Triflimide (HNTf2) in Organic Synthesis - Chemical Reviews (ACS

Review Cite This: Chem. Rev. 2018, 118, 10349−10392

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Triflimide (HNTf2) in Organic Synthesis Wanxiang Zhao† and Jianwei Sun*,‡ †

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State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China ‡ Department of Chemistry, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. China ABSTRACT: Triflimide (HNTf2) is a commercially available and highly versatile super Brønsted acid. Owing to its strong acidity as well as good compatibility with organic solvents, it has been widely employed as an exceptional catalyst, promoter, or additive in a wide range of organic reactions. On many occasions, triflimide has been demonstrated to outperform triflic acid (TfOH). The uniquely outstanding performance of triflimide also benefits from the low nucleophilicity and noncoordinating property of its conjugate base (Tf2N−). Therefore, it has been employed as a precursor toward a variety of cationic metal complexes or organic intermediates with enhanced reactivity or catalytic activity. In this Review, we describe these features and applications of triflimide in organic synthesis, including its synthesis, physical properties, and role as catalyst or promoter in organic reactions. At the end of this Review, another closely related reagent, triflidic acid (HCTf3), is also briefly introduced.

CONTENTS 1. Introduction 1.1. Overview about Triflimide 1.2. Synthesis of Triflimide 2. Reactions Catalyzed or Mediated by Triflimide 2.1. Cycloadditions 2.1.1. [2 + 2] Cycloadditions 2.1.2. [3 + 2] Cycloadditions 2.1.3. [4 + 2] Cycloadditions 2.1.4. [3 + 3] Cycloadditions 2.1.5. [4 + 3] Cycloadditions 2.1.6. [6 + 2] Cycloadditions 2.1.7. [2 + 2 + 1] Annulations 2.1.8. [2 + 2 + 2] Cycloadditions 2.2. Aldol Reactions 2.3. Allylation Reactions 2.4. Friedel−Crafts and Related Reactions 2.4.1. Intermolecular Reactions 2.4.2. Intramolecular Reactions 2.5. Michael Addition Reactions 2.6. Nazarov Cyclizations 2.7. Mannich Reactions 2.8. Sigmatropic Rearrangements 2.9. Polymerization Reactions 2.10. Glycosylation Reactions 2.11. Other Reactions 2.12. Use As a Cocatalyst or Additive 3. Relevant Triflidic Acid (HCTf3) and Its Analogues 3.1. Brief Introduction (Structure, Synthesis, Properties, etc.) 3.2. Their Participation in Organic Reactions 4. Summary and Outlook © 2018 American Chemical Society

Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

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1. INTRODUCTION 1.1. Overview about Triflimide

Triflimide (HNTf 2 ), also known as bis(trifluoromethanesulfonyl)imide, is a commercially available white crystalline solid. Because of the presence of two strongly electron-withdrawing trifluoromethanesulfonyl groups, triflimide belongs to the superacid family. Since its first synthesis in 1984,1 the study and exploitation of triflimide has evolved tremendously over the years. Prior to this Review, there have been sporadic introductory articles on this acid.2,3 For example, Takasu reviewed specifically on triflimide-catalyzed cycloaddition reactions4 as well as their applications in the synthesis of azaheterocycles and related molecules.5 Yamamoto6 and Akiyama7,8 have also had excellent review articles on strong Brønsted acids with special efforts devoted to some important reactions promoted by triflimide. Recently, triflimide has gained particularly increasing attention in organic synthesis as well as other areas, such as materials science.9−13 In this context, this

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DOI: 10.1021/acs.chemrev.8b00279 Chem. Rev. 2018, 118, 10349−10392

Chemical Reviews

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association of triflimide is encountered by bifurcated hydrogen bonds from the N−H group to the two oxygen atoms of the adjacent −SO2− fragments. To understand the acidity of triflimide, the structurally related and more widely known triflic acid (TfOH) is often used for comparison. These two acids have been listed together with other common acids to give a better idea of their acidity as well as the molar price (Table 1).19,20 Currently these two acids, particularly triflimide, are more expensive than other commonly used Brønsted acids, such as p-TsOH, AcOH, and H2SO4. Fortunately, triflimide is used in catalytic amounts in many cases. Triflimide was found to have stronger acidity than triflic acid in aprotic organic solvents20 and ionic liquids21,22 as well as in gas phase,23,24 although in aqueous media and AcOH this order is reversed.1,25 Surprisingly, HNTf2 neither protonates water even in low dielectric organic media nor forms a cluster, e.g., [(HNTf2)NTf2]−. However, it is prone to be solvated in anhydrous nonpolar solvents or ionic liquids.26 This is consistent with extensive delocalization of the negative charge of the counteranion Tf2N− from the nitrogen atom to large SO2−N−SO2 moiety, which also explains its noncoordinating feature and low nucleophilicity.27−29 Indeed, the Tf2N− anion is an extraordinarily weaker base than triflate anion TfO−.17,30,31 Down in this series, triflidic acid (HCTf3) is an even stronger Brønsted acid due to the presence of three CF3SO2 groups. As a related part of this Review, a brief introduction on this acid will also be provided at the end. Owing to its strong acidity as well as the low nucleophilicity and noncoordination feature of its counteranion Tf2N−, triflimide is particularly versatile in organic synthesis, serving as exceptional catalyst, precatalyst, promoter, or additive in a wide range of organic reactions. In this Review, these reactions have been organized by reaction types, such as cycloaddition reactions, aldol reactions, Friedel−Crafts reactions, etc. Particularly noteworthy is the fact that triflimide has been demonstrated to outperform triflic acid in many cases, making it a uniquely attractive Brønsted acid. It is worth noting that there have also been numerous examples using triflimide to prepare cationic metal complexes, which have been employed as active catalysts. However, this part is beyond the scope of this Review. Fortunately, there have been review articles that specifically covered this topic and could serve as a good starting point for further familiarization.32,33

Review aims to provide a more comprehensive introduction of this unique acid regarding its application in organic synthesis. Pure triflimide has a low melting point of 49−50 °C and a boiling point of 90−91 °C.1 It is highly hydroscopic and fumes in air. Therefore, it is suggested to handle it under dry and wellventilated conditions. However, compared with triflic acid (TfOH), a fuming liquid acid, triflimide is much more userfriendly. Because triflimide is soluble in water and most organic solvents, it is also a common practice to store and use this acid as a solution. Other physical properties of triflimide, such as density, viscosity, and ionic conductivity, have also been documented.14 Triflimide has also been well-characterized by spectroscopy, including NMR, IR, and Raman spectra.1,15,16 Moreover, in 1996, Aubke and co-workers confirmed its structure by singlecrystal X-ray diffraction experiment.17 As shown in Figure 1, the

Figure 1. ORTEP view of triflimide. Reproduced with permission from ref 17. Copyright 1996 American Chemical Society.

two CF3 groups point to the opposite directions of the central S−N−S unit. By taking this transoid orientation, the corresponding Tf2N− anion may have better charge delocalization. Initial calculations have also confirmed that the S−N−S angle has influence on its stability.18 From the packing in the unit cell (Figure 2), it is noteworthy that the intermolecular

Figure 2. Intermolecular association in triflimide by diverged hydrogen bonds. Reproduced with permission from ref 17. Copyright 1996 American Chemical Society.

1.2. Synthesis of Triflimide

Triflimide was first synthesized by Foropoulos and DesMarteau in 1984.1 In their pioneering study, the authors employed

Table 1. pKa Values of Common Brønsted Acids in Various Solvents entry

acid

1 2 3 4 5 6 7 8 9 10 11

PhOH CH3CO2H PhCO2H CF3CO2H H2SO4 HBr FSO3H TsOH TfOH HNTf2 Tf3CH

pricea ($/mol) 29.2 21.9 47.2 42.3

58.3 224.6 6194.4

pKa (AcOH)

pKa (DMSO) 18.0 12.3 11.1 3.45 1.4 0.9

11.4 7.0

4.2 7.8

0.3

pKa (DME)

pKa (MeCN)

pKa (H2O) 10.0 4.75 4.25

−2.5 −4.9 −10.5

8.7 6.6 1.5

−11.4 −11.9 −16.4

0.7 0.3 −3.7

−9.0 −1.6 −12 1.7

a

The prices are calculated based on Sigma-Aldrich. 10350


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in detail in the following part according to the π-system of the cycloaddition partners. It is worth noting that we did not intend to distinguish concerted and stepwise mechanisms due to the fact that some of these reactions may not be fully understood yet in this respect. Therefore, strictly speaking, some of these annulations are indeed formal cycloaddition processes. 2.1.1. [2 + 2] Cycloadditions. Four-membered carbocyclic rings, such as cyclobutane and cyclobutene, are important structural motifs widely present in bioactive molecules. These molecules also serve as versatile precursors in organic synthesis owing to their propensity toward ring-opening and ringexpansion reactions due to ring strain.38,39 However, efficient methods for the selective synthesis of these four-membered carbocyclic rings are still limited. Among them, [2 + 2] cycloaddition has been recognized as a powerful and direct approach. In these reactions, photochemical and thermal [2 + 2] cycloadditions have been known to be effective, but it often remains challenging to control both reactivity and selectivity. In the past decade, triflimide has been demonstrated to be a uniquely effective catalyst or precatalyst for a range of [2 + 2] cycloaddition reactions, complementing not only Lewis acids but also other commonly used Brønsted acids.40 In 2005, Inanaga, Takasu, and Ihara reported the first example of HNTf2-catalyzed efficient [2 + 2] cycloaddition of silyl enol ethers with α,β-unsaturated esters (Scheme 3).41 With 1 mol %

trifluoromethanesulfonyl amide (TfNH2) as the key intermediate, which was obtained by several steps from methanesulfonyl chloride via trifluoromethanesulfonyl fluoride CF3SO 2F (Scheme 1). Deprotonation of TfNH2 by NaOMe gave sodium Scheme 1. Initial Synthesis of Triflimide in 1984

triflic amide salt, which was silylated by hexamethyldisilazane. Further triflation by CF3SO2F led to the formation of sodium triflimide. Subsequent acidification by H2SO4 afforded triflimide in 48% overall yield (from CF3SO2F). In 1991, the same group made slight improvement on this synthetic procedure and achieved an overall yield of 80%.34 The improvement included simplification of purifications owing to the choice of more suitable solvents and equipment. In 2004, Caporiccio and co-workers reported new strategies for the synthesis of triflimide in their studies of the ionic conductivity of lithium salts of perfluoroalkanesulfonyl imides.35 In the two separate strategies, CF3SO2F was employed as starting material in both (Scheme 2). In the first approach,

Scheme 3. HNTf2-Catalyzed [2 + 2] Cycloaddition of Silyl Enol Ether with Acrylates and Propiolates

