Copper-mediated fluorination of arylboronate esters. Identification of a Copper(III) fluoride complex

Article abstract of DOI:10.1021/ja310909q

A method for the direct conversion of arylboronate esters to aryl fluorides under mild conditions with readily available reagents is reported. Tandem reactions have also been developed for the fluorination of arenes and aryl bromides through arylboronate ester intermediates. Mechanistic studies suggest that this fluorination reaction occurs through facile oxidation of Cu(I) to Cu(III), followed by rate-limiting transmetalation of a bound arylboronate to Cu(III). Fast C-F reductive elimination is proposed to occur from an aryl-copper(III)-fluoride complex. Cu(III) intermediates have been generated independently and identified by NMR spectroscopy and ESI-MS.

Full text of DOI:10.1021/ja310909q

Article
pubs.acs.org/JACS
Copper-Mediated Fluorination of Arylboronate Esters. Identification
of a Copper(III) Fluoride Complex
Patrick S. Fier,† Jingwei Luo,‡ and John F. Hartwig*,†
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Department of Chemistry, University of Victoria, P.O. Box 3065, Victoria, British Columbia V8W 3V6, Canada
S
* Supporting Information
ABSTRACT: A method for the direct conversion of arylboronate esters to
aryl fluorides under mild conditions with readily available reagents is reported.
Tandem reactions have also been developed for the fluorination of arenes and
aryl bromides through arylboronate ester intermediates. Mechanistic studies
suggest that this fluorination reaction occurs through facile oxidation of Cu(I)
to Cu(III), followed by rate-limiting transmetalation of a bound arylboronate to Cu(III). Fast C−F reductive elimination is
proposed to occur from an aryl−copper(III)−fluoride complex. Cu(III) intermediates have been generated independently and
identified by NMR spectroscopy and ESI-MS.
Scheme 2. Transition-Metal-Mediated Aryl Fluorination
INTRODUCTION
■
A wide range of materials and biologically active molecules
contain fluoroarenes. The presence of fluorine atoms in these
arenes often affects the reactivity, solubility, and stability of the
molecule. In medicinal chemistry, a fluorine atom is used to
block metabolic degradation and, thereby, to improve the
efficacy of lead compounds. In addition, fluorinated compounds
enriched in 18F are used as PET-imaging agents in medicine.
However, methods to synthesize aryl fluorides under mild
reaction conditions are limited.
readily available, are nontoxic, are shelf-stable, and often react
under mild conditions with good functional group tolerance.
Moreover, they can be prepared by methods, such as C−H
bond functionalization, that complement methods used to form
aryl iodides and phenols. Finally, reactions of arylboronate
esters can occur with reactivity that is orthogonal to that of aryl
iodides. However, no direct conversion of arylboron reagents to
aryl fluorides has been reported.
To overcome the limitations of classical methods for the
synthesis of aryl fluorides by the Halex1 or Balz−Schieman
reactions (Scheme 1),2 modern methods based on transition-
Scheme 1. Conventional Routes to Fluoroarenes
We report a straightforward copper-mediated fluorination of
arylboronate esters under mild conditions with good substrate
scope. We show that this reaction can be used in tandem with
the borylation of aryl C−H bonds to effect an overall C−H
bond fluorination and that it can be used in tandem with the
borylation of aryl bromides to convert aryl bromides to aryl
fluorides. Mechanistic experiments suggest that the fluorination
of arylboronate esters occurs by initial formation of a cationic
Cu(III) fluoride complex, which was identified spectroscopi-
cally. Stoichiometric reactions of this Cu(III) species show that
it is competent to be an intermediate in the fluorination
process.
