Abstract
This chapter describes representative examples of the photocatalytic fluorination and di- and trifluoromethylation of organic compounds mediated by metal complexes or metal oxides. These photocatalytic methods are useful for the synthesis of organofluorine compounds. The fundamental reaction design in each of the transformations is discussed, and general experimental procedures are included. Synthetic methodologies that involve defluorination processes or the incorporation of other fluorinated motifs are not considered in this chapter.
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1 Introduction
The installation of fluorine atom(s) or fluorinated groups in drug molecules often significantly improves their pharmacokinetics [1]. Therefore, the development of simple protocols for the synthesis of organofluorine compounds has attracted the attention of synthetic chemists [2, 3]. In particular, the late-stage installation of fluorine into various organic skeletons has become a promising approach for the rapid preparation and discovery of new drugs.
The use of radical species for late-stage bond formation is an attractive synthetic strategy due to the unique reactivities of radicals toward unactivated bonds and tolerance of various functional groups. In addition, recent progress in synthetic radical chemistry via photocatalysis, especially in photoredox catalysis [4,5,6,7,8,9,10] and photoinduced hydrogen atom transfer (HAT) [11,12,13] under mild conditions, has prompted many researchers to develop photocatalytic methodologies for the radical-mediated synthesis of a variety of organofluorine compounds [14,15,16,17,18,19]. In this chapter, processes for the photocatalytic di- and tr-ifluoromethylation and fluorination of organic substrates by metal complexes or metal oxides are discussed. The introduction of other fluorinated groups and their synthesis through defluorination processes, as well as reactions associated with metal-free photocatalysis, are not considered. Before describing representative examples, the basic concepts are briefly explained.
1.1 Basic Principles
Photoredox catalysis mediated by ruthenium polypyridyl complexes and iridium cyclometalated complexes (M) such as [Ru(bpy)3]2+ and fac-[Ir(ppy)3] (bpy: 2,2′-bipyridine; ppy: 2-pyridylphenyl) has become a useful redox tool in synthetic radical chemistry [4,5,6,7,8,9,10]. Fluoromethyl radicals (·RF) can be generated from appropriate redox-active electron-accepting (RF+) or electron-donating precursors (RF−) by the action of 1e−-reduction and 1e−-oxidation processes, respectively. As a matter of course, the photocatalyst plays a pivotal role not only in the generation of ·RF (step I) but also in the regeneration of the ground state catalyst (M) associated with the back 1e−-transfer process (step II), leading to the production of fluoromethylated compounds (P–RF), as shown in Fig. 53.1. The reaction sequence, which involves a series of single electron transfer (SET) processes, does not require sacrificial redox reagents, and therefore, is redox-neutral .
General mechanistic illustration of the photoredox-catalyzed introduction of fluoromethyl groups highlighted in this chapter
The discussion in the following sections will mostly focus on di- and tri-fluoromethylation through photoredox processes. In addition to fluoromethylation, photocatalytic fluorination via the generation of alkyl radicals (·R) followed by reaction with fluorine sources (F–LG) (Fig. 53.2) will be discussed.
General mechanism of photocatalytic fluorination highlighted in this chapter
Photoinduced HAT from aliphatic compounds (R–H) by metal oxides such as the decatungstate anion ([W10O32]4−) or uranyl cation [UO2]2+, and redox reactions of appropriate radical precursors (R–LG) by photoredox catalysis are accessible to alkyl radicals (·R).
2 Trifluoromethylation Reactions
Trifluoromethylation by photoredox catalysis, leading to the synthesis of various CF3-containing compounds, has been studied more extensively than methods for the introduction of other fluorinated groups. Radical trifluoromethylation with trifluoromethyl iodide (1) has been investigated since 1949, when Hazeldine discovered that 1 reacted with ethylene through the trifluoromethyl radical (·CF3) under relatively harsh conditions (e.g., heating at 250 °C or UV irradiation) [20, 21]. In photoredox reactions, the compounds shown in Fig. 53.3 have been frequently used as CF3 sources. They can be classified as electron-accepting (CF3+) or -donating (CF3−) reagents. Examples of the former include 1, CF3SO2Cl (2) [22], the Umemoto (3) [23], Yagupolskii-Umemoto (4) [24], and Togni (5) [25] reagents, and trifluoroacetic anhydride (7) [26]. Recently, the Umemoto II reagent (6) [27] was developed in response to the high cost of 3. The Langlois reagent (8) [28] is an example of an electron-donating reagent (CF3−).
