This is the peer reviewed version of the following article: “Nucleophilic Trifluoromethylation Reactions Involving Copper(I)
Species: From Organometallic Insights to Scope” which has been published in final form at:

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0037-1611776

This article may be used for non-commercial purposes in accordance with Thieme Terms and Conditions for Self-Archiving

Nucleophilic Trifluoromethylation Reactions Involving Copper(I) Species:
From Organometallic Insights to Scope
a,b
L.
Ángel L. Mudarra†a,b
Sara Martínez de Salinas†a
Pérez-Temprano
Mónica H. Pérez-Temprano*a
a

Institute of Chemical Research of Catalonia (ICIQ) Avgda.
Països Catalans, 16, 43007 Tarragona (Spain)

b
Department de Química Analítica I Química Orgànica,
Universitat Rovira i Virgili, C/Marcelli Domingo s/n, 43007
Tarragona (Spain)

† These

authors contributed equally to this work.

mperez@iciq.es

Click here to insert a dedication.

Received:
Accepted:
Published online:
DOI:

Abstract Over the last decades, trifluoromethyl copper(I) complexes have
played a key role as reactive species in the formation of C–CF3 bond-forming
reactions. This Short Review covers not only select examples of relevant Cumediated or catalyzed nucleophilic trifluoromethylation reactions, one of the
most active fields in organic synthesis, but also provides a comprehensive
picture of the real behavior of these copper species, including ubiquitous
cuprates, in the reaction media.
1
2
3
4
5
6

Introduction
Historical perspective of the identification of relevant
trifluoromethyl copper(I) species
In-situ generation of active trifluoromethyl copper(I) species
Well defined active trifluoromethyl copper(I) complexes
Recent advances on the reactivity of different trifluoromethylation
protocols
Conclusions

Key words trifluoromethylation, copper, ate-type complexes, catalysis,
organometallic chemistry

1

Introduction

The trifluoromethyl group is a prevalent motif in
pharmaceuticals, agrochemicals and materials due to its unique
capability to change physical, chemical and biological properties
of organic molecules.1 Thus, over the past years, the scientific
community has directed its efforts towards the development of
rapid and efficient strategies to install this privileged functional
group onto organic scaffolds.2 In this context, a tremendous
success has been achieved by using copper as mediator. Back in
the 60s, McLoughlin and Thrower reported a pioneering work
that allowed, for the first time, the perfluoroalkylation of
haloarenes involving Cu-Rf species.3 Since then, different types of
trifluoromethyl copper organometallic complexes, ranging from
in-situ generated “CuCF3” species to well-defined Cu(I)
trifluoromethyl complexes, have been proposed to play a key role
as intermediates in C–CF3 bond-forming reactions.2b,e,g,4

Scheme 1 Representative nucleophilic trifluoromethylation reactions
mediated by copper

This Short Review not only revisits selected and relevant
examples of nucleophilic trifluoromethylation reactions
involving trifluoromethyl copper(I) species but also gives an
organometallic perspective of overlooked aspects related to
these transformations where, in general, there is a lack of
fundamental understanding (Scheme 1). This is likely to the
potential involvement of different copper species as reaction
intermediates, including neutral and ionic complexes,
(cat)[Cu(CF3)X], X = halogen or CF3, whose characterization is far
from being trivial.4a-e In this regard, the real role of cuprates,
ubiquitous in Cu-mediated nucleophilic trifluoromethylations,
remains practically unexplored, due to the challenges associated
to their selective access in solution. Moreover, the scarce piece of
information about them is disseminated among the literature
and, sometime, shallowly mentioned. For this reason, we decided
to focus our attention on both the preparation and the synthetic
utility of the so-called “ligandless” in-situ generated [CuCF3] and
the well-defined trifluoromethyl copper(I) complexes specially
when the cuprates are explicitly mentioned. From our point of
view, these often-neglected cuprates could potentially be noninnocent spectators in the reaction and therefore, we will end up
this Short Review by discussing our recent contributions into this
field. 5

2

Historical Perspective of the identification of
relevant trifluoromethyl copper(I) species

As mentioned above, one of the main challenges associated to Cucatalyzed or mediated nucleophilic trifluoromethylation
reactions is the characterization of the copper species present in
solution. In order to facilitate reading comprehension, we
decided to start this Short Review covering, in chronological
order, the literature precedents focused on the identification of
the different trifluoromethyl copper species relevant for these
transformations (Scheme 2).
In 1986, Burton et al. described for the first time that the in-situformed mixture of “ligandless” [CuCF3] contained elusive and
complex species whose characterization was non-trivial.6
Initially, the authors observed a “ligandless” CuCF3 species ( = –
28.8 ppm) by 19F NMR spectroscopy when they performed the
reaction between CuBr and CF3CdX in DMF at –50 °C However,
when the solution was warmed up, two new species were
detected ( = –32.3 and –35.5 ppm). These three “CuCF3” species
show remarkably different reactivity towards air-oxidation,
trifluoromethylation and hydrolysis. In 1989, the same research
group performed further studies in order to provide a better
understanding of the nature of the copper species involved in the

“ligandless” [CuCF3].7 This was the first time that species such as
(CdI)[Cu(CF3)2] or (Cd)[Cu(CF3)I] (named in the paper as CuCF3·L
L = metal halide) was proposed to be part of the “ligandless”
[CuCF3]. However, it was not until 2008, when Kolomitsev et al.
confirmed that the term “ligandless” [CuCF3] was an
oversimplification. During the in-situ generation of [CuCF3] by
reaction of CuBr, KF and Me3SiCF3 in DMF/DMI as solvent at 0 °C
they observed that copper was speciated in three different
complexes: CuCF3-solvent, [Cu(CF3)2]– and [Cu(CF3)4]– exhibiting
three singlets in the 19F NMR spectrum: –28.8 ppm; –32.3 ppm
and –35.5 ppm, respectively. Further investigations revealed that
the signal at –35.5 ppm belongs to [Cu(CF3)4]–, a Cu(III) complex,
inert towards the activation of aryl halides.8
In 1988, Parker and co-workers reported the aromatic
trifluoromethylation
via
decarboxylation
of
sodium
trifluoromethyl carboxylates. In this work, the authors
performed mechanistic studies that pointed out the intermediacy
of a nucleophilic species, that they assigned as a heteroleptic
cuprate [Cu(CF3)I]–.9 A year later, the same heteroleptic cuprate
was proposed to be involved in the trifluoromethylation of aryl,
alkenyl and alkyl halides when using CuI and a new
trifluoromethyl source, methyl fluorosulphonyldifluoroacetate.10
However, the first time that this specie was characterized by 19F
NMR was in 2011, by Goossen et al., [Cu(CF3)I]– ( = –28.14 ppm).
11

