Silver-catalyzed late-stage fluorination

Article abstract of DOI:10.1021/ja105834t

Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination reactions for the synthesis of functionalized arenes are based on palladium. Here we present silver catalysis for carbon-fluorine bond formation. Our report is the first example of the use of the transition metal silver to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate scope presented here have not been demonstrated for any other fluorination reaction to date.

Full text of DOI:10.1021/ja105834t

Published on Web 08/09/2010
Silver-Catalyzed Late-Stage Fluorination
Pingping Tang, Takeru Furuya, and Tobias Ritter*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received July 1, 2010; E-mail: ritter@chemistry.harvard.edu
Abstract: Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods
for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination
reactions for the synthesis of functionalized arenes are based on palladium. Here we present silver catalysis
for carbon-fluorine bond formation. Our report is the first example of the use of the transition metal silver
to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate
scope presented here have not been demonstrated for any other fluorination reaction to date.
fluoride and high basicity of dry fluoride.6 Carbon-fluorine
Introduction
bond formation by transition metal catalysis is difficult,7 in part
Fluorinated aromatic compounds are used as pharmaceuticals,
agrochemicals, materials, and tracers for positron emission
tomography (PET).1 Fluorine incorporation often improves the
properties of functional molecules; for example, fluorine sub-
stituents can increase the metabolic stability and the rate and
extent of blood-brain barrier penetration of pharmaceuticals.2
Selective fluorination is important but challenging, especially
when the desired fluorinated molecules are complex, and
carbon-fluorine bond formation must occur at a late stage of
their synthesis.3 In this manuscript we present a silver-catalyzed
late-stage fluorination reaction of complex small molecules,
including polypeptides, polyketides, and alkaloids (eq 1). Our
report is the first example of silver catalysis for carbon-
heteroatom bond formation by cross-coupling chemistry. We
propose that silver-catalyzed late-stage fluorination proceeds by
a mechanism distinct from conventional cross-coupling chem-
istry.
due to strong ionic metal-fluoride bonding, and only a few
examples have been reported.8 Reductive elimination, the
product forming event in cross-coupling catalysis, becomes
increasingly difficult and requires harsher reaction conditions
in the bond formation series C-C, C-N, C-O, C-F.8d,9
Sanford8b and Yu8c have reported directed palladium-catalyzed
electrophilic aromatic fluorination. The advantage of both
transformations is the ability to convert C-H bonds into C-F
bonds. Challenges include the high reaction temperature (120-150
°C) and the need for directing and blocking groups on the arene
(4) For selected fluorination reactions, see: (a) Balz, G.; Schiemann, G.
Ber. Deutsch. Chem. Ges. 1927, 60, 1186. (b) Adams, D. J.; Clark,
J. H. Chem. Soc. ReV. 1999, 28, 225. (c) Sun, H.; DiMagno, S. G.
Angew. Chem., Int. Ed. 2006, 45, 2720. (d) Sandford, G. J. Fluorine
Chem. 2007, 128, 90. (e) Yamada, S.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2010, 49, 2215. (f) Anbarasan, P.; Neumann,
H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 2219.
(5) Baudoux, J.; Cahard, D. Org. React. 2007, 69, 347.
(6) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr. Opin. Drug DiscoVery
DeV. 2008, 11, 803.
(7) For stoichiometric and catalytic transition-metal-mediated C-F bond
formation reactions, see: (a) Tius, M. A.; Kawakami, J. K. Synth.
Commun. 1992, 22, 1461. (b) Tius, M. A.; Kawakami, J. K. Synlett
1993, 207. (c) Tius, M. A.; Kawakami, J. K. Tetrahedron 1995, 51,
3997. (d) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi,
J. P. J. Am. Chem. Soc. 2007, 129, 7736. (e) Kaspi, A. W.; Yahav-
Levi, A.; Goldberg, I.; Vigalok, A. Inorg. Chem. 2008, 47, 5. (f)
Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008,
47, 5993. (g) Gorske, B. C.; Mbofana, C. T.; Miller, S. J. Org. Lett.
2009, 11, 4318. (h) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009,
131, 16355.
