FUORINE CHEMISTRY

HEINZ STEINER
Solvias AG, Rmerpark 2, 4303 Kaiseraugst, Switzerland

Heinz Steiner

Synthesis of aromatic trifluoromethyl compounds:

The potential for large scale application

KEYWORDS: trifluoromethylation, trifluoromethylating reagents, trifluoromethyl aromatics, deoxofluorination.

Abstract

This article provides an overview on reagents and protocols for the synthesis of aromatic trifluoromethyl
compounds. The generation of trifluoromethylated aromatic building blocks, the deoxoflurination of
carboxylic acids, and the trifluoromethylation of aromatic precursors are covered by this review. Issues that favor or hinder the large
scale application of particular reagents and protocols are presented. Remarkably, only one out of more than 10 protocols covered
by this review is currently applied on large production scale, a few others have been applied on a 5 kg to 100 kg scale.

INTRODUCTION

THE TERM POTENTIAL FOR LARGE SCALE APPLICATION (2)

Trifluoromethylated aromatic rings are common motifs in

pharmaceutical and agrochemical active compounds as
well as in performance materials (1). For many decades,
formation of aryl-CF3 compounds has been limited to a few
traditional technologies, especially the perchlorination of
aromatic methyl-groups followed by exhaustive chlorinefluorine exchange using anhydrous HF (AHF) or SbF5, or the
deoxofluorination of carboxylic acids using sulfur tetrafluoride.
In recent years, a plethora of new reagents and protocols
have been developed at various universities, resulting in a
tremendously expanded synthetic toolkit for R&D chemists.
Whereas traditional methodologies are restricted to rather
basic compounds, modern protocols typically allow for latestage introduction of the trifluoromethyl substituent into quite
complex molecules. Its conceivable that these opportunities
will significantly increase the number of trifluoromethylated
aromatic molecules in the development pipelines of the
industry. Therefore, the need for industrially viable
trifluoromethylation processes increases. The aim of this article
is to highlight the most important issues and cost drivers in the
generation of aromatic trifluoromethyl compounds. Based on
the introduction into common reagents and protocols used
for the generation of aryl-CF3 compounds, the advantages
and disadvantages of a series of protocols are presented.
Formation of heteroaromatic CF3-compounds by cyclisation
using building blocks such as trifluoroacetic acid is outside the
scope of the present article.

When discussing the terms potential for large scale

application or viability for industrial application aspects
such as cost of goods, processing cost, hazard potential, or
process safety are of increasing importance. Similar aspects
are also discussed with respect to green chemistry.

26

In the current article the potential for large scale application

will be qualitatively assessed, regarding:
cost of starting materials, reagents, solvents, catalysts,
auxiliaries
chemoselectivity, regioselectivity, yield
processing cost
waste-generation
practicability of process, e.g. complexity of reagent
handling, need for containment.

REAGENTS FOR THE SYNTHESIS OF TRIFLUOROMETHYLATED

AROMATIC COMPOUNDS
Scheme 1 depicts typical routes pertaining to the selection of
important reagents that can be used for the synthesis of
trifluoromethylated aromatic compounds.
Whereas natural fluoride sources such as CaF2, KF, and NaF
cannot be used as primary fluorine-sources for the synthesis of
trifluoromethylated aromatic compounds, HF, SF4 and Ar-SF3

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

selective late-stage trifluoromethylation based on

an expensive reagent is more cost-efficient than a
10-step route including the use of a
trifluormethylated early intermediate.
In the following, the reagents depicted in Scheme
1 are briefly characterized. Prices given are
typically based on current Scifinder-prices. Retail
prices of various trifluoromethylating reagents
have been previously reviewed (3).
1st Level Reagents
Anhydrous Hydrogen Fluoride (AHF)(4)
Hydrogen fluoride is produced by treatment of
calcium fluoride with concentrated sulfuric acid.
Anhydrous hydrogen fluoride (AHF) is used in
industry in annual amounts of > 1000000 tonnes,
e.g. for the production of fluoropolymers or as
fluorination agent. Hydrogen fluoride is an acute
poison that immediately and permanently
damages lungs and eyes. In addition it is a
systemic poison since it interferes with the calcium
metabolism. Only a few manufacturers are able
to work with AHF because of its extremely
hazardous properties. AHF (bp: 19.5C) can only
be used in strictly closed apparatus (autoclaves)
Scheme 1. Routes to reagents for the synthesis of trifluoromethylated aromatic compounds.
installed in a secondary containment.
HF-monitoring and the highest level of personnel
protection has to be ensured. In addition, HF emission to the
(1st level reagents) are suitable reagents to convert
environment has to be prevented by highly efficient
functional groups, i.e. CCl3 groups or carboxylic acids into the
scrubbers. AHF is the cheapest and most important
CF3- group. Fluoroform, trifluoroacetates (sodium-,
fluorination reagent for industrial application. In April 2012 the
postassium-, methyl-), CClF2COOMe, and
price for AHF was USD 1250 / ton resulting in a cost of < USD 1 /
trifluoromethylsulfonyl chloride (2nd level reagents) are
mol aryl-CF3 (5).
amongst the most simple and therefore cost-effective

