Visible-Light-Induced Trifluoromethylation of Highly Functionalized Arenes and Heteroarenes in Continuous Flow

Article abstract of DOI:10.1055/s-0036-1588527

We report a continuous-flow protocol for the trifluoromethylation of arenes, heteroarenes, and benzofused heterocycles. This photoredox methodology relies on the use of solid sodium trifluoromethanesulfinate (CF ₃ SO ₂ Na) as the trifluoromethylating agent and the iridium complex [Ir{dF(CF ₃)ppy} ₂ ](dtbpy)]PF ₆ as the photoredox catalyst. A diverse set of highly functionalized heterocycles proved compatible with the methodology, and moderate to good yields were obtained within 30 minutes of residence time.

Full text of DOI:10.1055/s-0036-1588527

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
I. Abdiaj et al.
Paper
Synthesis
Visible-Light-Induced Trifluoromethylation of Highly Functional-
ized Arenes and Heteroarenes in Continuous Flow
Irini Abdiaja
Cecilia Bottecchiab
Jesus Alcazar*a
Timothy Noёl*b
a Janssen Research & Development, Jarama 75A, 45007 Toledo, Spain
jalcazar@its.jnj.com
b Department of Chemical Engineering and Chemistry, Micro Flow
Chemistry & Process Technology, Eindhoven University of Technology,
Den Dolech 2, 5612 AZ Eindhoven, The Netherlands
t.noel@tue.nl
Received: 07.06.2017
Accepted after revision: 07.07.2017
Published online: 09.08.2017
pensive Togni and Umemoto’s reagents, unstable triflyl
chloride (CF3SO2Cl), gaseous CF3I, and readily available tri-
fluoroacetic anhydride.4e,5 In addition, the Langlois reagent
(CF3SO2Na) can be regarded as an easy-to-handle, inexpen-
sive, and solid trifluoromethylating agent, capable of gener-
ating CF3 radicals in the presence of a strong oxidant (e.g., t-
BuOOH).6,7
As part of our interest to develop efficient continuous-
flow protocols as enabling tools for drug discovery, we en-
visioned a photocatalytic strategy for the trifluoromethyla-
tion of a variety of highly functionalized heteroarenes,
which are of interest in medicinal chemistry.4a,b,8 Such sub-
strates are often ignored in many reports, since these com-
pounds are known to be highly challenging and thus low
yielding. In order to develop a practical and widely applica-
ble methodology, we opted to use the stable, inexpensive,
and solid Langlois reagent (CF3SO2Na) as trifluoromethyl
source.
We commenced our investigations by performing lumi-
nescence quenching studies, which allowed us to rapidly
select the optimal photocatalyst for our transformation (see
Supporting Information).9 Among the photocatalysts tested,
the luminescence of both fac-Ir(ppy)3 and [Ir{dF(CF3)ppy}2]-
(dtbpy)]PF6 was significantly quenched by increasing equiv-
alents of CF3SO2Na, as depicted in Figure 1. This suggests
that the excited state of both photocatalysts can be reduc-
tively quenched by the Langlois reagent, thus generating a
CF3 radical. In particular, a high luminescence quenching
percentage of 58% was obtained for [Ir{dF(CF3)ppy}2](dtbpy)]-
PF6 in the presence of 300 equivalents of the Langlois re-
agent, while 2500 equivalents of CF3SO2Na were needed to
obtain a quenching percentage of only 44% in the case of
fac-Ir(ppy)3 (Figure 1). The higher quenching efficiency ob-
served with [Ir{dF(CF3)ppy}2](dtbpy)]PF6 is consistent with
the higher excited state reduction potential reported for
this catalyst compared to fac-Ir(ppy)3 [1.21 V vs 0.31 V, re-
DOI: 10.1055/s-0036-1588527; Art ID: ss-2017-e0328-op
Abstract We report a continuous-flow protocol for the trifluorometh-
ylation of arenes, heteroarenes, and benzofused heterocycles. This pho-
toredox methodology relies on the use of solid sodium trifluorometh-
anesulfinate (CF3SO2Na) as the trifluoromethylating agent and the
iridium complex [Ir{dF(CF3)ppy}2](dtbpy)]PF6 as the photoredox cata-
lyst. A diverse set of highly functionalized heterocycles proved compati-
ble with the methodology, and moderate to good yields were obtained
within 30 minutes of residence time.
Key words trifluoromethylation, photoredox catalysis, continuous
flow, Langlois reagent, visible light
Novel methodologies for the trifluoromethylation of
arenes and heteroarenes are in high demand in the chemi-
cal and pharmaceutical industry.1 In structure–activity re-
lationship (SAR) studies, the introduction of fluorine atoms
can greatly impact the electronic properties, acidity, and li-
pophilicity of drug candidates.2 These effects are due to the
high electronegativity of the fluorine atom, to its relatively
small radius, and to the less polarizable nature of C–F bonds
compared to C–H bonds.1b The replacement of methyl
groups with their trifluoromethyl counterparts represents
a conservative substitution in terms of steric hindrance,
while constituting a valuable strategy to block potential
metabolically labile sites in drug candidates, prolonging
their half-life and metabolic stability.1a
The initially reported trifluoromethylation protocols re-
lied on transition-metal-catalyzed cross-coupling methods,
but suffered from the need for prefunctionalized substrates
and stoichiometric amounts of metal salts.3 More recently,
several strategies reported in the literature demonstrated
the utility of photocatalytic protocols for the trifluorometh-
ylation of alkenes, thiols, heterocycles, and arenes.4 The
most commonly used trifluoromethyl sources include ex-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
I. Abdiaj et al.
Paper
Synthesis
spectively; both values reported versus the saturated
calomel electrode (SCE)].10 As reported by Glorius and co-
workers, a quenching percentage higher than 25% should
be considered as significant and relevant for photocata-
lytic reaction purposes.9b Therefore, we selected
[Ir{dF(CF3)ppy}2](dtbpy)]PF6 as the photocatalyst for our
further investigations.
