Copper-mediated fluorination of aryl iodides

Article abstract of DOI:10.1021/ja304410x

The synthesis of aryl fluorides has been studied intensively because of the importance of aryl fluorides in pharmaceuticals, agrochemicals, and materials. The stability, reactivity, and biological properties of aryl fluorides can be distinct from those of the corresponding arenes. Methods for the synthesis of aryl fluorides, however, are limited. We report the conversion of a diverse set of aryl iodides to the corresponding aryl fluorides. This reaction occurs with a cationic copper reagent and silver fluoride. Preliminary results suggest this reaction is enabled by a facile reductive elimination from a cationic arylcopper(III) fluoride.

Full text of DOI:10.1021/ja304410x

Communication
pubs.acs.org/JACS
Copper-Mediated Fluorination of Aryl Iodides
Patrick S. Fier and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
temperatures (Scheme 1).2 However, this reaction occurs
only with substrates that are activated toward nucleophilic
attack.
Recently, transition metal complexes have been used to
prepare fluoroarenes.3 Palladium-catalyzed fluorination of aryl
triflates has been reported (Scheme 2).4 Although these
ABSTRACT: The synthesis of aryl fluorides has been
studied intensively because of the importance of aryl
fluorides in pharmaceuticals, agrochemicals, and materials.
The stability, reactivity, and biological properties of aryl
fluorides can be distinct from those of the corresponding
arenes. Methods for the synthesis of aryl fluorides,
however, are limited. We report the conversion of a
diverse set of aryl iodides to the corresponding aryl
fluorides. This reaction occurs with a cationic copper
reagent and silver fluoride. Preliminary results suggest this
reaction is enabled by a facile reductive elimination from a
cationic arylcopper(III) fluoride.
Scheme 2. Metal-Mediated Aryl Fluorination
he unique stability, reactivity, and biological properties of
findings demonstrated that aryl electrophiles can undergo
fluorination in the presence of a transition metal catalyst, the
formation of a single product occurred only with substrates
bearing electron-withdrawing groups.4 The triflates for this
reaction are formed from phenols, and a reagent for the
conversion of phenols to aryl fluorides was reported more
recently.5 Methods for the conversion of aryl stannanes,6
boronic acids,7 and silanes8 to aryl fluorides with silver or
palladium and an electrophilic fluoride source also have been
published, but the aryl nucleophiles in these reactions are often
prepared from the aryl halide. Therefore, a method to convert
aryl halides to the corresponding aryl fluorides would be more
direct than the reactions of main group−aryl reagents.
Here, we report the fluorination of a set of functionally
diverse aryl iodides with a simple copper reagent and fluoride
source. The success of this reaction with a nucleophilic fluoride
reagent rests on the identification of an appropriate ligand for
copper. With the proper choice of ligand and source of fluoride,
the rapid decomposition of copper(I) fluorides is avoided.
Having recently developed copper-mediated fluoroalkyla-
tions9 of arenes, including reactions through unstable
fluoroalkyl intermediates, we studied copper systems for the
fluorination of aryl iodides. The strong metal−fluorine bond
causes C−F reductive elimination to be slower than competing
side reactions.3,10 However, Ribas and co-workers have shown
that a macrocyclic arylcopper(III) complex undergoes C−F
bond formation, suggesting that copper-mediated fluorination
of aryl electrophiles through high-valent copper is feasible.11
We hypothesized that reductive elimination from an
arylcopper(III) fluoride species would be facilitated by a non-
coordinating counterion and weakly donating ligands. Based on
T
fluorinated compounds make them useful in many
chemical disciplines. Compounds containing an aryl fluoride
moiety are common in pharmaceuticals and agrochemicals
because the site containing fluorine is stable toward
degradation, and this stability improves biological activity.
The conditions typically used to form aryl−fluorine bonds
are harsh; thus the fluorine is usually introduced into the arene
ring at the beginning of a synthesis or as part of a building
block. Improved methods for late-stage aromatic fluorination
would be important for diversification in medicinal chemistry.
Moreover, methods for aromatic fluorination with simple
sources of anionic fluoride would be valuable for the
preparation of 18F-labeled compounds used in positron
emission tomography (PET) imaging. Yet, no method has
been reported for the fluorination of electron-neutral to
electron-rich aryl halides.
