Rapid trifluoromethylation and perfluoroalkylation of five-membered heterocycles by photoredox catalysis in continuous flow

Article abstract of DOI:10.1002/cssc.201301282

Trifluoromethylated and perfluoroalkylated heterocycles are important building blocks for the synthesis of numerous pharmaceutical products, agrochemicals and are widely applied in material sciences. To date, trifluoromethylated and perfluoroalkylated hetero-aromatic systems can be prepared utilizing visible light photoredox catalysis methodologies in batch. While several limitations are associated with these batch protocols, the application of microflow technology could greatly enhance and intensify these reactions. A simple and straightforward photocatalytic trifluoromethylation and perfluoroalkylation method has been developed in continuous microflow, using commercially available photocatalysts and microflow components. A selection of five-membered hetero-aromatics were successfully trifluoromethylated (12 examples) and perfluoroalkylated (5 examples) within several minutes (8-20 min). Photo workflow: A simple and straightforward photocatalytic method for perfluoroalkylation in continuous flow is developed. A photo-microreactor, constructed from commercially available components, enables accelerated photocatalysis employing [Ru(bpy)₃Cl₂] as photocatalyst under irradiation by blue LED light. A series of electron-rich hetero-aromatics is successfully trifluoromethylated within 8-16 min. Also, a selection of hetero-aromatics is perfluoroalkylated within 10-20 min.

Full text of DOI:10.1002/cssc.201301282

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DOI: 10.1002/cssc.201301282
Rapid Trifluoromethylation and Perfluoroalkylation of
Five-Membered Heterocycles by Photoredox Catalysis in
Continuous Flow
Natan J. W. Straathof,[a] Hannes P. L. Gemoets,[a] Xiao Wang,[b] Jaap C. Schouten,[c]
Volker Hessel,[a] and Timothy Noꢀl*[a, d]
Trifluoromethylated and perfluoroalkylated heterocycles are
important building blocks for the synthesis of numerous phar-
maceutical products, agrochemicals and are widely applied in
material sciences. To date, trifluoromethylated and perfluoroal-
kylated hetero-aromatic systems can be prepared utilizing visi-
ble light photoredox catalysis methodologies in batch. While
several limitations are associated with these batch protocols,
the application of microflow technology could greatly enhance
and intensify these reactions. A simple and straightforward
photocatalytic trifluoromethylation and perfluoroalkylation
method has been developed in continuous microflow, using
Figure 1. Perfluoroalkylation of five-membered hetereocycles as an impor-
tant strategy for the preparation of drug candidates and advanced materi-
als.
commercially available photocatalysts and microflow compo-
nents. A selection of five-membered hetero-aromatics were
successfully trifluoromethylated (12 examples) and perfluoroal-
kylated (5 examples) within several minutes (8–20 min).
value in pharmaceutical manufacturing, as well as agrochemis-
try and material science (Figure 1).[3,4] This has stimulated the
The incorporation of fluorinated functional groups, such as the
trifluoromethyl (CF3) group, into chemical compounds has nu-
merous advantages, including improved chemical stability, ele-
vated lipophilicity, and increased binding selectivity.[1,2] The
presence of CF3 in a drug structure has a diminishing effect on
the metabolic oxidation by cytochrome P450 oxidase and in-
creases the bioactivity by affecting the compound’s distribu-
tion and absorption. In particular, the establishment of meth-
odologies for the incorporation of trifluoromethyl or perfluor-
oalkyl moieties to five-membered heterocycles is of great
development and improvement of novel trifluoromethylation
methodologies, which are of great importance for the produc-
tion of compounds with trifluoromethyl groups.[5–7]
Historically, the construction of the ArÀCF3 bond was per-
formed by means of metal-catalyzed cross-coupling meth-
ods,[8,9] using different CF3 sources such as Ruppert–Prakash re-
agents or the more recent Umemoto’s reagents[10,11] and
Togni’s reagents.[12] However, these methods often involve stoi-
chiometric amounts of metal salts and/or require the presence
of functional groups,[13–18] such as boronic acids, amides, or hal-
ides and pseudohalides, to establish the CF3 linkage. Moreover,
several synthetic methodologies have been reported which
[a] N. J. W. Straathof, H. P. L. Gemoets, Prof. Dr. V. Hessel, Dr. T. Noꢀl
Department of Chemical Engineering and Chemistry
Micro Flow Chemistry & Process Technology
Eindhoven University of Technology
C
employ radical trifluoromethylation ([CF3] ) to functionalize un-
activated CÀH bonds.[19] One of the most potent strategies in-
volves the use of photoredox catalysis to generate electrophilic
radicals.[20–27] Hereby, polypyridyl organometallic complexes,
such as [Ru(bpy)3Cl2], are activated by visible light and have
proven to be mild and more sustainable alternatives for tradi-
tional photochemistry utilizing UV energy.[28–31] Recently, the
MacMillan group reported a photocatalytic trifluoromethyla-
Den Dolech 2, 5612 AZ Eindhoven (The Netherlands)
E-mail: t.noel@tue.nl
[b] Dr. X. Wang
Harvard NeuroDiscovery Center
Harvard Medical School and Brigham & Women’s Hospital
65 Landsdowne Street, Cambridge, MA 02139 (USA)
[c] Prof. Dr. J. C. Schouten
tion of heterocycles using triflyl chloride (CF3SO2Cl, 1b) as
Department of Chemical Engineering and Chemistry
Chemical Reactor Engineering
[21,22]
C
a [CF3] source (Scheme 1a).