lower 32% isolated yield (entry 4). Increasing the amount of
Langlois reagent to three equivalents further boosted the
LC-MS yield to 54% (entry 5) (45% isolated yield). Notably,
under the same reaction conditions, the reaction with fac-
Ir(ppy)3 gave 38% yield (entry 6), thus confirming the choice
of the photocatalyst based on the luminescence quenching
studies. Increasing the reaction temperature to 60 °C did
not lead to a further improvement of the reaction yield (en-
try 7). Control experiments revealed the photocatalytic na-
ture of our protocol, as little to no product was observed in
the absence of either light or photocatalyst (entries 8 and
9). Finally, irradiation of the reaction mixture with a 365
nm UV lamp resulted in 46% of the target compound, which
can be attributed to the UV-tailing absorption of the iridi-
um photocatalyst (entry 10). Nevertheless, it should be not-
ed that, especially for the synthesis of densely functional-
ized drug candidates, irradiation with low-energy blue light
is preferred over higher-energy ultraviolet, to minimize the
occurrence of side reactions and compound degradation.11
Table 1 Optimization of Reaction Conditions for the Trifluoromethyla-
tion of Caffeine in Continuous Flowa
Figure 1 Luminescence quenching percentage of
[Ir{dF(CF3)ppy}2](dtbpy)]PF6 (squares) and fac-Ir(ppy)3 (dots) in the
presence of increasing amounts of Langlois reagent. Experimental condi-
tions: The solutions of both photocatalysts were prepared in degassed
acetonitrile with a 10 μM concentration. Solutions with increasing con-
centrations of quencher (CF3SO2Na) were prepared in degassed aceto-
nitrile and tested. Compared to the amount of catalyst present, the
concentrations and number of equivalents of CF3SO2Na employed were
the following: 25 mM (2500 equiv), 50 mM (5000 equiv), 100 mM
(10000 equiv), 300 mM (30000 equiv). For [Ir{dF(CF3)ppy}2](dtbpy)]PF6,
a concentration of 0.3 mM (300 equiv and corresponding to reaction
conditions) was also tested. For more details on the procedure followed
and for the calculation of the quenching percentages, see the Support-
ing Information.
Entry Changes from optimized conditionsa
Yield by
LC-MS (%)
1
2
20 min residence time, no oxidant
no oxidant, CF3SO2Na (1.5 equiv)
(NH4)2S2O8 (1 equiv), CF3SO2Na (1.5 equiv)
diacetoxyiodobenzene (1 equiv), CF3SO2Na (1.5 equiv)
none
5
12
3
48
4
32b
54 (45b)
38
5
6
fac-Ir(ppy)3 as photocatalyst
60 °C
7
50
The trifluoromethylation of caffeine was selected as the
benchmark reaction for our optimization studies in flow
(Table 1). The photoflow reactor consisted of a Vapourtec
UV-150 photoreactor equipped with a 10 mL capillary reac-
tor (i.d. 1.3 mm), which was subjected to 450 nm irradiation
(54 blue LEDs; 24 W). DMSO was chosen as a suitable sol-
vent, ensuring high solubility of the densely functionalized
substrates and thus avoiding the occurrence of microreac-
tor clogging. At 40 °C, unsatisfactory yields were observed
in flow for the trifluoromethylated caffeine (Table 1, entries
1 and 2). We rationalized that the addition of an oxidant
might assist the re-aromatization of the radical intermedi-
ate to the final product. Indeed, in the presence of
(NH4)2S2O8 (1 equiv) as an oxidant, an improved LC-MS
yield of 48% was obtained (entry 3). Next, diacetoxyiodo-
benzene was tested as the oxidant, but this resulted in a
8
no light
6
9
light, no [Ir{dFCF3(ppy)}2](dtbpy)]PF6
365 nm LEDs
–
10
46
a Reaction conditions: caffeine (0.2 mmol), [Ir{dF(CF3)ppy}2](dtbpy)]PF6 (1
mol%), CF3SO2Na (3 equiv), (NH4)2S2O8 (1 equiv), DMSO (2 mL; 0.1 M). Reac-
tions performed in a commercially available Vapourtec UV-150 photoreac-
tor, irradiation with 450 nm blue LEDs, 30 min residence time.
b Isolated yield.