Instead, aryl fluorides have been prepared by the Balz−
Schiemann reaction involving the decomposition of aryldiazo-
nium salts (Scheme 1).1 The acidic conditions, the toxicity of
Scheme 1. Conventional Routes to Fluoroarenes
the reagents, and the potential for explosions limit the synthetic
utility of the Balz−Schiemann reaction.1 Alternatively, aryl
fluorides bearing electron-withdrawing groups have been
prepared by the halogen exchange (halex) process in which
electron-deficient aryl chlorides or nitroarenes undergo
nucleophilic aromatic substitution with fluoride at high
Received: May 7, 2012
Published: June 18, 2012
© 2012 American Chemical Society
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Communication
Table 1. Fluorination of Aryl Iodides with (tBuCN)2CuOTf
and AgF
this logic, we found that the reaction of 4-butyl-1-iodobenzene
with (MeCN)4CuBF4 and AgF gave detectable amounts of aryl
fluoride. No reaction occurred in the absence of copper,
demonstrating that a direct reaction between AgF and ArI is
not occurring.
a
This initial result led us to investigate the effect of nitrile
ligands and counterions on the halogen exchange reaction.
Cationic copper complexes ligated by nitriles can be prepared
in multigram quantities within minutes from the reaction of
Cu2O with strong acids in the nitrile solvent (eq 1). By this
route, we prepared copper complexes containing different
nitriles and counterions (see Supporting Information (SI)).
These complexes were tested as mediators of the fluorination of
1-butyl-4-iodobenzene with AgF (eq 2). Reactions of this aryl
iodide with AgF in the presence of the complexes ligated by
tBuCN occurred in higher yields than those conducted with
complexes ligated by MeCN, PrCN, and PhCN. Reactions
a
i
Reactions were performed with 0.1 mmol of aryl iodide to determine
yields by 19F NMR spectroscopy with 1-bromo-4-fluorobenzene as an
conducted with copper complexes containing SbF6 and OTf as
counterion occurred in higher yields than those conducted with
copper complexes containing BF4 and PF6. Reactions
conducted with tBuCN-ligated CuOTf were more reproducible
than those conducted with tBuCN-ligated CuSbF6. An excess of
copper, relative to AgF, was critical for the reaction to occur in
high yields (see SI). Reactions conducted with CsF in place of
AgF gave the same aryl fluoride product, but in a 34% yield
with 30% of the arene side product.
internal standard added after the reaction. 19F NMR chemical shifts
b
were compared with those of the authentic aryl fluorides. Isolated
c
yield from a reaction with 0.5 mmol of ArI. Reactions were conducted
with 1 equiv of ArI, 2 equiv of (tBuCN)2CuOTf, and 1 equiv of of
d
AgF. Reactions were conducted with 3 equiv of ArI, 2 equiv of
(tBuCN)2CuOTf and 1 equiv of AgF.
The source of hydride leading to the arene side product was
investigated by deuterium-labeling experiments. The reaction
between 1a, (tBuCN)2CuOTf, and AgF with 2 equiv of D2O
formed the arene in 94% yield, with 54% incorporation of
deuterium into this product (eq 3). These data suggest that
tBuCN-ligated CuOTf was prepared in multigram quantites
t
from Cu2O, triflic acid, and BuCN (vide supra). When the
tBuCN-ligated CuOTf complex is prepared, four nitriles are
bound in a tetrahedral geometry.12 However, placing the solid
under vacuum at room temperature resulted in the loss of two
nitriles to give a compound with the formula (tBuCN)2CuOTf,
as determined by elemental analysis13 and X-ray crystallog-
raphy.14 This complex is stable to oxygen and absorbs moisture
from the air only slowly. Thus, this species can be weighed
quickly on the benchtop.
Reactions of the combination of (tBuCN)2CuOTf and AgF
with a range of aryl iodides are shown in Table 1. These data
show that electron-rich and electron-poor iodoarenes react to
form the aryl fluorides in good yields, as determined by NMR
spectroscopy. Sterically hindered aryl iodides (1h, 1i) reacted
to provide nearly quantitative yields of the aryl fluoride. Esters,
amides, aldehydes, ketones, and indole heterocycles were
tolerated under the reaction conditions. Reactions conducted
with AgF as the limiting reagent and an excess of aryl iodide
provided high yields of the aryl fluoride 2m. Conditions for
conducting fluorinations with limiting fluoride are important
for the use of this process to provide 18F-labeled product for
PET imaging. The aryl fluoride 2a was isolated in good yield on
a 0.5 mmol scale. The greatest challenge in the current
reactions is the separation of the major aryl fluoride product
from the arene side product. Methods for separation from the
arene and conditions for minimizing formation of the arene are
currently being studied.
adventitious water is one source of the hydro-dehalogenation
product, despite the use of anhydrous DMF15 and oven-dried
glassware. Indeed, the rigorous exclusion of water is essential
for high yields.
The reaction of 1a under the standard conditions with 5
equiv of CD3CN produced 12% of the arene side product with
45% incorporation of deuterium into this arene (eq 4). This
finding shows that the alpha proton of the nitrile is also a
source of hydride in the hydro-dehalogenation process. Thus,
the higher yields from reactions mediated by complexes of
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Communication
tBuCN than from those of the other nitriles can be attributed,
in part, to the absence of acidic protons on the ligand. The
arene side product from reactions run in DMF-d7 did not
contain deuterium, showing that arene does not form by
hydrogen atom abstraction from the solvent.
