Trifluoromethoxylation/trifluoromethylthiolation/trifluoro-methylselenolation strategy for the construction of heterocycles

Trifluoromethoxylation/trifluoromethylthiolation/trifluoro-methylselenolation strategy for the construction of heterocycles

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Xin Wang^a^,¹, Zhichuan Wang^a^,¹, Zhenjian Li^b, Kai Sun^*^,^a

Chinese Chemical Letters | 2023, 34(5) : 108045

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Chinese Chemical Letters | 2023, 34(5): 108045

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Trifluoromethoxylation/trifluoromethylthiolation/trifluoro-methylselenolation strategy for the construction of heterocycles

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Xin Wang^a^,¹, Zhichuan Wang^a^,¹, Zhenjian Li^b, Kai Sun^*^,^a

Affiliations

^a College of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China

^b State Key Laboratory of Tree Genetics and Breeding, Research Institute of Forestry, Chinese Academy of Forestry, Beijing 100091, China

Xin Wang was born in Heilongjiang, China and received her MS degree from Northeast Normal University in 2012. In July 2013, she joined the College of Chemistry and Chemical Engineering, Anyang Normal University. In 2019, she pursued her Ph.D. degree in Zhengzhou University. Her research program is drug design, structural identification and structural modification of natural products

Zhichuan Wang was born in Jiangsu, China in 1997. In 2015, he began his studies at the School of Pharmacy, Jilin Medical University. In 2020, he pursued his MS degree in YanTai University under the direction of associate professor Kai Sun. His current research is focused on radical CH functionalization

Zhenjian Li, Doctor, Forestry Research Institute, China Academy of Forestry, Associate researcher, Master's supervisor. He mainly engage in the research on the components and functions of medicinal Dendrobium; Collection and development of ornamental and medicinal Dendrobium germplasm resources

Kai Sun was born in Shanxi, China in 1983. He received his Ph.D. degree in organic chemistry from Northeast Normal University in 2013 under the supervision of Prof. Qian Zhang. In July 2020, he joined the College of Chemistry and Chemical Engineering, YanTai University, where he is an professor. His current research is focused on CH functionalization, radical chemistry and organic selenium chemistry

Published: 2023-05-15 doi: 10.1016/j.cclet.2022.108045

Outline

Abstract

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The XCF₃ groups (X = O, S, Se) play an increasingly important role in modern organic chemistry due to their unique electronegativity, lipophilic nature, metabolic stability, and bioavailability. Heterocyclic compounds are important scaffolds in many bioactive compounds and drugs. The incorporation of XCF₃ groups into heterocyclic compounds can change their physicochemical and biological properties, which injects new vitality into the application of heterocyclic compounds in many fields such as organic chemistry, the pharmaceutical chemistry, and life sciences. In this paper, the recent progress in the synthesis of F₃CX-containing heterocycles is reviewed, and the application scope and mechanism of some reactions are discussed.

Key words

Trifluoromethoxylation / Trifluoromethylthiolation / Trifluoromethylselenolation / Cyclization

Cite this Article

Xin Wang, Zhichuan Wang, Zhenjian Li, Kai Sun. Trifluoromethoxylation/trifluoromethylthiolation/trifluoro-methylselenolation strategy for the construction of heterocycles[J]. Chinese Chemical Letters, 2023 , 34 (5) : 108045 - . DOI: 10.1016/j.cclet.2022.108045

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1 Introduction

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Trifluoromethyl compounds play an important role in organic chemistry, the pharmaceutical chemistry, materials science, and many other fields [1-9], prompting organic chemists to connect heteroatoms (such as O, S, Se) with trifluoromethyl compounds to obtain new biological activities. The trifluoromethoxy-, trifluoromethylthio- and trifluoromethylseleno-groups have excellent electron-absorbing capacity (Hammett constants of OCF₃: σ_P = 0.35, σ_m = 0.38; Hammett constant of SCF₃: σ_P = 0.50 and σ_m = 0.40; Hammett constant of SeCF₃: σ_P = 0.44 and σ_m = 0.45), valuable lipophilicity (Hansch-Leo parameter of OCF₃: π_R = 1.04; Hansch-Leo parameter of SCF₃: π_R = 1.44; Hansch-Leo parameter of SeCF₃: π_R = 1.29), bioavailability, and metabolic stability [10-12]. In addition, oxygen, sulfur and selenium, as typical nonmetallic elements in the oxygen group, display little difference in structure and electronic properties, allowing the isostructural substitution of oxygen, sulfur and selenium atoms in drug molecules, and recognition by biological targets. However, the differences are sufficiently large to alter other properties and obtain a variety of biological activities. This has broad prospects in the field of medicinal chemistry and has further stimulated chemists' interest in introducing XCF₃ groups.

Heterocyclic compounds are the key scaffolds in many natural products, organic materials, agrochemicals, and pharmaceuticals [13-18]. Oxygen-containing and nitrogen-containing heterocyclic compounds accounted for 52% of the top 200 brand name drugs by retail sales in 2021 [19]. Therefore, the importance of building heterocyclic compounds is self-evident. By introducing trifluoromethoxy-, trifluoromethylthio-, and trifluoromethylseleno-groups into heterocyclic compounds, the physical and chemical properties of the compounds can be fine-adjusted, including the selectivity, stability, lipophilicity, and membrane permeability. In addition, the novelty of trifluoromethoxylated, trifluoromethylthiolated, and trifluoromethylselenolated heterocyclic compounds has prompted organic chemists to develop multifunctional and practical preparation methods. The rapid development of this field is largely due to the development of trifluoromethoxylation, trifluoromethylthiolation, and trifluoromethylselenolation reagents, including nucleophilic, electrophilic, and radical types [20-23].

