Synthetic applications of α,α-difluoroarylacetic acids and salts via decarboxylative functionalization

Wenqiang Mei† , Yilin Kong† and Guobing Yan *
College of Jiyang, Zhejiang A&F University, Zhuji 311800, China. E-mail: gbyan@zafu.edu.cn; Fax: (+86)575-8876-0148

First published on 8th July 2021

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Wenqiang Mei

Wenqiang Mei was born in Zhejiang, China, in 2001. He studied in Jiyang College of Zhejiang A&F University. His current research interests focus on the transition metal-catalyzed activation of inert chemical bonds and green synthetic chemistry.

Yilin Kong

Yilin Kong was born in Jiangxi, China, in 2001. She studied in Jiyang College of Zhejiang A & F University. Her current research interests focus on the transition metal-catalyzed activation of inert chemical bonds and green synthetic chemistry.

Guobing Yan

Guobing Yan was born in Jiangxi, China, in 1975. He obtained his B.Sc. degree from Jinggangshan Normal University, his M.Sc. degree from Suzhou University, and his Ph.D. degree from Tongji University in 2010. He spent two years in 2008 and 2009 as a visiting student in professor Jianbo Wang's laboratory at Peking University. In 2013, he joined Dr Dong's group at the University of Texas at Austin as a visiting professor and then returned to Lishui University in 2014. He has been at Lishui University since 2016 as a professor. In 2021, He moved to Zhejiang A&F University. His current research interests focus on the transition-metal-catalyzed activation of inert chemical bonds and green synthetic chemistry.

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1 Introduction

The incorporation of a difluoromethylene group into organic molecules can remarkably improve the physical, chemical, and biological properties of the parent compounds, such as lipophilicity, cell membrane permeability, metabolic stability and oral bioavailability.¹ Moreover, the CF₂ moiety has attracted particular attention in medicinal chemistry, due to its unique stability and an isosteric property as a carbonyl group or an ethereal oxygen atom.² In particular, difluoroalkylated arenes are important structural skeletons in biologically active molecules, such as c-Met inhibitors,³ thrombin inhibitors,⁴ inhibitors of D-amino acid oxidase⁵ and potent antiviral agents against HIV⁶ (Scheme 1).

Therefore, great efforts have recently been devoted to the development of new methods for the synthesis of α,α-difluorobenzylic compounds. Traditional methods to prepare these compounds are based on the deoxyfluorination of ketones and aldehydes with aminosulfur trifluorides, such as diethylaminosulfur trifluoride (DAST) or its derivatives.⁷ However, these reactions suffer from some issues of harsh reaction conditions, functional group incompatibility and the use of expensive and toxic fluorinated reagents, which can significantly restrict their widespread synthetic applications. In this context, an alternative approach is to directly introduce a difluoromethylene moiety into the desired position of the aromatic rings with transition metal catalysts.^8,9 Among these, palladium and nickel catalysts have been shown to be effective for this purpose.⁹ Although great progress has been made in the transition metal-catalyzed difluoromethylation, most of the substrates need to be pre-activated and synthesized in multiple steps. In recent years, the direct difluoromethylation of heteroarenes¹⁰ and direct fluorination of benzylic C–H bonds¹¹via a free radical strategy have emerged as an attractive approach to address these issues. Despite these achievements, the exploration of efficient and practical methods for the synthesis of difluoroalkylated arenes is in high demand.

In the past decades, transition metal-catalyzed decarboxylative cross-coupling reaction has become a powerful method for the formation of carbon–carbon and carbon–heteroatom bonds.¹² α,α-Difluoroarylacetic acids and their salts are stable, inexpensive and readily available, easy to store and simple to handle building blocks, which can serve as radical precursors for the preparation of fluorinated compounds via oxidative decarboxylative α,α-difluorobenzylation. Due to its notable advantages, the decarboxylative functionalization of α,α-difluoroarylacetic acids has been widely investigated in recent years, such as alkylation, allylation, alkynylation, arylation, fluorination and the formation of carbon–heteroatom (O and S) bonds, which are summarized in Scheme 2.