The synthesis of fluorinated arenes is challenging due to the
properties of fluorine.4 Electrophilic fluorination is often unse-
lective.5 Nucleophilic fluorination is complicated by strong
hydrogen bonding and the high hydration energy of the fluoride
anion, which results in the low nucleophilicity of hydrated
(8) (a) Subramanian, M. A.; Manzer, L. E. Science 2002, 297, 1665. (b)
Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 7134. (c) Wang, X.; Mei, T. S.; Yu, J. Q. J. Am. Chem. Soc.
2009, 131, 7520. (d) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang,
Y.; Garc´ıa-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325,
1661.
(1) (a) Yamazaki, T.; Taguchi, T; Ojima, I. In Fluorine in Medicinal
Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell:
United Kingdom, 2009. (b) Jeschke, P. ChemBioChem 2004, 5, 570.
(c) Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Commun.
2007, 1003.
(9) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 2004. (b) Muci, A. R.; Buchwald,
S. L. In Cross-Coupling Reactions; Miyaura, N., Ed.; Springer: Berlin,
2002. (c) Hartwig, J. F. Nature 2008, 455, 314. (d) Furuya, T.; Ritter,
T. J. Am. Chem. Soc. 2008, 130, 10060. (e) Ball, N. D.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 3796. (f) Furuya, T.; Benitez, D.;
Tkatchouk, E.; Strom, A. E.; Tang, P.; Goddard, W. A., III; Ritter, T.
J. Am. Chem. Soc. 2010, 132, 3793.
(2) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(3) (a) Wilkinson, J. A. Chem. ReV. 1992, 92, 505. (b) O’Hagan, D. Chem.
Soc. ReV. 2008, 37, 308. (c) Furuya, T.; Klein, J. E. M. N.; Ritter, T.
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12150 J. AM. CHEM. SOC. 2010, 132, 12150–12154
10.1021/ja105834t  2010 American Chemical Society

Silver-Catalyzed Late-Stage Fluorination
A R T I C L E S
Table 1. Silver Catalysis for Carbon-Fluorine Bond Formation
for regioselective fluorination. A breakthrough discovery in 2009
by Buchwald8d extended palladium-catalyzed cross-coupling
chemistry to nucleophilic fluorination. The reaction temperature
of 80-130 °C in combination with the basicity of fluoride is a
current challenge for the synthesis of molecules with protic
functional groups and the synthesis of complex aryl fluorides
by this method. In some cases, mixtures of regioisomers were
observed. A general, functional group-tolerant late-stage fluo-
rination of complex arenes has not yet been achieved by either
nucleophilic or electrophilic fluorination reactions.
Silver is used in heterogeneous oxidative catalysis on an
industrial scale.10 In homogeneous catalysis, silver is typically
used as a nonredox active Lewis acid, and its redox catalysis is
not well understood.11 Cross-coupling catalysis most commonly
relies on mononuclear complexes derived from transition metals
like palladium, with predictable two-electron redox pathways.
Silver undergoes one-electron redox chemistry and previously
has not been employed for carbon-heteroatom bond formation
by cross-coupling catalysis.
Results and Discussion
We have previously reported the electrophilic fluorination of
arylsilver complexes, which required two to three equivalents
of silver salt to obtain synthetically useful yields of aryl
fluorides.12 Here, we address the conceptual disadvantage of
our earlier results and present silver catalysis. The development
of silver catalysis was complicated by protodestannylation as
shown in Table 1. Addition of the electrophilic fluorinating
reagent F-TEDA-PF6 to arylstannane 1 in the presence of 10
mol % silver catalyst produced 68% of the undesired protod-
estannylated product 2a and only 30% of the desired fluorinated
product 2.
a Yields were determined by 19F and 1H NMR spectroscopy with
1-fluoro-3-nitrobenzene as
a standard. Yields of protodestannylated
products are given in parentheses. b 5.0 mol % Ag2O, 1.5 equiv of
F-TEDA-PF6, 2.0 equiv of NaHCO3, 1.0 equiv of NaOTf, 5.0 equiv of
MeOH, acetone, 65 °C, 4 h.
