Recent advances in visible-light-induced defluorinative functionalization of α-trifluoromethyl arylalkenes

Abstract

Fluorine-containing organic molecules have been widely utilized in the fields of medicinal chemistry, synthetic chemistry, agrochemistry and materials science, due to their higher lipophilicity, metabolic stability, cell membrane permeability, bioactivity, and other advantageous properties. Among these, gem-difluoroalkenes have emerged as privileged carbonyl bioisosteres in drug design, exemplified by antimalarial difluoroartemisinin derivatives. Recent breakthroughs in visible-light photocatalysis have enabled mild, radical-mediated allylic defluorination of these substrates through single-electron transfer (SET) processes followed by β-fluorine elimination. This review highlights cutting-edge photochemical strategies (2022–2025) for constructing gem-difluoroalkenes, emphasizing mechanistic insights and functional group compatibility. The development of these sustainable methods addresses critical challenges in fluoroorganic synthesis while expanding accessible molecular diversity for medicinal applications.

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Yanyan He

Yanyan He was born in Henan Province, China. She received her B.S. degree in chemistry from Henan Normal University (HNU) in 2015. She received his Master's degree in organic chemistry from Nanjing University (NJU) in 2018 under the supervision of Prof. Shouyun Yu. Her master's research focused on the methodology of organic photochemical reactions. In 2022, she joined Prof. Teck-Peng Loh's team at the College of Advanced Interdisciplinary Science and Technology, Henan University of Technology.

Leiyang, Lv

Leiyang Lv received his Ph.D degree from Renmin University of China (RUC) in 2017 under the guidance of Prof. Zhiping Li. After three years as a postdoctoral fellow with Prof. Chao-Jun Li at McGill University, he joined RUC as Outstanding Young Scholar. His research interests focus on the development of new catalytic systems to construct functional molecules especially the fluorinated ones as well as the sustainable organic synthesis.

Zhenhua Jia

Zhenhua Jia is a full professor and the executive director of the College of Advanced Interdisciplinary Science and Technology, Henan University of Technology. He received his BS in 2004 from Tianjin University and Ph.D in 2013 from Sun Yat-sen University and jointed with McGill University under the supervision of Prof. Albert S. C. Chan and Prof. Chao-Jun Li. Then, he continued to pursue his postdoctoral research at Marquette University, Chinese University of Hong Kong and University of Alberta with Prof. Chae S. Yi, Prof. Henry N. C. Wong, and Prof. Frederick G. West, respectively. In 2018, he joined Prof. Teck-Peng Loh's team and holds his current position. His research interest includes green and sustainable synthesis, and organic transformations under biocompatible conditions

Teck-Peng Loh

Teck-Peng Loh is a distinguished university professor of Chemistry at Nanyang Technological University, Singapore. Under the tutelage of Professor E. J. Corey, he obtained his Ph.D (1994) from Harvard University. He has been awarded outstanding researcher awards from both the National University of Singapore and Nanyang Technological University. In 2017, he received the Yoshida Prize (Japan) and the prestigious President's Science Award (individual) in Singapore. He has been elected Fellow, Academia of Sciences, Singapore (2018), and Fellow of the Academia of Sciences, Malaysia, since 2010. His research work mainly focuses on the development of new synthetic methodology, green chemistry, and the synthesis of natural and unnatural products.

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1 Introduction

Visible-light photoredox catalysis has emerged as a transformative synthetic platform, combining unique reactivity patterns, exceptional selectivity, and mild operating conditions to enable previously challenging transformations.¹ Photoredox catalysis has reshaped contemporary organic synthesis through the rational development of various visible-light-absorbing photocatalysts, including Ru/Ir complexes and organic dyes. Mechanistically, photoexcitation of the catalyst enables electron acceptance from a donor species, forming a strongly reducing one-electron-reduced intermediate capable of single-electron transfer (SET) processes.

Fluorine-containing organic molecules have been widely utilized in the fields of medicinal chemistry, synthetic chemistry, agrochemistry and materials science, due to their higher lipophilicity, metabolic stability, cell membrane permeability, bioactivity, and other advantageous properties compared to their parent molecules.² Over 20% of pharmaceuticals include at least one fluorine atom in their molecular structures.³ Specifically, gem-difluoroalkene units, which act as bioisosteres for the carbonyl group while offering improved biostability, have attracted significant interest in drug design and medicinal chemistry.⁴ For instance, isosterically modifying the carbonyl group in artemisinin with a gem-difluoroalkene moiety to create a difluoroartemisinin significantly enhances antimalarial activity, and a deoxyuridine analogue modified in this manner exhibits antiherpetic activity (Scheme 1).⁵ These developments not only expand the field of medicinal chemistry but also pave the way for novel therapeutic strategies. gem-Difluoroalkenes can serve as key precursors for a range of valuable fluoroorganic compounds, including monofluoroal-kenes, difluoromethylenes, difluorocyclopropanes, and trifluoromethylated products.⁶ Moreover, fluorine atom environmental management differs notably between pharmaceuticals and agrochemicals: pharmaceuticals release only trace C–F byproducts due to low dosages, while fluorinated agrochemicals pose substantial contamination risks via large-scale, annual use. Pesticide adjuvants, used in far greater quantities than active ingredients, further worsen risks by facilitating fluorinated compounds’ migration and bioaccumulation. This highlights the urgent need for highly selective defluorinative strategies to minimize byproducts and optimize environmental degradation pathways.

Scheme 1 Bioactive molecules containing gem-difluoroalkene scaffolds.

Many synthetic methodologies have been established to synthesize gem-difluoroalkenes. Traditional methods for synthesizing gem-difluoroalkenes include difluoroolefination of carbonyl, diazo, or hydrazone compounds, and organometallic- or strong base-mediated nucleophilic S_N2′-type addition to α-trifluoromethyl alkenes, followed by β-F elimination.⁷ The difluoroolefination of carbonyl compounds (via Wittig, Julia–Kocienski, or Horner–Wadsworth–Emmons reaction) is an effective synthetic strategy for constructing gem-difluorovinyl architectures (Scheme 2a, left).^7b,e,f,8 Nevertheless, these transformations typically necessitate strongly basic reaction conditions. The reaction between diazo compounds and difluorocarbene precursors also represents a viable method for synthesizing gem-difluoroethylenes (Scheme 2a, right).^7d,g,h,9 The trifluoromethyl group in α-trifluoromethyl alkenes serves as a widely utilized fluorine-containing synthon. The electron-deficient trifluoromethyl group in α-trifluoromethyl alkenes readily undergoes nucleophilic S_N2′ attack (Scheme 2b, left)^7g,10 or Giese addition (Scheme 2b, right),¹¹ often followed by β-fluorine elimination to form gem-difluoroalkenes. However, the nucleophilic S_N2′-type reaction involving organometallic reagents (e.g., organolithium or Grignard reagents) is air- and moisture-sensitive, leading to lesser substrate scope and lower functional group tolerance.¹² In contrast to harsh basic conditions required for S_N2′-type methods, visible light-induced radical addition of α-trifluoromethyl arylalkenes with various radical precursors offers a milder and more versatile approach to gem-difluoroethylene synthesis (Scheme 2c).^6c,11a,c,13 In this scenario, developing efficient and mild approaches through allylic defluorination of α-trifluoromethyl arylalkenes for preparing structurally diverse gem-difluoroalkenes with good group tolerability is undoubtedly in high demand and has garnered special interest in organic and medicinal chemistry.

