Trifluoromethyltrimethylsilane: Nucleophilic Trifluoromethylationand BeyondXiao Liu, Cong Xu, Mang Wang,* and Qun Liu*

Department of Chemistry, Northeast Normal University, Changchun 130024, China

CONTENTS

1. Introduction B2. Synthesis of Trifluoromethyltrimethylsilane B3. Reactions with Carbon Electrophiles C

3.1. Trifluoromethylation of Aldehydes and Ke-tones D

3.2. 1,4-Trifluoromethylation Reactions E3.3. Trifluoromethylation of 4-Nitroisoxazoles F3.4. Trifluoromethylation of Anhydrides and

Weinreb Amides F3.5. Trifluoromethylation of Imines H

3.5.1. Trifluoromethylation of Azirines H3.5.2. TMAF Mediated Trifluoromethylation of

Aldimines H3.5.3. HF Promoted Trifluoromethylation of

Imines H3.5.4. Trifluoromethylation of N-Tosyl Imines

Based on Phase-Transfer Catalysis I3.6. Direct Trifluoromethylation of Csp3−H Bond

Adjacent to a Nitrogen Atom JMethod A JMethod B J

3.7. Selective Trifluoromethylation of Multi-Functional Substrates K

3.8. Enantioselective Trifluoromethylation M3.8.1. Aldehydes and Ketones: With Cinchona-

Derived Quaternary Ammonium Fluo-ride Salts as Catalysts M

3.8.2. Aldehydes and Ketones: Phase-TransferCatalysis Mode N

3.8.3. Aldehydes and Ketones: CombinationCatalysis Mode O

3.8.4. Enantioselective Trifluoromethylation ofImines Q

3.9. Catalysts and Mechanisms Considerations Q3.9.1. Oxygen Centered Nucleophilic Catalysts Q3.9.2. Substrate-Directable Reaction R3.9.3. DMSO and Molecular Sieves S3.9.4. Amidine Base T3.9.5. N-heterocyclic Carbene or Phosphines

in DMF T

3.9.6. Lewis Acids T4. Reactions with B-, P-, and S-Based Electrophiles V

4.1. Preparation and Synthetic Applications of(Trifluoromethyl)trimethoxyborate V

4.2. Reactions with Phosphorus-Based Electro-philes W

4.3. Reactions with Sulfur-Based Electrophiles W5. Trifluoromethyltrimethylsilane As a Difluorocar-

bene Precursor W5.1. [2 + 1] Cycloaddition W5.2. Direct α-Difluoromethylation of Lithium

Enolates X5.3. Reaction of Difluorocarbene with Acetylene

Ethers Y6. Trifluoromethylation Involving Transition Metal

Complexes Z6.1. Cu-Catalyzed Trifluoromethylation of Allylic

Halides Z6.2. Trifluoromethylation of α-Haloketones with

CuCF3 AA6.3. Cu-Catalyzed Trifluoromethylation of Prop-

argylic Halides AB7. Synthesis of Benzotrifluorides Based on Pre-

Functionalization AB8. Electrophilic and Oxidative Trifluoromethylation

Reactions AF8.1. Shelf-Stable Electrophilic Trifluoromethylat-

ing Reagents AF8.2. Cyclic Hypervalent Iodine(III) Electrophilic

Trifluoromethylating Reagents AF8.3. Acyclic Hypervalent Iodine(III) Electrophilic

Trifluoromethylating Species and OxidativeTrifluoromethylation AH

8.4. Reactions Involving Trifluoromethyl Radical AI9. Perspectives and Conclusion AL10. Latest Developments ALAuthor Information AN

Corresponding Authors ANAuthor Contributions ANNotes ANBiographies AN

Acknowledgments AOAbbreviations AOReferences AP

Special Issue: 2015 Fluorine Chemistry

Received: August 27, 2013

Review

pubs.acs.org/CR

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1. INTRODUCTIONFluorine is the 13th most abundant element in the earth’s crust,where it occurs predominantly in the form of cryolite(Na3AlF6), fluorite (CaF2), and fluorapatite (Ca10(PO4)6F2).Despite its abundance in nature, in marked contrast, only a veryfew molecules bearing a C−F bond (one of the strongest inorganic compounds, Figure 1)1 are present in nature2−9 due to

the insolubility of its salts (cryolite, fluorite, and fluorapatite)and poor nucleophilicity of fluoride under natural conditions,which limits its delivery to aqueous biological systems.6

However, approximately 20−30% of modern pharmaceuticals(for example efavirenz, mefloquine, and sorafenib, etc. Figure2)6,9,10 and agrochemicals contain fluorine atoms becausefluorinated organic compounds have enhanced lipophilicity andmembrane permeability, elevated electronegativity and oxida-tion resistance. These are responsible for the more increasedmetabolic stability and bioavailability of fluorinated organiccompounds than their nonfluorinated analogues.2−13 As aconsequence, drug candidates with one or more fluorines havebecome common place and rapidly increasing efforts havefocused on developing efficient strategies, reagents, andcatalysts for the incorporation of, for example, CF3 into variousorganic structures via nucleophilic, electrophilic, and radicaltrifluoromethylations.9−22 In this context, a major challenge isthe development and utilization of diverse CF3 sources.However, in nucleophilic organometallic compounds, tri-

fluoromethyl lithium and magnesium cannot be employed forthe synthesis of trifluoromethylated compounds throughaddition reactions. These nucleophilic species are recognizedas being too unstable and difficult to prepare because of facileα-fluoride (M−F; M = Li or Mg) elimination.5 Whereby,trifluoromethyltrimethylsilane (TMSCF3 or Me3SiCF3, Rup-

pert−Prakash reagent) has been used extensively as a versatilereagent in organic synthesis in past two to three decades due tothe advantages of TMSCF3 such as it is easy to handle andstore, stable, and cost-effective over related derivatives.14−16,23

Because of the importance of the trifluoromethyl group inmaterials and medicinal chemistry research,1−12 it is notsurprising that there has been a rapid increase in thedevelopment of trifluoromethylation methods as evidenced byover 350 publications since 2008.24 Several microreviews orreviews, in part, on formation of trifluoromethylated (hetero)-arenes19,25−27 and direct trifluoromethylation of C−H bondinvolving the utility of Ruppert−Prakash reagent28 have beenpublished recently. A comprehensive review23 described thepreparation and synthetic utility of TMSCF3 from 1984, theyear of the seminal publication by Ruppert and co-workers forthe synthesis of TMSCF3, to 1997, including mainly thenucleophilic trifluoromethylation reactions of TMSCF3 withhard carbon electrophiles, such as nonenolizable aldehydes andketones, lactones, cyclic anhydrides, and azirines.In recent years, there has been an increasing wealth of

information about the structures of TMSCF3 and relatedreagents, catalysts, and reaction mechanisms. The aim of thisreview is to highlight a selection of important recentapplications of TMSCF3 as a versatile reagent for theintroduction of fluoromethyl groups not only in the form of“CF3

−”,23 but also in forms of “CF3+”, “:CF2”, “·CF3”, and even

“TMSCF2+” derived directly from this reagent. Accordingly,

special emphasis is placed on expansion of substrate scope anddevelopment of catalysts and catalytic reactions. In addition,several new fluoromethylating reagents or species generatedfrom TMSCF3 and fluoroform are covered to emphasizefeatures that may warrant further investigation. In addition, therelated applications of other homologous silanes are alsodescribed.

2. SYNTHESIS OFTRIFLUOROMETHYLTRIMETHYLSILANE

The CF3 group has the same electronegativity as chlorine(Figure 1), which makes it distinct from other alkyl groups suchas the methyl (CH3) group.

13 In perfluoroalkyl organometalliccompounds, perfluoroalkyl magnesium halides are more stablethan perfluoroalkyl lithium but still must be prepared at lowtemperature with pure magnesium. In comparison, trifluor-omethyl magnesium halides are more difficult to produce thanother alkyl magnesium halides including the longer chainperfluoroalkyl magnesium halides.5,23

The commercially available Ruppert−Prakash reagent,TMSCF3 1, is a colorless flammable liquid with a boilingpoint of 54−55 °C and density of 0.962 g/mL at 20 °C. Ingeneral, perfluoroalkyl silanes are relatively stable to acid andwater, which is a considerable advantage of perfluoroalkyl

Figure 1. Properties involving fluorine, trifluoromethyl group, andothers.

Figure 2. Examples of trifluoromethyl containing drugs.

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silanes, including 1, over related organometallic compounds.The first successful preparation of 1 was reported by Ruppertand co-workers29 in 1984 through the reaction of CF3Br (anozone depleting compound) and trimethylsilyl chloride(TMSCl) mediated by (Et2N)3P via a bromophilic attack totransfer CF3 group of CF3Br onto silicon of TMSCl (Scheme 1,

path a).29−32 TMSCF3 1 can be obtained in 75% yield by amodification of Ruppert’s procedure on a large-scale inanhydrous benzonitrile under dry nitrogen atmosphere at−30 to −78 °C,31 which is also applicable to the synthesis of(pentafluoroethy1)trimethylsilane (Me3SiC2F5, 50% yield) and(heptafluoropropy1)trimethylsilane (Me3SiC3F7, 68% yield).32

However, attempts to utilize more readily available phosphoruscompounds, such as Ph3P, (MeO)3P, or (EtO)3P as a promoterfor the reaction of CF3Br with TMSCl gave no trace of 1.32

Nowadays, there are various synthetic approaches to obtain1,29−34 including the reaction of CF3I with TMSCl in thepresence of tetrakis(dimethylamino)ethylene at −196 °C(Scheme 1, path b, 94% yield; CF3Br is ineffective in thiscase)33 and the magnesium metal-mediated reductive trifluor-omethylation of TMSCl with phenyl trifluoromethyl sulfide,sulfoxide, or sulfone as the trifluoromethyl source in DMF at 0°C to room temperature (Scheme 1, path c, 45−83% yield).34

More recently, 1 has been successfully prepared in 80%isolated yield by Prakash and co-workers through the reactionof nonozone depleting CHF3 (fluoroform, pKa 25−28 in water)with TMSCl using potassium hexamethyldisilazide (KHMDS)as the base (Scheme 2)24 via possibly the formation of apentacoordinated silicon species 2. It was demonstrated thatthe presence of K+ as the countercation of the base appears tobe rather important in the preparation of 1 from CHF3 andTMSCl. In sharp comparison, NaHMDS gave only a minorproduct, whereas LiHMDS failed to give the desired 1. Inaddition, the attempts to observe species 2 by NMRspectroscopy were not successful due to the extremely rapidrate of the subsequent reactions.24,35−37

A very important point for the Prakash’s reaction of TMSClwith CHF3 is that CHF3 is added (bubbled) slowly into amixture of TMSCl with KHMDS in toluene at low temperature(−85 °C),38 which enables the unstable trifluoromethylcarbanion generated from CF3H and KHMDS to be internallyquenched by TMSCl efficiently to form 1. In addition, thechemical hardness of M+ (M = Li, Na, K) and the differencebetween the values of decomposition energy of a keyintermediate MCF3 and the relative energy barrier for theformation of a Si−CF3 bond are predicted to be valuable forchoosing a base in the rational design of the reaction.39

The use of CHF3 as described above is very importantbecause CHF3, a powerful long-lasting greenhouse gas, is alarge volume byproduct of the industrial synthesis offluoropolymers and refrigerants.24,40 Significantly, the higher

alkyl-substituted analogues of trifluoromethylated silanes, suchas trifluoromethyl(triethyl)silane, trifluoromethyl(n-propyldimethyl)silane, trifluoromethyl(triisopropyl)silane, andtrifluoromethyl(t-butyldimethyl)silane, can also be prepared ingood to high yield (Scheme 2) by using Prakash’s method.24,38

3. REACTIONS WITH CARBON ELECTROPHILESIn 1999, Kolomeitsev and co-workers published the crystalstructure of a pentaorganosilicate, sulfonium salt 3((Me2N)3S

+[(CF3)2SiMe3]−, Scheme 3),35 featuring Si−C

bond lengths of 2.056 (axial) vs 1.882 Å (equatorial) havinga 29Si NMR resonance of −112 ppm.35,36 Compound 3 is stablein the solid state up to 0 °C but decomposes exothermally at0−5 °C with the formation of Me4N

+[Me3SiF2]−.35 In 2008,

Olejniczak, Katrusiak, and Vij determined the structure of

Scheme 1. Synthetic Methods for TMSCF3

Scheme 2. Preparation of Trifluoromethylated Silanes fromFluoroform

Scheme 3. Generation of Trifluoromethyl CarbanionEquivalent

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Me3SiCF3 1 by high-pressure freezing (in situ pressure frozenin a diamond anvil cell) by single-crystal X-ray diffraction at0.90(5) GPa/296 K.37 The crystal structure of 1 confirms thatthe Si−CF3 bond is longer and weaker than the Si−CH3 bondsand there are no strong intermolecular interactions between 1.This result supports the trifluoromethylating nature of 1 as theCF3 group is easily transferred in the presence of suitablecatalysts, the key factor in improving and developing thefluoromethylation reactions based on 1.For the increasing importance of trifluoromethylated

molecules, currently, there is a surge in interest in thedevelopment of trifluoromethylation methodologies andTMSCF3 1 is now the most practical and widely used reagent.In the research using 1 as the nucleophilic trifluoromethylaingreagent, the expansion of electrophilic substrate scope, theselectivity of the reaction and functional group tolerance havebeen and are still the subject of intense research.

3.1. Trifluoromethylation of Aldehydes and Ketones

Significant interest in the nucleophilic trifluoromethylationstarted from the successful generation of the stable equivalentof trifluoromethyl anion “CF3

−” under mild reaction conditionsfrom TMSCF3 1 at the end of 1980s. Prakash and co-workersreported the nucleophilic trifluoromethylation of carbonylsusing 1 as the nucleophilic CF3 species in the presence of acatalytic amount of tetrabutylammonium fluoride (TBAF) as aninitiator of 1 to give, for example, the correspondingtrifluoromethylated siloxy adducts under mild conditions.41 Inthe same year, Stahly and Bell described the monotrifluor-omethylation at a carbonyl group of p-quinone derivatives usingEt3SiCF3 or (n-Bu)3SiCF3 promoted (or catalyzed) by a varietyof Lewis bases, including KF, KHF2, Bu4NHF2, H4NHF2,NaCN, KCN, NaOH, LiN3, (Et2N)3P, (EtO)3P, DMAP (4-(dimethylamino)pyridine), K2CO3, etc. aimed at the synthesisof otherwise hardly accessible 4-trifluoromethylated phenolsand anilines.42 These pioneering works inspired the renaissanceof nucleophilic trifluoromethylation chemistry. Since then,there has been continued and growing interest in 1 as CF3species in organic synthesis.14−16,23,24

As discussed in previous reviews,16,23 TMSCF3 1 has becomethe most widely used reagent for nucleophilic trifluoromethy-lation of an increasing variety of electrophiles.14−16,23,43−47 Inthe reactions of 1 with carbonyl compounds, activation of 1with a Lewis base as catalyst under aprotic conditions togenerate an equivalent of trifluoromethyl anion is one of themost viable strategies for the application of the correspondingtransformations (Scheme 3).14−16,23,41 Generally for reactionsof aldehydes or ketones, fluoride ion acting as an initiator onlytakes part in the first catalytic cycle. The further activation of 1in subsequent catalytic cycles is to be undertaken by thealkoxide formed during the first catalytic cycle (Scheme 3). Inaddition, it has been found that Lewis acids, such as TiF4,Ti(OPr-i)4 and Cu(OAc)2, with or without ligands, caneffectively catalyze the trifluoromethylation of various alde-hydes with 1.48

A catalytic cycle of trifluoromethylation of aldehydes orketones involves the generation of unstable pentacoordinatedsilicon species 4 (Scheme 3).23 This autocatalytic cycle can beapplied to find the catalysts or initiators under suitable reactionconditions, including the counter cations and solvents.49,50 Thereactions of α-imino ketones with 1 generally lead to thecorresponding trifluoromethylated hydroxyimines, leaving theimino functionality intact due to its relatively lower reactivity.51

In addition to the formation of a trifluoromethyl anionequivalent (Scheme 3), it has been found that otherfluoromethyl species might also be involved under certainconditions depending on the nature of substrates, initiators/catalysts, solvents and reaction temperatures.19,23,24,52−54 Huand co-workers performed a one-pot sequential combination oftrifluoromethylation and [2 + 1] cycloaddition reaction of 1with 4′-(phenylethynyl)-acetophenone 5 containing both acarbonyl group and a triple bond. As a result, 1 enables both afluoride-initiated nucleophilic trifluoromethylation on thecarbonyl group and a NaI-promoted difluoromethylenationon the triple bond to give product 6 in 85% overall yield(Scheme 4).52 Therefore, TMSCF3 1 can serve both as anucleophilic trifluoromethylating reagent and as a difluor-ocarbene precursor under suitable reaction conditions.

Although less described in literature, the performance of 1under acidic conditions is worthy of a mention. It is known thatMe4Si readily reacts with the siliphilic triflic acid (TfOH) toafford Me3SiOTf with evolution of methane.55 Unlike Me4Si,difluoromethyltriflate (HCF2OTf) 7 is to be formed along withfluorotrimethylsilane 8, via seven-membered intermediate 9, bytreatment of 1 with TfOH (Scheme 5).56−58 This reaction can

be accelerated through the addition of a catalytic amount ofLewis acids such as SbF5 or TiCl4.

56−58 A mechanism involvingsimultaneous C−F and C−Si bond cleavage along with H−Fand O−Si bond formation has been proposed (Scheme 5).56−59Difluoromethyltriflate 7 is a nonozone-depleting liquid and hasvery recently been utilized as a convenient source ofdifluorocarbene by Fier and Hartwig.57

Due to the high electronegativity of fluorine (Figure 1), thenucleophilic CF3 species are considered as hard nucleophiles,which usually undergo 1,2-addition reactions with α,β-unsaturated carbonyl compounds.14−16,23,27,42,50 The reactionof 1 with divinyl ketones 11 (DVKs, usually acting as double

Scheme 4. One-Pot Sequential Trifluoromethylation andDifluoromethylenation

Scheme 5. Reaction of 1 with TfOH

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Michael acceptors)60 promoted by anhydrous NaOAc gives 1,2-adducts 12 in high to excellent yields. Hydrolysis of 12 undermild acidic conditions leads to the formation of α-trifluoromethyl allyl alcohols 13 (Table 1).61

Treatment of 13 with BF3·Et2O in 1,2-dichloroethane(DCE) results in a symmetry-allowed cyclization62,63 to deliver4-trifluoromethyl-1,2-diaryl-1,3-cyclopentadienes 15 in highyields (Scheme 6),61 which provides a convenient route to

mono-CF3 substituted cyclopentadienes, the analogue ofGassman’s ligand (1,2,3,4-tetramethyl-5-(trifluoromethyl)-cyclopentadiene).62 In the synthesis of cyclopentadienes, thedouble-bond isomers for example, 1-chloro-4-(2-methyl-4-(trifluoromethyl)cyclopenta-1,3-dienyl)benzene 15f and 1-chloro-4-(2-methyl-4-(trifluoromethyl)cyclopenta-1,4-dienyl)-benzene 15f′, are obtained in the ratio of 15f:15f′ = 3:1through a 1,5 H-shift (Scheme 6).61

Whereas, no reaction occurred by treatment of 1 with acetylketene dithioacetal 14 under identical conditions, due to therelatively softer nature of the carbonyl group of 14 resultingfrom the strong electron-donating (p−π conjugation) effect ofthe methylthio groups.64 In comparison, 13b could be preparedin only 36% yield using N-trifluoroacetyl O-trimethylsilyl vic-amino alcohols as nucleophilic trifluoromethylating reagents.65

Recently, Schoenebeck and co-workers reacted Bu3SnCF3 withketones or aldehydes under CsF activation at room temper-ature to afford trifluoromethylated stannane ethers in highyields.66 The advantage of the reaction is that only a mildlyacidic extraction (aqueous NH4Cl) is required to releasetrifluoromethyl alcohol products due to the relatively weaknessof the Sn−O bond compared to the Si−O bond (bonddissociation energies: ΔH(O−Sn) = 548 kJ/mol; ΔH(O−Si) =798 kJ/mol),67 which is more compatible with acid-sensitivefunctional groups and useful for late-stage synthesis.66

3.2. 1,4-Trifluoromethylation Reactions

Although reactions of 1 with α,β-unsaturated carbonyls leadingto trifluoromethylated alcohols via 1,2-addition have beenstudied in detail,14−16,23,27,42,50,61 there have been only a fewexamples of Michael and Michael-type reactions because themismatch between the relatively soft β-carbon of α,β-unsaturated carbonyls and the hard “CF3

−” species generated,for example, from 1/F− (Scheme 3). In 2003, Sevenard and co-workers reported the first successful 1,4-trifluoromethylation ofα,β-enones by introducing a strong electron-withdrawing CF3group at the β-position.68 Promoted by fluoride ion, 2-trifluoromethyl-4-quinolones and chromones 18 (Figure 3, Z

= O) serve as good Michael acceptors under nucleophilictrifluoromethylation conditions.68−70 In addition, the Knoeve-nagel condensation products of trifluoromethylchromone withdiethyl malonate, ethyl cyanoacetate, and Meldrum’s acid (forexample 20 in Figure 3) are suitable substrates for 1,6-addition.71 In comparison, in the case of coumarin 21 (Figure3), a mixture of 1,2- and 1,4-addition products are generatedand significantly enriched with the former (53% versus 8%).72

The reason for such an anomalous behavior of 18−20 ispossibly due to the additional −I activation of the β-position of

Table 1. 1,2-Trifluoromethylation of Divinyl Ketones

entry Ar R yield of 12 (%) yield of 13 (%)

1 4-MeC6H4 4-MeC6H4 12a, 95 13a, 922 Ph Ph 12b, 93 13b, 933 4-MeOC6H4 4-MeOC6H4 12c, 95 13c, 964 4-ClC6H4 4-ClC6H4 12d, 90 13d, 955 4-FC6H4 4-FC6H4 12e 89 13e, 906 4-ClC6H4 Me 12f, 95 13f, 94

Scheme 6. Synthesis of Mono-CF3 SubstitutedCyclopentadienes

Figure 3. Michael acceptors.