metal complexes have been sought (Scheme 2). Aryl triflates
react with CsF in the presence of a palladium catalyst to form
aryl fluorides, but isomeric products are obtained in many
cases.3 Arylstannanes,4 arylsilver,5 arylpalladium,6 and aryl-
nickel7 complexes have been reported to form aryl fluorides,
but the stannanes are toxic, and the silver, palladium, and nickel
complexes must be isolated after synthesis from arylboronic
acids (Ag, Pd) or aryl bromides (Ni). More recently, Ritter and
co-workers reported the direct conversion of phenols to aryl
fluorides with a difluoroimidazoline reagent,8 and we disclosed
the conversion of aryl iodides to aryl fluorides with
(tBuCN)2CuOTf and AgF.9
RESULTS AND DISCUSSION
■
1. Conditions for the Conversion of Arylboronate
Esters to Aryl Fluorides. To develop a method for the
Arylboron reagents are valuable alternative sources of aryl
groups for the synthesis of aryl fluorides because they are
Received: August 29, 2012
© XXXX American Chemical Society
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Table 1. Screen of F+ Reagents for the Fluorination of 1a
conversion of arylboron nucleophiles to aryl fluorides (Scheme
3), we focused initially on the fluorination of pinacol-derived
a
with (tBuCN)2CuOTf and AgF
Scheme 3. Copper-Mediated Fluorination of ArB(OR)2
entry
F+ source
conversion (%)
ArH (%)
ArF (%)
arylboronate esters (ArBPin). Pinacolate esters can be prepared
in quantitative yield by the reaction of boronic acids with
equimolar amounts of pinacol and can be prepared by C−H
bond functionalization and coupling of aromatic electrophiles
with boron reagents.10 ArBPin reagents are more stable to air
and moisture than other arylboronate esters and boronic acids,
and they can be purified by silica gel chromatography. They are
indefinitely stable on the bench. Finally, ArBPin reagents are
inert under many reaction conditions. Thus, the ArBPin can be
carried through a synthetic sequence conveniently without
cleaving the C−B bond.10
1
2
3
4
5
6
7
8
F-TEDA-BF4
F-TEDA-PF6
NFSI
91
100
100
100
100
84
37
73
90
100
87
9
27
26
10
0
[Cl2pyF]OTf
[pyF]OTf
1
[Me3pyF]BF4
[Me3pyF]OTf
[Me3pyF]PF6
[Me3pyF]PF6
[Me3pyF]PF6
56
64
75
24
38
82
13
12
57
39
88
b
9
97
c
10
100
a
Reactions were performed with 0.1 mmol of 1a in 2.0 mL of THF for
18 h. Yields were determined by gas chromatography with 1-bromo-4-
fluorobenzene as an internal standard added after the reaction.
Reactions were performed with KF in place of AgF. Reactions were
A variety of electrophilic fluorine sources (Figure 1) are
commercially available. These reagents vary in their reactivity,
b
c
performed with CsF in place of AgF.
decomposition of the F+ source. Finally, AgF does not react
with Cu(I) to form an unstable CuIF species.12
2. Scope of the Fluorination of Pinacolate Arylboron-
ate Esters. The combination of (tBuCN)2CuOTf, [Me3pyF]-
PF6, and AgF converted a range of arylboronate esters to the
corresponding aryl fluorides, and the scope of this process is
summarized in Table 2. The same reaction conditions were
suitable for the reactions of both electron-rich and electron-
deficient arylboronate esters. Substrates containing esters,
ketones, aldehydes, amides, nitriles, aryl halides, and some
heterocycles underwent fluorination in moderate to good yield.
In addition, the ortho-substituted boronate ester 1g provided 2-
fluorotoluene in 73% yield. The corresponding o-anisylboronic
ester (1s) also gave the aryl fluoride product, but in lower yield.
The amide-containing aryl fluoride 2o was isolated in good
yield on a 0.5 mmol scale from boronate ester 1o. The boron
byproduct in these fluorination reactions is F‑BPin. F‑BPin
undergoes hydrolysis to HO-BPin during aqueous workup and
is easily separated from the aryl fluoride product. The
conditions we developed for the fluorination of pinacolate
esters also induced the fluorination of boronic acids and other
boronic acid derivatives (Table 3).
The major side reaction in the fluorination of arylboronate
esters is protodeborylation to form the corresponding arene.
This side reaction occurs commonly during reactions of
arylboron reagents. The hydrogen atom in this process may
originate from multiple sources, including the solvent or
adventitious water.
To determine the source of the product of protodeboryl-
ation, a deuterium labeling experiment was conducted. The
reaction of 1a under the standard reaction conditions with 2
equiv of added D2O formed the arene side product in 50% yield
with 43% incorporation of deuterium in the arene (eq 1). The
arene side product from the reaction of 1a under the standard
reaction conditions in THF-d8 did not contain deuterium (eq
2). Thus, we suggest that the arene side product in the
fluorination of ArBPin results, in part, from a reaction with
adventitious water.
