Article

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Controlled Fluoroalkylation Reactions by Visible-Light Photoredox

Catalysis
Published as part of the Accounts of Chemical Research special issue Photoredox Catalysis in Organic
Chemistry.
Tanmay Chatterjee,, Naeem Iqbal,, Youngmin You, and Eun Jin Cho*,

Department of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea
Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, P.O. Box 577, Jhang Road, Faisalabad
38000, Pakistan

Division of Chemical Engineering and Materials Science, Ewha Womans University, Seoul 03760, Republic of Korea

CONSPECTUS: Owing to their unique biological, physical, and chemical properties, uoroalkylated organic substances have
attracted signicant attention from researchers in a variety of disciplines. Fluoroalkylated compounds are considered particularly
important in pharmaceutical chemistry because of their superior lipophilicity, binding selectivity, metabolic stability, and
bioavailability to those of their nonuoroalkylated analogues. We have developed various methods for the synthesis of
uoroalkylated substances that rely on the use of visible-light photoredox catalysis, a powerful preparative tool owing to its
environmental benignity and mechanistic versatility in promoting a large number of synthetically important reactions with high
levels of selectivity.
In this Account, we describe the results of our eorts, which have led to the development of visible-light photocatalytic methods
for the introduction of a variety of uoroalkyl groups (such as, CF3, CF2R, CH2CF3, C3F7, and C4F9) and
arylthiouoroalkyl groups (such as, CF2SPh, C2F4SAr, and C4F8SAr) to organic substances. In these studies, electrondecient carbon-centered uoroalkyl radicals were successfully generated by the appropriate choice of uoroalkyl source,
photocatalyst, additives, and solvent. The redox potentials of the photocatalysts and the uoroalkyl sources and the choice of
sacricial electron donor or acceptor as the additive aected the photocatalytic pathway, determining whether an oxidative or
reductive quenching pathway was operative for the generation of key uoroalkyl radicals. Notably, we have observed that
additives signicantly aect the eciencies and selectivities of these reactions and can even change the outcome of the reaction
by playing additional roles during its course. For instance, a tertiary amine as an additive in the reaction medium can act not only
as a sacricial electron donor in photoredox catalysis but also as a hydrogen atom source, an elimination base for
dehydrohalogenation of the intermediate, and also a Brnsted base for deprotonation. In the same context, the selection of
solvent is also critical since it aects the rate and selectivity of reactions depending upon its polarity and reagent solubilizing
ability and plays additional roles in the process, for example, as a hydrogen atom source.
By clearly understanding the roles of additives and solvent, we designed several controlled uoroalkylation reactions where
dierent products were formed selectively from the same starting substrates. In addition, we could exploit one of the most
important advantages of radical reactions, that is, the use of unactivated -systems such as alkenes, alkynes, arenes, and
heteroarenes as radical acceptors without prefunctionalization. Furthermore, uoroalkylation processes under mild roomtemperature reaction conditions tolerate various functional groups and are therefore easily applicable to late-stage modications
of highly functionalized advanced intermediates.

1. INTRODUCTION
Incorporation of uoroalkyl groups into molecules can
dramatically change their physical, chemical, and biological
properties, mainly due to the small size and high electro XXXX American Chemical Society

Received: May 24, 2016

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negativity of uorine, as well as the high CF bond dissociation
energy.1 In particular, uoroalkylated compounds are characterized by superior lipophilicity, binding selectivity, bioavailability, and metabolic stability to those of their nonuoroalkylated analogues. Owing to these characteristics, extensive
research eort has been dedicated to preparing pharmaceutical
and agrochemical agents bearing uoroalkyl moieties (Figure
1).25

Figure 2. Examples of triuoromethylation reactions of (hetero)arenes.

Figure 1. Pharmaceutical agents containing uoroalkyl groups.

During postdoctoral work in Prof. Buchwalds group, E. J.

Cho contributed to the development of Pd-catalyzed
triuoromethylation reactions of (hetero)arenes6 and alkenes.7
The works introduced the possibility of late-stage installation of
triuoromethyl (CF3) groups, one of the most attractive and
widely used uoroalkyl moieties (Figure 1), into organic
compounds and attracted considerable attention from
pharmaceutical chemists seeking new ecient triuoromethylation methods. Inspired by the attention given to these works,
Cho continued the development of new high-eciency
uoroalkylations with wide applicability. At the time of these
eorts, visible-light-induced radical processes had attracted
renewed interest because of their environmental benignity and
mechanistic versatility in promoting a large number of
synthetically important reactions with high levels of selectivity.
Visible-light photocatalytic reactions generally proceed under
mild conditions at ambient temperatures and pressures and as a
result have excellent functional-group compatibilities, overcoming the drawbacks of traditional methods that often require
highly toxic reagents and high-energy UV radiation, resulting in
poor selectivity and diculties with scale-up.
In addition, as illustrated in the representative examples of
triuoromethylation of (hetero)arenes shown in Figure 2,
visible-light-induced triuoromethylations show several advantages over two-electron-based reactions, despite the regioselectivity issue. The radical processes developed by the
MacMillan group8 and our group9 utilize unactivated arenes
and heteroarenes as substrates (without prefunctionalization)
with relatively inexpensive CF3 sources at room temperature.
Visible-light-induced uoroalkylation reactions4,5 typically
involve coordinatively saturated 4d or 5d transition metal
complexes, such as Ru(II) polypyridine complexes and
cyclometalated Ir(III) complexes, as photocatalysts. Figure 3
shows the most widely used Ru- and Ir-complexes in
uoroalkylations, including [Ru(bpy)3]Cl2, [Ru(phen)3]Cl2,
[Ir(dtbbpy)(ppy)2]PF6, fac-Ir(ppy)3, and fac-Ir(dFppy)3 [bpy

