Advancements and perspectives toward radical Truce–Smiles-type rearrangement

Abstract

Radical Smiles rearrangement as a potent synthetic platform for arene functionalization efficiently facilitates the construction of (hetero)aromatic groups under gentle reaction conditions, and has proven to be a valuable tool for the late-stage functionalization of pharmaceutical molecules of interest. The rapid expansion in this field has resulted in numerous new findings over the past five years, yet no specific review has been focused on the radical Truce–Smiles rearrangement so far. This review offers a comprehensive overview of recent progress in this field and contributes to future research. The synthetic tactics are reviewed by highlighting their product diversity, selectivity and applicability, and the mechanistic rationale where possible. It is expected that this minireview will serve as a source of inspiration for promoting the development of radical Truce–Smiles rearrangement for its potential in drug discovery.

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Yuxi Wang

Yuxi Wang, born in 2004 in Anhui Province, China, is currently a student in Professor Chao Shu's research group at the College of Chemistry, Central China Normal University. Her research primarily focuses on the development and application of innovative synthetic methodologies, particularly those involving radical-polar crossover cyclization reactions.

Xinyao Zhang

Xinyao Zhang, born in 2003 in Henan Province, China, is currently a student in Professor Shu's research group at the College of Chemistry, Central China Normal University. Her research primarily focuses on the development of radical sulfur chemistry.

Kexin Kong

Kexin Kong, born in 2005 in Henan Province, China, is currently a student in Professor Chao Shu's research group at the College of Chemistry, Central China Normal University. Her research primarily focuses on the development of radical sulfur chemistry.

Chao Shu

Chao Shu was born in Anhui Province, China. He earned his Ph.D. in 2017 from Xiamen University under the supervision of Professor Long-Wu Ye, specializing in transition-metal-catalyzed alkyne tandem reactions. Following this, he joined Professor V. K. Aggarwal's research group at the University of Bristol as a postdoctoral research associate, where he worked on radical boron chemistry. In 2021, he launched his independent academic career as a Full Professor at Central China Normal University. His current research interests center on the development of novel reactions, new reagents, and innovative strategies for organic synthesis.

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1. Introduction

The intramolecular nucleophilic (hetero)aromatic rearrangement in alkaline solution, commonly referred to as the Smiles rearrangement, is a long-established chemical reaction that has seen a renewed interest in recent times for the production of important arene and heteroarene compounds, which has been utilized as an additional approach to (hetero)arene functionalization and has a wide range of applications in modern synthetic chemistry.^1,2 To classical Smiles rearrangement, the aromatic ring needs to be activated by electron-withdrawing groups at the ortho- or para positions (such as nitro, sulfonyl, naphthyl and pyridyl), if in the absence of activating groups or electron-donating groups are attached to the aromatic ring, the rearrangement is slow or does not occur.

Then, the transformation of o-methyldiaryl sulfones to o-benzylbenzenesulfinic acids under butyllithium was developed by Truce and co-workers, this kind of carbon–carbon bond formation involved carbanion Smiles rearrangement (a nucleophilic carbanion with an electron-deficient aryl sulfone) in the presence of a strong base, especially, no activating group is necessary, is referred to as the Truce–Smiles rearrangement.^3–6 Numerous modifications of this anionic Truce–Smiles rearrangement have been reported since its initial discovery, offering a simple and reliable approach for incorporating (hetero)aryl groups into diverse organic compounds. Although great progress has been achieved in this field, the requirement of electron-deficient aryl group still remains an issue when avoiding the strong bases conditions. This limitation was found pathways to overcome through radical chemistry by the pioneering works by Speckamp and Motherwell,^7–11 who demonstrated the migration of electron-neutral and electron-rich aromatic rings (sulfonamides) for the synthesis of biaryl derivatives through less stable radical species as intermediates, not the previous polar intermediates. Subsequently, Zard reported that the synthesis of substituted 3-arylpiperidines and 3-arylpyrrolidines by radical 1,4 and 1,2-aryl migrations.¹²

Generally, the type of radical Truce–Smiles rearrangement is involved the formation of a spiro radical intermediate by carbon radical addition, followed by sulfur dioxide extrusion and final hydrogen abstraction, to form a new carbon-to-carbon bond (Scheme 1). Since then, this potent synthetic platform efficiently facilitates the construction of (hetero)aromatic groups under mild reaction conditions, and has proven to be an effective strategy for synthesizing and late-stage functionalizing pharmaceutical products of interest. Considerable progress has been achieved in the radical Truce–Smiles rearrangement, as evidenced by recent work from various research groups, which has been partly reviewed.^13–19 The rapid expansion in this field has resulted in numerous new findings over the past several years, yet no specific review has been focused on the radical Truce–Smiles rearrangement so far.²⁰ This mini-review aims to provide a comprehensive overview of the latest developments in the field, offering insights into its current state and contributing to future research, and the classic anionic Truce–Smiles rearrangement will not be discussed.^{3–6,21–25}

Scheme 1 Representative type of radical Truce–Smiles rearrangement.

The synthetic tactics are reviewed by highlighting their product diversity, selectivity and applicability, and the mechanistic rationale where possible. The review is broadly categorized on the basis of starting materials and the selected examples involving typical substrates with representative reaction mechanisms are presented. The objective of this minireview is to summarize and discuss the recent results on the radical Truce–Smiles rearrangement, we aim to provide a stepping stone for further investigations.

2. Alkene involved Truce–Smiles rearrangement

2.1 Activated alkene involved Truce–Smiles rearrangement

In 2018, Stenphenson's group conducted research on the aminoarylation of activated alkenes 1 with arylsulfonylacetamides 2 via radical Truce–Smiles rearrangement (Scheme 2). Using vinyl anisole and 1-naphthylsulfonylacetamide as model substrates, they systematically investigated factors such as photocatalysts, bases, reaction concentrations, and additives. They determined that [Ir(dF(CF₃ppy)₂)(5,5′-CF₃bpy)]PF₆ was the optimal photocatalyst, screened out suitable bases, and identified 0.1 M as the best reaction concentration. They also clarified the adverse effects of substances like pyridine on the photocatalyst. Based on the optimized conditions, the reaction has a wide substrate scope, showing good compatibility with various aryl groups and different structures of alkenes. The obtained 2,2-diarylethylamine compounds 3 containing adjacent stereocenters with complete anti-Markovnikov regioselectivity and excellent diastereoselectivity (dr > 20 : 1). Its significance lies in providing a new and efficient method for constructing carbon–carbon and carbon–nitrogen bonds. By using visible light driving, it is environmentally friendly and avoids the limitations of traditional transition metal catalysis. This provides a new strategy for the synthesis of medicinally valuable arylethylamine compounds, and has potential application prospects in fields such as drug research and development, and organic synthesis methodology (Scheme 2).