In this review, we mainly focus on the decarboxylative functionalization of α,α-difluoroarylacetic acids and salts, as well as a discussion of their mechanisms. Therefore, we sincerely hope that this review will serve as a handy reference for chemists interested in organofluorine chemistry and in discovering novel methods for the rapid introduction of the ArCF₂ group into target molecules.

2 Formation of carbon–carbon bonds

2.1 Reaction with alkene derivatives

Alkene derivatives are versatile synthetic building blocks in organic synthesis, in which the unsaturated carbon–carbon bonds could be either directly attacked by electrophiles or used as acceptors of free radical addition.¹³ Two functional groups could be simultaneously introduced into the carbon–carbon double bonds for various difunctionalization reactions of alkenes, which has the advantages of atom and step economy. This kind of reaction provides an efficient and practical strategy for the synthesis of complex and structurally diverse compounds of biological interest.

In 2016, Qing and co-workers developed the photoredox-catalyzed hydroaryldifluoromethylation of various alkenes with α,α-difluoroarylacetic acids as the difluoroalkylation reagents, which could provide a series of difluoroalkylated arenes in moderate to high yields (Scheme 3).¹⁴ This catalytic system exhibited a broad substrate scope with respect to both alkenes and α,α-difluoroarylacetic acids. In addition, a variety of functional groups could be tolerated in the reaction, such as alkyl bromide, alcohol, ether, epoxy, aldehyde, ketone, ester, phosphate, amide, nitrile, etc. However, the application of this novel protocol is problematic for the substrates of 1,2-disubstituted alkenes and styrenes. Moreover, it was found that the hypervalent iodine reagent was crucial for this reaction, which was used not only as an oxidant for the transformation of the Ir(III)* species into the Ir(IV) species, but also as a promoter of decarboxylation. Therefore, in order to obtain the desired products with high yields, an excess of BIOMe was required in the reaction.

For the mechanism shown in Fig. 1, initially, the Ir(III) catalyst under irradiation with visible light generates its excited-state Ir(III)*, which could be oxidized to the Ir(IV) species by a hypervalent iodine reagent (BIOMe), along with the formation of radical A and methoxy anions. At the same time, α,α-difluoroarylacetic acids react with BIOMe to form the ArCF₂-containing intermediate B, followed by a single-electron transfer with the Ir(IV) species to give the aryldifluoromethyl radical C, accompanied by the release of carbon dioxide and regeneration of the Ir(III) catalyst to complete the catalytic cycle. Subsequently, the addition of radical C into the carbon–carbon double bonds of alkenes affords the radical intermediate D, which could abstract hydrogen from NMP to give the desired products.

In 2017, Hao and Deng's groups independently reported the Ag(I)-catalyzed oxidative decarboxylative radical addition/cyclization of N-arylacrylamides with α,α-difluoroarylacetic acids (Scheme 4).^15,16 This protocol provided a simple and efficient approach for the construction of a variety of gem-difluoroalkylated oxindoles in moderate to good yields. In addition, the reaction exhibited excellent functional group tolerance and a broad scope of substrates. Interestingly, the reaction could proceed smoothly in aqueous solution, albeit in relatively less yields.¹⁶

A plausible mechanism was proposed, as shown in Fig. 2. Initially, the Ag(I) salt is oxidized by a persulfate anion to generate the Ag(II) species, followed by a single-electron transfer with α,α-difluoroarylacetic acid to afford the α,α-difluoromethylene aryl radical A, along with the release of CO₂. Subsequently, the addition of radical A into the double bond of N-arylacrylamides occurs to afford the radical intermediate B, which undergoes a subsequent intramolecular radical cyclization to give the aryl radical C. Finally, further oxidation by a persulfate anion or Ag(II) and dehydrogenation took place to furnish the desired products.