Figure 3. Examples of visible-light photocatalysts used in uoroalkylation reactions.

= 2,2-bipyridine; phen = 1,10-phenanthroline; dtbbpy = 4,4di-tert-butyl-2,2-bipyridine; ppy = 2-phenylpyridinate; dFppy =

2-(2,4-diuorophenyl)pyridinate]. Moreover, metal complexes
containing Pt, Cu, and Co and even organic dyes have also
been explored as photocatalysts.1015 In our studies, various Ru,
Ir, and newly developed Pt complexes were utilized.
A general proposed mechanism with a polypyridyl-based
transition metal complex ([MnLx]) is shown in Figure 4.1014
Photoexcitation of [M n L x ] produces an excited state,
[Mn+1Lx], that has an altered electronic distribution caused
by the metal-to-ligand charge transfer (MLCT). The
[Mn+1Lx] species is either a stronger reductant or stronger
oxidant than is its corresponding ground state [MnLx], and as a
result, it can participate in one of two possible single-electron
transfer (SET) processes depending on its redox potential and
the redox behavior of the substrate. The process in which
[Mn+1Lx] is reduced by an electron donor (ED) to form
[MnLx] is known as reductive quenching, and the process in
which [Mn+1Lx] is oxidized by an electron acceptor (EA) to
form [Mn+1Lx]+ is known as oxidative quenching. The [MnLx]
B

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radical from the uoroalkylating reagents, followed by its

addition to the substrates. In our studies, uoroalkyl radicals
were generated using various combinations of uoroalkyl
sources, photocatalysts, and amine additives. A redox potential
correlation diagram to estimate the theoretical feasibility of the
generation of uoroalkyl radicals with respect to the choice of
uoroalkyl source, photocatalyst, and additive is given in Figure
6a.
The photocatalysts ([Ru(bpy)3]Cl2,11 fac-Ir(ppy)3,11 and
Pt(ppy)acac16), uoroalkyl sources (CF3I (7) and BrCF2CO2Et
(8)), and tertiary amines (TEA, DIPEA, TMEDA) shown have
been used in our lab, and their redox potentials were measured
in CH3CN and given in volts versus a saturated calomel
electrode (SCE).
In a photocatalytic cycle, there are two possible routes for the
reductive generation of CF3 radicals from CF3I (7). The
photoexcited catalyst can directly transfer an electron to 7
(oxidative quenching pathway), followed by the reductive
regeneration of the catalyst by a sacricial ED. Alternatively, the
photoexcited catalyst can be rst reduced by SET from an ED
(reductive quenching pathway) that subsequently transfers an
extra electron to 7. According to the given redox potentials
(Figure 6), the photoexcited [Ru(bpy)3]2+ complex (E*[Ru(III)/Ru(II)*] = 0.81 V) cannot directly reduce 7
(Ered(CF3I) = 0.91 V) with a negative driving force associated
with step A in the photocycle (Figure 6a(i)), but it can easily be
reduced to the Ru(I) complex (E*[Ru(II)*/Ru(I)] = +0.77 V)
by tertiary amines such as TEA, DIPEA, and TMEDA
(Eox(TEA) = +0.73 V, Eox(DIPEA) = +0.65 V, Eox(TMEDA)
= +0.47 V) with positive driving force (step C, reductive
quenching pathway). Then, the one-electron reduced Ru(I)
complex (E[Ru(II)/Ru(I)] = 1.33 V) can deliver an extra
electron to 7 to generate the CF3 radical (step D). On the
other hand, the photoexcited fac-Ir(ppy)3 (E*[Ir(IV)/Ir(III)*]
= 1.73 V) and Pt(ppy)acac (E*[Pt(III)/Pt(II)*] = 2.07 V)
complexes can directly deliver an electron to 7 with positive
driving force (step E in photocycle a(ii) and step I in
photocycle a(iii), respectively), but the complexes (E*[Ir(III)*/Ir(II)] = +0.31 V and E*[Pt(II)*/Pt(I)] = +0.26 V)
cannot be reduced (step G in photocycle a(ii) and step K in
photocycle a(iii), respectively) by tertiary amines. Therefore,
the generation of CF3 radicals from CF3I with fac-Ir(ppy)3 and
Pt(ppy)acac should prefer the oxidative quenching pathway.
In the same context, it is expected that the photoexcited facIr(ppy)3 and Pt(ppy)acac can generate CF2CO2Et radicals
from BrCF2CO2Et (8) (Ered(BrCF2CO2Et) = 1.72 V) via the
oxidative quenching pathway (step E in photocycle a(ii) and
step I in photocycle a(iii), respectively), while the photoexcited
[Ru(bpy)3]Cl2 cannot yield the radical by either the oxidative
or reductive quenching pathway.
Additives, in particular bases, can signicantly aect the
eciencies and selectivities of these reactions and even change
the outcome of the reaction by playing additional roles during
the course of the reactions. For instance, a tertiary amine in the
reaction medium can act not only as a sacricial ED in
photoredox catalysis but also as a hydrogen atom donor, an
elimination base for dehydrohalogenation of the intermediate,
and also a Brnsted base for deprotonation (Figure 6b). For
example, uoroalkylations of an alkene with a uoroalkyl halide
(Rf X) could yield three dierent uoroalkylated products, that
is, the alkyl halide (23), alkene (24), or alkane (25), selectively,
depending on the role of the tertiary amine, as shown in Figure
6c. An atom transfer radical addition (ATRA) of 21 with Rf X

