Recent Advances in the Synthesis of Cyclic Sulfone Compounds with Potential Biological Activity

Abstract

In recent years, cyclic sulfone compounds, a subset of biologically active heterocyclic compounds, have gained considerable attention due to their potential in the development of novel active pharmaceutical ingredients. This review focuses on identifying simple, mild, environmentally friendly, and efficient synthesis methods. Various catalytic approaches for the synthesis of cyclic sulfone compounds are systematically reviewed, highlighting their advantages and potential applications in pharmaceutical development.

1. Introduction

Cyclic sulfones, as a class of heterocyclic compounds, have been widely exploited in organic synthesis, the pharmaceutical industry, and optoelectronic materials due to their remarkable chemical properties [1], biological activities [2], and optoelectronic properties [3]. Several bioactive cyclic sulfones are illustrated in Figure 1. For example, adociaquinones show inhibitory effects on cell proliferation and hold promise for treating diabetes and neurodegenerative diseases [4]. Amenamevir serves as a helicase–primase inhibitor [5], while Ziresovir is a promising respiratory syncytial virus (RSV) protein inhibitor [6]. Meticran functions as a diuretic agent [7]. Moreover, these cyclic sulfones also exhibit inhibitory effects (e.g., acting as a brain-penetrating cyclic hydroxyethylamine (cHEA) BACE1 inhibitor, a matrix metalloproteinase inhibitor, and a PET tracer for the imaging of α₇ nicotinic acetylcholine receptors (α₇ nAChRs)) [8,9,10], and demonstrate antimicrobial [11], antifungal [12], and anticancer activities [13] (Figure 1).

As such, the synthesis of cyclic sulfone frameworks has garnered significant interest from synthetic and pharmaceutical chemists, leading to the development of a variety of efficient approaches [14,15]. In this regard, as depicted in Scheme 1, the current synthetic strategies mainly involve (a) the oxidation of thioethers employing m-CPBA, H₂O₂, and KMnO₄ as oxidants [16,17,18], (b) Rh/phase transfer catalyst-catalyzed C-H insertion reaction with sulfonates [19,20], (c) Ru-catalyzed ring-closing metathesis (RCM) reactions of the corresponding dienes [21], (d) transition metal (Pd, Cu, and Fe)/photo-catalyzed insertion of sulfur dioxide (SO₂) using SO₂ surrogates [22,23], (e) Ni-catalyzed hydroalkylation reactions [24], and so on [25,26].

Despite recent extensive progress in the synthesis of cyclic sulfones, a timely and comprehensive summary of these advances is still needed. To highlight the key methods for the construction of cyclic sulfones over the last 20 years, this review focuses on various catalytic techniques, including metal-catalyzed cyclization, photocatalytic cyclization, and other emerging methodologies, organized into three sections. These strategies provide valuable insights into the efficient and environmentally friendly synthesis of cyclic sulfone derivatives.

2. Metal-Catalyzed Synthesis of Cyclic Sulfone Compounds

Recently, the use of SO₂ as a sulfonyl source for the synthesis of organosulfones has proven to be a powerful strategy, directly introducing the SO₂ group into organic frameworks [27,28]. Bench-stable solid DABCO-bis(sulfurdioxide) (DABSO) [29], inorganic sulfites M₂S₂O₅ (M = Na, K), and Na₂SO₃ are commonly selected as SO₂ surrogates. Specifically, in 2015, using DABSO as the SO₂ source, a research team led by Wu developed a copper(I)-catalyzed reaction that transforms 2-alkylalkynyl difluoroborates 1 into benzo[b]thiolan-1,1-dioxides 3, achieving yields of 40–75% (Scheme 2) [30]. This method effectively forms two new C-S bonds through a sequential tandem process.