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the α,β-unsaturated systems by the RF moiety.73 However,similar reaction with 2-trifluoromethyl-1-thiochromones (Fig-ure 3, when Z = S in 18) resulted only in 1,2-additionadducts.70

Dilman and co-workers showed that, promoted by acetateions, highly electrophilic alkenes, such as (E)-methyl 2-cyano-3-phenyl acrylate 22, arylidenemalononitriles 23,73 arylideneMeldrum’s acids (24),74 and 2-nitrocinnamates (25)75 bearingtwo germinal electron-withdrawing groups (Figure 3), aresuitable substrates for Michael addition with 1. Whereas, lessthan 15% yield of the Michael adduct was obtained withdimethyl 2-benzylidenemalonate as the substrate.73 Theseresults are roughly consistent with their electrophilicity by theestimation of the Mayr electrophilicity parameter based onquantitative structure−property relationships (QSPRs).76,77 Incomparison, the nucleophilic fluoroalkylation of chalcone withPhSO2CF2H in the presence of LiHMDS to give a mixture of1,2- and 1,4-adducts and the nucleophilic pentafluorophenyla-tion of nitroalkenes with pentafluorophenylmagnesium bro-mide to form 1,4-adducts have also been reported andattributed to the softer nature of these nucleophiles relativeto 1.78,79

3.3. Trifluoromethylation of 4-Nitroisoxazoles

Recently, Shibata and co-workers reported a nitro-activatedregio- and diastereoselective nucleophilic trifluoromethylationof 4-nitroisoxazoles 26.80 As a model reaction, the best resultwas obtained by treating 4-nitro-3,5-diphenyl-isoxazole 26awith 1 in the presence of NaOAc and cetyltrimethylammoniumbromide ([Me-(CH2)15N(Me)3]Br), leading to 4-nitro-3,5-diphenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole 27a in 95%yield (Table 2, entry 10). The importance of both initiators and

suitable additives is also demonstrated (entry 2 versus 8 andentry 8 versus 10).80 In comparison, in the presence of NaOAc,the reaction did not proceed when dichloromethane, THF, andtoluene were selected as the solvent, respectively, indicating theimportance of solvent choise.80

Under optimal conditions (entry 10), a series of trifluor-omethylated adducts, 5-trifluoromethyl-2-isoxazolines 27, areprepared in good to excellent yields (10 examples, 67−99%yields).80 In addition, 5-trifluoromethyl-2-isoxazolines 29

bearing a styryl group at 5-position are also synthesized (16examples, 67−96% yields) from the corresponding substrates28 (Scheme 7, for example, 29a in 87% yield). However, when

Me3SiCN instead of Me3SiCF3 was used, 1,6-adduct 30 wasselectively furnished in low yield (Scheme 7). Thus, thetrifluoromethylation reaction of 26 and 28 with 1 leads to asuccessful access to 5-trifluoromethyl-2-isoxazolines 27 and 29with the CF3 substituent on a quaternary carbon center.80

Similar to the trifluoromethylation of 2-trifluoromethyl-4-quinolones and analogues (Figure 3)68−71 it has been foundthat the nitro group is necessary to activate the substrate fortrifluoromethylation because no reaction can be observedbetween 3,5-diphenylisoxazole, the non-nitro analogue of 26aand 1 under the same reaction conditions. Shibata and co-workers gave a mechanism for the regio- and diastereoselectivetrifluoromethylation of 26/28, which involves the nucleophilic1,2-type addition of a “CF3

−” to a reactive tautomer 31 of 26/28 (Scheme 7),80 indicating the addition at the 5-position of anaromatic isoxazole ring is specific to the (hard) “CF3

−”compared to the stabilized (soft) nucleophiles.81,82

3.4. Trifluoromethylation of Anhydrides and WeinrebAmides

Trifluoromethyl ketones (TFMKs) and derivatives are highlyvaluable CF3-containing synthons in the construction of CF3-containing compounds.49,83−97 Interestingly, Colby and co-workers98 recently found that hexafluoroacetone hydrateamidinate complex can be used as a nucleophilic trifluor-omethylating reagent using a simple acid−base process basedon a report in 1968 by Prager and Ogden that hexafluor-oacetone hydrate 33 fragments in the presence of sodiumhydroxide to give, via its sodium salt (sodium 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-olate), trifluoroacetate and fluo-roform (Scheme 8a).99 Importantly, the reaction of etherealsolution of 33 with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)precipitates the hexafluoroacetone hydrate amidinate salt 35(Scheme 8b).98

Under basic conditions and elevated temperature, amidinatesalt 35 can release trifluoroacetate to generate fluoroform(Scheme 8b).98 Accordingly, the trifluoroacetate-release100−103

aldol reaction of 35 with p-anisaldehyde 36 to give 2,2,2-

Table 2. Reactions of 1 with 4-Nitroisoxazoles underDifferent Conditions

entry base 27a (yield %)a

1b n-Bu4NF·H2O2 K2CO3 283 KOH 444 t-BuOK 575 KF 596 CsF 577 LiOAc 678 NaOAc 809 KOAc 7810c NaOAc 95

aIsolated yields of 27a. bNo 27a was obtained. cThe reaction wasperformed in the presence of [Me-(CH2)15N(Me)3]Br (30 mol %).

Scheme 7. Trifluoromethylation of 4-Nitroisoxazoles

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trifluoro-1-(4-methoxyphenyl)ethanol 37 has been examined byColby and co-workers, showing the significant influence ofbases and additives on the reaction.98 The salt 35 is a stable,anhydrous solid (not hygroscopic, even after multiple exposuresto air for 3 months) and displays high solubility in DMF,DMSO, EtOAc, and CH3CN and partial solubility in tolueneand THF.98 On the other hand, salt 35 can also be used toprepare the difluoromethylated compound 39 (Scheme 8c) viadifluorocarbene (generated from salt 35) insersion into theCsp3−H bond of 38,98 the analogue of the anti-inflammatoryand analgesic drug ibuprofen. Thus, salt 35, which can beprepared in one synthetic step up to a multigram scale withoutany purification,98 has recently been commercialized by Sigma-Aldrich.104

However, in contrast, no solid complexes could be obtainedby the reaction of trifluoroacetaldehyde hydrate (CF3CH-(OH)2) with various amines attempted although the resultsusing CF3CH(OH)2 as an atom economical trifluoromethylanion equivalent under basic conditions are satisfied.105

TFMKs can be prepared by oxidation of α-trifluoromethylalcohols49,85 and other methods.83−85,106 For the preparation ofTFMKs, the trifluoromethylation of a suitably activatedcarbonyl derivative with 1 is a viable option for simplicity.Leadbeater and co-workers reported a novel route to accessTFMKs 41 from Weinreb amides 40 (N-methoxy-N-methyl-amide, serving as effective acylating reagents of organolithiumand organomagnesium)107 through effective acylations of 40with 1 in a two-step procedure without formation of the bis-trifluoromethylated product (Scheme 9).108

In these reactions, adducts 42 (for example 42a with R = 4-t-BuPh) are stable enough to be isolated in high yield (81%) andslowly revert back to 40a if left 42a for extended times in thesolvent, THF, (attributing to the Lewis basicity of THF).109

However, Weinreb amides 40a′−f′, bearing an aryl ring with asubstituent at the ortho position or bearing an α-branched alkylgroup, are inert to the reaction (Scheme 9) due to the sterichindrance.108 In the case of the reaction of α,β-unsaturated

Weinreb amides 43 with 1 under similar reaction conditions, alow yield of the desired TFMKs 44 (4 examples, 22−51%yields) was obtained along with 45 formed probably via an aza-Michael addition of the displaced N,O-dimethylhydroxylamineanion to the highly electrophilic alkene 44 (Scheme 9).108

The nucleophilic trifluoromethylation of phenyl ketoamides46 with 1 gives α-trifluoromethyl silyl ethers 47 (precursors ofα-trifluoromethylated α-alkoxy-aldehydes 48) in the presenceof a catalytic amount of initiator (Scheme 10) whatever the

reaction conditions used. In this case, no trace of addition ofthe trifluoromethyl group onto the amide moiety can beobserved because of the more reactive nature of the ketonefunctionality.51,110

Pohmakotr and co-workers showed that the correspondingTFMKs could be involved in the TBAT-catalyzed (10 mol %,TBAT: tetrabutylammonium triphenyldifluorosilicate) nucleo-philic trifluoromethylation of 1 to phthalic anhydride or

Scheme 8. Preparation and Reactions of HexafluoroacetoneHydrate Amidinate Salt

Scheme 9. Trifluoromethylating Reaction of WeinrebAmides

Scheme 10. Trifluoromethylation of Phenyl Ketoamides

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succinic anhydride followed by treatment of the adducts withGrignard reagents.111,112 Catalyzed by TBAT, trifluoromethy-lation of the masked maleic anhydride (cyclopentadiene-maleicanhydride adduct) with 1 followed by quenching with wateraffords the desired adduct in high diastereoselectivity and yieldby attacking of 1 from the less hindered convex side of thesubstrate (eq 1).113 Whereas, a complex mixture was producedfrom the reaction of maleic anhydride with 1 under similarreaction conditions even under low temperature (eq 2).113

Recently, a research for the addition reaction of 1 to phthalicanhydrides showed that CuI is a good catalyst (CuI: 10 mol %;1,10-phenanthroline (Phen): 10 mol %; KF: 2 equiv, giving 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one in 85%isolated yield)114 comparied with TBAF (no reaction wasobserved).114,115 These results suggest the importance of newcatalyst systems for the nucleophilic trifluoromethylationreactions.3.5. Trifluoromethylation of Imines

In nucleophilic trifluoromethylation reactions promoted byTBAF, the carbonyl group of an aldehyde or a ketone is morereactive than the imino group of an imine.51 In addition, iminesbearing a N-aryl or N-alkyl group are noticeably less reactivecompared to N-tosyl and N-sulfinyl imines. Nevertheless,several reports have documented successful results in whichvarious imines can react efficiently with 1 through the selectionof proper catalysts/promotors.3.5.1. Trifluoromethylation of Azirines. In 1994, 5 years

after the first example of trifluoromethylation of CO bondsof aldehydes and ketones with 1,34 Felix, Khatimi, and Laurentreported the trifluoromethylation of 1 on the CN bond ofreactive azirines 49 (Scheme 11).116 However, the reaction ofnonactivated N-alkylimine (n-propylbenzaldimine) with 1under similar conditions failed to produce desired adduct,116

indicating the synthesis of α-(trifluoromethyl)amines, the usefulintermediates for pharmaceutical and agrochemical prod-

ucts,10,43−47,117−119 through trifluoromethylation of imineswith 1 had been a formidable challenge.23

3.5.2. TMAF Mediated Trifluoromethylation of Aldi-mines. Recently, a careful study of the trifluoromethylation ofnonactivated aldimines with 1 was carried out by Yagupolskiiand co-workers in the presence of tetramethylammoniumfluoride (TMAF).44 They confirmed by low-temperature 19FNMR experiments that the reactions of benzylideneanilineswith 1 proceed, probably via the formation of tetramethy-lammonium amides (Figure 4, with benzylideneaniline as an

example), different from the reactions of 1 with aldehydes orketones via the pentacoordinated silicon species as in Scheme3.23 Consecutive reactions of the salts formed in situ withelectrophiles afford trifluoromethylated amines, including N-(2,2,2-trifluoro-1-phenylethyl)aniline by hydrolysis, N-methyl-N-(2,2,2-trifluoro-1-phenylethyl)aniline by silylation, and 1,1,1-trimethyl-N-phenyl-N-(2,2,2-trifluoro-1-phenylethyl)silanamineby methylation, respectively. Silylated amines are stable underneutral conditions but desilylate easily in the presence of acidsto form trifluoromethylated amines (Figure 4).44 These resultsdemostrate that TMSCF3 1 can be used for the introduction ofthe trifluoromethyl group into several unactivated imines undermild conditions using tetraalkylammonium fluorides asinitiators (CsF did not work),45 which deserves furtherinvestigation in detail.

3.5.3. HF Promoted Trifluoromethylation of Imines. In2008, Dilman and co-workers found that N-alkyl substitutedimines and enamines, which are unreactive under conventionalLewis basic conditions,23,43,116 can undergo nucleophilictrifluoromethylation with 1 in the presence of hydrofluoricacid (generated in situ by mixing potassium hydrodifluorideand trifluoroacetic acid (TFA)) under mild reaction con-ditions.120 This approach is a milestone in the trifluoromethy-lation of imines, which provides an efficient access to α-(trifluoromethyl)amines through the selective activation ofboth 1 and an imine functionality at the same time.10,43,117−119

Later, they demonstrated that this acidic condition can also beapplied to α-phenylthio, α-phenylsulfonyl, and α-diethylphos-phoryl substituted silicon compounds 52−54 as nucleophilic

Scheme 11. Trifluoromethylation of Azirines

Figure 4. TMAF mediated trifluoromethylation of benzylideneaniline.

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fluoroalkylating reagents via a similar mechanism (Scheme12).120−122

A dual activation mechanism for the HF-mediated reactionsinvolves, as a first step, the interaction of the substrate (imineor enamine) with H2F2 leading to the equilibrium formation ofmore reactive iminium ion and hydrodifluoride anion.Subsequently, the siliphilic hydrodifluoride (HF2

−) activatesthe silicon reagent (for example 1) to generate a five-coordinateintermediate, which reacts with iminium leading to the product(Scheme 12). It is proposed that the transfer of fluorinatedcarbanion from silicon to the iminium electrophile proceededin a concerted fashion. Otherwise, if the free carbanion wereformed, it would likely be rapidly quenched with acid present inthe reaction mixture.121,122

Dilman indicates that “while anhydrous HF is highlydangerous, in their protocol it is generated in situ by mixingeasily available and convenient chemicals (for example, KHF2and TFA). Furthermore, reactions can be performed inconventional glassware with no noticeable deterioration ofglass surface”.121,122 According to the results of Nenajdenko,Roschenthaler and co-workers, the HF-promoted nucleophilictrifluoromethylation of 5−7-membered cyclic imines 55−57bearing an alkyl, aryl or hetaryl group at the 2-position leads tothe desired 2-trifluoromethyl-pyrrolines 58, -piperidines 59 and-azepanes 60 (26 examples, 44−79% yields), respectively, undermild reaction conditions.123

In addition, treatment of cyclic trimers 61, the nonreactivecompounds under basic conditions,23,43,124,125 with 1 can alsolead to the formation of 2-trifluoromethyl substituted pyrroline62a and piperidine 62b in moderate yields under similarreaction conditions (Table 3).123 More recently, the elegantHF-mediated protocol has been employed to the synthesis of asmall library of structurally diverse primary amines bearing agerminal CF3 group starting from aldehydes or ketones via N-benzyl imines on a preparative scale (11.9−30.7 g).126

Meanwhile, it has been confirmed that all synthetic steps arehigh-yielding and neither the isolation of the intermediates orchromatographic purification of the products is necessary(Scheme 13, 10 examples, 41−93% overall yields).126

In another report on the HF-mediated reactions byMykhailiuk and co-workers, methyl 3-(benzylimino)-cyclobutanecarboxylate 67 gave α-(trifluoromethyl)amine 68in low yield. Similarly, α-(trifluoromethyl)amine 70 wasobtained in 47% yield under identical conditions (Scheme13).127 The realitively lower yield of 68 and 70 may indicate anadditional proximal steric hindrance in the correspondingcyclobutanimine precursors of 66a, 68, and 70 (Scheme 13,yields of 66a, 68, and 70 versus 66b and 66c). Now, the HF-mediated nucleophilic trifluoromethylation of imines hasbecome a general protocol with a wide substrate scopeincluding not only aldimines but also the less reactive acyclicand cyclic ketimines.43,122 In addition, Dilman’s method ischemoselective because the trifluoromethylation of an iminegroup proceeds faster than a carbonyl group under the reactionconditions (see ection 3.7).120

3.5.4. Trifluoromethylation of N-Tosyl Imines Basedon Phase-Transfer Catalysis. In 2012 Bernardi and co-workers presented a new approach to additions of siliconnucleophiles (including TMSCF3, TMSC3F7 and TMSC6F5) toimines based on the phase-transfer of phenoxides byammonium catalysts.128 As a result, various N-tosyl iminesderived from aromatic or heteroaromatic aldehydes react wellto furnish α-(trifluoromethyl)amines in good to excellent yields(11 examples, 59−97% yields) under mild reaction con-ditions.128 These recent protocols, especially the HF-mediatednucleophilic trifluoromethylation, not only expand the scope ofimine electrophiles but enrich the choice of catalysts, initiatorsand/or catalytic mode.43−47,120−123,127−130 In a recent report,Huang and co-workers found that, promoted by TBABF(tetrabutyl ammonium bifluoride, TBAF·HF), bistrifluomethy-lated amines (1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-aminederivatives) could be prepared in moderate to good yieldsfrom reactions of aryl nitriles with 1 under mild reactionconditions (eq 3, TBAF was ineffective under identicalconditions).46

Scheme 12. HF-Promoted Nucleophilic Fluoroalkylation Reactions of Imines

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3.6. Direct Trifluoromethylation of Csp3−H Bond Adjacentto a Nitrogen Atom

Direct functionalization of Csp3−H bond adjacent to a nitrogenatom is of importance for the synthesis of α-functionalizedamines.131,132 In 2011, Li and Mitsudera described a Cu-catalyzed oxidative trifluoromethylation of Csp3−H bond at theα-position of nitrogen in tetrahydroisoquinolines 71 to give 1-trifluoromethyl-tetrahydroisoquinoline derivatives 74 (Scheme14, Method A, with 2-phenyl-tetrahydroisoquinoline 71a as anexample).133 Later, Fu and co-workers reported the synthesis of74 from 71 using visible light irradiation catalyzed by RoseBengal (Scheme 14, Method B, with 71a as an example).134

In these reactions 72, a highly reactive electrophile,124,131−135

is likely the key intermediate formed via chemical oxidation by2,3-dichloro-5,6-dicyanobenzoquinone 75 (DDQ, Scheme 14,Method A) or by visible light and the photocatalyst RoseBengal 77 (RB, Scheme 14, Method B) in the presence ofmolecular oxygen, respectively. Table 4 gives the results of theoxidative trifluoromethylation of tetrahydroisoquinoline deriv-atives 71.133,134

Method A. Reactions were carried out on a 0.15 mmol scalein DMF (0.5 mL) under argon with 1/KF (3 equiv), DDQ 75(1.3 equiv), and CuI (10 mol %) at room temperature for 18 h.Yields were based on 71 and determined by 1H NMR methodsusing an internal standard, isolated yields in parentheses.

Method B. Reaction conditions: 71 (0.3 mmol), 1 (5equiv), KF (5 equiv), and RB 77 (5 mol %) in CH3CN (3.0mL) at room temperature under green LEDs (LED: lightemitting device) irradiation in the open air. Isolated yields.According to the experimental results (Table 4), both 2-aryl-

and 2-alkyl-substituted tetrahydroisoquinolines 71 are effectivesubstrates for the oxidative trifluoromethylation. The reactionof 1 with 2-benzyl, 2-pyridylmethyl and 2-allyl tetrahydroiso-quinolines 71j−71l affords the corresponding 1-trifluoromethy-lated tetrahydroisoquinolines 74j−74l regioselectively inmoderate to good yields (Method B for 71j and 71l only).Substrates bearing stronger electron-withdrawing groups suchas pivaloyl (Piv) 71r or tert-butoxycarbonyl (Boc) 71s do notreact, possibly due to the increased oxidation potential of thecorresponding amines caused by the electron-deficient natureof the α-carbon atom (Method B for 71l only). In addition, ithas been shown that no reaction occurs for tetrahydroisoquino-line 71q in both methods (Method A: no desired product;Method B: no reaction), agreeing with majority of recentstudies in the realm of Csp3−H bond functionalization adjacentto a tertiary nitrogen.131,132 The above methods provide analternative route to α-(trifluoromethyl)amines.9,43−47,117−119

The utility of visible light to realize the Csp3−Hfunctionalization adjacent to a tertiary nitrogen atom with insitu-generated iminium ions was first reported by Stephensonand co-workers in 2010.136 Visible-light-mediated reactionshave expanded rapidly because of operational simplicity andeconomy and are being used in more and more applications,132

including trifluoromethylation reactions.20,22,134,137,138 Forexample, trifluoromethylation of arenes and heteroarenes withCF3SO2Cl,

20 alkenes with CF3I,137 α-trifluoromethylation of

carbonyl compounds with CF3I,138 and hydrotrifluoromethyla-

Table 3. HF-Promoted Trifluoromethylation of CyclicImines

entry imine product R yield (%)

1 55a 58a Me 492 55b 58b cyclo-C6H11 683 55c 58c tert-C4H9 714 55d 58d Me-SCH2 755 55e 58e 4-MeC6H4 486 55f 58f 3-CF3C6H4 647 55g 58g 2-Thienyl 718 55h 58h 2-Furyl 609 55i 58i 3-Pyridyl 6810 56a 59a tert-C4H9 5611 56b 59b 3-Pyridyl 6712 57a 60a tert-C4H9 56

Scheme 13. HF-Promoted Trifluoromethylation of(Benzylimino)cyclobutanecarboxylates

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tion of unactivated alkenes with Umemoto reagent,139 through

the choice of a visible light excitable catalyst have been

described.

3.7. Selective Trifluoromethylation of Multi-FunctionalSubstrates

The reactions of α-imino ketones with 1 generally lead to the

corresponding trifluoromethylated hydroxyimines,51 indicating

Scheme 14. Oxidative Trifluoromethylation of Tetrahydroisoquinolines

Table 4. Oxidative Trifluoromethylation of Tetrahydroisoquinolines

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the hard nature of the nucleophilic CF3 species due to theirhigh electronegativity (Figure 1). However, the chemo-selectivity (one of the major challenges faced in contemporarysynthesis) of a reaction depends not only on the reagent usedand the nature of the substrates but also on the environmentalconditions, in which the reaction is operated.In research on the organofluorine chemistry by Fustero and

co-workers,140−142 they found that the reaction of 3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one 78 with 1 gave tri-fluoromethyl lactol 79 instead of trifluoromethyl amine 82(Scheme 15)142 due to the more reactive nature of the lactone

moiety toward 1 (hard nature).143−145 However, it has beenfound that compound 81 can be obtained in excellent yieldthrough the addition of Grignard reagent (soft nature, Figure1) at the imine moiety in the presence of a Lewis acid as theactivator of the imine functionality at low temperature (Scheme15).146

They also described a highly regio- and stereoselectivesynthesis of fluorinated 1,3-disubstituted isoindolines 84through a tandem reaction consisting of a diastereoselectiveaddition of 1 to Ellman’s N-(tert-butanesulfinyl)imines 83followed by an intramolecular aza-Michael reaction (Scheme16).147 In this reaction, compounds 85 are formed as singlediastereoisomers through trifluoromethylation at the iminemoiety of 83, indicating that the N-sulfinyl imine is morereactive than the carbonyl group of the α,β-unsaturated ester.Importantly, the catalyst-directed trifluoromethylation of

bifunctional (E)-2-(4-((benzylimino)methyl)phenoxy)-1-phe-nylethanone with 1 can give either the CF3-substituted amine(leaving carbonyl group intact) or CF3-substituted silyl ether(leaving imino group intact) chemoselectively, depending onthe selection of catalyst (eq 4).120

In 2010, Dilman and co-workers described for the first timethe introduction of a trifluoromethyl group into Morita−Baylis−Hillman adducts (MBH adducts).148 Catalyzed by n-Bu4NOAc, the reaction of acetylated MBH adduct 86 withMeSi(C6F5)3 87 can furnish the SN2′ (1,4-addition−elimi-nation) product 88 (Z/E = 94:6) in high yield with acetate asthe leaving group. However, under identical conditions, a 1:1

mixture of 89:90 is obtained in a combined yield of 30% via aSN2′- and a 1,2-addition pathway, respectively, from thereaction of 86 with 1 (Scheme 17).148 In comparison, usingDABCO (1,4-diazabicyclo[2.2.2]octane) as the catalyst, α-methylene-β-trifluoromethyl ester 91 is obtained in excellentyield by Shibata and co-workers.149 Thus, a mechanisminvolving a successive SN2′/SN2′ attack by DABCO and“CF3

−” (86 → 92 → 91) is proposed (Scheme 17).149 Sinceacetate ion is an initiator of 1 (Scheme 3), only a catalyticamount of n-Bu4NOAc

148 or DABCO (in this case, “CF3−” was

formed from the reaction 1 with in situ-generated AcO− from92)149 is required for the reactions (Scheme 17).150,151 On theother hand, the regioselective formation of 91 can be attributedto the hard nature of the β-C of intermediate 92 (having apositive charge) matching the hard nature of “CF3

−”.150

An extension of the DABCO catalyzed allylic alkylation tothe asymmetric allylic alkylation (AAA), a powerful tool formaking enantiomeric compounds,152,153 has led to the resultsthat, catalyzed by commercially available cinchona bis-alkaloid,(DHQD)2PHAL 95, the enantioselective trifluoromethylationof MBH carbonates 93 (no reaction is observed for 86 underidentical conditions for 120 h) affords chiral β-methylene-β-trifluoromethyl esters 94 in high enantioselectivities (up to 94%enantiomeric excess, Scheme 18).149 Therefore, the significantdifference between 86 and 93 in the reaction may be caused bythe steric demand of the bulky Boc group, which wouldinterfere in the stereoselective interaction of the olefin moietywith bis(cinchona alkaloid) catalyst (DHQD)2PHAL 95. Asimilar reaction was also observed by Jiang and co-workers forthe transformation of 96 to 97 (Scheme 18), in which thekinetics of the process is largely dependent on the electronicnature of the aromatic rings of 96 (favoring those with moreelectron-withdrawing groups).154

Scheme 15. Reactions of 3-Methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one

Scheme 16. Tandem Reaction of N-(tert-Butanesulfinyl)imines

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3.8. Enantioselective Trifluoromethylation

The catalytic enantioselective nucleophilic trifluoromethylationof carbonyl derivatives is one of the most important strategiesfor the preparation of optically active α-trifluoromethylatedalcohols and amines, which are becoming increasingly popularas chiral enantiopure synthons in the design of new drugs ormaterials.12,80,155−159

3.8.1. Aldehydes and Ketones: With Cinchona-Derived Quaternary Ammonium Fluoride Salts asCatalysts. Prompted by the report on the nucleophilictrifluoromethylation of 1 with carbonyl compounds catalyzedby TBAF,41 the first asymmetric trifluoromethylation wasdescribed in 1994 by Iseki, Nagai and Kobayashi.155 Catalyzedby N-[4-(trifluoromethyl)benzyl]cinchonium fluorides (Figure5, 99a or 99b, 1−20 mol %), the reaction of 1 with aldehydes/ketones gave the desired products in lower ee (ee: enantiomericexcess, 7 examples, 87−99% yields, 35−51% ee for aromaticaldehydes; 15% ee for octanal).155 Following this seminal study,

Caron and co-workers screened several structurally relatedcatalysts (the cinchona-derived quaternary ammonium fluoridesalts Figure 5)156,157 for the addition of a trifluoromethyl“anion” to aromatic ketones and aldehydes.158

However, the enantioselectivity of the reaction had beenfound to be affected by various factors (Scheme19),158

including: (1) catalyzed by CsF, silylated tertiary alcohol 101is obtained in quantitative yield from the reaction of acetylprotected acetophenone 100a with 1; (2) in the asymmetriccase catalyzed by 99a, (R)-102a is produced in moderate ee;(3) in the asymmetric case tested by the reaction of ketone100f with 1 using catalyst 99c in dichloromethane at −78 °Cproves to be a better choice for solvents and reactiontemperatures (product (R)-102f, 70% conversion, 78% ee);(4) among the reactions of 100a−f catalyzed by 99c, product(R)-102f is obtained with the greatest level of enantioselectivityfrom acetophenone 100f; (5) among the catalysts of 99a−k(4−20 mol %) for the reaction of 100f, catalyst 99j gives thebest result, 97% conversion, 92% ee using only 4 mol % of 99j.Although catalyst 99j shows the best result for the

transformation of acetophenone 100f to (R)-102f,139,140

unfortunately, the enantioselectivity exhibits a strong sub-strate-dependence. For example, substrates 103a−i giveunsatisfactory results (1−64% ee, Table 5).158 Whereas theresearch of Caron and co-workers gives an efficient procedurefor the preparation of the catalysts, cinchona-derivedquaternary ammonium fluoride salts 99 (Figure 5), simply bytreatment of cinchonine with benzyl halides (1.2 equiv) in thepresence of a catalytic amount of Bu4NI (3 mol %) in refluxingTHF. The advantage of using THF over the commonly usedtoluene is that any unreacted cinchonine remains in solution.