Scheme 2. New Synthetic Approaches by Caporiccio and Coworkers in 2004

lithium nitride (Li3N) served as nucleophile to form LiNTf2. Acidification by sulfuric acid produced triflimide in 69% overall yield. Alternatively, ammonium and trimethylamine could be used to react with CF3SO2F to form triethylammonium triflimide in 85% yield. Upon treatment with sulfuric acid, triflimide could be obtained in 94% yield after distillation. These two new approaches enjoyed both step-economy and better overall efficiency.

of HNTf2, the reaction proceeded smoothly even at −78 °C to form the corresponding cyclobutane with both good chemical yield and excellent stereoselectivity. Notably, the catalyst loading could be further decreased to 0.1 mol % to achieve even higher yield without erosion in diastereoselectivity, demonstrating a catalyst turnover number as high as ∼980. In contrast, the use of the well-known Lewis acid EtAlCl2 led to decreased yield and diastereoselectivity. More surprisingly, when triflic acid (TfOH) was used, no desired [2 + 2] cycloadduct was observed. These results clearly indicated the superiority of triflimide in these reactions. In addition to the formation of cyclobutane products using acrylates as the reaction partner, substituted cyclobutenes (3c−e) could also be formed when propiolates were employed. In 2015, the Tokuyama group employed this highly useful reaction as a key

2. REACTIONS CATALYZED OR MEDIATED BY TRIFLIMIDE 2.1. Cycloadditions

Cycloaddition reactions combine two or more components to provide rapid access to cyclic molecules, which represent a powerful strategy to build molecular complexity.36,37 Although Lewis acids have been well-established and dominant as catalysts for a wide range of cycloaddition reactions, Brønsted acids have also played indispensable roles in these reactions. Specifically, triflimide has been extensively demonstrated as a superb catalyst in miscellaneous cycloaddition reactions, such as [2 + 2], [3 + 2], and [4 + 2] cycloadditions, etc. These reactions are described 10351


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will be discussed in detail (vide infra). As a result, when alkyl enol ethers were used in place of silyl enol ethers, triflimide could not catalyze the corresponding [2 + 2] cycloaddition process, because the actual catalyst silyl triflimide could not be formed in this case (Scheme 6).45 To address this issue and avoid using air-

step in the construction of the B−E ring core of the natural product penitrem E (Scheme 4).42 Scheme 4. HNTf2-Catalyzed [2 + 2] Cycloaddition in a Synthesis toward Penitrem E

Scheme 6. HNTf2-Catalyzed [2 + 2] Cycloaddition of Alkyl Enol Ethers with Acrylates

sensitive Lewis acids (e.g., Et3SiNTf2 and EtAlCl2), in 2008 Takasu et al. employed the in situ generated Et3SiNTf2 by premixing triethylsilane and triflimide as effective catalyst to promote the desired [2 + 2] cycloaddition between alkyl enol ethers and acrylates. Unfortunately, only two enol ethers derived from cyclohexanone were found to be reactive nucleophilic partner for this reaction. Takasu et al. also discovered that allylsilanes can also be employed as suitable nucleophilic partners for the [2 + 2] cycloaddition with various types of electron-deficient olefins and alkynes (Scheme 7).46 For example, in the presence of catalytic

While the above cycloaddition reaction proceeds efficiently under cryogenic conditions, it was found that the same reaction could not give the desired product at room temperature due to significant decomposition of substrates and products via side reactions, including substrate oligomerization and retro-aldoltype ring-opening of the cycloadduct. Nevertheless, the same group introduced a flow microreactor system and successfully rendered this process to proceed with significantly enhanced efficiency at room temperature, thereby allowing potential applications in a more sustainable manner.43 In a separate report, the same group also observed an interesting phenomenon indicating that triflimide was also capable of inducing isomerization of silyl enol ethers to form the thermodynamically more stable form, and this isomerization could take place in a one-pot manner right before cycloaddition (Scheme 5).44 For example, treating 7 with a catalytic amount of

Scheme 7. HNTf2-Catalyzed [2 + 2] Cycloaddition of Allylsilanes 14

Scheme 5. HNTf2-Catalyzed One-Pot Isomerization and [2 + 2] Cycloaddition

HNTf2, the reaction between allylsilane 14 and methyl acrylate at 0 °C afforded the cyclobutene adduct 15 in 83% yield, albeit with a 1:1 mixture of diastereomers. Interestingly, the authors found that the reaction selectivity was sensitive to temperature. At room temperature, the same reaction gave 15 with better stereoselectivity, favoring the trans isomer. In the meantime, the cyclopentane product 16 was generated in 8% yield. Furthermore, in refluxing 1,2-dicholoroethane, the observed stereoselectivity was further improved to 11.5:1, and the side product 16 was formed in 38% yield. Similarly, it was proposed that the corresponding silyl triflimide (R3SiNTf2) generated in situ from HNTf2 and allylsilane served as the actual catalyst. The

HNTf2 at −10 °C followed by the addition of methyl acrylate 2 at −78 °C led to the formation of 9 in 86% yield, suggesting that isomerization took place almost completely in the first step. In contrast, keeping both steps at −78 °C resulted in almost no such isomerization, affording 10 in 66% yield. These results indicated that this catalytic isomerization process is temperature-dependent and under thermodynamic control. Mechanistically, triflimide might serve as a precatalyst to generate the actual silyl triflimide catalyst (TBSNTf2), which 10352


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hetero [2 + 2] cycloadditions. Some of these cycloadducts are unstable and thus prone to undergo further ring-opening, leading to new reaction products. For example, in 2006, Hsung reported an intramolecular metathesis between the ynamide and carbonyl functional groups (Scheme 10). In the presence of a

authors also believed that the reaction proceeds by a stepwise mechanism. After the Michael addition step, the resulting enolate intermediate can cyclize with the β-silyl cation to form cyclobutane. However, at a higher temperature, this favored pathway might be complicated by competitive formation of a pentavalent siliranium cation 17, which allows formation of the side product cyclopentane 16 featuring a formal silyl shift. Control experiments indicated that the cis isomer of 15 can be transformed to the trans isomer, indicating that the process is reversible. Propiolate 18 and acrylonitrile 20 were also excellent partners for this [2 + 2] cycloaddition process to form cyclobutene 19 and cyclobutane 21 in good yield. More recently, the Hsung group discovered that HNTf2 can efficiently promote the intramolecular Gassman’s cationic [2 + 2] cycloaddition without involvement of a silyl group to generate the silyl triflimide Lewis acid (Scheme 8).47 The initiation of the

Scheme 10. HNTf2-Catalyzed Intramolecular Yne−Carbonyl Metathesis

Scheme 8. HNTf2-Catalyzed Intramolecular Gassman’s [2 + 2] Cycloaddition substoichiometric amount of HNTf2, initial hetero-[2 + 2] cycloaddition of 28 forms the oxetene intermediate 29, which then undergoes electrocyclic ring-opening to afford the metathesis product 30 in 64% yield. While Lewis acid BF3− OEt2 was also successful in promoting this reaction, other Brønsted acids, such as p-nitrobenzenesulfonic acid and HOAc, proved to be inferior in terms of required loading and reaction efficiency, indicating the “magic” and complementary nature of HNTf2.49 In 2011, Takemoto, Takasu, and co-workers described an interesting intermolecular alkyne−imine metathesis, in which the torquoselectivity could be well-controlled by the Brønsted acid catalyst. For example, the key azetine 33 resulting from the [2 + 2] cycloaddition between ynamide 31 and aldimine 32 could either undergo outward or inward rotation in the subsequent 4π electrocyclic ring-opening. In the presence of triflimide, this ring-opening step favors outward rotation to form the anti-α,β-unsaturated amidine 34 as the major product (Scheme 11).50 In contrast, weaker acids, such as methanesulfonic acid (MsOH) and 10-camphorsulfonic acid (CSA), led to predominantly inward rotation to form the syn isomer. Density functional theory (DFT) calculations suggested that the torquoselectivity switch might be related to solvation degree of

process involves protonation of the acetal functionality to form an oxocarbenium intermediate 23, which then induces nucleophilic attack from the internal olefin followed by ringclosure. With hydrazine and hydroxyamide as temporary tethers, these reactions furnished the corresponding cyclobutane products with excellent regio- and diastereoselectivity, which may not be straightforward to achieve in an intermolecular process. While the tethers were robust under the highly acidic conditions, the authors also demonstrated that they could be cleaved easily to allow more flexible modifications. In a separate report, the same group confirmed that the above process proceeded in a stepwise manner.48 Furthermore, the authors also extended this process to an intermolecular version. For example, after comparison with other Brønsted acids and Lewis acids, HNTf2 was found to be a superior catalyst in the intermolecular cycloaddition between hemiaminal 25 and tetramethylethylene 26, leading to the formation of cyclobutane 27 in 82% yield (Scheme 9). Although only one example was demonstrated, more important variations, such as the corresponding asymmetric version, should be highly promising. In addition to C−C bond formation to form cyclobutane and cyclobutene molecules, HNTf2 is also capable of promoting

Scheme 11. HNTf2-Catalyzed [2 + 2] Cycloaddition of Ynamides and Imines

Scheme 9. HNTf2-Catalyzed Intermolecular Gassman’s [2 + 2] Cycloaddition

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low diastereoselectivity (Scheme 13).57 In contrast, triflic acid failed to catalyze this cycloaddition, resulting in no desired

the protonated form of azetine 33. With a strong acid promoter, the process may proceed via the cationic azetinium species, while an intimate ion pair model might be operative when a weak acid is used. Further experimental results on solvent effects supported this hypothesis. In a related study, the authors also observed that the substituent on the ynamides may also influence torquoselectivity.51 Moreover, in certain cases, the syn-α,β-unsaturated amidine products can have atropisomers, which may have potential applications in asymmetric synthesis. Unexpectedly, direct extension of the above reaction to ketimines proved to be less straightforward (Scheme 12a). For

Scheme 13. HNTf2-Catalyzed [3 + 2] Cycloaddition of Silyl Enol Ethers and Donor−Acceptor Cyclopropanes

