Fine Design of Photoredox Systems for Catalytic Fluoromethylation of

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Article pubs.acs.org/accounts

Fine Design of Photoredox Systems for Catalytic Fluoromethylation of Carbon−Carbon Multiple Bonds Published as part of the Accounts of Chemical Research special issue “Photoredox Catalysis in Organic Chemistry”. Takashi Koike* and Munetaka Akita* Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-27, 4259 Nagatsuta, Midori-ku, Yokohama, Kanagawa 226-8503, Japan

CONSPECTUS: Trifluoromethyl (CF3) and difluoromethyl (CF2H) groups are versatile structural motifs, especially in the fields of pharmaceuticals and agrochemicals. Thus, the development of new protocols for tri- and difluoromethylation of various skeletons has become a vital subject to be studied in the field of synthetic organic chemistry. For the past decades, a variety of fluoromethylating reagents have been developed. In particular, bench-stable and easy-to-use electrophilic fluoromethylating reagents such as the Umemoto, Yagupolskii−Umemoto, Togni, and Hu reagents serve as excellent fluoromethyl sources for ionic and carbenoid reactions. Importantly, the action of catalysis has become a promising strategy for developing new fluoromethylations. For the past several years, photoredox catalysis has emerged as a useful tool for radical reactions through visible-light-induced single-electron-transfer (SET) processes. Commonly used photocatalysts such as [Ru(bpy)3]2+ and fac-[Ir(ppy)3] (bpy = 2,2′bipyridine; ppy = 2-pyridylphenyl) have potential as one-electron reductants strong enough to reduce those fluoromethylating reagents, resulting in facile generation of the corresponding fluoromethyl radicals. Therefore, if we can design proper reaction systems, efficient and selective radical fluoromethylation would proceed without any sacrificial redox agents, i.e., via a redoxneutral process under mild reaction conditions: irradiation with visible light, including sunlight, below room temperature. It should be noted that examples of catalytic fluoromethylation of compounds with carbon−carbon multiple bonds have been limited until recent years. In this Account, we will focus on our recent research on photoredox-catalyzed fluoromethylation of carbon−carbon multiple bonds. First, choices of the photocatalyst and the fluoromethylating reagent and the basic concept involving a redox-neutral oxidative quenching cycle are explained. Then photocatalytic trifluoromethylation of olefins is discussed mainly. Trifluoromethylative difunctionalization reactions, i.e., simultaneous introduction of the CF3 group and a different functional group across carbon−carbon double bonds, are in the middle of the discussion. Oxy-, amino-, and ketotrifluoromethylation allow us to synthesize various organofluorine compounds bearing C(sp3)−CF3 bonds. In addition, the synthesis of valuable trifluoromethylated alkenes is also viable when the olefins have an appropriate leaving group or undergo deprotonation. The present reaction system features high functional group compatibility and high regioselectivity. Furthermore, future prospects, especially trifluoromethylative difunctionalization of alkynes and difluoromethylation of alkenes, are also discussed. efficient and selective incorporation of fluoromethyl groups into various organic skeletons is highly demanded. The use of reactive CF3 and CF2H radicals is a promising strategy for fluoromethylation of unsaturated hydrocarbons and aromatic

1. INTRODUCTION Fluoromethyl groups such as the trifluoromethyl (CF3) and difluoromethyl (CF2H) groups are useful structural motifs, especially in the fields of pharmaceuticals and agrochemicals, because they can improve the absorption, distribution, metabolism, and excretion (ADME) properties of drugs.1−6 Therefore, the development of simple methodologies for © XXXX American Chemical Society

Received: May 30, 2016

A

DOI: 10.1021/acs.accounts.6b00268 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article

Accounts of Chemical Research compounds.7,8 In general, when we design radical reactions, proper choices of radical precursors and initiating systems are essential elements. For example, in radical trifluoromethylation, CF3I, CF3SO2Cl, and CF3SO2Na have been used as conventional precursors and are activated by external stimuli such as heat, UV irradiation, and the action of redox agents.9−11 On the other hand, the application of bench-stable and easy-to-use electrophilic CF3 reagents such as the Umemoto (1a)12,13 Yagupolskii−Umemoto (1b),14,15 and Togni (1c) reagents,16,17 which were originally developed for ionic trifluoromethylation, to transition-metal- or organocatalyzed trifluoromethylation have become popular recently.18−23 Their reduction potentials (Figure 1), however, suggest that the intrinsic capability to accept a single electron provides a chance for them to be CF3 radical sources.

E1/2(M*/M+) of the commonly used photoredox catalysts are enough for reduction of the electrophilic fluoromethylating reagents 1, as compared in Figure 1. Basically, the excited photocatalyst M* with an oxidation potential lower than that of the reagent 1 can induce efficient SET to 1 followed by generation of fluoromethyl radicals (Scheme 1). However, to Scheme 1. Generation of Fluoromethyl Radicals through SET from a Photoexcited Photoredox Catalyst to a Fluoromethylating Reagent