2.1 Trifluoromethylation of Olefins
2.1.1 Synthesis of β-CF3-Substituted Alcohols and Amines and α-CF3-Substituted Ketones from Alkenes
Alkene difunctionalization is a straightforward strategy for the construction of vicinally substituted carbon frameworks in a single step. Although reactions involving the trifluoromethylation of olefins have historically been limited to halotrifluoromethylation [29], photoredox catalysis has recently realized the solvent-dependent, trifluoromethylative difunctionalization of aromatic alkenes (9) to produce oxy-, amino-, and keto-trifluoromethylated products (Fig. 53.4) [30,31,32]. Mechanistically, the processes involve solvolysis of a proposed CF3-substituted carbocationic species to give trifluoromethylated difunctionalized products (10) such as β-CF3-substituted alcohols and amines (via a Ritter-type reaction), or α-CF3 substituted ketones (via Kornblum-type oxidation), as shown in Fig. 53.4.
Hydroxy-Trifluoromethylation: General Procedures [30]
A 20 mL Schlenk tube was charged with 3•BF4 (0.26–0.28 mmol), fac-[Ir(ppy)3] (0.5 mol%), styrene derivative 9 (0.25 mmol), acetone (4.5 mL), and H2O (0.5 mL) under N2. The tube was irradiated by two 3 W blue LED lamps (425 nm) placed at a distance of 2–3 cm. After reaction completion, the mixture was poured into aqueous Na2SO3 solution. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and filtered. After concentration in vacuo, the residue was purified by chromatography on silica gel to afford product 10.
2.1.2 Synthesis of CF3-Alkanes from Olefins
The hydro-trifluoromethylation of alkenes allows access to alkanes containing a CF3 group [33,34,35]. The electron-donating Langlois reagent (“CF3−”, 8) reacts with aliphatic or electron-deficient alkenes (11) in the presence of a photoredox catalyst with high oxidizing power, [Ir{dF(CF3)ppy}2(dtbbpy)](PF6), to produce an anionic intermediate that is protonated by MeOH to give product 12 (Fig. 53.5) [36, 37].
Hydro-trifluoromethylation of alkenes [36]
Hydro-Trifluoromethylation: General Procedures [36]
The alkene (11, 0.25 mmol), catalyst ([Ir{dF(CF3)ppy}2(dtbbpy)](PF6), 2 mol%), and 8 (0.50 mmol) were placed in a Schlenk tube, to which MeOH (3 mL) was added under Ar atmosphere. The reaction mixture was stirred under irradiation by 36 W blue LEDs (distance from the lamp, ~3.0 cm) at room temperature. After 24 h, the mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. Product 12 was purified by flash column chromatography on silica gel.
2.1.3 Synthesis of Optically Active α-CF3-Substituted Aldehydes
The electron-rich enamine intermediate formed by the condensation of an aldehyde (13) with a chiral amine catalyst was found to couple with the CF3 radical in an enantioselective manner [38]. Photoredox catalysis with [Ir(ppy)2(dtbbpy)](PF6) was highly effective in generating the CF3 radical from CF3I (1) (Fig. 53.6).
Asymmetric α-trifluoromethylation of aldehydes by dual photoredox/chiral amine catalysis [38]
Asymmetric Trifluoromethylation Followed by In Situ Reduction: General Procedures [38]
To an oven-dried borosilicate test tube equipped with a magnetic stir bar, the chiral amine catalyst ((2R,5S)-2-t-butyl-3,5-dimethylimidazolidin-4-one•TFA, 20 mol%) and [Ir(ppy)2(dtbbpy)](PF6) (0.5 mol%) photocatalyst were added. The tube was flushed with argon and cooled to −78 °C before DMF (2.53 mL) was added. The resulting yellow solution was further degassed at −78 °C and gaseous CF3I (1) (~6.1 mmol) was then condensed into the tube. Subsequently, the aldehyde (13, 0.76 mmol) and 2,6-lutidine (0.84 mmol) were added. At −20 °C, the test tube was irradiated by a 26 W compact fluorescent light bulb placed at a distance of ~3 cm. After 7.5–8 h, the reaction mixture was transferred to a round-bottomed flask using CH2Cl2 (12 mL) at −78 °C. NaBH4 (7.6 mmol) was added followed by cold MeOH (10 mL, −78 °C). The reaction mixture was stirred for 1 h at −78 °C before being quenched with saturated aqueous NH4Cl solution. The resulting solution was extracted with Et2O, and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was then purified by column chromatography on silica gel to furnish the desired alcohol product.
2.2 Trifluoromethylation of Alkynes
2.2.1 Stereoselective Synthesis of Tetrasubstituted CF3-Alkenes from Alkynes
Multisubstituted CF3-alkenes are useful structural motifs, especially for biologically active molecules and organic functional materials [39,40,41]. One straightforward synthetic method for the preparation of these compounds is the trifluoromethylation of alkynes [42, 43]. As shown in Fig. 53.7, the reaction of an internal alkyne (15) with 4•OTf in the presence of the Ir catalyst, [Ir(ppy)2(dtbbpy)](PF6), and a base, 2,6-di-tert-butylpyridine, selectively affords a trans-CF3-alkenyl triflate (16), which undergoes Pd-catalyzed cross-coupling to give a tetrasubstituted CF3-alkene with the retention of stereochemistry [44].