Scheme 12. HNTf2-Catalyzed Reactions between Ynamides and Ketimines

product formation. The authors also evaluated a structurally similar polyfluorinated sulfonimide 46, but it gave slightly lower yield. In this reaction, both donor and acceptor motifs in the cyclopropane substrate were crucial to the reactivity. Cyclopropanes with only donor or acceptor exhibit no reactivity. Mechanistically, it was proposed that the in situ generated silyl triflimide served as the actual catalyst. During their studies, the Takasu group also observed an unexpected [3 + 2] cycloaddition between N-aryl imines and α,α-dimethylallylsilane catalyzed by triflimide (Scheme 14).58 Scheme 14. Formal [3 + 2] Cycloaddition with α,αDimethylallylsilane

example, the same group found that, when using acetophenone imine (36) as the reaction partner, N,N-divinylamine product 38 was formed, presumably via initial ynamide protonation and nucleophilic attack from the imine nitrogen lone pair followed by deprotonation via intermediate 37.52 Next, the authors probed the reactivity of benzophenone imines (39) where no αhydrogen is present (Scheme 12b). Surprisingly, the reaction afforded 3,4-dihydroquinoline-type products 41 and a small amount of the expected metathesis product α,β-unsaturated amidine 42.53 Unfortunately, the mechanism for the formation of 41 remained elusive. Control experiments indicated that the α,β-unsaturated amidine 42 could not be transformed to 3,4dihydroquinolines 41 under the reaction conditions, suggesting that it is unlikely to proceed by an intramolecular Friedel−Crafts mechanism or a thermal 6π-electrocyclization pathway via 42. 2.1.2. [3 + 2] Cycloadditions. Five-membered rings are prevalent motifs in biologically active natural products and pharmaceuticals. Among the various strategies, [3 + 2] cycloaddition between a simple π system and 1,3-dipolar reagents or their synthetic equivalents/analogues, including polarized cyclopropanes, provides one of the most convergent and expedient approaches for their construction.54,55 Recently, catalytic asymmetry [3 + 2] cycloadditions have also enabled efficient access to diverse and highly useful chiral five-membered ring structures.56 In 2006, Takasu and Ihara demonstrated the first example that HNTf2 could be a competent catalyst to promote efficient [3 + 2] cycloaddition. In the presence of 1 mol % of HNTf2, the cycloaddition of silyl enol ether 43 and donor−acceptor cyclopropane 44 proceeded efficiently at −78 °C to furnish the highly substituted cyclopentane 45 in 69% yield, albeit with

Interestingly, a range of silyl-substituted pyrrolidines could be obtained in moderate yield and diastereoselectivity. Similar to the previous formal silyl shift as a side pathway observed in the [2 + 2] cycloaddition examples shown in Scheme 7, it was proposed that this process also involves a 1,2-silyl shift following the initial C−C bond formation. This shift is partly driven by the relative stability of the resulting tertiary carbocation, as the authors did not observe such a shift in the absence of the two αsubstituents. Instead, a [4 + 2] cycloaddition was observed (vide infra). Vinylidenecyclopropanes are a special family of cyclopropanecontaining structures.59 Intimate connection to an allene moiety confers these molecules interesting reactivity and versatile utility in organic synthesis. Probably due to the absence of strong polarization of the cyclopropane motif by donors and acceptors, these molecules are typically thermally stable. However, upon certain activation by suitable electrophiles, these molecules normally react in a domino manner, leading to a series of bondcleavage and -formation events. 10354


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takes advantage of the multiple reactive carbocation intermediates involved. For example, carbocation 61 is generated following similar intermolecular C−C bond formation and cyclopropane opening. Subsequent cyclization utilizes the internal allene moiety to generate cation 62, which has a resonance form 63. With this properly positioned carbocation, further Friedel−Crafts cyclization takes place to deliver the observed product. The last cyclization step could proceed with different aryl groups depending on their electronic properties. Later on, the same group also demonstrated that, in the absence of an activated olefin partner, triflimide could trigger isomerization of vinylidenecyclopropanes to form substituted naphthalenes, which also involves trapping the carbocation intermediate in a Friedel−Crafts cyclization.62 Recently, Li, Wan, and co-workers have developed a HNTf2catalyzed formal [3 + 2] cycloaddition without using cyclopropane-based substrates (Scheme 17).63 Having known that

In 2009, Li and Shi developed an efficient triflimide-catalyzed [3 + 2] cycloaddition of vinylidenecyclopropanes with electrondeficient olefins, leading to the synthesis of a range of polysubstituted cyclopentanes in good to excellent yields (Scheme 15).60 The reaction was believed to begin with Scheme 15. HNTf2-Catalyzed [3 + 2] Cycloaddition of Vinylidenecyclopropanes with Activated Olefins

Scheme 17. HNTf2-Catalyzed Formal [3 + 2] Cycloaddition of Ynamides and Dioxazoles

protonation of the α,β-unsaturated carbonyl species by triflimide. Upon lowering the lowest unoccupied molecular orbital (LUMO) level in this activation, 1,4-nucleophilic addition by the vinylidenecyclopropane proceeds to form the cyclopropyl cation intermediate 56. Further ring-opening affords carbocation 57, which is stabilized by the diene π system. Further intramolecular nucleophilic attack by the enol moiety gives the observed cyclopentane product 55 and regenerates the acid catalyst. Shortly thereafter, the same group extended this cycloaddition to a cascade process. By employing ethyl 5,5-diarylpenta-2,3,4trienoates as the activated olefin partner, the authors were able to alter the cycloaddition pathway and combine it with a Friedel−Crafts cyclization. With triflimide as catalyst, the reaction between 58 and 59 provided rapid access to the polycarbocyclic structure 60, which was not easily accessible previously (Scheme 16).61 Mechanistically, the cascade process

ynamides can be effectively activated by triflimide, the authors found that the resulting ketiminium 67 could be trapped by dioxazoles 65 to trigger ring fragmentation with concomitant loss of acetone. Further cyclization and rearomatization generated a range of polysubstituted 4-aminooxazoles 66 in excellent yield. Notably, the process is so efficient that almost all the reactions were complete within 5 min at room temperature. It is also worth noting that triflimide exhibited superior catalytic activity in this reaction compared with other Brønsted acids. For example, trifluoroacetic acid (TFA) did not show any catalytic activity. After this discovery, the same group quickly reported the synthesis of aminoimidazoles with the same catalytic system using oxadiazolones in place of dioxazoles. Instead of acetone release in the aromatic ring fragmentation, this new process takes advantage of CO2 loss, thereby proceeding in a similar pathway. A range of N-sulfonyl ynamides substituted with aryl, heteroaryl, and alkyl groups all proceeded smoothly to afford the corresponding products in good yields (Scheme 18).64 However, unfortunately, the oxazolidinone-based ynamides could not participate in this process to give the corresponding

Scheme 16. HNTf2-Catalyzed Cascade Cyclization with 5,5Diarylpenta-2,3,4-trienoates

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Scheme 18. Synthesis of Aminoimidazoles by HNTf2Catalyzed Formal [3 + 2] Cycloaddition

Scheme 19. Competitive Diels−Alder Reaction of α,βUnsaturated Aldehydes and Ketones with Cyclopentadiene

aminoimidazole 73d. Nevertheless, the authors demonstrated that the typical substituents on the nitrogen, such as sulfonyl and benzyl groups, could be removed successfully, thereby allowing diverse derivatizations when needed. With good compatibility with different substituents, this process provided an attractive approach for the synthesis of substituted imidazoles. 2.1.3. [4 + 2] Cycloadditions. [4 + 2] Cycloaddition is arguably one of the most important and fundamental transformations in organic synthesis. With Diels−Alder reaction as a representative example, this family of reactions provides expedient access to six-membered cyclic molecules and has found extremely wide applications.65−67 A broad range of Lewis acids and Brønsted acids have been demonstrated to be capable of catalyzing [4 + 2] cycloadditions with excellent levels of regio-, chemo-, diastereo-, and enantioselectivity. Among them, HNTf2 is a particularly active catalyst. In 2005, Nakashima and Yamamoto reported an interesting competitive Diels−Alder reaction of cyclopentadiene 74 with α,β-unsaturated aldehyde 75 and ketone 76, leading to the formation of 2-hexen-4-one 77 and crotonaldehyde 78, respectively (Scheme 19).68 It was found that HNTf2 and the bulky Lewis acid B(C6F5)3 showed dramatically different chemoselectivities. With HNTf2 as catalyst, the reaction favored ketone 78, whose carbonyl oxygen is more basic than that in the aldehyde 75. However, with B(C6F5)3 as catalyst, the preference was reversed, with the aldehyde being more reactive. This selectivity divergence was explained by the sensitivity of bulky Lewis acid to steric effect and the tendency of Brønsted acid to interact with the more basic carbonyl group. Although Diels−Alder reaction is a powerful and reliable approach for the construction of substituted cyclohexenes, occasionally these reactions are not as straightforward as expected when sterically congested reactants are employed, presumably due to increased difficulty in achieving a geometrically accessible transition state. However, in 2007, Jung and Ho reported that HNTf2 exhibits superb catalytic activity in a formal [4 + 2] cycloaddition of hindered siloxydiene−dienophile pairs (Scheme 20a).69 Mechanistically, it was found that the reaction proceeds via a stepwise pathway, thereby obviating the same congested transition state in a concerted cycloaddition. For

example, in the presence of a catalytic amount of triflimide, the reaction of siloxydiene 79 and enone 80 took place smoothly at −78 °C, giving rise to the first Michael addition product 81. In the same pot, upon warming the reaction mixture to 0 °C, the second C−C bond was formed by means of another Michael addition within 10 min. Ultimately, the formal cycloaddition adduct 82 bearing three contiguous stereocenters was generated in 89% yield. The authors believed that the extraordinary efficiency benefited significantly from the strong Brønsted acidity of triflimide. Shortly after this discovery, the same group extended this catalytic system to an inverse-electron-demand Diels−Alder reaction in the context of the synthesis toward steroidal natural products rhodexin A and sarmentogenin 86 (Scheme 20b).70 Under similar conditions, hindered substrates acyldiene 83 and silyl enol ether 84 reacted efficiently to provide rapid access to the tricyclic adduct 85 with four contiguous stereocenters, which is already the core structure of the natural products. In following studies, the Jung group also made efforts to improve this catalytic system and utilized them in the synthesis of other useful molecules.71,72 Shortly after Jung’s initial report on the [4 + 2] cyclization, Takasu et al. documented an elegant multicomponent cycloaddition process that incorporated the same type of [4 + 2] annulation (Scheme 21).73 The three-component process of enone 87, siloxydiene 88, and acrylate 2 proceeded via sequential [4 + 2] and [2 + 2] cascade to form tricyclic product 90 with moderate overall yield and moderate diastereoselectivity. The inherent order of reactivity is probably governed by the electronic properties of these reactants. For example, the more electrophilic enone reacts prior to acrylates. Notably, triflimide was found to be superior to the Lewis acid EtAlCl2, which could not lead to any desired multicomponent reaction product. Later on, Takasu, Takemoto, and co-workers reported another triflimide-catalyzed domino process combining [4 + 2] cycloaddition and elimination process (Scheme 22).74 Triflimide catalyzed both steps efficiently to form the exocyclohexenones, which is complementary to the approach by [4 + 2] cycloaddition with Danishefsky dienes for the synthesis of endocyclohexenones. In these two examples, the authors also proposed a stepwise mechanism for the [4 + 2] annulation, which is consistent with Jung’s proposal. Indeed, a similar 10356


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Scheme 20. HNTf2-Catalyzed Formal [4 + 2] Cyclization of Hindered Substrates