accomplish a selective and efficient radical reaction, fine design of the whole reaction system, including appropriate choices of the photocatalyst M and the fluoromethylating reagent 1, is a key to success as described below. The number of publications on catalytic fluoromethylation of carbon−carbon multiple bonds has been rapidly growing for the past several years.31−35 Among them, photoredox catalysis has emerged as an outstanding strategy.36−38 As seminal works, the groups of MacMillan and Stephenson reported on photoredox-catalyzed trifluoromethylation of olefins such as enamines, enolsilanes, and aliphatic alkenes with CF3I as a CF3 radical precursor.39−41 In the present Account, we will focus on our recent works on radical fluoromethylation of carbon−carbon multiple bonds by the combination of photocatalysis and the fluoromethylating reagents 1 highlighted in Figure 1. The photoredox-catalyzed reaction developed by our group features (i) no need for extra redox reagents, i.e., redox-neutrality, and (ii) mild reaction conditions, i.e., irradiation with visible light, including sunlight, below room temperature. Discussion of trifluoromethylative difunctionalization reactions of alkenes such as oxy-, amino-, and ketotrifluoromethylation will be followed by discussion of the synthesis of CF3-alkenes via photocatalytic trifluoromethylation of olefins and alkynes. Finally, difluoromethylation of alkenes will be reviewed. Before the description of the main topics, the basic concept of our catalytic reaction system is explained.

Figure 1. Oxidation potentials of the photo-excited photoredox catalysts and the ground-state fluoromethylating reagents highlighted in this Account. aPotentials are reported values.27 bCyclic voltammetry was performed in acetonitrile at room temperature. cMeasured in dimethyl sulfoxide (DMSO) at room temperature. Abbreviations: Cp2Fe, ferrocene; tBu, tert-butyl group; Ts: p-toluenesulfonyl group.

2. BASIC CONCEPT The concept of our reaction system based on one of the two possible SET photoredox sequences, the oxidative quenching cycle, is shown in Scheme 2. First, visible-light irradiation causes excitation of the photoredox catalyst (M) to the excited triplet state (M*), where the electron in the higher-energy SOMO serves as a one-electron reductant as described above. Then the electrophilic fluoromethylating reagent (CF2X−L, 1) undergoes the first SET event from M* to generate the oxidized metal species (M+) and the fluoromethyl radical (· CF2X) with elimination of L. Addition of ·CF2X to the carbon− carbon multiple bond proceeds in a regioselective manner, so

Electron transfer is one of the useful stimuli to generate radical species from appropriate precursors. For the past several years, visible-light-driven photoredox catalysis with a metal complex (M) such as [Ru(bpy)3]2+ or fac-[Ir(ppy)3] has been regarded as a convenient catalytic system involving singleelectron-transfer (SET) processes.24−30 The excited triplet state of the photoredox catalyst (M*) contains an electron in the higher singly occupied molecular orbital (SOMO) and a hole in the lower SOMO and therefore can serve as either a oneelectron reductant or a one-electron oxidant, respectively. They play pivotal roles in the radical initiating system. The potentials B


Article

Accounts of Chemical Research

Scheme 3. Photocatalytic Hydroxytrifluoromethylationa

Scheme 2. Basic Concept of Fluoromethylation of Carbon− Carbon Multiple Bonds through Photoredox SET Processes Highlighted in the Present Account

that the more stable radical intermediate A′ is formed. Subsequently, M+ induces the second SET event from the radical intermediate A′, resulting in the formation of the αfluoromethylated carbocationic intermediate A, which is susceptible to nucleophilic addition or elimination to afford the final fluoromethylated products. In the presence of appropriate nucleophiles (Nu−), the corresponding difunctionalized products bearing the fluoromethyl group are formed with no need to add any sacrificial redox agents. Thus, the present concept allows us to access a variety of structurally diverse compounds bearing the fluoromethyl group from alkenes and alkynes.39−50

a

LED, light-emitting diode; Me, methyl group; Ph, phenyl group; Bpin, boronic acid pinacol ester group.

1a, was observed. When less reactive substrates were used, considerable amounts of trifluoromethylated dibenzothiophenes were obtained, resulting in lower yields of the desired products. It should be noted that the reaction system harnesses daylight as the light source (Scheme 4).51 Scheme 4. Sunlight-Driven Reaction

3. TRIFLUOROMETHYLATIVE DIFUNCTIONALIZATION OF ALKENES Trifluoromethylation of alkenes is one of the straightforward methods for the construction of a C(sp3)−CF3 bond. Furthermore, catalytic trifluoromethylative difunctionalization reactions of alkenes, i.e., simultaneous introduction of the CF3 group and a different functional group across carbon−carbon double bonds, are valuable protocols for the synthesis of structurally complex trifluoromethylated compounds in a single step, but such examples have been limited until recent years.31−34 In this section, the synthesis of a variety of β-CF3substituted compounds such as alcohols,51 heterocyclic compounds,52,53 amines,54 and ketones55 through photoredox-catalyzed trifluoromethylation will be discussed.

Furthermore, alcohols and carboxylic acids can also be used as O-nucleophiles 4 instead of water. For example, the reactions with methanol (MeOH) (4a), 2-methyl-2-butanol (Me2EtCOH) (4b), and acetic acid (AcOH) (4c) provide the corresponding CF3-ether (5aa and 5ba) and -ester (6ca) products (Scheme 5). These results suggest that the photocatalytic reaction of alkenes with the electrophilic CF3 reagent efficiently generates the α-CF3-substituted carbocationic