Scheme 17. Reaction of Moris-Baylis-Hillman Adducts with Fluorinated Silanes

Scheme 18. Asymmetric Allylic Trifluoromethylation ofMoris-Baylis-Hillman Carbonates

Figure 5. Cinchonine-derived catalysts.

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Thus, the ammonium salt can be obtained simply by filtrationfollowed by ion exchange with Dowex-F− in MeOH.158

3.8.2. Aldehydes and Ketones: Phase-Transfer Catal-ysis Mode. The catalytic enantioselective trifluoromethylationof carbonyl electrophiles using 1 as the trifluoromethyl transferreagent had met with much less success than the Mukaiyamaaldol type reaction.155,158,160 In 2007, a breakthrough in thisarea was made by Shibata and co-workers, they revealed astrategy for the in situ generation of quaternary ammoniumfluorides derived from cinchona alkaloids.161−164 Thisprocedure involves the external introduction of a more soluble

fluoride source than KF in low amounts which, combined witha polar cosolvent, allows the enantioselective trifluoromethyla-tion reaction to proceed efficiently in a phase-transfer catalysismode. As an example, more recently, Shibata and co-workersdescribed the first enantioselective synthesis of efavirenz 116via a five-step procedure by using a direct trifluoromethylationapproach as the key step.164 Optimization of reactionconditions, especially the ammonium bromides derived fromcinchonidine and quinine, enables them to obtain the keyintermediate of efavirenz (S)-114 in high yield and acceptableee from trifluoromethylation of alkynyl ketone 112 with 1

Scheme 19. Cinchona-Derived Quaternary Ammonium Fluoride Catalyzed Trifluoromethylation of Ketones

Table 5. Trifluoromethylation Reactions of Different Substratesa

aReaction conditions: catalyst (4 mol %), 1 (1.5 equiv) in CH2Cl2 at −50 °C.

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catalyzed by a combined 113/Me4NF system (Scheme 20).164

In this organocatalyzed asymmetric synthesis, a procedure

based on the combination of the readily available chiralammonium bromides of cinchona alkaloids with TMAF asextraneous fluoride (fluoride ion acting as the base to activate 1,also see Scheme 3)23 makes the operation simple andconvenient.160−164

Efavirenz 116 is a non-nucleoside reverse transcriptaseinhibitor (NNRTI) administered as a first-line treatmentagainst HIV.165 Alternatively, in the elegant synthesis of 116through the asymmetric addition of metalated acetylene to aryltrifluoromethyl ketone as a key step to give amino alcohol (S)-115 and analogues,166−170 and an asymmetric autocatalytic zincacetylide addition171 employing catalytic amounts of enantio-merically pure (S)-115 as part of a chiral cocktail have also beenreported (Scheme 21).170 In addition, a number of valuablesynthetic strategies for the enantioselective synthesis oftrifluoromethyl carbinols, such as Rh/phebox-catalyzed (phe-box: 2,6-bis(oxazolinyl)phenyl) alkynylation of α-ketoesters172

and aldol reactions with trifluoroacetophenones catalyzed bySingh’s catalyst ((2S)-N-[(1S)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarboxamide)173 have been recentlydeveloped as well.In the area of catalytic enantioselective trifluoromethylation

of carbonyl electrophiles with 1, the trifluoromethylation ofaldehydes has been comparatively less explored.155−159

Recently, Shibata and co-workers examined the enantioselectivetrifluoromethylation of aryl aldehydes (Table 6)174 using theircinchona alkaloid/TMAF combination strategy.161,162,164 Using

120 as the sterically demanding catalyst, trifluoromethylatedproducts 121−130 are obtained in high to excellent yields andmoderate to good ee values from the corresponding aldehydes(Table 6, 10 examples, 70−99% yields, 50−70% ee). Incomparison, product 121 was produced in 91% yield and 1% eecatalyzed by less sterically demanding catalyst 131 under similarreaction conditions.Accordingly, Shibata and co-workers described a phase-

transfer catalysis mechanism.174 This process involves thereaction of TMAF with 1 to generate trifluoromethyltetramethylammonium 132 with the release of stable Me3SiFand further to form chiral trifluoromethylammonium 133 andMe4NBr (TMAB) through the reaction of 132 with catalyst120. Chiral ammonium 133 has the ability to regulate thetrifluoromethylation of an aldehyde under asymmetric environ-ments. In this case, achiral ammonium 132 is also reactive toaldehyde which furnishes racemic products (Scheme 22).174

In the synthesis and synthetic applications of β-amino-α-trifluoromethyl alcohols,175−178 alcohols 137 are preparedbased on the phase-transfer catalysis mode from trifluorome-thylation of α-imino ketones (derived from aryl glyoxals) in thepresence of catalyst 135 and K2CO3 followed by reduction(Scheme 22).178 As the model reaction, 137a was obtained in85% yield and 67% ee. In comparison, KF was less effectivethan K2CO3 and KOH and gave the lowest ee (Scheme 22).178

From a certain perspective, the catalytic enantioselectivetrifluoromethylation of aldehydes has not been entirelyunderstood to date although some plausible explanationshave been presented.

3.8.3. Aldehydes and Ketones: Combination CatalysisMode. Feng and co-workers in 2007, the same year of theShibata’s method for the in situ generation of quaternaryammonium fluorides from cinchona,161 disclosed that acombination of disodium (R)-binaphtholate and cinchonaalkaloid-derived quaternary ammonium salts can afford thetrifluoromethylation products of aromatic aldehydes in up to71% ee by 10 mol % of catalyst loading (11 examples, 68−95%yields, 41−71% ee), while low ee values were obtained forelectron-rich aromatic aldehydes (around 40% ee).179 Thecombinatorial catalytic systems were later examined in detailsby Chen and co-workers.180,181 More recently, they reported ageneral catalytic enantioselective trifluoromethylation ofaromatic aldehydes using (IPr)CuF 138 (IPr: 1,3-bis(2′,6′-di-iso-propylphenyl)imidazol-2-ylidene) and salt 139 as catalystsunder argon atmosphere (Table 7).181 The reaction furnishes awide range of aromatic aldehydes to the correspondingproducts (R)-140a−l with the highest levels of ee to date. Inaddition, this reaction has the advantage of lower loading of

Scheme 20. Enantioselective Trifluoromethylation Approachto Efavirenz

Scheme 21. Enantioselective Synthesis of Efavirenz

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asymmetric organocatalyst182 (probably via a synergisticcatalytic mechanism)183 and in particular, applicable for

Table 6. Enantioselective Trifluoromethylation of Aromatic Aldehydes Catalyzed by 120/TMAF Combination

Scheme 22. Phase-Transfer Catalysis and a ProposedMechanism

Table 7. Cooperative Catalytic EnantioselectiveTrifluoromethylation of Aromatic Aldehydes

entry (R)-140 Ar time (h) yield (%) ee (%)

1 140a 2-naphthyl 1 90 752 140b Ph 2 80 603 140c 2-pyridyl 2 89 424 140d 4-BrC6H4 2 81 575 140e 3-ClC6H4 2 83 516 140f 3-FC6H4 2 87 517 140g 4-MeC6H4 1 88 688 140h 3-MeOC6H4 1 89 749 140i 2-MeOC6H4 1 88 7310 140j 6-MeO-2-naphthyl 2 83 5311 140k 3,4-O(CH2)OC6H3 2 92 8112 140l 4-EtSC6H4 2 85 73

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electron-donating aldehydes (Table 7, entries 7−12, 68−81%ee except for 140j in 53% ee).181

With the synthesis of 140a as an example under optimicalreaction conditions (Table 7), Chen and co-workers also foundthat (1) neither (IPr)CuF 138 (2 mol %) nor chiral salt 139 (2mol %) for a reaction period of 4 h is effective to promote theaddition of 1; (2) cocatalyzed by 139 (2 mol %) and(IPr)Cu(t-BuO) (2 mol %) and reacted for 4 h gives 140a with45% ee (57% yield) while the combination of 139 (2 mol %)with (IPr)CuCl (2 mol %) for 4 h gives no product; (3) 139 (5mol %) for 36 h affords 140a in 87% yield with 57% ee; and (4)139 (5 mol %)/(IPr)CuCl (5 mol %) for 48 h delivers 140a in84% yield with 67% ee.181 These results181 andothers157,184−188 indicate that fluoride ion acts as an initiatorfor the generation of the active (IPr)CuCF3 species 138′ in theproposed catalytic cycle (Scheme 23). The catalytic cycleinvolves: (a) activation of aldehyde by 139 through hydrogenbond interaction and formation of 138′ through CF3 transferbetween 138 and 1; (b) nucleophilic attack of 138′ on theactivated aldehyde to generate intermediate 141 with theenhanced chiral communication between quaternary ammo-nium and substrate by the [Cu] moiety; and (c) activation ofthe in coming 1 by the chiral alkoxide in 141 to effectivelyarrange the transition state 142 allowing the release of the silylether product 140′ and regeneration of 141, simultaneously(Scheme 23).3.8.4. Enantioselective Trifluoromethylation of

Imines. In 2009, 15 years after the first trifluoromethylationof 1 on the CN bond of reactive azirines116 and asymmetrictrifluoromethylation of 1 with aldehydes/ketones,155 the firstcatalytic asymmetric trifluoromethylation of a CN bond wasdisclosed by Shibata and co-workers.189 Prompted by theirsuccess in trifluoromethylation of carbonyl compounds using acatalyst system composed of readily available chiral bromidesalts of cinchona alkaloids and TMAF (Scheme 20),160−164 theyperformed the enantioselective trifluoromethylation of azome-thine imines 143 with 1 (Table 8).189

With the combination of 135/KOH or 145/KOH as thecatalyst, the reaction of 143 with 1 can lead to trifluoromethy-lated adducts 144 with up to 98% ee under optimal conditions(Table 8, Condition A).189 More recently, Shibata and co-workers proved that Solkane365mfc (1,1,1,3,3-pentafluorobu-tane, CF3CH2CF2CH3) is an environmental benign alternativesolvent for the enantioselective trifluoromethylation of 143catalyzed by 146/KOH (Table 8, Condition B, up to 96%ee).135 The above results demonstrate that high chemical yieldsand enantioselectivities can be achieved from the trifluor-

omethylation of azomethine imines 143 with 1 (Table 8)135,189

and the catalysts can be synthesized in one step fromcommercially available cinchonine.135,158,189,190 Whereas,under identical conditions (condition B) but catalyzed by135/KOH, adduct 144a was obtained in only 11% ee.135

In the research of the trifluoromethylation of N-tosylimines,128 Bernardi and co-workers described a single exampleof organocatalytic asymmetric trifluoromethylation of imineequivalent 149 using phase-transfer catalysis with phenoxides inthe presence of cinchona-derived quaternary ammoniumchloride 150 (Scheme 24).128,191 In a more recent report,Shibata and co-worker described an asymmetric aerobicepoxidation of β-trifluoromethyl-β,β-disubstituted enones byusing catalyst 139 to give enantiomerically enriched trifluor-omethylated epoxides with a tetrasubstituted carbon centers.192

A trifluoromethyl group can exert steric, electrostatic, andstereoelectronic effects on a reaction site, thereby affects itsreactivity. The size of a trifluoromethyl group is close to anisopropyl group and steric parameters and electrostatic effectsarising from the presence of fluorine atoms cause fluorine-containing compounds likely to be poor hydrogen-bondacceptors.190−192 While catalytic enantioselective trifluorome-thylation of carbonyl electrophiles and imines with 1 has gainedrecent success, the current chiral catalyst, mainly derived fromcinchona bark has significant limitations in substrate scope.Therefore, combined with mechanistic studies, the creation ofnew catalysts for enantioselective trifluoromethylation isneeded.193

3.9. Catalysts and Mechanisms Considerations

The X-ray diffraction structure of 1 confirms that the Si−CF3bond is longer and weaker than the Si−CH3 bonds,37 whichindicates the CF3 group can be preferentially transferred from 1to an electrophile in the presence of suitable nucleophiliccatalysts in general and leads to a better understanding on themechanism. In the nucleophilic trifluoromethylation reactionsusing 1 as the trifluoromethyl transfer reagent, nucleophiliccatalysts and/or initiators are essential, which have and willcontinue to reshape the applications of 1 as a versatile reagentin trifluoromethylation reactions since the first report byPrakash and co-workers using TBAF as an initiator.41

3.9.1. Oxygen Centered Nucleophilic Catalysts. Oxy-gen-containing nucleophiles are suitable catalysts in TMSCF3chemistry due to the high bond strength as well as the kineticlability of the silicon oxygen (Si−O) bond,1 which has beensuccessfully used to define the generation of trifluoromethylcarbanion equivalent for fluoride ion initiated mechanism ofnucleophilic trifluoromethylation of 1 with aldehydes and

Scheme 23. Proposed Mechanism for Cooperative Catalysis

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ketones (Scheme 3).23 The breakthrough in oxygen centeredactivators was achieved by Mukaiyama and co-workers. Theyfound that several oxygen-containing anions are suitable Lewisbase-catalysts in perfluoroalkylation of (perfluoroalkyl)-trimethylsilanes (TMSCF3, TMSC2F5, and TMSC3F7) withcarbonyl compounds,194−196 for example, the use of lithiumacetate as a catalyst in the trifluoromethylation of 1 with variousaldehydes and ketones (Table 9, entry 1)194,196 and N-tosylaldimines (Table 9, entry 2)195,196 using DMF as thesolvent under mild reaction conditions. It was also found thatDMSO is also a good solvent for the lithium acetate catalyzedtrifluoromethylation of 1 with 4-methoxybenzaldehyde (97%yield), however, THF, AcOEt, dichloromethane, toluene, andacetonitrile are not desirable solvents (no desired product at

all) and lithium trifluoroacetate, a weak Lewis base, did notpromote the reaction.196 Prakash and co-workers carried out anextensive set of experiments reinforcing oxygen centerednucleophilic catalysts, which confirms that amine N-oxide(trimethylamine N-oxide), carbonate (K2CO3) and phosphatesalts have efficient catalytic activity with the solvent, DMF, toenhance the reaction rate (Table 9, entries 3−5)197,198

3.9.2. Substrate-Directable Reaction. In addition tooxygen centered nucleophilic catalysts, other catalysts havingdifferent structures can also be used in the nucleophilictrifluoromethylation reactions, while, simple tertiary amines arenot included. In 1997, Fuchikami and co-workers found thatthe reaction of β- and γ-amino ketones with 1 afforded 1,2-adducts 153a and 153b in high yields, respectively, in the

Table 8. Enantioselective Trifluoromethylation of Azomethine Imines

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absence of external catalysts (Scheme 25).151 For comparison,only a trace amount of 153c was produced from δ-aminoketone 152c after 24 h of the reaction. These results indicatethat a simple tertiary amine is not an efficient catalyst for thetrifluoromethyl transfer of 1. Both cases of formation of TMS-protected trifluoromethylated alcohols 153a and 153b frombidentate 152a and 152b are likely driven by the high ability toform, for example, the corresponding pentacoordinated andhexacoordinated intermediates (or transition states) involving a

pseudointramolecular process.151,197 Thus, the low yield of 1,2-adduct 153c is possibly due to the less favorable seven-membered intermediate (formed from 152c) than five- and six-membered intermediates. These results suggest that thenucleophilicity of the CF3 group of 1 can be enhanced bythe electron-donating character of bidentate 152a and 152b,which makes the reaction proceed in an substrate-directablemode (Scheme 25).199,200 Typical examples of such reactionsinvolve transient interaction of a substrate functional groupwith the incoming reagent with the directing functionality (theamino group) being recovered intact in the final product.

3.9.3. DMSO and Molecular Sieves. The nucleophilictrifluoromethylation reactions of 1 with carbonyl compoundsare highly solvent dependent.196,197 In the presence of MS 4 Å(MS: molecular sieves) as dehydrating agents in the solvent,DMSO, trifluoromethylation of various aldehydes and ketones

Scheme 24. Asymmetric Trifluoromethylation of ImineEquivalent

Table 9. Catalysts/Promoters for Nucleophilic Trifluoromethylations

entry catalysts (mol %) electrophiles solvents ref

1 LiOAc (5%) aldehydes and ketones DMF 194, 1962 LiOAc (10%) N-tosylaldimines DMF 195, 1963 trimethylamine aldehydes and ketones DMF 1974 N-oxide (5−15%) aldehydes and ketones DMF 42, 1975 phosphate salts (2−20%) K2CO3 (1−20%) aldehydes and ketones DMF 1976 DMSO with MS 4 Å (see Scheme 26) aldehydes and ketones DMSO 2017 TBD 158 (5−10%, see Scheme 27) aldehydes and ketones DMF 2038 NHC 162 (0.5−1%, see Scheme 28) enolizable/nonenolizable aldehydes and α-keto esters DMF 2049 P(t-Bu)3 (10%) aldehydes and ketones DMF 21210 P(t-Bu)3 (100%) sulfonylimines DMF 21211 TTMPP (20%) N-unactivated imines DMF 21312 TTMPP (5%) aldehydes THF 21313 TTMPP (5%) ketones DMF 21314 TTMPP (20%) sulfonylimines DMPU 21315 KF (30 mol %), TBAB (30 mol %) isatoic anhydrides DMF 14416 Ti(OiPr)4 (10%) aldehydes DMF 4817 TiF4 (10%) aldehydes DMF 4818 Cu(OAc)2 (10%)/dppe (10%) aldehydes toluene 4819 TBABF (TBAF·HF, 2 eq, see eq 3) aryl nitriles THF 4720 TBAF (5−10%, see Scheme 3 and 4) aldehydes and ketones THF 41, 5221 NaOAc (1.5 eq, see Table 2) 4-nitroisoxazoles DMF 8022 KOAc (0.8 eq, see Scheme 50) 4-(trifluoromethanesulfonyl)isoxazoles DMSO 38823 CsF (20%, see Scheme 9) Weinreb amides Toluene 10824 TMAF (1 eq, see Figure 4) benzylideneaniline THF 4425 In-situ-generated HF (1 eq, see Scheme 12 and Table 3) imines MeCN/DMF 12026 TBABF (40%, see eq 3) aryl nitriles THF 4627 DABCO (5%, see Scheme 17) MBH aducts DMF 149

Scheme 25. Substrate-Directable Reaction

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with 1 can proceed very smoothly at room temperature for 10min to 1 h to give the corresponding trifluoromethylatedadducts in good to quantitative yields without a catalyst (16examples for aldehydes, 81−100% yields; 1 example forelectron-rich 4-(dimethylamino)benzaldehyde, 53% yield; 6examples for ketones including chalcone, 82−100% yields; noreaction for benzyl acetoacetate having acidic C−H bonds;Table 9, entry 6).201 As a model reaction of benzaldehyde with1 under similar reaction conditions, using DMF as the solventaffords the desired product in 86% yield, whereas, MeCN andCH2Cl2 are not effective. The desired product was obtained in48% yield for a reaction time of 6 h without the addition of MS4 Å. In sharp comparison, only gave 5% yield without theaddition of MS 4 Å but 1.0 equiv of water, indicating theimportant role of MS to absorb the small amount of waterpresent in the reaction system.202 A mechanism involvingDMSO coordinating to the silicon atom of 1 to form a CF3group nucleophilicity-enhancing species 156 was proposed(Scheme 26).201

3.9.4. Amidine Base. Matsukawa and co-workers recentlydescribed the trifluoromethylation of carbonyl compoundscatalyzed by commercially available TBD 158 (TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene, an amidine base, Table 9, entry7).203 A possible mechanism involves, first, the coordination ofTBD 158 to the silicon of 1 to activate the Si−CF3 bond(159); where the hydrogen-bonding activation of the carbonylcompound to form intermediate 160; reaction of the activatedsilylated nucleophile and carbonyl compound can then readilyreact to produce the ionic adduct and silylated TBD 161 andfinally, silylation between the ionic adduct and silylated 161 tofurnish the desired product with regeneration of TBD 158(Scheme 27).203

3.9.5. N-heterocyclic Carbene or Phosphines in DMF.Recent utilization of commercially available N-heterocycliccarbene 162 (NHC) as an efficient catalyst for trifluoromethy-lation of both enolizable and nonenolizable aldehydes and α-keto esters at room temperature requires only 0.5 mol % of 162in the solvent, DMF (Table 9, entry 8). The reaction ofbenzaldehyde with 1 catalyzed by 162 (10 mol %) gives 100%conversion within 20 min in DMF or 60 min in THF. Use oftoluene, methylene chloride or MTBE (methyl t-butyl ether) assolvents resulted in sluggish reactions.204 A possible mechanisminvolves coordination of the strong σ-donating 162 to thesilicon atom of 1 activating the Si−CF3 bond, formingintermediate 163; reaction of 163 with a carbonyl compoundto form intermediate 164 and further to give the silylatedadduct along with the regeneration of 162 (Scheme 28).205,206

An alternative mechanism via a pentavalent silicon intermediate165 accounts for the formation of intermediate 166 (Scheme28)207 upon both of the nucleophilicity of the strong σ-donating NHC150,204,208 and the catalytic activity of the oxygencentered nucleophilic intermediate 165 in the solvent,DMF.194−197

Similar to the strong σ-donating NHC,150,204,207,208 tritert-butylphosphine, a very strong electron-donating ligand, is alsoan efficient promoter for the trifluoromethylation of aldehydes,ketones, imides and imines in DMF (16 examples foraldehydes, 62−99% yields; 2 examples for ketones in 81 and84% yield, respectively; 5 examples for sulfonylimines, 41−80%yields, Table 9, entries 9 and 10).209−213 For the reaction of 2-naphthaldehyde, HMPA (hexamethylphosphoric triamide),DMA (dimethylacetamide) and DMSO are also efficientsolvents, whereas, MeCN, CH2Cl2, THF and Et2O are not.209