Scheme 2 Arylsulfonylacetamides as bifunctional reagents for alkenes aminoarylation by radical Truce–Smiles rearrangement.

The proposed catalytic cycle for this reaction was illustrated in Scheme 2. Single electron oxidation of alkene enables nucleophilic addition of arylsulfonylacetamide (C) to form β-amino alkyl radical intermediate (D). The radical undergoes regioselective cyclization at the ipso-position of the arene to give intermediate E. Entropically favored desulfonylation has two pathways to generate aminoarylation product H: one is rapid desulfonylation of E to form nitrogen-centered radical F followed by catalyst turnover, the other is homolytic fragmentation of C_Ar–S bond to produce G, then catalyst turnover and desulfonylation to give H.²⁶

In 2021, Nevado's group developed a novel method for the synthesis of acyclic amides containing an α-all-carbon quaternary center through an asymmetric radical Truce–Smiles rearrangement. During the special experimental process, p-tolyl-substituted N-arylsulfinyl acrylamides were used as the starting substrate. A variety of radical precursors, photocatalysts, and other reaction conditions were screened. The optimized reaction conditions were determined to use fac-Ir(ppy)₃ as the photocatalyst, in a mixed solvent of acetonitrile and water, with the addition of a base and temperature control. Furthermore, the scope of sulfonyl chlorides, different sites of the substrate, and various initiating radicals were investigated to verify the generality of the reaction. This research is of great significance as the synthesized acyclic amides 5a–5c containing an α-all-carbon quaternary center, which are not only widely present in bioactive molecules but also can be transformed into important compounds such as chiral acids, oxindoles, and amines. Overall, this method provides a new strategy for constructing chiral all-carbon quaternary centers, enriches organic synthesis methodology, and promotes the development of related fields such as drug research and development and total synthesis of natural products (Scheme 3).

Scheme 3 Asymmetric, visible light-mediated radical Truce–Smiles rearrangement to access acyclic amides.

Mechanistically, upon irradiation with visible light, the Ir^(III) photocatalyst is activated, leading to the generation of the starting radical R˙ from the corresponding sulfonyl or alkyl halide precursor. The radical R˙ adds to the double bond of N-arylsulfinyl acrylamide A via the transition state TS_I–II, forming a tertiary carbon-centered radical intermediate B in an endothermic process. Instead of going through a traditional Meisenheimer intermediate, intermediate B reacts through a spirocyclic transition state TS_II–III to generate a sulfur-oxygen-centered radical C in an exothermic reaction. The activation energy of this step reflects the energy cost associated with the loss of aromaticity during the reaction. Subsequently, the sulfur-oxygen-centered radical C is oxidized by Ir^(IV) and then reacts with two molecules of water, ultimately yielding the corresponding product D and sulfurous acid, which is consistent with the experimental result of no sulfur-containing gas being detected.²⁷

In 2021, Liang's team has made a substantial advance by devising a copper-catalyzed multicomponent reaction encompassing cycloketone oximes, sulfur dioxide, and activated alkenes. Employing activated alkene 6a, 6b and cyclobutanone oxime ether 7a, 7b as substrates, they executed a thorough optimization of reaction conditions involving a screening of copper salts, ligands, bases, and solvents to pinpoint the optimal reaction parameters for different product formations, while also comprehensively evaluating the substrate scope. A gram-scale experiment was conducted as well to ascertain the method's scalability and practical utility (Scheme 4).

Scheme 4 Copper-catalyzed radical aryl migration approach for the preparation of cyanoalkylsulfonylated oxindoles/cyanoalkyl amides.

This reaction enables the synthesis of cyanoalkylsulfonylated oxindoles and cyanoalkyl amides using an aryl migration strategy. Its significance lies in offering a novel avenue for constructing quaternary carbon centers, a challenging yet crucial task in organic synthesis. The in situ desulfonylation-mediated sulfur dioxide insertion obviates the need for additional sulfur dioxide sources, streamlining the process. With remarkable compatibility towards a diverse range of activated alkenes and consistent moderate to high yields of target products, this reaction presents a valuable synthetic tool for the construction of compounds containing cyanoalkyl and sulfonyl moieties, with far reaching implications for drug discovery and organic synthetic chemistry.

The proposed catalytic cycle for this transformation was illustrated in Scheme 4. Initially, iminyl radical B is generated via single electron transfer (SET) and N–O bond cleavage under a copper catalyst. B then undergoes β-C–C bond scission to form cyanoalkyl radical C, which was inserted by SO₂ group, producing radical intermediate D. Then D interacts with activated alkene 6 to form intermediate E, followed by ipso-cyclization on the sulfonyl aromatic ring to give F. F undergoes desulfonylation to form amidyl radical G, which captures a hydrogen atom to yield product J. If R² is an alkyl group, G can cyclize further to form aryl radical H, leading to product I via SET and β-H elimination.²⁸

Wu and co-workers successfully developed an enantioselective radical Truce–Smiles rearrangement strategy under photoredox catalysis in 2022. By using two complementary photoinduced sulfur dioxide insertion systems, they efficiently constructed chiral sulfones with quaternary chiral centers starting from various carbon radical precursors 10a and 10b, sulfur dioxide surrogates, and chiral acrylamides 9a and 9b. This achievement is of great significance that provides a new method for the synthesis of chiral sulfones, addressing the previous challenges in constructing chiral sulfones with quaternary chiral centers. The sulfur dioxide insertion strategy demonstrates good diversity and compatibility, and the in situ generation of radicals endows the reaction with excellent functional group compatibility and step economy. The late-stage functionalization experiments of bioactive molecules prove the potential application value of this strategy in fields such as drug research and development (Scheme 5).

Scheme 5 Accessing chiral sulfones bearing quaternary carbon stereocenters via photoinduced radical Truce–Smiles rearrangement.

Mechanistically, as an example, sodium dithionite undergoes homolytic cleavage to produce two sulfur dioxide radical anions (A), which can perform SET with aryldiazonium salt 10a, generating aryl radical (B) and releasing SO₂. Decomposition of sodium bisulfite may also contribute SO₂, improving conversion rates. Aryl radical B inserts into SO₂, forming sulfonyl radical (C), which adds to a double bond, giving radical intermediate (D). This intermediate undergoes Truce–Smiles rearrangement to deliver SO-centered radical (F) via an exothermic spirocyclic transition state (E). Radical F undergoes SET oxidation with aryldiazonium salt and reacts with NaOH to yield the final product G and NaHSO₃, allowing the cycle to continue. The introduction of a photocatalytic system (Mes-Acr⁺*) speeds up the oxidation of intermediate F to product G through SET, while Mes-Acr˙ facilitates the formation of aryl radical B from the diazonium salt, enhancing overall efficiency.²⁹

In 2023, Huang, Ji and co-workers developed a visible-light-induced cascade arylazidation of activated alkenes with trimethylsilyl azide (TMSN₃). Under optimized conditions, this reaction afforded α-aryl-β-azido amides and azidated oxindoles in moderate to good yields, demonstrating broad substrate scope with tolerance for electron-donating, electron-withdrawing, and sterically hindered substituents. A gram-scale experiment maintained 78% yield, confirming synthetic utility. The products were further transformed into β-amino amides and 1,2,3-triazoles, highlighting their value as nitrogen-containing building blocks. Compared to conventional methods requiring high temperatures or pre-functionalized reagents, this strategy offers a mild, atom-economical route to C(sp³)–N₃ bonds, expands alkene difunctionalization paradigms, and aligns with green chemistry principles. The demonstrated applicability to drug late-stage diversification suggests promising utility in medicinal chemistry (Scheme 6A).