Scheme 21. HNTf2-Catalyzed Cascade [4 + 2]/[2 + 2] Annulation

Scheme 23. Aza-Diels−Alder Reaction of 2-Siloxydienes with Aldimines

Scheme 22. HNTf2-Catalyzed Cascade [4 + 2] Elimination Process observed. This observation indicated that the actual catalyst should not be silyl triflimide generated in situ from the corresponding 2-siloxydiene and HNTf2. Indeed, control experiments with an alkyl dienol ether substrate, without involving a silyl group, also led to the corresponding product, suggesting that HNTf2 may be the actual catalyst and it activates the imine group by protonation. One year later, the same group reported an inverse-electrondemand cascade hetero-Diels−Alder reaction (the Povarov reaction). At 60 °C, HNTf 2 smoothly catalyzed the intermolecular C−C bond formation between aryl aldimine 98 and the electron-rich allylsilane 14 to form tetrahydroquinoline product 99 in 51% yield. Meanwhile, a byproduct quinolone 100 was also observed, which was believed to result from a hydrogen-transfer process between the direct product and imine substrate 98 (Scheme 24).76 Indeed, HNTf2 catalyzed both of the mechanistically distinct steps. Later on, the authors were able to improve this cascade process to favor the quinoline as the major product.77 2.1.4. [3 + 3] Cycloadditions. While [4 + 2] cycloaddition is the most popular and utilized approach for the assembly of sixmembered rings, [3 + 3] cycloaddition provides a valuable alternative. In particular, a wide range of hetero [3 + 3] cycloaddition reactions have been demonstrated to provide efficient access to heterocycles.78−80 While we are not aware of any example of HNTf2-catalyzed concerted [3 + 3] cycloaddition, a formal example of this type was documented. In 2011, Takasu and co-workers reported that bicyclic product 102 was observed from the reaction between silyl enol ethers 8 and acrylate 2 catalyzed by HNTf2, representing a

HNTf2-catalyzed cascade process combining sequential [4 + 2] and [3 + 2] annulations has also been documented.57 In addition to six-membered carbocyclic ring formation, HNTf2 is also capable of catalyzing hetero-Diels−Alder reactions for the synthesis of six-membered heterocycles. In 2006, Takasu et al. documented the first example of this type (Scheme 23).75 Specifically, in the presence of a catalytic amount of HNTf2, the aza-Diels−Alder cycloaddition between siloxydienes 95 and aldimines 96 proceeded at room temperature to form piperidin-4-one-derived silyl enol ethers 97. After simply desilylation, a range of useful piperidin-4-ones could be generated. The products were obtained as a mixture of diastereomers, with preference to the trans-isomer. It is noteworthy that the acid catalyst is compatible with the basic functional groups in the products. Furthermore, direct use of TBSNTf2 did not lead to the formation of the desired cycloadduct. Instead, decomposition of the siloxydiene was 10357


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example, they found that the [2 + 2] cycloadduct could be transformed to the [3 + 3] cycloadduct under the reaction conditions upon warming up. However, the reverse conversion is impossible at low temperature. The results suggested that the [2 + 2] pathway is under kinetic control and reversible. In the same report, an intermolecular version of this interesting reaction was also designed to give tricyclic product 106, demonstrating its application in rapid assembly of the core skeleton of clovanes, a family of natural products. 2.1.5. [4 + 3] Cycloadditions. Compared with common rings (e.g., 5- and 6-membered rings), 7-membered rings are relatively challenging to assemble, partly due to the disfavored entropic features and increased nonbonded interactions in the transition state. However, because of the ubiquitous presence of 7-membered rings in nature, various strategies have been devised for their preparation. Among them, [4 + 3] cycloaddition is among the most powerful and straightforward approaches.82,83 In the reported examples of [4 + 3] cycloaddition reactions to date, the use of allyl cation and dienes has been more or less a general reactant pair for this purpose. In 2012, Fuchigami, Namba, and Tanino reported a concise example of this type promoted by HNTf2.84 In this reaction, 2-(silyloxy)allyl alcohol bearing a methylsulfenyl substituent was employed as the oxyallyl cation precursor to react with the 4-carbon partner Nnosyl pyrrole. The desired bicyclic adduct tropinone 109 was formed as a single diastereomer in 85% yield (Scheme 26). The

Scheme 24. Hetero-Diels−Alder Reaction of Aryl Aldimine 98 and Allylsilanes 14

[3 + 3] cycloaddition. The reaction gave a moderate yield at refluxing chloroform (Scheme 25).81 In retrospect, this is a very Scheme 25. Formal [3 + 3] Cycloaddition of Silyl Enol Ethers

Scheme 26. HNTf2-Catalyzed [4 + 3] Cycloaddition Reactions of Pyrroles

unusual observation, because the same reactants and catalyst provided a [2 + 2] cycloadduct, as shown in Scheme 5. The difference is reaction temperature. Mechanistically, it was believed again that the in situ generated silyl triflimide served as the actual catalyst. Initial activation of the carbonyl group of acrylate triggers the intermolecular C−C bond formation to form silyl ketene acetal 103. At −78 °C, this intermediate prefers to undergo intramolecular cyclization to form cyclobutane 9, observed as the [2 + 2] cycloadduct. In contrast, at a temperature higher than −10 °C, it was found that this intermediate has a different option, which is internal proton transfer (path b, Scheme 25). The net result is to exchange positions of the nucleophilic and electrophilic motifs. Subsequent Claisen-type cyclization followed by catalyst generation and desilylation delivers the observed diketone 102. Thus, the overall reaction of this alternative pathway represents a formal [3 + 3] cycloaddition. The authors carried out careful control experiments and mechanistic studies by NMR spectroscopy. For

reaction was sensitive to the electron-withdrawing group on the pyrrole. Replacing Ns (2-nitrobenzenesulfonyl) with the more common Ts (p-toluenesulfonyl) group resulted in significantly decreased yield, together with the formation of monosubstituted pyrrole product by a simple Friedel−Crafts reaction. Notably, the methylsulfenyl substitution helps stabilize the oxyallyl cation intermediate, which also influences the reactivity in the subsequent cycloaddition process. Indeed, the authors found that this intermediate is not active enough toward sterically congested pyrrole partner. For example, with 2-methyl-Nnosylpyrrole, there was no cycloaddition product formation. 10358


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employed as the reaction partner, a formal [6 + 2] cyclization is expected. After a survey on a range of dipolarophiles, siloxy alkynes were found to be superior to react with such 1,6-amphoteric molecules. In the presence of a catalytic amount of HNTf2, the reaction of 114 and 115 proceeded efficiently at room temperature to form 8-membered lactone 116 in 71% yield. Other promoters, including Lewis acids and other Brønsted acids, led to lower efficiency or failure to give the desired lactone. A range of such 1,6-amphoteric molecules were demonstrated to be reactive, and the scope was reasonably good. Another notable feature of this process is that, unlike other typical medium-ring syntheses, high dilution of the reaction system is not necessary for high efficiency, thus demonstrating its potential in large-scale synthesis. On the basis of some preliminary mechanistic studies, the authors proposed two possible pathways for this process (Scheme 28). The first proposal involves initial internal opening of the oxetane ring by the aldehyde upon protonation, resulting in the highly electrophilic oxonium intermediate 117. Then intermolecular C−C bond formation with the siloxy alkyne nucleophile followed by ring-closure from the alkoxide in the 6position forms bicyclic intermediate 118. Subsequent protonation of the ether bridge induces its cleavage and subsequent silyl transfer to give the observed product 116. Alternatively, HNTf2 may also be capable of catalyzing the alkyne−aldehyde metathesis process via [2 + 2] to form α,β-unsaturated ester 122. Then, upon acid activation of the oxetane moiety, the internal carbonyl group participates in oxetane opening, and subsequent silyl transfer can also deliver the same product. Unfortunately, no concrete experimental results were obtained to rule out either of the two pathways. While the above formal [6 + 2] cycloaddition provided an attractive approach for medium-ring lactone synthesis, there remained a limitation in this process. In the 1,6-amphoteric molecules, the linker between the oxetane and aldehyde motifs must be aromatic. To address this limitation and expand the scope for medium-ring lactone synthesis, the same group developed another novel approach characterized by ringexpansion of small cyclic acetals with siloxy alkynes.88 As a further extension, in 2015, the same group reported a HNTf2-catalyzed efficient synthesis of medium-ring lactams, another family of useful molecules that pose significant challenges to synthetic chemists.89 In the presence of catalytic HNTf2, cyclic hemiaminal 124 and siloxy alkyne 115 underwent formal ring-expansion at room temperature to form 8membered lactam 125 in 74% yield (Scheme 29). Mechanistically, it was proposed that the hemiaminal initially forms iminium 126 upon acid activation, which then undergoes [2 + 2] cycloaddition with the electron-rich siloxy alkyne followed by ring-opening to deliver the observed product. This process represents a pioneering example of catalytic intermolecular reaction for medium-ring lactam synthesis. The authors found that the use of tosyl (Ts) as protecting group in the hemiaminal was crucial to the successful formation of the desired product. For example, replacement with tert-butyloxycarbonyl (Boc) did not form any desired product, as the carbonyl oxygen in Boc is more nucleophilic and can interfere and outcompete the [2 + 2] cycloaddition step. Other than HNTf2, TiCl4 was also found to be an excellent promoter for this reaction, but it must be used in superstoichiometric amounts (2 equiv) and in combination with 1 equiv of 2,4,6-collidine as additive.