Figure 1. Electrophilic fluorine (F+) reagents.
solubility, and stability. We tested the reactivity of the pinacol
ester of 4-butylphenylboronic acid (1a) with electrophilic
fluorine sources in the presence of a base and copper source.
The reactions of this arylboronic ester with the sterically
hindered and electron-rich 1-fluoro-2,4,6-trimethylpyridinium
(Me3pyF+) reagent formed the aryl fluoride in higher yields,
when combined with (tBuCN)2CuOTf and AgF,11 than those
conducted with other F+ sources (Table 1). The higher yields
with [Me3pyF]+ reagents than with other F+ sources appear to
result, in part, from a slower rate of heat- and base-induced
decomposition of the F+ source. In addition, ligation of 2,4,6-
trimethylpyridine to copper appeared to be important (vide
infra). The counterion of [Me3pyF]+ affected the yield; the
reactions conducted with [Me3pyF]PF6 occurred in higher
yields than the reactions conducted with [Me3pyF]BF4 and
[Me3pyF]OTf.
Electrophilic fluorine sources are susceptible to base-induced
decomposition. Thus, a base that promotes transmetalation of
the ArBPin without decomposing the F+ source is essential for
high conversion of ArBpin reagents to the corresponding aryl
fluoride. Reactions conducted with a series of alkoxide bases
gave modest yields (10−15%) of the aryl fluoride product in
the presence of (tBuCN)2CuOTf and [Me3pyF]PF6. Reactions
conducted with fluoride bases occurred in yields significantly
higher than those conducted with alkoxide bases. Reactions
conducted with AgF as base occurred in yields significantly
higher than those conducted with other fluoride bases we tested
(Table 1, entries 8−10). We propose that higher yields are
obtained with AgF than with other bases because the low
solubility and low nucleophilicity of AgF prevent it from
promoting transmetalation of the ArBPin to Cu(I) (vide infra).
Also, in contrast to stronger bases, AgF does not lead to the
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Table 2. Fluorination of ArBPin with (tBuCN)2CuOTf and
a
[Me3pyF]PF6
3. Fluorination of Arenes and Aryl Bromides via
Pinacolate Arylboronate Esters. Arylboronate esters can be
prepared by iridium-catalyzed C−H borylation,13 and this
process leads to the borylation at the least hindered C−H bond
of arenes. Our group has shown that Ir-catalyzed C−H
borylation can be used in tandem with reactions of the resulting
ArBPin as a two-step, one-pot route to diversely functionalized
arenes.14 We considered that a similar tandem process could be
used to achieve the fluorination of C−H bonds. Indeed, C−H
borylation with B2Pin2 catalyzed by the combination of
[Ir(COD)OMe]2 and dtbpy provided crude ArBPin inter-
mediates that underwent subsequent copper-mediated fluorin-
ation. The ArBPin formed by C−H borylation could be used
without purification. Conversion of the crude ArBpin to the
corresponding aryl fluoride occurred such that the two-step
process gave a good yield of the aryl fluoride (Table 4). Arenes
a
Table 4. Fluorination of Arenes via C−H Borylation
a
Reactions were performed with 0.1 mmol of 1 to determine yields by
19F NMR spectroscopy with 1-bromo-4-fluorobenzene as an internal
standard added after the reaction. 19F NMR chemical shifts were
b
compared with those of the authentic aryl fluorides. Isolated yield
from a reaction with 0.5 mmol of ArBPin. Reactions were conducted
c
at 80 °C.
a
Table 3. Fluorination of Boronic Acid Derivatives with
Reactions were performed with 0.1 mmol of arene. Yields were
a
(tBuCN)2CuOTf, [Me3pyF]PF6, and AgF
determined by 19F NMR spectroscopy with 1-bromo-4-fluorobenzene
as an internal standard added after the reaction. The borylation
reaction was performed with 1.5% [Ir] and 3.0% dtbpy. The
b
c
borylation reaction was performed with 0.5% [Ir] and 1.0% dtbpy.
d
The fluorination reaction was performed at 80 °C for 18 h.
entry
(OR)2
(OH)2
ArH (%)
ArF (%)
containing electron-donating and electron-withdrawing groups
reacted in comparable yield. Ketones, esters, amides, and aryl
halides were tolerated over the two-step procedure. This
sequence represents a simple strategy for a regioselective C−H
fluorination of arenes.