Figure 4. General mechanism of photoredox catalysis using

polypyridyl-based transition metal complexes.

complex is then regenerated by SET to or from a respective EA

or ED. The key feature of these reactions is that in both the
oxidative and reductive catalytic cycles, substrates or sacricial
additives can serve as the EDs and EAs to give free radical
intermediates for the organic transformations.
By utilizing visible-light photoredox catalysis, we developed a
variety of radical-mediated triuoromethylation, diuoroalkylation, and arylthiouoroalkylation processes in which unactivated alkenes, alkynes, arenes, and heteroarenes were
employed as substrates. Among the various electrophilic
uoroalkyl sources (Figure 5), including Tognis (1 and 2)

Figure 5. Examples of uoroalkyl sources utilized in visible-light

photoredox catalysis. Reagents highlighted in boxes were used in our
studies.

and Umemotos reagents (3 and 4), CF 3 I (7), and

BrCF2CO2Et (8) have been used as the respective triuoromethyl and diuoroalkyl sources in our studies because of
their low cost and ready availability. In addition, various other
uoroalkyl sources (1315) including arylthiouoroalkyl
sources (1719) were also utilized (Figure 5).
The uoroalkylation reactions can be generalized as the
visible-light photocatalyzed reductive formation of a uoroalkyl
C

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Figure 6. (a) Redox potential correlation diagram to estimate the theoretical feasibility of the generation of uoroalkyl radicals with respect to the
choice of uoroalkyl source, photocatalyst, and additive. (b) Potential roles of tertiary amines. (c) A general concept of controlled uoroalkylations
of an alkene depending on the various potential roles of amine additives.

the photocatalyst, sacricial ED/EA, and solvent, the nal

outcome of the reaction could be nely tuned.

could produce 23 (halo-uoroalkylation), which after HX

elimination by a tertiary amine could be converted into
uoroalkylated alkene product 24 (alkenyl-uoroalkylation).
Halo-uoroalkylated product 23 could also be generated from
intermediate 22 formed by the photocatalytic oxidation of 21.
Product 24 could also be formed from 22 through
deprotonation by the tertiary amine. Conversely, the amine
radical cation generated from a tertiary amine (e.g., steps C, F,
and J in the photocycles) can serve as a strong H atom donor to
21 to produce hydro-uoroalkylated product 25 (hydrouoroalkylation) since single-electron oxidation of a tertiary
amine dramatically lowers the strength of its -CH bonds.11

2.1. Fluoroalkylation Reactions of Alkenes

The viability of controlled uoroalkylation reactions through

the proper selection of the required reaction parameters was
rst indicated by the results of studies on the triuoromethylation of alkenes with CF3I, which aorded only the
triuoromethylated alkenes selectively over the corresponding
allyl-CF318 or CF3-iodoalkane19 products. For example, visiblelight irradiation of a solution of 1-dodecene (20a) and CF3I in
the presence of [Ru(phen)3]Cl2 and TMEDA in CH3CN leads
to rapid and selective formation of the CF3-substituted
iodoalkane product.20 This nding guided the design of a
method for selective generation of the corresponding CF3
alkene 26a.20 We reasoned that this goal could be accomplished
by using a tertiary amine, which would act as both an ED
additive in the photocatalytic cycle and a base to promote
elimination of HI from the initially formed CF3iodoalkane

2. FLUOROALKYLATION
Based on the above-mentioned concept, several controlled
uoroalkylation reactions were developed where dierent sets
of products were formed selectively from the same starting
substrates.17 By utilizing slight variations in the combinations of
D

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potentials of Pt complexes, as discussed in the Introduction

(Figure 6), an oxidative quenching cycle was expected to be
operative for the generation of CF3 radicals using CF3I, and
this hypothesis was conrmed by SternVolmer analysis of
photoluminescence quenching experiments. Figure 9 displays

product. The screening of amines led to the discovery that 1,8diazabicycloundec-7-ene (DBU) is ideal for this purpose.
Specically, E-CF3-substituted alkene 26 is produced selectively
upon visible-light irradiation of a solution of 20 and CF3I in the
presence of [Ru(phen)3]Cl2 and DBU in CH3CN (Figure 7).