Under the standard conditions, the reaction exhibited broad applicability and high efficiency. Substrates bearing various functional groups (e.g., F, Cl, Me, and ⁿBu) on the aromatic ring performed well in this transformation and successfully yielded the desired products 3. Additionally, substrates with different aryl (such as 4-ClC₆H₄, 4-CO₂EtC₆H₄, 2-OMeC₆H₄, and thienyl)-substituted acetylene motifs were tolerated, all proceeding in moderate to good yields. It is noteworthy that the reaction did not occur without morpholin-4-amine, highlighting that the reaction progressed via the N-morpholino-2-(phenylethynyl)benzenesulfonamide intermediate 4.

Based on the experimental findings, a plausible reaction mechanism was proposed. Initially, 2-alkynylphenyl diazotetrafluoroborate 1 reacts with SO₂ and morpholin-4-amine, generating intermediate 4. Subsequently, in the presence of a base, the S-N bond of sodium sulfite is cleaved, forming N-aminosulfonamide 5. This is followed by a metal-catalyzed intramolecular 5-endo ring cyclization, which leads to protonation and the formation of the desired product 3 (Scheme 2).

Afterwards, in 2016, the same group reported a similar Cu(I)-catalyzed method for the insertion of SO₂ into (2-alkynyl)boronic acid 7, resulting in the efficient construction of benzo[b]thiolan-1,1-dioxides 3′ in 60–95% yields (Scheme 3) [31]. The reaction was investigated using (2-alkynyl)boronic acid 7 as the model substrate in the presence of 10 mol% of copper (I) acetate in DMF at 100 °C. Under standard conditions, the substrates containing the methyl group and halogens (e.g., F, Cl) on the aromatic ring demonstrated good reactivity, affording the corresponding target products in 75–95% yields. In addition, substrates with various aryl (e.g., 4-ClC₆H₄, 4-MeC₆H₄, 4-OMeC₆H₄, and 4-^tBuC₆H₄) substituents (R²) attached to the triple bond were explored, affording the expected products in moderate to excellent yields. The n-butyl substituted acetylene unit was also screened, successfully obtaining products in 60% yield.

Building on this foundation, researchers continued to explore synthetic methods for cyclic sulfones to further expand their application scope. In 2017, Jiang’s research group disclosed a novel synthetic route for constructing diaryl-annulated sulfones molecules 9 and 10 through the SO₂/iodine (I) exchange of diaryliodonium salts 8 (Scheme 4) [32]. In this process, commercially available inorganic Na₂S₂O₅ served as a safe and convenient SO₂ surrogate. This synthetic reaction revealed broad functional group compatibility, with a range of functionalized, five-membered 9 and six-membered 10 cyclic-conjugated diaryl-annulated sulfones successfully obtained in moderate to good yields, regardless of whether the benzene ring contained electron-withdrawing (Cl, CN, CF₃, and COOEt) or electron-donating (Me, OMe, and NHAc) groups.

The proposed mechanism for this reaction involves the formation of a free radical intermediate 11 through the oxidation of Cu(I) to Cu(II). Intermediate 11 then captures Na₂S₂O₅, generating a free SO2 radical anion intermediate 12. Intermediate 12 is subsequently oxidized to intermediate 13, with Cu(II) being reduced back to Cu(I). The oxidative addition of aryl iodide to Cu(I) forms the Cu(III) aryl species 14, which undergoes an intramolecular ligand exchange to yield intermediate 15. Finally, reduction and elimination of intermediate 15 result in the formation of the desired cyclic sulfone product 9, along with the regeneration of the Cu(I) catalyst (Scheme 4).

In 2018, Laha and coworkers reported a novel palladium-catalyzed protocol to directly form fused biaryl and heterodiaryl sulfones 9′ through the intramolecular oxidative cyclization of two C(sp²) C−H bonds in biaryl sulfones 16 (Scheme 5) [33]. Variously substituted dibenzothiophene-5,5-dioxides 9′ could be smoothly prepared with yields ranging from 36% to 89%. It is worth mentioning that products 9′l and 9′m were effectively obtained using this reaction, as an α₇-nicotinic acetylcholine receptor agonist analog and an organic emitter, respectively.