Stereoselective trifluoromethylation of alkynes [44]
Stereoselective Trifluoromethylation of Alkynes: General Procedures [44]
A 20 mL Schlenk tube was charged with [Ir(ppy)2(dtbbpy)](PF6) (5 mol%), 4•OTf (0.50 mmol), the alkyne (15, 0.25 mmol), 2,6-di-tert-butylpyridine (0.50 mmol), and dry CH2Cl2 (5 mL) under N2. The tube was irradiated by two 3 W blue LED lamps (425 nm), placed at a distance of 2–3 cm, for 6 h at room temperature with stirring. Then, the reaction mixture was concentrated in vacuo. The residue was dissolved in Et2O, and the solution was washed with 1 M HCl aq. and water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 16. When separation of the product from the diphenyl sulfide formed as a by-product was difficult, the latter was converted to its oxide by treatment with meta-chloroperbenzoic acid (mCPBA).
2.3 Synthesis of CF3-Containing Heterocycles from Isocyanides
Heterocycles containing a CF3 group as a ring substituent are important intermediates and building blocks for pharmaceuticals, agrochemicals, and functional materials. The trifluoromethylation of isocyanides (17) affords CF3-substituted N-containing heteroaromatics (18) such as pyridines, isoquinolines, and phenanthridines through the intramolecular radical cyclization of the imidoyl radical intermediate (Fig. 53.8) [45,46,47].
Trifluoromethylation of Isocyanides: General Procedures [45]
A 10 mL round-bottomed flask equipped with a rubber septum was charged with 17 (0.20 mmol), 3•BF4 (0.30 mmol), the photocatalyst (1 mol%), and Na2HPO4 (0.30 mmol). The flask was evacuated and backfilled with argon three times. MeOH (2 mL) was added, and the mixture was irradiated with 5 W white LED strips. After the reaction was complete, the mixture was poured into a separatory funnel containing water and CH2Cl2. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo after filtration. The residue was purified by flash chromatography on silica gel to afford product 18.
2.4 Synthesis of CF3-Aromatics Through C–H Trifluoromethylation of Arenes
The direct C–H trifluoromethylation of aromatics is the most step-economical synthetic strategy for trifluoromethylated aromatics when simple arenes are used as starting materials [48,49,50]. The reaction of CF3SO2Cl (2) with arenes and heteroarenes (19) in the presence of [Ru(phen)3]Cl2 or Ir(Fppy)3 produces CF3-arenes (20). Poor regio- and site-selectivities are occasionally noted (Fig. 53.9) [48].
Trifluoromethylation of arenes [48]
Trifluoromethylation of Arenes: General Procedures [48]
An oven-dried vial was charged with the photocatalyst (1–2 mol%), dry K2HPO4 (1.5 mmol), 19 (0.50 mmol), and MeCN (0.125 M), and degassed by alternating vacuum evacuation and argon backfill at −78 °C. Reagent 2 (0.502.0 mmol) was then added and the solution was irradiated by a 26 W compact fluorescent light bulb at room temperature. After 24 h, the reaction mixture was purified by column chromatography to furnish product 20.
Several problems associated with large-scale photochemical reactions such as sluggishness and side reaction can be surmounted by the use of flow technology [51]. The photocatalytic trifluoromethylation reaction of inexpensive trifluoroacetic anhydride (7) with Boc-protected pyrrole (19a) in the presence of pyridine N-oxide (21) and [Ru(bpy)3]Cl2 (0.1 mol%) was applied on kilogram-scale under continuous flow conditions [50] (Fig. 53.10).
Continuous-flow trifluoromethylation of an arene under visible light [50]
2.5 Synthesis of CF3S Compounds from Thiols
A trifluoromethanesulfenyl group (CF3S) can significantly enhance the lipophilicity of an organic molecule. In general, introducing a CF3S group is superior to a CF3 group with respect to lipophilicity. A CF3S group can be formed by the trifluoromethylation of arene-, heteroarene-, and alkane thiols (22) with CF3I (1) using the Ru photocatalyst, [Ru(bpy)3]Cl2 (Fig. 53.11) [52]. In addition, continuous microflow photoreactions are significantly more effective than batch photoreactions. On the other hand, photocatalytic trifluoromethylthiolation is also feasible with the appropriate choice of easy-to-handle electrophilic CF3S reagents such as N-(trifluoromethylthio)pyrrolidine-2,5-dione, N-(trifluoromethylthio)phthalimide, and N-(trifluoromethylthio)saccharin [53,54,55].