Figure 9. (a) Decay of emission from 50 M Pt(OMeppy)acac in

CH3CN with increasing CF3I concentration. (b) Plot of electron
transfer rate as a function of CF3I concentration.

proles for decay of the luminescence of 50 M Pt(OMeppy)acac in CH3CN at 543 nm as a function of CF3I concentration
after nanosecond photoexcitation at 377 nm employing timecorrelated single photon counting (TCSPC), which is a
technique for uorescence lifetime measurement. Incremental
addition of CF3I (020 mM) to the solution causes a
signicant decrease in the emission lifetime (obs) of the Ptcomplex, demonstrating the occurrence of oxidative quenching
of electronically excited [PtIII(OMeppy)acac]* by CF3I
(Figure 9a). Pt(dFppy)acac and Pt(ppy)acac show similar
photoluminescence quenching behaviors. The rate constant of
photoinduced electron transfer (kPeT) values, determined by a
pseudo-rst-order t of the PeT rate vs CF3I concentration, are
8.76 108, 7.92 108, and 4.37 108 M1 s1 for
Pt(dFppy)acac, Pt(ppy)acac, and Pt(OMeppy)acac, respectively (Figure 9b). The generation of CF3 was further
supported by a photoinduced electron spin resonance (ESR)
signal with a g value of 2.004, corresponding to a free radical.
The general mechanism for photoredox catalysis was
discussed above. However, in fact, the mechanism for the
alkenyl-triuoromethylation is highly complicated and involves
several processes, as shown in Figure 10. Photoexcitation of
PtII(CN) promotes an electronic transition to a MLCT state.
Diusional collision of [PtIII(CN)]* with CF3I leads to the
reversible formation of an encounter complex
(([PtIII(CN)]* CF3I); path A in Figure 10). As supported
by the above photoluminescence quenching experiments
(Figure 9), the oxidative electron transfer from the Pt catalyst
to CF3I generates a geminate radical ion pair, ([PtIII(CN)]+
CF3I), which can undergo processes via two pathways, B and
C. Pathway B involves quenching to the original species (i.e.,
PtII(CN) and CF3I) by back electron transfer (BeT). The
other pathway C involves dissociation into [PtIII(CN)]+ and
CF3I, resulting in the formation of CF3 by cleavage of the
CI bond in CF3I. Radical addition of CF3 to alkene 20
forms radical 21. The catalytic cycle is completed by
regeneration of PtII(CN) with electron transfer from sacricial
EDs, such as TMEDA and DBU, and this reductive
regeneration process is experimentally supported by the data
for decay traces of [PtIII(CN)]+ to PtII(CN) in the presence
and absence of TMEDA. Alternatively, PtII(CN) can be

Figure 7. Ru-catalyzed alkenyl-triuoromethylation reactions.

In contrast to several other ecient methods recently described

for the synthesis of alkenyl-CF3 products,21,22 the one we
developed has advantageous features associated with the use of
unactivated alkenes as substrates, the formation of products
with excellent levels of chemo- (alkenyl-CF3 over CF3iodoalkane, and allyl-CF3) and stereoselectivity (E-isomer
over Z-isomer).
The alkenyl-triuoromethylation process also occurs eciently when Pt-complexes newly developed by us (Figure 8)
are employed as the photocatalyst.16 Based on the redox

Figure 8. Pt-catalyzed alkenyl-triuoromethylation reactions.

E

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diuoroalkylation processes using BrCF2CO2Et (8) in the

presence of fac-Ir(ppy)3, which was considered to be a suitable
photocatalyst for the generation of CF2CO2Et radicals, as
discussed in the Introduction (Figure 6).23 Unlike the
analogous triuoromethylation process, the use of DBU does
not induce formation of alkenyl-CF2CO2Et products, but rather
diuoroalkane 27 production (hydro-diuoroalkylation) is the
major pathway followed (Figure 12). This result is likely the

Figure 12. Hydro-diuoroalkylation reactions of aliphatic alkenes.

