Controlled Fluoroalkylation Reactions by Visible-Light Photoredox

Article pubs.acs.org/accounts

Controlled Fluoroalkylation Reactions by Visible-Light Photoredox Catalysis Published as part of the Accounts of Chemical Research special issue “Photoredox Catalysis in Organic Chemistry”. Tanmay Chatterjee,†,∥ Naeem Iqbal,‡,∥ Youngmin You,§ and Eun Jin Cho*,† †

Department of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, P.O. Box 577, Jhang Road, Faisalabad 38000, Pakistan § Division of Chemical Engineering and Materials Science, Ewha Womans University, Seoul 03760, Republic of Korea ‡

CONSPECTUS: Owing to their unique biological, physical, and chemical properties, fluoroalkylated organic substances have attracted significant attention from researchers in a variety of disciplines. Fluoroalkylated compounds are considered particularly important in pharmaceutical chemistry because of their superior lipophilicity, binding selectivity, metabolic stability, and bioavailability to those of their nonfluoroalkylated analogues. We have developed various methods for the synthesis of fluoroalkylated substances that rely on the use of visible-light photoredox catalysis, a powerful preparative tool owing to its environmental benignity and mechanistic versatility in promoting a large number of synthetically important reactions with high levels of selectivity. In this Account, we describe the results of our efforts, which have led to the development of visible-light photocatalytic methods for the introduction of a variety of fluoroalkyl groups (such as, −CF3, −CF2R, −CH2CF3, −C3F7, and −C4F9) and arylthiofluoroalkyl groups (such as, −CF2SPh, −C2F4SAr, and −C4F8SAr) to organic substances. In these studies, electrondeficient carbon-centered fluoroalkyl radicals were successfully generated by the appropriate choice of fluoroalkyl source, photocatalyst, additives, and solvent. The redox potentials of the photocatalysts and the fluoroalkyl sources and the choice of sacrificial electron donor or acceptor as the additive affected the photocatalytic pathway, determining whether an oxidative or reductive quenching pathway was operative for the generation of key fluoroalkyl radicals. Notably, we have observed that additives significantly affect the efficiencies and selectivities of these reactions and can even change the outcome of the reaction by playing additional roles during its course. For instance, a tertiary amine as an additive in the reaction medium can act not only as a sacrificial electron donor in photoredox catalysis but also as a hydrogen atom source, an elimination base for dehydrohalogenation of the intermediate, and also a Brønsted base for deprotonation. In the same context, the selection of solvent is also critical since it affects the rate and selectivity of reactions depending upon its polarity and reagent solubilizing ability and plays additional roles in the process, for example, as a hydrogen atom source. By clearly understanding the roles of additives and solvent, we designed several controlled fluoroalkylation reactions where different products were formed selectively from the same starting substrates. In addition, we could exploit one of the most important advantages of radical reactions, that is, the use of unactivated π-systems such as alkenes, alkynes, arenes, and heteroarenes as radical acceptors without prefunctionalization. Furthermore, fluoroalkylation processes under mild roomtemperature reaction conditions tolerate various functional groups and are therefore easily applicable to late-stage modifications of highly functionalized advanced intermediates.

1. INTRODUCTION Incorporation of fluoroalkyl groups into molecules can dramatically change their physical, chemical, and biological properties, mainly due to the small size and high electro© 2016 American Chemical Society

Received: May 24, 2016 Published: September 14, 2016 2284

DOI: 10.1021/acs.accounts.6b00248 Acc. Chem. Res. 2016, 49, 2284−2294

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Accounts of Chemical Research negativity of fluorine, as well as the high C−F bond dissociation energy.1 In particular, fluoroalkylated compounds are characterized by superior lipophilicity, binding selectivity, bioavailability, and metabolic stability to those of their nonfluoroalkylated analogues. Owing to these characteristics, extensive research effort has been dedicated to preparing pharmaceutical and agrochemical agents bearing fluoroalkyl moieties (Figure 1).2−5

Figure 2. Examples of trifluoromethylation reactions of (hetero)arenes.

Figure 1. Pharmaceutical agents containing fluoroalkyl groups.