In 2020, Jiang et al. reported a novel multi-component strategy catalyzed by [1,1′- ferrocenebis(diphenylphosphino)] dichloro palladium(II) (Pd(dppf)Cl₂), enabling the construction of five- to twelve-membered benzo-fused sulfones through a reductive cross-coupling reaction involving Na₂S₂O₅, aryl halides 17, and alkyl halides 18 (Scheme 6) [34]. The reaction was performed in DMSO at 100 °C using tin (Sn) as the reducing agent. A wide variety of electronically diverse aryl halides 17 were effectively transferred and gave the corresponding cyclic sulfones 19 in yields ranging from 39% to 92%, with smaller rings generally giving higher yields.

The proposed reaction mechanism involves the formation of a highly reactive alkyl radical intermediate 20 (ⁿBu·) through single-electron transfer between the ⁿBuBr 18 and Sn. This intermediate 20 reacts with Na₂S₂O₅ to generate sulfonyl radical 21, which is reduced by Sn to produce sulfonyl anion 22. Meanwhile, oxidative addition of aryl halide 17 to Pd⁰ forms intermediate 23, which then reacts with sulfonyl anion 22, yielding intermediate 24. The desired cyclic sulfones 19 were obtained through reduction and elimination, with the Pd⁰ catalyst being regenerated in the process (Scheme 6).

In 2022, Franckevičius and coworkers discovered a palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) reaction to afford enantioenriched α-difunctionalized cyclic sulfones 26 (Scheme 7) [9]. In this reaction, 5 mol% Tris(dibenzylideneacetone)dipalladium (0) [Pd₂(dba)₃] and 13 mol% (S,S)-ANDEN phenyl Trost ligand L4 were the best catalyst choices. A range of racemic ester- and ketone-substituted sulfone substrates 25 were investigated, and the relevant expected products 26 were isolated in moderate to excellent yields with high stereoselectivity. The innovation of this approach lies in achieving high levels of enantioselectivity through the dynamic kinetic resolution of E- and Z-enolate intermediates.

The reaction was initiated by oxidative addition of the Pd (0) catalyst to allyl ester 25. The resulting intermediate 27 is a loosely associated ion pair between a carboxylate and a π–allylpalladium(II) complex, which undergoes rapid CO₂ extrusion to give a mixture of E- and Z-enolates 28. Rapid isomerization occurs between (E)-28 and (Z)-28, presumably through a carbon-bound palladium enolate tautomer, followed by preferential allylic alkylation of (Z)-28 over (E)-28, leading to the formation of the enantioenriched product 26.

3. Photocatalytic Synthesis of Cyclic Sulfones

Nowadays, visible light-induced organic synthesis has gained considerable research attention and is considered as a green, sustainable, and cost-effective synthetic methodology for the preparation of diverse carbocyclic and heterocyclic compounds [35,36].

In 2021, Jiang and colleagues reported a novel photocatalytic three-component cycloaddition cascade reaction of 2-alkynylaryldiazonium tetrafluoroborates 1′ with γ-hydroxyl terminal alkynes 29 (Scheme 8) [37]. This transformation employed fac-tris(2-phenylpyridine)iridium (fac-Ir(ppy)₃) as the photocatalyst [38] and 4-nitrobenzoic acid as an additive under blue light irradiation; functionalized bicyclic sulfones 30 were obtained in good yields with high stereoselectivity (Z). The experimental results indicated that this photocatalytic cyclization was highly effective for γ-hydroxy terminal alkynes 29 bound to phenyl rings. Moreover, altering the substituents on acetylene motifs of 2-alkynylaryldiazonium tetrafluoroborates 1′ had minimal impact on reaction activity. Substrates 29 bearing Me, Cl, and Br at the C5 position of the aromatic ring were readily converted to the corresponding (Z)-products 30i–30k with acceptable yields and stereoselectivities (2:1 to 10:1 Z/E ratio). Further investigations showed that the aryl groups on secondary alcohols of 29 could be replaced with ethyl and n-butyl groups, thus expanding the scope of the photocatalytic reaction.