The observation of multiple copper species is not only found in
the in-situ synthetic routes but also when using the well-defined
complexes. In these cases, it has been observed that the neutral
LCu(CF3) (L = SIMes, phenanthroline) are in dynamic equilibrium
with the corresponding cuprate (L2Cu)[Cu(CF3)2], which are
inevitablely part of the synthesized “trifluoromethylating
agent”.4c-e

3.1

Fluoroform as synthetic equivalent of CF3–

Fluoroform is the ideal synthetic equivalent of the CF3– synthon.
It is cheap, readily available and a side product of the synthesis of
Teflon® which makes its use even more interesting. Furthermore,
fluoroform is a weak acid that can be deprotonated by strong
bases.12 The first time that HCF3 was utilized in the preparation
of [CuCF3] was reported in 2000, by Folléas and co-workers.13
They described the in-situ synthesis of the potassium
trifluoromethylated aminoalcoholate (K)[Me2NCH(O)CF3] using
CF3H and Dimsyl-K (potassium methylsulfinylmethylide) in DMF
at –40 °C. This aminoalcoholate reacted with copper iodide and
a stabilizing reagent such as DMEU (Dimethylol ethylene urea) to
give rise a new tetrahedral intermediate that evolved at room
temperature into [CuCF3] (47%) and N,N-dimethylformamide
(Scheme 4a). The transference of the CF3 in the copper
trifluoromethyl aminoalcoholate is crucial for the reaction to
proceed as described in a tentative mechanism shown in Scheme
4b. They observed by 19F NMR spectroscopy two different
species: :  = –25 ppm, presumably (DMF)CuCF3 and  = –30 ppm
[Cu(CF3)I]– and both could be involved in the formation of the
trifluoromethylated product.

Scheme 2 Timeline representing the highlights of the copper nucleophilic
trifluoromethylation reaction

Scheme 4 a) Formation of [CuCF3] using HCF3 and Dimsyl-K (See Ref. 13 for
further details). b) Proposed species in the reaction media during the
trifluoromethylation reaction

3

In-situ generation of active trifluoromethyl
copper(I) species

In this section, we will describe selected examples of synthetic
routes for accessing in-situ generated trifluoromethyl copper(I)
species and their applications in the synthesis of
trifluoromethylated organic scaffolds (Scheme 3). We have
organized this section based on the nature of the source that
provides the nucleophilic CF3 reagent to the copper: (i)
fluoroform; (ii) trifluoromethylated organic sources as
nucleophilic CF3 synthons and (iii) other trifluoromethyl
organometallic complexes that act as CF3 shuttle through a
transmetalation step. It should be highlighted that the commonly
named [CuCF3] refers to the complex mixture of copper species
described above, which includes the presence of cuprates.
F
H C

F
F

basic conditions

F
OD

C

F
F

Cu(I)
source

OD = Organic Donor
'activating conditions'

C

F
F

C

F
F

F
M

F
Cu

M = Hg, Zn, Cd

F
F
C
F

Scheme 3 Procedures to generate in-situ [CuCF3]

In 2011, Grushin et al. disclosed the direct cupration of
fluoroform. This involves the formation of trifluoromethyl
copper(I) complex using HCF3 without the necessity of organic
intermediates. This groundbreaking synthesis was achieved by
using a novel ate-type complex, [K(DMF)][Cu(OtBu)2], that
instantaneously reacts with HCF3 to yield [CuCF3] almost
quantitatively.4f,14 This complex is stable at –35 °C for days after
treatment with Et3N·3HF, affording solutions of [CuCF3] (95%
yield) as a mixture of (DMF)CuCF3 (85%) and [Cu(CF3)2]– (10%)
by 19F NMR analysis (Scheme 5). This solution could be used in
the trifluoromethylation of organometallic species, affording
(IPr)CuCF3 or [(TMEDA)Pd(Ph)CF3], and organic electrophiles. In
this regard, the authors were able to functionalize methyl iodide,
different aryl iodides, bearing electron-donating and withdrawing substituents, and selected heteroaryl iodides.

these pioneering works have inspired the use of other
trifluoromethylated acetates, in all the cases harsh conditions are
required to decarboxylate the corresponding salt.16 The
commonly accepted mechanistic scenario involves the formation
of nucleophilic [CuCF3] as reactive intermediates.17

Scheme 5 Cupration of fluoroform and representative examples of its
applicability (see Ref. 4f and 14 for further details)

In 2014, the same research group performed an exhaustive
experimental and computational study, in order to unravel the
mechanism of the nucleophilic Cu-mediated trifluoromethylation
using (DMF)CuCF3 as model system.4i Up until that date, only
scarce mechanistic hints could be found in the literature: i) the
common rate trend when using different aryl halides (Ar–I > Ar–
Br > Ar–Cl); ii) the prevalent employment of DMF as solvent and
iii) the use of radical clock experiments that discarded a radical
mechanism4c. In this venue, Grushin provided relevant
information to the field. The most likely scenario involved an
associative oxidative addition (OA), which is the rate determining
step, of the aryl halide to the (DMF)CuCF3 complex and,
subsequently, the reductive elimination (RE) from the Cu(III)
intermediate. This proposal is supported by the Hammett plot
correlation (p-,  positive) and DFT calculations, which agreed
with the experimental activation parameters (G‡exp ≈ 24
kcal/mol vs G‡DFT = 21.9 kcal/mol). Moreover, the ortho effect
was also investigated. Two parameters were found to be
important in the performance of the reaction with ortho
substitution pattern: the coordination of the substituent to the
copper center, which facilitates the oxidative addition transition
state, and the destabilization of the organic substrate by the
ortho-substituent respect to their para isomers. The same
correlation
was
found
in
coinage
metal-mediated
decarboxylation reactions.15
Further computational investigations were performed to
evaluate
other
potential
active
species
in
the
trifluoromethylation. The oxidative addition of the substrate
towards [Cu(CF3)2]– or [Cu(CF3)I]– are less prompted to take
place. However, this computational data was not supported by
experimental evidences and little was known at that time about
the potential reactivity of these cuprates due to the lack of a
selective synthetic route for accessing them (see Section 5).