Instead, monosubstitution by Friedel−Crafts reaction was observed as the major pathway.85 Another drawback of this process is the requirement of a large excess of triflimide (6 equiv). Therefore, the same group spent effort to improve this protocol. Their initial effort was the use of an oxygen analogue of 2-(silyloxy)allyl alcohol 108b, which was found to exhibit equally good reactivity in the desired cycloaddition. Furthermore, they envisioned that 2-siloxy acrolein should also be able to generate a similar oxyallyl cation. Moreover, it was expected to improve the reaction by decreasing the loading of triflimide. Indeed, as expected, a catalytic amount of triflimide was sufficient to promote the reaction to complete within 3 h at room temperature, leading to the [4 + 3] cycloadduct in 89% yield. In this reaction, a silyl shift is involved to deliver the observed product. Additional studies identified that other catalysts, such as Cu(OTf)2 and Sc(OTf)3, could also be equally active. It is worth noting that 2-substituted pyrroles are now viable substrates with this improved protocol. 2.1.6. [6 + 2] Cycloadditions. Efficient assembly of medium-sized rings (8−11-membered rings) has been a longstanding challenge in organic synthesis due to the disfavored thermodynamic and kinetic features (ring strain and high activation barrier) as well as transannular interactions of this type of ring formation. In particular, 8-membered lactones are notoriously difficult to make. However, they are useful substructures in a wide range of bioactive natural products. Previously known strategies for medium-sized lactone formation are typically ring-closing metathesis and intramolecular lactonization from seco acids. Because of intermolecular competition, these reactions are normally executed under high dilution conditions in order to favor the intramolecular pathway, although the effect is hard to predict. Therefore, these reactions are typically hard to scale up for large-scale applications. In 2012, Sun’s group designed novel 1,6-amphoteric molecules and successfully applied them in an intermolecular [6 + 2] cyclization process, leading to efficient synthesis of 8membered lactones (Scheme 27).86,87 In this design, aldehyde Scheme 27. Design of 1,6-Amphoteric Molecules for Medium-Ring Lactone Synthesis

and oxetane functional groups are linked by a two-carbon tether. The more electrophilic carbonyl is expected to accept nucleophilic attack. The resulting oxide anion then serves as an internal nucleophile to open the properly positioned oxetane moiety, which releases another nucleophilic oxide that is in a 6position relative to the aldehyde carbon, thereby forming a 1,6amphoteric type situation. If a two-carbon dipolarophile is 10359


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Scheme 28. Possible Mechanisms for the [6 + 2] Cyclization

Scheme 29. HNTf2-Catalyzed Intermolecular Ring Expansion of Cyclic Hemiaminals

Scheme 30. [2 + 2 + 1] Annulation of Alkynes, Nitriles, and Iodosobenzene

2.1.7. [2 + 2 + 1] Annulations. In 2013, Saito et al. reported that triflimide or triflic acid could promote an efficient [2 + 2 + 1] annulation between alkynes and nitriles with an oxidant to furnish substituted oxazoles with excellent regioselectivity.90 In their initial effort, iodosobenzene was employed as the oxygen source of the oxazole products. A variety of alkynes, including terminal and internal alkynes, all successfully underwent the [2 + 2 + 1] annulation in moderate to good yields (Scheme 30). Different from the previously reported gold-catalyzed transformation of this type, this metal-free process featured reversed regioselectivity.91 Mechanistic studies suggested that the Kosertype reagent PhI(OH)NTf2 generated from PhIO and HNTf2 might be the actual promoter. This reagent serves to activate the alkyne to generate alkenyliodonium triflimide 132 as the key intermediate. Subsequent nucleophilic attack by the nitrile followed by water addition and intramolecular cyclization results in a six-membered ring intermediate 134. Final reductive eliminate delivers the oxazole product. The authors carried out control experiments to substantiate this mechanism. For example, the triflate analogue of alkenyliodonium triflimide 132 was observed in the absence of nitrile, and the structure was confirmed by X-ray crystallography. Its chemical competence in this reaction was also demonstrated. It is worth noting that the same research group also reported a related synthesis of oxazoles using ketones and 1,3-dicarbonyl compounds, instead of

alkynes, with nitriles in the presence of HNTf2. The same type of oxazole products could be formed with good efficiency.92 Later on, the same group reported a catalytic version of this [2 + 2 + 1] annulation, in which iodobenzene was used in a catalytic amount in conjunction with meta-chloroperoxybenzoic acid as the stoichiometric oxidant.93 More recently, the same group also extended this process to the synthesis of bicyclic tetrahydrofuro[2,3-d]oxazoles by employing homopropargylic alcohols in place of simple alkynes. Mechanistically, it was believed that the internal alcohol nucleophile intercepts the vinyl triflimide moiety intramolecularly before nitrile addition, thus altering the pathway to form the bicyclic products.94 2.1.8. [2 + 2 + 2] Cycloadditions. Triflimide is known as an effective activator of electron-rich alkynes, including ynamides. 10360


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resulting from interception of the intermediate by the internal alkyne motif. The authors proposed that the reaction begins with ynamide protonation in the first step, forming keteniminium 138. There are two possible pathways from this interemdiate. In path a, nucleophilic attack by another ynamide forms vinyl keteniminium 139. Nitrile addition forms cyclic intermediate 141, which might proceed either stepwise (via 140) or in a concerted fashion. Finally, deprotonation of 141 delivers the pyridine product and regenerates the acid catalyst. Alternatively, keteniminium 138 might undergo nitrile attack to form 142 (path b), which then reacts with another ynamide molecule to form cyclic intermediate 144 via 143 (Scheme 32). A similar deprotonation closes the catalytic cycle. On the basis of DFT calculations and some control experiments, the authors believed that path a is kinetically more favorable and likely to be more reasonable. Particularly noteworthy is the smooth turnover of the strong acid catalyst in the presence of the basic pyridine product. This seemingly incompatible situation triggered the authors to probe whether it is the triflimide or the pyridine−HNTf2 adduct that serves as the actual catalyst. Indeed, the authors made the latter adduct and found that its catalytic activity was much lower, thus ruling out the possibility of this adduct as the actual catalyst. Further control experiments indicated that the ynamide substrates are so reactive that they outcompete the pyridine product in reacting with triflimide, thereby preventing catalyst deactivation and ensuring smooth turnover.

In 2016, Zhang, Sun, and co-workers discovered that this activation could be employed in a highly efficient [2 + 2 + 2] cycloaddition of ynamides and nitriles, leading to efficient synthesis of fully substituted pyridines.95 In the presence of 10 mol % of triflimide, 2 equiv of ynamides and 1 equiv of nitriles participated in the cycloaddition to form 2,4-diaminopyridines with high regioselectivity at room temperature (Scheme 31). Scheme 31. HNTf2-Catalyzed [2 + 2 + 2] Cycloaddition for Pyridine Synthesis

2.2. Aldol Reactions

This selectivity is highly noteworthy considering that the same reaction partners could lead to a different family of cycloaddition products, pyrimidines, when a gold catalyst was employed.96 It is also notable that triflimide exhibited superior catalytic activity when compared with other Brønsted acids, including triflic acid and trifluoroacetic acid. In addition to trimolecular [2 + 2 + 2] cycloaddition, the authors also found that the process could be highly concentration-dependent when an internal reaction motif is available, i.e., with a bimolecular option. For example, the reaction of cyanoalkyne 137 and acetonitrile at 1.0 M concentration gave the trimolecular cycloaddition product 136a preferentially. In contrast, at 0.05 M concentration, the same substrates led to a bicyclic pyridine 136b in 78% yield,

Aldol reaction is one of the most useful approaches to forge carbon−carbon bonds in organic synthesis.97 Although significant progress has been made in the development of useful catalytic aldol reactions in the last few decades, there still remain challenges in stereoselectivity control with some reaction partners. Mukaiyama aldol reaction employs silyl enol ethers as the enolate equivalent, in which the silyl group serves as a sterically demanding group that can positively influence diastereocontrol. It is important to note that Mukaiyama aldol reaction proceeds typically via an open transition model, which leads to significant challenge in diastereocontrol. In this context, Yamamoto and co-workers have made significant and systematic

Scheme 32. Possible Mechanisms for the [2 + 2 + 2] Cyclization

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adduct of the cross-aldol reaction with excellent diastereoselectivity and good yield. The authors proposed that the high efficiency and low catalyst loading likely benefit from the remarkable “self-repair” ability, particularly when there is adventitious moisture in the system that may destroy the silyl triflimide catalyst. The key point for this notion is that HNTf2 resulting from decomposition of the actual catalyst silyl triflimide can be turned back into the same silyl triflimide at the expense of a small amount of the silyl enol ether substrate (Scheme 34a). Therefore, this reaction is robust and does not require extremely dry condition. Owing partly to this feature, the reaction is indeed operationally simple.100 Additionally, it is worth mentioning that a series of methods are available for the generation of silyl triflimides from the HNTf2.101 For example, trimethylsilyl triflimide (TMSNTf2) can be prepared in good yields by mixing HNTf2 with a range of trimethylsilyl compounds, such as allyltrimethylsilane, vinyltrimethylsilane, phenyltrimethylsilane, and trimethylsilane. These reactions can sometimes be employed for in situ generation of the TMSNTf2 catalyst (Scheme 34b). In addition, such silyl triflimides can also be generated in situ from silyl compounds and ammonium triflimides, such as the salt between pentafluoroaniline and triflimide. The use of ammonium triflimides is more operationally simple than the direct use of triflimide, due to its hygroscopic and easy sublimation properties that may sometimes lead to a reproducibility issue.102 The β-hydroxy aldehydes and ketones generated from the HNTf2-catalyzed Mukaiyama aldol reactions are useful building blocks to access more complex chiral architectures. Indeed, Boxer and Yamamoto demonstrated a series of one-pot reactions using this HNTf2-catalyzed Mukaiyama aldol reaction (Scheme 35).103,104 For example, adduct 150 resulting from the crossaldol reaction between tris(trimethylsilyl)silyl enol ether 145 and aldehyde 149 could further react directly with different nucleophiles, such as silyl enol ether 151, vinyl Grignard reagent 153, and tribromomethyllithium 155. The corresponding syn1,3-diol products were formed in high overall yields and diastereoselectivity. The synthetic value of this protocol was further illustrated in the synthesis of the natural product (+)-cryptocarya diacetate 160 with high efficiency. This highly efficient cross-aldehyde−aldol reaction protocol was then extended by the same group to ketone-derived super silyl enol ethers.105 With essentially the same reaction system, the corresponding β-hydroxy ketones were obtained with excellent diastereoselectivity (Scheme 36). With acetonederived silyl enol ether 161 and chiral aldehyde 162, the major syn diastereomer was formed with 99:1 dr, consistent with the Felkin−Ahn model. In another case, the cyclohexanonederived silyl enol ether reacted with isobutyraldehyde to form

contributions. They have designed diverse innovative strategies and catalytic systems to achieve a wide range of efficient and diastereoselective Mukaiyama aldol reactions. In 2001, Yamamoto and co-workers discovered that silyl triflimide, which was generated in situ from the precatalyst HNTf2 and the silyl enol ether substrate, could efficiently catalyze Mukaiyama aldol reaction.98 In this pioneering example, the trimethylsilyl group was used for silyl enol ether; hence, the corresponding TMSNTf2 was the actual catalyst. With slow addition of the carbonyl reactant and proper choice of solvent, the reaction was highly efficient with the catalyst loading as low as only 0.3−1.0 mol %. Unfortunately, the diastereoselectivity was moderate. In 2006, the same group made a breakthrough by using tris(trimethylsilyl)silyl (TTMSS) group, also called “super silyl” group, for the silyl enol ether to achieve an extremely efficient aldehyde cross-aldol reaction.99 Specifically, by using treatment of silyl enol ether 145 and aldehyde with 0.05 mol % of HNTf2, a broad range of the β-hydroxy aldehydes (1:1 adduct) were produced in good yields with good diastereoselectivity (Scheme 33). The TTMSS group was proved to be uniquely effective in Scheme 33. HNTf2-Catalyzed Aldol Reaction of Silyl Enol Ether with Aldehydes

three aspects. First, the Lewis acid TTMSSNTf2 generated in situ is highly Lewis acidic (vs TMSNTf2), thus leading to high catalytic activity; second, the corresponding silyl enol ether with this super silyl group is highly nucleophilic, thereby leading to good reactivity; finally, the large size of this silyl group is extremely effective in controlling diastereoselectivity, and moreover, the silyl enol ethers of this type have reasonable stability that allows purification by chromatography. As a result, these cross-aldol reactions could generally have good to excellent diastereocontrol. In the same report, the authors also demonstrated that, with 2.2 equiv of the silyl enol ether substrate, a cascade process could take place to deliver the 2:1