Using TTMPP (tris(2,4,6-trimethoxyphenyl)phosphine, hav-ing strong electron-donating power) as the catalyst, aldehydes(in THF), ketones (in DMF) and N-tosylaldimines in DMPU(1,3-dimethyl-3,4,5,6-tetrahyde-2(1H)-pyrimidone) can reactwith 1 to give the corresponding adducts (Table 9, entries12−14).213 Interestingly the reaction of 1 with N-unactivatedimines120−122 is also successful catalyzed by TTMPP (Table 9,entry 11).213 In comparison other phosphines such astriphenylphosphine, tributylphosphine and tritert-butylphos-phine are not efficient.201

Considering the faster transfer of the CF3 group in thesolvent, DMF,194−197 Golubev and co-workers performed thetrifluoromethylation of 2H-3,1-benzoxazine-2,4(1H)-diones167 (the isatoic anhydride derivatives) with 1 in the presenceof a combination of KF and TBAB, which leads to the selectiveformation of N-substituted o-trifluoroacetylanilines 168 in goodto high yield (Scheme 29, Table 9, entry 15).144

3.9.6. Lewis Acids. In 2006, Shibata, Toru and co-workersdescribed the first Lewis acid-catalyzed trifluoromethylationreaction of aldehydes with 1. Catalysis by TiF4/DMF,Ti(OiPr)4/DMF or Cu(OAc)2/dppp/toluene under mildreaction conditions, the reaction gave satisfactory results(Table 9, entries 16−18, dppp: 1,2-bis(diphenylphosphino)-

Scheme 26. Trifluoromethylation in DMSO in the Presenceof MS 4 Å

Scheme 27. TBD-Catalyzed Trifluoromethylation

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ethane).48 In general, these results are in accordance with thesiliphilic nature of the counteranions of Lewis acids under thereaction conditions studied. In comparison, under identicalreaction conditions in a solution of DMF, SnCl4, AlCl3, BF3·Et2O, TiCl4, Cu(OTf)2, NiClO4·6H2O, Zn(OAc)2, and Pd-(OAc)2 are not efficient catalysts.48

The present progress in nucleophilic trifluoromethylationreactions, including the catalytic enatioselective version ofvarious imines with 1 mediated by hydrofluoric acid (generatedin situ), deserves more attention because it is not only the

realization of the trifluoromethylation of imines to providestructurally diverse primary amines bearing a germinal CF3group, but also a good selectivity to an imine instead of acarbonyl group (Scheme 13, eq 4 and Table 9, entry25).43,120−122,126,127 Furthermore, the TBABF promoteddouble trifluoromethylation of aryl nitriles to give bistri-fluomethylated amines (eq 3 and Table 9, entry 19) via areactive trifluoromethyl imine intermediate provides the firstexample for the direct trifluoromethylation of nitriles.46 In thisreaction, TBAF was ineffective under identical conditions,

Scheme 28. NHC-Catalyzed Trifluoromethylation

Scheme 29. KF/TBAB-Promoted Trifluoromethylation of Isatoic Anhydride Derivatives

Scheme 30. Preparation and Synthetic Applications of CF3-Substituted Boranes

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which may indicate that HF (from TBABF) plays a role for theactivation of both nitriles and trifluoromethyl imines.43,121,122

In addition, the observations that the trifluoromethylationreactions of enolizable/nonenolizable aldehydes and α-ketoesters catalyzed by NHC (Scheme 28 and Table 9, entry 8),204

4-nitroisoxazoles promoted by NaOAc (Table 2 and Table 9,entry 21), 4-(trifluoromethanesulfonyl)isoxazoles promoted byKOAc (Scheme 50 and Table 9, entry 22),388 Weinreb amidescatalyzed by CsF (Scheme 9 and Table 9, entry 23),108

benzylideneaniline promoted by TMAF (Figure 4 and Table 9,entry 24),44 and MBH aducts catalyzed by DABCO (Scheme17 and Table 9, entry 26)149 reflect some recent achievementsmainly in the nucleophilic trifluoromethylation reactions usingTMSCF3 1 as a versatile reagent depending on the activation of1 and/or carbon electrophiles.

4. REACTIONS WITH B-, P-, AND S-BASEDELECTROPHILES

Nucleophilic trifluoromethylation of hetero electrophiles isimportant to develop new methods for the preparation ofimportant trifluoromethylating, trifluoromethylthiolating re-agents,23,24,26,214−217 and Togni’s reagents, Umemoto’s re-agents and related species as well as described in section 8 ofthis review.

4.1. Preparation and Synthetic Applications of(Trifluoromethyl)trimethoxyborate

In the presence of KF, the reaction of TMSCF3 1 as anionicreagent with electrophilic trimethoxyborate gives potassium(trifluoromethyl)trimethoxyborate 170. Subsequent fluorina-tion of 170 can generate (trifluoromethyl)trifluoroborate 171in high yield (Scheme 30).214,215 Recently, 171 has beensynthesized directly from CF3H in up to 66% yield (Scheme30),24 however, the isolation of pure 170 from the reactionmixture is difficult due to decomposition of 170 under thereaction conditions (further reactions with residualKHMDS).24

Now, there is a convenient access to 170 in multigramquantities simply by stirring a mixture of 1, B(OMe)3, and KFin anhydrous THF over several hours.216,217 Compound 170 isa colorless, air-stable solid (each asymmetric unit cell containsthree molecules of 170 with one coordinated THF confirmedby X-ray crystal structure) and can be left in an open vessel forseveral days (no signs of decomposition were observed byNMR spectroscopic analysis). The salt melts at 116−118 °Cwith decomposition.216,217 Similarly, aryl(methoxy)-(trifluoromethyl)boranes 172 have also been prepared (Scheme30).218 Borate 172 is an air-stable solid and storable in a tightlyclosed flask at room temperature for months without noticeablechanges.218 The synthetic applications of 172 have beenstudied, such as the reaction with α-diazocarbonyl com-

Table 10. Reactions of Different Nucleophilic Trifluoromethyl Transfer Reagents with Aldehydes

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pounds218 and in three-component reactions with ethyldiazoacetate and imines.219

Recently, reagent 170 has been taken as a new source of CF3nucleophiles and successfully implemented the copper-catalyzed selective trifluoromethylation of aryl iodides216,217

and oxidative trifluoromethylation of arylboronates.220 As ananalogue of organotrifluoroborates,221,222 recent studies showthat 170 can also serve as a convenient reagent for nucleophilictrifluoromethylation of nonenolizable aldehydes and N-tosylimines leading to CF3-substituted alcohols and N-tosyl-amines in good yields (Scheme 30).223 Concerning the reactionmechanism, the transfer of the CF3-group of 170 to CO orCN bond can occur without either the intermediacy of a freeCF3 anion or radical.223 Table 10 gives a comparison of thetrifluoromethylation of nonenolizable aldehydes by using the“CF3

−” derived from CF3H24,224 to 170.223

Accordingly, the trifluoromethylation of aldehydes usingCF3H with P4-tBu as a sterically very demanding organo-superbase in DMF (Table 10, Method B) is successful, whereas,the bases such as DBU, TMG (1,1,3,3-tetramethylguanidine),TBD, P1-tBu, and P2-Et (see Table 10) in DMF are not.224 Upto now, there have been no examples of the trifluoromethy-lation of enolizable aldehydes or ketones (containing a CH-acidic methylene group) as the electrophiles using CF3H as the“CF3

−” source (for example, Table 10, 177 and 178).24,224

Therefore, the mechanisms for the reaction listed in Table 10needs to be elucidated considering the influence of variousfactors,24,38,39,221,223−233 to prompt the use of CF3H aspotentially, environmentally benign trifluoromethylating re-agents.24,224−228,232

4.2. Reactions with Phosphorus-Based Electrophiles

The use of 1 as a convenient CF3 source to generatetrifluoromethyl-containing phosphines was first described byMichalski’s and Hoge’s groups in 2001 through fluoride ioncatalyzed (CsF (10 mol%) or TBAF in THF at roomtemperature) nucleophilic displacement of F− from RR′P−Fcompounds to give RR′P−CF3 in high to excellent yields.234,235

Based on the similar procedure, a series of CF3-derivatives ofJosiphos’ ligands (one of the most successful ligand classes usedin asymmetric catalysis)236 have been prepared.237

4.3. Reactions with Sulfur-Based Electrophiles

Trifluoromethylation of sulfonyl fluorides with 1 was exploredby Yagupolski and colleagues in 1990. For example catalyzed byTASF (tris(dimethylamino)sulfonium difluorotrimethyl silico-nate), the reaction of benzenesulfonyl fluoride with 1 gives(trifluoromethylsulfonyl)benzene in excellent yield under mildconditions (eq 5).238 Utilizing this thiophilic nucleophilicreaction,239,240 S-trifluoromethyl ketene dithioacetals (andanalogues) are prepared by Portella and co-workers (eq6).64,239 This reaction has been successfully used for thetransformation of nucleophilic trifluoromethylating species intoelectrophilic one,241,242 such as the synthesis of N-protectedtrifluoromethyl-substituted sulfoximines (eq 7).243

A recent paper24 by Prakash and co-workers summarized thesynthesis of CF3S-containing compounds based on 1 andCF3H. The direct trifluoromethylation of elemental sulfur usingCF3H and subsequent oxidation would facilitate a straightfor-ward synthesis of trifluoromethanesulfonic acid (CF3SO3H),

24

a widely used Brønsted superacid and large-volume trifluor-omethylated product.244

The reaction of 1 with aromatic thiones to deliver a mixtureof (trifluoromethylthio)diarylmethane (major) and 1,1-diaryl-

2,2,2-trifluoroethanethiol assisted by TBAB has been re-ported.245 On the other hand, the reaction of 1 withdiethylaminosulfur trifluoride (DAST) derivatives and aprimary amine to form trifluoromethanesulfanylamides/tri-fluoromethanesulfanamides (for example, the unstable trifluor-omethyl difluorosulfur) has also been described by Billard,Langlois and co-workers (eq 8).246 Notably, using trifluor-omethanesulfanylamides/trifluoromethanesulfanamides as easy-to-handle equivalents of the trifluoromethanesulfanyl cation(CF3S

+) has proven successful in direct trifluoromethylthiola-tion with alkenes and alkynes,247 electron-rich aromaticcompounds,248,249 allylsilanes,250 and Grignard or lithiumreagents.251,252

5. TRIFLUOROMETHYLTRIMETHYLSILANE AS ADIFLUOROCARBENE PRECURSOR

A “naked” trifluoromethyl anion is exceedingly unstable andpromptly collapses at room temperature and even below todifluorocarbene (:CF2) and F− due to the destabilization of theCF3 anion by electrostatic repulsions between the anioniccharge and the p -electron pairs of the fluorineatoms.19,24,55,56,224−226 In addition, difluorocarbene is involvedin the reaction of 1 with TfOH (Scheme 5)56 and thepreparation of difluoromethylated molecule 39 using hexa-fluoroacetone hydrate amidinate salt 35 as the difluorocarbenesource under basic conditions (Scheme 8c).98

The decomposition of trifluoromethyl anion can be avoidedby deprotonating CF3H at −20 to −40 °C in DMF whichinstantly adds the resultant CF3 anion to give a hemiaminolateadduct [Me2NCH(O)CF3]

−. Although this hemiaminolateadduct still quickly decomposes at room temperature, it isstable at −20 °C for at least a few hours.224 It has beendemonstrated that the presence of K+ as the countercation ofthe base and a low temperature (−85 °C) of the reactionappear to be rather important in the preparation of “CF3

−” (seeScheme 2 and description thereof).24,38,39

5.1. [2 + 1] Cycloaddition

Developing new fluorination methods is of great interest inareas such as pharmaceuticals, agrochemicals and materials. In2011, Hu and co-workers found that treatment of phenyl-acetylene 181 and TMSCF2Cl 182-Cl catalyzed by n-Bu4NClin toluene in a pressure tube at 110 °C gave (3,3-difluorocycloprop-1-enyl)benzene 183 in high yield (Table11).253 This reaction is strongly affected by reaction conditions,including initiator/catalyst and/or its quantities, counteranion

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or cation of the initiator/catalyst, solvent, temperature and/oreven pressure (Table 11, also see Scheme 4).52,253 Interestingly,when TMSCF3 1 was used in place of 182-Cl, TMSCF3 1 wasrecovered,253 indicating Cl− can not be used to activate 1 at allunder identical conditions (Table 11, entry 8).A mechanism for the formation of difluorocarbene and

further [2 + 1] cycloaddition with electron-rich alkynes, forexample 181, involving reaction of Cl− with 182-Cl to releaseMe3SiCl via pentacoordinated silicon species 186 to formchlorodifluoromethyl anion 187 as the source of difluorocar-bene is proposed (Scheme 31).52,253 Importantly, the [2 + 1]cycloaddition is also applicable to electron-rich alkenes,providing difluorocyclopropanes, for example 185 (Table 11),in good to excellent yields.253 Accordingly, Hu, Prakash and co-workers described the generation of difluorocarbene from 1 in

the presence of excess amount of NaI (2.2 equiv) in THF at110 °C in a pressure tube and furnished a one-pot sequentialcombination of trifluoromethylation and [2 + 1] cycloadditionreaction of 1 with 4′-(phenylethynyl)-acetophenone 5 contain-ing both a carbonyl group and a triple bond (Scheme 4).52

5.2. Direct α-Difluoromethylation of Lithium Enolates

Difluorocarbene is a relatively stabilized carbene species (with asinglet ground state) owing to the interaction of the lone pairsof electrons on fluorine atoms with the carbene center. This islikely the reason why difluorocarbene does not react well withelectron-poor alkenes.52,206,253−255 Recently, Mikami and co-workers described the direct α-difluoromethylation of lithiumenolates of lactams 188 using an umpolung form of fluoroformas a difluoromethyl carbocation equivalent (“CHF2

+”) leads toan all-carbon quaternary center, for example, the synthesis of α-difluoromethyl product 189a from 188a (Scheme 32).232

A possible mechanism combined with DFT calculationsinvolving formation of homodimer intermediate 190 fromlithium enolate leading to mixed aggregate 191 and further toopen dimer, the eight-membered intermediate 192 wasdescribed (Scheme 32).232 The mechanism involves activationof inert C−F bond (490 kJ mol−1; C−C bond: 370 kJ mol−1;C−H bond: 420 kJ mol−1) through direct interaction with thelithium cation and subsequent C−C bond formation. In thecase of acyclic substrates, the difluoromethylation alsoproceeded with the 2-phenylpropanates to form α-difluor-omethyl products 193. The difluoromethylation reaction hasalso been successfully applied to the synthesis of the analogue194 of the anti-inflammatory and analgesic drug, ibuprofen(Scheme 32, also see Scheme 8).232

It has been found that (1) among the alkaline metal enolates(Li, Na, K) generated with the corresponding MHMDS, onlythe lithium enolate (from LiHMDS) gives 189a because of the

Table 11. [2 + 1] Cycloaddition Reactions InvolvingDifluorocarbene

entryMe3SiCF2X

(eq) solventinitiator(mol %)a

temp/°C

yield of 183(%)

1 182-Cl (1.5) THF ortoluene

none 110 0

2 182-Cl (1.5) THF n-Bu4NF(110)

110 0

3 182-Cl (1.5) THF n-Bu4NF (2) 110 394 182-Cl (1.5) THF NaCl 110 05 182-Cl (1.5) CH3CN n-Bu4NCl

(2)110 71

6 182-Cl (1.5) toluene n-Bu4NCl(2)

110 79

7 182-Br (1.5) toluene n-Bu4NCl(2)

110 67

8 1 (X = F,1.5)

toluene n-Bu4NCl(2)

110 0

9 182-Cl (1.0) toluene n-Bu4NCl(2)

110 82

10 182-Cl (2.0) toluene n-Bu4NCl(2)

25 0

11 182-Cl (2.0) toluene n-Bu4NCl(2)

80 53

Scheme 31. Generation and Reactions of DifluorocarbeneDerived from Me3SiCF2Cl

Scheme 32. α-Difluoromethylation of Lithium EnolatesUsing CF3H

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strong Li−F interaction,2−5 and (2) under identical conditionsno 189a is produced with lithium diisopropylamide (LDA) asthe base due to its less bulky, thereby leading to morecoordinated system. In addition, a detailed study on thereaction of α-benzyl-δ-lactam 188b with LiHMDS (Table 12)showed a significant effect of the amount of LiHMDS on thedifluoromethylation of the lithium enolate.232

The difluorocarbene intermediate is not involved in theabove reaction (Scheme 32).232 It is noteworthy thatfluoroform can now be used as a difluorocarbene source in aprocess for the conversion of phenols and thiophenols to theirdifluoromethoxy and difluorothiomethoxy derivatives undermild basic conditions.58

5.3. Reaction of Difluorocarbene with Acetylene Ethers

Significantly different from the [2 + 1] cycloaddition ofdifluorocarbene (derived from 1) to 4′-(phenylethynyl)-acetophenone (Scheme 4),52 O’Hagan and co-workers foundthat catalyzed by NaI the reaction of 1 with acetylene ethers195, the more electron-rich alkynes, gave fluorinated bicyclic[2.1.1]-hex-2-ene 196 (minor) and cyclohepta-1,4-diene 197(major), respectively, under mild reaction conditions (Scheme33).53

The reaction is proposed to involve a difluorocarbeneintermediate, providing further evidence of the versatility of 1in organic synthesis.52,53 When the reaction was carried out inthe presence of an equimolar amount of TEMPO ((2,2,6,6-tetramethyl-piperidin-1-yl)oxyl) as a radical scavenger, the 5-and 7-membered ring products 196 and 197 were notobserved, supporting radical pathways.53 However, accordingto the proposed mechanisms involving [2 + 1] intermediate198 in both cases for the formation of products 196 and 197,53

the difluorocarbene may be generated in a similar fashion asdescribed by Prakash and co-workers in their research on N-difluoromethylation of imidazoles and benzimidazoles (Scheme34).256 It was found that no desired product can be observedwhen KF or NaF instead of LiI was used as the promotor.Accordingly, Prakash described that Li+ cation plays a key rolein controlling the availability of fluoride in the reaction andpostulated that the generation of insoluble LiF during thecourse of the reaction would help to push the carbenegeneration reaction forward, thereby resulting in an increasedyield of the difluoromethylated product although a detailedmechanism has not yet been elucidated.52,53,256,257

In a recent report, Fier and Hartwig described thedifluoromethylation of phenols and thiophenols with a readilyavailable and nonozone-depleting liquid reagent, HCF2OTf 7(Scheme 5).57 This method allows difluoromethyl ethers andsulfides to be prepared within minutes at room temperature inaqueous solvent under basic conditions (eq 9). Mechanistic

studies show that the difluoromethylation proceeds through theinitial formation of difluorocarbene and subsequent nucleo-philic addition of the phenolate or thiophenolate anion todifluorocarbene.57

In addition, TMSCF3 1 has been successfully transformedinto (difluoromethyl)trimethylsilane (TMSCF2H) simply byreduction with sodium borohydride under mild reactionconditions.258 This method can be readily scaled up to a 10 gscale in 70% yield using dry diglyme as the solvent, which

Table 12. Effects of the Amount of LHMDSa

entry equiv of LHMDS temp/°C time (h) yield of 189b (%)

1 1 −78 14 172 2 −78 14 453 3 −78 14 254 2 rt 6 645 3 rt 6 24

a188b (0.1 mmol) was added to THF solution of LiHMDS at −78 °Cunder an argon atmosphere. The mixture was stirred at 0 °C for 30min, CF3H (5 equiv) was added at −95 °C, warmed to thetemperature indicated, and reacted for 6−14 h.

Scheme 33. Reaction of Difluorocarbene with AcetyleneEthers

Scheme 34. Proposed Mechanism for LiI MediatedFormation of Difluorocarbene

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enables TMSCF2H readily to be used in difluoromethylationreactions.259,260 In comparison, lower yield of TMSCF2H wasobtained with THF (10%) or DMSO (20%) as a cosolvent andno the desired TMSCF2H was observed in the solvent, DMSO.A mechanism involving an anion mobility of fluorine atom inCF3-group of 1 as the driving force has been proposed (Scheme35).258

6. TRIFLUOROMETHYLATION INVOLVINGTRANSITION METAL COMPLEXES

Although trifluoromethyl lithium and magnesium are recog-nized as being too unstable and difficult to prepare because offacile α-fluoride (M−F) elimination,5 formation of trifluor-omethyl transition-metal derivatives has drawn particularattention since TMS−CF3 species has been recognized as auseful tool for introducing a trifluoromethyl group into organichalides and related substrates under mild reaction conditions.6.1. Cu-Catalyzed Trifluoromethylation of Allylic Halides

Allylic halides are important substrates in organic synthesis.261

Although the nucleophilic allylic trifluoromethylation of 1 with

MBH adducts has been recently developed (see Schemes 17and 18),150,151,154 there is a common need for the under-standing of nucleophilic trifluoromethylation reactions of allylichalides to introduce Csp3−CF3 bonds. In 1989, Chen and Wufound that methyl fluorosulphonyldifluoroacetate(FSO2CF2CO2Me) readily eliminates CO2 and SO2 in thepresence of catalytic amount of CuI (12 mol %) in DMF at60−80 °C to produce CuCF3 species that can be used for allylictrifluoromethylation of allyl bromide and allyl iodide (in 70%and 74% yields respectively).262 In another case, however, theallylic trifluoromethylation of (E)-(3-bromoprop-1-enyl)-benzene with Et3SiCF3 in the presence of CuI (1.5 equiv)and KF (1.2 equiv) in DMF/NMP (1/1) (NMP = N-methylpyrollidone) at 80 °C for 24 h gives the desired productonly in low yield (23%).263

In 2012, Nishibayashi and co-workers reported an efficientnucleophilic trifluoromethylation of allylic halides with 1catalyzed by CuTc (CuTc: (thiophene-2-carbonyloxy)copper)(Table 13).264 In the reaction, the nature of solvent is one ofthe most important factors that affect the trifluoromethylation.Treatment of allylic halide 205a with 1 (1.5 equiv) in thepresence of a catalytic amount of CuI (5 mol %) and KF (1.5equiv) in THF at 60 °C for 20 h affords the allylictrifluoromethylation product 206a in 67% yield. However, theuse of DMF in place of THF, 206a is obtained in only 29%yield. Other solvents examined lead to 206a: 16% in NMP, 20%in DCE, 7% yield in toluene, and no 206a in hexane.264

Scheme 35. Preparation of (Difluoromethyl)trimethylsilane

Table 13. Cu-Catalyzed Trifluoromethylation of Allylic Halides

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The reaction occurs regioselectively at the α-position ofallylic halide 205a, no 206a′ from γ-trifluoromethylation isobserved.264 The presence of the CC double bond beta tothe halide group is necessary because no trifluoromethylatedproduct 208 was observed when using 1-bromopropane 207 asthe substrate. It has also been observed that (1) the reaction of(Z)-cinnamyl bromide 205a giving (E)-206a in 66% yield alongwith only a trace amount of (Z)-206a (Table 13); (2) 2 mol %of CuTc promotes the isomerization of (Z)-205a into (E)-205ain a ratio of 25:75 after 2 h and 1:99 after 20 h, respectively (inthe absence of CuTc, the ratio of (Z)-205a/(E)-205a reachingto 83:17 for 20 h) and (3) no isomerization of (Z)-206a into(E)-206a occurs under similar reaction conditions (Table13).264

The authors believed that these results indicate that CuTcmediates the isomerization of (Z)-205a into (E)-205a, whichthen undergoes trifluoromethylation to form (E)-206a via anallylcopper species derived from complexation of copper with205 as a key intermediate.264 Therefore, the initial step is theformation of CF3Cu

I from CuI and 1 activated by fluorideion.265,266 Oxidative addition of CF3Cu

I to allylic halide 205can result in the formation of an allylcopper(III) species.267,268

Finally, reductive elimination of an allylcopper(III) speciesgives trifluoromethylated product (E)-206 and regeneratesCuI,267,268 although a detailed mechanism is yet to beestablished.227,269

6.2. Trifluoromethylation of α-Haloketones with CuCF3

In recent years, copper-catalyzed/mediated trifluororomethyla-tion reactions have made significant progress, for example, inaromat ic t r ifluoromethy la t ion and re la ted reac -tions.19,25,264,270−280 The first report concerning the in situgeneration of CuCF3 was reported by Burton and Wiemers(Burton reagent derived from CF2BrC1 and CuBr) in 1986.274

In light of recent results,19,264,270−273,275 the well-definedtrifluoromethyl copper compounds as trifluoromethyl sourceshave been established, including N-heterocyclic carbenecomplexes of copper [(NHC)CuCF3],

275 phosphine- orphenanthroline-stabilized copper reagents [(Ph3P)3CuCF3],

276

and [(phen)CuCF3]278,279 derived from Me3SiCF3 1. These

CuCF3 compounds have been successfully applied to thetrifluoromethylation of aryl iodides/bromides and arylboronateesters. Of these compounds, (phen)CuCF3 and (Ph3P)3CuCF3are now commercially available. (Ph3P)3CuCF3 has also beenused for the trifluoromethylation of propargylic chlorides/bromides and trifluoroacetates to give the correspondingbranched allenylic or propargylic products, depending on thesubstrates and reaction conditions employed.21

The trifluoromethylcopper complex (phen)CuCF3 can beprepared in excellent yield by the reaction of [CuOtBu]4 with1,10-phenanthroline, followed by the addition of TMSCF3 1under mild conditions (Scheme 36).278 This method is alsoapplicable to the synthesis of (phen)CuCF2CF2CF3 (97%yield) using commercially available (perfluoropropyl)-trimethylsilane in place of 1.278 Isolated (phen)CuCF3 and(phen)CuCF2CF2CF3 are stable at room temperature undernitrogen atmosphere for over one month without decom-

position and has become the broadly applicable reagents fortrifluoromethylations and perfluoroalkylations of aryl iodides,bromides,278 and arylboronate esters.279

On the other hand, focusing on the efficient use of CHF3 asthe most intrinsic source of a trifluoromethyl group,24,40,224,232

Grushin and co-workers recently reported the first directcupration of fluoroform.225 The reaction employs inexpensivereagents (CuCl and tBuOK) and occurs at ambient temper-ature to furnish CuCF3 209 in up to over 90% yield (Scheme37). Decomposition of 209 is confirmed by monitoring 19FNMR, which can be avoided by adding Et3N(HF)3 to theCuCF3 solution (stable solution of the CuCF3 reagent).