3.2

Trifluoromethyl organic sources of nucleophilic
trifluoromethyl synthon

The use of trifluoroacetic acid derivatives as CF3 source for
accessing trifluoromethyl copper(I) species has been widely
studied due to their availability and convenience (Scheme 6) . In
this regard, Kondo and co-workers applied this synthetic route
for the first time in the decarboxylative trifluoromethylation
reaction of aryl iodides by combining sodium trifluoroacetate
and CuI.9a Later, in 1988, Chambers et al. expanded this
methodology to aryl bromides, heteroaryl iodides and vinyl
bromides.9b Interestingly, in this work they proposed the likely
intermediacy of [Cu(CF3)I]– since Hammett plot studies pointed
out the nucleophilic character of the active species. Although,

Scheme 6 Examples of synthesis of [CuCF3] using organic sources

An
alternative
to
the
direct
decarboxylation
of
trifluoromethylated acetates is the use of a difluoromethylene
moiety as a ‘masked’ CF3– synthon (Scheme 6). In this venue, it is
worth mentioning the important contribution by Chen and coworkers who, back in 1989, uncovered a route to access
trifluoromethyl
copper(I)
complexes
by
sequential
decarboxylation
and
SO2
extrusion
of
methyl
fluorosulphonyldifluoroacetate.10 This trifluoromethylating
agent is activated at 60 °C and it is compatible with catalytic
amounts of copper. Initially, the authors hypothesized the
formation of difluorocarbene as intermediate but their attempts
to trap it, using alkenes as acceptors, failed. Then, they proposed
the formation of a heteroleptic cuprate, [Cu(CF3)I]–, as the
reactive species in the nucleophilic trifluoromethylation reaction
(see Section 2). The same group reported in 2016 an alternative
route
to
prepare
[CuCF3]
through
a
decomposition/comproportionation sequence starting from
Cu(FO2SCF2CO2)2 and elemental copper (Scheme 7).18 This new
CF3 source is more efficient than the previous one for the
trifluoromethylation of aryl and heteroaryl iodides. In order to
gain mechanistic insights on the nature of the reactive species,
the authors monitored the reaction of Cu(FO2SCF2CO2)2 and Cu in
DMF by 19F NMR spectroscopy. Although at the beginning of the
reaction only [Cu(CF3)2]– was detected, over time (DMF)Cu(CF3)
was also observed. The proposed mechanism for the generation
of the active copper species is depicted in Scheme 7. Other less
used CF3 sources for the in-situ generation of [CuCF3] is
HalCF2CO2Me in combination with an external fluoride source
(Scheme 6).19

Scheme 7 Mechanism of the trifluoromethylation using Cu(FO2SCO2)2 and Cu
(See Ref. 18 for further details)

Another alternative to the decarboxylative route is the
combination of trifluoromethyl ketones, sulfone20 or sulfoxide
and a strong organic base such as tert-butoxides. In this context,
Mikami et al. studied the mechanism of the generation of the
trifluoromethyl copper(I) complexes starting from a pre-formed
K[Cu(OtBu)2] and trifluoromethyl aryl ketones.21 Strikingly,
tetrahedral intermediates (Scheme 8a) were detected at –30 °C
by 19F NMR spectroscopy and the evolution of the reaction
towards [CuCF3] was described when warming up the reaction
mixture.

Regarding trifluoromethylsulfoxides as CF3 source, in 2015, Hu
and co-workers developed a methodology for the
trifluoromethylation of aryl halides, activated aryl bromides,
terminal alkynes and aryl boronic acids.22 The reaction mixture
of CuCl, KOtBu and PhSOCF3 in DMF gave rise to a 99% yield of
[CuCF3] as a mixture of (DMF)CuCF3 (89%) and [Cu(CF3)2]–
(10%). As it was previously described by Grushin, the addition
of Et3N·3HF could stabilize the [CuCF3] species increasing the
amount of the cuprate salt (the proportion in this case is not
mentioned).

Scheme 9 Examples of synthesis of [CuCF3] using different transition metals

In 2011, Daugulis et al. introduced an interesting approach to this
field: the arylation of readily available 1H-perfluoroalkanes by its
deprotonation with a metal base such as TMP2Zn (TMP = bis2,2,6,6-tetramethylpiperidide) using catalytic amounts of copper
and phenanthroline as ligand (Scheme 10a).27 In the
transmetalation reaction from Zn to Cu, a mixture of
pentafluoroethyl copper complexes including heteroleptic and
homoleptic cuprates was again observed by 19F NMR. The
proposed reaction mechanism involved an initial deprotonation
of the perfluoroalkane by the zinc amide base. After that, the
transmetalation to CuCl takes place. Interestingly, they proposed
that this event could be the turnover-limiting step when using
certain perfluoroalkyl sources. Thus, once this reaction happens,
the cuprates can react with the aryl iodide directly or through
neutral species (Scheme 10b). The scope was quite limited in
terms of trifluoromethylated products obtaining only one
example in moderate yield (51%). However, products decorated
with perfluoroalkylated chains were generated in good yields.

Scheme 8 a) Formation of ketones as CF3 source (see Ref. 21 for further
details). b) Trifluoromethylation of aryl halides, terminal alkynes and aryl
boronic acids using [CuCF3] generated from phenyl trifluoromethyl sulfoxide
(see Ref. 22 for further details). c) Mixture of species represented by [CuCF3]

3.3

Transmetalation

In this section, we have considered the CF3 exchange from a
trifluoromethyl organometallic species to copper. We have
divided them in three categories: (i) transition metals;23 (ii)
silanes and stannanes and finally (iii) boron-containing species.

3.3.1

Transition metals

The first example of the formation of [CuCF3] by a group transfer
from a trifluoromethyl metal complex to copper was reported by
Yagupolskii and co-workers using Hg(CF3)2 or Hg(CF3)I.24 This
early report was applied in the activation of aliphatic, aromatic
and heterocycles molecules. In 1985, Burton et al prepared
different trifluoromethylated zinc and cadmium complexes such
as M(CF3)nX2-n that could transfer its CF3 moiety to copper.25 This
mixture of [CuCF3] species was able to activate iodobenzene
forming trifluorotoluene in 80% yield. In 1989, Burton et al.
proposed the presence of (CdI)[Cu(CF3)2] and (Cd)[Cu(CF3)I] in
the reaction mixture.7a In general, the CF3 transfer to copper(I)
salts from Cd-complexes is faster than from Zn-complexes.26
However, due to practical reasons, zinc has been more exploited
as starting material in this type of methodologies (Scheme 9).