Scheme 6 Visible-light-induced cascade arylazidation and fluorination of activated alkenes.

A plausible mechanism is proposed in Scheme 6A. Upon visible light irradiation, the 4DPAIPN photocatalyst is excited to an excited state. Subsequently, it undergoes a single electron transfer (SET) with trimethylsilyl azide (TMSN₃), generating the azide radical A (N₃˙) and the reduced photocatalyst species. The azide radical A adds to the activated alkene through a radical addition process, yielding the alkyl radical B. The alkyl radical B then undergoes intramolecular 5-ipso cyclization to form the intermediate C. Subsequently, the intermediate C rapidly undergoes desulfonylation to generate the key amidyl radical D. When R is an aryl group, the amidyl radical D undergoes a single electron transfer with the reduced photocatalyst species, followed by protonation to form the target product α-aryl-β-azido amide 14, and the photocatalyst is regenerated simultaneously. When R is an alkyl group, the more nucleophilic amidyl radical D triggers further cyclization and oxidative rearomatization reactions to produce the oxindole 15. In this process, a small amount of oxygen in the system can act as an oxidant to restore the photocatalyst to its initial state. In addition, the trimethylsilyl cation ((Me₃Si⁺)) hydrolyzes to form Me₃SiOH and (Me₃Si)₂O. The entire reaction realizes the visible-light-induced cascade arylazidation of activated alkenes with TMSN₃ through this series of steps.³⁰ A similar visible-light-induced radical Truce–Smiles rearrangement reactions of alkenes for the divergent synthesis of fluorine-containing oxindoles and amides has been reported in 2024 by Yang group (Scheme 6B).³¹ Recently, the Huang group developed a photochemical radical Truce–Smiles rearrangement reaction of N-sulfinyl acrylamides with bromodiffuoroacetamides to the synthesis of various aryl diffuoroglutaramides in moderate to good yields (Scheme 6C).³²

In 2024, Chen's group has developed a copper catalyzed silylarylation reaction of N-(arylsulfonyl)acrylamides by radical Truce–Smiles rearrangement. Through a tandem process involving silyl radical addition, 1,4-aryl migration, and desulfonylation, using silanes as the precursors of silyl radicals and DTBP (di-tert-butyl peroxide) as the initiator, a series of β-silyl amides 18 containing an α-all-carbon quaternary stereocenter have been successfully synthesized. This achievement holds significant importance as it introduces a novel method for the preparation of β-silyl amides, thereby enhancing the strategies for synthesizing silicon-containing compounds in organic chemistry. Of note, this reaction expands the application of radical tandem reactions in the synthesis of silicon-containing compounds, laying a foundation for subsequent related research and promoting the development of organic synthetic chemistry in the construction of silicon-containing functional molecules (Scheme 7).

Scheme 7 Copper catalyzed radical silylarylation of activated alkenes by radical Truce–Smiles rearrangement.

Scheme 7 illustrates a proposed mechanism for the silylarylation of activated alkenes. The process starts with the thermal decomposition of DTBP into a t-BuO radical (path a). Alternatively, DTBP can react with Cu^IL species to produce t-BuO radical, t-BuO anion, and Cu^II L species (path b). The Cu^II L species is then reduced to Cu^IL by silane. The t-BuO radical abstracts a hydrogen atom from silane 17, forming a silicon-centered radical, which then reacts with N-(arylsulfonyl)acrylamide 16 to create alkyl radical intermediate A. This radical undergoes 5-ipso cyclization to yield intermediate B, which produces amide radical C through a rapid 1,4-aryl migration and desulfonylation. Finally, radical C abstracts a hydrogen atom from silane or t-BuOH, resulting in product 18.³³

In 2024, Nevado's group innovatively developed a photoredox-mediated radical Truce–Smiles rearrangement by using chiral arylsulfinylamides 19 as multifunctional all-in-one reagents, they achieved the asymmetric intermolecular aminoarylation of alkenes 20, enabling the stereocontrolled construction of two adjacent C_sp³–C_sp² and C_sp³–N bonds across the π-system. The reaction features mild conditions, good functional group tolerance, and excellent regioselectivity, diastereoselectivity, and enantioselectivity. The research results can efficiently prepare optically pure β,β-diarylethylamines, aryl-α,β-ethylenediamines, and α-aryl-β-aminoalcohols, which are important structural units in pharmaceuticals, bioactive natural products, and transition metal ligands. This research not only enriches the types of asymmetric difunctionalization reactions of alkenes but also provides a new strategy for constructing nitrogen-containing chiral compounds (Scheme 8).

Scheme 8 Chiral arylsulfinylamides as reagents for visible light-mediated asymmetric alkene aminoarylations.

Mechanistically, after the olefin turns into radical cation B, aryl sulfonyl A adds at the β-carbon atom of alkene F, then releases benzyl radical C (ΔG = −25.2 kcal mol⁻¹) in an exothermic process. C Undergoes 1,4-aryl migration to create radical D centered on sulfur (ΔG = −38.5 kcal mol⁻¹). D is then oxidized to E by Ir^(II) to recycle the Ir^(III) catalyst, closing the photocatalytic cycle. An alternative transition state for the enantio-determining step, with A adding to the olefin radical cation B.³⁴

In 2024, Liu's group has successfully developed a visible – light induced difunctionalization reaction of activated alkenes through a radical Smiles rearrangement strategy, using Hantzsch esters as alkylation reagents, alkylsulfonylated oxindoles 24a and amides 24b were constructed via a tandem process of sulfur dioxide insertion, 1,4-aryl migration, desulfonylation, and cyclization. Different products were formed depending on the substituent groups of the nitrogen atom, and this reaction could be scaled up to the gram scale. It provides a new method for the difunctionalization of activated alkenes, enriching the strategies for constructing sulfur-containing compounds in organic synthesis. The combination of sulfur dioxide insertion and desulfonylation opens up a new route for the synthesis of sulfones. Hantzsch esters, as alkyl radical precursors, have the advantages of low toxicity, stability, and easy preparation, making this method more practical (Scheme 9).