225

Interestingly, the cupration reaction of fluoroform exhibits nosigns of difluorocarbene intermediacy if performed in DMF.225

Importantly, using fluoroform-derived CuCF3,237 Grushin and

co-workers have developed the effcient trifluoromethylation ofaryl iodides and bromides225 and trifluoromethylation of α-haloketones in DMF under mild reaction conditions (Table14).227 In addition, in the research for the trifluoromethylationof aryl boronic acids,138,281 Grushin’s method of using CuCF3as the trifluoromethylating reagent has the advantages ofoccurring at room temperature (and even below) and 1 atm ofair (molecular oxygen) as the oxidant to give the correspondingbenzotrifluorides in excellent yields (up to 99%) with highselectivity.281

As a nucleophilic synthon, 1 has been widely used to thenucleophilic trifluoromethylation reactions including nucleo-philic addition to the carbonyl group of enolizable/non-enolizable aldehydes and ketones and other carbon electro-philes (Table 9). Different from the above reactions, in whichthe preferred nucleophilic attack of the “CF3

−” anion occurspreferientially at the carbonyl group (hard−hard match),Grushin and co-workers found that the reaction of α-haloketones 210 with stabilized CuCF3 209 in DMF proceedssmoothly to furnish the corresponding 2,2,2-trifluoroethylke-tones 211 in up to 99% yield at room temperature, in which thenucleophilic trifluoromethylation occurs selectively at the alkylhalide carbon (Table 14).227

The above method not only exhibits high functional grouptolerance and gives high product yield in general, but haspotential for larger scale operations with the use of CuCF3(produced directly from fluoroform) and α-haloketones as thereadily available, easily accessible and inexpensive substrateswithout any premodification. An alternative procedure usesenolate and silyl enol ether substrates in radical or electrophilicα-trifluoromethylation with a strong base, or styrenes in radicaltrifluoromethylation with costly [Ph2SCF3]

+ OTf−, giving α-trifluoromethyl-acetophenones in low yields (20−40%).282,283A possible mechanism, for the nucleophilic trifluoromethy-

lation of the C−X bond of α-haloketones, through coordinationof the Cu-atom to the carbonyl and halide facilitatingsubstitution with the CF3 group, as in the Cu-catalyzed cross-

Scheme 36. Preparation of (phen)CuCF3

Scheme 37. Direct Cupration of Fluoroform

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coupling of alkylzinc reagents with α-chloroketones,284 hasbeen proposed but not discussed in detail.227 In addition, itneeds to be mentioned that a series of copper(I) trifluor-omethyl thiolate complexes have also been successfullysynthesized more recently by Weng, Huang and co-workersfrom the reaction of CuF2 with Me3SiCF3 1 and S8.

285 Thesewell-defined complexes, as useful trifluoromethylthiolatingreagents,286−288 are air-stable, which greatly facilitate their useand provide a model for the understanding of thetrifluoromethylthiolation process.285

Very recently Lishchynskyi and Grushin found that likeCHF3 (Scheme 37)225 but unlike other higher H-perfluor-oalkanes, C2F5H undergoes smooth cupration with [K(DMF)]-[(t-BuO)2Cu] at room temperature and atmospheric pressureto give structurally characterized [K(DMF)2][(t-BuO)Cu-(C2F5)] quantitatively. In comparison, the thermally stable[K(DMF)2][(t-BuO)Cu(C2F5)] is slightly less reactive towardelectrophiles than its CF3 analogue.

226

6.3. Cu-Catalyzed Trifluoromethylation of PropargylicHalides

As an extension of the nucleophilic trifluoromethylation ofallylic halides with 1 catalyzed by CuTc (Table 13),264

Nishibayashi and co-workers found that reactions of propargylichalides with 1 in the presence of a catalytic amount of CuTc (5mol%) and 1.5 equiv of KF can give the correspondingtrifluoromethylated products in good to high yields with a highselectivity.289 Reactions of primary propargylic chlorides occurregioselectively at the α-position to afford propargylictrifluoromethylated products, but trifluoromethylated allenescan be obtained from reactions of secondary propargylicchlorides (Scheme 38).289 Using other methods, stoichiometric

amounts of copper metal or copper salts are required to obtainthe trifluoromethylated products in good yields.269,280,290

Treatment of (R)-(3-chlorobut-1-ynyl)benzene with 1 affords(1,1,1-trifluoropenta-2,3-dien-2-yl)benzene in 83% yield with acomplete loss of optical purity, indicating the reaction does notproceed via an anti-SN2′ pathway (Scheme 38).289 In recentyears, Cu-mediated trifluoromethylations have been wellestablished, which considerably enlarge the range of metal-catalyzed/mediated trifluoromethylation and perfluoromethyla-tion and their practical applications.291,292

7. SYNTHESIS OF BENZOTRIFLUORIDES BASED ONPRE-FUNCTIONALIZATION

Different from the numerous known synthetic methods thatrely on substitution of a preexisting aromatic ring, Stahl and co-workers succeeded in palladium catalyzed aerobic dehydrogen-

Table 14. Trifluoromethylation of α-Haloketones with CuCF3a

aNote: Nonaromatic substrates and α-chloroketones were trifluoromethylated with 1.5 equiv of CuCF3. Isolated yields, 19F NMR yield inparentheses.

Scheme 38. Cu-Catalyzed Trifluoromethylation ofPropargylic Halides

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ative conversion of substituted cyclohexanones and cyclo-hexenones to phenols through postaromatization.293 Suchmethod significantly broadens the source of aromatic feedstockfor the facile access to cyclohexanone/cyclohexenone deriva-tives by prefunctionalization of the nonaromatic precur-sors.293,294

In 1989, Stahly and Bell described the monotrifluoromethy-lation of p-quinone derivatives 212 with Et3SiCF3 to give α-trifluoromethylated adducts 213.42 Further treatment of 213(or the corresponding alcohols) by dissolving metal reductionand by reductive amination resulted in the desired(trifluoromethy1)phenols 214a−c and (trifluoromethy1)-aniline 215, respectively (Scheme 39).42

Stahly’s method provides the first example for the synthesisof trifluoromethy1ated arenes based on nucleophilic trifluor-omethylation of carbonyl compounds.42,295 Later, using thereadily available 4-(triethylsilyloxy)-4-(trifluoromethyl)-cyclohexa-2,5-dienone 213a as substrate, Stahly and Jacksondescribed the synthesis of 2-[(trifluoromethyl)phenyl]-propionic acid 217 by a three-step reaction of 213a viaolefination with the Horner-Emmons reagent (methyl 2-(dimethylphosphono)acetate) followed by reduction (to giveethyl 2-(4-(trifluoromethyl)phenyl)propanoate) and hydrolysis

(Scheme 39).296 Acid 217 has been screened for pharmaco-logical activity and exhibited analgesic effects.296 In addition,Stahly’s method has also been extended to the synthesis ofH2[BiphenCF3] 220 (H2[BiphenCF3]: rac-3,3′-di-tert-butyl-5,5′-bistrifluoromethyl-6,6′-dimethyl-1,1′-biphenyl-2,2′-diol,Scheme 39)297 and 4-alkyl(trifluoromethyl)benzenes bearing asubstituent (MeO, Cl) either on the benzene ring or on thebenzylic position (Scheme 40).298,299 It was also found that afour-component system, CHF3/N(TMS)3/catalytic F−/cata-lytic DMF, behaves like the reagent 1 to react withnonenolizable carbonyl compounds, for example 4,4-dimethox-ycyclohexa-2,5-dienone, lead to the corresponding 1,2-adducts.298

More recently, Hu and co-workers revealed an unprece-dented silver-mediated vicinal trifluoromethylation−iodinationof arynes generated from 2-trimethylsilyl-phenyl triflates 231,which can introduce CF3 and I groups onto aromatic rings in asingle step to give o-trifluoromethyl iodoarenes 234 (Table 15),using excess of [AgCF3], CsF, TMP (2,2,6,6-tetramethylpiper-idine), and 1-iodophenylacetylene as iodine source.300

Similar to α-trifluoromethylated adducts 213 (Scheme 39),42

4-(trifluoromethyl)-4-(trimethylsilyloxy)cyclohexa-2,5-dienonederivatives 235 are readily prepared in a considerably high yield

Scheme 39. Synthesis of Trifluoromethy1ated Arenes from p-Quinones

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by reacting p-quinone derivatives301 with 1 under mild reaction

conditions.42,296−299 In our recent research, a new reaction, the

In(OTf)3 catalyzed 1,3-carbothiolation/aromatization of 235

has been developed (Table 16).302

This reaction enables two different functionalities, anucleophilic thiol (alkylthio groups of 236)64,303 and anucleophilic carbon (α-C of 236)64,304,305 generated in situfrom ketene dithioacetals 236 to be introduced byprefunctionalization into the “aromatic ring” formed via

Scheme 40. Synthesis of 4-Alkyl(trifluoromethyl)benzene Derivatives

Table 15. Silver-Mediated Vicinal Trifluoromethylation−Iodination of Arynes

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postaromatization293 in the ortho and para positions of the CF3group of 235 by the meta-double functionalization strategy(Scheme 41).302 The reaction proceeds in a single operationunder mild reaction conditions to give various trifluoromethy-lated arenes 237/237′ and 238, sharing important structurefeatures including phenylacetic acids306,307 and aryl sul-fides.308−311 Since the CF3 group is a ortho- and para-directingdeactivator in electrophilic aromatic substitution reactions, theabove method is potentially important for the synthesis of

otherwise hardly accessible highly functionalized trifluorome-

thylated arenes from readily available starting materials.Recently, to illustrate the utility of the tetrayne-based

formation of arynes and their functionalization, several

postaromatization functionalizations have been carried out by

Hoye’s and Lee’s groups, such as the preparation of 6-

trifluoromethylindoline in high yield based on thermal

hexadehydro Diels−Alder reaction312 and subsequent trapping

Table 16. meta-Double Functionalization of 4-(Trifluoromethyl)-cyclohexa-2,5-dienones

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of the resulting aryne intermediate by nucleophilic Me3SiCF3 1(eq 10).313

8. ELECTROPHILIC AND OXIDATIVETRIFLUOROMETHYLATION REACTIONS

Methods for the direct introduction of the trifluoromethylgroup are available through radical, nucleophilic, or electro-philic approaches.2−5,12,16,23 In nucleophilic trifluoromethyla-tion, the active species is the “CF3 anion”, which has beenrevolutionized since the discovery of trifluoromethyltrimethyl-silane 1 by Ruppert in 1984,29 and subsequent application byPrakash41 as described in sections 3, 4, 6 and 8 of this review. Incontrast, the electrophilic trifluoromethylation involving thedirect transfer of a trifluoromethyl group from 1 to anelectrophile by potentially practical oxidative process remains achallenge.8.1. Shelf-Stable Electrophilic TrifluoromethylatingReagents

Nowadays, since the initial discovery of the first electrophilictrifluoromethylating species by Yagupolskii and co-workers in1984,314 several important electrophilic trifluoromethylatingreagents (Figure 6) developed by Umemoto (239 in 1990 and

240 in 2007),314,315 Togni (241 in 2006),316−318 and Shibata(242 in 2008)319−321 have been described in detail else-where.314−316,320−326 These findings, no doubt, open a way forthe investigations of electrophilic trifluoromethylation.8.2. Cyclic Hypervalent Iodine(III) ElectrophilicTrifluoromethylating Reagents

Among electrophilic trifluoromethylating reagents, 1-(trifluor-omethyl)-1,2-benziodoxol-3(1H)-one 241a (Togni’s reagent II,for the preparation of this reagent, see Scheme 42)316,317,327,328

and 1-trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodox-ole 241b (Togni’s reagent I) have proved to be efficient inelectrophilic trifluoromethylation for a variety of nucleophiles

including soft nucleophiles such as thiols, phenolates (C-trifluoromethylation), phosphines and active methylenes. Inaddition, O-trifluoromethylation of aliphatic alcohols with 241ain the presence of catalytic amount of a zinc(II) salt as anactivator and N-trifluoromethylation of nitriles with 241a via aRitter-type reaction with Brønsted acids as activators undertransition metal-free conditions are also successful.28,318

Recently, using 241a (Togni’s reagent II), a number ofelegant transition metal-catalyzed trifluoromethylations havebeen reported, including terminal olefins (Cu-catalyzed),266,329

(hetero)arenes (catalyzed by Re complex),330 CuOAc-catalyzeddirect C2-trifluoromethylation of indoles,331 Fe(II)-catalyzedtrifluoromethylation of potassium vinyltrifluoroborates,332 and[(MeCN)4Cu]PF6-catalyzed olefinic trifluoromethylation ofenamides.333 As an application of 241b (Togni’s reagent I,316

for its one-pot synthesis, see eq 11),317 the Cu-catalyzed

trifluoromethylation of arylboronate esters has also beendescribed.334 These results indicate that activation of Togni’sreagents 241a and 241b is generally necessary. It has beenobserved that the C2-trifluoromethylation products are easilyproduced in the case of the reaction of 241a with electron-richindoles.330,331 In addition, for the reactions with a series ofelectron-rich nitrogen heterocycles, the trifluoromethyl groupof 241b is principally incorporated in the position adjacent tonitrogen.318

Although O-trifluoromethylation of aliphatic alcohols (withprimary or secondary alcohols as substrates or solvents) with241a in the presence of catalytic amount of Zn(NTf2)2 (zincbis(trifluoromethylsulfonyl)imide) is efficient,318,335 the O-trifluoromethylation of phenols remains a problem. A detailedresearch by Togni and co-workers for the reaction of 241a with2,4,6-trimethylphenol 246 (thus speculating that the “occupied”ortho and para positions could favor reaction at the oxygenatom) has been attempted. However, the results show that thedesired product, 1,3,5-trimethyl-2-(trifluoromethoxy)benzene247, can be detected but only as a minor product and thecyclohexadienones 248, 249, and 250 arising from theoxidation/trifluoromethylation of the starting phenol constitutethe major products (Scheme 41).327 Therefore, the mainproducts are generated by carbon instead of oxygenfunctionalization. Accordingly, as noted by Umemoto,314 thetrifluoromethylation ability of a reagent toward hardnucleophiles, such as the oxygen atom of a phenolate, stronglydepends on the hardness of the atom initially bearing the CF3unit. Reagent 241a can therefore be regarded as a soft reagentwith a particular affinity for soft nucleophiles such as thiols andprimary or secondary phosphines.From a mechanistic point of view, the observations are still

inconclusive as to the exact course of the trifluoromethyltransfer from 241a to phenols. The intermediate formation ofphenoxy-λ3-iodane species that would undergo nucleophilicattack by a transient trifluoromethyl anion is probable andwould reflect the general pattern of reactivity of a number ofknown hypervalent iodine compounds. Equally, a SET (singleelectron transfer) pathway not involving free radicals cannot beexcluded (Scheme 42). However, for both scenarios, solid

Scheme 41. meta-Double Functionalization Strategy

Figure 6. Electrophilic trifluoromethylating reagents.

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experimental evidence is still lacking.327 Several recent reportsinvolve the formation of λ3-iodane species and aryl trifluor-omethyl iodonium salt from Togni’s reagents, for example, inthe trifluoromethylation of alcohols335 and enantioselective-trifluoromethylation of aldehydes.336 However, to date,attempts for the direct preparation of an aryl trifluoromethyliodonium salt have failed because of a lack of stability of thisspecies.314,337−341

Togni and co-workers have provided a plausible hypothesisfrom their zinc-mediated trifluoromethylation of alcohols basedon the postulated formation of trifluoromethyl iodonium salts(Scheme 43).335 In this mechanism, reaction of 241a with thezinc salt (Zn(NTf2)2) forms the zinc dicarboxylate complex252, corresponding to the iodonium species as a 1:2 adduct(detected by ESI-MS methods). The species 252 then reactswith an alcohol to form intermediate 253, resulting from theaddition of an alcoholate to an iodonium moiety. A subsequentreductive elimination step is responsible for the formation oftrifluoromethyl ether 254 and species 255. Alternatively, theiodonium species 252 might undergo an intermolecular attackby the nucleophile leading to product formation via an SN2-type process, enhanced by the exceedingly large nucleofugality

of phenyliodonium derivatives. A 19F NMR measurement of thereaction mixture of 241a, p-nitrobenzyl alcohol, and Zn(NTf2)2has provided important mechanistic insights, by showing a shiftof the CF3 signal of the hypervalent iodine species of 241a fromδ = −33.0 to −26.9 ppm after a few minutes at roomtemperature and thus indicating the formation of a relativelystable intermediate which subsequently decayds under reactionconditions. On the other hand, according to the major peak(976) in the ESI-MS spectrum, Togni and co-workers assignthe structure of a zinc(II) dicarboxylate complex to the cation,[Zn(241a)2(NTf2)]

+, which reveals the very nature of theactivation process of 241a by Zn2+ and consists of the cleavageof the I−O bond, thus generates a more reactive (harder)trifluoromethyl iodonium species (Scheme 43).335

In addition, a crystalline material in the form of very thinplatelets, corresponding to the bis(triflimide) salt of thed i c a t i o n i c o c t a h ed r a l c omp l e x [Zn (241a ) 2 ( 4 -NO2C6H4CH2OH)2(H2O)2]

2+ has also been obtained througha systematic variation of the crystallization conditions andanalyzed by X-ray diffraction, which may be used to interpretthe formation of a trifluoromethyl iodonium species.335

Scheme 42. Preparation of 241a and Reaction with 2,4,6-Trimethylphenol

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8.3. Acyclic Hypervalent Iodine(III) ElectrophilicTrifluoromethylating Species and OxidativeTrifluoromethylation

As early as in 1978, the perfluoroalkylating reagents 256 and257 have been prepared by Yagupolskii and co-workers via, forexample, the condensation of bis(trifluoroacetoxy)-iodoperfluoroalkanes with toluene in trifluoroacetic acid for 3days (Figure 7).314,337 While iodonium salts including p-

tolylperfluoroalkyliodonium chlorides 256 and perfluoroalkyl-phenyliodonium triflates 257 have been successfully applied asthe electrophilic perfluoroalkylating reagents,314,337−340 theirtrifluoromethyl analogues (Figure 7, for example, 257: when RF= CF3) have not yet been successfully prepared since thecorresponding synthetic intermediates (CF3I(OCOCF3)2,CF3IF2, and CF3IO) have low stability compared to thosehaving RF groups with two or more carbons.314,337−341

Indeed, the preparation and the use of a simple hypervalentiodo compound as a source of electrophilic trifluoromethylatingspecies has long been a challenge to organic chemists since anearlier attempt, over 30 years ago.314,323,337−341 However, ourrecent experiments using in situ generated trifluoromethylphe-nyliodonium acetate 258a (Figure 7, R = H) has arguablypermitted the trifluoromethylation at α-C of ketene dithioace-tals 259/236. Thus, 3-(1,3-dithiolan-2-ylidene)-4,4,4-trifluor-obutan-2-one 260a was prepared in high yield by adding 1 to apremixed mixture of 259a, PhI(OAc)2 and KF in MeCN undernitrogen atmosphere and then stirred at room temperature for0.5 h (Table 17),342 providing a very simple access totrifluoromethyl ketene dithioacetals.343−345

Similar to Togni’s mechanism (Scheme 43, intermediater253), the formation of 260 may involve initially, the formationof PhI(CF3)(OAc) 258a from the reaction of PhI(OAc)2 with1 in the presence of KF as an activator and 258a quicklytransforms to phenyl(trifluoromethyl)iodonium 261 (Scheme44). Wherein, the necleophilic attack of the α-C of a ketenedithioacetal 259 (or 236) at iodonium 261 leads to thionium

Scheme 43. Mechanistic Hypothesis for Zn-MediatedElectrophilic Trifluoromethylation of Alcohols

Figure 7. Acyclic hypervalent iodine(III) electrophilic perfluorome-thylating species.

Table 17. α-Trifluoromethylation of Ketene Dithioacetalsa

entry 255/236 R′ R,Rtime(h) 260

isolated yield(%)

1 259a COMe (CH2)2 0.5 260a 882 259b COEt (CH2)2 0.5 260b 853 259c COPh (CH2)2 5.0 260c 744 259d COPh(4-

Cl)(CH2)2 0.5 260d 70

5 259e COPh(4-Me)

(CH2)2 0.5 260e 70

6 259f CO2Et (CH2)2 2.0 260f 757 259g CN (CH2)2 2.0 260g 688 259h COMe (CH2)3 0.5 260h 799 236g COMe Me 0.5 260i 5010 236k COMe Et 0.5 260j 6411 259i 4-ClPh Et 0.5 260k 8112 259j 4-FPh Et 0.5 260l 7113 259m 4-MeOPh Et 0.5 260m 80

aNote: The reaction of 259a under the identical reaction conditionswith TEMPO (0.5 equiv) gives 260a in 84% yield in 0.5 h, nearly thesame as described in Table 17, entry 1 (88%).342

Scheme 44. Mechanistic for α-Trifluoromethylation ofKetene Dithioacetals

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intermediate 262. The formation of C−CF3 bond via reductiveelimination followed by abstraction of the acidic proton of 263along with the release of HOAc finally gives trifluoromethylatedketene dithioacetals 260.342An in situ high resolution electro-spray ionization mass spectra (HRMS-ESI) of a mixture ofPhI(OAc)2 (1.0 mmol), TMSCF3 (2.0 equiv), and KF (2.0equiv) in MeCN (3.0 mL) shows a peak at m/z = 272.93822(calculated for [C7H5F3I, M]+: 272.93825) assigned toiodonium species [PhICF3)]

+ 261.342

Thus, the “acyclic hypervalent iodide trifluoromethylatingspecies” 258a (Scheme 44) seems to be formed by simplemixing of iodobenzene diacetate, 1 and an activator and can bedirectly applied to the sp2 C−H trifluoromethylation reactionsunder mild transition metal-free conditions. The trifluorome-thylation of indoles 264 to give 3-trifluoromethylindoles 265(Scheme 45) provides further support for the reactivity of the

electrophilic iodonium species 261.342 As a comparison,compound 265e can also be obtained in 62% yield under thereaction conditions: 264e (0.5 mmol), 1 (2.4 equiv),PhI(OAc)2 (1.2 equiv), K2PO3 (2.4 equiv), 4 Å MS (50 mg),and BQ (0.2 equiv), in MeCN at 85 °C for 6 h,346 via oxidativetrifluoromethylation using 1 as the CF3 source.