10
Scheme 10 a) Perfluoroalkylation of aryl halides (See Ref. 27 for further
details). b) Proposed reaction mechanism

Later, in 2013, Mikami described the trifluoromethylation of aryl
and heteroaryl iodides catalyzed by copper(I) salt and
phenanthroline using Zn(CF3)I, prepared in-situ from
trifluoromethyl iodide and Zn dust in DMPU (1,3-dimethyl3,4,5,6-tetrahydro-2-(1H)pyrimidone).28 The methodology was
not successful when using electron-donating substituents in the
aryl iodides (scheme 11a). In order to gain insight into each step
of the Cu-catalyzed Zn-mediated trifluoromethylation, they
performed a 19F NMR spectroscopic analysis, observing a Schlenk
equilibrium of Zn(CF3)I with Zn(CF3)2 and ZnI2. The addition of
CuI to this solution resulted in the transmetalation of the CF3
group from zinc to copper observing two singlet peaks of the
cuprate species, [Cu(CF3)I]– and [Cu(CF3)2]– (scheme 11b). In this
case, the neutral (DMPU)CuCF3 species ( ≈ −26 ppm), was not
observed. The addition of aryl iodide to this mixture led to the
formation of the trifluoromethyl organic molecule with the
consumption of the cuprates [Cu(CF3)I]– and [Cu(CF3)2]–. The
non-efficient and complex transmetalation reaction complicates
the mechanistic picture and the real potential of both cuprate
species in the trifluoromethylation of aryl halides was not clearly
disclosed. In 2015, the same group provided a mechanistic

proposal for the trifluoromethylation of aryl and heteroaryl
iodides using isolated Zn(CF3)2(DMPU)2, involving a CuI/III
catalytic cycle (scheme 11c).29 Again, the impossibility to access
selectively the copper species prevented the study of their real
role in the trifluoromethylation reaction.

described that the amount of [CuI2]– can affect the chemical shift
of [Cu(CF3)I]– species. Thus, they suggested that a more
appropriate way to denominate these species would be
{[Cu(CF3)I]x}x– {[CuI2]y}y.

12
Scheme 12 a) Scope and reaction conditions for the nucleophilic
trifluoromethylation of -diazoesters (See Ref. 33 for further details). b)
Scheme 11 a) Cu-catalyzed Zn-mediated trifluoromethylation of aryl halides

Proposed mechanism for nitrogen extrusion and C–C bond formation

(See Ref. 28 for further details). b) Species in the transmetalation reaction. c)

The broad applicability of Me3SiCF3 has allowed a shift in the
paradigm of traditional trifluoromethylation methodologies
based on cross-coupling concepts towards oxidative
trifluoromethylation reactions. This concept allows the
connection of nucleophilic CF3 with other nucleophiles under
oxidative conditions.34 In 2010, Qing et al. reported the first
example of the coupling of the Ruppert-Prakash reagent and
boronic acids or alkynes in the presence of [Cu(OTf)]·C6H6 or
CuI/phen, respectively (Scheme 13).35 In 2012, the same
research group reported the catalytic version of the aerobic
oxidative trifluoromethylation of terminal alkynes.36

Cu-catalyzed Zn-mediated trifluoromethylation of aryl halides using isolable Zn
reagents (See Ref. 29 for further details). d) Proposed reaction mechanism

3.3.2

R3MCF3 (M = Si, Sn)

Among the different nucleophilic trifluoromethylating sources,
trifluoromethyltrimethylsilane
(Me3SiCF3),
trifluoromethyltriethylsilane
(Et3SiCF3)
and
tributyl(trifluoromethyl)stannane
(Bu3SnCF3)
have
demonstrated their efficiency in combination with activators
such as fluorides or tert-butoxide salts. It is noteworthy to
mention that the most widely used Ruppert-Prakash reagent
(Me3SiCF3) is utilized not only for the in-situ formation of
“ligandless” [CuCF3] species but also to synthesize well-defined
trifluoromethyl copper(I) complexes (see Section 4).
In 1991, Fuchikami et al. applied for the first time the
introduction of a CF3 group onto organic halides using CuI,
Et3SiCF3 and KF.30 In 2009, the same reaction was reported in a
catalytic version using diamine ligands to favor the solubility of
the CuI and accelerate the transference of the CF3 moiety before
its decomposition.31 This elegant approach led to different
trifluoromethylation protocols using copper as catalyst and
silanes as the CF3 source.32
Later, in 2012, Hu and co-workers reported the use of Me3SiCF3
in the preparation of [CuCF3] for the trifluoromethylation of a
wide variety of -diazo esters containing aryl, benzyl, or other
alkyl substituent in moderate to excellent yield. (See Scheme
12a).33 To gain more insights into the reaction mechanism, they
tentatively described the composition of [CuCF3] species by 19F
NMR spectroscopy. Their proposal involves the activation of
[Cu(CF3)I]– by water, which scavenges the I– forming a hydrated
iodide ion, affording CuCF3·diazoester, the proposed active
species (See Scheme 12b). Their hypothesis was supported by the
decrease on the reaction efficiency when less amount of water
(<10 equiv) is used or external KI is added. Remarkably, they also

13
Scheme 13 General schematic for the oxidative trifluoromethylation of boronic
acids and terminal alkynes (See Ref. 34-35 for further details)

Interestingly, the authors pointed out the necessity of a slow
addition of Me3SiCF3 to the reaction mixture in order to avoid the
decomposition of the silane before the CF3 fragment is
transferred to the copper center. This step was limited by the
slow recovering of the copper catalyst. In this regard, in 2013,
Maseras and Jover proposed, based on DFT calculations, the
reductive elimination as the rate-determining step of the
oxidative trifluoromethylation, supporting the challenges
associated to the catalyst recovering (Scheme 14).37
Further mechanistic investigations using electrospray-ionization
mass spectrometry (ESI-MS) by Koszinowski et al. aimed to shed

light into the nature of the intermediates involved in these
transformations.38 In the absence of the alkyne component, the
homoleptic ate-type complexes [Cu(CF3)2]– and [Cu(CF3)4]– were
detected from the mixture of CuI, KF and Me3SiCF3 in different
solvents such as acetonitrile, tetrahydrofurane or N,N-dimethylformamide. Remarkably, when using the alkynes, the authors
detected copper(III) species such as [Cu(CF3)3R]–, presumably
the intermediate involved in the reductive elimination step. In
the presence of N,N-bidentate-ligands, the authors were able to
discard the intermediacy of [(N,N)Cu(CF3)R]– in the oxidative
process based on the unfruitful attempts to detect them even
when modifying the ancillary ligand. Despite this remarkable
mechanistic hint, a neutral N,N-bidentate-ligand-based
mechanism, such as the one proposed by Maseras, could be
simultaneously taking place and being overlooked using ESI MS
techniques.