Scheme 9 A radical Smiles rearrangement difunctionalization of activated alkenes via desulfonylation and insertion of sulfur dioxide relay strategy.

A proposed mechanism is illustrated in Scheme 9. Initially, the photocatalyst [Ru^II] is excited to its state [Ru^II]* upon light irradiation. This excited state then undergoes a SET with (NH₄)₂S₂O₈, yielding [Ru^III] species. Hantzsch ester A can be oxidized by either [Ru^III] or (NH₄)₂S₂O₈, resulting in the formation of isopropyl radical B, along with pyridine C and [Ru^II]. Subsequently, radical B captures SO₂, forming alkyl sulfonyl radical D, which reacts with alkene to generate radical E. Following this, radical E undergoes key ipso-cyclization, 1,4-aryl migration, and desulfonylation to produce radical G. If R is an alkyl group, radical G cyclizes intramolecularly to form intermediate H. Finally, intermediate H can be oxidized via SET by [Ru^III] or (NH4)₂S₂O₈ and undergoes deprotonation to yield the desired alkylsulfonylated oxindole If R is an aryl group, radical G abstracts a hydrogen atom from the medium, resulting in the formation of amide.³⁵

In 2024, Ma's team developed an efficient asymmetric photocatalytic acyl and alkyl radical Truce–Smiles rearrangement reaction for the synthesis of enantioenriched α-aryl amides. Using inexpensive, readily available, and removable chiral amino acids as auxiliaries and tetrabutylammonium decatungstate (TBADT) as a hydrogen atom transfer photocatalyst, α-substituted acrylamides 25 react with aldehydes or C–H containing precursors to synthesize enantioenriched α-aryl amides 27. The products exhibit excellent diastereoselectivities (dr 7 : 1 to >98 : 2). The reaction shows good compatibility with a variety of substrates, can be carried out on a gram scale, and of note, the chiral auxiliary is easy to remove. Through mechanistic studies, combined with experimental and density functional theory (DFT) calculations, the stereochemistry determining step of the reaction has been addressed. This research provides a new method for constructing 2-aryl-4-oxo or 2-aryl-4-substituted butanamides, enriching the asymmetric synthesis strategies. The highly functionalized α-aryl amides synthesized can serve as valuable building blocks for the preparation of various functionalized compounds and have potential applications in fields such as drug synthesis. This research also deepens our understanding of the mechanism of the radical Truce–Smiles rearrangement reaction and provides a theoretical basis for the development of subsequent related reactions (Scheme 10).

Scheme 10 Photocatalytic asymmetric acyl radical Truce–Smiles rearrangement for the synthesis of enantioenriched α-aryl amides.

From the proposed mechanism (Scheme 10) that starts with visible-light irradiation of TBADT, producing a long-lived excited state [TBADT]* ([W₁₀O₃₂]⁴⁻)*. This excited state abstracts a hydrogen atom from an aldehyde A, forming acyl radical E. The subsequent addition of E to α,β-unsaturated amide yields intermediate radical species F, which undergoes 1,5-ipso addition and 1,4-aryl migration via the spirocyclic transition state TS-X, leading to intermediate G. A desulfonylation step then forms the N-centered radical species H. Finally, product C is generated through a back-HAT with [W₁₀O₃₂]⁵⁻(H⁺) or, more likely, direct HAT from aldehyde A. This chain-propagating pathway is supported by the measured quantum yield (Φ = 17).³⁶

In 2024, Jiang, Zhang and co-workers successfully developed a novel method for the reaction of N-alkyl-N-(arylsulfonyl)methacrylamides 32 with 2-bromodifluoromethyl-1,3-benzodiazoles under mild reaction conditions. This method enables the aryl-difluoromethylenation of C=C bonds and the Truce–Smiles rearrangement via a reductive radical-polar crossover process, allowing for the efficient construction of a series of α-aryl-β-difluoromethylene amides with single regioisomers in good to excellent yields. It was found that a variety of N-arylsulfonyl acrylamides with different substituents and 2-bromodifluoromethyl-1,3-benzodiazole derivatives could smoothly participate in the reaction. Moreover, this reaction exhibited good tolerance towards various functional groups. It not only provides an innovative method for the aryl-difluoromethylenation of C=C bonds, greatly enriching the types of alkene difunctionalization reactions, but also avoids the use of photocatalysts and only uses inexpensive copper powder as a promoter, effectively reducing the reaction cost. Meanwhile, the reaction is concise in steps and has high atom economy. In addition, the synthesized α-aryl-β-difluoromethylene amides show potential application value in the fields of medicinal chemistry and bioactive molecule synthesis, which is expected to strongly promote the development of related fields (Scheme 11).

Scheme 11 Cu⁰-promoted Truce–Smiles rearrangement for aryl difluoromethylenation of C=C bonds.

A reaction mechanism is proposed in Scheme 11. Initially, 2-bromodifluoromethyl-1,3-benzodiazole 31 accepts an electron from Cu⁰. Through a SET event, it loses a bromine atom and generates the 1,3-benzodiazolic difluoromethyl radical A (ArCF₂˙), with Cu⁰ being transformed into Cu⁺ simultaneously. Next, the ArCF₂˙ radical readily attacks the terminal of the C=C bond in N-alkyl-N-(phenylsulfonyl)methacrylamide E, giving rise to the intermediate radical B. The in situ generated Cu⁺ then reduces the intermediate radical B via a SET. This reduction converts the radical into a carbon anion C, achieving a radical-polar crossover. During this process, Cu⁺ is oxidized to Cu²⁺, causing the reaction solution to turn dark blue. Subsequently, a 5-ipso cyclization occurs on the phenyl ring, accompanied by dearomatization, which leads to the formation of the Meisenheimer complex D. D undergoes re-aromatization, extruding SO₂ in the process to complete the 1,4-phenyl migration. Finally, after abstracting a hydrogen atom, the single regioisomer α-phenyl-β-difluoromethylene amide F is produced.³⁷

In 2024, Liu and co-workers discovered a novel method for the alkylarylation of alkenes under photoredox conditions, using arylsulfonyl acetate as a bifunctional reagent through photoinduced Truce–Smiles rearrangement. This method enables the simultaneous introduction of carboxylate-bearing alkyl groups and (hetero)aryl rings into a variety of alkenes through a radical addition/Smiles rearrangement cascade reaction, efficiently synthesizing valuable γ,γ-diaryl esters and γ-aryl esters. A complementary oxidative bifunctional reagent activation mode has been identified, and the reaction mechanism has been verified through multiple experiments and theoretical calculations. Moreover, this reaction features mild conditions, high atom and step economy, good functional group compatibility, and diverse product structures. Its unique activation mode expands the application scope of sulfonyl bifunctional reagents in alkene reactions. The synthesized γ,γ-diaryl esters and γ-aryl esters are widely present in bioactive compounds and natural products, and this method is expected to promote drug research and development and total synthesis of natural products in related fields (Scheme 12).