347−351

In a recent report, Qing and Chu have attempted theoxidative trifluoromethylation of indoles. They found that N-

methylindole 264g as the model gives products 268a and 265gin less than 20% yield and favors C2- instead of C3-trifluoromethylation (eq 12).350 Further optimization studiesusing N-methyl-3-methylindole 270 as a model leads to thesynthesis of a series of 2-trifluoromethylindoles 271 (Table 18,Condition A),350 similar to the report by Liu and co-workerscatalyzed by Pd(OAc)2 (Table 18, Condition B).351 In thesecases, 3-methyl-1-tosyl-1H-indole 270j and methyl 1-methyl-1H-indole-3-carboxylate 270k having a electron-withdrawinggroup on 1- or 3- position are not reactive enough (Table18),350,351 and no desired product was obtained from thereaction of 3-methyl-1H-indole 270l with 1 (Table 18).351

Using Liu’s conditions (Table 18, Condition B), 3-trifluoromethylindoles 265a and 265e (see Scheme 45) arealso synthesized in 65% and 66% yields, respectively.351 Amechanism involving the formation of the (Ar)PdIV−CF3intermediate generated through oxidation by PhI(OAc)2instead of “CF3

+” is proposed,351,352 sharing a commoncatalytic triad utilizing a sophisticated catalytic systems.351−353

In addition, it has been found that molecular oxygen can serveas the oxizing agent for the oxidative trifluoromethylation of 1with aryl/heteroaryl boronic acids354 or terminal alkynes (eq13)355 via a ligand replacement process independent of themetal based on DFT calculations.356

In general, transition-metal mediated trifluoromethylation iscomplicated by the strong metal−CF3 bond originating fromboth the polar contribution of the bond as well as backbondingfrom filled metal d orbitals into the σ*C−F bonds. This results ina high barrier for formation of the C−CF3 bond357 anddifferent performance of CF3 souces even under identicalconditions.358 The direct trifluoromethylation to give 2-trifluoromethylindoles using Togni’s reagents shows that241b is superior to 241a (catalyst: Zn(NTf2)2, giving 271 in17−98% yields in 24−48 h and no 3-trifluoromethylindolebeing obtained with 1-methyl-1H-indole as the substrate).359

Whereas, a mixture of 2- and 3-trifluoromethylindoles areobtained by using 241a catalyzed by CuOAc321,360 andmethyltrioxorhenium,330 respectively.8.4. Reactions Involving Trifluoromethyl Radical

More recently, Cu-catalyzed trifluoromethylation of N,N-dialkylhydrazones 272 via probably a CF3-radical-transfermechanism (Scheme 46)361 using Togni’s reagent 241a andAg-catalyzed hydrotrifluoromethylation of unactivated alkenes274 with 1 (Scheme 46)362 have been reported, respectively.In organic reactions, selective C−H functionalization is a

class of reactions that could lead to a paradigm shift in organicsynthesis, relying on selective modification of ubiquitious C−Hbonds of organic compounds.359,363,364 Recently, Brase and co-

Scheme 45. Synthesis of 3-Trifluoromethyl Indoles

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workers developed a new strategy based on the perfluor-oalkylation postmodification strategy364 of aromatic triazenes276 (Scheme 47).365−367 A series of o-trifluoromethylatedaromatic triazenes 277 were synthesized in moderate to goodyields from the reaction of triazenes 276 with AgCF3 generatedin situ from 1 and AgF using perfluorohexane (C6F14) as the

solvent. This reaction tolerates a broad range of functionalgroups, especially iodides and bromides. On the other hand, thetriazene group plays a dual role of, first, an ortho-directinggroup for the regioselective introduction of CF3, and, second,the transformation of triazene into the corresponding iodide278 through postmodification (Scheme 47).366

The above ortho-trifluoromethylation reaction was success-fully expanded to ortho-perfluoroalkylation and ethoxycarbo-nyldifluoromethylation of aromatic triazenes. Furthermore,transformations of the triazene moiety into the azide 282 andthe iodide 283 are also successful. In these cases, however,mono- and di-ortho-pentafluoroethylated products, for example279a/279a′ (RF = C2F5), 280a/280a′ (RF = C3F7), and 281a/281a′ (RF = CF2CO2Et) are generally obtained. (Scheme47).367

To explain these results, a coordination of a neutral AgCF3species to the triazene moiety (enabling the CF3 radical to begenerated regioselectively and attack at the ortho-position) anda good stabilization of the radical intermediate by the triazenemoiety are proposed (Scheme 48).367 Calculations (TPSS;

Table 18. Cu-Catalyzed Synthesis of 2-Trifluoromethyl Indoles

Scheme 46. Trifluoromethylation Involving CF3 Radical

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B3LYP) of reaction energies for the addition of atrifluoromethyl radical to various 4-iodosubstituted aromaticcompounds support the proposed mechanism.367,368

The reactions of Me3SiRF and AgF proceeded selectively andalmost quantitatively at room temperature in solvents such asMeCN, DMF, N-methylimidazole, and pyridine to give thecorresponding perfluoroorgano silver(I) species in approx-imately quantitative yields (19F NMR).369,370 Therefore, recentreports convincingly document that radical trifluoromethyla-

tions can be conducted on complex substrates with highregioselectivity using a variety of trifluoromethylating reagentsincluding Ruppert−Prakash reagent 1 depending on either thereaction conditions362,371−375 or substrate structures.364−368 Inaddition, it has been found that electron rich aromatic andheteroaromatic substrates can also be trifluoromethylated byusing catalytic amounts of AgF.376 In the reaction, a radicalmechanism has been proposed and 1,2-dimethyl-3-(trifluor-omethyl)-1H-indole 265a was obtained in lower yield (eq14)376 than in the case via the electrophilic mechanism

(Scheme 45, 76% yield).342 However, comparing with the useof 1 as the nucleophilic CF3 species, an explanation of theevents for generation of trifluoromethyl radical from 1 has notyet been conclusively established.17,376−381

Scheme 47. ortho-Perfluoroalkylation and Post-Modification of Aromatic Triazenes

Scheme 48. Mechanism of ortho-Perfluoroalkylation ofAromatic Triazenes

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As mentioned in section 2, the reaction conditions for thepreparation of TMSCF3 1 from fluoroform are critical due tothe high instability of “CF3

−” (Scheme 2).24 It was observedthat the in situ generated “CF3

−” from the reaction of 1 withTMAF in the solvent, dichloromethane, is capable of deliveringdichloromethide at −50 to 0 °C through proton-abstraction ofdichloromethane by “CF3

−” as a strong base.382 Whereas,reactions of 1 in the presence of “naked” fluoride (CsF and[15]crown-5 in anhydrous dimethoxyethane) proceed up to atemperature of 5 °C mainly with formation of “Me3Si(CF3)2

−”(also see salt 3 in Scheme 3),35 through the reaction of “CF3

−”with 1.383 It was also found that, catalyzed by Cu(OAc)2, thenucleophilic trifluoromethylation of 1 with (E)-N-benzylidene-quinolin-8-amines can proceed smoothly under mild reactionconditions.384 On the other hand, it is worth noting thatMe3SiCF3 can also act as the silicon source for the C−F bondactivation,385,386 which has recently been successfully applied tothe kinetic resolution of MBH-type allyl fluorides throughenantioselective allylic trifluoromethylation catalyzed bycommercially available bis(cinchona alkaloid) catalyst(DHQD)2PHAL 95 (also see Scheme 18).385

9. PERSPECTIVES AND CONCLUSION

Although a variety of C−CF3 bond forming reactions have beendeveloped from various trifluoromethylating reagents, in the 30years since trifluoromethyltrimethylsilane (TMSCF3) wassynthesized from CF3Br (an ozone depleting compound) andtrimethylsilyl chloride in 1984, TMSCF3 (Ruppert−Prakashreagent) has been and is still the most important CF3-centerednucleophilic trifluoromethylating reagent. New approaches, forexample the conversion of fluoroform into TMSCF3, are highlyattractive because fluoroform is a long-lasting greenhouse gasgenerated in large volumes during the manufacture of a varietyof end products such as Teflon and refrigerants. Moreover,Ruppert−Prakash reagent is now also a useful starting materialfor the synthesis of potassium (trifluoromethyl)-trimethoxyborate, the well-defined trifluoromethyl coppercompounds (for example, [(phen)CuCF3]), trifluoromethane-sulfanylamides/trifluoromethanesulfanamides used in trifluor-omethylthiolation, difluoromethyltriflate as a convenient sourceof difluorocarbene, (difluoromethyl)trimethylsi lane(TMSCF2H) used in difluoromethylation reactions, Togni’sreagents and related species as electrophilic trifluoromethylat-ing reagents.Nowadays, the chemistry based on Ruppert−Prakash reagent

has gained increasing attention due to the extensive use oftrifluoromethylated and difluoromethylated compounds inmodern pharmaceuticals, agrochemicals, and materials. Thecrystal structure of Me3SiCF3 confirmed that the Si−CF3 bondis longer and weaker than the Si−CH3 bonds. This observationis helpful to understand the reaction mechanisms and todevelope initiators/catalysts/mediators based on the structureand reactivity of the substrates as in the nucleophilictrifluoromethylation of aldehydes, ketones, 4-nitroisoxazoles,Weinreb amides, Morita−Baylis−Hillman adducts, aryl nitriles,especially, the development of using HF as the mediator for thehighly selective nucleophilic trifluoromethylation of Me3SiCF3with various imines through a dual activation mode. On theother hand, a general catalytic enantioselective trifluoromethy-lation of aromatic aldehydes using (IPr)CuF and cinchonaalkaloid-derived quaternary ammonium salts as the combina-tion catalysis mode has been realized. In addition, transition

metal mediated trifluoromethylation has largely contributed tostimulate the research of the chemistry of TMSCF3.Hopefully, Ruppert−Prakash reagent can also serve as

trifluoromethyl radical, difluorocarbene and trifluoromethylcation equivalent depending on the choise of catalysts/mediators, directing groups as on the aromatic rings, transitronmetal reagents, or oxidants under suitable reaction conditions.In the years ahead, challenges will involve developing catalyticenantioselective trifluoromethylation, finding environmentallyfriendly and cost-effective methods and conditions. Meanwhile,the recent series of important reports for the convenientutilization of fluoroform (the most intrinsic source of atrifluoromethyl group) in the preparation of TMSCF3 and invarious fluoromethylation reactions deserve special attention.

10. LATEST DEVELOPMENTSAt the time this manuscript was submitted for publication,several reports appeared on the applications of Ruppert−Prakash reagent 1. The continuing research on the direct α-difluoromethylation of lithium enolates of lactams 188 using anumpolung form of fluoroform as a difluoromethyl carbocation(CHF2

+) equivalent (section 5.2, Scheme 32 and Table 12)232

led Mikami and co-workers to investigate the reaction ofenolates with 1. As a result, the direct α-siladifluoromethylationof 1 with lithium enolates was recently demonstrated (27examples including acyclic substrates, 34−99% yields) via C−Fbond activation of 1.387 In this case, the reaction of γ-lactam188a as a model with TMSCF3 1 in place of fluoroform resultsin the formation of α-siladifluoromethylated product 284bearing an all-carbon quaternary center via eight-memberedintermediate 285, in which, 1 explaines its behavior as asiladifluoromethyl cation (TMSCF2

+) equivalent (Scheme49).387 Addition of an eqivalent of LiMe is important for the

formation of 284 owing to the release of methane, a very weakCH-acid. Otherwhise, for example using 2 equiv of LHMDS asthe base, the desilylated product 189a (see Scheme 32) isformed as the byproduct derived from protonation of 284 within situ-generated HMDS. The C−F bond activation of 1 ismetal-ion-depadent, accounting for the strong interactionbetween lithium and fluorine. In comparison, KHMDS orNaHMDS was ineffective.387 Mikami’s method provides thefirst example of using 1 as a “TMSCF2

+” equivalent through

Scheme 49. Direct α-Siladifluoromethylation of LithiumEnolates Using TMSCF3

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polarity inversion and has been successfully applied to thepreparation of α-siladifluoromethyl ibuprophene.387

Similar to the nucleophilic trifluoromethylation of 1 with 4-nitroisoxazoles 26 in which the nitro group is necessary toactivate the substrate for trifluoromethylation (Section 3.3,T a b l e 2 a n d S c h eme 7 ) , 8 0 r e a c t i o n s o f 4 -(trifluoromethanesulfonyl)isoxazoles 286 with 1 have recentlybeen developed for the diastereoselective synthesis of 5-trifluoromethyl-4-triflyl-2-isoxazolines 287 (Scheme 50).388 A

further modification of 287 (for example, 287a: R = Ph, Ar =Ph) by reaction with electrophilic halogenating reagents, suchas 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor), N-chlorosuccinimide(NCS), and N-bromosuccinimide (NBS), under mild reactionconditions (rt., 1 h in the solvent, MeCN), gave thecorresponding all-carbon functionalized isoxazolines 287a-F,287a-Cl, and 287a-Br, respectively (Scheme 50).388

The two studies on 4-nitroisoxazoles 26 and 4-(trifluoromethanesulfonyl)isoxazoles 286 showed the reactionsof 1 with 26, conducted in the presence of NaOAc andcetyltrimethylammonium bromide in DMF at room temper-ature, resulted in formation of 5-trifluoromethyl-2-isoxazolines27 in high to excellent yields.80 Whereas, under identivalconditions, 287a was obtained in lower yield (43%) comparingwith 91% yield under the optimized conditions in the absenceof cetyltrimethylammonium bromide as shown in Scheme50.388 In addition, the fluorination of nitro-analogue 27a (seeTable 2) with Selectfluor failed to provide the correspondingfluorinated product,388 probably due to the relatively muchlonger C−S bond (∼1.75 Å) in 287,64 which can reduce thesteric hindrance of the halogenation reaction of 287a comparedwith the shorter C−N bond (∼1.43 Å) in 5-trifluoromethyl-2-isoxazoline 26a.Iminiums124,131−135 and nitrones389,390 are highly reactive

toward nucleophilic trifluoromethylation. Wu and co-workersdescribed that catalyzed by AgSbF6, reactions of 2-alkynylarylaldimines 288 with 1 in the presence of HOAc proceededefficiently under mild reaction conditions to generate 1-(trifluoromethyl)-1,2-dihydroisoquinolines 289 in moderate toexcellent yield (Scheme 51).391 The reaction may proceed viaAgSbF6 catalyzed 6-endo cyclization of 288 to give iminiumintermediate 290 (section 3.6, Scheme 14)133,134 followed bynucleophilic trifluoromethylation.392

Recently, increasing attention has been directed to the use of1 as a source of electrophilic trifluoromethyl species with theuse of various oxidants (sections 8.3 and 8.4). Zhou and co-

workers synthesized 6-(trifluoromethyl)phenanthridines 292from reactions of 2-isocyanobiphenyls 291 with 1 under mildconditions in the solvent, NMP in the presence of BQ usingPhI(OAc)2 as oxidant (Scheme 52).

393 The yield of 292a (R1 =R2 = H) was improved from 43% (in the absence of BQ) to91% and, surprisingly, a radical mechanism without involve-ment of BQ was proposed.393

In research on the trifluoromethylation of internal olefinicC−H bond, concurrently with our studies on ketenedithioacetals (section 8.3, Table 17 and Scheme 44),342 3-(1,3-dithiolan-2-ylidene)-4,4,4-trifluorobutan-2-one 260a wasobtained in only 34% yield by Yu and co-workers by treatmentof acetyl ketene dithioacetal 259a with 1 using PhI(OAc)2 asoxidant catalyzed by Cu(OH)2/phen in the presence of KF at80 °C under an argon atmosphere,394 which is less favorablethan our results (88% yield; also see Table 19, Condition A).342

Under similar conditions but using Ag2CO3 (1.0 equiv) as theoxidant at 100 °C (Table 19, Condition B),394 260a wasproduced in 92% yield and a series of α-trifluoromethyl ketenedithioacetals 260 were prepared (36 examples, 47−92%yield).394

In fact, the necleophilic attack of the α-C of a ketenedithioacetal on electrophilic trifluoromethyl species is easy tooccur (Table 17 and Scheme 44),342 duo to ketenedithioacetals possess structural features that enable the olefiniclinkage to be activated by electron-releasing alkyltsulfur groups(p−π conjugation).64 Indeed, the synthesis of 4,4-dip-tolyl-3-(trifluoromethyl)but-3-en-2-one 294 required the use of twoequivalents of Ag2CO3 (eq 15).394

On the other hand, the research by Bi’s group on the C−Hα-trifluoromethylation of α,β-unsaturated carbonyl compoundsusing Togni’s reagent II 241a (1.5 equiv) via a single-electron-transfer (SET) process has the advantages of catalytic amount

Scheme 50. Diastereoselective Trifluoromethylation of 4-(Trifluoromethanesulfonyl)isoxazoles

Scheme 51. Synthesis of 1-(Trifluoromethyl)-1,2-dihydroisoquinolines

Scheme 52. Synthesis of 6-(Trifluoromethyl)phenanthridines

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of CuI (10 mol %), diverse substrates (enones, α,β-unsaturatedesters, thioesters and amides, 29 examples, 50−92% yields) andhigh regioselectivity (at α-position).395

In a recent report by Goossen’s group, a series oftrifluoromethyl thioethers 296 were prepared directly fromaryl and heteroaryl diazonium salts 295, sodium thiocyanateand 1 using copper thiocyanate as a catalyst via Sandmeyer-typereaction (Scheme 53).396 Detail mechanistic studies have

revealed that, (1) treatment of 4-methoxy-benzenediazoniumtetrafluoroborate with CuSCN, NaSCN, and Cs2CO3 in MeCNin the absence of 1 gave the corresponding aryl thiocyanate (1-methoxy-4-thiocyanatobenzene) and (2) in the presence of amixture of 1 and Cs2CO3, 1-methoxy-4-thiocyanatobenzenequickly reacted to form the trifluoromethyl thioether, (4-

methoxyphenyl)(trifluoromethyl)sulfane 296a,396 via thiophilicnucleophilic reaction238−240 of a cyanide leaving group by CF3.Additionally, a reference (ref 287) about an electrophilic

hypervalent iodine reagent (not shown) for trifluoromethylth-iolation was cited in section 6.2 of this review. Very recently,Buchwald and co-workers revealed that the reagent is athioperoxy compound based on a combination of analyticaltechniques, including the crystalline sponge method for X-rayanalysis.397

AUTHOR INFORMATION

Corresponding Authors

*E-mail: wangm452@nenu.edu.cn.*E-mail: liuqun@nenu.edu.cn.

Author Contributions

The manuscript was written through contributions of allauthors. All authors have given approval to the final version ofthe manuscript.

Notes

The authors declare no competing financial interest.

Biographies

Table 19. Preparation of α-Trifluoromethyl Ketene Dithioacetals

Scheme 53. Sandmeyer-Type TrifluoromethylthiolationReaction

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Xiao Liu received her BSc in Chemistry from Northeast Normal

University, China, in 2009, and joined Prof. Liu’s group pursuing her

doctoral studies at the same year in organic chemistry under the

supervision of Prof. Qian Zhang and Prof. Qun Liu. Her research

interests are in the field of synthesis of trifluoromethylated compounds

based on pre/post-functionalization methodologies.

Cong Xu was born in Changchun, China, in 1988. He studied

chemistry in Northeast Normal University (China), where he got his

Bachelor’s degree in science (2011). He is now pursuing his doctoral

studies at Northeast Normal University under the supervision of Prof.

Qun Liu and Prof. Mang Wang. His current research is focused on the

direct C−H trifluoromethylation reactions.

Mang Wang received her Ph.D. degree in 2003 in Changchun Institute

of Applied Chemistry, Chinese Academy of Sciences (Prof. Lianxun

Gao’s group). She then moved to Ecole Polytechnique Federale de

Lausanne, Switzerland, and worked with Prof. Kay Severin as a

postdoctoral fellow. In 2006, she started independent research projects

at the Department of Chemistry, Northeast Normal University

(China). Since 2011, she has been a full professor at the same

university. Her research focuses on novel organic synthetic methods

and applications.

Qun Liu studied chemistry at Northeast Normal University where hereceived his Ph.D. degree. He spent two years (1990 and 1998) in theUniversity of Southampton and the University of Glasgow under thesupervision of Prof. P. J. Kocienski. Since 1994 he has been a fullprofessor at Northeast Normal University. His research concerns thedevelopment of new synthetic methods and strategies andinvestigations towards understanding the mechanism.

ACKNOWLEDGMENTSThe authors acknowledge the reviewers and editors for theirthorough reading of the manuscript and valuable sugestions.We would like to thank all authors whose names are listed inthe references for their contributions to the chemistry describedin this review. We gratefully acknowledge the financial supportby the NSFC (21072027, 21272034, and 21372040) and NewCentury Excellent Talents in Chinese University (NCET-11-0613).

ABBREVIATIONSAc acetylAr arylBn benzylBoc tert-butoxycarbonylBu butylBz benzoylCuTc (thiophene-2-carbonyloxy)copperDABCO 1,4-diazabicyclo[2.2.2]octaneDAST diethylaminosulfur trifluorideDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCE 1,2-dichloroethaneDDHQ 2,3-dich1oro-5,6-dicyanohydroquinoneDDQ 2,3-dichloro-5,6-dicyanobenzoquinoneDMA dimethylacetamideDMAP 4-(dimethylamino)pyridineDME 1,2-dimethoxyethaneDMF dimethylformamideDMPU 1,3-dimethyl-3,4,5,6-tetrahyde-2(1H)-pyrimidoneDMSO dimethyl sulfoxidedppp 1,2-bis(diphenylphosphino)ethanedr diastereoisomeric ratioDVK divinyl ketoneee enantiomeric excessEt ethylHetAr heteroarylHex hexylHIV-RT human immunodeficiency virus type 1 reverseHMPA hexamethylphosphoric triamideIPr 1,3-bis(2′,6′-di-iso-propylphenyl)imidazol-2-ylidene

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KHMDS potassium hexamethyldisilazideLDA lithium diisopropylamideLED light emitting deviceLHMDS lithium hexamethyldisilazideLiHMDS lithium hexamethyldisilazideMe methylMes mesityl (2,4,6-trimethylphenyl)MS molecular sievesMTBE methyl tertiary-butyl etherNaHMDS soldium hexamethyldisilazideNBS N-bromosuccinimideNCS N-chlorosuccinimideNHC N-heterocyclic carbeneNMP N-methylpyrollidoneNNRTI non-nucleoside reverse transcriptase inhibitorNs 2-nitrobenzenesulfonylPG protecting groupPh phenylPhebox 2,6-bis(oxazolinyl)phenylPhen 1,10-phenanthrolinePiv pivaloylPr propylQSPR quantitative structure−property relationshipRB Rose BengalRF perfluoroalkylSelectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate)Solkane365mfc 1,1,1,3,3-pentafluorobutaneTASF tris(dimethylamino)sulfonium difluorotrimethyl silic-onateTBABF tetrabutyl ammonium bifluorideTBAF tetrabutylammonium fluorideTBAT tetrabutylammonium triphenyldifluorosilicateTBD 1,5,7-triazabicyclo[4.4.0]dec-5-eneTEMPO (2,2,6,6-tetramethyl-piperidin-1-yl)oxylTFA trifluoroacetic acidTFMK trifluoromethyl ketoneTfO triflate (trifluoromethanesulfonate)THF tetrahydrofuranTMAB tetramethylammonium bromideTMAF tetramethylammonium fluorideTMG 1,1,3,3-tetramethylguanidineTMP 2,2,6,6-tetramethylpiperidineTMS trimethylsilTol tolyl (methylphenyl)Ts (or Tos) tosyl (p-toluenesulfonyl)TTMPP tris(2,4,6-trimethoxyphenyl)phosphineZn(NTf2)2 zinc bis(trifluoromethylsulfonyl)imide

REFERENCES(1) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308−319.(2) Ojima, I. Fluorine in Medicinal Chmeistry and Chemical Biology;Wiley-Blackwell: Oxford, U.K., 2009.(3) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:Weinheim, Germany, 2004.(4) Prakash, G. K. S; Wang, F.; O’Hagan, D.; Hu, J.; Ding, K.; Dai, L.-X. Flourishing Frontiers in Organofluorine Chemistry, in OrganicChemistry-Breakthroughs and Perspectives; Wiley-VCH: Weinheim,Germany, 2012.(5) Schlosser, M., Ed.; Organometallics in Synthesis: A Manual; Wiley:New York, 2001.(6) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.2014, 114, 2432−2506.

