Catalytic activation of a single C-F bond in trifluoromethyl arenes

Article abstract of DOI:10.1039/c5sc03415a

Synthetic methods for the direct transformation of ArCF₃ to ArCF₂R would enable efficient diversification of trifluoromethyl arenes and would be of great utility in medicinal chemistry. Unfortunately, the development of such methods has been hampered by the fundamental properties of C-F bonds, which are exceptionally strong and become stronger with increased fluorination of the carbon atom. Here, we describe a method for the catalytic reduction of ArCF₃ to ArCF₂H through a highly selective activation of a single C-F bond. Mechanistic studies reveal separate reaction pathways for the formation of ArCF₂H and ArCH₃ products and point to the formation of an unexpected intermediate as the source of the unusual selectivity for the mono-reduction.

Full text of DOI:10.1039/c5sc03415a

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Catalytic activation of a single C–F bond in
trifluoromethyl arenes†
Cite this: DOI: 10.1039/c5sc03415a
*
Hester Dang, Aaron M. Whittaker and Gojko Lalic
Synthetic methods for the direct transformation of ArCF3 to ArCF2R would enable efficient diversification of
trifluoromethyl arenes and would be of great utility in medicinal chemistry. Unfortunately, the development
of such methods has been hampered by the fundamental properties of C–F bonds, which are exceptionally
strong and become stronger with increased fluorination of the carbon atom. Here, we describe a method
for the catalytic reduction of ArCF3 to ArCF2H through a highly selective activation of a single C–F bond.
Mechanistic studies reveal separate reaction pathways for the formation of ArCF2H and ArCH3 products
and point to the formation of an unexpected intermediate as the source of the unusual selectivity for the
mono-reduction.
Received 10th September 2015
Accepted 15th October 2015
DOI: 10.1039/c5sc03415a
www.rsc.org/chemicalscience
Fluorinated organic molecules play an important role in the to ArCF3 provided by synthetic methods developed in the last
pharmaceutical1,2 and agrochemical industries.3 Fluorine atoms two decades.6–9
are commonly introduced into organic molecules in an effort to
Unfortunately, selective functionalization of a single C–F
manipulate the physical and chemical properties of these bond in ArCF3 remains one of the great unmet challenges in
compounds, without making drastic changes to their overall organic chemistry. The problems associated with the selective
structure.4,5 Triuoromethylation of arenes is one of the most C–F functionalization become evident when we consider the
commonly used methods for uorination of organic molecules, fundamental properties of C–F bonds in ArCF3. The C–F bond is
and can be accomplished using one of the numerous synthetic the strongest single bond to carbon, with a bond dissociation
methods developed over the last two decades.6–9 This relatively energy (BDE) of 109 kcal molꢀ1 in CH3–F.21 Even a relatively
small structural change results in increased bioavailability, lip- weak C–F bond in benzyl uoride has a BDE of 99 kcal molꢀ1
ophilicity, and metabolic stability of aromatic compounds,10,11 (Scheme 1b).22 Not surprisingly, any transformation involving
and oen leads to an improved pharmacological prole. As the activation of such strong bonds is difficult to accomplish,
a result of the favorable pharmacological properties imparted by despite the signicant progress made in the eld of C–F bond
triuoromethylation, triuoromethyl arenes are extensively used activation.23–25 Furthermore, with increased uorination of
in medicinal chemistry and are present in a number of a carbon atom, C–F bonds become stronger and shorter, and
prescription drugs, including Prozac, Celebrex, and Januvia.