trifluoromethylating reagents. Further transformation results in

a broad range of 3rd level trifluoromethylating reagents, such
as trifluoromethyl iodide, trifluoromethyl trimethylsilane,
trifluoromethylphenyl ketone, or potassium
trifluoromethylsulfonate. Trifluoromethyltrimethylsilane have been
used to generate even more elaborated trifluoromethylating
reagents (4th level reagents) such as TrifluoromethylatorTM,
trifluoromethyl tris-triphenylphosphine copper,
potassium(trifluoromethyl)trimethylborate, or the electrophilic
trifluoromethylating reagents of Togni and Umemoto.
Regarding reagent cost the following general conclusion can
be drawn: The more elaborated, the higher the cost of a
reagent per mol of CF3 compound, i.e. a particular reagent
cannot be better priced than its precursor.

However, the cost impact of a particular trifluoromethylation

protocol per mole of trifluoromethylated intermediate doesnt
solely depend on the trifluoromethylating reagent, but also on
other cost-drivers, e.g. the cost of the substrate and other raw
materials, the cost for waste, and the yield of the purified
trifluoromethyl compound. The potential of a particular
reagent for a particular application can only be rated by an
in-depth analysis. For example, the cost of goods sold of a
trifluoromethylated intermediate can be lower when using an
expensive trifluoromethylation reagent but a cost-effective
process compared to a low-priced trifluoromethylation
reagent but an expensive process. Also, the most important
criterion is the cost of goods sold of the final active substance.
It might happen that a 8-step synthesis route including a

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

Sulfur Tetrafluoride (SF4) (6)

SF4 has been used as a deoxofluorination reagent for more
than 50 years. Furthermore, it serves as a starting material
for the preparation of DAST, DeoxofluorTM, or XtalFluorTM ,
reagents that selectively transform carboxylic acids into
acid fluorides without formation of trifluoromethyl
compounds. Sulfur tetrafluoride (bp: -82C) is a highly
reactive, toxic and corrosive gas which liberates AHF and
thionylfluoride upon exposure to moisture. Because of its
extremely hazardous properties SF4 can only be handled in
strictly closed apparatus (autoclaves) installed in a
secondary containment. HF-monitoring and utmost
protection of the operators has to be ensured. In addition,
scrubbers have to be in place to prevent emissions of any
SF4 and AHF to the environment. Of course, such measures
result in increased processing costs. However, since raw
materials (e.g. S, Cl2, NaF) are inexpensive, SF4 has great
potential as an economic fluorination reagent.
Unfortunately, SF4 cannot be easily obtained in ton
quantities because of regulatory transport restrictions. The
only viable concept for the industrial use of SF4 requires
on-site production. Several protocols for the synthesis of
SF4 have been established, e.g. the chlorination of sulfur
followed by chlorine-fluorine exchange (7). Apart from
direct synthesis, SF4 is obtained as a byproduct from the
production of SF6, which is produced in > 10000 tons a year
and used as a dielectric medium in the electric industry (8).
100 kg quantities of SF4 are currently available for about
USD 200/kg.

27

Arylsulfurtrifluoride (Ar-SF3) (9)

Recently, arylsulfurtrifluorides were established as
deoxofluorination reagents, e.g. 2,6-dimethyl-4-tert.butylphenylsulfurtrifluoride (Fluolead), a crystalline solid (mp:
66-67C) or PhSF3 a liquid (bp: 70C at 10 mm Hg).
Phenylsulfurtrifluoride is extremely moisture sensitive whereas
Fluolead only gradually reacts with moisture or water to form
HF. Ar-SF3 compounds can be generated by reaction of
diaryldisulfides with chlorine or bromine and potassium
fluoride. In the deoxofluorination of carboxylic acids two
equivalents of ArSOF are generated. ArSOF recycling might
be a prerequisite for a large scale application of Ar-SF3.
Currently, Fluolead is only commercially available in 100 g
quantities.
2nd Level Reagents
Fluoroform (CHF3) (10)
Fluoroform can be prepared by chlorine-fluorine exchange of
trichloromethane. However, about 20000 tons each year are
produced as byproduct in the industrial manufacturing of
fluoro polymers. In research, fluoroform is used as a
trifluoromethylation reagent and as starting material for the
preparation of 3rd level trifluoromethylating reagents.
Fluoroform is a non-toxic, ozone-friendly gas (bp: -82C). It has
a warming potential of >104 compared to CO2 and a >240year atmospheric lifetime. Fluoroform is highly attractive as a
CF3 source from the perspective of availability and cost, and
also of ecology, safety, and atom-economy. Fluoroform is
currently available for about USD 600/1 kg.
Sodium trifluoroacetate, Potassium trifluoroacetate, Methyl
trifluoroacetate, Methyl chlorodifluoroacetate (11)
Alkaline trifluoroacetates have been described as useful
reagents for trifluoromethylation by thermal decarboxylation
in the presence of CuI. Sodium trifluoroacetate and potassium
trifluoroacetate are toxic and very hygroscopic solids and
thus difficult to handle. Methyltrifluoroacetate (MTFA) requires
high reaction temperatures (140-180C) for the
decarboxylative trifluoromethylation reaction. Because of the
low boiling point of MTFA (43C) such reactions have to be
performed in autoclaves. These reagents benefit from the
fact, that the precursor trifluoroacetic acid (TFA) is produced
in large scale. TFA itself is widely used in organic chemistry, but
it hasnt been applied as a trifluoromethylating reagent so far.
MTFA is currently available in multi-kg amounts for about USD
60/kg, the current retail price of 1 kg TFA-Na is about USD 300.
Apart from MTFA also methyl chlorodifluoroacetate (MCDFA)
can be used for this type of decarboxylative chemistry. Its
advantages compared to MTFA are the lower vapor pressure
(bp: 79-81C) and the lower decarboxylation temperatures
(80-120C). MCDFA is a byproduct in the synthesis of TFA, its
current retail price of 1 kg is approx. USD 500.
Trifluoromethanesulfonylchloride (Triflic chloride; CF3SO2Cl)
(12)
CF3SO2Cl is a difficult to handle liquid because it is very
corrosive, low-boiling (bp: 30C) and it easily hydrolyses on air.
It can be synthesized by electro fluorination of methane
sulfonic acid of trifluoromethyl sulfonic acid (triflic acid)
followed by chlorination. Triflic chloride is not yet produced as
bulk chemical. However, based on the low retail price of triflic
acid (USD 100/1.7 kg), it certainly has the potential for a
reasonably priced bulk trifluoromethylating reagent.