In recent years, although reviews on trifluoromethoxylation, trifluoromethylthiolation, and trifluoromethylselenolation reactions have been published [24-34], systematic reviews exclusively on the synthesis of trifluoromethoxylated, trifluoromethylthiolated, and trifluoromethylselenolated heterocyclic compounds have not been reported. There are two main strategies to synthesize F₃CX-containing heterocyclic compounds, one of which is to activate the C–H bond of heterocyclic compounds under the external action of metal or non-metal catalysts and directly introduce the XCF₃ group. This method not only avoids the use of prefunctional groups or preactivated reaction substrates, resulting in the waste of resources, but also improves the economic efficiency of atomic use, reduces waste emissions, and adheres to the concept of "green chemistry". The second strategy is through the difunctionalization cyclization strategy of alkenes and alkynes to build F₃CX-group heterocyclic compounds, which allows the unstable intermediates involved in the reaction, and plays an important role in the process of building polyheterocycle and heteroatom-rich heterocyclic compounds. This paper reviews the recent progress in the synthesis of trifluoromethoxylated, trifluoromethylthiolated, and trifluoromethylselenolated heterocyclic compounds mainly published in the past 10 years. The direct C–H trifluoromethoxylation, trifluoromethylthiolation, and trifluoromethylselenolation of heterocycles, and the synthesis of trifluoromethoxylated, trifluoromethylthiolated, and trifluoromethylselenolated heterocyclic compounds by the difunctionalization cyclization of alkenes and alkynes are reviewed. In addition, the scope, limitation, and mechanism of the reaction are discussed.

2 Synthesis of trifluoromethylthiolated heterocycles

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Due to its unique lipophilicity and bioavailability, the trifluoromethylthiol group is widely found in bioactive drugs such as Toltrazuril, Baycox, Zolvix, and has attracted increased attention. The development of trifluoromethylthiolation reagents and new synthetic methods has invigorated the construction of trifluoromethylated heterocycles, which is the fastest growing platform compared with trifluoromethoxylated heterocycles and trifluoromethylselenated heterocycles. Therefore, we will first discuss the construction of trifluoromethylated heterocycle compounds from two aspects.

2.1 Direct C–H trifluoromethylthiolation of heterocycles

In 2013, Yang's group [35] reported a copper-catalyzed trifluoromethylthiolation of indoles with trifluoromethanesulfonyl hypervalent iodonium ylide as an SCF₃ source (Scheme 1). Trifluoromethanesulfonyl hypervalent iodonium ylide has a low cost and stable performance, and is reduced to active SCF₃ species by intramolecular rearrangement.

In 2015, Wang's group [36] developed the selective trifluoromethylthiolation of a variety of electron-rich arenes and olefins using N-trifluoromethylthio saccharin as a highly electrophilic trifluoromethylthiolating reagent in the presence of a Lewis acid catalyst such as Fe(Ⅲ) or Au(Ⅲ) (Scheme 2). N-Protected indoles and unprotected indoles all have good yield and functional group tolerance. In the same year, Li's group [37] also reported an Rh(Ⅲ)-catalyzed electrophilic C-2 trifluoromethylthiolation of indoles with N-trifluoromethylthiosaccharin as an electrophilic SCF₃ reagent (Scheme 3). It is noteworthy that the reaction occurred exclusively at the 3-position, when 1-phenyl-1H-indole was used as a substrate under standard conditions.

In 2015, Huang's group [38] reported a copper-catalyzed trifluoromethylthiolation of pyrroles with trifluoromethanesulfonyl hypervalent iodonium ylide as the SCF₃ source (Scheme 4). The reaction features mild reaction conditions, high reaction yields, and excellent functional group compatibility. Of note, 2,2′-dipyrromethane, which is the precursor of porphyrins, can be successfully converted into trifluoromethylthiolated products 11. When 4 equiv. of trifluoromethanesulfonyl hypervalent iodonium ylide is used, the yield of the product can reach 70%. When the ortho- positions of "N" are replaced by methyl, the 3-SCF₃ product can be obtained. The possible reaction mechanism was suggested by the results of control experiments and electrospray ionization (ESI)-mass spectral detection of the intermediates. First, trifluoromethanesulfonyl hypervalent iodonium ylide 2 is converted to carbene 15, which is balanced with oxathiirene 16, under the catalysis of copper. Next, oxathiirene 16 rearranges to obtain sulfoxide 17, to give the active intermediate, thioperoxoate 18, by intramolecular nucleophilic collapse. Finally, thioperoxoate 18 reacts with the nucleophile (Nu), and the desired product Nu-SCF₃ 20 is obtained through the transfer of the trifluoromethylthio group. Thioperoxoate 18 can also give CF₃SSCF₃ 19 in the absence of a nucleophile.

In 2016, Chachignon et al. [39] reported a metal-free C-3 trifluoromethylthiolation of indoles with CF₃SO₂Cl as the source of electrophilic SCF₃ and a phosphine as the reducing agent (Scheme 5). Notably, CF₃SO₂Cl is readily available compared with sophisticated SCF₃ reagents which are difficult to use on a larger scale. The possible reaction mechanism was suggested by nuclear magnetic resonance (NMR) analysis of the reaction mixture. Initially, the S–Cl bond in CF₃SO₂Cl is broken, which is triggered by the halogen bond between the positive electrostatic potential outside the chlorine atom in CF₃SO₂Cl 21 and the lone pair of electrons on the phosphorus atom in PMe₃ 22. The resulting chlorophosphonium sulfinate 25 is converted into CF₃SOCl 26 and OPMe₃ 27. Next, the S–Cl bond in CF₃SOCl 26 is broken, which is triggered by the halogen bond between the positive electrostatic potential outside the chlorine atom in CF₃SOCl 26 and the lone pair of electrons on the phosphorus atom in PMe₃ 22. The resulting product 29 is converted into the OPMe₃ 27, and the active intermediate product CF₃SCl 30. Finally, CF₃SCl 30 reacts with indole 31 to give the direct trifluoromethylthiolation product 33.

In 2017, Bu et al. [40] reported an electrophilic trifluoromethylthiolation of indoles and pyrroles with CF₃SO₂Na as the trifluoromethylthiolating reagent at room temperature (Scheme 6). The reaction conditions tolerate a range of functional groups, and indoles carrying electron-donating groups generally obtain higher yields than those with electron-withdrawing groups. However, the C-3 functionalized indole only gave trace C-2 SCF₃ product.