thus less reactive (Scheme 1b).26–28 As a result, selective func-
Diuoroalkyl arenes (ArCF2R) are analogues of ArCF3 that tionalization of a single C–F bond in ArCF3 poses an additional
hold great potential for applications in medicinal chemistry. selectivity challenge: the product of the C–F functionalization
Diuoroalkyl substituents have a similar effect on the phar- (ArCF2R) is inherently more reactive than the starting material
macokinetic properties of arenes as CF3 substituent.12 More- (ArCF3). Overcoming this selectivity problem has proven to be
over, they offer a greater structural and functional diversity,
which is oen critical in the optimization of bio-active lead
compounds.13 To fully exploit the potential of ArCF2R in
medicinal chemistry, transformations that would enable their
synthesis directly from ArCF3 precursors are needed (Scheme
1a).14–20 Direct mono-functionalization of ArCF3 would be the
most efficient strategy for diversication of this important class
of compounds, and would effectively leverage the reliable access
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
E-mail: lalic@chem.washington.edu
† Electronic supplementary information (ESI) available. CCDC 1423553. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5sc03415a
Scheme 1 Selective activation of a single C–F bond in ArCF3.
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particularly difficult. Only reported examples of the selective phosphine and N-heterocyclic carbene (NHC) ligands
monofunctionalization of ArCF3 are based on single electron completely inhibited the reaction. The presence of amines,
transfer reactions achieved by electrochemistry29 or alkali earth diamines, amides, and amino alcohols had a small, but
metal reduction.30,31 So far, no catalytic methods for function- consistently positive effect on selectivity. The greatest
alization of a single C–F bond in a triuoromethyl group have improvement was observed in the presence of 5 mol% of 2-
been reported in the literature.
pyridone (Table 1, entry 5). To facilitate further reaction opti-
In this report, we describe the discovery of a transition metal- mization, we decided to focus on gaining a better under-
catalyzed activation of a single C–F bond in ArCF3 that results in standing of the reaction mechanism and the source of the
the selective formation of ArCF2H. We present the results of observed selectivity.
mechanistic studies that provide insight into the source of the
unusual selectivity and the results of our exploration of the the formation of ArCH3 and that high selectivity can be achieved
substrate scope. only at a low conversion or with a low mass balance. However,
Our rst hypothesis was that ArCF2H is an intermediate in
We recently discovered that the reduction of 4-(4-MePh) the results of experiments in which we closely monitored the
C6H4CF3 (1) to 4-(4-MePh)C6H4CH3 (2) can be accomplished at progress of the reaction shown in entry 3 of Table 1 contradicted
room temperature using just 1 mol% of palladium(II) acetate as this hypothesis. We found that the conversion of the starting
ꢁ
a catalyst, in the presence of triphenylsilane and potassium tert- material reached 90% and stopped aer 11 hours at 45 C. At
butoxide (Table 1, entry 1). We also found that replacing this point, most of the fully reduced ArCH3 2 had already been
potassium tert-butoxide with sodium tert-butoxide abolishes formed (11%), while almost no ArCF2H 3 (4%) was present in
the reactivity. Even at a higher temperature reduction products the reaction mixture (see ESI for details†). At the same time
(ArCH3 and ArCF2H) are obtained in low yields (Table 1, entry 2). point, the major component of the reaction mixture was inter-
However, the addition of a copper co-catalyst restores the mediate X, which over the next 18 hours was converted into
reactivity, and leads to the formation of 4-(4-MePh)C6H4CF2H as ArCF2H 3 (Scheme 2). Over the same period, essentially no more
the major product of the reaction (Table 1, entry 3). Considering 2 was formed (12% vs. 11%). The same observations were made
that known methods for catalytic reduction of ArCF3 using when the reaction was performed in the presence of 2-pyridone
Lewis acid catalysis, early transition metal catalysis or late (Table 1, entry 5) (see ESI for details†). The only difference is
transition metal catalysis, produce only the fully reduced ArCH3 that 2-pyridone inhibits the formation of 2. Overall, the results
products,32–38 we were intrigued by the unusual selectivity of our of these experiments suggest that the formation of ArCH3 and
reduction reaction and decided to pursue the development of
a synthetic method for the selective mono-reduction of ArCF3.
In the initial experiments we conrmed that both copper and
palladium catalysts were necessary for the observed selectivity.