An alternative method to prepare arylboronate esters is the
borylation of aryl halides catalyzed by transition metals. Thus,
we evaluated whether aryl bromides would react in a one-pot
sequence to convert aryl bromides to aryl fluorides through
ArBPin intermediates. The combination of a simple palladium
precatalyst, B2Pin2, and KOAc15 led to the high conversion of
aryl bromides to ArBPin intermediates under conditions
suitable for the conversion of the ArBPin to the corresponding
1
2
3
4
5
6
5
37
23
60
15
12
45
46
18
0
BF3K
MIDA
catechol
neopentyl glycol
pinacol
70
75
a
Reactions were performed with 0.1 mmol of arylboron in 2.0 mL of
THF for 18 h. Yields were determined by gas chromatography with 1-
bromo-4-fluorobenzene as an internal standard added after the
reaction.
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ArF. The crude mixture from the borylation reaction was
filtered, concentrated, and subjected to the fluorination
conditions described above. Good yields of the aryl fluorides
were obtained over the two-step sequence without purification
of the intermediate ArBPin (Table 5). Because methods for the
direct fluorination of aryl bromides have not been reported, this
two-step strategy provides a unique conversion of aryl bromides
to aryl fluorides.
(eq 4). These results argue against a mechanism involving
initial formation of an arylcopper(I) species.
We also assessed whether arylsilver species are formed in the
reaction. Arylsilver species generated from arylboron reagents
have been shown to react with electrophilic fluorine sources to
provide aryl fluorides.5 However, we did not detect any reaction
of arylboronate 1a with AgF in THF at 50 °C over 18 h.
Furthermore, many of the reactions we conducted between
arylboronates and [Me3pyF]PF6 with other fluoride sources
(KF, CsF) formed aryl fluorides. Reactions conducted with AgF
occurred in higher yield than those with KF and CsF, but the
presence of AgF was not required for the aryl fluoride to form.
Thus, the fluorination of arylboronates with [Me3pyF]PF6 is
unlikely to occur through arylsilver intermediates. Finally, no
aryl fluoride was formed in the absence of copper.
Table 5. Fluorination of Aryl Bromides via Pd-Catalyzed
a
Borylation
To assess the potential that mechanism B of Scheme 4
occurs, we conducted a series of NMR spectroscopic
measurements of the reaction of (tBuCN)2CuOTf with
[Me3pyF]PF6. The 19F NMR spectrum of (tBuCN)2CuOTf
consists of a sharp singlet at −77.7 ppm in THF. [Me3pyF]PF6
is insoluble in THF, and no 19F NMR signals were observed for
a sample of [Me3pyF]PF6 suspended in THF.17 However,
equimolar amounts of (tBuCN)2CuOTf and [Me3pyF]PF6 in
THF generated a colorless, homogeneous solution within 5 min
at room temperature (eq 5). A new species was formed, as
a
Reactions were performed with 0.1 mmol of aryl bromide. Yields
were determined by 19F NMR spectroscopy with 1-bromo-4-
fluorobenzene as an internal standard added after the reaction.
4. Mechanistic Studies on the Fluorination of Aryl-
boronate Esters. The mechanism of the copper-mediated
fluorination of arylboronate esters was studied experimentally.
Two simplified reaction pathways are shown in Scheme 4. One
Scheme 4. Potential Reaction Pathways for the Fluorination
of ArBPin with (tBuCN)2CuOTf and Me3pyF-PF6
1
determined by H and 19F NMR spectroscopic and ESI-MS
measurements. Attempts to isolate this species in pure form
have been unsuccessful. Thus, we characterized this copper
complex in solution.
