Palladium(III)-catalyzed fluorination of arylboronic acid derivatives

Article abstract of DOI:10.1021/ja405919z

A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivatives is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd(III) intermediate that has been isolated and characterized.

Full text of DOI:10.1021/ja405919z

Communication
pubs.acs.org/JACS
Palladium(III)-Catalyzed Fluorination of Arylboronic Acid Derivatives
Anthony R. Mazzotti,‡ Michael G. Campbell,‡ Pingping Tang, Jennifer M. Murphy, and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
S
* Supporting Information
Scheme 1. Catalytic Fluorination of Aryl Trifluoroborates and
Isolated Pd(III) Intermediate 2
a
ABSTRACT: A practical, palladium-catalyzed synthesis of
aryl fluorides from arylboronic acid derivatives is
presented. The reaction is operationally simple and
amenable to multigram-scale synthesis. Evaluation of the
reaction mechanism suggests a single-electron-transfer
pathway, involving a Pd(III) intermediate that has been
isolated and characterized.
n the past decade there has been an increase in the number of
available methods for the installation of fluorine and fluorine-
I
containing functional groups into organic molecules.1 However,
the development of practical carbon−fluorine bond-forming
reactions to provide aryl fluorides still remains as one of the most
challenging transformations in the field of fluorination.1 In this
Communication, we report a palladium-catalyzed fluorination of
arylboronic acid derivatives, which allows for an operationally
simple, multigram-scale synthesis of functionalized aryl fluorides.
A metal-catalyzed fluorination of arylboronic acid derivatives has
not previously been reported. Kinetic studies suggest a
mechanism distinct from other known arene fluorination
reactions, which proceeds through a single-electron-transfer
(SET) pathway without the formation of organopalladium
species, and involving an unusual Pd(III) intermediate (2) that
has been isolated and characterized (Scheme 1).
a
terpy = 2,2′:6′,2″-terpyridine.
reported by Hartwig,6 and silver-mediated fluorination reactions
have been developed for aryl stannanes, aryl silanes, and
arylboronic acids.7 There are several other metal-mediated
fluorination reactions of arylboronic acid derivatives, using either
palladium8a or copper.8b,c Further development of the reported
metal-mediated reactions to use only catalytic quantities of the
transition metal has remained difficult. For arylboronic acid
derivatives, slow transmetalation of the arene from boron to the
transition metal complex is frequently a hurdle to achieving C−F
bond-forming catalysis.7c,8a
Herein we describe a palladium-catalyzed fluorination of
arylboronic acid derivatives, using terpyridyl Pd(II) complex 1 as
a precatalyst (Scheme 1). We propose a mechanism that
proceeds without the formation of organopalladium intermedi-
ates, which circumvents the problem of transmetalation from the
arylboron reagent. Complex 1 has been prepared in one step
from Pd(OAc)2, terpyridine (terpy), and HBF4 on decagram
scale, and all reagents used in the catalytic fluorination reaction
including 1 are stable to air and moisture. The reaction can be
performed in an open flask, and is effective for milligram to at
least multigram-scale synthesis of aryl fluorides, which are readily
isolated. Inseparable side products from protodeborylation were
not observed for the majority of substrates, which may also be
due in part to a mechanism that does not involve organo-
palladium intermediates. Protodeborylation is a common
problem for fluorination reactions of arylboronic acid deriva-
tives.8b,c
To date, only two catalytic reactions have been reported that
provide a general route to functionalized aryl fluorides:
Buchwald’s palladium-catalyzed fluorination of aryl triflates,2
and our group’s silver-catalyzed fluorination of aryl stannanes.3
Our silver-catalyzed reaction requires the preparation and use of
toxic aryl stannanes. The palladium-catalyzed nucleophilic
fluorination uses more readily available aryl triflates; it currently
requires dried fluoride salts and can give mixtures of constitu-
tional isomers for some substrates due to competing pathways in
addition to C−F reductive elimination. Work toward catalytic
C−H fluorination has been reported by the groups of Groves,4a
Sanford,4b,c and Yu.4d,e Direct C−H fluorination is ideal from a
perspective of step- and atom-economy, but the development of
catalysts that provide selectivity for a broad range of substrates
remains challenging.
