Review

Cite This: Chem. Rev. XXXX, XXX, XXX−XXX pubs.acs.org/CR

Triflimide (HNTf2) in Organic Synthesis

Wanxiang Zhao† and Jianwei Sun*,‡
†
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
Downloaded from pubs.acs.org by UNIV OF NEW ENGLAND on 09/25/18. For personal use only.

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 non-
coordinating 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.
Chem. Rev.

CONTENTS Author Information AL

Corresponding Author AL
1. Introduction A ORCID AL
1.1. Overview about Triflimide A Notes AL
1.2. Synthesis of Triflimide B Biographies AL
2. Reactions Catalyzed or Mediated by Triflimide C Acknowledgments AL
2.1. Cycloadditions C References AL
2.1.1. [2 + 2] Cycloadditions C
2.1.2. [3 + 2] Cycloadditions F
2.1.3. [4 + 2] Cycloadditions H
2.1.4. [3 + 3] Cycloadditions I
2.1.5. [4 + 3] Cycloadditions J 1. INTRODUCTION
2.1.6. [6 + 2] Cycloadditions K 1.1. Overview about Triflimide
2.1.7. [2 + 2 + 1] Annulations L
2.1.8. [2 + 2 + 2] Cycloadditions L Triflimide (HNTf 2 ), also known as bis(trifluoro-
2.2. Aldol Reactions M methanesulfonyl)imide, is a commercially available white
2.3. Allylation Reactions Q crystalline solid. Because of the presence of two strongly
2.4. Friedel−Crafts and Related Reactions R electron-withdrawing trifluoromethanesulfonyl groups, trifli-
2.4.1. Intermolecular Reactions R mide belongs to the superacid family. Since its first synthesis
2.4.2. Intramolecular Reactions T in 1984,1 the study and exploitation of triflimide has evolved
2.5. Michael Addition Reactions U tremendously over the years. Prior to this Review, there have
2.6. Nazarov Cyclizations V been sporadic introductory articles on this acid.2,3 For example,
2.7. Mannich Reactions V Takasu reviewed specifically on triflimide-catalyzed cyclo-
2.8. Sigmatropic Rearrangements W addition reactions4 as well as their applications in the synthesis
2.9. Polymerization Reactions X of azaheterocycles and related molecules.5 Yamamoto6 and
2.10. Glycosylation Reactions Y Akiyama7,8 have also had excellent review articles on strong
2.11. Other Reactions Z Brønsted acids with special efforts devoted to some important
2.12. Use As a Cocatalyst or Additive AE reactions promoted by triflimide. Recently, triflimide has gained
3. Relevant Triflidic Acid (HCTf3) and Its Analogues AI particularly increasing attention in organic synthesis as well as
3.1. Brief Introduction (Structure, Synthesis, other areas, such as materials science.9−13 In this context, this
Properties, etc.) AJ
3.2. Their Participation in Organic Reactions AJ Received: May 3, 2018
4. Summary and Outlook AK

© XXXX American Chemical Society A DOI: 10.1021/acs.chemrev.8b00279

Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews Review

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 well-
ventilated conditions. However, compared with triflic acid
(TfOH), a fuming liquid acid, triflimide is much more user-
friendly. 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 single-
crystal 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 delocaliza-
tion. 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.
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
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 pricea ($/mol) pKa (AcOH) pKa (DMSO) pKa (DME) pKa (MeCN) pKa (H2O)
1 PhOH 29.2 18.0 10.0
2 CH3CO2H 21.9 12.3 4.75
3 PhCO2H 47.2 11.1 4.25
4 CF3CO2H 42.3 11.4 3.45
5 H2SO4 7.0 1.4 −2.5 8.7
6 HBr 0.9 −4.9 6.6 −9.0
7 FSO3H −10.5 1.5
8 TsOH 58.3 −1.6
9 TfOH 224.6 4.2 0.3 −11.4 0.7 −12
10 HNTf2 6194.4 7.8 −11.9 0.3 1.7
11 Tf3CH −16.4 −3.7

a
The prices are calculated based on Sigma-Aldrich.

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trifluoromethanesulfonyl amide (TfNH2) as the key intermedi-
ate, 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 2. New Synthetic Approaches by Caporiccio and Co-
workers 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.
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
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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 ring-
expansion 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 %
Scheme 3. HNTf2-Catalyzed [2 + 2] Cycloaddition of Silyl
Enol Ether with Acrylates and Propiolates
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
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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
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-aldol-
type 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 5. HNTf2-Catalyzed One-Pot Isomerization and [2 +
2] Cycloaddition
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 temper-
ature-dependent and under thermodynamic control.
Mechanistically, triflimide might serve as a precatalyst to
generate the actual silyl triflimide catalyst (TBSNTf2), which
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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-
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
Scheme 7. HNTf2-Catalyzed [2 + 2] Cycloaddition of
Allylsilanes 14
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
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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 8. HNTf2-Catalyzed Intramolecular Gassman’s [2 +
2] Cycloaddition
process involves protonation of the acetal functionality to form
an oxocarbenium intermediate 23, which then induces
nucleophilic attack from the internal olefin followed by ring-
closure. 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 9. HNTf2-Catalyzed Intermolecular Gassman’s [2 +
2] Cycloaddition
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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
Scheme 10. HNTf2-Catalyzed Intramolecular Yne−Carbonyl
Metathesis
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 methane-
sulfonic 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
Scheme 11. HNTf2-Catalyzed [2 + 2] Cycloaddition of
Ynamides and Imines
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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 12. HNTf2-Catalyzed Reactions between Ynamides
and Ketimines
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 α-
hydrogen 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 3,4-
dihydroquinolines 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
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low diastereoselectivity (Scheme 13).57 In contrast, triflic acid
failed to catalyze this cycloaddition, resulting in no desired
Scheme 13. HNTf2-Catalyzed [3 + 2] Cycloaddition of Silyl
Enol Ethers and Donor−Acceptor Cyclopropanes
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. Cyclo-
propanes 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,α-
Dimethylallylsilane
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 α-
substituents. Instead, a [4 + 2] cycloaddition was observed (vide
infra).
Vinylidenecyclopropanes are a special family of cyclopropane-
containing 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 bond-
cleavage and -formation events.
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In 2009, Li and Shi developed an efficient triflimide-catalyzed
[3 + 2] cycloaddition of vinylidenecyclopropanes with electron-
deficient 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
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-2,3,4-
trienoates 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
Scheme 16. HNTf2-Catalyzed Cascade Cyclization with 5,5-
Diarylpenta-2,3,4-trienoates
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takes advantage of the multiple reactive carbocation inter-
mediates 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 isomer-
ization of vinylidenecyclopropanes to form substituted naph-
thalenes, which also involves trapping the carbocation
intermediate in a Friedel−Crafts cyclization.62
Recently, Li, Wan, and co-workers have developed a HNTf2-
catalyzed formal [3 + 2] cycloaddition without using cyclo-
propane-based substrates (Scheme 17).63 Having known that
Scheme 17. HNTf2-Catalyzed Formal [3 + 2] Cycloaddition
of Ynamides and Dioxazoles
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
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Scheme 18. Synthesis of Aminoimidazoles by HNTf2-
Catalyzed Formal [3 + 2] Cycloaddition
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 trans-
formations 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 geometri-
cally 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
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Scheme 19. Competitive Diels−Alder Reaction of α,β-
Unsaturated Aldehydes and Ketones with Cyclopentadiene
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 cyclo-
addition 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 diastereoselectiv-
ity. 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 Tri-
flimide catalyzed both steps efficiently to form the exocyclohex-
enones, 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
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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 22. HNTf2-Catalyzed Cascade [4 + 2] Elimination
Process
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 temper-
ature 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
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Scheme 23. Aza-Diels−Alder Reaction of 2-Siloxydienes with
Aldimines
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-electron-
demand 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 tetrahydroquino-
line 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 six-
membered 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] cyclo-
addition, 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
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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
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. Sub-
sequent 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
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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] cyclo-
addition 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 N-
nosyl pyrrole. The desired bicyclic adduct tropinone 109 was
formed as a single diastereomer in 85% yield (Scheme 26). The
Scheme 26. HNTf2-Catalyzed [4 + 3] Cycloaddition
Reactions of Pyrroles
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-N-
nosylpyrrole, there was no cycloaddition product formation.
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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. Further-
more, 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 intra-
molecular lactonization from seco acids. Because of intermo-
lecular 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 8-
membered 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 6-
position relative to the aldehyde carbon, thereby forming a 1,6-
amphoteric type situation. If a two-carbon dipolarophile is
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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 6-
position forms bicyclic intermediate 118. Subsequent proto-
nation 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 ring-
expansion 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 8-
membered lactam 125 in 74% yield (Scheme 29). Mechanis-
tically, 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.
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Scheme 28. Possible Mechanisms for the [6 + 2] Cyclization