B. Spectroscopic Characterization of a Cu(III) Fluoride
Intermediate. The 19F NMR spectrum of the reaction between
equimolar amounts of (tBuCN)2CuOTf and [Me3pyF]PF6 in
THF at room temperature consisted of a doublet at −72.0 ppm
due to the PF6 anion (J = 710 Hz), a broad peak at −71.4 ppm
due to the OTf group, and a doublet of doublets at −110.8
ppm (J = 66, 26 Hz) that we propose corresponds to a copper-
bound fluoride. The chemical shift of the triflate peak in the
new complex was 6.3 ppm downfield of the chemical shift of
(tBuCN)2CuOTf, suggesting that the triflate is bound to an
electrophilic site, such as the Cu(III) center in the proposed
product. Fluoride complexes of d8 transition-metal centers
containing weakly donating ligands have not been reported.
The 19F NMR spectra of phosphine-ligated PdII−F complexes
typically contain resonances near −300 ppm. In contrast, the
19F NMR spectra of PtII−F complexes contain signals as far
downfield as −107.6 ppm for trans-[Pt(Ph)(F)(PPh3)2].18 The
19F chemical shifts of alkali-metal fluorides are near −150 ppm.
Thus, the 19F chemical shift of the new copper species at
−110.8 ppm is consistent with that for a fluoride bound to a
cationic Cu(III) site. The sharp, well-resolved peaks in the
NMR spectra argue against the formation of a paramagnetic
Cu(II) species.
pathway (Scheme 4A) begins with transmetalation of the
ArBPin to Cu(I), followed by reaction of the arylcopper(I)
species with [Me3pyF]PF6. The second pathway (Scheme 4B)
begins with formation of a Cu(III) species from reaction of a
Cu(I) complex with an F+ source.
A. Experiments To Distinguish between Pathways A and B
by Initial Formation of Copper(I) Aryl or Copper(III) Fluoride
Intermediates. To evaluate the potential that mechanism A
occurs, we conducted the reaction between the known
phenylcopper16 and [Me3pyF]PF6, AgF, and BuCN in THF.
t
After 18 h at 50 °C no fluorobenzene was detected by 19F
NMR spectroscopy (eq 3). Furthermore, no reaction occurred
We propose that the doublet of doublets pattern of the
fluoride signal (J = 66, 26 Hz) results from scalar coupling
between the fluoride ligand and inequivalent α protons of a
between aryl pinacolboronate 1a and (tBuCN)2CuOTf with
added AgF in the absence of [Me3pyF]PF6 over 18 h at 50 °C
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t
bound THF. This coupling could result from a hydrogen-
bonding interaction or through-space coupling from the
electron pairs on the fluoride and the electron density in the
C−H bonds.19 The coupling constants for the fluoride peak are
similar in magnitude to 1J values from H−F hydrogen
bonds.19,20 Because coupling constants are largely dependent
on the relative locations and electron density of the coupled
atoms, conclusions about the origin of the splitting could not be
made on the basis of the magnitude of the coupling constants
alone. Thus, further experiments were performed to elucidate
the structure of the copper species formed in the reaction
between (tBuCN)2CuOTf and [Me3pyF]PF6.
To assess our proposal that the observed splitting is due to
coupling between the fluoride and a bound THF, we generated
this compound in THF-d8. The 19F NMR spectrum of the
complex generated in THF-d8 contains a singletrather than a
doublet of doubletsfor the fluoride, and this signal lies upfield
(−112.1 ppm) of that for the same peak in the 19F NMR
spectrum of the sample in THF (−110.8 ppm). The magnitude
of this upfield shift is similar to deuterium isotope effects
observed on the chemical shifts of alkyl and vinyl fluorides
containing vicinal deuterium atoms.19,21 These data show that
the fluoride is coupled to a bound THF.
To assess further how THF is coordinated to copper, the
copper complex was generated in 2,2-dideuteriotetrahydrofuran
(see the Supporting Information for the synthesis of 2,2-THF-
d2). If the coupling to fluorine occurred through interactions
with one hydrogen atom on each of carbons 2 and 5, a doublet
in the 19F NMR spectrum would be expected to be observed,
rather than the observed doublet of doublets in fully protiated
THF. However, if coupling occurred to two inequivalent
hydrogen atoms on the same carbon of the bound THF, then
two separate resonances, one a doublet of doublets and one a
singlet, would be expected to be observed in THF-d2 because
both isomers would be present in solution in similar amounts
(Figure 2).
at 1.33 ppm for free BuCN and no signals that could be
attributed to a bound nitrile. The spectrum also contains
resonances at δ 7.49, 2.66, and 2.48 ppm for a 2,4,6-
trimethylpyridine unit. These resonances are located downfield
of those of free 2,4,6-trimethylpyridine (δ 6.75, 2.36, and 2.20
ppm), and this chemical shift implies that 2,4,6-trimethyl-
pyridine is bound to copper.