Scheme 34. (a) Mechanism and Self-Repair Ability of the Catalytic System and (b) Synthesis of TMSNTf2

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siloxy methyl ketone 167 with LiHMDS promoted the aldol reaction with pivalaldehyde with excellent syn diastereoselectivity, forming 1,5-syn-diol 169 with 96:4 syn/anti ratio (Scheme 37). In sharp contrast, under the HNTf2-catalyzed Mukaiymama aldol conditions, the super silyl enol ether 171 with pivalaldehyde led to the formation of 1,5-anti-diol 172 with 97:3 anti/syn ratio. It was found that the use of super silyl group Si(TES)3 provided the best selectivity, indicating that the remote control by steric bulk is functional. Both reactions were efficient regarding chemical yield, although the diastereocontrol was opposite. The author proposed two different transitions states to rationalize the distinct diastereocontrol. The key difference is that in the former case the reaction proceeds through a six-membered ring closed transition state, while the Mukaiymama aldol reaction adopts an open transition state. The utility of this method was illustrated by simple reduction of 1,5diols to form synthetically useful 1,3,5-triols with excellent diastereoselectivity. Instead of incorporating a β-super silyloxy [tris(trimethylsilyl)silyloxy] group in the enolate partner, the same laboratory also evaluated the stereoselectivity control when such a bulky group was incorporated in the electrophilic partner.107 For example, when aldehydes 174 bearing a β-super siloxy group were employed to react with silyl enol ether 175, it was found that the steric bulk of the silyl group on the enol ether and the βsiloxy group on the aldehyde both had direct influence on diastereoselectivity (Scheme 38). The highest diastereoselectivity was obtained when the super silyl group was used in both positions.

Scheme 35. One-Pot Cross-Aldol Reaction and Nucleophilic Addition

Scheme 36. HNTf2-Catalyzed Aldol Reaction with Ketone Super Silyl Enol Ethers

Scheme 38. Diastereocontrol with β-Siloxy Aldehydes

adduct 166 with anti diastereomer as the major product (95:5 dr), which is remarkable in view of the disappointing diastereoselectivity obtained when the TBS- or TMS-enol ethers of cyclohexanone were used with other catalysts. The unusually high efficiency allowed further one-pot synthesis of a range of tertiary carbionls with high diastereoselectivity upon addition of different nucleophiles. On the basis of their existing efforts in Mukaiyama aldol cascade reactions, Yamaoka and Yamamoto further developed an efficient method to construct 1,5-diols from β-super siloxy ketones and aldehydes.106 It was amazing that the diastereoselectivity could be completely switched by the reaction conditions employed. Specifically, enolization of the β-super

Further modification on the two reaction partners would lead to more useful substituted aldol products that may not be otherwise easily accessible. For example, by using (Z)-α-halo silyl enol ethers 179, the Mukaiyama aldol reaction with benzaldehyde successfully proceeded to form anti-β-siloxy-αhaloaldehyde 180 in 99% yield with excellent diastereoselectiv-

Scheme 37. 1,5-Stereoselective Aldol Reactions

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ity (Scheme 39).108 However, when alkyl aldehyde 181 was employed, the yield decreased dramatically to 22% with HNTf2

(Scheme 41). These aldol products have the potential to further build polyketide fragments with high step-economy.

Scheme 39. Mukaiyama Cross-Aldol Reaction of α-Halo Silyl Enol Ether 179

Scheme 41. Synthesis of Polypropionates via HNTf2Catalyzed Mukaiyama Aldol Reaction

In principle, the Mukaiyama aldol products can continue to participate in additional aldol iteration, provided that the reaction partner silyl enol ether is in excess. Such iterative aldol reactions, if successful in a one-pot manner, would provide expedient synthesis of polyols. Indeed, one-pot double-aldol cascade reactions have been known. For example, simply by adding 2 or more equiv of the super silyl enol ether partner, the same conditions with HNTf2 catalyst at room temperature could lead to the formation of double-aldol products with good yield and diastereoselectivity.111 However, it is a significant challenge to extend this process to a triple-aldol cascade, probably due to the increased steric clash during interaction of (TMS)3SiNTf2 with the double-aldol product. Nonetheless, after substantial efforts in evaluating different additives, Yamamoto and coworkers found that the use of iodine-containing molecules as cocatalyst could increase the formation of the desired triplealdol product. Among them, iodobenzene was found to be a superior cocatalyst, leading to the desired 3,5,7-trisilyloxy aldehydes as the major products (Scheme 42). Obviously,

as the catalyst. Nevertheless, the authors were able to improve the reaction using the carbon acid 183 as the catalyst. This process represented the first Mukaiyama cross-aldol reaction of silyl enol ethers derived from α-halogenated acetaldehydes. It is also important to note that such stereoselective synthesis of αhaloaldehydes is highly useful. More recently, the same group also extended the reaction protocol to bis(super silyloxy) enol ethers, such as 185 (Scheme 40).109 The reaction provided a general method for highly synScheme 40. HNTf2-Catalyzed Aldol Process for the Formation of α,β-Dioxyaldehydes

Scheme 42. HNTf2-Catalyzed Triple-Aldol Cascade

stereoselective synthesis of α,β-dioxyaldehydes 186. A broad range of aldehydes, such as those having alkenyl and alkynyl groups, all participated successfully in this HNTf2-catalyzed Mukaiyama aldol reaction. Notably, iodobenzene served as an important additive in this reaction, which accelerated the reaction by activating the silylenium cation generated in situ. The synthetic value of this method was explored by transforming the resulting α,β-dioxyaldehydes to 1,2,3-triols in high yield through the addition of Grignard reagents. In addition, propionaldehyde-derived silyl enol ethers were also found to be useful nucleophiles for this type of cross-aldol reaction.110 It is amazing that both 2,3-syn and 2,3-anti products could be selectively formed simply by controlling the doublebond configuration of initial silyl enol ether. The Z-silyl enol ether gave the 2,3-syn product and the E-silyl enol ether afforded the 2,3-anti product, both with good diastereoselectivity

iodobenzene played a crucial role in generating the active species. After mechanistic studies enabled by mass and NMR spectroscopies, the authors proposed that iodobenzene might react with (TMS)3SiNTf2 to generate the actual catalyst 193, which might be responsible for the high reactivity for this triple cascade. 10364


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Scheme 43. Synthesis of Polymethoxy-1-alkene 200

carbon−heteroatom bonds.114 Transition metals have been dominantly employed as catalysts for allylation reactions. Recently, metal-free catalytic systems have also emerged to achieve efficient and environmentally friendly allylation reactions. Among them, HNTf2 has been demonstrated as a versatile catalyst for allylation of a range of functional groups, including aldehydes, α,β-unsaturated carbonyl compounds, and benzyl and allyl acetates. In 1998, Robertson and co-workers reported a pioneering example of using HNTf2 to catalyze allylation.115 In the presence of 10 mol % of HNTf2, allylation of enone 203 with allylsilanes 204 in a 1,4-addition manner proceeded with excellent efficiency (Scheme 45). In addition to cyclic enones, linear α,β-

The synthetic utility of this triple-aldol reaction was later demonstrated by the same group in the synthesis of two natural products.112 Polymethoxy-1-alkene 200 was isolated from tolytoxin-producing blue−green algae Tolypothrix conglutinate var. In its synthesis, the HNTf2-catalyzed triple-aldol reaction was employed as the key step (Scheme 43). The reaction between hexanal and super silyl enol ether 145 proceeded efficiently to form aldehyde 194. An additional aldol reaction with the enolate derived from ketone 197 produced 198 in the presence of LiHMDS. Next, simple functional group manipulations, including reduction, deprotection, and methylation, delivered product 200. The whole synthesis required only 10 steps and is currently the shortest route. In addition to intermolecular Mukaiyama aldol cascade processes, Izumiseki and Yamamoto also designed a very elegant cascade process involving an intermolecular/intramolecular aldol sequence (Scheme 44).113 The reaction

Scheme 45. HNTf2-Catalyzed Allylation of ElectronDeficient Olefins

Scheme 44. HNTf2-Catalyzed Intermolecular/ Intramolecular Mukaiyama Cascade

between disilyl enol ethers 201 and an aldehyde proceeded in the presence of a catalytic amount of HNTf2 to form the cyclic products 202 with four or more adjacent stereogenic centers. Different sized rings, including 5-, 6-, and 7-membered rings, could all be obtained. From these examples, it is evident that triflimide is extremely versatile in Mukaiyama aldol reactions. The success is also attributed to the ingenious utilization of the uniquely effective super silyl group. With these two factors, Mukaiyama aldol reactions have been advanced to a new height and proved useful in the stereoselective synthesis of a wide range of synthetic building blocks.

unsaturated ketones and esters were also reactive. Similar to other triflimide-catalyzed reactions using silyl-based nucleophiles (e.g., Mukaiyama aldol reaction), the actual catalyst in this allylation was also proposed to be the corresponding in situ generated silyl triflimide (TMSNTf2). In addition to the conjugate addition to electron-deficient olefins, the same catalytic system combining allylsilane and triflimide has also been versatile in the allylation of other electrophiles. For example, during their studies of Mukaiyama aldol reactions, Yamamoto and co-workers have also reported efficient Sakurai−Hosomi allylation of aldehydes.98,100 Furthermore, carbocations generated in situ could also be allylated

2.3. Allylation Reactions

Allylation reactions are a family of versatile and powerful transformations widely used to construct carbon−carbon and 10365


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methoxybenzyl acetate and allylsilane. It is important to note that the benzyl cation intermediate needs to be stabilized in order for the reaction to be successful. Indeed, no desired reaction was observed when benzyl acetate and thiophen-2ylmethyl acetate were employed. Nevertheless, Liu and coworkers further extended this allylation to allylic acetates as reactive precursors to the carbocation intermediates.118 The corresponding allylation products could be obtained in good yields, favoring the linear allylation products. The reaction was highly efficient with only 0.5 mol % of triflimide. In addition to using allyl silanes, allylboronates are also regular reagents for allylation reactions. In 2005, Hall and co-workers reported that triflimide could also catalyze the allylation of aldehydes with allylboronates.119 For example, allylboronate 215 bearing an ester group underwent smooth allylation, and the intramolecular lactonization proceeded spontaneously to form γ-butyrolactone 217 bearing an exocyclic methylene unit, a subunit of a large family of useful molecules (Scheme 48). The

under the same conditions. In 2010, Yang and Tian reported a catalytic coupling allylation of N-benzylic sulfonamides with allyl silanes to afford the corresponding substituted alkenes (Scheme 46).116 In this transformation, triflimide showed high Scheme 46. HNTf2-Catalyzed Allylation of N-Benzylic Sulfonamides

