Trifluoromethyltrimethylsilane: Nucleophilic Trifluoromethylation and Beyond Xiao Liu, Cong Xu, Mang Wang,* and Qun Liu* Department of Chemistry, Northeast Normal University, Changchun 130024, China 3.9.6. Lewis Acids 4. Reactions with B-, P-, and S-Based Electrophiles 4.1. Preparation and Synthetic Applications of (Trifluoromethyl)trimethoxyborate 4.2. Reactions with Phosphorus-Based Electrophiles 4.3. Reactions with Sulfur-Based Electrophiles 5. Trifluoromethyltrimethylsilane As a Difluorocarbene Precursor 5.1. [2 + 1] Cycloaddition 5.2. Direct α-Difluoromethylation of Lithium Enolates 5.3. Reaction of Difluorocarbene with Acetylene Ethers 6. Trifluoromethylation Involving Transition Metal Complexes 6.1. Cu-Catalyzed Trifluoromethylation of Allylic Halides 6.2. Trifluoromethylation of α-Haloketones with CuCF3 6.3. Cu-Catalyzed Trifluoromethylation of Propargylic Halides 7. Synthesis of Benzotrifluorides Based on PreFunctionalization 8. Electrophilic and Oxidative Trifluoromethylation Reactions 8.1. Shelf-Stable Electrophilic Trifluoromethylating Reagents 8.2. Cyclic Hypervalent Iodine(III) Electrophilic Trifluoromethylating Reagents 8.3. Acyclic Hypervalent Iodine(III) Electrophilic Trifluoromethylating Species and Oxidative Trifluoromethylation 8.4. Reactions Involving Trifluoromethyl Radical 9. Perspectives and Conclusion 10. Latest Developments Author Information Corresponding Authors Author Contributions Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 2. Synthesis of Trifluoromethyltrimethylsilane 3. Reactions with Carbon Electrophiles 3.1. Trifluoromethylation of Aldehydes and Ketones 3.2. 1,4-Trifluoromethylation Reactions 3.3. Trifluoromethylation of 4-Nitroisoxazoles 3.4. Trifluoromethylation of Anhydrides and Weinreb Amides 3.5. Trifluoromethylation of Imines 3.5.1. Trifluoromethylation of Azirines 3.5.2. TMAF Mediated Trifluoromethylation of Aldimines 3.5.3. HF Promoted Trifluoromethylation of Imines 3.5.4. Trifluoromethylation of N-Tosyl Imines Based on Phase-Transfer Catalysis 3.6. Direct Trifluoromethylation of Csp3−H Bond Adjacent to a Nitrogen Atom Method A Method B 3.7. Selective Trifluoromethylation of MultiFunctional Substrates 3.8. Enantioselective Trifluoromethylation 3.8.1. Aldehydes and Ketones: With CinchonaDerived Quaternary Ammonium Fluoride Salts as Catalysts 3.8.2. Aldehydes and Ketones: Phase-Transfer Catalysis Mode 3.8.3. Aldehydes and Ketones: Combination Catalysis Mode 3.8.4. Enantioselective Trifluoromethylation of Imines 3.9. Catalysts and Mechanisms Considerations 3.9.1. Oxygen Centered Nucleophilic Catalysts 3.9.2. Substrate-Directable Reaction 3.9.3. DMSO and Molecular Sieves 3.9.4. Amidine Base 3.9.5. N-heterocyclic Carbene or Phosphines in DMF © 2014 American Chemical Society

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Special Issue: 2015 Fluorine Chemistry Received: August 27, 2013 Published: April 22, 2014

702 683 | Chem. Rev. 2015, 115, 683−730

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1. INTRODUCTION Fluorine 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 very few molecules bearing a C−F bond (one of the strongest in organic compounds, Figure 1)1 are present in nature2−9 due to

pert−Prakash reagent) has been used extensively as a versatile reagent in organic synthesis in past two to three decades due to the advantages of TMSCF3 such as it is easy to handle and store, stable, and cost-effective over related derivatives.14−16,23 Because of the importance of the trifluoromethyl group in materials and medicinal chemistry research,1−12 it is not surprising that there has been a rapid increase in the development of trifluoromethylation methods as evidenced by over 350 publications since 2008.24 Several microreviews or reviews, in part, on formation of trifluoromethylated (hetero)arenes19,25−27 and direct trifluoromethylation of C−H bond involving the utility of Ruppert−Prakash reagent28 have been published recently. A comprehensive review23 described the preparation and synthetic utility of TMSCF3 from 1984, the year of the seminal publication by Ruppert and co-workers for the synthesis of TMSCF3, to 1997, including mainly the nucleophilic trifluoromethylation reactions of TMSCF3 with hard carbon electrophiles, such as nonenolizable aldehydes and ketones, lactones, cyclic anhydrides, and azirines. In recent years, there has been an increasing wealth of information about the structures of TMSCF3 and related reagents, catalysts, and reaction mechanisms. The aim of this review is to highlight a selection of important recent applications of TMSCF3 as a versatile reagent for the introduction 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 and development of catalysts and catalytic reactions. In addition, several new fluoromethylating reagents or species generated from TMSCF3 and fluoroform are covered to emphasize features that may warrant further investigation. In addition, the related applications of other homologous silanes are also described.

Figure 1. Properties involving fluorine, trifluoromethyl group, and others.

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. Figure 2)6,9,10 and agrochemicals contain fluorine atoms because fluorinated organic compounds have enhanced lipophilicity and membrane permeability, elevated electronegativity and oxidation resistance. These are responsible for the more increased metabolic stability and bioavailability of fluorinated organic compounds than their nonfluorinated analogues.2−13 As a consequence, drug candidates with one or more fluorines have become common place and rapidly increasing efforts have focused on developing efficient strategies, reagents, and catalysts for the incorporation of, for example, CF3 into various organic structures via nucleophilic, electrophilic, and radical trifluoromethylations.9−22 In this context, a major challenge is the development and utilization of diverse CF3 sources. However, in nucleophilic organometallic compounds, trifluoromethyl lithium and magnesium cannot be employed for the synthesis of trifluoromethylated compounds through addition reactions. These nucleophilic species are recognized as being too unstable and difficult to prepare because of facile α-fluoride (M−F; M = Li or Mg) elimination.5 Whereby, trifluoromethyltrimethylsilane (TMSCF3 or Me3SiCF3, Rup-

2. SYNTHESIS OF TRIFLUOROMETHYLTRIMETHYLSILANE The CF3 group has the same electronegativity as chlorine (Figure 1), which makes it distinct from other alkyl groups such as the methyl (CH3) group.13 In perfluoroalkyl organometallic compounds, perfluoroalkyl magnesium halides are more stable than perfluoroalkyl lithium but still must be prepared at low temperature with pure magnesium. In comparison, trifluoromethyl magnesium halides are more difficult to produce than other alkyl magnesium halides including the longer chain perfluoroalkyl magnesium halides.5,23 The commercially available Ruppert−Prakash reagent, TMSCF3 1, is a colorless flammable liquid with a boiling point of 54−55 °C and density of 0.962 g/mL at 20 °C. In general, perfluoroalkyl silanes are relatively stable to acid and water, which is a considerable advantage of perfluoroalkyl

Figure 2. Examples of trifluoromethyl containing drugs. 684 | Chem. Rev. 2015, 115, 683−730

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

Scheme 2. Preparation of Trifluoromethylated Silanes from Fluoroform

Scheme 1. Synthetic Methods for TMSCF3

path a).29−32 TMSCF3 1 can be obtained in 75% yield by a modification of Ruppert’s procedure on a large-scale in anhydrous 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 phosphorus compounds, such as Ph3P, (MeO)3P, or (EtO)3P as a promoter for the reaction of CF3Br with TMSCl gave no trace of 1.32 Nowadays, there are various synthetic approaches to obtain 1,29−34 including the reaction of CF3I with TMSCl in the presence of tetrakis(dimethylamino)ethylene at −196 °C (Scheme 1, path b, 94% yield; CF3Br is ineffective in this case)33 and the magnesium metal-mediated reductive trifluoromethylation 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 reaction of 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 a pentacoordinated silicon species 2. It was demonstrated that the presence of K+ as the countercation of the base appears to be rather important in the preparation of 1 from CHF3 and TMSCl. In sharp comparison, NaHMDS gave only a minor product, whereas LiHMDS failed to give the desired 1. In addition, the attempts to observe species 2 by NMR spectroscopy were not successful due to the extremely rapid rate of the subsequent reactions.24,35−37 A very important point for the Prakash’s reaction of TMSCl with CHF3 is that CHF3 is added (bubbled) slowly into a mixture of TMSCl with KHMDS in toluene at low temperature (−85 °C),38 which enables the unstable trifluoromethyl carbanion generated from CF3H and KHMDS to be internally quenched by TMSCl efficiently to form 1. In addition, the chemical hardness of M+ (M = Li, Na, K) and the difference between the values of decomposition energy of a key intermediate MCF3 and the relative energy barrier for the formation of a Si−CF3 bond are predicted to be valuable for choosing a base in the rational design of the reaction.39 The use of CHF3 as described above is very important because CHF3, a powerful long-lasting greenhouse gas, is a large volume byproduct of the industrial synthesis of fluoropolymers and refrigerants.24,40 Significantly, the higher

alkyl-substituted analogues of trifluoromethylated silanes, such as trifluoromethyl(triethyl)silane, trifluoromethyl(npropyldimethyl)silane, trifluoromethyl(triisopropyl)silane, and trifluoromethyl(t-butyldimethyl)silane, can also be prepared in good to high yield (Scheme 2) by using Prakash’s method.24,38

3. REACTIONS WITH CARBON ELECTROPHILES In 1999, Kolomeitsev and co-workers published the crystal structure 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) having a 29Si NMR resonance of −112 ppm.35,36 Compound 3 is stable in the solid state up to 0 °C but decomposes exothermally at 0−5 °C with the formation of Me4N+[Me3SiF2]−.35 In 2008, Olejniczak, Katrusiak, and Vij determined the structure of Scheme 3. Generation of Trifluoromethyl Carbanion Equivalent

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Me3SiCF3 1 by high-pressure freezing (in situ pressure frozen in a diamond anvil cell) by single-crystal X-ray diffraction at 0.90(5) GPa/296 K.37 The crystal structure of 1 confirms that the Si−CF3 bond is longer and weaker than the Si−CH3 bonds and there are no strong intermolecular interactions between 1. This result supports the trifluoromethylating nature of 1 as the CF3 group is easily transferred in the presence of suitable catalysts, the key factor in improving and developing the fluoromethylation reactions based on 1. For the increasing importance of trifluoromethylated molecules, currently, there is a surge in interest in the development of trifluoromethylation methodologies and TMSCF3 1 is now the most practical and widely used reagent. In the research using 1 as the nucleophilic trifluoromethylaing reagent, the expansion of electrophilic substrate scope, the selectivity of the reaction and functional group tolerance have been and are still the subject of intense research.

In addition to the formation of a trifluoromethyl anion equivalent (Scheme 3), it has been found that other fluoromethyl species might also be involved under certain conditions depending on the nature of substrates, initiators/ catalysts, solvents and reaction temperatures.19,23,24,52−54 Hu and co-workers performed a one-pot sequential combination of trifluoromethylation and [2 + 1] cycloaddition reaction of 1 with 4′-(phenylethynyl)-acetophenone 5 containing both a carbonyl group and a triple bond. As a result, 1 enables both a fluoride-initiated nucleophilic trifluoromethylation on the carbonyl group and a NaI-promoted difluoromethylenation on the triple bond to give product 6 in 85% overall yield (Scheme 4).52 Therefore, TMSCF3 1 can serve both as a nucleophilic trifluoromethylating reagent and as a difluorocarbene precursor under suitable reaction conditions. Scheme 4. One-Pot Sequential Trifluoromethylation and Difluoromethylenation

3.1. Trifluoromethylation of Aldehydes and Ketones

Significant interest in the nucleophilic trifluoromethylation started from the successful generation of the stable equivalent of trifluoromethyl anion “CF3−” under mild reaction conditions from TMSCF3 1 at the end of 1980s. Prakash and co-workers reported the nucleophilic trifluoromethylation of carbonyls using 1 as the nucleophilic CF3 species in the presence of a catalytic amount of tetrabutylammonium fluoride (TBAF) as an initiator of 1 to give, for example, the corresponding trifluoromethylated siloxy adducts under mild conditions.41 In the same year, Stahly and Bell described the monotrifluoromethylation at a carbonyl group of p-quinone derivatives using Et3SiCF3 or (n-Bu)3SiCF3 promoted (or catalyzed) by a variety of Lewis bases, including KF, KHF2, Bu4NHF2, H4NHF2, NaCN, KCN, NaOH, LiN3, (Et2N)3P, (EtO)3P, DMAP (4(dimethylamino)pyridine), K2CO3, etc. aimed at the synthesis of otherwise hardly accessible 4-trifluoromethylated phenols and anilines.42 These pioneering works inspired the renaissance of nucleophilic trifluoromethylation chemistry. Since then, there has been continued and growing interest in 1 as CF3 species in organic synthesis.14−16,23,24 As discussed in previous reviews,16,23 TMSCF3 1 has become the most widely used reagent for nucleophilic trifluoromethylation of an increasing variety of electrophiles.14−16,23,43−47 In the reactions of 1 with carbonyl compounds, activation of 1 with a Lewis base as catalyst under aprotic conditions to generate an equivalent of trifluoromethyl anion is one of the most viable strategies for the application of the corresponding transformations (Scheme 3).14−16,23,41 Generally for reactions of aldehydes or ketones, fluoride ion acting as an initiator only takes part in the first catalytic cycle. The further activation of 1 in subsequent catalytic cycles is to be undertaken by the alkoxide formed during the first catalytic cycle (Scheme 3). In addition, it has been found that Lewis acids, such as TiF4, Ti(OPr-i)4 and Cu(OAc)2, with or without ligands, can effectively catalyze the trifluoromethylation of various aldehydes with 1.48 A catalytic cycle of trifluoromethylation of aldehydes or ketones involves the generation of unstable pentacoordinated silicon species 4 (Scheme 3).23 This autocatalytic cycle can be applied to find the catalysts or initiators under suitable reaction conditions, including the counter cations and solvents.49,50 The reactions of α-imino ketones with 1 generally lead to the corresponding trifluoromethylated hydroxyimines, leaving the imino functionality intact due to its relatively lower reactivity.51

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

be accelerated through the addition of a catalytic amount of Lewis acids such as SbF5 or TiCl4.56−58 A mechanism involving simultaneous C−F and C−Si bond cleavage along with H−F and O−Si bond formation has been proposed (Scheme 5).56−59 Difluoromethyltriflate 7 is a nonozone-depleting liquid and has very recently been utilized as a convenient source of difluorocarbene by Fier and Hartwig.57 Due to the high electronegativity of fluorine (Figure 1), the nucleophilic CF3 species are considered as hard nucleophiles, which usually undergo 1,2-addition reactions with α,βunsaturated carbonyl compounds.14−16,23,27,42,50 The reaction of 1 with divinyl ketones 11 (DVKs, usually acting as double 686 | Chem. Rev. 2015, 115, 683−730

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Table 1. 1,2-Trifluoromethylation of Divinyl Ketones




yield of 12 (%)

yield of 13 (%)

1 2 3 4 5 6

4-MeC6H4 Ph 4-MeOC6H4 4-ClC6H4 4-FC6H4 4-ClC6H4

4-MeC6H4 Ph 4-MeOC6H4 4-ClC6H4 4-FC6H4 Me

12a, 95 12b, 93 12c, 95 12d, 90 12e 89 12f, 95

13a, 92 13b, 93 13c, 96 13d, 95 13e, 90 13f, 94

Michael acceptors)60 promoted by anhydrous NaOAc gives 1,2adducts 12 in high to excellent yields. Hydrolysis of 12 under mild acidic conditions leads to the formation of αtrifluoromethyl 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 deliver 4-trifluoromethyl-1,2-diaryl-1,3-cyclopentadienes 15 in high yields (Scheme 6),61 which provides a convenient route to