The proposed mechanism shows that a single-electron transfer (SET) process occurs between aryl diazotetrafluoroborate 1′ and the excited *Ir(III) complex, generating an aryl radical intermediate 31 and Ir(IV) species simultaneously. The aryl radical 31 then undergoes a reaction with Na₂S₂O₅, yielding an aryl sulfonyl radical 32. Radical 32 undergoes intermolecular addition, followed by a 6-exo-dig cyclization with γ-hydroxy terminal alkyne 29, forming the exocyclic vinyl radical 35 as the predominant isomer. Due to steric hindrance from aryl and hydroxymethyl groups, intermediate 34 is less favorable for hydrogen abstraction. Intermediate 35 undergoes a 1,6-HAT (hydrogen atom transfer) process, resulting in hydroxymethyl radical 36. This radical is subsequently oxidized by Ir(IV) to furnish the hydroxymethyl cation 37, which regenerates the Ir(III) complex. Finally, intermediate 37 undergoes deprotonation to yield the desired (Z)-thiochromene 1,1-dioxides 30 (Scheme 8).

In 2023, Huang’s research group reported an alkyl radical-initiated difunctionalization reaction of non-activated alkanes to synthesize the 2-benzoyl-1,1-dioxidothiochroman-4-yl derivatives 40 (Scheme 9) [39]. This reaction utilized α-carbon-based alkyl bromide 39 as the oxidant and 450 nm LEDs as the light source; α-allyl-β-ketosulfones 38 bearing various substituents could be transformed into the corresponding sulfones 40 in 29–68% yields, revealing that electron-donating groups favored the reaction. Additionally, different oxidants, such as α-bromoalkyl ester, 2-bromoacetophenones, and 2-(bromoacetyl)thiophene, also worked well.

The proposed mechanism is illustrated in Scheme 8. The photoexcited Ir(III)* catalyst is oxidized sufficiently to carry out SET with α-carbon-based alkyl bromide 39 forming Ir(IV) and alkyl radical 41. Radical 41 then adds to substrate 38, thereby producing alkyl radical 42. Radical 42 subsequently undergoes an intramolecular radical cyclization, resulting in the generation of the stable intermediate 43. The photocatalyst Ir^IV accepts an electron from intermediate 43 to afford cationic intermediate 44, which then delivers the final product 40 after deprotonation.

4. Other Methods for Synthesizing Cyclic Sulfones

Recently, as research continues to advance, researchers have developed a variety of metal-free and efficient methods for synthesizing cyclic sulfone compounds with complex structures and diverse functionalities [40]. By eliminating the use of metal catalysts, metal-free strategies reduce costs and environmental impact.

In 2019, Jiang and coworkers developed a radical-initiated, three-component double-ring cascade reaction mediated by DABSO (Scheme 10) [41]. Under mild and neutral redox conditions, the expected products, indeno [1,2-c]thiochromene 5,5-dioxide 46, could be obtained in 35–82% yields, with tolerance of various functional groups, including aryl, alkyl, and heterocyclic groups.

A radical mechanism was verified by 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) control experiments. The combination of DABSO and substrates 1″ generates the arylsulfonyl radical 47 and a tertiary amine (DABCO) radical cation. Radical 47 then adds to the triple bond of haloalkynes 45, providing the alkenyl radical intermediate 48. Intermediate 50 arises from intermediate 49 through further 6-exo-dig cyclization/5-endo-trig cyclization, which loses an electron to access intermediate 51. Subsequent deprotonation gives rise to the formation of product 46.