With the optimized reaction conditions in hand, our
photocatalytic trifluoromethylation strategy was evaluated
on a wide range of heteroarenes and arenes, as well as ben-
zofused heterocycles (Scheme 1). We focused our attention
specifically on halogen-bearing substrates, which are of
high value for drug discovery programs. In these programs,
such functionalized substrates are key building blocks for
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
I. Abdiaj et al.
Paper
Synthesis
the very popular cross-coupling methods, which allow the
construction of carbon–carbon or carbon–heteroatom
bonds.12
ent on the indole was well tolerated (2d; 50% isolated yield;
C2/C3, 1:1). We then explored our transformation on a se-
ries of benzimidazole derivatives. Unlike indoles, benzimid-
azoles showed higher reactivity for the C4 and C6 positions
on the aromatic ring.13 For example, (trifluoromethyl)ben-
zimidazole 2e was obtained in 50% yield as a separable mix-
ture of C4/C6 (3:2) isomers; the 2-bromo trifluoromethyl
derivative 2f was obtained in 52% yield (C4/C6, 3:2, separa-
ble mixture). Interestingly, 5-chlorobenzimidazole showed
different selectivity, and was trifluoromethylated at posi-
tions C4 and C7 (2g, 45%; C4:C7 2:1), probably due to the
electronic and steric effect of the chlorine atom. Notably,
the possibility to easily separate the regioisomers obtained
for compounds 2d to 2g renders our strategy advantageous
for the simultaneous synthesis of fluorinated analogues rel-
evant for medicinal chemistry SAR studies.
Next, we tested pyridone and pyrimidone, which are
frequently used scaffolds in the synthesis of novel active
pharmaceutical ingredients (APIs).14 Trifluoromethylated
pyrimidone 3a and bromopyridone 3b were obtained in
good to excellent yields (80% and 60%, respectively; Scheme
1). We further investigated the reactivity of pyridine, ob-
taining trifluoromethylated pyridine derivatives 3d, 3e, and
3f in modest yields (40%, 35%, and 53%, respectively). Fur-
thermore, phenylpyrazole could be trifluoromethylated on
the phenyl substituent and isolated in 28% yield (3g). Con-
versely, the tetrahydropyran-substituted 4-aminopyrazole
derivative 3h was trifluoromethylated at position C5 on the
pyrazole ring and isolated in a reasonable 45% yield. 3-Bro-
mo-2,5-dimethylpyridine was successfully trifluoromethyl-
ated, giving 3i in 38% yield.
Finally, we explored the scope of our methodology with
regard to unactivated arene substrates (Scheme 1). Trifluo-
romethylated mesitylene and iodomesitylene 3j and 3k
were obtained in good to excellent yields (53% and 80%, re-
spectively). Trifluoromethylation of unactivated arenes is a
particularly challenging transformation, often requiring
long reaction times (18–24 h), and has so far rarely been re-
ported in photoredox-based protocols.4h,15 Therefore, we
were pleased to observe significant product formation in
our system within only 30 minutes of reaction time. The
main reason for the remarkable acceleration of the reaction
rate observed in our protocol lies in the improved irradia-
tion of the reaction mixture obtained in the microflow re-
actor.11,16 Moreover, to showcase the potential of microreac-
tors in terms of productivity, we performed a scale-up ex-
periment on bromopyridone.16c,17 The Vapourtec UV-150
photoreactor was continuously run for 3.5 hours without
any intervention, affording 545 mg of trifluoromethylated
derivative 3b (56%).
Scheme 1 Scope of the trifluoromethylation of heteroarenes, benzo-
fused heterocycles, and arenes. Reagents and conditions: substrate (0.5
mmol), [Ir{dF(CF3)ppy}2](dtbpy)]PF6 (1 mol%), CF3SO2Na (3 equiv),
(NH4)2S2O8 (1 equiv), DMSO (2 mL, 0.1 M). Reactions performed in a
Vapourtec UV-150 photoreactor, irradiation with 450 nm blue LEDs, 30
min residence time, isolated yields. a Yield determined by LC-MS. b Regi-
oselectivity determined by 1H NMR analysis of the crude reaction mix-
ture.
In conclusion, we developed a continuous-flow trifluo-
romethylation strategy for arenes, heteroarenes, and ben-
zofused heterocycles. Luminescence quenching studies
were employed to accelerate initial protocol optimization
and to select the best photocatalyst for the transformation.
3-Methyl and 2-methylindole derivatives 2b and 2c
were obtained in satisfactory yields (62% and 69%, respec-
tively; Scheme 1). Notably, the presence of an iodo substitu-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
I. Abdiaj et al.
Paper
Synthesis
Easy-to-handle CF3SO2Na (Langlois reagent) was successful-
ly used as trifluoromethylating agent. A variety of sub-
strates of high interest in drug discovery programs were tri-
fluoromethylated in good to excellent yields. Moreover, bro-
mo-, chloro-, and iodo-containing substrates were well
tolerated, thus demonstrating the compatibility of our
methodology with cross-coupling methods. Process inten-
sification in a microflow reactor afforded reduced reaction
times (30 minutes residence time) and high productivity.
Therefore, we anticipate that our methodology will find ap-
plication in the late-stage functionalization of pharmaceu-
tical ingredients, as well as in the preparation of key inter-
mediates in drug discovery programs.
fied, reagents were obtained from commercial sources and used with-
out further purification. The reactions were carried out in a Va-
pourtec photoreactor UV-150 fixed on an E-series Vapourtec equip-
ment. 1H NMR spectra were recorded on Bruker DPX-400 or Bruker
AV-500 spectrometers with standard pulse sequences, operating at
400 MHz and 500 MHz, respectively. Chemical shifts (δ) are reported
in parts per million (ppm) downfield from tetramethylsilane (TMS),
which was used as an internal standard. 13C NMR spectra were re-
corded on the same spectrometers operating at 101 MHz and 126
MHz, respectively. 19F NMR spectra were recorded on the Bruker AV-
500 spectrometer operating at 471 MHz. All microfluidic fittings
were purchased from IDEX Health and Science. The syringes were
connected to the capillary using ¼-28 flat-bottom flangeless fittings.