Scheme 2 Synthetic routes to access gem-difluoroalkenes.

Consequently, substantial advances have been made in visible-light-driven allylic defluorination of α-trifluoromethyl arylalkenes via SET-triggered radical pathways, providing a general strategy for gem-difluoroalkene synthesis, in which the β-F elimination of CF₃ is achieved by a photo-induced radical/polar cross-cover (Scheme 2c). It is noted that alternative strategies for defluorinative functionalization of α-trifluoromethyl arylalkenes, such as transition-metal catalysis¹⁴ and electrochemical^14b,15 approaches have also been well summarized, providing critical complementary insights into this field. Although Sun et al. have discussed the recent advance in the transformations of trifluoromethyl alkenes,^14c we would provide a more comprehensive focus on the recent advance in visible-light-induced defluorinative functionalization of α-trifluoromethyl arylalkenes in this perspective review.

2 Metal-based photocatalysts

2.1 Ir-based photocatalysts

Alcohol-derived oxalate esters have emerged as versatile alkyl radical precursors in recent years, enabling efficient construction of diverse carbon–carbon bonds through photoredox or thermal activation.¹⁶ In 2022, Fu's group reported an effective method for synthesizing the structural diversity of β-gem-difluoroalkene esters through visible light-induced defluorinative alkoxycarbonylation of α-trifluoromethyl arylalkenes 3b with oxalates 3a (Scheme 3).¹⁷ Preliminary mechanistic studies indicated the involvement of alkoxycarbonyl radicals in the catalytic process. The long-lived excited state Ir(III)* could oxidized the oxalates 3a via a SET process, producing reduced Ir(II) species and the alkoxycarbonyl radicals 3d by releasing one equivalent of CO₂. 3e were then obtained by radical addition of 3d to the electron-deficient α-trifluoromethyl arylalkenes 3b. 3e were reduced by Ir(II) species to produce carbanions 3f, which rapidly eliminated anionic β-F to form β-gem-difluoroalkene esters 3c. Notably, the success of this strategy relied on intermolecular alkoxy-carbonyl radical addition to the electron-deficient α-trifluoromethyl arylalkene scaffold.

Scheme 3 Defluorinative alkoxycarbonylation of α-trifluoromethyl arylalkenes with oxalates.

In 2022, Shen and co-workers introduced a general strategy for the defluorinative alkylation of readily available α-trifluoromethyl alkenes 4b using α-silyl alcohols 4a as the radical precursors under irradiation of 6 W blue LEDs at room temperature, in which [Ir(dF(CF₃)ppy)₂(dtbbpy)]PF₆ was employed as the photocatalyst, collidine was used as additive in DCM (Scheme 4).¹⁸ A diverse array of α-trifluoromethyl alkenes 4b were tolerated with electron-poor, electron-rich, or neutral properties, successfully providing the desired difluoro allylic cyclobutanols 4c. Notably, several alkyl-substituted α-trifluoromethyl alkenes also proved suitable for this reaction, offering a versatile and modular platform for the synthesis of diverse gem-difluoroalkenes.

Scheme 4 Defluorinative alkylation of α-trifluoromethyl alkenes with α-silyl alcohols.

The gem-difluoroalkene structure serves as a critical pharmacophoric element in numerous agricultural insecticides. Syngenta's research demonstrated that the insecticidal efficacy of 1,1-difluorododec-1-ene derivatives is determined by this structural parameters: the pharmacophore configuration, the tail groups modifications, and the chain length of the bridging carbon chain.¹⁹ In 2022, Zhou et al. synthesized gem-difluoroalkenes 5c containing a distal carbonyl group through a defluorinative ring-opening gem-difluoroallylation of cycloalkanols 5a with α-trifluoromethyl alkenes 5b in the presence of Ir(dFCF₃ppy)₂(dCF₃bpy)(PF₆) and collidine in MeCN under blue LEDs irradiation at room temperature (Scheme 5).²⁰ The ring size and substituent on the alkyl chain of cycloalkanols can easily change the bridge between C=CF₂ and the carbonyl group. Therefore, the strategy allows modification of three structural elements in a single reaction for synthesizing more effective insecticides.

Scheme 5 Defluorinative ring-opening gem-difluoroallylation of cycloalkanols with α-trifluoromethyl alkenes.

In 2022, Hu and colleagues successfully developed a mild photocatalytic protocol for the coupling of xanthate salts 6a with α-trifluoromethyl arylalkenes 6b to produce the gem-difluoroallylation products 6c (Scheme 6).²¹ A proposed mechanism was suggested as follows. Initially, the xanthate anions 6a were oxidized by the photoexcited Ir(III)* to generate sulfur-centered radicals 6d. Subsequently, radicals 6d underwent rapid coupling with Ph₃P to produce the crucial phosphoranyl radicals 6e, which then underwent β-scission to form radical intermediates 6f. The fragmentation of 6f led to the formation of alkyl radicals 6g through the release of carbonyl sulfide. Addition of radicals 6g to the α-trifluoromethyl arylalkenes 6b generated new radical intermediates 6h. Subsequent reduction and β-fluoride elimination afforded the corresponding gem-difluoroalkene products 6c. This protocol disclosed a visible-light photocatalytic strategy for the highly efficient deoxygenative gem-difluorovinylation of aliphatic alcohols mediated by phosphoranyl radicals.

Scheme 6 Deoxygenative gem-difluorovinylation of aliphatic alcohols with α-trifluoromethyl arylalkenes.

Since Otto Roelen's pioneering work on the Fischer–Tropsch reaction documented transition-metal-catalyzed carbonylation in 1938, carbonylation has become an indispensable tool for synthesizing carbonyl-containing compounds in both academic and industrial.²² In 2022, Wu's group described a novel visible-light-mediated defluorinative carbonylation procedure that involves the cross-coupling of alkyl iodides 7a and α-trifluoromethyl arylalkenes 7b to access gem-difluoroalkenes 7c under mild reaction conditions (Scheme 7).²³ This work employs (Ir[dF(CF₃)ppy]₂(dtbpy))PF₆ as the photocatalyst under visible light to generate acyl radicals in the presence of carbon monoxide.

Scheme 7 Defluorinative carbonylation of alkyl iodides with α-trifluoromethyl arylalkenes.