Later, another approach based
on inexpensive gaseous trifluoroiodomethane (CF3I, 1a) was
developed by Cho and co-workers.[23,24] However, decisive limi-
tations are associated with these batch protocols, such as:
i) limited scale-up potential; ii) inefficient light transmission in
the batch reactor according to the Lambert–Beer law, especial-
ly when there is significant scattering of the incident light in
a heterogeneous mixture; iii) prolonged reaction times; and
Eindhoven University of Technology
Den Dolech 2, 5612 AZ Eindhoven (The Netherlands)
[d] Dr. T. Noꢀl
Ghent University
Department of Organic Chemistry
Krijgslaan 281 (S4), 9000 Ghent (Belgium)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201301282.
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bling a fast and robust approach
to trifluoromethyl- or perfluoro-
alkyl-functionalized
five-mem-
bered heteroarenes (Scheme 1b).
To develop a successful con-
tinuous flow procedure, we de-
signed an operationally simple
microflow setup from commer-
cially available components (Fig-
ure 2a). The microreactor was
constructed by using transparent
PFA capillary tubing (500 mm ID,
1/16“ OD, 200 mL Vmax) coiled
around a large transparent dis-
posable syringe. Next, the capil-
lary microreactor assembly was
placed inside a beaker in which
an array of blue light-emitting
diodes (LEDs) (3.12 W blue LED
stripe, 78 Lm, 39 LED, 97 cm
length, lmax =450–460 nm) was
Scheme 1. a) Reported trifluoromethylation batch protocols [Refs. [21,23]]. b) Accelerated trifluoromethylation
and perfluoroalkylation, enabled by continuous-flow.
iv) the complicated handling of gaseous reagents and insuffi-
cient interfacial contact area which leads to limited gas–liquid
mass transfer rate.
coiled in a spiral fashion. The CF3I gas flow rate was monitored
and controlled utilizing mass flow controller (MFC)
a
(mLminÀ1). The liquid flow rate was regulated by a syringe
pump, which introduces the liquid reagents (photocatalyst,
substrate, base and solvent) (mLminÀ1). A T-shaped micromixer
was used to combine the gas and liquid phase prior to irradia-
tion inside the photomicroreactor (see the Supporting Informa-
tion for more detailed information regarding the microfluidic
setup).
To overcome these limitations, we reasoned that the use of
continuous-flow processing would significantly enhance the
utility for the trifluoromethylation and perfluoroalkylation of
five-membered heterocycles. Due to their high surface-to-
volume ratios, microreactors offer the advantage of an in-
creased control over different process parameters (e.g., heat-
and mass-transfer, gas-liquid characteristics, residence time
control), which leads to a safer handling of hazardous com-
pounds.[32–36] In addition, the small dimensions in microreactor
technology allow for homogeneous irradiation of the entire re-
action mixture.[37,38] As a consequence of the relatively high ex-
tinction coefficient of photoredox catalysts, a considerable
amount of light is absorbed within the first few hundreds of
micrometers of the light path, which makes the use of micro-
reactor technology vital for successful scale-up by a number-
ing-up strategy.[39–44] Moreover, owing to the improved irradia-
tion of the reaction mixture, microflow chemistry also allows
to decrease the amount of photocatalyst without significant
loss of efficiency.[39] Herein, we report the first photocatalytic
trifluoromethylation and perfluoroalkylation of five-membered
heteroarenes in continuous microflow, which renders an extra
rapid and up-scalable, industrially relevant method to con-
struct the ArÀCF3 bond.
