Palladium-catalyzed fluorination of carbon-hydrogen bonds

Article abstract of DOI:10.1021/ja061943k

This communication describes the development of a new Pd-catalyzed method for the fluorination of carbon-hydrogen bonds. A key step of these transformations involves palladium-mediated carbon-fluorine couplinga much sought after, but previously unpreceden

Full text of DOI:10.1021/ja061943k

Published on Web 05/10/2006
Palladium-Catalyzed Fluorination of Carbon-Hydrogen Bonds
Kami L. Hull, Waseem Q. Anani, and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109
Received March 21, 2006; E-mail: mssanfor@umich.edu
Table 1. Palladium-Catalyzed Fluorination of 8-Methylquinoline
The substitution of hydrogen for fluorine can have a profound
effect on the biological activity, metabolism, solubility, hydropho-
bicity, and bulk properties of organic substances.1 As a result,
molecules containing carbon-fluorine bonds are extremely impor-
tant as pharmaceuticals, imaging agents, fine chemicals, and
materials.1 However, despite the great utility of this functional
group, relatively few synthetic approaches for the formation of C-F
bonds are currently available, and transition metal catalyzed
methods for C-F bond construction are particularly rare.1,2
Previous efforts in this area have aimed to develop palladium-
based catalysts for C-F bond formation3 since Pd catalysts have
found widespread application in a variety of related carbon-
heteroatom cross-coupling reactions.4 This prior work has pre-
dominantly focused on potential Pd0/II catalytic cycles, involving
oxidative addition of an aryl or alkyl halide (R-X) to Pd0,
metathesis of X- with F- at the resulting σ-alkyl/aryl PdII complex,
and, finally, C-F bond-forming reductive elimination to release
the fluorinated product. While the first two reactions in this
sequence are well-precedented,3 the final C-F coupling step (C )
aryl, alkyl) has not yet been achieved at PdII (or, to our knowledge,
at any other transition metal center) in either a stoichiometric or a
catalytic reaction manifold.5,6
a Conditions: 110 °C, 18 h. b Conditions: 110 °C, 1 h, 200 W; yields
of 1a, 1b, and 1c were determined by GC using naphthalene as an internal
standard.
associated with the thermal conditions led us to examine microwave
irradiation as a potentially faster way to assay a variety of catalysts,
solvents, and fluorinating oxidants.10 Gratifyingly, microwave
heating greatly accelerated the Pd-catalyzed fluorination of 1, and
the reactions generally proceeded within 1 h at 110 °C. Interestingly,
p-MeC6H4I(F)2 afforded only traces of the fluorinated product 1a
under both thermal and microwave conditions (Table 1, entry 4),
in contrast to the success of analogous iodine(III) oxidants in related
C-H bond acetoxylation7a,b,d and arylation reactions.7c However,
we were pleased to discover that N-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate (2) served as a highly effective F+ source upon
microwave irradiation, affording 1a in a dramatically improved 75%
GC (59% isolated) yield. Importantly, control reactions in the
absence of Pd catalyst showed none of the fluorinated product 1a.
The moderate 75% GC yield of 1a is due to incomplete conver-
sion (3% of 1 remained at the end of the reaction), as well as the
formation of two minor side productssphenylated product 1b (18%)
and acetoxylated product 1c (4%).11 We initially hypothesized that
phenylated product 1b was formed by Pd-catalyzed oxidative
coupling between 8-methylquinoline (1) and the benzene solvents
another transformation of significant potential importance and
utility.12 However, control experiments revealed that 1b is actually
generated by reaction of 8-fluoromethylquinoline (1a) with C6H6
in the presence of oxidant 2. This reaction does not appear to be
Pd-catalyzed, as it proceeds with comparable rates in the presence
and absence of Pd(OAc)2. While the detailed mechanism for
formation of 1b remains under investigation, preliminary results
suggest that it takes place via an electrophilic pathway.13
We reasoned that an alternative approach to this key C-F
coupling step would be to react a PdII alkyl/aryl intermediate with
an electrophilic fluorinating reagent (F+ source) to effect the
oxidative transformation of the Pd-C bond to a C-F bond (eq 1).