Alkyl radicals derived from organoboron species have been extensively utilized due to their readily available from both commercial and synthetic sources. In 2022, Wang et al. reported an Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ catalyzed defluorinative alkylation of a series of α-trifluoromethyl arylalkenes 8b using various alkylboronic acids 8a as radical precursors, assisted by K₃PO₄ in ethyl acetate (EA), under the irradiation of a 36 W blue LED at room temperature (Scheme 8).²⁴ The pivotal progress in the proposed mechanism was the complex A, composed of alkylboronic acids and K₃PO₄, that were oxidized by the excited state of photocatalyst to generate alkyl radicals, which subsequently underwent similar processes to give the desired gem-difluoroethylenes 8c. In this study, the authors disclosed that the pre-activation of alkylboronic acids by an organophosphorus reagent was crucial to reduce their oxidation potentials.

Scheme 8 Defluorinative alkylation of α-trifluoromethyl arylalkenes with alkylboronic acids.

The [1,2]-Brook rearrangement reaction, which has been widely used in anion relay chemistry, is a reversible mechanism that converts α-silyl oxyanions into α-silyloxy carbanions via a pentacoordinate silicon intermediate.²⁵ Nevertheless, radical Brook rearrangements mediated by SET process remain underexplored, primarily owing to the challenging generation of alkoxy radical intermediates.²⁶ In 2023, Zhang and co-workers reported the facile construction of gem-difluoro homoallylic alcohol derivatives 9c through radical [1,2]-Brook rearrangement by reacting α-trifluoromethyl arylalkenes 9b with aryl substituted silyl alcohols 9a (Scheme 9).²⁷ Based on the control experiments and previous reports, a possible mechanism was suggested. The excited Ir(III)* was reductively quenched by intermediates 9d to form the carbon centered radicals 9e. Subsequently, intermediates 9e added to the α-trifluoromethyl arylalkenes 9b, then the radical intermediates 9f were reduced to form the anions 9g through a single electron-transfer step. Finally, a consecutive β-fluoride elimination of carbanions 9g, followed by a fluoride-promoted desilylation of intermediates 9h, afforded the expected products 9c. Notably, this work introduced a complementary defluorinative strategy for probing the reactivity and synthetic utility of gem-difluoroalkenes and trifluoromethyl alkenes.

Scheme 9 Defluorinated alkylation of α-trifluoromethyl arylalkenes with aryl substituted silyl alcohols.

In contemporary drug design, bicyclo[1.1.1]pentanes (BCPs) represent a significant class of compounds frequently employed as linear spacer units to improve pharmacokinetic properties. Fluorine-containing BCPs are critical building blocks in pharmaceutical research.^2b,3b,28 In 2023, Jiang and co-workers reported a multicomponent reaction to construct gem-difluoroallylic bicyclo[1.1.1]pentanes 10c by defluorinative gem-difluoroallylation of [1.1.1] propellane 10b under blue LED irradiation at 30 °C in the presence of [Ir(ppy)₂(dtbbpy)]PF₆ in NMP : H₂O = 10 : 1 (Scheme 10).²⁹ This methodology utilizes commercially accessible arylsulfinates 10a to generate radical precursors and showed good functional group compatibility under mild reaction conditions.

Scheme 10 Defluorinative gem-difluoroallylation of [1.1.1]propellane to access gem-difluoroallylic bicyclo[1.1.1]pentanes.

Oxygen radicals play important roles in organic synthesis and biological processes.³⁰ In 2023, Rueping et al. reported a study on the O–H bond activation of β,γ-unsaturated oximes using 3-acetoxyquinuclidine as the hydrogen atom transfer (HAT) reagent and Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ as the photoredox catalyst (Scheme 11).³¹ Leveraging this strategy, a range of β,γ-unsaturated oximes 11a with diverse functional groups and different radical acceptors—particularly α-trifluoromethyl arylalkenes 11b, were investigated. Moreover, this transformation was substrate-dependent, proceeding efficiently only with α-trifluoromethyl arylalkenes bearing electron-donating or weakly electron-withdrawing substituents on the aryl ring.

Scheme 11 Defluorinative gem-difluoroallylation of β,γ-unsaturated oximes with α-trifluoromethyl arylalkenes.

The proposed mechanism was shown in Scheme 11. First, the 3-acetoxyquinuclidine 11d was oxidized by the excited state Ir(III)* to give amine radical cation 11e. Then, the β,γ-unsaturated oximes 11a donated a hydrogen atom to 11e to form the iminoxyl radicals 11f, which subsequently underwent a 5-exo-trig radical cyclization to produce the carbon-centered isoxazoline alkyl radicals 11g. The radical intermediates 11g afterwards added to the α-trifluoromethyl arylalkenes 11b to form the radical intermediates 11h, which were reduced to form the anions 11i through a single electron-transfer step. Finally, defluorination of 11i delivered the desired products 11c. The strategy efficiently tackles the high redox potential of oximes, complements the activation of the O–H bond by quinuclidine, and provides a general pathway for the formation of iminoxyl radicals.

In 2023, Wang’ group developed a defluorinative alkylation method for α-trifluoromethyl arylalkenes 12b using sodium tetraphenylborate 12a as the aryl radical precursor under the Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ catalysis, with irradiation from a 36 W blue LEDs at room temperature (Scheme 12).³² Crucially, bond α-scission and efficiently generate aryl radicals 12e. The DMSO served not only as a solvent but also as an activation reagent, enabling diarylboron radicals 12d to underwent C–B addition of these aryl radicals to α-trifluoromethyl arylalkenes 12b gave the carbon-centered radicals 12f, which were further reduced by Ir(II) to generate the carbanion intermediates 12g while regenerating the photocatalyst Ir(III). Finally, β-fluoride elimination afforded the gem-difluoroalkene products 12c. This method employed tetraarylborate salts as unconventional aryl radical precursors, which underwent visible-light-induced homolysis to generate aryl radicals in the presence of DMSO as an activating agent.

Scheme 12 Defluorinative gem-difluoroallylation of sodium tetraphenylborate with α-trifluoromethyl arylalkenes.

Benzylic C–H bonds are prevalent in natural products, pharmaceuticals, agrochemicals, and functional materials.³³ Significant attention has been devoted to developing various approaches for the direct functionalization of benzylic C–H bonds.³⁴ In 2023, Ji and colleagues realized a photoredox-catalyzed approach for the defluorinative benzylation of α-trifluoromethyl arylalkenes 13b with alkylarenes 13a (Scheme 13).³⁵ The reaction, conducted in acetone solvent using 1 mol% Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ as catalyst, 1.0 equivalent of NaBr and 3.0 equivalent of K₂HPO₄ under argon atmosphere, smoothly produced various structurally valuable benzylated gem-difluoroalkenes 13c in moderate to good yields (34–80%). Especially, several substrates bearing drug moieties were effectively converted into the desired products with good efficiencies. In the substrate scope, diverse functional groups were tolerated, enabling late-stage functionalization of structurally complex and functionalized molecules.

Scheme 13 Defluorinative benzylation of α-trifluoromethyl arylalkenes with alkylarenes.