We began our studies with the trifluoromethylation of N-
methylpyrrole 2 utilizing gaseous CF3I in the presence of
a base and [Ru(bpy)3Cl2] (1 mol%).[50] Initially, a residence time
of approximately 4 min was applied by combining a liquid
flow rate of 100 mLminÀ1 and a gas flow rate of 2 mLminÀ1.
Various organic nitrogen bases (2 equiv) were investigated,
such as DBU, TEA, DIPEA, and TMEDA (respectively 1,8-
diazabicyclo[5.4.0]undec-7-en, triethylamine, diisopropylethyla-
mine, and N,N,N’,N’-tetramethyl-1,2-diaminoethylene) (Fig-
ure 2b, entries 1–4). TMEDA proved to be the most effective
for this trifluoromethylation protocol, providing 81% conver-
sion within 4 min residence time (Figure 2b, entry 4). Next, the
flow rate of the liquid phase or the reactor length were adjust-
ed until a satisfactory residence time (tR) was obtained to ach-
ieve full conversion of the starting material (Figure 2b, en-
tries 5 and 6). With a residence time of 8 min, we were able to
achieve up to 99% conversion and the corresponding product
was obtained in 95% yield as judged by 19F NMR (Figure 2b,
entry 6). Subsequently, we also investigated different CF3I gas
flow rates (Figure 2b, entries 7 and 8). The optimal gas flow
rate was found to be 2 mLminÀ1 (4 equiv CF3I) (Figure 2b,
entry 6), as decreasing the CF3I flow gave lower conversions
(44–62%).
Based on our experience with continuous-flow chemis-
try,[45–47] we also felt that the presence of a gaseous reagent
(such as CF3I) would not obstruct our investigations and could
be perfectly dosed to the reaction mixture by means of a mass
flow controller. Furthermore, the presence of a gas phase leads
to segmented flow which in fact provides fast mixing (internal
circulation in the liquid phase), a large and well-defined inter-
facial area, intensified mass- and heat-transfer, and a reduced
axial dispersion.[48,49] Notwithstanding, a continuous-flow pro-
tocol also allowed for an accelerated reaction protocol, ena-
With the optimal conditions in hand, we conducted a series
of experiments to evaluate the scope of our continuous-micro-
flow trifluoromethylation method (Scheme 2). N-methylpyrrole
2a and a selection of indole derivatives 2b–2 f were efficiently
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Figure 2. a) Schematic representation of the continuous-flow setup for tri-
fluoromethylation of hetero-arenes. b) Optimization of the continuous-flow
reaction conditions. [a] Reactions were carried out using [Ru(bpy)3Cl2]
(1.0 mol%), base (2.0 equiv) in MeCN (0.2m), and irradiated by blue LEDs.
[b] Distribution; liquid flow rate, and gas flow rate are given in mLminÀ1 and
mLminÀ1, respectively. Residence time of 4 min and 3 min are performed in
a 200 mL Vmax microreactor, 8 min residence time was performed in
a 400 mL Vmax microreactor. (blue bars) Conversion, analyzed by GC with
a,a,a-trifluorotoluene as internal standard. (red bars) 19F NMR yield of the
product.
Scheme 2. Trifluoromethylation of five-membered hetero-arenes. [a] Reac-
tions were carried out using [Ru(bpy)3Cl2] (1.0 mol%), TMEDA (2.0 equiv),
CF3I (4.0 equiv) in MeCN (0.2m), and irradiated with blue LED, [b] Yield deter-
mined with 19F NMR with a,a,a-trifluorotoluene as an internal standard,
[c] An increased catalyst loading (4 mol%) was used. [d] MeCN:DMSO (9:1)
was used as solvent system.
trifluoromethylated within a residence time of 8 min and were
obtained in sufficiently pure form to allow for a simple purifi-
cation (65–95%). A slightly lower yield was obtained for 2-
methylindole 2e (65%), while 1,2-dimethylindole 2 f could be
smoothly trifluoromethylated in 79% yield. Trifluoromethyla-
tion of 1H-pyrrole-2-carboaldehyde 2g and methyl-1H-pyrrole-
2-carboxylate 2h resulted in the formation of a small amount
of precipitation, clogging the microreactor. This could be effi-
ciently prevented by using a slightly different solvent mixture
of DMSO/MeCN (1:9), which increased the solubility of the pre-
cipitate. However, an increased catalyst loading (4 mol%) was
required to compensate the lower rate of the photocatalytic
transformation in DMSO. The same method was applied to 2-
methylfuran and 2-methylthiophene, which were both success-
fully trifluoromethylated within 16 min of residence time (2i
and 2j). Likewise, 3-methylbenzofuran and 3-methylbenzothio-
phene were also trifluoromethylated and isolated in good yield
(73% and 55%, 2k and 2l).