Recently, Schoenebeck and co-workers reacted Bu3SnCF3 with ketones or aldehydes under CsF activation at room temperature to afford trifluoromethylated stannane ethers in high yields.66 The advantage of the reaction is that only a mildly acidic extraction (aqueous NH4Cl) is required to release trifluoromethyl alcohol products due to the relatively weakness of the Sn−O bond compared to the Si−O bond (bond dissociation energies: ΔH(O−Sn) = 548 kJ/mol; ΔH(O−Si) = 798 kJ/mol),67 which is more compatible with acid-sensitive functional groups and useful for late-stage synthesis.66

Scheme 6. Synthesis of Mono-CF3 Substituted Cyclopentadienes

3.2. 1,4-Trifluoromethylation Reactions

Although reactions of 1 with α,β-unsaturated carbonyls leading to trifluoromethylated alcohols via 1,2-addition have been studied in detail,14−16,23,27,42,50,61 there have been only a few examples of Michael and Michael-type reactions because the mismatch between the relatively soft β-carbon of α,βunsaturated carbonyls and the hard “CF3−” species generated, for example, from 1/F− (Scheme 3). In 2003, Sevenard and coworkers reported the first successful 1,4-trifluoromethylation of α,β-enones by introducing a strong electron-withdrawing CF3 group at the β-position.68 Promoted by fluoride ion, 2trifluoromethyl-4-quinolones and chromones 18 (Figure 3, Z

mono-CF3 substituted cyclopentadienes, the analogue of Gassman’s ligand (1,2,3,4-tetramethyl-5-(trifluoromethyl)cyclopentadiene).62 In the synthesis of cyclopentadienes, the double-bond isomers for example, 1-chloro-4-(2-methyl-4(trifluoromethyl)cyclopenta-1,3-dienyl)benzene 15f and 1chloro-4-(2-methyl-4-(trifluoromethyl)cyclopenta-1,4-dienyl)benzene 15f′, are obtained in the ratio of 15f:15f′ = 3:1 through a 1,5 H-shift (Scheme 6).61 Whereas, no reaction occurred by treatment of 1 with acetyl ketene dithioacetal 14 under identical conditions, due to the relatively softer nature of the carbonyl group of 14 resulting from the strong electron-donating (p−π conjugation) effect of the methylthio groups.64 In comparison, 13b could be prepared in only 36% yield using N-trifluoroacetyl O-trimethylsilyl vicamino alcohols as nucleophilic trifluoromethylating reagents.65

Figure 3. Michael acceptors.

= O) serve as good Michael acceptors under nucleophilic trifluoromethylation conditions.68−70 In addition, the Knoevenagel condensation products of trifluoromethylchromone with diethyl malonate, ethyl cyanoacetate, and Meldrum’s acid (for example 20 in Figure 3) are suitable substrates for 1,6addition.71 In comparison, in the case of coumarin 21 (Figure 3), a mixture of 1,2- and 1,4-addition products are generated and significantly enriched with the former (53% versus 8%).72 The reason for such an anomalous behavior of 18−20 is possibly due to the additional −I activation of the β-position of 687 | Chem. Rev. 2015, 115, 683−730

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the α,β-unsaturated systems by the RF moiety.73 However, similar reaction with 2-trifluoromethyl-1-thiochromones (Figure 3, when Z = S in 18) resulted only in 1,2-addition adducts.70 Dilman and co-workers showed that, promoted by acetate ions, highly electrophilic alkenes, such as (E)-methyl 2-cyano-3phenyl acrylate 22, arylidenemalononitriles 23,73 arylidene Meldrum’s acids (24),74 and 2-nitrocinnamates (25)75 bearing two germinal electron-withdrawing groups (Figure 3), are suitable substrates for Michael addition with 1. Whereas, less than 15% yield of the Michael adduct was obtained with dimethyl 2-benzylidenemalonate as the substrate.73 These results are roughly consistent with their electrophilicity by the estimation of the Mayr electrophilicity parameter based on quantitative structure−property relationships (QSPRs).76,77 In comparison, the nucleophilic fluoroalkylation of chalcone with PhSO2CF2H in the presence of LiHMDS to give a mixture of 1,2- and 1,4-adducts and the nucleophilic pentafluorophenylation of nitroalkenes with pentafluorophenylmagnesium bromide to form 1,4-adducts have also been reported and attributed to the softer nature of these nucleophiles relative to 1.78,79

bearing a styryl group at 5-position are also synthesized (16 examples, 67−96% yields) from the corresponding substrates 28 (Scheme 7, for example, 29a in 87% yield). However, when Scheme 7. Trifluoromethylation of 4-Nitroisoxazoles

3.3. Trifluoromethylation of 4-Nitroisoxazoles

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

Me3SiCN instead of Me3SiCF3 was used, 1,6-adduct 30 was selectively furnished in low yield (Scheme 7). Thus, the trifluoromethylation reaction of 26 and 28 with 1 leads to a successful access to 5-trifluoromethyl-2-isoxazolines 27 and 29 with the CF3 substituent on a quaternary carbon center.80 Similar to the trifluoromethylation of 2-trifluoromethyl-4quinolones and analogues (Figure 3)68−71 it has been found that the nitro group is necessary to activate the substrate for trifluoromethylation because no reaction can be observed between 3,5-diphenylisoxazole, the non-nitro analogue of 26a and 1 under the same reaction conditions. Shibata and coworkers gave a mechanism for the regio- and diastereoselective trifluoromethylation of 26/28, which involves the nucleophilic 1,2-type addition of a “CF3−” to a reactive tautomer 31 of 26/ 28 (Scheme 7),80 indicating the addition at the 5-position of an aromatic isoxazole ring is specific to the (hard) “CF3−” compared to the stabilized (soft) nucleophiles.81,82

Table 2. Reactions of 1 with 4-Nitroisoxazoles under Different Conditions



27a (yield %)a

1b 2 3 4 5 6 7 8 9 10c


28 44 57 59 57 67 80 78 95

3.4. Trifluoromethylation of Anhydrides and Weinreb Amides

Trifluoromethyl ketones (TFMKs) and derivatives are highly valuable CF3-containing synthons in the construction of CF3containing compounds.49,83−97 Interestingly, Colby and coworkers98 recently found that hexafluoroacetone hydrate amidinate complex can be used as a nucleophilic trifluoromethylating reagent using a simple acid−base process based on a report in 1968 by Prager and Ogden that hexafluoroacetone hydrate 33 fragments in the presence of sodium hydroxide to give, via its sodium salt (sodium 1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-olate), trifluoroacetate and fluoroform (Scheme 8a).99 Importantly, the reaction of ethereal solution 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, amidinate salt 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-


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

suitable additives is also demonstrated (entry 2 versus 8 and entry 8 versus 10).80 In comparison, in the presence of NaOAc, the reaction did not proceed when dichloromethane, THF, and toluene were selected as the solvent, respectively, indicating the importance of solvent choise.80 Under optimal conditions (entry 10), a series of trifluoromethylated adducts, 5-trifluoromethyl-2-isoxazolines 27, are prepared in good to excellent yields (10 examples, 67−99% yields).80 In addition, 5-trifluoromethyl-2-isoxazolines 29 688 | Chem. Rev. 2015, 115, 683−730

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Scheme 8. Preparation and Reactions of Hexafluoroacetone Hydrate Amidinate Salt

Scheme 9. Trifluoromethylating Reaction of Weinreb Amides

trifluoro-1-(4-methoxyphenyl)ethanol 37 has been examined by Colby and co-workers, showing the significant influence of bases and additives on the reaction.98 The salt 35 is a stable, anhydrous solid (not hygroscopic, even after multiple exposures to air for 3 months) and displays high solubility in DMF, DMSO, EtOAc, and CH3CN and partial solubility in toluene and THF.98 On the other hand, salt 35 can also be used to prepare the difluoromethylated compound 39 (Scheme 8c) via difluorocarbene (generated from salt 35) insersion into the Csp3−H bond of 38,98 the analogue of the anti-inflammatory and analgesic drug ibuprofen. Thus, salt 35, which can be prepared in one synthetic step up to a multigram scale without any purification,98 has recently been commercialized by SigmaAldrich.104 However, in contrast, no solid complexes could be obtained by the reaction of trifluoroacetaldehyde hydrate (CF3CH(OH)2) with various amines attempted although the results using CF3CH(OH)2 as an atom economical trifluoromethyl anion equivalent under basic conditions are satisfied.105 TFMKs can be prepared by oxidation of α-trifluoromethyl alcohols49,85 and other methods.83−85,106 For the preparation of TFMKs, the trifluoromethylation of a suitably activated carbonyl derivative with 1 is a viable option for simplicity. Leadbeater and co-workers reported a novel route to access TFMKs 41 from Weinreb amides 40 (N-methoxy-N-methylamide, serving as effective acylating reagents of organolithium and organomagnesium)107 through effective acylations of 40 with 1 in a two-step procedure without formation of the bistrifluoromethylated product (Scheme 9).108 In these reactions, adducts 42 (for example 42a with R = 4-tBuPh) are stable enough to be isolated in high yield (81%) and slowly revert back to 40a if left 42a for extended times in the solvent, THF, (attributing to the Lewis basicity of THF).109 However, Weinreb amides 40a′−f′, bearing an aryl ring with a substituent at the ortho position or bearing an α-branched alkyl group, are inert to the reaction (Scheme 9) due to the steric hindrance.108 In the case of the reaction of α,β-unsaturated

Weinreb amides 43 with 1 under similar reaction conditions, a low yield of the desired TFMKs 44 (4 examples, 22−51% yields) was obtained along with 45 formed probably via an azaMichael addition of the displaced N,O-dimethylhydroxylamine anion to the highly electrophilic alkene 44 (Scheme 9).108 The nucleophilic trifluoromethylation of phenyl ketoamides 46 with 1 gives α-trifluoromethyl silyl ethers 47 (precursors of α-trifluoromethylated α-alkoxy-aldehydes 48) in the presence of a catalytic amount of initiator (Scheme 10) whatever the Scheme 10. Trifluoromethylation of Phenyl Ketoamides

reaction conditions used. In this case, no trace of addition of the trifluoromethyl group onto the amide moiety can be observed because of the more reactive nature of the ketone functionality.51,110 Pohmakotr and co-workers showed that the corresponding TFMKs could be involved in the TBAT-catalyzed (10 mol %, TBAT: tetrabutylammonium triphenyldifluorosilicate) nucleophilic trifluoromethylation of 1 to phthalic anhydride or 689 | Chem. Rev. 2015, 115, 683−730

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ucts,10,43−47,117−119 through trifluoromethylation of imines with 1 had been a formidable challenge.23 3.5.2. TMAF Mediated Trifluoromethylation of Aldimines. Recently, a careful study of the trifluoromethylation of nonactivated aldimines with 1 was carried out by Yagupolskii and co-workers in the presence of tetramethylammonium fluoride (TMAF).44 They confirmed by low-temperature 19F NMR experiments that the reactions of benzylideneanilines with 1 proceed, probably via the formation of tetramethylammonium amides (Figure 4, with benzylideneaniline as an

succinic anhydride followed by treatment of the adducts with Grignard reagents.111,112 Catalyzed by TBAT, trifluoromethylation of the masked maleic anhydride (cyclopentadiene-maleic anhydride adduct) with 1 followed by quenching with water affords the desired adduct in high diastereoselectivity and yield by attacking of 1 from the less hindered convex side of the substrate (eq 1).113 Whereas, a complex mixture was produced from the reaction of maleic anhydride with 1 under similar reaction conditions even under low temperature (eq 2).113

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

In nucleophilic trifluoromethylation reactions promoted by TBAF, the carbonyl group of an aldehyde or a ketone is more reactive than the imino group of an imine.51 In addition, imines bearing a N-aryl or N-alkyl group are noticeably less reactive compared to N-tosyl and N-sulfinyl imines. Nevertheless, several reports have documented successful results in which various imines can react efficiently with 1 through the selection of proper catalysts/promotors. 3.5.1. Trifluoromethylation of Azirines. In 1994, 5 years after the first example of trifluoromethylation of CO bonds of aldehydes and ketones with 1,34 Félix, Khatimi, and Laurent reported the trifluoromethylation of 1 on the CN bond of reactive azirines 49 (Scheme 11).116 However, the reaction of nonactivated N-alkylimine (n-propylbenzaldimine) with 1 under similar conditions failed to produce desired adduct,116 indicating the synthesis of α-(trifluoromethyl)amines, the useful intermediates for pharmaceutical and agrochemical prod-

Figure 4. TMAF mediated trifluoromethylation of benzylideneaniline.

example), different from the reactions of 1 with aldehydes or ketones via the pentacoordinated silicon species as in Scheme 3.23 Consecutive reactions of the salts formed in situ with electrophiles afford trifluoromethylated amines, including N(2,2,2-trifluoro-1-phenylethyl)aniline by hydrolysis, N-methylN-(2,2,2-trifluoro-1-phenylethyl)aniline by silylation, and 1,1,1trimethyl-N-phenyl-N-(2,2,2-trifluoro-1-phenylethyl)silanamine by methylation, respectively. Silylated amines are stable under neutral conditions but desilylate easily in the presence of acids to form trifluoromethylated amines (Figure 4).44 These results demostrate that TMSCF3 1 can be used for the introduction of the trifluoromethyl group into several unactivated imines under mild conditions using tetraalkylammonium fluorides as initiators (CsF did not work),45 which deserves further investigation in detail. 3.5.3. HF Promoted Trifluoromethylation of Imines. In 2008, Dilman and co-workers found that N-alkyl substituted imines and enamines, which are unreactive under conventional Lewis basic conditions,23,43,116 can undergo nucleophilic trifluoromethylation with 1 in the presence of hydrofluoric acid (generated in situ by mixing potassium hydrodifluoride and trifluoroacetic acid (TFA)) under mild reaction conditions.120 This approach is a milestone in the trifluoromethylation of imines, which provides an efficient access to α(trifluoromethyl)amines through the selective activation of both 1 and an imine functionality at the same time.10,43,117−119 Later, they demonstrated that this acidic condition can also be applied to α-phenylthio, α-phenylsulfonyl, and α-diethylphosphoryl substituted silicon compounds 52−54 as nucleophilic

Scheme 11. Trifluoromethylation of Azirines

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Scheme 12. HF-Promoted Nucleophilic Fluoroalkylation Reactions of Imines

fluoroalkylating reagents via a similar mechanism (Scheme 12).120−122 A dual activation mechanism for the HF-mediated reactions involves, as a first step, the interaction of the substrate (imine or enamine) with H2F2 leading to the equilibrium formation of more reactive iminium ion and hydrodifluoride anion. Subsequently, the siliphilic hydrodifluoride (HF2−) activates the silicon reagent (for example 1) to generate a five-coordinate intermediate, which reacts with iminium leading to the product (Scheme 12). It is proposed that the transfer of fluorinated carbanion from silicon to the iminium electrophile proceeded in a concerted fashion. Otherwise, if the free carbanion were formed, it would likely be rapidly quenched with acid present in the reaction mixture.121,122 Dilman indicates that “while anhydrous HF is highly dangerous, in their protocol it is generated in situ by mixing easily available and convenient chemicals (for example, KHF2 and TFA). Furthermore, reactions can be performed in conventional glassware with no noticeable deterioration of glass surface”.121,122 According to the results of Nenajdenko, Röschenthaler and co-workers, the HF-promoted nucleophilic trifluoromethylation of 5−7-membered cyclic imines 55−57 bearing an alkyl, aryl or hetaryl group at the 2-position leads to the desired 2-trifluoromethyl-pyrrolines 58, -piperidines 59 and -azepanes 60 (26 examples, 44−79% yields), respectively, under mild reaction conditions.123 In addition, treatment of cyclic trimers 61, the nonreactive compounds under basic conditions,23,43,124,125 with 1 can also lead to the formation of 2-trifluoromethyl substituted pyrroline 62a and piperidine 62b in moderate yields under similar reaction conditions (Table 3).123 More recently, the elegant HF-mediated protocol has been employed to the synthesis of a small library of structurally diverse primary amines bearing a germinal CF3 group starting from aldehydes or ketones via Nbenzyl imines on a preparative scale (11.9−30.7 g).126 Meanwhile, it has been confirmed that all synthetic steps are high-yielding and neither the isolation of the intermediates or chromatographic purification of the products is necessary (Scheme 13, 10 examples, 41−93% overall yields).126