3.1. Oxytrifluoromethylation

Reactive carbocationic species readily undergo attack by various oxygen nucleophiles such as water, alcohols, and carboxylic acids. Thus, if α-CF3-substituted carbocationic intermediate A is generated from an alkene in the presence of an oxygen nucleophile, oxytrifluoromethylative difunctionalization of the carbon−carbon double bond can be achieved. To our delight, the reaction of styrene (2a) with Umemoto reagent 1a in the presence of 0.5 mol % fac-[Ir(ppy)3] in a 9:1 acetone/water mixture under visible-light irradiation (blue LEDs, λ = 425 ± 15 nm) afforded the hydroxytrifluoromethylated product 3a in 88% isolated yield in a regiospecific manner (Scheme 3). The present reaction showed broad scope and regioselectivity for both terminal and internal aromatic alkenes 2 (16 examples, 41−98% yield). However, aliphatic alkenes did not produce the corresponding products well. At that time, trifluoromethylation of dibenzothiophene, which is a residue of

Scheme 5. Photocatalytic Oxytrifluoromethylationa

a

C

Et, ethyl group; Ac, acetyl group. DOI: 10.1021/acs.accounts.6b00268 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article


13, and 14) resulted from anti addition with respect to the CF3 group and the nucleophile oxygen atom.

intermediate A1 in situ (Scheme 3). Furthermore, the experiment with alternating visible-light irradiation and shielding from light during the reaction resulted in repetition of progress and suspension of the reaction, respectively. These results suggest that usual radical chain propagation is not a main mechanistic component. When alkenoic acids 7 were subjected to the present photocatalytic system, intramolecular oxytrifluoromethylation proceeded in a highly endo- and diastereoselective manner to produce CF3-substituted endo-lactones 8 (19 examples, 28− 85% yield, up to >49:1 dr). The reactions of (E)- and (Z)-4phenyl-3-butenoic acid (E-7a and Z-7a) gave the same CF3lactone product 8a as a single isomer in good isolated yields via the common equilibrated carbocationic intermediate A2 (Scheme 6).52 Furthermore, when the reaction system was

3.2. Aminotrifluoromethylation

Organic nitrile works as an aminative reagent if it captures carbocationic species (i.e., Ritter-type amination57). When the reaction of 2a with 1a in the presence of 0.5 mol % [Ru(bpy)3](PF6)2 in acetonitrile (containing 1 equiv of water) was conducted, the aminotrifluoromethylated product 15a was obtained in 88% yield in a regiospecific manner (Scheme 8). The aminotrifluoromethylation exhibited signifiScheme 8. Photocatalytic Aminotrifluoromethylationa

Scheme 6. Intramolecular Oxytrifluoromethylation of Alkenoic Acidsa

a

a

Reactions of 2h and 2i were performed in a mixture of CH2Cl2 and MeCN because of the low solubility of the substrate in MeCN. Bz, benzoyl group.

MeCN, acetonitrile.

applied to cyclic alkenes bearing nucleophilic pendants such as amide (9 and 10) and alcohol (11),53,56 trifluoromethylative spirocyclization proceeded in a highly diastereoselective manner to afford CF3-containing spirooxazolines (12), spirooxazines (13), and spiroethers (14), respectively (Scheme 7). It should be noted that the structure of the nucleophilic pendant strongly influences the diastereoselectivity. However, the major isomers of the CF3-containing heterocycles (8, 12,

cant functional group tolerance (24 examples, 56−91% yield). For example, cinnamic acid ester 2g afforded the CF3containing amino acid derivative 15g in 80% yield. In addition, structurally complex, biologically active estrone derivative 2h and amino acid derivative 2i could be also applied to the present aminotrifluoromethylation.54 3.3. Ketotrifluoromethylation

Kornblum oxidation58 is a well-known reaction of alkyl halides with DMSO to afford aldehydes, and its mechanism involves deprotonation of the alkoxysulfonium intermediate resulting from the nucleophilic substitution of the two reagents. The similar intermediate B1 may be formed by the reaction of αCF3-substituted carbocationic intermediate A3 to give α-CF3substituted ketones 16 upon treatment with a base (Scheme 9). The reaction of β-methylstyrene (2e) with Togni reagent 1c in the presence of 2 mol % fac-[Ir(ppy)3] in DMSO under visible-light irradiation (blue LEDs, λ = 425 ± 15 nm) gave αCF3-substituted ketone 16e in 75% isolated yield (Scheme 9). As shown in Figure 1, the photoexcited fac-[Ir(ppy)3] species is strong enough to reduce 1c. In addition, o-iodobenzoate anion, which is generated in the first SET step, works as the base to deprotonate alkoxysulfonium intermediate B1. The scope was broad (21 examples, 28−87% yield), but the reaction of terminal aromatic alkenes was accompanied by the formation of CF3-alkenes Ar−CHCHCF3 (18). It should be noted that the reaction of α-cyclohexylstyrene (2k), an α-substituted styrene, also yielded the parent ketone compound 16a resulting

Scheme 7. Photocatalytic CF3-Spirocyclizationa

a Reactions of 9 and 10 were performed under irradiation with 425 nm blue LEDs. The reaction of 11 was conducted under irradiation with 470 nm blue LEDs.