consequence of the dierent nature of the radical intermediates,

that is, CF3 vs CF2CO2Et, and halide atoms, that is, I vs Br. In
the hydro-diuoroalkylation process, DBU serves as the ED to
the excited photocatalyst and a H atom donor to the radical
formed by CF2CO2Et addition to the alkene. The use of a
mixture of TMEDA and DBU and dichloromethane (DCM) as
the solvent are optimal for generation of hydro-diuoroalkylated products 27 in reactions of various aliphatic alkenes 20.
Conversely, changing the solvent from DCM to DMF and
the base from TMEDA/DBU to K2CO3 causes the fac-Ir(ppy)3
photocatalyzed reactions of electron-rich aromatic alkenes with
BrCF2CO2Et to form alkenyl-CF2CO2Et products 28 (Figure
13). However, reactions of electron-decient aromatic and

Figure 10. Detailed proposed mechanism for the Pt(II)-catalyzed

alkenyl-triuoromethylation.

recovered through the radical-polar mechanism, which involves

oxidation of 21 to the cation 22 (path D). In this case, 22 is
trapped by I to form 23, which can also be produced by radical
propagation between CF3I and 21 (path E). Additional
experiments to determine quantum yields of the Pt(II)
complexes with the alkene 1-dodecene indicate the signicant
involvement of radical propagation (path E) where the
quantum yield values exceed 100% for all three Pt(II)
complexes (Figure 11). Finally, E2 elimination assisted by
DBU in both the D and E pathways furnishes the alkenyl-CF3
product 26, with the generation of ammonium iodide salts.

Figure 13. Alkenyl-diuoroalkylation reactions.

aliphatic alkenes produce bromo-diuoroalkylated products 23,

which require subsequent treatment with DBU to be converted
to the corresponding alkenyl-CF2CO2Et products 28 with high
levels of both regio- and E/Z stereoselectivity. In this work, the
selection of solvent was critical by aecting the rate and
selectivity of reactions depending upon its polarity and reagent
solubilizing ability.
2.2. Fluoroalkylation Reactions of Alkynes

Alkynes 29 also serve as substrates for selective triuoromethylation reactions in a manner that depends on the reaction
conditions to produce three dierent types of triuoromethylated products, including triuoromethylated alkenyl iodides
30, alkenes 31, and alkynes 32.24 As the results presented in
Figure 14 show, subtle dierences in the nature of the
photocatalyst, base, and solvent can be utilized advantageously
to control the reactivity and selectivity of these processes.
Iodo-triuoromethylation reactions of alkynes with CF3I,
occurring in the presence of [Ru(phen)3]Cl2 and TMEDA in
CH3CN under visible-light irradiation occur through a
sequential radical-addition iodide-atom-transfer pathway. Both
aromatic and aliphatic alkynes participate in this process, which

Figure 11. Quantum yields for the triuoromethylation of 1-dodecene

by the Pt(II) complexes. The values were determined using standard
ferrioxalate actinometry (6.0 mM K3[Fe(C2O4)3], quantum yield = 1.1
at 420 nm).

Next, diuoroalkylation reactions of alkenes were investigated. The diuoroalkyl (CF2R) group is also an important
uoroalkyl group from a medicinal chemistry point of view in
that it can serve as a bioisostere of carbonyl and hydroxyl
groups in pharmaceutical agents. In addition, diuoroalkylation
can create a building block for further modications when using
a functionalized CF2 moiety, such as the CF2CO2Et group.
We carried out selective alkenyl-diuoroalkylation and hydroF

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Figure 14. Controlled triuoromethylation reactions of alkynes.

generates the corresponding products in excellent yields

(Figure 14). Notably, the iodo-triuoromethylated products
are valuable synthetic building blocks because they can be easily
converted to CF3-containing trisubstituted alkenes, a commonly found structural motif in pharmaceuticals and agrochemicals, utilizing various cross-coupling reactions. Conversely, selective hydro-triuoromethylation25 occurs in reactions photocatalyzed by fac-Ir(ppy)3 in the presence of DBU in
CH3CN/THF (1:1). In this work, THF was used as an
additional hydrogen atom source along with DBU. In a related
eort, we developed another radical-mediated hydro-triuoromethylation process that employs an inorganic electride as the
electron source, although it is not visible-light induced.26
The conditions required to carry out alkynyl-triuoromethylation reactions are quite dierent from those used in the iodoand hydro-triuoromethylation processes. Specically, alkynylCF3 products 32 are generated when fac-Ir(ppy)3-photocatalyzed reactions are conducted in 0.1 M KOtBu solutions
in DMF (Figure 14).
Among the three types of triuoromethylation reactions of
alkynes described above, the hydro-triuoromethylation process can be applied to the synthesis of -triuoromethyl ketones
starting with readily available propargylic alcohols 33.27 The
procedure involves visible-light-induced hydro-triuoromethylation of 33 with CF3I followed by double bond migration and
ketoenol tautomerism to yield the -triuoromethyl ketones
34 (Figure 15). A variety of propargylic alcohols can be
converted to the corresponding -triuoromethyl ketones when
the photoreactions are catalyzed by [Ru(bpy)3]Cl2 in the
presence of DBU in 0.1 M DMF (Figure 15). Only arylsubstituted propargylic alcohols serve as acceptable substrates
for this transformation, probably because conjugation with the
aryl group facilitates migration of the double bond, converting
33A to 33B.
In a manner that is similar to the controlled triuoromethylation of alkynes, selective triuoroethylation reactions of
alkynes 29 yielding two dierent allyl-CF3 products can be
performed using CF3CH2I 13 as the CH2CF3 radical source

Figure 15. Synthesis of -triuoromethyl ketones from propargylic

alcohols.