Scheme 12 Alkylarylation of alkenes with arylsulfonylacetate as bifunctional reagent via photoredox radical addition/smiles rearrangement cascade.

A plausible mechanism for this difunctionalization process is illustrated in Scheme 12. Initially, the photocatalyst (PC) is excited by blue light, leading to a SET with 34 in the presence of a base, generating alkyl radical A. This radical then adds electrophilically to the double bond of the alkene, forming benzyl radical B. Next, B undergoes ipso-addition to the aryl ring via a π–π stacked transition state (TS1) with a Gibbs free energy barrier of 14.6 kcal mol⁻¹, resulting in spiro radical intermediate C. Fragmentation occurs, releasing SO₂ through a stepwise process involving TS2 and TS3, producing alkyl radical E, with a computed exergonicity of −20.4 kcal mol⁻¹. Finally, the transient radical D is reduced by another SET event from PC⁻¹, followed by protonation to yield the desired alkene 36, while regenerating PC to complete the catalytic cycle.³⁸

In 2024, Guo's team developed a metal-free, photoredox – catalyzed cascade reaction for the alkylarylation of activated alkenesvia a ring-opening/radical Truce–Smiles rearrangement cascade. Using N-(arylsulfonyl)acrylamides 37 and cycloalkyl hydroperoxides 38 as starting materials, this reaction enables the selective construction of long-chain distal keto-amides with an all-carbon quaternary center at the α-position. It was found that the reaction has a wide substrate scope and good compatibility with various functional groups. Gram-scale synthesis and product derivatization experiments were also carried out, and the radical reaction mechanism was verified through control experiments. The reaction conditions are mild, and the photocatalyst is low-cost, overcoming the limitations of traditional Truce–Smiles rearrangement reactions that require high temperatures and additional additives. The synthesized long-chain distal keto-mides have potential applications in the fields of medicinal chemistry and natural product synthesis, and are expected to promote the development of related fields (Scheme 13).

Scheme 13 Photoredox-catalyzed radical Truce–Smiles rearrangement for the synthesis of distal ketoamides.

A probable mechanism is illustrated in Scheme 13. Initially, upon light irradiation, the photocatalyst (PC) is excited to PC*, which undergoes SET with cyclopentyl peroxide, generating alkoxyl radical A and PC˙⁺. Alkoxyl radical A then undergoes β-scission, forming keto-alkyl radical intermediate B. This radical attacks terminal alkene, producing tertiary radical intermediate C. Subsequently intramolecular ipso-cyclization on the sulfonyl aromatic ring of Intermediate C, followed by desulfonylation to yield the key amidyl radical intermediate E. The amidyl radical E abstracts a hydrogen atom from CH₃CN, resulting in the target product F and ˙CH₂CN. Lastly, the single-electron oxidation of ˙CH₂CN by PC˙⁺ generates ⁺CH₂CN and regenerates the PC.³⁹

2.2 Unactivated alkene involved Truce–Smiles rearrangement

In 2022, Liu's group disclosed a visible-light-induced alkylarylation reaction of unactivated alkenes. Through a metal-free radical addition/aryl migration cascade sequence, distal olefinic sulfonate was used as a unique molecular scaffold to achieve a domino process, enabling the synthesis of valuable alkylarylated alcohols in good yields with excellent diastereoselectivity. Mechanistic studies indicate that the reaction mainly proceeds through a visible-light-induced radical chain process. It provides a new strategy for the difunctionalization of unactivated alkenes, enriching the methods for constructing carbon–carbon bonds in organic synthesis. The reaction conditions are mild and environmentally friendly, and the starting materials are readily available, showing potential for industrial applications (Scheme 14).

Scheme 14 Visible-light induced alkylarylation of olefinic sulfonates via radical Truce–Smiles rearrangement cascade.

A plausible mechanism is outlined in Scheme 14. Initially, anion–π interactions lead to the formation of EDA complex A between acid–base pair (ABP) and the photocatalyst tetrafluoroborate (TPT). Upon blue LED irradiation, complex A produces excited species B. Single-electron transfer from ABP to TPT in excited B results in reductively quenched TPT C and radical species D. Both C and D can interact with ethyl 2-bromo-2,2-difluoroacetate, generating the key fluoroalkyl radical E via an SET event or halogen abstraction. Subsequently, electrophilic radical E adds to the double bond of sulfonate, forming alkyl radical F, which undergoes radical Smiles rearrangement to produce alkoxyl radical H. Finally, radical H either abstracts a hydrogen atom from ABP to form the desired product and regenerates radical D for the chain process or is reduced by C and then protonated to yield the target molecule.⁴⁰

In 2024, Hu's team pioneered an asymmetric remote C(sp³)–H arylation reaction under photoredox conditions, which utilizes 1,n-hydrogen atom transfer (1,n-HAT) and radical sulfinyl-Smiles rearrangement. This reaction can efficiently synthesize a diverse range of chiral α-arylated amides 45 with enantiomeric ratios of up to >99 : 1. Through the optimization of reaction conditions, the optimal conditions with Ir(dFppy)₃ as the photocatalyst were determined, and the applicability of various substrates and radical precursors was investigated. Mechanistic studies indicate that the aryl migration is the rate – and stereochemistry – determining step of the reaction, and the reaction involves processes such as radical initiation, 1,n-HAT, sulfinyl-Smiles rearrangement, and oxidative desulfurization. It provides a novel and efficient method for constructing chiral α-arylated amides, enriching the strategies in the field of asymmetric synthesis. The combination of 1,n-HAT and sulfinyl-Smiles rearrangement expands the application scope of related reaction types. The obtained chiral α-arylated amides have potential applications in medicinal chemistry and the synthesis of bioactive molecules, and this method is expected to provide the chance in drug discovery (Scheme 15).

Scheme 15 Asymmetric remote C(sp³)–H arylation via radical Truce–Smiles rearrangement.

