Palladium-Catalyzed Carbon–Fluorine and Carbon–Hydrogen Bond Alumination of Fluoroarenes and Heteroarenes

Article abstract of DOI:10.1002/anie.201706378

Through serendipitous discovery, a palladium bis(phosphine) complex was identified as a catalyst for the selective transformation of sp²C?F and sp²C?H bonds of fluoroarenes and heteroarenes to sp²C?Al bonds (19 examples, 1

Full text of DOI:10.1002/anie.201706378

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Accepted Article
Title: Palladium-Catalysed Carbon-Fluorine and Carbon-Hydrogen
Bond Alumination of Fluoroarenes and Heteroarenes
Authors: Mark Richard Crimmin, Wenyi Chen, Thomas Hooper,
Andrew White, and Jamues Ng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706378
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Palladium-Catalysed Carbon–Fluorine and Carbon–Hydrogen
Bond Alumination of Fluoroarenes and Heteroarenes
Wenyi Chen,‡ Thomas N. Hooper,‡ Jamues Ng, Andrew J. P. White, Mark R. Crimmin*
catalyst, this reagent effects the competitive hydrodefluorination
and C–F alumination of fluoroarenes. In all cases reported to
date, however, the selectivity for the more desirable C–F
alumination reaction over hydrodefluorination is low (<2:1).[27,28]
Abstract: Through serendipitous discovery,
a palladium
bis(phosphine) complex was identified as a catalyst for the
selective transformation of sp2C–F and sp2C–H bonds of
fluoroarenes and heteroarenes to sp2C–Al bonds (19 examples,
1 mol% Pd loading). The carbon–fluorine bond functionalization
reaction is highly selective for the formation of organoaluminum
products in preference to hydrodefluorination products
(selectivity = 4.4:1 to 27:1). Evidence is presented for a tandem
catalytic process in which hydrodefluorination is followed by
sp2C–H alumination.
Figure 1. Alumination of fluoroarenes.
Due to the large number of pharmaceuticals, agrochemicals and
organic materials that contain at least one fluorine atom,[1-3] the
selective functionalization of carbon–fluorine bonds remains an
important challenge in contemporary catalysis.[4,5] Perfluorinated
hydrocarbons are readily available at low cost through the
Fowler process.[6] Many groups have promoted the idea of the
selective defluorination of heavily fluorinated building blocks as
a synthetic entry point to fluorine contain molecules.[7] The vast
One strategy to circumvent the formation of hydrodefluorination
products would be to develop a catalyst that was capable of
sp2C–H alumination. This catalyst could cycle hydrofluoroarenes
back to the desired organometallic products and correct the
undesired hydrodefluorination pathway (Figure 1). There is
limited precedent for this approach with boron reagents. Braun
and coworkers have demonstrated stepwise hydrodefluorination
and C–H borylation as a means to achieve a net C–F borylation
of pentafluoropyridine with HBpin catalyzed by [Rh(PEt3)3(H)]
(HBpin = pinacolborane). This reaction is extremely slow and
proceeds over 21 days ultimately reaching a TON of 18.[29]
In this communication, we report commercially available
[Pd(PCy3)2] as a catalyst for selective sp2C–F and sp2C–H
alumination of fluoroarenes and heteroarenes with 1. Reactions
proceed at low catalyst loadings and, depending on the
substitution pattern of the fluoroarene, with both para- and meta-
regioselectivity.
Palladium based catalysts for C–F alumination were
developed following identification of catalytically active metal
impurity. During a substrate screen with Zr-based catalysts,
improved selectivity for sp2C–Al bond formation was observed
with the non-volatile biaryl 2a (Figure 2) compared to reactions
employing pentafluorobenzene. The data, however, were not
reproducible across different batches of 2a. Control reactions
revealed that not only was the Zr-catalyst unnecessary but the
reaction was dependent upon the impurity profile of 2a (Figure 2,
substrate A). The biaryl 2a was synthesised by a Pd-catalysed
cross-coupling, ICP-OES analysis of samples purified by hot
filtration and recrystallization revealed contamination with 0.4%
Pd. Trace metal contamination (below the detection limit of the
majority
of
studies,
however,
have
focused
on
hydrodefluorination (HDF) and cross-coupling protocols.[8-13]
These reactions have their limitations as the newly formed C–H
and C–C bonds have narrow reactivity. Only in the past few
years have methods emerged to form reactive building blocks
[14-18]
from unreactive fluorocarbons.