Figure 16. Selective iodo- and hydro-triuoroethylation reactions of

alkynes.

(Figure 16). 28 Iodo-triuoroethylated products 35 are

produced in these reactions when [Ru(bpy)3]Cl2 is utilized as
the photocatalyst and TMEDA as the base in CH3CN. In
contrast, hydro-triuoroethylated products 36 are generated
using fac-Ir(ppy)3 as the visible-light photocatalyst and a
mixture of K2CO3 and DBU as bases in DMF.
2.3. Fluoroalkylated Building Blocks

In continuing investigations in this area, we have explored the

use of uoroalkylation reactions to prepare CF3-groupcontaining building blocks that can be converted into various
CF3-containing target compounds. Because of their high
G

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propensity to undergo nucleophilic ring opening reactions,
three-membered systems such as epoxides and aziridines are
useful synthetic intermediates. Owing to this feature, we have
carried out studies targeted at the development of simple
methods to prepare triuoromethyl derivatives of these strained
ring systems. We envisaged that selective addition of CF3
radicals to the terminal carbon of allylic alcohols 37 or amines
38 would take place as part of pathways for generation of either
iodide 39 or carbocation 40 intermediates. We reasoned that
either 39 or 40 could be captured by intramolecular
nucleophilic substitution/addition to form the target CF3containing epoxides 41 or aziridines 42 (Figure 17).29

Figure 19. Synthesis of uoroalkylated aziridines.

2.4. Fluoroalkylation Reactions of Heteroarenes

Introduction of uoroalkyl groups to heteroarenes is of

considerable interest because most uorine-containing pharmaceutical agents have uoroalkyl moieties connected to
(hetero)aromatic ring systems (Figure 1). Various heteroarenes
43 undergo triuoromethylation with CF3I in the presence of 1
mol % [Ru(bpy)3]Cl2 and 2 equiv of TMEDA in CH3CN
under visible-light irradiation (Figure 20).9 During the

Figure 17. Synthesis of triuoromethylated epoxides and aziridines.

Studies testing this proposal have shown that allylic alcohols

37 are transformed to triuoromethylated epoxides 41 in
visible-light promoted reactions with CF3I that employ
[Ru(bpy)3]Cl2 and DBU in CH3CN (Figure 18). Moreover,

Figure 20. Triuoromethylation reactions of heteroarenes.

Figure 18. Synthesis of uoroalkylated epoxides.

preparation of the manuscript describing our work, MacMillan

et al. reported a highly ecient triuoromethylation of arenes
and heteroarenes that utilizes CF3SO2Cl and [Ru(phen)3]Cl2
or fac-Ir(dFppy)3 as the photocatalyst, as discussed in the
Introduction (Figure 2).8 Likewise, Noel et al. devised a
continuous ow triuoromethylation process that uses a
catalytic system that is similar to our conditions.30 In addition,
Pt(ppy)acac, which was developed in our studies of alkenyltriuorometylation reactions, has also been utilized to promote
heteroaryl-triuoromethylation reactions.16
We also carried out studies aimed at the development of a
photocatalytic method for preparation of CF2CO2Et-substituted arenes and heteroarenes (Figure 21).31 The results show
that visible-light irradiation of DMSO solutions containing

reaction of a diol was found to take place selectively to form a

triuoromethyl-epoxide 41b rather than a tetrahydropyran
derivative, showing that the allylic hydroxyl group preferably
participates in this reaction. This process is also amenable to
installation of other uoroalkyl groups, such as the respective
hepta- and nonauoroalkyls using C3F7I (14) and C4F9I (15).
Similarly, CF3-, C3F7-, and C4F9-containing aziridines 42 are
produced in reasonable yields using allylic amines 38 as
substrates and TMEDA as the base in visible-light promoted
reactions (Figure 19).
H

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Figure 21. Diuoroalkylation reactions of arenes and heteroarenes.