D


Article

Accounts of Chemical Research Scheme 9. Photocatalytic Ketotrifluoromethylationa

until recent years.62,63 As described in the previous sections, photocatalytic alkene difunctionalization involves CF3-substituted cationic intermediate A (Scheme 2). An elimination process from A may provide CF3-substituted alkenes 18 when A has an appropriate leaving group at the β-position.64,65 Furthermore, oxytrifluoromethylation of alkynes is also a promising protocol for the synthesis of tetrasubstituted CF3alkenes, as described below.66 In this section, the synthesis of CF3-alkenes from alkenyltrifluoroborates, multisubstituted alkenes, and internal alkynes will be discussed. 4.1. Trifluoromethylation of Alkenyltrifluoroborates

Alkenyltrifluoroborates serve as SOMO-philic reagents that may react with radical species to give alkenylated products after spontaneous deboronation.67 The reaction of potassium styryltrifluoroborate (17a) with Togni reagent 1c in the presence of 5 mol % [Ru(bpy)3](PF6)2 in MeOH afforded βtrifluoromethylstyrene (18a) in 81% yield with high E selectivity (E/Z = 98:2) (Scheme 10). The combination of Scheme 10. Photocatalytic Trifluoromethylation of Alkenyltrifluoroboratesa

a

Cy, cyclohexyl group.

from elimination of the α-alkyl substituent. This result suggests that another reaction mechanism operates because the corresponding alkoxysulfonium intermediate B2 cannot be dealkylated by the action of a base. An alternative reaction pathway may involve β-scission of the reactive alkoxy radical species C, which might be formed through one-electron reduction of intermediate B2 by the photoexcited Ir catalyst.55

4. SYNTHESIS OF TRIFLUOROMETHYLATED ALKENES Trifluoromethylated alkenes are a useful structural scaffold in biologically active compounds and organic functional materials, as shown in Figure 2.59−61 However, their step-economical synthesis based on simple trifluoromethylation has been limited

a

The yield of 18a and the stereoisomer ratios were determined by NMR spectroscopy.

[Ru(bpy)3]2+ as the photocatalyst and 1c as the CF3 source turned out to be crucial in terms of the yield and stereoselectivity, as the use of the Ir photocatalyst fac[Ir(ppy)3] and other CF3 sources resulted in unsatisfactory outcomes. The present photocatalytic system features (i) high E selectivity and (ii) the formation of CF3-alkenes bearing a variety of functional groups, especially π-electron-deficient heteroaromatics (22 examples, 56−93% yield, up to E/Z = 99:1).64 These results show that alkenyltrifluoroborates are good acceptors of the CF3 radical and that the boron-based group is readily eliminated under the present photocatalytic conditions. 4.2. Trifluoromethylation of Multisubstituted Alkenes

The stereoselective synthesis of multisubstituted CF3-alkenes can also be achieved by photoredox catalysis. As described in section 3.3, under the photocatalytic ketotrifluoromethylation conditions, CF3-alkenes 18 were obtained as byproducts. This result prompted us to investigate the reaction system that afforded CF3-alkenes 18 as the main products. The reaction of 1,1-diphenylethylene (2p) with Umemoto reagent 1a in the presence of 2 mol % [Ru(bpy)3](PF6)2 in DMSO selectively provided the corresponding CF3-alkene 18p in 82% NMR yield

Figure 2. Representative examples of valuable CF3-alkenes. E


Article

Accounts of Chemical Research (Scheme 11). Various 1,1-diaryl and triaryl alkenes can be applied to the present reaction (13 examples, 37−82% yield).65

Scheme 12. Photocatalytic CF3-Triflation and -Tosylation of Alkynesa

Scheme 11. Photocatalytic Trifluoromethylation of Multisubstituted Alkenesa

a

The yields of 18p and 18q were determined by NMR spectroscopy.

Remarkably, the electronic properties of substituents on the benzene ring significantly influenced the stereoselectivity. Furthermore, it is notable that the present reaction has a limitation with respect to α-alkylstyrenes. The reaction of αmethylstyrene (2d) gave a mixture of isomers 18d and 19d under similar reaction conditions (19d:18d = 2.5:1).68 These results imply that not only simple trifluoromethylation of olefins but also a highly programmed protocol for the selective and versatile synthesis of multisubstituted CF3-alkenes would be taken into consideration. For example, stepwise functionalizations of internal alkynes composed of a fine combination of photocatalytic trifluoromethylation and other catalyses can be designed, as described below.

a

Boc, tertiary butoxycarbonyl group; nBu, normal butyl group.

as unactivated alkenes and alkynes are used, considerable amounts of trifluoromethylated dibenzothiophenes are formed. Diphenyl sulfide formed from 1b is less reactive with respect to trifluoromethylation, resulting in a better CF3 source in the present reaction. While the trifluoromethanesulfonyloxytrifluoromethylation (CF3-triflation) of alkynes requires an excess amount of 1b with respect to alkyne, the CF3-alkenyl triflates 21 are formed in a highly stereoselective manner (15 examples, 30−86% yield, up to E/Z = 97:3). On the other hand, isolation of CF3-alkenyl triflates formed from the reaction of aryl alkynes bearing an electron-donating group (EDG) on the benzene ring was difficult because they are susceptible to hydrolysis. To overcome this problem, the corresponding CF3-alkenyl triflates were converted in situ to the CF3-alkenyl tosylates 22 by carrying out the reaction in the presence of a tosylate salt, which is more nucleophilic but still reactive enough for the Pdcatalyzed coupling reaction (vide infra). The CF3-tosylation also proceeded in a stereoselective manner to give alkenyl tosylates 22d−f, which have an EDG on the benzene ring (Scheme 12). It is notable that the resultant CF3-alkenyl sulfonates 21 and 22 undergo Pd-catalyzed coupling reactions without significant loss of the stereoselectivity, leading to the successful stereocontrolled synthesis of tetrasubstituted CF3-alkenes. For example, two stereoisomers of 18s were obtained separately and selectively with different combinations of alkynes 20a and 20d and the arylboronic acids (Scheme 13). Thus, the operationally simple synthesis of tetrasubstituted CF3-alkenes from internal aryl alkyl alkynes is achieved. The high stereoselectivity is attributed to (i) regioselective addition of the CF3 radical so as to form the more stable α-aryl radical A′ (Scheme 2) and (ii) nuceophilic attack of the sulfonate anion