(7) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.Rev. 2008, 37, 320−330.(8) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886.(9) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529−2591.(10) Muller, M.; Orben, C. M.; Schutzenmeister, N.; Schmidt, M.;Leonov, A.; Reinscheid, U. M.; Dittrich, B.; Griesinger, C. Angew.Chem., Int. Ed. 2013, 52, 6047−6049.(11) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369.(12) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305−321.(13) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470−477.(14) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123−131.(15) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613−7632.(16) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975−996.(17) Studer, A. A. Angew. Chem., Int. Ed. 2012, 51, 8950−8958.(18) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;Buchwald, S. L. Science 2010, 328, 1679−1681.(19) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,4475−4521.(20) Nagib, D. A.; MacMillan, D. W. Nature 2011, 480, 224−228.(21) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,14411−14415.(22) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034−9037.(23) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757−786.(24) Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A.Science 2012, 338, 1324−1327.(25) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012, 6679−6687.(26) Wu, X.-F.; Neumann, H.; Beller, M. Chem.Asian J. 2012, 7,1744−1754.(27) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.; Roy, S.Tetrahedron 2011, 67, 2161−2195.(28) Liu, H.; Gu, Z.; Jiang, X. Adv. Synth. Catal. 2013, 355, 617−626.(29) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25,2195−2198.(30) TMSCF3 had been purportedly prepared from a Pd-catalyzedreaction of CF3I and (Me3Si)2 in 1982, see: Eaborn, C.; Griffiths, R.W.; Pidcock, A. J. Organomet. Chem. 1982, 225, 331−341.(31) Ramaiah, P.; Krishnamurti, R.; Prakash, G. K. S. Org. Synth.1995, 72, 232−240.(32) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem.1991, 56, 984−989.(33) Pawelke, G. J. Fluorine Chem. 1989, 42, 429−433.(34) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68,4457−4463.(35) Kolomeitsev, A.; Rusanov, E.; Bissky, G.; Lork, E.;Roschenthaler, G.-V.; Kirsch, P. Chem. Commun. 1999, 1017−1018.(36) Couzijn, E. P. A.; Slootweg, J. C.; Ehlers, A. W.; Lammertsma,K. Z. Anorg. Allg. Chem. 2009, 635, 1273−1278.(37) Olejniczak, A.; Katrusiak, A.; Vij, A. J. Fluorine Chem. 2008, 129,1090−1095.(38) Detailed procedures for the preparation of 1 based on thePrakash’s reaction, see the Supporting Information of ref 24.(39) Luo, G.; Luo, Y.; Qu, J. New J. Chem. 2013, 37, 3274−3280.(40) Haufe, G. Science 2012, 338, 1298.(41) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.1989, 111, 393−395.(42) Stahly, G. P.; Bell, D. R. J. Org. Chem. 1989, 54, 2873−2877.(43) Dilman, A. D.; Levin, V. V. Eur. J. Org. Chem. 2011, 831−841.(44) Kirij, N. V.; Babadzhanova, L. A.; Movchun, V. N.; Yagupolskii,Y. L.; Tyrra, W.; Naumann, D.; Fischer, H. T.M.; Scherer, H. J.Fluorine Chem. 2008, 129, 14−21.(45) Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org. Lett. 2006, 8,3589−3592.(46) Huang, A.; Li, H.-Q.; Massefski, W.; Saiah, E. Synlett 2009,2518−2520.(47) Jiang, H.; Yan, L.; Xu, M.; Lu, W.; Cai, Y.; Wan, W.; Yao, J.; Wu,S.; Zhu, S.; Hao, J. J. Org. Chem. 2013, 78, 4261−4269.

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dx.doi.org/10.1021/cr400473a | Chem. Rev. XXXX, XXX, XXX−XXXAP

(48) Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.; Nakamura, S.;Toru, T. Chem. Commun. 2006, 2575−2577.(49) Cheng, H.; Pei, Y.; Leng, F.; Li, J.; Liang, A.; Zou, D.; Wu, Y.;Wu, Y. Tetrahedron Lett. 2013, 54, 4483−4486.(50) Chen, J.-L.; Chu, L.; Qing, F.-L. J. Fluorine Chem. 2013, 152,70−76.(51) Obijalska, E.; Mloston, G.; Utecht, G.; Heimgartner, H. J.Fluorine Chem. 2013, 151, 7−11.(52) Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.;Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed.2011, 50, 7153−7157.(53) Chia, P. W.; Bello, D.; Slawin, A. M. Z.; O’Hagan, D. Chem.Commun. 2013, 49, 2189−2191.(54) Hu, B.-L.; Li, C.-L.; Liao, Z.-Y.; Zhang, X.-G. Synlett 2013,2748−2750.(55) Demuth, M.; Mikhail, G. Synthesis 1982, 827.(56) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;Tartakovsky, V. A. J. Fluorine Chem. 2009, 130, 667−670.(57) Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2013, 52, 2092−2095.(58) Thomoson, C. S.; Dolbier, W. R. J. Org. Chem. 2013, 78, 8904−8908.(59) For a report on electrophilic cleavage of one silicon−carbonbond of pentacoordinate tetraorganosilanes, see: Shindo, M.;Matsumoto, K.; Shishido, K. Angew. Chem., Int. Ed. 2004, 43, 104−106.(60) Pan, L.; Liu, Q. Synlett 2011, 1073−1080.(61) Liu, X.; Xu, X.; Pan, L.; Zhang, Q.; Liu, Q. Org. Biomol. Chem.2013, 11, 6703−6706.(62) Gassman, P. G.; Mickelson, J. W.; Sowa, J. R., Jr. J. Am. Chem.Soc. 1992, 114, 6942−6944.(63) Wang, M.; Han, F.; Yuan, H.; Liu, Q. Chem. Commun. 2010, 46,2247−2249.(64) Pan, L.; Bi, X.; Liu, Q. Chem. Soc. Rev. 2013, 42, 1251−1286.(65) Joubert, J.; Roussel, S.; Christophe, C.; Billard, T.; Langlois, B.R.; Vidal, T. Angew. Chem., Int. Ed. 2003, 42, 3133−3136.(66) Sanhueza, I. A.; Bonney, K. J.; Nielsen, M. C.; Schoenebeck, F. J.Org. Chem. 2013, 78, 7749−7753.(67) Kerr, J. A. Chem. Rev. 1966, 66, 465−500.(68) Sosnovskikh, V. Y.; Sevenard, D. V.; Usachev, B. I.;Roeschenthaler, G.-V. Tetrahedron Lett. 2003, 44, 2097−2099.(69) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.;Roeschenthaler, G.-V. J. Org. Chem. 2003, 68, 7747−7754.(70) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.;Roeschenthaler, G.-V. J. Fluorine Chem. 2005, 126, 779−784.(71) Sosnovskikh, V. Y.; Usachev, B. I.; Permyakov, M. N.; Sevenard,D. V.; Roschenthaler, G. V. Russ. Chem. Bull. Int. Ed. 2006, 55, 1687−1689.(72) Sevenard, D. V.; Sosnovskikh, V. Y.; Kolomeitsev, A. A.;Konigsmann, M. H.; Roschenthaler, G.-V. Tetrahedron Lett. 2003, 44,7623−7627.(73) Dilman, A. D.; Levin, V. V.; Belyakov, P. A.; Struchkova, M. I.;Tartakovsky, V. A. Tetrahedron Lett. 2008, 49, 4352−4354.(74) Zemtsov, A. A.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.;Belyakov, P. A.; Tartakovsky, V. A. Tetrahedron Lett. 2009, 50, 2998−3000.(75) Zemtsov, A. A.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.;Tartakovsky, V. A. J. Fluorine Chem. 2011, 132, 378−381.(76) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807−1821.(77) Pereira, F.; Latino, D. A. R. S.; Aires-de-Sousa, J. J. Org. Chem.2011, 76, 9312−9319.(78) Shen, X.; Ni, C.; Hu, J. Helv. Chim. Acta 2012, 95, 2043−2051.(79) Kondratyev, N. S.; Zemtsov, A. A.; Levin, V. V.; Dilman, A. D.;Struchkova, M. I. Synthesis 2012, 2436−2440.(80) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro, M.; Shibata, N.Angew. Chem., Int. Ed. 2011, 50, 7803−7806 (for a recent report onthe nucleophilic trifluoromethylation of 1 with 4-(trifluoromethane-sulfonyl)isoxazoles, see ref 388).

(81) Baschieri, A.; Bernardi, L.; Ricci, A.; Suresh, S.; Adamo, M. F. A.Angew. Chem., Int. Ed. 2009, 48, 9342−9345.(82) Fiandra, C. D.; Piras, L.; Fini, F.; Disetti, P.; Moccia, M.; Adamo,M. F. A. Chem. Commun. 2012, 48, 3863−3865.(83) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111,455−529.(84) Nenajdenko, V. G.; Balenkova, E. S. Arkivoc 2011, 246−328.(85) Kelly, C. B.; Mercadantea, M. A.; Leadbeater, N. E. Chem.Commun. 2013, 49, 11133−11148.(86) O’Connor, M. J.; Boblak, K. N.; Topinka, M. J.; Kindelin, P. J.;Briski, J. M.; Zheng, C.; Klumpp, D. A. J. Am. Chem. Soc. 2010, 132,3266−3267.(87) Li, X.-J.; Xiong, H.-Y.; Hua, M.-Q.; Nie, J.; Zheng, Y.; Ma, J.-A.Tetrahedron Lett. 2012, 53, 2117−2120.(88) Cui, H.-F.; Wang, L.; Yang, L.-J.; Nie, J.; Zheng, Y.; Ma, J.-A.Tetrahedron 2011, 67, 8470−8476.(89) Sasaki, S.; Kikuchi, K.; Yamauchi, T.; Higashiyama, K. Synlett2011, 1431−1434.(90) Zheng, Y.; Xiong, H.-Y.; Nie, J.; Hua, M.-Q.; Ma, J.-A. Chem.Commun. 2012, 48, 4308−4310.(91) Duangdee, N.; Harnying, W.; Rulli, G.; Neudorfl, J.-M.; Groger,H.; Berkessel, A. J. Am. Chem. Soc. 2012, 134, 11196−11205.(92) Wang, T.; Ye, S. Org. Lett. 2010, 12, 4168−4171.(93) Wang, T.; Ye, S. Org. Biomol. Chem. 2011, 9, 5260−5265.(94) Yoshida, H.; Ito, Y.; Yoshikawa, Y.; Ohshita, J.; Takaki, K. Chem.Commun. 2011, 47, 8664−8666.(95) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810−8813.(96) Henseler, A.; Kato, M.; Mori, K.; Akiyama, T. Angew. Chem., Int.Ed. 2011, 50, 8180−8183.(97) Wu, Y.; Deng, L. J. Am. Chem. Soc. 2012, 134, 14334−14337.(98) Riofski, M. V.; Hart, A. D.; Colby, D. A. Org. Lett. 2013, 15,208−211.(99) Prager, J. H.; Ogden, P. H. J. Org. Chem. 1968, 33, 2100−2102.(100) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133,5802−5805.(101) John, J. P.; Colby, D. A. J. Org. Chem. 2011, 76, 9163−9168.(102) Han, C.; Salyer, A. E.; Kim, E. H.; Jiang, X.; Jarrard, R. E.;Powers, M. S.; Kirchhoff, A. M.; Salvador, T. K.; Chester, J. A.;Hockerman, G. H.; Colby, D. A. J. Med. Chem. 2013, 56, 2456−2465.(103) Han, C.; Kim, E. H.; Colby, D. A. Synlett 2012, 23, 1559−1563.(104) Sigma-Aldrich (product #L511315).(105) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Munoz, S.; Olah, G. A.J. Org. Chem. 2013, 78, 3300−3305.(106) Kelly, C. B.; Mercadante, M. A.; Hamlin, T. A.; Fletcher, M.H.; Leadbeater, N. E. J. Org. Chem. 2012, 77, 8131−8141.(107) For a review on Weinreb amides, see: Balasubramaniam, S.;Aidhen, I. S. Synthesis 2008, 3707−3738.(108) Rudzinski, D. M.; Kelly, C. B.; Leadbeater, N. E. Chem.Commun. 2012, 48, 9610−9612.(109) Yamazaki, T.; Terajima, T.; Kawasaki-Takasuka, T. Tetrahedron2008, 64, 2419−2424.(110) Nonnenmacher, J.; Massicot, F.; Grellepois, F.; Portella, C. J.Org. Chem. 2008, 73, 7990−7995.(111) Masusai, C.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.;Reutrakul, V.; Pohmakotr, M. J. Fluorine Chem. 2013, 154, 37−42.(112) Pharikronburee, V.; Punirun, T.; Soorukram, D.; Kuhakarn, C.;Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. Org. Biomol. Chem. 2013,11, 2022−2033.(113) Masusai, C.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.;Pakawatchai, C.; Saithong, S.; Reutrakul, V.; Pohmakotr, M. Org.Biomol. Chem. 2013, 11, 6650−6658.(114) Wu, M.; Wang, M.; Cao, S. Chin. J. Chem. 2013, 31, 945−949.(115) Doucet-Personeni, C.; Bentley, P. D.; Fletcher, R. J.; Kinkaid,A.; Kryger, G.; Pirard, B.; Taylor, A.; Taylor, R.; Taylor, J.; Viner, R.;Silman, I.; Sussman, J. L.; Greenblatt, H. M.; Lewis, T. J. Med. Chem.2001, 44, 3203−3215.

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dx.doi.org/10.1021/cr400473a | Chem. Rev. XXXX, XXX, XXX−XXXAQ

(116) Felix, C. P.; Khatimi, N.; Laurent, A. J. Tetrahedron Lett. 1994,35, 3303−3304.(117) Sani, M.; Volonterio, A.; Zanda, M. ChemMedChem 2007, 2,1693−1700.(118) Begue, J.-P.; Bonnet-Delpon, D.; Crousse, B.; Legros, J. Chem.Soc. Rev. 2005, 34, 562−572.(119) Acena, J. L.; Sorochinsky, A. E.; Soloshonok, V. A. Synthesis2012, 1591−1602.(120) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;Tartakovsky, V. A. Eur. J. Org. Chem. 2008, 5226−5230.(121) Kosobokov, M. D.; Dilman, A. D.; Struchkova, M. I.; Belyakov,P. A.; Hu, J. J. Org. Chem. 2012, 77, 2080−2086.(122) Kosobokov, M. D.; Dilman, A. D.; Levin, V. V.; Struchkova, M.I. J. Org. Chem. 2012, 77, 5850−5855.(123) Shevchenko, N. E.; Vlasov, K.; Nenajdenko, V. G.;Roschenthaler, G.-V. Tetrahedron 2011, 67, 69−74.(124) Levin, V. V.; Kozlov, M. A.; Dilman, A. D.; Belyakov, P. A.;Struchkova, M. I.; Tartakovsky, V. A. Russ.Chem. Bull. Int.Ed. 2009, 58,484−486.(125) Huang, W.; Ni, C.; Zhao, Y.; Zhang, W.; Dilman, A. D.; Hu, J.Tetrahedron 2012, 68, 5137−5144.(126) Radchenko, D. S.; Michurin, O. M.; Chernykh, A. V.; Lukin,O.; Mykhailiuk, P. K. Tetrahedron Lett. 2013, 54, 1897−1898.(127) Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.;Shishkin, O. V.; Tolmachev, A. A.; Komarova, I. V. Synthesis 2012,903−908.(128) Bernardi, L.; Indrigo, E.; Pollicino, S.; Ricci, A. Chem. Commun.2012, 48, 1428−1430.(129) Blazejewski, J.-C.; Anselmi, E.; Wilmshurst, M. P. TetrahedronLett. 1999, 40, 5475−5478.(130) Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed. 2013, 52,4312−4348.(131) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes,B. U. W. Chem.Eur. J. 2012, 18, 10092−10142.(132) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687−7697.(133) Mitsudera, H.; Li, C.-J. Tetrahedron Lett. 2011, 52, 1898−1900.(134) Fu, W.; Guo, W.; Zou, G.; Xu, C. J. Fluorine Chem. 2012, 140,88−94.(135) Okusu, S.; Kawai, H.; Xu, X.-H.; Tokunaga, E.; Shibata, N. J.Fluorine Chem. 2012, 143, 216−219.(136) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J. J.Am. Chem. Soc. 2010, 132, 1464−1465.(137) Iqbal, N.; Choi, S.; Kim, E.; Cho, E. J. J. Org. Chem. 2012, 77,11383−11387.(138) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Angew. Chem.,Int. Ed. 2011, 50, 6119−6122.(139) Mizuta, S.; Verhoog, S.; Engle, K. M.; Khotavivattana, T.;O’Duill, M.; Wheelhouse, K.; Rassias, G.; Medebielle, M.; Gouverneur,V. J. Am. Chem. Soc. 2013, 135, 2505−2508.(140) Fustero, S.; Sanz-Cervera, J. F.; Acena, J. L.; Sanchez-Rosello,M. Synlett 2009, 525−549.(141) Fustero, S.; Ibanez, I.; Barrio, P.; Maestro, M. A.; Catalan, S.Org. Lett. 2013, 15, 832−835.(142) Fustero, S.; Albert, L.; Acena, J. L.; Sanz-Cervera, J. F.; Asensio,A. Org. Lett. 2008, 10, 605−608.(143) Fustero, S.; Albert, L.; Mateu, N.; Chiva, G.; Miro, J.;Gonzalez, J.; Acena, J. L. Chem.Eur. J. 2012, 18, 3753−3764.(144) Shidlovskii, A. F.; Golubev, A. S.; Gusev, D. V.; Suponitsky, K.Y.; Peregudov, A. S.; Chkanikov, N. D. J. Fluorine Chem. 2012, 143,272−280.(145) Allendorfer, N.; Es-Sayed, M.; Nieger, M.; Bra se, S.Tetrahedron Lett. 2012, 53, 388−391.(146) Harwood, L. M.; Vines, K. J.; Drew, M. G. B. Synlett 1996,1051−1053.(147) Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Rodríguez, E.;Barrio, P. Org. Lett. 2010, 12, 5494−5497.(148) Zemtsov, A. A.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.;Belyakov, P. A.; Tartakovsky, V. A.; Hu, J. Eur. J. Org. Chem. 2010,6779−6785.

(149) Furukawa, T.; Nishimine, T.; Tokunaga, E.; Hasegawa, K.;Shiro, M.; Shibata, N. Org. Lett. 2011, 13, 3972−3975.(150) For a review on application of Lewis base activatedtrimethylsilyl nucleophiles, see: Gawronski, J.; Wascinska, N.;Gajewy, J. Chem. Rev. 2008, 108, 5227−5252.(151) Hagiwara, T.; Mochizuki, H.; Fuchikami, T. Synlett 1997, 587−588.(152) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921−2944.(153) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41,4101−4112.(154) Li, Y.; Liang, F.; Li, Q.; Xu, Y.-C.; Wang, Q.-R.; Jiang, L. Org.Lett. 2011, 13, 6082−6085.(155) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35,3137−3138.(156) Valero, G.; Companyo, X.; Rios, R. Chem.Eur. J. 2011, 17,2018−2037.(157) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229−1279.(158) Caron, S.; Do, N. M.; Arpin, P.; Larivee, A. Synthesis 2003,1693−1698.(159) Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.; Vazquez, E. Org.Process Res. Dev. 2007, 11, 1015−1024.(160) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526−533.(161) Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura, S.;Toru, T. Org. Lett. 2007, 9, 3707−3710.(162) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro, M.; Shibata, N. Org.Lett. 2010, 12, 5104−5107.(163) Briere, J.-F.; Oudeyer, S.; Dalla, V.; Levacher, V. Chem. Soc.Rev. 2012, 41, 1696−1707.(164) Kawai, H.; Kitayama, T.; Tokunaga, E.; Shibata, N. Eur. J. Org.Chem. 2011, 5959−5961.(165) Thompson, M. A.; Aberg, J. A.; Cahn, P.; Montaner, J. S. G.;Rizzardini, G.; Telenti, A.; Gatell, J. M.; Gunthard, H. F.; Hammer, S.M.; Hirsch, M. S.; Jacobsen, D. M.; Reiss, P.; Richman, D. D.;Volberding, P. A.; Yeni, P.; Schooley, R. T. JAMA 2010, 304, 321−333.(166) Pierce, M. E.; Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.;Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M.D.; Nguyen, D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N.J. Org. Chem. 1998, 63, 8536−8543.(167) Tan, L.; Chen, C.-Y.; Tillyer, R.; Grabowski, E. J. J.; Reider, P.J. Angew. Chem., Int. Ed. 1999, 38, 711−713.(168) Zhang, G.-W.; Meng, W.; Ma, H.; Nie, J.; Zhang, W.-Q.; Ma, J.-A. Angew. Chem., Int. Ed. 2011, 50, 3538−3542.(169) Chen, C. Y.; Richard, R. D.; Tan, L. PCT Int. Appl., WO9851676, 1998, CAN 130:24851.(170) Chinkov, N.; Warm, A.; Carreira, E. M. Angew. Chem., Int. Ed.2011, 50, 2957−2961.(171) Kawasaki, T.; Matsumura, Y.; Tsutsumi, T.; Suzuki, K.; Ito, M.;Soai, K. Science 2009, 324, 492−495.(172) Ohshima, T.; Kawabata, T.; Takeuchi, Y.; Kakinuma, T.;Iwasaki, T.; Yonezawa, T.; Murakami, H.; Nishiyama, H.; Mashima, K.Angew. Chem., Int. Ed. 2011, 50, 6296−6300.(173) Duangdee, N.; Harnying, W.; Rulli, G.; Neudorfl, J.-M.;Groger, H.; Berkessel, A. J. Am. Chem. Soc. 2012, 134, 11196−11205.(174) Kawai, H.; Mizuta, S.; Tokunaga, E.; Shibata, N. J. FluorineChem. 2013, 152, 46−50.(175) Obijalska, E.; Mloston, G.; Linden, A.; Heimgartner, H.Tetrahedron: Asymmetry 2008, 19, 1676−1683.(176) Mloston , G.; Obijalska, E.; Heimgartner, H. J. Fluorine Chem.2010, 131, 829−843.(177) Mloston , G.; Obijalska, E.; Heimgartner, H. J. Fluorine Chem.2011, 132, 951−955.(178) Obijalska, E.; Mloston , G.; Six, A. Tetrahedron Lett. 2013, 54,2462−2465.(179) Zhao, H.; Qin, B.; Liu, X.; Feng, X. Tetrahedron 2007, 63,6822−6826.(180) Wu, S.; Zeng, W.; Wang, Q.; Chen, F.-X. Org. Biomol. Chem.2012, 10, 9334−9337.