Trifluoromethylation of thiols [52]
Trifluoromethylation of Thiols: General Procedures [52]
An oven-dried vial was charged with [Ru(bpy)3]Cl2•6H2O (1.0 mol%), 22 (1.0 mol), and MeCN (4 mL) (mixture A). The mixture was degassed by the freeze-pump-thaw method. A second mixture (mixture B) was prepared with triethylamine (1.1 mmol) dissolved in degassed MeCN (1 mL). Thereafter, a gas-tight syringe was filled with gaseous 1 (200 psi, ~4 mmol), which was subsequently added to reaction mixture A (i.e., bubbled through the mixture over 10 min), followed by the dropwise addition of mixture B. The reaction mixture was placed ~5 cm away from a 24 W compact fluorescent light bulb. After reaction completion, the reaction mixture was diluted with Et2O and washed with 1 M aqueous HCl and then with aqueous NaHCO3. The combined water layers were extracted with Et2O, and the collected Et2O layers were concentrated in vacuo. The crude mixture was purified by flash chromatography to give product 23. When alkanenethiols were used as the substrate, PPh3 (1.0 mmol) and H2O (1.0 mmol) were added to mixture A prior to the addition of 1 .
3 Difluoromethylation Reactions
The difluoromethyl (CF2H) group is known to act as a bioisostere to hydroxyl and thiol units as well as a lipophilic hydrogen-bond donor. Thus, the CF2H group has become an attractive target in the design of drugs and agrochemicals. Photocatalytic difluoromethylation requires a more elaborate reaction design because the corresponding precursors (CF2H+ and CF2H−) are more limited (Fig. 53.12). In particular, the 1e-reduction of the electrophilic CF2H reagents (CF2H+) turns out to be much more difficult than that of CF3 reagents (CF3+) because of the decrease in the number of electronegative F atoms. Therefore, the number of reaction variants has not yet matched those of the aforementioned trifluoromethylation methods. In this section, the syntheses of (i) β-CF2H substituted alcohols from alkenes and (ii) CF2H-containing phenanthridines from isocyanides are illustrated.
3.1 Synthesis of β-CF2H Substituted Alcohol Derivatives from Alkenes
Known as a difluorocarbene source, the CF2H reagent 24 [56] serves as a CF2H radical precursor under reaction conditions similar to those described above for oxy-trifluoromethylation (Sect. 53.2.1), as shown in Fig. 53.13. In this case, CF2H-substituted alcohol derivatives 30 are obtained [62].
Oxy-difluoromethylation of alkenes [62]
Hydroxy-Difluoromethylation: General Procedures [62]
A 20 mL Schlenk tube was charged with 24 (0.25–0.28 mmol), fac-[Ir(ppy)3] (0.5–5 mol%), 9 (0.25–0.38 mmol), acetone (3.6 mL), and H2O (0.4 mL) under N2. The mixture was degassed by three freeze-pump-thaw cycles and refilled with N2. The tube was irradiated by two 3 W blue LED lamps (425 nm) placed at a distance of 2–3 cm. After completion of the reaction, brine was added and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel to afford product 30. Further purification by GPC was performed as required.
3.2 Synthesis of CF2H-Containing Phenanthridines from Isocyanides
In a manner analogous to the trifluoromethylation of isocyanides described above (Sect. 53.2.3), the photocatalytic difluoromethylation of isocyanides (17) with CF2H reagent 25 affords CF2H-substituted phenanthridines 31, as shown in Fig. 53.14 [63]. Under similar reaction conditions, CF2H reagent 26 can also be used [58].
Difluoromethylation of isocyanides [63]
Difluoromethylation of Isocyanides: General Procedures [63]
To an oven-dried borosilicate vial (8 mL) equipped with a magnetic stirrer, 2-isocyanobiphenyl 17 (0.2 mmol), fac-[Ir(ppy)3] (0.002 mmol), and Na2CO3 (0.4 mmol) were added. To this mixture, dioxane (2 mL), deionized water and 25 (0.4 mmol) were introduced under nitrogen. The vial was sealed and stirred under visible light at room temperature for 18 h. Then, the dioxane was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (12:1). Product 31 was obtained as a white solid .
4 Fluorination Reactions
Photocatalysis is usually associated with the generation of carbon-centered radicals from appropriate precursors. The generated organic radicals react with fluorine sources such as N-fluorobenzenesulfonimide (NFSI) or Selectfluor™ (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), or F-TEDA) to give fluorinated products [64,65,66,67,68,69,70]. In this section, the fluorination of alkanes, carboxylic acids, and alcohols is described.
4.1 Fluorination of Aliphatic C(sp3)–H Bonds
A well-characterized polyoxometalate photocatalyst, the tetrabutylammonium salt of decatungstate (((NBu4)4[W10O32]), TBADT), realizes the direct fluorination of unactivated C(sp3)–H bonds in alkanes (32) with NFSI as a fluorine source under mild conditions. Because aliphatic groups are common units in organic compounds, this fluorination reaction can become a powerful tool for the introduction of a fluorine atom into organic molecules. However, product 33 is usually obtained as a mixture of isomers (Fig. 53.15) [64], and selectivity is a problem to be solved. Hydrogen abstraction from 32 by the photoexcited TBADT under UV irradiation is the key process for the generation of alkyl radicals. The metal oxide [UO2]2+ has also served as a photocatalyst in the direct fluorination of alkanes [65].