Scheme 29. HNTf2-Catalyzed Intermolecular Ring Scheme 30. [2 + 2 + 1] Annulation of Alkynes, Nitriles, and
Expansion of Cyclic Hemiaminals 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 trans-
formation of this type, this metal-free process featured reversed
regioselectivity.91 Mechanistic studies suggested that the Koser-
type reagent PhI(OH)NTf2 generated from PhIO and HNTf2 alkynes, with nitriles in the presence of HNTf2. The same type
might be the actual promoter. This reagent serves to activate the of oxazole products could be formed with good efficiency.92
alkyne to generate alkenyliodonium triflimide 132 as the key Later on, the same group reported a catalytic version of this [2
intermediate. Subsequent nucleophilic attack by the nitrile + 2 + 1] annulation, in which iodobenzene was used in a catalytic
followed by water addition and intramolecular cyclization results amount in conjunction with meta-chloroperoxybenzoic acid as
in a six-membered ring intermediate 134. Final reductive the stoichiometric oxidant.93 More recently, the same group also
eliminate delivers the oxazole product. The authors carried out extended this process to the synthesis of bicyclic tetrahydrofuro-
control experiments to substantiate this mechanism. For [2,3-d]oxazoles by employing homopropargylic alcohols in
example, the triflate analogue of alkenyliodonium triflimide place of simple alkynes. Mechanistically, it was believed that the
132 was observed in the absence of nitrile, and the structure was internal alcohol nucleophile intercepts the vinyl triflimide
confirmed by X-ray crystallography. Its chemical competence in moiety intramolecularly before nitrile addition, thus altering
this reaction was also demonstrated. It is worth noting that the the pathway to form the bicyclic products.94
same research group also reported a related synthesis of oxazoles 2.1.8. [2 + 2 + 2] Cycloadditions. Triflimide is known as an
using ketones and 1,3-dicarbonyl compounds, instead of effective activator of electron-rich alkynes, including ynamides.
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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
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,
Scheme 32. Possible Mechanisms for the [2 + 2 + 2] Cyclization
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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 ketenimi-
nium 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.
2.2. Aldol Reactions
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
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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 diaster-
eoselectivity 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
N DOI: 10.1021/acs.chemrev.8b00279
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adduct of the cross-aldol reaction with excellent diastereose-
lectivity 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, vinyl-
trimethylsilane, 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 cross-
aldol 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 syn-
1,3-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 acetone-
derived 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 cyclohexanone-
derived silyl enol ether reacted with isobutyraldehyde to form
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Scheme 35. One-Pot Cross-Aldol Reaction and Nucleophilic
Addition
Scheme 36. HNTf2-Catalyzed Aldol Reaction with Ketone
Super Silyl Enol Ethers
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 diaster-
eoselectivity could be completely switched by the reaction
conditions employed. Specifically, enolization of the β-super
Scheme 37. 1,5-Stereoselective Aldol Reactions
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siloxy methyl ketone 167 with LiHMDS promoted the aldol
reaction with pivalaldehyde with excellent syn diastereoselec-
tivity, 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 1,5-
diols 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 β-
siloxy group on the aldehyde both had direct influence on
diastereoselectivity (Scheme 38). The highest diastereoselec-
tivity was obtained when the super silyl group was used in both
positions.
Scheme 38. Diastereocontrol with β-Siloxy Aldehydes
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-α-
haloaldehyde 180 in 99% yield with excellent diastereoselectiv-
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ity (Scheme 39).108 However, when alkyl aldehyde 181 was
employed, the yield decreased dramatically to 22% with HNTf2
Scheme 39. Mukaiyama Cross-Aldol Reaction of α-Halo Silyl
Enol Ether 179
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 α-
haloaldehydes 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 syn-
Scheme 40. HNTf2-Catalyzed Aldol Process for the
Formation of α,β-Dioxyaldehydes
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 double-
bond 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
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(Scheme 41). These aldol products have the potential to further
build polyketide fragments with high step-economy.
Scheme 41. Synthesis of Polypropionates via HNTf2-
Catalyzed 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 co-
workers found that the use of iodine-containing molecules as
cocatalyst could increase the formation of the desired triple-
aldol 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,
Scheme 42. HNTf2-Catalyzed Triple-Aldol Cascade
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.
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Scheme 43. Synthesis of Polymethoxy-1-alkene 200
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 manipu-
lations, 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/intra-
molecular aldol sequence (Scheme 44).113 The reaction
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.
2.3. Allylation Reactions
Allylation reactions are a family of versatile and powerful
transformations widely used to construct carbon−carbon and
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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-
Scheme 45. HNTf2-Catalyzed Allylation of Electron-
Deficient Olefins
unsaturated ketones and esters were also reactive. Similar to
other triflimide-catalyzed reactions using silyl-based nucleo-
philes (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 Fur-
thermore, carbocations generated in situ could also be allylated
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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
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-4-
methoxybenzene was produced in 90% isolated yield from p-
Scheme 47. HNTf2-Catalyzed Allylation of Benzyl Acetate
and Allylic Acetate
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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-2-
ylmethyl acetate were employed. Nevertheless, Liu and co-
workers 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
Scheme 48. HNTf2-Catalyzed Allylboration
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 cycliza-
tion 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 dimethoxy-
methane 223 (Scheme 50). The alkylation product 224 was
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Scheme 49. HNTf2-Catalyzed Synthesis of Tocopherol
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 51. HNTf2-Catalyzed Synthesis of Diarylmethanes
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 triflimide-
catalyzed oxygenative bimolecular Friedel−Crafts-type coupling
of ynamides.126 In the presence of the pyridine-N-oxide oxidant,
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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-trimethoxy-
benzene to afford the desired product 238 in 84% yield (Scheme
53). Although some weaker Brønsted acids were demonstrated
Scheme 53. Relay Catalysis for Tandem Isomerization/
Friedel−Crafts Sequence
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, Nomiya-
ma 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
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Scheme 54. HNTf2-Catalyzed Alkylation of Pyrroles
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
Scheme 55. HNTf2-Catalyzed Hydroarylation and
Hydroalkenylation of Vinylarenes
homo- and cross-hydroalkenylation of vinylarenes allowed rapid
access to a range of useful molecules. Among them, the anti-
insomnia 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
Scheme 56. HNTf2-Catalyzed Friedel−Crafts Acylation
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that triflimide could catalyze the cyclization of siloxy alkynes
with arenes (Scheme 57) to form substituted tetralone-derived
Scheme 57. HNTf2-Catalyzed Intramolecular Cyclization of
Siloxy Alkynes
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 58. HNTf2-Catalyzed Intramolecular Cyclization of
Ynamides
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-nitrobenzene-
sulfonic 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
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Scheme 59. HNTf2-Catalyzed [3 + 2] Annulation of Benzylic Scheme 61. HNTf2-Catalyzed Benzannulation for the
Alcohols with Alkenes 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-1,4-
benzoquinone (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, Ratovelo-
manana-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
catalysts, triflimide provided not only the best chemical yield but
activation of the carbonyl, followed by alkyne addition. The
also the fastest reaction rate. It is also worth mentioning that this
resulting vinyl cation intermediate is trapped by the arene motif
is the first Brønsted acid-catalyzed general hetero-Michael
in a Friedel−Crafts pathway and then isomerizes to the observed
addition. Later on, the same group carried out more mechanistic
naphthalene product. The reaction exhibited reasonably good
studies. When 2,6-di-tert-butylpyridine was added to the
scope regarding both partners and different functional groups.
reaction mixture, no reaction was observed, thus confirming
Interestingly, this strategy was further extended to epoxides and
that the proton is indeed the actual catalyst.141
acetals in place of the ketone functional group.
With the similar activation pathway, in 2007, Maruoka and co-
2.5. Michael Addition Reactions workers discovered that aryldiazoacetates could also serve as a
Michael addition reactions provide a straightforward con- reactive nucleophile to react with α-substituted acroleins in a
struction of β-functionalized carbonyl compounds. Lewis acids Michael-initiated cyclization process (Scheme 63).142 The
have been widely known as LUMO-lowering activators for α,β- reaction provides a stereoselective synthesis of tetrasubstituted
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Scheme 63. HNTf2-Catalyzed Michael-Initiated
Cyclopropanation
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 em-
ployed 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 com-
pounds 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).
Scheme 64. HNTf2-Catalyzed Asymmetric Aziridination
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
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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 65. HNTf2-Catalyzed Nazarov Cyclization
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 carbo-
nates 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
group was key to the observed high diastereoselectivity, because
it could rapidly collapse to minimize erosion of the stereo-
chemical integrity of the product. It is also remarkable that this
reaction generated two adjacent all-carbon quaternary stereo-
centers. 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 β-
amido 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 diastereoselec-
tivity 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
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Scheme 67. HNTf2-Catalyzed Synthesis of Pyrrolidine
Derivatives
In 2015, the same group employed a similar type of N,O-
acetals 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
The same group also extended the above protocol to the
Mannich reactions using trichloroacetimidated phthalimide-
derived 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, 1,3-
diketones, 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
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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
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 sp3-
hybridized stereogenic center.
In 2015, Dittrich and Bracher further applied this approach to
the synthesis of episterol.157 In the key step, hydrazone 323 was
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Scheme 71. HNTf2-Catalyzed Sigmatropic Rearrangement of Scheme 73. HNTf2-Catalyzed Chirality Transfer from Sulfur
N-Allylhydrazone 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 is noteworthy that the process with HNTf2 as initiator was much
1,4-chirality transfer from sulfur to carbon atom.158 Upon faster than that with TfOH.160
activation by triflimide, electron-rich alkynes, such as ynamides In 2010, Kakuchi and co-workers reported an efficient ring-
and thioalkynes, were susceptible to nucleophilic attack by the opening polymerization for the synthesis of poly(δ-valerolac-
chiral sulfoxide oxygen to form intermediate 327, which readily tone) (PVL) from δ-valerolactone (δ-VL) (Scheme 75).161
underwent [3,3]-sigmatropic rearrangement to give the α-
arylated products in good yields (Scheme 73). The chirality Scheme 75. HNTf2-Catalyzed Ring-Opening Polymerization
transfer was excellent in forming highly enantioenriched α-chiral of δ-Valerolactone
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.
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-trans- With 3-phenyl-1-propanol as the initiator and HNTf2 as the
fer polymerizations, cationic polymerizations, etc.159−166 catalyst, the reaction proceeded efficiently under mild
In 2002, Mignani and co-workers described a triflimide- conditions with precise control over the product molecular
catalyzed polymerization process for the synthesis of α,ω- weight. Other than 3-phenyl-1-propanol, a range of alcohols,
bis(trimethylsilyl)polydimethylsiloxanes (PDMS) with low such as 6-azidohexan-1-ol, (perfluorophenyl)methanol, and N-
molecular weight (<13 000 g/mol) from octamethylcyclote- (2-hydroxyethyl)maleimide, all successfully participated in this
trasiloxane (Scheme 74). Presumably the triflimide catalyst was ring-opening polymerization to afford the corresponding PVLs
used for activation of the silyl ether unit to initiate the process. It with predictable molecular weights.