For example, Rh- and Ni-
based catalysts have been reported for the C–F borylation of
fluoroarenes using diboranes as stoichiometric reagents.[19-21]
We, and others, have shown that low-valent main group
reagents, including Al(I),[22,23] Si(II),[24] Ge(II),[25] and Mg(I)–Mg(I)
species,[26] can achieve C–F activation of both sp2C–F and
sp3C–F bonds under mild conditions in the absence of catalyst.
As a complementary approach to the low-valent, chemistry
we have been interested in reactions of the β-diketiminate
stabilized aluminium dihydride 1 with fluoroarenes (Figure
1).[27,28] The advantage of using 1 over Al(I) precursors is its ease
of preparation on scale from LiAlH4.[27] In the presence of a
[a]
Ms Wenyi Chen, Dr. Tom Hooper, Mr Jamues Ng, Dr. Andrew. J. P.
White, Dr. Mark R. Crimmin
Department of Chemistry
Imperial College London, South Kensington, London, SW7 2AZ, UK.
E-mail: m.crimmin@imperial.ac.uk
‡
These authors contributed equally
Supporting information for this article is given via a link at the end of the
document. Experimental procedures, details of the DFT studies, single
crystal X-ray data and multinuclear NMR spectra (PDF). X-ray
crystallographic data (.cif). Editable NMR data are available as .mnova
and .mnpub via a repository DOI: 10.14469/hpc/2663
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10.1002/anie.201706378
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ICP-OES experiment) could be removed by adding at least one
chromatography step.
Figure 3. para-Selective C–F alumination of fluoroarenes.
The data suggest that residual Pd-contaminants are
responsible for the selective sp2C–F alumination reaction. The
hypothesis was confirmed by directly exposing the crude
samples of 2a to the catalytic conditions (Figure 2, substrate B).
Ultimately [Pd(PCy3)2] was identified as
a
convenient
commercially available precatalyst for the reaction (Figure 2,
substrate C). Employing palladium on charcoal, [PdCl2(PPh3)2],
or [Pd(PPh3)4] as precatalysts failed to give the desired products
(see supporting information, Table S2). A negative Hg(0) drop
experiment suggested that heterogeneous catalysis does not
play a role in the chemical transformation.
Figure 2. Identification of an impurity Pd catalyst.
Upon modification of the substrate to a 2,3,4,5-tetrafluorobiaryl,
the meta-selective C–F alumination pathway became dominant
(Figure 4). In these cases, the selectivities for C–Al bond
formation were lower (>4.4:1). Similar selectivities have been
observed during catalytic C–H borylation and assigned to the
steric accessibility of the para- and meta-C–H bonds of mono-
susbtituted arenes.[30]
Figure 4. meta-Selective C–F alumination of fluoroarenes.
The scope of the reaction was investigated using the optimized
conditions (1.2 equiv. of 1, 1 mol% [Pd(PCy3)2], 100°C in C6H6)
and a series of biaryls with electronically distinct substituents and
differing fluorine content were investigated. Pentafluorobiaryl
substrates yielded para-functionalised aluminium complexes as
the major product accompanied by minor amounts of
hydrodefluorination (Figure 3). The reaction tolerates CF3, OMe
and NMe2 groups on the remote aromatic ring and selectivities
for C–Al bond formation are high across the series (>11:1). The
aluminium products were assigned based on comparison of the
19F NMR data with analogues generated from oxidative addition
of substrates to Al(I) (see supporting information). Further
evidence for the structural assignment and validation of the in
situ yields was achieved by protic (methanol) work-up followed
by isolation of the hydrofluoroarenes. In addition to the expected
major para-HDF products, trace amounts of meta-HDF and
meta-para-disubstituted di-HDF products were observed. While
the parent organoaluminium species that give rise to these minor
products could not be assigned due to their low concentration, it
was clear from 19F NMR spectroscopic data that the HDF
products are not present in significant amounts prior to methanol
work up.
To test the hypothesis that C–F functionalization could occur by
sequential HDF and C–H activation, we also investigated biaryl
substrates with accessible C–H bonds in the para- and meta-
positions of the fluorinated ring. Selective C–H alumination was
achieved with 2,3,5,6-tetrafluorobiaryls (Figure 5).[31] Mixtures of
1 and [Pd(PCy3)2] are an extremely active catalyst system for this
reaction and the TOF reached ~1000 h-1 at 100 oC for the
conversion of 2k to 3k. Despite keen interest in the
functionalization of C–H bonds with boranes,[30] silanes,[32] and
stannanes,[33] corresponding alumination pathways are
extremely rare. Existing examples rely on the use of specialist
aluminium bases.[34-37] To the best of our knowledge, the
dehydrocoupling of sp2C–H and Al–H bonds represents a new
catalytic transformation.