A syringe pump (Fusion 200 Classic) equipped with 5 or 10 mL sy-
ringes was used to feed liquid reagents through a high purity perfluo-
roalkoxyalkane (PFA) capillary tubing (i.d. 1.3 mm) to a Tefzel® tee
mixer (i.d. 1.25 mm). The melting points were measured on DSC
equipment (Mettler 823 Toledo; method: 30–300 °C, 10 °C/min).
The UPLC (Ultra Performance Liquid Chromatography) measurement
was performed using an Acquity® IClass UPLC® (Waters) system com-
prising a sampler organizer, a binary pump with degasser, a column
oven, a diode-array detector (DAD), and a column as specified below.
The MS detector (Waters, SQD or QTOF) was configured with an ESCI
dual ionization source (electrospray combined with atmospheric
pressure chemical ionization). Nitrogen was used as the nebulizer
gas. The source temperature was maintained at 140 °C. Data acquisi-
tion was performed with MassLynx-Openlynx software. For IClass-
SQD, reversed phase UPLC was carried out on an RRHD Eclipse Plus-
C18 (1.8 μm, 2.1 × 50 mm) from Agilent, with a flow rate of
1.0 mL/min, at 50 °C. The gradient conditions used were: 95% A (0.5
g/L ammonium acetate solution + 5% acetonitrile), 5% B (acetonitrile),
to 40% A, 60% B in 1.2 min, to 5% A, 95% B in 0.6 min, held for 0.2 min.
Injection volume 1.0 μL. Low-resolution ESI mass spectra (single
quadrupole, SQD detector) were acquired by scanning from 100 to
1000 in 0.1 s using an interchannel delay of 0.08 s. The capillary nee-
dle voltage was 3 kV. The cone voltage was 25 V for positive ionization
mode and 30 V for negative ionization mode. For IClass-QTOF, re-
versed phase UPLC was carried out on a BEH-C18 (1.7 μm, 2.1 ×
50 mm) from Waters, with a flow rate of 1.0 mL/min, at 50 °C. The
gradient conditions used are: 95% A (0.5 g/L ammonium acetate solu-
tion + 5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 1.2 min,
to 5% A, 95% B in 0.6 min, held for 0.2 min. Injection volume 1.0 μL.
High-resolution ESI mass spectra were recorded on a Xevo G2-S QTOF
mass spectrometer (Waters) configured with an electrospray ioniza-
tion source, maintained at 140 °C, using nitrogen as the nebulizer gas,
argon as collision gas, and Lockmass device for mass calibration using
leucine-enkephalin as standard substance. Spectra were acquired ei-
ther in positive or in negative ionization mode, by scanning from 50
to 1200 Da in 0.1 s. In positive mode the capillary needle voltage was
0.25 kV and the cone voltage was 25 V. In negative mode the capillary
needle voltage was 2.0 kV and the cone voltage was 25 V.
Trifluoromethylation; General Procedure:
In an oven-dried vial equipped with a magnetic stirrer and a PTFE
septum, [Ir{dF(CF3)ppy}2](dtbpy)]PF6 (5.6 mg, 1 mol%) was added to a
mixture of the substrate (0.5 mmol, 1 equiv), CF3SO2Na (1.5 mmol, 3
equiv), and (NH4)2S2O8 (0.5 mmol, 1 equiv) in DMSO (5 mL). The solu-
tion was pumped into the Vapourtec photoreactor (fluoropolymer
tube, 1.3 mm i.d., 10 mL) and the liquid flowrate was set at 0.33
mL/min (30 min residence time). The reactor was irradiated with 54
blue LEDs (450 nm, total power 24 W). The reaction mixture collected
from the outlet was diluted with H2O and extracted with Et2O (3×).
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude was then pre-adsorbed
onto silica, dried in vacuo, and purified by flash chromatography to
yield the trifluoromethylated product.
1,3,7-Trimethyl-8-(trifluoromethyl)-7H-purine-2,6-dione (2a)6a
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
75:25); this afforded the desired product as a white solid.
Yield: 59 mg (45%); mp 130.9 °C.
1H NMR (500 MHz, CDCl3): δ = 4.14–4.19 (m, 3 H), 3.60 (s, 3 H), 3.42
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 155.5, 151.3, 146.5, 138.9, 119.5,
109.6, 33.2, 29.9, 28.2.
19F NMR (471 MHz, CDCl3): δ = –62.37 (s).
HRMS (ESI): m/z [M + H]+ calcd for C9H9F3N4O2: 263.0749; found:
263.0742.
3-Methyl-2-(trifluoromethyl)-1H-indole (2b)18
GC measurements were performed using a 6890 Series gas chromato-
graph (Agilent Technologies) system comprising a 7683 Series injec-
tor and auto sampler, J&W HP-5MS column (20 m × 0.18 mm, 0.18
μm) from Agilent Technologies coupled to a 5973N MSD mass selec-
tive detector (single quadrupole, Agilent Technologies). The MS detec-
tor was configured with an electronic impact ionization source/chem-
ical ionization source (EI/CI). EI low-resolution mass spectra were ac-
quired by scanning from 50 to 550 at a rate of 5.51 scans per second.