During postdoctoral work in Prof. Buchwald’s group, E. J. Cho contributed to the development of Pd-catalyzed trifluoromethylation reactions of (hetero)arenes6 and alkenes.7 The works introduced the possibility of late-stage installation of trifluoromethyl (CF3) groups, one of the most attractive and widely used fluoroalkyl moieties (Figure 1), into organic compounds and attracted considerable attention from pharmaceutical chemists seeking new efficient trifluoromethylation methods. Inspired by the attention given to these works, Cho continued the development of new high-efficiency fluoroalkylations with wide applicability. At the time of these efforts, visible-light-induced radical processes had attracted renewed interest because of their environmental benignity and mechanistic versatility in promoting a large number of synthetically important reactions with high levels of selectivity. Visible-light photocatalytic reactions generally proceed under mild conditions at ambient temperatures and pressures and as a result have excellent functional-group compatibilities, overcoming the drawbacks of traditional methods that often require highly toxic reagents and high-energy UV radiation, resulting in poor selectivity and difficulties with scale-up. In addition, as illustrated in the representative examples of trifluoromethylation of (hetero)arenes shown in Figure 2, visible-light-induced trifluoromethylations show several advantages over two-electron-based reactions, despite the regioselectivity issue. The radical processes developed by the MacMillan group8 and our group9 utilize unactivated arenes and heteroarenes as substrates (without prefunctionalization) with relatively inexpensive CF3 sources at room temperature. Visible-light-induced fluoroalkylation reactions4,5 typically involve coordinatively saturated 4d or 5d transition metal complexes, such as Ru(II) polypyridine complexes and cyclometalated Ir(III) complexes, as photocatalysts. Figure 3 shows the most widely used Ru- and Ir-complexes in fluoroalkylations, including [Ru(bpy)3]Cl2, [Ru(phen)3]Cl2, [Ir(dtbbpy)(ppy)2]PF6, fac-Ir(ppy)3, and fac-Ir(dFppy)3 [bpy

Figure 3. Examples of visible-light photocatalysts used in fluoroalkylation reactions.

= 2,2′-bipyridine; phen = 1,10-phenanthroline; dtbbpy = 4,4′di-tert-butyl-2,2′-bipyridine; ppy = 2-phenylpyridinate; dFppy = 2-(2,4-difluorophenyl)pyridinate]. Moreover, metal complexes containing Pt, Cu, and Co and even organic dyes have also been explored as photocatalysts.10−15 In our studies, various Ru, Ir, and newly developed Pt complexes were utilized. A general proposed mechanism with a polypyridyl-based transition metal complex ([MnLx]) is shown in Figure 4.10−14 Photoexcitation of [M n L x ] produces an excited state, [Mn+1Lx•−], that has an altered electronic distribution caused by the metal-to-ligand charge transfer (MLCT). The [Mn+1Lx•−] species is either a stronger reductant or stronger oxidant than is its corresponding ground state [MnLx], and as a result, it can participate in one of two possible single-electron transfer (SET) processes depending on its redox potential and the redox behavior of the substrate. The process in which [Mn+1Lx•−] is reduced by an electron donor (ED) to form [MnLx•−]− is known as reductive quenching, and the process in which [Mn+1Lx•−] is oxidized by an electron acceptor (EA) to form [Mn+1Lx]+ is known as oxidative quenching. The [MnLx] 2285


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radical from the fluoroalkylating reagents, followed by its addition to the substrates. In our studies, fluoroalkyl radicals were generated using various combinations of fluoroalkyl sources, photocatalysts, and amine additives. A redox potential correlation diagram to estimate the theoretical feasibility of the generation of fluoroalkyl radicals with respect to the choice of fluoroalkyl source, photocatalyst, and additive is given in Figure 6a. The photocatalysts ([Ru(bpy)3]Cl2,11 fac-Ir(ppy)3,11 and Pt(ppy)acac16), fluoroalkyl sources (CF3I (7) and BrCF2CO2Et (8)), and tertiary amines (TEA, DIPEA, TMEDA) shown have been used in our lab, and their redox potentials were measured in CH3CN and given in volts versus a saturated calomel electrode (SCE). In a photocatalytic cycle, there are two possible routes for the reductive generation of •CF3 radicals from CF3I (7). The photoexcited catalyst can directly transfer an electron to 7 (oxidative quenching pathway), followed by the reductive regeneration of the catalyst by a sacrificial ED. Alternatively, the photoexcited catalyst can be first reduced by SET from an ED (reductive quenching pathway) that subsequently transfers an extra electron to 7. According to the given redox potentials (Figure 6), the photoexcited [Ru(bpy)3]2+ complex (E*[Ru(III)/Ru(II)*] = −0.81 V) cannot directly reduce 7 (Ered(CF3I) = −0.91 V) with a negative driving force associated with step A in the photocycle (Figure 6a(i)), but it can easily be reduced to the Ru(I) complex (E*[Ru(II)*/Ru(I)] = +0.77 V) by tertiary amines such as TEA, DIPEA, and TMEDA (Eox(TEA) = +0.73 V, Eox(DIPEA) = +0.65 V, Eox(TMEDA) = +0.47 V) with positive driving force (step C, reductive quenching pathway). Then, the one-electron reduced Ru(I) complex (E[Ru(II)/Ru(I)] = −1.33 V) can deliver an extra electron to 7 to generate the •CF3 radical (step D). On the other hand, the photoexcited fac-Ir(ppy)3 (E*[Ir(IV)/Ir(III)*] = −1.73 V) and Pt(ppy)acac (E*[Pt(III)/Pt(II)*] = −2.07 V) complexes can directly deliver an electron to 7 with positive driving force (step E in photocycle a(ii) and step I in photocycle a(iii), respectively), but the complexes (E*[Ir(III)*/Ir(II)] = +0.31 V and E*[Pt(II)*/Pt(I)] = +0.26 V) cannot be reduced (step G in photocycle a(ii) and step K in photocycle a(iii), respectively) by tertiary amines. Therefore, the generation of •CF3 radicals from CF3I with fac-Ir(ppy)3 and Pt(ppy)acac should prefer the oxidative quenching pathway. In the same context, it is expected that the photoexcited facIr(ppy)3 and Pt(ppy)acac can generate •CF2CO2Et radicals from BrCF2CO2Et (8) (Ered(BrCF2CO2Et) = −1.72 V) via the oxidative quenching pathway (step E in photocycle a(ii) and step I in photocycle a(iii), respectively), while the photoexcited [Ru(bpy)3]Cl2 cannot yield the radical by either the oxidative or reductive quenching pathway. Additives, in particular bases, can significantly affect the efficiencies and selectivities of these reactions and even change the outcome of the reaction by playing additional roles during the course of the reactions. For instance, a tertiary amine in the reaction medium can act not only as a sacrificial ED in photoredox catalysis but also as a hydrogen atom donor, an elimination base for dehydrohalogenation of the intermediate, and also a Brønsted base for deprotonation (Figure 6b). For example, fluoroalkylations of an alkene with a fluoroalkyl halide (Rf X) could yield three different fluoroalkylated products, that is, the alkyl halide (23), alkene (24), or alkane (25), selectively, depending on the role of the tertiary amine, as shown in Figure 6c. An atom transfer radical addition (ATRA) of 21 with Rf X