The radical-mediated 1,n-hydrogen atom transfer (1,n-HAT) strategy has proven effective for site-selective modification of C(sp³)–H bonds over the past decade.³⁶ For instance, N-directed γ-C(sp³)–H functionalization of sulfamate esters through unique 1,6-HAT processes has opened new avenues in chemical synthesis. However, methods involving coupling partners remain in their infancy.³⁷ In 2024, Qin et al. discovered a protocol for photoredox-catalyzed N-directed defluorinative γ-C(sp³)–H allylation of sulfamate esters 14a with α-trifluoromethyl arylalkenes 14b to give the target products 14c in the presence of Ir[(dFCH₃ppy)₂(dtbbpy)]PF₆ as catalyst.³⁸ A proposed mechanism for this transformation was described in Scheme 14. First, a PCET-based N-radicals 14d formed through the combined action of Brønsted base and photoredox catalysis. Second, the N-radicals 14d underwent favorable N-directed 1,6-HAT to generate alkyl radical precursors 14e, which subsequently followed analogous steps to yield the target gem-difluoroalkene products 14c. Moreover, water served as an environmentally benign co-solvent in this transformation. Notably, this work offered a straightforward and practical strategy for the divergent synthesis of gem-difluoroalkene-containing sulfamate esters.

Scheme 14 N-directed defluorinative γ-C(sp³)–H allylation of sulfamate esters with α-trifluoromethyl arylalkenes.

As a proficient approach for initiating long-range inert C–H bond, the 1,5-HAT process is also a commonly method for generating alkyl radicals.^36a,39 In the same year, Wang and colleagues subsequently discovered a 1,5-HAT process for synthesizing gem-difluoroalkenes in photoredox-catalyzed reactions (Scheme 15).⁴⁰ In this transformation, various N-alkoxyphthalimides 15a served as radical precursors to generate alkyl radicals. These radicals then reacted with diverse α-trifluoromethyl arylalkenes 15b to afford numerous synthetically attractive gem-difluoroalkenes 15c in moderate to excellent yields under optimal conditions. Compared with conventional methods, the reactions proceeded under mild conditions with broad functional group tolerance, including compatibility with a wide range of sensitive and functionalized moieties.

Scheme 15 Photoredox catalyzed synthesis of gem-difluoroalkenes via 1,5-hydrogen atom transfer.

In 2024, Sun’ group developed new strategies for synthesizing δ,δ-difluoroallylic ketones and γ,γ-difluoroallylic ketones through a desulfurative/defluorinative alkylation procedure (Scheme 16).⁴¹ They successfully prepared a variety of γ,γ-difluoroallylic ketones 16b in moderate to high yields via the desulfurative gem-difluoroallylation of various α-thiol esters 16a, utilizing [Ir(ppy)₂(bpy)]PF₆ as the photocatalyst, DABCO as the base, and PPh₃ as the sulfur scavenger in DCM. Particularly, the gem-difluoroallylation modification of natural products was also successful. Additionally, they unexpectedly disclosed that thioic acids 16c and α-trifluoromethyl arylalkenes 16d were also compatible with these strategies. Furthermore, δ,δ-difluoroallylic ketones 16e were smoothly synthesized under similar conditions, employing [Ir(dF(CF₃)ppy)₂(dtbbpy)]PF₆ as the photocatalyst, Cs₂CO₃ as the base, and PPh₃ as the sulfur scavenger in a mixed solvent of DCM and H₂O.

Scheme 16 Photocatalytic synthesis of γ,γ-difluoroallylic ketones and δ,δ-difluoroallylic ketones via a desulfurative/defluorinative alkylation process.

2.2 Ru-based photocatalysts

The regioselective cross-coupling of gem-difluoroalkene motifs with the C–H bonds of simple arenes remains a challenge.

In 2022, Patureau and co-workers reported a photoredox-catalyzed late-stage defluorinative gem-difluoroallylation of (hetero)aryl frameworks using aryl sulfonium salts (17a) as radical precursors. The transformation proceeds under visible-light irradiation via site-selective direct C(sp²)–H functionalization, enabling the efficient installation of gem-difluoroallyl groups onto structurally complex molecules at a late stage (Scheme 17).⁴² They explored a diverse array of substrates, including aryl sulfonium salts 17a and α-trifluoromethyl arylalkenes 17b, with particular emphasis on derivatives of two important drugs: flurbiprofen and pyriproxyfen. This process was performed under mild and sustainable conditions using the [Ru(bpy)₃](PF₆)₂/TMEDA system in acetonitrile solvent. This discovery pretty supplemented the existing synthetic technology of fluorine-containing drugs.

Scheme 17 Late-stage defluorinative gem-difluoroallylation of aryl sulfonium salts with α-trifluoromethyl arylalkenes.

There are only few reports on using an S-centered radical route to prepare gem-difluoroallylsulfones. In 2023, Lei and co-workers developed a study for synthesizing a range of gem-difluoroallylsulfones 18c with moderate to good yields through a photo/Ni dual-catalyzed radical defluorinative sulfonylation of α-trifluoromethyl arylalkenes 18b.^13a They selected aryl sulfonium salts 18a as sulfonyl radical precursors for this transformation employing a dual catalytic system comprising photocatalyst Ru(bpy)₃(PF₆)₂ and nickel catalyst Ni(bpy)₃Cl₂ in MeCN at room temperature under blue LEDs irradiation. A proposed reaction mechanism was depicted in Scheme 18 based on previous reports.^12g,13i,43 First, the Ru(II)* preferentially oxidized sodium sulfinates 18a, generating the sulfonyl radicals 18e and Ru(I). The sulfonyl radicals 18e then added to α-trifluoromethyl arylalkenes 18b to form benzyl carbon radicals 18f. This radicals subsequently reacted with Ni(II) to produce alkyl-Ni(III) intermediates 18g, which further underwent β-fluoride elimination to produce the target products 18c. The catalytic cycle was ultimately completed through SET-mediated regeneration of both the Ru(II) and Ni(II). To be noted, this dual-catalytic system effectively suppressed the rapid oxygen-mediated side reactions triggered by trace amount of air, preventing the formation of α-trifluoromethyl-β-sulfonyl tertiary alcohol by-product.

Scheme 18 gem-Difluoroallylation of aryl sulfonium salts with α-trifluoromethyl arylalkenes.

The α-CF₃ amine motif serves as an effective surrogate for the natural peptide bond [CONH] in peptide mimics, significantly altering physical and biological properties such as cell membrane permeability, lipophilicity, and metabolic stability.⁴⁴ In 2023, Chen and colleagues introduced an innovative defluorinative α-C(sp³)–H alkylation for the synthesis of gem-difluoroallylated α-trifluoromethylamines 19c in good to excellent yields.⁴⁵ The reaction employed various N-trifluoroethyl hydroxylamine reagents 19a and diverse α-trifluoromethyl alkenes 19b in the presence of Ru(phen)₃(PF₆)₂ as photocatalyst, Hantzsch ester (HE) as the reductant, and Cs₂CO₃ as the base in CH₃CN under the irradiation of 24 W purple LEDs (Scheme 19). Furthermore, this protocol was also successfully applied to the late-stage functionalization of complexes, such as bioactive compounds and natural products.