4.3. Sulfonyloxytrifluoromethylation of Alkynes

Difunctionalization of internal alkynes is a key strategy for the synthesis of tetrasubstituted alkenes.69−71 The concept of trifluoromethylative difunctionalization of alkenes discussed in section 3 can be extended to alkynes. In particular, alkenyl sulfonates are synthetically useful electrophiles because they can undergo further functionalization such as palladium-catalyzed cross-coupling reactions, leading to diverse alkenyl compounds. Photocatalytic trifluoromethylation of alkynes in the presence of trifluoromethanesulfonate (TfO−) or p-toluenesulfonate (TsO−), an O-nucleophile, would allow us to access CF3-alkenyl sulfonates. To our delight, the reaction of 1phenylpropyne (20a) with the triflate salt of Yagupolskii− Umemoto reagent 1b in the presence of 5 mol % [Ir(ppy)2(dtbbpy)](PF6) and 2,6-di-tert-butylpyridine in CH2Cl2 under visible-light irradiation afforded CF3-alkenyl triflate 21a in 74% yield in a highly stereoselective manner (E/ Z = 96:4) (Scheme 12). The combination of the Ir photocatalyst and 1b turned out to be the best option in terms of yield, efficiency, and stereoselectivity. Umemoto reagent 1a is the most reactive reagent among the reagents highlighted in Figure 1. However, as mentioned in section 3.1, when less reactive substrates such F


Article


6. SUMMARY AND FUTURE PROSPECTS We have developed a useful strategy for access to α-CF3substituted carbocationic species A from the reaction of unsaturated hydrocarbons with electrophilic fluoromethylating reagents 1 generated by the action of photoredox catalysis. This species A undergoes the following various functionalizations (Scheme 15): (i) nucleophilic attack of water, alcohols,

Scheme 13. One-Pot Stereocontrolled Synthesis of Tetrasubstituted CF3-Alkenes

Scheme 15. Summary of the Catalytic Radical Fluoromethylation of Carbon−Carbon Multiple Bonds by Photoredox Catalysis Highlighted in This Account

from the side opposite to the strongly electronegative CF3 group.66 These results show that the present photocatalytic fluoromethylation can be applied not only to alkenes but also to other carbon−carbon multiple bonds through fine design of the reaction system.

5. DIFLUOROMETHYLATIVE DIFUNCTIONALIZATION Compared with trifluoromethylation, direct and catalytic introduction of the CF2H group (i.e., difluoromethylation) is still in an underdeveloped stage.72,73 On the other hand, various types of CF2H reagents for ionic or carbenoid reactions have been developed in recent years.74 From the viewpoint of synthetic ease and stability, Hu reagent 1d with the electronwithdrawing sulfoximine group (Figure 1) is a useful difluoromethylating reagent.75 In fact, the reaction of 2a with Hu reagent 1d under the ideal conditions for hydroxytrifluoromethylation (section 3.1) afforded the hydroxydifluoromethylated product 23a in 72% isolated yield (Scheme 14).

carboxylic acids, and amides; (ii) Ritter-type amination; (iii) Kornblum-type oxidation; and (iv) elimination such as deboronation and deprotonation. Fine design of the reaction system leads to the successful synthesis of a variety of trifluoromethylated compounds through redox-neutral processes. In addition, the chemistry shows the potential of photoredox catalysis for catalytic trifluoromethylation of alkynes and difluoromethylation. In general, the photoredox reaction system can be performed under mild reaction conditions, i.e., visible-light irradiation, including natural sunlight, below room temperature. This may be associated with high compatibility toward functional groups and stereoselective reactions. As further expansion and deepening the present photocatalytic fluoromethylation, the development of stereoselective asymmetric reactions is one of the challenges in the future. The sophisticated design of photocatalytic systems such as dual photoredox/asymmetric catalysis and new fluoromethylating reagents would be a hopeful strategy.

Scheme 14. Photocatalytic Oxydifluoromethylation of Alkenes

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (T. Koike). *E-mail: [email protected] (M. Akita). Author Contributions

Both authors contributed to the paper. Notes

The authors declare no competing financial interest.

The scope is significantly broad (20 examples, 32−88% yield).76 In addition, alcohols and carboxylic acids can also be used as O-nucleophiles in a manner similar to oxytrifluoromethylation mentioned above. Further exploration of photocatalytic difluoromethylation56 is underway in our laboratory.

Biographies Takashi Koike was born in 1977 in Toyama, Japan. He received his doctoral degree from Tokyo Institute of Technology in 2005 under the guidance of Prof. Takao Ikariya. After his graduate career, he G