Figure 4. General mechanism of photoredox catalysis using polypyridyl-based transition metal complexes.

complex is then regenerated by SET to or from a respective EA or ED. The key feature of these reactions is that in both the oxidative and reductive catalytic cycles, substrates or sacrificial additives can serve as the EDs and EAs to give free radical intermediates for the organic transformations. By utilizing visible-light photoredox catalysis, we developed a variety of radical-mediated trifluoromethylation, difluoroalkylation, and arylthiofluoroalkylation processes in which unactivated alkenes, alkynes, arenes, and heteroarenes were employed as substrates. Among the various electrophilic fluoroalkyl sources (Figure 5), including Togni’s (1 and 2)

Figure 5. Examples of fluoroalkyl sources utilized in visible-light photoredox catalysis. Reagents highlighted in boxes were used in our studies.

and Umemoto’s reagents (3 and 4), CF 3 I (7), and BrCF2CO2Et (8) have been used as the respective trifluoromethyl and difluoroalkyl sources in our studies because of their low cost and ready availability. In addition, various other fluoroalkyl sources (13−15) including arylthiofluoroalkyl sources (17−19) were also utilized (Figure 5). The fluoroalkylation reactions can be generalized as the visible-light photocatalyzed reductive formation of a fluoroalkyl 2286


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Figure 6. (a) Redox potential correlation diagram to estimate the theoretical feasibility of the generation of fluoroalkyl radicals with respect to the choice of fluoroalkyl source, photocatalyst, and additive. (b) Potential roles of tertiary amines. (c) A general concept of controlled fluoroalkylations of an alkene depending on the various potential roles of amine additives.

the photocatalyst, sacrificial ED/EA, and solvent, the final outcome of the reaction could be finely tuned.

could produce 23 (halo-fluoroalkylation), which after HX elimination by a tertiary amine could be converted into fluoroalkylated alkene product 24 (alkenyl-fluoroalkylation). Halo-fluoroalkylated product 23 could also be generated from intermediate 22 formed by the photocatalytic oxidation of 21. Product 24 could also be formed from 22 through deprotonation by the tertiary amine. Conversely, the amine radical cation generated from a tertiary amine (e.g., steps C, F, and J in the photocycles) can serve as a strong H atom donor to 21 to produce hydro-fluoroalkylated product 25 (hydrofluoroalkylation) since single-electron oxidation of a tertiary amine dramatically lowers the strength of its α-C−H bonds.11

2.1. Fluoroalkylation Reactions of Alkenes

The viability of controlled fluoroalkylation reactions through the proper selection of the required reaction parameters was first indicated by the results of studies on the trifluoromethylation of alkenes with CF3I, which afforded only the trifluoromethylated alkenes selectively over the corresponding allyl-CF318 or CF3-iodoalkane19 products. For example, visiblelight irradiation of a solution of 1-dodecene (20a) and CF3I in the presence of [Ru(phen)3]Cl2 and TMEDA in CH3CN leads to rapid and selective formation of the CF3-substituted iodoalkane product.20 This finding guided the design of a method for selective generation of the corresponding CF3− alkene 26a.20 We reasoned that this goal could be accomplished by using a tertiary amine, which would act as both an ED additive in the photocatalytic cycle and a base to promote elimination of HI from the initially formed CF3−iodoalkane