Scheme 19 Defluorinative α-C(sp³)–H alkylation for the synthesis of gem-difluoroallylated α-trifluoromethylamines.

Incorporating fluoroalkenes into the structural framework of trialkylamines is an appealing but uncharted transformation.^13n,45,46 In 2024, Yang et al. developed a photocatalytic multicomponent reductive aminoalkylation process for synthesizing fluorinated tertiary aliphatic homoallylamines 20d that integrated naturally occurring secondary alkylamines 20a, carbonyl compounds 20b, and readily available fluoroalkyl-substituted alkenes, such as α-trifluoromethyl alkenes 20c, using Ru(bpy)₃(PF₆)₂ as the photocatalyst, Hantzsch ester (HE) as the reductant, and propionic acid along with 4 Å MS as the additive in DMSO under irradiation with a 456 nm Kessil lamp at room temperature (Scheme 20).⁴⁷ The utility of this method is demonstrated through its broad functional group tolerance, successful derivatization of complex alkylamines, and applications in the synthesis of drug analogues.

Scheme 20 Photocatalytic multicomponent reductive aminoalkylation process for synthesizing group-rich fluorinated tertiary aliphatic homoallylamines.

3 Organo-photocatalysts

There has been rising attention in the challenging and essential construction of all-carbon quaternary centers. Photoredox-catalyzed gem-difluoroallylation of cesium tertiary alkyl oxalates 21a using 4CzIPN as the photocatalyst in MeCN without requiring base was disclosed by Yuan and colleagues in 2022 (Scheme 21).⁴⁸ In this method, oxalates served as activating groups for tertiary alcohols to generate tertiary alkyl radicals, enabling the construction of all-carbon quaternary centers. The transformation demonstrated great functional group tolerability for both cesium tertiary alkyl oxalates 21a and α-trifluoromethyl arylalkenes 21b, which has also been successfully applied to late-stage modifications of bioactive molecules.

Scheme 21 gem-Difluoroallylation of cesium tertiary alkyl oxalates to construct all-carbon quaternary centers.

Organosilicon compounds have numerous applications in organic synthesis,⁴⁹ material science,⁵⁰ medicinal chemistry.⁵¹ Among them, gem-difluoroallylsilanes have recently emerged as a privileged motif, garnering growing attention in chemical research. In 2022, Jing's group presented an environmentally friendly and simple method for photoredox metal-free allylic defluorinative silylation of α-trifluoromethyl arylalkenes 22b with hydrosilanes 22a by combining 4CzIPN as a photocatalyst and quinuclidine as the HAT reagent under 20 W blue LED irradiation in CH₃CN (Scheme 22).⁵² This method provided an alternative approach to prepare gem-difluoroallylsilanes, which showed good functional group compatibility in moderate to excellent yields. Notably, the required hydrosilanes – serving as silyl radical precursors – are commercially available and relatively inexpensive. Furthermore, this technique was suitable for individual α-trifluoromethyl arylalkenes with a double bond in the middle position. A feasible mechanism was proposed in Scheme 22. Stern–Volmer analysis revealed that the 4CzIPN* was primarily quenched by quinuclidine. The silyl radical intermediates 22d were formed when radical cation 22e abstracted a hydrogen atom from hydrosilanes 22a. 22d then added to α-trifluoromethyl arylalkenes 22b, forming radical intermediates 22f, which subsequently underwent another SET process and β-fluoride elimination to obtain the target products 22c.

Scheme 22 Allylic defluorinative silylation of α-trifluoromethyl arylalkenes with hydrosilanes.

A simple and versatile photocatalytic method enables the synthesis of unsaturated ketones bearing valuable gem-difluoroalkene moieties, which could benefit the pharmaceutical, agrochemical, and material industries. In 2022, Wu and co-workers developed a method to synthesize distal gem-difluoroalkenyl ketones 23c in moderate to excellent yields via organophotoredox-catalyzed ring-opening gem-difluoroallylation of nonstrained cycloalkanols 23a with a broad scope of α-trifluoromethyl arylalkenes 23b, utilizing Mes-2,7-Me₂-Acr-Me⁺ClO₄⁻ as organophotocatalyst, 2,4,6-collidine and [C₄MPr]⁺PF₆⁻ in DCM under the irradiation of 30 W blue LEDs lamp (Scheme 23).⁵³ Notably, this strategy enabled precise control over product chain length through the use of cyclic alcohols with defined ring sizes, providing an efficient and regioselective route to distal gem-difluoroalkenyl ketones.

Scheme 23 Ring-opening gem-difluoroallylation of nonstrained cycloalkanols with α-trifluoromethyl arylalkenes.

The direct and site-selective α-C(sp³)–H activation of THF remains challenging owing to its inherent inertness. In 2023, Zhong and colleagues introduced a metal-free and site-selective α-C–H gem-difluoroallylation of tetrahydrofuran 24a (Scheme 24).⁵⁴ In this work, various α-trifluoromethyl arylalkenes 24b were investigated in the presence of 4-CzIPN as a photocatalyst and ⁿBu₄NBr as a HAT catalyst in THF, under 450 nm LEDs irradiation in an air atmosphere. Overall, substrates containing electron-donating groups showed superior performance compared to those with electron-withdrawing groups. Furthermore, this methodology was practical and also applicable for the late-stage functionalization of several α-trifluoromethyl arylalkenes derived from natural products and pharmaceuticals. Based on the control experiments and mechanistic studies, the photocatalytic production of bromine radicals was critical to the success of the process, as indicated. Moreover, the feature of transition-metal-free aligned with green chemistry principles by avoiding metal contaminant and minimizing environmental impact.

Scheme 24 Site-selective α-C–H gem-difluoroallyslation of tetrahydrofuran with α-trifluoromethyl arylalkenes.

In 2023, Yuan's group depicted a 4CzIPN-catalyzed gem-difluoroallylation of carboxylic acids 25a with α-trifluoromethyl alkenes 25b via 1,5-HAT using Cs₂CO₃ as base, in MeCN at room temperature under 15 W blue LEDs irradiated (Scheme 25).⁵⁵ The resulting gem-difluoroalkene derivatives 25c were obtained with good functional group compatibility in moderate to excellent yields. Moreover, this method enabled the visible-light photocatalyzed gem-difluoroallylation of unactivated C(sp³)–H bonds, providing a site-selective approach to introduce gem-difluoroallyl groups into aliphatic frameworks.

Scheme 25 gem-Difluoroallylation of carboxylic acid with α-trifluoromethyl alkenes.