Photocatalytic fluorination of C(sp3)–H bonds [64]
Photocatalytic Fluorination of Alkanes: General Procedures [64]
Substrate 32 (0.30 mmol) was dissolved in a solution of MeCN (2 M) in a sealable reaction vessel equipped with a magnetic stir bar, and TBADT (2 mol%), NFSI (0.36 mmol), and NaHCO3 (10 mol%) were added. After sparging the resulting suspension with N2 for 5 min, the reaction vessel was sealed, and the mixture was stirred and irradiated (two 15-W UVB-BLB lamps, centered at 365 nm) at room temperature overnight. The resulting blue solution was treated with saturated NaHCO3 solution (1 mL) and extracted three times with CH2Cl2 (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography to afford product 33.
4.2 Decarboxylative Fluorination
A reliable method for the selective generation of organic radicals would solve the problem of non-regioselective fluorination. Photoredox catalysis enables the generation of organic radicals from carboxylic acids through decarboxylation [71, 72]. Thus, reactions of carboxylic acids 34 with Selectfluor in the presence of a photocatalyst proceed via selective fluorination at the position of carboxyl-group loss to afford fluorinated products 33 (Fig. 53.16) [66, 67].
Photocatalytic decarboxylative fluorination of aliphatic carboxylic acids [66]
Photocatalytic Decarboxylative Fluorination of Carboxylic Acids: General Procedures [66]
A solution of [Ir{dF(CF3)ppy}2(dtbbpy)](PF6) (7.0 μmol, 1 mol%), carboxylic acid 34 (0.7 mmol), Na2HPO4 (1.40 mmol), and Selectfluor (2.10 mmol) in a mixture of MeCN/H2O (1:1) was degassed by Ar sparging for 10 min, and then irradiated (at ~4 cm from the light source) with two 34 W blue LEDs. After the reaction was complete, the crude mixture was extracted with Et2O, and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (5–10% Et2O in pentane) afforded product 33.
4.3 Deoxyfluorination of Alcohols
The concept of decarboxylative fluorination (Sect. 53.4.2) can be extended to the reaction of oxalates 35 [68,69,70]. Since oxalates 35 are easily prepared from alcohols 36, the photocatalytic reaction leads to the formal deoxyfluorination of aliphatic alcohols (Fig. 53.17) [68]. Primary, secondary, and tertiary alcohols can be applied in the reaction.
Photocatalytic deoxyfluorination of alcohols [68]
Photocatalytic Deoxyfluorination of Oxalates: General Procedures [68]
A 40 mL glass vial equipped with a Teflon septum and magnetic stirring bar was charged with 35 (1 equiv), the Ir photocatalyst (1 mol%), Na2HPO4 or K2HPO4 (2.0 equiv), Selectfluor (1.1–4.5 equiv), and acetone/H2O (4:1) or MeCN/H2O (4:1). The resulting solution was then sparged with N2 for 3 min. The vial was sealed and placed at ~1 inch from the lamp. After reaction completion, the reaction mixture was diluted with Et2O or AcOEt and washed successively with water and brine. The combined aqueous washings were extracted with the appropriate organic solvent (2 × 25 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash column chromatography over silica gel afforded product 33 .
5 Conclusion
The introduction of fluorine, the most electronegative of all elements, into organic compounds presents a synthetic challenge. In response, radical reaction systems associated with photocatalysis have emerged as key technologies for the installation of fluorine atom(s) or a fluorinated unit in organic molecules. The basic principles highlighted in this chapter are versatile approaches that are applicable in other photocatalytic fluoroalkylations, which were not covered here. The further development of novel metal-based and metal-free photocatalysts will increase the practicality of these already-useful photocatalytic systems.