From the prosed mechanism, under white LED irradiation, the Ir^(III)* photocatalyst can reduce radical precursor, yielding perfluoroalkyl radical (R = ˙CF₂CO₂Et). Addition to the double bond of A forms a carbon-centered secondary radical intermediate B (ΔG^‡ = +14.2 kcal mol⁻¹, ΔG = −0.5 kcal mol⁻¹). 1,5-HAT occurs under optimal spatial orientation with diphenyl ether bromide assistance. The nucleophilic alkyl radical abstracts an electron-deficient α-H from the amide exothermically (ΔG^‡ = −24.1 kcal mol⁻¹), providing a more stable carbon-centered radical at the α-position of amide moiety C. Loss of aromaticity induces aromatic group migration, with an activation barrier of ΔG^‡ = +14.4 kcal mol⁻¹, the rate-determining step. Intermediate D quenches the oxidized photocatalyst, yielding product E with excellent absolute stereocontrol.⁴¹

In 2024, Nacsa's group employed a radical-based method for the alkyl-(hetero)arylation of unactivated olefins through radical Truce–Smiles rearrangement. By using simple alkyl-(hetero)aryl sulfones under photoredox conditions, they achieved the alkyl-(hetero)arylation of a variety of mono- to tetrasubstituted simple olefins 48. This method simultaneously introduced diversifiable alkyl groups with different degrees of substitution and (hetero)aryl groups, exhibited good diastereoselectivity in both cyclic and acyclic systems, successfully incorporated heteroarenes containing Lewis basic nitrogen atoms and simple benzene rings, and efficiently constructed tertiary and quaternary benzylic centers. The research also demonstrated the practicality of this method by synthesizing the analgesic oliceridine and verified the radical reaction mechanism through a series of experiments. It breaks through the limitations of traditional transition-metal-catalyzed alkyl-arylation reactions of unactivated olefins and provides a new strategy for the difunctionalization of simple olefins (Scheme 16).

Scheme 16 Alkyl–(hetero) arylation of unactivated olefins via radical Truce–Smiles rearrangement.

The reaction mechanism involves oxidizing alkyl-(heteroaryl) sulfonyl ketone (B) to generate alkyl radical G, catalyzed by a photochemical catalyst. This radical then reacts with a simple alkene (A), forming the first C–C bond and producing a new alkyl radical intermediate H. Intermediate H undergoes [1,4]-(heteroaryl) migration, facilitating the formation of the second C–C bond and the release of SO₂. Subsequently, the electron-deficient alkyl radical J engages with the reduced photochemical catalyst, leading to the formation of anionic species, which upon protonation yields the desired alkyl-(heteroaryl) product (Scheme 16).⁴²

In 2024, Stephenson's group developed an aminoarylation reaction of unactivated alkenes using aryl sulfinamide as a bifunctional reagent. Under mild conditions, a nitrogen radical is generated with a weakly oxidizing photocatalyst, which reacts with alkenes to form C–N bonds. Subsequently, a desulfinylative aryl migration involved radical Smiles–Truce rearrangement occurs to form C–C bonds, enabling the one-step construction of arylethylamine structures from alkenes. This reaction exhibits excellent regioselectivity and diastereoselectivity for a variety of activated and unactivated substrates. Moreover, the chiral information of the sulfinamide can be transferred to the new carbon stereocenter of the product, achieving traceless asymmetric alkene difunctionalization. It solves the challenges in alkene carboamination reactions and avoids the side reactions that occurred when using sulfonamides in the past (Scheme 17).

Scheme 17 Aminoarylation of unactivated alkene enabled by N-centred radical reactivity of sulfinamides.

The mechanism proposed in Scheme 17 begins with the deprotonation of sulfinamide A to form anion B. Photocatalytic oxidation of B produces sulfinamidyl radical C, which adds to an alkene to form radical adduct D. A Truce–Smilesrearrangement occurs from radical D, likely involving a dearomatized spirocyclic intermediate like E. Rearomatization promotes C–S bond homolysis, yielding N-sulfinyl radical F, which can either undergo direct homolysis or be cleaved by the reduced photocatalyst, resulting in SO and the corresponding amidyl radical or anion, and the product in the presence of hydrogen source.⁴³

In 2025, Zhou's team innovatively combined hydrogen atom transfer (HAT) with the Truce–Smiles rearrangement to develop a mild photo-induced radical hydroarylation reaction for synthesizing β-arylethylamines from unactivated allylsulfonamides. Studies on N-arylsulfonyl allylaniline substrates showed that introducing substituents at the ortho-position of the migrating aryl group can modulate reaction selectivity; density functional theory (DFT) calculations revealed that the steric hindrance from ortho-substitution raises the substrate's ground-state energy, favoring ipso-addition over ortho-addition and circumventing the competitive ortho-cyclization in traditional methods. This reaction features broad substrate scope, tolerating diverse substituents like electron-withdrawing and electron-donating groups, halogens, and heterocycles, and can yield β-arylethylamines with high steric hindrance, whose products can be further derivatized via arylation, etc. Significantly, this work improves the understanding of radical hydroarylation mechanisms, offers a new strategy for β-arylethylamine synthesis breaking free from the limitations of traditional Truce–Smiles rearrangements relying on activated alkenes and specific functional groups, and holds great potential in drug synthesis for constructing complex molecular structures, thus advancing organic synthetic chemistry (Scheme 18).

Scheme 18 Merging hydrogen-atom-transfer and the Truce–Smiles rearrangement for synthesis of β-arylethylamines from unactivated allylsulfonamides.

A plausible mechanism is outlined in Scheme 18. The photocatalytic cycle initiates with 405 nm excitation of Ph-benzoPTZ (PC), generating the excited-state species PC* , which undergoes a Stern–Volmer-quenched single-electron transfer (SET) with cobalt(II) salen (E_red = −1.60 V vs. SCE) to produce the radical cation PC˙⁺ and a cobalt(I) intermediate. Ground-state photocatalyst regeneration occurs via reduction by cyclohexyl-substituted Hantzsch ester (HEH-Cy), simultaneously generating a spectatorial cyclohexyl radical through HEH-Cy⁺ fragmentation. Parallel protonation of the Co(I) species forms the critical Co^III–H complex, which mediates hydrogen atom transfer (HAT) to N-arylsulfonyl allylaniline, yielding alkyl radical intermediate A and regenerating Co^II to complete the metal-hydride hydrogen atom transfer (MHAT) cycle. Reaction selectivity arises from ipso-aryl radical addition (B) via alkyl radical A, followed by sequential C–S bond cleavage to form intermediate C, N-desulfonylation generating nitrogen-centered radical D, and final reduction/protonation to β-arylethylamine. The synergistic roles of 2,6-dimethylpyridine and hexafluoroisopropanol (HFIP) were mechanistically essential, with control experiments confirming severe yield attenuation (<5% vs. 82%) and predominant starting material recovery in systems lacking photocatalyst, cobalt catalyst, Hantzsch ester, or light irradiation.^44,45a In 2024, Claraz reported an electrochemical sulfonylation/Truce–Smiles rearrangement of N-allylbenzamides, facilitating the synthesis of sulfone-containing β-arylethylamines and Saclofen analogues.^45b

3. Alkyne involved Truce–Smiles rearrangement

In 2020, Ye's team developed a photoredox-catalyzed regioselective ketyl-ynamide coupling-triggered cascade cyclization reaction, achieving the first radical Smiles rearrangement of ynamides. Under mild reaction conditions, using Hantzsch ester as the reducing agent, this reaction can efficiently convert a variety of substrates into 2-benzhydrylindoles with good yields. It can also achieve the divergent synthesis of 3-benzhydrylisoquinolines through similar processes and dehydrogenative oxidation. In addition, the ynamide radical Truce–Smiles rearrangement initiated by intermolecular photoredox catalysis via the addition of external radical sources was realized. It discovers an unprecedented desulfurative Smiles rearrangement reaction and provides a new method for the synthesis of important heterocyclic compounds such as 2-benzhydrylindoles and 3-benzhydrylisoquinolines, which are widely present in bioactive molecules and have potential application value in the field of drug synthesis (Scheme 19).

