Ma J, Zhuang S, Yu Z, Wu Y, Wu A. Org. Lett. 2022; 24: 7659
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• 16 Wang L, Shen Y, Wang Y, Wang H, Hao W, Jiang B. Adv. Synth. Catal. 2023; 365: 1693
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• 17 Hou X, Liu H, Huang H. Nat Commun. 2024; 12: 1480
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• 18 Li Y, Mao R, Wu J. Org. Lett. 2017; 3: 4472
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• 19 Li H, Zhang Y, Yang X, Deng Z, Zhu Z, Zhou P, Ouyang X, Yuan Y, Chen X, Yang L, Liu M, Shu C. Angew. Chem. Int. Ed. 2023; 135: e202300159
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• 20 Zhang Y, Zhou P, Yang X, Li H, Deng Z, Ren M, Shu C. Adv. Synth. Catal. 2023; 365: 3478
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• 21 Li H, Zhang Y, Zou X, Yang X, Zhou P, Ma X, Lu S, Sun Q, Shu C. ACS Catal. 2024; 14: 3664
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• 22 Li Z, Jiao L, Sun Y, He Z, Wei Z, Liao W. Angew. Chem. Int. Ed. 2020; 59: 7266
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• 23a Sun Y, Li C, Xi J, Wei Z, Liao W. Org. Chem. Front. 2023; 10: 705
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• 23b Sun Y, Li C, Xi J, Wei Z, Liao W. Org. Chem. Front. 2023; 10: 1592
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Corresponding Author

Publication History

Received: 10 March 2024

Accepted after revision: 06 April 2024

Accepted Manuscript online:
06 April 2024

Article published online:
22 April 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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For selected reviews, see:
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For our group’s previous work on sultine chemistry, see:
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  CrossrefPubMedSearch in Google Scholar
• 4b Zhu Z, Deng Z, Ouyang X, Shu C. Synlett 2023; 34: 1943
  Thieme ConnectSearch in Google Scholar
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  CrossrefSearch in Google Scholar

For selected reviews, see:
• 5a Emmett EJ, Willis MC. Asian J. Org. Chem. 2015; 4: 602
  CrossrefSearch in Google Scholar
• 5b Qiu G, Zhou K, Gao L, Wu J. Org. Chem. Front. 2018; 5: 691
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For selected recent examples, see:
• 6a He F.-S, Bao P, Yu F.-Y, Zeng L.-H, Deng W.-P, Wu J. Org. Lett. 2021; 23: 7472
  CrossrefPubMedSearch in Google Scholar
• 6b Li Y.-P, Chen S.-H, Wang M, Jiang X.-F. Angew. Chem. Int. Ed. 2020; 59: 8907
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  CrossrefPubMedSearch in Google Scholar
• 6d Chen L, Zhou M, Shen L, He X.-C, Li X, Zhang X.-M, Lian Z. Org. Lett. 2021; 23: 4991
  CrossrefPubMedSearch in Google Scholar
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• 8 Mao R, Zheng D, Xia H, Wu J. Org. Chem. Front. 2016; 3: 693
  CrossrefSearch in Google Scholar
• 9 Konishi H, Tanaka H, Manabe K. Org. Lett. 2017; 19: 1578
  CrossrefPubMedSearch in Google Scholar
• 10 Wang M, Chen S, Jiang X. Org. Lett. 2017; 19: 4916
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• 11 Meng Y, Wang M, Jiang X. Angew. Chem. Int. Ed. 2020; 59: 1346
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• 12 Meng Y, Wang M, Jiang X. CCS Chem. 2021; 3: 17
  CrossrefSearch in Google Scholar
• 13 Chen X, Tang B, He C, Ma J, Zhuang S, Wu Y, Wu A. Chem. Commun. 2020; 56: 13653
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• 14 Chen X, Wang H, He C, Wu C, Tang B, Hu Y, He C, Ma J, Zhuang S, Yu Z, Wu Y, Wu A. Org. Lett. 2022; 24: 7659
  CrossrefPubMedSearch in Google Scholar
• 15 Wu Y, Li C, Wei Z, Liao W. Org. Lett. 2022; 24: 9112
  CrossrefPubMedSearch in Google Scholar
• 16 Wang L, Shen Y, Wang Y, Wang H, Hao W, Jiang B. Adv. Synth. Catal. 2023; 365: 1693
  CrossrefSearch in Google Scholar
• 17 Hou X, Liu H, Huang H. Nat Commun. 2024; 12: 1480
  CrossrefPubMedSearch in Google Scholar
• 18 Li Y, Mao R, Wu J. Org. Lett. 2017; 3: 4472
  CrossrefPubMedSearch in Google Scholar
• 19 Li H, Zhang Y, Yang X, Deng Z, Zhu Z, Zhou P, Ouyang X, Yuan Y, Chen X, Yang L, Liu M, Shu C. Angew. Chem. Int. Ed. 2023; 135: e202300159
  CrossrefSearch in Google Scholar
• 20 Zhang Y, Zhou P, Yang X, Li H, Deng Z, Ren M, Shu C. Adv. Synth. Catal. 2023; 365: 3478
  CrossrefSearch in Google Scholar
• 21 Li H, Zhang Y, Zou X, Yang X, Zhou P, Ma X, Lu S, Sun Q, Shu C. ACS Catal. 2024; 14: 3664
  CrossrefSearch in Google Scholar
• 22 Li Z, Jiao L, Sun Y, He Z, Wei Z, Liao W. Angew. Chem. Int. Ed. 2020; 59: 7266
  CrossrefPubMedSearch in Google Scholar
• 23a Sun Y, Li C, Xi J, Wei Z, Liao W. Org. Chem. Front. 2023; 10: 705
  CrossrefSearch in Google Scholar
• 23b Sun Y, Li C, Xi J, Wei Z, Liao W. Org. Chem. Front. 2023; 10: 1592
  CrossrefSearch in Google Scholar