2. FLUOROALKYLATION Based on the above-mentioned concept, several controlled fluoroalkylation reactions were developed where different sets of products were formed selectively from the same starting substrates.17 By utilizing slight variations in the combinations of 2287


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potentials of Pt complexes, as discussed in the Introduction (Figure 6), an oxidative quenching cycle was expected to be operative for the generation of •CF3 radicals using CF3I, and this hypothesis was confirmed by Stern−Volmer analysis of photoluminescence quenching experiments. Figure 9 displays

product. The screening of amines led to the discovery that 1,8diazabicycloundec-7-ene (DBU) is ideal for this purpose. Specifically, E-CF3-substituted alkene 26 is produced selectively upon visible-light irradiation of a solution of 20 and CF3I in the presence of [Ru(phen)3]Cl2 and DBU in CH3CN (Figure 7).

Figure 9. (a) Decay of emission from 50 μM Pt(OMeppy)acac in CH3CN with increasing CF3I concentration. (b) Plot of electron transfer rate as a function of CF3I concentration.

profiles for decay of the luminescence of 50 μM Pt(OMeppy)acac in CH3CN at 543 nm as a function of CF3I concentration after nanosecond photoexcitation at 377 nm employing timecorrelated single photon counting (TCSPC), which is a technique for fluorescence lifetime measurement. Incremental addition of CF3I (0−20 mM) to the solution causes a significant decrease in the emission lifetime (τobs) of the Ptcomplex, demonstrating the occurrence of oxidative quenching of electronically excited [PtIII(OMeppy)•−acac]* by CF3I (Figure 9a). Pt(dFppy)acac and Pt(ppy)acac show similar photoluminescence quenching behaviors. The rate constant of photoinduced electron transfer (kPeT) values, determined by a pseudo-first-order fit of the PeT rate vs CF3I concentration, are 8.76 × 108, 7.92 × 108, and 4.37 × 108 M−1 s−1 for Pt(dFppy)acac, Pt(ppy)acac, and Pt(OMeppy)acac, respectively (Figure 9b). The generation of •CF3 was further supported by a photoinduced electron spin resonance (ESR) signal with a g value of 2.004, corresponding to a free radical. The general mechanism for photoredox catalysis was discussed above. However, in fact, the mechanism for the alkenyl-trifluoromethylation is highly complicated and involves several processes, as shown in Figure 10. Photoexcitation of PtII(C∧N) promotes an electronic transition to a MLCT state. Diffusional collision of [PtIII(C∧N)•−]* with CF3I leads to the reversible formation of an encounter complex (([PtIII(C∧N)•−]* CF3I); path A in Figure 10). As supported by the above photoluminescence quenching experiments (Figure 9), the oxidative electron transfer from the Pt catalyst to CF3I generates a geminate radical ion pair, ([PtIII(C∧N)]+ CF3I•−), which can undergo processes via two pathways, B and C. Pathway B involves quenching to the original species (i.e., PtII(C∧N) and CF3I) by back electron transfer (BeT). The other pathway C involves dissociation into [PtIII(C∧N)]+ and CF3I•−, resulting in the formation of •CF3 by cleavage of the C−I bond in CF3I•−. Radical addition of •CF3 to alkene 20 forms radical 21. The catalytic cycle is completed by regeneration of PtII(C∧N) with electron transfer from sacrificial EDs, such as TMEDA and DBU, and this reductive regeneration process is experimentally supported by the data for decay traces of [PtIII(C∧N)]+ to PtII(C∧N) in the presence and absence of TMEDA. Alternatively, PtII(C∧N) can be

Figure 7. Ru-catalyzed alkenyl-trifluoromethylation reactions.

In contrast to several other efficient methods recently described for the synthesis of alkenyl-CF3 products,21,22 the one we developed has advantageous features associated with the use of unactivated alkenes as substrates, the formation of products with excellent levels of chemo- (alkenyl-CF3 over CF3iodoalkane, and allyl-CF3) and stereoselectivity (E-isomer over Z-isomer). The alkenyl-trifluoromethylation process also occurs efficiently when Pt-complexes newly developed by us (Figure 8) are employed as the photocatalyst.16 Based on the redox

Figure 8. Pt-catalyzed alkenyl-trifluoromethylation reactions. 2288


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difluoroalkylation processes using BrCF2CO2Et (8) in the presence of fac-Ir(ppy)3, which was considered to be a suitable photocatalyst for the generation of •CF2CO2Et radicals, as discussed in the Introduction (Figure 6).23 Unlike the analogous trifluoromethylation process, the use of DBU does not induce formation of alkenyl-CF2CO2Et products, but rather difluoroalkane 27 production (hydro-difluoroalkylation) is the major pathway followed (Figure 12). This result is likely the

Figure 12. Hydro-difluoroalkylation reactions of aliphatic alkenes.

