Practical Photocatalytic Trifluoromethylation and Hydrotrifluoromethylation of Styrenes in Batch and Flow

Article abstract of DOI:10.1002/anie.201608297

Styrenes represent a challenging class of substrates for current radical trifluoromethylation and hydrotrifluoromethylation methods due to a myriad of potential side reactions. Herein, we describe the development of mild, selective and broadly applicable photocatalytic trifluoromethylation and hydrotrifluoromethylation protocols for these challenging substrates. The methods use fac-Ir(ppy)₃, visible light and inexpensive CF₃I and can be applied to a diverse set of vinylarene substrates. The use of continuous-flow photochemical reaction conditions allowed to reduce the reaction time and increase the reaction selectivity.

Full text of DOI:10.1002/anie.201608297

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608297
German Edition: DOI: 10.1002/ange.201608297
Photoredox Catalysis
Practical Photocatalytic Trifluoromethylation and
Hydrotrifluoromethylation of Styrenes in Batch and Flow
Natan J. W. Straathof, Sten E. Cramer, Volker Hessel, and Timothy Noꢀl*
Abstract: Styrenes represent a challenging class of substrates
for current radical trifluoromethylation and hydrotrifluoro-
methylation methods due to a myriad of potential side
reactions. Herein, we describe the development of mild,
selective and broadly applicable photocatalytic trifluorome-
thylation and hydrotrifluoromethylation protocols for these
challenging substrates. The methods use fac-Ir(ppy)3, visible
light and inexpensive CF3I and can be applied to a diverse set
of vinylarene substrates. The use of continuous-flow photo-
chemical reaction conditions allowed to reduce the reaction
time and increase the reaction selectivity.
O
lefins are versatile synthons for the synthesis of various
commodity chemicals. Consequently, numerous catalytic
methodologies have been developed allowing olefins to
engage into efficient carbon–carbon or carbon–heteroatom
bond forming reactions, such as, hydroformylations,[1] hydro-
aminations[2] and Wacker oxidations.[3] One specific example
that received a lot of attention in recent years is the
trifluoromethylation and hydrotrifluoromethylation of ole-
fins.[4] Trifluoromethylated compounds are important for the
pharmaceutical, agrochemical and material industries as this
substituent imparts important properties to a molecule, such
as improved bioavailability, lipophilicity and metabolic sta-
bility.[5]
While several examples on the trifluoromethylation of
terminal olefins have been reported, a direct and practical
À
route to C H functionalization of these structures remains
Figure 1. A) Reported protocols suffer from several disadvantages.
a challenging task and is often hampered by the need for
prefunctionalized substrates (Figure 1A).[6] In this context,
radical trifluoromethylation[7] and hydrotrifluoromethyla-
tion[8] strategies arose as efficient strategies to circumvent
the need for olefin prefunctionalization.[9] Despite the great
progress, styrene derivatives remain an unsolved case due to
the unique challenges with regard to unproductive polymer-
ization, product isomerization, oxidation,[10] dimerization[11]
and nucleophilic trapping (Figure 1B).[12] Therefore, a key
aspect in the development of new synthetic methods is the
efficient single electron oxidation of the benzylic radical to
suppress these undesired outcomes (Figure 1B). For example,
B) Outline synthetic strategy to access trifluoromethylated and hydro-
trifluoromethylated styrenes via photoredox catalysis and overview of
the common pitfalls. C) Our strategy for the photocatalytic radical
trifluoromethylation and hydrotrifluoromethylation of styrenes.
Qing et al. achieved a good selectivity for the desired
trifluoromethylated styrene compounds but required the
presence of electron-donating groups on the ortho position
to prevent a nucleophilic attack on the carbocation.[13]
A
versatile hydrotrifluoromethylation protocol for b-substituted
styrenes was developed by Nicewicz et al., but terminal
styrenes proved challenging due to their propensity for
undesired polymerization.[14] Nonetheless, a reliable and
broadly applicable strategy to access these seemingly simple
compounds remains underdeveloped but is highly desirable.
Herein, we report a facile method for both trifluorome-
thylation and hydrotrifluoromethylation of terminal and a- or
b-substituted styrenes via visible light photoredox catalysis
using CF3I as an inexpensive trifluoromethylation reagent
(Figure 1C). The method is mild (room temperature, visible
light, use of weak bases) and displays a broad substrate scope.