In another report on the HF-mediated reactions by Mykhailiuk and co-workers, methyl 3-(benzylimino)cyclobutanecarboxylate 67 gave α-(trifluoromethyl)amine 68 in low yield. Similarly, α-(trifluoromethyl)amine 70 was obtained in 47% yield under identical conditions (Scheme 13).127 The realitively lower yield of 68 and 70 may indicate an additional proximal steric hindrance in the corresponding cyclobutanimine precursors of 66a, 68, and 70 (Scheme 13, yields of 66a, 68, and 70 versus 66b and 66c). Now, the HFmediated nucleophilic trifluoromethylation of imines has become a general protocol with a wide substrate scope including not only aldimines but also the less reactive acyclic and cyclic ketimines.43,122 In addition, Dilman’s method is chemoselective because the trifluoromethylation of an imine group proceeds faster than a carbonyl group under the reaction conditions (see ection 3.7).120 3.5.4. Trifluoromethylation of N-Tosyl Imines Based on Phase-Transfer Catalysis. In 2012 Bernardi and coworkers presented a new approach to additions of silicon nucleophiles (including TMSCF3, TMSC3F7 and TMSC6F5) to imines based on the phase-transfer of phenoxides by ammonium catalysts.128 As a result, various N-tosyl imines derived from aromatic or heteroaromatic aldehydes react well to furnish α-(trifluoromethyl)amines in good to excellent yields (11 examples, 59−97% yields) under mild reaction conditions.128 These recent protocols, especially the HF-mediated nucleophilic trifluoromethylation, not only expand the scope of imine electrophiles but enrich the choice of catalysts, initiators and/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), bistrifluomethylated amines (1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-amine derivatives) could be prepared in moderate to good yields from reactions of aryl nitriles with 1 under mild reaction conditions (eq 3, TBAF was ineffective under identical conditions).46 691 | Chem. Rev. 2015, 115, 683−730

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Table 3. HF-Promoted Trifluoromethylation of Cyclic Imines

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





yield (%)

1 2 3 4 5 6 7 8 9 10 11 12

55a 55b 55c 55d 55e 55f 55g 55h 55i 56a 56b 57a

58a 58b 58c 58d 58e 58f 58g 58h 58i 59a 59b 60a

Me cyclo-C6H11 tert-C4H9 Me-SCH2 4-MeC6H4 3-CF3C6H4 2-Thienyl 2-Furyl 3-Pyridyl tert-C4H9 3-Pyridyl tert-C4H9

49 68 71 75 48 64 71 60 68 56 67 56

Direct functionalization of Csp3−H bond adjacent to a nitrogen atom is of importance for the synthesis of α-functionalized amines.131,132 In 2011, Li and Mitsudera described a Cucatalyzed oxidative trifluoromethylation of Csp3−H bond at the α-position of nitrogen in tetrahydroisoquinolines 71 to give 1trifluoromethyl-tetrahydroisoquinoline derivatives 74 (Scheme 14, Method A, with 2-phenyl-tetrahydroisoquinoline 71a as an example).133 Later, Fu and co-workers reported the synthesis of 74 from 71 using visible light irradiation catalyzed by Rose Bengal (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 by 2,3-dichloro-5,6-dicyanobenzoquinone 75 (DDQ, Scheme 14, Method A) or by visible light and the photocatalyst Rose Bengal 77 (RB, Scheme 14, Method B) in the presence of molecular oxygen, respectively. Table 4 gives the results of the oxidative trifluoromethylation of tetrahydroisoquinoline derivatives 71.133,134 Method A. Reactions were carried out on a 0.15 mmol scale in 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 methods using an internal standard, isolated yields in parentheses. Method B. Reaction conditions: 71 (0.3 mmol), 1 (5 equiv), KF (5 equiv), and RB 77 (5 mol %) in CH3CN (3.0 mL) at room temperature under green LEDs (LED: light emitting device) irradiation in the open air. Isolated yields. According to the experimental results (Table 4), both 2-aryland 2-alkyl-substituted tetrahydroisoquinolines 71 are effective substrates for the oxidative trifluoromethylation. The reaction of 1 with 2-benzyl, 2-pyridylmethyl and 2-allyl tetrahydroisoquinolines 71j−71l affords the corresponding 1-trifluoromethylated tetrahydroisoquinolines 74j−74l regioselectively in moderate to good yields (Method B for 71j and 71l only). Substrates bearing stronger electron-withdrawing groups such as pivaloyl (Piv) 71r or tert-butoxycarbonyl (Boc) 71s do not react, possibly due to the increased oxidation potential of the corresponding amines caused by the electron-deficient nature of the α-carbon atom (Method B for 71l only). In addition, it has been shown that no reaction occurs for tetrahydroisoquinoline 71q in both methods (Method A: no desired product; Method B: no reaction), agreeing with majority of recent studies in the realm of Csp3−H bond functionalization adjacent to a tertiary nitrogen.131,132 The above methods provide an alternative route to α-(trifluoromethyl)amines.9,43−47,117−119 The utility of visible light to realize the Csp 3 −H functionalization adjacent to a tertiary nitrogen atom with in situ-generated iminium ions was first reported by Stephenson and co-workers in 2010.136 Visible-light-mediated reactions have expanded rapidly because of operational simplicity and economy and are being used in more and more applications,132 including trifluoromethylation reactions.20,22,134,137,138 For example, trifluoromethylation of arenes and heteroarenes with CF3SO2Cl,20 alkenes with CF3I,137 α-trifluoromethylation of carbonyl compounds with CF3I,138 and hydrotrifluoromethyla-

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

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Scheme 14. Oxidative Trifluoromethylation of Tetrahydroisoquinolines

Table 4. Oxidative Trifluoromethylation of Tetrahydroisoquinolines

tion of unactivated alkenes with Umemoto reagent,139 through

3.7. Selective Trifluoromethylation of Multi-Functional Substrates

the choice of a visible light excitable catalyst have been

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


corresponding trifluoromethylated hydroxyimines,51 indicating 693 | Chem. Rev. 2015, 115, 683−730

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Scheme 16. Tandem Reaction of N-(tertButanesulfinyl)imines

the hard nature of the nucleophilic CF3 species due to their high electronegativity (Figure 1). However, the chemoselectivity (one of the major challenges faced in contemporary synthesis) of a reaction depends not only on the reagent used and the nature of the substrates but also on the environmental conditions, 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-5phenyl-5,6-dihydro-2H-1,4-oxazin-2-one 78 with 1 gave trifluoromethyl lactol 79 instead of trifluoromethyl amine 82 (Scheme 15)142 due to the more reactive nature of the lactone Scheme 15. Reactions of 3-Methyl-5-phenyl-5,6-dihydro-2H1,4-oxazin-2-one

mixture of 89:90 is obtained in a combined yield of 30% via a SN2′- and a 1,2-addition pathway, respectively, from the reaction of 86 with 1 (Scheme 17).148 In comparison, using DABCO (1,4-diazabicyclo[2.2.2]octane) as the catalyst, αmethylene-β-trifluoromethyl ester 91 is obtained in excellent yield by Shibata and co-workers.149 Thus, a mechanism involving a successive SN2′/SN2′ attack by DABCO and “CF3−” (86 → 92 → 91) is proposed (Scheme 17).149 Since acetate ion is an initiator of 1 (Scheme 3), only a catalytic amount of n-Bu4NOAc148 or DABCO (in this case, “CF3−” was formed from the reaction 1 with in situ-generated AcO− from 92)149 is required for the reactions (Scheme 17).150,151 On the other hand, the regioselective formation of 91 can be attributed to the hard nature of the β-C of intermediate 92 (having a positive charge) matching the hard nature of “CF3−”.150 An extension of the DABCO catalyzed allylic alkylation to the asymmetric allylic alkylation (AAA), a powerful tool for making enantiomeric compounds,152,153 has led to the results that, catalyzed by commercially available cinchona bis-alkaloid, (DHQD)2PHAL 95, the enantioselective trifluoromethylation of MBH carbonates 93 (no reaction is observed for 86 under identical conditions for 120 h) affords chiral β-methylene-βtrifluoromethyl esters 94 in high enantioselectivities (up to 94% enantiomeric excess, Scheme 18).149 Therefore, the significant difference between 86 and 93 in the reaction may be caused by the steric demand of the bulky Boc group, which would interfere in the stereoselective interaction of the olefin moiety with bis(cinchona alkaloid) catalyst (DHQD)2PHAL 95. A similar reaction was also observed by Jiang and co-workers for the transformation of 96 to 97 (Scheme 18), in which the kinetics of the process is largely dependent on the electronic nature of the aromatic rings of 96 (favoring those with more electron-withdrawing groups).154

moiety toward 1 (hard nature).143−145 However, it has been found that compound 81 can be obtained in excellent yield through the addition of Grignard reagent (soft nature, Figure 1) at the imine moiety in the presence of a Lewis acid as the activator of the imine functionality at low temperature (Scheme 15).146 They also described a highly regio- and stereoselective synthesis of fluorinated 1,3-disubstituted isoindolines 84 through a tandem reaction consisting of a diastereoselective addition of 1 to Ellman’s N-(tert-butanesulfinyl)imines 83 followed by an intramolecular aza-Michael reaction (Scheme 16).147 In this reaction, compounds 85 are formed as single diastereoisomers through trifluoromethylation at the imine moiety of 83, indicating that the N-sulfinyl imine is more reactive than the carbonyl group of the α,β-unsaturated ester. Importantly, the catalyst-directed trifluoromethylation of bifunctional (E)-2-(4-((benzylimino)methyl)phenoxy)-1-phenylethanone with 1 can give either the CF3-substituted amine (leaving carbonyl group intact) or CF3-substituted silyl ether (leaving imino group intact) chemoselectively, depending on the selection of catalyst (eq 4).120 In 2010, Dilman and co-workers described for the first time the introduction of a trifluoromethyl group into Morita− Baylis−Hillman adducts (MBH adducts).148 Catalyzed by nBu4NOAc, the reaction of acetylated MBH adduct 86 with MeSi(C6F5)3 87 can furnish the SN2′ (1,4-addition−elimination) product 88 (Z/E = 94:6) in high yield with acetate as the leaving group. However, under identical conditions, a 1:1 694 | Chem. Rev. 2015, 115, 683−730

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

Scheme 18. Asymmetric Allylic Trifluoromethylation of Moris-Baylis-Hillman Carbonates

Figure 5. Cinchonine-derived catalysts.

Caron and co-workers screened several structurally related catalysts (the cinchona-derived quaternary ammonium fluoride salts Figure 5)156,157 for the addition of a trifluoromethyl “anion” to aromatic ketones and aldehydes.158 However, the enantioselectivity of the reaction had been found to be affected by various factors (Scheme19),158 including: (1) catalyzed by CsF, silylated tertiary alcohol 101 is obtained in quantitative yield from the reaction of acetyl protected acetophenone 100a with 1; (2) in the asymmetric case catalyzed by 99a, (R)-102a is produced in moderate ee; (3) in the asymmetric case tested by the reaction of ketone 100f with 1 using catalyst 99c in dichloromethane at −78 °C proves to be a better choice for solvents and reaction temperatures (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 enantioselectivity from acetophenone 100f; (5) among the catalysts of 99a−k (4−20 mol %) for the reaction of 100f, catalyst 99j gives the best 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 substrate-dependence. For example, substrates 103a−i give unsatisfactory results (1−64% ee, Table 5).158 Whereas the research of Caron and co-workers gives an efficient procedure for the preparation of the catalysts, cinchona-derived quaternary ammonium fluoride salts 99 (Figure 5), simply by treatment of cinchonine with benzyl halides (1.2 equiv) in the presence of a catalytic amount of Bu4NI (3 mol %) in refluxing THF. The advantage of using THF over the commonly used toluene is that any unreacted cinchonine remains in solution.

3.8. Enantioselective Trifluoromethylation

The catalytic enantioselective nucleophilic trifluoromethylation of carbonyl derivatives is one of the most important strategies for the preparation of optically active α-trifluoromethylated alcohols and amines, which are becoming increasingly popular as chiral enantiopure synthons in the design of new drugs or materials.12,80,155−159 3.8.1. Aldehydes and Ketones: With CinchonaDerived Quaternary Ammonium Fluoride Salts as Catalysts. Prompted by the report on the nucleophilic trifluoromethylation of 1 with carbonyl compounds catalyzed by TBAF,41 the first asymmetric trifluoromethylation was described in 1994 by Iseki, Nagai and Kobayashi.155 Catalyzed by N-[4-(trifluoromethyl)benzyl]cinchonium fluorides (Figure 5, 99a or 99b, 1−20 mol %), the reaction of 1 with aldehydes/ ketones gave the desired products in lower ee (ee: enantiomeric excess, 7 examples, 87−99% yields, 35−51% ee for aromatic aldehydes; 15% ee for octanal).155 Following this seminal study, 695 | Chem. Rev. 2015, 115, 683−730

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

Table 5. Trifluoromethylation Reactions of Different Substratesa


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

Thus, the ammonium salt can be obtained simply by filtration followed by ion exchange with Dowex-F− in MeOH.158 3.8.2. Aldehydes and Ketones: Phase-Transfer Catalysis Mode. The catalytic enantioselective trifluoromethylation of carbonyl electrophiles using 1 as the trifluoromethyl transfer reagent had met with much less success than the Mukaiyama aldol type reaction.155,158,160 In 2007, a breakthrough in this area was made by Shibata and co-workers, they revealed a strategy for the in situ generation of quaternary ammonium fluorides derived from cinchona alkaloids.161−164 This procedure involves the external introduction of a more soluble

fluoride source than KF in low amounts which, combined with a polar cosolvent, allows the enantioselective trifluoromethylation reaction to proceed efficiently in a phase-transfer catalysis mode. As an example, more recently, Shibata and co-workers described the first enantioselective synthesis of efavirenz 116 via a five-step procedure by using a direct trifluoromethylation approach as the key step.164 Optimization of reaction conditions, especially the ammonium bromides derived from cinchonidine and quinine, enables them to obtain the key intermediate of efavirenz (S)-114 in high yield and acceptable ee from trifluoromethylation of alkynyl ketone 112 with 1 696 | Chem. Rev. 2015, 115, 683−730

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catalyzed by a combined 113/Me4NF system (Scheme 20).164 In this organocatalyzed asymmetric synthesis, a procedure