arenes 45, 3 mol % fac-Ir(ppy)3, 3 equiv of BrCF2CO2Et (8),

and 1.5 equiv of KO t Bu leads to formation of the
corresponding diuoroalkylated arenes 46. Heteroarenes 43
also participate in highly ecient versions of this process
(Figure 21), which require a lower catalyst loading (1 mol %),
lesser amounts of BrCF2CO2Et (2 equiv), and the weak bases
TEA or K3PO4. Various CF2CO2Et-substituted heteroarenes
47, including pyrroles, indoles, furans, thiophenes, benzothiophenes, and benzofurans, can be generated using this protocol.
It should be noted that related visible-light induced heteroaryldiuoroalkylation reactions have also been developed by Qing32
and Wang.33
In order to gain insight into the mechanism of these
reactions, emission lifetimes (obs) of fac-Ir(ppy)3 were
determined using nanosecond photoexcitation at 377 nm and
monitored at 520 nm employing the TCSPC technique (Figure
22a). While obs decreases with increasing BrCF2CO2Et

Figure 23. Proposed mechanism for diuoroalkylation reactions of

arenes.

and the carbocation precursor of the substitution product

(pathway a). Subsequent deprotonation of the cation by OtBu
produces the diuoroalkylated product 46. Alternatively,
deprotonation of radical 45A forms radical anion 45B, which
is reduced by SET to [IrIV(ppy)3]+ to regenerate IrIII(ppy)3 and
yield 46 (pathway b).
2.5. Arylthiouoroalkylation Reactions of Heteroarenes
and Alkenes

The introduction of uoroalkyl groups containing sulfur has

also attracted growing interest because the presence of sulfur
can further change the properties of molecules, and sulfur is
often an essential element for biological activity. The
importance of both sulfur and uoroalkyl moieties prompted
us to develop an arylthiouoroalkylation method for heteroarenes and alkenes where two functional groups are installed
simultaneously, showing the potential of the method for latestage modications in the development of functional
molecules.34 Several arylthiouoroalkyl reagents having dierent numbers of uorine atoms were utilized, which indicates
that this method might be easily utilized for ne-tuning of
properties in drug development by controlling the number of
uorine atoms in reagents.
First, arylthiouoroalkylations of heteroarenes 43 were
attempted utilizing the readily available phenylthiouoroalkyl
bromides BrCF 2 SPh (17), BrCF 2 CF 2 SPh (18), and
BrCF2CF2CF2CF2SPh (19) as sources of the carbon-centered
thiouoroalkyl radicals for the visible-light processes. Interestingly, the reactivity of the transformation is highly dependent
on the electron density of the carbon-centered radical
intermediate of the arylthiouoroalkyl sources. Compared to
the radical centers in CF2CF2SPh (natural atomic charge
0.746) and CF2CF2CF2CF2SPh (natural atomic charge 0.757),
that of CF2SPh (natural atomic charge 0.535) is less
electrophilic, probably due to the delocalization of the lone
pair of electrons on the neighboring sulfur. Depending on the
observed reactivity, dierent combinations of photocatalyst,
base, and solvent were employed.
A combination of 2 mol % fac-Ir(ppy)3 and 2 equiv of 2,6lutidine was used for phenylthiodiuoromethylations of 43 with
1.4 equiv of 17 in DMF (0.1 M) (Figure 24). Conversely, for
reactions of 43 with 1.4 equiv of 18 or 19, a combination of 2
3 mol % [Ru(phen)3]Cl2 and 2 equiv of TMEDA in MeCN
(0.1 M) was used (Figure 24). A variety of heteroarenes,
including pyrroles, furans, indoles, benzofurans, and benzothiophene, undergo phenylthiouoroalkylations in moderate to
good yields.

Figure 22. SternVolmer plots of fac-Ir(ppy)3 with (a) BrCF2CO2Et

and (b) TMEDA (blue circles) or KOtBu (red triangles). The inset in
panel a is a plot of electron transfer rate (1/ 1/0, where and 0
are phosphorescence lifetimes of fac-[Ir(ppy)3] in the presence and
absence of BrCF2CO2Et, respectively).

concentration, the rate of emission decay is not aected by

the presence of 30 mM TMEDA or 30 mM KOtBu (Figure
22b). These results indicate that quenching of the photoexcited
Ir complex by SET to BrCF2CO2Et is the key step in these
processes.
Based on these results, the mechanism for the diuoroalkylation of arenes 45 is proposed, as illustrated in Figure 23.
Visible-light photoexcitation of fac-IrIII(ppy)3 produces the
MLCT excited state [IrIVppy(ppy)2], which is quenched by
SET to BrCF2CO2Et, producing [IrIV(ppy)3]+ and the key
intermediate CF2CO2Et with bromide ion loss. Addition of

