Palladium-Catalyzed Trifluoromethylation of (Hetero)Arenes with CF3Br

Article abstract of DOI:10.1002/anie.201511131

The CF₃ group is an omnipresent motif found in many pharmaceuticals, agrochemicals, catalysts, materials, and industrial chemicals. Despite well-established trifluoromethylation methodologies, the straightforward and selective introduction of such groups into (hetero)arenes using available and less expensive sources is still a major challenge. In this regard, the selective synthesis of various trifluoromethyl-substituted (hetero)arenes by palladium-catalyzed C-H functionalization is herein reported. This novel methodology proceeds under comparably mild reaction conditions with good regio- and chemoselectivity. As examples, trifluoromethylations of biologically important molecules, such as melatonin, theophylline, caffeine, and pentoxifylline, are showcased.

Full text of DOI:10.1002/anie.201511131

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201511131
German Edition: DOI: 10.1002/ange.201511131
À
C H Activation
Palladium-Catalyzed Trifluoromethylation of (Hetero)Arenes with
CF3Br
Kishore Natte, Rajenahally V. Jagadeesh, Lin He, Jabor Rabeah, Jianbin Chen,
Christoph Taeschler, Stefan Ellinger, Florencio Zaragoza, Helfried Neumann,
Angelika Brückner, and Matthias Beller*
Abstract: The CF3 group is an omnipresent motif found in
many pharmaceuticals, agrochemicals, catalysts, materials, and
industrial chemicals. Despite well-established trifluoromethy-
lation methodologies, the straightforward and selective intro-
duction of such groups into (hetero)arenes using available and
less expensive sources is still a major challenge. In this regard,
the selective synthesis of various trifluoromethyl-substituted
À
(hetero)arenes by palladium-catalyzed C H functionalization
is herein reported. This novel methodology proceeds under
comparably mild reaction conditions with good regio- and
chemoselectivity. As examples, trifluoromethylations of bio-
logically important molecules, such as melatonin, theophylline,
caffeine, and pentoxifylline, are showcased.
F
luorinated compounds continue to be of major interest for
the synthesis of pharmaceuticals, agrochemicals, liquid crys-
tals, dyes, polymers, and functional materials. In general, the
introduction of a CF3 group leads to a significant change in the
physical properties of the parent molecule. For example,
trifluoromethylated drugs exhibit enhanced membrane per-
meability and increased bioavailability compared to their
nonfluorinated analogues.[1] Already today, around 25% of all
pharmaceuticals and 30% of the applied agrochemicals
contain at least one or even more trifluoromethyl substitu-
ents, or a fluorine atom.[2] The vast majority of the known
organofluorine compounds are made from relatively simple
building blocks. Methodologies to incorporate CF3 synthons
at a later stage of a given synthesis make use of sophisticated
trifluoromethylation reagents which are difficult to use on
a larger scale. For all these reasons, there exists a strong
interest in novel trifluoromethylation chemistry, which is also
the subject of intense research in industry and academia.[3]
Regarding synthesis, the most commonly applied industrial
trifluoromethylation involves the substitution of either car-
boxy or trichloromethyl groups by hazardous fluorinating
agents (Scheme 1).[4] Because of the harsh reaction conditions
Scheme 1. Trifluoromethylation of aryl and heteroaryl compounds.
DG=donating group.
required in these transformations, several recent alternative
trifluoromethylation protocols have been elegantly devel-
oped. Most of these alternative approaches are based on
either transition-metal-mediated[5] or metal-catalyzed cross-
coupling reactions[6] of arylboronic acids/esters, aryl halides,
and either anilines or the corresponding diazonium salts.[7]
Here, CF3 groups can be regioselectively introduced to
different aromatic scaffolds. However, multiple steps for the
preparation of the starting materials are required and
generation of the stoichiometric amounts of metal salts
decrease the overall synthetic efficiency.
À
To overcome such drawbacks, direct C H trifluoro-
methylation of (hetero)arenes has received considerable
attention.[2,3a,b] However, this chemistry is significantly less
developed despite the fact that it has great potential for
medicinal and agrochemical syntheses.[8] For example, direct-
ing-group-assisted palladium- or silver-catalyzed oxidative
trifluoromethylations were described by the groups of Yu[9]
and Bräse.[10] Furthermore, related palladium-[11] and copper-
catalyzed[12] oxidative trifluoromethylations were disclosed.
In addition, the synthesis of advanced trifluoromethylated
building blocks by radical processes were described by the
groups of MacMillan[13] and Baran[14] using either visible light
or tBuOOH (TBHP) to initiate CF3 radical formation from
eithr CF3SO2Cl or CF3SO2Na (Langlois reagent).