Scheme 21. Enantioselective Synthesis of Efavirenz

Scheme 20. Enantioselective Trifluoromethylation Approach to Efavirenz

120 as the sterically demanding catalyst, trifluoromethylated products 121−130 are obtained in high to excellent yields and moderate to good ee values from the corresponding aldehydes (Table 6, 10 examples, 70−99% yields, 50−70% ee). In comparison, product 121 was produced in 91% yield and 1% ee catalyzed by less sterically demanding catalyst 131 under similar reaction conditions. Accordingly, Shibata and co-workers described a phasetransfer catalysis mechanism.174 This process involves the reaction of TMAF with 1 to generate trifluoromethyl tetramethylammonium 132 with the release of stable Me3SiF and further to form chiral trifluoromethylammonium 133 and Me4NBr (TMAB) through the reaction of 132 with catalyst 120. Chiral ammonium 133 has the ability to regulate the trifluoromethylation of an aldehyde under asymmetric environments. In this case, achiral ammonium 132 is also reactive to aldehyde which furnishes racemic products (Scheme 22).174 In the synthesis and synthetic applications of β-amino-αtrifluoromethyl alcohols,175−178 alcohols 137 are prepared based on the phase-transfer catalysis mode from trifluoromethylation of α-imino ketones (derived from aryl glyoxals) in the presence of catalyst 135 and K2CO3 followed by reduction (Scheme 22).178 As the model reaction, 137a was obtained in 85% yield and 67% ee. In comparison, KF was less effective than K2CO3 and KOH and gave the lowest ee (Scheme 22).178 From a certain perspective, the catalytic enantioselective trifluoromethylation of aldehydes has not been entirely understood to date although some plausible explanations have been presented. 3.8.3. Aldehydes and Ketones: Combination Catalysis Mode. Feng and co-workers in 2007, the same year of the Shibata’s method for the in situ generation of quaternary ammonium fluorides from cinchona,161 disclosed that a combination of disodium (R)-binaphtholate and cinchona alkaloid-derived quaternary ammonium salts can afford the trifluoromethylation products of aromatic aldehydes in up to 71% ee by 10 mol % of catalyst loading (11 examples, 68−95% yields, 41−71% ee), while low ee values were obtained for electron-rich aromatic aldehydes (around 40% ee).179 The combinatorial catalytic systems were later examined in details by Chen and co-workers.180,181 More recently, they reported a general catalytic enantioselective trifluoromethylation of aromatic aldehydes using (IPr)CuF 138 (IPr: 1,3-bis(2′,6′-diiso-propylphenyl)imidazol-2-ylidene) and salt 139 as catalysts under argon atmosphere (Table 7).181 The reaction furnishes a wide range of aromatic aldehydes to the corresponding products (R)-140a−l with the highest levels of ee to date. In addition, this reaction has the advantage of lower loading of

based on the combination of the readily available chiral ammonium bromides of cinchona alkaloids with TMAF as extraneous fluoride (fluoride ion acting as the base to activate 1, also see Scheme 3)23 makes the operation simple and convenient.160−164 Efavirenz 116 is a non-nucleoside reverse transcriptase inhibitor (NNRTI) administered as a first-line treatment against HIV.165 Alternatively, in the elegant synthesis of 116 through the asymmetric addition of metalated acetylene to aryl trifluoromethyl ketone as a key step to give amino alcohol (S)115 and analogues,166−170 and an asymmetric autocatalytic zinc acetylide addition171 employing catalytic amounts of enantiomerically pure (S)-115 as part of a chiral cocktail have also been reported (Scheme 21).170 In addition, a number of valuable synthetic strategies for the enantioselective synthesis of trifluoromethyl carbinols, such as Rh/phebox-catalyzed (phebox: 2,6-bis(oxazolinyl)phenyl) alkynylation of α-ketoesters172 and aldol reactions with trifluoroacetophenones catalyzed by Singh’s catalyst ((2S)-N-[(1S)-1-hydroxydiphenylmethyl-3methylbutyl]-2-pyrrolidinecarboxamide)173 have been recently developed as well. In the area of catalytic enantioselective trifluoromethylation of carbonyl electrophiles with 1, the trifluoromethylation of aldehydes has been comparatively less explored.155−159 Recently, Shibata and co-workers examined the enantioselective trifluoromethylation of aryl aldehydes (Table 6)174 using their cinchona alkaloid/TMAF combination strategy.161,162,164 Using 697 | Chem. Rev. 2015, 115, 683−730

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

Scheme 22. Phase-Transfer Catalysis and a Proposed Mechanism

Table 7. Cooperative Catalytic Enantioselective Trifluoromethylation of Aromatic Aldehydes

asymmetric organocatalyst182 (probably via a synergistic catalytic mechanism)183 and in particular, applicable for 698




time (h)

yield (%)

ee (%)

1 2 3 4 5 6 7 8 9 10 11 12

140a 140b 140c 140d 140e 140f 140g 140h 140i 140j 140k 140l

2-naphthyl Ph 2-pyridyl 4-BrC6H4 3-ClC6H4 3-FC6H4 4-MeC6H4 3-MeOC6H4 2-MeOC6H4 6-MeO-2-naphthyl 3,4-O(CH2)OC6H3 4-EtSC6H4

1 2 2 2 2 2 1 1 1 2 2 2

90 80 89 81 83 87 88 89 88 83 92 85

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Scheme 23. Proposed Mechanism for Cooperative Catalysis

omethylation of azomethine imines 143 with 1 (Table 8)135,189 and the catalysts can be synthesized in one step from commercially available cinchonine.135,158,189,190 Whereas, under identical conditions (condition B) but catalyzed by 135/KOH, adduct 144a was obtained in only 11% ee.135 In the research of the trifluoromethylation of N-tosyl imines,128 Bernardi and co-workers described a single example of organocatalytic asymmetric trifluoromethylation of imine equivalent 149 using phase-transfer catalysis with phenoxides in the presence of cinchona-derived quaternary ammonium chloride 150 (Scheme 24).128,191 In a more recent report, Shibata and co-worker described an asymmetric aerobic epoxidation of β-trifluoromethyl-β,β-disubstituted enones by using catalyst 139 to give enantiomerically enriched trifluoromethylated epoxides with a tetrasubstituted carbon centers.192 A trifluoromethyl group can exert steric, electrostatic, and stereoelectronic effects on a reaction site, thereby affects its reactivity. The size of a trifluoromethyl group is close to an isopropyl group and steric parameters and electrostatic effects arising from the presence of fluorine atoms cause fluorinecontaining compounds likely to be poor hydrogen-bond acceptors.190−192 While catalytic enantioselective trifluoromethylation of carbonyl electrophiles and imines with 1 has gained recent success, the current chiral catalyst, mainly derived from cinchona bark has significant limitations in substrate scope. Therefore, combined with mechanistic studies, the creation of new catalysts for enantioselective trifluoromethylation is needed.193

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 optimical reaction conditions (Table 7), Chen and co-workers also found that (1) neither (IPr)CuF 138 (2 mol %) nor chiral salt 139 (2 mol %) for a reaction period of 4 h is effective to promote the addition of 1; (2) cocatalyzed by 139 (2 mol %) and (IPr)Cu(t-BuO) (2 mol %) and reacted for 4 h gives 140a with 45% ee (57% yield) while the combination of 139 (2 mol %) with (IPr)CuCl (2 mol %) for 4 h gives no product; (3) 139 (5 mol %) 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 in 84% yield with 67% ee. 1 8 1 These results 1 8 1 and others157,184−188 indicate that fluoride ion acts as an initiator for the generation of the active (IPr)CuCF3 species 138′ in the proposed catalytic cycle (Scheme 23). The catalytic cycle involves: (a) activation of aldehyde by 139 through hydrogen bond interaction and formation of 138′ through CF3 transfer between 138 and 1; (b) nucleophilic attack of 138′ on the activated aldehyde to generate intermediate 141 with the enhanced chiral communication between quaternary ammonium and substrate by the [Cu] moiety; and (c) activation of the in coming 1 by the chiral alkoxide in 141 to effectively arrange the transition state 142 allowing the release of the silyl ether product 140′ and regeneration of 141, simultaneously (Scheme 23). 3.8.4. Enantioselective Trifluoromethylation of Imines. In 2009, 15 years after the first trifluoromethylation of 1 on the CN bond of reactive azirines116 and asymmetric trifluoromethylation of 1 with aldehydes/ketones,155 the first catalytic asymmetric trifluoromethylation of a CN bond was disclosed by Shibata and co-workers.189 Prompted by their success in trifluoromethylation of carbonyl compounds using a catalyst system composed of readily available chiral bromide salts of cinchona alkaloids and TMAF (Scheme 20),160−164 they performed the enantioselective trifluoromethylation of azomethine imines 143 with 1 (Table 8).189 With the combination of 135/KOH or 145/KOH as the catalyst, the reaction of 143 with 1 can lead to trifluoromethylated adducts 144 with up to 98% ee under optimal conditions (Table 8, Condition A).189 More recently, Shibata and coworkers proved that Solkane365mfc (1,1,1,3,3-pentafluorobutane, CF3CH2CF2CH3) is an environmental benign alternative solvent for the enantioselective trifluoromethylation of 143 catalyzed by 146/KOH (Table 8, Condition B, up to 96% ee).135 The above results demonstrate that high chemical yields and enantioselectivities can be achieved from the trifluor-

3.9. Catalysts and Mechanisms Considerations

The X-ray diffraction structure of 1 confirms that the Si−CF3 bond is longer and weaker than the Si−CH3 bonds,37 which indicates the CF3 group can be preferentially transferred from 1 to an electrophile in the presence of suitable nucleophilic catalysts in general and leads to a better understanding on the mechanism. In the nucleophilic trifluoromethylation reactions using 1 as the trifluoromethyl transfer reagent, nucleophilic catalysts and/or initiators are essential, which have and will continue to reshape the applications of 1 as a versatile reagent in trifluoromethylation reactions since the first report by Prakash and co-workers using TBAF as an initiator.41 3.9.1. Oxygen Centered Nucleophilic Catalysts. Oxygen-containing nucleophiles are suitable catalysts in TMSCF3 chemistry due to the high bond strength as well as the kinetic lability of the silicon oxygen (Si−O) bond,1 which has been successfully used to define the generation of trifluoromethyl carbanion equivalent for fluoride ion initiated mechanism of nucleophilic trifluoromethylation of 1 with aldehydes and 699 | Chem. Rev. 2015, 115, 683−730

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Table 8. Enantioselective Trifluoromethylation of Azomethine Imines

ketones (Scheme 3).23 The breakthrough in oxygen centered activators was achieved by Mukaiyama and co-workers. They found that several oxygen-containing anions are suitable Lewis base-catalysts in perfluoroalkylation of (perfluoroalkyl)trimethylsilanes (TMSCF3, TMSC2F5, and TMSC3F7) with carbonyl compounds,194−196 for example, the use of lithium acetate as a catalyst in the trifluoromethylation of 1 with various aldehydes and ketones (Table 9, entry 1)194,196 and Ntosylaldimines (Table 9, entry 2)195,196 using DMF as the solvent under mild reaction conditions. It was also found that DMSO is also a good solvent for the lithium acetate catalyzed trifluoromethylation of 1 with 4-methoxybenzaldehyde (97% yield), however, THF, AcOEt, dichloromethane, toluene, and acetonitrile are not desirable solvents (no desired product at

all) and lithium trifluoroacetate, a weak Lewis base, did not promote the reaction.196 Prakash and co-workers carried out an extensive set of experiments reinforcing oxygen centered nucleophilic catalysts, which confirms that amine N-oxide (trimethylamine N-oxide), carbonate (K2CO3) and phosphate salts have efficient catalytic activity with the solvent, DMF, to enhance the reaction rate (Table 9, entries 3−5)197,198 3.9.2. Substrate-Directable Reaction. In addition to oxygen centered nucleophilic catalysts, other catalysts having different structures can also be used in the nucleophilic trifluoromethylation reactions, while, simple tertiary amines are not included. In 1997, Fuchikami and co-workers found that the reaction of β- and γ-amino ketones with 1 afforded 1,2adducts 153a and 153b in high yields, respectively, in the 700 | Chem. Rev. 2015, 115, 683−730

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Scheme 24. Asymmetric Trifluoromethylation of Imine Equivalent

Scheme 25. Substrate-Directable Reaction

pseudointramolecular process.151,197 Thus, the low yield of 1,2adduct 153c is possibly due to the less favorable sevenmembered intermediate (formed from 152c) than five- and sixmembered intermediates. These results suggest that the nucleophilicity of the CF3 group of 1 can be enhanced by the electron-donating character of bidentate 152a and 152b, which makes the reaction proceed in an substrate-directable mode (Scheme 25).199,200 Typical examples of such reactions involve transient interaction of a substrate functional group with the incoming reagent with the directing functionality (the amino group) being recovered intact in the final product. 3.9.3. DMSO and Molecular Sieves. The nucleophilic trifluoromethylation reactions of 1 with carbonyl compounds are 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

absence of external catalysts (Scheme 25).151 For comparison, only a trace amount of 153c was produced from δ-amino ketone 152c after 24 h of the reaction. These results indicate that a simple tertiary amine is not an efficient catalyst for the trifluoromethyl transfer of 1. Both cases of formation of TMSprotected trifluoromethylated alcohols 153a and 153b from bidentate 152a and 152b are likely driven by the high ability to form, for example, the corresponding pentacoordinated and hexacoordinated intermediates (or transition states) involving a

Table 9. Catalysts/Promoters for Nucleophilic Trifluoromethylations entry

catalysts (mol %)




1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

LiOAc (5%) LiOAc (10%) trimethylamine N-oxide (5−15%) phosphate salts (2−20%) K2CO3 (1−20%) DMSO with MS 4 Å (see Scheme 26) TBD 158 (5−10%, see Scheme 27) NHC 162 (0.5−1%, see Scheme 28) P(t-Bu)3 (10%) P(t-Bu)3 (100%) TTMPP (20%) TTMPP (5%) TTMPP (5%) TTMPP (20%) KF (30 mol %), TBAB (30 mol %) Ti(OiPr)4 (10%) TiF4 (10%) Cu(OAc)2 (10%)/dppe (10%) TBABF (TBAF·HF, 2 eq, see eq 3) TBAF (5−10%, see Scheme 3 and 4) NaOAc (1.5 eq, see Table 2) KOAc (0.8 eq, see Scheme 50) CsF (20%, see Scheme 9) TMAF (1 eq, see Figure 4) In-situ-generated HF (1 eq, see Scheme 12 and Table 3) TBABF (40%, see eq 3) DABCO (5%, see Scheme 17)

aldehydes and ketones N-tosylaldimines aldehydes and ketones aldehydes and ketones aldehydes and ketones aldehydes and ketones aldehydes and ketones enolizable/nonenolizable aldehydes and α-keto esters aldehydes and ketones sulfonylimines N-unactivated imines aldehydes ketones sulfonylimines isatoic anhydrides aldehydes aldehydes aldehydes aryl nitriles aldehydes and ketones 4-nitroisoxazoles 4-(trifluoromethanesulfonyl)isoxazoles Weinreb amides benzylideneaniline imines aryl nitriles MBH aducts


194, 196 195, 196 197 42, 197 197 201 203 204 212 212 213 213 213 213 144 48 48 48 47 41, 52 80 388 108 44 120 46 149

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with 1 can proceed very smoothly at room temperature for 10 min to 1 h to give the corresponding trifluoromethylated adducts in good to quantitative yields without a catalyst (16 examples for aldehydes, 81−100% yields; 1 example for electron-rich 4-(dimethylamino)benzaldehyde, 53% yield; 6 examples for ketones including chalcone, 82−100% yields; no reaction for benzyl acetoacetate having acidic C−H bonds; Table 9, entry 6).201 As a model reaction of benzaldehyde with 1 under similar reaction conditions, using DMF as the solvent affords the desired product in 86% yield, whereas, MeCN and CH2Cl2 are not effective. The desired product was obtained in 48% yield for a reaction time of 6 h without the addition of MS 4 Å. In sharp comparison, only gave 5% yield without the addition of MS 4 Å but 1.0 equiv of water, indicating the important role of MS to absorb the small amount of water present in the reaction system.202 A mechanism involving DMSO coordinating to the silicon atom of 1 to form a CF3 group nucleophilicity-enhancing species 156 was proposed (Scheme 26).201