consequence of the different nature of the radical intermediates, that is, •CF3 vs •CF2CO2Et, and halide atoms, that is, I vs Br. In the hydro-difluoroalkylation process, DBU serves as the ED to the excited photocatalyst and a H atom donor to the radical formed by •CF2CO2Et addition to the alkene. The use of a mixture of TMEDA and DBU and dichloromethane (DCM) as the solvent are optimal for generation of hydro-difluoroalkylated products 27 in reactions of various aliphatic alkenes 20. Conversely, changing the solvent from DCM to DMF and the base from TMEDA/DBU to K2CO3 causes the fac-Ir(ppy)3 photocatalyzed reactions of electron-rich aromatic alkenes with BrCF2CO2Et to form alkenyl-CF2CO2Et products 28 (Figure 13). However, reactions of electron-deficient aromatic and

Figure 10. Detailed proposed mechanism for the Pt(II)-catalyzed alkenyl-trifluoromethylation.

recovered through the radical-polar mechanism, which involves oxidation of 21 to the cation 22 (path D). In this case, 22 is trapped by I− to form 23, which can also be produced by radical propagation between CF3I and 21 (path E). Additional experiments to determine quantum yields of the Pt(II) complexes with the alkene 1-dodecene indicate the significant involvement of radical propagation (path E) where the quantum yield values exceed 100% for all three Pt(II) complexes (Figure 11). Finally, E2 elimination assisted by DBU in both the D and E pathways furnishes the alkenyl-CF3 product 26, with the generation of ammonium iodide salts.

Figure 13. Alkenyl-difluoroalkylation reactions.

aliphatic alkenes produce bromo-difluoroalkylated products 23, which require subsequent treatment with DBU to be converted to the corresponding alkenyl-CF2CO2Et products 28 with high levels of both regio- and E/Z stereoselectivity. In this work, the selection of solvent was critical by affecting the rate and selectivity of reactions depending upon its polarity and reagent solubilizing ability. 2.2. Fluoroalkylation Reactions of Alkynes

Alkynes 29 also serve as substrates for selective trifluoromethylation reactions in a manner that depends on the reaction conditions to produce three different types of trifluoromethylated products, including trifluoromethylated alkenyl iodides 30, alkenes 31, and alkynes 32.24 As the results presented in Figure 14 show, subtle differences in the nature of the photocatalyst, base, and solvent can be utilized advantageously to control the reactivity and selectivity of these processes. Iodo-trifluoromethylation reactions of alkynes with CF3I, occurring in the presence of [Ru(phen)3]Cl2 and TMEDA in CH3CN under visible-light irradiation occur through a sequential radical-addition iodide-atom-transfer pathway. Both aromatic and aliphatic alkynes participate in this process, which

Figure 11. Quantum yields for the trifluoromethylation of 1-dodecene by the Pt(II) complexes. The values were determined using standard ferrioxalate actinometry (6.0 mM K3[Fe(C2O4)3], quantum yield = 1.1 at 420 nm).

Next, difluoroalkylation reactions of alkenes were investigated. The difluoroalkyl (CF2R) group is also an important fluoroalkyl group from a medicinal chemistry point of view in that it can serve as a bioisostere of carbonyl and hydroxyl groups in pharmaceutical agents. In addition, difluoroalkylation can create a building block for further modifications when using a functionalized CF2 moiety, such as the −CF2CO2Et group. We carried out selective alkenyl-difluoroalkylation and hydro2289


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Figure 14. Controlled trifluoromethylation reactions of alkynes.

generates the corresponding products in excellent yields (Figure 14). Notably, the iodo-trifluoromethylated products are valuable synthetic building blocks because they can be easily converted to CF3-containing trisubstituted alkenes, a commonly found structural motif in pharmaceuticals and agrochemicals, utilizing various cross-coupling reactions. Conversely, selective hydro-trifluoromethylation25 occurs in reactions photocatalyzed by fac-Ir(ppy)3 in the presence of DBU in CH3CN/THF (1:1). In this work, THF was used as an additional hydrogen atom source along with DBU. In a related effort, we developed another radical-mediated hydro-trifluoromethylation process that employs an inorganic electride as the electron source, although it is not visible-light induced.26 The conditions required to carry out alkynyl-trifluoromethylation reactions are quite different from those used in the iodoand hydro-trifluoromethylation processes. Specifically, alkynylCF3 products 32 are generated when fac-Ir(ppy)3-photocatalyzed reactions are conducted in 0.1 M KOtBu solutions in DMF (Figure 14). Among the three types of trifluoromethylation reactions of alkynes described above, the hydro-trifluoromethylation process can be applied to the synthesis of β-trifluoromethyl ketones starting with readily available propargylic alcohols 33.27 The procedure involves visible-light-induced hydro-trifluoromethylation of 33 with CF3I followed by double bond migration and keto−enol tautomerism to yield the β-trifluoromethyl ketones 34 (Figure 15). A variety of propargylic alcohols can be converted to the corresponding β-trifluoromethyl ketones when the photoreactions are catalyzed by [Ru(bpy)3]Cl2 in the presence of DBU in 0.1 M DMF (Figure 15). Only arylsubstituted propargylic alcohols serve as acceptable substrates for this transformation, probably because conjugation with the aryl group facilitates migration of the double bond, converting 33A to 33B. In a manner that is similar to the controlled trifluoromethylation of alkynes, selective trifluoroethylation reactions of alkynes 29 yielding two different allyl-CF3 products can be performed using CF3CH2I 13 as the •CH2CF3 radical source