The source temperature was maintained at 230 °C. Helium was used
as the nebulizer gas. Data acquisition was performed with Chemsta-
tion-Open Action software. TLC was carried out on silica gel 60 F254
plates (Merck), using reagent grade solvents. Unless otherwise speci-
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a white amorphous solid.
Yield: 61.8 mg (62%).
1H NMR (400 MHz, CDCl3): δ = 8.18 (br s, 1 H), 7.64 (d, J = 8.1 Hz, 1 H),
7.37–7.41 (m, 1 H), 7.29–7.35 (m, 1 H), 7.15–7.23 (m, 1 H), 2.45 (q, J =
1.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 135.2, 128.1, 124.8, 124.6, 121.6,
122.2, 120.1, 114.1, 8.4.
19F NMR (471 MHz, CDCl3): δ = –58.65 (s).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
I. Abdiaj et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C10H8F3N: 200.0680; found:
6-(Trifluoromethyl)benzimidazole (2e-C6 isomer)
200.0683.
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a yellow oil.
2-Methyl-3-(trifluoromethyl)-1H-indole (2c)4f
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a white solid.
Yield: 19 mg (20%).
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.99 (s, 1 H), 7.74 (d, J =
8.6 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 1 H).
Yield: 68.7 mg (69%); mp 147.5 °C.
1H NMR (500 MHz, CDCl3): δ = 8.18 (br s, 1 H), 7.67 (br d, J = 7.5 Hz, 1
13C NMR (101 MHz, CDCl3): δ = 142.6, 128.7, 126.0, 125.7, 125.4,
123.3, 120.1.
H), 7.24–7.32 (m, 1 H), 7.09–7.22 (m, 2 H), 2.49 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 133.9, 121.8, 121.3, 120.2, 119.1,
117.3, 113.7, 110.7, 99.3, 12.4.
19F NMR (471 MHz, CDCl3): δ = –54.63 (s).
19F NMR (471 MHz, CDCl3): δ = –62.20 (s).
HRMS (ESI): m/z [M – H]– calcd for C8H5F3N2: 185.0331; found:
185.0337.
HRMS (ESI): m/z [M + H]+ calcd for C10H8F3N: 200.0680; found:
2-Bromo-4-(trifluoromethyl)benzimidazole (2f-C4 isomer)
200.0686.
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc, in
gradient from 100/0 to 50:50); this afforded the desired product as a
white solid.
5-Iodo-3-(trifluoromethyl)-1H-indole (2d-C3 isomer)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
90:10); this afforded the desired product as a transparent oil.
Yield: 40.2 mg (30%); mp 214.7 °C.
1H NMR (400 MHz, CD3OD): δ = 7.85 (s, 1 H), 7.68 (d, J = 8.6 Hz, 1 H),
7.55 (d, J = 8.6 Hz, 1 H).
Yield: 39 mg (25%).
1H NMR (400 MHz, CDCl3): δ = 8.47 (br s, 1 H), 8.10 (s, 1 H), 7.56 (dd,
J = 8.6, 1.6 Hz, 1 H), 7.51 (dd, J = 2.7, 1.3 Hz, 1 H), 7.23 (s, 1 H).
13C NMR (101 MHz, CD3OD): δ = 140.8, 131.2, 130.1, 126.2, 122.2,
120.8, 115.7, 113.7.
13C NMR (101 MHz, CDCl3): δ = 138.0, 134.9, 132.2, 128.4, 125.1,
19F NMR (471 MHz, CD3OD): δ = –62.40 (s).
125.0, 124.2, 113.5, 85.2.
19F NMR (471 MHz, CDCl3): δ = –57.37 (s).
HRMS (ESI): m/z [M – H]– calcd for C8H4BrF3N2: 262.9436; found:
262.9434.
HRMS (ESI): m/z [M – H]– calcd for C9H5F3IN: 309.9345; found:
309.9368.
2-Bromo-6-(trifluoromethyl)-1H-benzimidazole (2f-C6 isomer)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc, gra-
dient 100:0 to 50:50); this afforded the desired product as a white
solid.
5-Iodo-2-(trifluoromethyl)-1H-indole (2d-C2 isomer)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a transparent oil.
Yield: 26.7 mg (20%); mp 214.7 °C.
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.99 (s, 1 H), 7.74 (d, J =
8.6 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 142.6, 128.7, 126.0, 125.7, 125.4,
Yield: 39 mg (25%).
1H NMR (500 MHz, CDCl3): δ = 8.52 (br s, 1 H), 8.03 (s, 1 H), 7.58 (d, J =
10.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.85 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 135.2, 133.2, 130.9, 129.1, 126.7,
123.3, 120.1.
19F NMR (471 MHz, CDCl3): δ = –62.20 (s).
126.4, 121.9, 113.7, 103.4, 84.5.
19F NMR (471 MHz, CDCl3): δ = –60.73 (s).
HRMS (ESI): m/z [M – H]– calcd for C8H4BrF3N2: 262.9436; found:
HRMS (ESI): m/z [M – H]– calcd for C9H5F3IN: 309.9345; found:
262.9434.
309.9368.