Scheme 27. TBD-Catalyzed Trifluoromethylation

Scheme 26. Trifluoromethylation in DMSO in the Presence of MS 4 Å An alternative mechanism via a pentavalent silicon intermediate 165 accounts for the formation of intermediate 166 (Scheme 28)207 upon both of the nucleophilicity of the strong σdonating NHC150,204,208 and the catalytic activity of the oxygen centered nucleophilic intermediate 165 in the solvent, DMF.194−197 Similar to the strong σ-donating NHC,150,204,207,208 tritertbutylphosphine, a very strong electron-donating ligand, is also an efficient promoter for the trifluoromethylation of aldehydes, ketones, imides and imines in DMF (16 examples for aldehydes, 62−99% yields; 2 examples for ketones in 81 and 84% yield, respectively; 5 examples for sulfonylimines, 41−80% yields, Table 9, entries 9 and 10).209−213 For the reaction of 2naphthaldehyde, HMPA (hexamethylphosphoric triamide), DMA (dimethylacetamide) and DMSO are also efficient solvents, whereas, MeCN, CH2Cl2, THF and Et2O are not.209 Using TTMPP (tris(2,4,6-trimethoxyphenyl)phosphine, having 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 react with 1 to give the corresponding adducts (Table 9, entries 12−14).213 Interestingly the reaction of 1 with N-unactivated imines120−122 is also successful catalyzed by TTMPP (Table 9, entry 11).213 In comparison other phosphines such as triphenylphosphine, tributylphosphine and tritert-butylphosphine are not efficient.201 Considering the faster transfer of the CF3 group in the solvent, DMF,194−197 Golubev and co-workers performed the trifluoromethylation of 2H-3,1-benzoxazine-2,4(1H)-diones 167 (the isatoic anhydride derivatives) with 1 in the presence of a combination of KF and TBAB, which leads to the selective formation of N-substituted o-trifluoroacetylanilines 168 in good to high yield (Scheme 29, Table 9, entry 15).144 3.9.6. Lewis Acids. In 2006, Shibata, Toru and co-workers described the first Lewis acid-catalyzed trifluoromethylation reaction of aldehydes with 1. Catalysis by TiF4/DMF, Ti(OiPr)4/DMF or Cu(OAc)2/dppp/toluene under mild reaction conditions, the reaction gave satisfactory results (Table 9, entries 16−18, dppp: 1,2-bis(diphenylphosphino)-

3.9.4. Amidine Base. Matsukawa and co-workers recently described the trifluoromethylation of carbonyl compounds catalyzed by commercially available TBD 158 (TBD: 1,5,7triazabicyclo[4.4.0]dec-5-ene, an amidine base, Table 9, entry 7).203 A possible mechanism involves, first, the coordination of TBD 158 to the silicon of 1 to activate the Si−CF3 bond (159); where the hydrogen-bonding activation of the carbonyl compound to form intermediate 160; reaction of the activated silylated nucleophile and carbonyl compound can then readily react to produce the ionic adduct and silylated TBD 161 and finally, silylation between the ionic adduct and silylated 161 to furnish 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-heterocyclic carbene 162 (NHC) as an efficient catalyst for trifluoromethylation of both enolizable and nonenolizable aldehydes and αketo esters at room temperature requires only 0.5 mol % of 162 in the solvent, DMF (Table 9, entry 8). The reaction of benzaldehyde with 1 catalyzed by 162 (10 mol %) gives 100% conversion within 20 min in DMF or 60 min in THF. Use of toluene, methylene chloride or MTBE (methyl t-butyl ether) as solvents resulted in sluggish reactions.204 A possible mechanism involves coordination of the strong σ-donating 162 to the silicon atom of 1 activating the Si−CF3 bond, forming intermediate 163; reaction of 163 with a carbonyl compound to form intermediate 164 and further to give the silylated adduct along with the regeneration of 162 (Scheme 28).205,206 702 | Chem. Rev. 2015, 115, 683−730

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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

ethane).48 In general, these results are in accordance with the siliphilic nature of the counteranions of Lewis acids under the reaction conditions studied. In comparison, under identical reaction 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 trifluoromethylation reactions, including the catalytic enatioselective version of various imines with 1 mediated by hydrofluoric acid (generated in situ), deserves more attention because it is not only the

realization of the trifluoromethylation of imines to provide structurally diverse primary amines bearing a germinal CF3 group, but also a good selectivity to an imine instead of a carbonyl group (Scheme 13, eq 4 and Table 9, entry 25).43,120−122,126,127 Furthermore, the TBABF promoted double trifluoromethylation of aryl nitriles to give bistrifluomethylated amines (eq 3 and Table 9, entry 19) via a reactive trifluoromethyl imine intermediate provides the first example for the direct trifluoromethylation of nitriles.46 In this reaction, TBAF was ineffective under identical conditions, 703 | Chem. Rev. 2015, 115, 683−730

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

4.1. Preparation and Synthetic Applications of (Trifluoromethyl)trimethoxyborate

which may indicate that HF (from TBABF) plays a role for the activation of both nitriles and trifluoromethyl imines.43,121,122 In addition, the observations that the trifluoromethylation reactions of enolizable/nonenolizable aldehydes and α-keto esters 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 by KOAc (Scheme 50 and Table 9, entry 22),388 Weinreb amides catalyzed 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 (Scheme 17 and Table 9, entry 26)149 reflect some recent achievements mainly in the nucleophilic trifluoromethylation reactions using TMSCF3 1 as a versatile reagent depending on the activation of 1 and/or carbon electrophiles.

In the presence of KF, the reaction of TMSCF3 1 as anionic reagent with electrophilic trimethoxyborate gives potassium (trifluoromethyl)trimethoxyborate 170. Subsequent fluorination of 170 can generate (trifluoromethyl)trifluoroborate 171 in high yield (Scheme 30).214,215 Recently, 171 has been synthesized directly from CF3H in up to 66% yield (Scheme 30),24 however, the isolation of pure 170 from the reaction mixture is difficult due to decomposition of 170 under the reaction conditions (further reactions with residual KHMDS).24 Now, there is a convenient access to 170 in multigram quantities simply by stirring a mixture of 1, B(OMe)3, and KF in anhydrous THF over several hours.216,217 Compound 170 is a colorless, air-stable solid (each asymmetric unit cell contains three molecules of 170 with one coordinated THF confirmed by X-ray crystal structure) and can be left in an open vessel for several days (no signs of decomposition were observed by NMR spectroscopic analysis). The salt melts at 116−118 °C with decomposition. 216,217 Similarly, aryl(methoxy)(trifluoromethyl)boranes 172 have also been prepared (Scheme 30).218 Borate 172 is an air-stable solid and storable in a tightly closed flask at room temperature for months without noticeable changes.218 The synthetic applications of 172 have been studied, such as the reaction with α-diazocarbonyl com-

4. REACTIONS WITH B-, P-, AND S-BASED ELECTROPHILES Nucleophilic trifluoromethylation of hetero electrophiles is important to develop new methods for the preparation of important trifluoromethylating, trifluoromethylthiolating reagents,23,24,26,214−217 and Togni’s reagents, Umemoto’s reagents and related species as well as described in section 8 of this review. 704 | Chem. Rev. 2015, 115, 683−730

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pounds218 and in three-component reactions with ethyl diazoacetate and imines.219 Recently, reagent 170 has been taken as a new source of CF3 nucleophiles and successfully implemented the coppercatalyzed selective trifluoromethylation of aryl iodides216,217 and oxidative trifluoromethylation of arylboronates.220 As an analogue of organotrifluoroborates,221,222 recent studies show that 170 can also serve as a convenient reagent for nucleophilic trifluoromethylation of nonenolizable aldehydes and Ntosylimines leading to CF3-substituted alcohols and N-tosylamines in good yields (Scheme 30).223 Concerning the reaction mechanism, the transfer of the CF3-group of 170 to CO or CN bond can occur without either the intermediacy of a free CF3 anion or radical.223 Table 10 gives a comparison of the trifluoromethylation of nonenolizable aldehydes by using the “CF3−” derived from CF3H24,224 to 170.223 Accordingly, the trifluoromethylation of aldehydes using CF3H with P4-tBu as a sterically very demanding organosuperbase 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 Up to now, there have been no examples of the trifluoromethylation of enolizable aldehydes or ketones (containing a CHacidic 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 10 needs to be elucidated considering the influence of various factors,24,38,39,221,223−233 to prompt the use of CF3H as potentially, environmentally benign trifluoromethylating reagents.24,224−228,232

2,2,2-trifluoroethanethiol assisted by TBAB has been reported.245 On the other hand, the reaction of 1 with diethylaminosulfur trifluoride (DAST) derivatives and a primary amine to form trifluoromethanesulfanylamides/trifluoromethanesulfanamides (for example, the unstable trifluoromethyl difluorosulfur) has also been described by Billard, Langlois and co-workers (eq 8).246 Notably, using trifluoromethanesulfanylamides/trifluoromethanesulfanamides as easyto-handle equivalents of the trifluoromethanesulfanyl cation (CF3S+) has proven successful in direct trifluoromethylthiolation with alkenes and alkynes,247 electron-rich aromatic compounds,248,249 allylsilanes,250 and Grignard or lithium reagents.251,252

4.2. Reactions with Phosphorus-Based Electrophiles

5. TRIFLUOROMETHYLTRIMETHYLSILANE AS A DIFLUOROCARBENE PRECURSOR A “naked” trifluoromethyl anion is exceedingly unstable and promptly collapses at room temperature and even below to difluorocarbene (:CF2) and F− due to the destabilization of the CF3 anion by electrostatic repulsions between the anionic charge and the p-electron pairs of the fluorine atoms.19,24,55,56,224−226 In addition, difluorocarbene is involved in the reaction of 1 with TfOH (Scheme 5)56 and the preparation of difluoromethylated molecule 39 using hexafluoroacetone hydrate amidinate salt 35 as the difluorocarbene source under basic conditions (Scheme 8c).98 The decomposition of trifluoromethyl anion can be avoided by deprotonating CF3H at −20 to −40 °C in DMF which instantly adds the resultant CF3 anion to give a hemiaminolate adduct [Me2NCH(O)CF3]−. Although this hemiaminolate adduct still quickly decomposes at room temperature, it is stable at −20 °C for at least a few hours.224 It has been demonstrated that the presence of K+ as the countercation of the base and a low temperature (−85 °C) of the reaction appear to be rather important in the preparation of “CF3−” (see Scheme 2 and description thereof).24,38,39

The use of 1 as a convenient CF3 source to generate trifluoromethyl-containing phosphines was first described by Michalski’s and Hoge’s groups in 2001 through fluoride ion catalyzed (CsF (10 mol%) or TBAF in THF at room temperature) nucleophilic displacement of F− from RR′P−F compounds to give RR′P−CF3 in high to excellent yields.234,235 Based on the similar procedure, a series of CF3-derivatives of Josiphos’ ligands (one of the most successful ligand classes used in asymmetric catalysis)236 have been prepared.237 4.3. Reactions with Sulfur-Based Electrophiles

Trifluoromethylation of sulfonyl fluorides with 1 was explored by Yagupolski and colleagues in 1990. For example catalyzed by TASF (tris(dimethylamino)sulfonium difluorotrimethyl siliconate), the reaction of benzenesulfonyl fluoride with 1 gives (trifluoromethylsulfonyl)benzene in excellent yield under mild conditions (eq 5).238 Utilizing this thiophilic nucleophilic reaction,239,240 S-trifluoromethyl ketene dithioacetals (and analogues) are prepared by Portella and co-workers (eq 6).64,239 This reaction has been successfully used for the transformation of nucleophilic trifluoromethylating species into electrophilic one,241,242 such as the synthesis of N-protected trifluoromethyl-substituted sulfoximines (eq 7).243 A recent paper24 by Prakash and co-workers summarized the synthesis of CF3S-containing compounds based on 1 and CF3H. The direct trifluoromethylation of elemental sulfur using CF3H and subsequent oxidation would facilitate a straightforward synthesis of trifluoromethanesulfonic acid (CF3SO3H),24 a widely used Brønsted superacid and large-volume trifluoromethylated product.244 The reaction of 1 with aromatic thiones to deliver a mixture of (trifluoromethylthio)diarylmethane (major) and 1,1-diaryl-

5.1. [2 + 1] Cycloaddition

Developing new fluorination methods is of great interest in areas such as pharmaceuticals, agrochemicals and materials. In 2011, Hu and co-workers found that treatment of phenylacetylene 181 and TMSCF2Cl 182-Cl catalyzed by n-Bu4NCl in toluene in a pressure tube at 110 °C gave (3,3difluorocycloprop-1-enyl)benzene 183 in high yield (Table 11).253 This reaction is strongly affected by reaction conditions, including initiator/catalyst and/or its quantities, counteranion 705 | Chem. Rev. 2015, 115, 683−730

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the presence of excess amount of NaI (2.2 equiv) in THF at 110 °C in a pressure tube and furnished a one-pot sequential combination of trifluoromethylation and [2 + 1] cycloaddition reaction of 1 with 4′-(phenylethynyl)-acetophenone 5 containing both a carbonyl group and a triple bond (Scheme 4).52

Table 11. [2 + 1] Cycloaddition Reactions Involving Difluorocarbene

5.2. Direct α-Difluoromethylation of Lithium Enolates


Me3SiCF2X (eq)


182-Cl (1.5)


182-Cl (1.5)

THF or toluene THF

3 4 5

182-Cl (1.5) 182-Cl (1.5) 182-Cl (1.5)



182-Cl (1.5)



182-Br (1.5)





1 (X = F, 1.5) 182-Cl (1.0)


182-Cl (2.0)



182-Cl (2.0)




initiator (mol %)a

temp/ °C

yield of 183 (%)




n-Bu4NF (110) n-Bu4NF (2) NaCl n-Bu4NCl (2) n-Bu4NCl (2) n-Bu4NCl (2) n-Bu4NCl (2) n-Bu4NCl (2) n-Bu4NCl (2) n-Bu4NCl (2)



110 110 110

39 0 71













Difluorocarbene is a relatively stabilized carbene species (with a singlet ground state) owing to the interaction of the lone pairs of electrons on fluorine atoms with the carbene center. This is likely the reason why difluorocarbene does not react well with electron-poor alkenes.52,206,253−255 Recently, Mikami and coworkers described the direct α-difluoromethylation of lithium enolates of lactams 188 using an umpolung form of fluoroform as a difluoromethyl carbocation equivalent (“CHF2+”) leads to an all-carbon quaternary center, for example, the synthesis of αdifluoromethyl product 189a from 188a (Scheme 32).232 Scheme 32. α-Difluoromethylation of Lithium Enolates Using CF3H

or cation of the initiator/catalyst, solvent, temperature and/or even pressure (Table 11, also see Scheme 4).52,253 Interestingly, when TMSCF3 1 was used in place of 182-Cl, TMSCF3 1 was recovered,253 indicating Cl− can not be used to activate 1 at all under identical conditions (Table 11, entry 8). A mechanism for the formation of difluorocarbene and further [2 + 1] cycloaddition with electron-rich alkynes, for example 181, involving reaction of Cl− with 182-Cl to release Me3SiCl via pentacoordinated silicon species 186 to form chlorodifluoromethyl anion 187 as the source of difluorocarbene 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 coworkers described the generation of difluorocarbene from 1 in

A possible mechanism combined with DFT calculations involving formation of homodimer intermediate 190 from lithium enolate leading to mixed aggregate 191 and further to open dimer, the eight-membered intermediate 192 was described (Scheme 32).232 The mechanism involves activation of 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 the lithium cation and subsequent C−C bond formation. In the case of acyclic substrates, the difluoromethylation also proceeded with the 2-phenylpropanates to form α-difluoromethyl products 193. The difluoromethylation reaction has also been successfully applied to the synthesis of the analogue 194 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, only the lithium enolate (from LiHMDS) gives 189a because of the

Scheme 31. Generation and Reactions of Difluorocarbene Derived from Me3SiCF2Cl

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strong Li−F interaction,2−5 and (2) under identical conditions no 189a is produced with lithium diisopropylamide (LDA) as the base due to its less bulky, thereby leading to more coordinated system. In addition, a detailed study on the reaction of α-benzyl-δ-lactam 188b with LiHMDS (Table 12) showed a significant effect of the amount of LiHMDS on the difluoromethylation of the lithium enolate.232

Scheme 33. Reaction of Difluorocarbene with Acetylene Ethers

Table 12. Effects of the Amount of LHMDSa


equiv of LHMDS

1 2 3 4 5

1 2 3 2 3

temp/°C −78 −78 −78 rt rt

time (h)

yield of 189b (%)

14 14 14 6 6

17 45 25 64 24

a 188b (0.1 mmol) was added to THF solution of LiHMDS at −78 °C under an argon atmosphere. The mixture was stirred at 0 °C for 30 min, CF3H (5 equiv) was added at −95 °C, warmed to the temperature indicated, and reacted for 6−14 h.