We hypothesized that tributyltin triflate, generated by trans-
metalation from arylstannanes to AgOTf, is hydrolyzed in situ
to form triflic acid (TfOH),13 which is responsible for protod-
estannylation. Fluorination of purified arylsilver complexes,
without tributyltin triflate contamination, did not afford a
protodestannylated byproduct. Because common drying reagents
did not suppress protodestannylation, we evaluated bases to
neutralize acids that may form during catalysis and identified
sodium bicarbonate (NaHCO3), which, unlike many other bases
(see Supporting Information), was compatible with F-TEDA-
PF6 under the reaction conditions. The use of NaHCO3 had the
additional, though unanticipated, benefit that most of the formed
tributyltin bicarbonate precipitated and could be conveniently
removed by filtration. Precipitation of the tin residue facilitated
product purification, which is often cumbersome when organotin
reagents are used.14
same range of yields as other silver salts and, in contrast to
many soluble Ag(I) salts, is inexpensive ($1.0/g) and not
hygroscopic. The addition of NaOTf to the Ag2O-catalyzed
reaction increased the rate of fluorination, possibly due to the
conversion of insoluble Ag2O into a soluble Ag(I) compound
under the reaction conditions. While Ag2O is not soluble in
acetone itself, we confirmed the presence of an active, soluble
silver catalyst: Upon filtration of the reaction mixture after 5 h,
followed by addition of the same amount of all reagents except
the silver source, 80% of fluorinated product was observed,
based on total added stannane. We determined gravimetrically
by precipitation of AgCl that 92% of the silver remained in
solution as Ag(I) after fluorination. In the absence of silver
catalyst, less than 5% fluorination was observed at 90 °C. The
catalyst loading could be reduced to 1 mol % Ag2O with no
loss in yield; however, a longer reaction time and higher reaction
temperature were required.
Several soluble Ag(I) salts catalyzed fluorination with equal
efficiency, but silver oxide (Ag2O) was selected as the catalyst
of choice because it afforded the fluorinated products in the
Fluorination using 5 mol % of Ag2O afforded electron-
deficient (4), electron-rich (5), halogenated (6), and ortho,ortho
disubstituted arenes (7). The addition of 5 equiv of methanol
decreased the amount of protodestannylated product formed to
2-5% when 5 mol % of Ag2O was used; addition of MeOH
reduced the yield of fluorinated product at 1 mol % catalyst
loading. The role of MeOH is currently not understood. All
fluorination reactions were performed under ambient atmosphere
and in reagent grade acetone as solvent. The reaction temper-
ature of 65 °C is slightly above the boiling temperature of
acetone, and therefore, reactions were performed in closed
(10) Linic, S.; Barteau, M. A. In Handbook of Heterogeneous Catalysis;
Ertl, G., Kno¨zinger, H., Schu¨th, F., Weitkamp, J., Eds.; Wiley-VCH:
Weinheim, 2008.
(11) (a) Naodovic, M.; Yamamoto, H. Chem. ReV. 2008, 108, 3132. (b)
Weibel, J. M.; Blanc, A.; Pale, P. Chem. ReV. 2008, 108, 3149. (c)
´
Alvarez-Corral, M.; Mun˜oz-Dorado, M.; Rodr´ıguez-Garc´ıa, I. Chem.
ReV. 2008, 108, 3174. (d) Yamamoto, Y. Chem. ReV. 2008, 108, 3199.
(12) (a) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
1662. (b) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860.
(13) Mehring, M.; Nolde, C.; Schu¨rmann, M. Inorg. Chim. Acta 2009, 362,
745.
(14) Davis, A. G.; Gielen, M.; Pannell, K. H.; Tiekink, E. R. T. Tin
Chemistry-Fundamentals, Frontiers and Applications; Wiley: United
Kingdom, 2008.
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A R T I C L E S
Tang et al.
Table 2. Ag2O-Catalyzed Fluorination of Complex Small Molecules
a 20 mol % of AgOTf, 2 equiv of NaOTf, and 2 equiv of F-TEDA-PF6 were used at 90 °C. b 20 mol % of AgOTf, 2 equiv of NaOTf, and 5 equiv of
MeOH were used. The names under the molecules in Table 2 refer to the parent molecules and not to fluorinated analogs shown.
Chart 1. Limitations of the Presented Fluorination Reactiona
vessels. The reaction could also be performed at reflux with
yields decreased by about 10% and reaction times that are 3 h
longer.