Scheme 48. HNTf2-Catalyzed Allylboration catalytic activity, leading to excellent yield. In sharp contrast, other acids like sulfuric acid and triflic acid failed to give the desired allylation product. It was proposed that triflimide serves to help generate the carbocation intermediate in an SN1-type mechanism, and the superiority of triflimide is presumably attributed to its high acidity as well as the low nucleophilicity and compatibility of the counteranion (Tf2N−). In the same report, the authors also reported that, by replacing allyl silane with simple hydrosilane, triflimide could also catalyze the reduction of N-benzylic sulfonamides. A similar mechanism should be followed in these two processes. Almost at the same time, Ghosez and co-workers independently reported a similar allylation reaction.117 They employed acetate as the leaving group, rather than sulfonamide, for in situ generation of the carbocation intermediate (Scheme 47). For example, with the triflimide catalyst, 1-allyl-4methoxybenzene was produced in 90% isolated yield from p-

catalytic efficiency was equally good compared with triflic acid. To account for the high diastereoselectivity, the authors proposed a closed six-membered ring transition state, but the actual function of the acid catalyst remained elusive. 2.4. Friedel−Crafts and Related Reactions

Friedel−Crafts reactions represent one of the import approaches to form carbon−carbon bonds on arenes, in which catalysts are typically needed to activate the carbon-based electrophile. In conventional synthesis, commonly used catalysts for Friedel−Crafts reactions include Lewis acids (e.g., AlCl3, FeCl3, BF3, etc.) and Brønsted acids (e.g., H2SO4 and H3PO4). With in-depth investigations, there were emerging needs to seek out strong acid catalysts for achieving mild Friedel−Crafts reactions. In this context, triflimide has been identified to be quite competent in promoting a wide range of Friedel−Crafts reactions, including intramolecular and intermolecular ones. 2.4.1. Intermolecular Reactions. In 1996, Yamamoto and co-workers reported a pioneering example of using triflimide to catalyze a Friedel−Crafts alkylation reaction.120 With 10 mol % of triflimide, the intermolecular C−C bond-formation reaction between trimethylhydroquinone 218 and isophytol 219 in refluxing hexane proceeded to form tocopherol 221, also known as vitamin E, in only one operation (Scheme 49). The product was obtained in 95% yield, and the catalyst loading could be further reduced to as low as 1 mol % with slight erosion of yield (90%). Mechanistically, triflimide is likely to activate the tertiary alcohol to generate the reactive carbocation intermediate for the Friedel−Crafts reaction. Moreover, in the subsequent cyclization step, triflimide was also believed to play a role. Overall, triflimide is extremely effective, with which the mild reaction does not require azeotropic removal of water. Therefore, this protocol could be highly attractive for large-scale synthesis. This approach was later applied in the synthesis of troglitazone.121 In 2002, Cossy et al. demonstrated another HNTf2-catalyzed Friedel−Crafts alkylation using catechol 222 with dimethoxymethane 223 (Scheme 50). The alkylation product 224 was

Scheme 47. HNTf2-Catalyzed Allylation of Benzyl Acetate and Allylic Acetate

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Scheme 49. HNTf2-Catalyzed Synthesis of Tocopherol

Scheme 52. HNTf2-Catalyzed Hydroarylation of Ynamides

the reaction process was altered to form amides instead of enamides. In 2008, Sorimachi and Terada reported an efficient alkylation of arenes cocatalyzed by ruthenium and triflimide.127 In this reaction, the ruthenium catalyst was used for isomerization of the N-allylamide to enamide, which was then protonated by triflimide to generate the reactive imine electrophile for subsequent Friedel−Crafts alkylation with 1,3,5-trimethoxybenzene to afford the desired product 238 in 84% yield (Scheme 53). Although some weaker Brønsted acids were demonstrated

Scheme 50. HNTf2-Catalyzed Alkylation of Catechol with Dimethoxymethane

formed in 60% yield. Together with this study, the authors have also studied Mukaiyama aldol reaction using triflimide as catalyst.122 In a related reaction, Ghosez and co-workers described a benzylation of electron-rich arenes employing benzylic acetates as the carbocation precursor (Scheme 51). This reaction provided a rapid and efficient approach to synthesize diarylmethanes, an important family of compounds often with useful biological activity.123

Scheme 53. Relay Catalysis for Tandem Isomerization/ Friedel−Crafts Sequence

Scheme 51. HNTf2-Catalyzed Synthesis of Diarylmethanes

to be useful also for certain substrates, it is worth noting that, when these acids failed to promote the reaction in some other cases, triflimide had to be employed, thereby highlighting its superior activity. Traditionally, common alkylation reagents for the Friedel− Crafts reactions include alkyl halides, alkenes, alcohols, etc. The development of new alkylation reagents is in great demand. In addition to the above-mentioned alkylation reagents, Nomiyama and Tsuchimoto reported a triflimide-catalyzed efficient alkylation of pyrroles employing the combination of ketones and superstoichiometric amounts of triethylsilane as a set of alkylation reagents (Scheme 54).128 This approach is amenable to different functional groups, such as halides, alkenes, and alkynes. Mechanistic studies showed that the process involves overreaction to bis(pyrrole) product 244. However, this compound could reverse to the carbocation 245 for reduction by the silane to deliver the simple alkylation product. Triflimide is also acidic enough to activate olefins to generate the corresponding carbocation for Friedel−Crafts alkylation

As discussed in the [2 + 2 + 2] Cycloadditions section, triflimide is capable of activating the electron-rich triple bond in ynamides, leading to the formation of highly active intermediate. In 2005, Zhang reported an intermolecular C−C bond formation upon trapping the keteniminium by electron-rich arenes. Specifically, indole, pyrrole, and furan could all successfully react to form the corresponding vinylation products in good yield (Scheme 52). The authors also demonstrated the synthetic utility of this method by converting the resulting vinyl indole to carbazole via a Diels−Alder reaction.124,125 More recently, Shin and co-workers also reported a triflimidecatalyzed oxygenative bimolecular Friedel−Crafts-type coupling of ynamides.126 In the presence of the pyridine-N-oxide oxidant, 10367


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that triflimide could catalyze the cyclization of siloxy alkynes with arenes (Scheme 57) to form substituted tetralone-derived

Scheme 54. HNTf2-Catalyzed Alkylation of Pyrroles

Scheme 57. HNTf2-Catalyzed Intramolecular Cyclization of Siloxy Alkynes

reactions under mild conditions. Xia, Jiang, and co-workers successfully developed such a process to synthesize a range of 1,1-diarylalkanes, an important scaffold in therapeutic agents.129 For example, in the presence of a catalytic amount of HNTf2, vinylarenes reacted with a wide range of electron-rich arenes to furnish 1,1-diarylalkanes in excellent yields (Scheme 55). The

silyl enol ethers with high efficiency.133,134 The reaction proceeds with protonation of the siloxy alkyne triple bond, forming silyl ketenium ion 259. In the presence of a properly positioned arene nucleophile, the intramolecular Friedel−Crafts reaction takes places to form product 260. Importantly, other catalysts, such as TfOH, AgNTf2, and AgOTf, showed dramatically lower catalytic activity for this reaction, highlighting the unique features of triflimide. Shortly thereafter, Hsung and co-workers reported a ynamide counterpart of this process (Scheme 58).135 In a similar pattern,

Scheme 55. HNTf2-Catalyzed Hydroarylation and Hydroalkenylation of Vinylarenes

Scheme 58. HNTf2-Catalyzed Intramolecular Cyclization of Ynamides

homo- and cross-hydroalkenylation of vinylarenes allowed rapid access to a range of useful molecules. Among them, the antiinsomnia agent benzothiophene IV 251 could be synthesized efficiently from 4-fluorostyrene and benzothiophene. In addition to Friedel−Crafts alkylations, HNTf2 is also capable of promoting Friedel−Crafts acylation reactions.130−132 Among them, carboxylic acids were mostly used in conjunction with triflimide to generate acyl cation intermediate for the acylation process. In 2006, the groups of Shimada and Wähälä independently reported such acylation reactions. While the former had to use forcing conditions (200 °C), much more mild conditions were employed in the latter case owing to the use of microwave and ionic liquids (Scheme 56). 2.4.2. Intramolecular Reactions. Intramolecular Friedel− Crafts reactions are useful approaches to access arene-fused polycyclic structures. In 2004, Kozmin and co-workers reported

the ynamide is initially activated by triflimide to form keteniminium ion 262, which is then trapped by the internal tethered arene motif to form the cyclic product 263. In this reaction, triflimide was used only in 1 mol % loading, which showed obvious superior performance to typical π-Lewis acids, such as PtCl2, AgNTf2, and Brønsted acid para-nitrobenzenesulfonic acid. In 2015, Li reported an interesting triflimide-catalyzed synthesis of indane derivatives from the formal [3 + 2] cyclization of benzylic alcohols and alkenes.136 The carbocation generated from benzylic alcohols initiates an initial C−C bond formation from the alkene. The resulting carbocation then cyclizes back to the arene in an intramolecular Friedel−Crafts pathway to form the indane product (Scheme 59). A variety of benzylic alcohols and alkenes, including di- and trisubstituted alkenes, all participated successfully in this transformation with excellent stereoselectivity. Very recently, Thomson and co-workers employed the same initiation step, i.e., from benzylic alcohols and triflimide, and employed allylsilanes as the alkene partner to participate in a

Scheme 56. HNTf2-Catalyzed Friedel−Crafts Acylation

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Scheme 59. HNTf2-Catalyzed [3 + 2] Annulation of Benzylic Alcohols with Alkenes

Scheme 61. HNTf2-Catalyzed Benzannulation for the Synthesis of Naphthalenes

very similar process leading to various indane products.137 In the same report, the authors also discovered that the use of allylsilane 268 bearing an alcohol functionality could alter the Friedel−Crafts process to form a six-membered ring 270. Thus, the authors were able to apply this method in the synthesis of cinnamophilin A 271 after simple 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) oxidation (Scheme 60). This three-step synthesis was highly efficient with an overall yield of 40%. Scheme 60. HNTf2-Catalyzed Annulation of Allylsilanes with Benzylic Alcohols unsaturated carbonyl compounds toward Michael additions. Indeed, triflimide also has been demonstrated to serve as a uniquely effective catalyst in these reactions. In 2003, Wabnitz and Spencer reported pioneering examples of this type.140 With a catalytic amount of triflimide, conjugate additions of carbamates, alcohols, and thiols to α,β-unsaturated ketones, alkylidene malonates, and acrylimides proceeded smoothly under mild conditions (Scheme 62). Compared with other Scheme 62. HNTf2-Catalyzed Michael Additions