In 2018, Liu and coworkers [41] reported the trifluoromethylthiolation-based vicinal bifunctionalization of indoles using sodium trifluoromethanesulfinate as cheap and easily available reagents in the presence of phosphorus oxychloride or phosphorus oxybromide (Scheme 7). In addition, this protocol has been extended to sodium perfluoroalkane sulfinates (R_fSO₂Na), such as ClCF₂CF₂SO₂Na, n-C₄F₉SO₂Na, and n-C₆F₁₃SO₂Na, to give the corresponding products in moderate yields.

In 2018, Guo et al. [42] reported CuCl-catalyzed C-3 trifluoromethylthiolation of indoles in moderate to good yields with TfNHNHBoc as a SCF₃ source in the presence of dimethyl sulfoxide (Scheme 8). The reaction tolerated a variety of functional groups such as alkoxy-, hydroxyl–, fluoro-, chloro–, bromo– and ester-. However, the C-2 SCF₃ product was not obtained when the C-3 position of the indole ring was occupied by a substituent. Initially, TfNHNHBoc 37 is decomposed by heat to obtain CF₃SSCF₃ 20, which then reacts with CuCl to form the copper(Ⅲ) species 39. Next, this is attacked by indole 34 to form a copper(Ⅲ) species 40. Finally, the copper(Ⅲ) species 40 is reduced to produce the desired trifluoromethylthiolation product 38 and CuSCF₃. Anion exchange between CuSCF₃ and HCl releases CF₃SH and regenerates CuCl to continue the catalytic cycle. CF₃SH is oxidized by dimethyl sulfoxide (DMSO) to give CF₃SSCF₃.

In 2018, Jiang and coworkers [43] reported the C–H trifluoromethylthiolation of indoles and thiophenes using CF₃SOCl as the trifluoromethylthiolating reagent in the absence of a catalyst and reductant, and the C–H trifluoromethylthiolation of benzothiophenes and benzofurans in the presence of an Ag₂CO₃ catalyst (Scheme 9). Control experiments and the literature showed that the reaction mechanism is different from the previously reported methods using CF₃SO₂-based reagents such as CF₃SO₂Na and CF₃SO₂Cl. Path 1: CF₃SOCl 26 reacts with indole 31 to give the trifluoromethylsulfoxylated compound 45, which is reduced with CF₃SOCl to give the desired product 33. Path 2: CF₃SOCl 26 is decomposed into CF₃SO₂Cl 21 and CF₃SCl 30. CF₃SCl 30 reacts with indole 31 to give the desired product 33.

2.2 Cyclization of alkenes/alkynes to synthesize F₃CS-containing heterocycles

In 2014, Yin and Wang [44] developed the first silver-mediated radical aryltrifluoromethylthiolation of activated alkenes for the synthesis of trifluoromethylthiole-containing oxindoles (Scheme 10). The reaction features high functional group compatibility, including electron-donating groups (OMe and Me) and electron-withdrawing groups (CF₃, F, Cl, Br, I, CO₂Et, Ac and NO₂).

In 2014, Zhu et al. [45] reported the synthesis of trifluoromethylthiole-containing isoxazolines from unactivated alkenes and AgSCF₃ in the presence of the Cu(OAc)₂ catalyst (Scheme 11). The notable features of these reactions include moderate to good yields, high functional group compatibility, and the absence of other oxidants. It is noteworthy that the product can be synthesized in one step into a high-function Csp³-SCF₃-containing building block in 87% yield, which demonstrates the high potent application of this process.

In 2015, Fuentes and coworkers [46] reported a one-pot synthesis of F₃CS-containing indolo[2,1-a]isoquinolin-6(5H)-ones using N-[(2-ethynyl)arylsulfonyl]acrylamides reaction with AgSCF₃ (Scheme 12). The presence of electron-withdrawing substituents (fluorine, trifluoromethyl, methylcarboxylate) improves the efficiency of the reaction. This reaction pathway involves radical addition, 1,4-aryl migration, 5-endo-trig cyclization, and rearomatization. Initially, AgSCF₃ is oxidized by K₂S₂O₈ and generates the Ag(Ⅱ) cation and SCF₃ radical. The SCF₃ radical then attacks the alkenyl moiety in the N-acrylamide substrate 55 to give a radical intermediate 56. Next, the intermediate 56 is obtained by ipso-cyclization on Csp²−SO₂ atoms. After the rearomatization of intermediate 57, SO₂ is removed to obtain the radical intermediate 58 with 1,4-migration of the aryl sulfonyl group. The presence of adjacent alkyne groups in the substrate causes acyl radical cyclization to form a new vinyl radical intermediate 60. Finally, intermediate 61 is obtained by 5-endo-trig cyclization of the vinyl radical intermediate 60, and then rearomatized to give the desired product 62.

In 2016, Jin's group [47] reported the first synthesis of 3-trifluoromethylthiospiro[4,5]trienones using a series of substituted N-arylpropiolamides in reaction with AgSCF₃ (Scheme 13). The reaction features good yield and high functional group compatibility. However, the use of AgSCF₃ (1.5 equiv.) is not environmentally acceptable.

In 2016, Liu and coworkers [48] developed a new chiral bifunctional sulfide catalyst and a new shelf-stable electrophilic SCF₃ reagent, which are efficient in the enantioselective trifluoromethylthiolation of alkenes to synthesize trifluoromethylthiolated furan derivatives (Scheme 14). The reaction has moderate to good yields, enantioselectivities, and excellent diastereoselectivities (> 99:1 dr). The authors propose a possible reaction mechanism. First, 67 is converted to salt 69 in the presence of trifluoromethanesulfonic acid (TfOH). Next, the SCF₃ reagent reacts with 69 to produce (PhSO₂)₂NH and species 70. Species 70 reacts with enocarboxylic acid 71 to form the intermediate 72 by creating a trifluoromethylthiazide ion and hydrogen bond. Finally, the oxygen of the carbonyl group attacks the iridium ions to give the trifluoromethylthiolated furans 73 and compound 69.