Carbon-fluorine bond formation in these systems could proceed
by direct electrophilic attack of F+ on the PdII-C bond or via
oxidation to PdIV followed by C-F bond-forming reductive
elimination. Importantly, we have recently demonstrated that related
oxidizing conditions promote other challenging Pd-catalyzed C-X
coupling reactions (e.g., formation of C-Cl and C-Br bonds7a and
coupling between weakly nucleophilic acetate and electron-rich
arenes7a,d) that are not typically possible via conventional Pd0/II
catalytic cycles.8,9 We describe herein the application of this new
approach to the development of the first Pd-catalyzed C-H
activation/C-F bond-forming reaction.
Initial investigations focused on the Pd(OAc)2-catalyzed benzylic
fluorination of 8-methylquinoline (1). This substrate was selected
because it undergoes facile quinoline-directed C-H activation at
PdII to generate a σ-benzyl Pd species and, as such, has been shown
to serve as an excellent substrate for related Pd-catalyzed C-H
activation/oxidative functionalization reactions.7a-c As summarized
in Table 1, column 3, an initial screen of F+ reagents under thermal
reaction conditions (10 mol % of Pd(OAc)2, 110 °C, 13 h, benzene)
revealed that several effected the desired benzylic C-H bond
fluorination reaction, providing 1a in modest 9-36% yields along
with several other products (vide infra). The long reaction times
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C O M M U N I C A T I O N S
is derived from a preference for the formation of five-membered
(versus six-membered) palladacyclic intermediates.7 However, it
is interesting to note that arene C-H activation/fluorination via
six-membered palladacycles can be achieved if a five-membered
intermediate is not accessible (substrate 14, entry 11).
In conclusion, this paper describes the first example of a Pd-
catalyzed method for the formation of aromatic and benzylic C-F
bonds. In contrast to previous unsuccessful efforts in this area, these
reactions were achieved under oxidizing conditions, using electro-
philic (rather than nucleophilic) fluorinating reagents. The success
of these C-H activation/oxidative fluorination reactions suggests
a potentially general strategy for the fluorination of organometallic
Pd intermediates. Ongoing efforts in our labs seek to expand the
scope and to probe the mechanism of the current transformation,
as well as to exploit this approach for the development of new
metal-catalyzed C-F coupling reactions.
We next aimed to expand the scope of these reactions to the
fluorination of aromatic C-H bonds in substrates, such as phen-
ylpyridine 4 (eq 2). After some experimentation (see Table S1),
we determined that N-fluoropyridinium tetrafluoroborate (3) was
the optimal F+ source for this reaction, and that microwave
irradiation under similar conditions to those described for substrate
1 (10 mol % of Pd(OAc)2, 150 °C, 1.5 h, 0.5 mL of CH3CN in
trifluorotoluene) afforded the ortho-fluorinated product 4a in 69%
isolated yield. Notably, neither arylated side products analogous
to 1b nor acetoxylated side products analogous to 1c were observed
in reactions of substrate 4.14
Acknowledgment. We thank the NIH NIGMS (RO1-GM-
073836), the Camille and Henry Dreyfus Foundation, the Arnold
and Mabel Beckman Foundation, Amgen, Boehringer Ingelheim,
Merck, and Eli Lilly for support of this work. We are also grateful
to Novartis (graduate fellowship to K.L.H.) and the Margaret and
Henry Sokol Fund (summer fellowship to W.Q.A.).
Table 2. Substrate Scope of Pd-Catalyzed C-H Bond
Fluorination
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214-231 and
references therein.
(2) For metal-catalyzed R-fluorination of carbonyl compounds, see: (a)
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147-1155. (b) Ha-
mashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2005, 127, 10164-10165 and references therein.
(3) Grushin, V. V. Chem.sEur. J. 2002, 8, 1006-1014 and references therein.
(4) Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E. I., Ed.; Wiley-Interscience: New York, 2002.