15
Scheme 15 Comparative study between Me3SiCF3 and Bu3SnCF3 in the
transmetalation reaction and mechanistic proposals (see Ref. 39 for further
details)

3.3.3

Borates and borazines

In 2011, Goossen et al. disclosed the capability of potassium
(trifluoromethyl)trialkoxyborates as nucleophilic CF3 sources in
Cu-catalyzed trifluoromethylation reactions (Scheme 14a).11,40
During their stoichiometric experiments they detected the
formation of the heteroleptic cuprate [Cu(CF3)I]– when mixing
the potassium (trifluoromethyl)trimethoxyborate and equimolar
amounts of CuI in DMF at room temperature (Scheme 14b). The
catalyzed version was achieved by using 1,10-phenantroline as
ligand, that it is proposed to increase the nucleophilicity of the
metal center. This is subsequently translated into an acceleration
of the -bond metathesis step and, therefore, in a fast recovering
of the copper catalyst (Scheme 14c). The scope of this reaction
allowed the incorporation of trifluoromethyl group in good yields
in aryl iodides bearing electron-rich and -poor substituents.

14
Scheme 14 a) Mechanistic proposals for the oxidative coupling of terminal
alkynes and the trifluoromethyl moiety. b) Key intermediates proposed by
Maseras based on DFT calculations

Regarding the employment of stannanes, in 2012, Shoenebeck et
al. presented a new methodology combining Bu3SnCF3, as CF3
source, and CuI/KF for the nucleophilic trifluoromethylation of
aryl iodides (Scheme 15).39 The authors explained that the
trifluoromethylation reaction is performed by CuCF3·KBr and
[Cu(CF3)2]– based on 19F NMR spectroscopy. In addition, radical
mechanisms were discarded based on the lack of rearranged
product when using radical clock substrates. In this interesting
piece of work, although the complete mechanistic scenario for the
formation of the C–C was not deeply discussed, a comparison
between Me3SiCF3 and Bu3SnCF3 as transmetalating agents is
presented. The transmetalation is faster in the case of the
Ruppert-Prakash reagent but the overall performance in the
trifluoromethylation of aryl iodides is quite similar. Regarding
the scope, there is no a big difference between the use of the
silane or stannane. However, the trifluoromethyl silanes has been
by far more studied than the stannane and, therefore, more
information can be found in the literature.

16
Scheme 16 a) Cu-catalyzed trifluoromethylation of aryl halides using potassium
(trifluoromethyl)trialkylborates as CF3 source (See Ref. 40 for further details).
b) Transmetalation reaction. c) Proposed reaction mechanism

In 2018, Szymczak and co-workers presented an interesting
strategy for the introduction of a CF3 group into different
inorganic electrophiles using a fluoroform-derived borazine
(Scheme 17).41 In particular, the reaction of CuI and borazine-CF3
in DMSO gives rise a mixture of (DMSO)CuCF3 (19%) and
[Cu(CF3)I]– (63%) that reacts with 4-iodobiphenyl at 80 °C during
12 hours forming the trifluoromethyl organic molecule in 66%
yield.

17
Scheme 17 a) Transmetalation reaction from borazine to copper and the
trifluoromethylation reaction of 4-iodobiphenyl (See Ref. 41 for further details)

4

Well-defined active trifluoromethyl copper(I)
species

Over the past decade, different literature precedents have
demonstrated the exceptional activity of well-defined LCu(CF3)
complexes, supported by ancillary ligands, in stoichiometric
nucleophilic trifluoromethylation reactions. Most of these
neutral copper(I) complexes are in equilibrium in polar solvents
with salts containing the bis-trifluoromethyl cuprate as anion.
This is remarkable because the majority of these
trifluoromethylation reactions, as it will be shown, are performed
in DMF that shifts the equilibrium towards the ionic part.
We have organized this section based on the nature of the
ancillary ligand: (i) NHC-carbenes; (ii) bidentate nitrogen ligands
and (iii) phosphines. We discuss their synthesis, substrate scope
in the trifluoromethylation reactions and relevant mechanistic
features.

4.1

NHC-carbene copper (I) complexes

In 2008, Vicic et al. disclosed, for the first time, the synthesis of a
well-defined trifluoromethyl copper(I) complexes using
carbenes (SIiPr or IPr) as ancillary ligands.4b These stabilized
copper complexes were synthetized by the treatment of tertbutoxide copper derivatives with Me3SiCF3, affording
(SIiPr)Cu(CF3) in 91% yield and mixture of copper complexes for
L = IPr (Scheme 18a). The authors tested their ability as
trifluoromethylating agents, observing a higher activity when
using the copper compound stabilized with the saturated ligand
(SIiPr). They observed a dramatic solvent effect, being DMF
crucial to enhance the reactivity of the trifluoromethylation
reactions. Till that date, the employment of (SIiPr)CuCF3 or its insitu generation showed the best performance in
trifluoromethylation protocols. However, the formation of
trifluoromethylated products decorated with electron donating
groups is limited when using this procedure. The same year, the
scope of this methodology was extended to electron-rich aryl
halides by the use of (SIMes)CuCF3 (ASIMes).4c Interestingly, in
THF, this neutral complex is in equilibrium with an ionic part,
[(SIMes)2Cu][Cu(CF3)2] (BSIMes) that was characterized, for the
first time, by X-ray diffraction (Scheme 18b). The mixture of
ASIMes and BSIMes, in neat aryl halide or using the solvent mixture
benzene:DMI, exhibited a superior activity than the previously
described employing (SIiPr)CuCF3 (they compare neat reaction
conditions vs DMF). Kinetic studies suggested that (SIMes)CuCF3
(ASIMes) exhibited a higher activity as trifluoromethylating
reagent. However, since ASIMes and BSIMes are presented in the
reaction media is challenging to univocally stablish the origin of
this outstanding performance.

18
Scheme 18 a) Trifluoromethylating agents. b) Comparison of performance of
different trifluoromethylating reagents

4.2

(N^N) copper(I) complexes

In 2011, Hartwig et al. described the synthesis of (phen)Cu(CF3)
by the reaction of [CuOtBu]4 with 1,10-phenantroline, followed
by the addition of Me3SiCF3.4d Although this species was
previously proposed to be catalytically active in a seminal work
of Amii et al., in that work there was not any experimental
evidence of its formation.31 As described for [(SIMes)Cu(CF3)],
(phen)Cu(CF3) (Aphen) is in equilibrium with an ionic part,
[(phen)2Cu][Cu(CF3)2] (Bphen), in different solvents such as
dichloromethane,
tetrahydrofurane
and
N,Ndimethylformamide. Conductivity and spectroscopic techniques
were used to confirm the stoichiometric of the salt.