A new, bifunctional, chiral selenide catalyst was developed by Luo et al. [49] in 2017, which is efficient in the synthesis of F₃CS-containing chiral azaheterocycles using an Ns-protected olefinic sulfonamide reaction with (PhSO₂)₂NSCF₃ (Scheme 15). The reaction has good yield and excellent enantiomeric excess (ee) when substrates are (E)-alkenes, except sterically hindered 2-methylphenyl alkene which has poor ee relative to other alkenes. However, when the (Z)-alkene is utilized, there is no reaction because of the reactivity of the alkene or steric hindrance in the alkene.

In 2017, Pan et al. [50] reported the copper-assisted oxidative trifluoromethylthiolation of 2,3-allenoic acids with AgSCF₃ in the presence of (NH₄)₂S₂O₈ for the synthesis of trifluoromethylthiolated furan derivatives (Scheme 16). The reaction has moderate to good yields and a wide range of substrates. However, when 2-monosubstituted buta-2,3-dienoic acid (R¹ = R² = H) is utilized, only a trace of the desired products is obtained, which is replaced by a bis-trifluoromethylthiolated product.

In 2017, Dagousset et al. [51] reported the photocatalytic trifluoromethylthiolation of acrylamides with N-trifluoromethylthiosaccharin for the synthesis of F₃CS-containing oxindoles and isoquinolinediones (Scheme 17). Of note, when estrone-derived acrylamide is utilized, the desired product is obtained, showing that this method is applicable to the late-stage functionalization of complex molecules.

In 2022, Ren et al. [52] reported the synthesis of SCF₃-substituted dibenzazepines or dioxodibenzothiazepines through the cascade cyclization of N-benzyl-N-(2-ethynylaryl)amides (or N-(2-ethynylphenyl)-N-alkylbenzenesulfonamides) with AgSCF₃ (Scheme 18). This method is applicable to various electron-donating or electron-withdrawing groups substituted on the N-benzyl moiety of the amides, such as methyl, methoxy, trifluoromethyl, cyano, nitro and ester. Notably, the gram-scale production, late-stage modifications of the product further demonstrated the synthetic value of this reaction system. The yield of product decreased significantly after adding a free radical inhibitor such as 2,6-dibutyl-4-methylphenol (BHT) or 1,1-stilbene to the reaction system, which indicated that the reaction involves a free radical pathway. First, AgSCF₃ is oxidized by Na₂S₂O₈ to generate an SCF₃ radical. Then the addition of the SCF₃ radical to the alkynyl bond of 83 leads to the formation of the corresponding vinyl radical 84, which attacks the adjacent aromatic ring and produces intermediate 85. The intermediate 85 is further transformed into an aryl anion radical 86 after deprotonation. Finally, the desired product 87 is obtained through a one-electron oxidation process.

In 2022, Chen et al. [53] achieved a new access to F₃CS-containing dioxodibenzothiazepines by the Cu-assisted trifluoromethylthiolation and radical cascade cyclization of alkynes with AgSCF₃ (Scheme 19). The electron-donating (-Me, -OMe, -^tBu) or electron-withdrawing (-COOMe, -CN, -CF₃) groups substituted on the arylalkyne ring could react well with AgSCF₃ under typical conditions, and a variety of N-protected groups can be used in this transformation, such as -ⁱPr, -Bn, -Bz and -Boc. Notably, substrates with ortho-halogens (-F, -Cl, -Br) substituted on the arylalkyne ring exhibit better reactivity than substrates substituted with meta-halogens.

In 2022, a convenient protocol for the cascade cyclization of N-aryl-3-butenamides with AgSCF₃ was developed by Li and coworkers [54], which offers an efficient pathway for the construction of valuable F₃CS-substituted 3,4-dihydroquinolin-2-ones and azaspiro[4,5]dienones under different reaction conditions (Scheme 20). In the synthesis of azaspiro[4,5]dienones, various ortho- and meta-substituents such as CH₃, F, Cl, and Br are tolerated well in this method, but the yield of substrates with strong electron-withdrawing CF₃ substituents is lower. It is worth noting that the substituents are lost and the same product 96 is produced in similar yields under the same conditions when F, Cl, Br, OMe, and NO₂ are the para-substituents. In addition, when the substrate has a meta-substituent (-F, -Cl, -Br), the reaction for the synthesis of 3,4-dihydroquinolin-2-ones produces a mixture of two regioisomers (C2 and C6). Neither 90 nor 91 was formed after adding a free radical inhibitor such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT) to the reaction system, which indicates that the reaction system might proceed in a free radical way. First, AgSCF₃ is oxidized by K₂S₂O₈ to generate an SCF₃ radical. Subsequently, the alkyl radical species 93 is produced via the SCF₃ radical attacking the double bond of the substrate 92. Then, the vinyl radical 93 generates a spirocyclic intermediate 94 by ipso-addition 5-exo-type cyclization, or the fused cyclic ring intermediate 97 by ortho-addition 6-endo-type cyclization. In the presence of TBHP, intermediate 94 could be captured by the t-butylperoxy radical formed by the interaction of TBHP with the t-butyl radical, resulting in intermediate 95, which is further transformed into the desired product azaspiro[4,5]dienone 96 through the release of ^tBuOH. While intermediate 97 could also transformed into the cationic intermediate 98 by Ag²⁺ oxidation. Finally, the intermediate 98 is deprotonated to give the 3,4-dihydroquinone-2-one product 99.

3 Synthesis of trifluoromethylthiolated heterocycles

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The trifluoromethoxy group displays strong electron absorption and high lipophilicity, which plays an important role in the fields of medicine and pesticides, such as riluzole, flucarbazone-sodium for example. Due to the development of new trifluoromethoxylation reagents, which can be divided into free radical and nucleophilic types (Fig. 1) [23], more convenient and practical new synthetic strategies have emerged. In particular, the strategy of interacting hydroxyl groups with trifluoromethylating reagents to construct OCF₃ bonds eliminates the dependence on trifluoromethylated reagents, as discussed below.