References
Ojima, I. (ed.): Fluorine in Medicinal Chemistry and Chemical Biology. Wiley-Blackwell, Chichester (2009)
Liang, T., Neumann, C.N., Ritter, T.: Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 52, 8214–8264 (2013)
Yerien, D.E., Bonesi, S., Postigo, A.: Fluorination methods in drug discovery. Org. Biomol. Chem. 14, 8398–8427 (2016)
Narayanam, J.M.R., Stephenson, C.R.J.: Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011)
Prier, C.K., Rankic, D.A., MacMillan, D.W.C.: Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013)
Hu, J., Wang, J., Nguyen, T.H., Zheng, N.: The chemistry of amine radical cations produced by visible light photoredox catalysis. Beilstein J. Org. Chem. 9, 1977–2001 (2013)
Koike, T., Akita, M.: Visible-light radical reaction designed by Ru- and Ir-based photoredox catalysis. Inorg. Chem. Front. 1, 562–576 (2014)
Skubi, K.L., Blum, T.R., Yoon, T.P.: Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016)
Romero, N.A., Nicewicz, D.A.: Organic photoredox catalysis. Chem. Rev. 116, 10075–10166 (2016)
Marzo, L., Pagire, S.K., Reiser, O., König, B.: Visible-light photocatalysis: does it make a difference in organic synthesis? Angew. Chem. Int. Ed. 57, 10034–10072 (2018)
Ravelli, D., Protti, S., Fagnoni, M.: Decatungstate anion for photocatalyzed “window ledge” reactions. Acc. Chem. Res. 49, 2232–2242 (2016)
Capaldo, L., Ravelli, D.: Hydrogen atom transfer (HAT): a versatile strategy for substrate activation in photocatalyzed organic synthesis. Eur. J. Org. Chem. 2017, 2056–2071 (2017)
Suzuki, K., Mizuno, N., Yamaguchi, K.: Polyoxometalate photocatalysis for liquid-phase selective organic functional group transformations. ACS Catal. 8, 10809–10825 (2018)
Koike, T., Akita, M.: Trifluoromethylation by visible-light-driven photoredox catalysis. Top. Catal. 57, 967–974 (2014)
Barata-Vallejo, S., Bonesi, S.M., Postigo, A.: Photocatalytic fluoroalkylation reactions of organic compounds. Org. Biomol. Chem. 13, 11153–11183 (2015)
Koike, T., Akita, M.: Fine design of photoredox systems for catalytic fluoromethylation of carbon–carbon multiple bonds. Acc. Chem. Res. 49, 1937–1945 (2016)
Chatterjee, T., Iqbal, N., You, Y., Cho, E.J.: Controlled fluoroalkylation reactions by visible-light photoredox catalysis. Acc. Chem. Res. 49, 2284–2294 (2016)
Pan, X., Xia, H., Wu, J.: Recent advances in photoinduced trifluoromethylation and difluoroalkylation. Org. Chem. Front. 3, 1163–1185 (2016)
Koike, T., Akita, M.: New horizons of photocatalytic fluoromethylative difunctionalization of alkenes. Chem. 4, 409–437 (2018)
Hazeldine, R.N.: The reactions of fluorocarbon radicals. Part I. The reaction of iodotrifluoromethane with ethylane and tetrafluoroethylene. J. Chem. Soc., 2856–2861 (1949)
Studer, A.: A “renaissance” in radical trifluoromethylation. Angew. Chem. Int. Ed. 51, 8950–8958 (2012)
Kamigata, N., Fukushima, T., Yoshida, M.: Reaction of trifluoromethanesulphonyl chloride with alkenes catalyzed by a ruthenium(ii) complex. J. Chem. Soc. Chem. Commun., 1559–1560 (1989)
Umemoto, T.: Electrophilic perfluoroalkylating agents. Chem. Rev. 96, 1757–1777 (1996)
Umemoto, T., Ishihara, S.: Power-variable electrophilic trifluoromethylating agents. S-, Se-, and Te-(Trifluoromethyl)dibenzothio-, −seleno-, and -tellurophenium salt system. J. Am. Chem. Soc. 115, 2156–2164 (1993)
Charpentier, J., Früh, N., Togni, A.: Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 115, 650–682 (2015)
Beatty, J.W., Douglas, J.J., Cole, K.P., Stephenson, C.R.J.: A scalable and operationally simple radical trifluoromethylation. Nat. Commun. 6, 7919 (2015)
Umemomto, T., Zhang, B., Zhu, T., Zhou, X., Zhang, P., Hu, S., Li, Y.: Powerful, thermally stable, one-pot-preparable, and recyclable electrophilic trifluoromethylating agents: 2,8-difluoro- and 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium salts. J. Org. Chem. 82, 7708–7719 (2017)
Langlois, B.R., Laurent, E., Roidot, N.: Trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions. Tetrahedron Lett. 32, 7525–7528 (1991)
Wallentin, C.-J., Nguyen, J.D., Finkbeiner, P., Stephenson, C.R.J.: Visible light-mediated atom transfer radical addition via oxidative and reductive quenching of photocatalysts. J. Am. Chem. Soc. 134, 8875–8884 (2012)