A
13C NMR spectrum of the copper species was also
obtained. Because the copper species slowly decomposes at
room temperature, the 13C NMR spectrum was acquired at
−60 °C. The 13C NMR spectrum in THF-d8 contained
resonances for a bound Me3py (δ 158.9, 151.3, 124.4, 20.0, and
17.4 ppm), which were distinct from those for free Me3py (δ
158.1, 147.6, 121.3, 24.4, 20.7 ppm). These spectral data agree
with the 1H NMR spectral data indicating that Me3py is ligated
to copper.
An assessment of whether the triflate was free or bound and,
if bound, what binding mode it adopts was conducted by IR
spectroscopy. The IR spectrum of this complex in THF
contained characteristic bands for νas(SO) at 1251 and 1292
cm−1 (see the Supporting Information). The presence of two
vibrations and the 40 cm−1 difference between the two
vibrations is consistent with a bound, κ1 triflate ligand.23
Finally, the product of the reaction of (tBuCN)2CuOTf with
[Me3pyF]PF6 was analyzed by ESI-MS under an inert
atmosphere.24 A 1:1 ratio of (tBuCN)2CuOTf and [Me3pyF]-
PF6 was allowed to react at room temperature, and the solution
was continuously monitored on a Micromass Q-ToF
spectrometer in positive-ion mode over 10 min under an
inert atmosphere with electrospray ionization. The ions
(tBuCN)2Cu+ and [(Me3py)(THF)Cu(F)(OTf)]+ were ob-
served as the major peaks in the mass spectrum (see the
Supporting Information). The signal attributed to the cation
[(Me3py)(THF)Cu(F)(OTf)]+ has a mass to charge ratio of
424.10 for the base peak and the characteristic isotope pattern
of copper (Figure 3). Together, these data indicate that the
species formed from the reaction between (tBuCN)2CuOTf
and [Me3pyF]PF6 has the general formula [(Me3py)(THF)-
Cu(F)(OTf)(PF6)].
Figure 2. Fluoride peaks in the 19F NMR spectrum of the reaction
between (tBuCN)2CuOTf and [Me3pyF]PF6 in THF-d2.
Figure 3. Proposed formula and ESI-MS of the cationic portion of the
Cu(III) fluoride intermediate.
When the copper complex was generated in THF-d2, two
resonances in the 19F NMR spectrum were observed for the
fluorine atom, a doublet of doublets at −110.8 ppm and a
singlet at −112.0 ppm. The two isomers were present in
solution in a ratio of 1.5:1, favoring the isomer with hydrogen−
fluorine coupling by 0.2 kcal/mol.22 The coupling observed in
the 19F NMR spectrum demonstrates that the THF ligand is in
a conformation or a coordination sphere in which the geminal
α-protons of the bound THF molecule are inequivalent on the
NMR time scale.