In 2021, Lian and colleagues successfully established a method for synthesizing cyclic aliphatic sulfones through the sulfonyl cyclization of alkyl diiodides 52 and gaseous SO₂ (Scheme 11) [42]. The reaction of N,N-bis(2-iodoethyl)aniline 52, HCOOLi·H₂O and SO₂ in dimethylacetamide (DMA) at 50 °C for 16 h led to the formation of nitrogen-containing five- to nine-membered cyclic aliphatic sulfones 53. The substrate scope demonstrated the practicality of this method, as a variety of alkyl diiodides yielded moderate to high yields of cyclic sulfones with good efficiency. Notably, product 53g could be transformed to mTOR kinase inhibitors 54 and Alzheimer’s inhibitors 55 via multi-step synthesis.

The proposed mechanism involves the cleavage of the C-I bond in alkyl diiodide 52 to form alkyl radical intermediate 56. This radical then reacts with SO₂ to generate alkyl sulfonyl radical intermediate 57, which is in equilibrium with another radical intermediate 58. Subsequently, intermediate 58 is reduced by a formate radical cation, resulting in the formation of alkyl sulfonyl anion 59. This anion may exist in equilibrium with alkyl sulfonate 60, which undergoes intramolecular nucleophilic substitution to yield the desired cyclic sulfone.

In 2021, Hugelshofer and Bao reported a Michael reaction to form various 4,4-disubstituted nitro sulfones 63 using divinyl sulfone 61 and commercially available raw materials 62. Substituted alkyl nitro, benzyl nitro, and β-nitro ester derivatives, acting as active methylene nucleophiles, were smoothly introduced to a wide range of cyclic sulfones (Scheme 12) [43].

In addition, a sustainable, catalyst-free microwave method [44] has quickly gained prominence, which involves in situ aldoxime formation followed by a tandem aza-Michael addition-1,3-dipolar cycloaddition. This reaction system utilizes microwave radiation as an energy source, significantly reducing reaction time while eliminating the need for expensive catalysts, fully embodying the principles of green chemistry. Aldehyde 64, hydroxylamine hydrochloride 65, and potassium carbonate (K₂CO₃) were added to a microwave reactor, and the mixture was heated at 150 °C for 2 min to yield the corresponding aldoximes 66. These aldoximes 66 then reacted with divinyl sulfone 61 in the same pot to gain the desired product 67 (Scheme 13a) [45]. Aromatic, heteroaromatic, and aliphatic aldehydes were suitable substrates. The reaction could be carried out on a gram scale with high efficiency, offering facile access to bicyclo aza-sulfones. One year later, Banerjee and Chatterjee applied the microwave catalytic system to the double aza-Michael addition reaction (Scheme 13b) [46]. This reaction proceeds on the water surface under microwave irradiation at 150 °C for 10 min, where amines 68 and divinyl sulfone 61 were transformed into solid cyclic β-amino sulfones 69 with excellent yields. Both electron-rich and electron-deficient amines participated effectively in this transformation, demonstrating good functional group tolerance. In particular, the method is sustainable due to its reagent-free, metal-free, organic solvent-free, and 100% atom-economic nature.

In 2022, Xu and coworkers developed a pyridine-mediated [2 + 2] cycloaddition reaction to synthesize bifunctionalized 2H-thiete 1,1-dioxide derivatives 72 from readily available sulfonyl chloride 70 and dialkyl acetyl dicarboxylic acid 71 (Scheme 14) [47]. The reaction was conducted by stirring sulfonyl chloride 70, acetoacetyl dicarboxylic acid 71, pyridine, and tetrahydrofuran (THF) at room temperature under a nitrogen atmosphere for 24 h to yield the desired products 72. Various sulfonyl chlorides were tested, including di(pentan-3-yl) acetylenedicarboxylate. The results indicated that benzene sulfonyl chloride with electron-donating groups did not undergo the annulation. To assess the impact of steric hindrance in dialkyl acetyl dicarboxylates 71, diisopropyl acetyl dicarboxylate was tested with different electron-deficient benzyl sulfonyl chlorides. The findings revealed that stronger electron-withdrawing sulfonyl chlorides produced higher yields than their weaker counterparts. Additionally, for the same sulfonyl chloride, di(pentan-3-yl) esters yielded better results compared to the corresponding diisopropyl esters, highlighting the significant effect of steric hindrance on the reaction yield.