In 2019, Zhu and co-workers reported the photoredox-catalyzed acyldifluoroalkylation of unactivated alkenes with α,α-difluoroacetic acids as the difluoroalkylation reagents and PhI(OAc)₂ as the oxidant (Scheme 5).¹⁷ A variety of gem-difluorinated cyclic ketones could be obtained by this protocol, including chroman-4-ones, indanones, 3,4-dihydronaphthalen-1(2H)-ones, 2,3-dihydroquinolin-4(1H)-ones, and cyclopent-2-enones. In addition, a wide range of functional groups could be tolerated for the reaction, which makes it attractive for the fast construction of biologically active difluoroalkylated compounds.

In the mechanism shown in Fig. 3, initially, under irradiation with blue LEDs, the photocatalyst Ir(III) gives the excited state Ir(III)*, which undergoes a single-electron transfer with the hypervalent iodine(III) compound A generated in situ from PhI(OAc)₂ and difluoroacetic acids to afford a difluoromethyl radical B and Ir(IV) species, along with the release of carbon dioxide and the formation of PhI and PhCF₂CO₂⁻. Subsequently, the addition of radical B into the carbon–carbon double bond of 2-(allyloxy)benzaldehyde affords an alkyl radical C, followed by an attack on the carbonyl group to give the oxygen-centered radical D. A rapid and formal 1,2-hydrogen atom transfer occurs to produce the α-hydroxy carbon-centered radical E. Finally, the single-electron transfer oxidation between radical E and Ir(IV) species takes place to give the acyldifluoroalkylation products, along with the regeneration of the Ir(III) catalyst to complete the catalytic cycle.

Allyl sulfones were widely used as radical acceptors in radical chemistry and as reliable allylating reagents.¹⁸ Li and co-workers developed the silver-catalyzed decarboxylative allylation of α,α-difluoroarylacetic acids with allyl sulfones, which could provide a variety of β,β-difluorinated alkenes in good yields (Scheme 6).¹⁹ This reaction worked well in water and a wide range of functional groups could be tolerated. In addition, the scalability of the reaction and further elaboration of the products make it attractive with potential application value.

For the mechanism shown in Fig. 4, the Ag(I) salt is firstly oxidized by a persulfate anion to generate the highly reactive Ag(II) complex. Subsequently, the difluoroalkyl radical A is generated by the single-electron transfer between α,α-difluoroarylacetic acids and the Ag(II) complex. Finally, the addition of radical A into the carbon–carbon double bonds of allyl sulfone takes place to afford the radical intermediate B, which undergoes β-elimination of the sulfonyl radical to deliver the desired products.

2.2 Reaction with alkyne derivatives

Alkynes and their derivatives are among the most important building blocks in organic synthesis, due to their versatile transformations for the preparation of other functionalized compounds.²⁰ Heteroatom-substituted alkynes with enhanced reactivity are particularly interesting. Among these, ethynylbenziodoxolone (EBX) is one of the most powerful and useful alkynylating reagents, which has been increasingly investigated in recent years, because of its stability toward air and moisture.²¹

In 2016, Hashmi and co-workers reported the silver-catalyzed decarboxylative alkynylation of α,α-difluoroarylacetic acids with ethynylbenziodoxolone reagents (EBX) under mild conditions.^22a A wide range of functional groups could be tolerated in the reaction. In addition, a series of α,α-difluoromethylated alkynes could be obtained in moderate to good yields. The reaction provides a simple and practical method for the synthesis of α,α-difluoromethylated alkynes in aqueous solution. Remarkably, this decarboxylative process could also proceed smoothly without silver salts reported by Wu's group (Scheme 7).^22b

A plausible mechanism is proposed in Fig. 5. Initially, difluoroarylacetic acids undergo a decarboxylative process to generate a radical intermediate A in the presence of K₂S₂O₈, releasing a molecule of carbon dioxide. Subsequently, the addition of radical A into the carbon–carbon triple bond of TIPS-EBX produces an adduct radical intermediate B, followed by β-elimination to afford the desired products, along with the formation of a benziodoxolonyl radical C. Finally, further reduction and subsequent protonation form 2-iodobenzoic acid through the remaining difluoroacetic acids.