19
Scheme 19 Equilibrium between (phen)CuCF3 and [(phen)2Cu][Cu(CF3)2] in
different solvents

The described protocol for the trifluoromethylation of aryl
iodides afforded high yields of the desired products even when
using electron-donating substituents. On the other hand, the
trifluoromethylation of aryl bromides was shown to be
challenging even using higher temperatures and electron-poor
substrates. Regarding the mechanism, the use of radical clock
experiments supported the absence of radicals during the
transformation. The same research group has also reported the
functionalization of heteroaryl bromides4k and the oxidative
trifluoromethylation of arylboronate esters4g and aryl silanes4m
(Scheme 20). The arylboronate esters are generated by the
reaction of arenes or aryl bromides with B2pin2 using iridium or
palladium catalysts, respectively. Then, the trifluoromethyl
group replaces the boronate moiety in the aryl moiety under

oxidative Chan-Lam-type conditions.42 This new one-pot
methodology permitted not only the regioselective
functionalization of arenes but also the expansion of the scope to
aryl bromides. Regarding the aryl silanes, this new oxidative
protocol was extended to pharmaceutically active molecules,
inaccessible through other synthetic routes and using easily
accessible starting materials. It is worth mentioning that all the
aforementioned described reactions were performed in DMF
where there is a mixture Aphen: Bphen (0.01 M, 21:79 respectively).
Therefore, the participation of both complexes as
trifluoromethylating reagents could not be completely ruled out.
Remarkably, the broad applicability of (phen)CuCF3 resulted in
its commercialization, as Trifluoromethylator™.43
Scheme 21 a) Phosphine trifluoromethyl copper(I) complexes (See Ref. 4e for
further details). b) Trifluoromethylation reaction using (Ph3P)3Cu(CF3) and
(phen)Cu(PPh3)(CF3)

5

Scheme

20

a)

Different

trifluoromethylation

protocols

using

TrifluoromethylatorTM (See Ref. 4d,k,g,m for further details). b) Active
molecules using aryl silanes as starting materials (ref 4m) a(isolated yield)

4.3

Phosphine stabilized copper(I) complexes

In 2011, Grushin et al. reported an exhaustive study on the
straightforward preparation of (Ph3P)3Cu(CF3), previously
described by Komiya et al.44
and (phen)Cu(PPh3)(CF3),
analogous to Hartwig’s trifluoromethylator (see Scheme 21a).4e
The later one is in equilibrium at room temperature with
[(phen)2Cu][Cu(CF3)2] and PPh3 in CD2Cl2, analogous to the
examples described by Vicic and Hartwig.4b-c Both complexes
were exceptionally good as trifluoromethylating agents of aryl
and heteroaryl iodides. In the case of (Ph3P)3Cu(CF3), the addition
of additives such as phen, Bpy or tBu-bpy favored the reaction,
hampering the formation of side products like HCF3 and
PhCF2CF3.

Recent advances on the reactivity of different
trifluoromethylation protocols

In 2017, Vicic et al. published an interesting work that compares
the performance of previously described copper systems
(Scheme 22).45 In this report, the authors used as CF3 sources not
only well-defined trifluoromethyl copper reagents but also insitu generated [CuCF3] by mixing CuI/TMSCF3/KF.4c-e,30 To that
date, the described reaction conditions for the nucleophilic
trifluoromethylation protocols were remarkably different
hindering their comparison. In order to establish the relative
reactivity between the copper systems, the authors selected as
standard reaction conditions those described by Hartwig et al,
using 4-iodo-1,1’-biphenyl as model system and DMF as solvent.
After 24 hours at 50 °C, the in-situ generated (phen)Cu(CF3)
exhibited the best performance as trifluoromethylating agent.
Moreover, the authors also performed the nucleophilic
trifluoromethylation of 4-iodo-1,1’-biphenyl using the reported
conditions for each protocol. This implies the employment of
different solvents, temperature and concentrations. Under these
different reaction conditions, the in-situ generated
(SIMes)Cu(CF3) showed the best performance, pointing out the
crucial role of the solvent (benzene:DMI vs DMF). In general, the
in-situ formation of the complexes gave a better outcome than
the corresponding isolated ones. Interestingly, when using the
isolated or the in-situ generated (SIMes)Cu(CF3) for the
functionalization of electron-rich substrates, the authors
observed induction periods in the kinetic profiles of the product
formation, suggesting a non-trivial behavior of these copper
systems in solution. Based on their results, in this work, the
authors encouraged the benchmarking in trifluoromethylation
reactions to allow a fair comparison between new methods and
the previously described ones under the same reaction
conditions.

Scheme 22 a) Different copper trifluoromethylating reagents (See Ref. 45 for
further details). b) Standard conditions for the trifluoromethylation of 4iodobiphenyl

Despite the tremendous efforts on providing a comprehensive
mechanistic picture on Cu-mediated trifluoromethylation
reactions, there are still open questions that need to be
addressed. This strongly encouraged our group to devote our
efforts towards unveiling the real role of cuprate species in
nucleophilic trifluoromethylation reactions.5 Recently, we were
able to access, for the first time in a selective manner, [Cu(CF3)]2,
ubiquitous in all the aforementioned transformations. We carried
out the quantitative in-situ generation of these species through a
transmetalation reaction using its analogous silver ate-type
complex, (Cs)[Ag(CF3)]2 and CuI. Under the standard conditions
reported by Vicic, our salt outperformed the previously
described nucleophilic copper systems. A combined
experimental and computational studied uncovered a complex
mechanistic picture through a CuI/III process with the
participation of more reactive species such as (DMF)CuCF3,
generated through multiple equilibria. These results not only
give some hints about the behavior of different copper species in
trifluoromethylation reactions but also suggest that the ate-type
complexes actually act as a CF3 reservoir along these
transformations. However, we believe that this should not be
underestimated since these cuprates can generate more active
species even when the neutral well-defined complexes are used
as trifluoromethylating agent.

Scheme 23 a) Transmetalation reaction for the synthesis of (Cs)[Cu(CF3)2]. b)
Trifluoromethylation reaction using 4-iodobiphenyl as model system. c)
Speciation of copper species in solution. d) Substrate scope. e) X-ray structure
of (Cs)[Cu(CF3)2]. See Ref 5 for further details.

6

Conclusions

Over the past decades, trifluoromethyl copper(I) species have
demonstrated their extraordinary activity as CF3 sources in
nucleophilic trifluoromethylation reactions. These strategies
allow the access to a wide variety of trifluoromethylated organic
scaffolds, relevant in agrochemicals, pharmaceuticals or
materials. Currently, there are two different approaches to access
the active copper species in these transformations: their in-situ
generation in the reaction media or the employment of welldefined and isolable ones, stabilized by ancillary ligands. In both
cases, the investigation of the underlying reactions mechanisms
has been hampered by the complex mixture of copper species
observed in solution, involving neutral and/or ionic ones. In this
context, tremendous efforts have been made by the
organometallic community, merging experimental and
computational strategies, in order to elucidate the nature of the
reactive species, the dramatic effect of polar solvents in the
success of the reactions and the real role of cuprate species in
these transformations. Despite the major advances described in
this Short Review, we consider this field holds promising
prospects for the rational design and development of innovative
protocols based on knowledge-driven approaches.