In 2023, Zhou et al. reported a simple and mild strategy for the photocatalytic mono-gem-difuoroallylation of 1,3-benzodioxoles 26a with various α-trifluoromethyl arylalkenes 26b in the presence of 4CzIPN and 2,4,6-collidine in MeCN under the irradiation of 5 W blue LED.⁵⁶ A proposed mechanism of this transformation was depicted in Scheme 26. The 4CzIPN* oxidized 1,3-benzodioxoles 26a to produce radical cations 26d, which subsequently underwent deprotonation to generate the 1,3-benzodioxol-2-yl radicals 26e. These radicals added to the α-trifluoromethyl arylalkenes 26b to give intermediate radicals 26f. Reduction of 26f by 4CzIPN˙⁻ yielded the α-CF₃ carbanions 26g while regenerating the 4CzIPN catalyst. Finally, β-fluoride elimination of 26g afforded the target products 26c. To be noted, in this work the crucial 1,3-benzodioxol-2-yl radicals were formed via direct single-electron oxidation of the precursors, rather than through hydrogen atom abstraction pathway.

Scheme 26 Mono-gem-difuoroallylation of 1,3-benzodioxoles with α-trifluoromethyl arylalkenes.

Fluorinated amino acids (FAAs) are crucial components in organic synthesis and have numerous applications in medicinal and bio-organic chemistry.^4b,57 In 2023, Guo and colleagues disclosed a 4CzIPN-catalyzed, 2 W blue LEDs-driven α-C(sp³)–H gem-difluoroallylation of glycine derivatives and dipeptides 27a with α-trifluoromethyl alkenes 27b without any additives in DMSO (Scheme 27).⁵⁸ This method exhibited a broad substrate scope and excellent functional group tolerance, allowing the synthesis of diverse fluorine-containing amino acids and dipeptides 27c in good to excellent yields. Notably, the methodology demonstrated remarkable compatibility with biomolecules, highlighting its potential for biological applications. Additionally, a series of 2-trifluoromethyl 1,3-enynes also exhibited compatibility with this transformation.

Scheme 27 α-C(sp³)–H gem-difluoroallylation of glycine derivatives with α-trifluoromethyl alkenes.

In 2023, Zhu and co-workers reported an intriguing mono-defluorocarboxylation of diverse α-trifluoromethyl arylalkenes 28b with lithium formate 28a to access gem-difluorovinylacetic acids 28c (Scheme 28).⁵⁹ This transformation employed a catalytic system consisting of 4CzIPN as the photocatalyst, DABCO as the HAT catalyst, and K₂HPO₄ as the base, with 20 equivalents of H₂O in DMSO, under irradiation with a 3 W blue LEDs at room temperature. The reaction demonstrated excellent tolerance for sterically demanding functional groups, including TMS and vinyl moieties, ortho-substituted hindered substrates, and trisubstituted alkenes, as well as complex substrates derived from liquid crystals and natural products. A propose mechanism for the defluorocarboxylation was described in Scheme 28. The CO₂˙⁻ radical, generated via HAT by the DABCO radical cation, underwent Giese radical addition to the α-trifluoromethyl arylalkenes 28b to form radicalintermediates 28d. The target products 28c were obtained through sequential steps, including: (1) a SET process with 4CzIPN˙⁻ to regenerate 4CzIPN, and (2) β-fluoride elimination to afford the final products 28c. They speculated that although H₂O participated in the reaction, no side products 28c′ was detected. This observation suggests that both the reduction of 28d and the β-fluoride elimination occurred rapidly. In this work, the reactivity of CO₂˙⁻ radical anion plays a key role in driving the defluorinative transformation.

Scheme 28 Mono-defluorocarboxylation of multifarious α-trifluoromethyl arylalkenes with lithium formate to access gem-difluorovinylacetic acids.

Shortly later, Fu's group reported a similar defluorinative carboxylation of α-trifluoromethyl arylalkenes 29b that demonstrated good functional group compatibility (Scheme 29).⁶⁰ The reaction employed potassium formate 29a as the CO₂˙⁻ precursor under a 34 W LEDs irradiation, with catalytic 4DPAIPN as the photocatalyst, 2-methoxybenzenethiol as the HAT catalyst, and DBU as the base in DMSO at 30 °C. This strategy required only 2 h, providing an efficient alternative approach to synthesize structurally diverse gem-difluorovinylacetic acids 29c.

Scheme 29 Defluorinative carboxylation of α-trifluoromethyl arylalkenes with potassium formate.

Current cross-coupling protocols can efficiently create gem-difluoroalkenes. However, the construction of multi-fluorinated compounds, such as gem-difluoroalkene difluoroacetates found in some pharmaceuticals, under mild conditions remains challenging. In 2023, Chen and co-workers reported a defluorinative difluoroalkylation of α-trifluoromethyl arylalkenes 30b with bromodifluoro precursors 30a, which gave a range of difluoromethylene-containing gem-difluoroalkenes 30c mediated by the photoredox catalyst 4CzIPN in DMF under the irradiation of purple LEDs (Scheme 30).⁶¹ Notably, 2-bromo-2,2-difluoroacetamides 30a could serve as effective difluoroalkylating reagents only when they lacked an N–H bond or when the N–H bond was sterically hindered. Under these conditions, they could be converted into the corresponding gem-difluoroalkenes with excellent tolerance of functional groups.

Scheme 30 Defluorinative difluoroalkylation of α-trifluoromethyl arylalkenes with 2-bromo-2,2-difluoroacetates derivatives.

In 2023, Chen and colleagues presented a study on the monomasked formylation of α-trifluoromethyl alkenes 31b (Scheme 31).⁶² They utilized low-priced 1,3-dioxolane 31a as a masked formyl radical equivalent to provide significant amounts of masked formylated gem-difluoroalkenes 31c in moderate to high yields, through the synergistic combination of 4CzIPN as a catalyst and catalytic quinuclidine as a HAT reagent in MeCN. Moreover, this study disclosed a solvent-dependent switch between mono- and dimasked formylation of α-trifluoromethyl alkenes, enabling by organophotoredox-catalyzed C–F bond activation.

Scheme 31 Monomasked formylation of α-trifluoromethyl alkenes with 1,3-dioxolane.

The conversion of glycine into nonproteinogenic amino acids and the modification of glycine-containing peptides can significantly enhance their activity, pharmacokinetics, and pharmacological properties of these compounds compared to their natural counterparts.⁶³ In 2024, Chen et al. described a method for the 4CzIPN-catalyzed defluorinative gem-difluoroallylation of glycine derivatives 32a with α-trifluoromethyl alkenes 32b. This protocol used NaHCO₃ as base and blue LED as a light source, delivering a broad scope of gem-difluoroalkenes 32c in moderate to excellent yields (Scheme 32).⁶⁴ Additionally, this transformation utilized readily available starting materials, mild conditions, good functional group compatibility, providing an alternative procedure for the synthesis of alkylated gem-difluoroalkenes.

Scheme 32 Defluorinative gem-difluoroallylation of glycine derivatives with α-trifluoromethyl alkenes.