[*] Dr. K. Natte, Dr. R. V. Jagadeesh, Dr. L. He, Dr. J. Rabeah, J. Chen,
Dr. H. Neumann, Prof. Dr. A. Brückner, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse an der Universität Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Dr. C. Taeschler, Dr. S. Ellinger, Dr. F. Zaragoza
Lonza Ltd
Rottenstrasse 6, CH-3930 Visp (Switzerland)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201511131.
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(Table S1, entries 2–10). In fact, in the presence of stoichio-
metric amounts of Ag2O, Cu(OAc)2, and BQ (benzoquinone)
(slightly) improved yields are obtained (Table S1, entries 4, 6
and 9). To our surprise, addition of one equivalent of TEMPO
(2,2,6,6-tetramethylpiperidinyloxyl) in the presence of the
optimal palladium catalyst system led to 81% yield (69% of
the isolated product) of the desired product (Table S1,
entry 11)! Further optimization studies were conducted with
different solvents and bases (see Table S2). Apart from the
positive influence of TEMPO, the choice of the ligand
(BuPAd2) is also crucial for obtaining high product yields.
As shown in Table S1 (entries 12–22), in the presence of other
well-known mono- and bidentate phosphine ligands signifi-
cantly lower yields of the desired product are achieved. Only
traces of the desired product are obtained without any
phosphine ligand present (Table S1, entry 26). As expected,
no reaction occurred in the absence of Pd (Table S1,
entry 27).
Figure 1. Price of selected trifluoromethylating agents. TES=triethyl-
silyl, TMS=trimethylsilyl.
Despite all these achievements, an ongoing challenge in
the development of trifluoromethylation process is the use of
available and less expensive CF3 sources/reagents. The most
commonly used CF3 sources in organic synthesis and their
actual prices per mole are shown in Figure 1. Among the
commercially available trifluoromethylation sources, CF3Br
(commonly called as halon 1301) attracted our interest since
this reagent is relatively inexpensive and still available in
large quantities because of its use for fire suppression, etc.[15]
Comparing CF3Br with most other trifluoromethylation
reagents, this compound can be produced with much less
waste formation. However, it should be noted that CF3Br, like
most halofluorocarbons, has strong ozone depletion potential.
Hence, proper measurements should be taken to avoid
exposure of the reagent to the atmosphere. Despite the
general advantages, the use of CF3Br to generate trifluoro-
methylated products has been scarcely explored. Indeed, to
the best of our knowledge only two publications from the
group of Langlois, as well as Sugimori and co-workers,
reported the synthesis of regioisomeric trifluoromethylated
compounds in low yields.[16] In addition to CF3Br, we also
tested unactivated CF3H under our optimized reaction
conditions. Unfortunately we did not observe any trifluoro-
methylated product.
À
Having a reliable C H trifluoromethylation protocol in
hand, we examined the substrate scope by employing
structurally diverse arenes and heteroarenes. In the course
of this different substituted electron-rich arenes were trans-
formed into valuable trifluoromethylated compounds in
moderate to good yields. Benzenes bearing methoxy groups
at various positions are well-tolerated and the corresponding
products are obtained in good yields ( 1–4; Figure 2). In the
case of 1,2-dimethoxybenzene the sterically less hindered
regioisomer is formed preferentially. Notably, trifluoro-
methylation of chloro-, bromo-, and fluoro-substituted ani-
lines proceeded and gave the desired products, which
constitute industrial important building blocks, in a straight-
forward manner (5–9). The compatibility with halide and free
amino substituents illustrate an orthogonal reactivity to
À
conventional C X trifluoromethylation reactions. In addi-
tion, electron-withdrawing groups such as nitrile and ketone
are tolerated (10, 11, and 14). Notably, new trifluoromethy-
lated building blocks can be easily accessed by this method-
ology (12 and 13). The exclusive selectivity in these latter
cases is a practical advantage. The reaction also worked well
for non-activated arenes, thus giving moderate to good yields
of the corresponding trifluoromethylated products (15–17 and
19). Even sterically hindered pentamethylbenzene underwent
trifluoromethylation in moderate yield (18). Moreover,
naphthalene was successfully trifluoromethylated in 78%
yield and 3:1 regioselectivity (20).
Based on our previous work on perfluoroalkylations,[8k]
recently we became interested in exploring the use of CF3Br
À
for direct catalytic C H trifluoromethylations. In this respect,
À
we report herein the first palladium-catalyzed C H trifluoro-
methylation of unfunctionalized (hetero)arenes without the
necessity of directing groups.