There are a handful of modern stoichiometric arene
fluorination reactions. On gram and smaller scales, deoxyfluori-
nation with PhenoFluor5 is in our opinion currently the most
practical method to obtain a large variety of aryl fluorides, but it
requires stoichiometric amounts of PhenoFluor. Metal-mediated
procedures have been developed for a variety of arene precursors,
but frequently require superstoichiometric amounts of transition
metal. A copper-mediated fluorination of aryl iodides was
Received: June 12, 2013
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
a
a
Table 1. Fluorination of Aryl Trifluoroborates
Table 2. Effectiveness of Other Palladium Precatalysts
[Pd]
additive
yield (%)
1
2
none
none
96
95
95
[Pd(MeCN)4][BF4]2
Pd(OAc)2
none
b
NaBF4 (2.0 equiv)
NaBF4 (1.0 equiv)
91
Pd(O2CCF3)2
91
a
2 mol% [Pd] and 4 mol% terpy were used. Yields refer to isolated,
b
purified material. 5 mol% Pd(OAc)2 and 10 mol% terpy were used.
higher yields for precatalysts with coordinating anions such as
acetate. Palladium salts with halide anions were not suitable
precatalysts for the fluorination reaction. Ultimately, we found 1
to be the most convenient precatalyst because no additive was
needed, and due to its robust stability toward air and moisture as
compared to [Pd(MeCN)4][BF4]2. Complex 1 can be stored on
the benchtop under ambient conditions without observable
decomposition or decrease in catalytic reactivity for at least 6
months.
To highlight the reaction’s practical utility, we have
demonstrated that other common arylboron reagents are viable
substrates. In situ formation of aryl trifluoroborates via addition
of a mixture of NaF and KHF2 allowed for efficient fluorination of
pinacol boronic esters and arylboronic acids (eqs 1 and 2). The
ability to directly use a variety of arylboronic acid derivatives,
without the need for prior isolation of the aryl trifluoroborate,
allows for fluorination of a greater range of starting materials.
a
Yields refer to isolated material of ≥98% purity unless otherwise
b
c
noted. No NaF was used. 5 mol% 1 and 10 mol% terpy were used.
d
9% of a mixture of constitutional isomers (ortho- and meta-
fluorobenzamide).
As shown in Table 1, a wide variety of aryl trifluoroborates can
be fluorinated, including both electron-rich and electron-poor
arenes. DMF was found to be the optimal solvent for most
electron-rich and electron-neutral arenes, while acetonitrile
typically provided higher yields for arenes with electron-
withdrawing substituents. Ketones, primary amides, carboxylic
acids, esters, alcohols, basic heterocycles, aryl bromides, and
ortho,ortho′-disubstitution are tolerated in the reaction.
Competing formation of constitutional isomers is a challenge
for metal-catalyzed fluorination reactions.2 Such impurities are
usually difficult to separate from the desired aryl fluoride product.
The majority of the aryl fluorides shown in Table 1 were isolated
cleanly, with ≥98% purity. In particular, electron-rich aryl
trifluoroborates generally did not react to form inseparable side
products. Substrates with electron-withdrawing substituents are
more likely to give constitutional isomers and difluorinated
products along with the expected aryl fluoride product (typically
≤10%): substrate 3k is a representative example, which reacts to
form 4k along with 9% of ortho- and meta-fluorobenzamide.
Other electron-poor substrates such as 3c provided clean isolated
product. The Pd-catalyzed fluorination reaction is ineffective for
fluorination of heterocycles, and arenes bearing methoxy
substituents gave significant amounts of side products resulting
from demethylation.
We observed that MIDA esters of electron-rich arylboronic
acids can also undergo Pd-catalyzed fluorination, albeit in lower
yield and requiring a larger amount of Selectfluor reagent (Air
Products and Chemicals, Inc.) (eq 3). No aryl fluoride product
was obtained when either NaF or KHF2 was added, suggesting
that fluorination proceeds without formation of the aryl
trifluoroborate. MIDA esters of electron-poor arylboronic acids
did not afford product. The direct fluorination of MIDA
boronates, in the absence of exogenous fluoride anion, indicates
a mechanism in which the fluorine atom involved in C−F bond
formation is derived from Selectfluor, rather than added fluoride
anion.