Yasu, Y., Koike, T., Akita, M.: Three-component oxytrifluoromethylation of alkenes: highly efficient and regioselective difunctionalization of C=C bonds mediated by photoredox catalysis. Angew. Chem. Int. Ed. 51, 9567–9571 (2012)
Yasu, Y., Koike, T., Akita, M.: Intermolecular aminotrifluoromethylation of alkenes by visible-light-driven photoredox catalysis. Org. Lett. 15, 2136–2139 (2013)
Tomita, R., Yasu, Y., Koike, T., Akita, M.: Combining photoredox-catalyzed trifluoromethylation and oxidation with DMSO: facile synthesis of α-trifluoromethylated ketones from aromatic alkenes. Angew. Chem. Int. Ed. 53, 7144–7148 (2014)
Mizuta, S., Verhoog, S., Engle, K.M., Khotavivattana, T., O’Duill, M., Wheelhouse, K., Rassias, G., Médebielle, M., Gouverneur, V.: Catalytic hydrotrifluoromethylation of unactivated alkenes. J. Am. Chem. Soc. 135, 2505–2508 (2013)
Wilger, D.J., Gesmundo, N.J., Nicewicz, D.A.: Catalytic hydrotrifluoromethylation of styrenes and unactivated aliphatic alkenes via an organic photoredox system. Chem. Sci. 4, 3160–3165 (2013)
Straathof, N.J.W., Cramer, S.E., Hessel, V., Noël, T.: Practical photocatalytic trifluoromethylation and hydrotrifluoromethylation of styrenes in batch and flow. Angew. Chem. Int. Ed. 55, 15549–15553 (2016)
Zhu, L., Wang, L.-S., Li, B., Fu, B., Zhang, C.-P., Li, W.: Operationally simple hydrotrifluoromethylation of alkenes with sodium triflinate enabled by Ir photoredox catalysis. Chem. Commun. 52, 6371–6374 (2016)
Lefebvre, Q., Hoffmann, N., Rueping, M.: Photoorganocatalysed and visible light photoredox catalysed trifluoromethylation of olefins and (hetero)aromatics in batch and continuous flow. Chem. Commun. 52, 2493–2496 (2016)
Nagib, D.A., Scott, M.E., MacMillan, D.W.C.: Enantioselective a-trifluoromethylation of aldehyde via photoredox organocatalysis. J. Am. Chem. Soc. 131, 10875–10877 (2009)
Shimizu, M., Hiyama, T.: Modern synthetic methods for fluorine-substituted target molecules. Angew. Chem. Int. Ed. 44, 214–231 (2005)
Rivkin, A., Chou, T.-C., Danishefsky, S.J.: On the remarkable antitumor properties of fludelone: how we got there. Angew. Chem. Int. Ed. 44, 2838–2850 (2005)
Shimizu, M., Takeda, Y., Higashi, M., Hiyama, T.: 1,4-bis(alkenyl)-2,5-dipiperidinobenzenes: minimal fluorophores exhibiting highly efficient emission in the solid state. Angew. Chem. Int. Ed. 48, 3653–3656 (2009)
Iqbal, N., Jung, J., Park, S., Cho, E.J.: Controlled trifluoromethylation reactions of alkynes through visible-light photoredox catalysis. Angew. Chem. Int. Ed. 53, 539–542 (2014)
Han, H.S., Lee, Y.J., Jung, Y.-S., Han, S.B.: Stereoselective photoredox-caalyzed chlorotrifluoromethylation of alkynes: synthesis of tetrasubstituted alkenes. Org. Lett. 19, 1962–1965 (2017)
Tomita, R., Koike, T., Akita, M.: Photoredox-catalyzed stereoselective conversion of alkynes into tetrasubstituted trifluoromethylated alkenes. Angew. Chem. Int. Ed. 54, 12923–12927 (2015)
Tong, K., Zheng, T., Zhang, Y., Yu, S.: Synthesis of ortho-(fluoro)alkylated pyridines via visible light-promoted radical isocyanide insertion. Adv. Synth. Catal. 357, 3681–3686 (2015)
Cheng, Y., Yuan, X., Jiang, H., Wang, R., Ma, J., Zhang, Y., Yu, S.: Regiospecific synthesis of 1-trifluoromethylisoquinolines enabled by photoredox somophilic vinyl isocyanide insertion. Adv. Synth. Catal. 356, 2859–2866 (2014)
Wang, R., Jiang, H., Cheng, Y., Kadi, A.A., Fun, H.-K., Zhang, Y., Yu, S.: Somophilic isocyanide insertion: synthesis of 6-arylated and 6-trifluoromethylated phenanthridines. Synthesis. 46, 2711–2726 (2014)
Nagib, D.A., MacMillan, D.W.C.: Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature. 480, 224–228 (2011)
Iqbal, N., Choi, S., Ko, E., Cho, E.J.: Trifluoromethylation of heterocycles via visible light photoredox catalysis. Tetrahedron Lett. 53, 2005–2008 (2012)
Beatty, J.W., Douglas, J.J., Miller, R., McAtee, R.C., Cole, K.P., Stephenson, C.R.J.: Photochemical perfluoroalkylation with pyridine N-oxides: mechanistic insights and performance on a kilogram. Chem. 1, 456–472 (2016)
Cambié, D., Bottecchia, C., Straathof, N.J.W., Hessel, V., Noël, T.: Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016)