Next, we extended our focus by developing a continuous-
flow method for the photocatalytic perfluoroalkylation of
hetero-arenes using iodoperfluoroalkyl 1c (RCF2I). Perfluoroal-
kylation offers, besides the profound effects of the presence of
fluorine substituents for pharmaceuticals and materials,
a
straightforward pathway to introduce other functional
groups such as esters, ethers or other halogens. The continu-
ous-flow setup for the perfluoroalkylation was a simplified ver-
sion of the one used for the trifluoromethylation (Figure 3a).
Instead of a biphasic gas–liquid phase reaction, homogeneous
reaction conditions were used for perfluoroalkylation. More de-
tailed explanation regarding the micro flow setup construction
can be found in the Supporting Information.
Preliminary optimization studies were carried out to acquire
the optimal perfluoroalkylation conditions. A number of solu-
ble organic bases were tested (Figure 3). In contrast with the
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Scheme 3. Perfluoroalkylation of hetero-arenes. [a] Reactions were carried
out using Ru(bpy)3Cl2 (0.5 mol%), base (3.0 equiv) in MeCN, and irradiated
with blue LED. [b] 19F NMR yield of the product. [c] Ethyl 2-bromo-difluoroa-
cetate was used as the alkyl halide source.
Figure 3. a) Schematic representation of the continuous-flow setup for the
perfluoroalkylation of hetero-arenes. b) Optimization of the reaction condi-
tions. [a] Reactions were carried out using [Ru(bpy)3Cl2] (0.5 mol%), base
(3 equiv) nonafluoro-1-iodobutane (2 equiv) in MeCN, and irradiated by blue
LEDs. [b] Distribution; liquid/liquid flow rate are given in mLminÀ1 and
mLminÀ1, respectively. (blue bars) Conversion, analyzed by GC with a,a,a-tri-
fluorotoluene as internal standard. (red bar) 19F NMR yield of the product.
trifluoromethylation experiments, DBU gave a good yield for
the desired product (Figure 3b, entry 1). However, TMEDA pro-
vided the best results for the perfluoroalkylation in continuous
flow (Figure 3b, entry 4). DBU gave a dark solution upon irradi-
ation, leading to a less-efficient photon flux through the reac-
tion mixture. On the contrary, TMEDA remained a clear and
transparent solution even after prolonged irradiation times. To
further optimize the reaction conditions, a variety of solvents
were screened (see Supporting Information). The best results
were obtained in acetonitrile. Other polar solvents were less ef-
ficient, while the use of nonpolar solvents resulted in an in-
complete dissolution of the photoredox catalyst. With the opti-
mal conditions in hand, we evaluated the method by perfluor-
oalkylating a selection of five-membered hetero-arenes with
different perfluoro-1-iodoalkanes (Scheme 3). The construction
of perfluoroalkylated N-methylpyrrole 3a and a number of
indole analogues 3b and 3e was easily achieved within several
minutes (tR =10 min) and delivered the target compound in
good yields (53–88%). In addition, 3-methylindole was also re-
acted with perfluoro-2-iodopropane and ethyl 2-bromo-difluor-
oacetate, providing products 3c and 3d in good yield (99%
and 72%).
Scheme 4. Large scale trifluoromethylation and the reaction with low cata-
lyst loading. [a] Reactions were carried out using Ru(bpy)3Cl2 (1 or
0.05 mol%), TMEDA (2 equiv), 1 (2 mLminÀ1) in MeCN (100 mLminÀ1), micro-
reactor (Vmax: 250 mL or 1000 mL), and irradiated with Blue LED.
To exploit the advantages of our continuous-flow protocol,
we also performed a long durational reaction to demonstrate
its scalability and stability (Scheme 4). As such, we were able
to produce a substantial amount of trifluoromethylated 3-
methylindole 4a in less than 9 h (1.98 g, 9.5 mmol). Additional-
ly, we investigated whether it was feasible to decrease the cat-
alyst system in flow (Scheme 4). The catalyst loading could be
decreased (down to 0.05 mol%) without significant loss of effi-
ciency (75%). Such low catalyst loadings are of great interest
to the pharmaceutical industry and clearly show the process
intensification in microflow reactors.