A variety of commercially available Pd(II) salts can be used in
the fluorination reaction, as shown in Table 2. In general,
palladium salts with less coordinating anions gave the highest
yields. Anion metathesis using NaBF4 as an additive resulted in
We propose that the Pd-catalyzed fluorination reaction
proceeds via an outer-sphere pathway, involving an unusual
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Journal of the American Chemical Society
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Scheme 2. Proposed Mechanism for Pd-Catalyzed Fluorination, Synthesis and X-ray Structure of Pd(III) Intermediate 2, and DFT
a
Calculated Structure of Pd(II) Intermediate 5
a
terpy = 2,2′:6′,2″-terpyridine; Solv = solvent (DMF or MeCN). See Supporting Information for details of DFT calculations. X-ray structure of 2 is
shown with 50% probability ellipsoids; H-atoms, counteranions, and solvent molecules omitted for clarity.
mononuclear Pd(III) intermediate. A mechanism that is
consistent with the experimental data, as described below, is
shown in Scheme 2: first, turnover-limiting oxidation of a bis-
terpyridyl Pd(II) complex (5) by Selectfluor affords Pd(III) 2
and a Selectfluor radical cation; F• transfer from the Selectfluor
radical cation to an aryl trifluoroborate forms the C−F bond and
generates a delocalized radical; finally, SET from the radical to 2
regenerates 5, and provides a delocalized cation, which converts
to the aryl fluoride with loss of BF3. The generated BF3 can react
with fluoride anion or adventitious water, which may be why the
addition of one equivalent of NaF typically increases the yield of
aryl fluoride. Complexes of palladium in the +III oxidation state
are uncommon, and have only recently been identified as
relevant intermediates in organic and organometallic reactions.9
Aryl fluoride formation displayed a well-behaved kinetic
profile throughout the course of the catalytic reaction, and no
induction period was observed. Therefore, we were able to
experimentally determine the rate law using initial rate kinetics,
by monitoring aryl fluoride formation via 19F NMR spectroscopy.
The reaction displays first-order kinetic dependence on the
palladium catalyst, saturation kinetics with respect to terpyridine,
zero-order dependence on aryl trifluoroborate, and a non-integer
kinetic order of 1.4 with respect to Selectfluor. The saturation
crystallization afforded red needles of Pd(III) complex 2 in 62%
yield. The structure of 2 was determined by X-ray crystallography
(Scheme 2) and exhibits a Jahn−Teller distorted octahedral
geometry. The identity of 2 in MeCN solutions was confirmed by
EPR spectroscopy (g = 2.09 at 77 K), magnetic susceptibility, and
UV−vis/NIR spectroscopy. The Jahn−Teller distorted octahe-
dral geometry and the metric parameters of the terpyridine
ligands are consistent with a d7 configuration at Pd with an
2
unpaired electron in a dz -based orbital, rather than a ligand-
centered radical, which is also supported by the UV−vis/NIR
data and DFT calculations. In the solid state, 2 is stable for
months under ambient conditions. Pd(III) complex 2 is a
chemically competent catalyst in the fluorination reaction, and
was not observed to react with aryl trifluoroborates in the
absence of Selectfluor, consistent with the mechanism shown in
Scheme 2. Additionally, 2 was not observed to react further when
treated with additional Selectfluor, suggesting that a Pd(IV)
intermediate is not accessible under the reaction conditions.
The structure of the initial complex formed by 1 and
terpyridine, Pd(II) 5, is predicted to have a pseudo-octahedral
geometry, which is supported by DFT calculations. The
2
calculated HOMO of 5, shown in Scheme 2, is primarily of dz
parentage with respect to palladium and antibonding between
palladium and the apical pyridyl ligands. Removal of one electron
from the HOMO results in the Jahn−Teller distorted structure
displayed by 2. Selectfluor’s ability to act as a single-electron
oxidant has been supported through a combination of
experimental and theoretical studies.10 Electrochemical measure-
ments show that oxidation of Pd(II) 5 to Pd(III) 2 does not
proceed by outer-sphere SET, which suggests the formation of an
intermediate adduct between 5 and Selectfluor. The formation of
1
behavior observed for terpyridine, along with in situ H NMR
spectroscopy of the reaction mixture, indicates a catalyst resting
state consisting of an off-cycle equilibrium between bis-terpyridyl
Pd(II) complex 5 and a terpyridyl Pd(II) solvento complex (e.g.,
1). In DMF, the equilibrium of 5 with 1 and free terpyridine is
rapid, with a measured binding constant Ka = 3 × 103. The non-
integer kinetic order experimentally determined for Selectfluor
suggests that Selectfluor also participates in a rapid equilibrium
with 5, prior to turnover-limiting oxidation (vide infra).