3.1 Direct C–H trifluoromethoxylation of heterocycles

In 2018, Zheng and coworkers [55] reported a radical photocatalytic trifluoromethoxylation of (hetero)arenes (Scheme 21). The protocol uses redox-active cationic reagents, which enables the formation of the OCF₃ radical in a controllable and selective manner under visible-light photocatalytic conditions. These reactions have a wide range of substrates include mono-, di-, and tri-substituted (hetero)arenes, and good functional group tolerance, including a variety of electron-donating and electron-withdrawing substituents. It is noteworthy that diacetonefructose and l-menthol derivatives can afford the desired F₃CO-containing products in modest yields. Experimental and computational studies suggest this process involves radical mechanisms. Initially, Ru(bpy)₃²⁺ produces the triplet-excited state of *Ru(bpy)₃²⁺ under blue light-emitting diodes (LEDs). *Ru(bpy)₃²⁺ reacts with the redox-active cationic reagent to form Ru(bpy)₃³⁺, 104, and the OCF₃ radical. Next, the addition of OCF₃ radical to arene 105 forms cyclohexadienyl radicals 106. Finally, the cyclohexadienyl radical 106 is oxidized by Ru(bpy)₃³⁺ to afford the cyclohexadienyl cation 107, which is deprotonated to give the desired F₃CO-containing products 108.

In 2020, Deng's group [56] reported the silver-mediated C–H trifluoromethoxylation of (hetero)arenes (Scheme 22). It is noteworthy that silver salts afford exclusive ortho-position selective C–H trifluoromethoxylation of pyridines, while the method is also applied to the trifluoromethoxylation of natural products or drugs, such as etoricoxib and rosuvastatin, for example. The notable features of these reactions include their mild reaction conditions and excellent functional group tolerance. In addition, the reaction is applicable to the gram-scale synthesis of trifluoromethoxylated products, which demonstrates the practicality of this reaction.

3.2 Cyclization of alkenes/alkynes to synthesize F₃CO–containing heterocycles

In 2015, Chen et al. [57] reported the synthesis of 3-OCF₃-substituted piperidines in moderate yields using an unactivated alkene reaction with AgOCF₃ in the presence of a Pd(CH₃CN)₂Cl₂ catalyst (Scheme 23). Substrates with different sulfonyl protecting groups on nitrogen show a good yield, while substrates with Ns-protecting group have a yield of only 30% and substrates with Bn-protecting group give no yield. In addition, diastereoselectivity is poor when the reaction products are 3,5-cis and 3,5-trans isomers. A study of the mechanism indicates that high-valent palladium plays an important role in this process. The Pd^Ⅳ−OCF₃ showed better stability, and is more easily eliminated than β-fluorination, and leads to the formation of the C−OCF₃ bond.

3.3 Synthesis of F₃CO–containing heteroarenes through O–CF₃ bond formation

In 2015, Liu's group [58] reported the silver-mediated O-trifluoromethylation of unprotected phenols by O–CF₃ bond formation using CF₃SiMe₃ as a CF₃ source in the presence of AgOTf (Tf = trifluoromethanesulfonyl), 2-fluoropyridine, Selectfluor^TM, N-fluorobenzenesulfonimide (NFSI), and CsF (Scheme 24). The notable features of the reactions include moderate to good yields, high selectivity, and excellent functional group tolerance, such as nitrile, nitro, sulfone, amide, and ether moieties. However, nitrogen-containing heteroaryl substrates such as pyridine, quinoline, and benzothiazole cannot be tolerated under the reaction conditions, possibly due to the competitive coordination between nitrogen atoms and the silver centers. Excitingly, this protocol has been extended to the O-trifluoromethylation of benzoyl ezetimibe, a plasma cholesterol lowering drug, in 65% yield. According to the results of ¹⁹F NMR spectroscopy of the reaction mixture, a possible reaction mechanism is proposed. First, Ag^ⅠOTf reacts with CF₃SiMe₃ and CsF to generate the Ag^ⅠCF₃ species 130. Next, the Ag^ⅠCF₃ species 130 undergoes oxidative addition with Selectfluor^TM and NFSI to form the [Ag^Ⅲ(CF₃)(F)] complex 131, which reacts with phenol to provide the key intermediate [Ag^Ⅲ(CF₃)(OPh)] 131 through the exchange of fluoride and phenoxide. Finally, the reduction elimination of the intermediate 132 forms the desired O–CF₃ bonds and provides the desired product 125.

In 2016, Feng's group [59] reported the synthesis of F₃CO-containing pyridines and pyrimidines through O–CF₃ bond formation (Scheme 25). This strategy uses N-acetyl/methoxycarbonyl-N-pyridinyl/pyrimidinylhydroxylaminein as substrates and Togni reagent as a CF₃ source and chloroform (CHCl₃) as solvent, and affords the desired product in moderate to good yields at room temperature for 15 h. Under the reaction conditions, many functional groups and heteroaryl substituents can be tolerated. Notably, estrone and Tadalafil-conjugated pyridines can also be trifluoromethoxylated to afford the desired products in good yields, which demonstrates high potent application in a late-stage trifluoromethoxylation. The reaction can be inhibited in the presence of BHT, which indicates a possible involvement of a radical pathway in the reaction process. First, the deprotonation of 138 forms the N–hydroxyl anion 139, which performs a single electron transfer (SET) with Togni reagent I to produce an N-hydroxyl radical 140, trifluoromethyl radical, and alkoxide 141. The N–hydroxyl radical 140 reacts with the trifluoromethyl radical to produce oxytrifluoromethylhydroxylamine 142. Nextly, the N–O bond of the intermediate 142 is thermally induced to break, forming an ion pair 143, which rapidly recombines to produce 144. Finally, the intermediate 144 is converted to the desired product 145 by proton migration.