The difluorocarbene intermediate is not involved in the above reaction (Scheme 32).232 It is noteworthy that fluoroform can now be used as a difluorocarbene source in a process for the conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives under mild basic conditions.58 5.3. Reaction of Difluorocarbene with Acetylene Ethers

Scheme 34. Proposed Mechanism for LiI Mediated Formation of Difluorocarbene

Significantly different from the [2 + 1] cycloaddition of difluorocarbene (derived from 1) to 4′-(phenylethynyl)acetophenone (Scheme 4),52 O’Hagan and co-workers found that catalyzed by NaI the reaction of 1 with acetylene ethers 195, 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 (Scheme 33).53 The reaction is proposed to involve a difluorocarbene intermediate, providing further evidence of the versatility of 1 in organic synthesis.52,53 When the reaction was carried out in the presence of an equimolar amount of TEMPO ((2,2,6,6tetramethyl-piperidin-1-yl)oxyl) as a radical scavenger, the 5and 7-membered ring products 196 and 197 were not observed, supporting radical pathways.53 However, according to the proposed mechanisms involving [2 + 1] intermediate 198 in both cases for the formation of products 196 and 197,53 the difluorocarbene may be generated in a similar fashion as described by Prakash and co-workers in their research on Ndifluoromethylation of imidazoles and benzimidazoles (Scheme 34).256 It was found that no desired product can be observed when KF or NaF instead of LiI was used as the promotor. Accordingly, Prakash described that Li+ cation plays a key role in controlling the availability of fluoride in the reaction and postulated that the generation of insoluble LiF during the course of the reaction would help to push the carbene generation reaction forward, thereby resulting in an increased yield of the difluoromethylated product although a detailed mechanism has not yet been elucidated.52,53,256,257

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

studies show that the difluoromethylation proceeds through the initial formation of difluorocarbene and subsequent nucleophilic addition of the phenolate or thiophenolate anion to difluorocarbene.57 In addition, TMSCF3 1 has been successfully transformed into (difluoromethyl)trimethylsilane (TMSCF2H) simply by reduction with sodium borohydride under mild reaction conditions.258 This method can be readily scaled up to a 10 g scale in 70% yield using dry diglyme as the solvent, which 707 | Chem. Rev. 2015, 115, 683−730

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MBH adducts has been recently developed (see Schemes 17 and 18),150,151,154 there is a common need for the understanding of nucleophilic trifluoromethylation reactions of allylic halides to introduce Csp3−CF3 bonds. In 1989, Chen and Wu found that methyl fluorosulphonyldifluoroacetate (FSO2CF2CO2Me) readily eliminates CO2 and SO2 in the presence of catalytic amount of CuI (12 mol %) in DMF at 60−80 °C to produce CuCF3 species that can be used for allylic trifluoromethylation of allyl bromide and allyl iodide (in 70% and 74% yields respectively).262 In another case, however, the allylic 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 = Nmethylpyrollidone) at 80 °C for 24 h gives the desired product only in low yield (23%).263 In 2012, Nishibayashi and co-workers reported an efficient nucleophilic trifluoromethylation of allylic halides with 1 catalyzed by CuTc (CuTc: (thiophene-2-carbonyloxy)copper) (Table 13).264 In the reaction, the nature of solvent is one of the most important factors that affect the trifluoromethylation. Treatment of allylic halide 205a with 1 (1.5 equiv) in the presence of a catalytic amount of CuI (5 mol %) and KF (1.5 equiv) in THF at 60 °C for 20 h affords the allylic trifluoromethylation product 206a in 67% yield. However, the use 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

enables TMSCF2H readily to be used in difluoromethylation reactions.259,260 In comparison, lower yield of TMSCF2H was obtained with THF (10%) or DMSO (20%) as a cosolvent and no the desired TMSCF2H was observed in the solvent, DMSO. A mechanism involving an anion mobility of fluorine atom in CF3-group of 1 as the driving force has been proposed (Scheme 35).258 Scheme 35. Preparation of (Difluoromethyl)trimethylsilane

6. TRIFLUOROMETHYLATION INVOLVING TRANSITION METAL COMPLEXES Although trifluoromethyl lithium and magnesium are recognized as being too unstable and difficult to prepare because of facile α-fluoride (M−F) elimination,5 formation of trifluoromethyl transition-metal derivatives has drawn particular attention since TMS−CF3 species has been recognized as a useful tool for introducing a trifluoromethyl group into organic halides 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 Table 13. Cu-Catalyzed Trifluoromethylation of Allylic Halides

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The reaction occurs regioselectively at the α-position of allylic halide 205a, no 206a′ from γ-trifluoromethylation is observed.264 The presence of the CC double bond beta to the halide group is necessary because no trifluoromethylated product 208 was observed when using 1-bromopropane 207 as the substrate. It has also been observed that (1) the reaction of (Z)-cinnamyl bromide 205a giving (E)-206a in 66% yield along with only a trace amount of (Z)-206a (Table 13); (2) 2 mol % of CuTc promotes the isomerization of (Z)-205a into (E)-205a in a ratio of 25:75 after 2 h and 1:99 after 20 h, respectively (in the absence of CuTc, the ratio of (Z)-205a/(E)-205a reaching to 83:17 for 20 h) and (3) no isomerization of (Z)-206a into (E)-206a occurs under similar reaction conditions (Table 13).264 The authors believed that these results indicate that CuTc mediates the isomerization of (Z)-205a into (E)-205a, which then undergoes trifluoromethylation to form (E)-206a via an allylcopper species derived from complexation of copper with 205 as a key intermediate.264 Therefore, the initial step is the formation of CF3CuI from CuI and 1 activated by fluoride ion.265,266 Oxidative addition of CF3CuI to allylic halide 205 can result in the formation of an allylcopper(III) species.267,268 Finally, reductive elimination of an allylcopper(III) species gives trifluoromethylated product (E)-206 and regenerates CuI,267,268 although a detailed mechanism is yet to be established.227,269

position and has become the broadly applicable reagents for trifluoromethylations and perfluoroalkylations of aryl iodides, bromides,278 and arylboronate esters.279 On the other hand, focusing on the efficient use of CHF3 as the most intrinsic source of a trifluoromethyl group,24,40,224,232 Grushin and co-workers recently reported the first direct cupration of fluoroform.225 The reaction employs inexpensive reagents (CuCl and tBuOK) and occurs at ambient temperature to furnish CuCF3 209 in up to over 90% yield (Scheme 37). Decomposition of 209 is confirmed by monitoring 19F NMR, which can be avoided by adding Et3N(HF)3 to the CuCF3 solution (stable solution of the CuCF3 reagent).225 Scheme 37. Direct Cupration of Fluoroform

Interestingly, the cupration reaction of fluoroform exhibits no signs of difluorocarbene intermediacy if performed in DMF.225 Importantly, using fluoroform-derived CuCF3,237 Grushin and co-workers have developed the effcient trifluoromethylation of aryl iodides and bromides225 and trifluoromethylation of αhaloketones in DMF under mild reaction conditions (Table 14).227 In addition, in the research for the trifluoromethylation of aryl boronic acids,138,281 Grushin’s method of using CuCF3 as the trifluoromethylating reagent has the advantages of occurring at room temperature (and even below) and 1 atm of air (molecular oxygen) as the oxidant to give the corresponding benzotrifluorides in excellent yields (up to 99%) with high selectivity.281 As a nucleophilic synthon, 1 has been widely used to the nucleophilic trifluoromethylation reactions including nucleophilic addition to the carbonyl group of enolizable/nonenolizable aldehydes and ketones and other carbon electrophiles (Table 9). Different from the above reactions, in which the preferred nucleophilic attack of the “CF3−” anion occurs preferientially at the carbonyl group (hard−hard match), Grushin and co-workers found that the reaction of αhaloketones 210 with stabilized CuCF3 209 in DMF proceeds smoothly to furnish the corresponding 2,2,2-trifluoroethylketones 211 in up to 99% yield at room temperature, in which the nucleophilic trifluoromethylation occurs selectively at the alkyl halide carbon (Table 14).227 The above method not only exhibits high functional group tolerance and gives high product yield in general, but has potential for larger scale operations with the use of CuCF3 (produced directly from fluoroform) and α-haloketones as the readily available, easily accessible and inexpensive substrates without any premodification. An alternative procedure uses enolate and silyl enol ether substrates in radical or electrophilic α-trifluoromethylation with a strong base, or styrenes in radical trifluoromethylation with costly [Ph2SCF3]+ OTf−, giving αtrifluoromethyl-acetophenones in low yields (20−40%).282,283 A possible mechanism, for the nucleophilic trifluoromethylation of the C−X bond of α-haloketones, through coordination of the Cu-atom to the carbonyl and halide facilitating substitution with the CF3 group, as in the Cu-catalyzed cross-

6.2. Trifluoromethylation of α-Haloketones with CuCF3

In recent years, copper-catalyzed/mediated trifluororomethylation reactions have made significant progress, for example, in aromatic trifluoromethylation and related reactions.19,25,264,270−280 The first report concerning the in situ generation 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-defined trifluoromethyl copper compounds as trifluoromethyl sources have been established, including N-heterocyclic carbene complexes of copper [(NHC)CuCF3],275 phosphine- or phenanthroline-stabilized copper reagents [(Ph3P)3CuCF3],276 and [(phen)CuCF3]278,279 derived from Me3SiCF3 1. These CuCF3 compounds have been successfully applied to the trifluoromethylation of aryl iodides/bromides and arylboronate esters. Of these compounds, (phen)CuCF3 and (Ph3P)3CuCF3 are now commercially available. (Ph3P)3CuCF3 has also been used for the trifluoromethylation of propargylic chlorides/ bromides and trifluoroacetates to give the corresponding branched allenylic or propargylic products, depending on the substrates and reaction conditions employed.21 The trifluoromethylcopper complex (phen)CuCF3 can be prepared in excellent yield by the reaction of [CuOtBu]4 with 1,10-phenanthroline, followed by the addition of TMSCF3 1 under mild conditions (Scheme 36).278 This method is also applicable 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 under nitrogen atmosphere for over one month without decomScheme 36. Preparation of (phen)CuCF3

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Table 14. Trifluoromethylation of α-Haloketones with CuCF3a

Note: Nonaromatic substrates and α-chloroketones were trifluoromethylated with 1.5 equiv of CuCF3. Isolated yields, parentheses.


coupling of alkylzinc reagents with α-chloroketones,284 has been proposed but not discussed in detail.227 In addition, it needs to be mentioned that a series of copper(I) trifluoromethyl thiolate complexes have also been successfully synthesized more recently by Weng, Huang and co-workers from the reaction of CuF2 with Me3SiCF3 1 and S8.285 These well-defined complexes, as useful trifluoromethylthiolating reagents,286−288 are air-stable, which greatly facilitate their use and provide a model for the understanding of the trifluoromethylthiolation process.285 Very recently Lishchynskyi and Grushin found that like CHF3 (Scheme 37)225 but unlike other higher H-perfluoroalkanes, C2F5H undergoes smooth cupration with [K(DMF)][(t-BuO)2Cu] at room temperature and atmospheric pressure to 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 toward electrophiles than its CF3 analogue.226


F NMR yield in

Scheme 38. Cu-Catalyzed Trifluoromethylation of Propargylic Halides

amounts of copper metal or copper salts are required to obtain the 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 a complete loss of optical purity, indicating the reaction does not proceed via an anti-SN2′ pathway (Scheme 38).289 In recent years, Cu-mediated trifluoromethylations have been well established, which considerably enlarge the range of metalcatalyzed/mediated trifluoromethylation and perfluoromethylation and their practical applications.291,292

6.3. Cu-Catalyzed Trifluoromethylation of Propargylic Halides

As an extension of the nucleophilic trifluoromethylation of allylic halides with 1 catalyzed by CuTc (Table 13),264 Nishibayashi and co-workers found that reactions of propargylic halides with 1 in the presence of a catalytic amount of CuTc (5 mol%) and 1.5 equiv of KF can give the corresponding trifluoromethylated products in good to high yields with a high selectivity.289 Reactions of primary propargylic chlorides occur regioselectively at the α-position to afford propargylic trifluoromethylated products, but trifluoromethylated allenes can be obtained from reactions of secondary propargylic chlorides (Scheme 38).289 Using other methods, stoichiometric

7. SYNTHESIS OF BENZOTRIFLUORIDES BASED ON PRE-FUNCTIONALIZATION Different from the numerous known synthetic methods that rely on substitution of a preexisting aromatic ring, Stahl and coworkers succeeded in palladium catalyzed aerobic dehydrogen710 | Chem. Rev. 2015, 115, 683−730

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Scheme 39. Synthesis of Trifluoromethy1ated Arenes from p-Quinones

(Scheme 39).296 Acid 217 has been screened for pharmacological activity and exhibited analgesic effects.296 In addition, Stahly’s method has also been extended to the synthesis of H2[BiphenCF3] 220 (H2[BiphenCF3]: rac-3,3′-di-tert-butyl5,5′-bistrifluoromethyl-6,6′-dimethyl-1,1′-biphenyl-2,2′-diol, Scheme 39)297 and 4-alkyl(trifluoromethyl)benzenes bearing a substituent (MeO, Cl) either on the benzene ring or on the benzylic position (Scheme 40).298,299 It was also found that a four-component system, CHF3/N(TMS)3/catalytic F−/catalytic DMF, behaves like the reagent 1 to react with nonenolizable carbonyl compounds, for example 4,4-dimethoxycyclohexa-2,5-dienone, lead to the corresponding 1,2adducts.298 More recently, Hu and co-workers revealed an unprecedented silver-mediated vicinal trifluoromethylation−iodination of arynes generated from 2-trimethylsilyl-phenyl triflates 231, which can introduce CF3 and I groups onto aromatic rings in a single step to give o-trifluoromethyl iodoarenes 234 (Table 15), using excess of [AgCF3], CsF, TMP (2,2,6,6-tetramethylpiperidine), and 1-iodophenylacetylene as iodine source.300 Similar to α-trifluoromethylated adducts 213 (Scheme 39),42 4-(trifluoromethyl)-4-(trimethylsilyloxy)cyclohexa-2,5-dienone derivatives 235 are readily prepared in a considerably high yield

ative conversion of substituted cyclohexanones and cyclohexenones to phenols through postaromatization.293 Such method significantly broadens the source of aromatic feedstock for the facile access to cyclohexanone/cyclohexenone derivatives by prefunctionalization of the nonaromatic precursors.293,294 In 1989, Stahly and Bell described the monotrifluoromethylation of p-quinone derivatives 212 with Et3SiCF3 to give αtrifluoromethylated adducts 213.42 Further treatment of 213 (or the corresponding alcohols) by dissolving metal reduction and 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 synthesis of trifluoromethy1ated arenes based on nucleophilic trifluoromethylation of carbonyl compounds.42,295 Later, using the readily available 4-(triethylsilyloxy)-4-(trifluoromethyl)cyclohexa-2,5-dienone 213a as substrate, Stahly and Jackson described the synthesis of 2-[(trifluoromethyl)phenyl]propionic acid 217 by a three-step reaction of 213a via olefination with the Horner-Emmons reagent (methyl 2(dimethylphosphono)acetate) followed by reduction (to give ethyl 2-(4-(trifluoromethyl)phenyl)propanoate) and hydrolysis 711 | Chem. Rev. 2015, 115, 683−730

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

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

by reacting p-quinone derivatives301 with 1 under mild reaction

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

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).302 712 | Chem. Rev. 2015, 115, 683−730