No reaction was observed between precatalyst 1 and aryl
trifluoroborates in the presence or absence of exogenous
terpyridine ligand, and less than 5% background reaction was
observed between Selectfluor and the evaluated aryl trifluor-
oborates. When 1 was treated with one equivalent of terpyridine,
followed by one equivalent of Selectfluor, a color change from
orange to deep red occurred. The color persisted in MeCN, and
Scheme 3. Isotopic Labeling Experiment
C
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Journal of the American Chemical Society
Communication
Notes
such an adduct is also consistent with the non-integer kinetic
order measured for Selectfluor (1.4). The specific mode of
interaction between the palladium catalyst and Selectfluor is
unclear at this point, but is likely critical to the success of the
fluorination reaction; we speculate that the fluxional binding of
terpyridine in 5 is important to the observed reactivity (see
Supporting Information).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank J. R. Brandt for helpful discussions and assistance with
binding constant analysis, C. N. Neumann for performing 18F
experiments, NIH-NIGMS (GM088237) and NSF (CHE-
0952753) for funding, the NSF for a graduate fellowship for
A.R.M., and the DOE SCGF for a graduate fellowship for M.G.C.
The observation of turnover-limiting oxidation during
catalysis prevents us from studying the C−F bond-forming
step via kinetic analysis. We postulate that C−F bond formation
occurs via one of two pathways after initial oxidation of 5 by
Selectfluor: (1) direct F• transfer to the aryl trifluoroborate or (2)
SET from the aryl trifluoroborate to the Selectfluor radical cation,
to afford a radical cation, followed by nucleophilic attack of
fluoride. In both cases, one-electron oxidation of the resulting
radical by Pd(III) 2, as shown in Scheme 2, would afford product
and regenerate Pd(II) 5. We carried out an isotopic labeling
experiment to distinguish between the two pathways, in which
the fluorination reaction was performed in the presence of
exogenous [18F]fluoride. Aryl fluoride formation proceeded in
72% yield, but no incorporation of the 18F label was observed
(Scheme 3). While the SET/fluoride attack pathway via a tight
solvent cage mechanism cannot be rigorously excluded, the
absence of 18F incorporation suggests the F• transfer pathway for
C−F bond formation.
In previously reported metal-mediated or -catalyzed arene
fluorination reactions, including our group’s palladium- and
silver-mediated fluorination of arylboronic acids, carbon−
fluorine bond formation is proposed to occur via reductive
elimination from an aryl−metal fluoride complex.11 The
palladium-catalyzed fluorination reaction presented here is
unusual in that it seems to proceed without the formation of
organopalladium intermediates, yet provides high levels of
selectivity.
In conclusion, we have reported the first metal-catalyzed
fluorination of arylboronic acid derivatives. The reaction
proceeds under mild conditions, is tolerant toward moisture
and air, and is amenable to multigram-scale synthesis of
functionalized aryl fluorides. We propose a single-electron-
transfer mechanism involving a well-defined Pd(III) intermedi-
ate. This reaction provides a level of practicality and operational
simplicity not previously achieved by metal-catalyzed or
-mediated arene fluorination reactions, and does not generally
afford side products from protodemetalation, a common
problem for the synthesis of aryl fluorides. Drawbacks of the
reaction include the inability to fluorinate heterocycles and the
formation of constitutional isomers for some electron-poor
substrates.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, spectroscopic data for all new
compounds, details of DFT calculations, and crystallographic
data for 1, 2, S1, and S2 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
ritter@chemistry.harvard.edu
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Author Contributions
‡A.R.M. and M.G.C. contributed equally.
D
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