Scheme 19 Visible light induced ynamide smiles rearrangement for the synthesis of functionalized indoles andisoquinolines.

Scheme 19 outlines a possible mechanism. Initially, Ir^III is excited to Ir^III* upon visible light irradiation, leading to a SET with Hantzsch ester (HE), producing HE˙⁺ and Ir^II. Next, ynamide reacts with HE˙⁺ through SET with Ir^II, yielding the ketyl radical intermediate A. This ketyl radical then undergoes regioselective coupling with ynamide and Turce–Smiles rearrangement, forming the N-centered radical C while releasing SO₂. This imidyl radical C can exist as resonance structure D, stabilized by aromatic rings and a C=N double bond. Intermediate D can either abstract hydrogen from HE˙ through hydrogen atom transfer (HAT, path a) or undergo SET and protonation (path b), resulting in intermediate F, which is isolated when using benzoyl ynamide. The subsequent steps involve a combination of second photoredox catalysis with spin-center shift (SCS) and further SET, producing intermediate I. For ynamide 54a (n = 0), final protonation leads to indole K, while for ynamide 54b (n = 1), protonation followed by dehydrogenative oxidation yields isoquinoline L.⁴⁶

In 2020, Wu's group also successfully achieved a visible-light-mediated radical Smiles rearrangement reaction by using neutral eosin Y as a direct hydrogen atom transfer photocatalyst. This reaction can efficiently prepare novel N-heterocyclic compounds with an isothiazolidin-3-one 1,1-dioxide structure and a single diastereomer. Aldehydes, phosphine oxides, and various N-(hetero)arylsulfonyl propiolamides can participate, and it can tolerate a variety of functional groups. It can also be scaled up to gram scale. Mechanistic studies have verified the existence of acyl radical and vinyl radical intermediates. Some of the products showed potential anticancer activity in preliminary biological activity tests. It has demonstrated the unique advantages of the neutral eosin Y photocatalytic system in radical rearrangement reactions and provided a new direction for exploring new chemical reactions and constructing complex molecular structures (Scheme 20).

Scheme 20 The synthesis of isothiazolidione by a radical Turce–Smiles rearrangement.

A plausible mechanism is proposed in Scheme 20. The excited* eosin Y has a HAT with aldehyde, delivering an acyl radical A. Adding this acyl radical to N-arylsulfonyl propiolamide generates a vinyl radical species B, initiating the subsequent radical Smiles rearrangement to form a postulated sulfonyl radical C. Radical C underwent a 5-endo-trig cyclization to produce the α-carbonyl benzylic radical D. Finally, D can regenerate eosin Y via a reverse HAT (RHAT), and simultaneously yield the product.⁴⁷

Recently, Liu's group developed a novel method for the alkylarylation of alkynes under photoredox conditions, using arylsulfonylacetate as a bifunctional reagent. This method, via vinyl-radical intermediates, can simultaneously introduce (hetero)aryl rings and alkyl carboxylates into alkynes, enabling the preparation of all-carbon tetrasubstituted alkene derivatives 62. The research determined the optimal reaction conditions, such as using 4CzIPN as the photocatalyst and K₃PO₄·3H₂O as the base, and verified the applicability of various alkynes, different ester groups, and bifunctional reagents with different aromatic rings. The practical value of this method was demonstrated through experiments like gram-scale synthesis, preparation of fluorescent molecules, and anti-cancer drugs (Scheme 21).

Scheme 21 Photoredox catalytic alkylarylation of alkynes with arylsulfonylacetate as bifunctional reagent.

As shown in Scheme 21, under blue light, the photocatalyst (PC) is excited to its excited state, undergoing single-electron transfer with sulfone to generate alkyl radical A. A then adds to the triple bond of an alkyne, forming vinyl radical B, which subsequently undergoes addition to the benzene ring to form spiro radical C. Accompanied by the extrusion of SO₂, alkyl radical D is produced. This transient species then undergoes reduction through another SET event from PC⁻¹ and subsequent protonation, resulting in the formation of the desired alkene E. Meanwhile, PC is regenerated to complete the photo-redox cycle.⁴⁸

In 2024, Liu's group and co-workers reported the Conia-ene-type cyclization/Turce–Smiles rearrangement cascade reaction that focuses on functional group migration instead of the 1,5-hydrogen shift. Utilizing visible-light photoredox catalysis, this method effectively employs various alkyne-tethered α-sulfonyl esters to produce cyclic tetrasubstituted alkenes 64 with of notable biological and synthetic value. The approach also permits the synthesis of structurally similar cyclic-substituted lactones. Key benefits include mild reaction conditions, high atom and step economy, wide functional group tolerance, and structural diversity. This development not only overcomes the limitations associated with the 1,5-hydrogen shift in Conia-ene reactions but also expands the synthetic capabilities for producing important cyclic tetrasubstituted alkenes (Scheme 22).

Scheme 22 Photoredox catalyzed Conia–Ene-type cyclization/Turce–Smiles rearrangement cascade reactions to access substituted alkenes.

A mechanism was proposed where the ground-state photocatalyst is photoactivated to its excited state, which undergoes a SET with alkyne in the presence of NaOH to generate carbon-cantered radical A Initially. Thereafter, intramolecular 5-exo-dig cyclization occurs to render the vinyl radical species B, which then immediately ipso attaches the sulfonyl phenyl ring to give a spiro radical C. Finally, release of SO₂ gives the structurally stable radical D, which gains an electron from the reduced photocatalyst followed by protonation to afford the final product and close the photocatalytic cycle.⁴⁹ A chemo- and regioselective method for synthesizing 2-benzhydryl and 2,3-disubstituted indoles from alkynes is presented in 2023, involving cyclization followed by a regioselective Truce–Smiles (T–S) rearrangement.⁵⁰

4. Miscellaneous Truce–Smiles rearrangement

In 2019, Zhu and Xie's group devised a novel reaction based on photoredox catalysis and phosphoranyl radical chemistry, achieving the deoxygenative arylation of aromatic carboxylic acids. This reaction can efficiently construct a series of structurally diverse unsymmetrical diaryl ketones 67, including o-amino and o-hydroxy diaryl ketones, with broad substrate adaptability and good reaction yields. The reaction mechanism was explored in depth by DFT calculations, confirming its feasibility in thermodynamics and kinetics. This method can also be used for gram-scale preparation and applied to the synthesis of important heterocyclic skeletons as well as the total synthesis of the quinolone alkaloid (−)-yaequinolone A2 and a viridicatin derivative (Scheme 23).