In 2016, Liang et al. [60] reported the synthesis of ortho-N-heteroaromatic trifluoromethoxy derivatives in poor to good yields at 100 ℃ by site-specific O–CF₃ bond formation using ortho-hydroxy N-heterocycles as substrates, Togni's reagent as a CF₃ source, and CH₃NO₂ as solvent (Scheme 26). The reaction is affected by the substituent electron effect, and substrates containing electron-withdrawing groups generally have lower yields than substrates containing electron-donating groups. It is noteworthy that 330 g of 2–hydroxy-5-bromopyridine reacted with 200 g Togni's reagent in 6 L of CH₃NO₂ to give 84 g of the desired product (55% yield) and 152 g of 2–hydroxy-5-bromopyridine was recovered, which demonstrated the practicality of this reaction.

4 Synthesis of trifluoromethylselenolated heterocycles

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The selenotrifluoride group, which contains the important chemical elements, fluorine and selenium, also has good lipophilicity and potential biological activity. Chemists gradually realized that SeCF₃ is also a potential functional group similar to SCF₃. With the rapid development of organic fluorine and selenium chemistry [61-63], new trifluoromethylselenolation reagents (Fig. 2) [22,64] and synthetic strategies have emerged.

4.1 Direct C–H trifluoromethylselenolation of heterocycles

In 2018, Tlili, Billard and coworkers [65] reported the Pd-catalyzed trifluoromethylselenolation of 8-aminoquinoline with F₃CSeCl (Scheme 27). It is noteworthy that only C-5 trifluoromethylselenolations have been observed, with no other regioisomers being formed. The reaction has been extended to various amide and sulfonamide derivatives, as well as other fluoroalkyl groups including -CF₂CF₃, -CF₂H and -CF₂Br. First, the reaction begins with the formation of a complex 163 of 8-aminoquinoline amide 160 and lead acetate (Pd^ⅡL₂). Then, a new Pd^Ⅲ-complex 164 and a CF₃Se radical are provided by the SET process between the complex 163 and CF₃SeCl. Because of the intermolecular electron transfer between the ligand and metal, a Pd^Ⅲ-complex 164 forms the new cationic radical complex 165, which react with the CF₃Se radical to provide the cationic complex 166. Finally, the cationic complex 166 forms the desired product 162 and Pd^ⅡL₂ through a concerted proton transfer-demetallation.

In 2019, Zhao and coworkers [66] reported a practical and environmentally friendly strategy for the synthesis of 3-trifluoromethylthiolation products in moderate to excellent yields by employing TsSeCF₃ as a trifluoromethylselenolation reagent and FeCl₃ as an efficient activator (Scheme 28). The reaction tolerated indoles with both electron-donating and electron-withdrawing substituents.

The oxidative trifluoromethylselenolation of electron-rich (hetero)arenes by the nucleophilic [Me₄N][SeCF₃] reagent was developed by Han and coworkers in 2019 (Scheme 29) [67]. The reaction tolerated (hetero)arenes with both electron-donating and electron-withdrawing substituents, but longer reaction times were required to completely consume (hetero)arenes with electron-withdrawing substituents. This method features a wide range of substrates, good functional group tolerance, mild reaction conditions, and excellent regioselectivity. Based on the results of controlled experiments, the authors propose a possible mechanism. First, [Me₄N][SeCF₃] 169 is oxidized by an oxidant to provide an SeCF₃ radical 170, which can be further oxidized to provide ⁺SeCF₃ 172 or coupled to produce the CF₃SeSeCF₃ 171 byproduct. Next, indole 93 attacks ⁺SeCF₃ 172 to produce a cationic intermediate 173. Finally, the cationic intermediate 173 loses a proton to yield the desired product 175.

In 2020, Zordo-Banliat et al. [68] developed a new visible-light mediated aerobic C–H trifluoromethylselenolation of heteroarenes using the reagent [Me₄N][SeCF₃], which has been successfully applied to a wide range of indoles, azaindoles, and pyrroles bearing various functional groups (Scheme 30). This method was fully regioselective in favor of the 3-position, and it is noteworthy that no reaction took place in the case of 3-substituted indoles.

In 2021, Liu and coworkers [69] realized the TfOH-catalyzed selective trifluoromethylselenolation of benzofurans, as well as the FeCl₃-catalyzed intramolecular electrophilic ring-closure trifluoromethylselenolation of 1-methoxy-2-(arylethynyl)benzene derivatives by employing TsSeCF₃ as the electrophilic trifluoromethylselenolating reagent (Scheme 31). These methods feature mild reaction conditions as well as a stable and easily prepared trifluoromethylselenolating reagent. Based on relevant literature precedents, an electrophilic pathway was proposed. Regarding the TfOH-catalyzed selective trifluoromethylselenolation of benzofurans, TfOH promotes the nucleophilic attack of benzofuran 178 on TsSeCF₃, which is activated by TfOH, to produce the intermediate 180 and 4-methylbenzenesulfinic acid 179. Finally, the deprotonative aromatization of 180 provides the desired product 181. In terms of the FeCl₃-catalyzed cyclotrifluoromethylselenylation of 1-methoxy-2-(arylethynyl)benzene derivatives, the decomposition of TsSeCF₃ catalyzed by FeCl₃ gives an SeCF₃ cation, which is attacked by a triple bond moiety of alkyne 182 to form intermediate 183. Then, the intramolecular cyclization of intermediate 183 affords the intermediate 184. Finally, the methyl group of intermediate 184 is removed to give product 181 under the attack of 4-methylbenzene sulfonate or chloride anion.

In 2021, Tan and coworkers [70] reported N-acylated and 3-trifluoromethylselanylated indoles in good yields via the treatment of indoles with excess [Me₄N][SeCF₃] in the presence of acyl peroxides or their derivatives (Scheme 32). The reaction proceeded at room temperature under mild conditions and tolerated a range of functional groups. Both acyl peroxide and peroxycarboxylic acid were effective mediators, behaving not only as oxidants but also as acyl sources in the transformations.