Article


(17) Charpentier, J.; Früh, N.; Togni, A. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem. Rev. 2015, 115, 650−682. (18) Shibata, N.; Matsnev, A.; Cahard, D. Shelf-Stable Electrophilic Trifluoromethylating Reagents: A Brief Historical Perspective. Beilstein J. Org. Chem. 2010, DOI: 10.3762/bjoc.6.65. (19) Macé, Y.; Magnier, E. The New Age of Electrophilic Perfluoroalkylation Reactions. Eur. J. Org. Chem. 2012, 2012, 2479− 2494. (20) Barata-Vallejo, S.; Lantaño, B.; Postigo, A. Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents. Chem. - Eur. J. 2014, 20, 16806−16829. (21) Zhang, C. Recent Advances in Trifluoromethylation of Organic Compounds Using Umemoto’s Reagents. Org. Biomol. Chem. 2014, 12, 6580−6589. (22) Alonso, C.; Martinez de Marigorta, E.; Rubiales, G.; Palacios, F. Carbon Trifluoromethylation Reactions of Hydrocarbon Derivatives and Heteroarenes. Chem. Rev. 2015, 115, 1847−1935. (23) Wang, S.-M.; Han, J.-B.; Zhang, C.-P.; Qin, H.-L.; Xiao, J.-C. An Overview of Reductive Trifluoromethylation Reactions Using Electrophilic ‘+CF3’ Reagents. Tetrahedron 2015, 71, 7949−7976. (24) Yoon, T. P.; Ischay, M. A.; Du, J. Visible Light Photocatalysis as a Greener Approach to Photochemical Synthesis. Nat. Chem. 2010, 2, 527−532. (25) Narayanam, J. M. R.; Stephenson, C. R. J. Visible Light Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102−113. (26) Xuan, J.; Xiao, W.-J. Visible-Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2012, 51, 6828−6838. (27) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (28) Hari, D. P.; König, B. The Photocatalyzed Meerwein Arylation: Classic Reaction of Aryl Diazonium Salts in a New Light. Angew. Chem., Int. Ed. 2013, 52, 4734−4743. (29) Hopkinson, M. N.; Sahoo, B.; Li, J.-L.; Glorius, F. Dual Catalysis Sees the Light: Combining Photoredox with Organo-, Acid, and Transition-Metal Catalysis. Chem. - Eur. J. 2014, 20, 3874−3886. (30) Koike, T.; Akita, M. Visible-Light Radical Reaction Designed by Ru- and Ir-Based Photoredox Catalysis. Inorg. Chem. Front. 2014, 1, 562−576. (31) Egami, H.; Sodeoka, M. Trifluoromethylation of Alkenes with Concomitant Introduction of Additional Functional Groups. Angew. Chem., Int. Ed. 2014, 53, 8294−8308. (32) Merino, E.; Nevado, C. Addition of CF3 Across Unsaturated Moieties: a Powerful Functionalization Tool. Chem. Soc. Rev. 2014, 43, 6598−6608. (33) Xu, J.; Liu, X.; Fu, Y. Recent Advance in Transition-MetalMediated Trifluoromethylation for the Construction of C(sp3)−CF3 Bonds. Tetrahedron Lett. 2014, 55, 585−594. (34) Koike, T.; Akita, M. Recent Progress in Transition-MetalCatalyzed Trifluoromethylation of Olefins Using Electrophilic CF3 Reagents. J. Fluorine Chem. 2014, 167, 30−36. (35) Allen, A. E.; MacMillan, D. W. C. The Productive Merger of Iodonium Salts and Organocatalysis: A Non-photolytic Approach to the Enantioselective α-Trifluoromethylation of Aldehydes. J. Am. Chem. Soc. 2010, 132, 4986−4987. (36) Koike, T.; Akita, M. Trifluoromethylation by Visible-LightDriven Photoredox Catalysis. Top. Catal. 2014, 57, 967−974. (37) Barata-Vallejo, S.; Bonesi, S. M.; Postigo, A. Photocatalytic Fluoroalkylation Reactions of Organic Compounds. Org. Biomol. Chem. 2015, 13, 11153−11183. (38) Cho, E. J. Radical-Mediated Fluoroalkylations. Chem. Rec. 2016, 16, 47−63. (39) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis. J. Am. Chem. Soc. 2009, 131, 10875−10877. (40) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Photoredox Catalysis: A Mild, Operationally Simple Approach to the Synthesis of

joined the group of Professor Robert H. Grubbs at California Institute of Technology as a postdoctoral research scholar. In 2007 he returned to Tokyo Institute of Technology as an assistant professor of the Chemical Resources Laboratory, and now he is posted to the Institute of Innovative Research. His research interests are in synthetic organic chemistry and organometallic chemistry. Recently his efforts have been directed to the development of visible-light-driven photocatalysis. Munetaka Akita, who was born in Fukuoka, Japan, in 1957, is Professor and Director of the Laboratory for Chemistry and Life Science at Tokyo Institute of Technology. He received his Master’s and Ph.D. degrees from Kyoto University (with Prof. Makoto Kumada) and Osaka University (with Prof. Akira Nakamura), respectively. In 1984 he moved to Tokyo Institute of Technology as a research associate and was appointed as a professor in 2002. Recently his research interests have involved the application of carbon-rich organometallics to molecular devices, photoredox catalysis, and supramolecular systems based on anthracene.

■

ACKNOWLEDGMENTS The authors thank the JSPS (KAKENHI Grants 23750174, 26288045, 15K13689, 16H06038, and JP16H01009 in Precisely Designed Catalysts with Customized Scaffolding) and the Naito Foundation.