Scheme 23 Deoxygenative arylation of carboxylic acids by radical Turce–Smiles rearrangement.

In view of the proposed mechanism, the photoexcited Ir complex undergoes single-electron oxidation with triphenylphosphine, producing a triphenylphosphine radical cation. This cation can be captured by carboxylate anion (A) to afford intermediate B. Due to the strong affinity between phosphine and oxygen atoms, it undergoes β-scission of the C(acetyl)–O bond, generating an acyl radical C. The acyl radical C then undergoes intramolecular 1,6-ipso addition with the substrate to generate intermediate D rather than 1,7-ipso addition for intermediate E. Intermediate D undergoes radical rearrangement to afford a nitrogen-centered radical species F, along with the release of SO₂. Subsequent SET with Ir^II followed by protonation ultimately affords the desired product G. Of note, this deoxygenative arylation reaction selectively cleaves a strong carboxylic C bond (106 kcal mol⁻¹) and forms a weaker C bond (90 kcal mol⁻¹).⁵¹

In 2021, Whalley's group successfully developed a novel metal-free radical Truce–Smiles rearrangement reaction based on strain release. By generating primary alkyl radicals from the ring opening of 3-aminocyclobutanone oximes, this method enables mild and wide-scope arylation reactions at room temperature, effectively synthesizing 1,3-diamines and unnatural β-amino acids. The reaction uses the inexpensive organic dye eosin Y and can proceed efficiently under green LED irradiation with cyclic alkylamines as sacrificial reductants. The research optimized the reaction conditions and investigated the applicability of various aryl and heteroaryl migrating groups. It was found that the reaction has good compatibility with aromatic rings bearing different substituents and various heterocycles. The derivatization of the products also demonstrated the potential of the products in synthesizing important compounds. It provides a new strategy for constructing C(sp²)–C(sp³) bonds, breaking through the limitations of traditional Truce–Smiles rearrangement reactions in generating carbon-centered radicals (Scheme 24).

Scheme 24 Radical Truce–Smiles rearrangements by strain release for metal-free arylation.

A possible reaction mechanism is shown in Scheme 24. After the single-electron reduction of compound 68, it fragments into iminyl radical A and 2,4-dinitrophenolate. The intermediate A can then undergo an entropically favored β-scission reaction, opening the ring and generating the alkyl radical and the ipso position needed for the Truce–Smiles rearrangement (B). This alkyl radical was captured using TEMPO and identified by high-resolution mass spectrometry (HRMS) (D). The amidyl radical C, formed after rearrangement, can then receive a hydrogen atom from the trialkylamine base, resulting in the closed-shell Smiles product 69.⁵²

In 2022, Zhu's team collaborated and achieved a significant breakthrough in the study of ethylene difunctionalization reactions through radical Truce–Smiles rearrangement. After a systematic investigation of multiple reaction parameters, they determined that the optimal reaction conditions were using DMSO as the solvent, irradiating with a 30 W white LED strip, and adding diacetyl and 2,6-lutidine. This reaction has a wide substrate scope, and various heteroarenes and bifunctional reagents can participate in the reaction smoothly, enabling the effective construction of diverse diheteroarylated products 73. Moreover, the reaction can be conducted under normal pressure, showing good functional group tolerance, selectivity, and scalability, and it can easily achieve gram-scale synthesis (Scheme 25).

Scheme 25 Metal-free difunctionalization of ethylene through radical Turce–Smiles rearrangement.

Regarding the reaction mechanism, visible light causes the homolytic cleavage of the C–Br bond in bifunctional reagent A, generating a difluoromethyl radical B. B adds to ethylene to form a primary alkyl radical C. Then, C undergoes intramolecular heteroaryl migration and extrusion of SO₂ to form a nucleophilic radical intermediate E. E undergoes a Minisci-type addition with quinoxalinone F, and finally, through rearomatization, the product H is obtained. In this process, diacetyl plays a role in suppressing the decomposition of A. This research represents the first successful implementation of metal-free radical difunctionalization of ethylene. It provides a novel approach for rapidly constructing complex molecules from simple ethylene raw materials, holds great potential for applications in fine chemical fields such as drug development, and paves a new way for the research on radical functionalization of ethylene.⁵³

5. Conclusion and outlook

As mentioned above, the radical Truce–Smiles rearrangement strategy has emerged as a sophisticated platform for directed arylation reactions involving diverse alkene and alkyne substrates, along with various carbon, nitrogen, and oxygen radical sources, all under mild conditions that exhibit excellent functional group compatibility. This method enables the synthesis of a wide array of high-value compounds characterized by aromatic or heteroaromatic substitutions. By integrating novel catalytic mechanisms with traditional reaction frameworks, this approach showcases significant synthetic potential and broad applicability for radical Truce–Smiles rearrangements. We aspire that this mini-review will motivate readers to explore this research domain and serve as a practical guide for identifying suitable substrates to access desired frameworks via radical Truce–Smiles rearrangement, particularly within the context of drug discovery. In preparing for the manuscript, Yang, Liu and co-workers developed a catalytic enantioselective radical Truce–Smiles rearrangement enabled by the directed evolution of P450 radical aryl migratases.⁵⁴

Despite the advancements achieved in this field, several gaps remain to be filled. As noted in this review, there is a marked deficiency in asymmetric methods for rapidly obtaining chiral products, necessitating further exploration to uncover feasible alternatives for enantioselective radical Truce–Smiles rearrangements. The creation of novel chiral ligands within co-catalytic systems appears to be an emerging trend. Moreover, expanding the spectrum of sulfur-containing partners is vital for enhancing the synthetic utility of existing methodologies. While current practices commonly utilize sulfonyl acrylamides, their desulfonylated amide counterparts with fixed backbones are less frequently encountered in the core architectures of bioactive compounds. Thus, devising innovative transformations that enable the reutilization of the removed SO group is highly sought after.

In conclusion, the progress in the field of radical Truce–Smiles rearrangement is driven by advancements across multiple domains, even as challenges remain. Moving forward, it is essential to encourage interdisciplinary collaboration among synthetic chemistry, chemical biology, and medicine to foster further development in this area and explore its potential applications in pharmaceutical research.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

We are grateful for financial support from the National Key R&D Program (2023YFD1700500), National Natural Science Foundation of China (22301093), the Fundamental Research Funds for the Central Universities, the Central China Normal University (CCNU) and Wuhan Science and Technology Bureau.

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