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be isolated provided the reaction time was shortened and
temperature lowered relative to the standard conditions (1 h, 80
oC). At longer reaction times this species cleanly converted to
the previously reported C–O bond activation product.[38-39]
Tetrahydrofuran and 2,5-dimethylfuran did not react under the
optimised conditions, while benzoxazoles proved susceptible to
reduction and ring-opening by hydride attack with 1 in the
absence of a catalyst. X-ray crystal structures of several of the
products show little distortion of the 5-membered rings upon C–
H activation and confirmed the structural assignment (Figure 7).
The independent rates of C–F and C–H bond activation
were compared. The reactions of 2d and 2k with 1 were
monitored as a function of time (1 mol% catalyst, 50 °C). The C–
H bond reacts significantly faster than the C–F bond. Initial rate
data were fitted to first order kinetics giving rate constants of kC–
Figure 5. C–H alumination of fluoroarenes.
Having observed sp2C–H bond alumination of fluoroarenes, the
substrate scope was expanded to include non-fluorinated
aromatics. A range of heteroarenes (2m-s) including furans and
N-methylindole were reacted under similar reaction conditions to
produce the aluminated complexes (3m-s) in good yield. In all
cases, the reactions were selective for sp2C–H bonds over
sp3C–H bonds and for the 2-position of the heteroarene. Yields
calculated by NMR spectroscopy were found to be >78% and the
aluminated products could be isolated by crystallization in
modest yields (Figure 6). Control reactions between 2k-p with 1
in the absence of catalyst did not result in C–H alumination.
= 0.002 h-1 and kC–H = 0.166 h-1 (see supporting information).
F
In combination with the observation of small amounts of
hydrofluoroarenes in catalytic preparations with 2a-j, these data
suggest that C–F
alumination
proceeds
by
slow
hydrodefluorination followed by fast C–H alumination.
To probe the mechanism of hydrodefluorination,
[Pd(PCy3)2] was added to the fluorobiaryl 2a but no reaction was
observed, even after prolonged heating (18 h, 80 °C) or in the
presence of the β-diketiminate aluminum difluoride, [Al]-F2.[40] It
is possible that oxidative addition of C–F bonds to [Pd(PCy3)2] is
reversible and for 2a the equilibrium lies toward the Pd(0)
species. Braun and co-workers have shown that
pentafluoropyridine will undergo oxidative addition to
[Pd(PCy3)2].[41-43] Reproducing this reaction allowed clean
generation of trans-[Pd(F)(4-C5F4N)(PCy3)2]. Subsequent
reaction of trans-[Pd(F)(4-C5F4N)(PCy3)2] with 1 eq. of 1 at 25 oC
Figure 6. C–H alumination of heteroarenes.
resulted
in
immediate
formation
of
trans-[Pd(H)(4-C5F4N)(PCy3)2] along with [Al]-HF and [Al]-F2
which were identified by comparison of the NMR resonances to
the known literature values.[27] trans-[Pd(H)(4-C5F4N)(PCy3)2]
undergoes reductive elimination upon heating with a further 5
equiv.
of
pentafluoropyridine,
generating
2,3,5,6-
tetrafluoropyridine (Figure 8). Hence, each of the steps of the
catalytic cycle for hydrodefluorination has been experimentally
verified.
A similar reaction of 1 with benzofuran resulted in initial C–H
activation to produce the kinetic reaction product 3o that could
Figure 7. Selected crystal structures. Bond lengths (Å): 3l, Al–C 1.994(3); 3m, 1.970(3); 3p, Al–C 1.956(2).
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298.
Figure 8. Mechanism of hydrodefluorination and reaction to form
aluminated species.
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alumination of the resulting C–H bond (Figure 8).
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Synthesis of 3o by a non-catalytic route (see SI) showed that the
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We are grateful to the European Research Council (FluoroCat:
655474, FluoroFix:677367) and the Royal Society (UF090149).
Johnson Matthey are thanked for generous donation of PdCl2.
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Keywords: C–F activation • C–H activation • alumination •
fluoroarenes • hydrodefluorination
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Entry for the Table of Contents
COMMUNICATION
A palladium catalyst is reported for the
transformation of sp2C–F and sp2C–H
bonds of fluoroarenes and
Wenyi Chen, Thomas N. Hooper,
Jamues Ng, Andrew J. P. White,
Mark R. Crimmin*
heteroarenes into sp2C–Al bonds
Page No. – Page No.
Carbon–Fluorine and Carbon–
Hydrogen Bond Alumination of
Fluoroarenes and Heteroarenes:
Identification of an Impurity
Palladium Catalyst
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