4.2 Cyclization of alkenes/alkynes to synthesize F₃CSe-containing heterocycles

In 2018, an easy and practical protocol using alkynes and CF₃SeCl to access various F₃CSe-containing five- and six-membered-ring heterocycles was developed by Glenadel et al. [71] and coworkers, which has also been extended to other fluoroalkylselenyl groups (Scheme 33). It is noteworthy that the newly formed isocoumarins can be further converted into trifluoromethylselenolated isoquinolinones via a multistep pathway, which further proves its potential application prospects, particular in medicinal chemistry.

In 2022, Wang et al. [72] developed a copper-mediated double trifluoromethylselenolation and cyclization of terminal 2-alkynylanilines using [(bpy)-CuSeCF₃]₂ as the trifluoromethylselenolating reagent, which provided a useful tool for the synthesis of 2,3-bis(trifluoromethylseleno)indoles (Scheme 34). It is noteworthy that the delicate balance between the electronic and spatial properties of the N-protected groups is crucial for the reaction. The N-Ts and N-Ms groups gave the desired products in moderate to good yields, while the N-Ns groups gave the desired products in poor yields. In addition, Neither N-Me and N-Bz groups, nor N-unprotected groups gave any desired cyclization products. Desulfonylation of N-Ts 2,3-bis(trifluoromethylselenide) compounds, and further N-methylation of the product confirms the utility of this reaction. Based on the control experiments and isolated intermediates, a feasible reaction mechanism is proposed in Scheme 34. First, [(bpy)CuSeCF₃]₂ 195 could undergo a single electron oxidation by 1,2-benzendicarboxylicacid (DMP) to generate Cu^Ⅱ species 203. Then electrophilic trifluoromethylselenolation of Cu^Ⅱ species 203 with 2-ethylaniline led to intermediate 204. The alkynyl of intermediate 204 coordinates with 203 to form copper complex 205, and then 5-endo cyclization to give 3-copper indoler intermediate 206, which underwent oxidation and deprotonation to generate the intermediate 207. Finally, the reductive elimination of intermediate 207 gave the desired product 208.

In 2022, Shi et al. [64] reported the trifluoromethylthiolation/selenolation and lactonization of 2-alkynylbenzoate using a combination of BnS(O)CF₃/BnSe(O)CF₃ with Tf₂O as SCF₃/SeCF₃ reagents to produce a series of 4-(trifluoromethylseleno/selenolation)isocoumarins (Scheme 35). The reaction is not affected by the electronic properties or steric effects of the substituents. In particular, the desired 3-alkyl-substituted isocoumarins are obtained in moderate to good yields when the alkyne motif (R²) is substituted with an alkyl substituent including n-Bu, t-Bu, or cyclopropyl groups. Based on the results of relevant control experiments and previous literature reports, three possible reaction pathways were described, as shown in Scheme 35. This differs from the previous formation of thiovinyl intermediates, and is an alternative mechanistic pathway involving synergistic trifluoromethyl thiolation/selenation and lactonization processes.

In 2022, Lu et al. [73] developed a convenient protocol for the visible-light-promoted trifluoromethylselenolation of ortho-hydroxyarylenaminones with TsSeCF₃, which offers an efficient pathway for the construction of valuable trifluoromethylselenylated chromone derivatives (Scheme 36). The electron-donating (-Me, -OMe) or electron-withdrawing (-F, -Cl, -Br, -CN, -NO₂) groups substituted on the phenol react well with TsSeCF₃ under typical conditions, and the introduction of substituents at different positions of the benzene ring of enaminone has little effect on the reaction. In addition, the heterocyclic-substituted enaminones, such as thiophene, furan and benzofuran, can also be transformed to the desired products in good yields. The yield of product 228 is poor after adding a free radical inhibitor (TEMPO), which indicates that the reaction proceeds via a free radical pathway. First, the S–Se bond of TsSeCF₃ is homogenized under visible-light irradiation to generate CF₃Se radicals 170, which attack the alkenyl group of o-hydroxyphenyl enaminone 230 regioselectively to give a radical intermediate 230. Then, the radical intermediate 230 is rapidly oxidized by oxygen to form an imine intermediate 231. Finally, the intermediate 232 undergoes intramolecular cyclization and reductive elimination to yield the desired product 233.

In 2022, Wang et al. [74] developed a simple and mild protocol for the trifluoromethylselenolation of N-Ts 2-alkynylaniline with [(bpy)CuSeCF₃]₂ to synthesize a series of 3-(trifluoromethylseleno)indoles in air at room temperature (Scheme 37). Various N-protecting groups including N-Ts, N-Tf, N-Ns and N-Ms groups were tolerated well in this transformation, but N-Me, N-Bz and N-unprotected groups gave no desired cyclization product. This indicates that a delicate balance between the electronic and spatial properties of the N-protected groups is necessary for this reaction. In addition, the main merits of the method are that the reaction conditions are mild, insensitive to moisture or air, and have broad functional group tolerance.

5 Conclusions

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In summary, the synthesis of trifluoromethoxylated, trifluoromethylthiolated, and trifluoromethylselenolated heterocyclic compounds, as well as the scope, limitations and selected mechanisms of the reactions are reviewed. The successful examples described in this review convincingly demonstrate that efficient and practical methods have been developed to incorporate the XCF₃ groups (X = O, S, Se) into organic molecules, which has broad prospects in the field of medicinal chemistry. Among these synthesis methods, oxidative trifluoromethoxylation (thiolation/selenolation) activation via heterocyclic C–H bond activation is the most direct, efficient, and economical method that can avoid the use of prefunctional groups or preactivated reaction substrates. Further, the construction of F₃CX-containing (X = O, S, Se) heterocyclic compounds by the difunctionalization cyclization strategy of alkenes and alkynes is relatively mild and plays an important role in the construction of polyheterocycle and heteroatom-rich heterocyclic compounds. There are also some synthetic methods for constructing F₃CO-containing heterocycles by constructing O–CF₃ bonds. Although the substrate requires pretreatment, it is not limited to the need for trifluoromethoxylation reagents, which has important significance for the later derivatization of compounds.