Lower yields and conversions were obtained when the
reactions were conducted with an excess of AgF, relative to
(tBuCN)2CuOTf (see SI). To understand the deleterious effect
of excess AgF, we conducted reactions under the standard
conditions, but with added AgOTf and with added CsF (Table
2). Reactions run with 1 or 2 equiv of added AgOTf proceeded
cyclization should be much faster than the intermolecular
reaction of a Cu(II) intermediate with the fluoride source.
However, a fraction of the aryl iodide appears to react through
a radical pathway, as deduced by the observation of some
cyclized product. We suggest that this radical pathway is due to
the formation of a copper side product during the reaction.19
To gain additional data on whether this fluorination process
occurs through an initial electron-transfer reaction, we tested
the fluorination of 4-bromobenzophenone. The reduction
potential of this bromoarene is higher than that of some of
the aryl iodides in Table 1.20 Thus, the formation of an aryl
radical by an outer-sphere electron transfer with this aryl
bromide should occur at a rate that is comparable to the rate of
the reactions of aryl iodides.20 However, the aryl bromide
reacted to <30% conversion and formed the aryl fluoride in
only 19% yield (eq 5). A higher conversion of the aryl bromide
would be expected if the copper system reacted with the aryl
halide by a single-electron-transfer pathway.
Table 2. Effect of Added AgOTf and CsF on Aryl Iodide
a
Fluorination
entry
additive
ArF (%)
ArH (%)
conversion (%)
1
2
3
4
AgOTf (1 equiv)
AgOTf (2 equiv)
CsF (1 equiv)
18
5
13
22
23
25
60
51
71
59
100
92
CsF (2 equiv)
a
Reactions were performed with 0.1 mmol of 1a in 0.5 mL of DMF for
22 h. Yields were determined by gas chromatography with 1-bromo-4-
fluorobenzene as an internal standard added after the reaction.
Additional data were consistent with the absence of aryl
radicals. The reaction of 1-butyl-4-iodobenzene under the
standard fluorination conditions, but with 1 equiv of TEMPO
as a free radical trap, yielded the aryl fluoride in 74% yield with
93% conversion of the aryl iodide. In addition, reactions in
DMF-d7 did not lead to incorporation of deuterium into the
arene side product. If an aryl radical were formed, hydrogen
atom abstraction from the solvent, rather than from
adventitious water (vide supra), would be expected because
DMF is present in higher concentrations and has weaker X−H
bonds than those in water. Reactions run in the dark gave
identical results to those run in room light.
Nucleophilic attack of fluoride on an aryl iodide coordinated
to copper through the π system is an alternative mechanism.
However, the observation of arene side product suggests that
protonolysis of an arylcopper species occurs. Such a
protonolysis would not be expected to occur during
nucleophilic attack on a π-coordinated arene.17d,21
in much lower yields and lower conversions than those without
added AgOTf (Table 2). However, reactions run under the
standard conditions with 1 or 2 equivs of added CsF were not
as inhibited as the reactions with added AgOTf. These findings
suggest that the lower yields in the presence of excess AgF
result from the silver ion, rather than fluoride. The AgF may
mediate an unproductive redox reaction with copper to
generate a copper(0) or copper(II) species that does not
mediate the fluorination of aryl iodides.
Reactions of aryl halides with Cu(I) species have been
proposed in some cases to occur by radical intermediates16 and
in other cases to occur through Cu(III) intermediates formed
by oxidative addition of organic halides to a Cu(I) species.17 To
probe the potential intermediacy of aryl radicals during this
fluorination reaction, we conducted the process with o-(3-
butenyl)iodobenzene (Scheme 3). The corresponding aryl
Finally, fluorinations of aryl halides could occur through a
benzyne intermediate. Grushin and Marshall reported a
fluorination of aryl triflates with tetramethylammonium
fluoride, which resulted in constitutional isomers that were
consistent with an aryne intermediate.22 We detected only one
isomer in each reaction, and the fluorination of 2,6-
dimethyliodobenzene occurred in high yield. These data are
inconsistent with reaction through an aryne intermediate.