Scheme 72. Synthesis of Episterol via Rearrangement of N-Boc-hydrazones

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Scheme 76. HNTf2-Catalyzed Ring-Opening Polymerization of ε-Caprolactone, 1,5-Dioxepan-2-one, and Racemic Lactide

Subsequent studies from the same group successfully excellent performance as promoters for a range of these
extended this protocol to the ring-opening polymerization of reactions. In 2003, Toshima and co-workers reported that
ε-caprolactone, 1,5-dioxepan-2-one, and racemic lactide HNTf2 could catalyze glycosylation of glucopyranosyl diethyl
(Scheme 76). A wide range of alcohol initiators have also phosphite, the first glycosylation reaction using ionic liquid as
been demonstrated to be effective. The corresponding solvent (Scheme 78).168 Glycosyl phosphite 353 smoothly
polyesters were all obtained with controlled molecular
weights.162 In another separate example of ring-opening Scheme 78. HNTf2-Promoted Glycosylation in Ionic Liquid
polymerization, triflimide also showed excellent catalytic 354
property.163
HNTf2 has also been demonstrated to catalyze another family
of polymerization, group-transfer polymerization (GTP) with
the Mukaiyama−Michael reaction (Scheme 77). Pioneered by

Scheme 77. HNTf2-Promoted Group-Transfer

Polymerization

reacted with a variety of alcohols to give the corresponding

Kakuchi and co-workers, the group-transfer polymerization of
methyl methacrylate was initiated by ketene silyl acetal 347,
which reacted with triflimide to generate the actual catalyst
TMSNTf2. The polymerization proceeded to give poly(methyl
methacrylate) in a living manner, which was supported by
kinetic measurement and postpolymerization.164 Later on, the
same group further extended this polymerization to the use of
N,N-dimethylmethacrylamide.165,166 Compared with the con-
ventional initiator 1-methoxy-1-trimethylsiloxy-2-methyl-1-pro-
pene (MTS), (Z)-1-(dimethylamino)-1-trimethylsiloxy-1-pro-
pene (DATP) showed higher initiation efficiency. It is worth
mentioning that this protocol represents the first living
polymerization of acrylamides via group-transfer polymer-
ization.
2.10. Glycosylation Reactions
Owing to the biological importance of sugar molecules,
glycosylation reaction is an important tool to modify sugar-
based molecules. In this context, it has been a topic of intensive
investigations to develop efficient glycosylation reactions in the
past few decades.167 Among them, triflimide has exhibited
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glycosylation products in good yields, albeit with moderate
stereoselectivity. It is noteworthy that the ionic liquid could be
recycled and reused for 5 times without loss of efficiency.
Moreover, the catalyst loading could be decreased to 0.01 mol %
without obvious decrease in catalytic activity. It was believed
that the high acidity of triflimide is critically important for the
mild conditions and high efficiency.
In 2005, Hashimoto and co-workers disclosed a HNTf2-
promoted glycosylation reaction of 2-acetamido-2-deoxyglyco-
pyranosyl diethyl phosphites with alcohols to produce 1,2-trans-
β-linked glycosides (Scheme 79).169 A range of acceptor
alcohols, including sugar-based alcohols, all proceeded smoothly
to provide the corresponding glycosides in excellent yields with
excellent stereoselectivity. Treatment of the 2-acetamido-2-
deoxyglycopyranosyl diethyl phosphites with Lewis or Brønsted
acids generally led to the formation of oxazoline intermediate
359. However, alcohol nucleophile 357 did not react with
oxazoline 359 to give the desired glycoside product 358,
suggesting that the glycosylation likely proceeds through a
different mechanism. The authors proposed that the reaction
might involve a glycosyl triflimide intermediate formation
followed by SN2 replacement with the alcohol to furnish the
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Scheme 79. HNTf2-Mediated Glycosylations
final product. Recently, the same group applied this approach in
other glycosylations, including the synthesis of the tetrasacchar-
ide repeating unit of the polymeric O antigen isolated from
Acinetobacter baumannii serogroup O18.170,171
Later on, triflimide was also successfully employed by
Yamanoi and co-workers in the synthesis of trehalose mimics
through the glycosylation of glucopyranose 362.172,173 This
method provided ketopyranosidic linkages 364a and 364b with
α-anomeric configurations in good yields, although disacchar-
ides 364c and 364d were produced with moderate stereo-
selectivities (Scheme 80).
Scheme 80. Synthesis of Trehalose Mimic
The Schmidt glycosylation is a commonly used glycosylation
approach, in which the trichloroacetimidate (TCA) is employed
as the leaving group (Scheme 81).174 However, this reaction is
not generally stereoselective. Recently, Kowalska and Pedersen
have reported that triflimide or silyl triflimide could provide
good stereoselectivity control for efficient glycosylation
reactions. For example, in the presence of a catalytic amount
of HNTf2, substrate 365 bearing an α-TCA leaving group
reacted with various alcohols to give products favoring β-
glycosylation, while those with β-TCA group favored the
formation of α-glycosides.
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Scheme 81. HNTf2-Catalyzed O-Glycosylation Using
Trichloroacetimidate Leaving Group
2.11. Other Reactions
Other than the above different families of reactions, triflimide
has also been known to participate in a wide range of other
reactions. These reactions include many new strategies for
carbon−carbon and carbon−heteroatom bond formation as
well as novel cyclization and rearrangement processes. It is not
straightforward to group these reactions together. Therefore,
they are discussed separately in this section.
As illustrated in the previous sections, triflimide can activate
electron-rich alkynes, such as siloxy alkynes, by protonation at
the β-carbon, which can trigger various cationic reactions. In
2005, Sun and Kozmin described a triflimide-promoted 5-endo-
dig cyclization of 1-siloxy-1,5-diynes 367 to give β-halo enones,
which involves an unusual halogen abstraction from the
halogenated solvents.175 This reaction features good efficiency,
mild conditions, and excellent diastereoselectivity. Mechanisti-
cally, the reaction begins with chemoselective protonation of
electron-rich triple bond to form silyl ketenium ion
intermediate, which is trapped by the properly positioned
internal alkyne motif to form alkenyl cation 369. Due to the low
nucleophilicity of the triflimide counteranion and the high
activity of the alkenyl cation, the halide lone pair serves as the
nucleophile to terminate the intermediate by forming a carbon−
halogen bond. Further protodesilylation leads to the β-halo
enone product (Scheme 82). The excellent stereoselectivity was
attributed to the bulky size of the siloxy group. Various halides,
including chloride, bromide, and iodide, were all incorporated
successfully into the products employing CHCl3, CH2Br2, and
MeI as the halogen source, respectively. It is worth noting that
other acids, including TfOH, proved to be inferior for this
reaction.
In 2014, Thibaudeau, Evano, and co-workers described
another sequential polycyclization process induced by triflimide
activation of electron-rich triple bond (Scheme 83).176 At room
temperature, ynamide 373 underwent protonation readily to
generate the ketenium intermediate 374. Subsequently, the
properly positioned methyl group participated in an intra-
molecular1,5-hydride shift to form the highly conjugated
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Scheme 82. HNTf2-Promoted Cyclizations of 1-Siloxy-1,5-
diynes
Scheme 83. HNTf2-Catalyzed Polycyclization of Ynamide
373
iminium 375, which then reacted in additional intramolecular
cyclization and Friedel−Crafts reaction to form the polycyclic
product 376. This reaction is a novel polycyclization with high
efficiency in ring and bond formations. The polycyclic nitrogen
heterocycle is a common skeleton in natural products, such as
haouamine A 377.
In addition to iminium-induced 1,5-hydride shift, properly
positioned cationic iminium functionality can also induce similar
1,5-hydride shift and lead to interesting reactivity. For example,
in 2015, Akiyama and co-workers reported an efficient synthesis
of tetrahydroisoquinolines from trifluoromethyl-substituted
imines 378 catalyzed by triflimide (Scheme 84).177 Mechanis-
tically, protonation of the imine by triflimide generated highly
the electrophilic iminium 379. The presence of a benzylic
hydride in the 5-position then readily triggered the intra-
Scheme 84. HNTf2-Catalyzed [1,5]-Hydride Shift
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molecular [1,5]-H shift to give the carbocation intermediate
380. Subsequent intramolecular cyclization gave the observed
tetrahydroisoquinoline products 383. Interestingly, the authors
also found that the diastereoselectivity could be controlled by
tuning the substituent on the imine nitrogen. With the bulky p-
methoxyphenyl substituent, the cis-product was formed via
transition state 381, while without substituent on the nitrogen,
the reaction favored the trans-product via transition state 382.
Triflimide is not only able to protonate electron-rich alkynes,
such as siloxy alkynes and ynamides, but also competent in