Straathof, N.J.W., Tegelbeckers, B.J.P., Hessel, V., Wang, X., Noël, T.: A mild and fast photocatalytic trifluoromethylation of thiols in batch and continuous-flow. Chem. Sci. 5, 4768–4773 (2014)
Li, Y., Koike, T., Akita, M.: Photocatalytic trifluoromethylthiolation of aromatic alkenes associated with hydroxylation and akoxylation. Asian J. Org. Chem. 6, 445–448 (2017)
Honeker, R., Garza-Sanchez, R.A., Hopkinson, M.N., Glorius, F.: Visible-light-promoted trifluoromethylthiolation of styrenes by dual photoredox/halide catalysis. Chem. Eur. J. 22, 4395–4399 (2016)
Dagousset, G., Simon, C., Anselmi, E., Tuccio, B., Billard, T., Magnier, E.: Generation of the SCF3 radical by photoredox catalysis: intra- and intermolecular carbotrifluoromethylthiolation of alkenes. Chem. Eur. J. 23, 4282–4286 (2017)
Zhang, W., Wang, F., Hu, J.: N-Tosyl-S-difluoromethyl-S-phenylsulfoximine: a new difluoromethylation reagent for S-, N-, and C-nucleophiles. Org. Lett. 11, 2109–21112 (2009)
Tang, X.-J., Dolbier Jr., W.R.: Efficient Cu-catalyzed atom transfer radical addition reactions of fluoroalkylsulfonyl chlorides with electron-deficient alkenes induced by visible light. Angew. Chem. Int. Ed. 54, 4246–4249 (2015)
Rong, J., Deng, L., Tan, P., Ni, C., Gu, Y., Hu, J.: Radical fluoroalkylation of isocyanides with fluorinated sulfones by visible-light photoredox catalysis. Angew. Chem. Int. Ed. 55, 2743–2747 (2016)
Noto, N., Koike, T., Akita, M.: Metal-free di- and tri-fluoromethylation of alkenes realized by visible-light-induced perylene photoredox catalysis. Chem. Sci. 8, 6375–6379 (2017)
Lin, Q.-Y., Xu, X.-H., Zhang, K., Qing, F.-L.: Visible-light-induced hydrodifluoromethylation of alkenes with a bromodifluoromethylphosphonium bromide. Angew. Chem. Int. Ed. 55, 1479–1483 (2016)
Yatham, V.R., Shen, Y., Martin, R.: Catalytic intermolecular dicarbofunctionalization of styrenes with CO2 and radical precursors. Angew. Chem. Int. Ed. 56, 10915–10919 (2017)
Arai, Y., Tomits, R., Ando, G., Koike, T., Akita, M.: Oxydifluoromethylation of alkenes by photoredox catalysis: simple synthesis of CF2H-containing alcohols. Chem. Eur. J. 22, 1262–1265 (2016)
Zhang, Z., Tang, X., Dolbier Jr., W.R.: Photoredox-catalyzed tandem insertion/cyclization reactions of difluoromethyl and 1,1-difluoroalkyl radicals with biphenyl isocyanides. Org. Lett. 17, 4401–4403 (2015)
Halperin, S.D., Fan, H., Chang, S., Martin, R.E., Britton, R.: A convenient photocatalytic fluorination of unactivated C–H bonds. Angew. Chem. Int. Ed. 53, 4690–4693 (2014)
West, J.G., Bedell, T.A., Sorensen, E.J.: The uranyl cation as a visible-light photocatalyst for C(sp3)–H fluorination. Angew. Chem. Int. Ed. 55, 8923–8927 (2016)
Ventre, S., Petronijevic, F.R., MacMillan, D.W.C.: Decarboxylative fluorination of aliphatic carboxylic acids via photoredox catalysis. J. Am. Chem. Soc. 137, 5654–5657 (2015)
Rueda-Becerril, M., Mahé, O., Drouin, M., Majewski, M.B., West, J.G., Wolf, M.O., Sammis, G.M., Paquin, J.-F.: Direct C–F bond formation using photoredox catalysis. J. Am. Chem. Soc. 136, 2637–2641 (2014)
González-Esguevillas, M., Miró, J., Jeffrey, J.L., MacMillan, D.W.C.: Photoredox-catalyzed deoxyfluorination of activated alcohols with selectfluor. Tetrahedron. 75, 4222–4227 (2019)
Brioche, J.: One-pot synthesis of tertiary alkyl fluorides from methyl oxalates by radical deoxyfluorination under photoredox catalysis. Tetrahedron Lett. 59, 4387–4391 (2018)
Su, J.Y., Grünenfelder, D.C., Takeuchi, K., Reisman, S.E.: Radical deoxychlorination of cesium oxalates for the synthesis of alkyl chlorides. Org. Lett. 20, 4912–4916 (2018)
Xuan, J., Zhang, Z.-G., Xiao, W.-J.: Visible-light-induced decarboxylative functionalization of carboxylic acids and their derivatives. Angew. Chem. Int. Ed. 54, 15632–15641 (2015)
Schwarz, J., König, B.: Decarboxylativve reactions with and without light–a comparison. Green Chem. 20, 323–361 (2018)
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Koike, T. (2022). Synthesis of Organofluorine Compounds. In: Bahnemann, D., Patrocinio, A.O.T. (eds) Springer Handbook of Inorganic Photochemistry. Springer Handbooks. Springer, Cham. https://doi.org/10.1007/978-3-030-63713-2_53
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