(5) A single example of stoichiometric C-F coupling at PdII, where C )
acyl, has been reported. Fraser, S. L.; Antipin, V. N.; Khroustalyov, V.
N.; Grushin, V. V. J. Am. Chem. Soc. 1997, 119, 4769-4770.
(6) In contrast, the microscopic reverse of this processsC-F bond oxidative
additionsis well-known. For reviews, see: (a) Burdeniuc, J.; Jedlicka,
B.; Crabtree, R. H. Chem. Ber. Recl. 1997, 130, 145-154. (b) Richmond,
T. G. Top. Organomet. Chem. 1999, 3, 243-269. (c) Braun, T.; Perutz,
R. N. Chem. Commun. 2002, 2749-2757. For an example at Pd0, see:
(d) Jasim, N. A.; Perutz, R. N.; Whitwood, A. C.; Braun, T.; Izundu, J.;
Neumann, B.; Rothfeld, S.; Stammler, H. G. Organometallics 2004, 23,
6140-6149.
(7) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300-2301. (b) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 9542-9543. (c) Kalyani, D.; Deprez, N. R.; Desai, L.
V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330-7331. (d) Kalyani,
D.; Sanford, M. S. Org. Lett. 2005, 7, 4149-4152. (e) Desai, L. V.; Malik,
H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141-1144.
a Conditions: 7-10 mol % of Pd(OAc)2, 1.5-2 equiv of 2, C6H6,
microwave (1-4 h, 100-110 °C, 200-250 W). b Conditions: 10 mol %
of Pd(OAc)2, 2.5-4.5 equiv of 3, 0.12-0.5 mL of CH3CN, CF3C6H5,
microwave (1.5-2 h, 150 °C, 300 W).
(8) C-O coupling at PdII has strict electronic requirements: Widenhoefer,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6504-6511.
(9) C-Cl and C-Br couplings at PdII typically have unfavorable values of
Keq: Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 1533-1541.
(10) For C-H activation/functionalization reactions accelerated by microwave
heating, see: Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2005, 45, 1589-1591.
With these preliminary results in hand, we next surveyed the
substrate scope of quinoline/pyridine-directed benzylic and aromatic
fluorination. As summarized in Table 2, these reactions can be
utilized for the preparation of diverse fluorinated products and are
tolerant of many common functional groups, including aryl halides,
nonenolizable ketones and esters, trifluoromethyl substituents, and
methyl ethers. The compatibility with aryl bromides is both synthet-
ically useful (as these are readily elaborated further) and mecha-
nistically interesting (as these are often not tolerated under Pd0/II
catalysis). Benzylic C-H bonds that are remote from the pyridine
or quinoline directing group (e.g., in substrate 5, entry 1) are also
well-tolerated. Furthermore, with substrate 8, which contains both
benzylic and aromatic C-H bonds adjacent to the pyridine directing
group, the aromatic fluorination product was obtained exclusively.
Notably, the same selectivity is observed in Pd-catalyzed C-H
activation/acetoxylation reactions of related substrates7e and likely
(11) The OAc of 1c is derived from the Pd(OAc)2 catalyst, and this product
could be generated by either Pd-catalyzed or non-Pd-mediated reactions.
See the Supporting Information for a full discussion of these possibilities.
(12) For a review that discusses Pd-catalyzed oxidative coupling reactions,
see: Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420.
(13) Several results are consistent with an electrophilic mechanism for the
formation of 1b. For example, when the reaction was conducted in anisole,
both o- and p-substituted arylated products were obtained in a ∼1:1.1
ratio. Additionally, when the reaction was run in the presence a 1:1 mixture
of 1,4-dimethoxybenzene and C6H6, incorporation of the electron-rich (p-
MeO)2C6H3 group was favored (with a product ratio of 29:1). Ongoing
work seeks to more fully elucidate the mechanism of this unusual arylation
reaction.
(14) Additionally, 4a also does not react with aromatic solvents in the presence
of oxidants 2 or 3 to afford arylated side products analogous to 1b. These
data are consistent with the hypothesis that 1b is formed by an electrophilic
mechanism, possibly involving a transient benzylic cation.
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