The pharmaceutical industry is always looking for more effi-
cient strategies to introduce functional groups into drug candi-
dates. The functionalization of hetero-aromatics with perfluor-
oalkyl moieties is one of the important strategies to enhance
its biological, chemical and physical properties. Many, if not all,
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centrated in vacuo and purified by flask chromatography over
silica (5% EtOAc in petroleum ether) to yield the desired product.
of the current batch strategies are suffering from long reaction
times, high catalyst loadings, limited scalability, and operation-
al flexibility. We have successfully realized for the first time
a continuous-flow method for the fast radical trifluoromethyla-
tion and perfluoroalkylation of five-membered hetero-arenes
using inexpensive perfluoroalkyl sources (e.g., CF3I and
CF3(CF2)3I). The trifluoromethylation of five-membered hetero-
arenes (Scheme 2) was achieved within several minutes (8–
16 min) in continuous-flow due to the excellent light irradia-
tion of the reaction mixture, the increased gas-liquid mass
transfer of CF3I, and the excellent mixing achieved in liquid
slugs as a consequence of the Taylor flow regime.[47] In com-
parison, similar reactions required many hours (12–24 h) in
batch to achieve full conversion. Next, the continuous-flow
photocatalytic protocol was extended for homogeneous liquid
perfluoroalkylation reactions and we were able to perfluoroal-
kylate a number of five-membered hetero-aromatics in less
than 1 h of reaction time (10–20 min). The potential to use
lower catalyst loadings (as low as 0.05 mol% photoredox cata-
lyst) and to scale-up the photocatalytic process are additional
features of our continuous-flow protocol that are not easy to
achieve in a batch mode.
Acknowledgements
T.N. acknowledged financial support from the Dutch Science
Foundation for a VENI Grant (12464) and from the European
Union for a Marie Curie CIG Grant. Funding by the Advanced Eu-
ropean Research Council Grant (grant number: 267443 for V.H.
and grant number: 227010 for J.C.S.) is kindly acknowledged.
Keywords: flow chemistry
· heterocycles · homogeneous
catalysis · photochemistry · ruthenium
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Experimental Section
General trifluoromethylation continuous-flow procedure: An
oven-dried volumetric flask (5 mL) was loaded with heterocycle
(1 mmol), [Ru(bpy)3Cl2] (1 mol%), and TMEDA (2 mmol). The flask
was sealed with a septum and degassed by alternating vacuum
and argon cycles (three times). Anhydrous MeCN (5 mL) was added
and the mixture was loaded in a 5 mL syringe and mounted on
a syringe pump. The gaseous CF3I flow rate (2 mLminÀ1) was estab-
lished by means of a mass flow controller (MFC) and stabilized
prior to the start-up of the syringe pump, which applied a liquid
flow rate of 100 mLminÀ1. After operation the reaction mixture was
quenched and collected, concentrated in vacuo and purified by
silica column chromatography (5% EtOAc in petroleum ether) to
afford the desired product.
General perfluoroalkylation continuous-flow procedure: An
oven-dried volumetric flask (10 mL) was loaded with heterocycle
(2.8 mmol), [Ru(bpy)3Cl2] (0.5 mol%), and perfluorobuthyliodide
(5.6 mmol), fitted with a septum and degassed by alternating
vacuum and argon backfill, and filled with MeCN. A second volu-
metric flask (10 mL) was loaded with TMEDA (8.4 mmol) degassed
and filled with MeCN. Both mixtures were transferred to corre-
sponding syringes and loaded in the setup. The reaction mixtures
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were introduced into the microreactor with
a flow rate of
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50 mLminÀ1. The reaction mixture was collected, quenched, con-
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Received: November 29, 2013
Revised: February 23, 2014
Published online on && &&, 0000
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 0000, 00, 1 – 6
&
6
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These are not the final page numbers!

COMMUNICATIONS
N. J. W. Straathof, H. P. L. Gemoets,
X. Wang, J. C. Schouten, V. Hessel,
T. Noꢀl*
&& – &&
Rapid Trifluoromethylation and
Perfluoroalkylation of Five-Membered
Heterocycles by Photoredox Catalysis
in Continuous Flow
Photo workflow: A simple and straight-
forward photocatalytic method for per-
fluoroalkylation in continuous flow is
developed. A photo-microreactor, con-
structed from commercially available
components, enables accelerated pho-
tocatalysis employing [Ru(bpy)3Cl2] as
photocatalyst under irradiation by blue
LED light. A series of electron-rich
hetero-aromatics is successfully trifluor-
omethylated within 8–16 min. Also, a se-
lection of hetero-aromatics is perfluor-
oalkylated within 10–20 min.
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 0000, 00, 1 – 6
&
7
&
ÞÞ
These are not the final page numbers!