■

REFERENCES

(1) Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer: Berlin, 2000. (2) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Chichester, U.K., 2009. (3) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany, 2013. (4) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881−1886. (5) Hagmann, W. K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359−4369. (6) Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529−2591. (7) Dolbier, W. R., Jr. Structure, Reactivity, and Chemistry of Fluoroalkyl Radicals. Chem. Rev. 1996, 96, 1557−1584. (8) Studer, A. A. Renaissance” in Radical Trifluoromethylation. Angew. Chem., Int. Ed. 2012, 51, 8950−8958. (9) Haszeldine, R. N. The Reactions of Fluorocarbon Radicals. Part I. The Reaction of Iodotrifluoromethane with Ethylene and Tetrafluoroethylene. J. Chem. Soc. 1949, 2856−2861. (10) Kamigata, N.; Fukushima, T.; Terakawa, Y.; Yoshida, M.; Sawada, H. Novel Perfluoroalkylation of Alkenes with Perfluoroalkanesulphonyl Chlorides Catalysed by a Ruthenium(II) Complex. J. Chem. Soc., Perkin Trans. 1 1991, 627−633. (11) Langlois, B. R.; Laurent, E.; Roidot, N. Trifluoromethylation of Aromatic Compounds with Sodium Trifluoromethanesulfinate under Oxidative Conditions. Tetrahedron Lett. 1991, 32, 7525−7528. (12) Umemoto, T.; Ishihara, S. Power-Variable Trifluoromethylating Agents, (Trifluoromethyl)dibenzothio- and − selenophenium Salt System. Tetrahedron Lett. 1990, 31, 3579−3582. (13) Umemoto, T. Electrophilic Perfluoroalkylating Agents. Chem. Rev. 1996, 96, 1757−1777. (14) Umemoto, T.; Ishihara, S. Power-Variable Electrophilic Trifluoromethylating Agents. S-, Se-, and Te-(Trifluoromethyl)dibenzothio-, -seleno-, and − tellurophenium Salt System. J. Am. Chem. Soc. 1993, 115, 2156−2164. (15) Yang, J.-J.; Kirchmeier, R. L.; Shreeve, J. M. New Electrophilic Trifluoromethylating Agents. J. Org. Chem. 1998, 63, 2656−2660. (16) Eisenberger, P.; Gischig, S.; Togni, A. Novel 10-I-3 Hypervalent Iodine-Based Compounds for Electrophilic Trifluoromethylation. Chem. - Eur. J. 2006, 12, 2579−2586. H


Article

Accounts of Chemical Research α-Trifluoromethyl Carbonyl Compounds. Angew. Chem., Int. Ed. 2011, 50, 6119−6122. (41) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. Intermolecular Atom Transfer Radical Addition to Olefins Mediated by Oxidative Quenching of Photoredox Catalysts. J. Am. Chem. Soc. 2011, 133, 4160−4163. (42) 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. 2013, 135, 2505−2508. (43) Xu, P.; Xie, J.; Xue, Q.; Pan, C.; Cheng, Y.; Zhu, C. VisibleLight-Induced Trifluoromethylation of N-Aryl Acrylamides: A Convenient and Effective Method To Synthesize CF3-Containing Oxindoles Bearing a Quaternary Carbon Center. Chem. - Eur. J. 2013, 19, 14039−14042. (44) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Controlled Trifluoromethylation Reactions of Alkynes through Visible-Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2014, 53, 539−542. (45) Carboni, A.; Dagousset, G.; Magnier, E.; Masson, G. One Pot and Selective Intermolecular Aryl- and Heteroaryl-Trifluoromethylation of Alkenes by Photoredox Catalysis. Chem. Commun. 2014, 50, 14197−14200. (46) Tang, X.-J.; Thomoson, C. S.; Dolbier, W. R., Jr. PhotoredoxCatalyzed Tandem Radical Cyclization of N-Arylacrylamides: General Methods To Construct Fluorinated 3,3-Disubstituted 2-Oxindoles Using Fluoroalkylsulfonyl Chlorides. Org. Lett. 2014, 16, 4594−4597. (47) Bagal, D. B.; Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage, B. M.; Reiser, O. Trifluoromethylchlorosulfonylation of Alkenes: Evidence for an Inner-Sphere Mechanism by a Copper Phenanthroline Photoredox Catalyst. Angew. Chem., Int. Ed. 2015, 54, 6999−7002. (48) Sahoo, B.; Li, J.-L.; Glorius, F. Visible-Light PhotoredoxCatalyzed Semipinacol-Type Rearrangement: Trifluoromethylation/ Ring Expansion by a Radical-Polar Mechanism. Angew. Chem., Int. Ed. 2015, 54, 11577−11580. (49) Tang, X.-J.; Dolbier, W. R., Jr. Efficient Cu-catalyzed Atom Transfer Radical Addition Reactions of Fluoroalkylsulfonyl Chlorides with Electron-deficient Alkenes Induced by Visible Light. Angew. Chem., Int. Ed. 2015, 54, 4246−4249. (50) Lin, Q.-Y.; Xu, X.-H.; Zhang, K.; Qing, F.-L. Visible-LightInduced Hydrodifluoromethylation of Alkenes with a Bromodifluoromethylphosphonium Bromide. Angew. Chem., Int. Ed. 2016, 55, 1479−1483. (51) Yasu, Y.; Koike, T.; Akita, M. Three-component Oxytrifluoromethylation of Alkenes: Highly Efficient and Regioselective Difunctionalization of CC Bonds Mediated by Photoredox Catalysts. Angew. Chem., Int. Ed. 2012, 51, 9567−9571. (52) Yasu, Y.; Arai, Y.; Tomita, R.; Koike, T.; Akita, M. Highly Regioand Diastereoselective Synthesis of CF3-Substituted Lactones via Photoredox-Catalyzed Carbolactonization of Alkenoic Acids. Org. Lett. 2014, 16, 780−783. (53) Noto, N.; Miyazawa, K.; Koike, T.; Akita, M. AntiDiastereoselective Synthesis of CF3-Containing Spirooxazolines and Spirooxazines via Regiospecific Trifluoromethylative Spirocyclization by Photoredox Catalysis. Org. Lett. 2015, 17, 3710−3713. (54) Yasu, Y.; Koike, T.; Akita, M. Intermolecular Aminotrifluoromethylation of Alkenes by Visible-Light-Driven Photoredox Catalysis. Org. Lett. 2013, 15, 2136−2139. (55) 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. 2014, 53, 7144−7148. (56) Noto, N.; Koike, T.; Akita, M. Diastereoselective Synthesis of CF3- and CF2H-Substituted Spiroethers from Aryl-Fused Cycloalkenylalkanols by Photoredox Catalysis. J. Org. Chem. 2016, DOI: 10.1021/acs.joc.6b00953. (57) Ritter, J. J.; Minieri, P. P. A New Reaction of Nitriles. I. Amides from Alkenes and Mononitriles. J. Am. Chem. Soc. 1948, 70, 4045− 4048.