Furthermore, we found that in the absence of both catalysts,
starting material is fully recovered. Our initial attempts to
optimize the reaction focused on improving the conversion of
the starting material. We achieved complete conversion of 4-(4-
MePh)C6H4CF3 by increasing the catalyst loading and modi-
fying the ratio of the two catalysts (Table 1, entry 4). However,
these changes did not improve the yield and instead decreased
the selectivity. We also explored modifying the palladium
catalyst with various classes of ligands and found that
Scheme 2
Table 1 The discovery and initial optimization of monodefluorination reaction
Entrya
Catalyst
Base
2
3
Conversion
1
Pd(OAc)2 1 mol%
Pd(OAc)2 1 mol%
Pd(OAc)2 1 mol% & SIPrCuCl 1 mol%
Pd(OAc)2 3 mol% & SIPrCuCl 20 mol%
Pd(OAc)2 3 mol% & SIPrCuCl 20 mol% & 2-pyridone 5 mol%
KOt-Bu
94%
8%
12%
15%
3%
0%
7%
52%
51%
56%
100%
—
90%
100%
100%
2b
3b
4c
5c
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
a
b
c
Reaction conditions: Ph3SiH (4 equiv.), base (5 equiv.), DMF, 25 ꢁC, 1 h. Reaction performed at 45 ꢁC for 11 h then 60 ꢁC for 17 h. Reaction
performed at 45 ꢁC for 2 h, followed by 60 ꢁC for 17 h. Ar ¼ 4-(4-CH3Ph)C6H4; SIPr ¼ N,N0-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene; DMF
¼ N,N-dimethylformamide. All yields were determined by GC using an internal standard.
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Scheme 4 a) The effect of Brønsted acid b) Deuterium incorporation
studies
Scheme 3 Structure of intermediate X.
ArCF2H occurs through two independent reaction pathways,
and that ArCF2H and intermediate X are not intermediates in
the formation of ArCH3 (Scheme 2). Encouragingly, this nding
suggested that, at least in principle, high yields of ArCF2H can
be obtained with high selectivity.
the beginning of the reaction resulted in signicantly lower
yields.
To gain more information about the mechanism of decar-
bonylation and the role of the acid we performed isotope
labeling experiments. We found that the hydrogen atom in
ArCF2H 3 is derived from tert-butanol, and not from the silane
or from DMF (via intermediate X) (Scheme 4b) (see ESI for
details†). Based on these results, we favor the mechanism of
decarbonylation that involves a diuorobenzyl anion interme-
diate, akin to the haloform reaction. It is interesting to note that
the presence of the two intermediates (intermediate X and
diuorobenzyl anion) in this transformation provides a great
opportunity for the development of other transformations of
ArCF3.
Finally, we were interested in the fate of the uoride removed
from the ArCF3 and the mechanism of C–F activation. In a crude
reaction mixture we were not able to identify any silyl uoride,
which we expected to be the major byproduct of the reaction.
Instead, the only uoride-containing byproduct was KF. In
a control experiment, we found that Ph3SiF reacts with KOt-Bu
under the reaction conditions to produce KF and Ph3SiOt-Bu,
which further complicates interpretation of our ndings in the
context of the mechanism of the C–F activation.
The general understanding of the catalytic C–F activation by
transition metals suggest that ArCF2H would be more reactive
than ArCF3.21,39 However, in our reaction, we found that the
opposite is true. With 4-(4-MePh)C6H4CF2H as the substrate,
only ꢂ36% conversion is achieved at the time necessary for the
full conversion of ArCF3 1 (2 h at 45 ꢁC) (Scheme 5). One
mechanistic hypothesis that accounts for this unusual order of
reactivity (ArCF3 > ArCF2H) is C–F activation by a single electron
transfer: ArCF3 are better electron acceptors than ArCF2H,29
Our next goal was to determine the structure of intermediate
X. The analysis of the reaction mixture by mass spectrometry
suggested aldehyde 4 as the intermediate (Scheme 3). Further-
more, a reaction performed in DMF-d7 solvent resulted in the
formation of the mono-deuterated intermediate (mass
increased by 1 amu), indicating that the formyl group of
ArCF2CHO is likely derived from DMF. From the reaction
mixture containing intermediate X as the major species, we
were also able to isolate the 2,4-dinitrophenyl hydrazone of 4-(4-
MePh)C6H4CF2CHO (5) in 50% yield and characterize it by X-ray
crystallography (Scheme 3). On the other hand, attempts to
establish the presence of the aldehyde in the reaction mixture
by in situ methods were not successful.