28

3rd Level Reagents

Trifluoromethyl bromide (CF3Br)(13)
Trifluoromethyl bromide, also known as Halon 1301, has been
used for as a fire protecting and refrigeration agent on very
large scale, but also for trifluoromethylation reactions and for
the synthesis of trifluoromethyling reagents. The Montreal
Protocol requires that all production of new CF3Br be ceased
by January 1, 1994. Recycled Halon 1301 and inventories
produced before 1994 are now the only legal sources of
supply. Because of the Montreal Protocol, the viability of CF3Br
for industrial application is limited to critical uses which will
continue, i.e. uses that can claim to be connected with
national security (14).
Trifluoromethyl iodide (CF3I)(15)
Trifluoromethyl iodide has been tested as an alternative to
CBrF3 as a fire-suppressing agent. It is frequently utilized for
aromatic trifluoromethylation in R&D. CF3I (bp: -21C) is not
corrosive and can be handled in normal autoclaves. It is
probably carcinogenic to humans but not acute toxic. In
contrast to Halon 1301, CF3I is not covered by the Montreal
Protocol. 5 kg quantities of CF3I are currently available for
about USD 2000/kg. CF3I can be prepared by several
processes, e.g. the reaction of fluoroform with iodide and
oxygen.
A 1:1 adduct of trifluoromethyliodide with
tetrammethylguainidine (CF3I-TMG) was recently disclosed as
an easy to handle liquid trifluoromethylating reagent. A 30g
batch of the reagent stored at 0C showed no sign of
decomposition over two months (16).
Trifluoromethyltrimethylsilane (Me3SiCF3 ,TMSCF3) /
Trifluormethyltriethylsilane (Et3SiCF3 , TESCF3)(17)
TMSCF3 (Ruppert-Prakash reagent) is a stable and easy
to handle liquid trifluoromethylation reagent (bp: 55C)
which has extensively been used in R&D for three
decades. It can be handled without special equipment or
safety precautions. For R&D applications TESCF3 is often
preferred because its higher boiling point (56-57C at 60
mbar) allows higher reaction temperatures. Whereas the
original Ruppert preparation protocol of TMSCF3 is based
on CF3Br (17a), Prakash et al (10b) were able to react
fluoroform with Me3SiCl at -85C using potassium
hexamethyldisilazane (KHMDS) as a base. From a raw
material point of view, this is a very economical process,
since fluoroform is a large volume byproduct in the
synthesis of polytetrafluoroethylene and
trimethylchlorosilane is inexpensive. The most expensive
raw material in this synthesis is KHMDS. From a process
point of view, the very low temperature (-85C) seems to
be an obstacle. The same protocol is also well suited for
the synthesis of TESCF3. The current price of TMSCF3 is
about USD 3000/5 kg.
Metal trifluoromethanesulfinates (CF3SO2Na, CF3SO2K,
(CF3SO2)2Zn) (18, 19)
CF3SO2Na (Langlois reagent), CF3SO2K and (CF3SO2)2Zn (a
Baran reagent) are solid salts which can easily be prepared
from CF3SO2Cl and handled in air in standard laboratory
equipment without any special precaution. In combination
with tert.-butyl hydroperoxide (TBHP) they have been used as
radical trifluoromethylating reagents. These reagents are
currently commercially available in 5 g to 100 g portions.

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

Methyl fluorosulphonyldifluoroacetate (20)

Methyl fluorosulphonyldifluoroacetate was introduced in 1989
by Chen and Wu as a new trifluoromethylating reagent. It is a
easy to handle liquid with a boiling point of 118C. This
reagent can be prepared from chloroform, HF and SO3. It is
currently available for about USD 1000/1 kg.

examined. Variation of the boron substituent (e.g.

benzyloxy or 2-methoxyethyl) resulted in reagents with
similar reactivity but improved thermal stability, i.e. the
tris-benzyloxy derivative decomposes at temperatures >
170C. This reagent is currently commercially available
in gram quantities.