activating electron-normal carbon−carbon unsaturated bonds
to trigger subsequent cation-induced new bond formation.
Normal alkyne and olefin protonation is typically the first step to
generate the required active cation. Depending on the
substrates, these reactions feature diverse product structure
and novel reaction patterns.
Among these reactions, alkyne hydration is an important
process that conventionally required heavy metals like mercury
as the promoter. In 2000, Shirakawa and co-workers discovered
that triflimide was able to catalyze this process, thereby
providing a convenient route to diverse carbonyl compounds
(Scheme 85).178 While triflic acid was also found to be
Scheme 85. HNTf2-Catalyzed Hydration of Alkynes
catalytically active, the results showed that the performance of
triflimide was slightly better. The process is applicable to
terminal and internal alkynes with aliphatic and aromatic
substituents. It is worth noting that this transformation
proceeded with excellent regioselectivity.
In 2012, Naka and co-workers developed an alkyne hydration
reaction cocatalyzed by triflimide and a water-soluble cobalt
porphyrin complex (Scheme 86).179 A variety of terminal
alkynes with different functional groups, such as protected
alcohol, ester, alkene and halide, all underwent hydration
successfully to provide the corresponding ketone in excellent
Scheme 86. Hydration of Terminal Alkynes Cocatalyzed by
Cobalt and Triflimide
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yields and with perfect regioselectivity. Additionally, the cobalt
catalyst could be recovered by aqueous workup.
With a similar alkyne protonation as the initiation step,
Nagahora, Okuma, and co-workers developed an interesting
cyclization of ethynylbenzophenones for the synthesis of
indenones.180 Triflimide is highly efficient in promoting this
process under very mild conditions, although its loading was
stoichiometric. A plausible mechanism is shown in Scheme 87.
Scheme 87. HNTf2-Mediated Synthesis of Indenones from o-
Ethynylbenzophenones
Mechanistically, alkyne protonation forms the vinyl carbocation
intermediate 391, which is trapped by the internal phenyl group
followed by ring-opening to generate intermediate 393.
Subsequent intramolecular attack onto the acylium cation by
the CC bond and then loss of proton furnishes the indenone
product. In a separate report, trapping the vinyl cation
intermediate with carbonyl oxygen atom resulted in quantitative
formation of highly conjugated oxonium salts, a family of useful
functional molecules with biostability.181
More recently, Miura and co-workers have also taken
advantage of the same initiation step and developed an efficient
Conia-ene reaction of alkynyl ketones for the synthesis of
carbocycles under mild conditions.182 A range of ketones
tethered with an alkyne motif underwent efficient cyclization to
form cyclopent-1-enyl ketones (Scheme 88). It was found that
the use of HNTf2 only or the combination of HNTf2 and
In(OTf)3 could both lead to the same reaction product,
although the required reaction temperature was slightly
different.
Other than initiation by alkyne protonation, triflimide can
easily protonate carbon−carbon double bond to trigger a range
of reactions. In 2010, Jin, Himuro, and Yamamoto demonstrated
that HNTf2 could catalyze a cascade cycloisomerization of 1,7-
enynes leading to bicyclic products in moderate to excellent
yields (Scheme 89).183 The carbocation generated from double-
bond protonation is trapped by the alkyne triple bond. The
alkenyl cation 402 then undergoes anion-assisted intramolecular
cyclization to furnish the product. Alternatively, cation 402 can
also proceed in a 1,5-hydride shift and intramolecular cyclization
followed by deprotonation to form the same product.
Compared with triflimide activation of simple alkynes and
alkenes, protonation of allenes probably is more facile due to the
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Review
Scheme 88. HNTf2-Promoted Cyclization of Alk-5-ynyl
Ketones
Scheme 89. HNTf2-Catalyzed Cyclization of 1,7-Enynes
formation of relatively stable allylic cation intermediate. In 2011,
Bolte and Gagosz employed this initiation step in the synthesis
of a range of cyclic and spirobicyclic molecules containing
tetrahydrofuran and tetrahydropyran substructures (Scheme
90).184 The reaction is mechanistically quite interesting. After
activation by the triflimide or gold catalyst, the allene motif leads
to an allylic cation intermediate. Next, a hydride shift from the
nicely positioned ether group via a six-membered ring transition
state gives oxonium 409 or 413, which is then trapped by the
alkene followed by deprotonation to regenerate the acid catalyst
and deliver the final product. Interestingly, the authors also
observed a remarkable divergence in products when HNTf2 and
a gold complex were separately employed as catalyst.
Vogel and co-workers pioneered a series of reactions
exploiting SO2 in the Diels−Alder reaction with electron-rich
dienes for the stereoselective synthesis of polyfunctional
alkenes.185 In the early discovery of these reactions, the authors
typically employed Lewis acids as promoters. Later on, they
found that HNTf2 showed superior catalytic activity in the four-
component reaction, leading to rapid assembly of the densely
functionalized olefins 417 (Scheme 91).186 In the presence of 40
mol % of HNTf2, the reaction of (E,E)-silyloxydienes 404, silyl
enol ether 416, and SO2 reacted in a sequence of Diels−Alder
reaction, ring-opening, and Mukaiyama-aldol-type reaction.
Subsequent desilylation with tetra-n-butylammonium fluoride
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Scheme 90. Cyclization of Allenes Bearing an Ether Tether
Scheme 91. HNTf2-Catalyzed Condensation of Siloxydiene,
Silyl Enol Ether, and SO2
(TBAF) followed by alkylation gave the product in good overall
yield and with high stereoselectivity (Scheme 90). The reaction
is highly remarkable in terms of pot efficiency in the formation of
so many bonds. This reaction was later extended and applied in
the synthesis of a range of useful molecules, including natural
products.187,188
In 2007, Ko and Hsung reported a triflimide-promoted
anomeric substitution, in which an unusual dependence of
stereochemical outcome on the equivalence of HNTf2 was
observed.189 As shown in Scheme 92, carbamate 423 was
employed as the nucleophile to form cyclic aminal product 424
via the oxonium intermediate 422. Normally, anomeric effect
should have dominant influence on the diastereomeric control
during the nucleophilic addition. However, it was found that the
product diastereomeric ratio was influenced significantly by the
triflimide loading. Increasing the triflimide loading gradually led
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Review
Scheme 92. HNTf2-Promoted Anomeric Substitution
to improved diastereocontrol, culminating in excellent selectiv-
ity when 3.0 equiv of triflimide were used. Indeed, the two
isomers of the product were in equilibrium in the presence of
triflimide. Therefore, this ratio was controlled by this
thermodynamic equilibrium. Triflimide loading could influence
the equilibrium, as the product can only be sufficiently
protonated when a large amount of triflimide is used. This
rationale was also supported by the calculation results. In
comparison, the diastereomeric ratio was reduced when other
Brønsted acids or Lewis acids were employed, such as TFA and
BF3−OEt2.
Due to the unique properties of fluorine in pharmaceuticals
and materials, synthetic methods for efficient incorporation of
fluorine into organic molecules have gained more and more
attention. In 2011, Togni and co-workers described a Ritter-type
direct electrophilic trifluoromethylation promoted by triflimide.
In the presence of a catalytic amount of triflimide, the N-
trifluoromethylation reaction proceeded with Togni’s reagent
426 in acetonitrile with moderate efficiency (Scheme 93).190
Mechanistically, the trifluoromethylation reagent 426 is initially
protonated by HNTf2 to afford the intermediate 428, which was
supported by significant chemical shift of the CF3 signal in 19F
NMR spectrum. Subsequent coordination of nitrile results in
formation of the intermediate 429, which undergoes reductive
elimination to generate the key N-trifluoromethyl nitrilium ion
431. Further nucleophilic addition by triazole leads to the
formation of the observed product and regeneration of the
HNTf2 catalyst.
During the studies of this reaction, the authors observed direct
N-trifluoromethylation of the triazole nitrogen as a side pathway.
Starting from this observation, the authors made efforts to
further optimize the process by in situ silylation of the azoles
with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) catalyzed by
silica sulfuric acid (SSA). With the same trifluoromethylation
reagent, triflimide coupled with LiNTf2 was shown to catalyze
this process to give the N-trifluoromethylation products in
moderate yields (Scheme 94).191 A variety of electron-rich
nitrogen heterocycles with different substituents all successfully
participated in this transformation, thereby allowing further
applications with these stable N-trifluoromethylated com-
pounds.
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Scheme 93. HNTf2-Catalyzed Electrophilic N- Scheme 95. HNTf2-Catalyzed Hydrogenation Reaction