Triflimide has been also known to catalyze a range of other examples of cation-initiated, one-pot cascade reactions involving an intramolecular Friedel−Crafts step. For example, Ratovelomanana-Vidal and co-workers have recently reported a triflimide-catalyzed intermolecular benzannulation reaction between arylacetaldehydes and alkynes for the formation of polysubstituted naphthalenes with excellent regioselectivity (Scheme 61).138,139 The reaction is initiated by proton activation of the carbonyl, followed by alkyne addition. The resulting vinyl cation intermediate is trapped by the arene motif in a Friedel−Crafts pathway and then isomerizes to the observed naphthalene product. The reaction exhibited reasonably good scope regarding both partners and different functional groups. Interestingly, this strategy was further extended to epoxides and acetals in place of the ketone functional group.

catalysts, triflimide provided not only the best chemical yield but also the fastest reaction rate. It is also worth mentioning that this is the first Brønsted acid-catalyzed general hetero-Michael addition. Later on, the same group carried out more mechanistic studies. When 2,6-di-tert-butylpyridine was added to the reaction mixture, no reaction was observed, thus confirming that the proton is indeed the actual catalyst.141 With the similar activation pathway, in 2007, Maruoka and coworkers discovered that aryldiazoacetates could also serve as a reactive nucleophile to react with α-substituted acroleins in a Michael-initiated cyclization process (Scheme 63).142 The reaction provides a stereoselective synthesis of tetrasubstituted

2.5. Michael Addition Reactions

Michael addition reactions provide a straightforward construction of β-functionalized carbonyl compounds. Lewis acids have been widely known as LUMO-lowering activators for α,β10369


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reaction of 294 proceeded to form bicyclic products 295 in good to excellent yields and with high trans-selectivity (Scheme 65). Aryl and alkyl groups were all tolerated in this transformation.

Scheme 63. HNTf2-Catalyzed Michael-Initiated Cyclopropanation

Scheme 65. HNTf2-Catalyzed Nazarov Cyclization

cyclopropanes. An alternative mechanism of this process may involve 1,3-dipolar cycloaddition. However, the authors ruled out this possibility due to the chemical incompetence of the direct 1,3-dipolar cycloadduct under the standard conditions. Later, the same group developed a related efficient method for the asymmetric synthesis of aziridines using the Brookhart− Templeton aziridination reaction.143 The authors found that triflimide could catalyze this process between aldimines/ ketimines and diazo compounds. Camphorsultam was employed as a chiral auxiliary, which led to excellent diastereomeric induction. Although TfOH and BF3−OEt2 also showed good catalytic activity for α-methyl/ethyl-α-diazocarbonyl compounds to form the aziridination products with excellent diastereoselectivity as well, they failed to promote the efficient aziridination of α-unsubstituted α-diazocarbonyl compounds, e.g., 290. For example, the reaction catalyzed by TfOH typically gave the desired products 292 in low yield, together with a considerable amount of byproducts 293 via the migration of the Ar group via the diazonium intermediate. In sharp contrast, triflimide showed good catalytic performance in these reactions to form the desired aziridine products with better efficiency and excellent stereoselectivity (Scheme 64).

In 2013, Tius and co-workers documented another example of triflimide-catalyzed diastereospecific Nazarov cyclization of fully substituted dienones.147 In the presence of 20 mol % of triflimide, the highly polarized “push−pull” vinylogous carbonates 296 led to fully substituted cyclopentenones 297 in good yields (Scheme 66). The 2-(trimethylsilyl)ethoxymethyl (SEM) Scheme 66. HNTf2-Catalyzed Nazarov Cyclization of Fully Substituted Dienones

Scheme 64. HNTf2-Catalyzed Asymmetric Aziridination

group was key to the observed high diastereoselectivity, because it could rapidly collapse to minimize erosion of the stereochemical integrity of the product. It is also remarkable that this reaction generated two adjacent all-carbon quaternary stereocenters. Recently, the same group also applied this reaction in the synthesis of natural product rocaglamide.148 2.7. Mannich Reactions

Mannich reactions are important approaches for practical synthesis of amino carbonyl compounds from imines or imine precursors. As a super Brønsted acid, triflimide has been demonstrated as a well-suited catalyst for Mannich reactions. In 2005, Dalla and co-workers reported the first example in a βamido alkylation reaction, in which triflimide first promotes the in situ formation of N-acyliminium ions from N,O-acetals. Next, silyl enol ether 299 serves as the nucleophile to complete the intermolecular C−C bond formation, efficiently furnishing the α-amido alkylation product 300 with moderate diastereoselectivity under mild conditions (Scheme 67).149,150 In comparison with TIPSOTf and Sc(OTf)3, triflimide exhibited better catalytic activity, leading to a faster reaction rate. A similar process modified from this protocol was later applied in the synthesis of the natural product petrosin and its derivatives.151

2.6. Nazarov Cyclizations

Cyclopentenones are useful building blocks in organic synthesis and ubiquitous motifs in bioactive natural products. Nazarov cyclization provides an expedient method for the assembly of cyclopentenones from linear precursors.144,145 Both Lewis acids and Brønsted acids have been known to promote Nazarov cyclizations. In 2009, Bachu and Akiyama reported the first triflimide-catalyzed Nazarov cyclization.146 In this reaction, pyrrole was incorporated in the substrates to form pyrrole-fused bicyclic products, which were rarely studied before. Specifically, with 30 mol % of HNTf2 and under microwave irradiation, the 10370


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Scheme 67. HNTf2-Catalyzed Synthesis of Pyrrolidine Derivatives

Scheme 69. HNTf2‑Catalyzed One-Pot Amidoalkylation of Hydroxylactams

amidation reaction.154 With only 0.5 mol % of triflimide, the reaction reached almost quantitative yield within 20 min (Scheme 70). In contrast, the weak phenyl phosphinic acid typically required a much long reaction time. Scheme 70. HNTf2-Catalyzed Imine Amidation Reaction

In 2015, the same group employed a similar type of N,Oacetals in a tandem process involving a Friedel−Crafts step followed by gold-catalyzed intramolecular hydroarylation (Scheme 68).152 With this approach, a range of polycyclic compounds containing nitrogen heterocycles were produced in good yields and with moderate to good regioselectivity. Scheme 68. HNTf2-Catalyzed Tandem Imine Addition and Hydroarylation

2.8. Sigmatropic Rearrangements

The [3,3]-sigmatropic rearrangements are powerful reactions in organic synthesis. In 2010, Thomson and co-workers reported an interesting triflimide-catalyzed Stevens [3,3]-sigmatropic rearrangement of N-allylhydrazones 316. This process provided an efficient approach to construct σ-bond between two unfunctionalized sp3-carbons using a “traceless” bond-formation strategy, which is very unusual and may have important applications. In the same step, a stereodefined multisubstituted CC bond was also formed (Scheme 71).155 Two possible pathways were proposed by the authors. The first pathway begins with activation of the substrate by triflimide to trigger extrusion of CO2 and 2-methylpropene to give the intermediate 318, which then undergoes [3,3]-sigmatropic rearrangement to form 319. Deprotonation to regenerate the triflimide catalyst followed by elimination of N2 gas delivers the product. Alternatively, the N-allylhydrazone may undergo acid-catalyzed [3,3]-sigmatropic rearrangement first to form intermediate 321, which then releases CO2 and 2-methylpropene followed by N2 gas to complete the process. Further detailed DFT calculations combined with experiments led the authors to favor the latter pathway.156 Combined with these studies, the authors were able to further extend this process to the formation of a new sp3hybridized stereogenic center. In 2015, Dittrich and Bracher further applied this approach to the synthesis of episterol.157 In the key step, hydrazone 323 was

The same group also extended the above protocol to the Mannich reactions using trichloroacetimidated phthalimidederived N,O-acetals, which could be easily formed from the corresponding hydroxylactams and trichloroacetamide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). With the improved leaving ability of trichloroacetamides, triflimide was used to catalyze the N-acyliminium ion formation. Upon nucleophile addition, the Mannich products were generated in one pot with good to excellent yield (Scheme 69).153 Various nucleophiles, including silyl enol ethers, allyl silane, 1,3diketones, pyrrole, etc., were all suitable nucleophiles for this reaction. In addition to carbon nucleophile addition to imines or iminiums, triflimide could also catalyze heteronucleophilic addition to imines. In 2005, Antilla and co-workers reported that triflimide was extremely efficient in catalyzing an imine 10371


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Scheme 71. HNTf2-Catalyzed Sigmatropic Rearrangement of N-Allylhydrazone

Scheme 73. HNTf2-Catalyzed Chirality Transfer from Sulfur to Carbon

Scheme 74. HNTf2-Catalyzed Synthesis of PDMS

treated with triflimide to form the TBS-protected episterol in 19% yield with 50% isomers (Scheme 72). More recently, Maulide and co-workers reported a remarkable charge-accelerated [3,3]-sigmatropic rearrangement featuring 1,4-chirality transfer from sulfur to carbon atom.158 Upon activation by triflimide, electron-rich alkynes, such as ynamides and thioalkynes, were susceptible to nucleophilic attack by the chiral sulfoxide oxygen to form intermediate 327, which readily underwent [3,3]-sigmatropic rearrangement to give the αarylated products in good yields (Scheme 73). The chirality transfer was excellent in forming highly enantioenriched α-chiral carbonyl compounds. In contrast, with TfOH as the promoter, the chirality transfer specificity was significantly lower. The authors further carried out computational studies to rationalize the dependence of enantioselectivity on catalyst and substrates. This reaction represents an excellent example of exploitation of chiral sulfur reagents for asymmetric synthesis.

is noteworthy that the process with HNTf2 as initiator was much faster than that with TfOH.160 In 2010, Kakuchi and co-workers reported an efficient ringopening polymerization for the synthesis of poly(δ-valerolactone) (PVL) from δ-valerolactone (δ-VL) (Scheme 75).161 Scheme 75. HNTf2-Catalyzed Ring-Opening Polymerization of δ-Valerolactone

2.9. Polymerization Reactions

The development of efficient polymerization processes using a suitable catalyst is an important field in organic synthesis and materials science owing to the wide applications of polymer materials. As an unusually strong acid, triflimide has been demonstrated as a versatile initiator in many polymerization processes, including ring-opening polymerizations, group-transfer polymerizations, cationic polymerizations, etc.159−166 In 2002, Mignani and co-workers described a triflimidecatalyzed polymerization process for the synthesis of α,ωbis(trimethylsilyl)polydimethylsiloxanes (PDMS) with low molecular weight (

Triflimide (HNTf2) in Organic Synthesis - Chemical Reviews (ACS

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