2,2,2-Trifluoroacetophenone (21)
Aryl-trifluoromethylketones such as 2,2,2-Trifluoroacetophenone
have been described as an excellent trifluoromethyl source.
2,2,2-Trifluoroacetophenone is a liquid (bp: 153C) that can
be easily synthesized from bulk precursors, such as fluoroform
and bromobenzene. Therefore this is a potential low- to
medium-cost trifluoromethylating reagent for large scale
application. It is currently available for about USD 1000/1 kg.

Electrophilic trifluoromethylating reagents (26)

In 1984, Yagupolskii and co-workers (27) successfully achieved
electrophilic trifluoromethylation by means of
diaryl(trifluoromethyl)sulfonium salts such as 147531-11-1. Since
then, additional so-called shelf-stable electrophilic
trifluoromethylating reagents have been developed and
used in academic and industrial research. Figure 1 shows a
selection of such reagents.

Phenyltrifluoromethylsulphone (22)
Phenyltrifluoromethylsulphone is a liquid (bp:
203-205C) that can be easily synthesized from
bulk precursors, such as sodium trifluoroacetate
and benzenesulfonic chloride. Therefore this is
a potential medium-cost trifluoromethylating
reagent for large application. It is currently
available for about USD 3000/1 kg.

Figure 1. Common reagents for electrophilic trifluoromethylation.

4th Level Reagents

TrifluoromethylatorTM ((Phen)Cu-CF3) (23)
(Phen)Cu-CF3 is a convenient to handle, thermally stable,
single-component reagent for the trifluoromethylation of aryl
iodides introduced by the Hartwig-group. It can be
synthesized by the reaction of [CuOtBu]4 with
1,10-phenanthroline, followed by reaction with TMSCF3.
Currently TrifluoromethylatorTM is commercially available in
portions up to 100 g.
Trifluoromethyl-tris(triphenylphoshino)copper [(Ph3P)3Cu(CF3)] and
Phenanthroline-trifluoromethyltris(triphenylphosphine)copper
[(phen)Cu(PPh)3(CF3)](24)
[(Ph3P)3Cu(CF3)] and [(phen)Cu(PPh)3(CF3)] have been
prepared in multi-gram scale from
CuF2, PPh3 and TMSCF3 in high yield.
[(Ph3P)3Cu(CF3)] is oxygen- and moisturesensitive in solution, but it can be stored
and handled in air for at least a month
without decomposition. Currently these
reagents are commercially available in 5 g
quantities.
Potassium (trifluoromethyl)trimethoxyborate
(K[B(OMe)3CF3])(25)
Recently potassium (trifluoromethyl)
trimethoxyborate was introduced
by the Goossen-group as an easy to
handle CF 3 source. [B(OMe) 3 CF 3 ]K is
generated in quantitative yields by
stirring a mixture of TMSCF 3 , B(OH) 3 ,
and KF in anhydrous THF for one to two
days. The crystalline, air-stable salt
melts and decomposes at 116-118C.
Solution in polar organic solvents such
as DMF, start decomposing at approx.
80C. Accordingly, process safety both
for the preparation and the application
of this reagent has to be carefully

For example the Togni reagents can be exposed to moist air

for short periods of time without any apparent alteration.
Investigations of the thermal stability of Tognis reagents I and
II by Novasep Synthesis (28) indicated that some samples of
Tognis reagent II are impact-sensitive. The Togni group
concluded that the reagents are not explosive under typical
laboratory and reaction conditions and that these reagents
do not require severe safety measures (29). It is interesting to
note that Tognis reagent II is sold by retailers as a mixture with
diatomaceous earth in order to reduce explosibility.
The reagents depicted in Figure 1 are commercially available
in portions up to 100 g.

Scheme 2. Typical protocols for the preparation of trifluoromethylated aromatic

compounds. Phen* = 1,10-phenanthroline.

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

29

October 21-23, 2015

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METHODS FOR THE SYNTHESIS OF AROMATIC TRIFLUOROMETHYL

COMPOUNDS
As exemplified in Scheme 2 a broad choice of functional
group transformation are available for the synthesis of
aromatic trifluoromethyl compounds.
In the following, these protocols are briefly described.
Preparation of Aromatic Trifluoromethyl Compounds by
Fluorination / Deoxofluorination
Chlorination of Toluene followed by Chlorine / FluorineExchange
The only process used so far for the preparation of aryl-CF3
compounds on a large scale is based on the free radical
perchlorination of aromatic methyl groups followed by
chlorine-fluorine exchange by AHF (30). This process is very
economical, as only low-priced reagents (Cl2, HF) and
sometimes Lewis acid catalysts like FeCl3 or SbF3 are used.
Due to the harsh reaction conditions (Cl2-gas, AHF at 100180C), the scope of this reaction is limited to basic Aryl-CF3
compounds such as benzotrifluoride, chlorinated
benzotrichloride or 2,4-bis(trifluoromethyl)pyridine (31).
However, further functionalization of basic aryl-CF3
compounds results in a broad variety of substituted
benzotrifluorides (32). Due to the use of economic raw
materials and very large production volumes cost of goods
are << USD 100 / kg. However, processing of AHF is limited to
specialized companies.