Trifluoromethylation

effective. In contrast, the Hantzsch esters failed to give the

Scheme 94. HNTf2-Catalyzed Direct N-Trifluoromethylation
desired hydrogenation product with these olefin substrates. It is
thus notable that this protocol serves as an attractive alternative
for conventional transfer hydrogenation reactions.
The amide functionality is important in a range of useful
molecules of biological significance, such as peptides, proteins,
etc. Therefore, development of efficient synthetic methods for
amide synthesis is valuable in organic synthesis. Vinyl azides
have been known as a versatile synthon, leading to amide
functionality. In 2015, built on their existing expertise in this
type of molecule, Chiba and co-workers developed a new
catalytic strategy for the efficient synthesis of amides from vinyl
azides and alcohols (Scheme 96).193 Without the use of

Scheme 96. Tf2NH-Catalyzed Amide Synthesis from Vinyl

Azides

In 2016, Chatterjee and Oestreich reported a HNTf2-

catalyzed transfer hydrogenation of imines and alkenes using
cyclohexa-1,4-dienes as dihydrogen source, which is comple-
mentary to the well-established approaches with Hantzsch esters
(Scheme 95).192 Compared with Hantzsch esters using
dihydropyridine as the core structure, the reactivity of
cyclohexa-1,4-dienes appeared to be lower. Therefore, a
relatively strong acid promoter and typically higher temperature
were required for imine reduction reaction. As a result, triflimide
was found to be superior in promoting this transformation at 125
°C. Other weaker acids, such as TsOH and TfOH, gave either no
or low conversion. This transformation was proposed to proceed
through triflimide activation of the substrate (e.g., imine) to
provide the cationic intermediate 440. Subsequent hydrogen
transfer gives the reductive product and the ion pair
intermediate 441 (the Wheland complex), which undergoes
deprotonation to regenerate the triflimide catalyst. For imine
reduction or reductive amination reactions, this protocol has
many advantages over the established strategies. The authors superstoichiometric amounts of Lewis acids like BF3−OEt2, the
extended this protocol to enable previously unprecedented authors found that the process could be catalyzed by Brønsted
transfer hydrogenation of 1,1-di- and trisubstituted alkenes. It is acids, among which triflimide was found to give the highest
worth noting that the reaction proceeded with cyclohexa-1,4- catalytic activity. The corresponding amides were synthesized in
dienes as hydrogen source with exceptional efficiency at room good yields. The process was proposed to begin with
temperature. Triflimide exhibited equally excellent catalytic protonation of the alcohol followed by dehydration to give
activity, although other acids like TfOH and TsOH were also carbocation intermediate 445, which is trapped by the vinyl
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azide to afford the nitrilium ion 447 via loss of dinitrogen and a Scheme 98. Enantioselective Diels−Alder Reaction
1,2-shift of the R2 group. Subsequent water addition and Cocatalyzed by Chiral Diamine 454 and Triflimide
tautomerization leads to amide formation. This protocol was
demonstrated to be applicable to the synthesis of a diverse set of
amide compounds that could be further employed to construct
polyheterocyclic structures, such as pyrroloindolinones. In a
separate report, Yamamoto and co-workers also demonstrated
that triflimide was capable of promoting the cyclization of aryl
azides with intramolecular alkyne unit to form quinoline
products.194
In 2016, Wang et al. described an efficient method for the
synthesis of 1-substituted 1H-1,2,3,4-tetrazoles from amines,
triethyl orthoformate, and sodium azide in the presence of
triflimide.195 A variety of amines, including aryl and alkyl amines,
all participated in this transformation to produce 1-substituted
Scheme 99. Enantioselective [2 + 2] Cycloaddition Catalyzed
1H-1,2,3,4-tetrazoles in excellent yields (Scheme 97). This
by Ammonium Salt 457
approach featured mild conditions, experimental simplicity, and
the use of green solvent.