5-Chloro-2-methyl-7-(trifluoromethyl)-1H-benzimidazole (2g-C7
4-(Trifluoromethyl)benzimidazole (2e-C4 isomer)13
isomer)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a white amorphous solid.
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a white amorphous solid.
Yield: 23.8 mg (20%).
Yield: 27 mg (29%).
1H NMR (400 MHz, CDCl3): δ = 9.48 (br s, 1 H), 7.82 (br s, 1 H), 7.47 (s,
1 H), 2.68 (s, 3 H).
13C NMR (101 MHz, CD3OD): δ = 157.3, 128.1, 126.1, 123.4, 120.7,
105.2, 14.3.
19F NMR (471 MHz, CD3OD): δ = –62.87 (s).
HRMS (ESI): m/z [M – H]– calcd for C9H6ClF3N2: 233.0098; found:
1H NMR (500 MHz, CD3OD): δ = 8.20 (s, 1 H), 7.63–7.88 (br s, 1 H),
7.48 (br d, J = 7.2 Hz, 1 H), 7.31 (t, J = 7.8 Hz, 1 H).
13C NMR (126 MHz, CD3OD): δ = 164.1, 143.0, 133.2, 125.2, 123.1,
100.0, 99.8.
19F NMR (471 MHz, CD3OD): δ = –64.21 (s).
HRMS (ESI): m/z [M – H]– calcd for C8H5F3N2: 185.0331; found:
185.0337.
233.0108.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
I. Abdiaj et al.
Paper
Synthesis
5-Chloro-2-methyl-4-(trifluoromethyl)-1H-benzimidazole (2g-C4
Yield: 38.5 mg (40%); mp 213.4 °C.
isomer)
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 5.8 Hz, 1 H), 6.31 (dd, J = 5.9,
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a white amorphous solid.
0.8 Hz, 1 H), 5.00–5.20 (m, 2 H), 3.88 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 166.3, 156.6, 152.8, 124.9, 98.3, 56.1.
19F NMR (471 MHz, CDCl3): δ = –55.42 (s).
HRMS (ESI): m/z [M – H]– calcd for C7H7F3N2O: 191.0437; found:
Yield: 35.2 mg (30%).
1H NMR (500 MHz, CDCl3): δ = 9.50 (br s, 1 H), 7.74 (d, J = 8.4 Hz, 1 H),
7.34 (d, J = 8.4 Hz, 1 H), 2.66 (s, 3 H).
191.0423.
13C NMR (126 MHz, CDCl3): δ = 153.3, 143.5, 131.9, 127.0, 125.1,
122.9, 15.3.
19F NMR (471 MHz, CDCl3): δ = –57.09 (s).
HRMS (ESI): m/z [M – H]– calcd for C9H6ClF3N2: 233.0098; found:
2-Iodo-3-methoxy-5-(trifluoromethyl)pyridine (3e)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, pentane–Et2O,
90:10); this afforded the desired product as a transparent oil.
233.0108.
Yield: 52.9 mg (35%).
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.6 Hz, 1 H), 7.05 (d, J = 8.6
Hz, 1 H), 3.98 (s, 3 H).
5-(Trifluoromethyl)pyrimidin-4(3H)-one (3a)
The product was prepared according to the general procedure, after
which the solvent was evaporated in a Genevac turboevaporator over-
night. The rests of the reaction mixture were washed with CH2Cl2 and
the solvent was evaporated; the product was purified by flash chro-
matography (silica gel, MeOH–NH4OH, 9:1/CH2Cl2, 0–10%); this af-
forded the desired product as a yellow oil.
13C NMR (101 MHz, CDCl3): δ = 157.4, 140.4, 134.2, 121.0, 116.1,
111.7, 56.7.
19F NMR (471 MHz, CDCl3): δ = –66.70.
HRMS (ESI): m/z [M + H]+ calcd for C7H5F3INO: 303.9488; found:
303.9492.
Yield: 65.9 mg (80%).
2,5-Dimethyl-3-(trifluoromethyl)pyrazine (3f)
1H NMR (400 MHz, DMSO-d6): δ = 8.44 (s, 1 H), 8.40 (s, 1 H)
13C NMR (126 MHz, CDCl3): δ = 154.7, 152.1, 129.7, 121.9
19F NMR (471 MHz, CDCl3): δ = –65.35 (s).
The product was prepared according to the general procedure. The
organic layer was evaporated and the crude was analyzed by LC-MS
and GC-MS; yield: 53%.
HRMS (ESI): m/z [M – H]– calcd for C5H3F3N2O: 163.0124; found:
163.0129.
3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole (3g)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
40:60); this afforded the desired product as a transparent oil.
5-Bromo-3-(trifluoromethyl)-1H-pyridin-2-one (3b)19
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
50:50); this afforded the desired product as a yellow solid.
Yield: 29.7 mg (28%).
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.1 Hz, 2 H), 7.65–7.70 (m, 1
H), 7.62–7.74 (m, 2 H), 6.70 (d, J = 2.3 Hz, 1 H).
Yield: 72.6 mg (60%); mp 213.3 °C.
1H NMR (500 MHz, CDCl3): δ = 12.52–14.24 (m, 1 H), 7.92 (d, J = 2.0
Hz, 1 H), 7.76 (d, J = 2.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 136.0, 131.8, 129.5, 129.0, 128.8,
126.0, 125.7, 124.6, 122.6, 103.3.