companies available that offer process R&D and

production of up to multi-tonne amounts of
trifluoromethylated aromatic compounds by
deoxofluorination using SF 4 .
Recently, 2,6-dimethyl-4-tert.-butylphenylsulfurtrifluoride
(Fluolead) was introduced as a potential, less hazardous
substitute for SF4 (34). Two equivalents of arenesulfinylfluoride
result as a by-product that has to be separated from the
benzotrifluoride product. If the by-product can be recycled,
such a method could have some potential for large scale
application. However, scope and limitations of this
transformation have not been examined so far.
Preparation of Aromatic Trifluoromethyl Compounds by
Trifluoromethylation (1)
Introduction
Several strategies have been pursued for the introduction of the
trifluoromethyl group into aryl residues. Baran divided them into
two general categories: those that functionalize the inherently
reactive position of the substrate (innate trifluoromethylation)
and those that utilize substrate prefunctionalization or a directing
group (programmed trifluoromethylation) (35). Most often, the
substitution of a functional group respectively the coupling of an
aryl electrophile has been effected by the CuCF3 species,
originally identified by McLoughlin and Thrower (36) and further
developed by Kobayashi et al. (37). Scheme 4 gives an overview
of the most important aromatic trifluoromethylation concepts,
including nucleophilic, radical and electrophilic mechanism.

Deoxofluorination of Aromatic Carboxylic

Acids (33)
Sulfur tetrafluoride is a very reactive
deoxofluorination reagent for carboxylic
acids. The reaction tolerates a number of
other functional groups such as phenols,
amines, ethers or nitro groups and is also
applicable for a broad range of
heteroaromatic carboxylic acids.
Scheme 3 illustrates the scope of SF4-based
deoxofluorination of aromatic carboxylic
acids.
As the processing of SF 4 and AHF is
Scheme 4. Strategies for the introduction of the trifluoromethyl group into aryl residues.
limited to specialized companies and
SF 4 should be produced on-site, the
Nucleophilic reagents work best with electron-deficient
large scale industrial application of this technology has
arenes while electrophilic and radical CF3 species are more
started quite recently. Currently, there are only a few
suitable for electron-rich arenes such as amines and phenols.
Whereas programmed trifluoromethylation is highly sitespecific, innate trifluoromethylation usually results in the
formation of position isomers.

Scheme 3. SF4 based deoxofluorination of carboxylic acids (33).

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

Metal-CF3 complexes are the active nucleophilic

trifluoromethylation reagents. Usually the trifluoromethyl anion
is generated by transmetallation of the pronucleophile
resulting in a metal-bound CF3 group, e.g. CuCF3. Methyl
fluorosulfonyldifluoroacetate, sodium trifluoroacetate, methyl
chlorodifluoroacetate, trifluoromethyliodide, and
trifluoromethyltrimethylsilane are among the most often used
precursors. The preparation of CuCF3 requires moderate to
high temperatures. Recently, additional precursors were
introduced, enabling the formation of CuCF3 at room
temperature, e.g. fluoroform, PhCOCF3, PhSO2CF3, and

31

trifluoromethylating reagents are CHF3, CF3COOR (R = Na, K,

Me), and CClCF2COOMe followed by TMSCF3,
FSO2CF2COOMe, and PhCOCF3.
Sodium trifluoroacetate was introduced in 1981 for the coppermediated decarboxylative trifluoromethylation of aryl iodides
(44) Although already developed to large scale, such reagents
suffer from the fact that excess of salts (2 to 10 eq. of CF3COOM
and 2 to 5 eq. of CuI) is needed (11e). Another issue associated
with alkaline trifluormethylacetates is their hygroscopicity
because moisture favors the reduction of the aromatic halides
resulting in the formation of the corresponding hydrocarbons. In
1988 Carr, Chambers and Holmes (45) published the application
of this protocol for a broad range of iodo- and bromo-benzenes
and heterocyclic aromatic compounds.
Scheme 5. Methods for the formation of CuCF3.

potassium (trifluoromethyl)trimethoxyborate. CuCF3-DMF

solutions do not degrade for several days if stabilized with e.g.
Et3N(HF)3 (10a) or HCl in Et2O (21). Scheme 5 gives an
overview of some of the most important
precursors for CuCF3.

In 1989, Chen and Wu (20) described the use of methyl

fluorosulphonyldifluoroacetate for the trifluoromethylation of
aryl, alkenyl and benzyl halides. CuCF3I- is formed upon
heating the reagent with catalytic amounts of CuI upon
formation of CO2 and SO2, c.f. Scheme 7.