A copper(I) fluoride species is a potential intermediate in the
fluorination of aryl iodides. Unligated copper(I) fluoride is
unstable toward rapid and exothermic decomposition to Cu(0)
and CuF2,23 and only two copper(I) fluorides have been
reported. Both of these complexes contain strongly bound
Scheme 3. Probe for Aryl Radical Intermediates
radical undergoes 5-exo-trig cyclization with a rate constant of
108 s−1 to form 1-methylindane after hydrogen atom
abstraction.18 The reaction of o-(3-butenyl)iodobenzene
under the standard conditions gave <5% of the cyclized
product, with 15% of the aryl fluoride product; the remaining
mass balance consisted of 4-phenyl-1-butene. This finding
suggests that the formation of aryl fluoride does not occur
through an aryl radical intermediate because the rate of
ancillary ligands.24 To test the properties of a BuCN-ligated
t
copper(I) fluoride, (tBuCN)2CuOTf and AgF were combined
in DMF and allowed to react between room temperature and
140 °C. No new species were observed by 19F NMR
spectroscopy over the course of 8 h at room temperature, 80,
100, or 140 °C. The reaction between (tBuCN)2CuOTf and
the more reactive anhydrous tetra-n-butylammonium fluoride
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(2) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225.
led to rapid decomposition of the nitrile-ligated copper triflate
at room temperature without formation of a species that could
be detected by 19F NMR spectroscopy. The higher yields
obtained with AgF than with other fluorides might be due, at
least in part, to the low solubility of this fluoride source. The
slow background reaction of AgF with (tBuCN)2CuOTf leads
to a lower concentration of the copper(I) fluoride and thus a
lower rate of decomposition.
(3) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470.
(4) Watson, D. A.; Su, M. J.; Teverovskiy, G.; Zhang, Y.; Garcia-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(5) Tang, P. P.; Wang, W. K.; Ritter, T. J. Am. Chem. Soc. 2011, 133,
11482.
(6) (a) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009,
131, 1662. (b) Tang, P. P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc.
2010, 132, 12150.
A proposed reaction mechanism that is consistent with our
data and known chemistry of copper is shown in Scheme 4. In
(7) (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed.
2008, 47, 5993. (b) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860.
(8) Tang, P. P.; Ritter, T. Tetrahedron 2011, 67, 4449.
(9) (a) Fier, P.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(b) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed.
2012, 51, 536. (c) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793.
(10) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160.
(11) Casitas, A.; Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am.
Chem. Soc. 2011, 133, 19386.
Scheme 4. Proposed Mechanism for the Fluorination of 1
with (tBuCN)2CuOTf and AgF
(12) See SI.
(13) Calcd: C, 34.87; H, 4.79; N, 7.39. Found: C, 34.96; H, 4.88; N,
7.53.
t
this pathway, reversible oxidative addition of an aryl iodide to a
nitrile-ligated CuOTf forms an arylcopper(III) iodide contain-
ing a coordinated or loosely bound triflate. The rate and
equilibrium for oxidative addition are likely faster for copper
complexes containing the more donating tBuCN than for those
containing other nitriles, and this expectation is consistent with
the higher yields from reactions conducted with this ligand than
from those conducted with other nitriles. The electrophilicity of
a Cu(III) triflate might favor transmetalation of AgF with this
species, and we propose this reaction occurs to form an
arylcopper(III) fluoride that undergoes C−F bond formation.
In summary, we have developed an operationally simple
fluorination of aryl iodides with readily available reagents. This
reaction tolerates ether, amide, ester, ketone, and aldehyde
functional groups and occurs with some heterocyclic systems.
Moreover, it occurs in high yield with sterically hindered aryl
iodides. We propose that this reaction occurs by oxidative
addition to form a Cu(III) intermediate and C−F reductive
elimination from an arylcopper(III) fluoride. Work is ongoing
to extend the work described here to the synthesis of 18F-
labeled compounds for PET imaging.
(14) See the SI for the influence of the ratio of BuCN:Cu on the
fluorination of aryl iodides.
(15) Anhydrous DMF was purchased from Acros and stored over
molecular sieves, water content <0.005%.
(16) (a) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496. (b) Aalten, H.
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(18) Abeywickrema, A. N.; Beckwith, A. L. J. J. Chem. Soc., Chem.
Comm. 1986, 464.
(19) No cyclization was observed in the absence of copper.
(20) Enemaerke, R. J.; Christensen, T. B.; Jensen, H.; Daasbjerg, K. J.
Chem. Soc., Perkin Trans. 2 2001, 1620.
(21) (a) Cohen, T.; Cristea, I. J. Org. Chem. 1975, 40, 3649.
(b) Cohen, T.; Wood, J.; Dietz, A. G. Tetrahedron Lett. 1974, 3555.
(22) Grushin, V. V.; Marshall, W. J. Organometallics 2008, 27, 4825.
(23) Waddington, T. C. Trans. Faraday Soc. 1959, 55, 1531.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of all new com-
pounds, and crystallographic data (CIF) for (tBuCN)4CuOTf
and (tBuCN)2CuOTf. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (R37GM055382-14) for support of this
work and Ramesh Giri for checking the procedure. A
provisional patent application has been filed on this work.
REFERENCES
■
(1) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. A. J. Org. Chem. 1979, 44, 3872.
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