We used computational methods with DFT to assess
potential structures the Cu(III) fluoride species detected by
NMR spectroscopy and mass spectrometry. Energy minimiza-
tions of a complex containing one fluoride, one triflate, one
bound THF, one trimethylpyridine, and one PF6 unit were
conducted with DFT using WB97XD functionals that include
empirical dispersion corrections. These calculations indicated
that the stereoisomer shown in Figure 4 with the Me3py trans
and the triflate cis to THF is 9.3 kcal/mol more stable in the
gas phase than the isomer with the Me3py cis and the triflate
trans to THF. These calculations also indicated that the ground
state of [(Me3py)(THF)Cu(F)(OTf)(PF6)] is approximately
square pyramidal with hexafluorophosphate bound in the apical
The 1H NMR spectra of the new species reveals the identity
1
of the dative nitrogen ligands bound to copper. The H NMR
spectrum of (tBuCN)2CuOTf in THF-d8 consists of one singlet
t
1
at 1.41 ppm (free BuCN resonates at 1.32 ppm). The H
NMR spectrum of the new species in THF-d8 contains a singlet
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difluoride to form a copper(I) fluoride. Copper(I) fluoride
complexes are known to disproportionate rapidly to Cu(0) and
CuF2, and this disproportionation would account for the
paramagnetic species observed in the 19F NMR spectrum.12
Finally, the reaction of p-fluorophenylboronate 1l with
(tBuCN)2CuOTf, [Me3pyF]PF6, and AgF under the standard
reaction conditions was monitored, and this reaction led to a
new species that appears to be a second intermediate in the
fluorination of arylboronate esters The 19F NMR spectrum
after 20 min of the reaction of p-fluorophenylboronate 1l with
[(Me3py)(THF)Cu(F)(OTf))PF6)] and AgF at 50 °C showed
that greater than 90% of the arylboronate ester was converted
to a new species (eq 7). New resonances in the 19F NMR
Figure 4. Computed ground-state structure of [(Me3py)(THF)Cu-
(F)(OTf)(PF6)] in a THF solvent continuum.
position (Figure 4). Calculations performed with a THF
solvent continuum indicated that the neutral complex
containing a bound PF6 anion is more stable than the separated
ions by ΔH = 14.2 kcal/mol and ΔG = 2.1 kcal/mol. Although
further work on stable analogues of the new species is clearly
needed, binding of PF6 or slow rotation of the THF would
cause the complex to be chiral; this property would render the
geminal protons at THF diastereotopic and chemically
inequivalent. In the computed structure, the four inequivalent
α protons of the bound THF lie in an orientation with short
(2.4 and 2.6 Å) H−F distances that are consistent with the
spectrum were observed. A new signal corresponding to the p-
fluorine atom on the aryl ring (−115.7 ppm) resonated upfield
of that on the starting, free arylboronate ester (−108.7 ppm).
The peak corresponding to the CuIII−F species described above
was quickly consumed and was replaced by a broad peak at
−138 ppm. The intensity of the peak at −138 ppm was twice
that of the peak from the fluorine atom on the aryl group. The
resonance from the triflate was observed at −76 ppm, and this
peak was sharper and was located upfield of the triflate peak of
the cationic Cu(III) fluoride (−71.4 ppm, broad). The other
peaks observed in the 19F NMR spectrum were 1,4-
difluorobenzene (the product of fluorination of the arylboron-
ate ester), fluorobenzene (formed by protodeborylation),
internal standard, and F‑BPin. F‑BPin and 1,4-difluorobenzene
were formed in concert with consumption of the copper species
corresponding to the resonances at −115.7 and −138 ppm.
The new species formed from the reaction between
arylboronate 1l, (tBuCN)2CuOTf, [Me3pyF]PF6, and AgF
1
observation of JHF coupling in the 19F NMR spectra (vide
supra). Studies toward analogues of this Cu(III) species that are
sufficiently stable for isolation are ongoing.
C. Reactions of the Cu(III) Fluoride Intermediate with the
Reaction Components. The reactivity of the cationic copper-
(III) fluoride species was investigated to assess the competence
of this species to be an intermediate and to determine which
reagents react with this complex to form the aryl fluoride
product. The reaction of metal fluorides with arylboron
reagents to generate arylmetal species has been shown to
occur during palladium-catalyzed Suzuki cross-coupling.25
Thus, the Cu(III) fluoride could react directly with the
arylboronate ester to generate an (aryl)CuIII species and
F‑BPin. However, the copper(III) fluoride species (generated
in situ) did not undergo transmetalation with p-fluorophenyl-
boronate 1l, as determined by 19F NMR spectroscopy (eq 6).
The reaction of (tBuCN)2CuOTf with [Me3pyF]PF6 and 1l in
the absence of AgF did not lead to any detectable conversion of
the arylboronate ester over 18 h at 50 °C.