Originally, Cu was used in stoichiometric

amounts, but also catalytic protocols have
been developed, c.f. the following chapters.
Trifluoromethylation of Arene Diazonium Salts
In 2013 and 2014 Sandmeyer-type
trifluoromethylations were described by
Scheme 7. Coupling of aryl iodides and bromides with CuCF3 generated by decarboxylation.
Fu (38), Goossen (39), and Wang (40),
c.f. Scheme 6. Given the fact that
aromatic amines are easily accessible and therefore
In 1991, Su, Duang and Chen (11b) introduced
represent economic starting materials this approach is
chlorodifluoraacetate (MCDFA) as a convenient
particularly interesting from an industrial point of view.
trifluoromethylating reagent. This protocol was successfully
Goossens protocol looks most interesting, since it uses a sub
scaled to a multi-kg scale by Mulder et al (44). A catalytic
stoichiometric amount of copper, a medium-priced
protocol using 3 eq. MCDFA, 1,5 eq. KF, 0.1 eq. of copper
trifluoromethylating reagent (TMSCF3) and works at room
thiophene-2-carboxylate and 0.1 eq. of 1,10-phenanthroline
temperature.
resulted in 63% isolated yield. The use of a protocol based on
methyl fluorosulfonyldifluoroacetate resulted in 72% yield.
Trifluoromethylation of Aryl Halogenides
However, it was excluded from further development due to its
CF3Cu has widely being used for the nucleophilic substitution of
high cost and limited availability.
aryl halogenides by the trifluoromethyl anion. The reactivity
decreases in the following order: I > Br > Cl > F. In many cases
Examples of other catalytic trifluoromethylation protocols
costly aryl iodides have to be used as coupling partner as this
based on convenient to handle trifluoromethylating reagents
reaction does not work with less expensive aryl bromides or
under mild conditions include TESCF3 (42), potassium
chlorides. Originally, CuI was used in stoichiometric amounts
trifluoromethyltrimethoxyborate (25a), and
(41), but also catalytic protocols have been developed (42-43).
TrifluoromethylatorTM (23), c.f. Scheme 8.
From an reagent price point of view, the most interesting

Scheme 6. One-pot Sandmeyer trifluoromethylation.

32

Aryl chlorides are much more preferred starting materials than

aryl bromides and especially
aryl iodides from an
economic point of view. The
nucleophilic
trifluoromethylation of aryl
chlorides was achieved by
the Buchwald group using
palladium catalysts (43), c.f.
Scheme 9.
This protocol is clearly a
break-through in the field of
aromatic
trifluoromethylation.

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

Trifluoromethylation of
Aryl Boronic Acids and
Aryl Boronates
Arylboronic acids and
boronates have been
increasingly used as
substrates for siteselective
trifluoromethylation
reactions. Sanford et
al described a mild
and practical protocol
Scheme 8. Coupling of aryl iodides with catalytical amounts of CuCF3 generated from easy to handle
trifluoromethylating reagents.
for the substitution of
aryl and heteroaryl
boronic acids using NaSO2CF3 (Langlois reagent) and t-butyl
hydroperoxide (TBHP) as a source of CF3 radicals (48), the
Beller group developed a similar protocol, but catalytic in
copper (49). CF3I in the presence of a photocatalyst and
visible light was used by Sanford (50). Liu and Shen (51) and
the Shibata group (52) investigated the use of electrophilic
reagents for trifluoromethylation of aryl boronic acids. Tognis
reagent proved to be the reagent of choice for the catalytic
trifluoromethylation of a broad range of substituted aryl
boronic acids, c.f Scheme 11.
Scheme 9. Pd-catalyzed trifluoromethylation of aryl chlorides.

However, more efficient catalytic systems need to be

developed in order to achieve reasonable cost both for Pd
and ligand input, as well as for Pd-separation
Grushin et al (47) found that fluoroform-derived CuCF3 exhibits
high reactivity towards aryl and heteroaryl iodides and
bromides. CuCF3 is generated by reaction of [K(DMF)]
[Cu(OBu-t)2] (synthesized from CuCl and potassium tert.butylate in presence of DMF) with CHF3. Upon stabilization with
Et3N(HF)3 the resulting CuCF3 is stable at room temperature for
days. The inexpensive fluoroform, the high yields, and the
broad scope open great opportunities. However, the need for
excess amounts of copper and the elaborate procedure might
limit the potential for a broad industrial application of this
protocol. Scheme 10 illustrates this reaction.

Scheme 10. Coupling of aryl iodides and bromides with CuCF3

generated from CHF3.

An alternative protocol is based on the easy to handle Cu-CF3-1,10phenanthroline complex (TrifluoromethylatorTM). The high yield for a
broad choice of substituted aryl iodides might outweigh the
drawback of the need for an expensive reagent and stoichiometric
amounts of copper, especially for application in R&D.