Scheme 97. HNTf2-Catalyzed Synthesis of 1-Substituted 1H-

1,2,3,4-Tetrazoles

2.12. Use As a Cocatalyst or Additive

Triflimide has also served as a cocatalyst or additive for a wide
range of transformations. Sometimes these reactions indeed activated by hydrogen bonding intramolecularly for activation
employed triflimide as precatalyst or catalyst precursors, and it is and asymmetric induction in the cycloaddition process.
difficult to clearly define and distinguish these situations. For Almost at the same time, Sun and co-workers reported the
example, it has also been demonstrated that triflimide mixed employment of a similar cocatalyst system based on chiral
with silica gel could even serve as a very efficient heterogeneous triamine 461 and triflimide for an enantioselective Michael
catalyst.196 Covered in this section are those reactions addition of cyclohexanone to nitroolefins.200 As shown in
cocatalyzed or copromoted by HNTf2 more or less taking Scheme 100, the intermolecular C−C bond formation was
advantage of the high acidity of triflimide.
As a strong acid, HNTf2 was used in combination with chiral Scheme 100. Asymmetric Michael Addition Cocatalyzed by
amines to serve as a chiral Brønsted acid for asymmetric Triamine 461 and Triflimide
induction. In 2006, Ishihara and co-workers reported that a
diammonium salt prepared in situ from chiral 1,1′-binaphthyl-
2,2′-diamine and triflimide served as an excellent catalyst for the
asymmetric Diels−Alder reaction of α-acyloxyacroleins with
cyclic dienes (Scheme 98).197,198 Compared with other
Brønsted acids, such as C6F5SO3H and TfOH, triflimide
provided better enantioselectivity. Thus, a range of Diels−
Alder adducts were efficiently formed with good to excellent
stereocontrol.
In the following year, the same group extended this catalytic
system to the enantioselective [2 + 2] cycloaddition of
unactivated alkenes with α-acyloxyacroleins (Scheme 99).199
In this reaction, the ammonium salt 457 exhibited excellent
catalytic activity and enantiocontrol. With this catalyst, a range achieved with excellent efficiency, diastereoselectivity, and
of densely functionalized cyclobutanes were formed. In enantioselectivity. However, despite the reasonable scope of
comparison, the corresponding salts made from C6F5SO3H nitroolefins, this reaction showed a limited scope with respect to
and TfOH were essentially inactive. Mechanistically, it was the ketone partner. Only cyclohexanone worked well. Different
proposed that the primary amine functionality in the catalyst from the previous cases, the ratio between amine and acid was
covalently forms imine with the aldehyde substrate, which is 1:1. Therefore, the ammonium salt could still serve to form
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enamine with the ketone substrate and provide hydrogen-
bonding interaction.
Since 2012, Johnston and co-workers have also employed this
concept for highly efficient and enantioselective electrophilic
halogenative cyclization reactions.201,202 They sequentially
reported the formation of chiral iodolactones and iodophos-
phoramidates by electrophilic iodo-activation of unactivated
olefins followed by intramolecular nucleophilic cyclization. The
chiral ammonium salt catalyst was proposed to activate the
electrophilic halogen reagent, thereby further inducing chirality
in bond formation. The authors found that the use of triflimide
(rather than TfOH and other acids) to form these ammonium
salts could lead to improved enantioselectivity, although the
counteranion is achiral. It is notable that the cyclization process
of phosphoramidic acids concomitantly generated both C- and
P-chiral stereogenic centers, which proved to be highly useful
(Scheme 101).
Scheme 101. Enantioselective Iodocyclization of
Phosphoramidic Acids
More recently, the same laboratory further demonstrated that
such chiral ammonium salts could be employed as highly
effective catalysts in the enantioselective synthesis of β-fluoro
amines through a Mannich reaction between α-fluoro aryl
nitromethanes and imines (Scheme 102).203 With slight
modification of the electronic feature of the previously used
chiral amine, the corresponding triflimide salt was found to
provide excellent yield and enantioselectivity, albeit with
moderate diastereoselectivity. The resulting Mannich reaction
products could be easily converted to syn- and anti-β-fluoro
amines with high efficiency via radical-mediated denitration and
Scheme 102. Enantioselective Synthesis of β-Fluoro Amines
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removal of the Boc group by TFA. Therefore, the whole
approach represents a traceless activating group strategy for the
synthesis of chiral β-fluoro amines.
Other than chiral amines, achiral bases also form adducts with
triflimide and exhibit catalytic activity. For example, Rawal,
Kozmin, and co-workers demonstrated that pyridinium
triflimide could serve as an efficient catalyst in an interesting
cycloaddition reaction of siloxy alkynes with 1,2-diazines,
leading to a range of bioactive polyheterocyclic compounds.204
In addition to forming adducts with amines as useful Brønsted
acid catalysts, triflimide has been extremely successful in forming
adducts with Lewis acids to achieve Brønsted acid-assisted Lewis
acids. A notable example is the adducts between triflimide and
chiral oxazaborolidines first introduced by Ryu and Corey in
2003 (Scheme 103). Upon binding with triflimide, the Lewis
acidity of the chiral boron compounds was enhanced. The
authors have demonstrated that these compounds are broadly
versatile as effective catalysts in a wide range of asymmetric
transformations, including Diels−Alder reactions,205 cyanosily-
lation of aldehydes,206 tandem Michael/aldol reaction,207
Roskamp reaction,208 and so on (Scheme 102).209−212 It is
worth noting that triflimide was shown to be superior to other
acids, such as TfOH, with respect to not only better catalytic
activity and asymmetric induction but also enhanced stability of
the Lewis acid adducts.
Furthermore, triflimide has also been used in combination
with a range of transition metal catalysts for diverse reactions.
Among them, it has been extremely successful when used
together with gold catalysts. In 2010, Zhang and co-workers
developed a novel and efficient gold-catalyzed synthesis of
oxetan-3-ones from propargylic alcohols. It was proposed that,
under the oxidative conditions, the triple bond is converted to a
reactive α-oxo gold carbene intermediate, which undergoes
intramolecular carbene insertion into the O−H bond to afford
the oxetan-3-ones. The authors discovered that the addition of
triflimide additive, rather than MsOH, led to reduced side
product and improved reaction yield (Scheme 104).213
Later on, Hashmi et al. extended this similar oxidative
generation of α-oxo gold carbene intermediate to the synthesis
of 1,3-diketones from propargylic tertiary alcohols (Scheme
105). Mechanistically, the modification of substrates simply
allows a rearrangement to take place and alter the reaction
pathway. This process provided access to cyclic 1,3-diketones,
such as 4-, 5-, 12-, and 15-membered ring 1,3-diketones. The
authors also found that the use of triflimide was superior and its
role was proposed to trap the pyridine side product resulting
from the oxidant.214 More recently, Zhang and co-workers
further utilized this similar catalytic system in a one-pot
synthesis of medium-ring ketones from the alkynes.215
Since the seminal work of Zhang and co-workers utilizing gold
catalyst and triflimide, such a combination has been employed in
several other transformations. For example, Ye and co-workers
discovered that a gold-catalyzed efficient synthesis of
anthracenes from o-alkynyldiarylmethanes benefited from the
addition of triflimide as additive (Scheme 106).216 In a separate
study, Zhang, Xiao, and co-workers reported that gold and silver
could catalyze the cyclization of N-(2-perfluoroalkyl-3-alkynyl)-
hydroxylamines to pyrroles and cyclic nitrones, respectively
(Scheme 107).217 The product divergence is well-controlled by
the catalyst. In the case of gold-catalyzed pathway, triflimide was
again found to enhance the reactivity. Although the exact role of
triflimide was not fully investigated, it is likely involved for rapid
protonation, which sometimes inhibits side reactions.
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Scheme 103. Triflimide-Assisted Chiral Boron Lewis Acids
Scheme 104. Au-Catalyzed Synthesis of Oxetan-3-ones from Propargylic Alcohols
Other than gold catalysis, triflimide has also been demon-
strated to be beneficial when coupled with other metal-catalyzed
systems. In 2006, Arisawa and Yamaguchi described that
palladium catalyzed the synthesis of 1-alkylphosphonium salts
from highly selective anti-Markovnikov addition of triarylphos-
phines to terminal olefins. In this reaction, triflimide was a
critically important additive, while other acids, such as TfOH,
were inferior.218,219 It was shown that a slight excess of HNTf2
over phosphine was important for high efficiency, suggesting
that triflimide served not only as a hydrogen source but also as an
activator of the palladium catalyst. Thus, with this catalytic
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system, a range of 1-alkylphosphonium salts were formed
successfully (Scheme 108). In addition to starting from terminal
olefins, internal olefins could also be used to form the same type
of products owing to the ease of double-bond migration to the
terminal position in the presence of the palladium catalyst.
In 2012, Zhang and co-workers reported an efficient copper-
catalyzed cyclization of N-o-tolylbenzamides for the synthesis of
4H-3,1-benzoxazines. Under the optimized conditions, HNTf2
was employed as an additive. Other acid additives proved to be
much less effective. The authors proposed that triflimide
facilitates oxidation of the Cu(I) intermediate 516 to the
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Scheme 105. Au(I)-Catalyzed Oxidative Rearrangement of
Propargyl Alcohols to 1,3-Diketones
Scheme 106. Gold-Catalyzed Cyclization of o-
Alkynyldiarylmethanes
Scheme 107. Catalyst-Controlled Divergent Cyclization of N-
(2-Perfluoroalkyl-3-alkynyl) Hydroxylamines
Scheme 108. Palladium-Catalyzed Synthesis of 1-
Alkylphosphonium Salts from 1-Alkenes
Cu(III) intermediate 517, although the exact role remained
elusive (Scheme 109).220
In 2014, Klankermayer, Leitner, and co-workers reported a
ruthenium-catalyzed protocol for the efficient hydrogenation of
carboxylic and carbonic acid derivatives, in which triflimide also
served as a cocatalyst.221 Key to the success of this trans-
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Scheme 109. Copper-Catalyzed Cyclization of N-o-
Tolylbenzamides
formation was the formation of the cationic species [Ru-
(triphos)(solvent)(H)-(H2)]+, which was generated from
HNTf2 and the ruthenium catalyst. It is remarkable that,
without the acid additive, the desired reaction did not proceed. It
was proposed that the role of triflimide includes the control of
catalyst deactivation via decarbonylation (Scheme 110).
Scheme 110. Ru-Catalyzed Hydrogenation of Dimethyl
Carbonate
Recently, triflimide was also employed as an effective additive
in cobalt-catalyzed hydrogenation of carbon dioxide for the
synthesis of methanol by Beller and co-workers (Scheme
111).222 Without triflimide, the reaction essentially did not
Scheme 111. Hydrogenation of Carbon Dioxide to Methanol
proceed with only the Co(acac)3/triphos catalyst system.
Triflimide indeed significantly improved the turnover number
to 50. In contrast, triflic acid (TfOH) and LiNTf2 both failed to
serve the same purpose, suggesting that both acidity and weakly
coordinating counterion Tf2N− contribute to the enhanced
catalytic activity.
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In the past few years, Prokofjevs and Vedejs have discovered Scheme 113. Intermolecular Borylation of Nitrogen
that triflimide could also serve as an excellent “hydridophile” for Heterocycles
amine−borane complexes, thereby activating the borane for a
wide range of new bond-formation processes. In 2011, they first
discovered that triflimide promoted the aliphatic C−H
borylation more efficiently than the previously used trityl cation
hydridophile (Scheme 112).223,224 With only 5 mol % of HNTf2,