13C NMR (126 MHz, CDCl3): δ = 160.0, 143.8, 139.4, 121.5, 121.9, 97.7.
19F NMR (471 MHz, CDCl3): δ = –65.98.
HRMS (ESI): m/z [M – H]– calcd for C6H3BrF3NO: 239.9277; found:
19F NMR (471 MHz, CDCl3): δ = –62.58 (s).
HRMS (ESI): m/z [M – H]– calcd for C10H7F3N2: 211.0488; found:
211.0486.
239.9272.
1-Tetrahydropyran-4-yl-5-(trifluoromethyl)pyrazol-4-amine (3h)
2,4,6-Trimethoxy-5-(trifluoromethyl)pyrimidine (3c)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
50:50); this afforded the desired product as a dark yellow oil.
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
80:20); this afforded the desired product as a pink solid.
Yield: 52.9 mg (45%).
1H NMR (400 MHz, CDCl3): δ = 7.16 (s, 1 H), 4.24 (tt, J = 11.5, 4.0 Hz, 1
H), 4.10 (dd, J = 11.8, 4.6 Hz, 2 H), 3.50 (td, J = 12.2, 2.0 Hz, 2 H), 3.28–
3.42 (m, 2 H), 2.26 (qd, J = 12.4, 4.6 Hz, 2 H), 1.78–1.92 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 130.8, 130.0, 121.8, 114.9, 67.1, 57.0,
32.9.
Yield: 71.4 mg (60%); mp 123.6 °C.
1H NMR (500 MHz, CDCl3): δ = 4.03 (s, 6 H), 4.01 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.8, 165.0, 123.5, 89.3, 55.1, 55.0.
19F NMR (471 MHz, CDCl3): δ = –55.97 (s).
19F NMR (471 MHz, CDCl3): δ = –56.70 (s).
HRMS (ESI): m/z [M – H]– calcd for C9H12F3N3O: 234.2859; found:
4-Methoxy-3-(trifluoromethyl)pyridin-2-amine (3d)
The product was prepared according to the general procedure and
was purified by flash chromatography (silica gel, heptane–EtOAc,
40:60); this afforded the desired product as a yellow solid.
234.2855.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
I. Abdiaj et al.
Paper
Synthesis
3-Bromo-2,6-dimethyl-5-(trifluoromethyl)pyridine (3i)
P.; Stephenson, C. R. J. Nat. Commun. 2015, 6. (f) Straathof, N. J.
W.; Gemoets, H. P. L.; Wang, X.; Schouten, J. C.; Hessel, V.; Noël,
T. ChemSusChem 2014, 7, 1612. (g) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (h) Nagib, D. A.;
MacMillan, D. W. C. Nature 2011, 480, 224. (i) Iqbal, N.; Choi, S.;
Kim, E.; Cho, E. J. J. Org. Chem. 2012, 77, 11383. (j) Cui, L.;
Matusaki, Y.; Tada, N.; Miura, T.; Uno, B.; Itoh, A. Adv. Synth.
Catal. 2013, 355, 2203.
The product was prepared according to the general procedure. The or-
ganic layer was evaporated and the crude was analyzed by LC-MS;
yield: 38%.
1H NMR (400 MHz, CDCl3): δ = 7.97 (s, 1 H), 2.68 (s, 3 H), 2.62–2.64
(m, 3 H).
19F NMR (471 MHz, CDCl3): δ = –62.23.
(5) (a) Pan, X.; Xia, H.; Wu, J. Org. Chem. Front. 2016, 3, 1163.
(b) Barata-Vallejo, S.; Lantaño, B.; Postigo, A. Chem. Eur. J. 2014,
20, 16806.
1,3,5-Trimethyl-2-(trifluoromethyl)benzene (3j)
The product was prepared according to the general procedure. The or-
ganic layer was evaporated and the crude was analyzed by LC-MS;
yield: 53%.
(6) (a) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su,
S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 14411. (b) Wang, D.; Deng, G.-J.; Chen, S.; Gong, H.
Green Chem. 2016, 18, 5967. (c) Langlois, B. R.; Billard, T.;
Mulatier, J.-C.; Yezeguelian, C. J. Fluorine Chem. 2007, 128, 851.
(d) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991,
32, 7525. (e) Tordeux, M.; Langlois, B.; Wakselman, C. J. Org.
Chem. 1989, 54, 2452.
2-Iodo-1,3,5-trimethyl-4-(trifluoromethyl)benzene (3k)
The product was prepared according to the general procedure. The or-
ganic layer was evaporated and the crude was analyzed by LC-MS;
yield: 80%.
(7) (a) Lefebvre, Q. Synlett 2016, 28, 19. (b) Zhang, C. Adv. Synth.
Catal. 2014, 356, 2895.
(8) (a) Huck, L.; Berton, M.; de la Hoz, A.; Diaz-Ortiz, A.; Alcazar, J.
Green Chem. 2017, 19, 1420. (b) Wirth, T. ChemSusChem 2012, 5,
215. (c) Galloway, W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Nat.
Commun. 2010, 1, 1.