[*] N. J. W. Straathof, S. E. Cramer, Prof. Dr. V. Hessel, Dr. T. Noꢀl
Department of Chemical Engineering and Chemistry, Micro Flow
Chemistry & Process Technology
Eindhoven University of Technology
Den Dolech 2, 5612 AZ Eindhoven (The Netherlands)
E-mail: t.noel@tue.nl
Homepage: http://www.NoelResearchGroup.com
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608297.
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In addition, continuous-flow photochemistry allowed to
accelerate the trifluoromethylation protocol and to increase
the E/Z ratio of trifluoromethylated styrenes.
Our efforts to effect the targeted trifluoromethylation of
styrene (1) were initially focused on the use of Ru(bpy)3Cl2 as
a common photocatalyst[15] with CF3I as cheap and abundant
trifluoromethylating agent. Various bases and solvents were
screened but no product could be obtained with this photo-
catalyst (see the Supporting Information). Next, fac-Ir(ppy)3
was evaluated for this transformation (Table 1), as this
Having found optimal reaction conditions, we set out to
examine the scope of the photocatalytic trifluoromethylation
of styrenes in batch (Scheme 1). Our protocol was found to
readily accommodate a variety of styrenes (1-A–5-A). In
addition, the presence of chlorine or bromine substituents
were well tolerated providing opportunities for further
decoration of the molecule (6-A–8-A). Also ester- and
aldehyde-bearing derivatives were also well tolerated (9-A–
10-A). Furthermore, a variety of challenging vinylic hetero-
cycles, including pyridines, a pyrazine, and a thiazole, could be
exposed to the reaction conditions giving access to the
targeted trifluoromethylated compounds in satisfying yields
(11-A–14-A). More complex substrates, such as estrone-
derivative 15-A and silane 16-A, could be efficiently trifluoro-
methylated, highlighting the applicability of the described
methodology for the synthesis of compounds of interest to the
pharmaceutical and materials industry. Also a/b-disubstituted
styrenes proved to be a suitable substrate class (17-A–22-A).
Both b-methyl and a-methyl styrene could be efficiently
trifluoromethylated (17-A–18-A). Other b-substituted styr-
enes gave predominantly the E isomer in good to excellent
yields (19-A–22-A).
Table 1: Reaction discovery and optimization studies for the photo-
catalytic trifluoromethylation of styrene.[a]
Entry
Base/Solvent
Yield[b]
E/Z[b]
1
2
3
4
5
6
7
DBU/CH3CN
TMEDA/CH3CN
DBU/DMF
K2CO3/DMF
Cs2CO3/DMF
KOAc/DMF
CsOAc/DMF
Trace
Trace
Trace
–
–
–
–
3%, (35% after 72 h)
5%, (57% after 72 h)
76%
–
55:45
74:26
Despite the high yield for the desired compounds, the E/Z
ratio was often poor in batch. We hypothesized that the
thermodynamically most stable E-isomer was first formed
and subsequently transformed into the Z-isomer via an
energy transfer (ET) mechanism.[17] During the course of
our investigations, we observed that indeed the E/Z ratio was
reduced at longer reaction times (see the Supporting Infor-
mation). In order to obtain full conversion with a high E/Z
ratio at short reaction times, the photocatalytic trifluorome-
thylation of styrenes was carried out in a continuous-flow
photomicroreactor.[18] Such flow reactors are ideally suited to
carry out photochemical transformations[19] as they provide
homogeneous irradiation of the reaction mixture and facile
scale-up via numbering up.[20] The reaction could be com-
pleted in flow in less than an hour and the formation of the Z
isomer could be avoided resulting in excellent E/Z ratios for
1-A (see the Supporting Information). These observations
appeared to be generally true (Scheme 1). A significant
acceleration and a higher yield was observed when the
reaction was carried out in a photomicroreactor resulting in
a reduction of the reaction time (from 24–72 h in batch to 0.5–
1.5 h in flow). Notably, higher E/Z ratios were observed in all
cases which can be attributed to the significantly reduced
reaction time, thus avoiding the occurrence of isomerization
via an ET mechanism (see Supporting Information).