We selected a group of small molecules that contain several
functional groups and found that the Ag2O-catalyzed fluorination
reaction is general beyond simple arenes (Table 2). Biologically
active molecules such as carbohydrates, peptides, polyketides,
and alkaloids are compatible with fluorination, and molecules
derived from complex natural products such as taxol and
rifamycin were successfully fluorinated. It is worth mentioning
that fluorination can proceed in the presence of several functional
groups, including a vinyl ether, a dienone, alcohols, an allylic
alcohol, ethers and esters, and an oxetane. To date, no other
fluorination reaction has been shown to have a substrate scope
as broad as that shown in here. The practical reaction conditions
allowed for the gram-scale synthesis of dipeptide 15 in 92%
yield. For all fluorinated molecules shown in Table 2,
carbon-fluorine bond formation was performed as the final
synthetic step. The yield of protodestannylated byproducts was
less than 10% in all cases, which simplified purification of the
fluorinated molecules. Fluorination always occurred regiose-
lectively; no other regioisomers were detected. General high
regioselectivity of the silver-catalyzed fluorination is an ad-
ditional advantage over the known palladium-catalyzed fluorina-
tion reactions.
a The fluorination was attempted from the corresponding arylstannane:
5.0 mol % Ag2O, 1.5 equiv of F-TEDA-PF6, 2.0 equiv of NaHCO3, 1.0
equiv of NaOTf, 5.0 equiv of MeOH, acetone, 65 °C, 4 h. b 20 mol % of
AgOTf, 2 equiv of NaOTf, and 2 equiv of F-TEDA-PF6 were used at 90 °C.
E2 elimination of HF participate successfully in fluorination:
For example, both the quinoline and the bridgehead tertiary
amine of quinine (11) did not impede aryl fluorination. In
contrast to sulfides, which likely react as nucleophiles with
F-TEDA-PF6, sulfones are compatible with the reaction condi-
tions (20, 21). Fluorination of substrates with protic functional
groups that can be deprotonated by NaHCO3 proved problematic
(22). Carboxylate anions generated by the deprotonation of
carboxylic acids may react with AgOTf to form silver carboxy-
lates, which are less effective silver salts for silver-mediated
Limitations of the Ag-catalyzed fluorination reaction are
shown in Chart 1. We identified that basic functional groups
that react with the electrophilic fluorinating reagent unproduc-
tively are often not tolerated. Certain amines (19) may react
with F-TEDA-PF6 to form N-fluoro compounds that subse-
quently eliminate HF. Amines that lack ꢀ-hydrogen atoms for
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Silver-Catalyzed Late-Stage Fluorination
A R T I C L E S
Scheme 1. Late-Stage Fluorination of Ezetimibe and Strychnine
Scheme 2. Proposed Mechanism for Silver-Catalyzed Fluorination
a (i) PhNTf2, Et3N, DMAP, CH2Cl2, 23 °C, 95%; (ii) LiCl, 5 mol %
Pd(PPh3)4, (n-Bu3Sn)2, dioxane, 100 °C, 50%. b Ag2O (5 mol %), NaHCO3,
NaOTf, F-TEDA-PF6, acetone, 65 °C, 90%. c Et3N, 5 mol % Pd(PPh3)4,
(n-Bu3Sn)2, dioxane, 100 °C, 34%. d BnBr, acetone; AgOTf; Ag2O (5 mol
%), NaHCO3, NaOTf, F-TEDA-PF6, 65 °C. e 1,4-Cyclohexadiene, Pd/C,
MeOH, 40 °C, 60% for two steps.
with additional Ag(I) under conditions of catalysis. We suggest
that subsequent Ag-based fluorination affords a high-valent
arylsilver fluoride complex such as II. A multinuclear silver
complex, such as dinuclear complex II, may be responsible for
carbon-fluorine bond formation because two-electron redox
processes can be facilitated by metal-metal cooperation, in
which more than one metal contributes to the redox process.18
Carbon-fluorine reductive elimination from potential intermedi-
ate II provides aryl fluoride and regenerates the Ag(I) catalyst.
Indirect evidence for the presence of a multinuclear arylsilver
complex was obtained by fluorination of complex 31 with and
without additional Ag(I) (eqs 2, 3). Fluorination of the mono-
nuclear arylsilver complex 31 afforded aryl fluoride 32 in 47%
yield, while addition of one additional equivalent of AgOTf to
31 afforded 32 in 84% yield. We were unable to isolate a high-
valent Ag complex, but our results imply that a direct cleavage
of the carbon-silver bond of the aryl Ag(I) complex I by carbon
fluorination does not occur: Addition of 25 equiv of water to
the fluorination reaction of tributylarylstannane afforded phenols
as byproducts, as shown in the dashed box in Scheme 2. The
formation of phenols is consistent with fluoride-hydroxide
exchange at a high-valent silver complex, followed by
carbon-oxygen reductive elimination. Addition of the radical
inhibitor butylated hydroxytoluene (BHT) had no effect on the
yield of fluorination, which is also consistent with a high-valent
silver intermediate.
fluorination of arylstannanes. Alcohols, on the other hand, did
not affect successful fluorination (23).