2.3 Reaction with isocyanides

Isocyanides are versatile building blocks commonly utilized in organic synthesis, and they exhibit outstanding chemical reactivity, reacting with nucleophiles, electrophiles, radicals, and transition metals.²³ In 2016, Hao and co-workers reported the Ag(I)-catalyzed oxidative decarboxylation of α,α-difluoroarylacetic salts with isocyanides for constructing gem-difluoromethylenated phenanthridines under mild conditions (Scheme 8).²⁴ This protocol exhibited a broad substrate scope with respect to two coupling partners of α,α-difluoroarylacetic acids and isocyanides with wide functional group compatibility. In addition, a series of gem-difluoromethylenated phenanthridines could be obtained in moderate to good yields.

In the mechanism shown in Fig. 6, initially, the Ag(I) salt is oxidized by the persulfate to generate the reactive Ag(II) complex. A single-electron transfer process between the Ag(II) complex and α,α-difluoroarylacetic acids occurs to give the carboxyl radical A, followed by rapid decarboxylation to afford the difluoromethylene radical B, along with the release of a molecule of CO₂. Subsequently, the intermolecular addition of radical B into isocyanides takes place to form the imidoyl radical C, which undergoes intramolecular radical cyclization to generate a cyclohexadienyl-type radical D. The further oxidation by the sulphate radical anion affords the cyclohexadienyl cation E through a second single-electron transfer process. Finally, deprotonation and aromatization occur to deliver the desired products.

2.4 Reaction with heteroaromatic compounds

Heteroaromatic compounds are important intermediates in organic synthesis, which were used not only as building blocks in the synthesis of natural products, but also as key structural units of compounds with interesting biological activity.²⁵ Structural optimization of heteroaromatics through chemical alteration has particular significance in the drug discovery process. The transition metal-catalyzed facile and direct functionalization of the C(sp²)–H bond in heterocyclic compounds has been emerging as a powerful method for the formation of carbon–carbon and carbon–heteroatom bonds.²⁶ In addition, the radical strategy based on Minisci-type reaction is also an important method to realize the direct functionalization of heteroaromatic compounds.²⁷

In 2019, Hao and co-workers developed a novel and efficient method for the decarboxylative meta-C–H difluoromethylation of 2-arylpyridine derivatives catalyzed by a palladium catalyst under mild conditions (Scheme 9).²⁸ A variety of 2-arylpyridines with various substituents at the ortho- or para-position were compatible with this reaction and could be selectively difluoromethylated at the meta-position with moderate to good yields. In addition, a wide range of difluoroacetic acids also reacted smoothly to afford the corresponding meta-C–H difluoromethylated products.

A reasonable migratory insertion mechanism shown in Fig. 7 was proposed for the meta-C–H functionalization. Initially, the coordination of Pd(II) with the nitrogen atom of 2-arylpyridine produces the Pd(II) complex A, followed by oxidative addition with the aryl difluoromethylene radical B generated from α,α-difluoroarylacetic acids in the presence of (NH₄)₂S₂O₈ to generate the difluoromethylated Pd(III) intermediate C. Subsequently, the intermediate C undergoes a more favorable migratory insertion than the ortho-C–H activation, affording the dearomatized species D. The difluoromethyl group is installed at the meta-position by an intramolecular nucleophilic rearrangement to give intermediate E, which further undergoes sequential deprotonation and rearomatization to afford the desired meta-C–H difluoromethylated products, along with the regeneration of the active Pd(II) catalyst to complete the catalytic cycle.