Next, we turned our attention to develop a suitable
photocatalytic protocol for the hydrotrifluoromethylation of
styrenes. During the initial screening of our trifluoromethy-
lation protocol, we observed that in ethanol, along with 41%
of 1-A, 12% of the hydrotrifluoromethylated product was
formed (Table 2, entry 1). An increase in yield was observed
when dichloroethane/ethanol (9:1) was used as a solvent
mixture (Table 2, entries 2 and 3). However, the product came
along with many by-products, originating from for example,
overoxidation and dimerization reactions. Screening of
a small library of thiols and other H-atom donors revealed
that the addition of aromatic thiols resulted in a clean
89% (75%)[c]
Entry
Change from best
conditions (entry 7)
Yield
E/Z[c]
8
9
10
No light
No photocatalyst
No base
0%
0%
Trace
–
–
–
[a] Reaction conditions: fac-Ir(ppy)3 (1 mol%), styrene (0.5 mmol), base
(1.5 mmol), solvent (5 mL, 0.1m), visible light (2ꢁ24 W CFL), room
temperature, stirred for 18 hours. [b] Yield and E/Z values are
determined with 19F-NMR with a,a,a-trifluorotoluene as internal stan-
dard. [c] Volatile compound.
photocatalyst exhibits a higher reducing power in its excited
state (E1/2red [*Ir3+/Ir4+] = À1.72 V vs. SCE, compared to E1/2
red
[*Ru2+/Ru3+] = À0.81 V vs. SCE). As proven by a Stern–
Volmer kinetic analysis, this is sufficient to allow for oxidative
quenching of the excited state of the photocatalyst by CF3I
(E1/2 = À1.22 V vs. SCE in DMF).[16] The high quenching rate
(kq = 8.7 ꢀ 1010 mÀ1 sÀ1, with t0 = 1900 ns, resulting in a quench-
ing fraction of Q > 0.95) reveals that the required CF3 radicals
for the intended transformation can be efficiently generated.
No product could be obtained in the presence of amine bases,
presumably by reductive quenching of the excited state thus
hampering the CF3 radical formation process (Table 1,
entries 1–3). However, switching to mild inorganic bases,
which are not competent to quench the excited state of the
photocatalyst, resulted in the formation of the targeted
compound (Table 1, entries 4–7). Optimal results were
obtained by using CsOAc in DMF furnishing the trifluoro-
methylated styrene in good yield (89% 19F-NMR yield, 75%
isolated yield) within 18 hours (Table 1, entry 7). Control
experiments established the importance of the photocatalyst,
the presence of visible light and a suitable base as no reaction
was observed in the absence of any of these (Table 1,
entries 8–10).
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Scheme 1. Substrate scope for the photocatalytic trifluoromethylation of styrenes: 1) Batch reaction conditions: fac-Ir(ppy)3 (0.5 mol%), styrene
(0.5 mmol), CF3I (0.8–1.5 mmol), CsOAc (1.5 mmol), DMF (5 mL, 0.1m), visible light (2ꢁ24 W CFL), room temperature, stirred for 24 hours.
2) Continuous-flow reaction conditions: fac-Ir(ppy)3 (0.5 mol%), styrene (0.5 mmol), CF3I (0.8–1.5 mmol), CsOAc (1.5 mmol), DMF/MeOH
(4.5 mL/0.5 mL, 0.1m), visible light (3.12 W blue LED), room temperature. The residence time to reach full conversion is given for each
compound. 3) Reported yields are those of isolated compounds. The E/Z ratio was determined with 19F-NMR. [a] Reaction time of 48 hours. [b]
Combined yield of protected (60%) and unprotected (35%) compound. [c] Reaction time of 72 hours. [d] DMF/MeOH (4.5 mL/0.5 mL) used as
a solvent system. [e] DMF/MeOH (4.0 mL/1.0 mL) used as a solvent system. [f] Large scale reaction in flow: 3.9 gram isolated product (see the
Supporting Information).
Table 2: Reaction discovery and optimization studies for the photo-
ments demonstrated that the reaction did not proceed in the
absence of fac-Ir(ppy)3 or light (Table 2, entries 8 and 9).