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

postaromatization293 in the ortho and para positions of the CF3 group of 235 by the meta-double functionalization strategy (Scheme 41).302 The reaction proceeds in a single operation under mild reaction conditions to give various trifluoromethylated arenes 237/237′ and 238, sharing important structure features including phenylacetic acids306,307 and aryl sulfides.308−311 Since the CF3 group is a ortho- and para-directing deactivator in electrophilic aromatic substitution reactions, the above method is potentially important for the synthesis of

otherwise hardly accessible highly functionalized trifluoromethylated 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 6trifluoromethylindoline in high yield based on thermal hexadehydro Diels−Alder reaction312 and subsequent trapping 713 | Chem. Rev. 2015, 115, 683−730

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including soft nucleophiles such as thiols, phenolates (Ctrifluoromethylation), phosphines and active methylenes. In addition, O-trifluoromethylation of aliphatic alcohols with 241a in the presence of catalytic amount of a zinc(II) salt as an activator and N-trifluoromethylation of nitriles with 241a via a Ritter-type reaction with Brønsted acids as activators under transition metal-free conditions are also successful.28,318 Recently, using 241a (Togni’s reagent II), a number of elegant transition metal-catalyzed trifluoromethylations have been reported, including terminal olefins (Cu-catalyzed),266,329 (hetero)arenes (catalyzed by Re complex),330 CuOAc-catalyzed direct C2-trifluoromethylation of indoles,331 Fe(II)-catalyzed trifluoromethylation of potassium vinyltrifluoroborates,332 and [(MeCN)4Cu]PF6-catalyzed olefinic trifluoromethylation of enamides.333 As an application of 241b (Togni’s reagent I,316 for its one-pot synthesis, see eq 11),317 the Cu-catalyzed

Scheme 41. meta-Double Functionalization Strategy

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

8. ELECTROPHILIC AND OXIDATIVE TRIFLUOROMETHYLATION REACTIONS Methods for the direct introduction of the trifluoromethyl group are available through radical, nucleophilic, or electrophilic approaches.2−5,12,16,23 In nucleophilic trifluoromethylation, the active species is the “CF3 anion”, which has been revolutionized since the discovery of trifluoromethyltrimethylsilane 1 by Ruppert in 1984,29 and subsequent application by Prakash41 as described in sections 3, 4, 6 and 8 of this review. In contrast, the electrophilic trifluoromethylation involving the direct transfer of a trifluoromethyl group from 1 to an electrophile by potentially practical oxidative process remains a challenge.

trifluoromethylation of arylboronate esters has also been described.334 These results indicate that activation of Togni’s reagents 241a and 241b is generally necessary. It has been observed that the C2-trifluoromethylation products are easily produced in the case of the reaction of 241a with electron-rich indoles.330,331 In addition, for the reactions with a series of electron-rich nitrogen heterocycles, the trifluoromethyl group of 241b is principally incorporated in the position adjacent to nitrogen.318 Although O-trifluoromethylation of aliphatic alcohols (with primary or secondary alcohols as substrates or solvents) with 241a in the presence of catalytic amount of Zn(NTf2)2 (zinc bis(trifluoromethylsulfonyl)imide) is efficient,318,335 the Otrifluoromethylation of phenols remains a problem. A detailed research by Togni and co-workers for the reaction of 241a with 2,4,6-trimethylphenol 246 (thus speculating that the “occupied” ortho and para positions could favor reaction at the oxygen atom) has been attempted. However, the results show that the desired product, 1,3,5-trimethyl-2-(trifluoromethoxy)benzene 247, can be detected but only as a minor product and the cyclohexadienones 248, 249, and 250 arising from the oxidation/trifluoromethylation of the starting phenol constitute the major products (Scheme 41).327 Therefore, the main products are generated by carbon instead of oxygen functionalization. Accordingly, as noted by Umemoto,314 the trifluoromethylation ability of a reagent toward hard nucleophiles, such as the oxygen atom of a phenolate, strongly depends on the hardness of the atom initially bearing the CF3 unit. Reagent 241a can therefore be regarded as a soft reagent with a particular affinity for soft nucleophiles such as thiols and primary or secondary phosphines. From a mechanistic point of view, the observations are still inconclusive as to the exact course of the trifluoromethyl transfer from 241a to phenols. The intermediate formation of phenoxy-λ3-iodane species that would undergo nucleophilic attack by a transient trifluoromethyl anion is probable and would reflect the general pattern of reactivity of a number of known hypervalent iodine compounds. Equally, a SET (single electron transfer) pathway not involving free radicals cannot be excluded (Scheme 42). However, for both scenarios, solid

8.1. Shelf-Stable Electrophilic Trifluoromethylating Reagents

Nowadays, since the initial discovery of the first electrophilic trifluoromethylating species by Yagupolskii and co-workers in 1984,314 several important electrophilic trifluoromethylating reagents (Figure 6) developed by Umemoto (239 in 1990 and

Figure 6. Electrophilic trifluoromethylating reagents.

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

Among electrophilic trifluoromethylating reagents, 1-(trifluoromethyl)-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-benziodoxole 241b (Togni’s reagent I) have proved to be efficient in electrophilic trifluoromethylation for a variety of nucleophiles 714 | Chem. Rev. 2015, 115, 683−730

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

experimental evidence is still lacking.327 Several recent reports involve the formation of λ3-iodane species and aryl trifluoromethyl iodonium salt from Togni’s reagents, for example, in the trifluoromethylation of alcohols335 and enantioselectivetrifluoromethylation of aldehydes.336 However, to date, attempts for the direct preparation of an aryl trifluoromethyl iodonium salt have failed because of a lack of stability of this species.314,337−341 Togni and co-workers have provided a plausible hypothesis from their zinc-mediated trifluoromethylation of alcohols based on the postulated formation of trifluoromethyl iodonium salts (Scheme 43).335 In this mechanism, reaction of 241a with the zinc salt (Zn(NTf2)2) forms the zinc dicarboxylate complex 252, corresponding to the iodonium species as a 1:2 adduct (detected by ESI-MS methods). The species 252 then reacts with an alcohol to form intermediate 253, resulting from the addition of an alcoholate to an iodonium moiety. A subsequent reductive elimination step is responsible for the formation of trifluoromethyl ether 254 and species 255. Alternatively, the iodonium species 252 might undergo an intermolecular attack by the nucleophile leading to product formation via an SN2type process, enhanced by the exceedingly large nucleofugality

of phenyliodonium derivatives. A 19F NMR measurement of the reaction mixture of 241a, p-nitrobenzyl alcohol, and Zn(NTf2)2 has provided important mechanistic insights, by showing a shift of the CF3 signal of the hypervalent iodine species of 241a from δ = −33.0 to −26.9 ppm after a few minutes at room temperature and thus indicating the formation of a relatively stable intermediate which subsequently decayds under reaction conditions. On the other hand, according to the major peak (976) in the ESI-MS spectrum, Togni and co-workers assign the structure of a zinc(II) dicarboxylate complex to the cation, [Zn(241a)2(NTf2)]+, which reveals the very nature of the activation process of 241a by Zn2+ and consists of the cleavage of 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 thin platelets, corresponding to the bis(triflimide) salt of the dicationic octahedral complex [Zn(241a)2(4NO2C6H4CH2OH)2(H2O)2]2+ has also been obtained through a systematic variation of the crystallization conditions and analyzed by X-ray diffraction, which may be used to interpret the formation of a trifluoromethyl iodonium species.335 715 | Chem. Rev. 2015, 115, 683−730

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Indeed, the preparation and the use of a simple hypervalent iodo compound as a source of electrophilic trifluoromethylating species has long been a challenge to organic chemists since an earlier attempt, over 30 years ago.314,323,337−341 However, our recent experiments using in situ generated trifluoromethylphenyliodonium acetate 258a (Figure 7, R = H) has arguably permitted the trifluoromethylation at α-C of ketene dithioacetals 259/236. Thus, 3-(1,3-dithiolan-2-ylidene)-4,4,4-trifluorobutan-2-one 260a was prepared in high yield by adding 1 to a premixed mixture of 259a, PhI(OAc)2 and KF in MeCN under nitrogen atmosphere and then stirred at room temperature for 0.5 h (Table 17),342 providing a very simple access to trifluoromethyl ketene dithioacetals.343−345

Scheme 43. Mechanistic Hypothesis for Zn-Mediated Electrophilic Trifluoromethylation of Alcohols

Table 17. α-Trifluoromethylation of Ketene Dithioacetalsa

entry 255/236

8.3. Acyclic Hypervalent Iodine(III) Electrophilic Trifluoromethylating Species and Oxidative Trifluoromethylation

As early as in 1978, the perfluoroalkylating reagents 256 and 257 have been prepared by Yagupolskii and co-workers via, for example, the condensation of bis(trifluoroacetoxy)iodoperfluoroalkanes with toluene in trifluoroacetic acid for 3 days (Figure 7).314,337 While iodonium salts including p-

1 2 3 4

259a 259b 259c 259d



6 7 8 9 10 11 12 13

259f 259g 259h 236g 236k 259i 259j 259m

R′ COMe COEt COPh COPh(4Cl) COPh(4Me) CO2Et CN COMe COMe COMe 4-ClPh 4-FPh 4-MeOPh


time (h)


isolated yield (%)

(CH2)2 (CH2)2 (CH2)2 (CH2)2

0.5 0.5 5.0 0.5

260a 260b 260c 260d

88 85 74 70





(CH2)2 (CH2)2 (CH2)3 Me Et Et Et Et

2.0 2.0 0.5 0.5 0.5 0.5 0.5 0.5

260f 260g 260h 260i 260j 260k 260l 260m

75 68 79 50 64 81 71 80


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

Similar to Togni’s mechanism (Scheme 43, intermediater 253), the formation of 260 may involve initially, the formation of PhI(CF3)(OAc) 258a from the reaction of PhI(OAc)2 with 1 in the presence of KF as an activator and 258a quickly transforms to phenyl(trifluoromethyl)iodonium 261 (Scheme 44). Wherein, the necleophilic attack of the α-C of a ketene dithioacetal 259 (or 236) at iodonium 261 leads to thionium Scheme 44. Mechanistic for α-Trifluoromethylation of Ketene Dithioacetals

Figure 7. Acyclic hypervalent iodine(III) electrophilic perfluoromethylating species.

tolylperfluoroalkyliodonium chlorides 256 and perfluoroalkylphenyliodonium triflates 257 have been successfully applied as the electrophilic perfluoroalkylating reagents,314,337−340 their trifluoromethyl analogues (Figure 7, for example, 257: when RF = CF3) have not yet been successfully prepared since the corresponding synthetic intermediates (CF3I(OCOCF3)2, CF3IF2, and CF3IO) have low stability compared to those having RF groups with two or more carbons.314,337−341 716 | Chem. Rev. 2015, 115, 683−730

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methylindole 264g as the model gives products 268a and 265g in less than 20% yield and favors C2- instead of C3trifluoromethylation (eq 12).350 Further optimization studies using N-methyl-3-methylindole 270 as a model leads to the synthesis of a series of 2-trifluoromethylindoles 271 (Table 18, Condition A),350 similar to the report by Liu and co-workers catalyzed by Pd(OAc)2 (Table 18, Condition B).351 In these cases, 3-methyl-1-tosyl-1H-indole 270j and methyl 1-methyl1H-indole-3-carboxylate 270k having a electron-withdrawing group on 1- or 3- position are not reactive enough (Table 18),350,351 and no desired product was obtained from the reaction of 3-methyl-1H-indole 270l with 1 (Table 18).351 Using Liu’s conditions (Table 18, Condition B), 3trifluoromethylindoles 265a and 265e (see Scheme 45) are also synthesized in 65% and 66% yields, respectively.351 A mechanism involving the formation of the (Ar)PdIV−CF3 intermediate generated through oxidation by PhI(OAc) 2 instead of “CF3+” is proposed,351,352 sharing a common catalytic triad utilizing a sophisticated catalytic systems.351−353 In addition, it has been found that molecular oxygen can serve as the oxizing agent for the oxidative trifluoromethylation of 1 with aryl/heteroaryl boronic acids354 or terminal alkynes (eq 13)355 via a ligand replacement process independent of the metal based on DFT calculations.356

intermediate 262. The formation of C−CF3 bond via reductive elimination followed by abstraction of the acidic proton of 263 along with the release of HOAc finally gives trifluoromethylated ketene dithioacetals 260.342An in situ high resolution electrospray ionization mass spectra (HRMS-ESI) of a mixture of PhI(OAc)2 (1.0 mmol), TMSCF3 (2.0 equiv), and KF (2.0 equiv) in MeCN (3.0 mL) shows a peak at m/z = 272.93822 (calculated for [C7H5F3I, M]+: 272.93825) assigned to iodonium species [PhICF3)]+ 261.342 Thus, the “acyclic hypervalent iodide trifluoromethylating species” 258a (Scheme 44) seems to be formed by simple mixing of iodobenzene diacetate, 1 and an activator and can be directly applied to the sp2 C−H trifluoromethylation reactions under mild transition metal-free conditions. The trifluoromethylation of indoles 264 to give 3-trifluoromethylindoles 265 (Scheme 45) provides further support for the reactivity of the Scheme 45. Synthesis of 3-Trifluoromethyl Indoles

In general, transition-metal mediated trifluoromethylation is complicated by the strong metal−CF3 bond originating from both the polar contribution of the bond as well as backbonding from filled metal d orbitals into the σ*C−F bonds. This results in a high barrier for formation of the C−CF3 bond357 and different performance of CF3 souces even under identical conditions.358 The direct trifluoromethylation to give 2trifluoromethylindoles using Togni’s reagents shows that 241b is superior to 241a (catalyst: Zn(NTf2)2, giving 271 in 17−98% yields in 24−48 h and no 3-trifluoromethylindole being obtained with 1-methyl-1H-indole as the substrate).359 Whereas, a mixture of 2- and 3-trifluoromethylindoles are obtained by using 241a catalyzed by CuOAc321,360 and methyltrioxorhenium,330 respectively. 8.4. Reactions Involving Trifluoromethyl Radical

More recently, Cu-catalyzed trifluoromethylation of N,Ndialkylhydrazones 272 via probably a CF3-radical-transfer mechanism (Scheme 46)361 using Togni’s reagent 241a and Ag-catalyzed hydrotrifluoromethylation of unactivated alkenes 274 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 organic synthesis, relying on selective modification of ubiquitious C−H bonds of organic compounds.359,363,364 Recently, Bräse and co-

electrophilic iodonium species 261.342 As a comparison, compound 265e can also be obtained in 62% yield under the reaction 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 oxidative trifluoromethylation using 1 as the CF3 source.347−351 In a recent report, Qing and Chu have attempted the oxidative trifluoromethylation of indoles. They found that N-

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

solvent. This reaction tolerates a broad range of functional groups, especially iodides and bromides. On the other hand, the triazene group plays a dual role of, first, an ortho-directing group for the regioselective introduction of CF3, and, second, the transformation of triazene into the corresponding iodide 278 through postmodification (Scheme 47).366 The above ortho-trifluoromethylation reaction was successfully expanded to ortho-perfluoroalkylation and ethoxycarbonyldifluoromethylation of aromatic triazenes. Furthermore, transformations of the triazene moiety into the azide 282 and the iodide 283 are also successful. In these cases, however, mono- and di-ortho-pentafluoroethylated products, for example 279a/279a′ (RF = C2F5), 280a/280a′ (RF = C3F7), and 281a/ 281a′ (RF = CF2CO2Et) are generally obtained. (Scheme 47).367 To explain these results, a coordination of a neutral AgCF3 species to the triazene moiety (enabling the CF3 radical to be generated regioselectively and attack at the ortho-position) and a good stabilization of the radical intermediate by the triazene moiety are proposed (Scheme 48).367 Calculations (TPSS;

Scheme 46. Trifluoromethylation Involving CF3 Radical

workers developed a new strategy based on the perfluoroalkylation postmodification strategy364 of aromatic triazenes 276 (Scheme 47).365−367 A series of o-trifluoromethylated aromatic triazenes 277 were synthesized in moderate to good yields from the reaction of triazenes 276 with AgCF3 generated in situ from 1 and AgF using perfluorohexane (C6F14) as the 718 | Chem. Rev. 2015, 115, 683−730

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

tions can be conducted on complex substrates with high regioselectivity using a variety of trifluoromethylating reagents including Ruppert−Prakash reagent 1 depending on either the reaction conditions362,371−375 or substrate structures.364−368 In addition, it has been found that electron rich aromatic and heteroaromatic substrates can also be trifluoromethylated by using catalytic amounts of AgF.376 In the reaction, a radical mechanism has been proposed and 1,2-dimethyl-3-(trifluoromethyl)-1H-indole 265a was obtained in lower yield (eq 14)376 than in the case via the electrophilic mechanism

B3LYP) of reaction energies for the addition of a trifluoromethyl radical to various 4-iodosubstituted aromatic compounds support the proposed mechanism.367,368 Scheme 48. Mechanism of ortho-Perfluoroalkylation of Aromatic Triazenes

The reactions of Me3SiRF and AgF proceeded selectively and almost quantitatively at room temperature in solvents such as MeCN, DMF, N-methylimidazole, and pyridine to give the corresponding perfluoroorgano silver(I) species in approximately quantitative yields (19F NMR).369,370 Therefore, recent reports convincingly document that radical trifluoromethyla-

(Scheme 45, 76% yield).342 However, comparing with the use of 1 as the nucleophilic CF3 species, an explanation of the events for generation of trifluoromethyl radical from 1 has not yet been conclusively established.17,376−381 719 | Chem. Rev. 2015, 115, 683−730

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metal mediated trifluoromethylation has largely contributed to stimulate the research of the chemistry of TMSCF3. Hopefully, Ruppert−Prakash reagent can also serve as trifluoromethyl radical, difluorocarbene and trifluoromethyl cation equivalent depending on the choise of catalysts/ mediators, directing groups as on the aromatic rings, transitron metal reagents, or oxidants under suitable reaction conditions. In the years ahead, challenges will involve developing catalytic enantioselective trifluoromethylation, finding environmentally friendly and cost-effective methods and conditions. Meanwhile, the recent series of important reports for the convenient utilization of fluoroform (the most intrinsic source of a trifluoromethyl group) in the preparation of TMSCF3 and in various fluoromethylation reactions deserve special attention.