Funding Information
We thank the CERCA Programme/Generalitat de Catalunya and the
Spanish Ministry of Economy, Industry and Competitiveness (MINECO:
CTQ2016-79942-P, AIE/FEDER, EU) for the financial support. A. L. M.
thanks La Caixa-Severo Ochoa programme for a predoctoral grant.

References
(1) (a) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432. (b) Mueller,
K.; Faeh, C.; Diederich, F.; Science 2007, 317, 1881. (c) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320. (d) Ni, C.; Hu, J. Chem. Soc. Rev. 2016, 45, 5441. (e) Orsi, D. L.;
Altman, R. A. Chem. Commun. 2017, 53, 7168.
(2) For selected recent reviews on trifluoromethylation, see: (a)
Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (b)
Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475. (c)
Studer, A. Angew. Chem. Int. Ed. 2012, 51, 8950. (d) GarcíaMonforte, M. A.; Martínez-Salvador, S.; Menjón, B. Eur. J. Inorg.
Chem. 2012, 2012, 4945. (e) Ye, Y.; Sanford, M. S. Synlett 2012, 23,
2005. (f) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Asian J. 2012, 7,
1744. (g) Wang, H.; Vicic, D. A. Synlett 2013, 24, 1887. (h) BarataVallejo, S.; Lantaño, B.; Postigo, A. Chem. Eur. J. 2014, 20, 16806. (i)
Charpentier, J.; Früh, N.; Togni, A. Chem. Rev. 2015, 115, 650. (j) Liu,
X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683. (k) Yang, X.;
Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826. (l)
Alonso, C.; Martínez de Marigorta, E.; Rubiales, G.; Palacios, F. Chem.
Rev. 2015, 115, 1847.
(3) (a) McLoughlin, V. C. R.; Thrower, J. U.S. Patent 3408411, 1968. (b)
McLoughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.
(4) For representative examples on the synthesis and reactivity of
CuCF3 complexes, see: (a) Wiemers, D. M.; Burton, D. J. J. Am. Chem.
Soc. 1986, 108, 832. (b) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J.
Am. Chem. Soc. 2008, 130, 8600. (c) Dubinina, G. G.; Ogikubo, J.;
Vicic, D. A. Organometallics 2008, 27, 6233. (d) Morimoto, H.;
Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem. Int. Ed.
2011, 50, 3793. (e) Tomashenko, O. A.; Escudero-Adán, E. C.;
Martínez-Belmonte, M.; Grushin, V. V. Angew. Chem. Int. Ed. 2011,
50, 7655. (f) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz,
J.; Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901. (g) Litvinas, N.
D.; Fier, P. S.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 536. (h)
Novák, P.; Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2012,
134, 16167. (i) Konovalov, A. I.; Lishchynskyi, A.; Grushin, V. V. J.
Am. Chem. Soc. 2014, 136, 13410. (j) Lishchynskyi, A.; Berthon, G.;
Grushin, V. V. Chem. Commun. 2014, 50, 10237. (k) Mormino, M. G.;

(5)

(6)
(7)

(8)

(9)

(10)
(11)
(12)
(13)
(14)
(15)
(16)

(17)

(18)
(19)

(20)
(21)
(22)
(23)
(24)

Fier, P. S.; Hartwig, J. F. Org. Lett. 2014, 16, 1744. (l) Nebra, N.;
Grushin, V. V. J. Am. Chem. Soc. 2014, 136, 16998. (m) Morstein, J.;
Hou, H.; Cheng, C.; Hartwig, J. F. Angew. Chem. Int. Ed. 2016, 55,
8054.
Martínez de Salinas, S.; Mudarra, A. L.; Odena, C.; Martínez
Belmonte, M.; Benet-Buchholz, J.; Maseras, F.; Pérez-Temprano, M.
H. Chem. Eur. J. DOI: 10.1002/chem.201900496.
Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832 and
references cited therein.
(a) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc.,
Chem. Comm. 1989, 21, 1633. (b) Burton, D. J.; Wiemers, D. M. J.
Fluorine Chem. 1985, 29, 359.
Agnes, K.; Movchun, V.; Rodima, T.; Dansauer, T.; Rusanov, E. B.;
Leito, I.; Kaljurand, I.; Koppel, J.; Pihl, V.; Koppel, I.; Ovsjannikov, G.;
Toom, L.; Mishima, M.; Medebielle, M.; Lork, E.; Röschenthaler, G.V.; Koppel, I. A.; Kolomeitsev, A. A. J. Org. Chem. 2008, 73, 2607.
(a) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981,
1719. (b) Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker, D. G. J.
Chem. Soc., Perkin Trans. I 1988, 921.
Chen, Q.; Wu, S. J. Chem. Soc., Chem. Commun. 1989, 705.
Knauber, T.; Arikan, F.; Röschenthaler, G.-V.; Goossen, L. J. Chem.
Eur. J. 2011, 17, 2689.
(a) Shono,T.; Ishifune, M.; Okada, T.; Kashimura, S. J. Org. Chem.
1991, 56, 2. (b) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771.
Folléas, B.; Marek, I.; Normanta, J-F.; Saint-Jalmes, L. Tetrahedron
2000, 56, 275.
Lishchynskyi, A.; Novikov, M. A.; Martin, E.; Escudero-Adán, E. C.;
Novák, P.; Grushin, V. V. J. Org. Chem. 2013, 78, 11126.
Mudarra, A. L.; Martinez de Salinas, S.; Pérez-Temprano, M. H. Org.
Biomol. Chem. 2019, 17, 1655.
(a) Barbosa, H. J.; Collins, E. A.; Hamdouchi, C.; Hembre, E. J.;
Hipskind, P. A.; Johnston, R. D.; Lu, J.; Rupp, M. J.; Takakuwa, T.;
Thompson, R. C. U. S. Patent 7612067, 2009. (b) Lin, R. W.;
Davidson, R. I. Eur. Pat. Appl. EU 307519, 1989. (c) Lin, R. W.;
Davidson, R. I. U. S. Patent 4808748, 1989. (d) Davidson, R. I. U. S.
Patent 4814480, 1989. (e) Langlois, B. R.; Roques, N. J. Fluorine
Chem. 2007, 128, 1318.
a) Li, Y.; Chen, T.; Wang, H.; Zhang, R.; Jin, K.; Wang, X.; Duan, C.
Synlett 2011, 1713. b) Schareina, T.; Wu, X.-F.; Zapf, A.; Cotté , A.;
Gotta, M.; Beller, M. Top. Catal. 2012, 55, 426. c) Chen, M.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 11628. d) Lin, X.;
Hou, C.; Li, H.; Weng, Z. Chem. Eur. J. 2016, 22, 2075.
Zhao, G.; Wu, H.; Xiao, Z.; Chen, Q.-Y.; Liu, C. RSC Adv. 2016, 6,
50250.
(a) MacNeil, J. G. Jr.; Burton, D. J. J. Fluorine Chem., 1991, 55, 225.
(b) Duan, J-X.; Su, D-B.; Wu, J-P.; Chen, Q-Y. J. Fluorine Chem., 1994,
66, 167.
Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003, 5, 3253.
Serizawa, H.; Aikawa, K.; Mikami, K. Chem. Eur. J. 2013, 19, 17692.
Li, X.; Zhao, J.; Zhang, L.; Hu, M.; Wang, L.; Hu, J. Org. Lett. 2015, 17,
298.
(a) Burton, D. J.; Yang, Z. Y. Tetrahedron 1992, 48, 189. (b)
Morrison, J. A. Adv. Organomet. Chem. 1993, 35, 211.
Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. Synthesis
1980, 932.