These studies show that the F₃CX-containing (X = O, S, Se) heterocyclic compounds, which have good biological activity, have attracted the attention of chemists, and many synthetic methods have been developed. However, the current synthetic methods also face limitations. On the one hand, the synthesis of F₃CX-containing heterocyclic compounds largely depend on the development of trifluoromethoxylation, trifluoromethylthiolation, and trifluoromethylselenolation reagents. Although there are various kinds of trifluoromethoxylated, trifluoromethylthiolated, and trifluoromethylselenolated reagents, most are expensive, complicated to prepare, and have low atomic efficiency. It is very important to develop cheap, nontoxic, and atomically efficient trifluoromethoxylation, trifluoromethylthiolation and trifluoromethylselenolation reagents. On the other hand, the current synthetic method is relatively consistent, with most using metal, acid, or base catalysts to catalyze the generation of trifluoromethoxy-, trifluoromethylthio-, and trifluoromethylseleno-groups. With the development of XCF₃ (X = O, S, Se) radical transfer reagents, and some of the electrophilic XCF₃ transfer reagents having proven to have the potential to provide XCF₃ (X = O, S, Se) radicals, the use of milder, greener photocatalysis and electrocatalysis for the synthesis of F₃CX-containing (X = O, S, Se) heterocyclic compounds is an attractive and challenging option.

Declaration of competing interest

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

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This work was supported by the National Natural Science Foundation of China (No. 21801007).

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Year 2023 volume 34 Issue 5

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doi: 10.1016/j.cclet.2022.108045

Receive Date：2022-10-31
Online Date：2025-11-21
Published：2023-05-15

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Received：2022-10-31
Revised：2022-12-03
Accepted：2022-12-05

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^a College of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China

^b State Key Laboratory of Tree Genetics and Breeding, Research Institute of Forestry, Chinese Academy of Forestry, Beijing 100091, China

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Scheme 1 Copper-catalyzed trifluoromethylthiolation of indoles.

Scheme 2 Trifluoromethylthiolation of arenes with N-trifluoromethylthiosaccharin.

Scheme 3 Rh(Ⅲ)-catalyzed electrophilic C-2 trifluoromethylthiolation of indoles.

Scheme 4 Copper-catalyzed trifluoromethylthiolation of pyrroles with trifluoromethanesulfonyl hypervalent iodonium ylide.

Scheme 5 Copper-catalyzed trifluoromethylthiolation of pyrroles with trifluoromethanesulfonyl hypervalent iodonium ylide.

Scheme 6 Trifluoromethylthiolation of indoles and pyrroles with CF₃SO₂Na.

Scheme 7 POCl₃-promoted trifluoromethylthiolation-based vicinal bifunctionalization of indoles with CF₃SO₂Na.

Scheme 8 CuCl-catalyzed C-3 trifluoromethylthiolation of indoles.

Scheme 9 C–H trifluoromethylthiolation of indoles and thiophenes with CF₃SOCl.

Scheme 10 Silver-mediated aryltrifluoromethylthiolation of activated alkenes.

Scheme 11 Synthesis of trifluoromethylthiole-containing isoxazolines.

Scheme 12 Synthesis of SCF₃-containing indolo[2,1-a]isoquinolin-6(5H)-ones.

Scheme 13 Synthesis of 3-trifluoromethylthiospiro[4,5]trienones.

Scheme 14 Enantioselective trifluoromethylthiolation of alkenes.

Scheme 15 Synthesis of F₃CS-containing chiral azaheterocycles.

Scheme 16 Copper-assisted oxidative trifluoromethylthiolation of 2,3-allenoic acids with AgSCF₃.

Scheme 17 Photocatalytic trifluoromethylthiolation of acrylamides with N-trifluoromethylthiosaccharin.

Scheme 18 Cascade cyclization of aryl acetylenes with AgSCF₃.

Scheme 19 Copper-assisted trifluoromethylthiolation/radical cascade cyclization of alkynes with AgSCF₃.

Scheme 20 Syntheses of azaspiro[4,5]dienones and 3,4-dihydroquinolin-2-ones.

Fig. 1. Trifluoromethoxylation reagents.

Scheme 21 Photocatalytic trifluoromethoxylation of (hetero)arenes.

Scheme 22 Silver-mediated C–H trifluoromethoxylation of (hetero)arenes.

Scheme 23 Palladium-catalyzed intramolecular trifluoromethoxylation of alkenes.

Scheme 24 Silver-mediated O-trifluoromethylation of unprotected phenols.

Scheme 25 Synthesis of F₃CO-containing pyridines and pyrimidines.

Scheme 26 Direct O-trifluoromethylation of N-heteroaromatics.

Fig. 2. Trifluoromethylselenolation reagents.

Scheme 27 Pd-catalyzed trifluoromethylselenolation of 8-aminoquinoline.

Scheme 28 3-Trifluoromethylthiolation of indoles with TsSeCF₃.

Scheme 29 Trifluoromethylselenolation of (hetero)arenes with [Me₄N][SeCF₃].

Scheme 30 Visible-light mediated trifluoromethylselenolation of heteroarenes with [Me₄N][SeCF₃].

Scheme 31 TfOH-catalyzed trifluoromethylselenolation of benzofurans.

Scheme 32 Synthesis of N-acylated and 3-trifluoromethylselanylated indoles.

Scheme 33 Syntheses of fluoroalkylselenolated five- and six-membered-ring heterocycles.

Scheme 34 Synthesis of 2,3-bis(trifluoromethylseleno)indole.

Scheme 35 BnSe(O)CF₃/Tf₂O-mediated synthesis of 4-(trifluoromethylseleno)isocoumarins.

Scheme 36 Visible-light-promoted trifluoromethylselenolation of ortho-hydroxyarylenaminones.

Scheme 37 Synthesis of 3-(trifluoromethylseleno)indoles.

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