Scheme 112. N-Directed Aliphatic C−H Borylation Using

Borenium Cation Equivalents

Scheme 114. Hydroboration of Alkenes with N-Heterocyclic

the starting amine−borane complexes 521 underwent dehydro- Carbene−Boranes
genation to form the activated H-bridged cations 522, which led
to intramolecular C−H borylation to generate the amine
boranes 523 at 160 °C. With this improved protocol, a variety of
amine−borane complexes successfully participated in this
process with high efficiency. The same group also extended
this concept to intermolecular C−H borylation reactions. With
the newly developed boronium ion 530 synthesized from the 9-
borabicyclo[3.3.1]nonane (9-BBN) dimer, triflimide, and 1,8-
bis(dimethylamino)naphthalene, a variety of heterocycles
successfully underwent borylation with excellent efficiency
(Scheme 113).225
Shortly thereafter, the same group extended the above borane
activation approach to NHC−boranes for efficient hydro-
boration of alkenes.226 Similarly, the H-bridged cation 534 was
proposed to be the active intermediate for the actual
hydroboration. Upon oxidation by hydrogen peroxide, the Scheme 115. P-Directed Borylation of Phenols
corresponding alcohols were formed with excellent efficiency
and selectivity (Scheme 114). This NHC−borane complex was
later utilized by Curran and co-workers for hydroboration of
silyl-substituted alkenes and alkynes.227 Similar cationic hydrido
boron compounds have also been described using a similar
approach by Ghadwal et al. In 2015.228
Later on, like amine−boranes and NHC−boranes, phos-
phine−boranes were also employed as C−H borylation reagents
by the Vedejs group.229 The intermediate 537 was observed by
11
B NMR when the phosphine−borane 536 was treated with
triflimide. At 140 °C, intramolecular C−H bond borylation took
place to form 538, which was converted to the trifluoroborate
salt 540 or reduced to the isolable neutral complex 539 with
good overall efficiency (Scheme 115).