In our initial studies, we investigated the trifluoromethy-
lation of 1,4-dimethoxybenzene (1a) with CF3Br in the
presence of Pd(OAc)2 and BuPAd2 (n-butyl-di-1-adamantyl-
phosphine) as a ligand. This catalyst system was chosen
To demonstrate the potential utility of this reaction for
medicinal chemistry, the trifluoromethylation of different
heterocycles was investigated. 1,2- and 1,3-dimethyl-substi-
tuted indoles underwent smooth trifluormethylation, thus
giving high yields (21 and 22; Figure 2). Interestingly, the
reaction worked well for 2-acetyl-1-methylpyrrole and 2-
acetylpyrrole with good yields (23 and 24). Furthermore, N-
methyl pyrrole afforded the 2-trifluormethlyated product 25
as a single isomer. In addition, 2-methylthiophene was also
successfully trifluoromethylated (26). Importantly, selective
À
because it allows an efficient activation of various C X
bonds.[17] For effective catalytic testing, product yields were
determined primarily by 19F NMR spectroscopy. Indeed, 18%
of the desired product (1b) is obtained in the presence of
acetone and Cs2CO3 at 1308C after 40 hours (see entry 1 of
Table S1 in the Supporting Information). Testing various
commercially available monodentate and bidendate phos-
phine ligands (see entries 1–13 of Table S2) under these
reaction conditions led to lower yields or no product at all,
thus demonstrating the challenging nature of this trifluoro-
methylation reaction.
À
C H trifluoromethylation of biologically active molecules
such as melatonin, theophylline, caffeine, and pentoxifylline
led to the desired products in moderate to good yields upon
isolation (27 and 29–31). Finally, our protocol was applied
À
To improve the C H activation step and to enhance the
yield of the desired product, different oxidants were added
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trifluoromethylation occurred in the
absence of palladium, ligand, and
base.
Among the various additives,
TEMPO is the most efficient pro-
motor of this reaction (see Tables S1
and S2 and Scheme S1 in the Sup-
porting Information). Notably,
a
similar effect using Rupperts
reagent has been observed by Liu
and co-workers.[11a] As shown in
Figure 3, a radical mechanism is
proposed for this novel transforma-
tion based on EPR investigations.
More specifically, a mixture of Pd-
(OAc)2 and BuPAd2 suspended in
toluene saturated with CF3Br gave
a clear EPR signal, which corre-
sponds to a CF3 radical (see the
Supporting Information). This elec-
trophilic radical is supposed to react
directly with the arene. Subsequent
reaction with PdBrL2 leads to
HPdL2Br, which is detected by
NMR spectroscopy. Final quenching
with Cs2CO3 converts B into the
active species A and closes the
catalytic cycle. Interestingly, in this
mechanistic proposal the role of the
specific Pd0L2 complex is to cleave
À
the CF3 Br bond homolytically to
Figure 2. Palladium-catalyzed trifluoromethylation of (hetero)arenes: Substrate scope. Reaction
conditions: 1a (0.2 mmol), CF3Br (3–10 bar), Pd(OAc)2 (10 mol%), ligand (20 mol%), Cs2CO3
(2.0 equiv), TEMPO (1.0 equiv), acetone (0.5–2 mL), 1308C, 40-50h, N2 (15 bar). See the Supporting
Information for the reaction procedure for every substrate. [a] Yields of product isolated after column
chromatography. [b] Yields determined by 19F NMR spectroscopy using 1,4-difluorobenzene as an
internal standard. [c] Reaction scale on 5 grams (see the SI for reaction procedure).
release the CF3 radical. The positive
role of TEMPO is explained by its
function both as single-electron
reducing agent, as well as an oxidiz-
ing agent, which facilitates the
subtle interplay between the differ-
ent palladium species (for more
details see the Supporting Informa-
tion).
Scheme 2. Mechanistic studies: Selected control experiments.
successfully to an estrone derivative, but a mixture of two
regioisomeric products was obtained in 77% yield (28).
Notably, most of the trifluoromethylation experiments were
run on a 0.2–1 mmol scale. However, reactions on a 5 gram
scale are also possible (23 and 27).
To investigate the mechanism of this novel trifluoro-
methylation protocol, control experiments of the benchmark
reaction (1,4-dimethoxybenzene) and in situ spectroscopic
measurements were performed. As shown in Scheme 2, no
Figure 3. Proposed reaction mechanism.
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CF3Br. Compared to most trifluoromethylation protocols
there is no need to apply very costly CF3 reagents as well as
strong oxidants, or peroxides. Crucial for the success of this
transformation is the use of a specific palladium catalyst and
addition of TEMPO as a mild redox mediator. This method-
ology worked well for electron-rich and electron-neutral
arenes and heteroarenes, even on gram scale. Further
improvements of the catalyst performance are currently
under way in our laboratory.
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Acknowledgments
This research was funded by Lonza Ltd., the state of
Mecklenburg-Vorpommern, and the BMBF. We thank Dr.
C. Fischer, S. Buchholz, S. Leiminger, and S. Schareina for
their excellent technical and analytical support and for Dr. J.
Radnik for XPS measurements.
À
Keywords: arenes · C H activation · fluorine · palladium ·
radical chemistry
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2782–2786
Angew. Chem. 2016, 128, 2832–2836
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Received: December 2, 2015
Published online: January 25, 2016
2786 www.angewandte.org
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