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

In summary, a broad portfolio of copper-based

trifluoromethylation reagents and protocols is available for the
trifluoromethylation of boronic acids and boronates, providing
a high level of functional group tolerance. However, it has to
be noted that most of these protocols have only been
applied on very small scales, so far.
Innate Trifluoromethylation of Ar-H compounds
Several protocols are available for the trifluoromethylation of
ar-H substrates at their inherently reactive position (innate
trifluoromethylation (19)). The advantage of this concept is
that no prefunctionalization of the molecule is needed. The
most important potential problem is the formation of
undesired position isomers. For this reason most protocols
focus on heterocyclic substrates. Nagib and MacMillan (58)
reported a mild method for the trifluoromethylation of nonactivated arenes and heteroarenes via a radical- mechanism
using a photocatalyst and irradiation by a household bulb.
Ritter et. al. (16) developed a protocol for the direct
trifluoromethylation of electron-neutral to electron-rich arenes
using a novel 1:1 adduct of CF3I with tetramethylguanidine
(TMG), c.f. Scheme 13. Because the trifluoromethyl radical is
known to be an electrophile, the scope of these methods is
limited to electron-neutral to electron-rich arenes.
Scheme 13 also depicts Barans protocol for the innate
carbon-hydrogen functionalization of heterocycles based on
zinc trifluoromethylsulfinate (19). This protocol tolerates
reactive heteroaryl halides, nitriles, ketones, esters, and even
free carboxylic acids and esters, and is not sensitive to air or
moisture. In 2012 the Togni group published a protocol using
the electrophilic Tognis reagent and 0.05 to 0.1 equivalents of
a rhenium catalyst (59). However, for regioselectivity reasons
the scope of this protocol is restricted.
An iron-based radical aromatic trifluoromethylation was
published by Yamakawa et al in 2010 (60). A series of arenes
and heteroarenes was trifluoromethylated with CF3I in DMSO
in presence of 0.3 0.5 eq. FeSO4 or Cp2Fe and 2 to 10 eq. of

33

preparation or manufacture of a
trifluoromethylated aryl or
heteroaryl compound has to
consider many pros and cons of
the various methods. Some
criteria are proposed in Table 1.

Scheme 11. Cu-mediated coupling of arylboronic acids.

Scheme 12. Cu-mediated coupling of arylboronic acids and aryl boronates.

Criteria for a Qualitative Rating of

the Potential of Methods for
Manufacturing of Trifluoromethylated
Aromatic Compounds
An ideal process is based on a
low-cost substrate and reagent, as
well as on low cost for metals,
ligands, metal removal, and waste
disposal. Furthermore it is high
yielding, no difficult-to remove
byproducts are formed, and the
technology has already been
scaled into at least 1 kg to 100 kg
scale.
Needless to say that the most
important criterion for the route
selection is the total production cost
of the final active substance. I.e. a
short synthesis route including a
selective late-stage
trifluoromethylation based on an
expensive reagent could be more
cost-efficient than a multi-stage
route including a well-priced early
trifluormethylation step.
Many of the described reactions are
catalysed by metals. Toxicity and
environmental concern of metals
used for trifluoromethylation
decrease in the following order: Pd
> Re, Ru, Ir > Cu > Zn > Fe (63).

Scheme 13. Innate trifluoromethylation.

H2O2. Again, regioselectivity proved to be a serious problem

with many substrates. One notable exception is
5-trifluoromethyluracil. which has been produced in a 50 kg
scale in a 600 L reactor (61).
Recently, Brse et al disclosed a mild, metal free method for
radical perfluoroalkylation of (hetero)arenes, e.g.
trifluoromethylation of benzene derivatives, furanes, pyrroles,
and thiophenes with trifluoroacetic anhydride in presence of
urea-hydrogen peroxide (62).

POTENTIAL FOR LARGE SCALE APPLICATION

The previous chapters illustrate the enormous diversity of
reagents, strategies, and protocols available for the
synthesis of trifluoromethylated aromatic compounds. A
chemist who has to develop a process for the

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

Metal price decrease in the

following order: Pd, Ir >> Ru >> Cu,
Zn > Fe (64).
Therefore, efficient catalytic
processes are mandatory for Pd, Ru, and Ir. For Cu and Zn,
catalytic processes are highly desirable. However, for certain
applications even the use of stoichiometric amounts of
copper or zinc might be tolerable. For example a
stoichiometric copper-based protocol could be favorable
compared to a lower-yielding one catalytic in copper.
Separation of metals from products and waste water may
require additional process steps, e.g. adsorber treatment of
product solutions to remove Pd (65). Whereas metalcontaminated organic solvent based waste streams can
easily be incinerated (followed by metal recovery or disposal),
this isnt an option for highly diluted, water-based metals
wastes because of the high cost. In such cases a tailor-made
metal separation by precipitation, ion-exchange, reverseosmosis, biodegradation, or a combination of such
techniques has to be developed in order to fulfil the
governmental requirements (66).
Based on the criteria and the colors depicted in Table 1 the

35

classical methods and a selection of

modern protocols have been
qualitatively assessed regarding large
scale application, c.f Table 2.
Remarkably, only the classical process
consisting of chlorination of simple
toluene derivatives followed by chlorinefluorine exchange is currently used in a
multi ton scale. Three protocols have
been applied on a 1 kg to 100 kg scale,
the others have predominantly been
used in a mmol scale.