Late-stage fluorination is valuable for complex target mol-
ecules that are otherwise more challenging to obtain. We
selected the pharmaceutical ezetimibe and the natural product
strychnine to illustrate the advantage of late-stage fluorination
compared to conventional synthesis to access complex fluori-
nated molecules. Fluoro-deoxy-ezetimibe (26) was prepared in
a three-step sequence from available ezetimibe as shown in
Scheme 1. De novo synthesis of the fluorinated molecule 26
would require several more synthetic steps.15 The structure of
strychnine (27) is a challenge for the Ag-catalyzed fluorination
reaction because it does not possess a phenol functionality,
which is a convenient functional group for late-stage fluorination
as shown for ezetimibe (24). In addition, strychnine is an
alkaloid, which contains a tertiary amine that cannot be readily
protected as an amide or carbamate. Indeed, fluorination of
strychnine-derived arylstannane 29, obtained via known iodi-
nation of strychnine16 followed by stannylation, did not afford
any fluoro-strychnine (30), likely due to competing N-fluorina-
tion. However, in situ N-benzylation followed by Ag-catalyzed
fluorination of the resulting strychnine-derived ammonium salt
proceeded in 75% yield. Subsequent hydrogenolysis yielded
previously unknown fluoro-strychnine (30) in 60% overall yield
from 29 by late-stage fluorination.
Mechanistically, silver redox catalysis is much less understood
than, for example, palladium redox catalysis, in part due to its
scarcity.11 Cross-coupling catalysis most commonly relies on
mononuclear complexes derived from transition metals like
palladium, which typically undergoes predictable two-electron
redox pathways during reductive elimination, while silver
undergoes one-electron redox chemistry.
We propose the catalytic cycle shown in Scheme 2 for silver-
catalyzed fluorination: Aryl transmetalation from tin to Ag(I)
can afford arylsilver species such as I,12a,17 possibly aggregated
Conclusion
We present a silver-catalyzed fluorination reaction, which can
be applied to complex small molecules. The functional group
(15) Sasikala, C. H. V. A.; Reddy Padi, P.; Sunkara, V.; Ramayya, P.;
Dubey, P. K.; Bhaskar Rao Uppala, V.; Praveen, C. Org. Process Res.
DeV. 2009, 13, 907.
(18) (a) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (b) Powers,
D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem.
Soc. 2009, 131, 17050.
(16) Rosenmund, P. Chem. Ber. 1961, 94, 3342.
(17) Krause, E.; Schmitz, M. Ber. Deutsch. Chem. Ges. 1919, 52, 2150.
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A R T I C L E S
Tang et al.
tolerance and substrate scope presented here have not been
demonstrated for any other fluorination reaction to date. A
current disadvantage of the method is the need for the prepara-
tion of arylstannanes as starting materials. In addition, the
fluorination reaction reported by Buchwald can afford aryl
fluorides from triflates directly, while our fluorination reaction
requires an additional synthetic step from triflate or halide to
stannane. On the other hand, advantages of our fluorination
reaction compared to the Buchwald method are milder reaction
conditions, absence of constitutional isomers, and tolerance
toward protic functional groups, which make our fluorination
reaction particularly useful for late-stage fluorination of complex
small molecules, which may not be suitable for other fluorination
reactions.
nisms. Noteworthy is the C-F bond formation under compara-
tively mild reaction conditions, by reductive elimination from
a putative multinuclear high-valent silver fluoride complex.
Silver catalysis, with potential redox synergy between two or
more metals, is a new avenue for carbon-heteroatom cross-
coupling chemistry.
Acknowledgment. This work was supported by the NSF (CHE-
0952753) and NIH-NIGMS (GM088237). We thank Air Products
and Chemicals, Inc. for a generous donation of F-TEDA-BF4.
Supporting Information Available: Experimental procedures
and spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The Ag-catalyzed fluorination reaction likely proceeds through
a mechanism distinct from traditional cross-coupling mecha-
JA105834T
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