Figure 15. Synthesis of β-trifluoromethyl ketones from propargylic alcohols.

Figure 16. Selective iodo- and hydro-trifluoroethylation reactions of alkynes.

(Figure 16). 28 Iodo-trifluoroethylated products 35 are produced in these reactions when [Ru(bpy)3]Cl2 is utilized as the photocatalyst and TMEDA as the base in CH3CN. In contrast, hydro-trifluoroethylated products 36 are generated using fac-Ir(ppy)3 as the visible-light photocatalyst and a mixture of K2CO3 and DBU as bases in DMF. 2.3. Fluoroalkylated Building Blocks

In continuing investigations in this area, we have explored the use of fluoroalkylation reactions to prepare CF3-groupcontaining building blocks that can be converted into various CF3-containing target compounds. Because of their high 2290


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Accounts of Chemical Research propensity to undergo nucleophilic ring opening reactions, three-membered systems such as epoxides and aziridines are useful synthetic intermediates. Owing to this feature, we have carried out studies targeted at the development of simple methods to prepare trifluoromethyl derivatives of these strained ring systems. We envisaged that selective addition of •CF3 radicals to the terminal carbon of allylic alcohols 37 or amines 38 would take place as part of pathways for generation of either iodide 39 or carbocation 40 intermediates. We reasoned that either 39 or 40 could be captured by intramolecular nucleophilic substitution/addition to form the target CF3containing epoxides 41 or aziridines 42 (Figure 17).29

Figure 19. Synthesis of fluoroalkylated aziridines.

2.4. Fluoroalkylation Reactions of Heteroarenes

Introduction of fluoroalkyl groups to heteroarenes is of considerable interest because most fluorine-containing pharmaceutical agents have fluoroalkyl moieties connected to (hetero)aromatic ring systems (Figure 1). Various heteroarenes 43 undergo trifluoromethylation with CF3I in the presence of 1 mol % [Ru(bpy)3]Cl2 and 2 equiv of TMEDA in CH3CN under visible-light irradiation (Figure 20).9 During the

Figure 17. Synthesis of trifluoromethylated epoxides and aziridines.

Studies testing this proposal have shown that allylic alcohols 37 are transformed to trifluoromethylated epoxides 41 in visible-light promoted reactions with CF3I that employ [Ru(bpy)3]Cl2 and DBU in CH3CN (Figure 18). Moreover,

Figure 20. Trifluoromethylation reactions of heteroarenes. Figure 18. Synthesis of fluoroalkylated epoxides.

preparation of the manuscript describing our work, MacMillan et al. reported a highly efficient trifluoromethylation of arenes and heteroarenes that utilizes CF3SO2Cl and [Ru(phen)3]Cl2 or fac-Ir(dFppy)3 as the photocatalyst, as discussed in the Introduction (Figure 2).8 Likewise, Noel et al. devised a continuous flow trifluoromethylation process that uses a catalytic system that is similar to our conditions.30 In addition, Pt(ppy)acac, which was developed in our studies of alkenyltrifluorometylation reactions, has also been utilized to promote heteroaryl-trifluoromethylation reactions.16 We also carried out studies aimed at the development of a photocatalytic method for preparation of CF2CO2Et-substituted arenes and heteroarenes (Figure 21).31 The results show that visible-light irradiation of DMSO solutions containing

reaction of a diol was found to take place selectively to form a trifluoromethyl-epoxide 41b rather than a tetrahydropyran derivative, showing that the allylic hydroxyl group preferably participates in this reaction. This process is also amenable to installation of other fluoroalkyl groups, such as the respective hepta- and nonafluoroalkyls using C3F7I (14) and C4F9I (15). Similarly, CF3-, C3F7-, and C4F9-containing aziridines 42 are produced in reasonable yields using allylic amines 38 as substrates and TMEDA as the base in visible-light promoted reactions (Figure 19). 2291


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Figure 21. Difluoroalkylation reactions of arenes and heteroarenes.