CF2CO2Et to 45 generates diuoroalkyl substituted radical

45A, which reacts by one of two possible routes, the rst
pathway involving SET to [IrIV(ppy)3]+ regenerating IrIII(ppy)3
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3. CONCLUDING REMARKS
In this Account, we have summarized the results of our studies
on visible-light-induced photocatalytic uoroalkylation reactions. A theoretical concept based on redox potential values was
introduced to assess the feasibility of the generation of key
uoroalkyl radicals with respect to the choice of a given
combination of uoroalkyl source, photocatalyst, and amine
additive. In addition, it was shown that additives such as tertiary
amines signicantly aect the eciencies and selectivities of the
reactions and even change the outcome of the reaction by
playing additional roles during the course of the reactions, for
example, as hydrogen atom donor, elimination base, or
Brnsted base. By understanding the feasibility of the reaction
in the photocatalytic system and the additional roles of
additives, we designed several controlled uoroalkylation
reactions where dierent products were formed selectively
from the same starting substrates. Various triuoromethylation,
diuoroalkylation, and arylthiouoroalkylation reactions of
alkenes, alkynes, and (hetero)arenes proceeded eciently
under visible-light irradiation conditions. In addition, several
spectroelectrochemical and emission-quenching techniques
were employed to gain insight into the mechanism of these
photoreactions. We strongly believe that the synthetic methods
developed in our eorts will nd industrial applications owing
to the fact that they utilize eco-friendly visible light and mild
conditions and that they can be readily scaled-up.

Figure 24. Phenylthiouoroalkylation reactions of heteroarenes.

Alkenes 20 are also suitable substrates for phenylthiouoroalkylations, and a dierence in reactivity is observed when
reactions are carried out in the presence of 17 and 18 or 19
(Figure 25). In the case of reactions of alkenes with 17, the

AUTHOR INFORMATION

Corresponding Author

*E-mail: ejcho@cau.ac.kr.
Author Contributions

T.C. and N.I. contributed equally.

Notes

The authors declare no competing nancial interest.

Biographies
Tanmay Chatterjee received his Masters degree in chemistry in 2009
from the Indian Institute of Technology, Delhi, under the guidance of
Prof. N. G. Ramesh. Next, he joined the Indian Association for the
Cultivation of Science, Kolkata, to pursue doctoral studies on green
synthetic methodologies under the supervision of Prof. Brindaban C.
Ranu and received a Ph.D. degree in 2014. Then he moved to South
Korea and has been conducting research on visible-light photocatalysis
with Prof. Eun Jin Cho at the Chung-Ang University as a Research
Professor.

Figure 25. Phenylthiouoroalkylation reactions of alkenes.

same conditions as those used for heteroarenes produce either

cyclized products or alkenyl products selectively. Reactions of
aromatic alkenes aord phenylthiodiuoromethylated alkenes
54 as the major product through oxidation of the benzyl radical
intermediate 51 to the cation intermediate 52, followed by a
deprotonation step. Interestingly, aliphatic alkenes react to
produce cyclized products 53, either by radical or cationic
electrophilic substitution of the tethered phenyl ring in 51 or
52.
Conversely, the reactions of alkenes with 18 and 19 require
conditions dierent from those employed for heteroarenes [2
mol % fac-Ir(ppy)3 and 2 equiv of TMEDA in DCM (0.2 M)].
Reactions of aliphatic alkenes aord phenylthiouoroalkylated
alkanes 55 as major products through hydro-phenylthiouoroalkylation, while reactions of aromatic alkenes yield alkenyl
derivatives 56 as major products.

Naeem Iqbal completed his undergraduate studies at the University of

Agriculture, Faisalabad, in 2007, after which he moved to Hanyang
University (ERICA), South Korea, where he carried out doctoral
studies with Prof. Eun Jin Cho. His work was focused on the
development of visible-light photocatalysis, mainly for uoroalkylations, and led to a doctoral degree in 2016. Recently he joined the
National Institute of Biotechnology and Genetic Engineering
(NIBGE), Faisalabad, as an Assistant Professor in the drug discovery
and structural biology group.
Youngmin You received B.Sc. and M.Sc. degrees in chemical
engineering from Seoul National University, South Korea. He earned
his Ph.D. degree in materials science and engineering at SNU in 2007.
He joined the division of chemical engineering and materials science at
Ewha Womans University as an assistant professor in 2015. His
research interests include the discovery, understanding, and creation of
J

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new photofunctions for potential applications in bioimaging, display,

and photoredox catalysis.
Eun Jin Cho received her Chemistry undergraduate degree in 2002
and her Masters degree in 2004 from the Seoul National University,
South Korea, under the direction of Professor Eun Lee. She earned her
Ph.D. degree in 2008 from the University of WisconsinMadison,
USA, under the direction of Professor Daesung Lee, and undertook
postdoctoral training with Professor Stephen L. Buchwald at the
Massachusetts Institute of Technology. In 2011, she returned to South
Korea to begin her independent career at Hanyang University
(ERICA) as an Assistant Professor and moved to Chung-Ang
University as an Associate Professor in 2015. Research in the Cho
group is centered on development of new chemical reactions and the
synthesis of functional materials.

ACKNOWLEDGMENTS
We thank all co-workers involved in the studies covered in this
Account for their invaluable intellectual and experimental
contributions. The research described in this Account has been
supported by grants from the National Research Foundation of
Korea [Nos. NRF-2014R1A1A1A05003274, NRF-2014011165, and NRF-2012M3A7B4049657].

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