While the 1,5-HAT of N-centered radicals is well-established, the 1,2-HAT process has found far fewer synthetic applications, primarily due to its higher energy barrier and the geometric constraints of the three-membered transition state. In 2024, Yuan’ group discovered a mild C(sp³)–H gem-difluoroallylation of amides 33a with α-trifluoromethyl alkenes 33b, facilitated by a base-assisted formal 1,2-HAT of amidyl radicals (Scheme 33).⁶⁵ The proposed mechanism was illustrated in Scheme 33. Upon irradiation with 40 W Kessil 390 nm PR160 LEDs, the 4CzIPN* oxidized 33a to generate amidyl radicals 33d. Assisted by Na₂CO₃, an intramolecular formal 1,2-HAT process preferentially occurred, yielding α-amino alkyl radicals 33e, which then added to α-trifluoromethyl alkenes 33b, forming the α-trifluoromethyl radical intermediates 33f. Subsequent reductive quenching of the photocatalyst and β-fluoride elimination gave the desired products 33c. However, an intermolecular HAT process cannot be entirely excluded. Enantioselective construction of the target products through radical addition remains a formidable challenge. Nevertheless, the reaction manifold may be biased by chiral copper or iron complexes that serve as stereo-directing Lewis-acid catalysts. In addition, this method introduced a novel strategy for generating α-aminoalkyl radicals via the reductive quenching cycle of the photocatalyst.

Scheme 33 C(sp³)–H gem-difluoroallylation of amides with α-trifluoromethyl alkenes.

Quinazolin-4(3H)-ones constitute a significant class of N-heterocyclic compounds, demonstrating diverse pharmacological activities such as antibacterial, anti-inflammatory, anticancer, and antihypertensive properties.⁶⁶ In 2024, Guo et al. reported a 4CzIPN-photocatalyzed gem-difluoroallylation of spiro-dihydroquinazolinones 34a using α-trifluoromethyl arylalkenes 34b (Scheme 34).⁶⁷ Notably, α-trifluoromethyl arylalkenes bearing electron-donating groups (EDGs) or weak electron-withdrawing groups (WEWGs) at the para-position of the phenyl ring both exhibited excellent reactivity in this gem-difluoroallylation reaction, affording the desired products in moderate to good yields. This protocol enables the introduction of a fluorine-containing group at the designated position of quinazolin-4(3H)-ones. Additionally, it features mild, redox-neutral conditions, excellent atom economy, and good functional group compatibility, highlighting its considerable potential for organic synthesis applications.

Scheme 34 gem-Difluoroallylation of spiro-dihydroquinazolinones using α-trifluoromethyl arylalkenes.

Polychloroalkyl motifs are prevalent in pharmaceuticals, agrochemicals, and natural products, and their unique physicochemical properties have driven growing interest in the selective and efficient synthesis of these structural units.⁶⁸ In 2025, Hu’ group described a 30 W blue LEDs-driven selective defluorinative alkylation of α-trifluoromethyl arylalkenes 35b with readily available and inexpensive polychloroalkane feedstocks 35a as alkyl radical precursors, provided efficient access to a variety of polychloroalkylated gem-difluoroalkenes 35c at room temperature (Scheme 35).⁶⁹ When using 1 mol% of 4CzlPN and 1.2 equivalents of TMP in polyhaloalkanes 35a-1, the reaction enabled selective functionalization of C–H bonds in polychloroalkanes through HAT processes. Alternatively, when using 2 mol% of 4CzlPN and 4 equivalents of ⁱPrCyNH in polyhaloalkanes 35a-1, the reaction enabled selective activation of C–X bonds in polychloroalkanes 35a-2 through XAT processes. It is worth noting that the selective functionalization of C–H or C–X bonds in polychloroalkanes was controlled by the addition of an amine, without the need for toxic reagents and oxidants.

Scheme 35 Defluorinative alkylation of α-trifluoromethyl arylalkenes with polychloroalkanes.

Eosin Y is an attractive organic photocatalyst due to its low cost and easy preparation, combined with high photoredox efficiency and strong absorption throughout the visible-light region, enabling effective utilization of a broad range of irradiation wavelengths.⁷⁰ Chen and co-workers developed a defluorinative alkylation of α-trifluoromethyl arylalkenes 36b with N-alkoxyphthalimides 36a using Eosin Y as photocatalyst, Hantzsch ester (HE) as reductant, K₃PO₄ as base under irradiation of blue LEDs in MeCN in 2025 (Scheme 36).⁷¹ This method exhibited excellent chemoselectivity, favoring defluorinative alkylation over competing hydroalkylation pathways, delivered high product yields, and tolerated a broad range of functional groups, establishing a highly effective platform for the synthesis of structurally diverse and bioactive fluorinated compounds.

Scheme 36 Defluorinative alkylation of α-trifluoromethyl arylalkenes with N-alkoxyphthalimides.

In 2025, Keyume et al. reported a visible-light-induced defluorinative acylation of α-trifluoromethyl arylalkenes 37b with aromatic carboxylic anhydrides 37a, providing various γ,γ-difluoropropenyl ketones 37c under irradiation with a 10 W blue LED at room temperature (Scheme 37).⁷² In this reaction, 4CzIPN was employed as the photocatalyst, PPh₃ served as the reductant, and Cs₂CO₃ was used as the base in DMF. When anhydride 37d bears an electron-withdrawing substituent (e.g., para-Cl) on one aryl ring and an electron-donating substituent (e.g., para-OMe) on the other, the reaction proceeded exclusively through allylic defluoroacylation, affording product 37e as the sole product and possible 4-methoxybenzoylation product 37f was not detected. However, when aryl anhydride 37g bearing one meta-methyl substituent was used as the substrate, a mixture of benzoylation product 37h and meta-methylbenzoylation product 37i was obtained in a 54 : 46 ratio. Mechanistic studies suggested that reaction selectivity may be influenced by both electronic and steric effects of substituents on unsymmetrical anhydrides, with electron-withdrawing groups tending to facilitate C–O bond cleavage and steric bulk appearing to control regioselective acyl transfer.

Scheme 37 Defluorinative acylation of α-trifluoromethyl arylalkenes with aromatic carboxylic anhydrides.

4 Reactions with other photoinduced systems

4.1 Photocatalysts-free conditions

Since the groundbreaking research reported by Watson's group in 2017,⁷³ great interests have focused on the reactions of Katritzky salts, which can be easily synthesized through a one-step condensation of primary alkylamines with pyrylium salts and efficiently generate alkyl radicals.⁷⁴ In 2022, Zhang and colleagues reported a photoinduced, EDA-complex-mediated defluorinative alkylation of α-trifluoromethyl arylalkenes 38b with katritzky salts 38a under catalyst- and metal-free conditions(Scheme 38).⁷⁵ This approach afforded a sustainable strategy for synthesis of gem-difluoroalkenes with a broade substrate scope and excellent functional group compatibility, and suitability for late-stage bioactive molecules and drug derivatives. In this reaction, the electron donor–acceptor (EDA) complex formed between inexpensive organic reductants (electron donor) and Katritzky salts (strong electron acceptor) drives the transformation. When N-secondary alkyl Katritzky salts 38a-1 were employed, the reaction typically utilized Hantzsch ester (HE) or DIPEA as the reductant in DMA under blue LEDs irradiation at room temperature. Notably, switching to the more economical reductant Et₃N in DMSO under blue LEDs irradiation at 100 °C, the researchers made a significant observation: N-primary alkyl Katritzky salts 38a-2 could successfully participate in this reaction. This method is distinguished by using cheap and easily accessible organic reductants (Hantszch ester or Et₃N), thus enabling catalyst- and metal-free conditions.