(58) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver, W. M. A New and Selective Method of Oxidation. J. Am. Chem. Soc. 1957, 79, 6562. (59) Shimizu, M.; Hiyama, T. Modern Synthetic Methods for Fluorine-Substituted Target Molecules. Angew. Chem., Int. Ed. 2005, 44, 214−231. (60) Rivkin, A.; Chou, T.-C.; Danishefsky, S. J. On the Remarkable Antitumor Properties of Fludelone: How We Got There. Angew. Chem., Int. Ed. 2005, 44, 2838−2850. (61) Shimizu, M.; Takeda, Y.; Higashi, M.; Hiyama, T. 1,4Bis(alkenyl)-2,5-dipiperidinobenzenes: Minimal Fluorophores Exhibiting Highly Efficient Emission in the Solid State. Angew. Chem., Int. Ed. 2009, 48, 3653−3656. (62) Besset, T.; Poisson, T.; Pannecoucke, X. Recent Progress in Direct Introduction of Fluorinated Groups on Alkenes and Alkynes by means of C−H Bond Functionalization. Chem. - Eur. J. 2014, 20, 16830−16845. (63) Gao, P.; Song, X.-R.; Liu, X.-Y.; Liang, Y.-M. Recent Developments in the Trifluoromethylation of Alkynes. Chem. - Eur. J. 2015, 21, 7648−7661. (64) Yasu, Y.; Koike, T.; Akita, M. Visible-Light-Induced Synthesis of a Variety of Trifluoromethylated Alkenes from Potassium Vinyltrifluoroborates by Photoredox Catalysis. Chem. Commun. 2013, 49, 2037−2039. (65) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Direct C−H Trifluoromethylation of Di- and Trisubstituted Alkenes by Photoredox Catalysis. Beilstein J. Org. Chem. 2014, 10, 1099−1106. (66) Tomita, R.; Koike, T.; Akita, M. Photoredox-Catalyzed Stereoselective Conversion of Alkynes into Tetrasubstituted Trifluoromethylated Alkenes. Angew. Chem., Int. Ed. 2015, 54, 12923−12927. (67) Kim, H.; MacMillan, D. W. C. Enantioselective Organo-SOMO Catalysis: The α-Vinylation of Aldehydes. J. Am. Chem. Soc. 2008, 130, 398−399. (68) Asano, M.; Tomita, R.; Koike, T.; Akita, M. Trifluoromethylation of Aromatic Alkenes by Visible-Light-Driven Photoredox Catalysis: Direct Conversion of Alkenes to 3-Trifluoromethyl-1propenyl and 1,3-Bis(trifluoromethyl)-1-propenyl Derivatives. J. Fluorine Chem. 2015, 179, 83−88. (69) Itami, K.; Kamei, T.; Yoshida, J.-i. Diversity-Oriented Synthesis of Tamoxifen-type Tetrasubstituted Olefins. J. Am. Chem. Soc. 2003, 125, 14670−14671. (70) Suero, M. G.; Bayle, E. D.; Collins, B. S. L.; Gaunt, M. J. Copper-Catalyzed Electrophilic Carbofunctionalization of Alkynes to Highly Functionalized Tetrasubstituted Alkenes. J. Am. Chem. Soc. 2013, 135, 5332−5335. (71) Xue, F.; Zhao, J.; Hor, T. S. A.; Hayashi, T. Nickel-Catalyzed Three-Component Domino Reactions of Aryl Grignard Reagents, Alkynes, and Aryl Halides Producing Tetrasubstituted Alkenes. J. Am. Chem. Soc. 2015, 137, 3189−3192. (72) Hu, J.; Zhang, W.; Wang, F. Selective Difluoromethylation and Monofluoromethylation Reactions. Chem. Commun. 2009, 7465− 7478. (73) Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X. Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers. Chem. Eur. J. 2015, 21, 12836−12865. (74) Ni, C.; Hu, M.; Hu, J. Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis. Chem. Rev. 2015, 115, 765−825. (75) Zhang, W.; Wang, F.; Hu, J. N-Tosyl-S-difluoromethyl-Sphenylsulfoximine: A New Difluoromethylation Reagent for S-, N-, and C-Nucleophiles. Org. Lett. 2009, 11, 2109−2112. (76) Arai, Y.; Tomita, R.; Ando, G.; Koike, T.; Akita, M. Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H-Containing Alcohols. Chem. - Eur. J. 2016, 22, 1262−1265.

I


Fine Design of Photoredox Systems for Catalytic Fluoromethylation of

Recommend Documents