1
For example, in situ analysis of the reaction mixture by H
and 13C NMR indicated no presence of ArCF2CHO. Further-
more, a signicant amount of the aldehyde could be identied
in the mass spectrum only if the sample was exposed to air and
silica gel. Overall, these results are consistent with the idea that
intermediate X is a hemiacetal or a hemiaminal of ArCF2CHO 4,
or a silylated version of the two, and that the aldehyde is
revealed only in the presence of a protic acid (MeOH or
moisture).
Based on the hypothesis that intermediate X is a silylated
hemiacetal or a hemiaminal, we speculated that the relatively
slow conversion of intermediate X to the aldehyde before
decarbonylation to the diuoromethyl arene may be respon-
sible for the low yield of the desired product. We reasoned that
decomposition of the intermediate could be facilitated by the
presence of a mild Brønsted acid. Indeed, we found that if 1
equivalent of tert-butanol was added to the reaction mixture
aer full conversion of the 4-(4-MePh)C6H4CF3 is achieved,
there was a dramatic increase in both the rate of the reaction
and in the yield of ArCF2H. The complete conversion of inter-
mediate X was achieved in 2 hours at 60 ꢁC, and ArCF2H 3 was
obtained in 95% yield (Scheme 4). Similar results can be
accomplished using phenol as an acid. Addition of an acid at
Scheme 5 C–F activation of ArCF2H.
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although the difference in energy of s*C–F orbitals is oen too
The optimized reaction conditions shown in Table 2, were
small to allow good selectivity.40,41 This mechanism would also used in mono-reduction of several triuoromethyl arenes. We
explain why intermediate X is resistant to further reduction. found that the reaction can be accomplished in the presence of
Furthermore, mixtures of silanes and alkoxides have previously amines, ethers, and acetals with several biphenyl and aryl
been implicated in single electron chemistry.42,43 However, it is substrates. Reducible groups, such as aryl halides, nitro arenes,
important to note that the presence of transition metal catalysts or nitriles are reduced under the reaction conditions. ortho-
is essential for C–F activation. In the absence of transition Substituted triuoromethyl arenes provided low yields of the
metals, we can fully recover the starting material, in agreement desired products.
with the observations made by Grubbs and Stoltz.43
Aer exploring the mechanism of the mono-deuorination
reaction, we turned our attention to further the reaction opti-
Conclusions
mization and the exploration of the substrate scope. In the We have discovered a combination of palladium and copper
process, we found that SIPrCuCl could be replaced by signi- catalysts that allows selective activation of a single C–F bond in
cantly less expensive and commercially available CuF2 or CuBr, triuoromethyl arenes under relatively mild conditions. This
with CuF2 generally providing superior selectivity. Other cop- discovery allowed the development of a method for selective
per(I) and copper(II) salts gave signicantly lower yields of the reduction of ArCF3 to ArCHF2. More importantly, the unique
desired product and/or signicantly lower selectivity. We also mechanism of the reaction and the unusual source of the
found that consistently better selectivity could be obtained selectivity provide new opportunities for the development of
using KOSiMe3 instead of NaOt-Bu.
useful transformations based on selective C–F activation.
Acknowledgements
Table 2 Optimized reaction conditions and substrate scope
Financial support by NSF (NSF CAREER award #1254636) is
gratefully acknowledged. We gratefully acknowledge Sarah E.
Flowers for assistance with X-ray crystallography.
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