arenes 45, 3 mol % fac-Ir(ppy)3, 3 equiv of BrCF2CO2Et (8), and 1.5 equiv of KO t Bu leads to formation of the corresponding difluoroalkylated arenes 46. Heteroarenes 43 also participate in highly efficient versions of this process (Figure 21), which require a lower catalyst loading (1 mol %), lesser amounts of BrCF2CO2Et (2 equiv), and the weak bases TEA or K3PO4. Various CF2CO2Et-substituted heteroarenes 47, including pyrroles, indoles, furans, thiophenes, benzothiophenes, and benzofurans, can be generated using this protocol. It should be noted that related visible-light induced heteroaryldifluoroalkylation reactions have also been developed by Qing32 and Wang.33 In order to gain insight into the mechanism of these reactions, emission lifetimes (τobs) of fac-Ir(ppy)3 were determined using nanosecond photoexcitation at 377 nm and monitored at 520 nm employing the TCSPC technique (Figure 22a). While τobs decreases with increasing BrCF2CO2Et

Figure 23. Proposed mechanism for difluoroalkylation reactions of arenes.

and the carbocation precursor of the substitution product (pathway a). Subsequent deprotonation of the cation by −OtBu produces the difluoroalkylated product 46. Alternatively, deprotonation of radical 45A forms radical anion 45B, which is reduced by SET to [IrIV(ppy)3]+ to regenerate IrIII(ppy)3 and yield 46 (pathway b). 2.5. Arylthiofluoroalkylation Reactions of Heteroarenes and Alkenes

The introduction of fluoroalkyl groups containing sulfur has also attracted growing interest because the presence of sulfur can further change the properties of molecules, and sulfur is often an essential element for biological activity. The importance of both sulfur and fluoroalkyl moieties prompted us to develop an arylthiofluoroalkylation method for heteroarenes and alkenes where two functional groups are installed simultaneously, showing the potential of the method for latestage modifications in the development of functional molecules.34 Several arylthiofluoroalkyl reagents having different numbers of fluorine atoms were utilized, which indicates that this method might be easily utilized for fine-tuning of properties in drug development by controlling the number of fluorine atoms in reagents. First, arylthiofluoroalkylations of heteroarenes 43 were attempted utilizing the readily available phenylthiofluoroalkyl bromides BrCF 2 SPh (17), BrCF 2 CF 2 SPh (18), and BrCF2CF2CF2CF2SPh (19) as sources of the carbon-centered thiofluoroalkyl radicals for the visible-light processes. Interestingly, the reactivity of the transformation is highly dependent on the electron density of the carbon-centered radical intermediate of the arylthiofluoroalkyl sources. Compared to the radical centers in •CF2CF2SPh (natural atomic charge 0.746) and •CF2CF2CF2CF2SPh (natural atomic charge 0.757), that of •CF2SPh (natural atomic charge 0.535) is less electrophilic, probably due to the delocalization of the lone pair of electrons on the neighboring sulfur. Depending on the observed reactivity, different combinations of photocatalyst, base, and solvent were employed. A combination of 2 mol % fac-Ir(ppy)3 and 2 equiv of 2,6lutidine was used for phenylthiodifluoromethylations of 43 with 1.4 equiv of 17 in DMF (0.1 M) (Figure 24). Conversely, for reactions of 43 with 1.4 equiv of 18 or 19, a combination of 2− 3 mol % [Ru(phen)3]Cl2 and 2 equiv of TMEDA in MeCN (0.1 M) was used (Figure 24). A variety of heteroarenes, including pyrroles, furans, indoles, benzofurans, and benzothiophene, undergo phenylthiofluoroalkylations in moderate to good yields.

Figure 22. Stern−Volmer plots of fac-Ir(ppy)3 with (a) BrCF2CO2Et and (b) TMEDA (blue circles) or KOtBu (red triangles). The inset in panel a is a plot of electron transfer rate (1/τ − 1/τ0, where τ and τ0 are phosphorescence lifetimes of fac-[Ir(ppy)3] in the presence and absence of BrCF2CO2Et, respectively).

concentration, the rate of emission decay is not affected by the presence of 30 mM TMEDA or 30 mM KOtBu (Figure 22b). These results indicate that quenching of the photoexcited Ir complex by SET to BrCF2CO2Et is the key step in these processes. Based on these results, the mechanism for the difluoroalkylation of arenes 45 is proposed, as illustrated in Figure 23. Visible-light photoexcitation of fac-IrIII(ppy)3 produces the MLCT excited state [IrIVppy•−(ppy)2], which is quenched by SET to BrCF2CO2Et, producing [IrIV(ppy)3]+ and the key intermediate •CF2CO2Et with bromide ion loss. Addition of • CF2CO2Et to 45 generates difluoroalkyl substituted radical 45A, which reacts by one of two possible routes, the first pathway involving SET to [IrIV(ppy)3]+ regenerating IrIII(ppy)3 2292