1
was further characterized by H NMR spectroscopy. The aryl
protons of the boronate ester 1l resonate at 7.76 and 7.07 ppm
in THF-d8. The aromatic protons of the new species resonated
further upfield at 7.68 and 6.99 ppm. The 1H NMR spectrum of
the reaction solution also contained resonances for ligated
trimethylpyridine at δ 7.49, 2.63, and 2.46 ppm and for free
tBuCN at δ 1.33 ppm. These chemical shifts are similar to those
of the trimethylpyridine ligand in [(Me3py)Cu(F)(OTf)-
(THF)(PF6)] (δ 7.49, 2.66, and 2.48 ppm). The proton
resonances for the pinacolate group (δ 1.25 ppm) were shifted
upfield of those for the pinacolate group of 1l (δ 1.32 ppm).
The 11B NMR spectrum of the reaction between arylboron-
ate 1l, (tBuCN)2CuOTf, [Me3pyF]PF6, and AgF under the
standard reaction conditions showed >90% conversion of 1l (δ
30.4 ppm) to a new species within 20 min at 50 °C. This new
species corresponded to a 11B resonance at 4.5 ppm. As the
reaction progressed, the peak at 4.5 ppm decayed in concert
with the formation of F‑BPin (0.6 ppm). The chemical shift of
4.5 ppm is consistent with the formation of a four-coordinate
anionic arylboronate. These results suggest that the Ar−B bond
is present in the observed species.
The potential that the copper(III) fluoride species reacts with
AgF to form a copper(III) species containing two fluorides was
also investigated. If formed, a copper(III) difluoride could react
with the arylboronate ester to give an arylcopper(III) fluoride.
However, no new copper species from the reaction between the
copper(III) fluoride intermediate and AgF in THF over 18 h at
50 °C was detected by 19F NMR spectroscopy. The reaction of
the copper(III) fluoride with the more reactive, and more
soluble, tetrabutylammonium fluoride (TBAF) resulted in the
rapid formation of paramagnetic copper(II) species, as
determined by characteristic broad peaks in the NMR
spectrum. The formation of Cu(II) could result from N−F
reductive elimination of [Me3pyF]+ from an unstable Cu(III)
We propose that the copper complex formed from the
reaction of p-fluorophenylboronate 1l with (tBuCN)2CuOTf,
[Me3pyF]PF6, and AgF is a neutral arylboronate Cu(III)
fluoride. A potential structure of this complex is shown in
F
dx.doi.org/10.1021/ja310909q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 5. We propose that the two fluorine atoms give rise to a
ate complex. This fluoroarylboronate undergoes trans-
metalation to form an arylcopper(III) fluoride, which under-
goes reductive elimination to form the aryl fluoride product.
single broad 19F resonance due to a combination of
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, and tables giving experimental procedures,
characterization data for new compounds, and details of the
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 5. Proposed structure of the arylboronate Cu(III) fluoride
intermediate. L is 2,4,6-trimethylpyridine.
AUTHOR INFORMATION
■
stereoisomerism and transfer of the boron center from one
fluorine to the other. This species was formed in 90% yield
(based on the conversion of ArBPin).
Corresponding Author
jhartwig@berkeley.edu
We propose that the arylboronate Cu(III) fluoride complex
undergoes rate-limiting transmetalation of the aryl group to
copper. The aryl Cu(III) fluoride complex formed from
transmetalation would then undergo fast reductive elimination
of the Ar−F product. Fast reductive elimination of an aryl
fluoride is consistent with a recent report by Ribas and co-
workers in which an aryl Cu(III) fluoride complex was
proposed to be formed as an unobserved, reactive intermediate
during the reaction of a macrocylic aryl Cu(III) complex with
fluoride to form a macrocyclic fluoroarene.26
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH-NIGMS (R29-55382) for support of this
work, Yichen Tan for checking the procedure, Prof. J. Scott
McIndoe and Eric Janusson at the University of Victoria for
help in obtaining ESI-MS data, and Dr. Qian Li for help with
DFT calculations.
Scheme 5 shows a mechanism for the fluorination of
arylboronate esters with (tBuCN)2CuOTf, [Me3pyF]PF6, and
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SUMMARY AND CONCLUSIONS
■
In summary, we have developed an operationally simple, direct
method for the fluorination of arylboronate esters and revealed
the formation of two copper(III) fluoride intermediates. This
reaction occurs with readily available reagents under mild
conditions. Electron-rich, electron-deficient, ortho-substituted,
and diversely functionalized arylboronate esters undergo
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processes allow the fluorination of arenes and aryl bromides to
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