After that, the same group reported the efficient silver-catalyzed decarboxylative difluoromethylation of electron-deficient N-heteroarenes with α,α-difluoroarylacetic acids (Scheme 10).²⁹ A wide range of N-heteroarenes were suitable for the reaction, such as pyrazines, pyridine, quinoxaline, quinoline, and phenanthridine. In addition, this protocol provided a cost-effective and straightforward route to difluoromethylated heteroarenes in moderate to excellent yields with good selectivities. More importantly, the application of this methodology to the late-stage C–H difluoromethylation of bioactive heteroarenes would be of significant value.

In the mechanism shown in Fig. 8, initially, Ag(I) is oxidized by the persulfate to generate the Ag(II) species. A single-electron transfer process between the Ag(II) species and difluoroacetic acids takes place to produce the corresponding nucleophilic aryldifluoromethyl radical A, along with the release of CO₂. Subsequently, the addition of radical A into the protonated 2,5-dimethylpyrazine B gives a cyclohexadienyl-type radical cation C, which undergoes a deprotonation process to afford the radical intermediate D. Finally, further oxidation with the sulphate radical anion through a second single electron transfer process and then rearomatiztion occurs to deliver the difluoromethylated products.

N-Oxide compounds are very important intermediates in synthetic organic chemistry and in the chemical industry. The chemistry and applications of N-oxide compounds have received much attention due to their synthetic usefulness and biological importance. We have systematically summarized the transition metal-catalyzed functionalization of N-oxides via C–H activation.³⁰

More recently, Wang and co-workers developed a simple method for the C2-gem-aryldifluoromethylation of quinoline N-oxides with gem-difluoroacetates in the presence of potassium persulfate (Scheme 11).³¹ This reaction exhibited broad scope of substrates, good functional group compatibility, mild reaction conditions and high regioselectivity.

Their preliminary studies of the mechanism suggest that this reaction is likely to proceed through a radical pathway, as shown in Fig. 9. In the presence of potassium persulfate, α,α-difluoroarylacetate undergoes a decarboxylation process to generate a radical intermediate A, along with the release of carbon dioxide. Subsequently, the radical intermediate A attacks the C2-position of quinoline N-oxide selectively to give the radical intermediate B. A single-electron transfer further takes place to form the intermediate nitrogen cation C. Finally, the deprotonation delivers the desired oxidative coupling products.

Quinoxalin-2(1H)-ones represent a vital class of heterocyclic units, which are extensively utilized in synthetic chemistry, materials, natural products and pharmaceuticals.³² Recently, we systematically summarized the direct C3–H functionalization of quinoxalin-2(1H)-ones, such as arylation, alkylation, acylation, amination, amidation alkoxycarbonylation and phosphonation.³³ Because the skeleton has a wide range of biological activities, the structural modification of quinoxalin-2(1H)-ones has become a hot research topic and numerous related reports have been published in succession.

In 2019, Zhang and co-workers reported the decarboxylative radical coupling reaction of quinoxalin-2(1H)-ones with α,α-difluoroarylacetic acids under transition metal-free conditions (Scheme 12).³⁴ The reaction exhibited excellent functional group tolerability, a broader scope of substrates and mild reaction conditions. In addition, this protocol provided an attractive route to synthesize a series of difluoroarylmethylated quinoxalin-2(1H)-ones in moderate to good yields. After that, Wang and co-workers developed the visible light-induced decarboxylative C3-difluoroarylmethylation of quinoxalin-2(1H)-ones in water at room temperature.³⁵ Compared with Zhang's work,³⁴ this reaction is the more efficient, green and environment-friendly synthetic strategy for this purpose.

A plausible mechanism is proposed in Fig. 10. Initially, α,α-difluorophenylacetic acid in the presence of (NH₄)₂S₂O₈ undergoes a decarboxylation process to generate a radical intermediate A, along with the release of carbon dioxide. Subsequently, the radical addition at the C3-position of quinoxalin-2(1H)-ones selectively occurs to give the nitrogen-centered radical B, followed by a single-electron transfer to afford the intermediate nitrogen cation C. Finally, the deprotonation delivers the desired products.