Biosketches

(25) Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014.
(26) (a) Krause, L. J.; Morrison, J. A. J. Am. Chem. Soc. 1981,103, 2995.
(b) Krause, L. J.; Morrison, J. A. J. Chem. Soc., Chem. Commun. 1981,
1282. (c) Nair, H. K.; Morrison, J. A. Inorg. Chem. 1989, 28, 2816. (d)
Galiotos, J. K.; Morrison, J. A. Organometallics 2000, 19, 2603.
(27) Popov, I.; Lindeman, S.; Daugulis, O. J. Am. Chem. Soc. 2011, 133,
9286.
(28) Nakamura, Y.; Fujiu, M.; Murase, T.; Itoh, Y.; Serizawa, H.; Aikawa,
K.; Mikami, K. Beilstein J. Org. Chem. 2013, 9, 2404.
(29) Aikawa, K.; Nakamura, Y.; Yokota, Y.; Toya, W.; Mikami, K. Chem.
Eur. J. 2015, 21, 96.
(30) Urata, H.; Fuchikami, T. Tetrahedron 1991, 32, 91.
(31) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun., 2009, 1909.
(32) a) Mitsudera, H.; Li, C.-J. Tetrahedron Lett. 2011, 52, 1898; b) Xu, J.;
Xiao, B.; Xie, C.-Q.; Luo, D.-F.; Liu, L.; Fu, Y. Angew. Chem. Int. Ed.
2012, 124, 12719; c) Gonda, Z.; Ková cs, S.; Wé ber, C.; Gá ti, T.;
Mé szá ros, A.; Kotschy, A.; Nová k, Z. Org. Lett. 2014, 16, 4268.
(33) Hu, M.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2012, 134, 15257.
(34) Chu, L.; Qing, F-L. Acc. Chem. Res. 2014, 47, 1513.
(35) (a) Chu, L.; Qing, F-L. J. Am. Chem. Soc. 2010, 132, 7262. (b) Chu, L.;
Qing, F.-L. Org. Lett., 2010, 12, 5060.
(36) Jiang, X.; Chu, L.; Qing, F-L. J. Org. Chem. 2012, 77, 1251.
(37) Jover, J.; Maseras, F. Chem. Commun., 2013, 49, 10486.
(38) Weske, S; Schoop, R.; Koszinowski, K. Chem. Eur. J. 2016, 22, 11310.
(39) Sanhueza, I. A.; Nielsen, M. C.; Ottiger, M.; Schoenebeck, F. Helv.
Chim. Acta 2012, 95, 2231.
(40) Khan, B. A.; Buba, A. E.; Gooßen, L. J. Chem. Eur. J. 2012, 18, 1577.
(41) Geri, J. B.; Wolfe, M. M. W.; Szymczak, N. K. Angew. Chem. Int. Ed.
2018, 57, 1381.
(42) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron 1998, 39, 2933; (b) Lam, P. Y. S.; Clark, C. G.; Saubern,
S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
1998, 39, 2941.
(43) https://www.sigmaaldrich.com/catalog/product/aldrich/77769
2?lang=es&region=ES
(44) Usui, Y.; Noma, J.; Hirano, M.; Komiya, S. Inorg. Chim. Acta 2000,
309, 151.
(45) Kaplan, P. T.; Loyd, J. A.; Chin, M. T.; Vicic, D. A. Beilstein J. Org. Chem.
2017, 13, 2297.

Mó nica H. Pé rez-Temprano was born in Valladolid, Spain, in 1982. She
received her PhD degree at the University of Valladolid, under the supervision of Prof. Espinet and Prof. Casares, in 2011. Next, she moved to the
University of Michigan to work with Prof. Sanford on the synthesis and
reactivity of high-valent palladium(IV) complexes. In 2015, she began her
independent career as a Junior Group Leader at the Institute of Chemical
Research of Catalonia (ICIQ). Her research program is focused on the rational
design of more sustainable approaches for the synthesis of organic molecules
using fundamental organometallic chemistry.
AƵ ngel L. Mudarra was born in Escacena del Campo (Huelva, Spain) in 1992.
He received his B.S. degree in Chemistry from Universidad de Huelva (Huelva,
Spain) in 2014. In 2015, he got his MSc degree in “Advanced studies in
Molecular Chemistry” from the Universidad de Sevilla (Sevilla, Spain). Then,
he started his PhD studies at the Institute of Chemical Research of Catalonia
(ICIQ) under the supervision of Dr Mó nica H. Pé rez-Temprano and Prof. Feliu
Maseras. His PhD is focused on mechanistic investigations, combining
computational and experimental approaches, to understand and develop
bimetallic processes in the context of homogeneous catalysis.

Sara Martı́nez de Salinas received her B.Sc. degree in chemistry from the
University of Oviedo in 2010. Then, she obtained her M.Sc. degree in Synthesis
and Chemical Reactivity at the same university in 2011 under the supervision
of Prof. Elena Lastra. In 2015, she got her Ph.D. in organometallic chemistry
under the supervision of Prof. Elena Lastra working in rhodium systems. In
December 2015, she joined the group of Dr Mó nica H. Pé rez-Temprano as a
postdoctoral researcher and she is currently working to obtain the
fundamental understanding of relevant organometallic processes in the
context of bimetallic catalysis and trifluoromethylation.