Chemical Reviews Review

dx.doi.org/10.1021/cr400473a | Chem. Rev. XXXX, XXX, XXX−XXXAR

(181) Wu, S.; Guo, J.; Sohail, M.; Cao, C.; Chen, F.-X. J. FluorineChem. 2013, 148, 19−29.(182) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem.Soc. Rev. 2012, 41, 2406−2447.(183) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633−658.(184) Díez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009,109, 3612−3676.(185) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew.Chem., Int. Ed. 2011, 50, 523−527.(186) Sai, M.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2011,50, 3294−3298.(187) Opalka, S. M.; Park, J. K.; Longstreet, A. R.; McQuade, D. T.Org. Lett. 2013, 15, 996−999.(188) Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2745−2750.(189) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N.Angew. Chem., Int. Ed. 2009, 48, 6324−6327.(190) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara,Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194−13196.(191) Hernandez-Rodríguez, M.; Castillo-Hernandez, T.; Trejo-Huizar, K. E. Synthesis 2011, 2817−2821.(192) Kawai, H.; Okusu, S.; Yuan, Z.; Tokunaga, E.; Yamano, A.;Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2013, 52, 2221−2225.(193) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry2008, 19, 2633−2644.(194) Mukaiyama, T.; Kawano, Y.; Fujisawa, H. Chem. Lett. 2005, 34,88−89.(195) Kawano, Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34,422−423.(196) Kawano, Y.; Kaneko, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn.2006, 79, 1133−1145.(197) Prakash, G. K. S.; Panja, C.; Vaghoo, H.; Surampudi, V.;Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A. J. Org.Chem. 2006, 71, 6806−6813.(198) Prakash, G. K. S.; Vaghoo, H.; Panja, C.; Surampudi, V.;Kultyshev, R.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A.2007, 104, 3026−3030.(199) Nishiwaki, N.; Hirao, S.; Sawayama, J.; Saigo, K.; Kobiro, K.Chem. Commun. 2011, 47, 4938−4940.(200) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,1307−1370.(201) Iwanami, K.; Oriyama, T. Synlett 2006, 112−114.(202) Chen, W.-B.; Liao, Y.-H.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C.Green Chem. 2009, 11, 1465−1476.(203) Matsukawa, S.; Takahashi, S.; Takahashi, H. Synth. Commun.2013, 43, 1523−1529.(204) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.;Senanayake, C. H. Org. Lett. 2005, 7, 2193−2196.(205) Muzart, J. Tetrahedron 2009, 65, 8313−8323.(206) Fuchibe, K.; Koseki, Y.; Aono, T.; Sasagawa, H.; Ichikawa, J. J.Fluorine Chem. 2012, 133, 52−60.(207) Suzuki, Y.; Bakar, A.; Muramatsu, M. D. K.; Sato, M.Tetrahedron 2006, 62, 4227−4231.(208) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511−3522.(209) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,5606−5655.(210) Melaimi, M.; Soleilhavoup, M.; Bertrand, G. Angew. Chem., Int.Ed. 2010, 49, 8810−8849.(211) Reddy, V. P.; Vadapalli, A.; Sinn, E.; Hosmane, N. J.Organomet. Chem. 2013, 747, 43−50.(212) Mizuta, S.; Shibata, N.; Sato, T.; Fujimoto, H.; Nakamura, S.;Toru, T. Synlett 2006, 267−270.(213) Matsukawa, S.; Saijo, M. Tetrahedron Lett. 2008, 49, 4655−4657.(214) Molander, G. A.; Hoag, B. P. Organometallics 2003, 22, 3313−3315.(215) Kolomeitsev, A. A.; Kadyrov, A. A.; Szczepkowska-Sztolcman,J.; Milewska, M.; Koroniak, H.; Bissky, G.; Barten, J. A.; Roschenthaler,G.-V. Tetrahedron Lett. 2003, 44, 8273−8277.

(216) Knauber, T.; Arikan, F.; Roschenthaler, G.-V.; Gooßen, L. J.Chem.Eur. J. 2011, 17, 2689−2697.(217) Lavergne, T.; Degardin, M.; Malyshev, D. A.; Quach, H. T.;Dhami, K.; Ordoukhanian, P.; Romesberg, F. E. J. Am. Chem. Soc.2013, 135, 5408−5419.(218) Elkin, P. K.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.;Belyakov, P. A.; Arkhipov, D. E.; Korlyukov, A. A.; Tartakovsky, V. A.Tetrahedron Lett. 2011, 52, 5259−5263.(219) Elkin, P. K.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.;Arkhipov, D. E.; Korlyukov, A. A. Tetrahedron Lett. 2012, 53, 6216−6218.(220) Khan, B. A.; Buba, A. E.; Gooßen, L. J. Chem.Eur. J. 2012,18, 1577−1581.(221) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288−325.(222) Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2012,51, 9385−9388.(223) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;Tartakovsky, V. A. Tetrahedron Lett. 2011, 52, 281−284.(224) Kawai, H.; Yuan, Z.; Tokunaga, E.; Shibata, N. Org. Biomol.Chem. 2013, 11, 1446−1450.(225) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.;Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901−20913.(226) Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2013, 135,12584−12587.(227) Novak, P.; Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc.2012, 134, 16167−16170.(228) Shono, T.; Ishifune, M.; Okada, T.; Kashimura, S. J. Org. Chem.1991, 56, 2−4.(229) Tyrra, W.; Kremlev, M. M.; Naumann, D.; Scherer, H.;Schmidt, H.; Hoge, B.; Pantenburg, I.; Yagupolskii, Y. L. Chem.Eur.J. 2005, 11, 6514−6518.(230) Velazco, E. J.; Caffyn, A. J. M. Organometallics 2008, 27, 2402−2404.(231) Buergler, J. F.; Togni, A. Chem. Commun. 2011, 47, 1896−1898.(232) Iida, T.; Hashimoto, R.; Aikawa, K.; Ito, S.; Mikami, K. Angew.Chem., Int. Ed. 2012, 51, 9535−9538 (for a recent report using 1 as asiladifluoromethyl cation (TMSCF2

+) equivalent, see ref 387).(233) Levin, V. V.; Elkin, P. K.; Struchkova, M. I.; Dilman, A. D. J.Fluorine Chem. 2013, 154, 43−46.(234) Tworowska, I.; Dabkowski, W.; Michalski, J. Angew. Chem., Int.Ed. 2001, 40, 2898−2900.(235) Panne, P.; Naumann, D.; Hoge, B. J. Fluorine Chem. 2001, 112,283−286.(236) Colacot, T. J. Chem. Rev. 2003, 103, 3101−3118.(237) Brisdon, A. K.; Herbert, C. J. Coord. Chem. Rev. 2013, 257,880−901.(238) Kolomeitsev, A. A.; Movchun, V. N.; Kondratenko, N. V.;Yagupolski, Y. L. Synthesis 1990, 1151−1152.(239) Gouault-Bironneau, S.; Timoshenko, V. M.; Grellepois, F.;Portella, C. J. Fluorine Chem. 2012, 134, 164−171.(240) Timoshenko, V. M.; Portella, C. J. Fluorine Chem. 2009, 130,586−590.(241) Kondratenko, N. V.; Movchun, V. N.; Yagupolskii, L. M. J. Org.Chem. USSR (Engl. Transl.) 1989, 25, 1005−1006.(242) Yagupolskii, L. M.; Matsnev, A. V.; Orlova, R. K.; Deryabkin, B.G.; Yagupolskii, Y. L. J. Fluorine Chem. 2008, 129, 131−136.(243) Kowalczyk, R.; Edmunds, A. J. F.; Hall, R. G.; Bolm, C. Org.Lett. 2011, 13, 768−771.(244) Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J.Superacid Chemistry, 2nd ed.; Wiley: Hoboken, NJ, 2009.(245) Large-Radix, S.; Billard, T.; Langlois, B. R. J. Fluorine Chem.2003, 124, 147−149.(246) Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. J. Org. Chem.2008, 73, 9362−9365.(247) Alazet, S.; Zimmer, L.; Billard, T. Angew. Chem., Int. Ed. 2013,52, 10814−10817.(248) Ferry, A.; Billard, T.; Bacque, E.; Langlois, B. R. J. FluorineChem. 2012, 134, 160−163.

Chemical Reviews Review

dx.doi.org/10.1021/cr400473a | Chem. Rev. XXXX, XXX, XXX−XXXAS

(249) Yang, Y.; Jiang, X.; Qing, F.-L. J. Org. Chem. 2012, 77, 7538−7547.(250) Liu, J.; Chu, L.; Qing, F.-L. Org. Lett. 2013, 15, 894−897.(251) Baert, F.; Colomb, J.; Billard, T. Angew. Chem., Int. Ed. 2012,51, 10382−10385.(252) Tlili, A.; Billard, T. Angew. Chem., Int. Ed. 2013, 52, 6818−6819.(253) Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang, K.-W.; Hu, J.Chem. Commun. 2011, 47, 2411−2413.(254) Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585−1632.(255) Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D.Org. Lett. 2013, 15, 917−919.(256) Prakash, G. K. S.; Krishnamoorthy, S.; Ganesh, S. K.; Kulkarni,A.; Haiges, R.; Olah, G. A. Org. Lett. 2014, 16, 54−57.(257) Zhang, C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.-C.Coord. Chem. Rev. 2014, 261, 28−72.(258) Tyutyunov, A. A.; Boyko, V. E.; Igoumnov, S. M. Fluorine Notes2011, 74, 1−2.(259) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524−5527.(260) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13,5342−5345.(261) Marshall, J. A. Chem. Rev. 2000, 100, 3163−3186.(262) Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun. 1989,705−706.(263) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91−94.(264) Miyake, Y.; Ota, S.-i.; Nishibayashi, Y. Chem.Eur. J. 2012, 18,13255−13258.(265) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.; Gong,T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300−15303.(266) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang,J. J. Am. Chem. Soc. 2011, 133, 16410−16413.(267) Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle,C. A. J. Am. Chem. Soc. 2008, 130, 11244−11245.(268) Grigg, R. D.; Hoveln, R. V.; Schomaker, J. M. J. Am. Chem. Soc.2012, 134, 16131−16134.(269) Kawai, H.; Furukawa, T.; Nomura, Y.; Tokunaga, E.; Shibata,N. Org. Lett. 2011, 13, 3596−3599.(270) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed.2012, 51, 5048−5050.(271) Qing, F. Chin. J. Org. Chem. 2012, 32, 815−824.(272) Jin, Z.; Hammond, G. B.; Xu, B. Aldrichimica Acta 2012, 45,67−84.(273) García-Monforte, M. A.; Martínez-Salvador, S.; Menjon, B. Eur.J. Inorg. Chem. 2012, 4945−4966.(274) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108,832−834.(275) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.2008, 130, 8600−8601.(276) Tomashenko, O. A.; Escudero-Adan, E. C.; Belmonte, M. M.;Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655−7659.(277) Usui, Y.; Noma, J.; Hirano, M.; Komiya, S. Inorg. Chim. Acta2000, 309, 151−154.(278) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F.Angew. Chem., Int. Ed. 2011, 50, 3793−3798.(279) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed.2012, 51, 536−539.(280) Zhao, T. S. N.; Szabo, K. J. Org. Lett. 2012, 14, 3966−3969.(281) Novak, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem., Int.Ed. 2012, 51, 7767−7770.(282) Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem. Soc.2012, 134, 6976−6979.(283) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47, 6632−6634.(284) Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc. 2004, 126,10240−10241.

(285) Weng, Z.; He, W.; Chen, C.; Lee, R.; Tan, D.; Lai, Z.; Kong,D.; Yuan, Y.; Huang, K.-W. Angew. Chem., Int. Ed. 2013, 52, 1548−1552.(286) Chen, C.; Xie, Y.; Chu, L.; Wang, R. W.; Zhang, X.; Qing, F. L.Angew. Chem., Int. Ed. 2012, 51, 2492−2495.(287) Shao, X.; Wang, X.; Yang, T.; Lu, L.; Shen, Q. Angew. Chem.,Int. Ed. 2013, 52, 3457−3460 (In this paper, a new hypervalent iodinereagent for the transfer of an electrophilic trifluoromethylsulfur groupwas described. However, very recently, Buchwald and co-workersrevealed that the reagent is a thioperoxy compound based on acombination of analytical techniques, including the crystalline spongemethod for X-ray analysis. For details, see ref 397).(288) Chen, C.; Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134,12454−12457.(289) Miyake, Y.; Ota, S.; Shibata, M.; Nakajima, K.; Nishibayashi, Y.Chem. Commun. 2013, 49, 7809−7811.(290) Larsson, J. M.; Pathipati, S. R.; Szabo, K. J. J. Org. Chem. 2013,78, 7330−7336.(291) Landelle1, G.; Panossian, A.; Pazenok, S.; Vors, J.-P.; Leroux, F.R. Beilstein J. Org. Chem. 2013, 9, 2476−2536.(292) Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.; Zhang, X.;Collier, T. L.; Gouverneur, V.; Passchier, J. Nat. Chem. 2013, 5, 941−944.(293) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209−213.(294) Simon, M.-O.; Girard, S. A.; Li, C.-J. Angew. Chem., Int. Ed.2012, 51, 7537−7540.(295) Jones, R. G. J. Am. Chem. Soc. 1947, 69, 2346−2350.(296) Stahly, G. P.; Jackson, A. J. Org. Chem. 1991, 56, 5472−5475.(297) Singh, R.; Czekelius, C.; Schrock, R. R.; Muller, P.; Hoveyda,A. H. Organometallics 2007, 26, 2528−2539.(298) Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65,8848−8856.(299) Radix-Large, S.; Kucharski, S.; Langlois, B. R. Synthesis 2004,456−465.(300) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.; Zhao, J.; Hu, J. J. Am.Chem. Soc. 2013, 135, 2955−2958.(301) Abraham, I.; Joshi, R.; Pardasani, P.; Pardasani, R. T. J. Braz.Chem. Soc. 2011, 22, 385−421.(302) Liu, X.; Pan, L.; Dong, J.; Xu, X.; Liu, Q. Org. Lett. 2013, 15,6242−6245.(303) Dong, D.; Ouyang, Y.; Yu, H.; Liu, Q.; Liu, J.; Wang, M.; Zhu,J. J. Org. Chem. 2005, 70, 4535−4537.(304) Liu, Y.; Liu, J.; Wang, M.; Liu, J.; Liu, Q. Adv. Synth. Catal.2012, 354, 2678−2682.(305) Yu, H.; Jin, W.; Sun, C.; Chen, J.; Du, W.; He, S.; Yu, Z. Angew.Chem., Int. Ed. 2010, 49, 5792−5797.(306) Leon, T.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2013, 135,1221−1224.(307) Greenhalgh, M. D.; Thomas, S. P. J. Am. Chem. Soc. 2012, 134,11900−11903.(308) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596−1636.(309) Hao, G.-F.; Wang, F.; Li, H.; Zhu, X.-L.; Yang, W.-C.; Huang,L.-S.; Wu, J.-W.; Berry, E. A.; Yang, G.-F. J. Am. Chem. Soc. 2012, 134,11168−11176.(310) Jiang, C.-S.; Muller, W. E. G.; Schroder, H. C.; Guo, Y.-W.Chem. Rev. 2012, 112, 2179−2207.(311) Zhang, C.-P.; Vicic, D. A. J. Am. Chem. Soc. 2012, 134, 183−185.(312) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B.P. Nature 2012, 490, 208−212.(313) Wang, K.-P.; Yun, S. Y.; Mamidipalli, P.; Lee, D. Chem. Sci.2013, 4, 3205−3211.(314) Umemoto, T. Chem. Rev. 1996, 96, 1757−1778.(315) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007, 72,6905−6917.(316) Eisenberger, P.; Gischig, S.; Togni, A. Chem.Eur. J. 2006, 12,2579−2586.

Chemical Reviews Review

dx.doi.org/10.1021/cr400473a | Chem. Rev. XXXX, XXX, XXX−XXXAT

(317) Matousek, V.; Pietrasiak, E.; Schwenk, R.; Togni, A. J. Org.Chem. 2013, 78, 6763−6768.(318) Mace, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2479−2494.(319) Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M.Eur. J. Org. Chem. 2008, 3465−3468.(320) Urban, C.; Cadoret, F.; Blazejewski, J.-C.; Magnier, E. Eur. J.Org. Chem. 2011, 4862−4867.(321) Nomura, Y.; Tokunaga, E.; Shibata, N. Angew. Chem., Int. Ed.2011, 50, 1885−1889.(322) Prakash, G. K. S.; Wang, F. Chimica Oggi-Chemistry Today2012, 30, 30−36.(323) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem.2010, 6, 65.(324) He, Z.; Luo, T.; Hu, M.; Cao, Y.; Hu, J. Angew. Chem., Int. Ed.2012, 51, 3944−3947.(325) Mu, X.; Wu, T.; Wang, H.; Guo, Y.; Liu, G. J. Am. Chem. Soc.2012, 134, 878−881.(326) Matsnev, A.; Noritake, S.; Nomura, Y.; Tokunaga, E.;Nakamura, S.; Shibata, N. Angew. Chem., Int. Ed. 2010, 49, 572−576.(327) Stanek, K.; Koller, R.; Togni, A. J. Org. Chem. 2008, 73, 7678−7685.(328) More recently, it has been found that compound 231a and itsprecursor 234 have explosive properties, see: Fiederling, N.; Haller, J.;Schramm, H. Org. Process Res. Dev. 2013, 17, 318−319.(329) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50,9120−9123.(330) Mejía, E.; Togni, A. ACS Catal. 2012, 2, 521−527.(331) Shimizu, R.; Egami, H.; Nagi, T.; Chae, J.; Hamashima, Y.;Sodeoka, M. Tetrahedron Lett. 2010, 51, 5947−5949.(332) Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem.,Int. Ed. 2012, 51, 2947−2950.(333) Feng, C.; Loh, T.-P. Chem. Sci. 2012, 3, 3458−3462.(334) Liu, T.; Shao, X.; Wu, Y.; Shen, Q. Angew. Chem., Int. Ed. 2012,51, 540−543.(335) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.;Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332−4336.(336) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,4986−4987.(337) Yagupolskii, L. M.; Maletina, I. I.; Kondratenko, N. V.; Orda,V. V. Synthesis 1978, 835−837.(338) Umemoto, T.; Kuriu, Y. Tetrahedron Lett. 1981, 22, 5197−5200.(339) Umemoto, T.; Kuriu, Y. Chem. Lett. 1982, 65−66.(340) Umemoto, T.; Kuriu, Y.; Shuyama, H.; Miyano, O.; Nakayama,S.-I. J. Fluorine Chem. 1986, 31, 37−56.(341) Eisenberger, P. The development of new hypervalent iodinereagents for electrophilictrifluoromethylation. Thesis, EidgenossischeTechnische Hochschule, ETH Zurich: Zurich, 2007.(342) Xu, C.; Liu, J.; Ming, W.; Liu, Y.; Liu, J.; Wang, M.; Liu, Q.Chem.Eur. J. 2013, 19, 9104−9109 (for a recent report on theoxidative trifluoromethylation of 1 with ketene dithioacetals, see ref394)..(343) Yoshida, S.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9,5573−5576.(344) Kobatake, T.; Yoshida, S.; Yorimitsu, H.; Oshima, K. Angew.Chem., Int. Ed. 2010, 49, 2340−2343.(345) Kobatake, T.; Fujino, D.; Yoshida, S.; Yorimitsu, H.; Oshima,K. J. Am. Chem. Soc. 2010, 132, 11838−11840.(346) Wu, X.; Chu, L.; Qing, F.-L. Tetrahedron Lett. 2013, 54, 249−251.(347) Chu, L.; Qing, F.-L. Synthesis 2012, 1521−1525.(348) Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106−2109.(349) Jiang, X.; Chu, L.; Qing, F.-L. J. Org. Chem. 2012, 77, 1251−1257.(350) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298−1304.(351) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.Eur. J. 2011, 17,6039−6042.(352) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010,110, 824−889.

(353) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S. J. Am. Chem. Soc.2011, 133, 7577−7584.(354) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem.2011, 76, 1174−1176.(355) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262−7263.(356) Jover, J.; Maseras, F. Chem. Commun. 2013, 49, 10486−10488.(357) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed.2013, 52, 8214−8264.(358) Chen, Z.-M.; Bai, W.; Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.;Zhang, F.-M. Angew. Chem., Int. Ed. 2013, 52, 9781−9785.(359) Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem.2010, 131, 951−957.(360) Miyazaki, A.; Shimizu, R.; Egami, H.; Sodeoka, M. Heterocycles2012, 86, 979−983.(361) Pair, E.; Monteiro, N.; Bouyssi, D.; Baudoin, O. Angew. Chem.,Int. Ed. 2013, 52, 5346−5349.(362) Yasu, Y.; Koike, T.; Akita, M. Chem. Commun. 2013, 49, 2037−2039.(363) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.;Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51, 1244−1247.(364) Wang, C.; Huang, Y. Synlett 2013, 145−149.(365) Hafner, A.; Brase, S. Adv. Synth. Catal. 2013, 355, 996−1000.(366) Hafner, A.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 3713−3715.(367) Hafner, A.; Bihlmeier, A.; Nieger, M.; Klopper, W.; Brase, S. J.Org. Chem. 2013, 78, 7938−7948.(368) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464−5467.(369) Tyrra, W. E. J. Fluorine Chem. 2001, 112, 149−152.(370) Tyrra, W. E.; Naumann, D. J. Fluorine Chem. 2004, 125, 823−830.(371) Wu, X.; Chu, L.; Qing, F.-L. Angew. Chem., Int. Ed. 2013, 52,2198−2202.(372) Cai, S.; Chen, C.; Sun, Z.; Xi, C. Chem. Commun. 2013, 49,4552−4554.(373) Li, Y.; Wu, L.; Neumann, H.; Beller, M. Chem. Commun. 2013,49, 2628−2630.(374) Li, Z.; Cui, Z.; Liu, Z.-Q. Org. Lett. 2013, 15, 406−409.(375) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D.D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.;Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95−99.(376) Seo, S.; Taylor, J. B.; Greaney, M. F. Chem. Commun. 2013, 49,6385−6387.(377) Wang, Y.-F.; Lonca, G. H.; Chiba, S. Angew. Chem., Int. Ed.2014, 53, 1067−1071.(378) Li, L.; Deng, M.; Zheng, S.-C.; Xiong, Y.-P.; Tan, B.; Liu, X.-Y.Org. Lett. 2014, 16, 504−507.(379) Fu, W.; Xu, F.; Fu, Y.; Xu, C.; Li, S.; Zou, D. Eur. J. Org. Chem.2014, 709−712.(380) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D.Angew. Chem., Int. Ed. 2013, 52, 9747−9750.(381) Wang, X.; Xu, Y.; Mo, F.; Ji, G.; Qiu, D.; Feng, J.; Ye, Y.;Zhang, S.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2013, 135, 10330−10333.(382) Behr, J.-B.; Chavaria, D.; Plantier-Royon, R. J. Org. Chem.2013, 78, 11477−11482.(383) Tyrra, W.; Kremlev, M. M.; Naumann, D.; Scherer, H.;Schmidt, H.; Hoge, B.; Pantenburg, I.; Yagupolskii, Y. L. Chem.Eur.J. 2005, 11, 6514−6518.(384) Zhang, Y.-Q.; Liu, J.-D.; Xu, H. Org. Biomol. Chem. 2013, 11,6242−6245.(385) Nishimine, T.; Fukushi, K.; Shibata, N.; Taira, H.; Tokunaga,E.; Yamano, A.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2014, 53,517−520.(386) Haufe, G.; Suzuki, S.; Yasui, H.; Terada, C.; Kitayama, T.;Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2012, 51, 12275−12279.(387) Hashimoto, R.; Iida, T.; Aikawa, K.; Ito, S.; Mikami, K.Chem.Eur. J. 2014, 20, 2750−2754.

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(388) Kawai, H.; Sugita, Y.; Tokunaga, E.; Sato, H.; Shiro, M.;Shibata, N. ChemistryOpen 2014, 3, 14−18.(389) Khangarot, R. K.; Kaliappan, K. P. Eur. J. Org. Chem. 2013,2692−2698.(390) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001, 66,2572−2582.(391) Wang, X.; Qiu, G.; Zhang, L.; Wu, J. Tetrahedron Lett. 2014,55, 962−964.(392) Xiao, Q.; Sheng, J.; Ding, Q.; Wu, J. Eur. J. Org. Chem. 2014,217−221.(393) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15,4846−4849.(394) Mao, Z.; Huang, F.; Yu, H.; Chen, J.; Yu, Z.; Xu, Z. Chem.Eur. J. 2014, 20, 3439−3445.(395) Fang, Z.; Ning, Y.; Mi, P.; Liao, P.; Bi, X. Org. Lett. 2013, 16,1522−1525.(396) Danoun, G.; Bayarmagnai, B.; Gruenberg, M. F.; Goossen, L. J.Chem. Sci. 2014, 5, 1312−1316.(397) Vinogradova, E. V.; Muller, P.; Buchwald, S. L. Angew. Chem.,Int. Ed. 2014, 53, 3125−3128.

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