As mentioned in section 2, the reaction conditions for the preparation of TMSCF3 1 from fluoroform are critical due to the high instability of “CF3−” (Scheme 2).24 It was observed that the in situ generated “CF3−” from the reaction of 1 with TMAF in the solvent, dichloromethane, is capable of delivering dichloromethide at −50 to 0 °C through proton-abstraction of dichloromethane 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 a temperature 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, the nucleophilic trifluoromethylation of 1 with (E)-N-benzylidenequinolin-8-amines can proceed smoothly under mild reaction conditions.384 On the other hand, it is worth noting that Me3SiCF3 can also act as the silicon source for the C−F bond activation,385,386 which has recently been successfully applied to the kinetic resolution of MBH-type allyl fluorides through enantioselective allylic trifluoromethylation catalyzed by commercially available bis(cinchona alkaloid) catalyst (DHQD)2PHAL 95 (also see Scheme 18).385

10. LATEST DEVELOPMENTS At 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 αdifluoromethylation of lithium enolates of lactams 188 using an umpolung 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 of enolates with 1. As a result, the direct α-siladifluoromethylation of 1 with lithium enolates was recently demonstrated (27 examples including acyclic substrates, 34−99% yields) via C−F bond activation of 1.387 In this case, the reaction of γ-lactam 188a as a model with TMSCF3 1 in place of fluoroform results in the formation of α-siladifluoromethylated product 284 bearing an all-carbon quaternary center via eight-membered intermediate 285, in which, 1 explaines its behavior as a siladifluoromethyl cation (TMSCF2+) equivalent (Scheme 49).387 Addition of an eqivalent of LiMe is important for the

9. PERSPECTIVES AND CONCLUSION Although a variety of C−CF3 bond forming reactions have been developed from various trifluoromethylating reagents, in the 30 years since trifluoromethyltrimethylsilane (TMSCF3) was synthesized from CF3Br (an ozone depleting compound) and trimethylsilyl chloride in 1984, TMSCF3 (Ruppert−Prakash reagent) has been and is still the most important CF3-centered nucleophilic trifluoromethylating reagent. New approaches, for example the conversion of fluoroform into TMSCF3, are highly attractive because fluoroform is a long-lasting greenhouse gas generated in large volumes during the manufacture of a variety of end products such as Teflon and refrigerants. Moreover, Ruppert−Prakash reagent is now also a useful starting material for the synthesis of potassium (trifluoromethyl)trimethoxyborate, the well-defined trifluoromethyl copper compounds (for example, [(phen)CuCF3]), trifluoromethanesulfanylamides/trifluoromethanesulfanamides used in trifluoromethylthiolation, difluoromethyltriflate as a convenient source of difluorocarbene, (difluoromethyl)trimethylsilane (TMSCF2H) used in difluoromethylation reactions, Togni’s reagents and related species as electrophilic trifluoromethylating reagents. Nowadays, the chemistry based on Ruppert−Prakash reagent has gained increasing attention due to the extensive use of trifluoromethylated and difluoromethylated compounds in modern pharmaceuticals, agrochemicals, and materials. The crystal structure of Me3SiCF3 confirmed that the Si−CF3 bond is longer and weaker than the Si−CH3 bonds. This observation is helpful to understand the reaction mechanisms and to develope initiators/catalysts/mediators based on the structure and reactivity of the substrates as in the nucleophilic trifluoromethylation of aldehydes, ketones, 4-nitroisoxazoles, Weinreb amides, Morita−Baylis−Hillman adducts, aryl nitriles, especially, the development of using HF as the mediator for the highly selective nucleophilic trifluoromethylation of Me3SiCF3 with various imines through a dual activation mode. On the other hand, a general catalytic enantioselective trifluoromethylation of aromatic aldehydes using (IPr)CuF and cinchona alkaloid-derived quaternary ammonium salts as the combination catalysis mode has been realized. In addition, transition

Scheme 49. Direct α-Siladifluoromethylation of Lithium Enolates Using TMSCF3

formation of 284 owing to the release of methane, a very weak CH-acid. Otherwhise, for example using 2 equiv of LHMDS as the base, the desilylated product 189a (see Scheme 32) is formed as the byproduct derived from protonation of 284 with in situ-generated HMDS. The C−F bond activation of 1 is metal-ion-depadent, accounting for the strong interaction between lithium and fluorine. In comparison, KHMDS or NaHMDS was ineffective.387 Mikami’s method provides the first example of using 1 as a “TMSCF2+” equivalent through 720 | Chem. Rev. 2015, 115, 683−730

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polarity inversion and has been successfully applied to the preparation of α-siladifluoromethyl ibuprophene.387 Similar to the nucleophilic trifluoromethylation of 1 with 4nitroisoxazoles 26 in which the nitro group is necessary to activate the substrate for trifluoromethylation (Section 3.3, Table 2 and Scheme 7),80 reactions of 4(trifluoromethanesulfonyl)isoxazoles 286 with 1 have recently been developed for the diastereoselective synthesis of 5trifluoromethyl-4-triflyl-2-isoxazolines 287 (Scheme 50).388 A

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

Scheme 50. Diastereoselective Trifluoromethylation of 4(Trifluoromethanesulfonyl)isoxazoles

workers synthesized 6-(trifluoromethyl)phenanthridines 292 from reactions of 2-isocyanobiphenyls 291 with 1 under mild conditions in the solvent, NMP in the presence of BQ using PhI(OAc)2 as oxidant (Scheme 52).393 The yield of 292a (R1 = R2 = H) was improved from 43% (in the absence of BQ) to 91% and, surprisingly, a radical mechanism without involvement of BQ was proposed.393 Scheme 52. Synthesis of 6(Trifluoromethyl)phenanthridines

further modification of 287 (for example, 287a: R = Ph, Ar = Ph) by reaction with electrophilic halogenating reagents, such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-chlorosuccinimide (NCS), and N-bromosuccinimide (NBS), under mild reaction conditions (rt., 1 h in the solvent, MeCN), gave the corresponding 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 reactions of 1 with 26, conducted in the presence of NaOAc and cetyltrimethylammonium bromide in DMF at room temperature, resulted in formation of 5-trifluoromethyl-2-isoxazolines 27 in high to excellent yields.80 Whereas, under identival conditions, 287a was obtained in lower yield (43%) comparing with 91% yield under the optimized conditions in the absence of cetyltrimethylammonium bromide as shown in Scheme 50.388 In addition, the fluorination of nitro-analogue 27a (see Table 2) with Selectfluor failed to provide the corresponding fluorinated product,388 probably due to the relatively much longer C−S bond (∼1.75 Å) in 287,64 which can reduce the steric hindrance of the halogenation reaction of 287a compared with the shorter C−N bond (∼1.43 Å) in 5-trifluoromethyl-2isoxazoline 26a. Iminiums124,131−135 and nitrones389,390 are highly reactive toward nucleophilic trifluoromethylation. Wu and co-workers described that catalyzed by AgSbF6, reactions of 2-alkynylaryl aldimines 288 with 1 in the presence of HOAc proceeded efficiently under mild reaction conditions to generate 1(trifluoromethyl)-1,2-dihydroisoquinolines 289 in moderate to excellent yield (Scheme 51).391 The reaction may proceed via AgSbF6 catalyzed 6-endo cyclization of 288 to give iminium intermediate 290 (section 3.6, Scheme 14)133,134 followed by nucleophilic trifluoromethylation.392 Recently, increasing attention has been directed to the use of 1 as a source of electrophilic trifluoromethyl species with the use of various oxidants (sections 8.3 and 8.4). Zhou and co-

In research on the trifluoromethylation of internal olefinic C−H bond, concurrently with our studies on ketene dithioacetals (section 8.3, Table 17 and Scheme 44),342 3(1,3-dithiolan-2-ylidene)-4,4,4-trifluorobutan-2-one 260a was obtained in only 34% yield by Yu and co-workers by treatment of acetyl ketene dithioacetal 259a with 1 using PhI(OAc)2 as oxidant catalyzed by Cu(OH)2/phen in the presence of KF at 80 °C under an argon atmosphere,394 which is less favorable than our results (88% yield; also see Table 19, Condition A).342 Under similar conditions but using Ag2CO3 (1.0 equiv) as the oxidant at 100 °C (Table 19, Condition B),394 260a was produced in 92% yield and a series of α-trifluoromethyl ketene dithioacetals 260 were prepared (36 examples, 47−92% yield).394 In fact, the necleophilic attack of the α-C of a ketene dithioacetal on electrophilic trifluoromethyl species is easy to occur (Table 17 and Scheme 44),342 duo to ketene dithioacetals possess structural features that enable the olefinic linkage 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 two equivalents of Ag2CO3 (eq 15).394 On the other hand, the research by Bi’s group on the C−H α-trifluoromethylation of α,β-unsaturated carbonyl compounds using Togni’s reagent II 241a (1.5 equiv) via a single-electrontransfer (SET) process has the advantages of catalytic amount 721 | Chem. Rev. 2015, 115, 683−730

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Table 19. Preparation of α-Trifluoromethyl Ketene Dithioacetals

methoxyphenyl)(trifluoromethyl)sulfane 296a,396 via thiophilic nucleophilic reaction238−240 of a cyanide leaving group by CF3. Additionally, a reference (ref 287) about an electrophilic hypervalent iodine reagent (not shown) for trifluoromethylthiolation was cited in section 6.2 of this review. Very recently, Buchwald and co-workers revealed that the reagent is a thioperoxy compound based on a combination of analytical techniques, including the crystalline sponge method for X-ray analysis.397

of CuI (10 mol %), diverse substrates (enones, α,β-unsaturated esters, thioesters and amides, 29 examples, 50−92% yields) and high regioselectivity (at α-position).395 In a recent report by Goossen’s group, a series of trifluoromethyl thioethers 296 were prepared directly from aryl and heteroaryl diazonium salts 295, sodium thiocyanate and 1 using copper thiocyanate as a catalyst via Sandmeyer-type reaction (Scheme 53).396 Detail mechanistic studies have

AUTHOR INFORMATION Corresponding Authors

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

Scheme 53. Sandmeyer-Type Trifluoromethylthiolation Reaction

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

The authors declare no competing financial interest. Biographies

revealed that, (1) treatment of 4-methoxy-benzenediazonium tetrafluoroborate with CuSCN, NaSCN, and Cs2CO3 in MeCN in the absence of 1 gave the corresponding aryl thiocyanate (1methoxy-4-thiocyanatobenzene) and (2) in the presence of a mixture of 1 and Cs2CO3, 1-methoxy-4-thiocyanatobenzene quickly reacted to form the trifluoromethyl thioether, (4722 | Chem. Rev. 2015, 115, 683−730

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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.

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

ACKNOWLEDGMENTS The authors acknowledge the reviewers and editors for their thorough reading of the manuscript and valuable sugestions. We would like to thank all authors whose names are listed in the references for their contributions to the chemistry described in this review. We gratefully acknowledge the financial support by the NSFC (21072027, 21272034, and 21372040) and New Century Excellent Talents in Chinese University (NCET-110613).

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.

ABBREVIATIONS Ac acetyl Ar aryl Bn benzyl Boc tert-butoxycarbonyl Bu butyl Bz benzoyl CuTc (thiophene-2-carbonyloxy)copper DABCO 1,4-diazabicyclo[2.2.2]octane DAST diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDHQ 2,3-dich1oro-5,6-dicyanohydroquinone DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahyde-2(1H)-pyrimidone DMSO dimethyl sulfoxide dppp 1,2-bis(diphenylphosphino)ethane dr diastereoisomeric ratio DVK divinyl ketone ee enantiomeric excess Et ethyl HetAr heteroaryl Hex hexyl HIV-RT human immunodeficiency virus type 1 reverse HMPA hexamethylphosphoric triamide IPr 1,3-bis(2′,6′-di-iso-propylphenyl)imidazol-2-ylidene

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 École Polytechnique Fédérale 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. 723 | Chem. Rev. 2015, 115, 683−730

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KHMDS potassium hexamethyldisilazide LDA lithium diisopropylamide LED light emitting device LHMDS lithium hexamethyldisilazide LiHMDS lithium hexamethyldisilazide Me methyl Mes mesityl (2,4,6-trimethylphenyl) MS molecular sieves MTBE methyl tertiary-butyl ether NaHMDS soldium hexamethyldisilazide NBS N-bromosuccinimide NCS N-chlorosuccinimide NHC N-heterocyclic carbene NMP N-methylpyrollidone NNRTI non-nucleoside reverse transcriptase inhibitor Ns 2-nitrobenzenesulfonyl PG protecting group Ph phenyl Phebox 2,6-bis(oxazolinyl)phenyl Phen 1,10-phenanthroline Piv pivaloyl Pr propyl QSPR quantitative structure−property relationship RB Rose Bengal RF perfluoroalkyl Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) Solkane365mfc 1,1,1,3,3-pentafluorobutane TASF tris(dimethylamino)sulfonium difluorotrimethyl siliconate TBABF tetrabutyl ammonium bifluoride TBAF tetrabutylammonium fluoride TBAT tetrabutylammonium triphenyldifluorosilicate TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene TEMPO (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl TFA trifluoroacetic acid TFMK trifluoromethyl ketone TfO triflate (trifluoromethanesulfonate) THF tetrahydrofuran TMAB tetramethylammonium bromide TMAF tetramethylammonium fluoride TMG 1,1,3,3-tetramethylguanidine TMP 2,2,6,6-tetramethylpiperidine TMS trimethylsil Tol tolyl (methylphenyl) Ts (or Tos) tosyl (p-toluenesulfonyl) TTMPP tris(2,4,6-trimethoxyphenyl)phosphine Zn(NTf2)2 zinc bis(trifluoromethylsulfonyl)imide

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Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond.

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