3. RELEVANT TRIFLIDIC ACID (HCTF3) AND ITS

ANALOGUES
Because it is established that acids based on O−H and N−H
motifs bearing one or two trifluoromethylsulfonyl (Tf) groups
(e.g., TfOH and Tf2NH) are strong Brønsted acids with versatile
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utility in organic synthesis, it would not be difficult to envision
that, down in this series, carbon acids based on C−H bonds
carrying multiple Tf groups (e.g., Tf3CH) should also be
superacidic. Although studies regarding these acids have been
sporadic in the past three decades or so, this topic is gaining
increasing attention and is expected to flourish. Thus, in this
Review, we feel that it would be meaningful to introduce triflidic
acid (Tf3CH), an important yet less studied member in this
series of strong Brønsted acids. Because there is already an
excellent review on the synthesis of superacidic carbon acids,230
the focus of this section will be a general introduction to the
properties and applications of triflidic acid and its analogues in
organic reactions.231
3.1. Brief Introduction (Structure, Synthesis, Properties,
etc.)
As a set member of the carbon acid family, tris-
(trifluoromethanesulfonyl)methane (HCTf3, also called triflidic
acid) was first successfully synthesized by Turowsky and Seppelt
in 1988.232 After initial failure in trifluoromethylation of
HC(SO2OH)3 and oxidation of HC(SCF3)3, they finally
resorted stepwise triflation of methane. It was found that the
immediate precursor bis(triflyl) methane could be deprotonated
by MeMgBr (2 equiv) to generate a dianion, which was triflated
with CF3SO2F followed by protonation by sulfuric acid to form
HCTf3 (Scheme 116, method a). A key part of the purification
Scheme 116. Synthesis of HCTf3
was sublimation from sulfuric acid. Due to availability and
inconvenient handling of the gas reagent CF3SO2F, Waller,
Barrett, and co-workers later modified the triflation step to be
more practical using Tf2O and tBuLi.233
In their pioneering report, Turowsky and Seppelt was able to
obtain the X-ray crystal structure of triflide anion (Figure 3). It
was found that the central carbon shows sp2 hybridization and
the CS3 skeleton of this anion is thus planar. The orientation of
the CF3 groups is unsymmetrical: two CF3 groups are located
below the plane and the other one is above the plane. The 19F
and 1H NMR spectra of HCTf3 (in CD3CN) show a singlet at
−76.8 and 9.7 ppm, respectively. These observations may
Figure 3. ORTEP drawing of the Tf3C− anion with 50% probability
ellipsoids. Reproduced from ref 232. Copyright 1988 American
Chemical Society.
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suggest that the triflide anion is highly stabilized by effective
delocalization of the negative charge, hence implying that
Tf3CH is superacidic.
Indeed, triflidic acid was found to be a stronger Brønsted acid
than HNTf2 and TfOH in both gas phase and organic solvent,
with estimated pKa values of around −16.4 in DCE.20,23 Due to
the high acidity, caution has to be taken when handling this acid.
Typically, it is stored as the cesium salt, and sublimation from
sulfuric acid liberates the acid for use.
3.2. Their Participation in Organic Reactions
While the free triflidic acid itself has not been well-utilized in
organic synthesis, its analogues, including some chiral ones, have
been designed and used as catalysts or promoters in organic
synthesis. In 2000, Yamamoto and co-workers reported HCTf3
and its metal salts, such as scandium(III) and copper(II)
triflides, could effectively catalyze the debenzylation of benzyl
esters, benzyl ethers, and N-benzylamides.234 For example, both
HCTf3 and Sc(CTf3)3 catalyzed the reaction of benzyl
phenylacetate 543 in anisole to form carboxylic acid 544 in
almost quantitative yield (Scheme 117). The catalyst loading
could be reduced to as low as 0.1 mol %. For direct comparison,
triflimide catalyzed the same transformation with a much lower
rate.
Scheme 117. Debenzylation of Benzyl Phenylacetate
Catalyzed by HCTf3 or Sc(CTf3)3
Following that study, the same group designed and
synthesized a series of triflidic acid analogues.235−239 For
example, pentafluorophenylbis(triflyl)methane 547 is a strong
carbon acid and can be prepared over two steps from 2,3,4,5,6-
pentafluorobenzyl bromide in 86% overall yield (Scheme 118).
A polystyrene-bound analogue 548 was also synthesized as a
heterogeneous catalyst. Their catalytic activities were demon-
strated to be excellent in the acylation of (−)-menthol with
Scheme 118. Synthesis and Catalytic Activity of the
Perfluorophenylbis(triflyl)methane Acids
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benzoic anhydride. It was also found that the large size of the
counterion of these acids contributes to the high reaction
selectivity. In addition, this heterogeneous catalyst 548 was also
successfully employed in a series of other transformations, such
as Mukaiyama-aldol reaction, Mukaiyama−Michael addition,
Sakurai−Hosomi allylation, and so on.
In 2008, Taguchi and co-workers reported that the carbon
acid 554, Tf2CHCH2CHTf2, also served as a superacid catalyst
in Mukaiyama−Michael reactions.240−242 In the presence of
0.25 mol % of 554, the intermolecular C−C bond-formation
process proceeded at −78 °C to provide a variety of butenolides
with excellent yields from α,β-unsaturated ketones and
aldehydes (Scheme 119). The catalyst loading could be further
Scheme 119. Mukaiyama−Michael Reaction Catalyzed by
554
reduced to 0.05 mol % without affecting chemical efficiency.
Notably, when TfOH or Tf2NH was used as catalyst, these
transformations either gave low yield or low selectivity. It was
believed that the high acidity and the bulky size of the
counterion of the carbon acid were beneficial. The authors also
proposed that the actual catalyst in these reactions should be the
in situ generated Lewis acid R3Si−CTf2R′, which is similar to the
use of HNTf2 in those reactions employing silyl-based
nucleophiles. This catalytic system was also extended to a
Mukaiyama-aldol reaction by the same group (Scheme 120).243
Scheme 120. Mukaiyama Cross-Aldol Reaction Catalyzed by
554
As shown in Scheme 39, Yamamoto and co-workers also
demonstrated that carbon acid C6H5CHTf2 is superior to
HNTf2 in catalyzing Mukaiyama cross-aldol reactions between
halogenated silyl enol ethers and aldehydes.108
While these carbon acids have been demonstrated as
successful and superior catalysts in a number of reactions, a
much more challenging task is to design and develop useful
chiral carbon acids with both strong acidity and excellent ability
for asymmetric induction. In 2006, Yamamoto and co-workers
reported a pioneering example of this type.244 They grafted the
bis(triflyl)methyl group onto the chiral binaphthyl backbone,
thus resulting in the formation of chiral carbon acid 563
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Review
(Scheme 121). This acid was then demonstrated as a catalyst for
the efficient asymmetric Mannich reaction between silyl enol
Scheme 121. Asymmetric Mannich Reaction Catalyzed by
Chiral Carbon Acid 563
ether 559 and imine 560. Although moderate enantioselectivity
was obtained, this study represents this first exploitation of chiral
super carbon acid for asymmetric catalysis.
Recently, List and co-workers made a breakthrough on this
topic by introducing a novel chiral super carbon acid as a
precatalyst for an efficient asymmetric Diels−Alder reaction.245
This new carbon acid (567) combines the excellent chirality
environment from the binaphthyl backbone bearing bulky 3,3′-
substituents and the strong acidity resulting from the four
sulfonyl groups, two of which are CF3SO2 (Tf) groups properly
positioned with a CC double-bond bridge (Scheme 122).
This smart design bestowed excellent catalytic activity on this
acid, which can react with silyl enol ether 565 to generate an
effective silylium ion bearing the bulky chiral carbanion in situ.
This Lewis acid served as the actual catalyst in the
intermolecular Diels−Alder reaction between cyclopentadiene
74 and α,β-unsaturated esters 564. In the presence of only 1 mol
% of the catalyst 567, the corresponding adducts were efficiently
obtained with excellent enantioselectivity and diastereoselectiv-
ity. The process is expected to encourage future efforts in the
design and synthesis of more new chiral carbon acids as well as
further studies on their applications in asymmetric catalysis.
4. SUMMARY AND OUTLOOK
There is no doubt that triflimide, as a strong Brønsted acid, has
already played important roles in organic synthesis. The super
strong acidity combined with its weakly nucleophilic and
noncoordinating counteranion (Tf2N−) has bestowed this
molecule quite unique versatility as a catalyst, precatalyst,
cocatalyst, or additive in a wide range of organic transformations,
including carbon−carbon and carbon−heteroatom bond-
formation processes. Triflimide is particularly well-suited for
those reactions requiring strong Brønsted acid promotion and
involving highly electrophilic cationic intermediates. In these
reactions the high electrophilicity of the intermediate is often
critically important and should not be compromised by the
surrounding counterions that may be potentially nucleophilic. In
such cases, the performance between triflic acid and triflimide
could be quite different, particularly in relatively less-polar
organic solvents. Therefore, when triflic acid is mediocre or
better performance is expected, it is highly suggested that
triflimide should be evaluated. On many occasions, triflimide has
been demonstrated to outperform triflic acid (TfOH) in terms
of reaction efficiency or other aspects, such as catalyst loading,
reaction time, and temperature. An additional advantage is the
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Scheme 122. Asymmetric Diels−Alder Reaction Cocatalyzed by Chiral Carbon Acid 567 and Silyl Enol Ether 565
operational simplicity when handling triflimide as a solid (vs
triflic acid as a fuming liquid). Furthermore, the related super
carbon acid, triflidic acid (Tf3CH), and its analogues have also
been exploited in organic synthesis. The noteworthy perform-
ance of these super acids has also spurred preliminary efforts in
the design, synthesis, and exploitation of new chiral super
Brønsted acids for asymmetric catalysis. While significant
challenges still remain, particularly in achieving excellent
asymmetric induction while maintaining strong acidity and
excellent activity, it is certain that more and more important
applications based on triflimide will be expected in the future.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sunjw@ust.hk.
ORCID
Wanxiang Zhao: 0000-0002-6313-399X
Jianwei Sun: 0000-0002-2470-1077
Notes
The authors declare no competing financial interest.
Biographies
Wanxiang Zhao received his Ph.D. degree in chemistry from the Hong
Kong University of Science and Technology in 2014, under the
supervision of Professor Jianwei Sun. After spending three years as a
postdoctoral fellow in the University of Michigan (with Professor John
Montgomery) and the University of Utah (with Professor Peter Stang),
he moved to Hunan University as a full professor in 2017. His current
research efforts are focused on transition-metal catalysis and supra-
molecular catalysis.
Jianwei Sun graduated with B.S. and M.S. degrees in Chemistry from
Nanjing University in 2001 and 2004, respectively. In 2008, he obtained
his Ph.D. degree in Organic Chemistry from the University of Chicago
under the supervision of Prof. Sergey A. Kozmin. He then worked as a
postdoctoral fellow with Prof. Gregory C. Fu at Massachusetts Institute
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Review
of Technology. In August 2010, he became an Assistant Professor of
Chemistry at the Hong Kong University of Science and Technology. He
was promoted to Associate Professor in 2015. He is a recipient of the
Asian Core Program Lectureship Award, the Hong Kong Research
Grants Council Early Career Award, and the Thieme Chemistry Journal
Award.
ACKNOWLEDGMENTS
We thank Hong Kong RGC (16304115, 16302617, 16304714,
and 16311616) and Shenzhen STIC
(JCYJ20160229205441091) for financial support.
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DOI: 10.1021/acs.chemrev.8b00279
Chem. Rev. XXXX, XXX, XXX−XXX