A proposed mechanism involves the generation of sulfonic acid 73 from sulfonyl chloride in the presence of basic pyridine. Following the elimination of hydrochloric acid, pyridine acts as a nucleophile, attacking the sulfonyl group of sulfonic acid 73 to form zwitterionic intermediate 74. This intermediate then nucleophilically attacks dialkyl acetyldicarboxylic acid 71, contributing to the formation of another zwitterionic intermediate 75. The enoate of intermediate 75 is eliminated through intramolecular nucleophilic addition to sulfonyl pyridine, generating intermediate 76. Subsequently, intermediate 78 is isomerized via intermediate 77 to produce the final four-membered thiaheterocyclic derivatives 72.

Remarkably, in 2019, Sun and coworkers reported a solvent-controlled strategy to obtain benzo[b]thiophene-1,1-dioxides 3″ via a radical pathway (Scheme 15) [48]. The reaction was performed in 2,2,2-trifluoroethanol (TFE), rapidly occurring in the presence of simple hydrogen peroxide and potassium iodide (KI), without the need for any transition metal catalysts. The use of para-toluenesulfonyl hydrazone with a strong electron-donating methoxy group facilitated the controlled radical reaction, resulting in exceptionally high yields of 89% for product 3″c. It should be noted that product 3″d presents aggregation-induced emission (AIE) properties.

In recent years, base-promoted organic reactions have made significant advancements in the construction of C–S [49] or C–C [50] bonds. In 2023, Gharpure and coworkers reported an efficient method for the stereoselective synthesis of cyclic β-ketosulfones 82 using various sulfone-tethered alkynols 81 promoted by KOH (Scheme 16) [7]. This cascade transformation proceeded through a base-driven propargyl sulfone undergoing allene isomerization/intramolecular/hydroalkoxylation/retro-oxa-Michael/a 6-endo-trig Michael addition. Products 82f and 82g can be readily converted into the corresponding benzofuran-fused cyclic sulfones in 75% and 80% yields, respectively. With Cs₂CO₃ as the base, sulfone-tethered alkynyl acrylates 83 were transformed into spirocyclic β-ketosulfone 84 with yields ranging from 53% to 80%. This work features excellent substrate adaptability and synthetic applicability, paving the way for the green synthesis of more complex molecules.

5. Conclusions and Outlook

In summary, we have reviewed the latest advancements in the efficient synthesis of cyclic sulfones by catalytic protocols. Transition metal-catalyzed synthesis of cyclic sulfones highlights the regioselectivity and high yield across a diverse range of substrates; however, the reliance on specific catalysts, such as Pd(dppf)Cl₂ and Pd₂(dba)₃, may impose challenges in terms of scalability and cost. Furthermore, the reaction conditions may require careful optimization to accommodate a range of functional groups. Visible light-driven synthesis of cyclic sulfones aligns with the principles of green chemistry, making the process more sustainable. These reactions are conducted at room temperature, reducing the need for harsh chemicals or extreme conditions that could potentially degrade sensitive substrates. Photocatalytic methods, although promising, face challenges when scaling from the laboratory to industrial scale. Issues such as the cost of photocatalysts, light absorption efficiency, and reaction optimization for large-scale processes must be addressed.

Nevertheless, there is an ongoing high demand for novel, versatile, and sustainable methods for synthesizing structurally diverse cyclic sulfones and their applications in the construction of bioactive compounds and other useful derivatives. Meanwhile, experimental mechanistic studies will be crucial for gaining a deeper understanding of the reaction details. We anticipate that more groundbreaking and impactful work in this field will emerge in the near future.