Scheme 38 Defluorinative alkylation of α-trifluoromethyl arylalkenes with Katritzky salts.

More recently, transient EDA complexes have played a crucial role in photoinduced organic synthesis by generating radicals without requiring external transition metals or organic dye-based photoredox catalysts. In 2024, Fu's group described a general photoinduced reductive defluorinative decarboxylative alkylation of α-trifluoromethyl arylalkenes 39b via an EDA complex formed between iodide salts and N-hydroxyphthalimide esters (redox-active esters, RAEs) 39a (Scheme 39).⁷⁶ These esters were stable and can be easily prepared from the corresponding carboxylic acids.⁷⁷ The reaction afforded a variety of gem-difluoroalkenes 39c with broad functional group compatibility.

Scheme 39 Defluorinative decarboxylative alkylation of α-trifluoromethyl arylalkenes with N-hydroxyphthalimide esters (redox-active esters, RAEs).

Aryl and alkyl thianthrenium salts have emerged as significant electrophiles or radical precursors for various reactions mediated by metal or photoredox catalysts. In 2024, Fan and colleagues disclosed a visible-light-promoted defluoroallylation procedure involving α-trifluoromethyl arylalkenes 40a and aryl/alkyl thianthrenium salts, using DABCO as the initiator under 36 W blue LEDs irradiation, providing gem-difluoroalkenes with excellent functional group tolerance in moderate to excellent yields.⁷⁸ Interestingly, when aryl-substituted thianthrenium salts were used, the desired products 40b could be obtained in DMSO without adding the photocatalyst 4CzIPN. In contrast, reactions involving alkyl-substituted salts with 5 mol% of the organic photocatalyst 4CzIPN in CH₃CN to obtain the corresponding products 40c. The proposed mechanism is shown in Scheme 40. Aryl or alkyl thianthrenium salts 40d interacted with DABCO to form an EDA complex, resulting in the generation of the alkyl or aryl radicals 40e through a SET triggered by blue LEDs. For alkyl thianthrenium salts, the 4CzIPN photocatalyst could enhanced the efficiency of SET and facilitated the generation of alkyl radicals 40e. The radicals then underwent a series of similar processes, including addition reaction, single-electron reduction, and β-fluoride elimination, to afford the desired products and furnish the photoredox cycle. This method is notable for employing the inexpensive organic reductant DABCO to generate EDA complexes that facilitate radical formation without the need for an external photocatalyst.

Scheme 40 Defluorinative alkylation/arylation of α-trifluoromethyl arylalkenes with thianthrenium salts.

4.2 TBADT as photocatalyst

The direct functionalization of unactivated C(sp³)–H bonds in alkanes remains a significant challenge in modern synthetic chemistry. In 2024, Martínez-Balart and co-workers developed a photoredox-catalyzed HAT protocol that directly cleaves C(sp³)–H bond, enabling the defluorinative alkylation of α-trifluoromethyl arylalkenes 41b using unfunctionalized alkanes 41a as radical precursors (Scheme 41).⁷⁹ Notably, when using α-trifluoromethyl arylalkenes 41b bearing an electron-poor ring, a stronger basic system comprising LiOH (3 equiv.) and K₃PO₄ (1.5 equiv.) selectively afforded the gem-difluoroalkenes over the hydroalkylation products. Based on mechanistic investigations and previous studies of TBADT photocatalysis,⁸⁰ the authors proposed the following reaction mechanism: the excited-state decatungstate 41d facilitated hydrogen atom abstraction from the alkanes 41a, generating an alkyl radicals 41e. This radical then added to the α-trifluoromethyl arylalkenes 41b, forming radical intermediates 41f. Subsequently, the intermediates 41f underwent single-electron reduction by the doubly reduced decatungstate 41g, facilitated by the base, yielding carbanions 41h, which underwent β-fluoride elimination to produce the gem-difluoroalkene products 41c. Moreover, saturated hydrocarbons, such as gaseous alkanes, were directly employed as alkylating agents without the need for pre-activated radical precursors, enhancing both the step economy and atom economy of this strategy.

Scheme 41 Defluorinative alkylation of α-trifluoromethyl arylalkenes with unfunctionalized alkanes.

4.3 Semiconductors as photocatalysts

In 2023, Dai's group reported a heterogeneous photocatalyzed defluorinative gem-difluoroallylation of 1,3-dimethylimidazol-2-ylidene borane 42a, which served as the boryl radical precursor, with several α-trifluoromethyl arylalkenes 42b using stable CdS nanosheets as catalyst in CH₃CN under the irradiation of a 10 W blue LED (Scheme 42).⁸¹ In this work, the use of ultrathin CdS nanosheets as recoverable heterogeneous photocatalyst with high surface area and efficient light absorption facilitated the photoinduced defluorinative transformation while allowing easy catalyst recovery and reuse.

Scheme 42 Defluorinative gem-difluoroallylation of 1,3-dimethylimidazol-2-ylidene borane with α-trifluoromethyl arylalkenes.

5 Conclusions

In summary, we have summarized recent advances in visible-light-induced defluorinative functionalization of α-trifluoromethyl arylalkenes, enabling streamlined access to diversified fluorinated molecules. By harnessing the power of visible-light photocatalysis, these methods enable mild and efficient radical-mediated allylic defluorination through single-electron transfer (SET) processes, followed by β-fluorine elimination. This strategy provides a sustainable and robust platform for constructing privileged gem-difluoroalkene motifs, which are highly valuable as carbonyl bioisosteres in drug discovery. The ongoing development of these photochemical approaches, coupled with deeper mechanistic insights and improved functional group compatibility, has successfully addressed key synthetic challenges. Consequently, it substantially expands the toolbox for accessing diverse and complex fluorinated molecules, thereby opening new avenues for the application of such compounds in medicinal chemistry and related fields.

Author contributions

All authors contributed to the review and editing of the original manuscript.

Conflicts of interest

There are no conflicts of interest to declare.

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.

Acknowledgements

We gratefully acknowledge the financial support from the Distinguished University Professor grant (Nanyang Technological University) and the Agency for Science, Technology, and Research (A*STAR) under its MTC Individual Research Grant (M21K2c0114) and RIE2025 MTC Programmatic Fund (M22K9b0049) for T.-P. L. The Fundamental Research Funds for the Central Universities, and the Research Funds of Renmin University of China (No. 24XNKJ27, 202530195) for L. L.

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