Coumarin and its derivatives are naturally occurring molecules with a versatile range of biological activities. Their functionalization, particularly, the introduction of various functional groups at the C3-position of coumarin has been extensively investigated.³⁶ In 2020, Chen and co-workers reported the Fe(III)-catalyzed oxidative decarboxylative radical coupling reaction of α,α-difluoroarylacetic acids with coumarins (Scheme 13).³⁷ This catalytic system exhibited a broad substrate scope with respect to both the coupling partners. In addition, a wide range of functional groups could be tolerated in the reaction. A variety of C3-position difluoroarylmethylated coumarins could be obtained in moderate to good yields. Furthermore, the utilization of an iron catalyst made this reaction more advantageous, compared with traditional decarboxylation coupling using expensive transition-metal (silver and palladium) catalysts. More importantly, this protocol provided a simple and practical route to synthesize C3-position difluoroarylmethylated coumarin derivatives from readily available starting materials.

In the mechanism shown in Fig. 11, initially, the difluoromethyl intermediate radical A is generated from α,α-difluorophenylacetic acid via a rapid decarboxylation process in the presence of (NH₄)₂S₂O₈, accompanied by the release of carbon dioxide. Subsequently, the selective addition of radical A to the C3-position of coumarin gave radical B, followed by a single-electron transfer with the Fe(III) catalyst to give the intermediate carbon cation C, along with the formation of the Fe(II) species. Finally, the desired products can be obtained by deprotonation in the presence of DBU. Meanwhile, the Fe(II) species is oxidized by persulfate to generate the Fe(III) cation, completing the catalytic cycle.

2.5 Homocoupling reaction

Transition metal-catalyzed carbon–carbon bond formation is one of the most powerful methods in organic synthetic chemistry. Among these, homocoupling reaction is an important and efficient method for the synthesis of symmetric compounds. Recently, Hao and co-workers reported the Ag-catalyzed decarboxylative homocoupling reaction for the construction of tetrafluoroethylene-bridging aromatic compounds via radical dimerization under mild conditions (Scheme 14).³⁸ Although the reaction gave only moderate yields, this protocol provided a valuable and effective method for the synthesis of symmetric dimers linked by a tetrafluoroethylene-bridge from stable, inexpensive and readily available aryl difluorocarboxylic acids with only innocuous carbon dioxide as a by-product.

In the mechanism shown in Fig. 12, initially, the active Ag(II) species is generated by the oxidation of the Ag(I) salt with persulfate. Subsequently, α,α-difluoroarylacetic acids undergo a single-electron oxidative decarboxylation with the active Ag(II) species to afford the difluoromethyl radical A, along with the regeneration of the Ag(I) species. Finally, radical termination occurs via homocoupling of two difluoromethyl radicals to give the desired dimers containing a CF₂–CF₂ bridge.

3 Formation of carbon–heteroatom bonds

3.1 Fluorination

The formation of carbon–fluorine bonds is becoming increasingly important in the synthesis of fine chemicals and pharmaceuticals. Great progress has been made in the transition metal-catalyzed methods for the fluorination of organic molecules. Among these, the decarboxylative fluorination of carboxylic acids has been developed as an effective method to construct the C–F bond.³⁹

In 2013, Gouverneur and co-workers reported the Ag(I)-catalyzed decarboxylative fluorination of α,α-difluoroarylacetic acids with Selectfluor as a fluorination reagent for the synthesis of trifluoromethylarenes (Scheme 15).⁴⁰ This novel protocol provided a simple and practical route to trifluoromethylated compounds, which was distinguished from the classical methods relying on trifluoromethylating reagents. In addition, a wide range of functional groups could be tolerated and various trifluoromethylarenes were obtained in moderate to good yields. More importantly, the application of this operationally simple methodology to the late-stage fluorination of biologically active molecules would be of significant value.