(9) (a) Teders, M.; Gómez-Suárez, A.; Pitzer, L.; Hopkinson, M. N.;
Glorius, F. Angew. Chem. Int. Ed. 2017, 56, 902. (b) Hopkinson,
M. N.; Gómez-Suárez, A.; Teders, M.; Sahoo, B.; Glorius, F.
Angew. Chem. Int. Ed. 2016, 55, 4361. (c) Demissie, T. B.; Hansen,
J. H. Dalton Trans. 2016, 45, 10878.
Funding Information
The authors acknowledge the European Union for a Marie Curie ITN
Grant (Photo4Future, Grant No. 641861). Further financial support for
this work was provided by a VIDI grant (T.N., SensPhotoFlow, No.
14150).
Maeri
Cueri
TI
N
,
P
h
o
ot
4
F
u
uter
6(
4
1
8
6
1
V)
D
I,
I
S
e
nsP
h
o
otFolw
1(
4
1
5
0)
Acknowledgment
(10) Teegardin, K.; Day, J. I.; Chan, J.; Weaver, J. Org. Process Res. Dev.
2016, 20, 1156.
(11) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T.
Chem. Rev. 2016, 116, 10276.
The authors would like to thank Dr. José Manuel Alonso for the sup-
port with NMR analysis.
(12) (a) Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443.
(b) Alonso, N.; Miller, L. Z.; de M. Muñoz, J.; Alcázar, J.;
McQuade, D. T. Adv. Synth. Catal. 2014, 356, 3737. (c) Egle, B.;
Muñoz, J.; Alonso, N.; De Borggraeve, W.; de la Hoz, A.; Díaz-
Ortiz, A.; Alcázar, J. J. Flow Chem. 2014, 4, 22. (d) de M. Muñoz,
J.; Alcázar, J.; de la Hoz, A.; Díaz-Ortiz, A. Adv. Synth. Catal. 2012,
354, 3456. (e) Noël, T.; Musacchio, A. J. Org. Lett. 2011, 13, 5180.
(f) Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Angew.
Chem. Int. Ed. 2010, 49, 8082.
(13) Gao, G.-L.; Yang, C.; Xia, W. Chem. Commun. 2017, 53, 1041.
(14) (a) Linghu, X.; Wong, N.; Iding, H.; Jost, V.; Zhang, H.; Koenig, S.
G.; Sowell, C. G.; Gosselin, F. Org. Process Res. Dev. 2017, 21, 387.
(b) Peng, A.; Jiang, J.; Hu, P.; Luo, Y. J. Chromatogr., B 2010, 878,
2442.
(15) (a) Chang, B.; Shao, H.; Yan, P.; Qiu, W.; Weng, Z.; Yuan, R. ACS
Sustainable Chem. Eng. 2017, 5, 334. (b) Li, L.; Mu, X.; Liu, W.;
Wang, Y.; Mi, Z.; Li, C.-J. J. Am. Chem. Soc. 2016, 138, 5809.
(16) (a) Noёl, T. Photochemical Processes in Continuous-Flow Reac-
tors; World Scientific: New Jersey, 2017. (b) Tucker, J. W.;
Zhang, Y.; Jamison, T. F.; Stephenson, C. R. J. Angew. Chem. Int.
Ed. 2012, 51, 4144. (c) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.;
Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson,
R. I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.;
Berry, M. B.; Booker-Milburn, K. I. Chem. Eur. J. 2014, 20, 15226.
(d) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Beilstein J.
Org. Chem. 2012, 8, 2025.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588527.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References
(1) (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (c) Müller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881.
(2) (a) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem. 2014,
57, 2832. (b) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N.
A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller,
K. J. Med. Chem. 2015, 58, 9041.
(3) (a) Barata-Vallejo, S.; Postigo, A. Coord. Chem. Rev. 2013, 257,
3051. (b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475. (c) Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.;
Zhang, X.; Collier, T. L.; Gouverneur, V.; Passchier, J. Nat. Chem.
2013, 5, 941.
(4) (a) Straathof, N. J. W.; Cramer, S. E.; Hessel, V.; Noël, T. Angew.
Chem. Int. Ed. 2016, 55, 15549. (b) Bottecchia, C.; Wei, X. J.;
Kuijpers, K. P.; Hessel, V.; Noel, T. J. Org. Chem. 2016, 81, 7301.
(c) Lefebvre, Q.; Hoffmann, N.; Rueping, M. Chem. Commun.
2016, 52, 2493. (d) Chatterjee, T.; Iqbal, N.; You, Y.; Cho, E. J. Acc.
Chem. Res. 2016, 49, 2284. (e) Beatty, J. W.; Douglas, J. J.; Cole, K.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
I. Abdiaj et al.
Paper
Synthesis
(17) (a) Elliott, L. D.; Berry, M.; Harji, B.; Klauber, D.; Leonard, J.;
Booker-Milburn, K. I. Org. Process Res. Dev. 2016, 20, 1806.
(b) Abdiaj, I.; Alcázar, J. Bioorg. Med. Chem. 2016, in press; DOI:
10.1016/j.bmc.2016.12.041. (c) Su, Y.; Kuijpers, K.; Hessel, V.;
Noël, T. React. Chem. Eng. 2016, 1, 73.
(18) Pitre, S. P.; McTiernan, C. D.; Ismaili, H.; Scaiano, J. C. ACS Catal.
2014, 4, 2530.
(19) Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Haslam,
C. P.; Livermore, D.; Moses, A.; Nicholson, N. H.; Page, L. W.;
Slingsby, B.; Swarbrick, M. E. Bioorg. Med. Chem. 2009, 19, 6578.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H