CONCLUSIONS AND OUTLOOK

The synthetic toolbox for the synthesis of
aromatic trifluoromethyl compounds has
dramatically grown and is still expanding.
About three decades ago, only aromatic
methyl groups and carboxylic acids could
be converted to trifluoromethyl groups.
Today, trifluoromethyl groups can be
introduced by selective trifluormethlyation
of aryl-halides, aryl boronic acids and
boronates, aryl amines or even aryl
hydrogen compounds. In addition, some
of these trifluoromethylations can be
performed with relatively inexpensive
reagents such as CF3COONa or CHF3.

Table 1. Criteria for large-scale application. +: * s/c: substrate to catalyst ratio.

Substrate

Reagent Cost

Metal and
Catalyst
Cost

Specific
Requirements

Ar-CH3

Cl2 (3 eq.)
AHF (3 eq.)

0 - 0.1 eq.
Sb

Autoclave

Ar-NH2

Umemotos reagent
(1.5 eq.), t-BuONO

3 eq. Cu

Ar-NH2

t-BuONO (1 eq.)
p-TSA (1.5 eq.)
Me3SiCF3 (1.5 eq.)

CuSCN
(0.5 eq.)

Ar-COOH

SF4 (2.5 eq.)

AHF

Toxicity,
Eco-Toxicity of
Metals,
Reagents

Status
Quo of
Protocol /
Process

HCl

Cl2, AHF

100 tonnes

(30)
(31)
(32)

Cu

Cu

mmol

(40)

Cu

Cu

mmol

(39)

Autoclave

SOF2

SF4,
AHF

100 kg
(multitonnes)

(33)

ArSOF

mmol

(34)

Ar-COOH

ArSF3 (2.5 eq.)

Autoclave

Ar-Cl

TESCF3 (2 eq.)

0.05 eq. Pd
Brettphos

Strictly dry

Ar-I

CClF2COOMe
(2-4 eq.)
KF (1 eq.)

CuI
(1-1.5 eq.)

Ar-Br

CHF3 (1.5 eq.),

t-BuOK, Et3N.3HF

1.5 eq. Cu

Ar-I

TESCF3 (2 eq.)

0.1eq. Cu

Ar-I

TrifluoromethylatorTM
(1.2 eq.)

Ar-B(OH)2

Waste
Load

Pd

Ref.

mmol

(43)

There is also progress in the mechanistic

understanding of trifluoromethyation
reactions. Very recently, the group of Olah
and Prakash characterized the
trifluoromethanide anion with a [K(18crown-6)] countercation (67) and found
that CF3- possesses a significant lifetime at
sub-ambient temperatures. They showed
that the outcome of many nucleophilic
trifluoromethylation reactions can be
explained with the occurrence of the
CF3- intermediate. Such mechanistic
results are expected to provide a basis for
the development of further novel synthetic
trifluoromethylation protocols.

Cu

Cu

5 kg

(11b)
(20)
(44)

Strictly inert

Cu

Cu

mmol

(47)

Cu

Cu

mmol

(42)

Even though there is now a broad palette

1.2 eq. Cu

Cu

Cu

mmol

(36)

CF3SO2Na (3 eq.)
TBHP

1 eq. Cu

Cu
CF3SO2Na

Cu

mmol

(48)

Ar-B(OH)2

CF3I (5 eq.)

0.2 eq. Cu
0.01 eq. Ru

Day-light
irradiation

Cu
CF3I

Cu

mmol

(50)

Ar-B(OH)2

Tognis reagent
(1.2 eq.)

0.05 eq. Cu
Phen

Cu

Cu

mmol

(51)

Ar-Bpin

K[B(OMe)3CF3]
(2 eq.)
O2

Cu(OAc)
1 eq.

Cu

Cu

mmol

(25b)

Het-ar-H

CF3SO2Cl (1-4 eq.)

0.02 eq. Ru
Phen

Ru

mmol

(58)

Het-ar-H

CF3I (3 eq.)
H2O2 (2 eq.)

FeSO4 or
cp2Fe
(0.3 eq.)

CF3I

CF3I

40 kg

(60)
(61)

Het-ar-H

Zn(CF3SO2)2
(1-4 eq.)
TBHP (3-5 eq.)

Zn

Zn

Zn

mmol

(19)

of modern synthetic protocols available

for laboratory scale applications, large
scale synthesis of aryl-CF3 compounds still
relies mainly on the traditional sequence
- chlorination of a benzylic methyl group
followed by halogen exchange and
finally, if required, functionalization.
Deoxofluorination of carboxylic acids with
SF4 starts being applied on tonne scale,
but this approach is still significantly more
expensive than the traditional route.
Modern trifluoromethylation protocols are
increasingly used in research labs for the
small scale preparation of novel
biologically active compounds.

Ar-I

Day-light
irradiation

Table 2. Potential of selected trifluoromethylation methods for large scale application. Phen =
1,10-phenanthroline, Pin = pinacolato.

36

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

These modern protocols allow building up aryl-CF3 compounds

with substitution pattern that may be difficult to achieve using
the traditional route. It is interesting to see, how such compounds
will be prepared when they are needed in large quantities.
Today, there are only very few examples of trifluoromethylation
processes that have been developed to multi-kilogram scale.
However, in the light of the progress made in recent years we
expect that the situation will change and that the number of
scalable and cost-competitive trifluoromethylation processes will
increase in the near future.

12.

13.

14.

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