The optimized hydrotrifluoromethylation conditions
proved generally useful to a wide variety of different styrenes
(Scheme 2). High yields were obtained in most cases includ-
ing 2-vinylnaphthalene (3-B), styrenes bearing aliphatic (2-
B), hydroxy (4-B), acetyl-protected hydroxy (5-B) and
halogen functional groups (6-B–8-B) and 4-vinylpyridine (9-
B). Moreover, sterically more demanding substrates, such as
a- and b-substituted styrenes, were efficiently hydrotrifluoro-
catalytic hydrotrifluoromethylation of styrene.[a]
Entry Solvent
Aromatic thiol
Yield[b]
1
2
3
4
5
6
EtOH
–
–
–
12%[c,d]
25%[c]
27%[c]
CH2Cl2/EtOH (9:1)
Dichloroethane/EtOH (9:1)
Dichloroethane/EtOH (9:1) Thiophenol (20 mol%) 13%
Dichloroethane/EtOH (9:1) 4-HTP (20 mol%)
Dichloroethane/EtOH (9:1) 4-HTP (1.2 equiv)
23%
94%
(78%)[e]
Entry Change from best
conditions (entry 6)
Yield[b]
8
No light
0%
9
10
No photocatalyst
No dichloroethane
0%
55%
[a] Reaction conditions: fac-Ir(ppy)3 (1 mol%), styrene (1.0 mmol), 4-
HTP (1.2 mmol), dichloroethane/ethanol (18/2 mL, 0.05m), visible light
(2ꢁ24 W CFL), room temperature, stirred for 18 hours. [b] Yield are
determined with 19F-NMR with a,a,a-trifluorotoluene as internal stan-
dard. [c] Complex and inseparable reaction mixture, incl. overoxidation,
dimerization, etc. [d] Also, 41% of 1-A was observed. [e] Isolated yield
(volatile compound).
Scheme 2. Substrate scope for the photocatalytic hydrotrifluoromethy-
lation of styrenes: Batch reaction conditions: fac-Ir(ppy)3 (0.5 mol%),
styrene (1.0 mmol), CF3I (1.2 mmol), 4-HTP (1.2 mmol), dichloro-
ethane/ethanol (18/2 mL, 0.05m), visible light (2ꢁ24 W CFL), room
temperature, stirred for 24 hours. Reported yields are those of isolated
compounds.
conversion of the starting material (see the supporting
Information). Optimal results were obtained with 4-hydroxy-
thiophenol (4-HTP) and increasing the amount to 1.2 equiv
provided excellent yields (Table 2, entry 6). Control experi-
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methylated (10-B–13-B). Also for the hydrotrifluoromethy-
lation protocol, continuous-flow photomicroreactors served
as an enabling technology to reduce the reaction times of
photocatalytic transformations (from 18 h in batch to 50 min
in flow).
The products obtained by our trifluoromethylation and
hydrotrifluoromethylation protocol serve as useful synthetic
building blocks (Scheme 3A). As an example, we converted
In summary, we have established a robust methodology
for the trifluoromethylation and hydrotrifluoromethylation of
styrenes. Challenges associated with this substrate class were
efficiently overcome by using visible light photoredox catal-
ysis. The mild nature of the reaction conditions has been
exemplified by the broad substrate scope (28 examples
trifluoromethylation and 15 examples hydrotrifluoromethy-
lation). A substantial reduction in reaction time and a higher
E/Z selectivity for the trifluoromethylation process was
witnessed under continuous-flow photochemical conditions.
Other perfluoroalkyl halide coupling partners can be readily
engaged in these reaction protocols giving rise to perfluoro-
alkylated analogues. Extending this chemistry to other
challenging olefinic substrate classes is currently being
explored in our laboratory.
Acknowledgements
Financial support for this work was provided by a VIDI grant
(T.N., SensPhotoFlow, No. 14150) and a Marie Curie CIG
grant (T.N., Grant No. 333659). Also funding by the
Advanced European Research Council Grant (Grant
number: 267443 for V.H.) is kindly acknowledged. We
would like to thank Koen P. L. Kuijpers (TU/e) for help
with Stern–Volmer kinetics.
Keywords: continuous flow · hydrotrifluoromethylation ·
microreactor · photoredox catalysis · trifluoromethylation
Scheme 3. A) One-pot strategy combining photocatalytic trifluoro-
methylation/ cross-coupling of 4-ethenylphenyltrifluoroborate. B) Per-
fluoroalkylation and hydroperfluoroalkylation of styrene. For the reac-
tion conditions, see the Supporting Information. Reported yields are
those of isolated compounds. The E/Z ratio was determined with 19F-
NMR. [a] AcOH (1 mmol) was added to the reaction mixture, see the
Supporting Information.
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Revised: October 25, 2016
Published online: && &&, &&&&
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Communications
Photoredox Catalysis
N. J. W. Straathof, S. E. Cramer, V. Hessel,
T. Noꢁl*
&&&& — &&&&
Practical Photocatalytic
Trifluoromethylation and
Hydrotrifluoromethylation of Styrenes in
Batch and Flow
A robust photocatalytic methodology for
the radical trifluoromethylation and
hydrotrifluoromethylation of styrenes has
been developed. The mild nature of the
reaction conditions allowed to convert
a diverse set of vinylarenes. Continuous-
flow photochemistry enables the reduc-
tion of the reaction times and an en-
hancement of the reaction selectivity.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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