3.2 Formation of C–O bonds

The formation of C–O bonds is the most fundamental chemical transformation in organic synthesis. In the past decades, the transition-metal-catalyzed oxidative dehydrogenative cross-coupling strategy has advanced the construction of C–O bonds.⁴¹ More recently, the photo- and electrochemical technology serves as an important complement for this purpose.⁴²

In 2019, Baran and co-workers reported a novel and efficient method for the synthesis of hindered ethers from simple carboxylic acids with various alcohols by electrochemical oxidation.⁴³ The reaction exhibited a broad substrate scope with respect to both the coupling partners and excellent functional group tolerance. In particular, α,α-difluoroarylacetic acids were also compatible with this transformation, and could react not only with simple alcohols, but also with carboxylates to afford the corresponding hindered ethers and esters, respectively (Scheme 16).

For the mechanism shown in Fig. 13, it was speculated that the rate-limiting oxidation of a carboxylate on the anode could be involved in the reaction to generate a carbocation, followed by the nucleophilic attack by an alcohol or acid to afford the ether and ester products. Notably, it was found that the carbocations could also be intercepted by other simple nucleophiles, such as hydroxyl and fluoride ions, leading to the formation of hindered alcohols and even alkyl fluoride.

3.3 Formation of C–S bonds

Sulphur-containing organic molecules have found widespread applications in organic chemistry, natural products, pharmaceuticals and functional materials. In the past decades, there has been an increasing demand for organosulphur compounds with the transition metal-catalyzed construction of C–S bonds, which is of great importance in the synthesis of biologically active molecules and functional materials.⁴⁴

In 2020, Sanford and co-workers reported the nickel-catalyzed decarbonylative coupling reaction of fluoroalkyl carboxylic acids, in which fluoroalkyl thioesters could be transferred into analogous thioethers by decarbonylation.⁴⁵ A variety of stable, inexpensive and readily available fluoroalkyl carboxylic acids serve as the fluoroalkyl source in this transformation. For instance, the decarbonylative reaction of α,α-difluoroarylacetic acids could provide the corresponding fluorinated thioether with 57% yield, which is difficult to synthesize by the existing methods (Scheme 17).

A plausible mechanism was proposed for the decarbonylation in Fig. 14. Initially, the oxidative addition of fluoroalkyl thioester with a Ni(0) catalyst occurs to form the acyl-Ni(II) intermediate Avia the cleavage of C–S bonds, followed by the carbonyl deinsertion to give the Ni(II) species B. Finally, the Ni(II) species B undergoes reductive elimination to deliver the desired fluoroalkyl thioether products, along with the regeneration of the Ni(0) catalyst to complete the catalytic cycle.

4 Conclusions and perspectives

To summarize, we have presented an overview on the decarboxylative functionalization of α,α-difluoroarylacetic acids, mainly including alkylation, allylation, alkynylation, arylation, fluorination, the formation of carbon–heteroatom bonds, etc. Gathering mechanistic insights could help us understand the nature of these reactions, in which the decarboxylation was mainly promoted by silver salts and persulfate. Although great progress has been made in this field, these reactions still suffer from some limitations of substrates. For example, the substrates involved in such reactions are mainly confined to special alkenes, alkynes and heterocyclic compounds.

To overcome these central challenges, it is more important to extend the substrate scope of the existing methodologies, such as nonreactive alkenes, internal or terminal alkynes, and simple aromatics. In addition, the substrates containing nitrogen and phosphorus should be expanded to construct carbon–nitrogen and carbon–phosphorus bonds. Furthermore, the novel reaction types of α,α-difluoroarylacetic acids will be explored for the synthesis of fluorinated compounds. Finally, with the increasing demands for green and sustainable chemistry, an increasing need for new methodologies will continue to drive this field forwards. As a consequence, new exciting and innovative achievements are expected to appear in the near future.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the Project Sponsored of Advanced Talents by Zhejiang A&F University (no. 04251700031) for financial support.

Notes and references

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Footnote

† These authors contributed equally.

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