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3. CONCLUDING REMARKS In this Account, we have summarized the results of our studies on visible-light-induced photocatalytic fluoroalkylation reactions. A theoretical concept based on redox potential values was introduced to assess the feasibility of the generation of key fluoroalkyl radicals with respect to the choice of a given combination of fluoroalkyl source, photocatalyst, and amine additive. In addition, it was shown that additives such as tertiary amines significantly affect the efficiencies and selectivities of the reactions and even change the outcome of the reaction by playing additional roles during the course of the reactions, for example, as hydrogen atom donor, elimination base, or Brønsted base. By understanding the feasibility of the reaction in the photocatalytic system and the additional roles of additives, we designed several controlled fluoroalkylation reactions where different products were formed selectively from the same starting substrates. Various trifluoromethylation, difluoroalkylation, and arylthiofluoroalkylation reactions of alkenes, alkynes, and (hetero)arenes proceeded efficiently under visible-light irradiation conditions. In addition, several spectroelectrochemical and emission-quenching techniques were employed to gain insight into the mechanism of these photoreactions. We strongly believe that the synthetic methods developed in our efforts will find industrial applications owing to the fact that they utilize eco-friendly visible light and mild conditions and that they can be readily scaled-up.

Figure 24. Phenylthiofluoroalkylation reactions of heteroarenes.

Alkenes 20 are also suitable substrates for phenylthiofluoroalkylations, and a difference in reactivity is observed when reactions are carried out in the presence of 17 and 18 or 19 (Figure 25). In the case of reactions of alkenes with 17, the

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Author Contributions ∥

T.C. and N.I. contributed equally.

Notes

The authors declare no competing financial interest. Biographies Tanmay Chatterjee received his Master’s degree in chemistry in 2009 from the Indian Institute of Technology, Delhi, under the guidance of Prof. N. G. Ramesh. Next, he joined the Indian Association for the Cultivation of Science, Kolkata, to pursue doctoral studies on green synthetic methodologies under the supervision of Prof. Brindaban C. Ranu and received a Ph.D. degree in 2014. Then he moved to South Korea and has been conducting research on visible-light photocatalysis with Prof. Eun Jin Cho at the Chung-Ang University as a Research Professor.

Figure 25. Phenylthiofluoroalkylation reactions of alkenes.

same conditions as those used for heteroarenes produce either cyclized products or alkenyl products selectively. Reactions of aromatic alkenes afford phenylthiodifluoromethylated alkenes 54 as the major product through oxidation of the benzyl radical intermediate 51 to the cation intermediate 52, followed by a deprotonation step. Interestingly, aliphatic alkenes react to produce cyclized products 53, either by radical or cationic electrophilic substitution of the tethered phenyl ring in 51 or 52. Conversely, the reactions of alkenes with 18 and 19 require conditions different from those employed for heteroarenes [2 mol % fac-Ir(ppy)3 and 2 equiv of TMEDA in DCM (0.2 M)]. Reactions of aliphatic alkenes afford phenylthiofluoroalkylated alkanes 55 as major products through hydro-phenylthiofluoroalkylation, while reactions of aromatic alkenes yield alkenyl derivatives 56 as major products.

Naeem Iqbal completed his undergraduate studies at the University of Agriculture, Faisalabad, in 2007, after which he moved to Hanyang University (ERICA), South Korea, where he carried out doctoral studies with Prof. Eun Jin Cho. His work was focused on the development of visible-light photocatalysis, mainly for fluoroalkylations, and led to a doctoral degree in 2016. Recently he joined the National Institute of Biotechnology and Genetic Engineering (NIBGE), Faisalabad, as an Assistant Professor in the drug discovery and structural biology group. Youngmin You received B.Sc. and M.Sc. degrees in chemical engineering from Seoul National University, South Korea. He earned his Ph.D. degree in materials science and engineering at SNU in 2007. He joined the division of chemical engineering and materials science at Ewha Womans University as an assistant professor in 2015. His research interests include the discovery, understanding, and creation of 2293


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new photofunctions for potential applications in bioimaging, display, and photoredox catalysis. Eun Jin Cho received her Chemistry undergraduate degree in 2002 and her Master’s degree in 2004 from the Seoul National University, South Korea, under the direction of Professor Eun Lee. She earned her Ph.D. degree in 2008 from the University of WisconsinMadison, USA, under the direction of Professor Daesung Lee, and undertook postdoctoral training with Professor Stephen L. Buchwald at the Massachusetts Institute of Technology. In 2011, she returned to South Korea to begin her independent career at Hanyang University (ERICA) as an Assistant Professor and moved to Chung-Ang University as an Associate Professor in 2015. Research in the Cho group is centered on development of new chemical reactions and the synthesis of functional materials.

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ACKNOWLEDGMENTS We thank all co-workers involved in the studies covered in this Account for their invaluable intellectual and experimental contributions. The research described in this Account has been supported by grants from the National Research Foundation of Korea [Nos. NRF-2014R1A1A1A05003274, NRF-2014011165, and NRF-2012M3A7B4049657].

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Controlled Fluoroalkylation Reactions by Visible-Light Photoredox

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